STATUS EPILEPTICUS
STATUS EPILEPTICUS: MECHANISMS AND MANAGEMENT edited by Claude G. Wasterlain and David M. Treiman
THE MIT PRESS CAMBRIGE, MASSACHUSETTS LONDON, ENGLAND
© 2006 Massachusetts Institute of Technology All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means (including photocopying, recording, or information storage and retrieval) without permission in writing from the publisher. MIT Press books may be purchased at special quantity discounts for business or sales promotional use. For information, please email
[email protected] or write to Special Sales Department, The MIT Press, 55 Hayward Street, Cambridge, MA 02142. This book printed and bound in the United States of America. Library of Congress Cataloging-in-Publication Data Status epilepticus : mechanisms and management / Claude G. Wasterlain and David M. Treiman, editors. p. cm. Includes bibliographical references and index. ISBN 0-262-23245-6 1. Epilepsy. 2. Convulsions. 3. Epilepsy—Treatment. 4. Convulsions—Treatment. I. Wasterlain, Claude G. II. Treiman, David M. RC372.S769 2006 616.8¢53—dc22 2005058405 10
9
8
7
6
5
4
3
2
1
CONTENTS
Preface
xi
Contributors
xiii
I
STATUS EPILEPTICUS: HISTORY, DEFINITION, CLASSIFICATION, AND EPIDEMIOLOGY 1
1
Historical Overview
2
Definition and Classification of Status Epilepticus C G. W and J W. C 11
3
Incidence and Causes of Status Epilepticus
4
Prognosis after a First Episode of Status Epilepticus D C. H, and W. A H 33
5
Epidemiology of Childhood Status Epilepticus
B S. M
3
R J. DL
17
G L,
S S
39
II STATUS EPILEPTICUS: CLINICAL PHENOMENOLOGY 53 6
Generalized Convulsive Status Epilepticus
D M. T
7
Simple and Complex Partial Status Epilepticus P T, B Z, and F A
55
69
v
8
Absence Status P T, B Z, and F A 91
9
The Two Faces of Electrographic Status Epilepticus: The Walking Wounded and the Ictally Comatose D G. F 109
10
Status Epilepticus in Infancy and Childhood R S 113
11
Nonconvulsive Status Epilepticus in Children: With Special Reference to Electrical Status Epilepticus During Slow-Wave Sleep Syndrome (ESES Syndrome) S O, Y Y, K K, and N N 125
12
Status Epilepticus in the Neonate
J Y. W, S K, and
E M. M
135
III STATUS EPILEPTICUS: BIOLOGICAL MARKERS R P. S
13
Physiologic Responses to Status Epilepticus
14
Clinical Neuropathology in Convulsive Status Epilepticus H-J M and G V 163
15
Neuron-Specific Enolase in Status Epilepticus C M. DG, A L. R, J C, C N H, P S. G, and S S 169
16
Brain Imaging in Status Epilepticus
T R. H
IV BASIC MECHANISMS: PATHOPHYSIOLOGY
vi
147 149
177
207
17
Self-Sustaining Status Epilepticus A M. M, H L, D E. N, L S, K W. T, A P V, R S, A N, and C G. W 209
18
Pathophysiology of Seizure Circuitry in Status Epilepticus M E K, and W A. S 229
19
Neuroanatomy of Status Epilepticus
20
Role of GABAA Receptors in Status Epilepticus J K 267
21
Physiologic Mechanisms of Inhibition and Status Epilepticus I S 281
A H
D C. MI,
239
R L. M and
22
Glutamate and Glutamate Receptors in Status Epilepticus and B S. M 295
23
Metabotropic Receptors in Status Epilepticus
B S. M
24
The Role of Adenosine in Status Epilepticus M D 315
D Y and
V BASIC MECHANISMS: BRAIN DAMAGE
A G. C
305
325
25
Excitotoxicity in Status Epilepticus L E. A. M. M, L C, C H, and R L S 327
26
Seizure-Induced Damage in the Immature Brain: Overcoming the Burden of Proof K W. T and R S 339
27
Metabolic and Circulatory Adaptations to Status Epilepticus in the Immature Brain A N and A P V 349
28
Excitotoxicity and Seizures in the Immature Brain
29
Age-Specific Mechanisms of Status Epilepticus and S L. M 371
30
Developmental Differences in Seizure Susceptibility and Hippocampal Vulnerability: Molecular Correlates L K. F and E F. S 379
31
Seizures and Neurotrophic Factor Expression C M. G 389
32
Behavioral Consequences of Status Epilepticus in the Immature Brain G L. H, R K, Z L, M R. S, and C E. S 399
P Mˇ
367
J Vˇ , R W,
H I. K and
VI BASIC MECHANISMS: EPILEPTOGENESIS
407
33
Late Consequences of Status Epilepticus J P L, A V S, and E A. C 409
34
Epileptogenic Effects of Status Epilepticus Y S, L S, A M. M, and C G. W
35
423
Hippocampal Reactive Synaptogenesis from Status Epilepticus G W. M 441
vii
VII THERAPEUTIC PRINCIPLES 36
Neuroprotective Strategies in Status Epilepticus
37
Generalized Convulsive Status Epilepticus: Principles of Treatment E F and C M. DG 481
38
Therapeutic Attitudes and Therapeutic Algorithms C G. W 493
39
Approach to the Management of Neonatal Status Epilepticus H Z. A-H and M J. P 503
40
Management of Status Epilepticus in Infants and Children P E, A A, I H, P G, and R S 515
VIII PHARMACOTHERAPY
D G. F
463
523
41
Benzodiazepines for Initial Treatment of Status Epilepticus B K. A 525
42
Phenytoin in the Treatment of Status Epilepticus
43
Phenytoin and Fosphenytoin F M. P 545
44
Phenobarbital in the Treatment of Status Epilepticus
45
Valproate S D, R A W, and K L. P 561
46
Other Pharmacologic Therapy for Refractory Status Epilepticus A G. S and R S. F 569
I E. L
539
R. E R and
IX THERAPEUTIC MANAGEMENT
viii
461
E F
589
47
Approaches to Treating Status Epilepticus Outside the Hospital J W. M and G D. A 591
48
The Treatment of Status Epilepticus Patients in the Emergency Setting E P. S 597
49
Critical Care of the Status Epilepticus Patient
T P. B
607
553
50
The Impact of Status Epilepticus on Health Care Delivery Systems: Quality of Care and Access B G. V 615
51
Status Epilepticus: The Future D M. T 621
Index
C G. W and
623
ix
PREFACE The demon possesses him many times during the middle watch of the night. —Sakikku cuneiform, 7th century .. Attacks are strung like red beads on a black cord of continuing unconsciousness. —William Lennox, 1960
L’état de mal épileptique, this most extreme manifestation of the sacred disease, is still a major medical emergency and a major unresolved therapeutic problem, with a mortality of 27% in adults and a formidable array of medical and neurological sequellae. We have learned to control the fever and many of the metabolic complications that were so often fatal in earlier times, yet this condition remains poorly understood and still extolls an unacceptably high price from its victims. The first large meeting on status epilepticus was the tenth “Colloque de Marseilles” in 1962, which emphasized electroclinical description and classification. The Santa Monica meeting in 1980 brought basic science into the clinical picture, and the second international Santa Monica meeting in 1997 focused on mechanisms and management. Interest in status epilepticus has exploded in the past 20 years: while Shorvon found 370 publications on status epilepticus from 1965 to 1978, a PubMed search reveals 4227 publications on status epilepticus since 1979, including 1761 in the past five years. Because more than 20 years have passed since the publication of the first multiauthored book on status epilepticus and more than 10 years have passed since Shorvon’s beautiful monograph, there was a need for a comprehensive review of the considerable progress made in the last decade. The current book attempts this daunting task, but because the field has expanded so much in the past 10 years, it focuses on the two areas in which progress has been most rapid, namely basic mechanisms and treatment. Coverage of other areas of the field of status epilepticus is selective, rather than comprehensive. In the area of basic mechanisms, we have seen the emergence of a concept of what status epilepticus is and how it differs from serial or grouped seizures. With this has come an understanding of some of the complications of status epilepticus at the molecular level, and this should eventually lead to improved therapy. Because of the realization that neuronal apoptosis and necrosis can be triggered very quickly and that status epilepticus–induced damage may be highly epileptogenic, treatment strategies today differ from those of yesteryear by their far greater sense of urgency, including prehospital administration of anticonvulsants whenever feasible and rapid induction of general anesthesia when seizures do not quickly abate with treatment. However, the number of agents available to treat status epilepticus has not kept pace with the rapid expansion of our therapeutic armamentarium for epilepsy. The book is divided equally between studies of basic mechanisms in animal models and clinical studies, so that one can go from the reductionist experiment that isolates a small component of status to the complex clinical situation in which that component is a small and interactive part of a large array. Hopefully, this marriage of basic and clinical science
xi
will provide a scientific rationale for our clinical decisions and will help develop therapeutic attitudes that are firmly grounded in pathophysiology. This book is aimed at the diverse medical groups that deal with status epilepticus in addition to the investigators who study it: emergency room physicians, intensivists, pediatricians, neurologists and pediatric neurologists, anesthesiologists, pharmacists, emergency room and intensive care unit nurses, and internists. We hope that it will bridge the gap between these disciplines and will renew interest in this complex clinical and experimental problem. We thank Barbara Blackburn and Richard Beaver for editorial assistance. We also thank the Veterans Health Administration’s Research Service and the National Institute of Neurological Diseases and Stroke for their support.
Claude G. Wasterlain and Kerry W. Thompson West Los Angeles, California David M. Treiman Phoenix, Arizona
xii
CONTRIBUTORS A-H, H Z. Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania A, B K. Department of Clinical Pharmacy, University of California, San Francisco, San Francisco, California A, F Montreal Neurological Hospital and Institute, Montreal, Quebec, Canada A, G D. Department of Pharmacy, University of Washington, Seattle, Washington A, A Service de Neuropediatrie, Universite Paris VII Dennis-Diderot, Paris, France B, T P. Departments of Neurology, Surgery, Internal Medicine, The University of Virginia, Charlottesville, Virginia C, E A. Neurologia Experimental, UNIFESPEPM, São Paulo, SP, Brazil C, A G. Dept of Clinical Neurosciences, Institute of Psychiatry, Kings College, London, United Kingdom C, J W. Department of Neurology, Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California C, J Department of Neurology, Raul Carrea Institute for Neurological Research, Buenos Aires, Argentina C, L UNIFESP-EPM, Department of Physiology, São Paulo, SP, Brazil S, A V Neurologia Experimental, UNIFESP-EPM, São Paulo, SP, Brazil DG, C M. Department of Neurology, Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California DL, R J. Department of Neurology, Virginia Commonwealth University, Richmond, Virginia D, S Pharmacy Service, VA Greater Los Angeles Healthcare System, Los Angeles, California V, A P INSERM U.398, Strasbourg, France D, M Department of Pharmacology and Molecular Medicine, Faculty of Medicine and Human Biology, University of Auckland, Auckland, New Zealand E, P Service de Neuropediatrie, Universite Paris VII Dennis-Diderot, Paris, France F, E University of Alabama School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama F, R S. Department of Neurology, Stanford University School of Medicine, Palo Alto, California F, L K. Department of Neuroscience-Histology, New York College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, New York
F, D G. Experimental Neurology Laboratory, VA Greater Los Angeles Healthcare System, Sepulveda, California G, C M. Department of Neurobiology, University of California, Irvine, School of Medicine, Irvine, California G, P S. Department of Neurology, University of Southern California School of Medicine, Los Angeles, California G, P Service de Neuropediatrie, Universite Paris VII Dennis-Diderot, Paris, France H, C Department of Physiology, UNIFESPEPM, São Paulo, SP, Brazil H, A Neurology Department, Veterans Administration Greater Los Angeles Healthcare System, West Los Angeles, California H, W. A G.H. Sergievsky Center, Columbia University, New York, New York H, C N USC Epilepsy Program, University of Southern California School of Medicine, Los Angeles, California H, T R. Department of Neurology, Emory University, Atlanta, Georgia H, D C. G.H. Sergievsky Center, Columbia University, New York, New York H, G L. Center for Neuroscience at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire H, I Service de Neuropediatrie, Universite Paris VII Dennis-Diderot, Paris, France K, J Department of Neurology, University of Virginia, Charlottesville, Virginia K, M E University of Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania K, R Center for Neuroscience at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire K, K Department of Child Neurology, Okayama University Medical School, Okayama, Japan K, S Division of Pediatric Neurology, David Geffen School of Medicine and Mattel Children’s Hospital, University of California at Los Angeles, Los Angeles, California K, H I. Departments of Molecular and Medical Pharmacology and Pediatrics, University of California at Los Angeles, School of Medicine, Los Angeles, California L, J P Departamento de Neurologia, UNIFESP-EPM, São Paulo, SP, Brazil L, I E. College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
xiii
L, H Department of Neurology, Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California L, Z Department of Neurology, Medical College of Georgia, Augusta, Georgia L, G School of Public Health, Harvard University, Boston, Massachusetts M, R L. Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee Mˇ, P Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic M, G W. Division of Neurosurgery, Reed Neurological Research Center, University of California at Los Angeles, Medical Center, Los Angeles, California M, A M. Department of Neurology, Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California MI, D C. Institute for Neuroscience, Department of Psychology, Carleton University, Ottawa, Ontario, Canada M, H-J Epilepsy-Center Berlin, Evg. Krankenhaus, Königin Elisabeth Herzberge und VirchowKlinikum, Med. Fakultät der Humboldt-Universität, Berlin, Germany M, B S. GKT School of Biomedical Sciences, London, United Kingdom M, L E. A. M. UNIFESP-EPM, Department of Physiology, São Paulo, SP, Brazil M, J W. Departments of Neurology and Surgery, University of Washington, Seattle, Washingston M, E M. Section of Neurophysiology, Department of Neurology, Texas Medical Center, Houston, Texas M, S L. Department of Neurology, Albert Einstein College of Medicine, Bronx, New York N, D E. Department of Neurology, Geffen School of Medicine, University of California at Los Angeles, West Los Angeles, California N, A INSERM U 666, Faculte de Medecine, Strasbourg, France N, N Department of Child Neurology, Okayama University Medical School, Okayama, Japan O, S Department of Child Neurology, Okayama University Medical School, Okayama, Japan P, J. M Departments of Neurology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania P, K L. Neurology Service, Stroke Team, West Los Angeles Veterans Administration Medical Center, West Los Angeles, California P, F M. Neurology Service, Miami Veterans Administration Medical Center, Miami, Florida R, A L. Berlex Laboratories, Montville, New Jersey R, R. E Departments of Neurology and Psychiatry, International Center for Epilepsy, University of Miami, Miami, Florida S, R Departments of Neurology and Pediatrics, University of California, Los Angeles at School of Medicine, Los Angeles, California S, M R. Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut
xiv
S, S Department of Neurology, University of California, Irvine, School of Medicine, Long Beach, California S, S Epilepsy Management Center, Montefiore Medical Center, Bronx, New York S, Y National Utano Hospital, Ukyo-ku, Kyoto, Japan S, R P. Robert Stone Dow Chair of Neurology, Director of Neurobiology Research, Legacy Health Systems, Portland, Oregon S, E P. Department of Emergency Medicine, University of Illinois at Chicago, Chicago, Illinois S, R L UNIFESP-EPM, Department of Physiology, São Paulo, SP, Brazil S, E F. Department of Neuroscience and Neurology, Albert Einstein College of Medicine, Bronx, New York S, I School of Dentistry, University of California at Los Angeles, Los Angeles, California S, C E. Departments of Neurology and Pediatrics, University of Wisconsin, Madison, Wisconsin S, W A. Institute for Neuroscience, Department of Psychology, Carleton University, Ottawa, Ontario, Canada S, A G. The Queen’s Medical Center, Honolulu, Hawaii S, L Epilepsy Research Laboratory, University of California at Los Angeles, School of Medicine, West Los Angeles, California T, P Hopital Pasteur, Nice, France T, K W. Department of Neurology, University of California at Los Angeles, School of Medicine, Los Angeles, California T, D M. Department of Neurology, The Barrow Neurological Institute, Phoenix, Arizona V, G Institut of Neuropathology, von Bodelschwingh’sche Anstalten, Bielefeld, Germany Vˇ, J Department of Neurology, Albert Einstein College of Medicine, Bronx, New York V, B G. Department of Neurology, University of California at Los Angeles, Los Angeles, California W, R A Department of Neurology, Veterans Administration Greater Los Angeles Healthcare System, West Los Angeles, California W, C G. Department of Neurology, Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California W, J Y. Department of Pediatrics, David Geffen School of Medicine and Mattel Children’s Hospital, University of California at Los Angeles, Los Angeles, California W, R Department of Neurology, Albert Einstein College of Medicine, Bronx, New York Y, Y Department of Child Neurology, Okayama University Medical School, Okayama, Japan Y, D Department of Molecular Medicine & Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand Z, B Department of Sciences, Hopital du SacreCœur, Montreal, Quebec, Canada
I STATUS EPILEPTICUS: HISTORY, DEFINITION, CLASSIFICATION, AND EPIDEMIOLOGY
1
Historical Overview
.
Introduction This chapter provides a succinct historical review of our understanding of status epilepticus (SE). It begins with the clinical studies that led to the identification of the different forms of SE. It then takes up questions that have been addressed by experimental studies, and thereby provides an overview of the key themes of the book. In preparing this chapter I have benefited from information presented at the Marseille Colloquia (28, 56), from the volume that preceded this one (18), and especially from the book on SE by Simon Shorvon (73).
Early clinical history The earliest known medical description of epilepsy appears on tablet XXV–XXVI of the Sakikku cuneiform, 718–612 .. (38). It alludes to the unfavorable prognosis associated with multiple seizures in one night: “If the possessing demon possesses him many times during the middle watch of the night, and at the time of his possession his hands and feet are cold, he is much darkened, keeps opening and shutting his mouth, is brown and yellow as to the eyes . . . it may go on for some time, but he will die.” Today this possible fatal outcome is frequently emphasized as the primary feature differentiating repetitive or prolonged seizures from single seizures. The term état de mal first appeared in 1824 in the thesis of Louis Calmeil (8); the Anglo-Saxon latinized version, status epilepticus, appears in Bazire’s translation of Trousseau’s lectures (86). T-C S Trousseau (86) provided the first account of SE of the grand mal or tonic-clonic type, which drew attention to the evolving nature of the pattern of clinical seizures, a feature that suggested that something other than a simple repetition of tonic-clonic seizures was occurring. Trousseau also gave a clear account of petit mal status. Bourneville (5) provided a superb clinical account of tonicclonic status in which he described cardiovascular changes and the occurrence of hyperthermia. Hyperthermia as a characteristic of status, regardless of the etiology of the status, has since been widely recognized; in particular, it is associated with a poor neurologic outcome and cerebellar damage (clinically and at post mortem) (2). A series of 38 cases of SE was reported by Clark and Prout in 1903–1904 (17). They described the characteristic changes in seizure
expression associated with the transition from episodes of tonic activity alternating with coma to a stupor with loss of superficial and deep reflexes. Postmortem studies in seven patients revealed selective neuronal necrosis progressing to cell loss, most prominently in the second and third cortical laminae. They described the early appearance of chromatolytic changes (visible in Nissl preparations) of large pyramidal neurons in lamina III and the later neuronophagia and cell loss. L S Episodes of fugue were interpreted as epileptic by Charcot (16), and Hughlings Jackson (80) described prolonged episodes of psychomotor seizures. The proper recognition of limbic status came only after electroencephalography (EEG) became established in the 1940s. The definitive attribution of a fugue state to psychomotor SE was provided by Gastaut and colleagues in 1956 (28). Case histories of limbic status have been collected and reported in recent years (21, 84, 98). A study of the effects of blue mussel or domoate poisoning in 150 Canadians in 1987 (81) provided important insights into the clinical features and sequelae of prolonged limbic seizures, although the bilaterality of the pathology may be atypical for “spontaneous” limbic status. O F SE The nineteenth century also saw the classic description of West’s syndrome (94), with the clear recognition that repeated spasms could be a manifestation of sustained epileptic activity. Sustained focal cortical seizure activity was also recognized by Kojewnikoff (39) and is a feature of the encephalitic syndrome described by Rasmussen and colleagues (69). The EEG characterization of petit mal status with sustained spike-and-wave discharges at 2–3 Hz was provided by Lennox in 1945 (43).
Pathological consequences of generalized SE Pfleger in 1880 (64) observed discoloration (hortensia-like) of the amygdala and hippocampus in patients dying after SE and thought that vascular events associated with the seizure were causing local pathology. Clark and Prout’s observations (17) of the laminar cortical damage were the outstanding early contribution to the neuropathology of SE. Their observations of chromatolysis and neuronophagia were further documented by the German school of neuropathology. Spielmeyer (78) and
:
3
Scholz (70–72) described the acute neuronal cytopathology as “ischaemic cell change” and attributed it to vasospasm associated with the seizure. Descriptions of the pathology found in children dying shortly after prolonged febrile convulsions or SE slowly accumulated (1, 25, 60, 100) and showed the laminar cortical damage of Clark and Prout (17), cerebellar damage involving Purkinje cells, and a pattern of selective loss in the hippocampus similar to that recognized by Sommer in 1880 (77) as being a characteristic finding in institutionalized patients with severe generalized epilepsy. A link between hippocampal sclerosis and temporal lobe or psychomotor seizures was first described by Stauder in 1935 (79). The key observation linking the pathology of SE with the pathology of temporal lobe epilepsy came, however, from Alfred Meyer’s studies on the en bloc anterior temporal lobe specimens provided by Murray Falconer. In 1956, Cavanagh and Meyer (12) were the first to report that hippocampal sclerosis (or “mesial temporal sclerosis”) was the commonest specific pathological finding in complex partial seizures originating in the temporal lobe, and that the majority of such patients had experienced either a single episode of SE or complex febrile convulsions in late infancy or early childhood. This observation was emphasized by Falconer (24) and by Ounsted and colleagues (61) over the next 15 years, and has been confirmed in many studies since 1975 (7, 13, 14, 19, 37, 44, 45, 97). The hypothesis that a prolonged seizure in early life causes pathology in the hippocampus, amygdala, and piriform cortex that, over several years, leads to that temporal lobe becoming the focal source for complex partial seizures has become central to the thinking of many research groups and has received much experimental support (48). Limbic seizures induced by focal or systemic kainic acid provided the first experimental model of epileptogenesis secondary to SE (10, 26). Subsequently the systemic pilocarpine model (with or without lithium) was shown to induce spontaneous seizures more consistently (see discussion under Experimental Studies of SE). Electrically induced limbic SE can also lead to spontaneous seizures (58).
Classification of types of SE The clinical study of SE advanced little in the first half of the twentieth century. The application of EEG to the study of epilepsy was vigorously pursued in Marseille, and the Marseille Colloquia, convened by Henri Gastaut, provided an invigorating forum for the discussion of the pathophysiology of epilepsy and epileptic brain damage (56) and SE (31). The Xth Marseilles Colloquium, in 1962, was the first international meeting devoted to SE. It provided the first systematic classification of status (31). The definition of status proposed at that time (“a term used whenever a seizure per-
4
T 1.1 Clinical forms of status epilepticus État de (grand) mal Petit mal status EEG studies Infantile spasm EEG studies Epileptic fugue EEG studies Epilepsia partialis continua EEG studies Epileptic aphasia
Calmeil, 1824 (8) Trousseau, 1868 (86) Lennox, 1945 (43) West, 1841 (94) Gibbs and Gibbs, 1952 (32) Bright, 1831 (6) Charcot, 1889 (16) Gastaut et al, 1956 (28) Kojewnikoff, 1895 (39) Rasmussen et al, 1958 (69) Juul-Jensen and Denny-Brown, 1966 (36) Wieser et al, 1977 (96) Landau and Kleffner, 1957 (41)
sists for a sufficient length of time or is repeated frequently enough to produce a fixed or enduring epileptic condition”) was not innovative. The novel feature of the classification, however, was the proposal that there are as many types of SE as there are types of epileptic seizure. This was apparent from the case studies of that time in terms of clinical and EEG seizure type; that is, in addition to the classic tonic-clonic status (état de grand mal ) there was tonic status, myoclonic status, simple partial status, and complex partial status. A differentiation of status was also evident in terms of particular epilepsy syndromes and pathophysiologies (notably neonatal seizures, febrile seizures, and various childhood epilepsies, such as West’s syndrome, Landau-Kleffner syndrome), myoclonic status of coma, and the progressive myoclonic epilepsies. This broadening of the concept of SE greatly complicated discussion of the central issues of status. Clinical forms of SE are listed in Table 1.1.
The central conceptual issue of SE Is SE merely prolonged or repetitive seizures, or does something happen that makes it different in kind from the events associated with isolated seizures? Clearly, this question must be posed and answered for each and every type of SE. It is evident that tonic-clonic status has an evolutive pattern (in clinical and EEG terms) that is not shown by absence status or by epilepsia partialis continua. These three categories are also very different in terms of the associated pathologies. Generalized tonic-clonic status, hemispheric status, and limbic status would appear to have much in common, in that they all show an evolutive pattern that includes early increases in cerebral blood flow (CBF) and metabolic rate and later evidence of intracellular calcium accumulation and the onset of selective patterns of neuronal necrosis (ischemic cell change).
: , , ,
T 1.2 Transition from single seizure to status epilepticus: Experimental hypotheses Single seizure (1–15 minutes) Marked ionic shifts (Na+, K+, Ca2+, Cl-) and H2O redistribution. Metabolic enhancement (glycolysis, CMRO2, etc.) Delayed secondary effects (e.g., immediate early gene induction, endocrine activation, some neuroreceptor changes) Status epilepticus (transition at 15–90 minutes) Adenosine formation/release Failure of GABA-mediated inhibition Ca2+ loading of mitochondria Multiple enzyme activations (PLC, proteases, etc.) Multiple metabolic changes (poisoning of mitochondria, free radical generation) Metabotropic receptor effects (short and long term) IEGs–expression of neurotrophins, cytokines, etc. Receptor trafficking Electrical synchronization
For these syndromes, it appears likely that there is a similar answer to the question, What is the transition between the condition of a single seizure to the condition of SE? This question may have several answers, which may be congruent or not. Thus, an analysis based on clinical and EEG evidence may give a different time point from an answer based on neurochemistry, pharmacology, or cellular electrophysiology. It seems evident that satisfactory answers to these questions cannot be derived from clinical studies alone, and that animal experimental studies are required. Some of the key experimental hypotheses are listed in Table 1.2.
Experimental studies of SE Lennox and colleagues (42) and Zimmermann (99) reported some experiments on prolonged seizures induced in cats or kittens by metrazol, camphor, or thujone. Damage to cortical (laminae II and III) and cerebellar (Purkinje) neurons was described and thought to be related to hypoxia and hyperthermia (Purkinje cells). The experimental study of SE began in earnest, however, only 30 years ago, as suggested by the fact that the excellent volume, Experimental Models of Epilepsy, published in 1972 (68), does not have a chapter on models of SE. Spielmeyer (78) and his followers (70–72, 89) had emphasized the similarity, in terms of both the nature of the cellular degenerative changes and the pattern of selective vulnerability of epileptic or post-SE brain damage and ischemic/hypoxic brain damage, and concluded that the pathology after status was of an anoxic-ischemic type. Initially it was thought that vasospasm was part of the pathophysiology of epilepsy, but the direct observations of
Penfield and Jasper (63) showed that focal seizures were associated with a local enhancement of blood flow. This finding led to a greater emphasis on systemic respiratory and cardiovascular problems as potential factors contributing to brain damage. Thus, Meldrum and Brierley began a series of experiments in experimental primates (monkeys and baboons) with extensive physiologic monitoring, including arterial and cerebral venous blood gas measurements, during prolonged seizures induced by bicuculline or allylglycine (51–53). These studies showed that during the first 30 minutes of seizure activity, arterial pressure was elevated and cerebral venous oxygenation was enhanced. Body temperature rose, and blood glucose levels also tended to be elevated. Later, arterial pressure fell, blood glucose fell, and cerebral venous oxygen saturation returned to normal levels. The primary correlation with the occurrence of ischemic cell change in hippocampus and cortex was the duration of the seizure activity. Studies in paralyzed, ventilated baboons in which any systemic consequences of status were minimized (53) established that the duration of electrical seizure activity was the most important determinant of hippocampal pathology. Hyperpyrexia appeared to contribute to cerebellar damage, as indicated by experimental studies of hyperthermia and clinical observations in SE (2). The role of local electrical activity in initiating the process of acute neuronal necrosis was definitively established by the studies of Sloviter employing perforant path stimulation and examining the ipsilateral and contralateral hippocampus (74–76). A detailed historical analysis of the concept of activity-induced cell death in epilepsy has recently been published (47). Chapman and colleagues in 1977 (15) set up a similar model of SE induced by bicuculline in the rat, in which it was possible to measure regional CBF, and oxygen and glucose consumption and biochemical measurements of labile metabolites could be made by rapid freezing of the cerebral cortex. This model showed that there was a massive early increase in cerebral metabolic rate that initially was more than compensated for by increased CBF. The critical role of enhanced Ca2+ entry into neurons was emphasized by Meldrum and colleagues (22, 23, 33–35, 50, 51). Using the oxalate/pyroantimonate method for visualizing free calcium in electron microscopy, they showed a marked calcium loading of mitochondria focally in dendrites and in somata of selectively vulnerable neurons in the hippocampus. Such loading was evident at 30 minutes, becoming more severe in the following hours. Initially it was reversible, but when prolonged, it led to ischemic cell change. These findings have been reproduced in an in vitro model of hippocampal SE (62). The pathological consequences of limbic SE induced by kainate or pilocarpine have been widely studied since 1980 (3, 4, 9, 27, 59, 87, 88). In these models, damage to the
:
5
amygdala and the entorhinal and piriform cortices may be particularly prominent. Febrile convulsions were studied in kittens by Lennox and colleagues in 1954 (42), but modern experimental studies relating to the neonatal period and infancy were initiated by Wasterlain with studies of electroshock, then flurothyl and bicuculline in neonatal rats and subsequently in marmosets (20, 90–93). In the neonatal period, protein synthesis is impaired and growth is restricted, but the classic pattern of selective neuronal loss in the hippocampus is not seen. The lack of the characteristic hippocampal pathology when status is induced in neonatal rodents was subsequently confirmed for both the kainic acid model of limbic status (59) and the pilocarpine model (9, 67). Classic hippocampal damage can be induced from postnatal day 18 in both models. Vulnerability can sometimes be observed earlier than this, for example, at 15 days with perforant path stimulation in the rat (83, 84). SE induced by lithium-pilocarpine can, however, cause necrotic damage in the mediodorsal thalamus in 12-day-old rats (40). Hippocampal and medial temporal damage secondary to prolonged seizures induced by focal, intraventricular, or systemic kainate was shown to be followed, after a few weeks, by spontaneous limbic seizures (10, 26, 55, 59, 64). SE induced by systemic pilocarpine has, however, proved to lead to a more consistent pattern of spontaneous limbic seizures (9, 54, 87).
Therapy for SE Treatment in Europe in the nineteenth century involved blood-letting, trephining, application of ice to the skull or spinal cord, and the administration of a great variety of substances orally, subcutaneously, or rectally. By 1903, Clark and Prout (17) had concluded that trephining had a place only in posttraumatic SE and that venesection could be helpful if combined with intravenous (IV) saline, but the greatest benefit was obtained with an oral cocktail of morphine, opium, potassium bromide, and chloral hydrate, especially when given early or prophylactically, and that subcutaneous bromide was also useful. In the last 50 years the IV use of anticonvulsant agents has been reported to produce dramatic benefit in some cases. The use of IV paraldehyde was described by Whitty and Taylor in 1949 (95). The dramatic effect of IV phenytoin in children with SE was described by McWilliam in 1958 (46). In the early to mid1960s the effects of IV chlormethiazole (66) and diazepam (29, 57) were reported by French neurologists. The first full report of a controlled therapeutic trial yielding statistically significant results was published in 1998 (85). These studies concern elderly adults. We are still surprisingly ignorant of the optimal treatments in childhood, especially in the neonatal period.
6
Comment The study of SE has suffered a long period of neglect, and unfavorable clinical outcomes are still common. The problems have at last been defined and the tools for their experimental and clinical investigation are immediately to hand. It is to be hoped that this volume will be effective in guiding the appropriate studies. REFERENCES 1. Aicardi, J., and J. J. Chevrie. Convulsive status epilepticus in infants and children. Epilepsia 1970;11:187–197. 2. Aminoff, M. J., and R. P. Simon. Status epilepticus: Causes, clinical features and consequences in 98 patients. Am. J. Med. 1980;69:657–666. 3. Ben-Ari, Y. Limbic seizures and brain damage produced by kainic acid: Mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 1985;14:375–403. 4. Ben-Ari, Y., E. Tremblay, O. P. Ottersen, and B. S. Meldrum. The role of epileptic activity in hippocampal and “remote” cerebral lesions induced by kainic acid. Brain Res. 1980; 191:79–97. 5. Bourneville, D. M. L’état de mal épileptique. In D. M. Bourneville, ed. Recherches cliniques et thérapeutiques sur l’épilepsie et l’hystérie. Compte-rendu des observations recueillies a la Salpêtrière. Paris: Delahaye, 1876. 6. Bright, R. Reports of medical cases, selected with a view of illustrating the symptoms and cure of diseases by a reference to morbid anatomy. London: Taylor, 1831:2. 7. Bruton, C. J. The Neuropathology of Temporal Lobe Epilepsy. Oxford, U.K.: Oxford University Press, 1988. 8. Calmeil, L. F. De l’épilepsie, étudiée sous le rapport de son siège et de son influence sur la production de l’aliénation mentale. Thesis, University of Paris, 1824. 9. Cavalheiro, E. A., J. P. Leite, Z. A. Bortolotto, W. A. Turski, C. Ikonomidou, and L. Turski. Long-term effects of pilocarpine in rats: Structural damage of the brain triggers kindling and spontaneous recurrent seizures. Epilepsia 1991; 32:778–782. 10. Cavalheiro, E. A., D. Riche, and G. Le Gal La Salle. Long-term effects of intrahippocampal kainic acid injection in rats: A method for inducing spontaneous recurrent seizures. Electroencephalogr. Clin. Neurophysiol. 1982; 53:581–589. 11. Cavalheiro, E. A., D. F. Silva, W. A. Turski, F. L. Calderazzo, Z. A. Bortolotto, and L. Turski. The susceptibility of rats to pilocarpine-induced seizures is age-dependent. Brain Res. 1987;465:43–58. 12. Cavanagh, J. B., and A. Meyer. Aetiological aspects of Ammon’s horn sclerosis associated with temporal lobe epilepsy. BMJ 1956;2:1403–1407. 13. Cendes, F., F. Andermann, and F. Dubeau. Early childhood prolonged febrile convulsions, atrophy and sclerosis of mesial structures, and temporal lobe epilepsy: An MRI volumetric study. Neurology 1993;43:1083–1087. 14. Cendes, F., F. Andermann, and P. Gloor. Atrophy of mesial temporal structures in patients with temporal lobe epilepsy: Cause or consequence of repeated seizures? Ann. Neurol. 1993;34:795–801.
: , , ,
15. Chapman, A. G., B. S. Meldrum, and B. K. Siesjö. Cerebral metabolic changes during prolonged epileptic seizures in rats. J. Neurochem. 1977;28:1025–1035. 16. Charcot, J. M. Clinical Lectures on the Diseases of the Nervous System (T. Savill, trans.). London: New Sydenham Society, 1889. 17. Clark, L. P., and T. P. Prout. Status epilepticus: A clinical and pathological study in epilepsy. Am. J. Insanity 1903;60:291– 306; 1904;60:645–675, 61:81–108. 18. Delgado-Escueta, A. V., C. G. Wasterlain, D. M. Treiman, and R. J. Porter, eds. Status Epilepticus: Mechanisms of Brain Damage and Treatment. Adv. Neurol. 1983:34. 19. Duncan, J. S., and H. J. Sagar. Seizure characteristics, pathology, and outcome after temporal lobectomy. Neurology 1987; 37:405–409. 20. Dwyer, B. E., and C. G. Wasterlain. Selective focal inhibition of brain protein synthesis during generalised bicuculline seizures in newborn marmoset monkeys. Brain Res. 1984;309: 109–121. 21. Engel, J., B. I. Ludwig, and M. Fetell. Prolonged partial complex status epilepticus. Neurology 1978;28:863–869. 22. Evans, M., T. Griffiths, and B. S. Meldrum. Early changes in the rat hippocampus following seizures induced by bicuculline or -allylglycine: A light and electron microscope study. Neuropathol. Appl. Neurobiol. 1983;9:39–52. 23. Evans, M. C., T. Griffiths, and B. S. Meldrum. Kainic acid seizures and the reversibility of calcium loading in vulnerable neurons in the hippocampus. Neuropathol. Appl. Neurobiol. 1984;10:285–302. 24. Falconer, M. A. Mesial temporal (Ammon’s horn) sclerosis as a common cause of epilepsy: Aetiology, treatment and prevention. Lancet 1974;2:767–770. 25. Fowler, M. Brain damage after febrile convulsions. Arch. Dis. Child. 1957;32:67–76. 26. Franck, J. E., and P. A. Schwartzkroin. Do kainate-lesioned hippocampi become epileptogenic? Brain Res. 1985;329: 309–313. 27. Fujikawa, D. G. The temporal evolution of neuronal damage from pilocarpine-induced status epilepticus. Brain Res. 1996; 725:11–22. 28. Gastaut, H., J. Roger, and A. Roger. Sur la signification de certaines fugues épileptiques: État de mal temporal. Rev. Neurol. 1956;94:298–301. 29. Gastaut, H., R. Naquet, R. Poiré, and C. A. Tassinari. Treatment of status epilepticus with diazepam (valium). Epilepsia 1965;6:167–182. 30. Gastaut, H. A propos d’une classification symptomatologique des états de mal épileptiques. In H. Gastaut, J. Roger, and H. Lob, eds. Les états de mal épileptiques. Paris: Masson, 1967;1–8. 31. Gastaut, H., J. Roger, and H. Lob, eds. Les états de mal épileptiques. Paris: Masson, 1967. 32. Gibbs, F., and E. Gibbs. Atlas of Electroencephalography. Vol 2. Cambridge, Mass.: Addison-Wesley, 1952. 33. Griffiths, T., M. C. Evans, and B. S. Meldrum. Intracellular calcium accumulation in rat hippocampus during seizures induced by bicuculline or -allylglycine. Neuroscience 1983;10: 385–395. 34. Griffiths, T., M. C. Evans, and B. S. Meldrum. Intracellular sites of early calcium accumulation in the rat hippocampus during status epilepticus. Neurosci. Lett. 1982;30:329–334. 35. Griffiths, T., M. C. Evans, and B. S. Meldrum. Status epilepticus: The reversibility of calcium loading and acute neuronal pathological changes in the rat hippocampus. Neuroscience 1984;12:557–567.
36. Juul-Jensen, P., and D. Denny-Brown. Epilepsia partialis continua. Arch. Neurol. 1966;15:563–578. 37. Kim, J. H., P. O. Guimaraes, M. Y. Shen, L. M. Masukawa, and D. D. Spencer. Hippocampal neuronal density in temporal lobe epilepsy with and without gliomas. Acta Neuropathol. (Berl.) 1990;80:41–45. 38. Kinnier Wilson, S. A., and E. H. Reynolds. Translation and analysis of a cuneiform text forming part of a Babylonian treatise on epilepsy. Med. Hist. 1990;34:185–198. 39. Kojewnikoff, A. Y. Eine besondere Form von corticaler Epilepsie. Neurol. Zentralb. 1895;14:47–48. 40. Kubová, H., R. Druga, K. Lakasiuk, L. Suchomelová, R. Haugvicová, I. Jirmanová, and A. Pitkänen. Status epilepticus causes necrotic damage in the mediodorsal nucleus of the thalamus in immature rats. J. Neurosci. 2001;21:3593–3599. 41. Landau, W. M., and F. Kleffner. Syndrome of acquired aphasia with convulsive disorder in children. Neurology 1957;7:523–530. 42. Lennox, M. A., W. A. Sibley, and H. M. Zimmerman. Fever and febrile convulsions in kittens: A clinical, electroencephalographic, and histopathological study. J. Pediatr. 1954;45:179–190. 43. Lennox, W. The petit mal epilepsies: Their treatment with tridione. JAMA 1945;129:1069–1073. 44. Mathern, G. W., T. L. Babb, B. G. Vickrey, M. Melendez, and J. K. Pretorius. Traumatic compared to non-traumatic clinical-pathologic associations in temporal lobe epilepsy. Epilepsy Res. 1994;19:129–139. 45. McMillan, T., G. E. Powell, I. Janota, and C. E. Polkey. Relationships between neuropathology and cognitive functioning in temporal lobectomy patients. J. Neurol. Psychiatry 1987;50:167–176. 46. McWilliam, P. K. A. Intravenous phenytoin sodium in continuous convulsions in children. Lancet 1958;2:1147–1149. 47. Meldrum, B. S. Concept of activity-induced cell death in epilepsy: Historical and contemporary perspectives. Prog. Brain Res. 2002;135:3–11. 48. Meldrum, B. S. First Alfred Meyer Memorial Lecture. Epileptic brain damage: A consequence and a cause of seizures. Neuropathol. Appl. Neurobiol. 1997;23:185–201. 49. Meldrum, B. S. Metabolic effects of prolonged epileptic seizures and the causation of epileptic brain damage. In F. C. Rose, ed. Metabolic Disorders of the Nervous System. London: Pitman, 1981:175–187. 50. Meldrum, B. S. Metabolic factors during prolonged seizures and their relation to nerve cell death. In A. V. DelgadoEscueta, C. G. Wasterlain, D. M. Treiman, and R. J. Porter, eds. Status Epilepticus: Mechanisms of Brain Damage and Treatment. Adv. Neurol. 1983;34:261–273. 51. Meldrum, B. S., and J. B. Brierley. Prolonged epileptic seizures in primates: Ischaemic cell change and its relation to ictal physiological events. Arch. Neurol. 1973;28:10–17. 52. Meldrum, B. S., R. W. Horton, and J. B. Brierley. Epileptic brain damage in adolescent baboons following seizures induced by allylglycine. Brain 1974;97:417–428. 53. Meldrum, B. S., R. A. Vigoroux, and J. B. Brierley. Systemic factors and epileptic brain damage: Prolonged seizures in paralysed artificially ventilated baboons. Arch. Neurol. 1973;29: 82–87. 54. Mello, L. E. A. M., E. A. Cavalheiro, and A. M. Tan. Circuit mechanisms of seizures in the pilocarpine model of chronic epilepsy: Cell loss and mossy fibre sprouting. Epilepsia 1993; 34:985–995.
:
7
55. Menini, C., B. S. Meldrum, D. Riche, C. Silva-Comte, and J. M. Stutzmann. Sustained limbic seizures induced by intraamygdaloid kainic acid in the baboon: Symptomatology and neuropathological consequences. Ann. Neurol. 1980;8: 501–509. 56. Morin, G., and H. Gastaut. Colloque sur les problèmes d’anatomie normale et pathologique posés par les décharges épileptiques. Acta Med. Belg. (Bruxelles) 1956. 57. Naquet, R., R. Soulayrol, G. Dolce, C. A. Tassinari, R. Broughton, and H. Loeb. First attempt at treatment of experimental status epilepticus in animals and spontaneous status epilepticus in man with diazepam. Electroencephalogr. Clin. Neurophysiol. 1965;18:424–427. 58. Nissinen, J., T. Halonen, E. Koivisto, and A. Pitkänen. A new model of chronic temporal lobe epilepsy induced by electrical stimulation of the amygdala in rat. Epilepsy Res. 2000;38:177–205. 59. Nitecka, L., E. Tremblay, G. Charton, J. P. Bouillot, M. L. Berger, and Y. Ben-Ari. Maturation of kainic acid seizurebrain damage syndrome in the rat. II. Histopathological sequelae. Neuroscience 1984;13:1073–1094. 60. Norman, R. M. The neuropathology of status epilepticus. Med. Sci. Law 1964;4:46–51. 61. Ounsted, C., J. Lindsay, and R. Norman. Biological Factors in Temporal Lobe Epilepsy. London: Heinemann, 1966: 1–135. 62. Pal, S., S. Sombati, D. D. Limbrick, and R. J. DeLorenzo. In vitro status epilepticus causes sustained elevation of intracellular calcium levels in hippocampal neurons. Brain Res. 1999;851:20–31. 63. Penfield, W., and H. Jasper. Epilepsy and the Functional Anatomy of the Human Brain. Boston: Little, Brown, 1954. 64. Pfleger, L. Beobachtungen über Schrumpfung und Sclerose des Ammonshorn bei Epilepsie. Allg. Zeitschr. Psychiatr. 1880; 36:359–365. 65. Pisa, M., P. R. Sanberg, M. E. Corcoran, and H. C. Fibiger. Spontaneously recurrent seizures after intracerebral injections of kainic acid in rat: A possible model of human temporal lobe epilepsy. Brain Res. 1980;200:481–487. 66. Poiré, R., P. Royer, M. Degraeve, and C. Rustin. Traitement des états de mal épileptiques par le “CTZ base” (dérivé de la fraction thiazolique de la vitamine B1): Etude électroclinique. Rev. Neurol. 1963;108:112–126. 67. Priel, M. R., N. F. Dos Santos, and E. A. Cavalheiro. Developmental aspects of the pilocarpine model of epilepsy. Epilepsy Res. 1996;26:115–121. 68. Purpura, D. P., J. K. Penry, D. M. Woodbury, D. B. Tower, and R. D. Walter. Experimental Models of Epilepsy. New York: Raven Press, 1972. 69. Rasmussen, T., J. Olszewski, and D. Lloyd-Smith. Focal seizures due to chronic encephalitis and epilepsy. Neurology 1958;8:435–445. 70. Scholz, W. The contribution of pathoanatomical research to the problem of epilepsy. Epilepsia 1959;1:36–55. 71. Scholz, W. Die Krampfschädigungen des Gehirns. Berlin: Springer, 1951. 72. Scholz, W. Über die Entstehung des Hirnbefundes bie der Epilepsie. Ztg. Ges. Neurol. Psychiatr. 1933;145:471–515. 73. Shorvon, S. D. Status Epilepticus: Its Clinical Features and Treatment in Children and Adults. Cambridge, U. K.: Cambridge University Press, 1994:1–382. 74. Sloviter, R. S. “Epileptic” brain damage in rats induced by sustained electrical stimulation of the perforant path. I. Acute
8
75.
76.
77.
78. 79. 80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90. 91. 92.
electrophysiological and light microscopic studies. Brain. Res. Bull. 1983;10:675–697. Sloviter, R. S., and B. P. Damiano. Sustained electrical stimulation of the perforant path duplicates kainate-induced electrophysiological effects and hippocampal damage in rats. Neurosci. Lett. 1981;24:279–284. Sloviter, R. S., E. Dean, A. L. Sollas, and J. H. Goodman. Apoptosis and necrosis induced in different hippocampal neuron populations by repetitive perforant path stimulation in the rat. J. Comp. Neurol. 1996;366:516–533. Sommer, W. Erkrankung des Ammonshornes als aetiologisches Moment der Epilepsie. Arch. Psychiatr. Nervenkr. 1880;10: 631–675. Spielmeyer, W. Die Pathogenese des Epileptischen Krampfes. Zeitschr. Ges. Neurol. Psychiatr. 1927;109:501–520. Stauder, K. H. Epilepsie und Schlafenlappen. Arch. Psychiatr. Nervenkr. 1935;104:181–211. Taylor, J. Selected Writings of Hughlings Jackson. Vol. 1. On Epilepsy and Epileptiform Convulsions. London: Hodder & Stoughton, 1931. Teitelbaum, J. S., R. J. Zatorre, S. Carpenter, D. Gendron, A. C. Evans, A. Gjedde, and N. R. Cashman. Neurologic sequelae of domoic acid intoxication due to the ingestion of contaminated mussels. N. Engl. J. Med. 1990;322:1781– 1787. Thompson, K., A. M. Holm, A. Schousboe, P. Popper, P. Micevych, and C. Wasterlain. Hippocampal stimulation produces neuronal death in the immature brain. Neuroscience 1998;82:337–348. Thompson, K., and C. Wasterlain. Partial protection of hippocampal neurons by MK-801 during perforant path stimulation in the immature brain. Brain Res. 1997;751: 96–101. Treiman, D. M., and A. V. Delgado-Escueta. Complex partial status epilepticus. In A. V. Delgado-Escueta, C. G. Wasterlain, D. M. Treiman, and R. J. Porter, eds. Status Epilepticus: Mechanisms of Brain Damage and Treatment. New York: Raven Press, 1983:69–81. Treiman, D. M., P. D. Meyers, N. Y. Walton, J. F. Collins, et al. A comparison of four treatments for generalized convulsive status epilepticus. N. Engl. J. Med. 1998;339: 792–798. Trousseau, A. Lectures on Clinical Medicine Delivered at the Hotel Dieu, Paris. Vol. 1 (P. V. Bazire, trans.). London: New Sydenham Society, 1868. Turski, L., C. Ikonomidou, W. A. Turski, Z. A. Bortolotto, and E. A. Cavalheiro. Review: Cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: A novel experimental model of intractable epilepsy. Synapse 1989;3:154–171. Tuunanen, J., T. Halonen, and A. Pitkänen. Status epilepticus causes selective regional damage and loss of GABAergic neurons in the rat amygdaloid complex. Eur. J. Neurosci. 1996;8:2711–2725. Veith, G. Anatomische Studie über die Ammonshornesklerose im Epileptikergehirn. Dtsch. Ztg. Nerv. 1970;197:293– 314. Wasterlain, C. G. Mortality and morbidity from serial seizures: An experimental study. Epilepsia 1974;15:155–174. Wasterlain, C. G. Recurrent seizures in the developing brain are harmful. Epilepsia 1997;38:728–734. Wasterlain, C. G., and T. E. Duffy. Status epilepticus in immature rats. Arch. Neurol. 1976;33:821–827.
: , , ,
93. Wasterlain, G. G., D. G. Fujikawa, L. Penix, and R. Sankar. Pathophysiological mechanisms of brain damage from status epilepticus. Epilepsia 1993;34:S37-S53. 94. West, W. J. On a peculiar form of infantile convulsions. Lancet 1841;1:724–725. 95. Whitty, C. W. M., and M. Taylor. Treatment of status epilepticus. Lancet 1949;2:591–594. 96. Wieser, H. G., H. P. Graf, C. Bernoulli, and J. Siegfried. Quantitative analysis of intracerebral recordings in epilepsia partialis continua. Electroencephalogr. Clin. Neurophysiol. 1977;44: 558–572. 97. Williamson, P. D., J. A. French, and V. M. Thadani. Characteristics of medial temporal lobe epilepsy. II. Interictal and ictal scalp electroencephalography, neuropsychological testing, neuroimaging, surgical results, and pathology. Ann. Neurol. 1993;34:781–787. 98. Wolf, P. Zur Klinik und Psychopathologie des Status Psychomotoricus. Nervenarzt 1970;41:603–610. 99. Zimmerman, H. M. The basis of convulsive attacks in children: An experimental study. N. Y. Pathol. Soc. 1959;35: 801–810. 100. Zimmerman, H. M. The histopathology of convulsive disorders in children. J. Pediatr. 1938;13:859–890.
:
9
2
Definition and Classification of Status Epilepticus
. .
Definition Status epilepticus (SE) is one of the few illnesses named not by the physicians who treated it but by the patients who suffered from it. The expression état de mal was coined by the patients at the Salpêtrière, the world’s first neurologic hospital, and reached the medical literature through the doctoral thesis of Louis Calmeil (6), then became latinized as status epilepticus in Bazire’s English translation of the 1867 lectures of Armand Trousseau in London (44). Although Trousseau and Bourneville (5) recognized the existence of stages in SE, and Clark and Prout (9) identified SE as being different from single epileptic seizures, the first attempt at a formal definition came at the 1962 Marseilles Colloquium, where Gastaut defined it as “epileptic seizures which are so frequently repeated and so prolonged as to create a fixed and enduring epileptic condition” (15). The definition and classification of SE were further refined by Gastaut in the World Health Organization’s 1973 publication, Dictionary of Epilepsy (18), in the 1974 Handbook of Clinical Neurology (35), and in the 1975 Handbook of Electroencephalography and Clinical Neurophysiology (20). Gastaut also proposed a formal classification of status epilepticus (Table 2.1) at the first Santa Monica meeting, in 1980 (12, 16). C B D SE Is SE simply a cluster of severe seizures, or is it a separate condition with its own unique pathophysiology? Trousseau expressed the uniqueness of SE as early as 1867: “In that form of status epilepticus when the convulsions are practically continuous, something specific happens which demands an explanation” (44). Indeed, recent experimental evidence strongly suggests that SE is a separate phenomenon and not simply a series of seizures. Seizure-like stimulation of some excitatory pathways in the brain easily triggers SE. Once it is established, stimulation can be stopped and seizures continue. Moreover, these self-sustaining seizures can be suppressed for hours with a synaptic blocker, yet when that blocker’s effects wane, the seizures return in the absence of any further stimulation, implying that self-sustaining SE is maintained by an underlying change in excitability (31). The transition from serial seizures to SE is modulated by neuropeptides, neurotrans-
mitters, and receptor trafficking (29–31), and anticonvulsants that are effective against serial seizures are often ineffective against established, self-sustaining SE (32). At the second Santa Monica meeting (37) there was a vigorous debate over the basis for defining and classifying SE. Many participants suggested definitions based on seizure durations ranging from 5 to 30 minutes. Others defined SE by the subject’s failure to recover consciousness before seizure recurrence. This criterion is retained in our definition, since it permits the inclusion of cases in which severe seizures are associated with long interictal intervals. Engel has proposed that SE is defined by the failure of normal mechanisms to terminate a seizure (14). A logical conclusion of that premise would be to define SE statistically, as a seizure duration that is clearly outside the range of “normal” seizure duration, for example 5 standard deviations (SD) removed from the mean. The definition of SE proposed later in the chapter is in accord with that line of thought. T C “I SE” Ever since Gastaut defined SE as a fixed and enduring epileptic condition, the medical literature has struggled to determine the minimal duration and severity of seizures that constitute SE. Simple as it may be, such a determination is essential to clinical trials and therapeutic guidelines. Some of the dilemmas created by these attempts at a more precise definition are discussed in Shorvon’s outstanding book (36) and are beyond the scope of this chapter. Yet we must recognize that seizures are rarely fixed, that the boundaries of what constitutes a seizure vary with the method of observation (e.g., electroencephalographic [EEG] or clinical), and that the most useful definition may vary with our main objective. For example, many epileptologists apply the treatment of status when faced with the admittedly unusual event of continuous generalized motor seizures lasting 5 minutes, which suggests that a seizure duration of 5 minutes meets their operational definition of SE. Reducing the definition of status to that extent, however, would enormously complicate epidemiologic studies by including in population studies a large number of patients who may not experience full-blown SE.
:
11
T 2.1 1983 classification of SE Primary Generalized Convulsive Status Tonic-clonic status Myoclonic status Clonic-tonic-clonic status Secondary Generalized Convulsive Status Tonic-clonic status with partial onset Tonic status Subtle generalized convulsive status Simple Partial Status Partial motor status Unilateral status Epilepsia partialis continua Nonconvulsive Status Absence status—typical or atypical Complex partial status
C B D B S D The duration of what is accepted as SE has been shrinking progressively, from 30 minutes in the guidelines of the Epilepsy Foundation of America’s Working Group on Status Epilepticus (51) to 20 minutes (2), and to 10 minutes in the Veterans Affairs (VA) cooperative trial on the treatment of SE (42). Most recently, Wasterlain (at the 1997 Santa Monica meeting), Lowenstein and Alldredge (25), Lowenstein, Bleck, and Macdonald (26), and Meldrum (33) have proposed an operational definition of SE that defines the time when severe seizures should be treated as SE. Those several authors have proposed that 5 minutes of continuous generalized convulsive seizures is sufficient to fulfill that criterion. Videotape-telemetry studies show that the mean duration of generalized convulsive seizures in adults ranges from 62.2 seconds (n = 120) to 52.9 ± 14 seconds (n = 50) (very close to the 1-minute estimate of Gastaut and Broughton [19]) for the behavioral manifestations and averages 59.9 ± 12 seconds for the EEG manifestations. None of those seizures lasted 2 minutes (21, 39). Therefore, the operational definition of SE as 5 minutes of continuous generalized convulsive activity is probably too conservative, since it defines status by a seizure duration that is 18–20 SD removed from the norm, restricting it to an extremely rare event. It might be more logical to treat with intravenous (IV) drugs after 2 minutes of continuous seizure activity (4–5 SD outside the norm), as proposed by Theodore and colleagues (39). However, in practice, there is essentially no difference between 2 and 5 minutes, since it takes more than 3 minutes to deliver the first IV injection. A definition of 5 minutes of continuous seizures has two advantages: first, it reconciles the definition of status with
12
the almost universal emergency room practice of treating those patients as if they had SE, and second, it places the definition of status far outside the norm for seizure duration, clearly indicating that something distinctly unusual and severe is occurring. However, we propose to call it impending status epilepticus, since not all such patients are in SE, and a significant proportion will stop seizing spontaneously in the next few minutes. The Richmond data provide support for this concept: more than 40% of the seizures lasting from 10 to 29 minutes stopped spontaneously without treatment (32), and they had an overall mortality of 2.6% versus 19% for SE (P < 0.001). We define impending status epilepticus as “continuous seizures lasting more than 5 minutes, or intermittent clinical or electrographic seizures lasting over 15 minutes without full recovery of consciousness between seizures.” This recognizes the need to treat those patients intravenously with high-dose anticonvulsants, since their risk of developing frank SE is high, but it also acknowledges that not all of those patients are in frank SE. By adopting a new category of impending SE, these patients will receive proper urgent medical care but will not contaminate morbidity and mortality statistics, outcome measures, or clinical trials with a subpopulation that is not in frank SE. Frank SE continues to use the definition of the EFA’s working group on SE. We also agree with Shorvon (36) and others that different definitions and classifications are needed for different age groups. The current definition should apply to adults and children over 5 years of age. Different criteria should be used for neonates, and yet other criteria for infants and young children. We will not discuss in this chapter the definition of SE in the neonate (for which we refer the reader to Shorvon’s 1994 book [36] and to Wasterlain and Vert’s book, Neonatal Seizures [48]), or the definition of SE in infants and children. In that age group, the high incidence of febrile seizures, which frequently last longer than 5 minutes (22), and their generally benign outcome may change the risk-benefit ratio of status versus treatment, so that most physicians have retained the traditional definition of SE as seizures lasting more than 30 minutes. E B D B S D The traditional argument that SE should be defined as the minimal duration of seizure that produces brain damage has collapsed with the demonstration (7) that even single seizures without a tonic component can produce neuronal loss in experimental animals. We know that generalized convulsive seizures in primates produce neuronal death much more quickly than nonconvulsive seizures (34), and therefore deserve prompt therapeutic attention, but we have no solid data on the minimum seizure duration sufficient to damage the human brain. On the other hand, the demonstration in animal experiments that repeated, brief, seizurelike discharges through excitatory pathways set in motion
: , , ,
self-sustaining seizures (32, 45, 47), which rapidly become resistant to standard anticonvulsants (29), would suggest that treatment should be administered before self-sustaining seizures become established. In the rat, this can take place within 15 minutes (32) or 10 afterdischarges (45). Unfortunately, we have little information on the timing or even the existence of these phenomena in humans. Therefore, experimental data give us a sense of urgency without providing us with a precise time frame for defining or treating SE. I T R O? Intravenous medications undoubtedly entail significant risks: respiratory and even cardiovascular depression can result, some anticonvulsants impair cardiac conduction and can generate arrhythmias, allergic reactions often take the form of anaphylactic shock, idiosyncratic reactions may be more severe than with other forms of administration. Therefore, single generalized seizures that have not been documented to last more than 2 minutes and seizures that are benign or remain focal should not be treated with IV anticonvulsants; oral loading is usually feasible and much safer. A D I SE We propose the following definition, which should be used by clinicians making diagnostic and therapeutic decisions: An acute epileptic condition characterized by continuous generalized convulsive seizures for at least 5 minutes, or by continuous nonconvulsive seizures (clinical or electrographic) or focal seizures for at least 15 minutes, or by two seizures without full recovery of consciousness between them.
A D SE We propose the following definition of SE, which should be used by epidemiologists and other clinical investigators conducting studies of SE: An acute epileptic condition characterized by continuous seizures (partial or generalized, convulsive or nonconvulsive) for at least 30 minutes, or by 30 minutes of intermittent seizures without full recovery of consciousness between seizures.
Classification It is not often recognized that classifications have specific purposes and that several classifications of the same phenomenon can be useful, depending on their goal. Many useful classifications of SE have been published and will not be repeated here. They are based on the symptomatology of the seizures (such as the 1983 classification by Gastaut, given in Table 2.1, or the classifications of Walsh and Delgado-Escueta [46] or Leppik [23]) or on the epileptic syndromes (36), with limited attempts at using pathophysiology (43). We propose two new classifications for specific purposes: first, a therapeutically oriented “clinical” classification of status, which should be helpful in directing treatment, and second, a semiologic classification,
which should be useful for a precise description of seizure phenomenology and for accurate categorization of all the seizure types involved in SE. These attempts are inspired by the systems proposed during the current discussions for new classifications of epileptic seizures. A C C Semiologic classifications, while providing an accurate description that is useful for later comparison or for following the evolution of the illness, do not provide therapeutic guidance for the clinician. The treatment-oriented classification (Table 2.2) outlined below divides SE according to a mix of clinical, EEG, and therapeutic criteria into broad categories that are therapeutically
T 2.2 A clinical classification of status epilepticus Generalized Convulsive Status Epilepticus Tonic-clonic (frank or subtle) or clonic-tonic-clonic: With focal onset (clinical or EEG) With generalized onset (clinical and EEG) Tonic Clonic Myoclonic Multifocal (clinical or EEG) Generalized (clinical and EEG) Treat vigorously with rapid IV infusion of high doses of anticonvulsants. The seizure type determines the choice of anticonvulsant. Exceptions include intolerance to a particular drug. Complex Partial (Limbic) Status Epilepticus Treat as for GCSE with focal onset. Exceptions: same as for GCSE. Absence Status Epilepticus (Spike-Wave Stupor) Treatment is controversial, usually with IV benzodiazepines. Electrographic Status Epilepticus Generalized with impairment of consciousness: Usually a form of “subtle” SE; treat as for GCSE. Generalized without impairment of consciousness: No need for IV treatment. During sleep: No need for IV treatment. Focal: No need for IV treatment. Unilateral Status Epilepticus With spread to hemiconvulsions: Treat as for GCSE. Epilepsia partialis continua: No need for IV treatment. Note: By clinical we mean an operational (treatment-oriented) classification of SE that facilitates the clinician’s therapeutic decisions. This classification does not address neonatal SE or SE in infancy or early childhood, which includes febrile SE. It should be used only for children more than 5 years old and for adults. Abbreviations: SE, status epilepticus; GCSE, generalized convulsive status epilepticus; EEG, electroencephalography; IV, intravenous.
:
13
meaningful, and provides a useful complement to the semiologic, syndrome-oriented, and pathophysiologic classifications described by others (36). For example, from a therapeutic viewpoint, it makes no difference whether generalized convulsive status epilepticus (GCSE) is tonicclonic or clonic-tonic-clonic, or whether it is primary or secondarily generalized, since both will be treated the same way, and thus they have not been separated here, despite the great differences in etiology and seizure mechanisms between them. Therefore, the inclusion of therapeutic criteria differentiates this “clinical” classification from Gastaut’s 1983 (16) classification and from the International League Against Epilepsy’s classification of epileptic seizures (10, 11, 15). Similarly, complex partial and absence seizures are sometimes difficult to differentiate on clinical grounds alone, but because they are therapeutic opposites, one must carefully differentiate between them before treating, and therefore they are placed in completely different categories here (but not in the semiologic classification that follows). A brief list of key therapeutic exceptions is included in the classification. Tonic SE associated with Lennox-Gastaut syndrome, for example, can be aggravated by benzodiazepines (38), which are usually quite beneficial in tonic status symptomatic of frontal lobe lesions in adults. GCSE in the progressive myoclonus epilepsies is often dramatically triggered by fosphenytoin or phenytoin, agents that are most useful in treating other forms of GCSE (1, 24). Finally, the clinical manifestations of frank and “subtle” SE (40, 41) are quite different, yet these conditions are grouped in the same category because they require the same treatment. Semiologic classifications have advantages and drawbacks; they give us a tool to accurately describe the seizures and are useful for the clinical localization of the seizure focus. Since their purpose is simply to accurately describe and classify seizure behavior, our classification excludes pathophysiologic, EEG, or syndromal considerations, which would contaminate the objective description of the seizures (see Table 2.3). For example, partial complex SE and absence SE are very different entities, requiring different treatments, yet both are manifested primarily by a clouding of consciousness, and they may be impossible to distinguish in the absence of additional data, such as past history, EEG, or associated manifestations. A semiologic classification should make no attempt to interpret the clouding of consciousness by bringing in these extraneous considerations, but because it separates description from interpretation and achieves a very precise and objective description of the type of seizures observed, it greatly facilitates both diagnostic and therapeutic decisions. The current classification is inspired by the Cleveland Clinic’s classification of epileptic seizures (27) and uses both a classification of the type of SE and a classification of the type of individual seizure observed during status.
14
D T SE Our description characterizes the pattern of seizure activity rather than the details of each individual seizure. GCSE usually manifests with intermittent generalized motor seizures “strung like red beans on a black thread of unconsciousness” (49). It is important to recognize that both clinical and EEG manifestations are not fixed but evolve during the course of status. For example, the motor manifestations of GCSE may become more limited and less vigorous with time, without losing their significance. This, of course, is the “subtle” form of GCSE (40). Because complex partial and absence seizures cannot always be distinguished clinically, the most accurate term to describe them is “generalized nonconvulsive status epilepticus,” since essentially all generalized nonconvulsive seizures manifest with an impairment of consciousness (the term dialeptic, with interruption, also provides a good description of the phenomenon). It is also important to recognize that most patients experience only a partial impairment of consciousness; the complete loss of contact seen at the onset of partial complex or absence seizures evolves with time into a “cloudy state” in which some consciousness is retained. This evolution may represent the nonconvulsive equivalent of “subtle” GCSE. For each patient, the description should include the type of status, followed by a detailed sequential description of seizure types. D S T Because seizures frequently wax and wane during SE, in a semiologic classification it is most useful to describe them as a sequence. A seizure type needs to be described accurately for each seizure, and successive seizures can be described simply in chronological order (for example, left thumb clonic Æ left corner of mouth clonic Æ left arm clonic Æ left hemiconvulsion Æ generalized). From a semiologic viewpoint, Gastaut’s statement that “there are as many types of status epilepticus as there are types of epileptic seizures” is undoubtedly correct. A few individual seizure types require comment. Complex motor seizures include seizures with manifestations, such as motor automatisms, that are frequently associated with psychic phenomena but are inherently composed of complex motor activity, and other manifestations such as versive or dystonic movements. Complex motor seizures include inhibitory motor seizures, which are sometimes hard to distinguish from postictal manifestation, and include weakness or paralysis, seizures with loss of posture, falls (head drop), negative myoclonus, astatic seizures with ictal falls not necessarily due to a loss of tone, and aphasic seizures in which a patient develops speech arrest or inability to understand spoken language. Sensory seizures can also have positive or negative manifestations and may be simple or complex. They may involve any of the senses and are relatively common. They are classified as sensory if the sensory manifestations are the main
: , , ,
T 2.3 A semiologic classification of status epilepticus Type of Status Epilepticus Generalized convulsive Frank Subtle Nonconvulsive with loss of consciousness (dialeptic) With complete loss of consciousness With partial loss of consciousness Partial Convulsive Nonconvulsive Type of Seizure Motor Simple Tonic Clonic Myoclonic Complex Versive Dystonic Automatisms Other (e.g., salaam, pedaling) Inhibitory Paralytic Atonic Astatic Akinetic Negative myoclonic Aphasic Sensory Somatosensory: simple, complex Auditory: simple, complex Visual: simple, complex Olfactory: simple, complex Gustatory: simple, complex Psychic With cognitive manifestations With psychiatric manifestations Autonomic Dialeptic With complete loss of consciousness With partial loss of consciousness Modifiers: Left, right, bilateral, symmetric, asymmetric, axial, generalized; specific symptom and location (e.g., left arm clonic seizure; dialeptic seizure with orobuccal automatisms) Indicate sequence (e.g., versive-loss of consciousness-tonicclonic) Indicate duration, especially for loss of consciousness. Indicate frequency, pattern of occurrence, precipitants, severity and postictal deficits.
component of the seizure, and as psychic if the complexity of the sensory phenomena makes the psychic component dominant. They include manifestations such as gelastic seizures, visual distortions such as macropsia or micropsia, and complex somatosensory phenomena such as the feeling of a wind passing over one’s body (aura). The duration of isolated seizures is much shorter for absences (seconds) than for complex partial seizures (30 seconds to 2 minutes), but this distinction blurs during the evolution of SE and becomes useless. Some myoclonic states, such as postanoxic multifocal myoclonus following cardiac arrest (8) or the prolonged negative myoclonic seizures seen in benign neonatal convulsions (idiopathic) or in Aicardi’s syndrome or Ohtahara’s syndrome, are not included in this classification. We agree with Shorvon (36) that they should be classified under “status myoclonicus.” This work was supported by the Research Service of VHA (CGW) and by Research Grant NS 13515 from NINDS (CGW), and by a K08 Award from NINDS ( JWYC).
REFERENCES 1. Aminoff, M., and R. Simon. Status epilepticus: Causes, clinical features and consequences in 98 patients. Am. J. Med. 1980;69:657–666. 2. Benbadis, S. R., P. Thomas, and G. Pontone. A prospective comparison between two seizure classifications. Seizure 2001; 10:247–249. 3. Bleck, T. P. Convulsive disorders: Status epilepticus. Clin. Neuropharmacol. 1991;14:191–198. 4. Blume, W. T., S. F. Berkovic, and O. Dulac. Search for a better classification of the epilepsies. In J. Engel, Jr., and T. A. Pedley, eds. Epilepsy: A Comprehensive Textbook. Philadelphia: LippincottRaven, 1998:779–788. 5. Bourneville, D. L’état de mal epileptique. In Recherches cliniques et therapeutiques sur l’epilepsie et l’hysterie. Compte-rendu des observations recueillies a la Salpêtrière. Paris: Delahaye, 1876. 6. Calmeil, L. F. De l’epilepsie, étudies sous le rapport de son siege et de son influence sur la production de l’alienation mentale. Thesis, University of Paris, 1824. 7. Cavazos, J. E., and T. P. Sutula. Progressive neuronal loss induced by kindling: A possible mechanism for mossy fiber synaptic reorganization and hippocampal sclerosis. Brain Res. 1990;527(1):1–6. 8. Celesia, C. G., M. M. Grigg, and E. Ross. Generalized status myoclonicus in acute anoxic and toxic-metabolic encephalopathies. Arch. Neurol. 1988;45:781–784. 9. Clark, L., and T. Prout. Status epilepticus: A clinical and pathological study in epilepsy. Am. J. Insanity 1903–1904;60: 291–306. 10. Commission on Terminology of the International League Against Epilepsy. A proposed international classification of epileptic seizures. Epilepsia 1964;5:297–306. 11. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489–501.
:
15
12. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989; 30:389–399. 13. Delgado-Escueta, A. V., A. A. Ward, Jr., D. M. Woodbury, and R. J. Porter, eds. Basic Mechanisms of the Epilepsies: Molecular and Cellular Approaches. Adv. Neurol. 1986;44 (whole issue). 14. Engel, J., Jr. Classification of the International League Against Epilepsy: Time for reappraisal. Epilepsia 1998;39:1014–1017. 15. Gastaut, H. A propos d’une classification symptomatologique des états de mal epileptiques. In H. Gastaut, J. Roger, and H. Lob, eds. Les états de mal epileptiques. Paris: Masson, 1967:1–8. 16. Gastaut, H. Classification of status epilepticus. Adv. Neurol. 1983;34:15–35. 17. Gastaut, H. Clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1970;11:102–113. 18. Gastaut, H., ed. Dictionary of Epilepsy. Part 1. Definition. Geneva: World Health Organization, 1973. 19. Gastaut, H., and R. Broughton. Epileptic Seizures: Clinical and Electrographic Features, Diagnosis and Treatment. Springfield, Ill.: Charles C Thomas, 1972:25–90. 20. Gastaut, H., and A. Tassinari. Handbook of Electroencephalography and Clinical Neurophysiology. 1975. 21. Kramer, R., and P. Levisohn. The duration of secondarily generalized tonic-clinic seizures (abstract). Epilepsia 1992;33:68. 22. Lennox-Buchthal, M. A. Febrile convulsions. In Handbook of Clinical Neurology. Vol. 15. The Epilepsies (O. Magnus and A. M. Lorentz de Haas, eds.). Amsterdam: North Holland Publishing Co., 1974:246–263. 23. Leppik, L. E. Status epilepticus. Neurol. Clin. 1986;4:633–643. 24. Lowenstein, D., and B. Alldredge. Status epilepticus at an urban public hospital in the 1980s. Neurology 1993;43:483–488. 25. Lowenstein, D. H., and B. K. Alldredge. Current concepts: Status epilepticus. N. Engl. J. Med. 1998;338:970–976. 26. Lowenstein, D. H., T. Bleck, and R. L. Macdonald. It’s time to revise the definition of status epilepticus. Epilepsia 1999;40: 120–122. 27. Luders, H., et al. A new epileptic seizure classification based exclusively on ictal semiology. Acta Neurol. Scand. 1999;99(3): 137–141. 28. Luders, H., et al. Semeiological seizure classification. Epilepsia 1998;39:1006–1013. 29. Mazarati, A. M., R. A. Baldwin, R. Sankar, and C. G. Wasterlain. Time-dependent decrease in the effectiveness of antiepileptic drugs during the course of self-sustaining status epilepticus. Brain Res. 1998;814:179–185. 30. Mazarati, A. M., H. Liu, and C. G. Wasterlain. Opioid peptide pharmacology and immunocytochemistry in an animal model of self-sustaining status epilepticus. Neurosci. 1999;89:167–173. 31. Mazarati, A. M., and C. G. Wasterlain. N-methyl--asparate receptor antagonists abolish the maintenance phase of selfsustaining status epilepticus in rat. Neurosci. Lett. 1999;265: 187–190. 32. Mazarati, A. M., C. G, Wasterlain, R. Sankar, and D. Shin. Self-sustaining status epilepticus after brief electrical stimulation of the perforant path. Brain Res. 1998;18:10070–10077. 33. Meldrum, B. S. The revised operational definition of generalized tonic-clonic (TC) status epilepticus in adults (comment). Epilepsia 1999;40:123–124. 34. Meldrum, B. S., and J. B. Brierley. Prolonged epileptic seizures in primates: Ischemic cell change and its relation to ictal physiological events. Arch. Neurol. 1973;28:10–17.
16
35. Roger, J., H. Lob, and C. A. Tassinari. Status epilepticus. In Handbook of Clinical Neurology. Vol. 15. The Epilepsies (O. Magnum and A. M. Lorentz de Haas, eds.). Amsterdam: North Holland Publishing Co. 1974:145–188. 36. Shorvon, S. Status Epilepticus: Its Clinical Features and Treatment in Children and Adults. Cambridge, U.K.: Cambridge University Press, 1994. 37. Status Epilepticus: Mechanisms and Management. An International Symposium. Abstracts of the Second International Conference on Status Epilepticus, Santa Monica, Calif., 1997. 38. Tassinari, C. A., C. Dravet, J. Roger, J. P. Cano, and H. Gastaut. Tonic status epilepticus precipitated by intravenous benzodiazepine in five patients with Lennox-Gastaut syndrome. Epilepsy 1972;13:421–435. 39. Theodore, W., R. Porter, P. Albert, et al. The secondarily generalized tonic-clonic seizure: A videotape analysis. Neurology 1994;44:1403–1407. 40. Treiman, D. Generalized convulsive status epilepticus in the adult. Epilepsia 1993;34(Suppl. 1):S2–S11. 41. Treiman, D., C. DeGiorgio, S. Salisbury, and C. Wickholdt. Subtle generalized convulsive status epilepticus. Epilepsia 1984;25:263. 42. Treiman, D., P. Meyers, N. Walton, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus: Cooperative Study Group. N. Engl. J. Med. 1998;330:792–798. 43. Treiman, D. M., N. Y. Walton, C. Wickboldt, and C. DeGiorgio. Predictable sequence of EEG changes during generalized convulsive status epilepticus in man and three experimental models of status epilepticus in the rat. Neurology 1987;37:244–245. 44. Trousseau, A. Lectures on Clinical Medicine Delivered at the Hotel Dieu, Paris, 1868. Vol. 1. (P. V. Bazire, trans.). London: New Sydenham Society, 1868. [Clinique medicale de L’Hotel-de Paris, tome Ire. Paris: Bailliere et Fils, 1868]. 45. Vicedomini, J. P., and J. V. Nadler. A model of status epilepticus based on electrical stimulation of hippocampal afferent pathways. Exp. Neurol. 1987;96:681–691. 46. Walsh, G. O., and A. V. Delgado-Escueta. Status epilepticus. Neurol. Clin. 1993;11:835–856. 47. Wasterlain, C. G. Mortality and morbidity from serial seizures: An experimental study. Epilepsia 1974;15:155–176. 48. Wasterlain, C. G., and P. Vert. Neonatal Seizures. New York: Raven Press, 1990. 49. Wilson, S. Neurology. Baltimore: Williams & Wilkins, 1940. 50. Wolf, P. International classification of the epilepsies. In J. Engel, Jr., and T. A. Pedley, eds. Epilepsy: A Comprehensive Textbook. Philadelphia: Lippincott-Raven, 1998:773–778. 51. Working Group on Status Epilepticus. Treatment of convulsive status epilepticus: Recommendation of the Epilepsy Foundation of America’s Working Group on Status Epilepticus. JAMA 1993;270:854–859.
: , , ,
3
Incidence and Causes of Status Epilepticus
.
Introduction This chapter reviews the epidemiology and clinical presentation of status epilepticus (SE) in Richmond, Virginia. A database was established at Virginia Commonwealth University to accrue the first population-based information on the natural presentation of SE in a controlled and validated community setting. SE occurred with an absolute incidence of 41 patients per 100,000 population per year in Richmond, Virginia. The frequency of total SE occurrences was 50 patients per 100,000 residents per year, and the overall mortality in this population was 22%. The elderly population had a mortality exceeding 38%. In addition, infants less than one year old were found to have the highest incidence of SE in the overall Richmond population, but the overall elderly population as a major age group had the largest number of cases in comparison to pediatric and young adult cases. The absolute incidence and occurrences of SE in this population proved to be underestimates because of inability (for various reasons) to document all cases of SE. Using validation mechanisms, the underreporting of SE in hospital charts and by physicians was corrected, and estimates for the occurrence of SE were obtained. Extrapolating from the Richmond database, more than 4.5 million cases of SE occur worldwide every year, with almost 1 million deaths per year. The costs associated with SE in the United States may exceed $4.5 billion annually. These figures—prevalence rates and costs—indicate not only the severity and significance of clinical SE, but also the potential costs to society in terms of dollars and chronic health care problems. In Richmond, nonwhite patients had a much higher incidence of and mortality from SE than white patients. Partial SE was the most common form of seizure initiating SE, and generalized tonic-clonic SE was the most common final stage of seizure type in SE. Age, etiology, and seizure duration were found to contribute to mortality. Acute and remote cerebrovascular accidents were the major causes in adults, and infections with fever were the most common cause in children. A significant number of individuals with SE had no previous history of epilepsy. In the elderly population, 70% of the patients had no previous history of epilepsy. The role of the genetic predisposition to
develop SE in contributing to the frequency and presentation of SE in the population is presented. The results of this study provide a summary of the first population-based epidemiological study on SE and provide important clinical features and outcome data on this major medical and neurological condition presenting in both academic and community hospital settings in the Richmond, Virginia, area.
Status epilepticus Status epilepticus is a major neurologic and medical emergency (14, 15). The acute medical management of this condition has been extensively reviewed (2, 4, 5, 11, 13, 15, 21, 31, 34, 38, 41, 44, 54, 57–59). Although there have been several advances in the treatment of this condition over the last three decades, SE is still associated with one of the highest morbidities and mortalities of any neurologic condition (1, 3, 7, 8, 12, 18–20, 22, 24, 25, 27, 32, 33, 36, 39, 42, 46, 47, 53, 56), and therefore the clinical presentation of this condition and the cause of its high mortality need careful investigation. SE is difficult to study because it occurs not only in people with epilepsy but also in individuals with acute systemic and neurologic illnesses (18, 19, 24, 25, 39). Thus, SE is not a simple unified entity, and sophisticated clinical evaluation of large population-based studies is needed before any generalizations about clinical outcome, causes of morbidity and mortality, and treatment can be made. Despite the complexity of the clinical presentation of SE, several studies of SE have provided information concerning some of the important clinical features of this condition (2–5, 13, 20–22, 24, 25, 31, 32, 34, 35, 38, 39, 41, 42, 44, 53–55, 58) and have yielded insights into factors predictive of outcome (25, 28, 32, 39, 50, 53). The initial clinical studies on SE provided many insights into this clinical condition. Epidemiologic data from retrospective analyses (24) and some preliminary prospective data (20) have also allowed an estimate of the natural rate of SE in a population. However, as emphasized by Hauser (24), there is a significant need for prospective, population-based studies of SE to obtain a comprehensive picture of this complex condition. Furthermore, data obtained in hospital-based, tertiary
:
17
care facilities may not be completely relevant to the overall medical community and the total presentation of SE. Thus, to obtain a fuller understanding of SE, it is essential to conduct prospective, population-based studies of SE in a well-characterized community setting. This chapter reviews data obtained by the Virginia Commonwealth University Status Epilepticus Research Study, a validated, populationbased, prospective study of SE in Richmond (12, 18, 19). The data have provided new insights into this important clinical condition.
First population-based epidemiologic study of SE To study the epidemiology of SE, a large population-based, prospectively collected database of cases of SE seen in the Richmond metropolitan area was established at Virginia Commonwealth University (18, 19). The database includes information on patients presenting to all hospitals in the greater Richmond metropolitan area (Figure 3.1). Both academic and community hospitals are represented. Patients residing in the city of Richmond who experienced SE while in a neighboring suburb and who went to a hospital not within the city limits of Richmond were therefore included in the database. SE cases were prospectively identified by the SE research team and evaluated on a daily basis. The case histories and charts of all persons with potential SE were reviewed in order to determine whether each identified case met the International League Against Epilepsy (ILAE) criteria for SE (19). Thus, only individuals with continuous seizures or intermittent seizures without regaining consciousness for 30 minutes or longer were included in the database. The ILAE definition of SE was used so that all identified cases would meet the current standards of inclusion for the definition of SE. The SE research team was on call round-the-clock so as to collect accurate data on the clinical presentation of SE in a prospective, timely manner. Approximately 80% of the potential SE cases reviewed met the ILAE definition of SE. The ILAE definition is rigorous, however, and because not all cases of SE can be completely documented to meet it (because of an unreliable history or unknown duration of SE), the incidence as reported in any study represents an underestimate of the true incidence and presentation of SE in the community. This observation notwithstanding, the Virginia Commonwealth University database is as representative as possible. Clinical research has indicated that a reexamination of the definition of SE is needed (16, 40, 49, 50, 52). Initial data obtained in epilepsy monitoring units indicated that tonic-clonic seizures lasted less than 2 minutes (52), and that more than 90% of routine seizures lasted less than 1 minute. Based on these observations, it has been suggested that the definition of SE be changed to include seizures lasting any-
18
F 3.1 Presentation and intake of patients in the Virginia Commonwealth University SE study. Patients presenting with SE in the greater Richmond metropolitan area (GRMA) enter the database from community hospitals and the MCV Hospital. Community hospital patients are identified by physician referral. Clinical information is entered into the database by form entry and coordinated in the relational database. Patients from the MCV Hospital who are entered into the database are treated for SE and hospitalized in the intensive care unit (ICU) or inpatient services, depending on their clinical condition. Patients admitted to the hospital are handled in the same manner as the community hospital patients and are evaluated with form entry and inclusion in the relational database. Patients admitted to the ICU offer special opportunities for advanced research studies on outcome and physiologic effects on mortality and morbidity. These patients are evaluated both with form entry and with continuous computer monitoring of physiologic parameters such as blood pressure, pulse, intracranial pressure, and other electrophysiologic data, such as EEG and evoked potentials. These data are both entered into the relational database, and also stored and analyzed by the computer monitoring laboratory facility, which provides a unique opportunity to collect data on acute SE. Data on all patients are then analyzed in the relational database and used for outcome studies or for epidemiologic evaluation. This analysis emphasizes the uniformity of form entry and data computation by a highly trained team of researchers. Evaluating each patient with the same rigorous criteria provides the highest assurance of reliable and appropriate data collection.
where from 5 minutes up to 20 minutes or more (40). The need to reevaluate the definition has drawn broad interest among epileptologists (16, 40, 49, 50, 52). Nevertheless, no large series of patients with prolonged seizures (lasting from 10 to 29 minutes) has been evaluated, nor have these patients been compared with patients with SE in a controlled, population-based epidemiologic study. It is essential to acquire data of this type, because efforts to redefine SE currently must rely on a small number of studies and a very select population of seizure patients (16, 40, 49, 50, 52). Despite the importance of understanding and redefining SE, only a few studies have addressed longer durations of seizure activity in the general population (16, 49, 50). Shinnar et al. (49) reported that in children, many seizures
: , , ,
do not terminate in 12–13 minutes, and suggested a possible seizure threshold effect to develop SE. A retrospective analysis of the data in our database indicated that seizures lasting from 10 to 29 minutes are not uncommon in the general population, accounting for more than 30% of the cases of SE overall (16). In this study, data were collected on 81 patients with seizures lasting 10 to 29 minutes for comparison with patients with SE in the same 2-year period. Prolonged seizures that did not meet the current definition of SE had the same distribution of causes as SE and were seen in all age groups (16). Thus, seizures lasting 10 to 29 minutes were not rare in the greater Richmond population and had the same causes as SE. There was, however, a significant difference in mortality between these groups. The overall mortality of the SE patients was 19%, but in the group with seizures lasting 10 to 29 minutes it was 2.6% (P < 0.001). In addition, more than 40% of the seizures lasting 10 to 29 minutes stopped spontaneously without any anticonvulsant treatment (16). This surprising finding indicates that patients in whom seizures will stop spontaneously should be identified so that the effect of these patients can be taken into account in clinical trials for the treatment of SE. These patients would meet the criteria for a definition of SE of seizures lasting 30 minutes or longer. If this type of research is not conducted, clinical trials of SE that include patients with seizure durations lasting 10 minutes or longer may yield very misleading results. These initial studies demonstrated the feasibility of collecting information on a large sample of patients with seizures lasting 10 to 29 minutes, as identified in the Richmond database and at other epilepsy centers. Because the prevalence of SE is much higher when SE is identified prospectively than retrospectively, it is possible that the group with prolonged seizures could account for half or more of the total number of SE cases in our study. This study is expected to provide important data essential for redefining SE, and should also provide epidemiologic data on the frequency of seizures lasting 10 to 29 minutes. However, data are being collected on a wide range of seizure durations. If the definition of SE were changed to include seizures lasting from 5 to 10 minutes, the incidence of SE would increase significantly. Each case was fully reviewed during the patient’s hospitalization or immediately following discharge. This rapid and timely prospective review allowed a more accurate assessment of the data on each patient than could be achieved with a retrospective analysis. A timeline for each SE case was developed so that the duration of SE, electroencephalographic (EEG) characteristics, and other clinical data could be recorded and entered into a computerized database for statistical and epidemiologic analysis (see Figure 3.1). An important part of this study was the validation of the database. A complete review of SE presentations was per-
F 3.2 SE case identification and validation. Shown are two pathways following an occurrence of SE in the greater Richmond metropolitan area. When SE cases are not reported to the SE team, they are recognized by specific mechanisms designed to check for unreported cases: review of hospital computer records, review of EEG evaluation sheets, and review of ER records. (Other mechanisms to identify unreported cases include review of ambulance records and of 911 calls to ER personnel.) By comparing the identified cases not reported to the SE team with the cases that are reported, the team can validate the database (38). With this technique, it is possible to formulate more reliable estimates of the incidence and frequency of SE in the Richmond population (38, 39). However, even this vigorous data collection technique does not uncover all SE cases.
formed to critically evaluate the completeness of case ascertainment (18, 19). This review, conducted on a regular basis, evaluated all hospital ICD-9 codes for seizures (computer records), 911 reports, ER seizures, cases of SE collected on hospital rounds, all EEG laboratory reports, and ICU and ER records (Figure 3.2). Through this review, investigators were able to achive a high degree of accuracy in determining essentially all cases of SE that presented in the greater Richmond metropolitan area (18, 19). The review was conducted at regular intervals during the epidemiologic study, thereby providing an internal mechanism for verifying the accuracy of the database. The definitions of SE, patient age, mortality rates, recurrence rates, history of epilepsy, etiologies, seizure types, ethnicity, and other clinical variables have been discussed in the literature (12, 18, 19). T I P D C We (20) and others (24, 25) have found that it is difficult to study SE from a retrospective review of hospital records because
:
19
of the complex clinical nature of SE. Because hospital records often do not fully document all aspects of SE and the seizure presentation, retrospective data are inconclusive in efforts to understand the natural presentation of SE. For example, a retrospective review conducted at Virginia Commonwealth University found that more than 60% of the SE cases in Richmond community hospitals were not recorded in ICD-9 codes or were not well documented in the hospital chart. Most of the clinical information concerning the duration of seizure activity, seizure type, length of treatment, and follow-up care was incomplete or omitted. Thus, retrospective data analyses resulted in a major bias in patient selection and an incomplete picture of the complex clinical nature of SE. To obtain a more accurate picture of the natural presentation of SE, prospective studies are necessary. These studies have several distinct advantages. First, they allow a more standardized and complete collection of appropriate clinical data. By aggressively identifying and evaluating SE cases when they occur, the Virginia Commonwealth University SE team was able to record the necessary clinical, demographic, laboratory, and other data in each case in a standardized fashion while the patient was still in the hospital. A clinical data form entry system carefully developed for this purpose was used. This type of data collection allowed the SE team to interview family members, nurses, and hospital personnel to acquire the information needed to study SE. Thus, when information such as the duration of SE or the clinical presentation was not appropriately recorded in the chart, the research team had a second chance to acquire the information. Prospective data collection also allows much more accurate data collection. The prospective evaluation of each case in the same time frame in which the data were being collected allowed more accurate record keeping and analysis of the clinical data. Thus, despite an often incomplete hospital record, the SE team can make sure all the necessary information is collected in each case while the patient is still in the hospital. Improved data collection leads to a second major advantage of prospective studies, the accurate analysis of clinical variables associated with SE. This is especially important in evaluating SE seizure types. Our retrospective studies found that normal charting insufficiently documents seizure type during SE. Descriptions of seizure types were omitted or inadequate in more than 65% of routine hospital records for seizure patients. Prospective data collection brings the accuracy of description of seizure types in SE to almost 95%. An accurate description is extremely important for understanding the types of seizures presenting in SE. The identification of nonconvulsive SE by prospective evaluation of EEG records is a third area in which prospective data collection is essential. Nonconvulsive SE is a more
20
subtle presentation of SE. Without prospective data analysis, it is underestimated by more than 80%. A fourth advantage of prospective data analysis is that it allows the evaluation of appropriate control populations to investigate the role of etiology, age, seizure duration, ethnicity, and other variables in determining outcome in SE. There are no well-developed control populations for etiology or other variables in the literature on SE. With prospective data collection, however, control populations can be developed. Prospective analysis also contributes to a more informed picture of morbidity and mortality in SE populations. By prospectively evaluating SE and having a more accurate data evaluation of the true incidence of SE, a more accurate determination of mortality and incidence can be obtained. In sum, prospective evaluation enhances data collection and recording, uncovers a more accurate incidence of associated variables, leads to a truer description of seizure type, and allows comparison with a control population in the community. The research conducted with Virginia Commonwealth University’s prospectively acquired database forms the first prospective population-based, epidemiologic study of SE (18, 19) and has yielded several new insights into the total clinical presentation of this condition.
Incidence of SE From the database, the validated incidence rate of SE in Richmond was 41 per 100,000 individuals per year (Figure 3.3). The incidence rates or pediatric, young adult, and elderly populations were 38, 27, and 86 per 100,000 per year (Figure 3.4). Thus, in our population, the elderly had the highest incidence of SE. Insofar as the elderly population will dramatically increase in the United States over the next 10 to 15 years, SE is expected to become a more common condition in our population (12, 20). Because the rigorous ILAE definition of SE was followed, which does not fully represent some seizure types, and because we identified an underestimate of SE cases seen at community hospitals (through our validation procedures), these incidence rates represent an underestimate of the incidence of SE in the Richmond population. Using estimated correction values for the validation of SE in both community and university hospitals, we obtained an approximate incidence rate of SE in Richmond of 61 per 100,000 population per year (see Figure 3.3). A more detailed distribution of the incidence of SE by age is provided in Figure 3.5. This age distribution of SE is bimodal, with the highest rates seen during the first year of life and again after age 60. In young children up to 12 months old, the incidence as high as 156 per 100,000 individuals per year. This figure indicates the importance of studying SE early in life, as well as in the elderly population. SE in the elderly has been studied (12,
: , , ,
20). The elderly population has several specific etiologic and clinical parameters that differentiate it from the overall population. The frequency of SE was also evaluated taking into account recurrent episodes. Fifty SE episodes per 100,000 population per year occurred in Richmond. Using estimated correction values (based on validation data) pointed to 78 episodes of SE per 100,000 population per year (see Figure 3.3). The total number of episodes of SE per year is an important variable for evaluating the morbidity and mortality associated with SE, since the total number of episodes is proportional to the number of SE events that occur in the population.
F 3.3 Frequency and total number of SE episodes and SE deaths in Richmond, Virginia, and the United States. SE cases are the number of patients presenting with one episode of SE per year. SE episodes are the number of occurrences of SE per year in the population. SE deaths are the number of deaths that occurred in association with SE per year. Shown are the actual and estimated values based on validation by case ascertainment studies in Richmond (38, 39). The estimates projected for the U.S. population assume that the Richmond community is representative of the overall population of the United States.
F 3.4 Incidence of SE for the total, pediatric, adult, and elderly population in Richmond. The data represent the incidence
O SE U S W Our prospective studies of SE in Richmond uncovered an absolute incidence of SE of 41 per 100,000. By using a prospective data collection methodology, it is possible to achieve a much higher ascertainment of individual cases. Several other studies (24–26, 37) have also provided valuable information concerning the incidence and clinical presentation of SE in other areas of the United States (24–26, 61) and in other countries (9, 30, 51). The first estimate of the incidence of SE came from Rochester, Minnesota (24, 25), and was determined using retrospective data analysis. The incidence was approximately 15 per 100,000. More recent studies from this team using the same type of data analysis indicated a slight increase in incidence in the decades from 1965 to 1984 of 18.1 per 100,000 (26). Studies in California (61) utilizing a retrospective evaluation of a statewide hospital discharge database to identify cases of generalized convulsive SE gave a peak incidence of approximately 8.5 per 100,000. When this figure is corrected to account for the underestimation of SE in discharge summaries and for the exclusion of other types of SE, the incidence is comparable with figures reported in other studies. The research group in Hessen, Germany (30), conducted a
of SE per year per 100,000 population in each age group (38, 39).
:
21
F 3.5 Age-specific distribution of the incidence of SE per year per 100,000 in Richmond, Virginia. By incidence is meant the number of patients who experienced a first episode of SE in Richmond per year per 100,000 population in each age group.
These figures do not include patients with recurrent episodes of SE. The population for each age group was obtained from the 1990 U.S. Census Bureau for Richmond, Virginia (38).
prospective population-based study over a 2-year period and estimated the incidence of SE in this city to be 17.1 per 100,000 population. This figure is very close to the Rochester, Minnesota, incidence. A study from the Frenchspeaking part of Switzerland by Coeytaux and colleagues (9) found an incidence of 10.3 per 100,000. Although there are some variations in these studies, a range of 8–41 per 100,000 population has been found. Given the differences in the methods of data collection and nature of the populations in these studies, the incidence figures determined in each study are fairly close to one another. The differences in the incidence figures may reflect different methods of data collection or varying ability to correctly determine cases of SE in medical records. We have found that it is very difficult to identify cases of SE from ICD-9 codes, discharge summaries, and retrospective chart review. The higher incidence figure in the Richmond study may in part reflect the prospective nature of the study. However, environmental differences, genetic differences, ethnic differences, and other variables may contribute to the different incidence determinations for SE reported in these studies. The data reviewed later under Ethnic Origin in SE suggest that the ethnic mix of the population may play an important role in determining the incidence of this condition. Correcting the Richmond data for the higher percentage of African Americans in the population gave an incidence very close to the Rochester and Hessen data. Further studies are needed to more fully evaluate the effects of genetic factors and ethnicity on the incidence of SE. Because the data obtained in the Virginia Commonwealth University study were obtained by prospective case evaluation by a dedicated team of investigators, this study provides a reasonable source of epidemiologic data and can be used as a starting point for estimating the overall impact of SE in
the world population, including mortality. Extrapolating the study figures to the U.S. 1991 census population of 249,924,000 shows that approximately 119,000 to 195,000 SE events occur per year in the United States (see Figure 3.3). These figures do not include cases in neonates or cases in patients not referred to hospitals, such as patients in nursing homes or state facilities. The number of patients with SE who experienced at least one episode of SE per year in the United States was estimated to be 102,000 to 152,000 per year. Extrapolating again to the world’s population, based on the 1997 census, of 5.8 billion, approximately 4.5 million SE events occur per year worldwide. The number of SE cases that develop per year in the world is estimated at 3.5 million. These estimates begin to suggest the immense cost to society of this major neurologic and medical emergency. The data presented in Table 3.1 are conservative estimates of U.S. and world cases and deaths. Both the World Health Organization and the ILAE have recently noted that the vast majority of individuals throughout the world do not receive proper treatment for epilepsy. In many nonindustrial countries, epilepsy either is not treated or is totally inadequately treated, despite the availability of modern anticonvulsant therapies. Thus, the number of SE cases worldwide and the total mortality and morbidity from SE are probably much higher than the figures projected for the United States, and higher than the figures given in Table 3.1. Our group has developed estimates of the cost of treating SE in an urban hospital (56). The cost of care for SE in the United States per year is approximately $3–4 billion. Projecting the population of the United States to the world suggests that SE would cost more than $70–93 billion per year on an international basis. Thus, understanding, treating, and controlling SE represents a major international
22
: , , ,
T 3.1 United States and world SE cases and deaths projected from the Richmond population
SE cases SE episodes SE deaths
United States
World
152,000 195,000 42,000
3,527,920 4,525,950 974,820
Note: Estimates of SE cases, episodes, and deaths are based on projections from the data from the Richmond, Virginia, study (38, 39). The populations used to determine these values for the United States and the world were approximately 250 million and 5.8 billion individuals. The data indicate that worldwide, almost 1 million individuals die each year due to SE.
public health need. Currently, there is no acknowledgment of the increased risk or cost of SE in the diagnostic codes or level-of-care issues. SE is treated no differently than a simple seizure. Studies are needed to more precisely ascertain the health care costs of SE to society and to improve the recognition and understanding of SE by hospital and health agency coding and billing systems. R SE Using the epidemiologic data in the Richmond study, it is possible to determine an age-specific recurrence rate of SE. Recurrence of SE in the Richmond population was much more common during the first year of life (18, 19). In the Richmond population, 13% of patients experienced repeat episodes of SE. Recurrence rates in the pediatric, adult, and elderly populations were 35%, 7%, and 10%. Thus, recurrence of SE was the most common in the pediatric population, very uncommon in the middle years of life, and increased again in the elderly. Despite the higher recurrence rate of SE in the pediatric population, this recurrence rate was not associated with an increased mortality from SE (18, 19).
SE seizure types Prospective data collection allows a much more accurate evaluation of seizure types in SE because the research team can obtain information from witnesses who observed the seizures during the initial presentation in each case. The SE seizure types observed in Richmond, Virginia, are listed in Table 3.2. Partial and secondarily generalized SE in both children and adults were the major seizure types identified. These results point to a new observation concerning the presentation of SE seizure types, namely, the initiation of SE by partial seizures is the most common form of SE. Approximately 69% of adults with SE and 64% of children with SE presented with partial SE as the initial seizure type. This is a new and important finding indicating that generalized
T 3.2 SE seizure types in Richmond, Virginia
Final seizure type Generalized Partial Onset seizure type Generalized Partial Partial SE Simple Complex Partial, secondarily generalized Generalized GTC Absence Myoclonic Electrographic
Pediatric
Adult
Total
71 29
74 26
74 26
36 64
31 69
32 68
29 0 36
22 4 43
23 3 42
36 0 0 0
27 1 3 1
29 1 2 1
Note: Data are expressed as percentage of SE cases with each seizure type (38, 39). The final seizure type represented the major seizure type during SE. Onset seizure type included partial, secondarily generalized, as partial onset.
tonic-clonic SE, although an important form of SE, is not the major initial seizure type. Rather, partial SE is the most common initial seizure type. Because it is impossible to witness all initial SE events, the incidence of partial SE is probably significantly higher than the values given in Table 3.2 for the general population. Table 3.2 also shows the distribution of SE seizure types in adult and pediatric populations (12, 18, 19). When seizures did not secondarily generalize, simple partial SE was more common than partial complex SE in both children and adults. Partial SE with secondary generalization was the most common seizure type in both adults and children, and generalized tonic-clonic SE was the major form of SE as the final seizure type in this study. Generalized absence SE was uncommon in this population in both children and adults. Myoclonic SE was uncommon but was seen in both populations; it was more common in adults than in children. Electrographic SE or nonconvulsive SE was also observed in this study. These results indicate that the majority of SE cases in the general population start with partial seizures. The mechanism that prevents partial seizures from terminating allows these seizures to spread throughout the brain and develop into generalized tonic-clonic seizures in a high percentage of patients. Inability to terminate these seizures eventually leads to the development of SE. Understanding this mechanism and the inability to inhibit or stop generalized seizure activity is important to fully understanding the pathophysiology of SE and warrants further investigation.
:
23
N SE Nonconvulsive SE (NCSE), or electrographic SE, is often very difficult to detect. Patients often do not show any signs of seizure activity. Our prospective data collection methods and coordination of electrophysiology studies on comatose patients in the ICU and hospital settings allowed us to do a large study of the occurrence of NCSE. More than 95% of comatose patients at the Virginia Commonwealth University hospital complex are evaluated by neurology and EEG studies. Using this database, we found that 8% of comatose patients without any overt clinical signs of seizure activity manifested NCSE (54). This figure highlights the potential underestimation of NCSE on a national or international level. Many hospitals do not have round-the-clock or weekend EEG availability, and not all neurologists or other physicians routinely order EEGs for all comatose patients. Thus, many cases of NCSE never come to medical attention. With the large incidence of coma, it is essential that this potentially lethal form of SE be diagnosed. Further studies on the incidence of NCSE are required to more fully understand the clinical presentation of this condition.
Etiology of SE The causes of SE in children and adults are shown in Figures 3.6 and 3.7. In our study, the major cause of SE in children was infection with fever, accounting for more than 52% of all cases. Remote symptomatic causes (39%) and low antiepileptic drug levels (LAED) (21%) also accounted for a significant percentage of cases in children. The other causes in children accounted for less than 10% of the total cases. A much different etiologic picture emerged in the adult population. Although adults had cases that were precipitated by infections with fever, these cases accounted for a much
F 3.6 Etiology of SE in pediatric patients. Some patients had more than one cause identified. The causes included anoxia, hypoxia, cerebrovascular accident (CVA), hemorrhage, tumor, systemic infections with fever, CNS infections, metabolic, low
24
lower percent of the total. In adults, three major causes emerged: LAED (34%), remote symptomatic causes (24%), and cerebrovascular accident (CVA) (22%). Anoxia/ hypoxia, metabolic causes, and alcohol and drug withdrawal each represented between 10% and 20% of all cases of SE. The remote symptomatic group in adults was a category composed primarily of remote CVA and hemorrhage. Combining the CVAs included in the remote symptomatic group and the CVA-alone category, almost 50% of the adult cases of SE were caused by acute or remote cerebrovascular disease in patients with no previous history of epilepsy. In sum, several major etiologic factors contribute to the development of SE in children and adults in the general population. The profile of etiologic risk factors is significantly different in children and adults but is representative of the general disease groups that are most common in these age groups. In children, the most common cause is febrile seizures or infections with fever. In adults, the most common causes of SE are acute or remote cerebrovascular disease and LAED in individuals with epilepsy. The relationship of specific etiology to the presentation and prognosis of SE is an important area for future investigation (18, 19). E O SE The presentation of SE in white and nonwhite patients was evaluated. As shown in Figure 3.8, nonwhite individuals had a higher incidence of SE across all age ranges than white patients. The increased incidence in nonwhite patients was especially significant in the older and younger age groups. The frequency of SE in nonwhite individuals less than 1 year old was above 300 per 100,000, and the frequency in nonwhite elderly patients exceeded 200 per 100,000 individuals. These results provide striking evidence that ethnicity may be an important risk factor for SE. Further studies are needed to determine how much of the
antiepileptic drug levels (LAED), drug overdose, trauma, remote causes, and idiopathic. Data are expressed as the percent of cases with each cause.
: , , ,
F 3.7 Etiology of SE in adult patients. Some patients had more than one cause identified. Causes included anoxia, hypoxia, cerebrovascular accident (CVA), hemorrhage, tumor, systemic infections with fever, CNS infection, metabolic, low antiepileptic
drug levels (LAED), drug overdose, EtOH (alcohol-related), trauma, remote, and idiopathic. Data are expressed as the percent of cases with each cause.
F 3.8 Age-specific distribution of the incidence of SE for white (white bars) and nonwhite (black bars) patients. Data are expressed as the number of patients with a first episode of SE per
year per 100,000 in Richmond, Virginia, for each age group. Populations of white and nonwhite individuals in each age group were determined from 1990 U.S. Census Bureau data (38).
difference in incidence can be attributed to socioeconomic or cultural differences. As noted earlier, our prospective population-based studies of SE in Richmond disclosed an absolute incidence of SE of 41 per 100,000. This incidence was about two times that of SE in the predominantly white (Caucasian) Hessen, Germany (30), and Rochester, Minnesota (24–26), studies. The incidence in the white population alone in Richmond was approximately 19 per 100,000, which compares well with the incidence figures for the two other predominantly white populations (24–26, 30). However, the nonwhite, African-American population in Richmond had a much higher incidence of SE, 57 per 100,000. Because Richmond is over 50% African American, the higher incidence in this group can partially account for the higher incidence in the overall Richmond population.
It is essential to further evaluate these ethnic disparities in the incidence and mortality of SE. Our study is uniquely qualified to evaluate these differences in comparing the incidence in the African-American and Caucasian populations, since we have an almost equal proportion of white and African Americans in Richmond and both populations have a broad spectrum of financial, educational, and cultural diversity. Our studies are directed at determining if the higher incidence of SE in the African-American population is associated with differences in etiologic presentations, socioeconomic factors, employment factors, genetic factors, or some other variables. However, further studies are also needed to evaluate the incidence of SE in the Hispanic and Asian populations and other geographicethnic groups.
:
25
F 3.9 Epilepsy history of SE patients for the total population, children, adult, young adult, and elderly patients. The data are expressed as the percentage of patients in each age category
with a history of epilepsy. Each age category was defined as described previously (38, 39).
P H E In studies of SE based primarily on neurologic practice settings, the most common cause of SE was lowered antiepileptic drug levels in patients with epilepsy who stopped taking their anticonvulsant medications. However, a population-based analysis of SE shows that SE can be caused by or associated with numerous other medical, surgical, and physical conditions in the absence of a previous history of epilepsy. Unless SE is evaluated in a population setting, an incomplete distribution of etiologic presentations is obtained. The percentage of SE patients with a previous history of epilepsy is shown in Figure 3.9. Rates are shown for the total, pediatric, adult, young adult, and elderly populations. In the elderly population, 70% of patients who developed SE had no previous history of epilepsy. In pediatric patients and in young adults, a previous history of epilepsy was noted in 38% and 54%, respectively. Although SE occurred in patients with epilepsy, the lack of a seizure history, especially in the elderly, does not protect against the development of SE. These results indicate that SE in the elderly is primarily caused by non-epilepsy-related factors. It is essential to educate internists, surgeons, and other physicians who care for these populations as to the importance of evaluating for and diagnosing SE, since many of these cases will show up in nonneurological settings in association with postsurgical problems, medical complications, and other disease states. This represents an important challenge for the epileptologist in the years ahead.
that the mortality from SE varies from 11% to 34% (24, 25). This significant difference in mortality rates across clinical studies is accounted for primarily by the different distributions of causes and difference in patient ages in the various studies. Determining the mortality from SE in a prospective, population-based study would go far toward understanding the risk factors for death from this condition. The mortality from SE for pediatric, adult, and elderly populations was evaluated for the Richmond population (12, 18, 19, 53). The overall mortality in the entire Richmond population, including adults and children, was 22%. For children alone it was 3%. This lower mortality in the pediatric population is consistent with observations of Maytal and colleagues (42) and Dunn (22) indicating that children have a lower mortality from SE than adults. Adults below the age of 60 have a mortality of approximately 14%, and the elderly have a mortality of 38%. The age distribution of mortality for the Richmond population (Figure 3.10) emphasizes the dramatic increase in mortality with age. Although the mortality in the elderly is highest, the mortality from SE in younger adults is considerable when compared with death rates from other neurological diseases. Understanding the causes of this significant mortality and finding possible ways of preventing complications associated with SE are a major challenge for the neurologist. Employing the mortality rate for the Richmond community, it is possible to estimate the number of deaths expected from SE per year in the U.S. population, as well as in the world population (see Table 3.1). The estimated number of deaths from SE per year in the United States is approximately 22,000–42,000. Extrapolating this figure to the world population, approximately 975,000 individuals per year die from SE. These estimates underscore the importance of understanding the clinical presentation and cause of death from this major neurologic emergency.
Mortality from SE Several large case studies of SE have described determinants of mortality from SE (1, 3, 7, 8, 12, 18–20, 22, 24, 25, 27, 30, 33, 36, 42, 43, 46, 47, 53, 56). These reports indicate
26
: , , ,
F 3.10 Age-specific distribution of mortality from SE in Richmond, Virginia. The data are expressed as the number of deaths per 100,000 population per year. The population for each
age group was obtained from the 1990 U.S. Census Bureau for Richmond, Virginia (38).
Outcome of SE
using novel treatment approaches, given that there are several acceptable therapies for SE, will require the ability to predict with significant accuracy outcomes with survival rates poorer than 50%–60%. Thus, validated outcome scales will be essential to develop new treatments for SE. Etiology has been shown to be useful in predicting outcome in SE (8, 24, 25, 53). Leppik initially described the important role that etiology plays in predicting outcome (32, 34, 35). The mortality for each cause of adult cases of SE are presented in Figure 3.11. Anoxia and hypoxia were associated with the highest mortality in both children and adults. Other causes, such as alcohol withdrawal or LAED, were associated with a significantly lower mortality. The pediatric population essentially has no mortality associated with SE, and only a small number of deaths in patients with significant neurologic complications were seen in children. These studies demonstrate the importance of etiology in determining outcome. Waterhouse et al. (60) have shown that cerebrovascular injury and SE have a synergistic effect. Using appropriate control-matched populations, these investigators found that the type of etiology may play a role in increasing the mortality and morbidity associated with SE. The combination of an underlying neurological injury of a specific etiology and the excitotoxicity associated with SE produces a synergistic injury with higher mortality than that associated with either the etiology or the SE alone (60). These results provide an exciting opportunity to consider therapeutic interventions during the acute process of the underlying etiology and its association with SE in attempting to decrease morbidity and mortality. Another variable that plays a major role in outcome and refractoriness in SE is seizure duration (20, 39, 53). For this reason, evaluating the causes of refractory SE and developing new treatments for it is an important area for future
Using prospective data analysis, it is possible to evaluate predictive indicators of outcome in SE (17–20). Being able to predict outcome has several important advantages that are useful to clinicians. Thus, a major goal of the Medical College of Virginia’s Epilepsy Institute is to develop a practical outcome scale that can be used to predict mortality in SE. At the present time we are working on the Richmond Outcome Scale, which will be able to predict mortality with a 90% or greater accuracy in patients with SE. This scale requires the collection of approximately six to ten variables relating to the presentation of SE, with data collection initiated within 24 hours of the onset of SE. A simpler and more condensed clinical scale is being developed to predict outcome with a greater than 80% accuracy within the first hour of a patient’s presentation with SE. Recent results (17) indicate that applying logistic regression analysis to important clinical predictors of outcome will allow us to develop predictive scales for use by clinicians in predicting outcomes in SE. In addition, the use of clinical outcome scales should have a positive impact on physicians’ ability to treat patients with SE. These scales will allow clinicians to evaluate the severity of SE cases, and to initiate appropriate ICU treatment of patients with the more severe cases. In addition, the scales will help the clinician provide information to families about the likelihood of specific outcomes in each case. In light of the significant mortality associated with SE, these outcome scales will help clinicians recognize and express to families that patients die not because of poor medical care but because of the underlying pathophysiology of the disease. Another major use of outcome scales is to allow research programs to initiate new treatment protocols for SE. To be able to obtain human investigation committee approval for
:
27
F 3.11 Mortality from SE in adults, by etiology. The data are expressed as the percent mortality for each cause of SE. The causes are as presented in Figure 3.7.
investigation. Age also has been shown to be an important variable in outcome in SE (53). The elderly population is much more at risk for mortality and morbidity than the younger population. Boggs and colleagues (6) have shown that underlying cardiovascular disease is a risk factor that may increase the mortality from SE in the elderly. The elderly are also much more susceptible to brain injury because they lack the plasticity and the recuperative powers of the younger brain (10, 29). Response to treatment is another important variable that contributes to outcome in SE. Identifying the major variables that predict outcome in SE forms the initial basis for developing an accurate outcome scale. It is important to have a population-based database with a large enough population size so that several analyses can be done using sophisticated multiregression, nonlinear analyses to determine whether each variable influencing outcome does so independently of other variables or synergistically. So far it has been possible to show that specific causes of SE, age, and seizure duration play independent roles in determining outcome (17, 53).
New advances through epidemiological studies Population-based epidemiologic studies of SE have provided important information concerning the incidence and overall mortality of this major neurologic condition (18, 19). In addition, these results indicate that almost a quarter of a million episodes of SE occur per year in the United States and as many as 4.5 million cases may occur in the world each year (see Table 3.1). The number of deaths per year in the world estimated from SE (Table 3.1) approaches 1 million. These numbers are more meaningful when it is considered that they are based on conservative evaluations. Only cases that could be 100% documented by rigid definitional requirements were included in our study. The large number of cases that
28
were not witnessed at onset or in which seizure duration could not be determined accurately had to be excluded from these studies. The cost estimates of $4 billion per year in the United States (45) and more than $90 billion in the world economy, if SE was treated properly, represent a major public health issue for the United States and for the world. Another important finding that has developed from epidemiologic studies of SE is that generalized tonic-clonic SE is not the most common seizure type of SE. Because SE is associated with numerous etiologic conditions and with several focal pathologies in the brain, it is not surprising that partial seizures are the initial precipitating event in the majority of SE cases. However, it is clear that the majority of partial SE cases will eventually secondarily generalize. The most common final seizure type in SE is generalized tonic-clonic SE. A large portion of the population is at risk to develop SE even though the individuals have no seizure history. In the adult population, CVA represents a major cause of SE (12, 18, 19). Both acute and subacute cerebrovascular injury to the brain are associated with SE (12). The relationship between brain injury and the development of continuous seizure discharge has not been carefully evaluated. The high frequency of SE in relationship to CVA indicates that further human and animal investigations should be initiated to evaluate the causal relationship between brain injury and the development of continuous seizure discharge. The basic mechanisms that regulate the generalization of seizure activity and the inability to shut off seizure discharge following a CVA are an important area for further research. The finding that the combination of a CVA and SE produces a synergistic increase in mortality (60) raises the important possibility that this condition is similar to the combination of injuries seen with head injury (29, 48). The combination of multiple small injuries in succession has
: , , ,
a much greater synergistic effect on mortality and morbidity than of the injuries combined (29, 48). This important finding in association with the relationship between SE and etiology is an exciting area for future investigation. This result also raises the importance of having controlled etiology populations to compare to SE. It is essential to develop population-based, controlled etiologies in combination with the etiologies plus SE in comparing outcomes both for morbidity and mortality. A G P M C I SE SE is precipitated by numerous medical and neurologic conditions (18, 19, 24, 25). In evaluating the specific causes of SE and control populations in the Richmond database, it became apparent that only a small fraction of the precipitating causes ever resulted in SE. The susceptibility of some individuals to develop SE in association with conditions such as LAED, cerebrovascular disease, metabolic disease, anoxia, or other conditions raises the possibility that there may be underlying susceptibilities in individuals to precipitate SE. However, the other possibility is that the severity of the underlying etiology may be contributing to the development of SE. To evaluate this possibility studies were conducted on the role of CVA in precipitating SE. This research (55) demonstrated that the size or severity of the CVA in both control and SE patients was similar. Thus, it could not be postulated that larger or more severe CVAs resulted in SE. There had to be some type of underlying susceptibility in the individual patient for SE to develop. In an attempt to evaluate potential susceptibility to develop SE, we utilized the human twin registry at the Medical College of Virginia of Virginia Commonwealth University to study the genetic predisposition to develop SE. Using the twin database, it was established that there is a genetic predisposition to develop SE (10). These results provide the first evidence that genetic background may contribute to the susceptibility to develop SE given certain insults to the central nervous system. Studying the genetics of SE is particularly difficult, since this tendency may only be evident when a precipitating cause of SE is encountered, such as an initial seizure, CVA, head injury, or other cause. However, this is an important and challenging aspect of research in SE, since it may provide an insight into predicting which patients are at high risk for developing this condition. Being able to predict these patients may play an important role in therapeutic intervention and preventative strategies to significantly reduce the morbidity and mortality associated with SE. Although data have been provided that SE has a genetic predisposition, it is also possible that a specific type of brain injury may also precipitate SE in a nongenetically susceptible individual. The potential role of genetic predisposition
and the actual pathophysiology of SE offers an exciting and challenging area for future research to predict and understand patients at risk for developing SE. The incidence and clinical presentation of SE in a population may be significantly influenced by genetic factors as well as environmental risks. Understanding these variables offers exciting challenges in treating this condition in the future. The work reported in this chapter represents an ongoing collaboration with the status epilepticus research team at the Medical College of Virginia of Virginia Commonwealth University. The assistance and efforts of my research colleagues are greatly appreciated. This work was supported by National Institutes of Health Program Project Grant P50 NS25630, research grant R01 NS23350, the Sophie and Nathan Gumenick Research Fund, and the Milton L. Markel Neuroscience and Alzheimer’s Research Fund (R.J.D.).
REFERENCES 1. Aicardi, J., and J. J. Chevrie. Convulsive status epilepticus in infants and children: A study of 239 cases. Epilepsia 1970; 11:187–197. 2. Alldredge, B. K., A. M. Gelb, S. M. Isaacs, M. D. Corry, F. Allen, S. Ulrich, M. D. Gottwald, N. O’Neil, J. M. Neuhaus, and D. H. Lowenstein. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N. Engl. J. Med. 2001;354(9):631–637. 3. Aminoff, N. J., and R. P. Simon. Status epilepticus: Causes, clinical features and consequences in 98 patients. Am. J. Med. 1980;69:657–666. 4. Bassin, S., T. L. Smith, and T. P. Bleck. Clinical review: Status epilepticus. Crit. Care 2002;6(2):137–142. 5. Bleck, T. Convulsive disorders: Status epilepticus. Clin. Neuropharmacol. 1991;14:191–198. 6. Boggs, J. G., A. Marmarou, J. P. Agnew, L. I. D. Morton, A. R. Towne, E. J. Waterhouse, J. M. Pellock, and R. J. DeLorenzo. Hemodynamic monitoring prior to and at the time of death in status epilepticus. Epilepsy Res. 1998;31: 199–209. 7. Celesia, G. G. Prognosis in convulsive status epilepticus. In A. Delgado-Escueta, C. Wasterlain, D. Treiman, and R. Porter, eds. Status Epilepticus: Mechanisms of Brain Damage and Treatment. New York: Raven Press, 1983:55–59. 8. Claassen, J., J. K. Lokin, B. F. Fitzsimmons, F. A. Mendelsohn, and S. A. Mayer. Predictors of functional disability and mortality after status epilepticus. Neurology 2002;58(1):139–142. 9. Coeytaux, A., P. Jallon, B. Galobardes, and A. Morabia. Incidence of status epilepticus in French-speaking Switzerland: (EPISTAR). Neurology 2000;55(5):693–697. 10. Corey, L. A., J. M. Pellock, J. G. Boggs, L. L. Miller, and R. J. DeLorenzo. Evidence for a genetic predisposition for status epilepticus. Neurology 1998;50(2):558–560. 11. Delgado-Escueta, A., C. G. Wasterlain, D. M. Treiman, and R. J. Porter. Management of status epilepticus. N. Engl. J. Med. 1982;36:1337–1340. 12. DeLorenzo, R. J. Clinical and epidemiological study of status epilepticus in the elderly. In A. J. Rowan and R. E. Ramsey, eds. Seizures and Epilepsy in the Elderly. Newton, Mass.: Butterworth-Heinemann, 1997:191–205.
:
29
13. DeLorenzo, R. J. Management of status epilepticus. Virginia Med. Q. 1996;123:103–111. 14. DeLorenzo, R. J. Status epilepticus. In R. T. Johnson, ed. Current Therapy in Neurologic Disease. Vol. 3. Philadelphia: B.C. Decker, 1990:47–53. 15. DeLorenzo, R. J. Status epilepticus: Concepts in diagnosis and treatment. Semin. Neurol. 1990;2:396–405. 16. DeLorenzo, R. J., L. K. Garnett, A. R. Towne, E. J. Waterhouse, J. G. Boggs, L. Morton, M. A. Choudhry, T. Barnes, and D. Ko. Comparison of status epilepticus with prolonged seizure episodes lasting from 10 to 29 minutes. Epilepsia 1999;40(2):164–169. 17. DeLorenzo, R. J., D. Ko, A. Towne, L. K. Garnett, J. G. Boggs, E. J. Waterhouse, and L. I. D. Morton. Prediction of outcome in status epilepticus. Epilepsia 1997;38(8):210. 18. DeLorenzo, R. J., J. M. Pellock, A. R. Towne, and J. G. Boggs. Epidemiology of status epilepticus. J. Clin. Neurophysiol. 1995; 12(4):316–325. 19. DeLorenzo, R. J., A. R. Towne, D. Ko, et al. Prospective population-based epidemiological study of status epilepticus in Richmond, VA. Neurology 1996;46:1029–1032. 20. DeLorenzo, R. J., A. R. Towne, J. M. Pellock, and D. Ko. Status epilepticus in children, adults and the elderly. Epilepsia 1992;33(Suppl. 4):515–525. 21. Dodson, W. E., R. J. DeLorenzo, T. A. Pedley, S. Shinnar, D. M. Treiman, and B. B. Wannamaker. The treatment of convulsive status epilepticus: Recommendations of the Epilepsy Foundation of America’s working Group on Status Epilepticus. JAMA 1993;270(7):854–859. 22. Dunn, D. W. Status epilepticus in children: Etiology, clinical features, and outcome. J. Child Neurol. 1988;3:167–173. 23. Gastaut, H. Classification of status epilepticus. In A. V. Delgado-Escueta, C. G. Wasterlain, D. M. Treiman, and R. R. Porter, eds. Status Epilepticus: Mechanisms of Brain Damage and Treatment. Adv. Neurol. 1983;34:15–35. 24. Hauser, W. A. Status epilepticus: Epidemiology considerations. Neurology 1990;40(Suppl. 2):9–12. 25. Hauser, W. A. Status epilepticus: Frequency, etiology, and neurological sequelae. In A. V. Delgado-Escueta, C. G. Wasterlain, D. M. Treiman, and R. J. Porter, eds. Status Epilepticus: Mechanisms of Brain Damage and Treatment. Adv. Neurol. 1983;34:3–14. 26. Hesdorffer, D. C., G. Logroscino, G. Cascino, J. F. Annegers, and W. A. Hauser. Incidence of status epilepticus in Rochester, Minnesota, 1965–1984. Neurology 1998;50(3):735–741. 27. Hunter, R. A. Status epilepticus: History, incidence and problems. Epilepsia 1959;60(1):162–188. 28. Jaitly, R. K., J. A. Sgro, A. R. Towne, et al. Prognostic value of EEG monitoring after status epilepticus: A prospective adult study. J. Clin. Neurophysiol. 1997;14(4):326–334. 29. Kelly, J. P., J. S. Nichols, C. M. Filley, K. O. Lillehei, D. Rubinstein, and B. K. Kleinschmidt-DeMasters. Concussion in sports: Guidelines for the prevention of catastrophic outcome. JAMA 1991;266:2867–2869. 30. Knake, S., F. Rosenow, M. Vescovi, W. H. Oertel, H. H. Mueller, A. Wirbatz, N. Katsarou, and H. M. Hamer. Incidence of status epilepticus in adults in Germany: A prospective, population-based study. Epilepsia 2001;42:714–718. 31. Leppik, I. E. Diagnosis and treatment of status epilepticus. Merritt Putnam Q. 1987;4(2):3–13. 32. Leppik, I. E. Status epilepticus. Clin. Ther. 1985;7:272–278. 33. Leppik, I. E. Status epilepticus. Neurol. Clin. 1986;4:633–643. 34. Leppik, I. E. Status epilepticus: The next decade. Neurology 1990;40(Suppl. 2):4–9.
30
35. Leppik, I. E. Status epilepticus. In E. Wyllie, ed. The Treatment of Epilepsy: Principles and Practice. Philadelphia: Lea & Febiger, 1993:678–683. 36. Logroscino, G., D. C. Hesdorffer, G. Cascino, J. F. Annegers, E. Bagiella, and W. A. Hauser. Long-term mortality after a first episode of status epilepticus. Neurology 2002;58(4): 537–541. 37. Logroscino, G., D. C. Hesdorffer, G. Cascino, J. F. Annegers, and W. A. Hauser. Time trends in incidence, mortality, and case-fatality after first episode of status epilepticus. Epilepsia 2001;42(8):1031–1035. 38. Lowenstein, D. H., and B. K. Alldredge. Status epilepticus. N. Engl. J. Med. 1998;338:970–976. 39. Lowenstein, D. H., and B. K. Alldredge. Status epilepticus at an urban public hospital in the 1980s. Neurology 1992;43: 483–488. 40. Lowenstein D. H., T. Bleck, and R. Macdonald. It’s time to revise the definition of status epilepticus. Epilepsia 1999; 40:120–122. 41. Mayer, S. A., J. Claassen, J. Lokin, F. Mendelsohn, L. J. Dennis, and B. F. Fitzsimmons. Refractory status epilepticus: Frequency, risk factors, and impact on outcome. Arch. Neurol. 2002; 59(2):205–210. 42. Maytal, J., S. Shinnar, S. L. Moshe, and L. A. Alvarez. Low morbidity and mortality of status epilepticus in children. Pediatrics 1989;83:323–331. 43. Oxbury, J. M., and C. W. M. Whitty. Causes and consequences of status epilepticus in adults: A study of 86 cases. Brain 1971; 94:733–744. 44. Payne, T. A., and T. P. Bleck. Status epilepticus. Crit. Care Clin. 1997;13(1):17–38. 45. Penburthy, L., A. Towne, L. K. Garnet, and R. J. DeLorenzo. Costs of status epilepticus. Epilepsia 1997;38(8):225. 46. Roger, J., H. Lob, and C. A. Tassinari. Status epilepticus. In P. J. Vinken and G. W. Bruyn, eds. Handbook of Clinical Neurology. Vol. 15. New York: Elsevier, 1974:169–178. 47. Rowan, A. J., and D. F. Scott. Major status epilepticus: A series of 42 patients. Acta Neurol. Scand. 1970;46:573–584. 48. Saunders, R. L., and R. D. Harbaugh. The second impact in catastrophic contact sports head trauma. JAMA 1984;252: 538–539. 49. Shinnar, S., A. T. Berg, S. L. Moshe, and R. Shinnar. How long do new-onset seizures in children last? Ann. Neurol. 2001;49(5): 659–664. 50. Shinnar, S., J. M. Pellock, A. T. Berg, C. O’Dell, S. M. Driscoll, J. Maytal, S. L. Moshe, and R. J. DeLorenzo. Short-term outcomes of children with febrile status epilepticus. Epilepsia 2001; 42(1):47–53. 51. Sillanpää, M., and S. Shinnar. Status epilepticus in a population-based cohort with childhood-onset epilepsy in Finland. Ann. Neurol. 2002;52(3):303–310. 52. Theodore, W., R. Porter, P. Albert, et al. The secondarily generalized tonic-clonic seizure: A videotape analysis. Neurology 1994;41:1403–1407. 53. Towne, A. R., J. M. Pellock, D. Ko, and R. J. DeLorenzo. Determinants of mortality in status epilepticus. Epilepsia 1994;5(1):27–36. 54. Towne, A. R., E. J. Waterhouse, J. G. Boggs, L. K. Garnett, A. J. Brown, J. R. Smith, and R. J. DeLorenzo. Prevalence of nonconvulsive status epilepticus in comatose patients. Neurology 2000;54(2):340–345. 55. Treiman, D. M. Convulsive status epilepticus. Curr. Treat. Options Neurol. 1999;1(4):359–369.
: , , ,
56. Treiman, D. M. Generalized convulsive status epilepticus in the adult. Epilepsia 1993;34:S2–S11. 57. Treiman, D. M. Status epilepticus. In R. T. Johnson, ed. Current Therapy of Neurologic Disease. Vol. 2. Philadelphia: B.C. Decker, 1987:38–42. 58. Treiman, D. M., P. D. Meyers, N. Y. Walton, J. F. Collins, C. Colling, A. J. Rowan, A. Hanforth, E. Faught, V. P. Calabrese, B. M. Uthman, R. E. Ramsy, and M. B. Mamdani. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N. Engl. J. Med. 1998;399(12):792–798. 59. Waterhouse, E. J., L. K. Garnett, A. R. Towne, L. D. Morton, T. Barnes, D. Ko, and R. J. DeLorenzo. Prospective population-based study of intermittent and continuous convulsive status epilepticus in Richmond, Virginia. Epilepsia 1999;40(6): 752–758. 60. Waterhouse, E. J., J. K. Vaughan, T. Y. Barnes, J. G. Boggs, A. R. Towne, L. Garnett, and R. J. DeLorenzo. Synergistic effect of status epilepticus and ischemic brain injury on mortality. Epilepsy Res. 1998;31:199–209. 61. Wu, Y. W., D. W. Shek, P. A. Garcia, S. Ahao, and S. C. Johnston. Incidence and mortality of generalized convulsive status epilepticus in California. Neurology 2002;58(7):1070– 1076.
:
31
4
Prognosis after a First Episode of Status Epilepticus
, . , .
Introduction There is wide variation in the reported prognosis among people with status epilepticus (SE). This variation relates to differences in the definition of SE, the etiologic classification of SE, the definition of outcomes, and the study of outcomes in heterogeneous populations. The most important cause of variation is the source of cases, which is an indirect measure of disease severity and etiology. A study from the Netherlands found a sixfold variation in mortality associated with SE across medical care facilities (26). Mortality was lowest in an epilepsy center (1.9%), intermediate in community hospitals (6.7%), and highest in large hospitals and university clinics (11.9%). This variation was related to differences in the mix of etiology of SE in patients seen at these centers. Another example of heterogeneity may be seen in studies reported in this book. The case-fatality ratio was 21% in the population-based studies in Rochester, Minnesota, and Richmond, Virginia (8, 9, 20), but 55% in the Veterans Administration clinical trial of SE treatments (see Treiman, Chapter 6, this volume). The use of population-based data can provide insights into the frequency of adverse outcomes following SE. In addition, population-based data can allow comparison of outcomes in individuals with seizures or epilepsy but without SE to determine the contribution of SE. It also allows comparison with the frequency of events and outcomes in the general population. This chapter examines the prognosis for SE from a population-based study of people with convulsive disorders and epilepsy (9, 11, 13).
The Rochester, Minnesota, study: Source of patients and definitions D For the studies conducted in Rochester, Minnesota, we defined SE as a convulsion of any type lasting 30 minutes or more, or multiple seizures occurring for a similar duration without an intervening period of lucidness. We have excluded individuals with electrical SE (identified on electroencephalography [EEG] alone) without clear clinical manifestations, individuals with seizures of less than 30 minutes’ duration that stopped after the use of intravenous
medication, and individuals with multiple seizures with intervening intervals of lucidity and normal function. This 30-minute definition was selected when abstraction for these studies started in 1980 and was based on reports suggesting that seizures in baboons lasting 30 minutes or longer were associated with neuronal damage (23, 24). S P We used the population-based convulsive disorder data set from Rochester, Minnesota, to address questions regarding outcome following SE. SE is seldom recorded as a final diagnosis by clinicians. Hence, we reviewed all medical records of the 2,654 incidence cases of convulsive disorders that came to medical attention between 1935 and 1984 to identify individuals who had experienced one or more episodes of SE (10). There was virtually never a statement in the medical record about the actual duration of SE, and SE was seldom included among the discharge diagnoses. Cases were identified by screening all incidence cases of convulsive disorders by one of us (W.A.H.) (13). The duration of SE was estimated through review of records written by outcall physicians, ambulance personnel, emergency room personnel, and inpatient personnel, including nurses, house staff, and attending physicians. Few individuals in this cohort underwent EEG monitoring either during or after their episode(s) of SE, so the total duration of SE may be underestimated when compared with criteria used in the Veterans Administration clinical trial. C C We classified SE based upon the classification of convulsive disorders used in previous epidemiologic studies in the community (11), taking into account modifications recommended by the Commission on Epidemiology and Prognosis of the International League Against Epilepsy (7) and the adaptations of Maytal et al. (22). This same classification was described and used in a recent hospital-based series (3). Essentially, the classification requires two independent axes of classification: the first related to the clinical manifestations of the seizures, based on the International League Against Epilepsy’s seizure type (6), the second based on an etiologic classification that takes into account temporal relationships between SE and neurologic and systemic insults (7, 13).
, , :
33
Incidence of SE For short-term mortality to be compared across studies the incidence must first be known, because mortality depends on incidence and the case-fatality ratio. The lowest reported incidence of SE per 100,000 population was from Switzerland (9.9/100,000) (5). This study did not include myoclonic SE. SE incidence was higher in males (12.1; 95% confidence interval [CI]: 9.8–14.5) than in females (7.8; 95% CI: 6–9.7), with a male-female sex ratio of 1.5. The incidence was higher in Rochester, Minnesota (18.1/100,000; CI: 15.9–21.1), where the incidence was almost twofold greater in males than in females (14). In Richmond, Virginia, the incidence was even higher (41/100,000) (8; see also DeLorenzo, Chapter 3, this volume). When the incidence in Richmond was stratified by ethnic group, however, the incidence in whites was lower (20/100,000) than in other ethnic groups, mainly African American (57/100,000). The incidence in whites alone in Richmond was similar to that found in the Rochester study (8, 14). The incidence was similar in a population-based study conducted in the metropolitan area of Marburg, Germany (15.8/100,000; 95% CI: 11.2–21.6) (17). A study conducted in California using a hospital discharge database estimated the incidence of generalized convulsive SE to be 6.2/100,000 with a trend for decreasing incidence over time from 1991 to 1998 (29). This lower incidence when compared with community-based studies suggests that reliance on diagnostic rubrics will miss a considerable number of cases. The incidence of generalized SE in Rochester was 4.7 per 100,000, but it was 7.5 per 100,000 if those with secondary generalized SE were included. Trends in age-specific incidence are consistent across the community-based studies: high in the very young and high in the elderly (Figure 4.1).
Mortality We determined short- and long-term mortality among the 201 residents of Rochester, Minnesota, who experienced a first episode of SE between January 1, 1965, and December 31, 1984 (19, 20). The index episode of SE was the first seizure for the majority of individuals. More than half of all cases of SE occurred in situations other than epilepsy or unprovoked seizures. No deaths occurred among the 17 children with SE associated with a childhood febrile illness, and these cases were excluded from further analysis of mortality. S-T M (30-) Case-fatality ratio We defined short-term mortality as death occurring within the first 30 days following SE (20). This definition follows analytic strategies used in patients with
34
F 4.1 Incidence of status epilepticus. The crude incidence rate was 17 per 100,000 population. The incidence rate adjusted to the 1990 U.S. population was 16.2 per 100,000 population. The age-specific incidence curve is U-shaped. The highest incidence occurred in young children (85 years, 111/100,000). The incidence was less than 10 per 100,000 population between ages 10 and 60 years.
cerebrovascular and cardiovascular disease and has been the definition of mortality used in the only other populationbased study of SE mortality (7). The case fatality in the first month after SE was 21%. Although similar to the case fatality of 22% reported from the community-based study of SE in Richmond, Virginia, differences in classification of SE and ethnic heterogeneity of the populations make further comparisons difficult (8; see also DeLorenzo, Chapter 3, this volume). The case fatality was much lower in Switzerland (7.6%) (5). Of the deaths, 30.8% occurred in children (90 minutes) and focal febrile seizures that in two cases progressed to mesial temporal sclerosis. The changes were not seen in children with prolonged febrile seizures that were generalized. In addition, the children had evidence of preexisting focal pathology, such as a temporal lobe arachnoid cyst. Similar findings in a study that examined children both acutely and long term were reported by Scott et al. (101, 102). Another recent MRI study (52) found evidence of subtle preexisting hippocampal abnormalities that were associated with familial febrile seizures. When very prolonged, these were associated with mesial temporal sclerosis. The finding of mesial temporal sclerosis in this report was retrospective. Whereas these recent studies demonstrate that mesial temporal sclerosis can occur as a consequence of very prolonged febrile seizures, they also suggest that the event is uncommon and may require a preexisting temporal lobe abnormality to occur. Thus, this association is unlikely to account for most cases of mesial temporal lobe epilepsy (71, 106). Interestingly, these recent clinical reports are consistent with very recent pathologic and animal data. Mathern and colleagues have described a high incidence of small areas of
46
heterotopias and subtle migration defects in the temporal lobes of patients undergoing temporal lobectomy for medically refractory mesial temporal lobe epilepsy, some of whom have a history of prior febrile convulsions (81, 82). Germano et al. (60) have recently reported that, in a rat hyperthermia model of febrile seizures, immature rats with experimentally induced neuronal migration defects have a lower threshold to hyperthermia-induced seizures and are more susceptible to irreversible hippocampal neuronal damage than control immature rats without migration defects. The evolving concept is that preexisting pathology was responsible for the febrile seizure being both focal and prolonged and caused the brain to be more susceptible to seizure-induced damage (106). The event is sufficiently uncommon that the association is not seen in epidemiologic studies. Recently, a large cohort of children with febrile SE has been assembled that will hopefully allow more detailed study of the association between these seizures and mesial temporal sclerosis (117). The development of experimental models of febrile seizures will soon shed further light on this issue. The results of Germano et al. (60) have already been discussed. Baram and colleagues recently developed an immature rat model of febrile seizures (11). Interestingly, the findings in this immature rat model of prolonged febrile seizures show that these seizures do not result in loss of hippocampal and amygdala neurons but cause significant, yet transient, structural alterations (11, 125). In addition, these seizures lead to longlasting functional changes in the hippocampal circuit, consisting of increased presynaptic GABA release, (30), yet enhanced susceptibility to further seizures (44). Some of these longlasting changes are due to changes in the distribution of subunits of the hyperpolarization-activated, mixed-cation channels (h-channels), which leads to increased seizure susceptibility (30, 44, 45, 124). The animal data are extensively reviewed in a recent monograph on febrile seizures (11). Further animal studies of this model may lead us to a better understanding of what is occurring in children with prolonged febrile seizures (10). Acute symptomatic SE Approximately 15%–30% of children who experience seizures in association with an acute insult will subsequently develop epilepsy (62,107). However, while acute symptomatic seizures, including SE, are associated with an increased risk of subsequent epilepsy in patients with acute CNS injury, it is unclear whether children with acute symptomatic SE are at higher risk for subsequent epilepsy than children with briefer acute symptomatic seizures (61–65). The use of AEDs reduces the incidence of acute symptomatic seizures but does not alter the proportion who subsequently develop epilepsy, suggesting that these seizures usually are more a marker of damage than the cause of the damage (54, 90, 108, 123).
: , , ,
Recurrent SE We have already reviewed the issue of which children are at risk for developing SE. Also of interest is the question of who is at risk for developing recurrent episodes of SE. While the question is of interest in both adults and children, most of the available data are in children. Studies of SE in children report that 11%–25% of children with SE will experience at least two episodes (5, 22, 36, 43, 47, 87, 115, 122). These studies included both prospectively and retrospectively identified cases. In a prospective study (115), we followed 95 children from the time of their first episode of SE. Sixteen children (17%) experienced recurrent status, including five with three or more episodes. Fourteen (88%) had prior neurologic abnormalities. The risk of recurrent SE in the remote symptomatic and progressive encephalopathy group was almost 50%, compared with only 3% in children who were otherwise neurologically normal. The neurologically abnormal group constituted 32 (34%) of the 95 children, but they accounted for 14 (88%) of 16 children with recurrent SE and all five children with three or more episodes of SE. Driscoll et al. (43) reported similar findings in a retrospective review of the Richmond, Virginia, SE data set. Thus, it would appear that the risk of recurrent SE is primarily in children with preexisting neurologic abnormalities. This is also the population that is at higher risk for developing seizures (15, 77, 79, 112) and SE in the first place (5, 38, 41, 46, 47, 62, 86, 87, 132, 135). Data from the prospective greater Richmond population-based study of SE also report a much higher risk of recurrent SE in children than in adults (37). As previously discussed, studies of children who present with a first unprovoked seizure (112, 113) or with febrile seizures (15) indicate that while a prolonged initial seizure does not alter recurrence risk, if the child does experience recurrent seizures, the recurrence is likely to be prolonged. Recent data from large cohorts of patients with childhoodonset epilepsy provide additional support for the concept that there is a group of children with an increased susceptibility to having prolonged seizures. A population-based study of childhood-onset epilepsy from Finland reported that 27% of patients with childhood-onset epilepsy experienced at least one episode of SE. The majority of initial cases of SE occurred at or prior to the diagnosis of epilepsy. Of those that had one episode, approximately half experienced two or more episodes of SE (122). Conversely, if the child did not have an episode of status within 2 years of the onset of the seizure disorder, the likelihood of status occurring later in life was very low. Similar data, though with a shorter duration of follow-up, were reported from the community-based study of newly diagnosed childhood-onset epilepsy in Connecticut (22). A recent review of SE occurring in the context of drug trials also found that the patients most likely to expe-
rience SE during a trial of a new AED were those with prior episodes of status (109). Further support for this position comes from studies of twins that show that if one twin experiences an episode of SE, the other twin is at high risk not just for seizures but for an episode of SE (35). The combined available data suggest that the occurrence of SE is a marker of a predisposition to prolonged seizures rather than a cause of subsequent seizures. It can be a marker either of a damaged brain or of a genetic predisposition to prolonged seizures. There is clearly a subgroup of children with a predisposition to prolonged seizures. If one views SE as the failure of inhibitory processes that terminate a seizure, then this should not be surprising. The mechanisms that underlie seizure susceptibility may be different than the mechanisms by which seizures are turned off. Patients with refractory epilepsy in monitoring units have frequent seizures, almost all of which are very brief. In contrast, there is a subgroup of children who tend to have longer seizures, and these signal a predisposition to prolonged seizures rather than necessarily to frequent seizures (114).
Summary SE is a common event in childhood, with children under age 2 at highest risk. In young children, SE occurs primarily in children who are neurologically normal and with no prior history of unprovoked seizure. In older children, it occurs primarily in those who are known to have prior unprovoked seizures and who are often also neurologically abnormal. The morbidity and mortality of SE are low and are primarily a function of the underlying etiology. The epidemiologic data suggest that, in the absence of an underlying neurologic abnormality or insult, childhood SE, though often a marker for preexisting CNS pathology, is not associated with detectable long-term sequelae. More studies are needed on the consequences of very prolonged febrile seizures, which appear to have different pathophysiologic consequences than other types of seizures in children. This work was supported in part by NIH grants R01 NS26151 and R01 NS043209 from the National Institute of Neurological Disorders and Stroke.
REFERENCES 1. Abou-Khalil, B., E. Andermann, F. Andermann, A. Olivier, and L. F. Quesney. Temporal lobe epilepsy after prolonged febrile convulsions: Excellent outcome after surgical treatment. Epilepsia 34:878–883. 2. Aicardi, J. Consequences and prognosis of convulsive status epilepticus in infants and children. Jpn. J. Psychiatr. Neurol. 1986;40:283–290.
:
47
3. Aicardi, J., J. Amsili, and J. J. Chevrie. Acute hemiplegia in infancy and childhood. Dev. Med. Child Neurol. 1969;11: 162–173. 4. Aicardi, J., and J. J. Chevrie. Consequences of status epilepticus in infants and children. In A. V. Delgado-Escueta, C. G. Wasterlain, D. M. Treiman, and R. J. Porter, eds. Status Epilepticus. New York: Raven Press, 1983:115–125. 5. Aicardi, J., and J. J. Chevrie. Convulsive status epilepticus in infants and in children: A study of 239 cases. Epilepsia 1970;11:187–197. 6. Aminoff, M. J., and R. P. Simon. Status epilepticus: Causes, clinical features and consequences in 98 patients. Am. J. Med. 1980;69:657–666. 7. Annegers, J. F., W. A. Hauser, L. R. Elveback, and L. T. Kurland. The risk of epilepsy following febrile convulsions. Neurology 1979;29:297–303. 8. Annegers, J. F., W. A. Hauser, and S. B. Shirts, et al. Factors prognostic of unprovoked seizures after febrile convulsions. N. Engl. J. Med. 1987;316:493–498. 9. Annegers, J. F., S. B. Shirts, W. A. Hauser, and L. T. Kurland. Risk of recurrence after an initial unprovoked seizure. Epilepsia 1986;27:43–50. 10. Baram, T. Z., M. Eghbal-Ahmadi, and R. A. Bender. Is neuronal death required for seizure-induced epileptogenesis in the immature brain. Prog. Brain Res. 2002;135:365–375. 11. Baram, T. Z., A. Gerth, and L. Schultz. Febrile seizures: An age appropriate model. Dev. Brain Res. 1997;246:134–143. 12. Baram, T. Z., and S. Shinnar, eds. Febrile Seizures. San Diego, Calif.: Academic Press, 2002. 13. Berg, A. T. The epidemiology of seizures and epilepsy in children. In S. Shinnar, N. Amir, and D. Branski, eds. Childhood Seizures. Basel, Switzerland: S. Karger, 1995:1–10. 14. Berg, A. T., S. R. Levy, E. J. Novotny, and S. Shinnar. Predictors of intractable epilepsy in childhood: A case control study. Epilepsia 1996;37:24–30. 15. Berg, A. T., and S. Shinnar. Complex febrile seizures. Epilepsia 1996;37:126–133. 16. Berg, A. T., and S. Shinnar. Do seizures beget seizures? An assessment of the clinical evidence in humans. J. Clin. Neurophysiol. 1997;14:102–110. 17. Berg, A. T., and S. Shinnar. The risk of seizure recurrence following a first unprovoked seizure: A quantitative review. Neurology 1991;41:965–972. 18. Berg, A. T., and S. Shinnar. Unprovoked seizures in children with febrile seizures: Short term outcome. Neurology 1996;47: 562–568. 19. Berg, A. T., S. Shinnar, W. A. Hauser, and J. M. Leventhal. Predictors of recurrent febrile seizures: A metaanalytic review. J. Pediatr. 1990;116:329–337. 20. Berg, A. T., S. Shinnar, W. A. Hauser, et al. Predictors of recurrent febrile seizures: A prospective study of the circumstances surrounding the initial febrile seizure. N. Engl. J. Med. 1992;327:1122–1127. 21. Berg, A. T., S. Shinnar, S. R. Levy, and F. M. Testa. Childhood-onset epilepsy with and without preceding febrile seizures. Neurology 1999;53:1742–1748. 22. Berg, A. T., S. Shinnar, S. R. Levy, and F. M. Testa. Status epilepticus in children with newly diagnosed epilepsy. Ann. Neurol. 1999;45:618–623. 23. Berg, A. T., S. Shinnar, S. R. Levy, F. M. Testa, S. SmithRapaport, and B. Beckerman. Early development of intractable epilepsy in children: A prospective study. Neurology 2001;56:1445–1452.
48
24. Bruton, C. J. The Neuropathology of Temporal Lobe Epilepsy. New York: Oxford University Press, 1988:1–158. 25. Camfield, P., C. Camfield, K. Gordon, and J. Dooley. What types of epilepsy are preceded by febrile seizures? A population based study of children. Dev. Med. Child Neurol. 1994;36:887–892. 26. Cavazzuti, G. B., P. Ferrari, and M. Lalla. Follow-up study of 482 cases with convulsive disorders in the first year of life. Dev. Med. Child Neurol. 1984;26:425–437. 27. Cendes, F., and F. Andermann. Do febrile seizures promote temporal lobe epilepsy? Retrospective studies. In T. Z. Baram and S. Shinnar, eds. Febrile Seizures. San Diego, Calif.: Academic Press, 2002:63–76. 28. Cendes, F., F. Andermann, and F. Dubeau, et al. Early childhood prolonged febrile convulsions, atrophy and sclerosis of mesial structures, and temporal lobe epilepsy: An MRI volumetric study. Neurology 1993;43:1083–1087. 29. Cendes, F., F. Andermann, and P. Gloor, et al. Atrophy of mesial structures in patients with temporal lobe epilepsy: Cause or consequence of repeated seizures. Ann. Neurol. 1993;34:795–801. 30. Chen, K., T. Z. Baram, and I. Soltesz. Febrile seizures in the immature brain result in persistent modification of neuronal excitability in limbic circuits. Nat. Med. 1999;5:888–894. 31. Chevrie, J. J., and J. Aicardi. Convulsive disorders in the first year of life: Neurological and mental outcome and mortality. Epilepsia 1978;19:67–74. 32. Chevrie, J. J., and J. Aicardi. Duration and lateralization of febrile convulsions: Etiological factors. Epilepsia 1975;16: 781–789. 33. Commission on Classification and Terminology of the International League Against Epilepsy: Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489–501. 34. Commission on Epidemiology and Prognosis, International League Against Epilepsy. Guidelines for epidemiologic studies on epilepsy. Epilepsia 1993;34:592–596. 35. Corey, L. A., J. M. Pellock, J. G. Boggs, L. L. Miller, and R. J. DeLorenzo. Evidence for a genetic predisposition for status epilepticus. Neurology 1998;50:558–560. 36. DeLorenzo, R. J., W. A. Hauser, A. R. Towne, J. G. Boggs, J. M. Pellock, L. Penberthy, L. Garnett, C. A. Fortner, and D. Ko. A prospective population-based epidemiological study of status epilepticus in Richmond, Virginia. Neurology 1996; 46:1029–1035. 37. DeLorenzo, R. J., J. M. Pellock, A. R. Towne, and J. G. Boggs. Epidemiology of status epilepticus. J. Clin. Neurophysiol. 1995; 12:316–325. 38. DeLorenzo, R. J., A. R. Towne, and J. M. Pellock, et al: Status epilepticus in children, adults and the elderly. Epilepsia 1992;33(Suppl. 4):S15–S25. 39. Dodrill, C. B. Correlates of generalized tonic-clonic seizures with intellectual, neuropsychological, emotional and social function in patients with epilepsy. Epilepsia 1986; 27:399–411. 40. Dodrill, C. B., and A. J. Wilensky. Intellectual impairment as an outcome of status epilepticus. Neurology 1990;40(Suppl. 2):23–27. 41. Dodson, W. E., R. J. DeLorenzo, T. A. Pedley, S. Shinnar, D. M. Treiman, and B. B. Wannamaker. The treatment of convulsive status epilepticus: Recommendations of the Epilepsy Foundation of America’s Working Group on Status Epilepticus. JAMA 1993;270:854–859.
: , , ,
42. Doose, H., and E. Volzke. Petit mal status in early childhood and dementia. Neuropaediatrie 1979;10:10–14. 43. Driscoll, S. M., A. R. Towne, J. M. Pellock, and R. J. DeLorenzo. Recurrent status epilepticus in children (abstract). Neurology 1990;40(Suppl. 1):297. 44. Dube, C. Do prolonged febrile seizures in an immature rat model cause epilepsy? In T. Z. Baram and S. Shinnar, eds. Febrile Seizures. San Diego, Calif.: Academic Press, 2002: 216–229. 45. Dube, C., K. Chen, M. Eghbal-Ahmadi, K. Brunson, I. Soltesz, and T. Z. Baram. Prolonged febrile seizures in the immature rat model enhance hippocampal excitability longterm. Ann. Neurol. 2000;47:336–344. 46. Dulac, O., P. Aubourg, and A. Chercoury, et al: Infantile status epilepticus: Clinical, etiological and prognostic aspects. Rev. Electroencephalogr. Neurophysiol. 1985;14:255–262. 47. Dunn, W. D. Status epilepticus in children: Etiology, clinical features and outcome. J. Child Neurol. 1988;3:167–173. 48. Ellenberg, J. H., D. G. Hirtz, and K. B. Nelson. Do seizures in children cause intellectual deterioration? N. Engl. J. Med. 1986;314:1085–1088. 49. Ellenberg, J. H., and K. B. Nelson. Febrile seizures and later intellectual performance. Arch. Neurol. 1978;35:17–21. 50. Falconer, M. Genetic and related etiological factors in temporal lobe epilepsy: A review. Epilepsia 1971;12:13–31. 51. Falconer, M. A., E. A. Serafetinides, and J. A. N. Corsellis. Etiology and pathogenesis of temporal lobe epilepsy. Arch. Neurol. 1964;10:233–248. 52. Fernandez, G., O. Effenberger, and B. Vinz, et al. Hippocampal malformation as a cause of familial febrile convulsions and subsequent hippocampal sclerosis. Neurology 1998; 50:909–917. 53. Fowler, M. Brain damage after febrile convulsions. Arch. Dis. Child. 1957;32:67–76. 54. Foy, P. M., D. W. Chadwick, and N. Rajgopalan, et al. Do prophylactic anticonvulsant drugs alter the pattern of seizures after craniotomy? J. Neurol. Neurosurg. Psychiatry 1992;55: 753–757. 55. French, J. A., P. D. Williamson, and M. Thadani, et al. Characteristics of medial temporal lobe epilepsy. I. Results of history and physical examination. Ann. Neurol. 1993;34: 774–780. 56. Fujiwara, T., S. Ishida, and M. Mlyakoshi. Status epilepticus in childhood: A retrospective study of initial convulsive status and subsequent epilepsies. Folia Psychiatr. Neurol. Jpn. 1979; 33:337–344. 57. Fujiwara, T., M. Watanabe, H. Nakamura, T. Kudo, K. Yagi, and M. Seino. A comparative study of absence status epilepticus between children and adults. Jpn. J. Psychiatr. Neurol. 1988;42:497–508. 58. Gastaut, H. Dictionary of Epilepsy. Part I. Definitions. Geneva: World Health Organization, 1973. 59. Gastaut, H., F. Poirer, G. Pagan, G. Salomon, M. Toga, and M. Vigoroux. HHE syndrome: Hemiconvulsions, hemiplegia, epilepsy. Epilepsia 1960;1:418–447. 60. Germano, I. M., Y. F. Zhang, E. F. Sperber, and S. L. Moshe. Neuronal migration disorders increase susceptibility to hyperthermia-induced seizures in developing rats. Epilepsia 1996;37:902–910. 61. Gross-Tsur, V., and S. Shinnar. Convulsive status epilepticus in children. Epilepsia 1993;34(Suppl. 1):S12–S20. 62. Hauser, W. A. Status epilepticus: Epidemiologic considerations. Neurology 1990;40(Suppl. 2):9–13.
63. Hauser, W. A. Status epilepticus: Frequency, etiology and neurological sequellae. In A. V. Delgado-Escueta, C. G. Wasterlain, and D. M. Treiman, et al., eds. Status Epilepticus Adv. Neurol. 1983;34:3–14. 64. Hauser, W. A., V. E. Anderson, and R. B. Loewenson. Seizure recurrence after a first unprovoked seizure. N. Engl. J. Med. 1982;307:522–528. 65. Hauser, W. A., J. F. Annegers, and L. T. Kurland. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984. Epilepsia 1993;34:453–468. 66. Hauser, W. A., and D. C. Hesdorffer. Epilepsy: Frequency, Causes and Consequences. New York: Demos, 1990. 67. Hauser, W. A., and L. T. Kurland. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia 1975;16:1–66. 68. Hauser, W. A., S. S. Rich, J. F. Annegers, and V. E. Anderson. Seizure recurrence following a first unprovoked seizure: An extended follow-up. Neurology 1990;40:1163–1170. 69. Haut, S. R., S. Shinnar, S. L. Moshe, C. O’Dell, and A. D. Legatt. The association between seizure clustering and convulsive status epilepticus in patients with intractable complex partial seizures. Epilepsia 1999;1832–1834. 70. Hesdorffer, D. C., G. Logroscino, G. Cascino, J. F. Annegers, and W. A. Hauser. Incidence of status epilepticus in Rochester, Minnesota, 1965–1984. Neurology 1998;50:735– 741. 71. Knudsen, F. U. Febrile seizures: Treatment and prognosis. Epilepsia 2000;41:2–9. 72. Knudsen, F. U. Recurrence risk after first febrile seizure and effect of short-term diazepam prophylaxis. Arch. Dis. Child. 1985;60:1045–1049. 73. Knudsen, F. U., A. Paerregaard, R. Andersen, and J. Andresen. Long term outcome of prophylaxis for febrile convulsions. Arch. Dis. Child. 1996;74:13–18. 74. Lawson, J. A., S. Vogrin, A. F. Bleasel, M. J. Cook, L. Burns, L. McAnally, J. Pereira, and A. M. Bye. Predictors of hippocampal, cerebral, and cerebellar volume reduction in childhood epilepsy. Epilepsia 2000;41:1540–1545. 75. Lindsay, J., C. Ounsted, and P. Richards. Long-term outcome in children with temporal lobe seizures. Dev. Med. Child Neurol. 1979;21:285–298. 76. Logroscino, G. Mortality after incident status epilepticus: A retrospective cohort study. Doctoral thesis. Columbia University, 1997. 77. Margerison, J. H., and J. A. N. Corsellis. Epilepsy and the temporal lobes. Brain 1966;89:499–530. 78. Maher, J., and R. S. McLachlan. Febrile convulsions: Is seizure duration the most important predictor of temporal lobe epilepsy? Brain 1995;118:1521–1528. 79. Mathern, G. W., T. L. Babb, P. S. Mischel, H. V. Vinters, J. K. Pretorius, J. P. Leite, and W. J. Peacock. Childhood generalized and mesial temporal epilepsies demonstrate different amounts and patterns of hippocampal neuron loss and mossy fiber synaptic reorganization. Brain 1996;119:965–987. 80. Mathern, G. W., T. L. Babb, J. K. Pretorius, M. Melendez, and M. F. Levesque. The pathophysiologic relationships between lesion pathology, intracranial ictal EEG onsets, and hippocampal neuron losses in temporal lobe epilepsy. Epilepsy Res. 1995;21:133–147. 81. Mathern, G. W., T. L. Babb, B. G. Vickrey, M. Melendez, and J. K. Pretorius. The clinical-pathologic mechanisms of hippocampal neuronal loss and surgical outcomes in temporal lobe epilepsy. Brain 1995;118:105–118.
:
49
82. Mathern, G. W., J. K. Pretorius, and T. L. Babb. Influence of the type of initial precipitating injury and at what age it occurs on course and outcome in patients with temporal lobe seizures. J. Neurosurg. 1995;82:220–227. 83. Matsumoto, A., K. Watanabe, M. Sugiura, T. Negoro, E. Takaesu, and K. Iwase. Long term prognosis of convulsive disorder in the 1st year of life. Epilepsia 1983;24:321–329. 84. Maytal, J., G. Novak, C. Ascher, and R. Bienkowski. Status epilepticus in children with epilepsy: The role of antiepileptic drug levels in prevention. Pediatrics 1996;98:1119–1121. 85. Maytal, J., and S. Shinnar. Febrile status epilepticus. Pediatrics 1990;86:611–616. 86. Maytal, J., and S. Shinnar. Status epilepticus in children. In S. Shinnar, N. Amir, and D. Branski, eds. Childhood Seizures. Basel: S. Karger, 1995:111–122. 87. Maytal, J., S. Shinnar, S. L. Moshe, and L. A. Alvarez. Low morbidity and mortality of status epilepticus in children. Pediatrics 1989;83:323–331. 88. Metsaranta, P., M. Koivikko, J. Peltola, and K. Eriksson. Outcome after prolonged convulsive seizures in 186 children: Low morbidity, no mortality. Dev. Med. Child Neurol. 2004;46: 4–8. 89. Mikati, M. A., W. L. Lee, and G. R. DeLong. Protracted epileptiform encephalopathy: An unusual form of partial complex status epilepticus. Epilepsia 1985;26:563–571. 90. Moshe, S. L., and S. Shinnar. Early Intervention. In J. Engel, Jr., ed. Surgical Treatment of the Epilepsies. 2nd ed. New York: Raven Press, 1993:123–132. 91. National Institutes of Health. Febrile Seizures: Consensus Development Conference Summary. Vol. 3, No. 2. Bethesda, Md.: National Institutes of Health, 1980. 92. Nelson, K. B., and J. H. Ellenberg. Antecedents of seizure disorders in early childhood. Am. J. Dis. Child. 1986;140: 1053–1061. 93. Nelson, K. B., and J. H. Ellenberg. Prognosis in children with febrile seizures. Pediatrics 1978;61:720–727. 94. Oxbury, J. M., and C. W. Whitty. Causes and consequences of status epilepticus in adults: A study of 86 cases. Brain 1971;94:733–744. 95. Phillips, S. A., and R. J. Shanahan. Etiology and mortality of status epilepticus in children: A recent update. Arch. Neurol. 1989;46:74–76. 96. Roger, J., H. Lob, and C. A. Tassinari. Status epilepticus. In P. L. Vinken and C. W. Bruyn, eds. Handbook of Clinical Neurology. The Epilepsies. Amsterdam: Elsevier, 1974;15:145–188. 97. Rosman, N. P., T. Colton, and J. Labazzo, et al. A controlled trial of diazepam administered during febrile illnesses to prevent recurrence of febrile seizures. N. Engl. J. Med. 1993;329:79–84. 98. Rosman, N. P., J. L. Labazzo, and T. Colton. Factors predisposing to afebrile seizures after febrile convulsions and preventive treatment. Ann. Neurol. 1993;34:452. 99. Rowan, A. J., and D. F. Scott. Major status epilepticus. Acta Neurol. Scand. 1970;46:573–584. 100. Sagar, H. J., and J. M. Oxbury. Hippocampal neuron loss in temporal lobe epilepsy: Correlation with early childhood convulsions. Ann. Neurol. 1987;22:334–340. 101. Scott, R. C., D. G. Gadian, M. D. King, W. K. Chong, T. C. Cox, B. G. Neville, and A. Connely. Magnetic resonance imaging findings within 5 days of status epilepticus in childhood. Brain 2002;125(Pt. 9):1951–1959. 102. Scott, R. C., M. D. King, D. G. Gadian, B. G. Neville, and A. Connely. Hippocampal abnormalities after prolonged
50
103. 104.
105.
106. 107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
febrile convulsion: Longitudinal MRI study. Brain 2003; 126(Pt. 11):2551–2557. Shalev, R. S., and N. Amir. Complex partial status epilepticus. Arch. Neurol. 1983;40:90–92. Shinnar, S. Do febrile seizures lead to temporal lobe epilepsy? Prospective and epidemiological studies. In T. Z. Baram, and S. Shinnar, eds. Febrile Seizures. San Diego, Calif.: Academic Press, 2002:87–101. Shinnar, S. Febrile seizures. In K. E. Swaiman, and S. Ashwal, eds. Pediatric Neurology: Principles and Practice. 3rd. ed. St Louis, Mo.: Mosby, 1999:676–682. Shinnar, S. Prolonged febrile seizures and mesial temporal sclerosis. Ann. Neurol. 1998;43:411–412. Shinnar, S., and T. L. Babb. Long term sequellae of status epilepticus. In J. Engel, Jr., and T. A. Pedley, eds. Epilepsy: A Comprehensive Text. Philadelphia: Lippincot-Raven, 1997: 755–763. Shinnar, S., and A. T. Berg. Does antiepileptic drug therapy prevent the development of “chronic” epilepsy? Epilepsia 1996;37:701–708. Shinnar, S., A. T. Berg, and S. L. Moshe. The effect of status epilepticus on the long term outcomes of a cohort of children prospectively followed from the time of their first idiopathic unprovoked seizure. Presented at the European Child Neurology Society meetings, March 1995, Eilat, Israel. Shinnar, S., A. T. Berg, and S. L. Moshe, et al. Long term outcomes of children with epilepsy after withdrawal of antiepileptic drugs. Epilepsia 1994;35(Suppl. 8):34. Shinnar, S., A. T. Berg, and S. L. Moshe, et al. Risk of seizure recurrence following a first unprovoked seizure in childhood: A prospective study. Pediatrics 1990;85:1076–1085. Shinnar, S., A. T. Berg, and S. L. Moshe, et al. The risk of seizure recurrence following a first unprovoked afebrile seizure in childhood: An extended follow-up. Pediatrics 1996;98:216–225. Shinnar, S., A. T. Berg, S. L. Moshe, and R. Shinnar. How long do new-onset seizures in children last? Ann. Neurol. 2001;49:659–664. Shinnar, S., A. T. Berg, D. M. Treiman, W. A. Hauser, D. C. Hesdorffer, J. C. Sackellares, I. Leppik, M. Sillanpää, and K. W. Sommerville. Status epilepticus and tiagabine therapy: Review of safety data and epidemiologic comparisons. Epilepsia 2001;42:372–379. Shinnar, S., J. Maytal, L. Krasnoff, and S. L. Moshe. Recurrent status epilepticus in children. Ann. Neurol. 1992;31: 598–604. Shinnar, S., and S. L. Moshe. Age specificity of seizure expression in genetic epilepsies. In V. E. Anderson, W. A. Hauser, I. E. Leppik, J. L. Noebels, and S. S. Rich, eds. Genetic Strategies in Epilepsy Research. New York: Raven Press, 1991:69–85. Shinnar, S., J. M. Pellock, A. T. Berg, C. O’Dell, S. M. Driscoll, J. Maytal, S. L. Moshe, and R. J. DeLorenzo. Shortterm outcomes of children with febrile status epilepticus. Epilepsia 2001;42:47–53. Shinnar, S., J. M. Pellock, and S. L. Moshe, et al. In whom does status epilepticus occur: Age related differences in children. Epilepsia 1997;38:907–914. Silanpää, M. Remission of seizures and prediction of intractability in long-term followup. Epilepsia 1993;34: 930–936. Silanpää, M. Social functioning and seizure status of young adults with onset of epilepsy in childhood: An epidemiologi-
: , , ,
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
cal 20-year follow-up study. Acta Neurol. Scand. 1983;68(Suppl. 96):7–77. Sillanpää, M., M. Jalava, O. Kaleva, and S. Shinnar. Longterm prognosis of seizures with onset in childhood. N. Engl. J. Med. 1998;338:1715–1722. Sillanpää, M., and S. Shinnar. Status epilepticus in a population-based cohort with childhood-onset epilepsy in Finland. Ann. Neurol. 2002;52:303–310. Temkin, N. R., S. S. Dikmen, A. J. Wilensky, J. Keihm, S. Chabal, and H. R. Winn. A randomized double-blind study of phenytoin for the prevention of post-traumatic seizures. N. Engl. J. Med. 1990;323:497–502. Thon, N., K. Chen, I. Aradi, and I. Soltesz. Physiology of limbic hyperexcitability after experimental complex febrile seizures: Interactions of seizure induced alterations at multiple levels of neuronal organization. In T. Z. Baram and S. Shinnar, eds. Febrile Seizures. San Diego, Calif.: Academic Press, 2002:203–213. Toth, Z., X. X. Yan, S. Haftoglou, C. E. Ribak, and T. Z. Baram. Seizure-induced neuronal injury: Vulnerability to febrile seizures in immature rat model. J. Neurosci. 1998; 18:4285–4294. Towne, A. R., J. M. Pellock, D. Ko, and R. J. DeLorenzo. Determinants of mortality in status epilepticus. Epilepsia 1994;35:27–34. van Esch, A., I. R. Ramlal, H. A. Steensel-Moll, E. W. Steyerberg, and G. Derksen-Lubsen. Outcome after febrile status epilepticus. Dev. Med. Child Neurol. 1996;38:19–24. VanLandingham, K. E., E. R. Heinz, J. E. Cavazos, and D. V. Lewis. MRI evidence if hippocampal injury following prolonged, focal febrile convulsions. Ann. Neurol. 1998;43: 413–426. Verity, C. M., and J. Golding. Risk of epilepsy after febrile convulsions: A national cohort study. B. M. J. 1991;303: 1373–1376. Verity, C. M., R. Greenwood, and J. Golding. Long-term intellectual and behavioral outcomes of children with febrile convulsions. N. Engl. J. Med. 1998;338:1723–1728. Verity, C. M., E. M. Ross, and J. Golding. Outcome of childhood status epilepticus and lengthy febrile convulsions: Findings of national cohort study. B. M. J. 1993;307:225–228. Vigevano, F., and S. Gregory. Status epilepticus in the pediatric age. In C. Dirocco and F. Vigevano, eds. Neurologic Emergencies in Infancy and Childhood. Rome: Ricerca Scientifica Editrice, 1987:69–80. Wolf, S. M., A. Carr, and D. C. Davis, et al. The value of phenobarbital in the child who has had a single febrile seizure: A controlled prospective study. Pediatrics 1977;59: 378–385. Wolf, S. M., and A. Forsythe. Epilepsy and mental retardation following febrile seizures in childhood. Acta Paediatr. Scand. 1989;78:291–295. Yager, J. Y., M. Cheang, and S. S. Seshia. Status epilepticus in children. Can. J. Neurol. Sci. 1988;15:402–405.
:
51
II STATUS EPILEPTICUS: CLINICAL PHENOMENOLOGY
6
Generalized Convulsive Status Epilepticus
. If an epilepsy demon falls again and again upon him, his eyes are suffused with blood and he blinks his eyes; —if his lower cheek area twitch and his hands and feet are extended; if when the exorcist comes to see him hope is perishing that he will ever regain consciousness, he will die. —All Diseases, ca. 718–612 ..
The first description of the entity known today as status epilepticus (SE) appeared on a cuneiform tablet of the Babylonian medical diagnostic text Sakikku (All Diseases), written more than 2,500 years ago (172). The text describes a series of convulsions—recognizable today as overt generalized convulsive status epilepticus—and notes the evolution from repeated overt convulsions to more subtle symptoms, such as eye blinks and muscle twitches during coma, as described in the passage at the head of this chapter. Subsequent references to SE in medical writings over the next two millennia are sparse. Neither Hippocrates nor Galen described status in their extensive writings on epilepsy. It was not until the nineteenth century that SE was again systematically reviewed and the terms état de mal (17) and status epilepticus (163) were introduced. Most early discussions of SE referred to grand mal status, now called generalized convulsive status epilepticus (GCSE). Although other forms of SE are mentioned in the late nineteenth- and early twentieth-century literature, none was studied in detail until 1964, when the first major conference on SE was held in Marseilles (44).
Definition SE is now defined in one of two ways: (1) as recurrent epileptic seizures without full recovery of neurologic function between the seizures, or (2) as continuous seizure activity lasting 30 minutes or more. If the first definition is used, then GCSE can be defined as recurrent generalized convulsions without complete recovery of neurologic function (usually assessed by level of consciousness) between seizures. However, if GCSE is allowed to continue untreated or is inadequately treated, so that seizure activity persists, there is an evolution from overt to subtle motor manifestations. This evolution has been described in both clinical (148, 155) and experimental (48, 89) GCSE. Overt GCSE is easily
recognized as recurrent generalized convulsions without full recovery of neurologic function between seizures. In 1984 Treiman and colleagues (160) proposed that the term subtle generalized convulsive status epilepticus be used whenever a patient in GCSE exhibits profound coma and ictal discharges on the electroencephalogram (EEG), but only subtle rhythmic motor activity, such as focal twitches of the eyelid, face, jaw, trunk, or extremities, or nystagmoid jerks of the eyes. This concept of GCSE as a dynamic state, with evolution through progressive clinical stages from overt to subtle motor manifestations over time, was a rediscovery of a phenomenon first recognized by Bourneville in 1876 (12) in the first full clinical description of SE, and further elaborated by Clark and Prout in their extensive and detailed study of SE, published in 1903 and 1904 (22–24). Although overt GCSE may evolve into subtle GCSE if inadequately treated, a history of overt GCSE is not essential to make the diagnosis of subtle GCSE. Sometimes subtle GCSE may appear de novo after a severe insult to the brain. Full motor expression of seizure activity appears to depend on a relatively healthy brain. The greater the degree of encephalopathy present, the more subtle is the convulsive activity. Thus, overt GCSE may evolve into subtle GCSE because inadequately treated seizure activity is itself encephalopathogenic, or GCSE may start with only subtle motor manifestations, if the episode of status is the result of some other encephalopathic insult. Patients who develop SE as a consequence of a severe insult to the brain (hypoxia, profound ischemia, severe CNS infection) may present with subtle or electrical GCSE. Privitera and colleagues (123) studied 29 patients with subtle GCSE; only 30% had a witnessed generalized tonic-clonic seizure prior to the onset of coma. Drislane and Schomer (32) identified 48 patients with “generalized electrographic status epilepticus” (ESE), which they considered similar to subtle GCSE; fewer than half of the patients had discrete convulsions preceding EEG identification of ESE. In the case of severe encephalopathy, there may be no motor activity observed. Some investigators have used the term nonconvulsive status epilepticus for this situation (29, 31, 32, 60, 82). However, Treiman suggested that this entity be labeled electrical GCSE (148, 149, 151, 155) or GCSE with electrographic seizures only (153), because such
:
55
a presentation is the end-stage of the spectrum of clinical features that occur in GCSE during its evolution. Furthermore, the term nonconvulsive SE is used for SE with associated nonconvulsive seizures, such as complex partial SE and absence SE, in which the clinical presentation is of an epileptic twilight state and not the profound coma of endstage GCSE (31, 61, 62, 77). Thus, there is danger of combining very different types of SE if patients with subtle GCSE are included. The term myoclonic SE has also been applied to some instances of subtle GCSE, which also creates the problem of combining dissimilar entities: (1) SE that is a complication of generalized myoclonic epilepsy (where consciousness is generally preserved) and (2) encephalopathy with epileptic myoclonus (where the patient is in profound coma). Therefore, Treiman (148) argued that the term myoclonic SE should be reserved for SE in myoclonic epilepsy. Not all patients with SE as a complication of an encephalopathic insult have epileptic myoclonus, but some do, and they probably have a different prognosis than other patients with subtle GCSE.
Epidemiology GCSE is the most common type of status, and many case series in the past included only GCSE. Two large population-based studies of the epidemiology of SE have been published. DeLorenzo and colleagues (28) attempted to identify all cases of SE in the greater Richmond, Virginia, area. From their data they calculated an annual incidence of SE of 41 per 100,000 population, with about 70% presenting with GCSE. Richmond has a large African-American population. The Richmond population is 43% white and 57% nonwhite. Among white patients with SE, the annual incidence is 20 per 100,000. This incidence is similar to the 18.3 per 100,000 found in the mostly (96%) white Rochester, Minnesota, population (54), in good agreement with Shorvon’s (137) estimate of 18–28 per 100,000 population annual cases of convulsive status in the United States and United Kingdom, and slightly higher than the 15 per 100,000 population reported for the canton of Geneva in Switzerland (61). The incidence of SE in developing countries is likely to be much higher, but population-based data are not yet available (44, 57). Overall, the available data suggest there are between 60,000 and 150,000 cases of SE in the United States each year and perhaps as many as 3.5 million cases worldwide, most of which are cases of GCSE. In children, more than 90% of status is GCSE (35, 87).
Etiology There are many causes of SE, and most series have not differentiated among different types of status, although GCSE accounts for the large majority. Hauser (51) suggested that
56
:
about one-third of cases are the first presentation of newonset epilepsy, one-third occur in patients with established epilepsy or febrile convulsions, and one-third occur as the result of acute insult to the brain. The cause of status as an initial presentation of new-onset epilepsy is age dependent and is similar to the cause of new-onset epilepsy that does not present as SE. In most series, head trauma, tumor, cerebrovascular insults, and CNS infection account for the bulk of the cases. Medication change or antiepileptic drug (AED) noncompliance is a common cause of SE in patients with established epilepsy. In children, chronic epilepsy, febrile seizures, CNS infection, and metabolic disease are the most common causes of GCSE (78); recurrent episodes occur most often in neurologically abnormal children (130). The causes of overt and subtle presentations of GCSE differ. Table 6.1 presents the etiology of overt and subtle GCSE in patients who participated in the Veterans Affairs cooperative comparative treatment study (159). There was a much higher incidence of anoxic encephalopathy and other life-threatening disorders in the group of patients with subtle GCSE, laboratory abnormalities were more common in this group (162), and most of the patients were seen in the intensive care units of participating hospitals.
Pathophysiology SE occurs when there is a failure of the mechanisms that terminate a single seizure and normally produce a refractory period before another seizure can occur. This may occur as the result of excessive excitation, impaired neuronal inhibition, or a combination of both factors. A number of mechanisms may be responsible for termination of seizures, including activation of Na+-K+ adenosine triphosphatase (42, 52, 80), acidification of the extracellular environment that stabilizes neuronal membranes (19), blockade of Nmethyl--aspartate channels by Mg2+, and activation of K+ conductances and thus repolarization of neurons (6, 141). Endogenous opioids may also contribute to seizure termination and to the postictal refractory period (123). A role for neuropeptide Y has also been proposed (2, 71, 119, 139). Failure of these seizure-stopping mechanisms, or the occurrence of a strong excitatory stimulus, may result in repeated or prolonged seizures. Coulter and DeLorenzo (26) reported that SE is difficult to produce in vitro in normal extracellular medium, and thus suggested that seizure-terminating mechanisms must be quite robust. They found it necessary to include reciprocally connected entorhinal cortex in their hippocampal slice preparation, thus closing the normal excitatory limbic loop. This allowed generation of epileptic discharges of long duration, which progress through a sequence of morphologic changes (120) remarkably similar to the sequence described by Treiman et al. (161) in GCSE in humans.
T 6.1 Characteristics of overt and subtle generalized convulsive status epilepticus (GCSE) Parameter Evaluated Number of patients Age (yr), mean ± SD Veterans (%) Male (%) Not pretreated acutely (%) Previous history of acute seizures (%) Previous history of epilepsy (%) Previous history of status epilepticus (%) Median duration of status prior to enrollment (hr) Etiologic factors present*: Remote neurologic (%) Acute neurologic (%) Life-threatening medical condition (%) Cardiopulmonary arrest (%) Therapeutic or recreational drug toxicity (%) Alcohol withdrawal (%)
Overt GCSE
Subtle GCSE
384 58.6 ± 15.6 70.1 82.3 51.3 54.2 42.4 12.8 2.8
134 62.0 ± 15.1 80.6 85.1 51.5 25.4 12.7 4.5 5.8
69.5 27.3 32.0 6.3 6.3 6.5
34.3 37.3 56.7 38.1 5.2 0.7
* Some patients had more than one etiologic factor present. Table from Treiman et al. (165).
Clearly, some alteration of neuronal function, either acute or chronic, must be necessary to allow failure of seizureterminating mechanisms. Dube et al. (33) observed that prolonged hyperthermia-induced convulsions in rat pups markedly lowered the threshold for status induction in adults by low-dose kainic acid in vivo or by Schaeffer collateral stimulation in hippocampal-entorhinal cortex slices. A variety of acute neurologic insults either lower seizure threshold or result in excessive excitation or inhibitory failure. Penicillin (presumably the result of GABA antagonism via an allosteric modulation of the GABA receptor) has been reported to cause GCSE experimentally (97, 113) and clinically (68, 86). The neurotoxin domoic acid, a structural analogue of glutamate and kainite, caused GCSE when contaminated mussels were ingested accidently (33, 112). A number of organophosphorus cholinesterase inhibitor nerve agents produce SE in experimental animals by inhibiting acetylcholine esterase and thus allowing excessive synaptic concentrations of the excitatory neurotransmitter, acetylcholine (129). Atropine and other anticholinergic compounds block development of organophosphorus compound–induced seizures but are far less effective once SE has developed (89, 90, 129). Once status does occur, regardless of the precipitating cause, several mechanisms may contribute to continuing seizure activity, including alterations in calcium- and calmodulin-dependent kinase II activity (72), increases in substance P (83), and impairment of GABA-mediated inhibition (63, 64, 67). An experimental study suggests that such a loss
of inhibition may be due to altered GABAA receptor function. Kapur and Macdonald (68) found a marked reduction in whole-cell GABA receptor currents in hippocampal dentate granule cells isolated acutely from rats undergoing lithium/pilocarpine-induced SE compared with cells from naive controls. GABA receptor currents from SE rats were less sensitive to diazepam and zinc, but retained their sensitivity to GABA and pentobarbital. These investigators concluded that prolonged seizure activity in this model rapidly alters the functional properties of hippocampal dentate granule cell GABA receptors. They proposed structural rearrangement in the subunit composition of the GABAA receptor as one possible mechanism for such an alteration. Brooks-Kayal et al. (14) provided support for this hypothesis. Single-cell messenger RNA amplification was used to show selective changes in dentate granule cell GABAA receptor subunit composition after experimental SE induction. Walton and Treiman (166) reported that the NMDA receptor channel blocker, dizoclipine, reversed seizure-induced refractoriness to benzodiazepines in prolonged experimental SE. These studies of attenuation of GABA-mediated inhibition during SE help explain the observation that the order of drug administration may influence its efficacy in experimental SE (167). Phenytoin followed 10 minutes later by diazepam is more effective in controlling seizure activity in the cobalt-homocysteine model of secondarily generalized convulsive SE in the rat than identical doses of diazepam followed 10 minutes later by phenytoin. It may be that phenytoin sufficiently reduces excitation that there is recovery of
:
57
GABAA receptor sensitivity to diazepam and thus reestablishment of the capacity for GABA-mediated inhibition. Previous studies have shown that NMDA receptors become activated during hippocampal stimulation (8) and that NMDA antagonists block the deterioration of GABA-mediated inhibition (65). Furthermore, NMDA receptor antagonists abolish the maintenance phase of self-sustaining SE in the perforant path stimulation model (90), and a role for NMDA receptors in the late stages of cholinesterase inhibitor-induced SE has been proposed (89, 128).
Clinical features Treiman (147) characterized GCSE as paroxymal or continuous tonic and/or clonic convulsive motor activity that may be symmetric or asymmetric, overt or subtle, and is associated with marked impairment of consciousness and with bilateral (although frequently asymmetric) ictal discharges on the EEG. This broad description of GCSE emphasizes its dynamic character. Over the last 15 years it has been recognized that not only is there a progression from overt to increasingly subtle motor activity (48, 148, 153), but there is also a predictable progression of EEG changes (161), refractoriness to treatment (157, 160), degree of histologic damage (40), and physiologic changes (38, 93, 134, 164) if GCSE is allowed to continue untreated or inadequately treated. Overt GCSE is characterized by recurrent primarily or secondarily generalized tonic-clonic convulsions, each of which evolves in the same manner as a single generalized tonic-clonic seizure. Each discrete convulsion begins with tonic stiffening, either focal or generalized, which is then replaced by clonic jerking, which increases in amplitude and decreases in frequency until abrupt cessation of the clonic jerks. The average duration of the tonic and clonic phases initially is about 90 seconds but tends to shorten as GCSE progresses (124). Roger et al. (124) reported a frequency of four to five convulsions per hour, but 20 or more attacks per hour were frequently described in the era before effective drug therapy became available (17, 22–24) and may be seen even today (131). Postictal coma is gradually replaced by increasing consciousness, but if another convulsion occurs before complete recovery to full alertness and normal mental function, the patient is considered to be in GCSE. If overt GCSE continues without complete suppression of ictal discharges on the EEG, the ongoing seizure activity is itself encephalopathogenic, and there is a gradual evolution of behavioral manifestations to more subtle motor convulsions and eventually complete cessation of all visible seizure activity (48). However, the rapidity of the change from overt to subtle motor activity is highly variable and appears to be largely determined by the precipitating cause of GCSE.
58
:
Evolution from overt to subtle motor manifestations of GCSE has not been reported in primarily generalized tonicclonic SE, but Roger et al. (124) described attenuation of initial generalized tonic-clonic activity to tonic activity only. Just as there is a progression from overt to subtle convulsive activity, there also is a progression of predictable changes in the ictal discharges on the EEG if GCSE is allowed to progress without effective treatment (161) (Figures 6.1 to 6.5). Initially, discrete electrographic seizures—identical in morphology to individual generalized convulsions like those recorded on epilepsy monitoring units—are recorded during generalized convulsions. However, as GCSE progresses and motor activity becomes increasingly attenuated, the discrete seizures begin to merge to produce waxing and waning of amplitude, frequency, and distribution of the ictal discharges. This transitional period is followed by a prolonged period of continuous ictal activity, with little variation in the morphology of the EEG rhythms. Eventually another transitional pattern occurs, as continuous ictal discharges are punctuated by low-voltage, relatively flat periods. These flat periods become longer as ictal discharges shorten, until finally periodic epileptiform discharges (PEDs) on a low-voltage background are seen. This sequence of progressive EEG changes was initially postulated after review of 109 EEGs recorded during GCSE, 60 of which exhibited one or more ictal patterns in the sequence just described (161), and has been confirmed by the observation of the same sequence in at least eight different models of experimental SE in the rat (48, 70, 73, 85, 96, 161). Just as there is considerable variation in the rate of evolution from overt to subtle convulsive activity in GCSE, there is also considerable variation in the rate of progression through these EEG patterns in both humans and rats, most likely determined by the etiology of GCSE or the experimental technique used to induce SE in the experimental models. Progression through at least part of the sequence has also been reported in complex partial SE (105). However, Nei et al. (103) reported they were unable to detect a predictable sequence of EEG changes in their restrospective review of 36 SE ictal records, but only 23 of their 50 cases of SE were classified as convulsive, and their recordings may not have been long enough to detect sequential changes. Not all patients with subtle GCSE or late EEG patterns start out with discrete electrographic seizures on their EEG. Just as the initial clinical expression of GCSE may be subtle or even without any motor activity, if the precipitating encephalopathic insult is sufficiently severe, the initial EEG pattern may be one of continuous ictal discharges with or without flat periods or PEDs. There has been considerable controversy over the ictal nature of PEDs, with some investigators (43, 138, 142, 169) viewing PEDs as an injury pattern that reflects cerebral
F 6.1 Discrete generalized tonic-clonic seizures with interictal slowing, recorded prior to treatment in a 39-year-old man. The example shows the end of the clonic phase of the seizure and
the appearance of postictal slowing. (Reprinted with permission from Treiman et al. [161].)
F 6.2 Merging of discrete seizures, recorded prior to treatment in a 64-year-old man. Ictal discharges are continuous, but with waxing and waning of frequency and amplitude. An increase
in frequency and amplitude can be seen beginning on the right side of the recording. (Reprinted with permission from Treiman et al. [161].)
F 6.3 Continuous ictal discharges recorded prior to treatment in a 68-year-old man. Examples were recorded 16 minutes apart. Continuous ictal activity persisted for 101 minutes, stopping
only after phenytoin infusion was completed and 4 minutes after the end of lorazepam infusion. (Reprinted with permission from Treiman et al. [161].)
F 6.4 Continuous ictal discharges with flat periods recorded prior to treatment in a 68-year-old man. The seizure focus is clearly in the left hemisphere, but the spread of ictal activity to the right
hemisphere can be seen as well. (Reprinted with permission from Treiman et al. [161].)
60
:
F 6.5 Periodic epileptiform discharges on a flat background recorded prior to treatment in a 64-year-old man. (Reprinted with permission from Treiman et al. [161].)
dysfunction rather than ongoing seizure activity. Others have suggested that PEDs are a fragment of GCSE (20) and common in end-stage GCSE (136). Treiman (148, 150, 152, 154) has argued that to exclude PEDs from the other ictal sequences observed in experimental models of SE, where the entire EEG sequence can be observed without administering antiepileptic drugs, is arbitrary, especially because there is a gradual evolution from the continuous ictal discharge pattern to PEDs. Furthermore, Handforth and colleagues, using 2-deoxyglucose studies in experimental SE in the rat (49) and positron emission tomography studies in a human patient (48), observed hypermetabolism in specific areas of the brain when PEDs were observed on the EEG. Finally, although PEDs are seen in the late, treatmentresistant stages of GCSE, anticonvulsants abolish PEDs in at least some cases. Response to treatment is influenced by a number of factors. Treiman and colleagues demonstrated that the later the EEG stage, the more resistant to treatment the episode of SE will be in both human GCSE (157) and experimental SE in the rat (165). The longer the duration of GCSE (160) and the more subtle the motor manifestations (159), the more difficult GCSE is to stop and the more likely neuronal damage will occur (40, 101). A number of physiologic changes occur during inadequately treated clinical (164) and untreated experimental (91, 134) GCSE, and progress during prolonged SE (15, 16,
91, 164). The initial event is a massive release of catecholamines into the circulation (7, 45, 51, 133), which results in increased systemic, pulmonary, and left atrial pressure, heart rate, and plasma glucose concentration (7, 9–11, 21, 45, 54, 57, 74–76, 93, 94, 98, 115–117, 137, 168), and the potential for cardiac arrhythmias (18, 79, 93, 94, 126, 168). Respiratory function is frequently impaired early in SE (5, 69, 111), and pulmonary edema is common in experimental SE (69, 135) and may occur in human GCSE (108). Acidosis, due to a combination of respiratory failure and systemic lactate release, has been observed frequently in clinical GCSE (1, 13, 171, 174) and also in experimental SE (9, 10, 34, 37, 54, 57, 58, 93, 168). Hyperpyrexia has been known since the nineteenth century to occur during early SE (12, 22–24) and is the most important physiologic cause of poor outcome following an episode of SE (1). SE-induced cerebellar damage has been reported following sustained hyperpyrexia in baboons (92, 95) and in human GCSE (134). When the white blood cell (WBC) count is also elevated during an episode of GCSE in which hyperpyrexia is seen, an infectious etiology may be assumed by the clinician. However, peripheral WBC counts are frequently elevated during GCSE (1), and a low-grade pleocytosis in the cerebral spinal fluid (CSF) may also occur. Barry and Hauser (3) found, however, that the CSF WBC count was never above 30/mm3 in the absence of another cause for CSF pleocytosis.
:
61
Diagnosis The diagnosis of GCSE is not difficult when a patient presents with a series of primarily or secondarily generalized convulsions and remains comatose between the seizures. Typically, there is some degree of recovery between seizures, perhaps even to the point of capacity for verbal communication. However, unless there is complete recovery before the next seizure, with no clinical, EEG, or laboratory evidence of residual effects of the preceding seizure, the patient meets the definition of GCSE and should be treated accordingly. EEG monitoring during GCSE is extremely useful but is not essential if the effect of treatment and the patient’s progress can be ascertained by clinical observation. Clearly, if there is progressive recovery of consciousness toward return to a normal mental state following treatment of GCSE, it is not necessary to verify success by EEG recording. However, if there is no recovery and the patient remains in a coma, verification of cessation of all epileptiform discharges on the EEG is essential, because continuing electrical seizure activity may cause profound neuronal damage, even in the absence of any motor convulsions. In addition to the five ictal EEG patterns described earlier, other ictal discharges may include paroxysmal or continuous slow waves, spike-wave discharges, and certain burst-suppression patterns (150). Once the episode of GCSE is stopped, a search for the underlying etiology must be undertaken and, if different, the precipitating cause of the episode must be sought. This evaluation should include a careful review of the patient’s medical, neurologic, and medication history, a search for systemic illness by blood cell count and serum chemistry determinations, cerebral imaging studies, and a consideration of the possibility of CNS infection, with a lumbar puncture to obtain CSF for analysis if indicated. Although relatively uncommon except in epilepsy centers, the possibility of pseudo-GCSE must be entertained under some circumstances. Clues that should alert the clinician to the possibility of pseudostatus include variability of clinical appearance from seizure to seizure, the inability to sustain continuous motor activity without brief pauses, the appearance of alpha activity on the EEG during such pauses when the record is not obscured by muscle artifact, retained pupillary response, eye closure during convulsive activity, and resistance to eye opening. Pseudo-GCSE has been discussed by a number of investigators (4, 46, 55, 102, 109, 110, 121, 122, 132, 144, 169, 172).
Pathology and mortality Animal data make it abundantly clear that GCSE, if sufficiently prolonged, may cause neuronal damage and even
62
:
death. Although systemic complications such as hypoxia, hypoglycemia, lactic acidosis, and especially hyperpyrexia may exacerbate neuronal damage caused by sustained seizure activity (9, 95, 134, 137), observation of neuronal damage in normoglycemic, well-ventilated animals supports the concept that electrical seizure activity itself contributes substantially to SE-induced neuronal damage (58, 81, 100, 106, 145). SE-induced neuronal damage has been demonstrated in a number of animal models (36, 41, 56, 107, 127, 140). Continuous seizure activity for as little as 20 minutes has been associated with detectable hippocampal neuronal loss in pilocarpine-induced experimental SE (40). The pathologic consequences of GCSE are more difficult to ascertain in human subjects, because pathologic changes associated with the cause of SE and those that are the consequence of SE cannot easily be differentiated. However, neuronal damage in neocortex, hippocampus, thalamus, and cerebellum has been reported in children and adults dying shortly after an episode of GCSE (25, 39, 104, 114, 125). DeGiorgio and colleagues (27), in a case-matched control study of neuronal loss after GCSE in five hippocampal regions, found the greatest loss in SE cases and less cell loss in case-matched controls, compared with age-matched controls without CNS insult, thus suggesting a direct role of GCSE in neuronal cell loss in humans. Progressive hippocampal sclerosis and atrophy (103, 143, 170) and other focal lesions (men, morimoto, Nixon) have also been demonstrated by magnetic resonance imaging following GCSE. Mortality rates of 5%–50% following GCSE have been reported since the introduction of bromides (50, 156), although most deaths do not occur during the episode of GCSE and have been attributed to the underlying cause of the status episode. Mortality rates in three large SE series have been reported. Towne et al. (151) studied the Richmond database. They reported a 20.7% mortality within 30 days of an episode of “generalized SE,” in which they included primarily and secondarily generalized tonic-clonic, absence, and myoclonic seizures. Most were cases of GCSE. Duration longer than 1 hour and age older than 60 both predicted a substantially higher 30-day mortality. Logroscino et al. (86) found a 17.9% 30-day mortality after the first episode of SE in 84 patients in the Rochester series with primarily or secondarily generalized SE. The 30-day mortality in 19 patients with myoclonic SE, which they considered equivalent to subtle GCSE, was 68%. Treiman et al. (159), in the VA treatment study of GCSE, reported a 30-day mortality of 27.0% in patients with overt GCSE and 64.7% in patients with the subtle form. Thirty-day mortality was substantially higher in patients older than 65 in both overt and subtle groups (158). Mean ages in the two groups in the VA study were 58.6 years and 62.0 years, respectively (159). A recent
population-based study in Bologna, Italy (170), reported a similarly high mortality of 39% (33% if postanoxic cases are excluded).
Summary GCSE was first described in a Babylonian medical text more than 2,500 years ago, but it received little attention until the nineteenth century. GCSE is the most common type of SE, accounting for at least 70% of all SE cases and more than 90% of cases in children. It is now recognized to be a dynamic entity, with progression from overt to subtle clinical presentations and through a predictable sequence of EEG changes if untreated or inadequately treated. The longer the duration the more difficult it is to stop and the more neuronal damage is done. Most GCSE occurs in the very young and very old. There are at least 40,000 and perhaps more than 100,000 cases of GCSE in the United States each year, and at least 3 million cases annually worldwide. Head trauma, brain tumor, cerebral infarction, CNS infection, hypoxia, and preexisting epilepsy are the most common causes of GCSE in adults; in children, chronic epilepsy, febrile seizures, CNS infection, and metabolic disease are the most common causes. With the advent of effective drugs for the management of GCSE, death directly caused by GCSE is rare, but 30-day mortality, which largely reflects the underlying cause of the episode of GCSE, is high, especially in cases of subtle GCSE. The diagnosis is made by clinical observation of repeated convulsions without full recovery between the seizures, or by observation of ictal discharges on the EEG when the clinical manifestations are subtle. EEG monitoring is essential to verify successful treatment if this cannot be ascertained on clinical grounds. Mechanisms underlying the progression of GCSE and SE-induced neuronal damage are beginning to be elucidated, but much work remains to be done to achieve sufficient understanding to develop consistently effective treatment. REFERENCES 1. Aminoff, M. J., and R. P. Simon. Status epilepticus: Causes, clinical features and consequences in 98 patients. Am. J. Med. 1980;69:657–666. 2. Baraban, S. C., G. Hollopeter, J. C. Erickson, P. A. Schwartzkroin, and R. D. Palmiter. Knock-out mice reveal a critical antiepileptic role for neuropeptide Y. J. Neurosci. 1997;17:8927–8936. 3. Barry, E., and W. A. Hauser. Pleocytosis after status epilepticus. Arch. Neurol. 1994;51:190–193. 4. Bateman, D. E. Pseudostatus epilepticus. Lancet 1989;2: 1278–1279. 5. Bean, J. W., D. Zee, and B. Thom. Pulmonary changes with convulsions induced by drugs and oxygen at high pressure. J. Appl. Physiol. 1966;21:865–872.
6. Bennett, M. R., R. Kerr, and K. Nichol. Adenosine modulation of potassium currents in postganglionic neurones of cultured avian ciliary ganglia. Br. J. Pharmacol. 1991;104: 459–465. 7. Benowitz, N. L., R. P. Simon, and J. R. Copeland. Status epilepticus: Divergence of sympathetic activity and cardiovascular response. Ann. Neurol. 1986;19:197–199. 8. Bertram, E. H., and E. W. Lothman, NMDA receptor antagonists and limbic status epilepticus: A comparison with standard anticonvulsants. Epilepsy Res. 1990;5:177–184. 9. Blennow, G., J. B. Brierley, B. S. Meldrum, and B. K. Siesjö. Epileptic brain damage: The role of systemic factors that modify cerebral energy metabolism. Brain 1978;101:687–700. 10. Blennow, G., J. Folbergrová, B. Nilsson, and B. K. Siesjö. Cerebral metabolic and circulatory changes in the rat during sustained seizures induced by DL-homocysteine. Brain Res. 1979;179:129–146. 11. Blennow, G., J. Folbergrová, B. Nilsson, and B. K. Siesjö. Effects of bicuculline-induced seizures on cerebral metabolism and circulation of rats rendered hypoglycemic by starvation. Ann. Neurol. 1979;5:139–151. 12. Bourneville, D. M. L’état de mal epileptique: Recherches cliniques et therapeutiques sur l’epilepsie et l’hysterie. Compte-rendu des observations recueilles a la Salpêtrière. Paris: Delahaye, 1876. 13. Brivet, F., M. Bernardin, P. Cherin, J. Chalas, P. Galanaud, and J. Dormont. Hyperchloremic acidosis during grand mal seizure lactic acidosis. Intensive Care Med. 1994;20:27–31. 14. Brooks-Kayal, A. R., M. D. Shumate, H. Jin, T. Y. Rikhter, and D. A. Coulter. Selective changes in single cell GABA(A) receptor subunit expression and function in temporal lobe epilepsy. Nat. Med. 1998;4:1166–1172. 15. Brown, J. K., and I. H. M. I. Hussain. Status epilepticus. I. Pathogenesis. Dev. Med. Child Neurol. 1991;33:3–17. 16. Brown, J. K., and I. H. M. I. Hussain. Status epilepticus. II. Treatment. Dev. Med. Child Neurol. 1991;33:97–109. 17. Calmeil, J. De l’épilepsie, étudiée sous le rapport de son siège et de son influence sur la production de l’aliénation mentale. Thesis, University of Paris, 1824. 18. Carnel, S. B., P. L. Schraeder, and C. M. Lathers. Effect of phenobarbital pretreatment on cardiac neural discharge and pentylenetetrazol-induced epileptogenic activity in the cat. Pharmacology 1985;30:225–240. 19. Caspers, H., E. J. Speckmann, and A. Lehmenkuhler. DC potentials of the cerebral cortex: Seizure activity and changes in gas pressures. Rev. Physiol. Biochem. Pharmacol. 1987;106: 127–178. 20. Celesia, G. G., M. M. Grigg, and E. Ross. Generalized status myoclonicus in acute anoxic and toxic-metabolic encephalopathies. Arch. Neurol. 1988;45:781–784. 21. Chapman, A. G., B. S. Meldrum, and B. K. Siesjö. Cerebral metabolic changes during prolonged epileptic seizures in rats. J. Neurochem. 1977;28:1025–1035. 22. Clark, L. P., and T. P. Prout. Status epilepticus: A clinical and pathological study in epilepsy. [Part 1.] Am. J. Insanity 1903; 60:291–306. 23. Clark, L. P., and T. P. Prout. Status epilepticus: A clinical and pathological study in epilepsy. [Part 2.] Am. J. Insanity 1903; 60:645–699. 24. Clark, L. P., and T. P. Prout. Status epilepticus: A clinical and pathological study in epilepsy. [Part 3.] Am. J. Insanity 1904;61:81–108. 25. Corsellis, J. A. N., and C. J. Bruton. Neuropathology of status epilepticus in humans. In A. V. Delgado-Escueta, C. C.
:
63
26.
27.
28.
29.
30.
31. 32.
33.
34.
35. 36.
37.
38. 39. 40.
41.
42.
43. 44.
45.
64
Wasterlain, D. M. Treiman, and R. J. Porter, eds. Status Epilepticus: Mechanisms of Brain Damage and Treatment. Adv. Neurol. 1983;34:129–139. Coulter, D. A., and R. J. DeLorenzo. Basic mechanisms of status epilepticus. In A. V. Delgado-Escueta, W. A. Wilson, R. W. Olsen, and R. J. Porter, eds. Jasper’s Basic Mechanisms of the Epilepsies. Adv. Neurol. 1999;79:725–733. DeGiorgio, C. M., U. Tomiyasu, P. S. Gott, and D. M. Treiman. Hippocampal pyramidal cell loss in human status epilepticus. Epilepsia 1992;33:23–27. DeLorenzo, R. J., W. A. Hauser, A. R. Towne, et al. A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology 1996;46: 1029–1035. DeLorenzo, R. J., E. J. Waterhouse, A. R. Towne, et al. Persistent nonconvulsive status epilepticus after the control of convulsive status epilepticus. Epilepsia 1998;39:833–840. Drislane, F. W. Evidence against permanent neurologic damage from nonconvulsive status epilepticus. J. Clin. Neurophysiol. 1999;16:323–331. Drislane, F. W. Nonconvulsive status epilepticus in patients with cancer. Clin. Neurol. Neurosurg. 1994;96:314–318. Drislane, F. W., and D. L. Schomer. Clinical implications of generalized electrographic status epilepticus. Epilepsy Res. 1994;19:111–121. Dube, C., K. Chen, M. Eghbal-Ahmadi, K. Brunson, I. Soltesz, and T. Z. Baram. Prolonged febrile seizures in the immature rat model enhance hippocampal excitability long term. Ann. Neurol. 2000;47:336–344. Duffy, T. E., D. C. Howse, and F. Plum. Cerebral energy metabolism during experimental status epilepticus. J. Neurochem. 1975;24:925–934. Dunn, D. W. Status epilepticus in children: Etiology, clinical features, and outcome. J. Child Neurol. 1988;3:167–173. Evans, M., T. Griffiths, and B. Meldrum. Early changes in the rat hippocampus following seizures induced by bicuculline or -allylglycine: A light and electron microscope study. Neuropathol. Appl. Neurobiol. 1983;9:39–52. Folbergrová, J., M. Ingvar, and B. K. Siesjö. Metabolic changes in cerebral cortex, hippocampus, and cerebellum during sustained bicuculline-induced seizures. J. Neurochem. 1981;37:1228–1238. Fountain, N. B., and E. W. Lothman. Pathophysiology of status epilepticus. J. Clin. Neurophysiol. 1995;12:326–342. Fowler, M. Brain damage after febrile convulsions. Arch. Dis. Child 1957;32:67–76. Fujikawa, D. G. The temporal evolution of neuronal damage from pilocarpine-induced status epilepticus. Brain Res. 1996; 725:11–22. Fujikawa, D. G., S. S. Shinmei, and B. Y. Cai. Lithiumpilocarpine-induced status epilepticus produces necrotic neurons with internucleosomal DNA fragmentation in adult rats. Eur. J. Neurosci. 1999;11:1605–1614. Fukuda, A., and D. A. Prince. Excessive intracellular Ca2+ inhibits glutamate-induced Na(+)-K+ pump activation in rat hippocampal neurons. J. Neurophysiol. 1992;68:28–35. Gaches, J. Activites periodiques en EEG. Rev. Electroencephalogr. Neurophysiol. Clin. 1971;1:9–33. Garzon, E., R. M. Fernandes, and A. C. Sakamoto. Analysis of clinical characteristics and risk factors for mortality in human status epilepticus. Seizure 2003;12(6):337–345. Gastaut, H., J. Roger, and H. Lob, eds. Les états de mal épileptiques. Paris: Masson, 1967.
:
46. Gravenstein, J. S., A. H. Anton, S. M. Wiener, and A. G. Tetlow. Catecholamine and cardiovascular response to electroconvulsive therapy in man. Br. J. Anaesth. 1965;37:833–839. 47. Gunatilake, S. B., H. J. De Silva, and G. Ranasinghe. Twentyseven venous cutdowns to treat pseudostatus epilepticus. Seizure 1997;6:71–72. 48. Handforth, A., J. T. Cheng, M. A. Mandelkern, and D. M. Treiman. Markedly increased mesiotemporal lobe metabolism in a case with PLEDs: Further evidence that PLEDs are a manifestation of partial status epilepticus. Epilepsia 1994; 35:876–881. 49. Handforth, A., and D. M. Treiman. Functional mapping of the late stages of status epilepticus in the lithium-pilocarpine model in rat: A 14C-2-deoxyglucose study. Neuroscience 1995;64:1075–1089. 50. Handforth, A., and D. M. Treiman. A new, nonpharmacologic model of convulsive status epilepticus induced by electrical stimulation: Behavioral/electroencephalographic observations and response to phenytoin and phenobarbital. Epilepsy Res. 1994;19:15–25. 51. Hauser, W. A. Status epilepticus: Epidemiologic considerations. Neurology 1990;40(Suppl. 2):9–13. 52. Havens, L. L., M. S. Zileli, A. DiMascio, L. Boling, and A. Goldfien. Changes in catecholamine response to successive electric convulsive treatments. J. Ment. Sci. 1959;105:821–829. 53. Heinemann, U., and H. D. Lux. Undershoots following stimulus-induced rises of extracellular potassium concentration in cerebral cortex of cat. Brain Res. 1975;93:63–76. 54. Hesdorffer, D. C., G. Logroscino, G. Cascino, J. F. Annegers, and W. A. Hauser. Incidence of status epilepticus in Rochester, Minnesota, 1965–1984. Neurology 1998;50: 735–741. 55. Horton, R. W., B. S. Meldrum, T. A. Pedley, and J. R. McWilliam. Regional cerebral blood flow in the rat during prolonged seizure activity. Brain Res. 1980;192:399–412. 56. Howell, S. J., L. Owen, and D. W. Chadwick. Pseudostatus epilepticus. Q. J. Med. 1989;71:507–519. 57. Hui, A. C., G. M. Joynt, H. Li, and K. S. Wong. Status epilepticus in Hong Kong Chinese: Aetiology, outcome and predictors of death and morbidity. Seizure 2003;12(7):478– 482. 58. Ingvar, M., P. F. Morgan, and R. N. Auer. The nature and timing of excitotoxic neuronal necrosis in the cerebral cortex, hippocampus and thalamus due to flurothyl-induced status epilepticus. Acta Neuropathol. 1988;75:362–369. 59. Ingvar, M., and B. K. Siesjö. Local blood flow and glucose consumption in the rat brain during sustained bicuculline induced seizures. Acta Neurol. Scand. 1983;69:129–144. 60. Ingvar, M., B. Söderfeldt, J. Folbergrová, H. Kalima, Y. Olsson, and B. K. Siesjö. Metabolic, circulatory, and structural alterations in the rat brain induced by sustained pentylenetetrazole seizures. Epilepsia 1984;25:191–204. 61. Jallon, P., A. Coeytaux, B. Galobardes, and A. Morabia. Incidence and case-fatality rate of status epilepticus in the Canton of Geneva. Lancet 1999;353:1496. 62. Jordan, K. G. Nonconvulsive status epilepticus in acute brain injury. J. Clin. Neurophysiol. 1999;16:332–340. 63. Kaplan, P. W. Assessing the outcomes in patients with nonconvulsive status epilepticus: Nonconvulsive status epilepticus is underdiagnosed, potentially overtreated, and confounded by comorbidity. J. Clin. Neurophysiol. 1999;16:341–352. 64. Kaplan, P. W. Nonconvulsive status epilepticus in the emergency room. Epilepsia 1996;37:643–650.
65. Kapur, J., and D. A. Coulter. Experimental status epilepticus alters gamma-aminobutyric acid type A receptor function in CA1 pyramidal neurons. Ann. Neurol. 1995;38:893–900. 66. Kapur, J., and E. W. Lothman. Loss of inhibition precedes delayed spontaneous seizures in the hippocampus after tetanic electrical stimulation. J. Neurophysiol. 1989;61:427– 434. 67. Kapur, J., and E. W. Lothman. NMDA receptor activation mediates the loss of GABAergic inhibition induced by recurrent seizures. Epilepsy Res. 1990;5:103–111. 68. Kapur, J., and R. L. Macdonald. Rapid seizure-induced reduction of benzodiazepine and Zn2+ sensitivity of hippocampal dentate granule cell GABAA receptors. J. Neurosci. 1997;17:7532–7540. 69. Kapur, J., J. L. Stringer, and E. W. Lothman. Evidence that repetitive seizures in the hippocampus cause a lasting reduction of GABAergic inhibition. J. Neurophysiol. 1989; 61:417–426. 70. Kaufman, D. M., M. H. Miller, and N. H. Steigbigel. Subdural empyema: Analysis of 17 recent cases and review of the literature. Medicine (Baltimore) 1975;54:485–498. 71. Kiessling, M., K. A. Hossman, and P. Kleihues. Pulmonary edema during bicuculline-induced seizures in rats. Exp. Neurol. 1981;74:430–438. 72. Kim, J.-M., N. Y. Walton, and D. M. Treiman. EEG patterns of high-dose pilocarpine-induced status epilepticus in rats. Epilepsia 1997;38(Suppl. 8):225–226. 73. Klapstein, G. J., and W. F. Colmers. Neuropeptide Y suppresses epileptiform activity in rat hippocampus in vitro. J. Neurophysiol. 1997;78:1651–1661. 74. Kochan, L. D., S. B. Churn, O. Omojokun, A. Rice, and R. J. DeLorenzo. Status epilepticus results in an N-methyl-aspartate receptor-dependent inhibition of Ca2+/calmodulindependent kinase II activity in the rat. Neuroscience 2000; 95:735–743. 75. Koplovitz, I., and J. P. Skvorak. Electrocorticographic changes during generalized convulsive status epilepticus in soman intoxicated rats. Epilepsy Res. 1998;30:159–164. 76. Kreisman, N. R., J. C. LaManna, M. Rosenthal, and T. J. Sick. Oxidative metabolic responses with recurrent seizures in rat cerebral cortex: Role of systemic factors. Brain Res. 1981;218:175–188. 77. Kreisman, N. R., J. C. Magee, and B. L. Brizzee. Relative hypoperfusion in rat cerebral cortex during recurrent seizures. J. Cereb. Blood Flow Metab. 1991;11:77–87. 78. Kreisman, N. R., M. Rosenthal, and T. J. Sick. Oxidative metabolic responses during recurrent seizures are independent of convulsant, anesthetic, or species. Neurology 1983;33: 861–867. 79. Krumholz, A. Epidemiology and evidence for morbidity of nonconvulsive status epilepticus. J. Clin. Neurophysiol. 1999;16: 314–322. 80. Lacroix, J., C. Deal, M. Gauthier, E. Rousseau, and C. A. Farrell. Admissions to a pediatric intensive care unit for status epilepticus: A 10-year experience. Crit. Care Med. 1994;22: 827–832. 81. Lathers, C. M., and P. L. Schraeder. Autonomic dysfunction in epilepsy: Characterization of autonomic cardiac neural discharges associated with pentylenetetrazol-induced epileptogenic activity. Epilepsia 1982;23:633–647. 82. Lewis, D. V., and W. H. Schuette. NADH fluorescence, [K+]0 and oxygen consumption in cat cerebral cortex during direct cortical stimulation. Brain Res. 1976;110:523–535.
83. Lindvall, O., M. Ingvar, and F. H. Gage. Short term status epilepticus in rats causes specific behavioral impairments related to substantia nigra necrosis. Exp. Brain Res. 1986;64: 143–148. 84. Litt, B., R. J. Wityk, S. H. Hertz, et al. Nonconvulsive status epilepticus in the critically ill elderly. Epilepsia 1998;39:1194– 1202. 85. Liu, H., A. M. Mazarati, H. Katsumori, R. Sankar, and C. G. Wasterlain. Substance P is expressed in hippocampal principal neurons during status epilepticus and plays a critical role in the maintenance of status epilepticus. Proc. Natl. Acad. Sci. U. S. A. 1999;96:5286–5291. 86. Logroscino, G., D. C. Hesdorffer, G. Cascino, J. F. Annegers, and W. A. Hauser. Short-term mortality after a first episode of status epilepticus. Epilepsia 1997;38:1344–1349. 87. Lothman, E. W., E. H. Bertram, J. W. Bekenstein, and J. B. Perlin. Self-sustaining limbic status epilepticus induced by “continuous” hippocampal stimulation: Electrographic and behavioral characteristics. Epilepsy Res. 1989;3:107–119. 88. Malone, A. J., Jr., S. Field, J. Rosman, and W. P. Shemerdiak. Neurotoxic reaction to oxacillin. N. Engl. J. Med. 1977;296: 453. 89. Maytal, J., S. Shinnar, S. L. Moshe, and L. A. Alvarez. Low morbidity and mortality of status epilepticus in children. Pediatrics 1989;83:323–331. 90. Mazarati, A. M., and C. G. Wasterlain. N-methyl--aspartate receptor antagonists abolish the maintenance phase of selfsustaining status epilepticus in rat. Neurosci. Lett. 1999;265: 187–190. 91. McDonough, J. H., Jr., and T. M. Shih. Neuropharmacological mechanisms of nerve agent-induced seizure and neuropathology. Neurosci. Biobehav. Rev. 1997;21:559–579. 92. McDonough, J. H., Jr., L. D. Zoeffel, J. McMonagle, T. L. Copeland, C. D. Smith, and T. M. Shih. Anticonvulsant treatment of nerve agent seizures: Anticholinergics versus diazepam in soman-intoxicated guinea pigs. Epilepsy Res. 2000;38:1–14. 93. Meldrum, B. S. Metabolic factors during prolonged seizures and their relation to nerve cell death. In A. V. DelgadoEscueta, C. G. Wasterlain, D. M. Treiman, and R. J. Porter, eds. Status Epilepticus: Mechanisms of Brain Damage and Treatment. Adv. Neurol. 1983;34:261–275. 94. Meldrum, B. S., and J. B. Brierley. Prolonged epileptic seizures in primates: Ischemic cell change and its relation to ictal physiological events. Arch. Neurol. 1973;28:10–17. 95. Meldrum, B. S., and R. W. Horton. Physiology of status epilepticus in primates. Arch. Neurol. 1973;28:1–9. 96. Men, S., D. H. Lee, J. R. Barron, and D. G. Munoz. Selective neuronal necrosis associated with status epilepticus: MR findings. Am. J. Neuroradiol. 2000;21:1837–1840. 97. Meldrum, B. S., and B. Nilsson. Cerebral blood flow and metabolic rate early and late in prolonged epileptic seizures induced in rats by bicuculline. Brain 1976;99:523–542. 98. Meldrum, B. S., R. A. Vigouroux, and J. B. Brierley. Systemic factors and epileptic brain damage: Prolonged seizures in paralyzed artificially ventilated baboons. Arch. Neurol. 1973; 29:82–87. 99. Mikati, M. A., A. Chronopoulos, and G. L. Holmes. Stages of kainic acid (KA)-induced status epilepticus (SE) in the prepubescent brain and response to phenobarbital (Ph). Neurology 1992;42(Suppl. 3):364. 100. Monaco, F., R. Mutani, G. P. Sech, and A. Russo. La distribuzione cerebrale di difenilidantoina nello stato di male
:
65
101.
102.
103.
104.
105.
106.
107.
108.
109. 110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
66
epilettico generalizzato e focale da penicillina nel gatto. Boll. Lega. Ital. Epilessia. 1985;51–52:243–244. Morimoto, T., M. Fukuda, Y. Suzuki, M. Kusu, and K. Kida. Sequential changes of brain CT and MRI after febrile status epilepticus in a 6-year-old girl. Brain Dev. 2002;24:190–193. Naquet, R., B. S. Meldrum, E. Balzano, and J. P. Charrier. Photically-induced epilepsy and glucose metabolism in the adolescent baboon (Papio papio). Brain Res. 1970;18:503–512. Nei, M., J. M. Lee, V. L. Shanker, and M. R. Sperling. The EEG and prognosis in status epilepticus. Epilepsia 1999;40: 157–163. Nevander, G., M. Ingvar, R. Auer, and B. K. Siesjö. Irreversible neuronal damage after short periods of status epilepticus. Acta Physiol. Scand. 1984;120:155–157. Nevander, G., M. Ingvar, R. Auer, and B. K. Siesjö. Status epilepticus in well-oxygenated rats causes neuronal necrosis. Ann. Neurol. 1985;18:281–290. Ney, G. C., C. Zimmerman, and N. Schaul. Psychogenic status epilepticus induced by a provocative technique. Neurology 1996;46:546–547. Nixon, J., D. Bateman, and T. Moss. An MRI and neuropathological study of a case of fatal status epilepticus. Seizure 2001;10(8):588–591. Nohria, V., N. Lee, R. D. Tien, et al. Magnetic resonance imaging evidence of hippocampal sclerosis in progression: A case report. Epilepsia 1994;35:1332–1336. Norman, R. M. The neuropathology of status epilepticus. Med. Sci. Law 1964;4:46–51. Nowack, W. J., and I. A. Shaikh. Progression of electroclinical changes in complex partial status epilepticus: Filling in the blanks. Clin. Electroencephalogr. 1999;30:5–8. O’Connell, B. K., J. Towfighi, W. A. Kofke, and R. A. Hawkins. Neuronal lesions in mercaptopropionic acidinduced status epilepticus. Acta Neuropathol. 1989;77:47–54. Olney, J. W., T. deGubareff, and R. S. Sloviter. “Epileptic” brain damage in rats induced by sustained electrical stimulation of the perforant path. II. Ultrastructural analysis of acute hippocampal pathology. Brain Res. Bull. 1983;10:699–712. Oxbury, J. M., and C. W. M. Whitty. Causes and consequences of status epilepticus in adults: A study of 86 cases. Brain 1971;94:733–744. Pakalnis, A., M. E. Drake, Jr., and B. Phillips. Neuropsychiatric aspects of psychogenic status epilepticus. Neurology 1991;41:1104–1106. Pakalnis, A., J. Paolicchi, and E. Gilles. Psychogenic status epilepticus in children: Psychiatric and other risk factors. Neurology 2000;54:969–970. Paydarfar, D., F. L. Eldridge, S. C. Scott, R. T. Dowell, and P. G. Wagner. Respiratory responses to focal and generalized seizures in cats. Am. J. Physiol. 1991;260:R934–R940. Perl, T. M., L. Bedard, T. Kosatsky, J. C. Hockin, E. C. Todd, and R. S. Remis. An outbreak of toxic encephalopathy caused by eating mussels contaminated with domoic acid. N. Engl. J. Med. 1990;322:1775–1780. Petsche, H., P. Rappelsberger, R. Vollmer, and O. Prohaska. Das Phänomen der Synchronisierung im Penicillinstatus und dessen Veränderung unter Clonazepam. EEG EMG Z. Elektroenzephalogr. Elektromyogr. Verwandte Geb. 1977;8:1–17. Pfleger, L. Beobachtungen über Schrumpfung und Sclerose des Ammonshornes bei Epilepsie. Allg. Z. Psychiatr. 1880; 36:359–365. Pinard, E., A. S. Rigaud, D. Riche, R. Naquet, and J. Seylaz. Continuous determination of the cerebrovascular changes
:
121.
122.
123.
124.
125.
126. 127.
128.
129.
130. 131.
132.
133.
134.
135.
136.
137. 138. 139.
140.
induced by bicuculline and kainic acid in unanaesthetized spontaneously breathing rats. Neuroscience 1987;23:943–952. Pinard, F., E. Tremblay, Y. Ben-Ari, and J. Seylaz. Blood flow compensates oxygen demand in the vulnerable CA3 region of the hippocampus during kainate-induced seizures. Neuroscience 1984;13:1039–1049. Plum, F., J. B. Posner, and B. Troy. Cerebral metabolic and circulatory responses to induced convulsions in animals. Arch. Neurol. 1968;18:1–13. Privitera, M., M. Hoffman, J. L. Moore, and D. Jester. EEG detection of nontonic-clonic status epilepticus in patients with altered consciousness. Epilepsy Res. 1994;18:155–166. Qian, J., W. F. Colmers, and P. Saggau. Inhibition of synaptic transmission by neuropeptide Y in rat hippocampal area CA1: Modulation of presynaptic Ca2+ entry. J. Neurosci. 1997;17:8169–8177. Rafiq, A., Y. F. Zhang, R. J. DeLorenzo, and D. A. Coulter. Long-duration self-sustained epileptiform activity in the hippocampal parahippocampal slice: A model of status epilepticus. J. Neurophysiol. 1995;74:2028–2042. Rechlin, T., T. H. Loew, and P. Joraschky. Pseudoseizure “status.” J. Psychosom. Res. 1997;42:495–498. Reuber, M., S. M. Enright, and P. J. Goulding. Postoperative pseudostatus: Not everything that shakes is epilepsy. Anaesthesia 2000;55:74–78. Rocha, L., J. Engel, Jr., and R. F. Ackermann. Effects of chronic naloxone pretreatment on amygdaloid kindling in rats. Epilepsy Res. 1991;10:103–110. Roger, J., H. Lob, and C. A. Tassinari. Status epilepticus. In P. J. Vinken, and G. W. Bruyn, eds. The Epilepsies. Vol. 15. New York: American Elsevier, 1974:145–188. Scholtz, W. Uber die Entstehung des Hirnbefundes bei der Epilepsie. Z. Gesamte Neurol. Psychiatr. 1933;145:471–515. Schraeder, P. L., and C. M. Lathers. Cardiac neural discharge and epileptogenic activity in the cat as an animal model for unexplained death. Life Sci. 1983;32:1371–1382. Schwob, J. E., T. Fuller, J. L. Price, and J. W. Olney. Widespread patterns of neuronal damage following systemic or intracerebral injections of kainic acid: A histological study. Neuroscience 1980;5:991–1014. Shih, T. M., and J. H. McDonough, Jr. Neurochemical mechanisms in soman-induced seizures. J. Appl. Toxicol. 1997;17: 255–264. Shih, T. M., and J. H. McDonough, Jr. Organophosphorus nerve agents–induced seizures and efficacy of atropine sulfate as anticonvulsant treatment. Pharmacol. Biochem. Behav. 1999;64:147–153. Shinnar, S., J. Maytal, L. Krasnoff, and S. L. Moshe. Recurrent status epilepticus in children. Ann. Neurol. 1992;31: 598–604. Shorvon, S. Status Epilepticus: Its Clinical Features and Treatment in Children and Adults. Cambridge, U.K.: Cambridge University Press, 1994. Shorvon, S. D. Pseudostatus epilepticus. Lancet 1989;2:485. Simon, R. P. Physiologic consequences of status epilepticus. Epilepsia 1985;26(Suppl. 1):S58–S66. Simon, R. P., M. J. Aminoff, and N. Benowitz. Changes in plasma catecholamines after tonic-clonic seizures in man: Possible role in sudden death during seizures. Neurology 1984;34:255–257. Simon, R. P., L. L. Bayne, R. F. Tranbaugh, and F. R. Lewis. Elevated pulmonary lymph flow and protein content during status epilepticus in sheep. J. Appl. Physiol. 1982;52:91–95.
141. Snodgrass, S. M., K. Tsuburaya, and C. Ajmone-Marsan. Clinical significance of periodic lateralized epileptiform discharges: Relationship with status epilepticus. J. Clin. Neurophysiol. 1989;6:159–172. 142. Söderfeldt, B., G. Blennow, H. Kalimo, Y. Olsson, and B. K. Siesjö. Influence of systemic factors on experimental epileptic brain injury: Structural changes accompanying bicuculline-induced seizures in rats following manipulations of tissue oxygenation or alpha-tocopherol levels. Acta Neuropathol. 1983;60:81–91. 143. Spehlmann, R. Special epileptiform patterns. In R. Spehlmann, ed. EEG Primer. Amsterdam: Elsevier, 1981: 309–340. 144. Sperk, G., and H. Herzog. Anticonvulsant action of neuropeptide Y: Neuropeptide Y may act as an endogenous anticonvulsant through Y5 receptors suggesting a new target for antiepileptic drugs. Nat. Med. 1997;3:728–729. 145. Sperk, G., H. Lassmann, H. Baran, S. J. Kish, F. Seitelberger, and O. Hornykiewicz. Kainic acid induced seizures: Neurochemical and histopathological changes. Neuroscience 1983;10: 1301–1315. 146. Spuler, A., and P. Grafe. Adenosine, “pertussis-sensitive” G-proteins, and K+ conductance in central mammalian neurones under energy deprivation. Neurosci. Lett. 1989; 98:280–284. 147. Striano, S., F. A. De Falco, F. Zaccaria, A. Fels, S. Natale, and G. Vacca. Paroxysmal lateralized epileptiform discharges (PLEDs): Clinical-EEG correlations in twenty cases. Acta Neurol. 1986;8:1–12. 148. Tien, R. D., and G. J. Felsberg. The hippocampus in status epilepticus: Demonstration of signal intensity and morphologic changes with sequential fast spin-echo MR imaging. Radiology 1995;194:249–256. 149. Toone, B. K., and J. Roberts. Status epilepticus: An uncommon hysterical conversion syndrome. J. Nerv. Ment. Dis. 1979;167:548–552. 150. Towfighi, J., W. A. Kofke, B. K. O’Connell, C. Housman, and J. M. Graybeal. Substantia nigra lesions in mercaptopropionic acid induced status epilepticus: A light and electron microscopic study. Acta Neuropathol. 1989;77:612– 620. 151. Towne, A. R., J. M. Pellock, D. Ko, and R. J. DeLorenzo. Determinants of mortality in status epilepticus. Epilepsia 1994;35:27–34. 152. Treiman, D. M. Electroclinical features of status epilepticus. J. Clin. Neurophysiol. 1995;12:343–362. 153. Treiman, D. M. Generalized convulsive, nonconvulsive, and focal status epilepticus. In E. Feldman, ed. Current Diagnosis in Neurology. St. Louis: Mosby–Year Book, 1994:11–18. 154. Treiman, D. M. Generalized convulsive status epilepticus. In J. Engel, Jr., and T. A. Pedley, eds. Epilepsy: A Comprehensive Textbook. Philadelphia: Lippincott-Raven, 1997:669–680. 155. Treiman, D. M. Generalized convulsive status epilepticus in the adult. Epilepsia 1993;34(Suppl. 1):S2–S11. 156. Treiman, D. M. Neocortical status epilepticus. In P. D. Williamson, A. M. Siegel, D. W. Roberts, V. M. Thadani, and M. S. Gazzaniga, eds. Neocortical Epilepsies. Adv. Neurol. 2000; 84:243–251. 157. Treiman, D. M. Status epilepticus. In J. Resor and H. Kutt, eds. The Medical Treatment of Epilepsy. New York: Marcel Dekker, 1992:183–193. 158. Treiman, D. M. Status epilepticus. Baillieres Clin. Neurol. 1996; 5:821–839.
159. Treiman, D. M. Treatment of status epilepticus. In J. Engel, Jr., and T. A. Pedley, eds. Epilepsy: A Comprehensive Textbook. Philadelphia: Lippincott-Raven, 1997:1317–1323. 160. Treiman, D. M., C. M. DeGiorgio, S. Salisbury, and C. Wickboldt. Subtle generalized convulsive status epilepticus. Epilepsia 1984;25:653. 161. Treiman, D. M., and A. V. Delgado-Escueta. Status epilepticus. In R. A. Thompson, and J. R. Green, eds. Critical Care of Neurological and Neurosurgical Emergencies. New York: Raven Press, 1980:53–99. 162. Treiman, D. M., P. D. Meyers, and the DVA Status Epilepticus Cooperative Study Group. Utility of the EEG pattern as a predictor of success in the treatment of generalized convulsive status epilepticus. Epilepsia 1991;32(Suppl. 3):93. 163. Treiman, D. M., P. D. Meyers, and N. Y. Walton. Status epilepticus in the elderly: Nosology and therapy. In A. J. Rowan and R. E. Ramsay, eds. Seizures and Epilepsy in the Elderly. Boston: Butterworth-Heinemann, 1997:207–215. 164. Treiman, D. M., P. D. Meyers, N. Y. Walton, and the DVA Status Epilepticus Cooperative Study Group. Duration of generalized convulsive status epilepticus: Relationship to clinical symptomatology and response to treatment. Epilepsia 1992;33(Suppl. 3):66. 165. Treiman, D. M., P. D. Meyers, N. Y. Walton, et al. A comparison of four treatments for generalized convulsive status epilepticus. N. Engl. J. Med. 1998;339:792–798. 166. Treiman, D. M., N. Y. Walton, and C. Kendrick. A progressive sequence of electroencephalographic changes during generalized convulsive status epilepticus. Epilepsy Res. 1990;5: 49–60. 167. Treiman, D. M., N. Y. Walton, P. D. Meyers, and the VA Status Epilepticus Cooperative Study Group. Generalized convulsive status epilepticus: A frequent complication of serious medical illness. Epilepsia 1994;35(Suppl. 8):33. 168. Trousseau, A. Lectures on Clinical Medicine Delivered at the Hotel Dieu, Paris. London: New Sydenham Society, 1868. 169. Tuxhorn, I. E., and H. S. Fischbach. Pseudostatus epilepticus in childhood. Pediatr. Neurol. 2002;27(5):407–409. 170. Vignatelli, L., C. Tonon, R. D’Alessandro, and the Bologna Group for the Study of Status Epilepticus. Incidence and short-term prognosis of status epilepticus in adults in Bologna, Italy. Epilepsia 2003;44(7):964–968. 171. Walton, N. Y. Systemic effects of generalized convulsive status epilepticus. Epilepsia 1993;34(Suppl. 1):S54–S58. 172. Walton, N. Y., and D. M. Treiman. Motor and electroencephalographic response of refractory experimental status epilepticus in rats to treatment with MK-801, diazepam, or MK-801 plus diazepam. Brain Res. 1991;553:97–104. 173. Walton, N. Y., and D. M. Treiman. Rational polytherapy in the treatment of status epilepticus. In I. E. Leppik and R. W. Homan, eds. Rational Polypharmacy. Epilepsy Res. 1996;Suppl. 11:123–139. 174. Walton, N. Y., and D. M. Treiman. Response of status epilepticus induced by lithium and pilocarpine to treatment with diazepam. Exp. Neurol. 1988;101:267–275. 175. Wasterlain, C. G. Mortality and morbidity from serial seizures: An experimental study. Epilepsia 1974;15:155–176. 176. Westmoreland, B. F., D. W. Klass, and F. W. Sharbrough. Chronic periodic lateralized epileptiform discharges. Arch. Neurol. 1986;43:494–496. 177. Wieshmann, U. C., F. G. Woermann, L. Lemieux, et al. Development of hippocampal atrophy: A serial magnetic resonance imaging study in a patient who developed epilepsy
:
67
178.
179. 180.
181.
68
after generalized status epilepticus. Epilepsia 1997;38:1238– 1241. Wijdicks, E. F., and R. D. Hubmayr. Acute acid-base disorders associated with status epilepticus. Mayo Clin. Proc. 1994; 69:1044–1046. Wilner, A. N., and P. R. Bream. Status epilepticus and pseudostatus epilepticus. Seizure 1993;2:257–260. Wilson, J. V. K., and E. H. Reynolds. Translation and analysis of a cuneiform text forming part of a Babylonian treatise on epilepsy. Med. Hist. 1990;34:185–198. Winocour, P. H., A. Waise, G. Young, and K. J. Moriarty. Severe, self-limiting lactic acidosis and rhabdomyolysis accompanying convulsions. Postgrad. Med. J. 1989;65:321– 322.
:
7
Simple and Complex Partial Status Epilepticus
, , S can assume as many forms as there are varieties of epileptic seizures. —Gastaut, 1967
Introduction The subdivision of focal seizures into simple partial seizures and complex partial seizures was adopted by the Commission on Classification and Terminology of the International League Against Epilepsy in 1981 (42). These terms were applied to status epilepticus (SE) by Gastaut in 1983 (72), with alteration of consciousness used to differentiate elementary or simple partial status epilepticus (SPSE) from complex partial status epilepticus (CPSE). Although Shorvon has recently attempted a syndromic classification of SE (191) that takes into account age, cerebral maturation, and pathophysiologic mechanisms, there is no recognized alternative to the dichotomy of simple versus complex based on altered consciousness. This chapter therefore follows the existing classification, although two types of problems are associated with it. The first is that SE of different types cannot in fact be reduced to the types of seizures of which they are composed, but are distinct clinical entities, which may be very different from the seizure types to which their names refer. The second is that a separation of SE into two large categories based exclusively on alteration of consciousness does not appear justified on any pathophysiologic, anatomic, or prognostic ground, resulting in forms of ambiguous classification such as nonconvulsive SE of frontal origin or aphasic SE. Alteration of consciousness is also notoriously difficult to define and therefore to evaluate clinically (79).
Simple partial status epilepticus SPSE is characterized by “a fixed and enduring condition” resulting from the persistence or the repetition of partial seizures with no alteration of consciousness or secondary generalization (71, 72, 182). These conditions are theoretically met when a simple partial seizure lasts more than 30 minutes (47) or when the seizures recur in such a way that there are interictal neurologic signs indicative of neuronal exhaustion in the specific cortical areas implicated in the
ictal activity. This chapter discusses in turn convulsive SPSE, which is frequent, easy to diagnose, and often carries a severe prognosis, and nonconvulsive SPSE, which is difficult to diagnose because of its rarity and its unusual clinical features. C SPSE Somatomotor SPSE Somatomotor SPSE is characterized by repeated partial motor seizures, preserved consciousness, and preserved neurovegetative regulation (71, 72, 182). The cardinal clinical finding is repeated clonic jerks with localization depending on the localization of the epileptogenic lesion in the primary motor cortex (38). Parts of the body with an extensive cortical representation are most commonly involved, particularly the thumb, the mouth, the periocular muscles, and the big toe. Frequent and successive seizures occur, characterized by segmental jerks of progressively increasing amplitude and decreasing frequency. During the interictal periods, the neurologic examination shows a progressively increasing motor deficit in the same localization as the clonic jerks. In those rare instances in which a BravaisJacksonian march occurs, the discharges spread over the motor cortex but still remain relatively localized. The clonic jerks, at times preceded by a tonic component, then spread over the side of the body, with a successive segmental involvement of each limb. Although rare, cheiro-oral propagation, or the march of myoclonic contractions from the thumb to the ipsilateral labial muscles, is characteristic (48, 71, 163). Forced adversion, initially of the eyes and then of the head, at times associated with postural manifestations, may precede the motor manifestations when the epileptic focus is located in the contralateral dorsolateral intermediate frontal region (48, 182) and must be differentiated from the oculoclonic occipital SE described by Palem et al. (160) and Kanazawa et al. (100). The electroencephalogram (EEG) shows more or less well-defined paroxysmal discharges over contralateral rolandic regions (72), often hidden by muscle artifact when the jerks involve the hemiface (Figure 7.1). In many instances, these focal seizures represent the prodromal phase of a secondarily generalized SE. The
, , :
69
F 7.1 Simple partial somatomotor status epilepticus involving the right side of the face and presenting as repeated seizures lasting 5 minutes and repeating every 8 minutes in a 58-year-old man. Facial jerks are seen as muscle artifacts in right frontal and
temporal regions, associated with a rhythmic 2-Hz spike-and-wave focus over the left central region. Interictally, there was a progressively increasing right facial weakness. The CT scan showed a left central intracerebral hemorrhage.
prognosis and implications for treatment are then those of this type of SE. Somatomotor SPSE may also develop into epilepsia partialis continua (99), with persisting myoclonic jerks replacing the discrete somatomotor seizures (Figure 7.2). Somatomotor SPSE is usually related to symptomatic or cryptogenic epilepsies of the central region. Patients whose seizures begin with this form of SE typically have acute or subacute lesions of the rolandic region, particularly of vascular or neoplastic origin (71, 72). In very rare instances, focal SE may be followed by the development of focal chronic epilepsy (20).
living in wooded areas in western Russia in association with Russian spring-summer tick-borne encephalitis (112), which later became endemic in Siberia (159). Two major forms of EPC have been described. The first (EPC 1) occurs with nonspecific lesions of the central region. The second (EPC 2) is characteristic of a rare but well-documented syndrome, Rasmussen’s chronic encephalitis (8, 183). EPC of nonspecific etiology, on EPC 1, occurs in adults and children. It is characterized by somatomotor partial seizures followed by permanent or intermittent segmental myoclonus in the same region that is resistant to medical treatment (15, 16, 38). The myoclonic jerks in EPC 1 are classically unilateral and are of variable amplitude, distribution, and rhythmicity. They occur with preservation of consciousness and are resistant to antiepileptic drugs (188), as well as to injections of botulinum toxin (202). They are thus different from the myoclonic SE that may occur in comatose patients (202). EPC 1 most frequently involves one side of the face or one upper extremity and is usually responsible for moderate
Epilepsia partialis continua According to Obeso et al. (155), epilepsia partialis continua (EPC) is defined as “spontaneous regular or irregular clonic twitching of cerebral cortical origin sometimes aggravated by action or sensory stimuli, confined to one part of the body and continuing for hours, days, or weeks.” EPC has been included in the present classification of epileptic syndromes (42) with the eponym Kojewnikow syndrome. Kojewnikow described EPC in Russian peasants
70
:
F 7.2 Epilepsia partialis continua in a 67-year-old man with a right central tumour. Persisting jerks are recorded at the left wrist (arrows) and alternate with recurring somatomotor seizures of the left upper extremity. The EEG shows rhythmic slow activity,
predominantly over the right hemisphere. The end of the seizure is marked by a 15-second afterdischarge. Recurrent jerks at the left wrist (arrows) are of lower amplitude than before because of the associated Todd’s paresis.
interference with function of the limb (Figure 7.3). In the most disabling cases there is involvement of the rolandic operculum, and these cases are characterized by velolinguopalatine epileptic myoclonus (Foix-Chavany-Marie syndrome), responsible for dysphagia, dysarthria, or anarthria (68, 154, 203, 208). In these cases, a strictly unilateral epileptic discharge of opercular origin produces bilateral motor expression because of the bilateral projections of the inferior corticonuclear pathways. A similar syndrome of idiopathic origin consists of hemifacial clonic jerks, drooling, and anarthria and may very rarely complicate the course of benign epilepsy of childhood, with centrotemporal spikes (41, 56, 64). EPC 1 is classically associated with epileptogenic lesions of the rolandic motor cortex, which may be of vascular (205), neoplastic (15, 16), infectious (36), inflammatory (17, 153), or posttraumatic (205) origin. Recent work using modern imaging methods has shown an elevated frequency of focal cortical dysplastic lesions in EPC 1 (6, 67, 121, 122, 161). Severe prolonged migrainous symptoms and prolonged partial SE, typically taking the form of EPC 1, are characteristic features of the MELAS syndrome (mitochon-
drial encephalomyopathy, lactic acidosis, and strokelike episodes) (7). Late-onset EPC may also reveal Kufs’ disease (70). EPC 1 is progressive insofar as the underlying lesion may be progressive and may respond to appropriate neurosurgical intervention. Other etiologic factors include metabolic encephalopathies, particularly nonketotic hyperglycemia (39, 194). A case of EPC 1 associated with an NADH-coenzyme Q reductase deficiency has been reported (9). More recently, three patients with lung cancer and positive anti-Hu antibodies developed EPC, which in this context was clearly related to a paraneoplastic disorder (187). Polygraphic recording in EPC 1 shows that the myoclonic jerks are characterized by cocontraction of agonist and antagonist muscles. The EEG may show continuous or intermittent low-amplitude focal abnormalities in the central regions, at times correlated with the myoclonic jerks (see Figure 7.3). Jerk-locked back-averaging studies (188, 227) may show that the latency between the cortical event and the myoclonic jerk is compatible with corticospinal transmission. This type of investigation may be improved by using a “rectified” recording of the electromyogram, and
, , :
71
F 7.3 Epilepsia partialis continua in a 22-year-old woman with symptomatic partial epilepsy and left rolandic focal cortical dysplasia. The epilepsy was characterized by right hemifacial somatomotor seizures at night, becoming secondarily generalized and epilepsia partialis continua with rapid myoclonic jerks of the right eyelid and corner of the mouth occurring daily for 2–4 hours at a time, usually at the end of the afternoon. The myoclonus is
seen as muscle artifact over the right frontal regions and in the electro-oculogram. At rest (left recording), there is associated lowamplitude irregular theta activity over the left centroparietal region. With the arms held out (right recording), epileptic negative myoclonus of the proximal part of the right upper limb is seen, with periodic loss of muscle tone associated with the epilepsia partialis continua (arrowheads).
may be complemented by topographic studies using dipole source localization (34). When the neurophysiologic results are ambiguous, functional imaging with single-photon emission computed tomography (SPECT) or positron emission tomography may clarify the situation (45, 83, 108, 203) and permit follow-up studies (200). The pathogenesis of EPC 1 has been discussed for some time. Initial studies, based on the topographic distribution of the causal lesions, suggested that there was uncoupling between subcortical structures, presumed responsible for the myoclonic jerks, and cortical structures, presumed responsible for the epileptic seizures (99). More recent studies using depth electrode recording argue for a common neocortical origin of both these clinical manifestations, with the same epileptic region being responsible for both somatomotor seizures and continuous clonic activity (37, 38, 231). EPC 2 is an independent severe and progressive neurologic disease known as Rasmussen’s encephalitis. It was discovered and extensively studied by the Montreal school (8, 156, 169). The anatomic substrate of the disease may be an autoimmune chronic encephalitis characterized by autoan-
tibodies directed against type 3 glutamatergic receptors (176). Rasmussen’s encephalitis is a devastating neurologic disease of childhood that typically begins between ages 1 and 14 years. In half of cases there is a history of recent and apparently viral infection. The central regions are preferentially involved, and the epilepsy manifests principally as simple partial seizures. The disease then progresses, with neurologic signs related to the insidious destruction of the involved hemisphere: severe epilepsy, characterized by several types of partial seizures and secondary generalized seizures; hemiparesis, which may initially be limited to a loss of fine movements of the fingers; abnormal movements; deterioration in cognitive function; and language disturbances when the dominant hemisphere is involved. EPC of variable expression is found in half of the cases. Imaging studies (Figure 7.4 and Color Plate 1) show a progressive and widespread unilateral atrophy associated with subtle signs of white matter inflammation (6, 8, 225). Findings on functional imaging and magnetic resonance imaging (MRI) spectroscopy (35) usually correlate well with the anatomic and
72
:
F 7.4 Rasmussen’s encephalitis of 3 years’ duration in a 12year-old girl. T2-weighted MR imaging shows unilateral left cortical and subcortical atrophy. Interictal HMPAO SPECT imaging
shows significant hypoperfusion of the left hemisphere, predominantly over centroparietal regions. (See Color Plate 1.)
electroclinical information (Figure 7.4). Late-onset Rasmussen’s encephalitis, beginning in adult life, is rare (142). A brain biopsy shows encephalitic changes, which may be subtle. Medical treatment is often disappointing: corticosteroids, plasmapheresis, immune globulins, intraventricular interferon, and zidovudine have been used (51, 86, 132). Functional hemispherectomy arrests the progression of the disease, leaving variable motor and cognitive deficits (224). The timing of surgery is often difficult and must be extensively discussed with the patient’s family.
patients should be documented extensively. In the personal experience of one of the authors (P.T.), among approximately 100 episodes of partial SE investigated in 10 years, only four such patients were encountered, one each with visual, auditory, somatosensory, and somatoinhibitory symptoms. Nonconvulsive SPSE is a fixed and prolonged epileptic state characterized by “elementary” ictal symptoms (72), which may be visual, auditory, somatosensory, inhibitory, vegetative, cognitive or affective, occurring without impairment of consciousness. This condition appears to be similar to prolonged simple partial seizure with elementary symptomatology (49). Aphasic SE, usually included in this group,
N SPSE Nonconvulsive SPSE is a diagnostic challenge: it is rare, the symptoms are unusual, and the
, , :
73
is discussed later in the chapter. Although intact consciousness is a diagnostic criterion for SPSE, several published cases (61, 81, 89, 141, 193, 230, 232, 236) show that this pattern may develop into CPSE and may thus represent the prodromal phase of this condition. Visual nonconvulsive SPSE may manifest with negative symptoms such as cortical blindness (13, 18, 61, 89), amounting to “status epilepticus amauroticus” (13). Positive symptomatology with simple or complex visual hallucinations may be responsible for more or less pronounced behavioral changes (43, 96, 160, 196). The EEG shows ictal occipital discharges, which are most often bilateral. In auditory nonconvulsive SPSE, only positive symptoms are thus far recognized, exemplified by a patient described by Wieser et al. (230, 233) who experienced musical hallucinations associated with continuous ictal activity in the right Heschl’s gyrus. Somatosensory nonconvulsive SPSE is rare (72, 184). We were able to identify one such patient with a parietal astrocytoma. The symptoms included somatosensory seizures with a jacksonian march characterized by paresthesias and
causalgic sensations. Eight patients with somatoinhibitory SPSE have been described in the literature (Figure 7.5). The clinical pattern in this entity is particularly misleading. It may include hemiparesis (12), hemiasomatognosia (209), or alien-hand syndrome (63), and may suggest Todd’s paralysis (213), acute stroke (209), or behavioral disturbances (63). Four cases of SPSE with vegetative symptoms have been reported (130, 193). Symptoms included prolonged “auras” characterized by episodes of rising epigastric sensations, a butterfly sensation in the stomach, and olfactory hallucinations. SPSE with cognitive symptoms is difficult to investigate. Sacquegna et al. (180) described a patient in whom extensive neuropsychological testing showed errors in reading and writing, in mental arithmetic, and in visual construction tasks. Behavior and alertness were normal. The EEG showed left temporo-occipital ictal activity. Matsuoka et al. (137) described a patient with ideational, ideomotor, and constructional apraxia, finger agnosia, left-right confusion, and agraphia associated with biparietal ictal EEG discharges. In a case report, Wieser et al. assessed cognitive
F 7.5 Right-sided somatoinhibitory SPSE in a 69-year-old woman with right frontoparietal cryptogenic partial epilepsy. Left hemiparesis, left hemihypoesthesia, left visual neglect, and left epileptic nystagmus are associated with continuous high-amplitude spike-and-wave discharges from the right centrotemporoparietal
region. Consciousness was maintained. No lesion was found on imaging studies. The clinical signs disappeared rapidly after the SE terminated, and there was no persistent neurologic deficit. (Reprinted with permission from Thomas et al. [209].)
74
:
functions with tachistoscopic tasks (232) and demonstrated impairment of lexical decision task performances during sustained left hippocampal discharges. SPSE with affective symptoms is mostly characterized by prolonged periods of ictal fear. Henriksen (89) described a patient with right mesial temporal ictal activity and SE, during which the patient “screamed as if possessed with terror.” McLachlan and Blume (141) and Zappoli et al. (236) described two similar patients exhibiting intense fear. Alteration of consciousness occurred later in the course of SE in these patients. Affective disinhibition with a pusillanimous euphoric state may also be observed in some patients with nonconvulsive SPSE of frontal origin (see below).
Complex partial status epilepticus The first case of etat de mal temporal (temporal lobe SE) was reported in 1956 by Gastaut et al. (74). The patient, a 56year-old nurse, had a prolonged amnestic fugue state during which she lived outdoors in the hills behind the coast near Marseilles, going to neighboring villages only to seek something to drink. After 1 month she was apprehended and hospitalized with severe malnutrition. The possibility of an acute psychosis was ruled out by the EEG, which showed left temporal ictal discharges occurring every 5–10 minutes, during which memory functions were disturbed. This new entity was quite unlike absence status, since the disturbance of consciousness was related to recurrent focal ictal discharges rather than to generalized ictal activity. CPSE N L R Until the mid-1980s, one of the distinguishing features of CPSE was believed to be its rarity. This is understandable if one considers that the initial reports equated CPSE with a prolonged epileptic fugue (poriomania), which was of course difficult to document with ictal EEG (138). The Xth Marseilles Colloquium of October 1962, devoted to SE, focused on generalized epilepsies, with the result that this impression of rarity was further reinforced (Roger, 1995, personal communication): of the 137 patients presented, only one had a partial epilepsy (71). The small number of cases published by 1967 explains why Gastaut, in his first classification of SE (71), did not feel it necessary to create a specific category for temporal lobe SE. In fact, in 1970, Oller-Daurella (158) could find only three adequately documented cases in the literature (31, 74, 162). Roger et al. (174) therefore wrote in 1974 that “temporal lobe SE has rarely been described electrographically and clinically.” A similar bias in case finding may also explain why Celesia (33) found only two cases of CPSE in his series of 60 patients with SE and why, 8 years later, Courjon et al. (44) found only a single patient with “nonconvulsive SE with complex partial seizures” in a series of 90 consecutive patients with SE.
Ballenger et al. (14) described eight new patients in 1983 and retained only those 17 of the previously described patients whose cases were well documented by ictal EEG out of the approximately 50 published observations over the previous 30 years (22, 46, 53, 61, 62, 74, 84, 85, 88, 94, 128, 133, 139, 140, 141, 148, 235). In 1986, Tomson et al. (215) challenged this notion of rarity. Between 1983 and 1985, there was a great increase in well-documented cases, with approximately 40 new cases being reported (1, 14, 54, 58, 145, 151, 167, 179, 186, 217, 221, 232, 234, 236). As Delgado-Escueta and Treiman (49) remarked, this impressive expansion is probably related to the widespread use of video-EEG monitoring. Nevertheless, most of the 100 observations available in 1986 were isolated case reports, and the relative incidence of CPSE is still unclear. Two studies have addressed the frequency of CPSE as a variety of nonconvulsive SE. Tomson et al. (215) found that CPSE accounted for 5 of 10 patients with nonconvulsive SE, and Rohr-Le Floch et al. (177) found 28 cases of CPSE (47%) in a series of 60 cases of nonconvulsive SE. Between 1986 and January 2000, approximately 100 new cases were published in 42 different reports (5, 10, 19, 23, 26, 40, 52, 57, 59, 66, 87, 93, 98, 105, 112, 113, 116, 118, 124–126, 129, 131, 144, 149, 150, 157, 166, 173, 175, 177, 181, 182, 185, 197, 204, 210, 214, 215, 222, 226, 236). CPSE has become almost commonplace and relatively easy to diagnose, as suggested by the number of patients recently reported from medical emergency departments (40, 57, 93, 105, 127, 177, 182, 214). Nevertheless, the approximately 200 reported cases differ widely in age at onset, clinical presentation, the course of the episodes, and the presumed etiology and localization of the underlying seizure generator. Only five studies comprising 17 patients reported depth electrode studies during CPSE occurring by chance during intensive monitoring (49, 101, 226, 232, 234). T, D, P A CPSE Following the proposed International Classification of Epileptic Seizures (72, 73), the term complex partial status epilepticus was proposed in 1978 by Markand et al. (133) and by Engel et al. in the same year (61), as well as by Mayeux and Lüders (139). This term was then almost universally adopted. Other terms, such as “temporal lobe status” (74), “psychomotor status” (31, 110, 221), “status psychomotoricus” (235), “limbic status” (232), “recurrent temporal seizures” (147) and “prolonged epileptic twilight state with automatisms” (62), have almost disappeared. In 1969, Heintel (88) proposed a definition based on the model of convulsive SE. He described only a single clinical pattern characterized by a simple series of temporal lobe complex partial seizures without interictal return to normal consciousness. This definition was modified in 1975 by Gastaut (73) and Gastaut and Tassinari (75), who described
, , :
75
two distinct clinical forms of CPSE, a discontinuous form and a continuous form. The discontinuous form was described as comprising “closely spaced temporal seizures with classic psychomotor, psychosensory, or psychoaffective symptoms with full or almost full recovery of consciousness in between.” The continuous form was described as “a continuous long lasting episode of mental confusion with or without automatic behaviour and psychosensory or psychoaffective phenomena.” Mayeux and Lüders (139) added EEG information to these definitions. The discontinuous form is characterized by recurrent ictal activity, while the continuous form is characterized by continuous ictal activity. In both cases, the ictal discharges may be localized to the temporal region either initially or secondarily. The most ambitious phenomenological classification of CPSE was proposed by Treiman and Delgado-Escueta in a series of articles published between 1974 and 1987 (49, 62, 217–219). These authors distinguished two major electroclinical types of CPSE. The first and most characteristic type was described in an initial series of 11 patients (217). Two clearly distinct electroclinical phases alternate in the course of a single such episode. The first phase is characterized by “a continuous twilight state, with partial and amnesic responsiveness, partial speech and quasi-purposeful complex reactive automatisms.” The EEG shows diffuse abnormal slow waves predominating over posterior regions, at times mixed with rapid rhythms. This phase alternates with episodes of “staring, total unresponsiveness, speech arrest and stereotyped automatisms” associated with ictal rhythmic discharge at 6–20 Hz involving initially the mesial temporal region before spreading to lateral temporal areas. The fundamental clinical characteristic of this type of CPSE, presumably related to cyclic disorganization of amygdaloid and hippocampal function, is the cyclic nature of the disturbance of consciousness. This characteristic sets it apart from absence status, in which the fluctuation of symptoms is not as regular and not as marked. Delgado-Escueta and Treiman (49) later accepted the possibility that the mesial temporal structures could be secondarily involved by discharge from an extratemporal epileptic focus in the posterior temporal neocortex, the opercular region, the occipital lobe, or the frontal lobe (49). In these cases the clinical pattern was also cyclic but included clinical features linked to early ictal involvement of these respective cortical areas. The second type of CPSE, presumably arising from ictal disorganization of frontal lobe function without involvement of mesial temporal structures, is characterized by a continuous confusional state without any marked cyclic pattern. These cases can be distinguished from absence status only by the EEG, which shows continuous or intermittent ictal discharges with a variable distribution over the scalp (49).
76
:
Although this phenomenologic approach is of great conceptual interest, its validity is open to question (190). The cyclic pattern described above and considered the most characteristic pattern accounts for only a minority of published cases. Moreover, during a single episode, the first pattern is often followed by the second, so that far from being independent clinical syndromes, the cyclic and continuous forms may represent extremes on the same continuum. In addition, depth electrode studies, though scanty (49, 230, 232, 234), show that consciousness is disturbed only when the ictal discharge involves extratemporal structures (147) or becomes bilateral (230). The cyclic disturbance of consciousness was seen in only 6 of the 16 patients studied (49, 234), who for the most part had extratemporal CPSE (234). There has also been a rather poor correlation between simultaneous depth electrode and scalp EEG recording (230, 232, 234), and thus anatomic and electroclinical correlations based on surface recording must remain speculative. In 1994, Shorvon (190) concluded that a broad and intentionally imprecise definition was the least unsatisfactory solution to the great diversity of clinical and EEG presentations. He proposed the following definition, which accounts for the majority of published cases: “CPSE is a prolonged epileptic episode in which fluctuating or frequently recurring focal electrographic epileptic discharges, arising in temporal or extratemporal regions, result in a confusional state with variable clinical symptoms.” The term CPSE nevertheless implies an alteration of consciousness, a term which is itself open to criticism: in many patients with CPSE, the clinical presentation is more suggestive of a selective dysfunction of certain neocortical associative regions rather than a diffuse and homogeneous alteration of consciousness. In many cases, it appears quite arbitrary to distinguish different clinical forms only on the basis of altered consciousness. We favor the approach adopted by Gloor (79), who suggested that the term complex partial should apply to all partial seizures characterized by disturbances of cognitive function. Indeed, as observed in partial seizures, alteration of consciousness in partial SE has no localizing value on its own (79), and a purely topographic classification of nonconvulsive SE would be without doubt more useful than a classification based solely on the electroclinical criteria currently in force (177). We illustrate these terminologic problems at the end of this chapter, in a discussion of two clinical forms of nonconvulsive SE that are difficult to classify, frontal nonconvulsive SE and aphasic SE. A, I, T F, E CPSE The age at which CPSE occurs is extremely variable. The youngest patient described was less than 1 year old (226) and the oldest was 79 years old (24). A slight female preponderance was noted by Shorvon (190).
There are no reliable data on the true incidence of CPSE. Shorvon, based on his personal experience, believes that approximately 15% of patients with partial epilepsy will have at least one episode of CPSE. The annual incidence of CPSE in adults would thus be approximately of 35 per 1 million population, representing 8,750 new cases each year in the United States (191). This incidence might therefore be higher than that of tonic-clonic SE. Most patients have a preexisting partial epilepsy, more often symptomatic than cryptogenic (221), localized to temporal or extratemporal regions and of different causes (14, 105, 182, 214). In some cases the underlying epilepsy is manifested only by tonic-clonic seizures (85). The interval between the first seizure and the first episode of SE may be quite long, 49 years in one case (177). CPSE may occur in severe myoclonic epilepsy of childhood (208) in the lateonset form of MELAS (124, 125). Risk factors for CPSE in patients with established epilepsy include stopping or changing antiepileptic drugs, alcohol use, sleep deprivation, fever, the catamenial period, anesthesia, and surgery (14, 40). CPSE more often appears at the onset of epilepsy in adults than in children (2, 140, 186). When the episode of status is related to an acute CNS lesion, the clinical findings related to the lesions may mask those related to the status, making the initial EEG and clinical evaluation difficult (93). In contrast to absence status, toxic and metabolic precipitating factors are relatively uncommon. In patients without previous epilepsy, acute or chronic causes of CPSE include crack cocaine use (157), electroconvulsive therapy (222, 228), intravenous contrast agent use (129), meningeal carcinomatosis (52), epidural metastases (197), neurosyphilis (87, 124, 166), Alzheimer’s disease (11), and drugs such as cyclosporin (10), ciprofloxacin (98), lithium (181), theophylline (116), diazepam and midazolam (paradoxic response) (3), and vigabatrin (175). The implication of tiagabine in recommended doses remains controversial (189), because in most cases, a benzodiazepine-responsive toxic encephalopathy may also be considered (65, 163, 195, 198, 220). Among unusual causes, Fujiwara et al. (66) reported a case of recurrent CPSE clearly correlated with alcohol use, and Thomas et al. (210) reported a case of CPSE during pregnancy that could only be controlled after the induction of labor and delivery. The duration of CPSE is extremely variable, ranging from 1 hour (140) to several months (40). Mikati et al. described an 11-year-old boy with “protracted epileptiform encephalopathy” lasting more than 4 months, with a benign outcome (145). Cockerell et al. (40) described a patient who was considered to persist in CPSE for 18 months despite vigorous treatment, even longer than a similar case that lasted for 7 months (173). CPSE is frequently recurrent, especially in patients with known epilepsy, found in seven of eight patients described by Ballenger et al. (14) and in 17 of 20
patients described by Cockerell et al. (40). At times recurrences are periodic and unaffected by various adjustments of medications (5, 40, 190). C C CPSE The clinical features of CPSE are extremely variable, depending on ictal disorganization of various anatomophysiologic networks, each of them with a distinct topography and epileptogenicity. Mesial temporal structures are only rarely the only areas involved. Therefore, it appears to us that any description of a typical clinical form, if one indeed exists, must be reductionist. The most typical symptoms include a more or less marked clouding of consciousness, which may be cyclic or continuous, accompanied by automatisms of variable complexity and disturbed affective function, which may at times be responsible for gross behavioral disturbances. Clouding of consciousness The alteration of consciousness is of variable intensity but is usually marked and associated with total or more often partial amnesia for the episode (177, 193). Occasional patients may be lethargic or even stuporous (126, 145). A mild clouding of consciousness, which may even be absent, and without amnesia is frequent in CPSE of frontal lobe origin (177). Detailed neuropsychological evaluation may be needed in those cases to confirm the diagnosis (177). In patients with sustained episodes of confusion, Karbowski (107) notes that the clinical presentation may be easily confused with absence status. In these patients, the ictal discharges are often continuous. In patients with cyclic periods of confusion, the deterioration in level of consciousness outside of the interictal periods makes it possible to differentiate this from a postictal encephalopathy (14, 28). Automatisms Epileptic automatisms of variable type (oroalimentary, gestural, ambulatory) and complexity (elementary, simple, complex) are almost always present during CPSE (14, 31, 177). Treiman and Delgado-Escueta (217) believe that simple oro-alimentary and/or gestural automatisms associated with altered consciousness, alternating cyclically with more or less marked confusion and reactive automatisms, are almost pathognomonic of CPSE of mesial temporal origin. This opinion is shared by Munari et al. (147) on the basis of depth electrode recordings. In contrast, in the series of Rohr-Le Floch et al. (177), 44% of temporal forms of CPSE were characterized by complex rather than simple gestural automatisms. These complex automatisms were, however, rarely as coordinated and sudden as those seen in isolated complex partial seizures (190). For these authors (177), simple gestural automatisms are nonspecific signs, also encountered in absence status and in CPSE of extratemporal origin. Prolonged fugue states are also nonspecific (177) but may allow the diagnosis to be made retrospectively (74, 138).
, , :
77
Associated signs There are several reports of tonic-clonic seizures at the onset of CPSE (14, 62, 177). Unlike absence status, CPSE only rarely ends with a convulsive seizure. Disturbances of language are usual during CPSE. These are at times limited to reduced verbal fluency with imprecise and stereotyped responses. Prolonged ictal aphasia has been classified in the literature as CPSE or aphasic SE (54, 140) and will be discussed later with intermediate clinical forms. Ideational or ideomotor apraxia (94), at times associated with a true Gerstmann’s syndrome (137) has been described with parietal lobe involvement. Clinical manifestations of CPSE may rarely be confined to isolated anterograde and retrograde global amnesia (74, 144). The amnesia may also be associated with other focal manifestations (124). Wieser (230) reported depth electrode studies in such a patient in whom the memory disturbances were associated with ictal discharge in both hippocampi. Ictal changes in the person’s emotional state, almost always unpleasant, appear to be characteristic of CPSE of temporal origin (14, 61, 107, 128, 133, 177, 221, 230, 235). In some cases the clinical picture is dominated by sustained terror (89, 141, 236). Rohr-Le Floch et al. (177) found that all the patients in their experience were uneasy, anxious, or frightened, and at times negativistic, irritable, suspicious, or frankly aggressive. Gelastic seizures have been reported in only one patient (78). Visual hallucinations (145) and complex auditory hallucinations (136, 145, 230), related to involvement of specific sensory areas, have been reported. Matsumoto et al. (136) described a patient in whom these hallucinations reappeared fleetingly 1 week after the status had stopped; they related this course to “forced normalization.” Although patients whose primary observable phenomena are motor must be excluded from the definition of CPSE, in some cases focal motor manifestations may occur. Parcellary adversive movements are frequent. They may be intermittent or sustained and may involve much of the body or be limited to the eyes (14, 22, 58, 61, 62, 84, 139, 148). Adversive movements may be ipsilateral to the ictal discharge (88) and may be associated with epileptic nystagmus (210). When the CPSE occurs in the form of serial seizures, these movements may be useful indicators of the beginning of the individual seizures (58). Low-amplitude lateralized clonic movements may be present (62). Velopalatine myoclonus may occur (60), but bilateral eyelid and facial myoclonus, typical of absence status, has not been reported. Vegetative signs such as pallor, hyperventilation, pupillary dilation, hypersalivation, burping, and changes in gastrointestinal motility are common. Three instances of an unusual presentation with confusion or memory disturbance and intermittent fever have been reported (59, 144, 185).
78
:
Focal neurologic deficits in CPSE, such as hemiparesis, hemianopsia, or hemihypesthesia, were reported by Hilkens and De Weerd (93). L E CPSE The EEG is the key to diagnosis. Only in this way can CPSE be clearly differentiated from absence status, nonepileptic behavior disturbance (54), dementia (170), or metabolic (30) or cerebrovascular disease (24, 150). Other entities in the differential diagnosis are similar to those for other nonconvulsive SE (see Thomas et al., Chapter 8, this volume). Electroencephalography The characteristic EEG sign of CPSE is focal paroxysmal activity that is continuous (Figure 7.6) or occurs in discrete recurring seizures. In the latter, the EEG is comparable to that seen in patients with isolated complex partial seizures. The seizures begin with low-voltage fast activity, which has localizing value, followed by focal rhythmic theta activity, which is gradually replaced by slow waves (49, 216). The interictal tracing can show different types and degrees of abnormality. When the paroxysmal activity is continuous, spikes, spike-and-wave complexes, or focal rhythmic or pseudorhythmic sharp and slow waves occur (133, 139, 216), often alternating with short periods of lowamplitude fast activity. The first of these patterns often evolves into the second in the course of the episode (216). The scalp distribution of the paroxysmal activity is variable. An intermittent or sustained focal discharge clearly localized to one cortical area is rare, as is a strictly temporal localization (80). In most cases the ictal abnormalities are widespread and occur over several lobes, involving frontotemporal, temporoparietal, or temporooccipital regions. Other patterns occasionally observed include intermittent widespread involvement of one or both hemispheres, ictal activity that shifts from side to side, and activity that may shift to one region of the contralateral hemisphere in the course of a single episode (61, 114). A confusional state with periodic lateralized epileptiform discharges (PLEDs) was described in elderly patients by Terzano et al. (204). This syndrome, the existence of which as an independent entity is not yet accepted, may represent a specific EEG manifestation of CPSE at the onset of a primary degenerative dementing illness. In a comatose patient with PLEDs, hyperperfusion on SPECT resolved with further aggressive treatment (4). Other laboratory examinations Transient focal abnormalities are occasionally seen on imaging studies. Hypodensity with (29) or without (114) contrast enhancement, hyperintensity in T2-weighted MR images (22, 90, 114, 123, 124), ictal hyperperfusion on SPECT (22, 212), and a clear frontal increase in lactate signal on proton magnetic resonance spectroscopy (146) have been reported. These abnormalities appear to be related to the edema and hyperperfusion
F 7.6 Continuous form of neocortical complex partial status epilepticus arising from the left temporal region in a 45-yearold woman with symptomatic left temporal partial epilepsy. She had had an arteriovenous malformation excised 20 years earlier and was noncompliant with antiepileptic drugs. Symptoms included mild confusion, aphasia of comprehension, and right visual neglect with macroptic illusions. The EEG (left recording,
average reference) shows continuous pseudorhythmic slow spike and wave activity over left anterior and midtemporal regions and low-amplitude intermittent rapid discharge in the same area. Intravenous administration of 15 mg of diazepam led to transitory slowing of the paroxysmal activity (right recording). The SE ceased without sequelae after IV phenytoin administration.
associated with the seizures (22, 90, 114, 123), but they may also be indicative of low-grade primary brain tumor (90). In our experience (212), the ictal SPECT may provide reliable localizing information and can be particularly useful in differentiating temporal from extratemporal episodes (Figure 7.7).
Figure 7.6) is much more frequent than in absence status: in the series of Granner and Lee (80), 90% of cases of generalized SE responded to IV diazepam but only 60% of cases of CPSE responded. Refractory cases always require identification and correction of the causes and immediate trigger of the status. In our experience, the greater the delay in diagnosis, the greater the likelihood of failure. Because parenteral lorazepam is not available in France, we follow a specific but classic protocol (48, 49), combining IV diazepam, 2 mg/min until the status stops or to a total dose of 20 mg, and IV fosphenytoin, 20–25 mg phenytoinequivalent per kilogram at once, at a rate no faster than 150 mg/min. Lorazepam is commonly used in Canada and the United States. Cases that are still difficult to control may require pentobarbital anesthesia, a possibility that occurred in approximately one-fifth of our personal series (unpublished observations). Propofol administered IV may also be useful (23), as well as oral topiramate (171).
E T CPSE Treating the episodes of CPSE is difficult. The response to intravenous (IV) benzodiazepines is variable. Although spectacular results may be obtained with the first injection (57, 133, 139), the necessary dose is often greater than that needed in absence status (190). When the EEG abnormalities are diffuse, IV benzodiazepine may reduce the extent of the discharge and cause the underlying epileptic focus to be better circumscribed (80). Initial failure to respond to injected benzodiazepine or recurrence of the SE within the first hour after injection (see
, , :
79
F 7.7 Ictal, then postictal HMPAO SPECT scans in a 42year-old man with de novo complex partial status epilepticus of right frontal origin, characterized clinically by affective disinhibition and mild confusion. The EEG showed continuous slow spikeand-wave activity over the right frontotemporal region. The ictal
SPECT (top series) shows right anterior frontal hyperperfusion. A SPECT study performed 72 hours after the end of the SE is normal (bottom series). MRI was normal. Investigations showed active neurosyphilis. (See Color Plate 2.)
P CPSE Although experimental partial SE of the limbic system induced using pilocarpine, kainic acid, or various protocols involving electrical stimulation (95, 115) can cause neuronal damage, the great majority of patients are successfully treated without sequelae, even after several recurrences (40, 55). Transient disturbances of memory, cognitive function, or personality are, however, common and in our experience resolve after several days to weeks. Hilkens and De Weerd (93) believe that the CPSE occurring with an acute brain lesion may cause long-term worsening of the associated neurologic dysfunction. A significant increase in neurospecific enolase, a marker of neuronal dysfunction,
has been reported in a series of eight consecutive adult patients (47). Although there is little argument that generalized SE can produce any lasting deficits, there is still debate over the morbidity of CPSE (102–104, 106). However, some rare unfavorable outcomes are well known. Patients described by Treiman et al. (49, 219) and Engel et al. (61) had severe, prolonged amnesia, which was permanent in one case. A similar unfavorable outcome was obvious in a patient with limbic CPSE of very long duration (personal observation) (Figure 7.8 and Color Plate 2). Krumholz et al. (118) reported a series of 10 consecutive patients with three
F 7.8 A 48-year-old woman with right temporal lobe epilepsy had afebrile limbic complex partial status epilepticus related to an abrupt discontinuation of previous antiepileptic treatment. Status was both underdiagnosed and undertreated and lasted 18 days, with frequent limbic seizures, either right temporal or (middle part of the figure) left temporal. The first MRI study (top series), performed 16 days after the beginning of status, showed T2 hypersignal and T1 hyposignal of both anterior part of parahip-
pocampal gyri. A lumbar puncture was normal. A polymerase chain reaction test of CSF was negative for herpes simplex. There was no finding suggestive of a paraneoplastic encephalitis. Pentobarbital anesthesia finally stopped the epileptic seizures. Long-term evolution was marked by serious memory disturbances, related on neuropsychological testing to axial amnesia. A control MRI study performed 2 years after the SE began showed bilateral hippocampal atrophy with a right-sided predominance (lower series).
80
:
, , :
81
deaths, four patients with permanent memory disturbance, which was severe in two cases, and three instances of memory and cognitive disturbances lasting longer than 3 months. Most of these patients had had mesial temporal CPSE lasting longer than 36 hours. Although the use of major IV anticonvulsants can confer morbidity (106), these reports argue in favor of early diagnosis and vigorous treatment of all patients with CPSE, especially when the limbic system is likely involved by the epileptic discharges (107).
Clinical forms intermediate between SPSE and CPSE Two clinical entities, frontal lobe nonconvulsive SE and aphasic SE, are difficult to classify. Frontal lobe nonconvulsive SE, relatively recently described, may occur in the form of SPSE or CPSE. The involvement of highly specialized association areas in aphasic SE can result in complex cognitive dysfunction; some of these cases may best be described as SPSE and others as CPSE. N F SE Nonconvulsive frontal SE is a relatively well-defined entity since the work of Williamson et al. (234), who found frontal lobe origin in five of eight patients with CPSE who were studied with depth electrodes, and by Rohr-Le Floch et al. (177), who described the principal characteristics of this syndrome based on 19 cases. Earlier reports employed terms such as “borderline cases of petit mal status” (92), “absence status with focal characteristics” (152), and “transitional petit mal status” (82). Nonconvulsive frontal SE is characterized by prolonged periods of cognitive disturbance associated with unilateral or bilateral frontopolar ictal discharges, at times accompanied by visible focal ictal signs (152, 177). In order to be diagnostic, the EEG must include an adequate number of channels and montages to record from anterior frontal regions (177). In 65 cases meeting these criteria and published since 1971 in 22 different papers (1, 27, 66, 69, 76, 92, 97, 119, 120, 126, 135, 143, 152, 164, 172, 177, 199, 201, 206, 212, 215, 234), the average age was 40 years (range, 13–84 years) and 59% of the patients were women. Patients with no previous history of epilepsy accounted for 36% of cases, and focal frontal lesions were found in 35%. Two electroclinical varieties can be described. The first is characterized by subtle disturbances of cognitive function associated with behavioral disturbances, such as disinhibition or even affective indifference with lack of spontaneous activity and emotionality (Figure 7.9). The neurologic examination shows only some perseveration and difficulty in the performance of complex motor tasks (120, 164, 177, 211, 212). The EEG shows unilateral and relatively localized
82
:
frontopolar ictal discharges. This type of frontal lobe nonconvulsive SE thus appears to be a variety of SPSE with affective or cognitive symptoms rather than a CPSE (211, 212). In the second type, a clear-cut alteration of consciousness occurs and is associated with ictal epileptiform activity involving both frontal regions simultaneously (Figure 7.10), or eventually developing into absence status from an initial frontopolar focus (1, 27, 119). The EEG then shows bilateral, asymmetric, paroxysmal activity (absence status with focal features; see Thomas et al., Chapter 8, this volume). In contrast to the first type, the electroclinical features are those of a CPSE of extratemporal origin. A SE Of the reported cases of aphasic SE (27, 32, 46, 50, 53, 77, 81, 85, 109, 111, 134, 136, 165, 168, 178, 210, 223), only a few (32, 46, 111, 178) meet the diagnostic criteria proposed in 1988 by Rosenbaum et al. (178): the patient must speak during seizures, the language produced must be aphasic (that is, nonfluent, dysnomic, or paraphasic), consciousness must be preserved, and the EEG must show a strict correlation between the ictal discharges and the aphasic episodes. In many patients (85, 210, 223, 229), the ictal episodes are characterized by negative aphasic signs consisting either of a suspension of speech or a reduction in fluency associated with abnormalities in comprehension of varying degree. The aphasic manifestations in the strict sense of the word are found only in the interictal period and appear to be a form of Todd’s paresis resulting from metabolic exhaustion of specific neuronal areas governing language (46). During the ictal period, it is often difficult to know if the suspension of language is indeed accompanied by aphasia or alteration of consciousness unless, as in the case report of Gilmore et al. (77), a test of syntactic comprehension is used. The validity of this test does not in fact depend on the ability to produce speech. Aphasic manifestations have also been reported in CPSE in the more general sense. These manifestations include periodic suspension of language, possibly representing speech arrest rather than aphasia (54, 140), expressive aphasia with intact comprehension associated with left frontotemporal ictal discharges (85), and, with left posterior temporal discharges, receptive or fluent aphasia, which may fluctuate (111) or be continuous (53). In a single case report (50), an isolated inability to vocalize was associated with right frontoparietal discharges. Such episodes have been reported with homonymous hemianopia (93, 94, 128) and even cortical blindness (61). The occurrence of a relatively pure aphasic nonconvulsive partial SE as described above, as well as the mixed syndromes, can explain at least partly why aphasic SE has been
F 7.9 Right frontal nonconvulsive SE in a 47-year-old man with symptomatic right frontal partial epilepsy related to a falx meningioma operated on 2 years earlier. Clinically, there was no confusion or alteration of awareness, only affective indifference with lack of spontaneous activity and emotion. The EEG shows
prolonged recurring trains of polyspike-and-wave discharges of progressively higher amplitude and lower frequency over the right frontal region, with phase reversals at electrode F4. Periods of flattening of the EEG indicate the beginning of a new run of discharges. Note that temporal regions are relatively untouched.
at times classified as SPSE and at other times as CPSE. According to one school of thought (72, 93, 182, 217), complete preservation of consciousness is one of the defining characteristics of aphasic SE. Another school (14, 53, 165, 177, 190) holds that when aphasic SE occurs in the form of repeated seizures with persisting disturbances of language during the interictal period, aphasic SE and CPSE are one and the same, with aphasic SE being simply one topographic variant of the other.
electroclinical correlations, followed by vigorous treatment of both seizures and causative factors, will prevent, in somatomotor SPSE, the evolution toward a life-threatening secondarily generalized SE, and in CPSE, the occurrence of serious memory or cognitive deficits. However, in this latter form, as noted by Kaplan et al. (105), a high degree of clinical suspicion is essential, especially in psychiatric or mentally retarded patients or in patients with acute cerebral lesions. It is hoped that better understanding of pathophysiologic mechanisms involved in CPSE, due to new imaging and neurophysiological techniques and neuropsychological ictal investigations, will aid in research to delineate the various anatomic networks underlying this heterogeneous but fascinating condition.
Comment Given the pleiomorphic clinical features of nonconvulsive SPSE and CPSE, these are some of the more difficult neurologic conditions to diagnose early in their course. The diagnostic cornerstone of these forms of SE remains the EEG. Emergency diagnosis of nonconvulsive SE is one of the main arguments for maintaining rapid access to EEG from the emergency department. An effective and rapid diagnostic management, allowing when necessary accurate
This work was supported in part by a grant from the Programme Hospitalier de Recherche Clinique, CHRU Nice, French Ministry of Health (P.T.). The authors thank M. J. Breloin for assistance with the figures, and Eva Paquet and Roula Vrentzos for preparing the English-languge translation.
, , :
83
F 7.10 First presentation of epilepsy in a 52-year-old woman in the form of bifrontal complex partial status epilepticus with recurring seizures. Clinically, a sustained confusional state was regularly interrupted every 5 minutes by slight turning of the head and eyes to the left, followed by complete loss of contact for 80–100 seconds. The EEG shows ictal discharges of the same duration over both frontotemporal regions. At the end of each train of
discharges, the return to the baseline confusional state was marked by an inappropriate smile. MRI was normal. Ictal SPECT showed hyperperfusion over the right frontobasal region. This instance of SE was particularly difficult to treat, requiring pentobarbital anesthesia, but the patient recovered without sequelae. (Reprinted with permission from Thomas et al. [212].)
REFERENCES 1. Aguglia, U., P. Tinuper, and G. Farnarier. Etat confusionnel critique à point de départ frontal chez le sujet âgé. Rev. EEG Neurophysiol. 1983;13:174–179. 2. Aicardi, J. Status epilepticus. In J. Aicardi, ed. Epilepsy in Children. 2nd ed. New York: Raven Press, 1996:284–309. 3. Al Tahan, A. Paradoxic response to diazepam in complex partial status epilepticus. Arch. Med. Res. 2000;31:101–104. 4. Ali, I. I., N. A. Pirzada, and B. V. Vaughn. Periodic lateralized epileptiform discharges after complex partial status epilepticus associated with increased focal cerebral blood flow. J. Clin. Neurophysiol. 2001;18:565–569. 5. Ambrosetto, G., P. Tinuper, and C. A. Tassinari. Marfan’s syndrome, recurrent complex partial status epilepticus and myoclonus: A case report. Clin. Electroencephalogr. 1988;19: 33–36. 6. Andermann, F. Epilepsia partialis continua and other seizures arising from the precentral gyrus: High incidence in patients with Rasmussen syndrome and neuronal migration disorders. Brain Dev. 1992;14:338–339. 7. Andermann, F., E. Lugaresi, G. S. Dvorkin, and P. Montagna. Malignant migraine: The syndrome of prolonged classical migraine, epilepsia partialis continua, and repeated strokes.
84
:
8.
9.
10.
11.
12.
13. 14.
A clinically characteristic disorder probably due to mitochondrial encephalopathy. Funct. Neurol. 1986;1:481–486. Andermann, F., and T. Rasmussen. Chronic encephalitis and epilepsy: An overview. In F. Andermann, ed. Chronic Encephalitis and Epilepsy: Rasmussen’s syndrome. Boston: ButterworthHeinemann, 1991:283–289. Antozzi, C., S. Franceschetti, G. Filippini, et al. Epilepsia partialis continua associated with NADH-coenzyme Q reductase deficiency. J. Neurol. Sci. 1995;129:152–161. Appleton, R. E., K. Farrell, P. Teal, S. A. Hashimoto, and P. K. Wong. Complex partial status epilepticus associated with cyclosporin A therapy. J. Neurol. Neurosurg. Psychiatry 1989; 52:1068–1071. Armon, C., G. W. Peterson, and B. H. Liwnicz. Alzheimer’s disease underlies some cases of complex partial status epilepticus. J. Clin. Neurophysiol. 2000;17:511–518. Armon, C., R. A. Radtke, and A. H. Friedman. Inhibitory simple partial (non-convulsive) status epilepticus after intracranial surgery. J. Neurol. Neurosurg. Psychiatry 2000;69:18–24. Ayala, H., and S. Stephenson. Status epilepticus amauroticus. Boll. Accad. Med. Roma 1929;55:288–290. Ballenger, C. E., D. W. King, and B. B. Gallagher. Partial complex status epilepticus. Neurology 1983;33:1545–1552.
15. Bancaud, J., A. Bonis, S. Trottier, J. Talairach, and O. Dulac. L’épilepsie partielle continue: Syndrome et maladie. Rev. Neurol. 1982;138:802–814. 16. Bancaud, J., and J. Talairach. Clinical semiology of frontal lobe seizures. In P. Chauvel, A. V. Delgado-Escueta, E. Halgren, and J. Bancaud, eds. Frontal Lobe Seizures and Epilepsy. Adv. Neurol. 1992;57:3–58. 17. Bansal, S. K., I. M. Sawhney, and J. S. Chopra. Epilepsia partialis continua in Sjögren’s syndrome. Epilepsia 1987;28: 362–363. 18. Barry, E., N. M. Sussmann, T. M. Bosley, and R. N. Harner. Ictal blindness and status epilepticus amauroticus. Epilepsia 1985;26:577–584. 19. Bartolomei, F., and J. L. Gastaut. Complex partial status epilepticus provoked by hyponatremia. Eur. Neurol. 1998; 40:53–54. 20. Bartolomei, F., J. Regis, A. Donnet, and J. L. Gastaut. Development of focal chronic epilepsy following focal status epilepticus in adult patients. Neurophysiol. Clin. 1999;29: 271–276. 21. Bauer, G. Psychische Veränderungen bei kontinuierlichen epileptischen Entladungen. Schweitz Arch. Neurol. Neurochir. Psychiatr. 1975;116:241–255. 22. Bauer, J., H. Stefan, W. J. Huk, et al. CT, MRI and SPECT neuroimaging in status epilepticus with simple partial and complex partial seizures: Case report. J. Neurol. 1989;236: 296–299. 23. Begemann, M., A. J. Rowan, and S. Tuhrim. Treatment of refractory complex-partial status epilepticus with propofol: Case report. Epilepsia 2000;41:105–109. 24. Behrens, J. M. Psychomotor status epilepticus masking as a stroke. Postgrad. Med. 1980;68:223–226. 25. Belafsky, M., S. Carwille, P. Miller, S. Waddell, J. BoxleyJohnson, and A. V. Delgado-Escueta. Prolonged epileptic twilight states: Continuous recordings with nasopharyngeal electrodes and video-tape analysis. Neurology 1978;28: 239–245. 26. Bequet, D., E. Bodiguel, J. L. Renard, and J. Goasguen. Etat de mal partiel complexe temporal. Rev. Neurol. 1990;146: 147–150. 27. Berkovic, S. F., F. Andermann, M. Aubé, R. M. Rémillard, and P. Gloor. Nonconvulsive confusional frontal status. Epilepsia 1985;26:529. 28. Biton, V., J. R. Gates, and L. De Padua Sussman. Prolonged postictal encephalopathy. Neurology 1990;40:963–966. 29. Blatt, I., S. Jackson, and R. M. Dashieff. Aphasic status epilepticus with reversible contrast enhancement on CT. Epilepsia 1992;33(Suppl. 3):S4. 30. Bogdanovic, M. D., D. Kidd, A. Briddon, J. S. Duncan, and J. M. Land. Late onset heterozygous ornithine transcarbamylase deficiency mimicking complex partial status epilepticus. J. Neurol. Neurosurg. Psychiatry 2000;69:813–815. 31. Bonduelle, M., C. Sallou, J. Guillard, and J. J. Gaussel. L’état de mal psychomoteur: Ses rapports avec les automatismes et les psychoses aiguës épileptiques. Rev. Neurol. 1964;110: 365–370. 32. Boudouresques, J., J. Roger, and H. Gastaut. Crises aphasiques subintrantes chez un épileptique temporal. Rev. Neurol. 1962;106:381–393. 33. Celesia, G. C. Modern concepts of status epilepticus. JAMA 1976;235:1571–1574. 34. Celesia, G. G., L. Parmeggiani, and M. Brigell. Dipole source localization in a case of epilepsia partialis continua without
35.
36.
37.
38.
39.
40.
41.
42.
43. 44.
45.
46.
47.
48.
49.
50.
51.
premyoclonic EEG spikes. Electroencephalogr. Clin. Neurophysiol. 1994;90:316–319. Cendes, F., F. Andermann, K. Silver, and D. L. Arnold. Imaging of axonal damage in vivo in Rasmussen’s syndrome. Brain 1995;118:753–758. Chalk, C. H., P. G. McManis, and G. D. Cascino. Cryptococcal meningitis manifesting as epilepsia partialis continua of the abdomen. Mayo. Clin. Proc. 1991;66:926–929. Chauvel, P., C. Liegeois-Chauvel, P. Marquis, and J. Bancaud. Distinction between the myoclonus-related potential and the epileptic spike in epilepsia partialis continua. Electroencephalogr. Clin. Neurophysiol. 1986;64:304–307. Chauvel, P., S. Trottier, J. P. Vignal, and J. Bancaud. Somatomotor seizures of frontal lobe origin. In P. Chauvel, A. V. Delgado-Escueta, E. Halgren, and J. Bancaud, eds. Frontal Lobe Seizures and Epilepsy. Adv. Neurol. 1992;57: 185–243. Cochin, J. P., D. Hannequin, T. Delangre, E. GueganMassardier, and P. Augustin. Epilepsie partielle continue revelatrice d’un diabete sucre. Rev. Neurol. 1994;150: 239–241. Cockerell, O. C., M. C. Walker, J. W. Sander, and S. D. Shorvon. Complex partial status epilepticus: A recurrent problem. J. Neurol. Neurosurg. Psychiatry 1994;57:835–837. Colamaria, V., V. Sgro, R. Caraballo, et al. Status epilepticus in benign rolandic epilepsy manifesting as anterior operculum syndrome. Epilepsia 1991;32:329–334. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489–501. Corin, S. Visual status epilepticus. Neurology 1974;23:434. Courjon, J., M. H. Fournier, and F. Mauguière. Les états de mal chez les épileptiques adultes suivis dans un hôpital neurologique. Rev. EEG Neurophysiol. 1984;14:175–179. Cowan, J. M., J. C. Rothwell, R. J. Wise, and C. D. Marsden. Electrophysiological and positron emission studies in a patient with cortical myoclonus, epilepsia partialis continua and motor epilepsy. J. Neurol. Neurosurg. Psychiatry 1986;49: 796–807. De Pasquet, E. G., E. S. Gaudin, A. Bianchi, and S. A. De Mendilaharsu. Prolonged and monosymptomatic dysphasic status epilepticus. Neurology 1976;26:244–247. DeGiorgio, C. M., P. S. Gott, A. L. Rabinowicz, C. N. Heck, T. D. Smith, and J. D. Correale. Neuron-specific enolase, a marker of acute neuronal injury, is increased in complex partial status epilepticus. Epilepsia 1996;37:606–609. Delgado-Escueta, A. V., and F. Enrile-Bacsal. Combination therapy for status epilepticus: Intravenous diazepam and phenytoin. In A. V. Delgado-Escueta, C. G. Wasterlain, D. M. Treiman, and R. J. Porter, eds. Status Epilepticus. Adv. Neurol. 1983;43:477–485. Delgado-Escueta, A. V., and D. M. Treiman. Focal status epilepticus: Modern concepts. In H. Lüders, and R. P. Lesser, eds. Epilepsy: Electroclinical Syndromes. London: Springer-Verlag, 1987:347–391. DeToledo, J. C., A. Minagar, and M. R. Lowe. Persisting aphasia as the sole manifestation of partial status epilepticus. Clin. Neurol. Neurosurg. 2000;102:144–148. DeToledo, J. C., and D. B. Smith. Partially successful treatment of Rasmussen’s encephalitis with zidovudine: Symptomatic improvement followed by involvement of the contralateral hemisphere. Epilepsia 1994;35:352–355.
, , :
85
52. Dexter, D. D., Jr., B. F. Westmoreland, and T. L. Cascino. Complex partial status epilepticus in a patient with leptomeningeal carcinomatosis. Neurology 1990;40:858–859. 53. Dinner, D. S., H. Lüders, R. Lederman, and T. E. Gretter. Aphasic status epilepticus: A case report. Neurology 1981; 31:888–890. 54. Drake, M. E., and J. E. Coffey. Complex partial status epilepticus simulating psychogenic unresponsiveness. Am. J. Psychiatry 1983;140:800–801. 55. Drislane, F. W. Evidence against permanent neurologic damage from nonconvulsive status epilepticus. J. Clin. Neurophysiol. 1999;14:323–331. 56. Drislane, F. W., A. S. Blum, and D. L. Schomer. Focal status epilepticus: Clinical features and significance of different EEG patterns. Epilepsia 1999;40:1254–1260. 57. Dunne, J. W., Q. A. Summers, and E. G. Stewart-Wynne. Nonconvulsive status epilepticus: A prospective study in an adult general hospital. Q. J. Med. 1987;62:117–126. 58. Egawa, I., J. Yamamoto, Y. Yamada, and Y. Hishikawa. Three epileptic patients suffering from period of frequent complex partial seizures and diagnostic criteria for epileptic status. Folia Psychiatr. Neurol. Jpn. 1984;38:111–120. 59. El-Ad, B., and M. Y. Neufeld. Periodic febrile confusion as a presentation of complex partial status epilepticus. Acta Neurol. Scand. 1990;82:350–352. 60. Emre, M. Palatal myoclonus occurring during complex partial status epilepticus. J. Neurol. 1992;239:228–230. 61. Engel, J., B. Ludwig, and M. Fetell. Prolonged partial complex status epilepticus: EEG and behavioral observations. Neurology 1978;28:863–869. 62. Escueta, A. V., J. Boxley, N. Stubbs, G. Wadell, and W. A. Wilson. Prolonged twilight state and automatisms: A case report. Neurology 1974;24:331–339. 63. Feinberg, T. E., D. M. Roane, and J. Cohen. Partial status epilepticus associated with asomatognosia and alien handlike behaviors. Arch. Neurol. 1998;55:1574–1576 [Published erratum appears in Arch. Neurol. 1999;56:24]. 64. Fejerman, N., and A. M. Di Blasi. Status epilepticus of benign partial epilepsies in children: Report of two cases. Epilepsia 1987;28:351–355. 65. Fitzek, S., S. Hegemann, D. Sauner, D. Bonsch, and C. Fitzek. Drug-induced nonconvulsive status epilepticus with low dose of tiagabine. Epileptic Disord. 2001;3:147–150. 66. Fujiwara, T., M. Watanabe, K. Matsuda, M. Senbongi, K. Yagi, and M. Seino. Complex partial status epilepticus provoked by the ingestion of alcohol: A case report. Epilepsia 1991;32:650–656. 67. Fusco, L., E. Bertini, and F. Vigevano. Epilepsia partialis continua and neuronal migration anomalies. Brain Dev. 1992; 14:323–328. 68. Fusco, L., and F. Vigevano. Reversible operculum syndrome caused by progressive epilepsia partialis continua in a child with left hemimegalencephaly. J. Neurol. Neurosurg. Psychiatry 1991;54:556–558. 69. Gall, M. V., G. Scollo-Lavizzari, and H. Becker. Absence status in the adult: New results including computerized transverse axial tomography. Eur. Neurol. 1978;17:121–128. 70. Gambardella, A., G. Pasquinelli, R. Cittadella, et al. Kufs’ disease presenting as late-onset epilepsia partialis continua. Neurology 1998;51:1180–1182. 71. Gastaut, H. À propos d’une classification symptomatique des états de mal épileptiques. In H. Gastaut, J. Roger, and H. Lob, eds. Les états de mal épileptiques. Paris: Masson, 1967:1–8.
86
:
72. Gastaut, H. Classification of status epilepticus. In A. V. Delgado-Escueta, C. G. Wasterlain, D. M. Treiman, and R. J. Porter, eds. Status Epilepticus. Adv. Neurol. 1983;34:83–92. 73. Gastaut, H. Clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1970;11:102–113. 74. Gastaut, H., J. Roger, and A. Roger. Sur la signification de certaines fugues épileptiques: A propos d’une observation électroclinique d’ “état de mal temporal.” Rev. Neurol. 1956;94: 298–301. 75. Gastaut, H., and C. A. Tassinari. Status epilepticus. In A. Remond, ed. Handbook of Electroencephalography and Clinical Neurophysiology. Vol. 13. Amsterdam: Elsevier, 1975:39–45. 76. Geier, S. Prolonged psychic epileptic seizures: A study of the absence status. Epilepsia 1978;19:431–445. 77. Gilmore, R. L., and K. M. Heilman. Speech arrest in partial seizures: Evidence of an associated langage disorder. Neurology 1981;31:1016–1019. 78. Glassman, J. N., D. Dryer, and J. R. McCartney. Complex partial status epilepticus presenting as gelastic seizures. Gen. Hosp. Psychiatry 1986;8:61–64. 79. Gloor, P. Consciousness as a neurological concept in epileptology: A critical review. Epilepsia 1986;27(Suppl. 2):S14–S26. 80. Granner, M. A., and S. I. Lee. Nonconvulsive status epilepticus: EEG analysis in a large series. Epilepsia 1994;35:42–47. 81. Grimes, D. A., and A. Guberman. De novo aphasic status epilepticus. Epilepsia 1997;38:945–949. 82. Guberman, A., G. Cantu-Reyna, D. Stuss, and R. Broughton. Nonconvulsive généralized status epilepticus: Clinical features, neuropsychological testing and long-term follow-up. Neurology 1986;36:1284–1291. 83. Hajek, M., A. Antonini, K. L. Leenders, and H. G. Wieser. Epilepsia partialis continua studied by PET. Epilepsy Res. 1991;9:44–48. 84. Hamanaka, T. Zum Problem des Status psychomotorische Anfälle. J. Clin. Psychiatry 1972;14:592–603. 85. Hamilton, N. G., and T. Matthews. Aphasia: The sole manifestation of focal status epilepticus. Neurology 1979;29: 745–748. 86. Hart, Y. M., M. Cortez, F. Andermann, et al. Medical treatment of Rasmussen’s syndrome (chronic encephalitis and epilepsy): Effect of high-dose steroids or immunoglobulins in 19 patients. Neurology 1994;44:1030–1036. 87. Heald, A., S. Connolly, and P. Hudgson. Neurosyphilis presenting as complex partial status epilepticus. Eur. Neurol. 1996;36:111–112. 88. Heintel, H. Status von tonischen Dämmerattacken. Arch. Psychiatr. Nervenkr. 1969;212:117–125. 89. Henriksen, G. F. Status epilepticus partialis with fear as clinical expression. Epilepsia 1973;14:39–46. 90. Henry, T. R., I. Drury, J. A. Brunberg, P. B. Pennell, P. E. McKeever, and A. Beydoun. Focal cerebral magnetic resonance changes associated with partial status epilepticus. Epilepsia 1994;35:35–41. 91. Hess, D. C., and K. D. Sethi. Epilepsia partialis continua in multiple sclerosis. Int. J. Neurosci. 1990;50:109–111. 92. Hess, R., G. Scollo-Lavizzari, and F. E. Wyss. Borderline cases of petit mal status. Eur. Neurol. 1971;5:137–154. 93. Hilkens, P. H. E., and A. W. De Weerd. Non-convulsive status epilepticus as cause for focal neurological deficit. Acta. Neurol. Scand. 1995;92:193–197. 94. Hojo, K., and Y. Fukushima. A case of partial status epilepticus with various neuropsychological symptoms. Folia Psychiatr. Neurol. Jpn. 1979;33:291–294.
95. Hosford, D. A. Animal models of nonconvulsive status epilepticus. J. Clin. Neurophysiol. 1999;16:306–313. 96. Huott, A. D., D. S. Madison, and E. Niedermeyer. Occipital lobe epilepsy: A clinical and electroencephalographic study. Eur. Neurol. 1974;11:325–339. 97. Inoue, Y., T. Fujiwara, K. Matsuda, et al. Ring chromosome 20 and nonconvulsive status epilepticus: A new epileptic syndrome. Brain 1997;120:939–953. 98. Isaacson, S. H., J. Carr, and A. J. Rowan. Ciprofloxacininduced complex partial status epilepticus manifesting as an acute confusional state. Neurology 1993;43:1619–1621. 99. Juul-Jensen, P., and D. Denny-Brown. Epilepsia partialis continua. Arch. Neurol. 1966;15:563–578. 100. Kanazawa, O., A. Sengoku, and I. Kawai. Oculoclonic status epilepticus. Epilepsia 1989;30:121–123. 101. Kanemoto, K., T. Tomikimi, and J. Kawasaki. Prolonged postictal confusion as a manifestation of continuous complex partial status epilepticus: A depth EEG study. Seizure 2000; 9:151–155. 102. Kaplan, P. W. Assessing the outcomes in patients with nonconvulsive status epilepticus: Nonconvulsive status epilepticus is underdiagnosed, potentially overtreated, and confounded by comorbidity. J. Clin. Neurophysiol. 1999;16:341–352. 103. Kaplan, P. W. Behavioral manifestations of nonconvulsive status epilepticus. Epilepsy Behav. 2002;3:122–139. 104. Kaplan, P. W. No, some types of nonconvulsive status epilepticus cause little permanent neurologic sequelae (or: “The cure may be worse than the disease”). Neurophysiol. Clin. 2000;30:377–382. 105. Kaplan, P. W. Nonconvulsive status epilepticus in the emergency room. Epilepsia 1996;37:643–650. 106. Kaplan, P. W. Prognosis in nonconvulsive status epilepticus. Epileptic Disord. 2000;2:185–193. 107. Karbowski, K. Status psychomotoricus: Klinische und electroencephalographische Aspekte. In K. Karbowski, ed. Status psychomotoricus und seine differential Diagnose. Bern: Verlag Hans Huber, 1980. 108. Katz, A., A. Bose, S. J. Lind, and S. S. Spencer. SPECT in patients with epilepsia partialis continua. Neurology 1990;40: 1848–1850. 109. Kirshner, H. S., T. Hughes, T. Fakhoury, and B. Abou-Khalil. Aphasia secondary to partial status epilepticus of the basal temporal language area. Neurology 1995;45:1616–1618. 110. Kitagawa, T., K. Takahashi, K. Matsushima, and R. Kawahara. A case of polonged confusion after temporal lobe psychomotor status. Folia Psychiatr. Neurol. Jpn. 1979;33: 279–284. 111. Knight, R. T., and J. Cooper. Status epilepticus manifesting as reversible Wernicke’s aphasia. Epilepsia 1986;27:301–304. 112. Kojevnikov, A. Y. A particular type of cortical epilepsy (epilepsia corticalis sive partialis continua). In F. Andermann, ed. Chronic Encephalitis and Epilepsy: Rasmussen’s Syndrome. Boston: Butterworth-Heinemann, 1991:245–262. 113. Komsuoglu, S. S., M. Ozmenoglu, C. Ozcan, and H. Gurhan. Complex partial status epilepticus. Clin. Electroencephalogr. 1988;19:167–171. 114. Kramer, R. E., H. Luders, R. P. Lesser, et al. Transient focal abnormalities of neuroimaging studies during focal status epilepticus. Epilepsia 1987;28:528–532. 115. Krsek, P., A. Mikulecka, R. Druga, Z. Hlinak, H. Kubova, and P. Mares. An animal model of nonconvulsive status epilepticus: A contribution to clinical controversies. Epilepsia 2001;42:171–180.
116. Krieger, A. C., and M. Takeyasu. Nonconvulsive status epilepticus in theophylline toxicity. J. Toxicol. Clin. Toxicol. 1999;37:99–101. 117. Krumholz, A. Epidemiology and evidence for morbidity of nonconvulsive status epilepticus. J. Clin. Neurophysiol. 1999; 16:314–322. 118. Krumholz, A., G. Y. Sung, R. S. Fisher, E. Barry, G. K. Bergey, and L. M. Grattan. Complex partial status epilepticus accompanied by serious morbidity and mortality. Neurology 1995;45:1499–1504. 119. Kudo, T., K. Sato, K. Yagi, and M. Seino. Can absence status epilepticus be of frontal lobe origin? Acta Neurol. Scand. 1995:92:472–477. 120. Kugoh, T., and K. Hosokawa. Mental dullness associated with left frontal continuous focal discharges. Folia Psychiatr. Neurol. Jpn. 1977;31:473–480. 121. Kuzniecky, R., S. Berkovic, F. Andermann, D. Melanson, A. Olivier, and Y. Robitaille. Focal cortical myoclonus and rolandic cortical dysplasia: Clarification by magnetic resonance imaging. Ann. Neurol. 1988;23:317–325. 122. Kuzniecky, R., and R. Powers. Epilepsia partialis continua due to cortical dysplasia. J. Child Neurol. 1993;8:386–388. 123. Lansberg, M. G., M. W. O’Brien, A. M. Norbash, M. E. Moseley, M. Morrell, and G. W. Albers. MRI abnormalities associated with partial status epilepticus. Neurology 1999; 52:1021–1027. 124. Lee, B. I., B. C. Lee, Y. M. Hwang, et al. Prolonged ictal amnesia with transient focal abnormalities on magnetic resonance imaging. Epilepsia 1992;33:1042–1046. 125. Leff, A. P., A. W. McNabb, M. G. Hanna, C. R. Clarke, and A. J. Larner. Complex partial status epilepticus in late-onset MELAS. Epilepsia 1998;39:438–441. 126. Lim, L., P. Yagnik, P. Schraeder, and S. Wheeler. Ictal catatonia as a manifestation of non convulsive status epilepticus. J. Neurol. Neurosurg. Psychiatry 1986;49:833–836. 127. Litt, B., R. J. Wityk, S. H. Hertz, P. D. Mullen, H. Weiss, D. D. Ryan, and T. R. Henry. Nonconvulsive status epilepticus in the critically ill elderly. Epilepsia 1998;39: 1194–1202. 128. Lugaresi, E., P. Pazzaglia, and C. A. Tassinari. Differentiation of “absence status” and “temporal lobe status.” Epilepsia 1971;12:77–87. 129. Lukovitz, T. G., C. E. Fadul, J. M. Pipas, and P. D. Williamson. Nonconvulsive status epilepticus after intravenous contrast medium administration. Epilepsia 1996;37: 1117–1120. 130. Manford, M., and S. D. Shorvon. Prolonged sensory or visceral symptoms: An under-diagnosed form of nonconvulsive focal (simple partial) status epilepticus. J. Neurol. Neurosurg. Psychiatry 1992;55:714–716. 131. Manning, D. J., and L. Rosenbloom. Non-convulsive status epilepticus. Arch. Dis. Child. 1987;62:37–40. 132. Maria, B. L., D. M. Ringdahl, J. P. Mickle, et al. Intraventricular alpha interferon therapy for Rasmussen’s syndrome. Can. J. Neurol. Sci. 1993;20:333–336. 133. Markand, O. N., G. L. Wheeler, and S. L. Pollack. Complex partial status epilepticus (psychomotor status). Neurology 1978;28:189–196. 134. Marrosu, F., A. Brundu, M. G. Rachele, and G. Marrosu. Epileptic aphasia as dynamic disturbance: A case report. Acta Neurol. (Naples) 1983;5:43–46. 135. Masnou, P., F. Salefranque, H. Megas, and J. N. Vidart. Activité critique subintrante et épilepsie frontale: Rôle dans
, , :
87
136.
137.
138. 139.
140.
141. 142.
143.
144.
145.
146.
147.
148. 149. 150.
151.
152.
153.
154.
155. 156.
88
la genèse de troubles du comportement. Epilepsies 1995;6: 235–239. Matsumoto, A., T. Takeuchi, and T. Kumagai. A case of complex partial status epilepticus: Serial EEGs and clinical symptoms change. J. Jpn. Epilepsy Soc. 1986;4:48–57. Matsuoka, H., T. Okuoma, T. Ueno, and H. Saito. Impairment of parietal cortical functions associated with episodic prolonged spike-and-wave discharges. Epilepsia 1986;27: 432–436. Mayeux, R., P. Alexander, D. F. Benson, J. Brandt, and J. Rosen. Poriomania. Neurology 1979;29:1616–1619. Mayeux, R., and H. Lüders. Complex partial status epilepticus: Case report and proposal for diagnostic criteria. Neurology 1978;28:957–961. McBride, M. C., E. C. Dooling, and E. V. Oppenheimer. Complex partial status epilepticus in young children. Ann. Neurol. 1981;9:526–530. McLachlan, R. S., and W. Blume. Isolated fear in complex partial status epilepticus. Ann. Neurol. 1980;8:639–641. McLachlan, R. S., J. P. Girvin, W. T. Blume, and H. Reichman. Rasmussen’s chronic encephalitis in adults. Arch. Neurol. 1993;50:269–274. Melamed, E., S. Lavy, Z. Argov, and M. Feinsod. Absence and automatisms associated with an orbitofrontal meningioma. J. Clin. Psychiatry 1979;40:44–45. Meo, R., L. Bilo, S. Striano, P. Ruosi, A. Estranero, and C. Nocerino. Transient global amnesia accompanied by fever. Seizure 1995;4:311–317. Mikati, M., W. Lee, and G. R. Delong. Protracted epileptiform encephalopathy: An unusual form of partial complex status epilepticus. Epilepsia 1985;26:563–571. Mueller, S. G., S. S. Kollias, A. H. Trabesinger, A. Buck, P. Boesiger, and H. G. Wieser. Proton magnetic resonance spectroscopy characteristics of a focal cortical dysgenesis during status epilepticus and in the interictal state. Seizure 2001;10:518–524. Munari, C., M. Soncini, P. Brunet, et al. Sémiologie électroclinique des crises temporales subintrantes. Rev. EEG Neurophysiol. 1985;15:289–298. Murasaki, M. Psychomotor status: Case report and proposal for classification. Folia Psychiatr. Neurol. Jpn. 1979;33:353–357. Murasaki, M., and A. Takahashi. Complex partial status epilepticus. Jpn. J. Psychiatry 1988;42:515–519. Musolino, R., L. Marabello, P. De Domenico, et al. Complex partial status epilepticus simulating an ischemic insult: Case report. Ital. J. Neurol. Sci. 1991;12:207–210. Nakada, T., H. Lee, I. L. Kwee, and A. M. Lerner. Epileptic Kluver-Bucy syndrome: Case report. J. Clin. Psychiatry 1984;45:87–88. Niedermeyer, E., F. Fineyre, T. Riley, and S. Uematsu. Absence status (petit mal status) with focal characteristics. Arch. Neurol. 1979;36:417–421. Nyquist, P. A., G. D. Cascino, and M. Rodriguez. Seizures in patients with multiple sclerosis seen at Mayo Clinic, Rochester, Minn, 1990–1998. Mayo Clin. Proc. 2001;76: 983–986. Noachtar, S., A. Ebner, O. W. Witte, and R. J. Seitz. Palatal tremor of cortical origin presenting as epilepsia partialis continua. Epilepsia 1995;36:207–209. Obeso, J. A., J. C. Rothwell, and C. D. Marsden. The spectrum of cortical myoclonus. Brain 1985;108:193–224. Oguni, H., F. Andermann, and T. B. Rasmussen. The natural history of the syndrome of chronic encephalitis and epilepsy:
:
157.
158. 159.
160.
161.
162.
163.
164.
165. 166.
167.
168.
169.
170.
171.
172.
173.
174.
175.
A study of the MNI series of forty-eight cases. In F. Andermann, ed. Chronic Encephalitis and Epilepsy: Rasmussen’s Syndrome. Boston: Butterworth-Heinemann, 1991:7–36. Ogunyemi, A. O., G. E. Locke, L. D. Kramer, and L. Nelson. Complex partial status epilepticus provoked by “crack” cocaine. Ann. Neurol. 1989;26:785–786. Oller-Daurela, L. Les crises épileptiques psychiques de longue durée. Rev. Neuropsychiatr. Infant 1970;18:548–557. Omorokov, L. I. Kojevnikov’s epilepsy in Siberia. In F. Andermann, ed. Chronic encephalitis and epilepsy: Rasmussen’s syndrome. Boston: Butterworth-Heinemann, 1991:263–270. Palem, R., L. Force, and J. Esvan. Hallucinations critiques epileptiques et délire (à propos d’un état de mal oculoclonique). Ann. Med. Psychol. 1980;2:161–190. Palmini, A., A. Gambardella, F. Andermann, et al. Intrinsic epileptogenicity of human dysplastic cortex as suggested by corticography and surgical results. Ann. Neurol. 1995;37: 476–487. Passouant, P., N. Duc, J. Cadilhac, and J. Mienvielle. Accès confusionnel de longue durée et décharge épileptique temporale au cours d’une paralysie générale. Rev. Neurol. 1957;96: 229–332. Piccinelli, P., R. Borgatti, E. Perucca, A. Tofani, G. Donati, and U. Balottin. Frontal nonconvulsive status epilepticus associated with high-dose tiagabine therapy in a child with familial bilateral perisylvian polymicrogyria. Epilepsia 2000; 41:1485–1488. Picornell Darder, I., M. Conde, and J. Carbonell. Etat de mal post-traumatique à symptomatologie uniquement psychique. Rev. EEG Neurophysiol. 1978;8:341–344. Primavera, A., G. P. Bo, and S. Venturi. Aphasic status epilepticus. Eur. Neurol. 1988;28:255–257. Primavera, A., C. Solaro, and L. Cocito. De novo status epilepticus as the presenting sign of neurosyphilis. Epilepsia 1998;39:1367–1369. Pritchard, P. B., and D. B. O’Neal. Nonconvulsive status epilepticus following metrizamide myelography. Ann. Neurol. 1984;16:252–254. Racy, A., M. A. Osborn, B. A. Vern, and G. F. Molinari. Epileptic aphasia: First onset of prolonged monosymptomatic status epilepticus in an adult. Arch. Neurol. 1980;37:419–422. Rasmussen, T., J. Olzewski, and D. L. Lloyd-Smith. Focal seizures due to chronic localized encephalitis. Neurology 1958;8:435–445. Rees, J. H., S. J. Smith, D. M. Kullmann, N. P. Hirsch, and R. S. Howard. Creutzfeldt-Jakob disease presenting as complex partial status epilepticus: A report of two cases. J. Neurol. Neurosurg. Psychiatry 1999;66:406–407. Reuber, M., J. Evans, and J. M. Bamford. Topiramate in drugresistant complex partial status epilepticus. Eur. J. Neurol. 2002;9:111–112. Rey, M., and J. J. Papy. Etats d’obnubilation critique d’origine frontale: Un diagnostic clinique difficile. Rev. EEG Neurophysiol. 1987;17:377–385. Roberts, M. A., and P. R. Humphrey. Prolonged complex partial status epilepticus: A case report. J. Neurol. Neurosurg. Psychiatry 1988;51:586–588. Roger, J., H. Lob, and C. A. Tassinari. Status epilepticus. In O. Magnus, and A. M. Lorentz de Haas, eds. Handbook of Clinical Neurophysiology. Vol. 15. The Epilepsies. Amsterdam: North Holland, 1974:145–188. Rogers, D., J. Bird, and P. Eames. Complex partial status after starting vigabatrin. Seizure 1993;2:155–156.
176. Rogers, S. W., P. I. Andrews, L. C. Gahring, et al. Autoantibodies to glutamate receptor GluR3 in Rasmussen’s encephalitis. Science 1994;265:648–651. 177. Rohr-Le Floch, J., G. Gauthier, and A. Beaumanoir. Etats confusionnels d’origine épileptique: Intérêt de l’EEG fait en urgence. Rev. Neurol. 1988;144:425–436. 178. Rosenbaum, D. H., M. Siegel, M. A. Barr, and A. J. Rowan. Epileptic aphasia. Neurology 1986;36:822–825. 179. Russell, D., I. M. Anke, R. Nyberg-Hansen, O. Slettnes, O. Sortland, and T. Veger. Complex partial status epilepticus following myelography with metrizamide. Ann. Neurol. 1980;8: 325–327. 180. Sacquegna, T., P. Pazzaglia, A. Baldrati, P. De Carolis, R. Gallassi, and M. Maccheroni. Status epilepticus with cognitive symptomatology in a patient with partial complex epilepsy. Eur. Neurol. 1981;20:319–325. 181. Schindler, B. A., and D. Ramchandani. Partial complex status epilepticus in a lithium-toxic patient. Psychosomatics 1993;34: 521–524. 182. Scholtes, F. B., W. O. Renier, and H. M. Meinardi. Nonconvulsive status epilepticus: Causes, treatment, outcome in 65 patients. J. Neurol. Neurosurg. Psychiatry 1996;61:93–95. 183. Schomer, D. L. Focal status epilepticus and epilepsia partialis continua in adults and children. Epilepsia 1993;34(Suppl. 1):S29–S36. 184. Scott, J. S., and R. L. Masland. Occurrence of “continuous symptoms” in epileptic patients. Neurology 1952;2:297–301. 185. Semel, J. D. Complex partial status epilepticus presenting as fever of unknown origin. Arch. Intern. Med. 1987;147: 1571–1572. 186. Shalev, R. S., and N. Amir. Complex partial status epilepticus. Arch. Neurol. 1983;40:90–92. 187. Shavit, Y. B., F. Graus, A. Probst, R. Rene, and A. J. Steck. Epilepsia partialis continua: A new manifestation of anti-Hu-associated paraneoplastic encephalomyelitis. Ann. Neurol. 1999;45:255–258. 188. Shibasaki, H., Y. Yamashita, S. Tobimatsu, and R. Neshige. Electroencephalographic correlates of myoclonus. Adv. Neurol. 1986;43:357–372. 189. Shinnar, S., A. T. Berg, D. M. Treiman, W. A. Hauser, D. C. Hesdorffer, J. C. Sackellares, I. Leppik, M. Sillanpää, and K. W. Sommerville. Status epilepticus and tiagabine therapy: Review of safety data and epidemiologic comparisons. Epilepsia 2001;42:372–379. 190. Shorvon, S. Complex partial status epilepticus. In S. Shorvon, ed. Status Epilepticus: Its Clinical Features and Treatment in Children and Adults. Cambridge, U.K.: Cambridge University Press, 1994:116–130. 191. Shorvon, S. Definition, classification and frequency of status epilepticus. In S. Shorvon, ed. Status Epilepticus: Its Clinical Features and Treatment in Children and Adults. Cambridge, U.K.: Cambridge University Press, 1994:21–30. 192. Shorvon, S. Epilepsia partialis continua. In S. Shorvon, ed. Status Epilepticus: Its Clinical Features and Treatment in Children and Adults. Cambridge, U.K.: Cambridge University Press, 1994:84–98. 193. Shorvon, S. Nonconvulsive simple partial status epilepticus. In S. Shorvon, ed. Status Epilepticus: Its Clinical Features and Treatment in Children and Adults. Cambridge, U.K.: Cambridge University Press, 1994:110–116. 194. Singh, B. M., and R. J. Strobos. Epilepsia partialis continua associated with nonketotic hyperglycemia: Clinical and biochemical profile in 21 patients. Ann. Neurol. 1980;8:155–160.
195. Skodda, S., I. Kramer, J. F. Spittler, and W. Gehlen. Nonconvulsive status epilepticus in two patients receiving tiagabine add-on treatment. J. Neurol. 2001;248:109–112. 196. Sowa, M. V., and S. Pituck. Prolonged spontaneous complex visual hallucinations and illusions as ictal phenomena. Epilepsia 1989;30:524–526. 197. Steg, R. E., A. R. Frank, and D. M. Lefkowitz. Complex partial status epilepticus in a patient with dural metastases. Neurology 1993;43:2389–2392. 198. Steinhoff, B. J., and K. M. Eckardt. Clinical and EEG findings in complex partial status epilepticus with tiagabine. Seizure 1999;8:197. 199. Striano, S., F. Barbieri, L. Bilo, P. Ruosi, and M. Soricellis. Recurrent frontal status epilepticus with polymorphic clinical features: A case report. Acta Neurol (Naples) 1990;12:193–199. 200. Sztriha, L., L. Pavics, and E. Ambrus. Epilepsia partialis continua: Follow-up with 99mTc-HMPAO-SPECT. Neuropediatrics 1994;25:250–254. 201. Takeda, A. Complex partial status epilepticus of frontal lobe origin. Jpn. J. Psychiatry 1988;42:525–530. 202. Tarsy, D., and S. C. Schachter. Botulinum toxin treatment is not effective for epilepsy partialis continua. Mov. Disord. 1995;10:357–358. 203. Tatum, W. O., M. R. Sperling, and J. G. Jacobstein. Epileptic palatal myoclonus. Neurology 1991;41:1305–1306. 204. Terzano, M. G., L. Parrino, A. Mazzuchi, and G. Moretti. Confusional states with periodic lateralized epileptiform discharges (PLEDs): A peculiar epileptic syndrome in elderly. Epilepsia 1986;27:446–457. 205. Thomas, J. E., T. J. Reagan, and D. W. Klass. Epilepsia partialis continua: A review of 32 cases. Arch. Neurol. 1977;34:266–275. 206. Thomas, P., and F. Andermann. Absence status in elderly patients is most often situation-related. In A. Malafosse, P. Genton, E. Hirsch, C. Marescaux, D. Broglin, and R. Bernasconi, eds. Idiopathic Generalized Epilepsies: Clinical, Experimental and Genetic Aspects. London: John Libbey, 1994:95–109. 207. Thomas, P., P. Barrès, and M. Chatel. Complex partial status epilepticus of extra-temporal origin: Report of a case. Neurology 1991;41:1147–1149. 208. Thomas, P., M. Borg, G. Suisse, and M. Chatel. Opercular myoclonic-anarthric status epilepticus. Epilepsia 1995;36: 281–289. 209. Thomas, P., K. Giraud, H. Alchaar, and M. Chatel. Ictal asomatognosia with hemiparesis. Neurology 1998;51:280–282. 210. Thomas, P., B. Kullmann, and M. Chatel. Etat de mal épileptique à expression aphasique. Rev. Neurol. 1991;147: 246–250. 211. Thomas, P., and Y. Mottin. Etat de mal frontal non convulsif. Rev. Neurol. 1997;153:421–426. 212. Thomas, P., B. Zifkin, O. Migneco, C. Lebrun, J. Darcourt, and F. Andermann. Nonconvulsive status epilepticus of frontal origin. Neurology 1999;52:1174–1183. 213. Tinuper, P., U. Aguglia, S. Laudadio, and H. Gastaut. Prolonged ictal paralysis: Electroencephalographic confirmation of its epileptic nature. Clin. Electroencephalogr. 1987;18:12–14. 214. Tomson, T., U. Lindbom, and B. Y. Nilsson. Nonconvulsive status epilepticus in adults: Thirty two consecutive patients from a general hospital population. Epilepsia 1992;33: 829–835. 215. Tomson, T., E. Svanborg, and J. E. Wedlund. Nonconvulsive status epilepticus: High incidence of complex partial status. Epilepsia 1986;27:276–285.
, , :
89
216. Treiman, D. M. Electroclinical features of status epilepticus. J. Clin. Neurophysiol. 1995;12:343–362. 217. Treiman, D. M., and A. V. Delgado-Escueta. Complex partial status epilepticus. In A. V. Delgado-Escueta, C. G. Wasterlain, D. M. Treiman, and R. J. Porter, eds. Status Epilepticus. Adv. Neurol. 1983;34:69–81. 218. Treiman, D. M., and A. V. Delgado-Escueta. Status epilepticus. In R. A. Thompson, and J. R. Green, eds. Critical Care in Neurologic and Neurosurgical Emergencies. New York: Raven Press, 1980:53–99. 219. Treiman, D. M., A. V. Delgado-Escueta, and M. A. Clark. Impairment of memory following complex partial status epilepticus. Neurology 1981;31(Suppl. 4):S109. 220. Trinka, E., T. Moroder, M. Nagler, W. Staffen, W. Loscher, and G. Ladurner. Clinical and EEG findings in complex partial status epilepticus with tiagabine. Seizure 1999;8: 41–44. 221. Van Rossum, J., and A. A. W. Groeneveld-Ockhuysen. Psychomotor status. Arch. Neurol. 1985;42:989–993. 222. Varma, N. K., and S. I. Lee. Nonconvulsive status epilepticus following electroconvulsive therapy. Neurology 1992;42: 263–264. 223. Vernea, J. Partial status epilepticus with speech arrest. Proc. Austr. Assoc. Neurol. 1974;11:223–228. 224. Villemure, J. G., F. Andermann, and T. Rasmussen. Hemispherectomy for the treatment of epilepsy due to chronic encephalitis. In F. Andermann, ed. Chronic Encephalitis and Epilepsy: Rasmussen’s Syndrome. Boston: ButterworthHeinemann, 1991:235–244. 225. Vining, E. P., J. M. Freeman, J. Brandt, B. S. Carson, and S. Uematsu. Progressive unilateral encephalopathy of childhood (Rasmussen’s syndrome): A reappraisal. Epilepsia 1993;34: 639–650. 226. Wakai, S., M. Ikehata, H. Nihira, et al. “Obtundation status (Dravet)” caused by complex partial status epilepticus in a patient with severe myoclonic epilepsy in infancy. Epilepsia 1996;37:1020–1022. 227. Watanabe, K., Y. Kuroiwa, and Y. Toyokura. Epilepsia partialis continua: Epileptogenic focus in motor cortex and its participation in transcortical reflexes. Arch. Neurol. 1984;41: 1040–1044. 228. Weiner, R. DECT-induced status epilepticus and further ECT: A case report. Am. J. Psychiatry 1981;138:1237–1238. 229. Wells, C. R., D. R. Labar, and G. E. Solomon. Aphasia as the sole manifestation of simple partial status epilepticus. Epilepsia 1992;33:84–87. 230. Wieser, H. G. Temporal lobe or psychomotor status epilepticus: A case report. Electroencephalogr. Clin. Neurophysiol. 1979; 48:558–572. 231. Wieser, H. G., H. P. Graf, C. Bernouilli, and J. Siegfried. Quantitative analysis of intracerebral recordings in epilepsia partialis continua. Electroencephalogr. Clin. Neurophysiol. 1977;44: 14–22. 232. Wieser, H. G., S. Hailemariam, M. Regard, and T. Landis. Unilateral limbic epileptic status activity: Stereo EEG, behavioural and cognitive data. Epilepsia 1985;26:19–29. 233. Wieser, H. G., H. Hungerbüler, A. M. Siegel, and A. Buck. Musicogenic epilepsy: Review of the literature and case report with ictal single photon emission tomography. Epilepsia 1997;38:200–207. 234. Williamson, P. D., D. D. Spencer, S. S. Spencer, et al. Complex partial status epilepticus: A depth electrode study. Ann. Neurol. 1985;18:647–654.
90
:
235. Wolf, P. Zur Klinik und Psychopathologie des Status psychomotoricus. Nervenartz 1970;41:603–610. 236. Zappoli, R., G. Zaccara, L. Rossi, G. Arnetoli, and A. Amantini. Combined partial temporal and secondary generalised status epilepticus: Report of a case with fear bouts followed by prolonged confusion. Eur. Neurol. 1983;22: 192–204.
8
Absence Status
, ,
Introduction Status epilepticus may be classified for practical purposes into convulsive status epilepticus, which must be rapidly stopped to prevent death or neurologic sequelae, and nonconvulsive status epilepticus (NCSE), in which the diagnosis is not obvious and must be confirmed by urgent electroencephalography (EEG). NCSE may be further classified into nonconfusional and confusional forms (100, 183). Nonconfusional NCSE is characterized by various somatosensory, visual, auditory, psychic, or vegetative symptoms that by definition occur without any impairment of consciousness. Confusional NCSE, by contrast, is characterized by some degree of clouding of consciousness. NCSEs are classically also divided on the basis of the ictal EEG into absence status epilepticus (ASE) and complex partial status epilepticus (CPSE). CPSE is characterized by continuous or rapidly recurring complex partial seizures that may involve temporal or extratemporal regions, or both (see Thomas et al., Chapter 7, this volume). ASE is the most frequent form of NCSE and often constitutes a diagnostic challenge. By definition, it is accompanied by predominantly symmetric synchronous ictal discharges and has heterogeneous clinical and EEG manifestations.
Historical perspective Well before the advent of EEG, nonconvulsive confusional states were recognized as epileptic by Pritchard, Trousseau, Jackson, Wilks, Colman, and Clark and Prout (166). In one of his Tuesday lectures in January 1888, Charcot described a healthy 37-year-old deliveryman with episodes of prolonged automatisms during which he walked from place to place throughout Paris. Charcot believed that this “poriomania,” or prolonged ambulatory fugue state, was related to an epileptic breakdown of consciousness (33, 74) and later proposed a trial of potassium bromide, an early antiepileptic drug. In 1927, Ratner described for the first time a confusional state lasting several hours in a child with pyknoleptic absence (93). Ratner recognized the ictal nature of this confusion and considered it a form of SE. In 1938, several years after the introduction of the EEG, W. G. Lennox recorded periods of continuous spike-and-wave discharges and altered level of consciousness, after insulin-induced hypoglycemia in one of his cousins, a child with absence epilepsy. Lennox
believed that this represented very brief absences in rapid succession without a return to the usual level of consciousness, and in 1945 he suggested the term Petit Mal status to describe this pattern (113, 114). The first case of ASE documented in a young adult had been published three years earlier by Putnam and Merritt in 1941 (150).
Concepts of absence status and problems in terminology and classification P M S For about a decade following the original description by Lennox, the term Petit Mal status was used without further qualification in several isolated case reports (17, 71, 103, 125, 153). Interest in this syndrome then appeared to wane until the work of Niedermeyer and Kalifeh (130), who reported that during ASE, the alteration of consciousness seemed to be less profound than that noted during typical absence attacks. Similarly, the EEG expression of these was also atypical, consisting of spike-and-wave discharges that were neither as regular nor as continuous as those of absence seizures. Also, these epileptic confusional states could appear in patients with severe epilepsy associated with mental retardation. These authors preferred the less specific and more descriptive term spike-wave stupor rather than Petit Mal status. Lob expressed similar reservations in his doctoral thesis (120, 121). The term Petit Mal status suggested that the patient had a preexisting but well-characterized type of epilepsy, the “Petit Malabsence,” now described as childhood absence epilepsy (36). However, it became clear that these forms of SE could occur in patients whose epilepsy manifested with seizure types other than absence seizures and who had no history of idiopathic generalized epilepsy, and even in patients with no history of epilepsy. Moreover, the term Petit Mal status implied, according to Lennox’s original description, a clinical pattern limited to prolonged or serial typical absence attacks that were sufficiently close together to give rise to a prolonged disturbance of consciousness, and an EEG pattern limited to the classic ictal 3-Hz spike-and-wave pattern. The problems arising from use of the term Petit Mal status, the variety of clinical presentations, the etiologic and pathogenic questions raised by these events, and the lack of precise definitions of the terms used may explain the extraordinary development in the 1950s and 1960s of new names for what were very similar clinical entities. Shorvon
, , :
91
(164, 165) referred to this situation as a “nosographic labyrinth.” Some of these terms included “prolonged epileptic twilight state with almost continuous wave-spikes” (201), “prolonged alterations in behavior associated with a continuous EEG spike-and-dome abnormality” (24), “epilepsia minoris continua” (59), “simple epileptic confusional state” (66), “prolonged behavioral disturbance as ictal phenomena” (75), “spike-wave stupor, ictal stupor” (130), and “minor status epilepticus” (28). T A A S In an attempt to unify the concept, the Commission on Classification and Terminology of the International League Against Epilepsy in 1970 retained the term absence status, which Gastaut, Roger, and Lob had proposed in October 1962 during the Xth Marseilles Colloquium (63–65). This term was also adopted by the expert committee of the World Health Organization in the Dictionary of Epilepsy (66). The definition of absence status was intentionally loose: a prolonged or repeated absence seizure, thus representing status epilepticus. Clinically, AS is essentially or exclusively characterized by impairment of consciousness of varying intensity, persisting hours to days, occasionally leading to an epileptic fugue. The EEG findings exceptionally consist of continuous or discontinuous rhythmic 3 Hz SW discharges similar to those encountered in typical absence seizures; more often one finds more or less rhythmic SW or polyspike-wave (PSW) discharges sometimes interrupted by slow background activity.
Unfortunately, despite Gastaut’s efforts at unification, terminological confusion continued. Although many authors adopted the term absence status without reservation (7, 32, 61, 68, 76, 109, 124, 129, 132, 152, 164), semantic disorder persisted, and many new terms appeared after 1970, among them “centrencephalic condition of prolonged disturbance of consciousness” (81), “ictal psychosis” (197), “prolonged confusion as an ictal state” (52), “acute prolonged ictal confusion” (188), and “generalized nonconvulsive status epilepticus” (79). Although the Commission on Classification and Terminology (63–65) advised against use of the term Petit Mal status, it continued to be widely used in scientific reports (8, 14, 45, 49, 69, 70, 87, 102, 134, 136, 155, 160, 171, 192). This term has become familiar and is encountered to the present day, especially informally among neurologists. Finally, a third group of authors took an approach to definition that was diametrically opposed to that of Gastaut and used the term absence status literally, reserving it only for those episodes of SE made up of a succession of typical absence attacks, and used other terms, such as Petit Mal status (145), spike-wave stupor (11, 37, 156), or generalized nonconvulsive status epilepticus (79), to describe any other electroclinical forms. This only led to greater difficulties in terminology and classification.
92
:
In a further attempt at clarification, Gastaut suggested at the 1983 Santa Monica Colloquium a new classification of AS (65), distinguishing “typical” AS, with an excellent prognosis, occurring in patients with idiopathic generalized epilepsy and characterized by a simple confusional state with rhythmic 3-Hz spike-and-wave discharges, and “atypical” absence status, occurring mainly in patients with symptomatic and/or cryptogenic generalized epilepsy. This atypical variety could be conceptualized as a transient exacerbation of the epileptic symptomatology superimposed on a chronic epileptogenic encephalopathy, such as the Lennox-Gastaut syndrome (13). Episodes of atypical AS were characterized by periods of confusion accompanied by more marked motor manifestations and associated with spike-and-wave discharges slower than 3 Hz, with a variable rhythmicity and regularity (65). Moreover, these atypical AS episodes were clearly distinguishable from typical AS episodes by their associated clinical features, including pseudoataxia and/or pseudodementia, their prolonged duration (several days or several weeks), their tendency to recur, and their pronounced resistance to treatment, benzodiazepines usually being ineffective (44, 60, 137, 169). Gastaut thus suggested the clinical and nosographic limits of these two types of AS, but the two forms could at times occur in the same patient. This was further described by Beaumanoir et al. (13) in the Lennox-Gastaut syndrome and by Brotkorb et al. (30) in mentally retarded adults, leading to further attempts at subclassification of atypical AS, which have unfortunately been little used since (163, 164). N C U C Newly reported cases that could not be correctly classified added yet further difficulties. New terms were again proposed by several authors: “borderline petit mal status” (87), “transitional petit mal status” (164), and “absence status with focal characteristics” (129). These events were occasionally encountered in patients with localization-related epilepsy and were characterized by EEG patterns with focal features that were considered too significant to justify their classification within the group of generalized epilepsies (61, 87, 129). This “imperfectly generalized” ictal pattern was compared to the focalictal discharges of CPSE (see Thomas et al., Chapter 7, this volume) and helped blur the distinctions between the two entities. New theoretical pathophysiologic mechanisms were discussed, mainly based on the works of Tükel and Jasper in Montreal and on stereo-EEG (depth electrode) studies by Bancaud and Talairach in Paris, who demonstrated that a single epileptic focus could give rise to secondary bilaterally synchronous discharges, particularly when this focus involved mesial-frontal structures (10, 138, 186). Several authors had indeed emphasized the similarities between certain forms of AS and CPSE of frontal origin (3,
61, 155, 176, 179). These similarities are probably not fortuitous: several reports show the transformation from CPSE with frontopolar focal ictal discharges into an AS with a perfectly bilateral and symmetric EEG pattern (2, 19, 109, 129, 157, 172, 176). These occasional but well-documented reports may explain the development of AS with “generalized” discharges during the course of an extratemporal localization-related epilepsy, especially of frontal lobe origin (9, 109, 176). “D N” A S L O A further group of patients was described in which AS first occurred in elderly subjects with no previous history of seizures. In 1964, Shev underlined the rarity of AS in adults (162). Isolated cases were described by Elian (51) and by Amand (5). In 1971, Schwartz and Scott (161) published four cases of AS appearing “de novo” in middle-aged or elderly adults with no previous history of seizures. They suggested that these cases could represent “the extreme end of a continuum of petit mal epilepsy extending from childhood to middle age.” However, later observations showed that this is not usually so. Since 1971, about 100 such patients have been described in the literature (11, 26, 37, 48, 52, 54, 55, 70, 76, 86, 109, 110, 114, 133, 146, 148, 152, 156, 172, 173, 175, 178, 179, 186–190, 193, 196, 197). Different designations have been used: “isolated petit mal status presenting de novo in middle age” (85, 160), “senile petit mal epilepsy” (133), “de novo minor status epilepticus of late onset” (11), “toxic ictal confusion in middle age” (186, 187), and “de novo absence status of late onset” (55, 172, 173, 175). The average age of the patients is in the sixth decade, and there is a clear preponderance of women. Many of the subjects have preexisting psychiatric symptoms. In three-quarters of the cases, the AS occurs with a toxic or metabolic systemic disorder (173, 187). Among triggering factors, psychotropic drugs seem to be prominent and were present in 39 individuals in a series of 79 such patients (172). The AS may occur with high doses of psychotropic drugs or with a sudden withdrawal of the medication: several reports have emphasized the role of benzodiazepine withdrawal (48, 94, 175). A combination of factors such as a simultaneous toxic and metabolic encephalopathy is characteristic. These data indicate that “de novo” AS is more often an acute symptomatic seizure rather than the late resurgence of a hypothetical childhood absence epilepsy. This clinical entity is thus probably best designated situation-related AS and should be included in the current syndromic classification of the epilepsies (36) among the “special syndromes—situation-related seizures” (165, 173, 186). C C A S The pathophysiology of ASE is not well understood, and it would
therefore be misleading to classify these events according to rigid clinical criteria. Like absence seizures, ASE can occur within a broad neurobiologic continuum and can complicate virtually any epileptic syndrome (1, 18). We believe that it is preferable to conceptualize the different forms of ASE as individual events within the natural history of a particular form of epilepsy, although certain forms may represent the beginning of an encephalopathy that manifests clinically with episodes of ASE. The prognostic implications of ASE are thus related more to the epileptic syndrome within which they occur than to the electroclinical characteristics of the episodes themselves. We believe that four types of ASE may be recognized (Figure 8.1): typical absence status (or Petit Mal status), atypical absence status (or spike-wave stupor); de novo absence status of late onset (situation-related nonconvulsive status epilepticus), and absence status with focal features. However, it must be clearly recognized that the vast majority of cases appear to be transitional forms between these better defined clinical entities. Typical absence status Typical AS occurs as part of an idiopathic generalized epilepsy most often characterized by absences. Isolated impairment of consciousness, at times with subtle jerks of the eyelids, is the essential symptom. The EEG correlates with repetitive absence seizures and shows symmetric and bilaterally synchronous spike-and-wave or polyspike-and-wave complexes faster than 3 Hz (Figure 8.2), but this pattern is often not strictly maintained as the event continues. The immediate prognosis is excellent: intravenous (IV) benzodiazepine injection stops the AS. Atypical absence status Atypical AS occurs in patients with symptomatic or cryptogenic epilepsies and is characterized by a fluctuating confusional state with more prominent tonic and/or myoclonic and/or lateralized ictal manifestations than occur in typical AS (138). The EEG shows continuous or intermittent diffuse irregular slow spike-and-wave or polyspike-and-wave complexes (Figure 8.3). The immediate prognosis is guarded, as these episodes tend to recur and to be resistant to medication. De novo absence status of late onset This condition is characterized by toxic or metabolic precipitating factors leading to seizures in middle-aged or elderly subjects with no previous history of attacks. Patients often have a history of psychiatric illness with multiple psychotropic drug intake. The electroclinical characteristics (Figure 8.4) and the immediate prognosis are variable. These episodes of AS generally represent acute symptomatic seizures and may not recur if the triggering factors can be controlled or corrected. Long-term antiepileptic drugs thus may not be needed.
, , :
93
F 8.1 The nosography of absence status. Most cases represent transitional forms between the four distinct and well-defined clinical entities.
Absence status with focal features This condition occurs in subjects with a preexisting or newly developing localizationrelated epilepsy, most often of extratemporal origin. The EEG shows bilateral but often asymmetric ictal discharges (Figure 8.5). Many of these cases may represent CPSE of frontal lobe origin (176), and the EEG may not conclusively distinguish these from AS, especially late in the episode. The immediate prognosis is variable but is reportedly poor in critically ill elderly patients (116).
Epidemiology Lob et al. (121) found that of 148 patients collected by 1962, 93% had preexisting epilepsy, and 92% of these patients had a form of idiopathic generalized epilepsy. Nevertheless, only 16% of these had only absence seizures. Only 11 patients had
94
:
no history of epilepsy. Porter and Penry (146) found that 85% of patients had preexisting epilepsy. Of the patients discussed by Rohr-Le Floch et al. (156), 78% had preexisting epilepsy, and all of these had idiopathic generalized epilepsy. Dalby (40) found that 6.2% of patients with idiopathic generalized epilepsy had had episodes of AS. Patients with absences more often had AS (9.3%) than those who did not (3.4%). In patients with childhood- and adolescence-onset absence epilepsy, the incidence of AS has varied: 5.8% of patients according to Loiseau and Cohadon (122), 9.9% for Livingston et al. (118), 28.3% for Lorentz de Haas and Magnus (123), 37.7% for Oller-Daurella (140). However, with a 100 per million prevalence of absence epilepsy and a 1% occurrence of AS in these patients, Shorvon estimated the annual incidence of typical AS to be very low, occurring in about 1 per million persons in the general population (164).
F 8.2 Typical absence status in a 15-year-old girl with juvenile absence epilepsy. AS followed withdrawal of valproate and administration of carbamazepine. The only clinical signs were cognitive slowing and subtle eyelid myoclonus. The EEG shows bursts
of 3-Hz polyspike-and-wave activity organized in brief absences lasting 4–6 seconds. The EEG was almost normal between these bursts.
AS has been reported in SCGE such as the LennoxGastaut syndrome in 15%–40% of patients (46, 140). Other studies (13, 47) show that almost all these patients have periods of epileptic confusional states at one time or another. In a mentally handicapped population, the annual incidence of NCSE is estimated at 100–200 cases per million (166). No reliable data are available to estimate the occurrence of de novo AS of late onset. Studies from emergency wards of general hospitals in which EEG is immediately available, generally in cities of 1 million or more, describe two to five new cases per year (155, 158, 178, 179).
in some patients with CPSE of presumed amygdalohippocampal origin (181).
Clinical features The cardinal clinical sign of AS is variable clouding of consciousness, ranging from subtle subjective impairment of thought processes to severe stupor with incontinence. Subtle motor signs are seen in half the patients. In 90% of cases the confusional symptoms fluctuate, this fluctuation being most marked when the level of consciousness is relatively well preserved (155). This fluctuation is an important factor in favor of the ictal nature of the confusional state. However, impairment of consciousness in AS is never clearly organized in a cyclic and a discontinuous way, as may be observed
C C Although the alteration of consciousness in AS is best represented by a continuum (7), recognition of four grades of severity in disturbance of consciousness (120, 154, 164) may be useful in clinical practice. This classification was based on the largest series of AS, the 148 cases collected at the time of the 1962 Marseilles Colloquium (62). Slight clouding Slight clouding of consciousness is present in 19% of cases. This consists of simple slowing of thought processes and expression, often so subtle that only the patient himself can recognize it. There is no true mental confusion (8, 144). Patients with recurrent AS may learn to recognize these periods, which may be defined as “bad days” or described as “a lack of efficiency” or “the inability to perform at a normal level” (7). Lennox (113) reported the case of a physician who continued his work but felt himself unable to make difficult diagnoses during his episodes. Dongier (43) described a businessman who was able to drive his car but recognized that he was unable to brake soon enough before an obstacle.
, , :
95
F 8.3 Atypical absence status in a 15-year-old boy with Lennox-Gastaut syndrome. His head and eyes were slightly turned to the right and he was moderately confused, with periocular myoclonia and hypersalivation. The EEG shows almost continuous
irregular bilateral 2-Hz spike-and-wave complexes with left centrotemporal predominance. IV benzodiazepines and phenytoin were ineffective. Only high-dose IV methylprednisolone (5 mg/kg) led to cessation of the episode. This AS episode lasted 16 days.
Patients with the mildest degree of disturbance have no apparent psychological disturbance, are oriented in time and space, and are able to speak fluently. They are aware of what is happening to them and are not amnestic for their periods of AS. Shorvon (164) noted the frequent and striking dissociation between these mild clinical manifestations and the impressive ictal EEG abnormalities. Although these patients are able to carry on with typical activities of daily living, they are unable to normally perform complex intellectual tasks involving choices, strategy, planning, or initiative. A patient described by Rigal et al. (154) attempted to take the bus to work despite a transport strike, eventually reached her office, and worked throughout the morning. The only unusual thing her colleagues noted was that she did not stop for lunch at noon. Some of the mild
manifestations of intellectual dysfunction may be expressed as somatic symptoms, particularly headache: one of our patients reported a 2-day history of unusual moderate frontal tension-like headache that immediately disappeared when her AS ceased with IV benzodiazepine (unpublished personal observation). Formal neuropsychological testing, in one report including dichotic listening (57), may be necessary to document mild degrees of altered consciousness in AS (133, 196). In our experience, the Stroop test, which requires sustained attention, is sensitive and quickly administered (75). Roger, Lob, and Tassinari (155) noted that the most sensitive neuropsychological tests in AS were those requiring sustained attention, sequencing of tasks, and spatial ability. Neuropsychological deficits may also suggest a more localized
96
:
F 8.4. De novo AS in a 50-year-old man with no history of epilepsy, occurring after withdrawal of benzodiazepines (clorazepate, 200 mg/d; lorazepam, 12.5 mg/d; triazolam, 2 mg/d). He
was stuporous and confused, with eyelid myoclonia. The EEG shows continuous slow diffuse irregular polyspike-and-wave complexes. AS stopped 12 hours after a 50-mg oral dose of clorazepate.
disturbance (69, 164), typically with sparing of language, unlike some cases of CPSE. Vuillemier et al. (196) described a patient with pronounced isolated pure retrograde amnesia.
clumsily and slowly, and sequential tasks are usually interrupted more because of attention difficulties than because of a true apraxia. Automatic behavior of variable complexity may occur during these periods of confusion, which are otherwise marked by a global reduction of activity. Simple gestural automatisms are frequent. More elaborate motor patterns, which appear to represent a combination of complex automatisms and the behavioral disturbance caused by the clouding of consciousness, are associated with perseverative and compulsive features, a highly suggestive feature of AS. One of our patients repeatedly tried to put her fingers into electrical outlets. Another patient began his episode of AS while leaving the psychiatric ward; as a gesture of farewell, he repeatedly kissed his nurse on the cheek over 15 times. These complex automatisms may occasionally be responsible for prolonged fugue states (poriomania) which may
Marked clouding of consciousness Marked clouding of consciousness is most typical and is reported in 64% of cases. A frank confusional state occurs, with disturbance of alertness, attention, memory, judgment, and language, and with some agnosia and apraxia. The patients are severely disoriented. They are usually calm, immobile, and indifferent, with little or no spontaneous language or motor activity. Simple commands are obeyed only after repeated requests, often correctly but very slowly and after some delay. Patients are usually unable to follow more complex commands. Language is reduced to fragmented, hesitant, and at times irrelevant responses interrupted by long pauses. Echolalia and palilalia may be present. Motor tasks are performed
, , :
97
F 8.5. AS with focal characteristics, possibly frontal CPSE, in a 55-year-old woman with cryptogenic left frontocentral epilepsy. She was moderately confused, with some emotional disinhi-
bition, echolalia, and palilalia. The EEG shows bilateral 1.5-Hz slow spike-and-wave complexes with clear left frontotemporal predominance.
sometimes have an explicit goal. A patient of Friedlander and Feinstein (60) suddenly left his home and went directly to the EEG laboratory. At times some of these behaviors may cause legal problems; examples include compulsive masturbation (92), episodes of disrobing in public (59), and destructive behavior (7). In these cases there is a variable degree of amnesia for the confusional episode. When the AS is characterized by marked fluctuations, the patient can often report fragmented memories of events during the episode.
A S Myoclonus Myoclonus is the most frequent and most suggestive associated sign, occurring in about half of cases (155, 156). It is an important diagnostic clue, as it does not occur in CPSE (156). A history of myoclonic episodes associated with confusion can suggest a retrospective diagnosis of AS, especially in patients with preexisting IGE. The myoclonus of AS is characterized by bilateral jerks of the eyelids or face, most often subtle and intermittent, and more easily diagnosed with the patient’s eyes closed. Mann and Leslie (126) emphasized “vibration of the eyelashes.” Myoclonic jerks may occasionally involve the arms and hands. This may be asymmetric, falsely suggesting a localization-related SE (155). Rarely, they may be so marked as to dominate the presentation, overlapping clinically with myoclonic SE (171, 185). Two episodes of AS documented in patients with juvenile myoclonic epilepsy were characterized by myoclonus just like the patients’ typical morning myoclonic jerks (106). Epileptic negative myoclonus may also be intermingled with the positive myoclonic jerks (unpublished personal observation).
Profound clouding of consciousness Profound clouding of consciousness is reported in 7% of cases. Even with vigorous stimulation, only very brief and limited motor or verbal responses can be elicited. The patients remain motionless. They are frequently incontinent, cannot move without help, and are unable to feed themselves. Lethargic stupor Lethargic stupor is reported in 8% of cases. This resembles catatonic stupor with apparent suspension of all psychic activity. Patients are motionless, with eyes turned upward, and are incontinent of urine and stool. They are completely dependent and react only to strong, painful stimulation.
98
:
Other clinical manifestations Psychiatric manifestations have been reported in atypical AS. These include aggressive behavior, hallucinations, illusions, experiential phenomena, and psychotic depression (7, 43, 56, 75, 89). These symptoms are very unusual and, if present, are never as marked as those that occur in CPSE (156).
Establishing the diagnosis When a reliable clinical history can be obtained and the beginning of the confusional state is reportedly sudden, its epileptic nature may be suspected. However, for obvious reasons, continuous EEG documentation prior to hospitalization is very rare. Primary or secondarily generalized tonic-clonic seizures may appear at the beginning (7, 12, 54, 79) or more classically at the end of ASE. When the seizures occur at the onset, the unusually long duration of the presumed postictal confusional period should raise a suspicion of the diagnosis, and EEG should therefore be performed urgently. Convulsive seizures may also occur during the course of an episode of ASE (7). The delay in diagnosis is often long. Rohr-Le Floch et al. (156) found that the correct diagnosis was made at the time of initial clinical examination in only 4 of 60 cases (7%). In 18 (30%) of 60 cases, the diagnosis was a prolonged postictal state. In recent series (95, 172), delays in diagnosis ranged from 8 hours to 4 days. As noted by Kaplan (100), the altered mental status of ASE may be attributed to a metabolic disturbance or to excessive psychotropic drug use or withdrawal, each of which may also induce AS. In these cases, impaired consciousness can result in a combination of ASE and encephalopathy, and it may be impossible to assess the relative part played by these two factors. Furthermore, in SCGE, subtle worsening of cognitive impairment may be difficult to discern in a patient with mental retardation. In most cases, nonictal events are first suspected before the diagnostic EEG is obtained. Even when NCSE is suspected, ASE may be clinically indistinguishable from CPSE, especially of frontal lobe origin. The most frequent initial diagnoses have included prolonged postictal confusion, prolonged postictal encephalopathy, various psychiatric diagnoses such as depression, acute or interictal psychoses, Ganser’s syndrome, puerperal psychosis, and hysteria; medication overdose or idiosyncratic reaction to antiepileptic drugs, toxic or metabolic encephalopathy, overdose of psychotropic drugs, psychotropic drug withdrawal, amnesia or automatisms related to a short-acting benzodiazepine, transient global amnesia, frontal lobe stroke, aphasia, and transient unresponsiveness in the elderly (23, 80, 84, 95, 156, 158, 178, 179). A catatonic state clinically similar to ASE and reversed by IV benzodiazepines, but without EEG abnormalities, and a similar state during ifosfamide-induced
confusion were reported by Louis and Pflaster (123) and by Simonian et al. (166), respectively. In recent years, several papers in the literature have tended to lump together NCSE, subtle SE, myoclonic SE, and EEG patterns suggestive of SE in comatose patients (93, 108). For instance, Mayer et al. included seven patients with “nonconvulsive status epilepticus” in “comatose or obtunded patients” (127), and among the patients studied by Towne et al. (180), 8% of comatose patients had “an EEG pattern suggestive of SE,” a pattern whose validity has been challenged by Benbadis et al. (15). This conceptual extension appears to have been caused by some degree of misinterpretation of EEG findings. Prominent generalized paroxysmal activity in comatose patients is usually the expression of a very severe encephalopathy rather than of NCSE (131). As proposed by Kaplan (98, 101), the term electrographic SE in coma is more appropriate, in its neutrality, to characterize generalized seizure activity in deeply obtunded patients with severe brain injury. Similarly, “subtle” SE (182), the extreme end of an untreated or insufficiently treated generalized tonic-clonic SE with minimal clinical expression, cannot and must not be confused with NCSE because the context of occurrence, clinical features, prognosis, and treatment are dramatically different. Severe mental confusion in ASE may express itself as catatonia, but this presentation is radically different from a comatose state.
EEG, therapeutic trial of benzodiazepines, and immediate use of other drugs Emergency EEG is the key to confirmation of the diagnosis of AS. EEG confirms the ictal nature of the confusion and settles issues of differential diagnosis. The main practical problem is to think of the diagnosis and to rapidly obtain the EEG: Kaplan notes that in most instances, “the diagnosis was all too evident in retrospect, and frequently missed or delayed initially” (100). Timely diagnosis of NCSE is one of the main reasons for maintaining rapid access to EEG from the emergency ward (104). EEG C A S The essential EEG feature of AS is a bilateral, synchronous, symmetric paroxysmal activity that is unreactive to sensory stimulation. The most characteristic tracings show continuous trains or frequently repeated bursts of polyspike-and-slow-wave complexes or slow spike-and-wave complexes that are diffuse, rhythmic, and nonreactive (179). The EEG manifestations may nevertheless be so variable that, as Porter and Penry (145) noted, “virtually any generalized continuous or nearly continuous abnormality could be a substrate for this syndrome.” Roger, Lob, and Tassinari (154) found that half of the cases of ASE in patients with idiopathic generalized
, , :
99
epilepsy had continuous, usually rhythmic, bilaterally synchronous and symmetric spike-and-wave or polyspike-andwave discharges with a bifrontal predominance and a frequency between 1.5 and 3 Hz. More rarely, the discharges were discontinuous and broken up into bursts separated by more or less normal background rhythms. Continuous spikeand-wave activity could also become discontinuous during the same EEG recording. Only rarely does the spike-and-wave activity occur at precisely 3 Hz. In 80% of cases it ranges from 1 to 2.5 Hz. Granner and Lee (77) reported on 59 patients with ASE whose paroxysmal activity ranged in frequency from 1.0 to 3.5 Hz, with a mean of 2.2 ± 0.6 Hz. Only 7% had an ictal EEG pattern of typical absence. One-fourth of the patients showed some focal predominance of their paroxysmal activity. More rarely, the spike-and-wave activity may be unusually rapid, from 4 to 6 Hz (61), or unusually slow, slower than 1 Hz (87). Other variants of the ictal epileptiform activity include irregular slow spike-and-wave activity (17), slow waves with sporadic spike-and-wave complexes (154, 177), rhythmic triphasic slow waves (160, 198), and a polyspike
F 8.6 A positive diagnostic and therapeutic trial of IV benzodiazepines in an 82-year-old woman with de novo AS. The EEG shows continuous irregular polyspike-and-slow-wave activity which
100
10–20 Hz recruiting rhythm (113, 151). Polygraphic recording in patients with SCGE (167) shows that this last variant may also occur with subtle tonic SE associated with confusion. In these unusual EEG presentations, correct identification of AS is a challenging problem, given the fact that any rhythmic EEG activity recorded during a confusional state does not inevitably correspond to AS (15). There is no clear correlation between the degree of altered consciousness and the EEG. Stupor may, however, be more frequently associated with the pattern of continuous rhythmic 3-Hz spike-and-wave activity (164). T T B The IV injection of a benzodiazepine during the EEG recording is mandatory in order to confirm the ictal nature of the episode (Figure 8.6). There may indeed be difficulties in distinguishing true ictal epileptiform EEG patterns from interictal or nonictal EEG discharges (101), such as, for example, runs of triphasic sharp waves in hepatic encephalopathy (Figure 8.7). We use 10-mg ampules of diazepam or 1-mg ampules of clonazepam (not available in the United States). The injection must be given slowly in successive boluses over
stops 140 seconds after injection of 1 mg of clonazepam. Her level of consciousness returned to normal.
:
F 8.7 A false diagnosis of absence status in a 43-year-old stuporous woman with idiopathic generalized epilepsy and posthepatitic cirrhosis. The correct diagnosis was acute hyperammonemic encephalopathy (arterial ammonia, 453 mmol/L) related to valproate and preexisting chronic hepatic failure. The EEG
shows rapid generalized spike-and-wave discharges on a background of diffuse rhythmic runs of 2-Hz triphasic slow waves. IV benzodiazepines had no effect on the EEG and the clinical condition. Discontinuation of valproate led to total recovery without sequelae.
30–60 seconds each and must produce rapidly progressive disappearance of the paroxysmal activity, leading to normalization of the EEG; spike-and-wave or polyspike-andwave discharges are typically replaced by low-amplitude diffuse beta activity (see Figure 8.6). The effective doses are usually relatively low. An average of 3.8 mg of diazepam has been reported (77). Normalization of the EEG must also be associated with disappearance of the confusion, which may be dramatic when immediate or may take minutes or even hours in elderly patients. For a therapeutic trial to be considered successful, both EEG and clinical normalization must occur. Recording must be continued for at least 60 minutes after EEG normalization to detect any early recurrence of ASE, and follow-up recording is needed if there is any later alteration of consciousness, to diagnose any possible recurrence of ASE. The clinical improvement is usually clear-cut and remarkable. In cases with very mild clouding of consciousness, we
recommend administering two sets of cognitive tasks, one prior to injection and the second 60 minutes later. We used a standardized battery of tasks that can be performed in less than 20 minutes, including orientation in time and place, personal information, digit span, serial 7s subtraction, the Stroop test, copy and recall of the Rey-Osterreith Complex Figure, and reproduction of rhythmic alternative drawings inspired by some of Luria’s figures (174). Each subtest is semiquantitatively scored from 0 to 5. A significant improvement should occur following benzodiazepine injection. If IV access is not available, or if there is a high risk of respiratory depression in an elderly patient, a single oral dose of 1 mg/kg of clobazam, a rapidly absorbed benzodiazepine, has been proposed as an alternative (67), though we have also used lower doses (Figure 8.8). With this regimen, clinical and EEG improvement is often noticeable after approximately 10 minutes and complete cessation of the AS usually occurs within 15–30 minutes. There are usually
, , :
101
F 8.8 A positive diagnostic and therapeutic trial of oral clobazam, 0.5 mg/kg, in an 81-year-old woman with AS and respiratory insufficiency. The EEG shows arrhythmic generalized
polyspike-and-slow-wave activity that stopped 90 minutes after the oral intake of a single 30-mg dose of clobazam.
no noticeable effects on vigilance, and respiratory depression does not occur. Other antiepileptic drugs may be used with similar results, including IV lorazepam (95), parenteral valproate (34, 72, 97), phenytoin (6), phenobarbital (120), and propofol (38). The prolonged use of propofol may, however, cause severe or lethal systemic complications in children and must be avoided (16, 27, 82). IV valproate may avoid some of the morbidity of repeated doses of a benzodiazepine or prolonged infusions of propofol: for children in AS, a loading dose of 20 mg/kg has been suggested, followed by maintenance infusion of 1 mg/kg/hr in noninduced patients and 2 mg/kg/hr in those taking multiple drugs (88). The potential neurologic morbidity of ASE, which is most often a relatively benign event, especially with typical ASE, must be weighed against the possible morbidity of IV antiepileptic drugs, and overtreatment must be avoided (98). AS may recur following IV benzodiazepine. This may be treated by a further dose of benzodiazepine or with a second antiepileptic drug (IV valproate, phenytoin, or fosphenytoin). In our personal series, as also noted by Granner and Lee, recurrence seems more frequent when the ASE is associated with asymmetric EEG manifestations, suggesting the
possibility of secondary bilateral synchrony with an initial localized onset (77, 172). A paradoxical worsening of the electroclinical picture has been reported in the atypical ASE of the Lennox-Gastaut syndrome after benzodiazepine injection (117).
102
Etiologic factors in absence status Endocrine factors appear important in women of childbearing age. The catamenial period (120, 128), pregnancy (49), the immediate postpartum period (14, 37), and menopause (154) have all been implicated. Drug-related factors are clearly important in many cases, particularly but not exclusively in de novo ASE of late onset. Many authors (48, 79, 95, 96, 146, 172, 186) suggest an etiologic role for psychotropic medication either taken in excess, alone or in association with other drugs, or during rapid drug withdrawal (55). Many psychotropic drugs have been implicated, in order of frequency and probable causality: benzodiazepines, neuroleptics (especially butyrophenones), tricyclic antidepressants, lithium, meprobamate, viloxazine, methaqualone, barbiturates, and monoamine oxidase inhibitors. In a patient whose ASE had been caused by with-
:
drawal of several psychotropic medications, including a benzodiazepine, the injection of flumazenil led to a transient worsening of the AS (173). Many cases have also been reported to occur in relation to other drugs. Only some of these are known to lower the convulsive threshold: bemegride and metrazol (120), theophylline (190), cyclosporin (42), ifosfamide (166, 198), baclofen (200), metformin (26, 79), cimetidine (186), ceftazidine (106), diuretics (26), and piperazine (58). Cases have been reported with the use of antiepileptic drugs, including one during a valproate-related encephalopathy that was partially reversed by flumazenil (168). Therapeutic concentrations of carbamazepine and/or phenytoin may exacerbate idiopathic generalized epilepsy in the specific form of AS (140). This paradoxical response seems to be a particular risk for patients with absences, underscoring the value of an adequate syndromic approach (29, 140). More recently, tiagabine has been implicated in episodes of atypical AS in patients with intractable partial seizures: excess GABA-mediated thalamic inhibition has been proposed to explain this, with GABA receptors playing a critical role, as shown by the ability of baclofen to induce AS (50, 53, 200). However, in most cases, EEG data were not really convincing of the ictal nature of the disorder, and this issue remains controversial (162). True syndromic aggravation related to tiagabine use has also been associated with typical AS in IGE (107). Metabolic disturbances, either isolated or associated with drugs, are frequently reported: hyponatremia (26, 52), hypocalcemia (21, 191), hypoglycemia (79, 113), hypokalemia (26), decompensated chronic renal or hepatic failure (21, 52, 192), psychogenic polydipsia with metabolic imbalance (52), and cobalamin deficiency (2). Metrizamide deserves special mention. Five cases of AS have been reported following the use of this agent during myelography (4, 135, 148, 193), and one case after carotid angiography (190). A single case was recently described after intrathecal fluorescein injection (35). Other nonspecific triggering factors have also been reported occasionally and the mechanism by which they lead to AS is speculative: alcohol (52, 86, 186), antiepileptic drug withdrawal (110), hyperventilation (25, 68, 83, 112), intermittent photic stimulation (112), television (112), and electroconvulsive therapy (78, 120). Cases following surgery (7, 39), mild head trauma (7, 115), severe head trauma (79), fever (79), cancer (52, 152), neurosyphilis (147), stress, grief, or fatigue were typically associated with disturbances of the sleep-wake cycle (7, 79, 120). Genetic factors may also be implicated (29). In contrast to the number and variety of possible etiologic factors, no focal lesions have ever been seen in AS on imaging studies. However, elderly patients often show mild to moderate cortical-subcortical atrophy with frontal pre-
dominance, presumably of vascular or degenerative origin. It has been suggested that various toxic and/or metabolic factors may express themselves more easily in brains structurally damaged by such nonspecific lesions (61). An isolated case report of atypical AS has been reported in the context of a syndrome of increased intracranial pressure and transient MRI abnormalities (31). Another patient with newonset AS had unilateral frontal hyperperfusion on ictal single-photon emission computerized tomography (172). AS has been associated with other neurologic syndromes. Inoue et al. (91), reported six cases of ring chromosome 20 (RC 20) and epilepsy with prolonged confusional states resistant to antiepileptic drugs associated with bilateral highvoltage ictal slow waves, occasionally beginning with focal frontal EEG activity. They proposed that this constituted a new syndrome (90). In a recent video-EEG study of three patients with RC 20, bifrontal rythmic sharp or slow waves was the main EEG pattern (143). AS was also recently described in a child with the congenital bilateral perisylvian syndrome (170), in patients with “eyelid myoclonia with absences” syndrome (195), in the “perioral myoclonias with absences” syndrome (22, 141, 198), and in another syndrome of “idiopathic generalized epilepsy with phantom absences” of undetermined onset (142).
Natural history of absence status and long-term treatment The spontaneous duration of each episode of AS is variable and ranges from about half an hour to several weeks (7, 66, 95). Most episodes last from 6 to 72 hours, only exceptionally exceeding 1 week (39, 66). In most typical cases, spontaneous cessation of the ASE is sudden, with striking clinical improvement. Some patients fall asleep and awaken normal. However, the episode most often ends in a tonic-clonic convulsion. ASE generally has no effect on the natural history of any preexisting epilepsy, though Wirrell et al. suggest that it is a factor predicting that childhood absence epilepsy will not remit (201). In idiopathic generalized epilepsy, the occurrence of ASE appears to have no appreciable effect on subsequent seizure frequency, and the patients’ cognition and mentation remain normal, as recently reviewed by Drislane (47, 97). The influence of ASE on the cognitive prognosis in SCGE is not as clear. In most instances AS does not appear to have any significant effect (118, 154). This is, however, a subject of debate. Doose and Völzke believe that repetitive ASE may aggravate intellectual deterioration in children with myoclonic-astatic epilepsy (45). Manning and Rosenbloom described 13 children with atypical ASE followed by a deterioration in their mental handicap, suggesting aggressive treatment for their epilepsy (127). Some adult patients were
, , :
103
reported to show significant increases in neurospecific enolase, a marker of neuronal damage (41, 150). ASE has an inconsistent tendency to recur. Most patients do not have recurrent ASE, some have a few episodes, and others have a marked tendency to experience recurrence despite antiepileptic drugs. Andermann and Robb described a man with idiopathic generalized epilepsy who had had more than 500 episodes of ASE between the ages of 40 and 65 years (7). When ASE occurs with a preexisting idiopathic generalized epilepsy, the drug of choice to prevent recurrence is valproate (20, 89): in a series of 18 patients with idiopathic generalized epilepsy, the rate of recurrent attacks during a 4.4-year period was reduced with valproate from 5.7 to 0.6 attacks per year (20). Trimethadione, ethosuximide, phenytoin, barbiturates, and carbamazepine have also been used, with less favorable results (7, 145). The long-term prognosis is clearly guarded in epileptic patients with SCGE or evidence of EEG focalization. However, in elderly patients, the identification and correction of probable triggering factors may be sufficient to prevent recurrence (173). This work was supported in part by a grant from the Programme Hospitalier de Recherche Clinique, CHRU Nice, the French Ministry of Health. The authors thank Eva Paquet and Roula Vrentzos for preparing the English translation of the text.
REFERENCES 1. Agathonikou, A., C. P. Panayiotopoulos, S. Giannakodimos, and M. Koutroumanidis. Typical absence status in adults: Diagnostic and syndromic considerations. Epilepsia 1998;39: 1265–1276. 2. Aguglia, U., A. Gambardella, R. L. Oliveri, G. De Sarro, M. Zappia, and A. Quattrone. De novo epileptic confusional status in a patient with cobalamin deficiency. Metab. Brain Dis. 1995;10:233–238. 3. Aguglia, U., P. Tinuper, and G. Farnarier. État confusionnel critique à point de départ frontal chez le sujet âgé. Rev. EEG Neurophysiol. 1983;13:174–179. 4. Ahmed, I., R. Pepple, and R. P. Jones. Absence status epilepticus resulting from metrizamide and Omnipaque myelography. Clin. Electroencephalogr. 1988;19:37–42. 5. Amand, G. États d’absence et états confusionnels prolongés au delà de 60 ans. Rev. EEG Neurophysiol. 1971;13:174–179. 6. Amit, R., M. Rottem, and S. Yatziv. Termination of absence status and suppression of inter-ictal bursts with phenytoin: Case report. Clin. Electroencephalogr. 1986;17:173–175. 7. Andermann, F., and J. P. Robb. Absence status: A reappraisal following review of thirty-eight patients. Epilepsia 1972;13: 177–187. 8. Assael, M. I. Petit mal status without impairment of consciousness. Dis. Nerv. Syst. 1972;33:526–528. 9. Bancaud, J., and J. Talairach. Clinical semiology of frontal lobe seizures. In P. Chauvel, A. V. Delgado-Escueta, E. Halgren, and J. Bancaud, eds. Frontal Lobe Seizures and Epilepsy. Adv. Neurol. 1992;57:3–58.
104
10. Bancaud, J., J. Talairach, P. Morel, et al. “Generalized” epileptic seizures elicited by electrical stimulation of the frontal lobe in man. Electroencephalogr. Clin. Neurophysiol. 1974;37:275–282. 11. Bateman, D. E., J. C. O’Grady, C. J. Willey, B. P. Longley, and D. D. Barwick. De novo minor status epilepticus of late onset presenting as stupor. BMJ 1983;287:1673–1674. 12. Bauer, G., F. Aichner, and U. Mayr. Nonconvulsive status epilepticus following generalized tonic-clonic seizures. Eur. Neurol. 1982;21:411–419. 13. Beaumanoir, A., G. Foletti, M. Magistris, and D. Volanschi. Status epilepticus in the Lennox-Gastaut syndrome. In E. Niedermeyer, and R. Degen, eds. The Lennox-Gastaut Syndrome. New York: Alan R. Liss, 1988:283–299. 14. Beaumanoir, A., P. Jenny, and M. Jekiel. Étude de quatre “petit mal status” post-partum. Rev. EEG Neurophysiol. 1980; 10:381–385. 15. Benbadis, S. R., W. O. Tatum, IV, A. R. Towne, E. J. Waterhouse, and L. Garnett. Prevalence of nonconvulsive status epilepticus in comatose patients. Neurology 2000;55: 1421–1423. 16. Bendiksen, A., and L. M. Larsen. Convulsions, ataxia and hallucinations following propofol. Acta Anaesthesiol. Scand. 1998;42:739–741. 17. Bendix, T. Petit mal status. Electroencephalogr. Clin. Neurophysiol. 1964;17:210–211. 18. Berkovic, S. F., F. Andermann, E. Andermann, and P. Gloor. Concepts of absence epilepsies: Discrete syndromes or biological continuum? Neurology 1987;37:993–1000. 19. Berkovic, S. F., F. Andermann, M. Aubé, R. M. Rémillard, and P. Gloor. Nonconvulsive confusional frontal status. Epilepsia 1985;26:529. 20. Berkovic, S. F., F. Andermann, A. Guberman, D. Hipola, and P. F. Bladin. Valproate prevents the recurrence of absence status. Neurology. 1989;39:1294–1297. 21. Berkovic, S. F., and P. F. Bladin. Absence status in adults. Clin. Exp. Neurol. 1982;19:198–207. 22. Bilgic, B., B. Baykan, C. Gurses, and A. Gokyigit. Perioral myoclonia with absence seizures: A rare epileptic syndrome. Epileptic Disord. 2001;3:23–27. 23. Biton, V., J. R. Gates, and L. de Padua Sussman. Prolonged postictal encephalopathy. Neurology 1990;40:963–966. 24. Bornstein, M., D. Coddon, and S. Song. Prolonged alterations in behavior associated with a continuous EEG (spike and dome) abnormality. Neurology 1956;6:444–448. 25. Boudin, G., J. Barbizet, and S. Masson. Étude de la dissolution de la conscience dans trois cas de petit mal avec crises prolongées. Rev. Neurol. 1958;99:483–487. 26. Bourrat, C., P. Garde, M. Boucher, and A. Fournet. États d’absence prolongés chez des patients âgés sans passé épileptique. Rev. Neurol. 1986;142:696–702. 27. Bray, R. J. Propofol infusion syndrome in children. Paediatr. Anaesth. 1998;8:491–499. 28. Brett, E. M. Minor epileptic status. J. Neurol. Sci. 1966;3:52–75. 29. Brinciotti, M., C. Mazzei, F. Galletti, and M. Matricardi. Genetic aspects of nonconvulsive status epilepticus. Eur. Neurol. 1991;31:384–387. 30. Brodtkorb, E., T. Sand, A. Kristiansen, and T. Torbergsen. Non-convulsive status epilepticus in the adult mentally retarded: Classification and role of benzodiazepines. Seizure 1993;2:115–123. 31. Callahan, D. J., and M. J. Noetzel. Prolonged absence status epilepticus associated with carbamazepine therapy, increased
:
32. 33. 34.
35.
36.
37.
38.
39.
40. 41.
42.
43.
44.
45. 46.
47.
48.
49. 50.
intracranial pressure, and transient MRI abnormalities. Neurology 1992;42:2198–2201. Cascino, G. D. Nonconvulsive status epilepticus in adults and children. Epilepsia 1993;34(Suppl. 1):S21–S28. Charcot, J. M. Clinical Lectures on the Diseases of the Nervous System (T. Savill, trans.). London: New Sydenham Society, 1889. Chez, M. G., M. S. Hammer, M. Loeffel, C. Nowinski, and B. T. Bagan. Clinical experience of three pediatric and one adult case of spike-and-wave status epilepticus treated with injectable valproic acid. J. Child Neurol. 1999;14:239–242. Coeytaux, A., A. Reverdin, P. Jallon, and A. Nahory. Nonconvulsive status epilepticus following intrathecal fluorescein injection. Acta Neurol. Scand. 1999;100:278–280. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389–399. Courjon, J., M. H. Fournier, and F. Mauguière. Les états de mal chez les épileptiques adultes suivis dans un hôpital neurologique. Rev. EEG Neurophysiol. 1984;14:175–179. Crouteau, D., M. Shevell, B. Rosenblatt, M. E. Dilenge, and F. Andermann. Treatment of absence status in the LennoxGastaut syndrome with propofol. Neurology 1998;51:315–316. D’Agostino, M. D., F. Andermann, F. Dubeau, M. Fedi, and A. Bastos. Exceptionally long absence status: Multifactorial etiology, drug interactions and complications. Epileptic Disord. 1999;1:229–232. Dalby, M. A. Epilepsy and 3-per-Second Spike and Wave Rhythms. Copenhagen: Munksgaard, 1969. DeGiorgio, C. M., C. N. Heck, A. L. Rabinowicz, P. S. Gott, T. Smith, and J. Correale. Serum neuron-specific enolase in the major subtypes of status epilepticus. Neurology. 1999;52: 746–749. Delpont, E., P. Thomas, J. Gugenheim, R. M. Chichmanian, M. H. Mahagne, G. Suisse, and C. Dolisi. Syndrome confusionnel critique au cours d’un traitement par cyclosporine. Neurophysiol. Clin. 1990;20:207–215. Dongier, S. À propos des états de mal généralisés à expression confusionnelle: Étude de la déstructuration de la conscience au cours del’état de petit mal. In H. Gastaut, J. Roger, and H. Lob, eds. Les états de mal épileptiques. Paris: Masson, 1967:10–118. Doose, H. Nonconvulsive status epilepticus in childhood: Clinical aspects and classification. In A. V. Delgado-Escueta, C. G. Wasterlain, D. M. Treiman, and R. J. Porter, eds. Status Epilepticus. Adv. Neurol. 1983;34:83–92. Doose, H., and E. Völzke. Petit mal status in early childhood. Neuropediatrie 1979;10:10–14. Dravet, C., O. Natale, A. Magaudda, J. L. Larrieu, M. Bureau, J. Roger, and C. A. Tassinari. Les états de mal dans le syndrome de Lennox-Gastaut. Rev. EEG Neurophysiol. 1985;15:361–368. Drislane, F. W. Evidence against permanent neurologic damage from nonconvulsive status epilepticus. J. Clin. Neurophysiol. 1999;16:323–331. Dunne, J. W., Q. A. Summers, and E. G. Stewart-Wynne. Non-convulsive status epilepticus: A prospective study in an adult general hospital. Q. J. Med. 1987;62:117–126. Dyro, F. M. Petit mal status epilepticus in a pregnant adult. J. Maine Med. Assoc. 1977;68:179–181. Eckardt, K. M., and B. J. Steinhoff. Nonconvulsive status epilepticus in two patients receiving tiagabine treatment. Epilepsia 1998;39:671–674.
51. Elian, M. Petit-mal-like discharge in the EEG of adults. Electroencephalogr. Clin. Neurophysiol. 1969;27:216–221. 52. Ellis, J. M., and S. I. Lee. Acute prolonged confusion in later life as an ictal state. Epilepsia 1977;19:119–128. 53. Ettinger, A. B., O. G. Bernal, M. R. Andriola, S. Bagchi, et al. Two cases of nonconvulsive status epilepticus in association with tiagabine therapy. Epilepsia 1999;40:1159–1162. 54. Fagan, K. J., and S. I. Lee. Prolonged confusion following convulsions due to generalized nonconvulsive status epilepticus. Neurology 1990;40:1689–1694. 55. Fernandez-Torre, J. L. De novo absence status of late onset following withdrawal of lorazepam: A case report. Seizure 2001;10:433–437. 56. Fernandez-Torre, J. L., and A. G. Diaz-Castroverde. Nonconvulsive status epilepticus in elderly individuals: Report of four representative cases. Age Ageing 2004;33(1):78–81. 57. Ferner, R. E., and C. P. Panayiotopoulos. “Phantom” typical absences, absence status and experiential phenomena. Seizure 1993;2:253–256. 58. Fincham, R. W., T. Yamada, D. D. Schotellius, S. M. S. Hayrch, and A. Damasio. Electroencephalographic absence status with minimal behavior change. Arch. Neurol. 1979;36: 176–178. 59. Floch, J. J. Les états d’absences de l’épilepsie. Thesis, University of Bordeaux, 1967. 60. Friedlander, W. J., and G. H. Feinstein. Petit mal status: Epilepsia minoris continua. Neurology 1956;6:357–363. 61. Fujiwara, T., M. Watanabe, and H. Nakamura. A comparative study of absence status epilepticus between children and adults. Jpn. J. Psychiatry Neurol. 1988;42:497–508. 62. Gall, M. V., G. Scollo-Lavizzari, and H. Becker. Absence status in the adult: New results including computerized transverse axial tomography. Eur. Neurol. 1978;17:121–128. 63. Gastaut, H. À propos d’une classification symptomatique des états demal épileptiques. In H. Gastaut, J. Roger, and H. Lob, eds. Les états de mal épileptiques. Paris: Masson, 1967:1–8. 64. Gastaut, H. Classification of status epilepticus. In A. V. Delgado-Escueta, C. G. Wasterlain, D. M. Treiman, and R. J. Porter, eds. Status Epilepticus. Adv. Neurol. 1983;36:83–92. 65. Gastaut, H. Clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1970;11:102–113. 66. Gastaut, H. Dictionnaire de l’épilepsie. Geneva: World Health Organization, 1973:63–64. 67. Gastaut, H., R. Bernard, R. Naquet, and J. Wilson. Étude électroclinique quotidienne d’un état confusionnel épileptique simple ayant duré un mois. Rev. Neurol. 1956;94: 298–301. 68. Gastaut, H., P. Tinuper, U. Aguglia, and E. Lugaresi. Traitement de certains états de mal par ingestion d’une dose unique de clobazam. Rev. EEG Neurophysiol. 1984;14:203–206. 69. Geier, S. Prolonged psychic epileptic seizures: A study of the absence status. Epilepsia 1978;19:431–445. 70. Geier, S., J. Bancaud, A. Bonis, and M. Enjelvin. Enregistrement télé-EEG detrois crises épileptiques prolongées classées comme des épisodes de petit mal status. Rev. EEG Neurophysiol. 1977;7:201–202. 71. Gibberd, F. B. Petit mal status presenting de novo in middle age. Lancet 1972;1:269–270. 72. Gibbs, F. A., and E. L. Gibbs. Atlas of Electroencephalography. Vol. 2. Epilepsy. Cambridge, Mass.: Addison-Wesley, 1952. 73. Giroud, M., and R. Dumas. Traitement des états de mal épileptiques par le valproate de sodium. Neurophysiol. Clin. 1988;18:21–32.
, , :
105
74. Goetz, C. G. Charcot, the Clinician: The Tuesday Lessons. New York: Raven Press, 1987. 75. Golden, J. C. Stroop Color and Word Test. Chicago: Stoelting, 1978. 76. Goldensohn, E. S., and A. P. Gold. Prolonged behavioral disturbances as ictal phenomena. Neurology 1960;10:1–9. 77. Goldmann, J. W., G. Glastein, and A. H. Adams. Adult onset absence status: A report of six cases. Clin. EEG 1981;12: 199–204. 78. Granner, M. A., and S. I. Lee. Nonconvulsive status epilepticus: EEG analysis in a large series. Epilepsia 1994;35:42–47. 79. Grogan, R., D. R. Wagner, T. Sullivan, and D. Labar. Generalized nonconvulsive status epilepticus after electroconvulsive therapy. Convuls. Ther. 1995;11:51–56. 80. Guberman, A., G. Cantu-Reyna, D. Stuss, and R. Broughton. Nonconvulsive generalized status epilepticus: Clinical features, neuropsychological testing and long-term follow-up. Neurology 1986;36:1284–1291. 81. Haimovic, I. C., and H. R. Beresford. Transient unresponsiveness in the elderly: Report of five cases. Arch. Neurol. 1992;49:35–37. 82. Hajnsek, F., and V. Dürrigl. Some aspects of so-called “petit mal status.” Electroencephalogr. Clin. Neurophysiol. 1970;28:322. 83. Hanna, J. P., and M. L. Ramundo. Rhabdomyolysis and hypoxia associated with prolonged propofol infusion in children. Neurology 1998;50:301–303. 84. Hasaerts, R., and J. Titeca. Corrélations électrocliniques des pointes-ondes: À propos d’un cas de petit mal status et d’épilepsie minoris continua avec fugues et épisodes confusionnels. Acta. Neurol. Psychiatr. Belg. 1958;58:142–154. 85. Hauser, P., O. Devinsky, M. De Bellis, W. H. Theodore, and R. M. Post. Benzodiazepine withdrawal delirium with catatonic features. Arch. Neurol. 1989;46:696–699. 86. Heathfield, K. W. G. Isolated petit mal status presenting de novo in middle age. Lancet 1972;1:492. 87. Hersch, E. L., and R. F. Billings. Acute confusional state with status petit mal as a withdrawal syndrome and five year follow-up. Can. J. Psychiatry 1988;33:157–159. 88. Hess, R., G. Scotto-Lavizzari, and F. E. Wyss. Borderline cases of petit mal status. Eur. Neurol. 1971;5:137–154. 89. Hovinga, C. A., M. F. Chicella, D. F. Rose, S. K. Eades, J. T. Dalton, and S. J. Phelps. Use of intravenous valproate in three pediatric patients with nonconvulsive or convulsive status epilepticus. Ann. Pharmacother. 1999;33:579–584. 90. Iivanainen, M., L. Bergström, A. Nuutila, and M. Viuraki. Psychosis-like absence status in elderly patients: Successful treatment with sodium valproate. J. Neurol. Neurosurg. Psychiatry 1984;47:965–969. 91. Inoue, Y., T. Fujiwara, K. Matsuda, et al. Ring chromosome 20 and nonconvulsive status epilepticus: A new epileptic syndrome. Brain 1997;120:939–953. 92. Jacome, D. E., and M. S. Risko. Absence status manifested by compulsive masturbation. Arch. Neurol. 1983;40:523–524. 93. Janz, D. Status epilepticus and frontal lobe lesions. J. Neurol. Sci. 1964;1:446–457. 94. Jordan, K. G. Nonconvulsive status epilepticus in acute brain injury. J. Clin. Neurophysiol. 1999;16:332–340. 95. Kanemoto, K., T. Miyamoto, and R. Abe. Ictal catatonia as a manifestation of de novo absence status epilepticus following benzodiazepine withdrawal. Seizure 1999;8(6): 364–366. 96. Kaplan, P. W. Assessing the outcomes in patients with nonconvulsive status epilepticus: Nonconvulsive status epilepticus
106
97. 98.
99.
100. 101. 102. 103. 104. 105.
106.
107.
108.
109.
110.
111. 112. 113.
114. 115.
116. 117.
118.
119.
:
is underdiagnosed, potentially overtreated, and confounded by comorbidity. J. Clin. Neurophysiol. 1999;16:341–352. Kaplan, P. W. Behavioral manifestations of nonconvulsive status epilepticus. Epilepsy Behav. 2002;3:122–139. Kaplan, P. W. Intravenous valproate treatment of generalized nonconvulsive status epilepticus. Clin. Electroencephalogr. 1999; 30:1–4. Kaplan, P. W. No, some types of nonconvulsive status epilepticus cause little permanent neurologic sequelae (or: “The cure may be worse than the disease”). Neurophysiol. Clin. 2000;30:377–382. Kaplan, P. W. Nonconvulsive status epilepticus. Semin Neurol. 1996;16:33–40. Kaplan, P. W. Nonconvulsive status epilepticus in the emergency room. Epilepsia 1996;37:643–650. Kaplan, P. W. Prognosis in nonconvulsive status epilepticus. Epileptic Dis. 2000;2:185–193. Karbowski, K. Der Petit Mal Status. Schweiz. Med. Wochenschr. 1976;106:973–981. Kellaway, P., and D. Chao. Prolonged status epilepticus in petit mal. Electroencephalogr. Clin. Neurophysiol. 1955;7:145. Khan, R. B., P. K. Yerremsetty, D. Lindstrom, and L. J. McGill. Emergency EEG and factors associated with nonconvulsive status epilepticus. J. Natl. Med. Assoc. 2001;93: 359–362. Kimura, S., and T. Sobayashi. Two patients with juvenile myoclonic epilepsy and nonconvulsive status epilepticus. Epilepsia 1996;37:275–279. Klion, A. D., J. Kallsen, C. T. Cowl, and W. M. Nauseef. Ceftazidime-related nonconvulsive status epilepticus. Arch. Intern. Med. 1994;154:586–589. Knake, S., H. M. Hamer, U. Schomburg, W. H. Oertel, and F. Rosenow. Tiagabine-induced absence status in idiopathic generalized epilepsy. Seizure 1999;8:314–317. Krumholz, A. Epidemiology and evidence for morbidity of nonconvulsive status epilepticus. J. Clin. Neurophysiol. 1999; 16:314–322. Kudo, T., K. Sato, K. Yagi, and M. Seino. Can absence status epilepticus be of frontal lobe origin? Acta Neurol. Scand. 1995; 92:472–477. Lee, S. I. Nonconvulsive status epilepticus: Ictal confusion in later life. Arch. Neurol. 1985;42:778–781. Lennox, W. G. Epilepsy and Related Disorders. Boston: Little, Brown, 1960. Lennox, W. G. États confusionnels et stuporeux dans l’épilepsie (données électrocliniques). Rev. Neurol. 1956;95: 603–604. Lennox, W. G. The petit mal epilepsies: Their treatment with tridione. JAMA 1945;129:1069–1074. Lim, L., P. Yagnik, P. Schraeder, and S. Wheeler. Ictal catatonia as a manifestation of nonconvulsive status epilepticus. J. Neurol. Neurosurg. Psychiatry 1986;49:833–836. Lion, P. A case of post-traumatic petit mal status. Electroencephalogr. Clin. Neurophysiol. 1967;22:96–97. Litt, B., R. J. Wityk, S. H. Hertz, P. D. Mullen, et al. Nonconvulsive status epilepticus in the critically ill elderly. Epilepsia 1998;39:1194–1202. Livingston, J. H., and J. K. Brown. Diagnosis and management of non-convulsive status epilepticus. Pediatr. Rev. Commun. 1988;2:283–315. Livingston, J. H., and J. K. Brown. Non-convulsive status epilepticus resistant to benzodiazepines. Arch. Dis. Child. 1987;62:41–44.
120. Lob, H. Les états de Mal généralisés à expression confusionelle (états de petit mal). Thesis, Marseilles, 1964. 121. Lob, H., J. Roger, R. Soulayrol, H. Régis, and H. Gastaut. Les états de mal généralisés à expression confusionelle. In H. Gastaut, J. Roger, and H. Lob, eds. Les états de mal épileptiques. Paris: Masson, 1967:91–109. 122. Loiseau, P., and F. Cohadon. Le petit mal et ses frontières. Paris: Masson, 1970. 123. Lorentz de Hass, A. M., and O. Magnus. Recherches électroniques chez 72 épileptiques avec troubles mentaux épisodiques. Rev. Neurol. 1956;95:594–595. 124. Louis, E. D., and N. L. Pflaster. Catatonia mimicking nonconvulsive status epilepticus. Epilepsia 1995;36:943–945. 125. Lugaresi, E., P. Pazzaglia, and C. A. Tassinari. Differentiation of “absence status” and “temporal lobe status.” Epilepsia 1971;12:77–87. 126. Mann, R., and B. Leslie. Status epilepticus occurring in petit mal. Bull. Los Angeles Neurol. Soc. 1954;19:96. 127. Manning, D. J., and L. Rosenbloom. Non-convulsive status epilepticus. Arch. Dis. Child. 1987;62:37–40. 128. Mayer, S. A., J. Claassen, J. Lokin, F. Mendelsohn, L. J. Dennis, and B. F. Fitzsimmons. Refractory status epilepticus: Frequency, risk factors, and impact on outcome. Arch. Neurol. 2002;59:205–210. 129. Ming, X., and P. W. Kaplan. Fixation-off and eyes closed catamenial generalized nonconvulsive status epilepticus with eyelid myoclonic jerks. Epilepsia 1998;39:664–668. 130. Niedermeyer, E., F. Fineyre, T. Riley, and S. Uematsu. Absence status (petit mal status) with focal characteristics. Arch. Neurol. 1979;36:417–421. 131. Niedermeyer, E., and R. Khalifeh. Petit mal status (“spikewave stupor”): An electro-clinical appraisal. Epilepsia 1965;6: 250–262. 132. Niedermeyer, E., and M. Ribeiro. Considerations of nonconvulsive status epilepticus. Clin. Electroencephalogr. 2000; 31:192–195. 133. Nightingale, S., and J. L. Welch. Psychometric assessment in absence status. Arch. Neurol. 1982;39:516–519. 134. Nishiura, N., and T. Oiwa. Epilepsy above 70 years of age: Four cases with spike and wave complex. Folia Psychiatr. Neurol. Jpn. 1979;33:263–268. 135. Novak, J., P. Corke, and N. Fairley. “Petit mal status” in adults. Dis. Nerv. Syst. 1971;32:245–248. 136. Obeid, T., B. Yaqub, C. Panayiotopoulos, S. Al Jasser, A. Shabaan, and N. E. Hawass. Absence status epilepticus with computed tomographic brain changes following metrizamide myelography. Ann. Neurol. 1988;24:582–584. 137. Oftedal, S. I. Status petit mal in elderly subject. Electroencephalogr. Clin. Neurophysiol. 1974;36:208. 138. Ohtahara, S., E. Oka, Y. Yamatogi, et al. Non-convulsive status epilepticus in childhood. Folia Psychiatr. Neurol. Jpn. 1979;33:345–351. 139. Ohtsuka, Y., M. Sato, and E. Oka. Nonconvulsive status epilepticus in childhood localization-related epilepsy. Epilepsia 1999;40:1003–1010. 140. Oller-Daurella, L. Les états confusionnels épileptiques (états d’absence). Acta Neurol. Belg. 1974;74:265–267. 141. Osorio, I., R. C. Reed, and J. N. Peltzer. Refractory idiopathic absence status epilepticus: A probable paradoxical effect of phenytoin and carbamazepine. Epilepsia 2000;41:887–894. 142. Panayiotopoulos, C. P. Treatment of typical absence seizures and related epileptic syndromes. Paediatr. Drugs 2001;3: 379–403.
143. Panayiotopoulos, C. P., C. D. Ferrie, M. Koutroumanidis, S. Rowlinson, and S. Sanders. Idiopathic generalised epilepsy with phantom absences and absence status in a child. Epileptic Disord. 2001;3:63–66. 144. Petit, J., A. Roubertie, Y. Inoue, and P. Genton. Nonconvulsive status in the ring chromosome 20 syndrome: A video illustration of 3 cases. Epileptic Disord. 1999;1: 237–241. 145. Picornell Darder, I., M. Condé, and J. Carbonell. État de malpost-traumatique à symptomatologie uniquement psychique. Rev. EEG Neurophysiol. 1978;8:341–344. 146. Porter, R. J., and J. K. Penry. Petit mal status. In A. V. Delgado-Escueta, C. G. Wasterlain, D. M. Treiman, and R. J. Porter, eds. Status Epilepticus. Adv. Neurol. 1983;34:61–67. 147. Primavera, A., L. Giberti, P. Scotto, and L. Cocito. Nonconvulsive status epilepticus as a cause of confusion in later life: A report of 5 cases. Neuropsychobiology 1994;302: 148–152. 148. Primavera, A., C. Solaro, and L. Cocito. De novo status epilepticus as the presenting sign of neurosyphilis. Epilepsia 1998;39:1367–1369. 149. Pritchard, P. B., and D. B. O’Neal. Nonconvulsive status epilepticus following metrizamide myelography. Ann. Neurol. 1984;16:252–254. 150. Putnam, T. J., and H. H. Merritt. Dullness as a mental equivalent. Arch. Neurol. Psychiatry 1941;45:797–813. 151. Rabinowicz, A. L., J. D. Correale, K. A. Bracht, T. D. Smith, and C. M. DeGiorgio. Neuron-specific enolase is increased after nonconvulsive status epilepticus. Epilepsia 1995;36: 475–479. 152. Rennick, M., C. Perez-Borja, and E. A. Rodin. Transient mental deficits associated with recurrent prolonged epileptic clouded states. Epilepsia 1969;10:397–405. 153. Richard, P., and R. P. Brenner. Absence status: Case reports and a review of the literature. Encephale 1980;6:385–392. 154. Rigal, J., A. Fournier, and J. Raymond. Fugue comitiale et petit mal status. Ann. Med. Psychol. 1963;2:748–754. 155. Roger, J., H. Lob, and C. A. Tassinari. Status epilepticus. In O. Magnus, and A. M. Lorentz de Haas, eds. Handbook of Clinical Neurophysiology. Vol. 15. The Epilepsies. Amsterdam: North Holland, 1974:145–188. 156. Rohr-Le Floch, J., G. Gauthier, and A. Beaumanoir. États confusionnels d’origine épileptique: Intérêt de l’EEG fait en urgence. Rev. Neurol. 1988;144:425–436. 157. Rumpl, E., and H. Hinterhuber. Unusual “spike and wave stupor” in a patient with manic-depressive psychosis treated with amitryptyline. J. Neurol. 1981;226:131–135. 158. Sano, J., H. Fukuta, Y. Maeda, et al. A case of epilepsy characterized by spike-wave stupor followed for long period. Jpn. J. Psychiatr. Neurol. 1991;45:485–486. 159. Scholtes, F. B., W. O. Renier, and H. M. Meinardi. Non convulsive status epilepticus: Causes, treatment, outcome in 65 patients. J. Neurol. Neurosurg. Psychiatry 1996;61:93–95. 160. Schwab, H. A case of status epilepticus in petit mal. Electroencephalogr. Clin. Neurophysiol. 1953;5:441–442. 161. Schwartz, M. S., and D. F. Scott. Isolated petit mal status presenting de novo in middle age. Lancet 1971;2:1399–1401. 162. Shev, E. Syndrome of status petit mal in the adult. Electroencephalogr. Clin. Neurophysiol. 1964;17:466. 163. Shinnar, S., A. T. Berg, D. M. Treiman, W. A. Hauser, D. C. Hesdorffer, J. C. Sackellares, et al. Status epilepticus and tiagabine therapy: Review of safety data and epidemiologic comparisons. Epilepsia 2001;42:372–379.
, , :
107
164. Shorvon, S. Absence status. In Status Epilepticus: Its Clinical Features and Treatment in Children and Adults. Cambridge, U.K.: Cambridge University Press, 1994:76–84. 165. Shorvon, S. De novo absence status epilepticus of late onset. In Status Epilepticus: Its Clinical Features and Treatment in Children and Adults. Cambridge, U.K.: Cambridge University Press, 1994:135–137. 166. Shorvon, S. Definition, classification and frequency of status epilepticus. In Status Epilepticus: Its Clinical Features and Treatment in Children and Adults. Cambridge, U.K.: Cambridge University Press, 1994:21–30. 167. Simonian, N. A., F. G. Gilliam, and K. H. Chiappa. Ifosfamide causes adiazepam-sensitive encephalopathy. Neurology 1993;43:2700–2702. 168. Skardoutsou, A., K. A. Voudris, and E. A. Vagiakou. Nonconvulsive status epilepticus associated with tiagabine therapy in children. Seizure 2003;12(8):599–601. 169. Sommerville, E. R., and J. Bruni. Tonic status epilepticus presenting as confusional state. Ann. Neurol. 1983;13:549–551. 170. Steinhoff, B. J., and S. R. Stodieck. Temporary abolition of seizure activity by flumazenil in a case of valproate-induced non-convulsive status epilepticus. Seizure 1993;2:261–265. 171. Stores, G. Non-convulsive status epilepticus in children. In T. A. Pedley, and B. S. Meldrum, eds. Recent Advances in Epilepsy. 3. Edinburgh: Churchill Livingstone, 1986:295–310. 172. Tagawa, T., Y. Itagaki, M. Kobayashi, T. Sano, and K. Sumi. Nonconvulsive status epilepticus in a child with congenital bilateral perisylvian syndrome. Pediatr. Neurol. 1999;21:579– 582. 173. Terzano, M. G., F. Gemignani, and D. Mancia. Petit mal status with myoclonus: Case report. Epilepsia 1978;19: 385–392. 174. Thomas, P., and F. Andermann. Absence status in elderly patients is most often situation-related. In A. Malafosse, P. Genton, E. Hirsch, C. Marescaux, D. Broglin, and R. Bernasconi, eds. Idiopathic Generalized Epilepsies: Clinical, Experimental and Genetic Aspects. London: John Libbey, 1994:95–109. 175. Thomas, P., A. Beaumanoir, P. Genton, C. Dolisi, and M. Chatel. “De novo” absence status: Report of 11 cases. Neurology 1992;42:104–110. 176. Thomas, P., C. Lebrun, and M. Chatel. “De novo” absence status as a benzodiazepine withdrawal syndrome. Epilepsia 1993;34:355–358. 177. Thomas, P., C. Lebrun, and M. Chatel. True and false nonconvulsive confusional status epilepticus. J. Neurol. 1992; 239(Suppl. 2):S72. 178. Thomas, P., B. Zifkin, O. Migneco, C. Lebrun, J. Darcourt, and F. Andermann. Nonconvulsive status epilepticus of frontal origin. Neurology 1999;52:1174–1183. 179. Thompson, S. W., and A. H. Greenhouse. Petit mal status in adults. Ann. Intern. Med. 1968;68:1271–1279. 180. Tomson, T., U. Lindbom, and B. Y. Nilsson. Nonconvulsive status epilepticus in adults: Thirty-two consecutive patients from a general hospital population. Epilepsia 1992;33: 829–835. 181. Tomson, T., E. Svanborg, and J. E. Wedlund. Nonconvulsive status epilepticus: High incidence of complex partial status. Epilepsia 1986;27:276–285. 182. Towne, A. R., E. J. Waterhouse, J. G. Boggs, L. K. Garnett, A. J. Brown, J. R. Smith, Jr., et al. Prevalence of nonconvulsive status epilepticus in comatose patients. Neurology 2000;54: 340–345.
108
183. Treiman, D. M. Electroclinical features of status epilepticus. J. Clin. Neurophysiol. 1995;12:343–362. 184. Treiman, D. M., N. Y. Walton, and C. Kendrick. A progressive sequence of electroencephalographic changes during generalized convulsive status epilepticus. Epilepsy Res. 1990;5: 49–60. 185. Tucker, W. M., and F. M. Forster. Petit mal epilepsy occurring in status. Arch. Neurol. Psychiatry 1950;64:823–827. 186. Tükel, K., and H. Jasper. The electroencephalogram in parasagittal lesions. Electroencephalogr. Clin. Neurophysiol. 1952;4: 481–494. 187. Van Leeuwen, W. S., F. Jennekens, and C. E. Sterk. A case of petit mal status with myoclonus. Epilepsia 1969;10:407–414. 188. Van Sweden, B. Toxic “ictal” confusion in middle age: Treatment with benzodiazepine. J. Neurol. Neurosurg. Psychiatry 1985;48:472–476. 189. Van Sweden, B., and F. Mellerio. Toxic ictal confusion. J. Epilepsy 1988;1:157–163. 190. Van Zandycke, M., L. C. Orban, and H. Van der Eecken. Acute prolonged ictal confusion resembling petit mal status presenting “de novo” in later life. Acta Neurol. Belg. 1980; 80:174–179. 191. Vercelletto, M., and J. L. Gastaut. Les épilepsies débutant après soixante ans. Rev. EEG Neurophysiol. 1981;11:537–544. 192. Vickrey, B. G., and F. H. Bahls. Nonconvulsive status epilepticus following cerebral angiography. Ann. Neurol. 1989;25: 199–201. 193. Vignaendra, V., A. O. Frank, and C. L. Lim. Absence status in a patient with hypocalcemia. Electroencephalogr. Clin. Neurophysiol. 1977;43:429–433. 194. Vignaendra, V., L. Thiam Ghee, and L. Chong Lee. Petit mal status in a patient with chronic renal failure. Med. J. Austr. 1976;2:258–259. 195. Vollmer, M. E., H. Weiss, C. Beanland, and A. Krumholz. Prolonged confusion due to absence status following metrizamide myelography. Arch. Neurol. 1985;42:1005–1007. 196. Vuillemier, P., P. A. Despland, and F. Regli. Failure to recall (but not to remember): Pure transient amnesia during nonconvulsive status epilepticus. Neurology 1996;46:1036– 1039. 197. Wakamoto, H., H. Nagao, K. Manabe, H. Kobayashi, and M. Hayashi. Nonconvulsive status epilepticus in eyelid myoclonia with absences: Evidence of provocation unrelated to photosensitivity. Neuropediatrics 1999;30:149–150. 198. Weiner, R. D., A. D. Whanger, C. W. Erwin, and W. P. Wilson. Prolonged confusional state and EEG seizure activity following concurrent ECT and lithium use. Am. J. Psychiatry 1980; 137:1452–1453. 199. Wells, C. E. Transient ictal psychosis. Arch. Gen. Psychiatry 1975;32:1201–1203. 200. Wengs, W. J., D. Talwar, and J. Bernard. Ifosfamide-induced nonconvulsive status epilepticus. Arch. Neurol. 1993;50:1104– 1105. 201. Wirrell, E. C., C. S. Camfield, P. R. Camfield, K. E. Gordon, and J. M. Dooley. Long-term prognosis of typical childhood absence epilepsy: Remission or progression to juvenile myoclonic epilepsy. Neurology 1996;47:912–918. 202. Zak, R., G. Solomon, F. Petito, and D. Labar. Baclofeninduced generalized nonconvulsive status epilepticus. Ann. Neurol. 1994;36:113–114. 203. Zappoli, R. Two cases of prolonged epileptic twilight state with almost continuous “wave-spikes.” Electroencephalogr. Clin. Neurophysiol. 1955;7:421–423.
:
9
The Two Faces of Electrographic Status Epilepticus: The Walking Wounded and the Ictally Comatose
. I we consider only those instances of nonconvulsive status epilepticus (NCSE) in which no clinical signs of seizure activity are evident, purely electrographic SE. NCSE has traditionally been divided into two broad categories: absence SE (ASE) and complex partial SE (CPSE). In ASE, the seizure discharges are bilaterally synchronous and either generalized or frontally predominant. In CPSE, on the other hand, seizure discharges originate focally, but often spread to become bilaterally synchronous. The two primary types of CPSE are those with temporal lobe onset and those with frontal lobe onset. The latter may be difficult to distinguish from ASE, especially if the electroencephalogram (EEG) is obtained after the discharges have become bilateral. In such instances, any focality uncovered following treatment (e.g., asymmetric disappearance or persistence of discharges) would point to CPSE of frontal lobe onset. NCSE may present clinically over a wide spectrum with respect to behavioral manifestations, from barely noticeable or absent clinical signs in ambulatory outpatients to stuporous individuals with only motor responses to deep pain (see Thomas et al., Chapter 7, this volume). However, in addition to the two forms of NCSE, ASE and CPSE, there are also many reports of comatose patients without clinical signs of seizure activity but with EEG evidence of electrographic SE, often a periodic epileptiform discharge (PED) pattern. Some believe that these patients should be put into a separate category of SE and not be lumped together with patients in NCSE. These patients may have had preceding generalized convulsive SE (3; Treiman, Chapter 6, this volume), but they may also present without any preceding history of epilepsy or SE (2, 5, 6). In this chapter we are concerned with apparently normal ambulatory outpatients (“the walking wounded”) on the one hand and the unresponsive, comatose inpatient (“the ictally comatose”) on the other. In both instances an EEG is necessary to establish the diagnosis. In both instances the EEG will usually suggest the approach to antiepileptic drug (AED) treatment.
The ambulatory outpatient with electrographic SE The wide range of clinical presentation of patients with the absence form of NCSE, from those with no clinical signs and normal appearance to those who are stuporous and barely responsive, is well documented (1; see Thomas et al., Chapter 7, this volume). It is the former group, estimated to account for 19% of cases of ASE (see Thomas et al., Chapter 7, this volume), in which there is often a long delay to diagnosis but in which cognitive deficits, often subtle, are found once the individuals are tested. These deficits may be eliminated over time as electrographic seizure discharges are suppressed, as the following case illustrates. 1 A 64-year-old man had sustained three episodes of generalized NCSE, the first two episodes 3 weeks apart and the last 7 years later. An EEG obtained during the third episode in December 1990 showed bilaterally synchronous 2- to 2.5-Hz spike-andslow-wave discharges frontotemporally, occupying 33% of total EEG time (Figure 9.1). During the EEG recording the patient appeared “normal;” during a 52-second run of spike-and-slowwave discharges he subtracted from 100 to 0 by 1s, with two mistakes. Divalproex sodium (Depakote) was started in December 1990, and the percentage of spike-and-wave discharges per EEG decreased to 2%–4% from October 1992 to September 1994, during which time the patient continued to take divalproex sodium. His last EEG in 1996 showed less than 1% spike-and-slow-wave discharges. Neuropsychological testing over a 9-year period, from May 1987 to June 1996, showed a progressive, 23-point increase in full-scale IQ (from 102 to 125), with an increase in verbal IQ from 103 to 133. Frontal executive function deficits also normalized, and this coincided with a reduction in the amount of spike-and-slowwave discharges on the EEG. The patient died in April 1999 at age 64; no further information regarding his death is available.
This case has been reported in detail (4) and illustrates the fact that ambulatory outpatients may have episodes of NCSE without clinical manifestations, so that an EEG is required to establish the diagnosis. Moreover, persistent cognitive impairment, or epileptiform encephalopathy, that is caused by but is not simply time-locked to seizure discharges may persist for years in the setting of frequent electrographic seizure discharges. This patient’s history suggests that if
:
109
F 9.1 This ambulatory patient showed marked cognitive improvement as electrographic spike-and-slow-wave discharges were suppressed over a 9-year period. This EEG was obtained during the patient’s third episode of NCSE, in which bilaterally synchronous, 2–2.5 Hz spike-and-slow-wave discharges were
present frontotemporally, occupying 33% of total EEG time. The spike-and-slow-wave discharges lasted from 0.5 to 52 seconds; during the 52-second run of spike-and-slow-wave discharges the patient appeared “normal” and subtracted from 100 to 0 by 1s, with two mistakes.
spike-and-slow-wave discharges are substantially reduced or eliminated, substantial cognitive improvement can occur over a prolonged period of time. This observation requires confirmation by further studies of similar patients.
tality. Less than fully responsive patients must undergo prompt EEG evaluation to diagnose and treat subclinical electrographic SE as quickly as possible. The following case report illustrates this point.
The comatose inpatient with electrographic SE
2 A 56-year-old man with type I diabetes mellitus, end-stage renal disease, and sensory neuropathy who had been undergoing hemodialysis three times a week for 2 years was admitted to Sepulveda Veterans Affairs Medical Center on December 7, 1993, because of episodes of falling up to three times a day for 1 month, as well as episodes of disorientation for 3 months. He was alert and oriented, with psychomotor retardation, wide-based gait, and decreased sensation in the distal lower extremities. An EEG obtained on December 10, 1993, showed mild slowing and hyperventilationinduced 1–2 second bursts of bilaterally synchronous, 2.5-Hz spikeand-slow-wave discharges frontotemporally (Figure 9.2A). He was discharged on phenytoin on December 12, 1993.
Up to 19% of comatose patients with no overt clinical evidence of seizures are found to have NCSE on EEG testing (2, 6). Continuous EEG monitoring in the ICU has shown that nonconvulsive seizures and SE are the most common form (5). Young et al. (7) found that overall mortality in those with nonconvulsive seizures was 33% (16/49), whereas in those with NCSE it was 57% (13/23). Seizure duration and delay to diagnosis were the critical factors in increased mor-
110
:
:
F 9.2 These EEGs were obtained in an ambulatory patient who became ictally comatose, but recovered with cognitive deficits. (A) Hyperventilation-induced 1–2 second bursts of bilaterally synchronous 2.5-Hz spike-and-slow-wave discharges frontotemporally. This pattern suggests idiopathic generalized epilepsy. (B) Continuous, generalized, bilaterally synchronous, periodic 1-Hz sharp-
wave discharges (GPEDs), an electrographic pattern of SE that may be found in comatose patients with a generally poor prognosis for recovery. (C) Electroencephalogram obtained 2 days after that shown in B shows improvement, with low-amplitude GPEDs that are present only intermittently.
111
The patient was readmitted 4 days later because he was found unresponsive to commands. He was hypoglycemic and in renal failure. His serum potassium was 7.6 mmol/L, blood urea nitrogen was 104 mg/dL, serum creatinine was 13.3 mg/dL, and serum glucose was 43 mg/dL. Four days after admission the patient’s blood tests had returned to normal, but he remained unresponsive, so a neurologic consultation was obtained. The patient was found to be unresponsive, with spontaneous head and left leg movements, neutral plantar responses, and no response to painful stimuli; an EEG was recommended. The EEG, done that day, showed continuous, generalized, bilaterally synchronous periodic 1-Hz sharp wave discharges (GPEDs), indicating that the patient was in electrographic SE (Figure 9.2B). He was given lorazepam, 6 mg, and phenytoin, 1,400 mg intravenously (IV), with elimination of GPEDs. However, on the fifth hospital day an EEG showed resumption of discontinuous GPEDs. He was given 1 g of phenobarbital IV, and on the sixth hospital day he turned his head to voice and moved his upper extremities and left lower extremity spontaneously. An EEG obtained that day showed intermittent lowamplitude GPEDs (Figure 9.2C). By hospital day 10 he was awake, looking around the room, and moving all his extremities, and on the following day he responded appropriately to verbal commands. An EEG obtained on hospital day 12 showed moderate slowing, with intermittent 2–8 second frontal intermittent rhythmic delta activity (FIRDA). The patient’s serum phenytoin level was 13.5 mg/dL, and the serum phenobarbital level was 20 mg/dL. Following discharge, in March 1995, two awake and stage I sleep EEGs were obtained and were normal. A brain magnetic resonance imaging study performed in May 1995 showed mild cortical atrophy. A neuropsychological assessment in August 1995 noted that he had a bachelor of science degree in engineering, but he had not worked since 1982. His score on the Mini-Mental State Exam was 25 out of 30. Scores on the Wechsler Adult Intelligence Scale-Revised (WAIS-R) revealed a verbal IQ of 95, a performance IQ of 78, and a full-scale IQ of 88. His attention and concentration were fair to poor, his performance on memory tasks was variable, his visuospatial skills and frontal lobe functioning were poor, and he was severely depressed. In February 1998 he had a psychiatric admission because of suicidal ideation. At discharge he was irritable, but organized in his thinking. He died in November 1998 at age 60. No further information regarding his death is available.
This patient presented with a history of confusional episodes for 3 months and an EEG suggestive of idiopathic generalized epilepsy (Figure 9.2A). On readmission 4 days after discharge he was in renal failure, hypoglycemic, and comatose. An EEG was necessary to establish the presence of GPEDs and NCSE, but it was obtained 4 days after admission, during which time he was probably in NCSE. Although the prognosis is quite poor in critically ill patients with NCSE in this setting, the patient recovered. However, it is likely that the patient suffered significant brain damage, because neuropsychological testing 20 months later showed impairment in attention and concentration, memory, frontal lobe function, and visuospatial orientation, as well as fullscale and subtest IQ scores well below what would be predicted based on his educational background. A delay in diagnosis is common in this setting (7), but the outcome
112
would improve if EEG monitoring of comatose patients were part of the initial evaluation of such patients (2).
Conclusions Those individuals at the two extremes with respect to presentation of electrographic SE, the apparently normal “walking wounded” and the ictally comatose, have no clinical signs pointing to the diagnosis, and therefore an EEG is needed to establish the diagnosis. In both groups there may be a significant delay to diagnosis, which can increase morbidity in both groups and mortality in the latter group. Morbidity and mortality in the ictally comatose can be reduced substantially by incorporating EEG monitoring into the initial evaluation of comatose patients. Morbidity in the walking wounded with frequent or prolonged subclinical epileptiform discharges may not be evident clinically, and neuropsychological testing may be needed to uncover cognitive deficits. Improvement in cognitive function can occur with the suppression or elimination of subclinical epileptiform discharges, but may be delayed and occur over a prolonged period of time, which points to the need for careful and extended follow-up of such individuals. This work was supported by the Medical Research Service, Office of Research and Development, Department of Veterans Affairs. The collaboration of Eliot Licht in studying the ambulatory outpatient described in this chapter is gratefully acknowledged.
REFERENCES 1. Andermann, F., and J. P. Robb. Absence status: A reappraisal following review of thirty-eight patients. Epilepsia 1972;13: 177–187. 2. Claassen, J., S. A. Mayer, R. G. Kowalski, et al. Detection of electrographic seizures with continuous EEG monitoring in critically ill patients. Neurology 2004;62:1743–1748. 3. DeLorenzo, R. J., E. J. Waterhouse, A. R. Towne, et al. Persistent nonconvulsive status epilepticus after control of convulsive status epilepticus. Epilepsia 1998;39:833–840. 4. Licht, E. A., R. H. Jacobsen, and D. G. Fujikawa. Chronically impaired frontal lobe function from subclinical epileptiform discharges. Epilepsy Behav. 2002;3:96–100. 5. Lowenstein, D. H., and M. J. Aminoff. Clinical and EEG features of status epilepticus in comatose patients. Neurology 1992;42:100–104. 6. Towne, A. R., E. J. Waterhouse, J. G. Boggs, et al. Prevalence of nonconvulsive status epilepticus in comatose patients. Neurology 2000;54:340–345. 7. Young, G. B., K. G. Jordan, and G. S. Doig. An assessment of nonconvulsive seizures in the intensive care unit using continuous EEG monitoring: An investigation of variables associated with mortality. Neurology 1996;47:83–89.
:
10
Status Epilepticus in Infancy and Childhood
. , ,
Introduction This chapter focuses on the clinical aspects of status epilepticus (SE) during childhood. The etiology, presentation, and prognosis of SE during childhood are characterized by distinctive features that reflect different stages in brain development. For example, the sensitivity of preschool-aged children to fever-induced convulsions is not seen in neonates or in children older than 5 or 6 years. Specific types of SE such as absence SE and the syndrome of continuous spikewaves during slow-wave sleep, as well as neonatal seizures, are discussed in detail in other chapters.
Classification An operational classification of SE in children entails distinguishing between convulsive and nonconvulsive SE. The convulsive type includes generalized or partial tonic, generalized or partial clonic, generalized tonic-clonic, and generalized myoclonic types. Nonconvulsive SE is characterized by subtle clinical signs and includes complex partial, simple partial, absence, and even generalized convulsive status epilepticus (GCSE), which are clinically subtle entities. According to the International League Against Epilepsy classification (Table 10.1), any of the seizure types can evolve into SE (Table 10.2). Generalized tonic-clonic SE is the most commonly recognized type. This condition can present as repeated tonic-clonic seizures without consciousness being regained between seizures or as continuous seizures. If recurrent seizures are allowed to persist without treatment or with inadequate treatment, a progressive diminution in convulsive activity occurs, so that the clinical motor manifestations of these seizures become increasingly subtle. This entity was termed by Treiman subtle generalized convulsive status epilepticus (118–121). Subtle GCSE is defined as profound coma, with convulsive activity limited to nystagmoid movements of the eyes or intermittent brief clonic twitches of the extremities or trunk, and bilateral ictal discharges on the electroencephalogram (EEG). A progressive attenuation of recurrent generalized tonic-clonic seizures evolving to only recurrent tonic activity has also been described (87), further suggesting that an increasing duration of SE may result in
clinical and electrographic dissociation of these seizures. If GCSE continues for a prolonged period of time, all motor activity may cease, while ictal discharges on EEG persist. This condition is then termed electrical GCSE. This electroclinical dissociation can be seen in neonates, as well as in severely ill children and adults (73, 95, 96). Generalized clonic SE occurs in normal children in approximately half of cases and is associated with prolonged febrile seizures; the remaining half of cases are distributed among children with acute and chronic encephalopathies (21). Generalized tonic SE occurs predominantly in children with Lennox-Gastaut syndrome. It has also been known to be precipitated in these children by benzodiazepine administration. Like generalized clonic SE and generalized tonic SE, generalized myoclonic SE occurs predominantly in children (80). Myoclonic SE can occur in patients with primary (idiopathic) generalized epilepsies (primary myoclonic SE) such as juvenile myoclonic epilepsy, childhood absence epilepsy, and juvenile absence epilepsy. Symptomatic generalized epilepsies can also result in myoclonic SE (secondary myoclonic SE) and include Doose’s syndrome, LennoxGastaut syndrome, and epilepsy with myoclonic absences. Absence status epilepticus (ASE) is also variably called petit mal status, spike-wave stupor, minor SE, epileptic twilight state, and status pyknolepticus. ASE is defined as a prolonged generalized absence seizure. Classically, ASE is associated with continuous alteration of consciousness, as opposed to the cyclical variation of consciousness more commonly seen in complex partial status epilepticus (CPSE) (35). ASE is further subdivided into typical and atypical absence status, corresponding to prolonged typical and atypical absence seizure, respectively. The latter usually lasts longer, has a higher incidence of postural tone change, is more often associated with an abnormal interictal EEG, may occur with other seizure types, may be associated with mental retardation or developmental delay, and may have a faster or slower ictal EEG than the 3-Hz spike-and-wave pattern that characterizes typical absence seizures. CPSE may be difficult to distinguish from ASE through clinical manifestations alone, and typically EEG is needed to
, , :
113
T 10.2 Proposed classification of status epilepticus
T 10.1 The International League Against Epilepsy classification of epileptic seizures I. Partial (focal, local) seizures A. Simple partial seizures (consciousness not impaired) 1. With motor symptoms 2. With somatosensory or special sensory symptoms 3. With autonomic symptoms 4. With psychic symptoms B. Complex partial seizures (with impairment of consciousness) 1. Beginning as simple partial seizures and progressing to impairment of consciousness 2. With no other features 3. With features as in simple partial seizures 4. With automatisms C. With impairment of consciousness at onset 1. With no other features 2. With features as in simple partial seizure 3. With automatisms D. Partial seizures evolving to secondarily generalized seizures 1. Simple partial seizures evolving to generalized seizures 2. Complex partial seizures evolving to generalized seizures 3. Simple partial seizures evolving to complex partial seizures to generalized seizures II. Generalized seizures (convulsive or nonconvulsive) A. Absence seizures 1. Absence seizures 2. Atypical absence seizures B. Myoclonic seizures C. Clonic seizures D. Tonic seizures E. Tonic-clonic seizures F. Atonic seizures (astatic seizures) III. Unclassified epileptic seizures (includes all seizures that cannot be classified because of inadequate or incomplete data and some that defy classification in hitherto described categories). This includes some neonatal seizures, such as rhythmic eye movements, chewing, and swimming movements.
distinguish between these two types of nonconvulsive SE. By definition, CPSE is characterized by impairment of consciousness. However, the clinical manifestations of CPSE can be quite subtle and varied, and suspicion for this entity must remain high for accurate diagnosis and treatment. At one end of the spectrum, affected patients may have mild clouding of consciousness or bland confusion, which can be either continuous or intermittent; at the other extreme, unresponsive obtundation or bizarre, almost psychotic, agitation can be seen (33, 61, 64, 69, 89, 112, 113, 130). Until recently, the concept of epileptic fugue was disputed and attributed to psychiatric disease (68). However, patients in an epileptic fugue with well-documented CPSE lasting days or months have been described, including patients with intermittent
114
Partial Convulsive Tonic
Hemiclonic status epilepticus, hemiconvulsion-hemiplegia-epilepsy, hemi-grand mal status epilepticus
Clonic Nonconvulsive Simple Complex partial
Focal motor status, focal sensory, epilepsia partialis continua Epileptic fugue state, prolonged epileptic stupor, prolonged epileptic confusional state, temporal lobe status epilepticus, psychomotor status epilepticus, continuous epileptic twilight state
Generalized Convulsive Tonic-clonic Tonic Clonic Myoclonic Nonconvulsive Absence
Undetermined Subtle Neonatal
Grand mal, epilepticus convulsivus
Myoclonic status epilepticus Spike-and-wave stupor, spike-and-slow-wave or 3/second spike-and-wave status epilepticus, petit mal, epileptic fugue, epilepsia minora continua, epileptic twilight state, minor status epilepticus Epileptic coma Erratic status epilepticus
episodes of acute psychotic behavior (14, 85, 104). Such a phenomenon has been described in children as well (69). Simple partial SE often presents as rhythmic clonic or myoclonic movements with full level of consciousness. When this condition lasts for hours or days, it is known as epilepsia partialis continua (EPC) (13, 108). Although EPC is commonly seen in adults after a stroke, in children it is often associated with Rasmussen’s encephalitis.
Epidemiology The annual incidence of SE in the United States, regardless of the type of SE, is estimated at 102,000–152,000 (19, 60). However, the true incidence of SE is not well defined, and those figures probably represent an underestimate as a consequence of underrecognition and underreporting of SE. The incidence of SE has a bimodal distribution, with the highest rates seen in young children up to 12 months old and again in adults older than 60 years (19–21). Approximately
:
half of the cases of SE occur in children under the age of 3 years (101). According to one study, up to 70% of children who have epilepsy that begins before 1 year of age will experience an episode of SE (40). In a study of children who initially presented in SE, 30% of those who were followed prospectively developed epilepsy later in life (67). Approximately half of the patients in that study were judged to have idiopathic or febrile SE, while the remainder had symptomatic causes. Among those previously diagnosed as having epilepsy, reported estimates of SE range from 0.5% to 6.6%. Within 5 years of the initial diagnosis of epilepsy, 20% of all patients will experience an episode of SE. Of all cases of SE, GCSE is the most common type. However, this may reflect the relative ease of recognizing GCSE compared with other forms of SE. In one study, about 70% of both adults and children with SE had GCSE (20). The incidence of myoclonic SE is not established. Although primary myoclonic SE is quite rare, secondary myoclonic SE is comparatively far more frequent (38). ASE is estimated to occur in 5%–10% of persons with primary generalized epilepsy (16, 57). In patients with known absence seizures, the incidence of ASE has been placed at 3% (3, 41). One report noted that approximately 75% of the ASE cases occurred in the pediatric population (40 years), and hypotension requiring vasopressors during the pentobarbital coma. A relapse after the pentobarbital coma depends on treatment of underlying condition. Patients with chronic epilepsy, infection, or focal lesions fared better than patients with multiple medical problems (37, 90). Respiratory depression can occur with multiple doses of benzodiazepines, and the doses were often lower than the recommended dose for the treatment of SE (106).
Prognosis The outcome of SE varies according to the age of the patient, the underlying etiology, the duration of SE (>60 minutes has a worse prognosis), and the underlying neurologic and systemic condition of the patient (90). Death from SE is usually due to the underlying disease or to respiratory, cardiovascular, or metabolic complications. The mortality in children has decreased since 1970, when it was 11% and a poor neurologic or cognitive outcome occurred in 53% (1). By 1989 the mortality had fallen to 3%–6% (36, 65, 67). This drop in mortality may be due to the introduction of
118
benzodiazepine therapy, the widespread availability of pediatric intensive care facilities, and the change in the definition of status to 30 minutes from the 1-hour criterion used by Aicardi and Chevrie (1). In general, children have a lower mortality from SE than adults (3%–15%), although they have a higher occurrence of generalized SE. Death is twice as common in elderly patients with SE as in young children. Children more easily recover from illness than do adults, and the causes of SE in children are generally more benign (1, 19, 51, 67, 82). The most common causes in children are infection and fever, which are associated with a low mortality. Anoxia is more common in adults and poses a higher risk of death in both children and adults (102). As suggested earlier, etiology is the main determinant of surving or dying from SE. The etiology of SE can be divided into six categories: (1) acute symptomatic, which accounts for most mortality in patients with new neurologic conditions such as encephalitis, acute metabolic disorder, head trauma, and stroke, (2) known epilepsy due to noncompliance or intractability, which has a low mortality regardless of etiology, (3) febrile SE, which has a low mortality if one can rule out another process such as encephalitis, (4) a first seizure in idiopathic epilepsy, which has a low mortality (71), (5) remote symptomatic, an etiologic category that includes acquired, developmental, or congenital CNS malformation and epileptic syndromes (these have a high morbidity but a low mortality), and (6) idiopathic, a category associated with a low morbidity and low mortality rate. Long-term complications include chronic epilepsy (20%–40%), encephalopathy (6%–15%), and focal neurologic deficits (9%–11%) (30). Cognitive or persistent neurologic deficits and further seizures occur most frequently with a symptomatic etiology (remote and acute) and in children less than 3 years old. It is possible that the prognosis of the underlying disorder is worsened by an episode of convulsive SE (103). However, it is difficult to determine what complications can be attributed to GCSE and what complications result from the underlying etiology. Chronic encephalopathy and brain atrophy occur in 6%–15% of patients as result of diffuse cortical injury (2, 24, 29). Children’s development may be affected, with 9%–11% developing focal neurologic signs, but most children had this before they had GCSE (1, 67). It is possible that hippocampal sclerosis may develop after a bout of SE. Although febrile status is associated with a low incidence of neurologic deficits or cognitive impairment, the risk of subsequent epilepsy is 21%, which is much higher than the population risk of 1%. Half will have complex partial seizures, and most of these patients have hippocampal sclerosis (123). Approximately 50% of adult patients with temporal lobe epilepsy due to mesial temporal lobe sclerosis have a history of prolonged febrile convulsions in childhood
:
(104). Up to 75% of children with temporal lobe epilepsy are found to have hippocampal sclerosis on MRI (39). In addition, there are several case series showing radiologic evolution to mesial temporal lobe epilepsy (98, 110, 128). Although the association of prolonged febrile convulsions and mesial temporal sclerosis is controversial and outside the scope of this chapter, an enlightened view would accept that mesial temporal sclerosis is probably both a cause and an effect of seizures (107). Neonates have a high mortality and morbidity because of the underlying etiology. The neurologic complication rate among infants less than 1 year old is 29%, in children 1–3 years old it is 11%, and children older than 3 years it is 6%. In 30% of patients chronic seizures develop, with neurologic sequelae. Therefore, younger infants are at higher risk for neurologic sequelae such as mental retardation, behavioral problems, focal motor deficits, and chronic epilepsy (59). There is a higher risk in infants because infants have a higher prevalence of SE or because of the underlying etiology. It is not clear whether this is because neonatal seizures affect brain development or whether the seizures are a symptom of the underlying brain insult or dysfunction (72). Persistent electrographic seizures after clinical seizures have stopped are common in neonates (85) at the initial visit disclosed that all four patients in group I with a spike-wave index above 85% showed mental subnormality, with IQ scores below 85 at follow-up (Figure 11.3). Three of five patients in group II have retained an IQ in the normal range, and none of five patients in group III showed mental subnormality. Based on these observations, we stress the significance of a spike-wave index above 85%, as Tassinari insisted (51, 53), but we can accept over 50% as a criterion for diagnosing epilepsy with CSWS, considering the uniformity of general clinical features. The spike-wave index ranged from 32% to 41% in our patients with ABPE, and from 31% to 87% in those with NSENM. It is above 85% in typical cases of epilepsy with CSWS and 52%–78% in atypical cases with clinical symp-
:
F 11.3 Mental prognosis at the final follow-up. (A) Relation between spike-wave index and mental prognosis. (B) Relation between duration of continuous spike waves during slow-wave sleep (CSWS) and mental prognosis. Group I comprised patients
with spike-wave indices of 85% or higher; group II, patients with spike-wave indices of 50%–84%; and group III, patients with spikewave indices of 25%–49%.
toms typical for epilepsy with CSWS, despite a spike-wave index below 85% (35). When we examined the correlation between duration of CSWS and cognitive performance, none of the patients with CSWS of less than 2 years’ duration had an IQ less than 85, but all patients with CSWS persisting longer than 2 years showed a regression of IQ to below 85. CSWS was not supressed within 2 years in any group I patient. These observations support the hypothesis that mental deterioration strongly correlates with a higher spike-wave index and a longer duration of CSWS. The importance of early diagnosis and early suppression of CSWS is thus clear. This close relationship between diffuse spike-and-wave discharges and mental deterioration may contribute to neurophysiologic studies of dementia.
the concept of hereditary impairment of brain maturation, which they proposed as the common pathogenetic factor for the age-related epilepsies. The changing course of the manifestation mode of epileptic discharges before and after the appearance of CSWS was followed in 15 patients with epilepsy with CSWS (Figure 11.5). CSWS often evolved from a pattern of combined focal and diffuse discharges into a focal spike pattern or suppression of epileptic discharge. It is noteworthy that the final localization of focal spikes was most often frontal. Morikawa et al. (34) observed the appearance of frontal foci with the disappearance of CSWS. These findings suggest the importance of cortical epileptic foci in CSWS.
P Although these three types of ESES syndrome are usually resistant to therapy at first, and although ESES persists for more than a year with alternating remissions and relapses, long-term follow-up confirmed its final disappearance in all of our patients. Thus, seizure and EEG prognosis may be fair (34, 35, 48, 53). The prognosis for cognitive function, however, cannot be estimated to be fair except for ABPE, as mentioned earlier. In 29 cases of ESES syndrome, CSWS usually appeared in childhood, between ages 3 years 0 months and 13 years 1 month, and disappeared by age 15 years (3 years 6 months in the youngest, 15 years 10 months in the oldest) in all cases with adequate follow-up (Figure 11.4). Accordingly, ESES syndrome is an age-related condition with a strong developmental component; age is a major factor in its manifestation. It is interesting that Doose et al. (13–15, 23) tried to understand epilepsy with CSWS through
P CSWS Because the pathophysiology of epilepsy with CSWS has not been fully investigated, the ILAE classification placed epilepsy with CSWS with “epilepsies and epileptic syndromes, undetermined whether focal or generalized” (8). We investigated the pathophysiology of CSWS using a new method of EEG analysis (30, 31). In three children with epilepsy with CSWS, interhemispheric small time differences (TDs) during spike-wave activity on the EEG were estimated by coherence and phase analysis via a twodimensional autoregressive model for differentiation between primary bilateral synchrony and secondary bilateral synchrony (SBS) (57). Maximal TDs at the onset of apparently bilateral synchronous spike-wave bursts ranged from 12.0 to 26.5 msec (mean, 20.3 msec), showing consistent leading hemispheres in eight bursts in the three patients (30). Therefore, SBS was suggested as the pathophysiology of ESES in these cases. Some other studies also supported SBS in this condition (54). Examination of intraburst TD
.:
131
F 11.4 Electroclinical course of three groups of patients with almost continuous spike waves during slow-wave sleep (CSWS). Group I comprised patients with spike-wave indices of
85% or higher; group II, patients with spike-wave indices of 50%–84%; and group III, patients with spike-wave indices of 25%–49%.
CSWS 15
F 11.5 Changing pattern of epileptic discharges in ESES syndrome. F, focal discharge; D, diffuse discharge. Numbers refer to numbers of patients.
variation showed no consistent disappearance of TDs during the latter part of the bursts. Therefore a role of the corpus callosum was suggested in the generation of SBS in epilepsy with CSWS (30). Park et al. (41) demonstrated increased metabolic activity at the right superior temporoparietal area by FDG PET in a case of epilepsy with CSWS, suspecting secondary bilateral synchrony for manifesting CSWS. These facts suggest that epilepsy with CSWS should be categorized into localization-related epilepsy, and that
132
CSWS appears on the basis of the mechanisms of SBS. In light of the finding of metabolic abnormalities involving the focal cortical area on FDG PET, Maquet et al. (32) suspected the cortical dysfunction, especially associative cortices, and, interestingly, its relation to the deterioration of cognitive function observed in CSWS. This work was supported by a Reseach Grant (No. 82-01-05) for Nervous and Mental Disorders from the Ministry of Health and Welfare of Japan.
:
REFERENCES 1. Aicardi, J., and J. J. Chevrie. Atypical benign partial epilepsy of childhood. Dev. Med. Child Neurol. 1982;24:281–292. 2. Arzimanoglou, A., R. Guerrini, and J. Aicardi. Aicardi’s Epilepsy in Children. 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2004:152–155, 176–187, 241–261. 3. Baumgartner, C., I. Podreka, A. Olbrich, et al. Epileptic negative myoclonus: An EEG-single-photon emission CT study indicating involvement of premotor cortex. Neurology 1996; 46:753–758. 4. Beaumanoir, A., G. Foletti, M. Magistris, and D. Volanschi. Status epilepticus in the Lennox-Gastaut syndrome. In E. Niedermeyer and R. Degen, eds. The Lennox-Gastaut Syndrome. New York: Alan R. Liss, 1988:283–299. 5. Berg, A. T., S. Shinnar, S. R. Levy, and F. M. Testa. Status epilepticus in children with newly diagnosed epilepsy. Ann. Neurol. 1999;45:618–623. 6. Brenner, R. P. Is it status? Epilepsia 2002;43(Suppl. 3):103–113. 7. Brett, E. M. Minor epileptic status. J. Neurol. Sci. 1966;3:52–75. 8. Commission on Classification and Terminology of the International League Against Epilepsy. Revised classification of epilepsies, epileptic syndromes and related seizure disorders. Epilepsia 1989;30:389–399. 9. Dalla Bernardina, B., E. Fontana, and F. Darra. Myoclonic status in non-progressive encephalopathies. In J. Roger, M. Bureau, C. Dravet, P. Genton, C. A. Tassinari, and P. Wolf, eds. Epileptic Syndromes in Infancy, Childhood and Adolescence, 3rd ed. London: John Libbey, 2002:137–144. 10. De Negri, M. Electrical status epilepticus during sleep (ESES). Different clinical syndromes: Towards a unifying view? Brain Dev. 1997;19:447–451. 11. de Saint-Martin, A., R. Carcangiu, A. Arzimanoglou, R. Massa, P. Thomas, J. Motte, et al. Semiology of typical and atypical rolandic epilepsy: A video-EEG analysis. Epileptic Disord. 2001;3:173–181. 12. Doose, H. Nonconvulsive status epilepticus in childhood: Clinical aspects and classification. In A. V. Delgado-Escueta, C. G. Wasterlain, D. M. Treiman, and R. J. Porter, eds. Status Epilepticus. Adv. Neurol. 1983;34:83–92. 13. Doose, H., and W. K. Baier. Benign partial epilepsy and related conditions: Multifactorial pathogenesis with hereditary impairment of brain maturation. Eur. J. Pediatr. 1989;149: 152–158. 14. Doose, H., A. Hahn, B. A. Neubauer, J. Pistohl, and U. Stephani. Atypical “benign” partial epilepsy of childhood or pseudo-Lennox syndrome. Part II. Family study. Neuropediatrics 2001;32:9–13. 15. Doose, H., B. Neubauer, and G. Carlsson. Children with benign focal sharp waves in the EEG: Developmental disorders and epilepsy. Neuropediatrics 1996;27:227–241. 16. Dravet, C., M. Bureau, H. Oguni, Y. Fukuyama, and O. Cokar. Severe myoclonic epilepsy in infancy (Dravet syndrome). In J. Roger, M. Bureau, C. Dravet, P. Genton, C. A. Tassinari, and P. Wolf, eds. Epileptic Syndromes in Infancy, Childhood and Adolescence. 3rd ed. London: John Libbey, 2002:81–103. 17. Engel, J. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: Report of the ILAE task force on classification and terminology. Epilepsia 2001;42: 796–803. 18. Fejerman, N., R. Caraballo, and S. N. Tenembaum. Atypical evolutions of benign localization-related epilepsies in children: Are they predictable? Epilepsia 2000;41:380–390.
19. Galanopoulou, A. S., A. Bojkö, F. Lado, et al. The spectrum of neuropsychiatric abnormalities associated with electrical status epilepticus in sleep. Brain Dev. 2000;22:279–295. 20. Gastaut, H. Classification of status epilepticus. In A. V. Delgado-Escueta, C. G. Wasterlain, D. M. Treiman, and R. J. Porter, eds. Status Epilepticus. Adv. Neurol. 1983;34:15–35. 21. Granner, M. A., and S. I. Lee. Nonconvulsive status epilepticus: EEG analysis in a large series. Epilepsia 1994;35: 42–47. 22. Guerrini, R., C. Dravet, P. Genton, M. Bureau, J. Roger, G. Rubboli, and C. A. Tassinari. Epileptic negative myoclonus. Neurology 1993;43:1078–1083. 23. Hahn, A., J. Pistohl, B. A. Neubauer, and U. Stephani. Atypical “benign” partial epilepsy or pseudo-Lennox syndrome. Part I. Symptomatology and long-term prognosis. Neuropediatrics 2001;32:1–8. 24. Hauser, W. A. Status epilepticus: Frequency, etiology, and neurological sequelae. In A. V. Delgado-Escueta, C. G. Wasterlain, D. M. Treiman, and R. J. Porter, eds. Status Epilepticus. Adv. Neurol. 1983;34:3–14. 25. Hesdorffer, D.C., G. Logroscino, G. Cascino, et al. Incidence of status epilepticus in Rochester, Minnesota, 1965–1984. Neurology 1998;50:735–741. 26. Jayakar, P. B., and S. S. Seshia, Electrical status epilepticus during slow-wave sleep. J. Clin. Neurophysiol. 1991;8:299–311. 27. Kaplan, P. W. Assessing the outcomes in patients with nonconvulsive status epilepticus: Nonconvulsive status epilepticus is underdiagnosed, potentially overtreated, and confounded by comorbidity. J. Clin. Neurophysiol. 1999;16:341–352. 28. Kaplan, P. W. Nonconvulsive status epilepticus. Semin. Neurol. 1996;16:33–40. 29. Kobayashi, K., N. Murakami, H. Yoshinaga, H. Enoki, Y. Ohtsuka, and S. Ohtahara. Nonconvulsive status epilepticus with continuous diffuse spike-and-wave discharges during sleep in childhood. Jpn. J. Psychiatr. Neurol. 1988;42:509–514. 30. Kobayashi, K., N. Nishibayashi, Y. Ohtsuka, E. Oka, and S. Ohtahara. Epilepsy with electrical status epilepticus during slow sleep and secondary bilateral synchrony. Epilepsia 1994; 35:1097–1103. 31. Kobayashi, K., Y. Ohtsuka, E. Oka, and S. Ohtahara. Primary and secondary bilateral synchrony in epilepsy: Differentiation by estimation of interhemispheric small time differences during short spike-wave activity. Electroencephalogr. Clin. Neurophysiol. 1992;83:93–103. 32. Maquet, P., E. Hirsch, M. N. Metz-Lutz, J. Motte, D. Dive, C. Marescaux, and G. Franck. Regional cerebral glucose metabolism in children with deterioration of one or more cognitive functions and continuous spike-and-wave discharges during sleep. Brain 1995;118:1497–1520. 33. Matsumoto, A., T. Kumagai, K. Miura, S. Miyazaki, C. Hayakawa, and T. Yamanaka. Epilepsy in Angelman syndrome associated with chromosome 15q deletion. Epilepsia 1992;33:1083–1090. 34. Morikawa, T., M. Seino, and K. Yagi. Long-term outcome of four children with continuous spike-waves during sleep. In J. Roger, M. Bureau, C. Dravet, F. E. Dreifuss, A. Perret, and P. Wolf, eds. Epileptic Syndromes in Infancy, Childhood and Adolescence. 2nd ed. London: John Libbey, 1992:257–265. 35. Nishibayashi, N. [Longitudinal study of the epilepsy with continuous spike-waves during slow wave sleep.] J. Jpn. Epilepsy Soc. 1996;14:1–11 (in Japanese). 36. Obeso, J. A., J. Artieda, and A. Burleigh. Clinical aspects of negative myoclonus. In S. Fahn, M. Hallett, H. O. Lüders, and
.:
133
37. 38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49. 50.
51.
52.
53.
C. D. Marsden, eds. Negative Motor Phenomena. Adv. Neurol. 1995;67:1–7. Ohtahara, S. [ESES syndrome.] Igaku No Ayumi 1997;183: 96–102 (in Japanese). Ohtahara, S., Y. Ohtsuka, H. Yoshida, et al. [A peculiar type of non-convulsive status epilepticus in childhood. In Annual Report of Research: Pathogenesis and Management of Epilepsy.] Tokyo: Ministry of Health and Welfare of Japan, 1983:67–76 (in Japanese). Ohtahara, S., E. Oka, Y. Yamatogi, Y. Ohtsuka, T. Ishida, N. Ichiba, et al. Non-convulsive status epilepticus in childhood. Folia Psychiatr. Neurol. Jpn. 1979;33:345–351. Ohtsuka, Y., H. Yoshida, M. Matsuda, et al. [A peculiar type of non-convulsive status epilepticus in childhood: A clinical and electroencephalographic study.] J. Jpn. Epilepsy Soc. 1983;1:107–115 (in Japanese). Park, Y. D., J. M. Hoffman, R. A. Radtke, and G. R. DeLong. Focal cerebral metabolic abnormality in a patient with continuous spike waves during slow-wave sleep. J. Child Neurol. 1994;9:139–143. Patry, G., S. Lyagoubi, and C. A. Tassinari. Subclinical “electrical status epilepticus” induced by sleep in children. Arch. Neurol. 1971;24:242–252. Rossi, P. G., A. Parmeggiani, A. Posar, et al. Landau-Kleffner syndrome (LKS): Long-term follow-up and links with electrical status epilepticus during sleep (ESES). Brain Dev. 1999;21:90–98. Rubboli, G., L. Parmeggiani, and C. A. Tassinari. Frontal inhibitory spike component associated with epileptic negative myoclonus. Electroencephalogr. Clin. Neurophysiol. 1995;95: 201–205. Shahani, B. T., and R. R. Young. Physiological and pharmacological aids in the differential diagnosis of tremor. J. Neurol. Neurosurg. Psychiatry 1976;39:772–783. Shorvon, S. Status epilepticus: Its Clinical Features and Treatment in Children and Adults. Cambridge, U.K.: Cambridge University Press, 1994. Sillanpää, M, and S. Shinnar. Status epilepticus in a population-based cohort with childhood-onset epilepsy in Finland. Ann. Neurol. 2002;52:303–310. Smith, M. C., and T. J. Hoeppner. Epileptic encephalopathy of late childhood: Landau-Kleffner syndrome and the syndrome of continuous spikes and waves during slow-wave sleep. J. Clin. Neurophysiol. 2003;20:462–472. Stores, G., Z. Zaiwalla, and A. Hoshika. Non-convulsive status epilepticus. Arch. Dis. Child. 1995;73:106–111. Sugimoto, T., A. Yasuhara, T. Ohta, N. Nishida, S. Saitoh, J. Hamabe, et al. Angelman syndrome in three siblings: Characteristic epileptic seizures and EEG abnormalities. Epilepsia 1992;33:1078–1082. Tassinari, C. A. [New perspective in epileptology. In Japanese Epilepsy Association, ed. Trends in Modern Epileptology.] Tokyo: International Public Seminar on Epileptology, 1981;42–59 (in Japanese). Tassinari, C. A., G. Rubboli, L. Parmeggiani, et al. Epileptic negative myoclonus. In S. Fahn, M. Hallett, H. O. Lüders, and C. D. Marsden, eds. Negative Motor Phenomena. Adv. Neurol. 1995;67:181–197. Tassinari, C. A., G. Rubboli, L. Volpi, C. Billard, and M. Bureau. Electrical status epilepticus during slow sleep (ESES or CSWS) including acquired epileptic aphasia (LandauKleffner syndrome). In J. Roger, M. Bureau, C. Dravet, P. Genton, C. A. Tassinari, and P. Wolf, eds. Epileptic Syndromes in
134
54.
55.
56. 57.
58.
59.
60.
:
Infancy, Childhood and Adolescence. 3rd ed. London: John Libbey, 2002:265–283. Tassinari, C. A., G. Rubboli, L. Volpi, S. Meletti, G. d’Orsi, M. Franca, et al. Encephalopathy with electrical status epilepticus during slow sleep or ESES syndrome including the acquired aphasia. Clin. Neurophysiol. 2000;111(Suppl. 2): S94–S102. Towne, A. R., E. J. Waterhouse, J. G. Boggs, et al. Prevalence of nonconvulsive status epilepticus in comatose patients. Neurology 2000;54:340–345. Treiman, D. M. Electroclinical features of status epilepticus. J. Clin. Neurophysiol. 1995;12:343–362. Tükel, K., and H. Jasper. The electroencephalogram in parasagittal lesions. Electroencephalogr. Clin. Neurophysiol. 1952;4: 481–494. Veggiotti, P., F. Beccaria, R. Guerrini, et al. Continuous spikeand-wave activity during slow-wave sleep: Syndrome or EEG pattern? Epilepsia 1999;40:1593–1601. Vuilleumier, P., P. A. Despland, and F. Regli. Failure to recall (but not to remember): Pure transient amnesia during nonconvulsive status epilepticus. Neurology 1996;46:1036–1039. Wieser, H. G. Simple partial status epilepticus. In J. Engel, Jr. and T. A. Pedley, eds. Epilepsy: A Comprehensive Textbook. Philadelphia: Lippincott-Raven, 1997:709–723.
12
Status Epilepticus in the Neonate
.
Introduction At the first International Symposium on Status Epilepticus, held at the University of California, Los Angeles, in 1980, the concept was advanced that neonatal seizures may be either of epileptic or nonepileptic origin, and the clinical and electroencephalographic (EEG) characteristics of each group were described (39). Eventually this work led to the characterization and classification of neonatal seizures based on both clinical features and presumed pathophysiology (40, 54, 55). Subsequent clinical studies of the neonate by several investigators have resulted in further detailed characterization and classification, clarification of epidemiology, an increased understanding of pathophysiology of various seizure types, identification of trends in risk and etiologic factors, assessment of methods for predicting long-term outcomes, the development of new therapeutic strategies, and ongoing evaluation of the roles of EEG, EEG-video monitoring, and computer-directed, automated EEG seizure detection in diagnosis and management (1, 5, 10, 11, 15, 21, 27, 40, 43, 55, 64, 67, 73, 77, 78, 97). Although there is now a better understanding of which seizure types may be epileptic in origin, several questions concerning this specific type of neonatal seizure remain unresolved. Two questions in particular are relevant to this discussion: What constitutes status epilepticus (SE) in the neonate? Does this designation have clinical significance for the newborn infant beyond the finding of an epileptic seizure of any duration? These questions are best broached with the understanding that most clinical investigations of neonatal seizures have not distinguished seizures based on pathophysiology, and the seizures have not been described in terms of frequency, duration, or degree of refractoriness to antiepileptic drugs (AEDs). Thus, conclusions about neonatal SE must be drawn from more general studies about neonatal seizures, with recognition of the limitations of this type of analysis.
Definitions The traditional definition of SE—30 minutes of sustained seizure activity or repetitive seizures without full recovery— may not be appropriate for the neonate (77, 78, 82–84). In some neonates, seizures may be frequent and prolonged from
their onset and may be refractory to AED therapy. Current clinical practice does not allow long periods of observation of ongoing neonatal seizures or the EEG recording of seizure activity without intervention. Although in an individual newborn, there is the potential for seizures to be brief and nonrecurrent (even in the absence of AED treatment), there are no consistent methods of predicting which neonate will have persistent and prolonged seizures. In clinical practice, the first seizure observed or recorded in a neonate is typically treated as the onset of SE—the infant is evaluated for etiology and treated acutely with etiology-specific therapy, general management of airway and cardiovascular support, and AEDs, in much the same manner as older children and adults who are thought to be experiencing SE. Thus, there is an operant definition of neonatal SE, one that may limit the understanding of the natural course of seizures in the neonate but that is currently determined by a prevailing clinical perspective that almost all neonatal seizures must be treated acutely and aggressively. Other definitions of neonatal SE are more quantitative. For example, Scher and colleagues have suggested that the diagnosis of SE can be made when the cumulative duration of seizures recorded during one continuous EEG session is 50% or greater than the total duration of the recording, whatever its length (76–78). Despite these considerations, the definition of neonatal SE remains elusive and arbitrary. For example, at our center, 5–10 minutes of electrical seizure activity recorded on EEG, either as a single seizure or as recurrent seizures, is considered SE, although in practice, that term is rarely used, and the phrase “prolonged and recurrent seizure activity” is more often used to characterize this condition.
Predisposition to SE in the neonate The neonate is more predisposed to seizures than are older children and adults. This situation results from a number of factors that coexist early in life. The perinatal period is one of rapid brain growth and development, manifested by changes in brain structure and function. The rapid growth rate and the sequence of development make the immature brain susceptible to injury. In addition, the perinatal period is a relatively hostile environment for the neonate, as it is characterized by a wide range of potential etiologic and risk factors for brain injury.
:
135
T 12.1 Factors that enhance epileptogenesis in the immature brain Enhanced cellular excitation Increased chance of neuronal firing, since small changes in current across immature membranes result in relatively large voltage changes Hyperexcitable state due to accumulation of extracellular potassium resulting from: • Delayed glia development • Slow ion pump, exchangers, and transporter systems • Immature enzyme systems Enhanced synaptic excitation Abundance of excitatory synapses High density of receptors for excitatory neurotransmitters Paucity of inhibitory receptors Some inhibitory neurotransmitters appear to be excitatory early in development Different molecular composition of excitatory and inhibitory receptors Enhanced propagation of an epileptic discharge Diminished ability to restrict focal discharges, weak surround inhibition Amplification of epileptic activity by substantia nigra reticularis
There are also intrinsic neurobiological factors that enhance epileptogenesis in the immature brain. Current concepts of epileptogenesis in the immature brain are discussed elsewhere in this book, but some features are reviewed here (Table 12.1). The developing brain is more likely than the mature brain to generate epileptic seizure activity owing to properties that enhance cellular and synaptic excitation and promote maintenance and propagation of seizure activity (4, 5, 12, 18, 20, 23–26, 29, 31, 41, 44, 57, 59, 60, 71, 79, 88, 93, 94). This may be clinically manifested as the tendency for seizures to occur frequently and to be more prolonged.
Epidemiology of neonatal seizures The reported incidence of neonatal seizures has varied as a result of differences in study methodology, case ascertainment method, and the period and the geographic location of the respective studies: 5.1 per 1,000 live births during the period 1959–1966 (National Collaborative Perinatal Project [19]), 3.5 per 1,000 for the period 1985–1989 (Fayette County, Kentucky [43]), 2.5 per 1,000 for 1990–1994 (Newfoundland, Canada [73]), and 1.8 per 1,000 for 1992–1994 (Harris County, Texas [75]). Within the neonatal seizure population, determining the precise incidence of SE is difficult, because neonatal SE is not uniformly defined. In addition, the first seizure witnessed in an individual newborn is most often treated as if it were
136
the onset of SE, thus preventing an accurate characterization of the natural history and duration of a particular seizure or series of seizures. Finally, many epidemiologic studies of neonatal seizures do not differentiate between epileptic and nonepileptic origin, further obscuring the true incidence of seizures caused by various pathophysiologic mechanisms. Few investigators have applied a strict definition of SE in the study of neonates. However, Scher and colleagues (77, 78) studied full-term and preterm (£31 weeks’ gestational age) infants and compared the incidence of SE, which they defined as either continuous seizure activity recorded on EEG for 30 minutes or recurrent electrical seizures during 50% of the recording time of a diagnostic EEG. They found that 33% (11/35) of full-term infants and 9% (3/33) of preterm infants with seizures met one or both criteria for SE. Defining SE as seizures comprising 50% of the EEG accounted for more cases than the absolute time of seizures of 30 minutes’ duration.
Classification of neonatal seizures Whatever definition of neonatal SE is used, the seizures themselves must first be accurately characterized and classified according to pathophysiologic mechanisms so that the seizures considered are of epileptic origin. This is an initial critical but often overlooked point in some clinical studies. The results of bedside EEG-polygraphic-video monitoring of neonates suggest that seizures early in life may be of epileptic or nonepileptic origin (54, 55). These studies (by Mizrahi and Kellaway) evaluated clinical characteristics of seizures, their relationship to EEG seizure activity, the response of the infant to tactile stimulation (to determine if the seizures were provoked), and the response of the infant to restraint during seizures (to determine if the seizures could be arrested with this maneuver). The resulting classification differentiated seizure types based on their mechanism of initiation. This work led to more specific terminology. Thus, in the neonate, the term seizure may be used in its generic sense, that is, to designate abnormal, repetitive, stereotypic and paroxysmal clinical events. Some seizures are generated by an epileptic mechanism; others are best thought of as exaggerated or abnormal reflex behaviors, referred to as brainstem release phenomena (39, 55). Seizures of nonepileptic origin are not considered to constitute SE, even if they are recurrent and prolonged. A classification of neonatal seizures based on presumed pathophysiology is listed in Table 12.2, and clinical and EEG features are listed in Table 12.3. When clinical seizures are classified according to their temporal relationship to electrical seizure activity, they are considered to be electroclinical when the clinical and electrical events overlap in time, clinical only when clinical events occur in
:
T 12.2 Classification of paroxysmal clinical events of the neonate in relation to electrical seizure activity and presumed pathophysiology Clinical seizures with a consistent electrocortical signature (Electroclinical) Pathophysiology—Epileptic Clonic A. Unifocal 1. Limb 2. Facial 3. Hemiconvulsive B. Multifocal 1. Alternating 2. Bilateral, asynchronous C. Axial 1. Abdominal 2. Diaphragm
Myoclonic A. Generalized B. Focal Spasms (Generalized) A. Flexion B. Extension C. Mixed extension-flexion
Tonic A. Focal 1. Ocular (sustained eye deviation) 2. Limb posturing 3. Asymmetric Clinical seizures without a consistent electrocortical signature (Clinical only) Pathophysiology—Presumed nonepileptic Myoclonic A. Generalized B. Focal C. Multifocal (fragmentary)
Tonic A. Generalized 1. Symmetric a. Flexion b. Extension c. Mixed flexion-extension
Motor automatisms (Stereotypic complex movements) A. Oral-buccal-lingual movements 1. Chewing 2. Sucking B. Ocular signs 1. Random eye movements 2. Blinking, rhythmic eye opening
C. Limb (movements of progression) 1. Pedaling 2. Swimming
Clinical events that may occur simultaneously or in association with motor or behavioral events with or without electrocortical signature Pathophysiology dependent on the pathophysiology of associated motor or behavioral events Autonomic Nervous System Signs A. Respiratory 1. Tachypnea 2. Respiratory arrest B. Cardiac 1. Tachycardia 2. Bradycardia C. Cardiovascular 1. Hypertension 2. Hypotension
D. Vasomotor 1. Flushing 2. Pallor E. Pupillary dilation F. Salivation G. Other
Electrographic seizures not associated with clinical seizures (Electrical only) Pathophysiology—Epileptic
T 12.3 Clinical characteristics, classification, and presumed pathophysiology of neonatal seizures Classification
Characterization
Focal clonic
Repetitive, rhythmic contracts of muscle groups of the limbs, face, or trunk May be unifocal or multifocal May occur synchronously or asynchronously in muscle groups on one side of the body May occur simultaneously but asynchronously on both sides Cannot be suppressed by restraint Pathophysiology: epileptic Sustained posturing of single limbs Sustained asymmetrical posturing of the trunk Sustained eye deviation Cannot be provoked by stimulation or suppressed by restraint Pathophysiology: epileptic Sustained symmetric posturing of limbs, trunk, and neck May be flexor, extensor, or mixed extensor/flexor May be provoked or intensified by stimulation May be suppressed by restraint or repositioning Presumed pathophysiology: nonepileptic Random, single, rapid contractions of muscle groups of the limbs, face, or trunk Typically not repetitive or may recur at a slow rate May be generalized, focal, or fragmentary May be provoked by stimulation Presumed pathophysiology: may be epileptic or nonepileptic May be flexor, extensor, or mixed extensor/flexor May occur in clusters Cannot be provoked by stimulation or suppressed by restraint Pathophysiology: epileptic
Focal tonic
Generalized tonic
Myoclonic
Spasms
Motor automatisms Ocular signs
Oral-buccallingual movements Progression movements
Complex purposeless movements
Random and roving eye movements or nystagmus (distinct from tonic eye deviation) May be provoked or intensified by tactile stimulation Presumed pathophysiology: nonepileptic Sucking, chewing, tongue protrusions May be provoked or intensified by stimulation Presumed pathophysiology: nonepileptic Rowing or swimming movements Pedaling or bicycling movements of the legs May be provoked or intensified by stimulation May be suppressed by restraint or repositioning Presumed pathophysiology: nonepileptic Sudden arousal with transient increased random activity of limbs May be provoked or intensified by stimulation Presumed pathophysiology: nonepileptic
the absence of electrical seizure activity, and electrical only when no clinical events are present despite the presence of electrical seizure activity.
Etiology Common causes of neonatal seizures are listed in Table 12.4. Few studies have indicated which etiologic or risk
138
factors for seizures in the neonate may be most closely associated with SE. It may be thought that the seizures most likely to be the most recurrent and prolonged are those associated with the most severe brain injury. However, this association is not uniformly true, although it is a more accurate generalization when seizures that can be treated with etiology-specific therapy are excluded. Thus, the relatively benign cause of hypocalcemia can be associated with SE
:
T 12.4 Common etiologic factors associated with neonatal seizures Hypoxia-ischemia Intracranial hemorrhage Intraventricular Intracerebral Subdural Subarachnoid Infection—CNS Meningitis Encephalitis Intrauterine Infarction—CNS Metabolic Hypoglycemia Hypocalcemia Hypomagnesemia Chromosomal abnormalities Congenital anomalies of the brain Neurodegenerative disorders Inborn errors of metabolism Benign neonatal convulsions Benign familial neonatal convulsions Drug withdrawal or intoxication Note: Etiologic factors are listed in relative order of frequency. Not listed is unknown etiology, which may be encountered in up to 10% of cases (55).
until the infant is treated with calcium. On the other hand, for some causes there may be no specific treatment, such as hypoxic-ischemic encephalopathy, infarction, intracerebral hemorrhage, cerebral dysgenesis, and the secondary injury of central nervous system (CNS) infection. In these instances, the severity of injury will most likely determine whether an infant will experience seizures, whether the seizures will be recurrent or prolonged, and when there may be adverse sequelae associated with seizures.
Impact of seizures on prognosis Although the immature brain may be more susceptible than the mature brain to developing seizures, it may also be more resistant than the mature brain to seizure-induced injury. However, the specific effects seizure may have on the developing brain are still debated (11, 28, 29, 30, 59, 97, 100, 102, 103). Historically, both basic science and clinical investigations have failed to determine precisely what, if any, enduring adverse effects seizures may produce in the neonate and how they can be differentiated from those induced by etiology or by therapy (63). However, more recent studies suggest otherwise (38, 42, 103). Mechanisms of seizure-induced brain injury suggested by studies of either immature or mature animals include neuronal necrosis and cell death due to excessive release of exci-
tatory amino acids (3, 13, 14, 62, 87, 89, 96), hippocampal injury resulting in recurrent seizures (85, 86, 91, 92), seizureinduced brain growth retardation (37, 46, 98, 99, 101), seizure-induced alteration of animal learning and behavior (33, 35, 90), and seizure-induced alteration of brain pathways (22, 80). The relevance of some of these findings to the neonate may be limited, because the immature brain may be resistant to some of these mechanisms of injury, such as excitatory amino acid–induced injury or the development of recurrent seizures after hippocampal injury. In addition, some effects, such as brain growth retardation, may be transient and reversible. In addition, animal studies are confounded by a number of variables: the various methods of seizure induction, differentiation of the effect of seizures from their method of induction, the lack of concordant findings among different species, and the limited relationship of the severity of experimentally induced seizures compared with the seizures that occur in humans. Most important, most animal investigations of the adverse effect of seizures on the immature brain focus on hippocampal seizure onset and subsequent injury. The use of these models may have limited value in the assessment of the true impact of seizures in the neonate, since most neonatal seizures may not originate in or involve hippocampus but rather are neocortical. However, most recently, animal studies suggest that there are age-related, seizure-induced changes in brain development that include altered synaptogenesis and a reduction in neurogenesis (31, 34, 38, 42). Clinical studies are more limited, because methodology does not allow adequate differentiation of cause from effect. In addition, most clinical studies of the outcome of neonatal seizures do not distinguish seizure types based on presumed pathophysiology. Thus, studied populations may include infants with both epileptic and nonepileptic seizures. When seizures of epileptic origin are considered, frequency and duration may not be characterized. Therefore, there is little clinical information to distinguish the relative effects, if any, of brief and infrequent seizures from those which can be characterized as SE. In addition, it may be difficult to differentiate any adverse effects caused by prolonged abnormal electrical activity of the brain from the concomitant, sustained clinical seizure activity that may adversely alter systemic homeostasis such as blood pressure, respiration, and heart rate. Also, in order to determine the true long-term outcome for neonates who experience early seizures, longitudinal studies should include assessment of neurologic status, memory, language, academic achievement, and behavior, and the eventual development of chronic epilepsy. However, such comprehensive studies have not been performed. Currently, however, clinical studies suggest that etiology, rather than the seizure themselves, is the main determinant of long-term outcome (7, 10, 16, 32, 64, 97).
:
139
The precise impact of SE on the neonate has not been determined. The results of clinical studies that have been performed indicate that there is a high incidence of death associated with the occurrence of neonatal seizures and, in survivors, high incidences of neurologic impairment, developmental delay, and postneonatal epilepsy. Several clinical studies report similar findings concerning outcome. Ortibus and colleagues (64) reported that 28% of those with neonatal seizures died, 22% were neurologically normal at an average of 17 months of age, 14% had mild abnormalities, and 36% had severe abnormalities. Mizrahi and colleagues (52) conducted a prospective study of full-term infants with clinical and electrical seizures confirmed by EEG-video monitoring who were then followed for 2 years. Twenty-five percent died, 25% had abnormal neurologic examinations, 25% had developmental delay (either Bayley Developmental Assessment of Mental Development Index or Psychomotor Developmental Index less than 80), and 25% had postneonatal epilepsy when followed up to 2 years of age. Brunquell and colleagues (9) found that 30% of patients with neonatal seizures died. Of the survivors, 59% had abnormal neurologic examinations, 40% were mentally retarded, 43% had cerebral palsy, and 21% had postneonatal epilepsy when followed up to a mean of 3.5 years. Postneonatal epilepsy has been reported to occur in 20%–30% of survivors of neonatal seizures (9, 10, 19, 64, 77). Clancy and Legido (16) found a higher rate of postneonatal epilepsy (56%), although their study population had relatively high risk factors for CNS dysfunction. When seizures do occur in the postneonatal period, they most often do so within the first 6 months of life (19); seizures may then be either partial or generalized (104). It is difficult to assess the contribution of various factors that may determine outcome: the direct effect of seizures on the developing brain, the indirect effect of seizures, direct or indirect effects of AEDs, or the effect of the underlying cause of seizures. Although immature animals are more resistant to some types of seizure-induced brain injury than older animals (93), there eventually may be functional abnormalities in older animals who had seizures during the neonatal period. These abnormalities include impairment of visual-spatial memory and reduced seizure threshold, in part related to altered synaptogenesis and reduction in neurogenesis (31, 34). In clinical practice it may appear that seizure duration may influence outcome. Some infants who experience brief and infrequent seizures may have a relatively good long-term outcome, while those with prolonged seizures may not do as well. However, easily controlled seizures or self-limited seizures may be the result of transient, successfully treated or benign CNS disorders in neonates, while medically refractory neonatal seizures may be the result of more sustained,
140
less treatable, or more severe brain disorders. McBride and colleagues (49) found that a greater amount of electrographic seizure activity correlated with a subsequent relative increase in mortality and morbidity in at-risk infants in general and in infants with perinatal asphyxia. In addition, other investigators, using 1H MRS in neonates, found an association of seizure severity with impaired cerebral metabolism measured by lactate/choline and compromised neuronal integrity measured by N-acetylaspartate/choline and suggested this to be evidence of brain injury not limited to structural damage detected by MRI (51). Despite these considerations, the dominant factor that appears to predict outcome is the underlying cause of the seizures rather than the presence, duration, or degree of brain involvement of the epileptic seizures themselves. In previous clinical studies, normal outcomes occurred with increasing frequency in association with the following causes: hypoxic-ischemic encephalopathy, infection, hemorrhage, hypoglycemia, and hypocalcemia (6, 17, 40, 45, 47, 55, 74, 97). Seizure type may also predict outcome, in part owing to the degree of CNS dysfunction typically associated with various categories of seizures (9, 55). Focal clonic and focal tonic seizures may suggest a relatively good outcome primarily because these seizure types are typically associated with relatively confined brain injury and spared CNS function. Generalized tonic posturing and motor automatisms suggest a poor outcome because they are associated with diffuse CNS dysfunction. In addition to these factors, syndromic classification may also suggest prognosis (51, 95). Two syndromes of neonatal seizures have been consistently associated with catastrophic outcomes, early myoclonic encephalopathy and early infantile epileptic encephalopathy (2). Two others are consistently associated with a relatively good outcome, benign neonatal convulsions and benign familial neonatal convulsions (70). Multivariant analyses have considered a number of clinical variables to more precisely define predictors of outcome, including features of the interictal EEG from one or serial recordings, the ictal EEG, the neurologic examination at the time of seizures, the character or duration of the seizures, etiology, findings on neuroimaging, conceptional age, and birth weight (10, 64). Multiple rather than single factors appear to be most accurate in predicting outcome. However, all variables related to a single factor, the degree of brain injury at the time of seizure occurrence, and this in turn related to etiology.
Treatment and response of neonatal seizures to AEDs The decision to initiate AED therapy in neonates with seizures is based on seizure type, frequency, duration, and
:
T 12.5 Current strategies in the diagnosis and management of neonatal status epilepticus Initial clinical diagnosis Characterization and classification Determine seizures to be of epileptic origin EEG confirmation Basic clinical/medical support Assessment for etiology Institution of etiologic-specific therapy Institution of AED therapy for prolonged seizures Continued therapy until cessation of clinical seizures EEG monitoring for persistence of electrical seizure activity Increase first- and second-line AEDs to high therapeutic levels if needed Intermittent EEG surveillance after initial monitoring of response Clinical follow-up Discontinuation of AEDs 2 weeks after the last seizure (perform EEG prior to discontinuation)
T 12.6 EEG and neonatal seizures Ictal Features Ictal patterns appear as “all-or-nothing.” Electrical seizures are difficult to stop once they begin. Electroclinical seizures—electrical and clinical seizures coincide. Electrical seizures may occur with no clinical seizures: Seizures discharges of the depressed brain Paroxysmal alpha seizure pattern Electrical seizures in the pharmacologically paralyzed neonate “Decoupled” electrical seizures Interictal Features Interictal epileptiform discharges are rare. Character of the background EEG provides diagnostic and prognostic data. Data from references 9, 36, 53, and 54.
See Mizrahi and Kellaway (55) for further details.
the likelihood of seizure recurrence (40). The details of AED treatment are given elsewhere (1, 40, 66, 72, 97) and are beyond the focus of this report, but the causes of AED treatment are summarized briefly in Table 12.5. In brief, AED therapy consists of acute administration of phenobarbital, followed by additional doses, depending on response. Phenytoin is added if the seizures persist. However, controlled trials indicate that each drug may control seizures to the same degree when given in therapeutic doses, although neither is as effective as once thought (8, 68). There is an increasing role for benzodiazepines in the acute treatment of neonatal seizures, including such AEDs as diazepam, lorazepam, and midazolam (48, 61, 65, 81). They have been used acutely as the first AED and as adjuvant therapy when others have failed. When neonates are treated for electroclinical seizures, there is a characteristic response to AED that has important implications for the determination of SE and the continued AED therapy. Typically, the initial response of electroclinical seizures to AED therapy is the cessation of clinical seizures. However, the electrical seizures may persist in the absence of clinical seizures. This is referred to as decoupling of the clinical from electrical seizure (55, 56). If the infant is assessed clinically for initial response to AEDs, there is the possibility that EEG seizures will continue to be present and go unrecognized. If recurrent or prolonged, they may constitute electrical SE. If EEG monitoring is used during AED therapy and electrical seizures are identified, continued AED therapy may eventually eliminate them. However, there are instances in which electrical seizures persist and eventually prove to
be refractory to even high-dose and multiple AED therapy, with the infant remaining in so-called electrical SE. This is an unresolved clinical problem, insofar as such vigorous therapy carries its own risks, which include hypotension, bradycardia, respiratory depression, and further CNS depression.
EEG and neonatal seizures As in older children and adults, EEG in the neonate is a valuable tool in the diagnosis and management of seizures. The neonatal EEG has some features that are unique to this age group and this clinical problem (36, 53, 56, 69) (Table 12.6). The interictal EEG may provide important information concerning etiology, degree, and severity of the acute brain injury, and prognosis. However, the interictal EEG is limited in predicting the predisposition for seizure activity to occur, since sharp waves, when present, are rarely considered potentially epileptogenic. The ictal EEG displays a wide range of manifestations of electrical seizure activity. An important finding is that such activity may occur in the absence of clinical events. Thus, the EEG is critical in the diagnosis of prolonged and recurrent seizures in the neonate. The use of EEG-video monitoring has become more widespread and has been a valuable tool in the assessment of seizures in this age group. However, prolonged monitoring to screen for seizures poses a difficult logistical problem, because maintaining ideal recording conditions in the neonatal intensive care unit requires intense technical supervision. More recently, on-line computerized analysis of neonatal EEG to detect electrical seizure activity has
:
141
been investigated and appears promising (21). However, its most consistent and accurate application is also dependent on the technical quality of the primary EEG recording.
Comment Overall, there are many experimental and clinical issues that require further clarification in the consideration of SE in the neonate. The most basic experimental issue is the development of models that accurately reflect the neocortical seizures that human neonates experience. The most basic clinical issue is the determination of a precise definition of SE. In addition, it is still not clear whether prolonged and recurrent neocortical seizures in the neonate (or their vigorous treatment with AEDs) are responsible for any adverse outcome, although emerging data from animal models suggest an association with eventual abnormalities of memory, learning, and behavior. There are also other important therapeutic concerns, since in some neonates, electrical seizures may persist although clinical seizures have been controlled with AEDs, and since some electrical seizures cannot be controlled despite high-dose polypharmacy. There are also limited strategies in the surveillance for recurrent electrical seizures. The future challenges in the investigations of the diagnosis and management of neonatal SE are based upon the recognition of these limitations. However, the clinical reality also requires that a care plan be developed (Table 12.5) that recognizes the gaps in our understanding of seizures and SE in the neonate. This work was supported in part by a grant from the National Institute of Neurological Disorders and Stroke, National Institutes of Health (contract NS-1-12316), and the Peter Kellaway Research Endowment, Baylor College of Medicine, Houston, Texas.
REFERENCES 1. Aicardi, J. Neonatal seizures. In Epilepsy in Children. International Review of Child Neurology Series. 2nd ed. New York: Raven Press, 1994:217–252. 2. Aicardi, J., and S. Ohtahara. Severe neonatal epilepsies with suppression-burst pattern. In J. Roger, M. Bureau, C. Dravet, P. Genton, C. A. Tassinari, and P. Wolf, eds. Epileptic Syndromes in Infancy, Childhood and Adolescence. 3rd ed. London: John Libbey, 2002:33–44. 3. Albala, B. J., S. L. Moshé, and R. Okada. Kainic-acidinduced seizures: A developmental study. Dev. Brain Res. 1984; 13:139–148. 4. Ben-Ari, Y., E. Cherubini, R. Corradetti, and J. L. Gaiarsa. Giant synaptic potentials in immature rat CA3 hippocampal neurones. J. Physiol. 1989;416:303–325. 5. Ben-Ari, Y., E. Cherubini, and K. Krnjevic. Changes in voltage dependence of NMDA currents during development. Neurosci. Lett. 1988;94:88–92.
142
6. Bergman, I., M. J. Painter, R. P. Hirsch, P. K. Crumrine, and R. David. Outcome in neonates with convulsions treated in an intensive care unit. Ann. Neurol. 1983;14:642–647. 7. Boylan, G. B., R. M. Pressler, J. M. Rennie, M. Morton, P. L. Leow, R. Hughes, et al. Outcome of electroclinical, electrographic, and clinical seizures in the newborn infant. Dev. Med. Child Neurol. 1999;41:819–825. 8. Boylan, G. B., J. M. Rennie, R. M. Pressler, G. Wilson, M. Morton, and C. D. Binnie. Phenobarbitone, neonatal seizures, and video-EEG. Arch. Dis. Child. Fetal Neonatal Ed. 2000;86:F165–F170. 9. Brunquell, P. J., C. M. Glennon, F. J. DiMario, Jr., T. Lerer, and L. Eisenfeld. Prediction of outcome based on clinical seizure type in newborn infants. J. Pediatr. 2002;140: 707–712. 10. Bye, A. M. E., C. A. Cunningham, K. Y. Chee, and D. Flanagan. Outcome of neonates with electrographical identified seizures, or at risk of seizures. Pediatr. Neurol. 1997;16:225–231. 11. Camfield, P. R. Recurrent seizures in the developing brain are not harmful. Epilepsia 1997;38:735–737. 12. Cherubini, E., J. L. Galarsa, and Y. Ben-Ari. GABA: An excitatory transmitter in early postnatal life. Trends Neurosci. 1991;14:515–519. 13. Choi, D. W. Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. Trends Neurosci. 1988;11:465–469. 14. Choi, D. W. Glutamate toxicity and diseases of the nervous system. Neuron 1988;1:623–624. 15. Clancy, R. R., and A. Legido. The exact ictal and interictal duration of electroencephalographic neonatal seizures. Epilepsia 1987;28:537–541. 16. Clancy, R. R., and A. Legido. Postnatal epilepsy after EEGconfirmed neonatal seizures. Epilepsia 1991;32:69–76. 17. Clancy, R., S. Malin, D. Laraque, S. Baumgart, and D. Younkin. Focal motor seizures heralding stroke in full-term neonates. Am. J. Dis. Child. 1985;139:601–606. 18. Coyle, J. T., and S. J. Enna. Neurochemical aspects of the ontogenesis of GABAergic neurons in the rat brain. Brain Res. 1976;111:119–133. 19. Ellenberg, J. H., D. G. Hirtz, and K. B. Nelson. Age at onset of seizures in young children. Ann. Neurol. 1984;15; 127–134. 20. Garant, D. S., and K. Gale. Neural mechanisms of anticonvulsant effects mediated by substantia nigra in rats. In R. J. Porter, R. H. Mattson, A. A. Ward, and M. Dam, eds. Advances in Epileptology. XVth Epilepsy International Symposium. New York: Raven Press, 1984:31–35. 21. Gotman, J., D. Flanagan, B. Rosenblatt, A. Bye, and E. M. Mizrahi. Evaluation of an automatic seizure detection method for the newborn EEG. Electroencephalogr. Clin. Neurophysiol. 1997;103(3):363–369. 22. Grigonis, A. M., and E. H. Murphy. The effects of epileptic cortical activity on the development of callosal projections. Dev. Brain Res. 1994;77:251–255. 23. Hablitz, J. J. Spontaneous ictal-like discharges and sustained potential shifts in the developing rat neocortex. J. Neurophysiol. 1987;58:1052–1965. 24. Hablitz, J. J., and U. Heinemann. Alterations in the microenvironment during spreading depression associated with epileptiform activity in the immature neocortex. Dev. Brain Res. 1989;46:243–252.
:
25. Hablitz, J. J., W. L. Lee, D. A. Prince, et al. Excitatory amino acids NMDA receptor involvement in epileptogenesis in the immature neocortex. In G. Avanzini, J. Engel, R. Fariello, et al, eds. Neurotransmitters in Epilepsy. Epilepsy Res. Suppl 8. New York: Elsevier Science, 1992. 26. Hagland, M. M., and P. A. Schwartzkroin. Role of Na-K pump potassium regulation and IPSPs in seizures and spreading depression in immature rabbit hippocampal slices. J. Neurophysiol. 1990;63:225–239. 27. Holmes, G. L. Diagnosis and Management of Seizures in Children. Philadelphia: W. B. Saunders, 1987:253. 28. Holmes, G. L. Do seizures cause brain damage? Epilepsia 1991;32(Suppl. 5):S14–S28. 29. Holmes, G. L. Epilepsy in the developing brain: Lessons from the laboratory and clinic. Epilepsia 1997;38:12–30. 30. Holmes, G. L. The long-term effects of seizures on the developing brain: Clinical and laboratory issues. Brain Dev. 1991; 13:393–409. 31. Holmes, G. L. Seizure-induced neuronal injury: Animal data. Neurology 2002;59(Suppl. 5):S3–S6. 32. Holmes, G. L., and Y. Ben-Ari. The neurobiology and consequences of epilepsy in the developing brain. Pediatr. Res. 2001;49:320–325. 33. Holmes, G. L., A. Chronopoulos, C. E. Stafstrom, M. A. Mikati, S. J. Thurber, P. A. Hyde, et al. Effects of kindling on subsequent learning, memory, behavior, and seizure susceptibility. Brain Res. 1993;73:71–77. 34. Holmes, G. L., R. Khazipov, and Y. Ben-Ari. New concepts in neonatal seizures. Neuroreport 2002;21:13(1):A3–A8. 35. Holmes, G. L., S. J. Thurber, Z. Liu, C. E. Stafstrom, A. Gatt, and M. A. Mikati. Effects of quisqualic acid and glutamate on subsequent learning, emotionality, and seizure susceptibility in the immature and mature animal. Brain Res. 1993; 623:325–328. 36. Hrachovy, R. A., E. M. Mizrahi, and P. Kellaway. Electroencephalography of the newborn. In D. Daly and T. A. Pedley, eds. Current Practice of Clinical Electroencephalography. 2nd ed. New York: Raven Press, 1990:201–242. 37. Jensen, F. E., C. D. Applegate, and D. Holtzman, et al. Epileptogenic effect of hypoxia in the immature rodent brain. Ann. Neurol. 1991;29:629–637. 38. Jensen, F. E., and T. Z. Baram. Developmental seizures induced by common early-life insults: Short- and long-term effects on seizure susceptibility. Ment. Retard. Dev. Disabil. Res. Rev. 2000;6:253–258. 39. Kellaway, P., and R. A. Hrachovy. Status epilepticus in newborns: A perspective on neonatal seizures. In A. V. Delgado-Escueta, C. G. Wasterlain, D. M. Treiman, and R. J. Porter, eds. Status Epilepticus. Adv. Neurol. 1983;34:93–99. 40. Kellaway, P., and E. M. Mizrahi. Clinical, electroencephalographic, therapeutic, and pathophysiologic studies of neonatal seizures. In C. G. Wasterlain and P. Vert, eds. Neonatal Seizures: Pathophysiology and Pharmacologic Management. New York: Raven Press, 1990:1–13. 41. Killisch, I., C. G. Dotti, D. J. Laurie, H. Lüddens, and P. H. Seeburg. Expression patterns of GABAA receptor subtypes in developing hippocampal neurons. Neuron 1991;7: 927–936. 42. Lado, F. A., R. Sankar, D. Lowenstein, and S. L. Moshé. Agedependent consequences of seizures: Relationship to seizure frequency, brain damage, and circuitry reorganization. Ment. Retard. Dev. Disabil. Res. Rev. 2000;6:242–252.
43. Lanska, M. J., D. J. Lanska, R. J. Baumann, et al. A population-based study of neonatal seizures in Fayette County, Kentucky. Neurology 1995;45:724–732. 44. Laurie, D. J., W. Wisden, and P. H. Seeberg. The distribution of the thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. J. Neurosci. 1992;12:4151–4172. 45. Lombroso, C. T. Prognosis in neonatal seizures. Adv. Neurol. 1983;34:101–113. 46. Lowenstein, D. H., S. Shimosaka, Y. T. So, et al. The relationship between electrographic seizure activity and neuronal injury. Epilepsy Res. 1991;10:49–54. 47. Mannino, F. L., and D. A. Trauner. Stroke in neonates. J. Pediatr. 1983;10:605–610. 48. Maytal, J., G. P. Novak, and K. C. King. Lorazepam in the treatment of refractory neonatal seizures. J. Child Neurol. 1991;6:319–323. 49. McBride, M. C., N. Laroia, and R. Guillet. Electrographic seizures in neonates correlate with poor neurodevelopmental outcome. Neurology 2000;55:506–513. 50. Michelson, H. B., and E. W. Lothman. An in vivo electrophysiologic study of the ontogeny of excitatory and inhibitory processes in rat hippocampus. Dev. Brain Res. 1989;47: 113–122. 51. Miller, S. P., J. Weiss, A. Barnwell, D. M. Ferriero, B. Latal-Hajnal, A. Ferrer-Rogers, et al. Seizure-associated brain injury in term newborns with perinatal asphyxia. Neurology 2002;58:542–548. 52. Mizrahi, E. M., R. R. Clancy, J. K. Dunn, D. Hirtz, L. Chapieski, S. McGaun, et al. Neurologic impairment, developmental delay and postnatal seizures 2 years after EEGvideo documented seizures in near-term and term neonates: Report of the Clinical Research Centers for Neonatal Seizures. Epilepsia 2001;42(Suppl. 7):102. 53. Mizrahi, E. M., R. A. Hrachovy, and P. Kellaway. Atlas of Neonatal Electroencephalography. Baltimore: Lippincott Wilkins & Williams, 2004. 54. Mizrahi, E. M., and P. Kellaway. Characterization and classification of neonatal seizures. Neurology 1987;37: 1837–1844. 55. Mizrahi, E. M., and P. Kellaway. Diagnosis and Management of Neonatal Seizures. New York: Lippincott-Raven, 1998. 56. Mizrahi, E. M., and P. Kellaway. The response of electroclinical neonatal seizures to antiepileptic drug therapy. Epilepsia 1992;33(Suppl. 3):114. 57. Monyer, H., P. H. Seeburg, and W. Wisden. Glutamateoperated channels: Developmentally early and mature forms arise by alternative splicing. Neuron 1991;6:799–810. 58. Moshé, S. L. Seizures in the developing brain. Neurology 1993;43:S3–S7. 59. Moshé, S. L., and E. F. Sperber. Substantia nigra-mediated control of generalized seizures. In G. Gloor, R. Kostopoulos, M. Naquet, and P. Avoli, eds. Generalized Epilepsy: Cellular, Molecular and Pharmacological Approaches. Boston: Birkhauser, 1990:355–367. 60. Mutani, R., K. J. Futamachi, and D. A. Prince. Potassium activity in immature cortex. Brain Res. 1984;75: 27–39. 61. Nordli, D. R., and D. C. DeVivo. Classification of infantile seizures: Implications for identification and treatment of inborn errors of metabolism. J. Child Neurol. 2002;17 (Suppl. 3):S3–S7.
:
143
62. Olney, J. W., R. C. Collins, and R. S. Sloviter. Excitotoxic mechanisms of epileptic brain damage. Adv. Neurol. 1986;44: 857–877. 63. Olney, J. W., C. Young, D. F. Wozniak, V. Jevtovic-Todorovic, and C. Ikonomidou. Do pediatric drugs cause developing neurons to commit suicide? Trends Pharmacol. Sci. 2004;25(3): 135–139. 64. Ortibus, E. L., J. M. Sum, and J. S. Hahn. Predictive value of EEG for outcome and epilepsy following neonatal seizures. Electroencephalogr. Clin. Neurophysiol. 1996;98:175–185. 65. Painter, M. J., and J. Alvin. Choice of anticonvulsants in the treatment of neonatal seizures. In C. G. Wasterlain and P. Vert, eds. Neonatal Seizures. New York: Raven Press, 1990: 243–256. 66. Painter, M. J., and L. M. Gaus. Neonatal seizures: Diagnosis and treatment. J. Child Neurol. 1991;6:101–108. 67. Painter, M. J., M. B. Minnigh, L. Gaus, M. Scher, B. Brozanski, and J. Alvin. Neonatal phenobarbital and phenytoin binding profiles. J. Clin. Pharmacol. 1994;34:312–317. 68. Painter, M. J., M. S. Scher, A. D. Stein, S. Armatti, Z. Wang, J. C. Gardiner, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N. Engl. J. Med. 1999;341:485–489. 69. Patrizi, S., G. L. Holmes, M. Orzalesi, and F. Allemand. Neonatal seizures: Characteristics of EEG ictal activity in preterm and full-term infants. Brain Dev. 2003;25(6): 427–437. 70. Plouin, P., and V. E. Anderson. Benign familial and nonfamilial neonatal seizures. In J. Roger, M. Bureau, C. Dravet, et al., eds. Epileptic Syndromes in Infancy, Childhood and Adolescence. 3rd ed. London: John Libbey, 2002:3–13. 71. Poulter, M. O., J. L. Barker, A.-M. O’Carroll, S. J. Lolait, and L. C. Mahan. Differential and transient expression of GABAA receptor alpha-subunit mRNAs in the developing rat CNS. J. Neurosci. 1992;12:2888–2900. 72. Rennie, J. M., and G. B. Boylan. Neonatal seizures and their treatment. Curr. Opin. Neurol. 2003;16:177–181. 73. Ronen, G. M., and S. Penney. The epidemiology of clinical neonatal seizures in Newfoundland, Canada: A five-year cohort. Ann. Neurol. 1995;38:518–519. 74. Rose, A. L., and C. T. Lombroso. A study of clinical, pathological, and electroencephalographic features in 137 full-term babies with a long-term follow-up. Pediatrics 1970; 45:404–425. 75. Saliba, R. M., J. F. Annegers, D. K. Waller, J. E. Tyson, and E. M. Mizrahi. Incidence of neonatal seizures in Harris County, Texas, 1992–1994. Am. J. Epidemiol. 1999;150(7): 763–769. 76. Scher, M. S. Controversies regarding neonatal seizure recognition. Epileptic Disord. 2002;4:139–158. 77. Scher, M. S., K. Aso, M. Beggarly, M. Y. Hamid, D. A. Steppe, and M. J. Painter. Electrographic seizures in preterm and full-term neonates: Clinical correlates, associated brain lesions, and risk for neurologic sequelae. Pediatrics 1993;91: 128–134. 78. Scher, M. S., M. Y. Hamid, D. A. Steppe, M. E. Beggarly, and M. J. Painter. Ictal and interictal electrographic seizure durations in preterm and term neonates. Epilepsia 1993;34: 284–288. 79. Schwartzkroin, P. A. Development of rabbit hippocampus. Dev. Brain Res. 1982:2:469–486. 80. Schwartzkroin, P. A. Plasticity and repair in the immature central nervous system. In P. A. Schwartzkroin, S. L. Moshé,
144
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95. 96.
97.
:
J. L. Noebels, and J. W. Swann, eds. Brain Development and Epilepsy. New York: Oxford University Press, 1995:234–267. Sheth, R. D., D. J. Buckley, A. R. Gutierrez, M. Gingold, J. B. Bodensteiner, and S. Penney. Midazolam in the treatment of refractory neonatal seizures. Clin. Neuropharm. 1996;19:165–170. Shorvon, S. D. Clinical forms of status epilepticus. In Status Epilepticus. Chap. 3. New York: Cambridge University Press, 1994:34–138. Shorvon, S. D. Definition, classification and frequency of status epilepticus. In Status Epilepticus. Chap. 2. New York: Cambridge University Press, 1994:21–33. Shorvon, S. D. Prognosis and outcome of status epilepticus. In Status Epilepticus. Chap. 6. New York: Cambridge University Press, 1994:293–312. Sloviter, R. S. The functional organization of the hippocampal dentate gyrus and its relevance to the pathogenesis of temporal lobe epilepsy. Ann. Neurol. 1994;35:640–654. Sloviter, R. S. Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat: The dormant basket cell hypothesis and its possible relevance to temporal lobe epilepsy. Hippocampus 1991;1:41–66. Sloviter, R. S., and D. W. Dempster. Epileptic brain damage is replicated qualitatively in the rat hippocampus by central injection of glutamate or aspartate but not by GABA or acetylcholine. Brain Res. Bull. 1985;15:39–60. Sperber, E. F., K. Haas, and S. L. Moshé. Mechanism of kindling in developing animals. In J. A. Wada, ed. Kindling 4. New York: Plenum Press, 1990:157–167. Sperber, E. F., K. Z. Haas, P. K. Stanton, and S. L. Moshé. Resistance of the immature hippocampus to seizure-induced synaptic reorganization. Dev. Brain Res. 1991;60:89–93. Stafstrom, C. E., G. L. Holmes, A. Chronopoulos, S. Thurber, and J. L. Thompson. Age-dependent cognitive and behavior deficits following kainic acid-induced seizures. Epilepsia 1993; 34:420–432. Sutula, T. P. Experimental models of temporal lobe epilepsy: New insights from the study of kindling and synaptic reorganization. Epilepsia 1990:31(Suppl. 3):S45–S54. Sutula, T. P. The pathology of the epilepsies: Insights into the causes and consequences of epileptic syndromes. In W. E. Dodson and J. M. Pellock, eds. Pediatric Epilepsies: Diagnosis and Treatment. New York: Demos, 1993:37–44. Swann, J. W. Synaptogenesis and epileptogenesis in developing neural networks. In P. A. Schwartzkroin, S. L. Moshé, J. L. Noebels, and J. W. Swann, eds. Brain Development and Epilepsy. New York: Oxford University Press, 1995:195– 233. Swann, J. W., R. J. Brady, K. L. Smith, and M. G. Pierson. Synaptic mechanisms of focal epileptogenesis in the immature nervous system. In J. W. Swann and A. Messer, eds. Disorders of the Developing Nervous System: Changing View on Their Origins, Diagnoses, and Treatment. New York: Alan R. Liss, 1988: 19–49. Tharp, B. R. Neonatal seizures and syndromes. Epilepsia 2002;43(Suppl. 3):2–10. Thurber, S., M. A. Mikati, C. E. Stafstrom, F. E. Jensen, and G. L. Holmes. Quisquatic acid-induced seizures during development: A behavioral and EEG study. Epilepsia 1994;35: 868–875. Volpe, J. J. Neonatal seizures. In Neurology of the Newborn. Chap. 5. Philadelphia: W. B. Saunders, 1995:172–207.
98. Wasterlain, C. G. Effects of neonatal status epilepticus on rat brain development. Neurology 1976;26:975–986. 99. Wasterlain, C. G. Neonatal seizures and brain growth. Neuropadiatrie 1978;9:213–228. 100. Wasterlain, C. G. Recurrent seizures in the developing brain are harmful. Epilepsia 1997;38:728–734. 101. Wasterlain, C. G., and B. E. Dwyer. Brain metabolism during prolonged seizures in neonates. Adv. Neurol. 1983;34:241–260. 102. Wasterlain, C. G., D. G. Fujikawa, L. Penix, and R. Sankar. Pathophysiological mechanisms of brain damage from status epilepticus. Epilepsia 1993;34(Suppl. 1):S37–S53. 103. Wasterlain, C. G., J. Niquet, H. Liu, R. Sankar, A. M. Mazarati, L. Suchomelova, et al. Seizure-induced neuronal death in the immature brain. In T. Sutula and A. Pitkanen, eds. Do Seizures Damage the Brain? Prog. Brain Res. 2002;135: 335–353. 104. Watanabe, K., K. Miura, J. Natsume, F. Hayakawa, S. Furune, and A. Okumura. Epilepsies of neonatal onset: Seizure type and evolution. Dev. Med. Child Neurol. 1999; 41(5):318–322.
:
145
III STATUS EPILEPTICUS: BIOLOGICAL MARKERS
13
Physiologic Responses to Status Epilepticus
. D epilepticus (SE), a host of physiologic changes occur in the brain, other organs, and the circulation, many of which influence the risk of central nervous system (CNS) injury. Early observations on brain injury in epilepsy and theories of its pathogenesis were reviewed in a previous volume on SE, in which the theory that intracellular calcium toxicity is the ultimate factor responsible was also presented (44). This chapter summarizes the systemic physiologic changes and alterations in cardiopulmonary function during SE and their implications for cell death. The concepts of (1) a dissociation between electroencephalographic (EEG) seizure duration and neural injury and (2) epileptic tolerance will be presented.
Systemic responses to SE H The “fever curve” was a well-known feature of SE in reports from the turn of the twentieth century. The fact that the temperature elevation was proportional to the duration of SE was clearly demonstrated (Figure 13.1). Temperatures as high as 109°F were reported. Although the degree of temperature elevation was thought to be a strong index of SE severity and a predictor of mortality, recoveries from SE with temperatures above 104°F were reported (12). The modern experience is similar. Hyperthermia was found in 75 of 90 personally studied patients admitted to an emergency room in SE (Figure 13.2). Temperatures reached 42°C (107°F) in two patients in whom SE persisted longer than 9 hours. In only four of 75 patients was an infectious etiology found; thus, SE itself is the usual explanation for fever in this setting. Some degree of hypothermia occurred in eight patients in SE due to drug overdose, hypoglycemia, or hypothyroidism (2). The time course of the temperature elevation during SE has been studied in experimental primates. Temperatures rose gradually over the first 2 hours of SE to maxima of 42° to 43°C. With cessation of myoclonic activity, temperatures fell (45). In parallel studies in paralyzed, ventilated primates, less temperature elevation (1° to 2.7°C) was observed, and this was attributed to increased heat production in brain, heart, and liver (46). Following cessation of SE, hyperthermia may persist for some period, which may be
estimated from the period of temperature elevation found after a single convulsion (mean duration, 21.8 hours (79) (Figure 13.3). A temperature elevation increases the risk of brain damage during SE. The neuropathologic change in experimental primates correlated with the duration of hyperthermia above 40°C; the cerebellum was particularly vulnerable (45, 46). Hyperthermia also exacerbated neuropathologic changes in rodents during flurothyl-induced SE. Selective neuronal necrosis was exacerbated in neocortex and pannecrosis increased in globus pallidus and substantia nigra with hyperthermia of 39.5°C for 45 minutes. Hypothermia attenuated SE-induced damage compared with findings in normothermic controls. Temperature elevations to 41°C for 10 minutes extended the damage to the hippocampus (43). Studies of kainic acid–induced seizures in rat addressed the effect of temperature on the duration of seizures. Hyperthermia increased and hypothermia decreased the duration of SE. Further, hyperthermic animals developed SE from subconvulsive kainate doses. The more prolonged seizures in the hyperthermic animals were associated with increased brain damage (42). Hyperthermia itself may cause seizures (febrile convulsions of childhood). Excitatory amino acid neurotransmitters have been implicated in the induction and generation of resultant brain injury. In a model of hyperthermia-induced seizures in neonatal rats, the seizure threshold (temperature rise need to induce seizures) was increased in the presence of glutamate receptor blockade (50). Further, increased concentrations of glutamate are found in cortical perfusates during hyperthermic induction and during the subsequent seizure (51). Because the excitatory neurotransmitter glutamate can function as a neurotoxin in the brain, these observations suggest a possible explanation for the exacerbation of neuronal injury during SE associated with hyperthermia. Febrile seizures in the developing brain have been shown to produce persistent modification of limbic circuits, a finding that questions the benign nature of these events (22). C Virtually immediate and marked increases in plasma catecholamine concentrations occur
:
149
F 13.1 Data from a 19-year-old man with idiopathic epilepsy since age 3. The relationship between the number of seizures (vertical band) and the increase in temperature, pulse, and
respiratory rate is shown. (Reprinted with permission from Clark and Prout [12].)
F 13.2 Rectal temperature recorded in 90 patients with SE (three had an infective etiology). (Reprinted with permission from Aminoff and Simon [2].)
150
:
F 13.3 Postictal fever in 27 patients without documented infection. Thin lines indicate temperature above 37.8°C (100°F);
thick lines indicate temperature above 38.3°C (101°F). (Reprinted with permission from Wachtel et al. [79].)
with the initiation of SE and are sustained for a number of hours. During SE in paralyzed, ventilated sheep, norepinephrine concentrations are greater than 150% of control levels and epinephrine concentrations are nearly 400-fold higher than in nonconvulsing animals (6) (Figure 13.4). A similar phenomenon occurs following single spontaneous seizures in man (65) (Figure 13.5). These changes are associated with a parallel and marked elevation in systemic blood pressure and heart rate. The blood pressure, however, returns to baseline within 1 hour, while the tachycardia persists for the duration of the catecholamine elevation (6) (Figure 13.6). The mechanism for this divergence of sympathetic activity during status is unknown, but desensitization of vascular adrenergic receptors and hypovolemia are possible causes. An additional consequence of SE is an increase in plasma potassium levels. Potassium concentrations following single seizures were normal in patients studied by Orringer et al. (54). In freely convulsing primates, elevations to a mean of 8.7 mEq/L occurred. Hyperkalemia was not found in paralyzed, ventilated animals, suggesting skeletal muscle breakdown as the cause (45, 46). However, hyperkalemia (3.8 ± 0.4 mEq/L to 5.7 ± 0.6 mEq/L) has been described during SE in paralyzed, ventilated sheep. This hyperkalemia is presumably catecholamine-mediated, with a-adrenergic predominating over b-adrenergic effects (11, 83). Generalized vasoconstriction is a consequence of the norepinephrine elevation (21, 80, 87), and denervation and adrenalectomy block these changes (87). The pressure effects are diminished late in SE owing to decreased sensitivity of the vasculature for norepinephrine (6, 45, 87). Elevations in
plasma epinephrine concentrations are also substantial (6, 19) and could precipitate cardiac arrhythmia (14, 41). The potential for centrally induced arrhythmias is clear (73), but ECG monitoring during SE shows mainly sinus tachycardia (37), although axis changes, conduction abnormalities, and ischemic patterns (9) have been reported. Holter monitoring of 10 patients in SE at the San Francisco General Hospital produced similar results (unpublished observations). The benignity of SE-induced heart rhythm changes is seen in a large animal model: sheep surviving or dying during SE had similar ECG findings (33). Elevation in plasma epinephrine concentrations also results in elevation of plasma glucose levels (44). Because hyperglycemia increases the risk of ischemic brain injury (58), and because the neuropathology of ischemic cell change is seen in both SE and ischemia, the potentially injurious effect of hyperglycemia during SE is of concern. However, experimental elevation of plasma glucose to 500 mg/100 mL did not alter the neuropathologic consequences in -allylglycine-induced SE in rat. In addition, hypoglycemia attenuated injury by decreasing seizure duration (72). Thus, brain lactate content increases and intracellular pH decreases in SE with hyperglycemia may not have neuropathologic consequences (77). Catecholamines also demarginate leukocytes (a leukemoid reaction). Such a phenomenon occurred in 50 of 80 personally studied patients in SE without evidence of infection. The white blood cell (WBC) counts ranged from 12,700 to 28,800 cells/mm3 (12). Polymorphonuclear (PMN) cells predominated in 17 patients and lymphocytes in 11, and a normal differential was found in 15. Bands were seen in
:
151
F 13.4 Plasma norepinephrine and epinephrine responses to bicuculline-induced SE in five paralyzed, ventilated sheep (mean ± SEM). Asterisks indicate a significant difference from pressure
value (P < 0.05). (Reprinted with permission from Benowitz et al. [6].)
only one patient. Thus, the elevated peripheral WBC count seen in the setting of SE lacks the immature forms (left shift) characteristic of leukocytosis from infection. Similar data have been reported regarding SE in children: 60% of 114 had an elevated WBC count (23).
T 13.1 CSF findings in a patient with hepatic encephalopathy prior to and following a seizure flurry caused by worsening hepatic failure
S-I CSF P A benign, transient, cerebrospinal fluid (CSF) pleocytosis may occur following multiple seizures, prolonged seizures, or SE (2, 4, 63) (Table 13.1). A similar syndrome has been described following status in SE (23). Some 10%–20% of such patients are affected. The number of cells seen is modest, 80 cells/mm3 being the maximum in 20 personally observed patients (2, 25, 63). Maximal CSF cell counts are found 24 hours following cessation of the convulsions rather than shortly after the seizures. There is often a PMN predominance in the first 48 hours, especially with higher CSF cell counts; lymphocytes predominate subsequently. The cell count normalizes over 3–4 days. A modest elevation in the protein content of the CSF may be found as well.
152
:
Hospital Day 1 16 17 (a.m.) 17 (p.m.) 20
Seizures
WBCs/mm3
% PMNs
4
1 1 80 28 9
84 68 0
Data courtesy of William Powers, St. Louis.
The cause of postictal pleocytosis is uncertain, but prolonged or repetitive seizures are required in our experience in adults. In 98 patients specifically studied for CSF abnormalities in the setting of individual seizures, only two had pleocytosis. One of these had six isolated seizures and 65 cells/mm3; the second had a single convulsion that lasted
F 13.5 Time course of changes in plasma epinephrine and norepinephrine levels following a single generalized tonic-clonic convulsion in 17 patients. Geometric means (±SE) are shown. The
number of subjects in whom data were obtained is shown in parentheses. Asterisk indicates P < 0.05. (Reprinted with permission from Simon et al. [65].)
for 30 minutes with 10 cells/mm3 (25). Pleocytosis was not seen following one, two, or three seizures in 28, 18, and 14 patients, respectively (25). Although a report suggesting a similar phenomenon after single simple, complex partial, or single generalized tonic-clonic seizures has appeared (20), our experience in adults and that of Wong et al. in children (84) support its rarity except in SE or when the blood-brain barrier is abnormal. A transient breakdown of the blood-brain barrier is suggested as a possible cause of postictal pleocytosis. A single seizure will produce a maximal elevation of systemic blood pressure over baseline (5). In experimental animals, the incidence of breakdown of the blood-brain barrier is proportional to the number of convulsions (55). Rapid marked hypertension such as occurs with seizures can increase blood-brain barrier permeability within 30 seconds after the induction of hypertension (31, 70). A recently observed case emphasizes the component of blood-brain barrier abnormality in this syndrome. A young woman with a clinical and MRI picture typical of hypertensive encephalopathy as evidence of a preictal alteration in the blood-brain barrier had two generalized convulsions. CSF
examination a few hours later showed an opening pressure of 260 mm H2O, 28 WBCs/mm3, and a protein content of 260 mg/100 mL. Four days later the opening pressure was normal, only 3 WBCs/mm3 were seen, and the protein content had fallen to 69 mg/dL. Although blood-brain barrier permeability changes probably explain the elevated protein concentration sometimes seen in postictal pleocytosis, an explanation for the cellular response is less clear. In this regard, however, a patient with hypertensive encephalopathy had a neutrophilic pleocytosis with no other explanation (47). A A marked, rapidly developing acidosis is associated with SE in animals and man. In rats during SE induced by pentylenetetrazol, the pH falls from 7.3 to 6.8 within 4 minutes (70). SE induced by bicuculline in baboons results in a marked fall in pH that begins within 1–3 minutes and reaches a nadir (6.47–6.86) within 15–20 minutes (45). In sheep, during bicuculline-induced SE of 20 minutes’ duration, the arterial pH falls continually (Figure 13.7), reaching 6.80 (33). In paralyzed, ventilated sheep, the pH fall during SE is only 0.1 pH unit (69) (Figure 13.8).
:
153
F 13.6 Responses of systemic arterial blood pressure and heart rate to SE induced by bicuculline injection (time 0). Seizure activity persisted for the duration of the experiment in paralyzed,
ventilated sheep (n = 5). Asterisks indicate a significant difference from preseizure value (P < 0.05). (Reprinted with permission from Benowitz et al. [6].)
F 13.7 Arterial blood pH during bicuculline-induced status in unanesthetized sheep. (Modified with permission from Johnston et al. [33].)
154
:
F 13.8 Brain extracellular fluid (ECF) pH, arterial blood pH, and brain lactate levels during bicuculline-induced SE (seizure onset at time 0) in sheep (n = 12, 12, and 4 for brain pH, arterial
pH, and brain lactate, respectively). (Reprinted with permission from Simon et al. [69].)
Human data are similar. In 70 personally studied adult patients from an emergency department, 84% were acidotic and 32% had pH values less than 7.00 (2); a respiratory component of the acidosis (elevated Pa2) is found in one-half of patients (2, 81). In another series of 38 patients, 84% were acidotic (81). In a report of 97 children, a pH of less than 7.00 was found in 12% (23). Although there may be a hyperchloremic component (10), the major cause of the acidosis is peripheral lactate production from anaerobic metabolism in muscle. pH values in arterial blood of man measured within 40–60 seconds of maximal exercise to exhaustion also show marked lactic acidosis, with values as low as 6.8 (30). Although a peripheral source of the lactate predominates, a component of the acidosis is from cerebral venous lactate. This contribution can be estimated from studies in paralyzed, ventilated primates, in which the mean arterial pH during seizures was 7.33 (lowest value recorded, 7.07) (46). Brain pH measurements during SE in sheep demonstrated a fall to 6.70 over 30 minutes, with no further change during 4 hours of monitoring; a parallel elevation in brain lactate occurred (69) (Figure 13.8). The rate of resolution of the acidosis in SE can be inferred from human data following single seizures. In man, the pH recorded within 4 minutes of the termination of a single seizure was 7.14 ± 0.06 (54). As in SE patients, a respiratory component of the acidosis was present as well (Pa2 = 31–65 mm Hg; mean, 45). This acidosis normalizes as lactate is metabolized, with mean pH values of 7.14 ±
0.04 at 0–4 minutes following a single seizure, 7.24 ± 0.05 at 15 minutes, 7.31 ± 0.04 at 30 minutes, and 7.38 ± 0.04 at 60 minutes (54). In the absence of cardiac failure, SE-induced brain injury does not appear to be exacerbated by acidosis. In one personally studied patient population, three of 59 acidotic patients had residual neurologic impairment, compared with two of 10 patients with normal pH values (2). Detailed neuropathologic examinations have been performed in experimental primates following up to 5 hours of SE. An inverse correlation between arterial blood pH and neuropathologic change was demonstrated. The mean pH in animals with no, moderate, or severe neuropathologic damage was 6.92, 7.08, and 7.14, respectively (45). Although profound acidosis such as that produced during experimental ischemia with hyperglycemia is injurious to brain (35), more modest acidosis such as that seen in brain during seizures has been shown to be protective in excitotoxic injury (oxygen/glucose deprivation or glutamate exposure) in tissue culture (26, 76). The potentially protective effect of acidosis during seizures has two components. Acidosis has an anticonvulsant effect both in man (the ketogenic diet) (82) and in experimental animals (85). In experimental animals, acidosis induced by ventilation with 15% carbon dioxide was maximally anticonvulsant. In a hippocampal slice model of epileptiform bursting, acidosis induced by varying concentrations of carbon dioxide increased the interburst seizure interval at pH 6.7 and reversibly blocked all status-like discharges at pH 6.2 (78).
:
155
A neuroprotective effect of acidosis was demonstrated using hypercarbic ventilation during bicuculline-induced status in rat; neuronal injury was assessed immunocytochemically by heat-shock protein expression. Reduced SE duration and independently reduced pH decreased neuronal injury in vulnerable neurons of hippocampus and thalamus (60). The neuroprotective and anticonvulsant effects could be explained by the H+-mediated inhibition of the excitatory amino acid glutamate acting on NMDA channel currents (74). Acid-sensing ion channels in brain are downregulated by seizures, but the effect of this modulation is uncertain (7). Hypoxia is also a frequent component of SE. Hypoxia can result in hypotension, cerebral hypoperfusion, and ischemic brain injury (16). The effect of hypoxia alone in SE is to attenuate its electrographic intensity. The result is a decrease in SE duration with a resultant decrease in neuropathology (8). When seizure duration in hypoxic animals is experimentally controlled to be equal to that in nonhypoxic animals, no difference in SE-induced neuropathology is seen (62). The association between seizure duration and blood gas abnormalities was also studied during electroconvulsive therapy in dogs. Seizure duration was directly related to oxygen content and inversely related to carbon dioxide content (15); similar data have been reported in a hyperthermic seizure model in neonatal rat (49) and in kainateinduced seizures in rat (1).
Drug kinetics in SE Both the profound changes in blood and brain pH during seizures and alteration in blood-brain barrier permeability affect the uptake of anticonvulsant drugs administered during SE. The concentration of weak acids like phenobarbital (pKa 7.4) in brain is increased with systemic acidosis and decreased with alkalosis (27). In freely convulsing animals, the fall in blood pH is much greater than the fall in brain pH. In this setting, phenobarbital is partitioned into brain, with levels achieved being twice normal. When animals are paralyzed and ventilated during SE, the fall in blood pH is prevented. A fall in brain pH occurs, however, and phenobarbital is accordingly partitioned out of brain (68). The opposite effect is seen with a weak base such as lidocaine (pKa 7.86) (67). Drugs with a pKa well beyond the physiologic range, such as phenytoin (pKa 8.06), are not partitioned based on pH. Drugs administered early in SE, during the hypertensive phase, when the blood-brain barrier is disrupted, reach higher levels in brain than are achieved during the established phase of SE (69). Explanations for this finding include recruitment of additional capillary exchange surface in brain and increased drug delivery to brain due to increased
156
:
brain-blood flow. Opening of the blood-brain barrier is the most appealing explanation, however, since it occurs with the institution of hypertension and resolves within 10 minutes of cessation of the hypertensive surge (31). In experimental seizures, blood-brain barrier opening occurs within 1–4 minutes of seizure onset and is associated with blood pressure elevation greater than 50 mm Hg over baseline (71). The ultrastructural correlate of this blood-brain barrier alteration is capillary pinocytosis (55). Thus, anticonvulsant uptake into the brain during SE, while difficult to predict in a given patient, varies according to the integrity of the blood-brain barrier, the pH gradient between blood and brain, and the pKa of the drug.
Systemic and pulmonary vascular hypertension Status is associated with vasoconstriction and an elevation in vascular pressures. In sheep, systemic arterial pressure peaks within the first minutes of SE at approximately 125 mm Hg over baseline. Hypertension persists for 40 minutes or more and subsequently falls to control levels or below, even though SE continues (45, 66). In the early phase of SE, increased cerebral perfusion pressure combined with loss of cerebrovascular autoregulation (Figure 13.9) results in cerebral blood flow (CBF) elevations of 200%–600% of control (46, 69). The increased CBF is reflected in an increased CSF pressure, with values from 800–950 mm H2O recorded during single seizures in man (80). In paralyzed, ventilated humans monitored during pentylenetetrazol-induced seizures, systolic and diastolic pressure elevations of 85 and 42 mm Hg, respectively, occurred (80). In experimental animals, the increase in systemic pressures following single or sustained seizures is the same. In the pulmonary circulation (pulmonary artery and left atrium), however, vascular pressure elevations are proportional to the number of seizures induced, and are maximal with SE (5). In sheep, pressure elevations in the pulmonary artery and left atrium are respectively 156% and 217% of control values after a single seizure, but in SE, these elevations reached 226% and 685% of control values (5). The duration of seizure-induced pulmonary vascular hypertension is brief, with pressures returning to baseline in approximately 15 minutes, independent of the duration of SE. The elevations in pulmonary vascular pressure, although brief, result in a sustained increase in pulmonary transcapillary fluid flux and altered capillary permeability as assessed by transcapillary albumin conductance (66) (Figure 13.10). The permeability alterations in the pulmonary capillaries are presumably due to barotrauma (3), as blockade of the pressure elevation by cervical spinal cord transection (66) or vascular shunting during seizures prevents the change in capillary fluid flux (32). Thus, the elevations in pulmonary vascular pressures are likely to be responsible for the
F 13.9 Mean arterial blood pressure (MABP) and cerebral blood flow (CBF) during bicuculline-induced SE (seizure onset at
time 0) in sheep (n = 8) (CBF vs. MABP, P > 0.0001). (Reprinted with permission from Simon et al. [69].)
F 13.10 Pulmonary lymph flow, calculated pulmonary microvascular pressure, and calculated pulmonary transcapillary albumin conductance before and during bicuculline-induced SE in nine paralyzed, halothane-anesthetized sheep (solid line) and four
sheep with status and cervical spinal cord transections (dashed line). Values are presented as means ± SD. (Reproduced with permission from Simon et al. [66].)
pulmonary edema seen postictally, especially following repeated seizures (18).
Sudden death At autopsy, neurogenic pulmonary edema is a marker of the epileptic sudden death syndrome. It was found in seven of seven patients from the Allegheny County, Pennsylvania, Coroner’s Office (75), in 44 of 52 patients from the Chicago Coroner’s Office (40), in 38 of 44 patients from the Denver Coroner’s Office (24), and in 26 of 42 patients in a Norwegian study (38). The severity of pulmonary edema alone is inadequate to cause death, but its presence essentially excludes a cardiac arrhythmia as the cause, because a fatal arrhythmia would not provide enough time for pulmonary edema fluid to accumulate ante mortem. An animal model of sudden death during seizures has been developed. SE is induced by intravenous bicuculline in awake, unanesthetized, chronically instrumented sheep. Some such animals die suddenly, and only these animals have pulmonary edema at autopsy. The animals that die in comparison with those that survive in SE are not different in regard to EEG, ECG, plasma catecholamine concentrations, or systemic blood pressure elevations. However, the elevations in pulmonary artery and left arterial pressure are 60% higher in the sudden death animals. Presumably, this marked degree of pulmonary hypertension accounts for the pulmonary edema. Both elevations in pulmonary vascular pressure and sudden death appear to be due to centrally induced apnea. The sudden-death animals were characterized by a fall in p2 and an elevation in P2, similar to changes induced by tracheal cross-clamping. The resultant hypoxia induces additional pulmonary vasoconstriction, which increases pulmonary vascular pressures beyond seizure-induced elevations (33). Apnea is also the most likely cause of the human epileptic sudden death syndrome (52). Ventilatory patterns studied during SE in unanesthetized sheep showed irregular breathing patterns during EEG spiking and rapid, deep ventilation when periods of EEG slowing intervened. Episodes of apnea occurred in all animals. Apnea was not due to airway obstruction, as it occurred in spite of tracheostomy. Apnea was found during either expiration or inspiration, making the tonic phase of the seizures an unlikely cause of apnea, because tonic contraction would have produced apnea in inspiration if the diaphragm were contracted, or apnea in inspiration if chest wall muscle contraction were causative (34). The portion of the ventilatory cycle maintained during apnea may be a chance occurrence, as apnea induced during temporal lobe stimulation stopped ventilation when the stimulation was initiated (53).
158
:
Modulation of brain injury during seizures Prolonged seizures may result in brain injury; in the limbic system, the hippocampus is a major target. Some data support the concept that seizure duration and neuronal injury during SE may be pathophysiologically distinct (13, 39). During limbic seizures induced by kainate, administration of a glutamate antagonist into the ventricular system of the rat brain attenuates neuronal injury without altering seizure duration as monitored by the EEG. A few depth macro-electrode observations suggest that firing of target neurons is also not altered (13). Because limbic seizures may be modulated through a small area of deep prepiriform cortex (57), this site was investigated as a potential region modulating neuronal injury in limbic seizures. Glutamate antagonists injected into this site, but not a millimeter away, attenuated kainate-induced neuronal injury in hippocampus without altering seizure duration as monitored by EEG (36, 64). The mechanism by which this dissociation between seizure duration and injury occurs is uncertain but may involve N-methyl--asparate (NMDA)-induced reduction in the amplitude and duration of EPSPs (48). Nonetheless, dissociation of EEG activity from brain injury through modulation of activity in a specific brain region offers a circuit-specific approach to protect the brain from excitotoxic damage. Further, these observations suggest that in the presence of anticonvulsants, many of which modulate the excitatory glutamatergic system (17), the brain may be less vulnerable to ongoing seizures. In 1970 Rowan and Scott offered clinical data indicating that the interval between onset of SE and the initiation of treatment determines the risk for resultant brain injury (59) (Figure 13.11).
Epileptic tolerance During prolonged seizures, changes in gene expression occur in target neurons. Among the gene products that are upregulated are the stress proteins and the bcl-2 family of genes regulating apoptosis (28). Changes in gene expression may alter susceptibility to neuronal death. Limbic seizures that induce the induction of heat-shock proteins confer, for a period of days, reduced susceptibility to seizure-induced injury during subsequent periods of SE (61). Following single seizures that cause hippocampal injury, the proto-oncogene bcl-2, which is a suppresser of apoptotic cell death, is expressed in CA1 neurons, a region of hippocampus that is injured yet survives. Bcl-2 mRNA is expressed in CA3, a region that is marked by neuronal death. The bcl-2 protein is not translated in this region. However, expression of the bax protein, a bcl-2 family member that dimerizes with bcl-2 to inactivate it, is increased over baseline at 24 hours in CA3. Thus, the ultimate physiologic consequence of SE—neuronal death in brain—may depend at the cellular level on
F 13.11 Polygraph tracing of airway flow and EEG activity during bicuculline-induced SE in a sheep, showing irregular ventilation associated with seizure activity but deep, regular breath-
ing during EEG (7) slowing. (Reprinted with permission from Johnston et al. [34].)
the balance of newly induced gene products (30). Additional evidence demonstrates that genes induced by DNA damage may play a role in this regard as well (29, 86). The consequence of these gene changes is protection from injury or the phenomenon of tolerance. Following seizures, the brain is resistance to seizure-induced brain injury (61), and such tolerance mechanisms may be broadly relevant, as they protect against ischemic injury as well (56).
modify cerebral energy metabolism. Brain 1978;101(4): 687–700. Boggs, J. G., J. A. Painter, and R. J. DeLorenzo. Analysis of electrocardiographic changes in status epilepticus. Epilepsy Res. 1993;14(1):87–94. Brivet, F., M. Bernardin, P. Cherin, J. Chalas, P. Galanaud, and J. Dormont. Hyperchloremic acidosis during grand mal seizure lactic acidosis. Intensive Care Med. 1994;20(1): 27–31. Brown, M. J., D. C. Brown, and M. B. Murphy. Hypokalemia from beta2-receptor stimulation by circulating epinephrine. N. Engl. J. Med. 1983;309(23):1414–1419. Clark, L. P., and T. P. Prout. Status epilepticus: A clinical and pathological study in epilepsy. Am. J. Insanity 1902–1903; 59:291–306, 645–675. Clifford, D. B., J. W. Olney, A. M. Benz, T. A. Fuller, and C. F. Zorumski. Ketamine, phencyclidine, and MK-801 protect against kainic acid-induced seizure-related brain damage. Epilepsia 1990;31(4):382–390. Clutter, W. E., D. M. Bier, S. D. Shah, and P. E. Cryer. Epinephrine plasma metabolic clearance rates and physiologic thresholds for metabolic and hemodynamic actions in man. J. Clin. Invest. 1980;66(1):94–101. Crawford, C. D., P. Butler, and A. Froese. Arterial PaO2 and PaCO2 influence seizure duration in dogs receiving electroconvulsive therapy. Can. J. Anaesth. 1987;34:437–441. Cross, C. E., P. A. Rieben, C. I. Barron, and P. F. Salisbury. Effects of arterial hypoxia on the heart and circulation: An integrative study. Am. J. Physiol. 1963;205(5):963–970. Croucher, M. J., J. F. Collins, and B. S. Meldrum. Anticonvulsant action of excitatory amino acid antagonists. Science 1982;216(4548):899–901. Darnell, J. C., and S. J. Jay. Recurrent postictal pulmonary edema: A case report and review of the literature. Epilepsia 1982;23(1):71–83. Devinsky, O., S. Emoto, D. S. Goldstein, R. Stull, R. J. Porter, W. H. Theodore, et al. Cerebrospinal fluid and serum levels of dopa, catechols, and monoamine metabolites in patients with epilepsy. Epilepsia 1992;33(2):263–270. Devinsky, O., S. Nadi, W. H. Theodore, and R. J. Porter. Cerebrospinal fluid pleocytosis following simple, complex partial,
This research was supported in part by NIH grants Nos. K07 NS 00437, GM 18470, HL 33198, and NS24728-09.
9.
10.
11.
12.
13. REFERENCES 1. Amano, S., T. Obata, F. Hazama, N. Kashiro, and M. Shimada. Hypoxia prevents seizures and neuronal damages of the hippocampus induced by kainic acid in rats. Brain Res. 1990;523(1):121–126. 2. Aminoff, M. J., and R. P. Simon. Status epilepticus: Causes, clinical features and consequences in 98 patients. Am. J. Med. 1980;69(5):657–666. 3. Bachofen, H., S. Schurch, and E. R. Weibel. Experimental hydrostatic pulmonary edema in rabbit lungs: Barrier lesions. Am. Rev. Respir. Dis. 1993;147(4):997–1004. 4. Barry, E., and W. A. Hauser. Pleocytosis after status epilepticus. Arch. Neurol. 1994;51(2):190–193. 5. Bayne, L. L., and R. P. Simon. Systemic and pulmonary vascular pressures during generalized seizures in sheep. Ann. Neurol. 1981;10(6):566–569. 6. Benowitz, N. L., R. P. Simon, and J. R. Copeland. Status epilepticus: Divergence of sympathetic activity and cardiovascular response. Ann. Neurol. 1986;19(2):197–199. 7. Biagini, G., K. Babinski, M. Avoli, M. Marcinkiewicz, and P. Seguela. Regional and subunit-specific downregulation of acid-sensing ion channels in the pilocarpine model of epilepsy. Neurobiol. Dis. 2001;8(1):45–58. 8. Blennow, G., J. B. Brierley, B. S. Meldrum, and B. K. Siesjo. Epileptic brain damage: The role of systemic factors that
14.
15.
16.
17.
18.
19.
20.
:
159
21.
22.
23.
24. 25.
26.
27.
28.
29.
30. 31.
32.
33.
34.
35.
36.
37.
38.
and generalized tonic-clonic seizures. Ann. Neurol. 1988;23(4): 402–403. Doba, N., H. R. Beresford, and D. J. Reis. Changes in regional blood flow and cardiodynamics associated with electrically and chemically induced epilepsy in cat. Brain Res. 1975;90(1): 115–132. Dube, C., K. Chen, M. Eghbal-Ahmadi, K. Brunson, I. Soltesz, and T. Z. Baram. Prolonged febrile seizures in the immature rat model enhance hippocampal excitability long term. Ann. Neurol. 2000;47(3):336–344. Dunn, D. W. Status epilepticus in children: Etiology, clinical features, and outcome. J. Child. Neurol. 1988;3(3): 167–173. Earnest, M. P., G. E. Thomas, and R. A. Eden. Sudden unexpected death in epilepsy. Neurology 1988;38:248–249. Edwards, R., J. W. Schmidley, and R. P. Simon. How often does a CSF pleocytosis follow generalized convulsions? Ann. Neurol. 1983;13(4):460–462. Giffard, R. G., H. Monyer, C. W. Christine, and D. W. Choi. Acidosis reduces NMDA receptor activation, glutamate neurotoxicity, and oxygen-glucose deprivation neuronal injury in cortical cultures. Brain Res. 1990;506(2):339–342. Goldberg, M. A., C. F. Barlow, and L. J. Roth. The effects of carbon dioxide on the entry and accumulation of drugs in the central nervous system. J. Pharmacol. Exp. Ther. 1961;131: 308–318. Henshall, D. C., T. Araki, C. K. Schindler, J. Q. Lan, K. L. Tiekoter, W. Taki, et al. Activation of Bcl-2-associated death protein and counter-response of Akt within cell populations during seizure-induced neuronal death. J. Neurosci. 2002; 22(19):8458–8465. Henshall, D. C., J. S. Sinclair, and R. P. Simon. Relationship between seizure-induced transcription of the DNA damageinducible gene GADD45, DNA fragmentation and neuronal death in focally evoked limbic epilepsy. J. Neurochem. 1999; 73:1573–1583. Hermansen, L., and J. B. Osnes. Blood and muscle pH after maximal exercise in man. J. Appl. Physiol. 1972;32(3):304–308. Johansson, B. B., and L. E. Linder. Reversibility of the bloodbrain barrier dysfunction induced by acute hypertension. Acta Neurol. Scand. 1978;57(4):345–348. Johnston, S. C., T. M. Darragh, and R. P. Simon. Postictal pulmonary edema requires pulmonary vascular pressure increases. Epilepsia 1996;37(5):428–432. Johnston, S. C., J. K. Horn, J. Valente, and R. P. Simon. The role of hypoventilation in a sheep model of epileptic sudden death. Ann. Neurol. 1995;37(4):531–537. Johnston, S. C., R. Siedenberg, J. K. Min, E. H. Jerome, and K. D. Laxer. Central apnea and acute cardiac ischemia in a sheep model of epileptic sudden death. Ann. Neurol. 1997; 42(4):588–594. Katsura, K., T. Kristian, M. L. Smith, and B. K. Siesjo. Acidosis induced by hypercapnia exaggerates ischemic brain damage. J. Cereb. Blood Flow Metab. 1994;14(2):243–250. Kawaguchi, K., and R. P. Simon. Deep prepiriform cortex modulates neuronal cell death in global ischemia. J. Cereb. Blood Flow Metab. 1997;17(3):356–360. Keilson, M. J., W. A. Hauser, and J. P. Magrill. Electrocardiographic changes during electrographic seizures. Arch. Neurol. 1989;46(11):1169–1170. Kloster, R., and T. Engelskjon. Sudden unexpected death in epilepsy (SUDEP): A clinical perspective and a search for risk factors. J. Neurol. Neurosurg. Psychiatry 1999;67(4):439–444.
160
:
39. Lason, W., J. N. Simpson, and J. F. McGinty. Effects of D-(-)aminophosphonovalerate on behavioral and histological changes induced by systemic kainic acid. Neurosci. Lett. 1988; 87(1–2):23–28. 40. Leestma, J. E., T. Walczak, J. R. Hughes, M. B. Kalelkar, and S. S. Teas. A prospective study on sudden unexpected death in epilepsy. Ann. Neurol. 1989;26(2):195–203. 41. Lepeschkin, E., H. Marchet, G. Schroeder, R. Wagner, E. DePaula, P. Silva, et al. Efect of epinephrine and norepinephrine on the electrocardiogram of 100 normal subjects. Am. J. Cardiol. 1960;5:594–603. 42. Liu, Z., A. Gatt, M. Mikati, and G. L. Holmes. Effect of temperature on kainic acid-induced seizures. Brain Res. 1993; 631(1):51–58. 43. Lundgren, J., M. L. Smith, G. Blennow, and B. K. Siesjo. Hyperthermia aggravates and hypothermia ameliorates epileptic brain damage. Exp. Brain Res. 1994;99(1): 43–55. 44. Meldrum, B. S. Metabolic factors during prolonged seizures and their relation to nerve cell death. In A. V. DelgadoEscueta, C. G. Wasterlain, D. M. Treiman, and R. J. Porter, eds. Status Epilepticus. Adv. Neurol. 1983;34:261–275. 45. Meldrum, B. S., and R. W. Horton. Physiology of status epilepticus in primates. Arch. Neurol. 1973;28(1):1–9. 46. Meldrum, B. S., R. A. Vigouroux, and J. B. Brierley. Systemic factors and epileptic brain damage: Prolonged seizures in paralyzed, artificially ventilated baboons. Arch. Neurol. 1973;29(2): 82–87. 47. McDonald, C. K., M. L. Waters, and F. M. Griffin, Jr. Case report: Neutrophilic CSF pleocytosis in hypertensive encephalopathy. Am. J. Med. Sci. 1993;306(3):167–168. 48. Mody, I., P. K. Stanton, and U. Heinemann. Activation of Nmethyl--aspartate receptors parallels changes in cellular and synaptic properties of dentate gyrus granule cells after kindling. J. Neurophysiol. 1988;59(3):1033–1054. 49. Morimoto, T., M. Fukuda, Y. Aibara, H. Nagao, and K. Kida. The influence of blood gas changes on hyperthermia-induced seizures in developing rats. Brain Res. Dev. Brain Res. 1996; 92(1):77–80. 50. Morimoto, T., K. Kida, H. Nagao, K. Yoshida, M. Fukuda, and S. Takashima. The pathogenic role of the NMDA receptor in hyperthermia-induced seizures in developing rats. Brain Res. Dev. Brain Res. 1995;84(2):204–207. 51. Morimoto, T., H. Nagao, M. Yoshimatsu, K. Yoshida, and H. Matsuda. Pathogenic role of glutamate in hyperthermiainduced seizures. Epilepsia 1993;34(3):447–452. 52. Nashef, L., and S. Brown. Epilepsy and sudden death. Lancet 1996;348(9038):1324–1325. 53. Nelson, D. A., and C. D. Ray. Respiratory arrest from seizure discharges in limbic system: Report of cases. Arch. Neurol. 1968;19(2):199–207. 54. Orringer, C. E., J. C. Eustace, C. D. Wunsch, and L. B. Gardner. Natural history of lactic acidosis after grand-mal seizures: A model for the study of an anion-gap acidosis not associated with hyperkalemia. N. Engl. J. Med. 1977; 297(15):796–799. 55. Petito, C. K., J. A. Schaefer, and F. Plum. Ultrastructural characteristics of the brain and blood-brain barrier in experimental seizures. Brain Res. 1977;127(2):251–267. 56. Plamondon, H., N. Blondeau, C. Heurteaux, and M. Lazdunski. Mutually protective actions of kainic acid epileptic preconditioning and sublethal global ischemia on hippocampal neuronal death: Involvement of adenosine A1 receptors
57. 58.
59. 60.
61.
62.
63. 64.
65.
66.
67.
68.
69.
70.
71.
72.
73. 74.
75.
76.
77.
and K(ATP) channels. J. Cereb. Blood Flow Metab. 1999; 19(12):1296–1308. Piredda, S., and K. Gale. A crucial epileptogenic site in the deep prepiriform cortex. Nature 1985;317(6038):623–625. Pulsinelli, W. A., J. B. Brierley, and F. Plum. Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann. Neurol. 1982;11(5):491–498. Rowan, A. J., and D. F. Scott. Major status epilepticus: A series of 42 patients. Acta Neurol. Scand. 1970;46(4):573–584. Sasahira, M., T. Lowry, and R. P. Simon. Neuronal injury in experimental status epilepticus in the rat: Role of acidosis. Neurosci. Lett. 1997;224(3):177–180. Sasahira, M., T. Lowry, R. P. Simon, and D. A. Greenberg. Epileptic tolerance: Prior seizures protect against seizureinduced neuronal injury. Neurosci. Lett. 1995;185(2):95–98. Sasahira, M., R. P. Simon, and D. A. Greenberg. Neuronal injury in experimental status epilepticus in the rat: Role of hypoxia. Neurosci. Lett. 1997;222(3):207–209. Schmidley, J. W., and R. P. Simon. Postictal pleocytosis. Ann. Neurol. 1981;9(1):81–84. Shimosaka, S., Y. T. So, and R. P. Simon. Deep prepiriform cortex modulates kainate-induced hippocampal injury. Neuroscience 1994;61(4):817–822. Simon, R. P., M. J. Aminoff, and N. L. Benowitz. Changes in plasma catecholamines after tonic-clonic seizures. Neurology 1984;34(2):255–257. Simon, R. P., L. L. Bayne, R. F. Tranbaugh, and F. R. Lewis. Elevated pulmonary lymph flow and protein content during status epilepticus in sheep. J. Appl. Physiol. 1982;52(1):91–95. Simon, R. P., N. L. Benowitz, and S. Culala. Motor paralysis increases brain uptake of lidocaine during status epilepticus. Neurology 1984;34(3):384–387. Simon, R. P., N. Benowitz, R. Hedlund, and J. Copeland. Influence of the blood-brain pH gradient on brain phenobarbital uptake during status epilepticus. J. Pharmacol. Exp. Ther. 1985;234(3):830–835. Simon, R. P., J. R. Copeland, N. L. Benowitz, P. Jacob III, and J. Bronstein. Brain phenobarbital uptake during prolonged status epilepticus. J. Cereb. Blood Flow Metab. 1987;7(6):783–788. Sokrab, T. E., H. Kalimo, and B. B. Johansson. Endogenous serum albumin content in brain after short-lasting epileptic seizures. Brain Res. 1989;489(2):231–236. Suzuki, R., C. Nitsch, K. Fujiwara, and I. Klatzo. Regional changes in cerebral blood flow and blood-brain barrier permeability during epileptiform seizures and in acute hypertension in rabbits. J. Cereb. Blood Flow Metab. 1984;4(1):96–102. Swan, J. H., B. S. Meldrum, and R. P. Simon. Hyperglycemia does not augment neuronal damage in experimental status epilepticus. Neurology 1986;36(10):1351–1354. Talman, W. T., and P. Kelkar. Neural control of the heart: Central and peripheral. Neurol. Clin. 1993;11(2):239–256. Tang, C. M., M. Dichter, and M. Morad. Modulation of the N-methyl--aspartate channel by extracellular H+. Proc. Natl. Acad. Sci. U.S.A. 1990;87(16):6445–6449. Terrence, C. F., G. R. Rao, and J. A. Perper. Neurogenic pulmonary edema in unexpected, unexplained death of epileptic patients. Ann. Neurol. 1981;9(5):458–464. Tombaugh, G. C., and R. M. Sapolsky. Mechanistic distinctions between excitotoxic and acidotic hippocampal damage in an in vitro model of ischemia. J. Cereb. Blood Flow Metab. 1990;10(4):527–535. Tomlinson, F. H., R. E. Anderson, and F. B. Meyer. Effect of arterial blood pressure and serum glucose on brain intracellu-
78.
79.
80.
81.
82. 83.
84.
85. 86.
87.
lar pH, cerebral and cortical blood flow during status epilepticus in the white New Zealand rabbit. Epilepsy Res. 1993; 14(2):123–137. Velisek, L., J. P. Dreier, P. K. Stanton, U. Heinemann, and S. L. Moshe. Lowering of extracellular pH suppresses lowMg(2+)-induces seizures in combined entorhinal cortexhippocampal slices. Exp. Brain Res. 1994;101(1):44–52. Wachtel, T. J., G. H. Steele, and J. A. Day. Natural history of fever following seizure. Arch. Intern. Med. 1987;147(6): 1153–1155. White, P. T., P. Grant, J. Mosier, and A. Craig. Changes in cerebral dynamics associated with seizures. Neurology 1961;11: 354–361. Wijdicks, E. F., and R. D. Hubmayr. Acute acid-base disorders associated with status epilepticus. Mayo Clin. Proc. 1994;69(11): 1044–1046. Wilder, R. The effect of ketonemia on the course of epilepsy. Mayo Clin. Bull. 1921;2:307–308. Williams, M. E., R. M. Rosa, P. Silva, R. S. Brown, and F. H. Epstein. Impairment of extrarenal potassium disposal by alpha-adrenergic stimulation. N. Engl. J. Med. 1984;311(3): 145–149. Wong, M., B. L. Schlaggar, and M. Landt. Postictal cerebrospinal fluid abnormalities in children. J. Pediatr. 2001; 138(3):373–377. Woodbury, D. M., and R. Karler. The role of carbon dioxide in the nervous system. Anesthesiology 1960;21:687. Zhu, R. L., S. H. Graham, J. Jin, R. A. Stetler, R. P. Simon, and J. Chen. Kainate induces the expression of the DNA damage-inducible gene, GADD45, in the rat brain. Neuroscience 1997;81(3):707–720. Zweifler, R. M., E. M. Slaven, L. L. Rihn, J. C. Magee, and N. R. Kreisman. Renal hemodynamic changes during serial seizures in rats. Am. J. Physiol. 1991;261(5 Pt. 2):H1508–H1513.
:
161
14
Clinical Neuropathology in Convulsive Status Epilepticus
- C epilepticus (CSE) is often a disastrous event in epileptology. Morphological studies in experimental SE showed tremendous changes in brain pathology (2, 5, 8, 11). Clinical observations demonstrate that the course of an epileptic syndrome can significantly change after SE (1, 14). The clinical changes were attributed to hypothesized brain pathology following SE (4, 13). We studied the brains of 650 patients with epilepsy who died between 1955 and 1980. The predominant brain pathology, suggested to be of ictogenic origin, was elective parenchymal necrosis (hypoxic vascular, ischemic lesion; Figures 14.1 to 14.3), with predominant involvement of the hippocampal complex (12). But many investigations also support the conclusion that these lesions cause the seizures. These lesions are independently generated from seizures and become ictogenic after further developmental progress (6, 9).
Clinical findings Of the 650 patients, 96 (15%) had survived CSE, 49 with parenchymal lesions and 47 without (Table 14.1). In 27%, hippocampal sclerosis and an elective parenchymal necrosis of the neocortex were identified. This figure is in the same range as that for the entire study group of 650 patients, with 30.5% of cases exhibiting hippocampal sclerosis (9). Neocortical elective parenchymal necrosis was found in 3% of survivors of CSE, compared with 5.6% of the entire group. These figures indicate that the development of SE does not change the rate of elective parenchymal necrosis in the brain of patients with epilepsy. Thirty-two patients had initial CSE and 64 had intercurrent CSE (Table 14.2). Parenchymal ischemic lesions were identified in 75% of the patients who had initial CSE but in only 40% of those who had intercurrent SE. This finding probably indicates that this type of pathologic change is related to the etiological event responsible for the initial CSE. The recurrence of SE did not significantly affect the proportion of cases without parenchymal lesions. No ischemic lesions were identified in 25% of patients with initial CSE as an isolated event and in 31% of patients with initial CSE and recurrent SE. No ischemic lesions were iden-
tified in 60% of patients with intercurrent CSE as an isolated event and in 62% of those with recurrent SE. Surprisingly, even recurrent SE did not change significantly the prevalence of ischemic lesions. More extended sclerotic ischemic lesions (ulegyria) are much more involved in initial episodes of SE (intercurrent, 35%, isolated, 46%) than in intercurrent SE (intercurrent, 15%, recurrent, 20%). Cases with recurrent SE are also more related to these sclerotic lesions. In general these figures also support the hypothesis that the analyzed lesions are much more related to the causative factors of initial CSE than they are a consequence of the seizures themselves. This is also supported by the fact that recurrent SE does not modify the figures of the nonaffected specimen. In cases with intercurrent SE but recurrent events, there is the same rate of parenchymal necrosis in both groups. The hypothesis that the ischemic lesions analyzed might be related to the causative factors is also supported by our observation that in the 49 patients with ischemic lesions, 80% did not have any other pathologic deviation (Table 14.3). In contrast, only 8% of the 47 patients with nonischemic lesions and SE did not have any other pathologic lesions. The detailed pathologic findings in this group of 47 patients with grand mal SE and no ischemic lesions are given in the table. Leading findings are migration disturbances, seen in almost 50% of the cases (Table 14.4). The conclusion that nonictal factors are responsible for the pathologic changes is also supported by the analysis of elective parenchymal necrosis in patients with final (terminal) convulsive SE. Out of 59 patients with final SE, 29 had epilepsy and 30 had no epilepsy (Table 14.5). Of the patients with epilepsy, 76% had no elective parenchymal necrosis, whereas only 40% of patients without epilepsy had no elective parenchymal necrosis. This finding suggests that the pathologic changes seen are more related to the pathologic event that causes the pathologic lesion and initiates the epileptogenic functional disturbances. An analysis of etiologic factors responsible for final SE in patients without epilepsy shows that the etiology itself is responsible for the elective parenchymal necrosis (Table 14.6). Morphometric studies of neuron density in the hippocampus clearly showed that the status epilepticus does not
:
163
F 14.1 mental SE.
Single cell necrosis in the hippocampus in experi-
F 14.2 Hippocampal sclerosis, with cell loss predominantly in sectors CA1 and CA4.
164
:
F 14.3 sclerosis.
Macroscopic view of unilateral hippocampal
influence the neuron density of the pyramidal cell layer. We analyzed 29 control patients without epilepsy, 27 patients with temporal lobe epilepsy, and 12 patients with primary generalized idiopathic epilepsy. On morphometric analysis,
T 14.1 Results in patients who survived status epilepticus, out of 650 patients with epilepsy No. Who Survived Grand Mal SE
96 (15%)
With ischemic lesions With HS With EPN/NC With ulegyria Without ischemic lesions
49 26 3 20 47
(51%) (27%) (3%) (21%) (49%)
Abbreviations: HS, hippocampal sclerosis; EPN, elective parenchymal necrosis; NC, neocortex.
neuron density in sector CA4 (H3) was influenced by the total number of grand mal seizures but not by the generation of SE (6). We were able to analyze in detail the influence of SE in different clinical epilepsy syndromes—Lennox-Gastaut syndrome (n = 30), generalized idiopathic epilepsies (n = 15), and temporal lobe epilepsies (n = 27). Five patients with Lennox-Gastaut syndrome had grand mal status. Hippocampal sclerosis in this subgroup with CSE was 20%, in the same range as for the whole group (Table 14.7). Also, cerebellar lesions, the predominant finding in this group (10), were seen in 60%, again in the same range as for the whole group (67%). In the group of 15 patients with generalized idiopathic epilepsies, only one patient had grand mal SE (Table 14.8). In this patient we found a circumscribed elective parenchymal necrosis in the mesial thalamic nucleus. The distribution of this lesion was the same as demonstrated in our study of thalamic lesions after global ischemia (7). This patient
T 14.2 Frequency of lesions in initial and intercurrent status epilepticus
n = 32: Initial SE Recurrent (n = 18) n = 64: Intercurrent status Recurrent (n = 34)
HS/EPN (%)
Ulegyria (%)
40 23 25 18
35 46 15 20
No Ischemic Lesions (%) 25 31 60 62
:
165
T 14.3 Results in 96 patients with grand mal status epilepticus: Association between ischemic lesions and other lesions With/Without Ischemic Lesions
No Other Lesions
Ischemic lesions 49 No ischemic lesions 47
39 (80%) 4 (8%)
T 14.6 Etiological factors in final status epilepticus in patients without epilepsy (n = 30) Group
Factor
Infants (n = 15)
Hyperpyrexia Pertussis Encephalitis Unknown Hypotension Pertussis Toxicosis Encephalitis Hyperpyrexia Unknown Cardiac arrest Hypertensive Angiopathy Other
Children (n = 9) T 14.4 Pathologic findings in 47 patients with grand mal status epilepticus without ischemic lesions Finding
No. of Patients Adult (n = 6)
Microdysgenesis Severe migration disturbances Phacomatosis Trauma Meningitis/encephalitis Vascular disease Lencencephalopathy
11 11 7 5 5 2 2
EPN
No EPN
7
3
2
3
6
2
1 1 4
T 14.7 Lennox-Gastaut syndrome (n = 30) Group/Lesion
T 14.5 Elective parenchymal necrosis and final (terminal) status epilepticus in patients with and without epilepsy
Epilepsy (n = 29) No epilepsy (n = 30)
1
EPN (%)
No EPN (%)
24 60
76 40
No. of Patients
Grand mal (n = 5) Hippocampal sclerosis Cerebellar lesions Total group (n = 30) Hippocampal sclerosis Cerebellar lesions
1 3 6 20
T 14.8 Generalized idiopathic epilepsy (n = 15)
sustained an intercurrent cardiac arrest after a suicide attempt. Of the 27 patients with temporal lobe epilepsy, nine had SE (Table 14.9). Of these nine patients, only 44% had hippocampal sclerosis, compared with 56% in the whole temporal lobe group. Only the frequency of cerebellar lesions was increased, 66%, compared with 41% for the entire study group. Although this finding could not be demonstrated in other epilepsy syndromes, this slight increase in cerebellar involvement might not be a consequence of the status event. Thus, the cerebellar involvement in this syndrome might more frequently be related etiologically to the development of CSE.
Comment In general, SE did not alter the overall rate of elective parenchymal necrosis in patients with epilepsy. The patho-
166
:
Status Grand mal SE (n = 1) Hippocampal lesion Cerebellar lesion EPN in thalamus
No. of Patients
0 0 1
logic pattern identified might be related more to causative factors, both of epilepsy and of CSE. The pathologic findings identified are related to the etiologic factors, as indicated by the histologic pattern and the functional epileptogenic deviation. This relationship in particular is supported by our observations in patients with final (terminal) SE. The morphometric data show that not SE, but the total number of grand mal seizures alters the neuron density in one subsector of the hippocampus (CA4). The hippocampal
T 14.9 Temporal lobe epilepsy in patients with nonconvulsive status epilepticus (n = 27) Group/Lesion
No. of Patients
Grand mal SE (n = 9) Hippocampal sclerosis Cerebellar lesions Total group (n = 27) Hippocampal sclerosis Cerebellar lesions
4 6 15 11
sclerosis is related neither to the total amount of grand mal seizures nor to the SE, however. Finally, the morphologic analysis in cases with grand mal SE in distinct epilepsy syndromes showed no changes in the frequency and pattern of neuropathologic findings. These findings in human neuropathology must be scrutinized in the light of experimental data. It should be emphasized that the elective parenchymal necrosis and hippocampal sclerosis discribed in humans, seem not to be the appropriate subject for discussing the pathologic consequences of SE. From experimental studies we know the excitotoxic and metabolic effects on the single neuron, resulting in neuronal death (3, 15–17). These findings cannot be overlooked. However, our interpretation of pathologic findings in human CSE should not be biased by these experimental data. It is important to carefully analyze the experimental design and question whether the model is comparable to human CSE.
8. Meencke, H. J., H. Takahashi, M. Straschill, and J. CervosNavarro. Early ischemic lesions of the hippocampal neurons in experimental status epilepticus. Fortschr. Neurol. Psychiatr. 1984;52:116–121. 9. Meencke, H. J., and G. Veith. Hippocampal sclerosis in epilepsy. In H. Lüders, ed. Epilepsy Surgery. New York: Raven Press, 1991:705–715. 10. Meencke, H. J., and G. Veith. Neuropathologische Aspekte des myoklonisch-astatischen Petit Mal (Lennox-Syndrome). In R. Kruse, ed. Epilepsie 84. Reinbeck: Einhorn-Presse, 1985: 305–313. 11. Meldrum, B. S. Metabolic factors during prolonged seizures and their relation to nerve cell death. Adv. Neurol. 1983;34: 261–275. 12. Norman, R. M. The neuropathology of status epilepticus. Med. Sci. Law 1964;4:46–51. 13. Oxbury, J. M., and Whitty, C. W. M. Causes and consequences of status epilepticus in adults: A study of 86 cases. Brain 1971;94:733–744. 14. Rowan, A. J., and D. F. Scott. Major status epilepticus: A series of 42 patients. Acta Neurol. Scand. 1970;146:573–584. 15. Sloviter, R. S. Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. Science 1987;235:73–76. 16. Sloviter, R. S. Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat: The “dormant basket cell” hypothesis and its possible relevance to temporal lobe epilepsy. Hippocampus 1991;1: 41–66. 17. Tremblay, E., O. P. Ottersen, C. Rovira, and Y. Ben-Ari. Intraamygdaloid injections of kainic acid: Regional metabolic changes and their relation to the pathological alterations. Neuroscience 1983;8:299–315.
REFERENCES 1. Aicardi, J., and J. Chevrie. Consequences of status epilepticus in infants and children. Adv. Neurol. 1983;34:115–125. 2. Blennow, G., J. B. Brierly, B. S. Meldrum, and B. K. Siesjo. Epileptic brain damage: The role of systemic factors that modify cerebral energy metabolism. Brain 1978;101:687– 700. 3. Charriaut Marlangue, C., D. Aggoun Zouaoui, A. Represa, and Y. Ben-Ari. Apoptic features of selective neuronal death in ischemia, epilepsy and gp 120 toxicity (review). Trends Neurosci. 1996;19:109–114. 4. Hauser, W. A. Status epilepticus: Etiology and neurological sequelae. Adv. Neurol. 1983;34:3–14. 5. Ingvar, M. H., and B. K. Siesjo. Local blood flow and oxygen consumption in the rat brain during sustained bicucullineinduced seizures. Acta Neurol. Scand. 1983;68:128–144. 6. Meencke, H. J., S. Lund, and G. Veith. Bilateral hippocampal sclerosis and secondary epileptogenesis. Epilepsy Res. Suppl. 1996;12:335–342. 7. Meencke, H. J., G. H. Schneider, and G. Stoltenburg-Didinger. Thalamusschäden nach Herzkreislaufstillstand und Reanimation. Aktuelle Probleme der Neuropathologie 4, 1978;4:138–148.
:
167
15
Neuron-Specific Enolase in Status Epilepticus
. , . , , , . ,
Introduction Generalized convulsive status epilepticus (GCSE) is a medical emergency that causes brain injury in hippocampus, cerebellum, and cortex, even in paralyzed and mechanically ventilated animals (8, 10, 12, 21, 23). However, human studies of SE are limited and select for the most severe cases, which are frequently plagued by confounding variables, especially previous epilepsy, acute neurologic insults, hypoxia, and hypotension (8). The true degree of brain injury in human survivors of SE is poorly understood. With the decline in mortality from SE to 3%, there is increased emphasis on the neurologic sequelae of brain injury in survivors of status (18). Our concern has evolved from how best to stop status to how to minimize the degree of brain injury in survivors. Further, there is a growing consensus that subtypes of status, specifically subclinical and complex partial status, cause brain injury and should be treated earlier and more aggressively (7, 10, 16, 40). In order to assess brain injury in human survivors of SE, markers of brain injury are needed. Without specific markers of brain injury, the degree of brain injury can only be inferred or estimated. Markers of brain injury could provide an estimate of the degree of brain injury in SE. Markers could define subtypes of SE requiring aggressive intervention, and could serve as an outcome measure for new treatments and interventions. For a marker to be valuable for clinical and experimental use in SE, it should be sensitive and specific for neuronal injury, sensitive to the duration and outcome of status, reliable, and easily measured. Such an in vivo marker could accelerate our understanding of the optimal treatment of SE and its subtypes. Neuron-specific enolase may be one such marker.
Neuron-specific enolase Enolase is a key enzyme for energy metabolism and is present in the cytoplasm of all cells (19, 20, 33, 35, 42). Enolase, or 2-phospho--glycerate hydrolase, is one enzyme of the glycolytic pathway for the conversion of glucose
to pyruvate. Enolase converts 2-phospho--glycerate to phosphoenolpyruvate. Enolase exists as a dimer of two subunits, alpha, beta, or gamma. There are five isoenzymes of enolase, depending on which subunits make up the dimers: aa, bb, gg, ab, ag. Brain enolases contain only alpha and gamma subunits: neurons contain only gamma-gamma enolase, neuroectodermal tissue may have alpha-gamma or gamma-gamma, and glia only contain alpha-alpha enolase, which is virtually identical to liver enolase, also an alphaalpha enolase. Gamma enolase is referred to as neuronspecific enolase (NSE) because of its specificity for neurons. NSE contains two identical 39,000-dalton gamma subunits and has a molecular weight of 78,000 daltons. The term NSE replaces the old terminology brain-specific protein, or neuron-specific protein, which was commonly used in the literature in the 1970s and 1980s. NSE is detected in serum and cerebrospinal fluid (CSF) using a standard radioimmunoassay (RIA) technique (19, 20, 23). The commercially available RIA is a double-antibody RIA based on the technique originally described by Pahlman et al. (23). NSE in the sample competes with a fixed quantity of I125 NSE for binding sites on antibodies specific to NSE. I125 NSE antibody is incubated for 3 hours at 23°C with either standardized concentrations of NSE or plasma samples. Bound and unbound NSE are separated, the I 125 is counted using a spectrophotometer, and the concentration of NSE is calculated using a standard curve (23). N V NSE Multiple investigators have studied the normal range of NSE. Zeltzer et al. reported normal values in a study of NSE as a marker of neuroblastoma (41). The mean NSE in 30 normal adults was 5.2 ng/mL (SD 1.1 ng/mL). The mean normal value in 30 infants and children was 7.2 ng/mL (SD 2.1 ng/mL). They defined 15 ng/mL as an abnormal value for children in their series. Ko et al., using a similar RIA technique, reported a mean serum NSE value in 20 normal children of 8.38 ng/mL (SD 4.4 ng/mL), with a range of 3.5– 15.2 ng/mL (15). Persson reported a mean serum NSE of 7 ng/mL (SD 1.6 ng/mL) and a range of 2–13 ng/mL in 152 normal controls (25). Schaarschmidt et al. reported a
.: -
169
mean serum NSE of 10.8 ng/mL (range, 2–20 ng/mL; normal limit 20 ng/mL (normal limit defined as mean plus 3 ¥ SD). NSE E C Epileptic control values are nearly identical to those of normal control subjects (5). We collected serum NSE samples from 13 people with chronic epilepsy who had no history of SE and were seizure-free for 7 days (5). The mean serum NSE level in the epileptic control subjects was 4.61 ng/mL ± 1.74 ng/mL. There was no significant difference from normal control values (5.02 ng/mL). Rabinowicz et al. reported baseline NSE values in 15 subjects with epilepsy undergoing video telemetry, and found a mean NSE of 7.6 ng/mL ± 3.7 ng/mL (26). The slightly higher values in this population likely reflect the fact that subjects with seizures within 7 days prior to measurement were not excluded (26). NSE: A M N I If NSE is specific to neurons and neuroectodermal tissue, is NSE also specific for neuronal injury? The central question of the specificity of NSE for neuronal and not glial injury was answered by Lafon-Cazol et al. (17). They studied NSE release in cultured
170
:
neurons (cerebeller granule cells) and cultured glial cells. After exposure to phenazine methosulfate, a specific neuronal toxin, the glial cultures produced a negligible (98% smaller) rise in NSE levels compared to neuronal cultures, which produced significant elevations of NSE. Lafon-Cazal provide direct in vitro evidence that neuronal cell death is accompanied by significant rises in NSE levels, and that NSE is an excellent means to quantify cell death of neurons in culture. NSE is a powerful marker in animal models of cerebral ischemia, including focal infarction and global ischemia (10, 13, 36). CSF NSE levels correlate with the duration of ischemia and the size of cerebral infarction. Steinberg et al., using a rat model of forebrain ischemia, occluded the four major cranial vessels and sampled CSF NSE levels from the cisterna magna (36). After occlusion, CSF NSE elevations occurred as early as 2 hours, and remained elevated up to 192 hours. Maximum CSF NSE levels were nine times those in sham control rats. Interestingly, if seizures accompanied ischemia, NSE levels were up to 17 times control levels. The duration of ischemia correlated with a nearly linear rise in NSE levels, and peak CSF NSE levels at 30 minutes of ischemia were significantly higher than at 10 or 20 minutes. Similarly, Hatfield and McKernan, in a rat model of middle cerebral artery (MCA) occlusion, found a good correlation between CSF NSE and the volume of cerebral infarction (11). NSE is also a marker for global ischemia in humans (11, 29). Roine et al. studied CSF, serum NSE, and CSF CK-BB levels after out-of-hospital cardiac arrest, and correlated outcome with levels of these markers (29). CSF NSE levels averaged 99.7 ng/mL in those with poor outcome after cardiac arrest, versus 10.7 ng/mL in those with good outcome and 6.4 ng/mL in normal controls. No subjects with CSF NSE levels greater than 24 ng/mL recovered (100% predictive of poor outcome). Both CSF NSE and CSF CK were highly predictive of 3-month outcome. Serum NSE, though less sensitive to brain injury than CSF NSE, had a high specificity for predicting good and poor outcomes. When serum NSE levels were greater than 17 ng/mL, serum NSE correctly predicted poor outcome in 79% of subjects (29). Kittaka et al. found that NSE is a good marker with which to study new treatments for focal ischemia (14). They studied the correlation between NSE and infarct volume in a rodent model of MCA occlusion. Within 10 minutes of MCA occlusion, intraperitoneal nicardipine, 1.2 mg/kg, was administered to eight rats. Nicardipine was then given again at 8, 16, 24 hours. The nicardipine-treated rats had a 19% reduction in the size of the stroke compared with untreated control rats. The NSE levels in MCA-occluded rats versus sham controls were significantly elevated, threefold, at 24 hours. Interestingly, the nicardipine-treated rats demon-
strated 50% lower NSE levels at 24 hours, a 42% reduction at 48 hours, and a 59% reduction at 72 hours. This study provides powerful evidence that NSE may be an excellent screening tool for new therapies in stroke (14). NSE I S Royds et al. first reported levels of NSE in seizures in 1983 (30). They surveyed CSF NSE levels in 212 subjects with a wide range of neurologic disorders, including epilepsy. They found NSE was elevated in four of nine subjects with “epileptic fits” within 5 days prior to lumbar puncture. In what is likely the first documented level of NSE in SE, Royds et al. reported, “The highest gamma enolase value (35.1 ng/mL) occurred in a patient who exhibited continuous seizure activity electrophysiologically” (30). Ko et al., in a similar survey of NSE in meningitis, tumors, Reye’s syndrome, and other neurologic disorders, reported NSE levels in 43 children with febrile convulsions and 25 children with seizures (15). Although there was no specific reference to SE, Ko et al. found that most children with febrile seizures had normal CSF and serum NSE levels (mean serum NSE, 8.14 ng/mL; SD 4.16 ng/mL; range, 3.7–12.1 ng/mL). Children with nonfebrile seizures had mean serum NSE levels of 14.17 ± 4.58 ng/mL (range, 7.2–24.1 ng/mL). Though not directly addressed, some children with high NSE levels may indeed have had SE, for Ko et al. indicate, “Patients with frequent attacks, or whose seizures were difficult to control, had higher levels of NSE in both the CSF and serum” (15). Tanabe et al. reported serum and CSF NSE levels in a cohort of 53 patients with febrile seizures, 36 with generalized seizures and the reminder with partial onset seizures (38). Only CSF NSE levels in patients with partial onset seizures showed a statistically significant correlation with seizure duration. However, a limitation of this study relates to the sampling points for both serum and CSF, which was limited to just one. In febrile seizures, Rodríguez Núñez et al. reported NSE levels in 90 children with febrile seizures, 73 with simple febrile seizures and 17 with complex febrile seizures. Neither group showed statistically significant changes, suggesting that neither type of seizure causes significant neuronal damage, at least early (28). Rabinowicz et al. reported serum NSE values after single complex partial and generalized tonic-clonic seizures during epilepsy video monitoring (26). They studied 25 subjects, 15 with epilepsy and 10 with nonepileptic seizures. The mean serum NSE level in four subjects after generalized tonic-clonic seizures was 16.5 ng/mL (range, 14–18 ng/mL), and the mean serum NSE after complex partial seizures was 10.32 ng/mL (range, 3–20 ng/mL). No NSE levels greater than 20 ng/mL were found. The mean serum NSE level for the four patients with tonic-clonic seizures increased from a baseline of 8.1 ng/mL to 16.5 ng/mL. In the group with complex partial seizures, three of nine patients had elevated serum NSE levels after
a single seizure, but for the group, the mean serum NSE level was not significantly elevated in those with complex partial seizures (26). NSE levels after individual tonic-clonic seizures are generally within normal limits or only mildly elevated. Buttner et al. evaluated patients with serum NSE levels at different time points after a single tonic-clonic seizure (1). NSE was sampled after 5 minutes and again at 6, 24, and 48 hours. NSE showed a diagnostic sensitivity of 55.6% and a positive predictive value of 100% at each time point. Similar findings were reported by Palmio et al. in 22 patients with single undiagnosed and untreated tonic-clonic seizures (24). Both serum and CSF samples were collected within 24 hours after a seizure (mean 15 hours), and values were within the normal range except in two patients. Interestingly, both patients had either prolonged or serial seizures, a finding that underscores once again the concept of prolonged seizures or repetitive seizures as a factor in NSE elevation. Suzuki et al. published the relationship between serum and CSF NSE values in 18 patients with West’s syndrome (37). They found no correlation between NSE levels and clinical response or seizure duration. Overall, NSE is less valuable as a marker of individual seizures and more relevant as a marker of prolonged or repetitive seizures—that is, in SE.
NSE in SE In 1995, the first prospective study of NSE in status was reported (5). In this study, 19 subjects with SE underwent serial NSE determinations at 24, 48, and 72 hours and 7 days after the diagnosis of SE was made. The mean peak serum NSE level was significantly elevated compared with that in normal controls (mean peak serum NSE, 24.87 ng/mL vs. 5.36 ng/mL, P = 0.0001). NSE levels peaked within 24 hours of diagnosis of SE, and for the group as a whole, the 24-hour serum NSE level was 17.75 ng/mL. Serum NSE levels peaked within 24 hours of the diagnosis of SE and remained above the upper limit of normal for the first 3 days after the diagnosis of SE, normalizing by the seventh day. NSE was elevated even in the absence of an acute neurologic insult. In the 11 (out of 19) patients who had remote symptomatic or idiopathic status (defined as no acute neurologic insult within 30 days), the mean peak serum NSE level was significantly higher than in controls (15.44 ng/mL vs. 5.36 ng/mL, P = 0.0001). Outcome was highly correlated with the peak serum NSE, and serum NSE was inversely correlated with the 1-week Glasgow Outcome Score (r = 0.6, P = 0.005). Further, duration was highly correlated with the peak serum NSE value. The mean duration of SE in those with normal NSE levels was 3.1 hours, versus 15.5 hours (P = 0.002). This provided the first prospective evidence that NSE met the critical requirements for a valid marker for status: the marker should
.: -
171
NSE in the major subtypes of SE Complex partial status epilepticus (CPSE) was once deemed to be an obscure and benign condition. Recent reports provide growing evidence that CPSE is indeed a common and potentially lethal form of SE (16). Krumholz et al. estimate that CPSE accounts for about 20% of cases of SE and have reported a series of 10 subjects with CPSE who had poor outcomes or permanent brain injury (16). Is serum NSE elevated in nonconvulsive SE (NCSE) and CPSE? In a prospective series of 11 subjects with remote symptomatic CPSE, we identified eight subjects with CPSE without an acute neurologic insult (remote symptomatic/ idiopathic) (7, 27). All patients met Treiman and DelgadoEscueta’s criteria for CPSE: recurrent complex partial seizures without full recovery of consciousness or a continuous epileptic twilight state with cycling between unresponsive and partially unresponsive phases lasting longer than 30 minutes, and an ictal EEG confirming recurrent epileptiform patterns (39). The mean peak NSE in our eight patients was 21.81 ng/mL, which is four times higher than in normal subjects or epileptic controls, and the mean duration of status was 15 hours (7). The surprisingly high NSE levels in CPSE likely reflect the long duration of CPSE, which averaged 15 hours in this group. The long durations of CPSE found by Krumholz et al. (16) and by our group (7) reflect a lack of recognition by family and emergency staff, a delay before treatment is initiated, and the common tendency not to treat CPSE as aggressively as GCSE. We believe that the high elevation of NSE provides further data to justify the treatment of CPSE as a potentially lethal emergency, with the potential for significant brain injury, a notion firmly supported by animal data (7, 9, 15). In our series of 31 subjects with SE, 12 patients met criteria for GCSE (9). Twelve subjects were identified with CPSE. Six patients were identified with myoclonic SE, characterized by continuous multifocal twitching in a comatose patient with an ictal EEG with continuous epileptic discharges or electrical seizures. One patient had absence status, characterized by a confusional state with a simultaneous continuous generalized spike-and-wave EEG pattern.
172
:
Figure 15.1 summarizes the NSE levels for the major subtypes and for normal and epileptic controls. The mean peak NSE level in the 31 patients was 22.17 ng/mL (SD 20.14 ng/mL), significantly higher than in the normal control group (5.02 ng/mL, P = 0.0001). Nineteen of the 31 patients had no neurologic insult and were classified as having remote symptomatic SE. The peak NSE level in the remote symptomatic SE group was 18.12 ng/mL, significanlty higher than in normal control subjects (P = 0.001). Of the 31 patients, 24 (77%) had a serum NSE level greater than 11 ng/mL, the upper limit of normal. The mean duration of SE in those with high serum NSE levels was 21.08 hours, compared with 6.14 hours in those with normal serum NSE levels (P = 0.03). The duration of SE was longer in those with an acute neurologic insult (30.73 hours vs. 9.49 hours, P = 0.04), and the outcome was significantly worse in those with an acute neurologic insult (1-week Glasgow Outcome Score 4.47 vs. 2.33, P = 0.003. The relationship between status subtype and duration is shown in Figure 15.2 (6). We believe the high NSE levels in CPSE are evidence that brain injury occurs in CPSE and point to a need for earlier treatment. The high levels of NSE in survivors of CPSE confirm the work by Fountain and Lothman in animals that CPSE causes brain injury (10). This finding echoes the sentiment of Krumholz et al. that CPSE is a medical emergency, with the potential to cause neuronal injury and permanent cognitive impairment (16). Educating family members about CPSE and its potential for lethality, at-home intervention with rectal diazepam, and earlier activation of the EMS system for individuals with prolonged confusion or clustering of seizures are steps that could be taken to minimize the morbidity from CPSE. Because CPSE represents about 25% of the 60,000–250,000 new cases of SE each year, such steps could have a major impact on public health.
Mechanism of NSE release Critical to an understanding of NSE as a marker of SE is its mechanism of release. Is NSE simply released by 30 23.9 ng/mL
be specific for the brain, and should correlate with the duration and the outcome. Problematically, seven of 19 subjects, some with a prolonged duration of SE, had normal NSE values. The frequent false negative values may indeed be a function of timing and sampling frequency. Samples were obtained at 24-hour intervals, some as late as 24 hours after the SE episode. Thus, more frequent samples, drawn early after the onset of SE, are likely to reduce the number of false negative values of serum NSE, and may improve its value as a predictor of outcome and severity of status (5).
20 14.1 10
5.6
5.02
NL
Epileptic
0 GTC
Complex
F 15.1 Relative values of NSE for normal controls and the major subtypes of SE. Values are expressed as the average peak NSE level for each group.
F 15.2 NSE level versus duration of SE for each subgroup. The mean NSE level is expressed in ng/mL (left axis), versus duration of SE in hours (right axis).
depolarizing neurons, independent of brain injury? Is NSE elevated in serum as a result of transfer from the CSF to the serum compartment? Does this transfer occur as a result of seizures or brain injury? Is the synthesis of NSE increased during seizures and SE? These are questions that need exploration. Schreiber et al. studied gene expression of NSE in rats exposed to kainic acid and found that NSE messenger RNA did not increase for the first 16 hours after the onset of SE (34). At 5 days, the amount of NSE mRNA was actually diminished in kainate-vulnerable regions. This observation supports the concept that the synthesis of NSE is not increased after injury or seizures. Rather, one can infer that CSF levels of NSE are increased by diffusion across a depolarized or injured cell membrane. Recent animal data indeed suggest that the elevated levels of NSE after SE are due to neuronal injury (34). Sankar et al. studied serum NSE levels in neonatal rat pups in a lithium pilocarpine model of SE (31). Serum NSE levels were substantially increased compared with levels in control rats. NSE from 4-week-old rats in SE ranged up to 35 ng/mL, compared with control values of 9.3 ng/mL. Serum NSE elevations were clearly associated with histologic evidence of neuronal injury in cingulate, piriform, and entorhinal cortex and hippocampus. One-weekold neonatal rats with low NSE levels suffered no significant neuronal injury. This provides support that not only is NSE elevated in SE, but when it is elevated, it is associated with brain injury (34). Elevated levels of NSE in the serum compartment may be explained by an increased permeability of the blood-
brain barrier (4). Correale recently reported a study of CSF NSE and blood-brain barrier permeability after SE (4). CSF NSE levels were significantly elevated compared with levels in controls, and the CSF/serum albumin quotient, a measure of the permeability of the blood-brain barrier, was substantially increased after SE. Thus, the elevations in serum NSE are likely due to increased permeability of the blood-brain barrier to NSE.
Other promising markers of status In addition to NSE, a variety of biologic markers of brain injury due to SE have been investigated. Biologic markers of SE include cortisol, lactate, endorphins, CPK, and N-acetylcysteine. Calabrese and DeLorenzo’s group have reported that serum cortisol was predictive of neurologic outcome after status, and more predictive than endorphin (3). In a cohort of 27 subjects with SE, Calabrese et al. sampled blood and CSF cortisol within 12 hours of the cessation of SE. They compared these values with values in seven controls with single or multiple seizures who were not in SE (3). The normal control group had a mean cortisol level of 520 nmol/L. Status patients had a mean cortisol level of 900 nmol/L. Cortisol was significantly correlated with global measures of outcome, the Glasgow Coma Scale score, and the Glasgow Outcome Score. Calabrese hypothesized not only that cortisol is a measure of the severe physiologic stress that occurs in SE, but also that elevations of cortisol may enhance brain injury through cortisol’s binding to receptors in hippocampus and through activation of phospholipase C
.: -
173
(3). Although cortisol is not a specific marker of brain injury, its role should be further studied. Another marker of brain injury that shows significant promise for clinical application is imaging of N-acetylaspartate (NAA) using MRI spectroscopy (9). Immunohistochemistry in the rat brain confirms that NAA is fairly specific to neurons and can be used to assess neuronal cell loss or injury (9, 22). In disorders known to cause neuronal death, such as stroke, global ischemia, and Alzheimer’s disease, the ratio of NAA to creatinine/phosphocreatinine is reduced. Ebisu’s group has studied NAA using a kainate model of SE in 11 rats (9). The absolute value of NAA was reduced significantly in rostral and caudal hippocampus, amygdala, and piriform cortex. Interestingly, there was no significant reduction in frontal or parietal cortex. This pattern of cell loss is typical in pathologic studies after kainate-induced status and provides clear in vivo evidence that SE causes cell loss and that MRI spectroscopy is a potentially powerful clinical tool. Other markers include CSF lactate, which is a marker of the degree of acidosis present in the brain after SE (2). CSF lactate levels are significantly elevated in patients with severe outcomes after SE. Mean lactate levels in status patients who died or who had poor functional recovery were 5.36 nmol/L, compared with 2.99 nmol/L in status patients with good outcome and only 1.60 nmol/L in normal controls. Although lactate is elevated partially as a function of intense muscle contraction, CSF lactate’s correlation with outcome is very promising (2).
Potential limitations of NSE and the need for further research NSE is a promising and exciting new marker of SE, but studies to date raise questions that need to be explored. In the study by DeGiorgio et al., seven of 19 subjects with SE had normal NSE levels (5). As noted earlier, this result could be explained by low sampling frequency, and the sensitivity of NSE may increase with more frequent and earlier sampling. Therefore, future studies should sample NSE immediately after the onset of status and at 30-minute to 1-hour intervals for the first 24 hours, which is the time period during which NSE peaks (5). Further, care should be taken to avoid using samples which are hemolyzed, which can cause a spurious elevation in the NSE level. The central question about NSE levels in SE is whether NSE is elevated after seizures, independent of neuronal injury. One could speculate that the elevated levels of serum NSE are primarily due to increased diffusion of NSE across a more permeable blood-brain barrier, causing a simple transfer of NSE from the CSF compartment to the serum compartment. This explanation would not account for the significant increase in CSF NSE seen after SE but could
174
:
explain the mild elevations in serum NSE seen after individual generalized tonic-clonic seizures. As noted earlier, data provided by Sankar et al. support the hypothesis that elevated levels of NSE after SE are associated with neuronal injury (31). Sankar et al. showed that after SE, elevations in serum NSE are accompanied by histologic evidence of neuronal injury. In animals with normal NSE levels, the histology remained normal. Clearly, this is an area for further study, and the relative magnitudes of NSE after SE and after single seizures should be studied in larger numbers.
Summary NSE is a marker of neuronal injury that is elevated after focal and global ischemia. Serum NSE levels are elevated after GCSE and CPSE, conditions known to be associated with neuronal injury. Serum NSE is correlated with the duration and outcome of GCSE, and animal data confirm that elevated serum levels of NSE in SE correlate with histologic evidence of neuronal injury. Further study of NSE as a marker of status is clearly indicated. NSE may provide new insight into the different subtypes of status and may accelerate the search for better treatments for this lethal and disabling neurologic emergency. REFERENCES 1. Buttner, T., B. Lack, M. Jager, W. Wunsche, W. Kuhn, T. Muller, et al. Serum levels of neuron-specific enolase and s100 protein after single tonic-clonic seizures. J. Neurol. 1999; 246:459–461. 2. Calabrese, V. P., H. D. Gruemer, K. James, N. Hranowsky, and R. J. DeLorenzo. Cerebrospinal fluid lactate levels and prognosis in status epilepticus. Epilepsia 1991;32:816–821. 3. Calabrese, V. P., H. D. Gruemer, H. L. Tripathi, W. Dewey, C. A. Fortner, and R. J. DeLorenzo. Serum cortisol and cerebrospinal fluid beta-endorphins in status epilepticus: Their possible relation to prognosis. Arch. Neurol. 1993;50:689–693. 4. Correale, J., A. L. Rabinowicz, C. N. Heck, C. M. DeGiorgio, W. J. Loskota, and C. M. DeGiorgio. Status epilepticus increases CSF levels of neuron-specific enolase and alters the blood-brain barrier. Neurology 1998;50:1388–1391. 5. DeGiorgio, C. M., J. D. Correale, P. S. Gott, et al. Serum neuron-specific enolase in human status epilepticus. Neurology 1995;45:1134–1137. 6. DeGiorgio, C. M., C. N. Heck, A. L. Rabinowicz, P. S. Gott, T. Smith, and J. Correale. Serum neuron-specific enolase in the major subtypes of status epilepticus. Neurology 1999;52: 746–749. 7. DeGiorgio, C. M., P. S. Gott, A. L. Rabinowicz, C. N. Heck, T. D. Smith, and J. Correale. Neuron-specific enolase, a marker of acute neuronal injury, is increased in complex partial status epilepticus. Epilepsia 1996;37:606–609. 8. DeGiorgio, C. M., U. Tomiyasu, P. S. Gott, and D. Treiman. Hippocampal pyramidal cell loss in human status epilepticus. Epilepsia 1992;33:23–27. 9. Ebisu, T., W. D. Rooney, S. H. Graham, M. W. Weiner, and A. A. Maudsley. N-acetylaspartate as an in vivo marker of neu-
10. 11.
12. 13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
ronal viability in kainate-induced status epilepticus: 1H magnetic resonance spectroscopic imaging. Cereb. Blood Flow Metab. 1994;14:373–382. Fountain, N. B., and E. W. Lothman. Pathophysiology of status epilepticus. J. Clin. Neurophysiol. 1995;12:326–342. Hatfield, R., and R. McKernan. CSF neuron-specific enolase as a quantitative marker of neuronal damage in a rat stroke. Brain Res. 1992;577:249–252. Holmes, G. Do seizures cause brain damage? Epilepsia 1991; 32:S14–S28. Karkela, J., E. Bock, and S. Kaukinen. CSF and serum brain specific creatinine kinase isoenzyme (CK-BB), neuron-specific enolase and neural cell adhesion molecule as prognostic markers for hypoxic brain injury after cardiac arrest in man. J. Neurol. Sci. 1993;116:100–109. Kittaka, M., S. L. Giannotta, V. Zelman, et al. Attenuation of brain injury and reduction of neuron-specific enolase by nicardipine in systemic circulation following focal ischemia and reperfusion in a rat model. J. Neurosurg. 1997;87: 731–737. Ko, F. J., C. H. Chiang, C. C. Wu, and L. Wu. Studies of neuron-specific enolase levels in serum and cerebrospinal fluid of children with neurological diseases. Gaoxiong Yi Xue Ke Xue Za Zhi 1990;6:137–143. Krumholz, A., G. Y. Sung, R. S. Fisher, E. Barry, G. K. Bergey, and L. M. Grattan. Complex partial status epilepticus accompanied by serious morbidity and mortality. Neurology 1995;45:1499–1504. Lafon-Cazal, M., I. Bougault, R. Steinberg, J. P. Pin, and J. Bockaert. Measurement of y-enolase release, a new method for selective quantification of neurotoxicity independently from glial lysis. Brain Res. 1992;593:63–68. Lowenstein, D. H., and B. K. Alldredge. Status epilepticus at an urban public hospital in the 1980s. Neurology 1993;43: 483–488. Marangos, P. J., D. Schmechel, A. M. Parma, R. L. Clark, and F. K. Goodwin. Measurement of neuron-specific (NSE) and non-neuronal (NNE) isoenzymes of enolase in rat, monkey and human nervous tissue. J. Neurochem. 1979;33: 319–329. Marangos, P. J., A. P. Zis, R. L. Clark, and F. K. Goodwin. Neuronal, non-neuronal and hybrid forms of enolase in brains: Structural, immunological and functional comparisons. Brain Res. 1978;150:117–133. Meldrum, B. S. Metabolic factors during prolonged seizures and their relation to nerve cell death. Adv. Neurol. 1983;34: 261–275. Moffett, J. R., M. A. Namboodiri, C. B. Cangro, and J. H. Neale. Immunohistochemical localization of N-acetylaspartate in rat brain. NeuroReport 1991;2:131–134. Pahlman, S., T. Esscher, P. Bergvall, et al. Purification and characterization of human neuron-specific enolase: Radioimmunoassay development. Tumor Biol. 1984;5:127– 139. Palmio, J., J. Peltola, P. Vuorinen, S. Laine, J. Suhonen, and T. Keränen. Normal CSF neuron-specific enolase and S-100 protein levels in patients with recent noncomplicated tonicclonic seizures. J. Neurol. Sci. 2001;183:27–31. Persson, L., H. G. Hardemark, J. Gustafsson, G. Rundstrom, I. Mendel-Hartvig, T. Esscher, et al. S-100 protein and neuronspecific enolase in cerebrospinal fluid and serum: Markers of cell damage in human central nervous system. Stroke 1987;18:911–918.
26. Rabinowicz, A. L., J. Correale, R. B. Boutros, W. T. Couldwell, C. W. Henderson, and C. M. DeGiorgio. Neuronspecific enolase is increased after single seizures during inpatient video/EEG monitoring. Epilepsia 1996;37:122–125. 27. Rabinowicz, A. L., J. Correale, K. Bracht, T. Smith, and C. M. DeGiorgio. Neuron-specific enolase is elevated after nonconvulsive status epilepticus. Epilepsia 1995;36:475–479. 28. Rodríguez-Núñez, A., E. Cid, J. Rodríguez-García, F. Camiña, S. Rodríguez-Segade, and M. Castro-Gago. Cerebrospinal fluid purine metabolite and neuron-specific enolase concentrations after febrile seizures. Brain Dev. 2000;22:427–431. 29. Roine, R. O., H. Somer, M. Kaste, L. Viinikka, and S. L. Karonen. Neurological outcome after out-of-hospital cardiac arrest. Arch. Neurol. 1989;46:753–756. 30. Royds, J. A., W. R. Timperley, and C. B. Taylor. Levels of enolase and other enzymes in the cerebrospinal fluid as indices of pathologic change. J. Neurol. Neurosurg. Psychiatry 1988;19: 1140–1144. 31. Sankar, R., D. H. Shin, and C. G. Wasterlain. Serum neuronspecific enolase is a marker for neuronal damage following status epilepticus in the rat. Epilepsy Res. 1997;28:129–136. 32. Schaarschmidt, H., H. W. Prange, and H. Reiber. Neuronspecific enolase concentrations in blood as a prognostic parameter in cerebrovascular diseases. Stroke 1994;24:558– 565. 33. Schmechel, D., P. J. Marangos, A. P. Zis, M. Brightman, and F. K. Goodwin. Brain enolases as specific markers of neuronal and glial cells. Science 1978;199:313–315. 34. Schreiber, S. S., N. Sun, G. Tocco, M. Baudry, and C. M. DeGiorgio. Expression of neuron-specific enolase in adult rat brain following status epilepticus. Exp. Neurol. 1999;159: 329–331. 35. Shimizu, A., F. Suzuki, and K. Kato. Characterization of alpha alpha, beta beta, gamma gamma and alpha gamma human enolase isoenzymes, and preparation of hybrid enolases from homodimeric forms. Biochem. Biophys. Acta 1983; 748:278–284. 36. Steinberg, R., C. Gueniau, H. Scarna, et al. Experimental brain ischemia: Neuron-specific enolase level in cerebrospinal fluid as an index of neuronal damage. J. Neurochem. 1984;43: 19–24. 37. Suzuki, Y., Y. Toribe, M. Goto, T. Kato, and Y. Futagi. Serum and CSF neuron-specific enolase in patients with West syndrome. Neurology 1999;53:1761–1764. 38. Tanabe, T., S. Suzuki, K. Hara, S. Shimakawa, E. Wakamiya, and H. Tamai. Cerebrospinal fluid and serum neuron-specific enolase levels after febrile seizures. Epilepsia 2001;42:504– 507. 39. Treiman, D. M., and A. V. Delgado-Escueta. Complex partial status epilepticus. In A. V. Delgado-Escueta, C. G. Wasterlain, D. M. Treiman, and R. J. Porter, eds. Status Epilepticus: Mechanisms of Brain Damage and Treatment. Adv. Neurol. 1983;34:69–81. 40. Working Group on Status Epilepticus. Treatment of convulsive status epilepticus: Recommendations of the Epilepsy Foundation of America Working Group on Status Epilepticus. JAMA 1993:270:854–859. 41. Zeltzer, P. M., A. M. Parma, A. Dalton, S. E. Siegal, P. J. Marangos, H. Sather, et al. Raised neuron-specific enolase in serum of children with metastatic neuroblastoma. Lancet 1983(Aug. 13):361–363. 42. Zomzely-Neurath, C. E. Nervous-system-specific proteins: 143-2 protein, antigen alpha and neuron-specific enolase. Scand. J. Immunol. Suppl. 1982;9:1–40.
.: -
175
16
Brain Imaging in Status Epilepticus
.
Introduction Brain imaging is essential in the clinical diagnosis and therapy of status epilepticus (SE) and provides a highly useful set of tools for clinical and experimental investigations of the pathophysiology of SE. After a first episode of generalized convulsive SE (GCSE) is controlled, emergency cranial X-ray computed tomography (CT) is indicated to exclude conditions that require immediate neurosurgical intervention. Complex partial SE (CPSE) and simple partial SE (SPSE) also require structural brain imaging. Brain magnetic resonance imaging (MRI) should be performed on a nonemergency basis days or weeks after CT, to detect lesions missed on CT and to add diagnostic specificity to CT findings. Partial SE often causes focal cerebral T2 signal increases, which can be misdiagnosed as neoplasia, with the patient subjected to inappropriate surgical treatment, but which usually resolve after several weeks. Permanent brain injury due to GCSE, and possibly also to CPSE or SPSE, can be demonstrated with structural MRI and studied with a variety of imaging techniques. The pathophysiology of SE can be studied in parallel clinical-experimental research, using brain imaging in human epilepsies and experimental models of epilepsy. In humans or animals, positron emission tomography (PET), single-photon emission computed tomography (SPECT), and functional MRI (fMRI) map regional synaptic activity levels, as reflected in glucose metabolic and blood flow alterations, which are particularly useful in mapping partial SE. The severity and distribution of some metabolic changes induced by SE can be measured in humans and animals, by performing lactate imaging with MR spectroscopy (MRS) or diffusion-weighted MRI (dwMRI), soon after GCSE is terminated. The greatest difference between imaging studies of human epilepsies and experimental epilepsies lies not in the imaging techniques themselves but rather in the ability to image untreated, progressive dysfunctions of SE and to perform baseline imaging before the onset of SE, a protocol that is ethically acceptable only in animal models. Brain imaging is useful for determining the early and late structural and metabolic sequelae of SE. Conventional brain imaging is based on four tomographic techniques, each of which detects one type of transmitted
or emitted energy to construct an anatomic map of brain structure or function: X-ray CT, nuclear magnetic resonance scanning (including structural MRI, fMRI, MRS, and dwMRI), PET, and SPECT. These techniques are noninvasive and capable of imaging the entire brain simultaneously (although MRS often samples only part of the brain, for technical reasons), with best spatial resolution ranging from approximately 1 mm to 10 mm. The anatomically configured images most often are viewed as a series of planar slices (tomograms), but they can also be reconstructed as threedimensional surfaces or fields. Each small-volume element (voxel) of these brain images is displayed in a color or grayscale intensity that represents a single value for the particular imaging modality. In general, other brain imaging techniques differ fundamentally from these four techniques, either because other techniques are invasive (e.g., autoradiography, which requires tissue destruction, and optical imaging, which requires craniotomy and incision of the dura) or because they display data that do not represent a single measured value for each voxel (e.g., volumetric dipole modeling of electrophysiologic data, which displays a set of possible solutions to the “inverse problem” of electrophysiologic signal generation). The methodological principles of CT, MRI-MRS, PET, and SPECT in brain imaging and their applications in epilepsy have been reviewed in detail elsewhere (13, 68, 93, 108). This chapter reviews clinical studies of SE that use the four conventional brain imaging techniques. Additionally, this chapter reviews studies that use these techniques in experimental models of SE, either to elucidate the basis of SE-related neuroimaging abnormalities that occur in humans or to study the pathophysiology of SE itself. Autoradiography and other invasive techniques have demonstrated regional alterations in brain perfusion, glucose metabolism, inhibitory and excitatory neurotransmitter concentrations, and neuroreceptor availabilities during and following experimental SE, and have demonstrated reversible and irreversible neuronal injuries due to SE (62, 83, 110, 205). Brain lesions due to injuries that generate experimental SE, and the associated biochemical and microphysiologic dysfunctions, cannot be studied directly in humans. In some experimental SE models, imaging maps a specific
:
177
abnormality to sites that are subsequently shown to have neuronal loss. If the same type of imaging maps the same abnormality following clinical SE, one may reasonably infer that a human likely has localized neuronal loss that cannot be directly measured during a patient’s life. In particular, MRS mapping of N-acetylaspartate (NAA) density has been proposed as an in vivo surrogate for histologic neuronal densitometry. As discussed later in the chapter, transitory lactate elevations on MRS and water diffusibility decreases on dwMRI also may mark sites of permanent SE-induced brain injury. This chapter describes currently established neuroimaging applications (mainly structural brain imaging) in the clinical care of SE, followed by a review of imaging-based pathophysiologic studies in human and experimental SE.
Neuroimaging in the clinical diagnosis of SE G C SE Detection of structural brain lesions in the diagnosis of GCSE Structural brain imaging is essential for the etiologic diagnosis of GCSE. Acute intracranial hemorrhage of any type (epidural, subdural, subarachnoid, lobar, diencephalic, or posterior fossa) may present with GCSE as the initial manifestation. Lobar hemorrhages (Figure 16.1) appear particularly likely to cause GCSE (182). Other acute, subacute, or chronic structural brain lesions also may first come to clinical attention due to GCSE (Figures 16.2 to 16.5). Emergency neurosurgical intervention is required for some acute or chronic-progressive lesions that are associated with GCSE in order to prevent death or severe, permanent brain injury. Such lesions can be effectively diagnosed only with brain CT or MRI. Finding a possible nonstructural cause of GCSE does not exclude the presence of a structural cause of GCSE. For example, withdrawal of chronic antiepileptic drug (AED) therapy in a patient with a history of single grand mal seizures might precipitate GCSE, but the finding of an unexpectedly low AED level at the time of GCSE does not in itself exclude a brain lesion (see Figure 16.3). Brain imaging should be performed only after GCSE has been fully controlled, however. Delays in controlling GCSE may permit irreversible brain injury to occur due to SE-related excitotoxicity, even in the absence of a lesion that might be detected with neuroimaging. The causes of GCSE can be categorized as acute symptomatic, remote symptomatic, and idiopathic (64). Acute cerebral lesions obviously can act as acute symptomatic causes of GCSE. Some chronic cerebral lesions also can act as acute symptomatic causes of GCSE, based on acute progression in associated mass effect, intravascular thrombogenic effect, or other acute effects of chronic lesions. Remote symptomatic causes of GCSE include chronic lesions of the same types that can cause partial-onset seizures or
178
:
F 16.1 Acute cerebral hemorrhage detected with CT, following GCSE. CT was performed after GCSE was controlled in a 63-year-old man with no prior history of seizures. The CT images showed two areas of acute hemorrhage, in the left insula and the left cingulate gyrus. The emergency room physician had not obtained a history of head injury or other acute insults or illnesses from the patient’s family. Several days after SE was controlled, the patient’s postictal cognitive function improved, and he remembered falling headfirst on a slippery sidewalk, just prior to prolonged loss of consciousness. Brain left is on image right.
generalized-onset seizures without SE. In some individuals, such lesions may have been identified by imaging before the onset of GCSE, owing to the earlier occurrence of isolated seizures or of other neurologic signs or symptoms. In other cases GCSE may be the initial clinical manifestation of a chronic lesion that first brings the lesion to medical attention. Table 16.1 contains a partial list of such acute and chronic lesions, emphasizing the lesions that are most often associated with GCSE. Some lesions that are discovered during evaluation for GCSE represent part of a larger syndrome, including glial hamartomas in tuberous sclerosis and infarctions in the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS). Patients with MELAS often present with GCSE, CPSE, or epilepsia partialis continua (80, 114, 138, 163). In MELAS, acute infarction can have the same initial MRI appearance as does the transitory, focal cerebral edema of partial SE (a phenomenon that is discussed later in the
F 16.2 Chronic focal encephalomalacia detected with CT, following GCSE. CT was performed after GCSE was controlled in a 35-year-old man with no prior history of seizures. The CT images showed chronic focal encephalomalacia of the right frontal lobe. The emergency room physician did not obtain a history of any recent insults or illnesses from the patient’s family members, but they noted that he had been in a coma for about 2 days after a closed head injury in a motor vehicle accident 5 years earlier. He had been clumsy with the left hand since then, and examination shortly after termination of GCSE revealed mild left arm weakness without reflex changes. Brain left is on image right.
chapter), but follow-up MRI will clarify whether infarction occurred in association with SE. Similarly, the cerebral vasospasm of eclampsia and other forms of hypertensive encephalopathy can cause multifocal cerebral ischemia and edema, and multifocal cerebral edema might also be caused by SE in itself (4, 198), but follow-up MRI will clarify whether macroscopic foci of chronic encephalomalacia developed. Occasionally SE is the initial manifestation of a syndrome of multisystem disease, such as sarcoidosis or the hemorrhagic shock-encephalopathy syndrome, and the associated brain imaging abnormalities may be useful in diagnosing and treating the underlying syndrome (132, 188). Sometimes GCSE occurs late in the course of demyelinating or neurodegenerative conditions diagnosed after dementia or other dysfunctions were evident, and imaging will simply reflect the underlying disorder (56, 171). Rarely, in patients with medically refractory SE, surgical intervention
F 16.3 Acute hydrocephalus detected with CT, following GCSE. CT was performed after GCSE was controlled in a 23year-old woman with mild mental retardation. The CT images showed acute hydrocephalus. Her parents gave the emergency room physician a history of nonprogressive developmental delay of unknown etiology, and of three grand mal seizures between ages 12 and 18 years. She was chronically receiving phenytoin, and her phenytoin level was 5.5 mg/mL during the episode of GCSE, but previously had averaged 17 or 18 mg/mL. There was no history of recent headaches or other new complaints, nor were changes in alertness, gait, or other behaviors observed by the parents prior to the onset of GCSE. Ventriculoperitoneal shunting was performed emergently following CT, and no persisting, new deficits were apparent on examination 1 week later. Brain left is on image right.
might be supported by imaging abnormalities, although not all such patients have causative lesions (33, 104, 133). A patient cannot be considered to have a fully established diagnosis of idiopathic GCSE unless optimal brain imaging (with MRI) has excluded subtle malformations of cortical development and other cerebral lesions (see Figure 16.5). The recognition of subtle lesions is important in prognostication with regard to seizure recurrence, and is also useful in selecting the AED or surgical therapy that is most appropriate to the particular epileptic syndrome (174). Thus, optimal brain imaging is required for the full clinical diagnosis of GCSE, and is also necessary for the adequate diagnosis of every case of GCSE included in epidemiologic studies that address etiology.
:
179
F 16.4 Glioma detected with MRI (but not with CT), following GCSE. A normal brain CT was obtained after GCSE was controlled in a 59-year-old man who had no prior history of seizures. The emergency room physician attributed GCSE to cessation of chronic ethanol use 3 days before the onset of GCSE. After inpatient substance abuse treatment, the patient was brought to the epilepsy clinic by his wife for a second opinion on indica-
tions for continuing phenytoin, in light of ongoing abstinence from ethanol. At that time the neurologic examination and interictal EEG were normal. Brain MRI was performed to complete the evaluation of GCSE. MRI showed a right frontal lesion with mild mass effect and mild edema of adjacent subcortical white matter. Biopsy revealed a fibrillary astrocytoma, which was then resected. Brain left is on image right.
F 16.5 Malformation of cortical development detected with MRI (but not with CT), following GCSE. A 25-year-old woman presented in GCSE, in the setting of focal motor (left arm clonic) and grand mal seizures of 19 years’ duration. Phenytoin and valproate levels were in the patient’s usual range, and no acute exacerbating factors were identified. After control of GCSE, a brain CT scan, with and without contrast, was obtained and was
normal, as it had been on numerous earlier occasions. She then underwent brain MRI, which revealed apparent focal cortical dysplasia. These T1-weighted coronal images show a widespread region of right frontal lobe malformation, with reduction in gyration, cortical thinning, and multiple foci of apparent subcortical neuronal heterotopia over the right frontal lobe. Brain left is on image right.
T 16.1 Structural neuroimaging of macroscopic cerebral lesions associated with status epilepticus Typical X-Ray CT Features Acute–Subacute Cerebrovascular Disease and Trauma Acute/subacute/chronic Hyperdense/isodense/hypodense blood in intracranial hemorrhage brain tissue, or in subarachnoid, subdural, or epidural space, often with mass effect
Acute cerebral infarction
No changes, or hypodense lesion (sometimes with hyperdense puncta due to small hemorrhages)
Hypertensive encephalopathy (including eclampsia)
No changes, or single or multifocal hypodense (ischemic) or hyperdense (hemorrhagic) lesion(s)
Acute anoxic encephalopathy (cardiorespiratory arrest before GCSE)
No changes, or widespread indistinctness of gray-white junction
Chronic, Pre- or Postnatal Infarction and Trauma Encephalomalacia Focal atrophy with hypodense tissue
Porencephaly
Water-density, intra-axial cyst, without rim enhancement
Ulegyria
Rarely detected
Schizencephaly
Single deep cleft extending from a dorsolateral cortical surface to a lateral ventricle
Infectious or Autoimmune Processes Acute meningitis Chronic meningitis Cerebral abscess Acute bihemispheric encephalitis
Acute limbic encephalitis due to herpesvirus
Meningeal enhancement sometimes detected Meningeal enhancement sometimes detected Water-density, intra-axial cyst, with rim enhancement No changes or hypodense lesion (sometimes with hyperdense puncta due to small hemorrhages) Normal or slight unilateral temporal enhancement
Rasmussen’s encephalitis
Normal or slight unilateral cerebral enhancement early in course; unilateral encephalomalacia later
Cerebral cysticercosis
Punctate or small areas of lucency and/or calcification, usually multiple
Typical MRI Features
Mixed paramagnetic effects (T1 and T2 decreases) and protein effects (T1 increases and T2 decreases) of blood in brain tissue, or in subarachnoid, subdural, or epidural space, varying with age of hemorrhage; often mass effect or adjacent cerebral edema Focal area of T1 decrease and T2 increase, often with adjacent edema, sometimes with punctate T1–T2 signal decreases due to small hemorrhages Multifocal bihemispheric foci of T1 decrease and T2 increase, often with adjacent edema, sometimes with punctate T1–T2 signal decreases due to small hemorrhages Generalized or multifocal bihemispheric T1 decrease and T2 increase
Focal atrophy with T2 increase and T1 decrease, often with paramagnetic effect of hemosiderin (T2 and T1 decreases) MRI often gives more specific anatomic correlation of cysts, and more clearly excludes mural nodules and other features of nonporencephalic cysts Focal T2 increases and T1 decreases at sulcal bases, clearly distinguishable from neoplasia Same as X-Ray CT, but MRI shows that the cleft is lined with gray matter; MRI may demonstrate additional anomalies, including adjacent focal cortical dysplasias Meningeal enhancement consistently detected Meningeal enhancement consistently detected CSF-intensity, intra-axial cyst, with rim enhancement Multifocal or widespread cortical T2 increase, often with T1 decrease, over both hemispheres T2 signal increase, with T1 signals decreased, over mesial temporal, insular, inferior frontal, and/or cingulate cortex; alterations usually unilateral or markedly asymmetric T2 signal increased, with T1 signals decreased, over precentral gyrus and adjacent areas unilaterally, early in course; increasingly widespread signal changes and progressive atrophy later in course Punctate or small areas of T1 signal decrease and T2 signal increase, usually multiple (continued )
:
181
T 16.1 (continued)
Intracranial Neoplasm Astrocytoma
Typical X-Ray CT Features
Typical MRI Features
Solid components: hypodense lesion, often partially enhancing, often with mass effect Cystic components: water-density cyst, sometimes with enhancing mural nodule
Solid components: T2 signal increased, with T1 signals decreased, increased or isointense to surrounding brain, often with mass effect and adjacent edema Cystic components: T1 and T2 signals isointense with CSF, but proton density signals may be more intense for cystic regions than CSF Similar to astrocytoma, but often has greater signal heterogeneity, more calcification, and a more superficial location Readily detected, but no features distinct from those of gliomas Similar to astrocytoma, except that adjacent edema is rare Meningeal thickening or mass, usually with enhancement Gadolinium useful in detecting small cerebral metastases, unlike primary cerebral neoplasms
Oligodendroglioma
Similar to astrocytoma, but calcification may cause punctate hyperdensities
Ganglioglioma and gangliocytoma
Often in inferior temporal areas, obscured by beam-hardening artifacts
Dysembryoplastic neuroepithelial tumor Meningioma Cerebral metastasis Hamartoma Arteriovenous malformation
Extra-axial, intracranial mass, usually with enhancement Single or multiple enhancing lesions, often with mass effect Hypodense lesion, with enhancing curvilinear components
Cavernous angioma
Rarely detected
Glial hamartoma (isolated, or multiple in tuberous sclerosis)
Hypodense lesion, without enhancement, without mass effect
Cortical Dysplasia Focal cortical dysplasia
Rarely or never detected
Regional heterotopia and other dysplasias
Rarely or never detected
Band heterotopia
Rarely or never detected
Focal polymicrogyria
Rarely or never detected
Bilateral perisylvian malformation Hemimegalencephaly
Occasionally detected, with nonspecific findings of enlarged sylvian fissures Moderate to marked enlargement of part or all of one hemisphere
Lissencephaly
Variable degrees of absence of cortical gyration
182
:
Complex curvilinear signal voids; may be adjacent to cerebral gliosis (T2 increased, T1 decreased) or hemosiderin deposition (T1 and T2 decreased) Core of inhomogeneous T1 and T2 signal increases and decreases, rimmed by paramagnetic effect of hemosiderin (T2 and T1 decreases) Poorly demarcated but discrete lesion with T2 increase and T1 isointensity, without mass effect, in cortex and white matter Small or widespread areas of cortical irregularity (as cortical thinning or thickening) and subcortical neuronal ectopia, of T2 increase with T1 isointense to surrounding brain, less discrete than glial hamartomas Small or widespread areas of subcortical neuronal ectopia, as T1 decreases and T2 increases in subcortical white matter; regional gyration of cortex may be increased (polymicrogyria) or decreased (pachygyria) Bilateral strips of subcortical neuronal ectopia, as T1 decreases and T2 increases in subcortical white matter One or more regions of cortex with increased density of sulci and narrowed gyral crests Bilateral enlargement of the sylvian fissures, with bilateral opercular polymicrogyria Same as X-ray CT, but MRI shows that cortex is thickened and gyri are shallow or absent, with areas of prolonged T1 and T2 signal in cortex and white matter Variable degrees of absence of cortical gyration, usually generalized
T 16.1 (continued)
Phakomatoses Sturge-Weber syndrome
Neurofibromatosis Tuberous sclerosis
Other Pathology Acute hydrocephalus
Typical X-Ray CT Features
Typical MRI Features
Hemicerebral or lobar atrophy, often with linear cortical calcification, and enhancement of overlying meninges
Hemicerebral or lobar atrophy, often with linear cortical T1 and T2 decreases, enhancement of overlying meninges, and enhancing choroid plexus nodularity Single or multiple enhancing cortical-subcortical masses Variably small or large regions of T1 decreases and T2 increases in subcortical white matter, often patchy or discretely nodular, often near ventricles, and often extending into cortex with variable disturbances of cortical thickness and gyration
Single or multiple enhancing corticalsubcortical masses Variably small or large regions of hypodensity in subcortical white matter, often near ventricles
Ventriculomegaly, often with mild hypodensity of periventricular white matter; sometimes detects mass lesion obstructing CSF flow
Hippocampal sclerosis
Rarely or never detected
Hemiconvulsion-hemiplegiaepilepsy syndrome
Unilateral hemispheric atrophy
Limbic encephalitis due to paraneoplastic syndrome
Normal or slight unilateral temporal enhancement
Etiologic diagnosis of GCSE with CT versus MRI Brain MRI has superseded CT in essentially all nonemergency cerebral structural evaluations of epilepsy, owing to (1) the superior spatial resolution of MRI, (2) the presence of beamhardening artifacts that obscure tissues adjacent to densely calcified bone on CT, and (3) the more specific characterization of structural details with MRI than with CT. Several types of signal (based on several physical characteristics of protons and on water density in brain tissue) determine regional image intensity on brain MRI, whereas only one type of signal (attenuation of X-rays, based on tissue electron density) determines image intensity on CT. The identification of internal inhomogeneities of solid or cystic lesion structure can greatly increase the specificity of lesion diagnosis, and such inhomogeneities often are detected with MRI and not with CT. Among 18 children with recurrent SE, CT demonstrated cerebral lesions in 18% and brain MRI did so in 55% of cases (74). Nonetheless, cranial CT is the preferred neuroimaging modality for emergency evaluation in GCSE, because (1) CT detects essentially all of the lesions and other
Ventriculomegaly, with T1 decrease and T2 increase of periventricular white matter; sometimes detects lesion obstructing cerebral aqueduct or other sites that was not visualized with CT Focal hippocampal atrophy with T2 increase, often with T1 decrease and loss of internal architecture, and sometimes with atrophy of adjacent neocortex or other extrahippocampal abnormalities Unilateral hemispheric atrophy, usually with greater atrophy of cortical than of subcortical gray matter T2 signal increased, with T1 signals decreased, over mesial temporal, insular, inferior frontal and/or cingulate cortex; alterations usually unilateral or markedly asymmetric
structural pathologies that require emergency neurosurgical intervention (see Table 16.1), (2) CT is available at all times in emergency departments and other clinical settings that are capable of supporting the initial care of patients with GCSE, whereas MRI is less widely available, (3) CT can be performed safely and rapidly in individuals who have ferromagnetic implants or other contraindications to MRI (such as cardiac pacemakers), and (4) CT is less expensive than MRI. In many cases it will be desirable to perform brain MRI following CT in patients with GCSE, either because MRI can demonstrate cerebral lesions that are not detected with CT or because MRI can provide additional data to increase diagnostic specificity for characterization of a lesion that was initially detected with CT (see Table 16.1). Some of these lesions may require timely, although not emergency, neurosurgical therapy (e.g., Figure 16.4). Recognition of these lesions also may contribute to determination of optimal medical therapy and to prognostication. Brain MRI usually is not performed urgently in patients whose brain CT scan is normal after SE and whose episode of GCSE is found to
:
183
be attributable to a particular nonlesional cause of GCSE. In particular, for patients with previously diagnosed epilepsy, post-GCSE MRI usually would not be performed if brain MRI had already been performed before the episode of GCSE and if the GCSE was attributable to withdrawal of AED therapy; even in such situations, repeating brain MRI after SE might be indicated by special considerations, such as new focal findings on the neurologic examination following SE. On the other hand, an episode of GCSE may have more than one cause. In particular, the discovery of marked decreases in AED levels at the time of GCSE compared with previously higher levels in individuals with established epilepsies should not lead one to assume that medication noncompliance was the sole cause of SE (e.g., Figure 16.3). Some might argue that MRI should be performed in all adults with GCSE who have not previously or recently undergone MRI, even when the brain CT is normal and a metabolic or other potential cause of GCSE is present. Prospective observational or randomized studies have not been completed to establish the sensitivity and specificity of brain CT or MRI in the evaluation of GCSE. Nonetheless, it is clear that standard neurologic practice in the United States requires the performance of CT in the full evaluation of GCSE (or, alternatively, the specific delineation of reasons why CT is not necessary in the particular individual). The Working Group on Status Epilepticus of the Epilepsy Foundation of America published the recommendation that all adults with GCSE should undergo brain structural imaging unless definitive brain imaging has previously been performed and there is nothing to suggest new pathology beginning after previous imaging (37). This position is consistent with standard practice in the United States and is not controversial. The Working Group suggested that not all children with GCSE necessarily require brain imaging at any point after GCSE, but it did not provide specific criteria for identification of those children with GCSE who will never need to undergo CT or MRI. Despite consensus among neurologists concerning the importance of neuroimaging to detect causative lesions after GCSE is controlled, many emergency department physicians do not always request CT after GCSE. A survey of some 100 emergency physicians at the 1996 annual meeting of the American College of Emergency Physicians revealed that 71% of respondents requested brain CT or MRI for all newonset SE, while 29% requested brain imaging only if SE was accompanied by focal neurologic signs or history of cancer (E. Sloan, personal communication). Neurologists who see patients following emergency room care of GCSE must not assume that brain imaging was previously performed. My personal experience suggests that when a neurologist is asked to evaluate an adult who has had GCSE within the past year and who has never undergone brain imaging (including emergency CT, following the initial therapy of SE), most would order brain MRI. When faced with an adult who
184
:
has had an episode of GCSE within the last several days and who did not undergo brain imaging after this episode of GCSE but did have technically adequate brain imaging performed before this episode of GCSE, neurologists often consider these factors to support performance of post-GCSE imaging: (1) evidence of new (post-SE) transitory or persisting focal cerebral dysfunction on the history or physical examination, (2) new, persisting generalized cerebral dysfunction identified on the history or examination, (3) absence of AED withdrawal or other explanation for the occurrence of GCSE, (4) refractoriness of GCSE to initial therapy, (5) early recurrence of GCSE, (6) new difficulty in controlling isolated convulsive or nonconvulsive seizures after GCSE, and (7) new, unexplained abnormalities on interictal EEG after GCSE. When asked to evaluate a child who has had an episode of GCSE within the past several days and who has never undergone brain imaging, neurologists often consider these factors to support performance of post-GCSE imaging: (1) evidence of focal seizure onset, (2) evidence of transitory or persisting focal cerebral dysfunction on the history or examination, (3) evidence of persisting generalized cerebral dysfunction on the history or examination, (4) absence of fever, AED withdrawal, or other explanation for the occurrence of GCSE, (5) refractoriness of GCSE to initial therapy, (6) early recurrence of GCSE, (7) new difficulty in controlling convulsive or nonconvulsive seizures after GCSE, (8) a history of head injury preceding GCSE, and (9) epileptiform abnormalities or focal slowing on interictal EEG after GCSE. In many cases CT has already been performed before the neurologist sees the patient, so the question is whether to perform MRI. Recurrence of GCSE is not rare, occurring in approximately 13% of individuals with GCSE in one series (29). The rate of new lesion detection on repeat CT after a recurrence of GCSE, when the CT scan was normal after the initial episode of GCSE, is unclear. Prospective studies of neuroimaging in GCSE would be useful to evaluate current practices in the diagnosis of GCSE and to determine the association of particular cerebral structural abnormalities with GCSE, through comprehensive epidemiologic studies. Etiologic investigations of SE are never complete without MRI data, whether the purpose is patient care or determining the epidemiology of SE. The high incidence of idiopathic SE reported in older series of GCSE must be viewed with considerable suspicion, given the absence of brain MRI or even CT imaging in these series. Optimal evaluation of therapeutic protocols for GCSE, CPSE, and EPC also will require that each patient have technically adequate MRI data, because a greater prevalence of highly epileptogenic lesions in one treatment group will generate an unintentional bias against the efficacy of the therapy used for that group. Imaging of myoclonic SE and subtle GCSE Generalized status myoclonicus (myoclonic SE or myoclonic SE with coma) and
some states of subtle GCSE feature continuous unconsciousness and irregularly repetitive facial and somatic myoclonus. Myoclonic SE and subtle GCSE often manifest similar EEG alterations (78, 195). Subtle GCSE is preceded by overt GCSE. Generalized status myoclonicus is not preceded by overt GCSE, and most often occurs following cardiopulmonary arrest. Generalized status myoclonicus is associated with severe neuronal ischemic injury distributed throughout the central nervous system (CNS) (210), and presumably CT and MRI would demonstrate this injury. Inadequately treated or refractory GCSE with overt convulsions can be followed by subtle GCSE, which may be associated with myoclonus or other movements, or with no movements at all. If the pathophysiology of subtle GCSE differs from that of generalized status myoclonicus, as might be suspected in patients who were mechanically ventilated and have not been significantly anoxic, it might be predicted that the pathologic changes and therefore the neuroimaging findings would differ between these electroclinically similar entities. Brain CT probably has been performed in many patients who were comatose after cardiopulmonary arrest, both before and after generalized status myoclonicus developed; surprisingly, several series of such patients have not reported brain imaging, despite the inclusion of detailed clinical and electroencephalographic (EEG) observations. It is unclear whether neuroimaging has any diagnostic role, including that of prognostication, in generalized status myoclonicus. Reports of brain imaging following subtle GCSE also are lacking. C P SE Detection of structural brain lesions in the etiologic diagnosis of CPSE Complex partial SE requires definitive structural neuroimaging for a full etiologic diagnosis. Unlike overt GCSE, which is readily recognized by its clinical manifestations, the diagnosis of CPSE always requires EEG (43, 57, 82). Appropriate medical therapy should be instituted immediately on electrophysiologic diagnosis of CPSE, after which CT or MRI can be performed. In a consecutive series of 10 patients with CPSE of frontal lobe origin, MRI showed neoplasia in three patients (in one of whom the episode of CPSE was the only clinical manifestation of the tumor), other frontal lobe abnormalities in three patients, and normal brain structure in four patients (193). In some cases, the immediate precipitant of CPSE may be discontinuation of AEDs in a patient with previously diagnosed and treated complex partial seizures. If such a patient has previously had high-quality brain MRI performed and the CPSE responds promptly to appropriate therapy, there usually is no reason to repeat neuroimaging after termination of CPSE. In the absence of MRI performed before CPSE, brain MRI should always be performed following termination of CPSE, even if the CT scan was normal or showed nonspecific abnormalities (Figures 16.6 and 16.7). As discussed earlier, CT
F 16.6 Acute limbic encephalitis detected with MRI (but not with CT) following CPSE. MRI was performed after CPSE was controlled in a 31-year-old man who had no prior history of seizures. He was brought to the emergency room for the acute onset of waxing and waning periods of unresponsiveness with subtle facial movements, superimposed on stupor. A cranial CT scan, with and without contrast, was normal. Emergency EEG showed frequent electrographic seizures of persistent left temporal maximum, with focal left temporal persistent polymorphic delta activity and widespread theta-delta slowing between electrographic seizures. Parenteral benzodiazepines and phenytoin controlled the CPSE. The following morning, brain MRI showed findings typical of limbic encephalitis, with asymmetric bilateral amygdalar, hippocampal, temporal polar, insular, and orbitofrontal T2 increases. This axial MR image shows greater T2 increase over the left hippocampus and temporal pole than over the right hippocampus. Lumbar puncture revealed CSF lymphocytosis, with negative bacterial, fungal, and herpesvirus titers and cultures; cytology was also negative. Urologic examination revealed a small testicular mass, which on resection was found to be a seminoma, with negative metastatic workup. The final diagnosis was seminoma, with a paraneoplastic syndrome of limbic encephalitis. Brain left is on image right.
:
185
F 16.7 Resolving focal gray and white matter MRI signal changes after CPSE. A 24-year-old woman with temporal lobe epilepsy for 16 years had CPSE for 1 week, with right temporal maximum on ictal EEG recordings obtained after 6 days in SE. Parenteral phenytoin and phenobarbital were required to terminate the CPSE. A brain CT scan was normal. Brain MRI was performed 4 weeks later, and axial T2-weighted images are shown in the upper half of the figure. This scan showed cerebral edema as increased T2 signal over the entire right temporal lobe, extending
into the insula, without definite mass effect. Another MRI study performed 1 month later showed marked decrease in the volume of cerebral edema, without gadolinium enhancement, but with mild mass effect over the right anterior-mesial temporal region (as shown in the bottom row of images). Anterior temporal lobectomy and tissue revealed a gemistocytic astrocytoma. Ongoing complex partial seizures ceased after temporal lobectomy. Brain left is on image right. (This case was previously reported by Henry et al. [67].)
misses many cerebral lesions that are detected with MRI in localization-related epilepsies. Brain MRI is necessary to detect focal cortical dysplasias in CPSE, although microscopic cortical dysplasias rarely underlie CPSE in patients who have normal findings on brain MRI (58, 122, 209).
(17, 26, 67, 96), suggesting that cytotoxic edema sometimes occurs on the basis of CPSE. In one such case, a large volume of T2 signal increase in a temporal lobe did not resolve completely on a second MRI study after CPSE; with new evidence of mass effect on this second MRI study, temporal lobectomy was performed and astrocytoma was found in the tissue specimen (see Figure 16.7). The distribution and time course of partial-SE-related MR signal alterations can be partially discerned from the many case reports of this phenomenon (Table 16.2). These transitory focal T2 increases of CPSE occur at the site of ictal onset, in areas adjacent to the site of ictal onset, and in areas that receive dense projections from the ictal onset zone, most typically including the ipsilateral thalamus and in some cases also the contralateral cerebellum (2, 27, 67, 88, 90, 96, 99, 118, 152, 179). The available reports indicate that transitory CPSE-related T2 increases have been detected following durations of CPSE as brief as 1 day and as long as 3 weeks.
Detection of focal cerebral edema versus foreign tissue lesions in CPSE Brain MRI in some cases shows transitory focal cerebral edema following CPSE (2, 8, 17, 26, 27, 67, 88, 90, 92, 96, 99, 117, 118, 126, 152, 177, 179, 185). These focal T2 signal increases should not be misdiagnosed as neoplasia or other lesions for which stereotaxic biopsy or resection is indicated. The initial reports of focal T2 increases early after CPSE, with subsequent resolution of these signal changes, emphasized a purely white matter location of the T2 increases (8, 90, 152, 179, 185). These reports suggested vasogenic edema as the cause of these focal changes. In later reports, several instances of definite gray matter involvement were noted
186
:
T 16.2 Summary of reported temporal relationships of transitory focal cerebral edema on MRI in clinical partial status epilepticus
Study Chan et al. (17), case 5 Chan et al. (17), case 6 Cox et al. (26) De Carolis et al. (27), case 1 De Carolis et al. (27), case 2 Fazekas et al. (46) Henry et al. (67), case 1 Henry et al. (67), case 2 Juhasz et al. (77) Kirshner et al. (88) Kramer et al. (90) Lansberg et al. (96), case 1 Lansberg et al. (96), case 3 Lee et al. (99) Meierkord et al. (109), case 2 Marchison et al. (117) Nohria et al. (126) Riela et al. (152) Sperner et al. (172) Stone et al. (179) Stübchen (180) Tien et al. (194), case 1 Tien et al. (194), case 2
Type of Partial SE
Duration of Partial SE
Timing of MRI Showing Focal T2 Signal Increases (from End of SE)
Probably CP Probably CP CP CP CP SP CP CP SP CP CP CP CP CP SP CP CP CP CP CP SP SP SP
NR NR 3 wk 7d “Several” d >2 h† 9d 7d 4 wk 4d 18 d 16 d 2d 12 d NR NR† 50 min “Several” d NR 7 d† 4d 2 hr 50 min
1 mM)
268
:
Subunit Subtypes a and b with g2 a1, a2, a3, or a5 with g2, b a1 with g2, b a2, a3 with g2, b a5 with g2, b a4 or a6 with g2, b a and b without g2 a1 and b with g2 a4 or a6, b, g2, d or e and any a, b b2 or b3 present a6 and b2 or b3 present a4 and b2 or b3 present a1, a2, a3, or a5 or b1 present
brain, and each subtype confers distinct pharmacologic properties. Although immunoprecipitation studies have not been performed on isolated preparations of dentate gyrus, whole-brain immunopurification using d-specific antibody has been reported demonstrating that the d subunit is associated with the a1, a2, b2/3, and g2 subtypes. This study provided no information regarding expression of a2, a4, b1, or g1 subtypes by granule cells. Immunoprecipitation studies did not reveal if subtype combinations precipitated from brains were functionally expressed by granule cells. Finally, these studies did not determine if more than one GABAA receptor isoform was expressed by single granule cells. P D G C GABAA R The pharmacologic properties of GABAA receptor currents recorded from hippocampal dentate granule cells acutely dissociated from 28- to 35-day-old rats were characterized using the whole-cell patch-clamp technique (22). Granule cells were voltage clamped to 0 mV, and GABA was applied using a modified U-tube rapid application technique. GABAA receptor sensitivity Concentration-response curves were obtained from individual granule cells for GABA concentrations ranging from 3 to 1,000 mM (Figure 20.1A). EC50s for individual cells (n = 5) ranged from 30 to 113 mM (median, 34 mM). The data from individual cells were pooled
F 20.1 GABA concentration-response relationship for a dentate granule cell isolated from a 30-day-old rat. (A) Traces from a single neuron showing responses to six concentrations of GABA. The concentration of GABA eliciting the current appears below the trace, and the bar indicates the duration of GABA application. (B) Pooled data from six neurons. Each point represents the mean
and fitted to a sigmoidal logistic function. Mean GABA EC50 was 46 mM ± 10 mM, maximal current was 842 ± 54 pA, and the Hill slope was 1.2. Diazepam enhancement of GABAA receptor currents Diazepam (1–1,000 nM) was co-applied with 10 mM GABA (Figure 20.1B). There was no enhancement of GABAA receptor current by 1 or 10 nM diazepam (n = 11 cells). However, higher concentrations of diazepam (30 nM–1 mM) uniformly enhanced GABAA receptor currents in a concentrationdependent fashion (Figure 20.2A). Detailed diazepam concentration-response relationships were obtained in six cells. The data from these cells could be fitted to a sigmoidal function, with EC50 values ranging from 96 nM to 317 nM (median, 122 nM) (Figure 20.2B). Because the GABAA receptor currents in all the dentate granule cells were uniformly enhanced by diazepam, the concentration-response data from these cells were pooled. The enhancement of GABAA receptor current by diazepam was a sigmoidal function of diazepam concentration with a Hill slope of 1.2 ± 0.3, maximal enhancement of 210% ± 10%, and an EC50 of 158 nM ± 13 nM (Figure 20.2C). Zolpidem enhancement of GABAA receptor currents Zolpidem enhanced hippocampal dentate granule cell GABAA receptor currents in all nine cells studied. Complete concentration-response data were obtained in seven cells and could be
of five observations, and error bars show SEMs. The line was the best fit of the data to a sigmoidal function. The EC50 was derived from the equation for the sigmoidal function that best fitted the data. (Reprinted with permission from Kapur and Macdonald [22].)
:
269
F 20.2 Diazepam enhanced dentate granule cell GABAA receptor currents. (A) Traces from a single neuron. The concentrations of drug applied with 10 mM GABA are shown below the traces. Horizontal bars show the duration of application of the drug. Recovery between drug applications is not shown. (B) Diazepam concentration-dentate granule cell GABAA receptor
current enhancement relationship data for seven neurons were plotted individually. (C) Each point represents the mean of seven observations in B; the error bars show SEMs. The lines are the best fit of the data to a sigmoidal function. The EC50 was derived from the equation for the sigmoidal function that best fitted the data. (Reprinted with permission from Kapur and Macdonald [22].)
fitted to a sigmoidal function in each case (Figure 20.3A). EC50 values for zolpidem enhancement of GABAA receptor currents for individual cells varied from 40 nM to 126 nM (median, 64 nM) (Figure 20.3B). The data from individual cells were pooled. Zolpidem enhanced granule cell GABAA receptor currents with an EC50 of 75 nM ± 13 nM, a maximal enhancement of 165% ± 6%, and a Hill slope of 1.1 + 0.4 (Figure 20.3C).
IC50 of Zn2+ inhibition of the whole group of dentate granule cell GABAA receptor currents was similar to the median value of the individual IC50 values, also suggesting a single population of cells. More recently, the complement of GABAA receptor subunits in dentate granule cells was explored by means of immunohistochemistry and by amplification of the subunit mRNAs collected during electrophysiologic recordings (4, 62). Amplification of mRNA from the dentate granule cells revealed expression of a1, a2, a4, b1, b2, b3, g2, d, and e subunits. The complement of GABAA receptor mRNAs expressed in the human dentate granule cells is similar to that expressed in rats (3). Immunohistochemistry for GABAA receptor subunits expressed in the hippocampus revealed expression of a1, a2, a4, a5, b1, b3, and d subunits.
Zinc reduction of GABAA receptor currents The action of Zn2+ on 30 mM GABAA receptor currents in hippocampal dentate granule cells was studied. Zn2+, ranging in concentration from 1 to 1,000 mM, was co-applied with GABA after obtaining stable GABAA receptor currents. In eight hippocampal dentate granule cells, GABAA receptor currents were reduced by Zn2+ in a concentration-dependent fashion (Figure 20.4A). Zn2+ inhibition of GABAA receptor currents was similar among all granule cells tested: currents in all cells were inhibited by 100 mM, and none was inhibited by 1 mM Zn2+. The Zn2+ IC50 values for individual cells also were distributed over a narrow range, from 13 to 51 mM (median, 29 mM; Figure 20.4B). Because the data obtained from individual granule cells suggested a homogeneous population of cells, the data were pooled and fitted to a single sigmoidal concentration-response curve (Figure 20.4C). The IC50 of Zn2+ inhibition of GABAA receptor currents was 28.5 mM ± 11 mM, the maximal inhibition of GABAA receptor currents was 77% ± 3%, and the Hill slope was 2.0 ± 0.4 (n = 8). The
270
:
Acute changes in the treatment of SE Status epilepticus was induced in Sprague-Dawley rats by intraperitoneal (IP) injection of 3 mEq/kg of lithium chloride, followed 20 hours later by 50 mg/kg of pilocarpine (17). Following pilocarpine injection, the rats were observed continuously for the occurrence of behavioral seizures. The time to onset of behavioral seizures was recorded, and behavioral seizures were observed. Behavioral seizures evoked by lithium-pilocarpine were as described previously (53). Seizure termination was defined as the absence of forelimb clonus or falling, facial twitching, and stop-and-stare
F 20.3 Zolpidem enhanced dentate granule cell GABAA receptor currents. (A) Traces from a single neuron. The concentrations of drug applied with 10 mM GABA are shown below the traces. Horizontal bars show the duration of application of the drug. Recovery between drug applications is not shown. (B) Zolpidem concentration-response relationship for GABAA receptor
current enhancement. Data for seven neurons are plotted individually. (C) Each point represents the mean of seven observations in B; the error bars show SEMs. The lines are the best fit of the data to a sigmoidal curve. The EC50 was derived from the equation for the sigmoidal function that best fitted the data. (Reprinted with permission from Kapur and Macdonald [22].)
F 20.4 (A) Zn2+ inhibited dentate granule cell GABAA receptor currents. (A) Traces from a single neuron. Drug concentrations applied with 30-mM GABA are shown below the trace. Horizontal bars show the duration of drug application. Recovery between drug applications is not shown. Note the Zn2+ inhibition of GABAA receptor currents was incomplete. (B) Zn2+ concentration-response relationship for GABAA receptor current
inhibition. Data are from eight neurons plotted individually. (C) Each point represents the mean of the data from eight neurons in B; the error bars show SEMs. The lines were the best fit of the data to a sigmoidal function. The IC50 was derived from the equation for the sigmoidal function that fitted the data. (Reprinted with permission from Kapur and Macdonald [22].)
:
271
activity. Additionally, resumption of normal behavior within 30 minutes of drug injection was assessed. Diazepam was administered 10 minutes or 45 minutes after pilocarpine injection. The fraction of rats that stopped having seizures within 5 minutes of diazepam injection was plotted against log diazepam dose. The data were fitted to a sigmoidal doseresponse curve, with the maximum fixed to 100% and minimum to 0%. The ED50 values were derived from the equation that best fitted the data. Behavioral seizures began 3–5 minutes after the injection of pilocarpine. Behavioral seizures during lithiumpilocarpine-induced SE were characterized by immobility, repetitive chewing, head nodding, vibrissal twitching, and forelimb clonus, with or without rearing and falling, as previously described (53, 63). Four rats were not treated with an anticonvulsant drug, and they continued to have seizures for 2 hours. After 10 minutes of seizures, diazepam (20 mg/kg) terminated seizures in all treated animals (n = 3). However, after 45 minutes of seizures (SE), diazepam (20 mg/kg) terminated the seizures in none of the animals (n = 3). Seizure termination was defined as absence of behavioral convulsion, facial twitching, and stop-and-stare activity. Additionally, resumption of normal behavior within 30 minutes of drug injection was assessed. A detailed analysis of diazepam dose and fraction of animals becoming seizure-free (response) was performed in a total of 30 rats. Increasing doses of diazepam from 2 mg/kg to 20 mg/kg were administered after 10 minutes of seizures. Five rats were treated with 2 mg/kg, and three rats in each group were treated with 7.5 mg/kg, 10 mg/kg, and 20 mg/kg of diazepam. After 45 minutes of seizures, three rats were each administered 20 mg/kg, 30 mg/kg, 50 mg/kg and 100 mg/kg of diazepam. At high doses of diazepam (50 and 100 mg/kg), behavioral seizures appeared terminated, but the rats were extremely sedated, and resumption of normal activity did not occur. The dose-response data were fitted to a sigmoidal dose-response relationship and the ED50 values for diazepam control of behavioral seizures after 10 minutes and 45 minutes of seizures were derived (Figure 20.5). The dose-response curve showed that the ED50 for diazepam-induced termination of seizures shifted from 4.2 mg/kg when diazepam was administered after 10 minutes of continuous seizures to 40 mg/kg when diazepam was administered after 45 minutes of continuous seizures. The precise time course of the development of refractoriness to benzodiazepines during SE has been described elsewhere. In the first set of experiments, the benzodiazepine diazepam was given 10, 20, 30, or 45 minutes following the injection of pilocarpine into adolescent rats pretreated with lithium. Confirming the prior observation, there was an almost 10-fold increase in the dose of diazepam required to terminate behavioral changes (seizures) observed following the injection of pilocarpine in 50% of animals at 45
272
:
F 20.5 Diazepam was effective in controlling brief (10minute) seizures but lost efficacy after prolonged (45-minute) seizures. Seizures were induced in 70- to 150-g rats by intraperitoneal (IP) injection of 3 mEq/kg of LiCl, followed 16–24 hours later by 50 mg/kg IP injection of pilocarpine. Behavioral seizures started within 1–5 minutes in all rats. Diazepam was administered 10 minutes (solid squares, solid line, n = 14) or 45 minutes (solid circles, dashed line, n = 12) after pilocarpine injection. The percentage of rats that stopped having seizures within 5 minutes of diazepam injection was plotted against log diazepam dose. The data were fitted to a sigmoidal dose-response curve with the maximum fixed to 100% and the minimum to 0%. The ED50 values were derived from the equation that best fitted the data. (Reprinted with permission from Kapur and Macdonald [24].)
minutes as compared with 10 minutes. At the intermediate time points, termination of behavioral changes and the recovery of normal function did not appear to be dose dependent. The development of pharmacoresistance to benzodiazepine was characterized further by timing diazepam administration to a clinical seizure stage—the onset of forelimb clonus (seizure stage S3 as defined by Racine [52])—or to an ictal electrographic stage, continuous 3- to 4-Hz spikeand-wave activity (electrographic equivalent to S3 in this study). When diazepam was administered at the onset of S3, clinical seizure termination and eventual recovery of normal function were observed to occur in a dose-dependent fashion (ED50 = 1.6 mg/kg). However, when diazepam was administered 10 minutes after the onset of S3, clinical seizure termination and eventual recovery of normal function within a 3-hour time interval were not observed in more than 90% of the animals, despite diazepam doses of 20 mg/kg. Comparable findings were observed when diazepam dosing was based on the electrographic equivalent of S3. In the final set of experiments, similar experiments were performed using phenobarbital, a GABAA agonist, and phenytoin, a sodium channel blocker that suppresses repetitive firing of action potentials. Like diazepam, phenobarbital was efficacious when administered before or at the onset of S3 but not when administered 10 minutes after the onset of S3. In contrast, phenytoin was not effective at any time point.
In summary, this study demonstrates that in the lithiumpilocarpine model of SE, the development of pharmacoresistance to drugs that enhance GABAA receptor current, diazepam and phenobarbital, occurs rapidly after the onset of forelimb clonus and ictal spike-and-wave activity. How pharmacoresistance to benzodiazepines develops is not known. Insofar as diazepam exerts its anticonvulsant effect primarily by enhancing GABAergic inhibition by acting on GABAA receptors (36), we hypothesized that seizures altered the functional properties of GABAA receptors. The seizures could potentially alter the modulation of GABAA receptor by various drugs, such as enhancement by benzodiazepines, barbiturates, and neurosteroids and antagonism by penicillin, picrotoxin, bicuculline, and Zn2+. We characterized GABAA receptor currents recorded from acutely isolated hippocampal dentate granule cells, their potentiation by benzodiazepines and barbiturates, and their inhibition by Zn2+.
Involvement of hippocampal GABAA receptors in SE H I SE Several lines of evidence suggest that the hippocampal/parahippocampal loop can sustain seizures during SE. In functional mapping studies combining EEG and 2-deoxyglucose (2-DG) mapping of metabolic activity during SE, increased glucose utilization occurred in hippocampus and parahippocampal structures; subiculum, parasubiculum, and entorhinal cortex; and
F 20.6 Stabilization of GABAA receptor currents after access. Traces are from two neurons, from a cell isolated from a control animal (top) and from an animal undergoing SE (bottom). The durations of GABA application are indicated by bars. Two minutes elapsed between each GABA application. (A) GABAA receptor currents elicited from hippocampal dentate granule cells
limbic structures, including the amygdala and extralimbic structures (63). Similarly, combined hippocampal/parahippocampal slices sustain SE. Thus, it is important to understand the functional properties of hippocampal GABAA receptors and how they are modified by SE. D G C GABAA R C R U SE Whole-cell voltage clamp recordings were made from dentate granule cells (26, 46) acutely isolated from control rats or from same-age rats that had sustained 45 minutes of continuous seizures (SE) (23). When access was initially established in granule cells from control rats, 10 mM GABAA receptor currents increased slightly and became stable in 2–4 minutes (run-up) (Figure 20.6A). The stable response compared with the first response increased 174% ± 47% (n = 4) (Figure 20.7). In contrast, GABAA receptor currents evoked from hippocampal neurons from animals undergoing SE required 10 minutes to stabilize (Figure 20.6B), and the run-up was larger (374% ± 66%, n = 5, P < 0.05; Figure 20.7). Once stable responses to 10 mM GABA were obtained, GABA was applied to granule cells at concentrations ranging from 1 to 1,000 mM (Figure 20.8). For each of the groups, data from individual cells were pooled and fitted to a sigmoidal logistic equation. In neurons from control animals, the mean GABA EC50 for GABAA receptors was 42 mM ± 19 mM (n = 17), similar to that of neurons from animals undergoing SE, 33 mM ± 14 mM (n = 9) (P > 0.05). The
isolated from control animals rapidly increased to a relatively stable amplitude. (B) GABAA receptor currents elicited from hippocampal dentate granule cells isolated from animals undergoing SE took longer to stabilize and showed a greater increase in amplitude. (Reprinted with permission from Kapur and Macdonald [24].)
:
273
F 20.7 Run-up of GABAA receptor currents after access. Granule cell GABAA receptor peak currents were normalized to the initial current evoked by 10 mM GABA after access. Means and SEMs of peak normalized GABAA receptor currents from five neurons from animals undergoing SE and four neurons from control animals are plotted. (Reprinted with permission from Kapur and Macdonald [24].)
F 20.9 Diazepam enhancement of GABAA receptor currents from dentate granule cells from control animals and from cells isolated from rats following 45 minutes of seizures. 300 nM diazepam enhanced GABAA receptor current in dentate granule cells from control animals but not from cells isolated from rats following 45 minutes of seizures. The traces are from two different neurons. Horizontal bars showed the duration of application of the drug. (A) 300 nM diazepam was applied with 10 mM GABA to a dentate granule cell from a control animal. (B) 300 nM diazepam was applied with 6 mM GABA to a granule cell isolated from a rat following SE. A lower concentration of GABA was used to compensate for a small left shift of the GABA concentration-response curve in cells from animals undergoing SE (equipotent GABA concentration). (Reprinted with permission from Kapur and Macdonald [24].)
cells isolated from control rats or from those undergoing SE after stabilization of currents.
F 20.8 GABA concentration dependency. GABA concentration-normalized GABAA receptor peak current relationships are plotted for 17 neurons isolated from control animals and nine neurons isolated from animals undergoing SE. Concentrationresponse data were obtained after stabilization of currents. Each point represents the mean of normalized peak currents; error bars show SEMs. The line was the best fit of data to a sigmoidal function. The EC50 and Imax were derived from the equation for the sigmoidal function that best fitted the data. (Reprinted with permission from Kapur and Macdonald [24].)
maximal GABAA receptor current in cells from control animals was 962 ± 109 pA (n = 19), similar to that of cells from animals undergoing SE, 820 ± 188 pA (n = 9). Thus, after SE there was increased run-up of GABAA receptor currents after initial access, but once stable currents had been obtained, the EC50 and maximal GABA current for dentate granule cell GABAA receptors were similar to those measured in neurons from control animals. Modulation of GABAA receptor currents was studied in dentate granule
274
:
D E GABAA R C W D G C R U SE In hippocampal dentate granule cells from control animals, when 10 mM GABA was co-applied with 300 nM diazepam, GABAA receptor currents were enhanced in all neurons by 68% ± 10% (n = 6) (Figure 20.9A). In contrast, in dentate granule cells from animals undergoing SE, 300 nM of diazepam inconsistently enhanced 6 or 10 mM GABAevoked GABAA receptor currents by 10% ± 6% (n = 5) (P < 0.001, grouped t test) (Figure 20.9B). Diazepam concentration-response curves were obtained for enhancement of GABAA receptor currents from neurons from both naive animals and animals subjected to SE. In neurons from naive animals, 1 mM or 3 mM of diazepam elicited maximal enhancement of GABAA receptor currents, while in neurons from rats undergoing SE, 3 mM of diazepam elicited more enhancement of GABAA receptor currents than 1 mM diazepam. Since diazepam causes a left shift of the GABA concentration-response curve, the same amount of diazepam will cause more enhancement of GABAA receptor currents if applied with a lower GABA
concentration. Additionally, the GABA EC50 was slightly (but not statistically significantly) left-shifted in granule cells acutely isolated from rats undergoing SE compared with controls. In this situation it was important to use equipotent GABA concentrations, not equal GABA concentrations. In four neurons from rats undergoing SE, varying concentrations of diazepam were co-applied with 6 mM GABA (instead of 10 mM); however, the diazepam EC50 and maximal enhancement in these experiments were similar to those measured with diazepam co-applied with 10 mM GABA. The data from these experiments were pooled. In neurons from control animals, 1 mM of diazepam enhanced GABAA receptor currents by 92% ± 6% (n = 6), but in neurons from animals undergoing SE, 3 mM of diazepam only enhanced GABAA receptor currents by 51% ± 8% (n = 5) (P < 0.05, grouped t test) (Figure 20.10). The EC50 for diazepam enhancement of GABAA receptor currents in neurons from control animals was 195 nM ± 12 nM, and the EC50 in neurons from animals undergoing SE was 4.4 mM ± 0.25 mM (see Figure 20.10). Thus, the prolonged seizures of SE reduced the potency and efficacy of diazepam for the enhancement of granule cell GABAA receptor currents. Z S GABAA R C W D G C R U SE Since Zn2+ modulation of recombinant GABAA receptor currents varies inversely with benzodiazepine sensitivity (14, 61), Zn2+ inhibition of granule cell GABAA receptor currents was studied. Zn2+ was less potent in inhibiting GABAA receptor currents recorded from granule cells isolated from animals undergoing SE than from control granule cells. In
F 20.10 Diazepam concentration-dentate granule cell GABAA receptor current enhancement relationships. Diazepam concentration-response curves were obtained for neurons isolated from control animals (solid squares, solid line, n = 9) and for neurons isolated from animals undergoing SE (solid circles, dashed line, n = 12). Higher concentrations of diazepam inhibited GABAA receptor current, as previously reported (De Deyn and Macdonald [10]). (Reprinted with permission from Kapur and Macdonald [24].)
neurons from control animals, GABAA receptor currents were inhibited 59% ± 4% (n = 8) by 100 mM Zn2+, but in neurons isolated from animals undergoing SE, the inhibition was reduced to 39% ± 6% (n = 6) (P < 0.05, grouped t test) (Figure 20.11). Zn2+, ranging in concentration from 1 to 1,000 mM, was co-applied with GABA to define the mechanism of the reduced Zn2+ block (Figure 20.12). In dentate granule cells from control rats, GABAA receptor currents were reduced by Zn2+ in a concentration-dependent fashion, with an IC50 of 30 mM ± 3.6 mM (n = 12). In dentate granule cells isolated from animals undergoing SE, the IC50 of Zn2+ inhibition of GABAA receptor currents was 123 mM ± 15 mM (n = 10) (P < 0.01, grouped t test). The maximal inhibition of GABAA receptor currents by Zn2+ was unchanged, 78% ± 3% in neurons from control animals and 90% ± 16% in neurons from animals undergoing SE. Thus, the prolonged seizures of SE reduced the potency of Zn2+ without altering the efficacy of inhibition of granule cell GABAA receptor currents. P E GABAA R C W U C R U SE In neurons from control animals, GABAA receptor currents elicited by 10 mM GABA were enhanced 77% ± 7% (n = 6) by 30 mM pentobarbital (Figure 20.13A), while in neurons from animals undergoing SE, GABAA receptor currents elicited by 10 mM GABA were enhanced 62% ± 11%
F 20.11 Zn2+ inhibition of GABAA receptor currents in dentate granule cells from control animals from animals undergoing SE. 100 mM Zn2+ inhibited GABAA receptor currents in dentate granule cells from control animals more than in granule cells from animals undergoing SE. The traces are from two different neurons. 100 mM Zn2+ was co-applied with 30 mM GABA. Horizontal bars show the duration of application of the drug. (A) Traces from a dentate granule cell isolated from a control animal. (B) Traces from a granule cell isolated from an animal undergoing SE. (Reprinted with permission from Kapur and Macdonald [24].)
:
275
F 20.12 Zn2+ concentration-dentate granule cell GABAA receptor current reduction relationships. Zn2+ concentrationdentate granule cell GABAA receptor current inhibition relationships were obtained from neurons isolated from control animals (solid squares, solid line, n = 12) and from neurons isolated from animals undergoing SE (solid circles, dashed line, n = 12). The lines were the best fit of the data to a sigmoidal function. The IC50 and Hill slope were derived from the equation for the sigmoidal function that best fitted the data. (Reprinted with permission from Kapur and Macdonald [24].)
F 20.13 Pentobarbital enhancement of GABAA receptor currents from dentate granule cells from control animals and from cells isolated from animals undergoing SE. 30 mM pentobarbital equally enhanced GABAA receptor currents in dentate granule cells from control animals and from animals undergoing SE. The traces are from two different neurons. 30 mM pentobarbital was coapplied with 10 mM GABA. Horizontal bars show the duration of application of the drug. (A) Traces from a dentate granule cell isolated from a control animal. (B) Traces from a granule cell isolated from an animal undergoing SE. (Reprinted with permission from Kapur and Macdonald [24].)
276
:
F 20.14 Pentobarbital concentration-dentate granule cell GABAA receptor current enhancement relationships. Pentobarbital concentration-dentate granule cell GABAA receptor current enhancement relationships were obtained for neurons isolated from control animals (solid squares, solid line, n = 7) and from neurons isolated from animals undergoing SE (solid circles, dashed line, n = 6). The lines were the best fit of the data to a sigmoidal function. The EC50 and Hill slope were derived from the equation for the sigmoidal function that best fitted the data. (Reprinted with permission from Kapur and Macdonald [24].)
(n = 3) by 30 mM pentobarbital (P > 0.05, grouped t test) (Figure 20.13B). Concentration-response curves were obtained by coapplying 1–300 mM pentobarbital with 10 mM GABA to neurons obtained from control animals and from animals undergoing SE (see Figure 20.10). In dentate granule cells from control animals, the pentobarbital EC50 was 42 mM ± 15 mM (n = 6), and in neurons from animals undergoing SE the pentobarbital EC50 was not significantly different (36 ± 8 mM, n = 6) (see Figure 20.9). Maximal enhancement of GABAA receptor currents by pentobarbital in neurons from control rats (190% ± 55%) and in neurons from animals undergoing SE (158% ± 20%) was not significantly different (P > 0.05, grouped t test). Thus, the prolonged seizures of SE did not alter the pentobarbital EC50 or maximal enhancement of GABAA receptor currents in dentate granule cells.
Discussion D L E T SE This study demonstrated that the prolonged seizures of SE reduce the ability of diazepam to terminate SE. This refractoriness to diazepam resulted from an increase in diazepam EC50 but not the maximal enhancement of GABAA receptor current by diazepam. This phenomenon of refractoriness to diazepam has been previously reported in both humans (74) and rats (70). Several possible mechanisms can be hypothesized to explain the loss of diazepam effectiveness
in the treatment of the prolonged seizures of SE: seizures may become more intense, there may be enhanced excitatory transmission, or there may be altered inhibition. Past studies indicate that the hippocampus is involved in the generation of SE (24, 33, 67) and that hippocampal GABAergic inhibition is altered during SE (20, 21, 25). These studies suggest that the refractoriness of seizures to diazepam might result from altered GABAA receptor function in the hippocampus. The experiments reported here support such a hypothesis. P GABAA R F D SE During SE, GABAA receptor-mediated inhibition in the hippocampus is reduced both in the CA1 region and in dentate gyrus (20, 21, 59). One proposed mechanism for the reduction in inhibition is a specific alteration in the functional properties of GABAA receptors (20). This study demonstrates directly that two functional properties of GABAA receptors, diazepam enhancement and Zn2+ inhibition of GABAA receptor currents, are altered by the prolonged seizures. This plasticity of GABAA receptors in the hippocampus may play a role in the pathogenesis and treatment of SE. Seizures in the hippocampus reduce GABAergic inhibition, and the findings presented here demonstrate that this is due in part to changes in GABAA receptor function. The reduction in diazepam sensitivity of dentate granule cell GABAA receptors parallels the loss of effectiveness of diazepam in the treatment of experimental SE. It is possible that changes in the diazepam sensitivity of dentate granule cell GABAA receptors reflect a reduction of diazepam sensitivity in the treatment of SE. Additionally, pentobarbital sensitivity of GABAA receptors on dentate granule cells isolated from animals undergoing SE was preserved. This suggested that SE alters specific properties of GABAA receptors rather than causing a generalized dysfunction of the receptor. SE T L E H D E H GABAA R Studies investigating the role of GABAA receptor-mediated inhibition in the hippocampus in kindling and other models of temporal lobe epilepsy are the most comparable to the current study. However, the brief seizures of temporal lobe epilepsy and the prolonged seizures of SE are distinct phenomena. Close to 50% of those having an episode of SE have not previously experienced a seizure (12). Epileptic seizures are brief, and data from epilepsy monitoring units indicate that the majority of seizures terminate spontaneously within 10 minutes (54). In contrast, SE is a syndrome consisting of a very prolonged seizure with continuous evolution of the neurologic state, worsening cerebral metabolism, a steady rise in core temperature, a rise in blood pressure, lactic acidosis, hyperglycemia (39), and increased catecholamine levels (58). Hippocampal injury and neuronal loss occur due to SE in
humans (11, 43) and in most animal models of SE (2, 8, 15, 40, 60). However, whether individual brief seizures cause neuronal loss remains controversial (2, 7, 71). It is thus expected that SE and chronic temporal lobe epilepsy have different effects on hippocampal dentate granule cell GABAA receptors. In kindling, subconvulsive electrical stimulation applied repeatedly to various regions of the brain evokes progressively prolonged behavioral and electrographic seizures that terminate in generalized tonic-clonic seizures. However, there are important differences between the gradual plasticity occurring during the kindling process and the rapidly evolving changes of SE reported here. Several studies have reported enhanced [3H] muscimol and [3H ] benzodiazepine binding in hippocampal membranes (57) and specifically in the hippocampal dentate gyrus (38, 66). This increase in the hippocampal dentate granule cell GABAA receptors following kindling was associated with an increase in the amplitude of miniature inhibitory postsynaptic currents and enhancement of paired pulse depression of kindled dentate gyrus (48). These long-term changes in GABAA receptormediated inhibition in the dentate gyrus were likely to be antiepileptic in nature. The findings of this study, however, do not contradict studies on the kindling model. Although inhibitory neurotransmission in the dentate gyrus was enhanced during kindling and diminished during SE, the changes in kindling were slower to develop compared with the rapid changes occurring during SE. In electrical stimulation models of epilepsy, GABAA receptor-mediated inhibition in the dentate gyrus was chronically reduced, but this reduction was hypothesized to be due to circuit rearrangement and dormancy of basket cells (59). Recently, Buhl et al. (6) demonstrated enhanced Zn2+ sensitivity of hippocampal dentate granule cell GABAA receptors following kindling, and suggested that this increased sensitivity resulted in a collapse of the augmented inhibition during seizures. Gibbs et al. (16) found increased GABAA receptor density and enhanced GABAA receptor Zn2+ sensitivity in another model of chronic temporal lobe epilepsy. Several important distinctions between these studies and this report pertain. First, the reduced diazepam sensitivity demonstrated here has not been reported in the past. Second, the changes that were observed in these studies were acute, occurring over minutes, while previous reports documented changes that were chronic, occurring over several weeks. Finally, previous studies reported increased Zn2+ sensitivity of hippocampal dentate granule cell GABAA receptors, whereas the current study reports diminished Zn2+ sensitivity of granule cell GABAA receptors. P M M A GABAA R F This rapid selective loss of benzodiazepine and Zn2+ sensitivity is a novel form of GABAA
:
277
receptor plasticity, and the underlying molecular basis is unclear. Diminished benzodiazepine sensitivity with the development of benzodiazepine tolerance occurred over a prolonged period of time (52). During development of cerebellar granule cells, benzodiazepine sensitivity of GABAA receptors is lost during maturation in parallel with increasing expression of the a6 subtype of the GABAA receptor. Similarly, the development of tolerance to benzodiazepines requires chronic benzodiazepine administration. This selective loss of benzodiazepine and Zn2+ sensitivity may result from altered structural composition or an altered state of phosphorylation of GABAA receptors. Diazepam sensitivity of GABAA receptors requires the presence of the g2 subtype with a b subtype and either a1, a2, a3, or a5 subtypes (35, 51). Recombinant GABAA receptors expressed without the g2 subtype were highly sensitive to Zn2+ (IC50 < 10 mM), whereas GABAA receptors expressed with the g2 subtype were relatively insensitive to Zn2+ (14, 61). Thus, one explanation for the acute reduction of diazepam sensitivity of hippocampal dentate granule cell GABAA receptors after seizures would be a loss of the g2 subtype from the receptor; however, this loss would not explain the diminished Zn2+ sensitivity of these receptors. Another potential explanation for diminished diazepam and Zn2+ sensitivity would be an altered a subtype expression, since a subtypes are known to alter both Zn2+ and diazepam sensitivity of the GABAA receptors. For example, recombinant GABAA receptors with a4 or a6 subtype with a b subtype and a g2 subtype have low diazepam and Zn2+ sensitivities (55). Recent studies using confocal laser microscopy and postembedding immunogold electron microscopy suggest that GABAA receptors containing the a1, a2, and g2 subunits are present in the subsynaptic membrane, while a4 and d subunits are expressed in the extrasynaptic membrane (44, 45, 62). The synaptic receptors mediate synaptic or phasic inhibition, while extrasynaptic receptors mediate tonic inhibition. Refractoriness to benzodiazepines during SE could result from shift of the a4 and d subunit-containing receptors from the extrasynaptic to the synaptic location, and reduction of a1 and g2 subunit-containing receptors at the synapses. The a4 and d subunit-containing GABAA receptors are expressed in dentate granule cells of naive rats (3, 4), and they are extrasynaptic in naive rat dentate granule cells (44, 64). Seizures may alter GABAA receptor function by other mechanisms, such as posttranslational modification of GABAA receptors or release of endogenous benzodiazepinelike substances. Modification of GABAA receptors by phosphorylation is well demonstrated (32, 34, 35), and seizures are known to modulate activities of cyclic AMP-dependent protein kinase, calcium-calmodulin-dependent protein kinase, and calcium-phospholipid-dependent protein kinase (19, 49). However, it remains to be shown that posttransla-
278
:
tional modification can alter the benzodiazepine and Zn2+ sensitivity of GABAA receptors. REFERENCES 1. Bateson, A. N., A. Lasham, and M. G. Darlison. Gammaaminobutyric acidA receptor heterogeneity is increased by alternative splicing of a novel beta-subunit gene transcript. J. Neurochem. 1991;56:1437–1440. 2. Bertram, E. H., and E. W. Lothman. Morphometric effects of intermittent kindled seizures and limbic status epilepticus in the dentate gyrus of the rat. Brain Res. 1993;603:25–31. 3. Brooks-Kayal, A. R., M. D. Shumate, H. Jin, D. D. Lin, T. Y. Rikhter, K. L. Holloway, et al. Human neuronal gammaaminobutyric acid(A) receptors: Coordinated subunit mRNA expression and functional correlates in individual dentate granule cells. J. Neurosci. 1999;19:8312–8318. 4. Brooks-Kayal, A. R., M. D. Shumate, H. Jin, T. Y. Rikhter, and D. A. Coulter. Selective changes in single cell GABA(A) receptor subunit expression and function in temporal lobe epilepsy. Nat. Med. 1998;4(10):1166–1172. 5. Brooks-Kayal, A. R., M. D. Shumate, H. Jin, T. Y. Rikhter, M. E. Kelly, and D. A. Coulter. Gamma-aminobutyric acid(A) receptor subunit expression predicts functional changes in hippocampal dentate granule cells during postnatal development. J. Neurochem. 2001;77(5):1266–1278. 6. Buhl, E. H., T. S. Otis, and I. Mody. Zinc-induced collapse of augmented inhibition by GABA in a temporal lobe epilepsy model. Science 1996;271:369–373. 7. Cavazos, J. E., I. Das, and T. P. Sutula. Neuronal loss induced in limbic pathways by kindling: Evidence for induction of hippocampal sclerosis by repeated brief seizures. J. Neurosci. 1994;14(5 Pt. 2):3106–3121. 8. Clifford, D. B., J. W. Olney, A. Maniotis, R. C. Collins, and C. F. Zorumski. The functional anatomy and pathology of lithium-pilocarpine and high-dose pilocarpine seizures. Neuroscience 1987;23:953–968. 9. Cutting, G. R., L. Lu, B. F. O’Hara, L. M. Kasch, C. Montrose-Rafizadeh, D. M. Donovan, et al. Cloning of the gamma-aminobutyric acid (GABA) rho 1 cDNA: A GABA receptor subunit highly expressed in the retina. Proc. Natl. Acad. Sci. U.S.A. 1991;88:2673–2677. 10. De Deyn, P. P., and R. L. Macdonald. Effects of non-sedative anxiolytic drugs on responses to GABA and on diazepaminduced enhancement of these responses on mouse neurones in cell culture. Br. J. Pharmacol. 1988;95:109–120. 11. DeGiorgio, C. M., U. Tomiyasu, P. S. Gott, and D. M. Treiman. Hippocampal pyramidal cell loss in human status epilepticus. Epilepsia 1992;33:23–27. 12. DeLorenzo, R. J., W. A. Hauser, A. R. Towne, J. G. Boggs, J. M. Pellock, L. Penberthy, et al. A prospective, populationbased epidemiologic study of status epilepticus in Richmond, Virginia. Neurology 1996;46:1029–1035. 13. DeLorey, T. M., and R. W. Olsen. Gamma-aminobutyric acidA receptor structure and function. J. Biol. Chem. 1992; 267:16747–16750. 14. Draguhn, A., T. A. Verdorn, M. Ewert, P. H. Seeburg, and B. Sakmann. Functional and molecular distinction between recombinant rat GABAA receptor subtypes by Zn2+. Neuron 1990;5:781–788. 15. Fujikawa, D. G., A. H. Daniels, and J. S. Kim. The competitive NMDA receptor antagonist CGP 40116 protects against
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
status epilepticus-induced neuronal damage. Epilepsy Res. 1994;17:207–219. Gibbs, J. W., M. D. Shumate, and D. A. Coulter. Differential epilepsy-associated alterations in postsynaptic GABAA receptor function in dentate granule and CA1 neurons. J. Neurophysiol. 1997;77:1924 –1938. Honchar, M. P., J. W. Olney, and W. R. Sherman. Systemic cholinergic agents induce seizures and brain damage in lithium-treated rats. Science 1983;220:323–325. Jones, D. M., N. Esmaeil, S. Maren, and R. L. Macdonald. Characterization of pharmacoresistance to benzodiazepines in the rat Li-Pilocarpine model of status epilepticus. Epilepsy Res. 2002;50:301–312. Jope, R. S., L. Song, and K. Kolasa. Inositol trisphosphate, cyclic AMP, and cyclic GMP in rat brain regions after lithium and seizures. Biol. Psychiatry 1992;31:505–514. Kapur, J., and D. A. Coulter. Experimental status epilepticus alters GABAA receptor function in CA1 pyramidal neurons. Ann. Neurol. 1995;38:893–900. Kapur, J., and E. W. Lothman. Loss of inhibition precedes delayed spontaneous seizures in the hippocampus after tetanic electrical stimulation. J. Neurophysiol. 1989;61:427– 434. Kapur, J., and R. L. Macdonald. Pharmacological properties of g-aminobutyric acidA receptors from acutely dissociated rat dentate granule cells. Mol. Pharmacol. 1996;50: 458– 466. Kapur, J., and R. L. Macdonald. Rapid seizure-induced reduction of benzodiazepine and Zn2+ sensitivity of hippocampal dentate granule cell GABAA receptors. J. Neurosci. 1997;17: 7532–7540. Kapur, J., and R. L. Macdonald. Status epilepticus: A proposed pathophysiology. In S. Shorvon et al., eds. The Treatment of Epilepsy. Oxford, U.K.: Blackwell Science, 1996:258–268. Kapur, J., J. L. Stringer, and E. W. Lothman. Evidence that repetitive seizures in the hippocampus cause a lasting reduction of GABAergic inhibition. J. Neurophysiol. 1989;61: 417– 426. Kay, A. R., and R. K. Wong. Isolation of neurons suitable for patch-clamping from adult mammalian central nervous systems. J. Neurosci. Methods 1986;16:227–238. Kleingoor, C., M. Ewert, G. von Blankenfeld, P. H. Seeburg, and H. Kettenmann. Inverse but not full benzodiazepine agonists modulate recombinant a6b2t2 GABAA receptors in transfected human embryonic kidney cells. Neurosci. Lett. 1991; 130:169–179. Kofuji, P., J. B. Wang, S. J. Moss, R. L. Huganir, and D. R. Burt. Generation of two forms of the g-aminobutyric acid A receptor g2-subunit in mice by alternative splicing. J. Neurochem. 1991;56:713–715. Lasham, A., E. Vreugdenhil, A. N. Bateson, E. A. Barnard, and M. G. Darlison. Conserved organization of gaminobutyric acidA receptor genes: Cloning and analysis of the chicken b4-subunit gene. J. Neurochem. 1991;57:352–355. Laurie, D. J., P. H. Seeburg, and W. Wisden. The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. II. Olfactory bulb and cerebellum. J. Neurosci. 1992;12: 1063–1076. Laurie, D. J., W. Wisden, and P. H. Seeburg. The distribution of thirteen GABAA receptor subunit mRNAa in the rat brain. III. Embryonic and postnatal development. J. Neurosci. 1992;12:4151– 4172. Lin, Y.-F., M. D. Browning, E. M. Dudek, and R. L. Macdonald. Protein kinase C enhances recombinant bovine
33.
34.
35. 36.
37.
38.
39. 40.
41.
42.
43.
44.
45.
46.
47. 48.
49.
a1b1g2L GABAA receptor whole-cell currents expressed in L929 fibroblasts. Neuron 1994;13:1421–1431. Lothman, E. W., E. H. Bertram III, and J. L. Stringer. Functional anatomy of hippocampal seizures. Prog. Neurobiol. 1991;37:1–82. Macdonald, R. L. Ethanol, g-aminobutyrate typeA receptors, and protein kinase C phosphorylation. Proc. Natl. Acad. Sci. U.S.A. 1995;92:3633–3635. Macdonald, R. L., and R. W. Olsen. GABAA receptor channels. Annu. Rev. Neurosci. 1994;17:569–602. Macdonald, R. L., R. E. Twyman, T. Ryan-Jastrow, and T. P. Angelotti. Regulation of GABAA receptor channels by anticonvulsant and convulsant drugs and by phosphorylation. Epilepsy Res. Suppl. 1992;9:265–277. McKernan, R. M., K. Quirk, R. Prince, P. A. Cox, N. P. Gillard, C. I. Ragan, and P. Whiting. GABAA receptor subtypes immunopurified from rat brain with alpha subunitspecific antibodies have unique pharmacological properties. Neuron 1991;7:667–676. McNamara, J. O., A. M. Peper, and V. Patrone. Repeated seizures induce long-term increase in hippocampal benzodiazepine receptors. Proc. Natl. Acad. Sci. U.S.A. 1980;77: 3029–3032. Meldrum, B. S., and R. W. Horton. Physiology of status epilepticus in primates. Arch. Neurol. 1973;28:1–9. Meldrum, B. S., R. A. Vigouroux, and J. B. Brierley. Systemic factors and epileptic brain damage: Prolonged seizures in paralyzed, artificially ventilated baboons. Arch. Neurol. 1973;29: 82–87. Mertens, S., D. Benke, and H. Mohler. GABAA receptor populations with novel subunit combinations and drug binding profiles identified in brain by alpha 5- and delta-subunitspecific immunopurification. J. Biol. Chem. 1993;268: 5965–5973. Nayeem, N., T. P. Green, I. L. Martin, and E. A. Barnard. Quaternary structure of the native GABAA receptor determined by electron microscopic image analysis. J. Neurochem. 1994;62:815–818. Nohria, V., N. Lee, R. D. Tien, E. R. Heinz, J. S. Smith, G. R. DeLong, et al. Magnetic resonance imaging evidence of hippocampal sclerosis in progression: A case report. Epilepsia 1994;35:1332–1336. Nusser, Z., and I. Mody. Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells. J. Neurophysiol. 2002;87:2624–2628. Nusser, Z., W. Sieghart, and P. Somogyi. Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells. J. Neurosci. 1998;18: 1693–1703. Oh, K.-S., C.-J. Lee, J. W. Gibbs, and D. A. Coulter. Postnatal development of GABAA receptor function in somatosensory thalamus and cortex: Whole-cell voltage clamp recordings in acutely isolated rat neurons. J. Neurosci. 1995;15:1341–1351. Olsen, R. W., and A. J. Tobin. Molecular biology of GABAA receptors. Fed. Am. Soc. Exp. Biol. J. 1990;4:1469–1480. Otis, T. S., Y. De Koninck, and I. Mody. Lasting potentiation of inhibition is associated with an increased number of gaminobutyric acid type A receptors activated during miniature inhibitory postsynaptic currents. Proc. Natl. Acad. Sci. U.S.A. 1994;91:7698–7702. Perlin, J. B., S. B. Churn, E. W. Lothman, and R. J. DeLorenzo. Loss of type II calcium/calmodulin-dependent kinase activity correlates with stages of development of electrographic
:
279
50.
51.
52.
53.
54. 55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65. 66.
67.
seizures in status epilepticus in rat. Epilepsy Res. 1992;11: 111–118. Pritchett, D. B., and P. H. Seeburg. g-Aminobutyric acidA receptor a5-subunit creates novel type II benzodiazepine receptor pharmacology. J. Neurochem. 1990;54:1802–1804. Pritchett, D. B., H. Sontheimer, B. D. Shivers, S. Ymer, H. Kettenmann, P. R. Schofield, and P. H. Seeburg. Importance of a novel GABAA subunit for benzodiazepine pharmacology. Nature 1989;338:582–585. Rabow, L. E., S. J. Russek, and D. H. Farb. From ion currents to genomic analysis: Recent advances in GABAA receptor research. Synapse 1995;21:189–274. Racine, R. J. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr. Clin. Neurophysiol. 1972;32:281–294. Ramsay, R. E. Treatment of status epilepticus. Epilepsia 1993;34(Suppl. 1):S71–S81. Saxena, N. C., and R. L. Macdonald. Properties of putative cerebellar GABAA receptor isoforms. Mol. Pharmacol. 1996; 49:567–579. Schofield, P. R., M. G. Darlison, N. Fujita, D. R. Burt, F. A. Stephenson, H. Rodriguez, et al. Sequence and functional expression of the GABA A receptor shows a ligand-gated receptor super-family. Nature 1987;328:221–227. Shin, C., H. B. Pedersen, and J. O. McNamara. gAminobutyric acid and benzodiazepine receptors in the kindling model of epilepsy: A quantitative radiohistochemical study. J. Neurosci. 1985;5:2696–2701. Simon, R. P., M. J. Aminoff, and N. L. Benowitz. Changes in plasma catecholamines after tonic-clonic seizures. Neurology 1984;34:255–257. Sloviter, R. S. Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat: The “dormant basket cell” hypothesis and its possible relevance to temporal lobe epilepsy, Hippocampus 1991; 1:41–66. Sloviter, R. S., E. Dean, A. L. Sollas, and J. H. Goodman. Apoptosis and necrosis induced in different hippocampal neuron populations by repetitive perforant path stimulation in the rat. J. Comp. Neurol. 1996;366:516–533. Smart, T. G., S. J. Moss, X. Xie, and R. L. Huganir. GABAA receptors are differentially sensitive to zinc: Dependence on subunit composition. Br. J. Pharmacol. 1991;103: 1837–1839. Sperk, G., C. Schwarzer, K. Tsunashima, K. Fuchs, and W. Sieghart. GABA(A) receptor subunits in the rat hippocampus. I. immunocytochemical distribution of 13 subunits. Neuroscience 1997;80:987–1000. Stringer, J. L., and E. W. Lothman. Reverberatory seizure discharges in hippocampal-parahippocampal circuits. Exp. Neurol. 1992;116:198–203. Sun, C., W. Sieghart, and J. Kapur. Synaptic and extrasynaptic distribution of g-aminobutyric acid type A receptor subunits in rat hippocampal dentate granule cells (abstr.). Epilepsia 2002;43(suppl. 7):145. Treiman, D. M. The role of benzodiazepines in the management of status epilepticus. Neurology 1990;40:32– 42. Valdes, F., R. M. Dasheiff, F. Birmingham, K. A. Crutcher, and J. O. McNamara. Benzodiazepine receptor increases after repeated seizures: Evidence for localization to dentate granule cells. Proc. Natl. Acad. Sci. U.S.A. 1982;79:193–197. VanLandingham, K. E., and E. W. Lothman. Self-sustaining limbic status epilepticus. I. Acute and chronic cerebral meta-
280
:
68.
69.
70.
71.
72.
73.
74.
bolic studies: Limbic hypermetabolism and neocortical hypometabolism. Neurology 1991;41:1942–1949. von Blankenfeld, G., S. Ymer, D. B. Pritchett, H. Sontheimer, M. Ewert, P. H. Seeburg, and H. Kettenmann. Differential benzodiazepine pharmacology of mammalian recombinant GABAA receptors. Neurosci. Lett. 1990;115:269–273. Wafford, K. A., S. A. Thompson, D. Thomas, J. Sikela, A. S. Wilcox, and P. J. Whiting. Functional characterization of human g-aminobutyric acidA receptors containing the a4 subunit. Mol. Pharmacol. 1996;50:670–678. Walton, N. Y., and D. M. Treiman. Response of status epilepticus induced by lithium and pilocarpine to treatment with diazepam. Exp. Neurol. 1988;101:267–275. Watanabe, Y., R. S. Johnson, L. S. Butler, D. K. Binder, B. M. Spiegelman, V. E. Papaioannou, and J. O. McNamara. Null mutation of c-fos impairs structural and functional plasticities in the kindling model of epilepsy. J. Neurosci. 1996;16: 3827–3836. Whiting, P., R. M. McKernan, and L. L. Iversen. Another mechanism for creating diversity in g-aminobutyrate type A receptors: RNA splicing directs expression of two forms of g2 subunit, one of which contains a protein kinase C phosphoryaltion site. Proc. Natl. Acad. Sci. U.S.A. 1990;87:9966–9970. Wisden, W., D. J. Laurie, H. Monyer, and P. H. Seeburg. The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon. J. Neurosci. 1992;12:1040–1062. Yaffe, K., and D. H. Lowenstein. Prognostic factors of pentobarbital therapy for refractory generalized status epilepticus. Neurology 1993;43:895–900.
21
Physiologic Mechanisms of Inhibition and Status Epilepticus
Introduction The delicate balance between excitation and inhibition is a crucial factor in normal brain function. A disruption of this balance in favor of excitation may lead to seizures and neuronal injury. g-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system (CNS). GABA is released from GABAergic neurons and acts on target cells to activate the GABAA, GABAB, and GABAC receptor subtypes. During prolonged seizures such as status epilepticus (SE), large shifts in transmembrane gradients and intense activation of receptors for various neurotransmitters may contribute to short- or longterm decreases in inhibition. This chapter describes the various mechanisms that contribute to decreased GABAergic inhibition during SE and considers the possible causes and cellular mechanisms of long-term changes in GABAergic inhibition that occur as a consequence of SE.
Physiology of GABAergic inhibition In the adult brain, GABA-mediated inhibition serves to limit neuronal excitability, and although there are special instances in which GABAergic activity may be considered excitatory, the overall effects of GABA are depressant. Synaptic release of GABA from inhibitory interneurons results in the activation of GABAA, GABAB, and GABAC receptors. The GABAA and GABAC receptors are multisubunit proteins that form chloride ion–selective channels. The GABAB receptors affect calcium or potassium channel activation via G proteins. The GABAA ionotropic receptors (GABAARs) are a family of heteropentamers formed from a family of at least 17 related subunits (a1–6, b1–4, g1–4, d, e, and p) that confer on the resultant GABAARs different sensitivities to GABA and to modulatory drugs (71). The GABAC ionotropic receptors are composed of r subunits (r1–3) and are spatially, functionally, and pharmacologically highly distinct from the GABAARs (11). Presently, the involvement of GABAC receptors in SE or its consequences is unknown, and they will not be discussed in this review. The metabotropic GABAB receptors appear to exist as heterodimers of GABAB1 and GABAB2 subunits that combine
to form a fully functional receptor (39, 54, 59, 97, 135). Two splice variants of the GABAB1 receptor have also been identified (59) and were subsequently shown to contribute to presynaptic, postsynaptic, and extrasynaptic receptor localization (20, 41, 95). P I Release of GABA from interneurons activates postsynaptic GABAARs, leading to fast inhibitory postsynaptic potentials (IPSPs), while GABAB receptors mediate slow IPSPs via K+ channel activation. Figure 21.1 illustrates the voltage dependence of stimulusevoked IPSPs and the separation of the slow and fast IPSP components with the use of selective receptor antagonists. In addition, spillover of GABA released in the synaptic cleft and the presence of ambient GABA (5, 65, 124) activate extrasynaptic GABAARs. Persistent activation of extrasynaptic GABAARs results in a tonic inhibitory influence on neurons. This small but significant GABAergic current has been observed in various brain regions (7, 12, 81, 89, 99). Immunocytochemical studies in these brain regions have provided evidence that the relative densities and subunit composition of extrasynaptic GABAARs is quite different from that of synaptic GABAARs (15, 33, 82, 83, 101, 109). Functional studies determined that extrasynaptic GABAARs activate at lower GABA concentrations and desensitize more slowly than the synaptic GABAARs (8, 13, 47, 81, 98). The differences in subunit composition also lead to considerable pharmacologic differences between the synaptic and extrasynaptic GABAARs (47, 81, 98). Figure 21.2 illustrates some of the differences between synaptic and extrasynaptic GABAAR activation and blockade in a hippocampal pyramidal neuron. Several lines of evidence also point to distinctions between synaptic and extrasynaptic GABAB receptors and their associated conductances. Thus, GABAB receptor antagonists (e.g., CGP 35348) have different effects on responses to exogenous GABA compared with baclofen (53, 91, 108). Also, K+ currents activated by synaptic GABA release are not blocked by external Cs+, whereas baclofen-induced K+ currents are sensitive to Cs+ (53). In addition, exogenous GABA was demonstrated to activate both Ba2+-sensitive and -insensitive currents, whereas baclofen-induced currents and synaptic
:
281
A
B
10
CNQX + APV
0 -110
-100
-90
-80
-70
-60
Vm (mV)
-5
-10
C
CNQX+APV
Vh = -65 mV
20 mV 100 ms
-15
300 pA
-20
CNQX+APV + BMI
CNQX+APV+BMI + CGP 35348
Peak early IPSP (mV)
5
WASH
5 mV 150 ms F 21.1 Voltage dependence and pharmacologic isolation of inhibitory postsynaptic responses recorded with a potassium acetate–filled microelectrode in a rat hippocampal CA1 neuron in vitro. (A) Voltage responses (upper traces) to current injection (lower traces) and direct stimulation (arrow) of interneurons near the recording site in the presence of non-NMDA (CNQX, 10 mM) and NMDA (APV, 40 mM) receptor blockade. (B) Peak early IPSP
plotted versus the voltage just prior to the stimulus from traces in A. The early IPSP reversal potential was estimated at -78 mV from a second-order regression to the points. (C) Selective block of the early IPSP by the GABAAR antagonist bicuculline methiodide (BMI, 5 mM). The late IPSP is then blocked by the GABAB receptor antagonist CGP 35348 (250 mM). Partial recovery is seen after wash in CNQX (10 mM) and APV (40 mM).
GABAB receptor-mediated IPSPs in hippocampal CA1 neurons are completely blocked by external Ba2+ (91, 92).
responses to GABA is illustrated in Figure 21.3C. In addition, tonic activation of presynaptic GABAB receptors has been demonstrated in several brain regions (3, 17, 37).
P I Presynaptically, GABA causes inhibition via decreased transmitter release. This is achieved either by Cl- channel-mediated depolarization of the terminal membrane potential when GABAA receptors are activated (76, 144) or by K+ channel-mediated hyperpolarization when GABAB receptors are activated (76). Perhaps even more important is the presynaptic inhibition due to GABAB receptor-mediated decreases in calcium channel activation (28, 141) and the subsequent decrease in transmitter release (52). When GABA receptors are located on glutamatergic neuron terminals, their activation will lead to a decrease in excitation. However, when GABA receptors are located on the terminals of inhibitory interneurons (autoreceptors), their activation will decrease inhibition by decreasing GABA release. An example of presynaptic GABAB receptor-mediated decrease in postsynaptic
282
:
Development of GABAergic inhibition GABAergic neurons are generated early in the brain. Stimulus-evoked synaptic release of GABA occurs at an early postnatal age (143). However, GABA receptors undergo dramatic functional changes during early postnatal development. The transient appearance of depolarizing GABAAR-mediated synaptic responses with a peculiar pharmacologic profile has been reported (10, 115). During early postnatal development, only depolarizing responses to GABAAR activation are observed in the rodent hippocampus (10, 80, 119), owing largely to the immaturity of the extrusion systems for Cl- (134) and the likely involvement of HCO3- flux in the depolarizing responses. Further, GABAAR activation during the first 2 weeks of postnatal development
F 21.2 Pharmacologic separation of GABAAR-mediated synaptic and extrasynaptic (tonic) currents in a rat hippocampal CA1 neuron. The neuron was voltage-clamped at 0 mV during whole-cell recording with a Cs-gluconate-filled patch electrode. Tetrodotoxin (TTX), glutamate receptor blockers CNQX and APV, and the GABAB receptor blocker CGP 54626 were applied in the bath solution. Outward miniature inhibitory postsynaptic currents (mIPSCs, fast upward deflections in the current trace) are
B
CNQX + APV
10
10 mV 100 ms
5 0 -120 -110 -100
Vm (mV)
-90
-80
-70
-60 -5
Peak late IPSP (mV)
A
superimposed on the tonic holding current during the recording. Addition of the selective glycine receptor antagonist strychnine (1 mM) has no effect on the kinetic parameters of the averaged mIPSCs (top traces). However, addition of the GABAAR blocker gabazine (1 mM) selectively blocks the mIPSCs, leaving the tonic current intact. Subsequent application of diazepam (0.3 mM) increases the tonic current. Addition of the GABAAR antagonist picrotoxin (50 mM) completely blocks the tonic current.
-10 -15
300 pA
C
-20
CNQX + APV + CGP 35348
CNQX + APV
Vh = -98 mV
F 21.3 Voltage dependence of the late IPSP and presynaptic inhibition of GABA responses in a rat dentate granule cell. (A) Voltage responses (upper traces) to current injection (lower traces) and presynaptic stimuli (arrow) in the outer molecular layer of the dentate gyrus. (B) Graph of peak late IPSP plotted versus the voltage just prior to the stimulus from traces in A. The late IPSP reversal potential was estimated at -98 mV from a second-order
5 mV 50 ms
regression to the points. (C) Presynaptic paired-pulse stimulus applied near the recording site evokes a markedly smaller second response. The holding potential was -98 mV to minimize the effects of postsynaptic GABAB receptor activation. Application of the GABAB receptor antagonist CGP 35348 (250 mM) increased the size of the second response, suggesting the involvement of GABAB receptors in the reduction of the second response.
seems to play a predominantly excitatory role (23, 43). In neonatal hippocampal CA3 neurons, GABAARs act synergistically with N-methyl--aspartate (NMDA) receptors to increase intracellular Ca2+ (64). Inhibition during the first 2 weeks of postnatal development appears to be mediated by presynaptic GABAB receptors, whereas postsynaptic GABAB receptor-mediated inhibition appears to be delayed (42, 43, 70). These dramatic changes in GABAergic inhibition during neonatal development likely contribute to the greater susceptibility of the immature brain to seizures. The excitatory role played by GABAARs during early development also suggests that GABAA receptor-enhancing drugs may be of limited benefit as anticonvulsants during early postnatal development.
SE-induced early changes in GABAergic inhibition Some of the early events that lead to decreased inhibition involve ionic gradient changes accompanying sustained seizure activity. One consequence of these ionic changes is a depolarizing shift of the reversal potential for the GABAAR-mediated synaptic currents. The main contributors to this shift in the GABA current reversal potential are (1) increased extracellular [K+], (2) increased intracellular Cl- loading of neurons, and (3) contribution of HCO3- flux through the GABAAR ionophore. Extracellular [K+] rises during epileptiform seizures (38). Increasing extracellular [K+] causes a positive shift of the reversal potential of the GABAAR-mediated IPSPs in central neurons (75, 140). This occurs because the maintenance of low intracellular [Cl-] in central neurons depends in part on the cotransport system for Cl- and K+ ions (121, 122). For example, increasing extracellular [K+] from 2.5 to 15 or 30 mM shifts the reversal potential of the GABA-evoked currents in the depolarizing direction by about 10 mV for each of the above extracellular [K+] changes (Figure 21.4). Intense activation of the GABAAR/chloride channel complex during epileptiform activity will also cause intracellular [Cl-] to rise. The resultant depolarizing shift in the Cl- reversal potential contributes to the decrement of the GABAA receptor-mediated IPSPs. This point is illustrated with whole-cell patch-clamp recordings from CA1 neurons (Figure 21.5). When the patch pipette [Cl-] is changed from 17 to 72 mM, about a 25-mV depolarizing shift in the GABA reversal potential occurs for any given extracellular [K+] (142). Large shifts in the reversal potential for the GABA currents were reported in CA1 neurons after 45 minutes of pilocarpine-induced SE (56). Activity-dependent collapse of opposing concentration gradients for HCO3- and Cl- that permeate the GABAAR/ chloride ionophore were proposed to account for the dendritic depolarizing responses observed during intense activation of GABAergic interneurons (111, 112). The depolarizing
284
:
responses appear to be sufficient to decrease the voltagedependent Mg2+ block of the NMDA receptor, because the depolarizations are reduced by NMDA receptor blockers (112). This GABAA receptor-mediated excitation is therefore likely to contribute to increased NMDA receptor activation during seizures in a manner analogous to the synergistic effects of GABAA receptor activation on NMDA receptors observed during neonatal development (64).
Mechanisms that contribute to decreased release of GABA Several mechanisms contribute to the decreased release of GABA during seizures. During SE, large region-specific changes in the rate of GABA synthesis and turnover have been documented (133). For example, a decreased GABA turnover rate in the hippocampus during SE is suggestive of decreased GABA release (133). One mechanism by which a decrement in GABA release may occur is activation of autoreceptors on interneuron presynaptic terminals, discussed earlier in this chapter (see Figure 21.3C). Another way in which a decrement in GABA release may occur is by activation of metabotropic glutamate receptors (mGluRs). For example, in the hippocampal CA1 area, activation of mGluRs reduces synaptically evoked IPSPs (32, 67). Reduced transmission at excitatory synapses onto inhibitory interneurons (32, 35), and reduced transmission at inhibitory synapses onto CA1 pyramidal neurons (32, 55), was proposed to account for the reduced IPSPs. In contrast, others showed marked excitation of specific interneuron subtypes by mGluR activation (74). Thus, regional differences in the distribution of multiple mGluR subtypes may confer pro- or anticonvulsant properties, depending on which neuronal pathway is activated. Reduction of GABA release may also occur via a depolarization-induced diffusible retrograde messenger. Considerable evidence suggests that brief depolarizations of postsynaptic cells that produce increases in intracellular calcium result in decreased spontaneous or evoked release of GABA lasting 1–2 minutes (1, 93, 94). This occurs in the absence of appreciable effects on postsynaptic responses to exogenously applied GABA. Activation of presynaptic cannabinoid CB1 receptors with exogenous agonists mimics the depolarization-induced reduction of GABA release, while CB1 receptor antagonists block this phenomenon (58, 85, 139). The precise nature of the retrograde signaling molecule(s) has yet to be elucidated, but the endocannabinoids anandamide and 2-arachidonylglycerol appear to be the most likely candidates (34, 113). This mechanism is likely to operate during the sustained seizures. SE produces time-dependent changes in CB1R protein expression. Hippocampal CB1Rs are located almost exclusively on the presynaptic terminal arborizations of
A
+
+
2.5 mM [K ]o
+
15 mM [K ]o
Vh0 = -59 mV
30 mM [K ]o
-52 mV
-42 mV
200 pA 400 ms
60 mV
B GABA current (pA)
800 400 0 -400 -800
-90
-70
-50
-30
-10
Voltage (mV) F 21.4 Reversal potential of GABA-evoked currents is dependent on extracellular [K+]. In whole-cell patch-clamp recordings from hippocampal CA1 neurons in rat brain slices, GABA is applied by picospritzer near the cell body of the recorded neuron, resulting in outward or inward currents, depending on the mem-
brane voltage at the time of drug application. When the extracellular potassium is increased from 2.5 to 15 or 30 mM, the reversal potential of the peak recorded currents plotted in part B shifts in the depolarizing direction by about 10 mV for each of the extracellular [K+] changes. (Adapted with permission from Zhang et al. [142].)
cholecystokinin-containing basket cells (58, 125), which form a network of fibers impinging on the cell bodies and proximal dendrites of principle excitatory neurons such as the CA1 pyramidal cells (Figure 21.6A). At 1 week after pilocarpine-induced SE, CB1R protein is reduced in the rat hippocampus (Figure 21.6). Such CB1R decreases would be expected to relieve the endocannabinoid system–mediated suppression of inhibition. However, CB1R expression returns to control levels at 1 month after SE (Figure 21.6). Furthermore, in the same model others have shown selective upregulation of CB1Rs in the CA1 region of the hippocampus at 1 year after SE (131). Long-term increases in CB1R expression and function were also observed after a single prolonged febrile seizure in rats (21). Taken together, these data suggest that presynaptic regulation of GABA release is mediated by multiple transmitter systems. These systems are altered by SE, and the longlasting changes in plasticity may contribute to the pathophysiology of epilepsy.
SE-induced decreases in GABAA receptor function A variety of activity-dependent processes result in decreased postsynaptic GABAA receptor function. One of these is receptor desensitization, which would be expected to occur during sustained activation of GABAA receptors (18, 57). A decrease in the number of GABAA receptors is another. In the absence of changes in receptor affinity, there occurs a marked decrease in the number of GABA-binding sites in rat forebrain homogenates after SE (57). Changes in the state of receptor phosphorylation may also account for some of the decreases in GABAA receptor function. This issue is complicated by the fact that different protein kinases seem to phosphorylate different GABAA receptor subunit combinations, producing either an enhancement or inhibition of receptor function, depending on which kinase is involved (24, 71, 78, 132).
:
285
-20
[Cl-] p 17.2 mM
E GABA (mV)
72.2 mM -40
-60
-80 1.0
10.0
log [K+ ]o (mM)
F 21.5 Reversal potential of GABA-evoked currents is dependent on intracellular [Cl-] and extracellular [K+]. Each set of data points came from two () and three () neurons recorded in whole-cell clamp configuration. Patch pipette [Cl-] was adjusted to 17.2 mM () or 72.2 mM () to mimic the effects of intracellular Cl- loading. Note the large depolarizing shift in EGABA with the high intracellular [Cl-]. The linear regression lines were computed from the pooled data, with slopes of 14.3 mV () and 15.8 mV () per 10-fold change in extracellular [K+]. (Adapted with permission from Zhang et al. [142].)
It has also been known for quite some time that changes in the level of intracellular calcium ions affect GABAAR function. The large increases in intracellular [Ca2+] that are expected to occur during prolonged seizures have been shown to decrease GABAAR activation (22, 30). In hippocampal neurons, calcium influx through the NMDA receptor activates calmodulin and a calmodulin-dependent phosphatase (calcineurin), which then dephosphorylates the GABAAR protein, leading to decreased receptor function (114).
SE-induced long-term changes in GABAergic inhibition The kainate and pilocarpine animal models of SE produce widespread brain damage and the delayed occurrence of limbic and generalized convulsions (19, 25). Electrical stimulation of the perforant path under urethane anesthesia in adult rats produces neuronal injury that is restricted to the hippocampus, has an excitotoxic appearance similar to that induced by kainic acid (87, 103, 105), and is associated with a loss of frequency-dependent paired pulse inhibition in the dentate gyrus (104), as well as the progressive development of spontaneous recurrent seizures (102). The type of hippocampal damage that is seen in animal models of SE is remarkably similar to that seen in human patients with temporal lobe epilepsy (31, 46, 60). Spontaneous seizures have been tentatively explained either by the sprouting and reorganization of recurrent excitatory connections (6, 25, 26, 96, 110, 117, 118, 120) or by the loss (2, 84) or deafferentation (9, 104) of inhibitory interneurons in the hippocampus. Based on the animal models of SE, one might expect that a loss or deafferentation of some hilar GABAergic
286
:
interneurons would lead to decreased inhibitory synaptic potentials. Several studies demonstrated granule cell hyperexcitability in slices from human epileptic hippocampus. These studies also indicated the involvement of NMDA receptors in this hyperexcitability (50, 51, 128). However, solid quantitative evidence for decreased synaptic GABAergic inhibition has been rather elusive in studies on human tissue from hippocampal resections in intractable cases of temporal lobe epilepsy (63, 130). This has been due, in part, to the difficulty of obtaining appropriate nonepileptic controls to compare with human epileptic tissue. Another possible reason is the documented ability of the dentate gyrus to recover from the loss of inhibition. For example, pairedpulse recordings in human epileptic dentate gyrus indicate that in addition to a loss of inhibitory input, there is also an increase in inhibition that is dependent on the pathway of stimulation (129). In animal models of temporal lobe epilepsy, many studies have shown that, in contrast to the persistently depressed GABAergic function in the CA1 area of the hippocampus, the dentate gyrus, after an initial loss, seem to undergo compensatory increases in GABAAR-mediated paired-pulse inhibition (29, 86, 102, 116, 126) and increased postsynaptic responsiveness of neurons to GABAAR agonists (88, 123, 127). Increased postsynaptic responsiveness to GABA could arise from increases in the number of postsynaptic GABAARs (88), sprouting of GABAergic interneurons (27), or changes in the subunit composition and sensitivity of GABAARs. In the hippocampus, consequences of SE include differential changes in the GABAAR subunit composition in the dentate gyrus compared with the CA1 region, including changes in the sensitivity to benzodiazepines and zinc (42, 73). Chapter 20 provides a detailed description of GABAAR subunit composition changes after SE. Selective alterations in GABAAR subunit composition have been demonstrated in the surgical specimens from TLE patients with hippocampal sclerosis, where prominent upregulation, mainly of the a2 subunit, was seen on somata and apical dendrites of dentate granule cells and a striking rearrangement of a3 subunit immunoreactivity occurred from the soma to the distal dendrites of CA2 pyramidal neurons (69). Dramatic changes in subunit composition of hippocampal synaptic and extrasynaptic GABAARs have also been demonstrated in models of ethanol (16, 66) and progesterone (106, 107) withdrawal hyperexcitability. Interestingly, GABAAR-mediated synaptic inhibition is compromised in epileptic human dentate gyrus, but this is observed only after high-frequency activation of the perforant path (48). In both human and rat epileptic hippocampal slices, GABA current depression produced by a high-frequency stimulus could be blocked by the NMDA receptor antagonist APV. Inclusion of the calcium buffer BAPTA in the recording pipettes also blocked the depression of GABA currents by high-frequency stimulation, suggest-
F 21.6 CB1R expression changes in rat hippocampus after pilocarpine-induced SE. (A) Pseudocolor image of CB1R immunoreactivity (CB1R-ir) in the CA1 pyramidal cell area. Note the dense plexus of CB1R-ir fibers (fluoroscein signal) surrounding the somata and proximal dendrites of CA1 neurons (rhodamine signal). A polyclonal antibody against the NMDA receptor subunit C/D (gift of Dr. Juan Carlos Marvizon) was used to label CA1 neurons and a C-terminal-directed polyclonal antibody (gift of Dr. Ken Mackie) was used to label CB1Rs. Scale bar = 40 mm. (B and C) Low-magnification images of CB1R-ir in hippocampal sections
from a control rat (B) and a rat 1 week after SE (C). Sections were processed simultaneously for CB1R immunoreactivity to allow for direct comparisons between treatments. The two digital images were obtained at identical microscope and camera settings. Note the large decreases in CB1R-ir 1 week after SE. Scale bar = 200 mm. (D) Examples of exposed Western blot gels from naive and pilocarpine controls and from hippocampi of rats at 1 week and 1month after SE. (E) Summary graph of SE-induced CB1R protein changes in rat hippocampi. Note the reversible decreases in CB1R protein in hippocampi of rats 1 week after SE. (See Color Plate 6.)
ing a postsynaptic calcium-dependent mechanism for the GABA current depression (49). In this case, a reduction in GABAergic synaptic inhibition is secondary to the increased NMDA receptor activity in the epileptic dentate gyrus. In the epileptic entorhinal cortex, hyperexcitability is also attributed in part to increased NMDA receptor activation (40). In this brain region, however, blockade of NMDA receptors does not restore GABAergic IPSPs, even though when IPSPs are evoked by direct stimulation of interneurons they appear similar to those recorded from control brain slices (40). Altered GABA transporter function was also reported in the human epileptic hippocampus (36). In intracellular recordings from slices of human sclerotic hippocampus, GABA application produced very prolonged responses in dentate granule cells compared with GABA responses in granule cells from tumor-related temporal lobe epilepsy
patients (138). When a GABA transport inhibitor is applied, it greatly prolongs the GABA responses in the tumor group but has relatively little effect on the duration of responses in the sclerotic tissue (138). This also is a region-specific phenomenon because CA2 pyramidal neurons in sclerotic tissue and granule cells in nonsclerotic tissue do not exhibit prolonged responses to GABA (137). Decreased GABA transporter function has been suggested to contribute to the maintenance of the epileptogenic state (36), or alternatively may represent a protective mechanism that allows released GABA to persist in the extracellular space to dampen the excessive excitability of granule cells, at least during the interictal phase (90, 138). In addition to the alterations in GABAA receptor function, longlasting changes in the GABAB receptor function have also been documented. The most dramatic changes were observed in a model of SE-induced temporal lobe epilepsy
:
287
A
control 20 mV 100 ms
B
stimulated 20 mV 100 ms
300 pA
control stimulated
5
D
control
0 -5 -10 -15
stimulated
0
slow IPSP (mV)
slow IPSP (mV)
C
300 pA
-2 -4
*
-6 -8
-20 -110
-100
-90
-80
-70
-60
membrane potential (mV)
-10
n=8
n = 11
F 21.7 Comparison of voltage-dependent synaptic responses in granule cells from control rat (A) and a rat in which SE had been induced 1 month earlier by perforant-path stimulation (B). The cell membrane potential (upper traces) was varied by current pulse injection (bottom traces), and a presynaptic stimulus (100 mA, 0.2 msec) was applied at the arrow. The locations of recording and stimulating electrodes, as well as the size of current pulses (lower traces) and presynaptic stimuli (100 mA, 0.2 msec), were very similar for both cells. Note the smaller amplitude of the slow IPSP (plotted in C as solid
circles) compared to that in A. Also note the unusually small fast IPSP component. (C) Plot of the peak slow IPSP versus membrane potential just prior to synaptic stimuli from traces in A (open circles) and B (closed circles). (D) Comparison of slow IPSP amplitudes from control (8 cells, 8 slices, 5 rats) and stimulated animals (11 cells, 11 slices, 8 rats). Due to variability in resting membrane potentials between individual cells, the slow IPSP values for all cells were estimated at -70 mV from first- or secondorder regressions to the data, as illustrated in C. *P < 0.05 versus group means.
in the hippocampal CA1 region (68). In this hippocampal region, a profound dysfunction in both pre- and postsynaptic GABAB receptor-mediated activity was demonstrated 1 month after SE (73). By contrast, downregulation of only presynaptic GABAB receptors was proposed in a model of kainate-induced seizures, without decreases in postsynaptic GABAB receptor function (45). Also, decreased presynaptic GABAB receptor function selective to glutamatergic synaptic terminals was observed after kindlinginduced seizures in the amygdala (4). Our recordings in dentate granule cells of rats 1 month after SE induced by perforant path stimulation showed a significant reduction in the GABAB receptor-mediated synaptic responses in stimulated rats compared with nonstimulated controls (Figure 21.7), without significant changes in presynaptic GABAB
receptor activation (134). Recordings from dentate granule cells of patients with medial temporal lobe epilepsy (MTLE) were also demonstrated to have reduced GABAB receptormediated IPSPs when compared with the tumor epilepsy group, which did not show the characteristic cell loss and synaptic reorganization of MTLE (136). Taken together, these studies indicate that SE-induced decreases in GABAB receptor function are region specific and that the magnitude of the decrease and the location of the affected receptors (pre- versus postsynaptic) are also dependent on the brain region studied. Decreased activity of postsynaptic GABAB receptors on CA1 pyramidal and dentate granule cells could provide a partial explanation for the chronic epileptogenicity of these regions after SE. The slow IPSP has been shown to act as a
288
:
powerful inhibitory mechanism for control of the NMDA receptor-mediated responses (77). Blockade of GABAB receptors in partially disinhibited hippocampal slices results in prolonged burst discharges of pyramidal cells (72, 100). The reduced slow IPSPs in hippocampal neurons after SE could similarly permit greater activation of NMDA receptors, thus leading to the epileptiform burst discharges observed in vivo. In summary, a variety of mechanisms contribute to the reduction of GABAergic inhibition during SE. The longterm consequences of SE include decreases in GABA transport and a persistent reduction in both GABAA and GABAB receptor-mediated inhibition that exhibits considerable regional specificity. The current challenge is to elucidate the precise mechanisms by which such decreases in GABAA and GABAB receptor function occur. This work was supported by a National Science Foundation grant No. IBN952351 and NIH grants Nos. NS38331 and AA07680. I thank Tim DeLorey, Richard Olsen, and Claude Wasterlain for helpful discussions and comments on the manuscript.
REFERENCES 1. Alger, B. E., and T. A. Pitler. Retrograde signaling at GABAAreceptor synapses in the mammalian CNS. Trends Neurosci. 1995;18:333–340. 2. Andre, V., C. Marescaux, A. Nehlig, and J. M. Fritschy. Alterations of hippocampal GABAergic system contribute to development of spontaneous recurrent seizures in the rat lithium-pilocarpine model of temporal lobe epilepsy. Hippocampus 2001;11:452–468. 3. Aroniadou-Anderjaska, V., F. M. Zhou, C. A. Priest, M. Ennis, and M. T. Shipley. Tonic and synaptically evoked presynaptic inhibition of sensory input to the rat olfactory bulb via GABAB heteroreceptors. J. Neurophysiol. 2000;84:1194– 1203. 4. Asprodini, E. K., D. G. Rainnie, and P. Shinnick-Gallagher. Epileptogenesis reduces the sensitivity of presynaptic gammaaminobutyric acidB receptors on glutamatergic afferents in the amygdala. J. Pharmacol. Exp. Ther. 1992;161:1011–1021. 5. Attwell, D., B. Barbour, and M. Szatkowski. Nonvesicular release of neurotransmitter. Neuron 1993;11:401–407. 6. Babb, T. L., W. R. Kupfer, J. K. Pretorius, P. H. Crandall, and M. F. Levesque. Synaptic reorganization by mossy fibers in human epileptic fascia dentate. Neuroscience 1991;42:351– 363. 7. Bai, D., G. Zhu, P. Pennefather, M. F. Jackson, J. F. Macdonald, and B. A. Orser. Distinct functional and pharmacological properties of tonic and quantal inhibitory postsynaptic currents mediated by g-aminobutyric acidA receptors in hippocampal neurons. Mol. Pharmacol. 2001;59:814–824. 8. Banks, M. I., and R. A. Pearce. Kinetic differences between synaptic and extrasynaptic GABAA receptors in CA1 pyramidal cells. J. Neurosci. 2000;20:937–948. 9. Bekenstein, J. W., and E. W. Lothman. Dormancy of inhibitory interneurons in a model of temporal lobe epilepsy. Science 1993;259:97–100.
10. Ben-Ari, Y., E. Cherubini, R. Corradetti, and J. L. Gaiarsa. Giant synaptic potentials in immature rat CA3 hippocampal neurons. J. Physiol. (Lond.) 1989;416:303–325. 11. Bormann, J. The “ABC” of GABA receptors. Trends Pharmacol. Sci. 2000;21:16–19. 12. Brickley, S. G., S. G. Cull-Candy, and M. Farrant. Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors. J. Physiol. (Lond.) 1996;497(Pt. 3):753–759. 13. Brickley, S. G., S. G. Cull-Candy, and M. Farrant. Singlechannel properties of synaptic and extrasynaptic GABAA receptors suggest differential targeting of receptor subtypes. J. Neurosci. 1999;19:2960–2973. 14. Brünig, I., S. Penschuck, B. Berninger, J. Benson, and J. M. Fritschy. BDNF reduces miniature inhibitory postsynaptic currents by rapid downregulation of GABAA receptor surface expression. Eur. J. Neurosci. 2001;13:1320–1328. 15. Brünig, I., E. Scotti, C. Sidler, and J. M. Fritschy. Intact sorting, targeting, and clustering of g-aminobutyric acid A receptor subtypes in hippocampal neurons in vitro. J. Comp. Neurol. 2002;443:43–55. 16. Cagetti, E., J. Liang, I. Spigelman, and R. W. Olsen. Withdrawal from chronic intermittent ethanol treatment changes subunit composition, reduces synaptic function, and decreases behavioral responses to positive allosteric modulators of GABAA receptors. Mol. Pharmacol. 2003;63: 53–64. 17. Canning, K. J., and L. S. Leung. Excitability of rat dentate gyrus granule cells in vivo is controlled by tonic and evoked GABAB receptor-mediated inhibition. Brain Res. 2000;863: 271–275. 18. Cash, D. J., and K. Subbarao. Two desensitization processes of GABA receptor from rat brain: Rapid measurements of chloride ion flux using quench-flow techniques. FEBS Lett. 1987;217:129–133. 19. Cavalheiro, E. A., J. P. Leite, A. Z. Bortolotto, W. A. Turski, C. Ikonomidou, and L. Turski. Long-term effects of pilocarpine in rats: Structural damage of the brain triggers kindling and spontaneous recurrent seizures. Epilepsia 1991; 32:778–782. 20. Charles, K. J., M. L. Evans, M. J. Robbins, A. R. Calver, R. A. Leslie, and M. N. Pangalos. Comparative immunohistochemical localisation of GABAB1a, GABAB1b and GABAB2 subunits in rat brain, spinal cord and dorsal root ganglion. Neuroscience 2001;106:447–467. 21. Chen, K., A. Ratzliff, L. Hilgenberg, et al. Long-term plasticity of endocannabinoid signaling induced by developmental febrile seizures. Neuron 2003;39:599–611. 22. Chen, Q. X., A. Stelzer, A. R. Kay, and R. K. S. Wong. GABAA receptor function is regulated by phosphorylation in acutely dissociated guinea-pig hippocampal neurons. J. Physiol. (Lond.) 1990;420:207–221. 23. Chestnut, T. J., and J. W. Swann. Disinhibitory actions of the GABAA agonist muscimol in immature hippocampus. Brain Res. 1989;502:365–374. 24. Churn, S. B., A. Rana, K. Lee, J. T. Parsons, A. De Blas, and R. J. DeLorenzo. Calcium/calmodulin-dependent kinase II phosphorylation of the GABAA receptor a1 subunit modulates benzodiazepine binding. J. Neurochem. 2002;82: 1065–1076. 25. Cronin, J., and E. F. Dudek. Chronic seizures and collateral sprouting of dentate mossy fibers after kainic acid treatment in rats. Brain Res. 1988;474:181–184.
:
289
26. Cronin, J., A. Obenaus, C. R. Houser, and F. E. Dudek. Electrophysiology of dentate granule cells after kainate-induced synaptic reorganization of the mossy fibers. Brain Res. 1992; 573:305–310. 27. Davenport, C. J., W. J. Brown, and T. L. Babb. Sprouting of GABAergic and mossy fiber axons in dentate gyrus following intrahippocampal kainate in the rat. Exp. Neurol. 1990;109: 180–190. 28. Davies, C. H., and G. L. Collingridge. The physiological regulation of synaptic inhibition by GABAB autoreceptors in rat hippocampus. J. Physiol. (Lond.) 1993;472:245–265. 29. De Jonge, M., and R. J. Racine. The development and decay of kindling-induced increase in paired-pulse depression in the dentate gyrus. Brain Res. 1987;412:318–328. 30. De Koninck, Y., and I. Mody. The effects of raising intracellular calcium on synaptic GABAA receptor-channels. Neuropharmacology 1996;35:1365–1374. 31. de Lanerolle, N. C., J. H. Kim, R. J. Robbins, and D. D. Spencer. Hippocampal interneuron loss and plasticity in human temporal lobe epilepsy. Brain Res. 1989;495:387– 395. 32. Desai, M. A., C. J. McBain, J. A. Kauer, and P. J. Conn. Metabotropic glutamate receptor-induced disinhibition is mediated by reduced transmission at excitatory synapses onto interneurons and inhibitory synapses onto pyramidal cells. Neurosci. Lett. 1994;181:78–82. 33. Devor, A., J. M. Fritschy, and Y. Yarom. Spatial distribution and subunit composition of GABAA receptors in the inferior olivary nucleus. J. Neurophysiol. 2001;85:1686–1696. 34. Di Marzo, V., A. Fontana, H. Cadas, et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 1994;372:686–691. 35. Doherty, J., and R. Dingledine. Reduced excitatory drive onto interneurons in the dentate gyrus after status epilepticus. J. Neurosci. 2001;21:2048–2057. 36. During, M. J., K. M. Ryder, and D. D. Spencer. Hippocampal GABA transporter function in temporal-lobe epilepsy. Nature 1995;376:174–177. 37. Emri, Z., J. P. Turner, and V. Crunelli. Tonic activation of presynaptic GABAB receptors on thalamic sensory afferents. Neuroscience 1996;72:689–698. 38. Fertziger, A. P., and J. B. Ranck. Potassium accumulation in interstitial space during epileptiform seizures. Exp. Neurol. 1970;26:571–585. 39. Filippov, A. K., A. Couve, M. N. Pangalos, F. S. Walsh, D. A. Brown, and S. J. Moss. Heteromeric assembly of GABABR1 and GABABR2 receptor subunits inhibits Ca2+ current in sympathetic neurons. J. Neurosci. 2000;20:2867– 2874. 40. Fountain, N. B., J. Bear, E. H. Bertram III, and E. W. Lothman. Responses of deep entorhinal cortex are epileptiform in an electrogenic rat model of chronic temporal lobe epilepsy. J. Neurophysiol. 1998;80:230–240. 41. Fritschy, J. M., V. Meskenaite, O. Weinmann, M. Honer, D. Benke, and H. Mohler. GABAB-receptor splice variants GB1a and GB1b in rat brain: Developmental regulation, cellular distribution and extrasynaptic localization. Eur. J. Neurosci. 1999;11:761–768. 42. Fukuda, A., I. Mody, and D. A. Prince. Differential ontogenesis of presynaptic and postsynaptic GABAB inhibition in rat somatosensory cortex. J. Neurophysiol. 1993;70:448–452. 43. Gaiarsa, J.-L., H. McLean, P. Congar, et al. Postnatal maturation of gamma-aminobutyric acidA and B-mediated inhibi-
290
:
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
tion in the CA3 hippocampal region of the rat. J. Neurobiol. 1995;26:339–349. Gibbs, J. W., M. D. Shumate, and D. A. Coulter. Differential epilepsy-associated alterations in postsynaptic GABA(A) receptor function in dentate granule and CA1 neurons. J. Neurophysiol. 1997;77:1924–1938. Haas, K. Z., E. F. Sperber, S. L. Moshe, and P. K. Stanton. Kainic acid-induced seizures enhance dentate gyrus inhibition by downregulation of GABAB receptors. J. Neurosci. 1996;16:4250–4260. Houser, C. R., J. E. Myashiro, B. E. Swartz, G. O. Walsh, J. R. Rich, and A. V. Delgado-Escueta. Altered patterns of dynorphin immunoreactivity suggest mossy fiber reorganization in human hippocampal epilepsy. J. Neurosci. 1990;10: 267–282. Hutcheon, B., P. Morley, and M. O. Poulter. Developmental change in GABAA receptor desensitization kinetics and its role in synapse function in rat cortical neurons. J. Physiol. (Lond.) 2000;522(Pt. 1):3–17. Isokawa, M. Decrement of GABAA receptor-mediated inhibitory postsynaptic currents in dentate granule cells in epileptic hippocampus. J. Neurophysiol. 1996;75:1901–1908. Isokawa, M. Modulation of GABAA receptor-mediated inhibition by postsynaptic calcium in epileptic hippocampal neurons. Brain Res. 1998;810:241–250. Isokawa, M., G. Avanzini, D. M. Finch, T. L. Babb, and M. F. Levesque. Physiologic properties of human dentate granule cells in slices prepared from epileptic patients. Epilepsy Res. 1991;9:242–250. Isokawa, M., and I. Fried. Extracellular slow negative transient in the dentate gyrus of human epileptic hippocampus in vitro. Neuroscience 1996;72:31–37. Issacson, J. S., and B. Hille. GABAB-mediated presynaptic inhibition of excitatory transmission and synaptic vesicle dynamics in cultured hippocampal neurons. Neuron 1997;18: 143–152. Jarolimek, W., M. Bijak, and U. Misgeld. Differences in the Cs block of baclofen and 4-aminopyridine induced potassium currents of guinea pig CA3 neurons in vitro. Synapse 1994; 18:169–177. Jones, K. A., B. Borowsky, J. A. Tamm, et al. GABAB receptors function as a heteromeric assembly of the subunits GABABR1 and GABABR2. Nature 1998;396:674– 679. Jouvenceau, A., P. Dutar, and J.-M. Billard. Presynaptic depression of inhibitory postsynaptic potentials by metabotropic glutamate receptors in rat hippocampal CA1 pyramidal cells. Eur. J. Pharmacol. 1995;281:131–139. Kapur, J., and D. A. Coulter. Experimental status epilepticus alters gamma-aminobutyric acid type A receptor function in CA1 pyramidal neurons. Ann. Neurol. 1995;38:893–900. Kapur, J., E. W. Lothman, and R. J. DeLorenzo. Loss of GABAA receptors during partial status epilepticus. Neurology 1994;44:2407–2408. Katona, I., B. Sperlagh, A. Sik, et al. Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J. Neurosci. 1999;19:4544–4558. Kaupmann, K., B. Malitschek, V. Schuler, et al. GABABreceptor subtypes assemble into functional heteromeric complexes. Nature 1998;396:683–687. Kim, J. H., P. O. Guimaraes, M.-Y. Shen, L. M. Masukawa, and D. D. Spencer. Hippocampal neuronal density in tem-
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71. 72.
73.
74.
75.
poral lobe epilepsy with and without gliomas. Acta Neuropathol 1990;80:41–45. Kitter, J. T., K. McAnish, and S. J. Moss. Mechanisms of GABAA receptor assembly and trafficking: Implications for the modulation of inhibitory neurotransmission. Mol. Neurobiol. 2002;26:251–268. Kneussel, M. Dynamic regulation of GABAA receptors at synaptic sites. Brain Res. Brain Res. Rev. 2002;39:74– 83. Knowles, W. D., I. A. Awad, and M. H. Nayel. Differences of in vitro electrophysiology of hippocampal neurons from epileptic patients with mesiotemporal sclerosis versus structural lesions. Epilepsia 1992;33:601–609. Leinekugel, X., I. Medina, I. Khalilov, Y. Ben-Ari, and R. Khazipov. Ca2+ oscillations mediated by the synergistic excitatory actions of GABAA and NMDA receptors in the neonatal hippocampus. Neuron 1997;18:243– 255. Lerma, J., A. S. Herranz, O. Herreras, V. Abraira, and D. R. Martin. In vivo determination of extracellular concentration of amino acids in the rat hippocampus: A method based on brain dialysis and computerized analysis. Brain Res. 1986;384: 145–155. Liang, J., E. Lagetti, R. W. Olsen, and I. Spigelman. Altered pharmalogy of synaptic and extrasynaptic GABAA receptors on hippocampal CA1 pyramidal neurons is consistent with subunit changes in a model of alcohol withdrawal and dependence. J. Pharmacol. Exp. Ther. 2004;310:1234– 1245. Liu, Y.-B., J. F. Disterhoft, and N. T. Slater. Activation of metabotropic glutamate receptors induces long-term depression of GABAergic inhibition in hippocampus. J. Neurophysiol. 1993;69:1000–1004. Lothman, E. W., E. H. Bertram, J. Kapur, and J. L. Stringer. Recurrent spontaneous hippocampal seizures in the rat as a chronic sequela to limbic status epilepticus. Epilepsy Res. 1990;6:110–119. Loop, F., H. G. Wieser, Y. Yonekawa, A. Aguzzi, and J. M. Fritschy. Selective alterations in GABAA receptor subtypes in human temporal lobe epilepsy. J. Neurosci. 2000;20:5401– 5419. Luhmann, H. J., and D. A. Prince. Postnatal maturation of the GABAergic system in rat neocortex. J. Neurophysiol. 1991; 65:247–263. Macdonald, R. L., and R. W. Olsen. GABAA receptor channels. Anno. Rev. Neurosci. 1994;17:569–602. Malouf, A. T., C. A. Robbins, and P. A. Schwartzkroin. Phaclofen inhibition of the slow inhibitory postsynaptic potential in hippocampal slice cultures: A possible role for the GABAB-mediated inhibitory postsynaptic potential. Neuroscience 1990;35:53–61. Mangan, P. S., and E. W. Lothman. Profound disturbances of pre- and postsynaptic GABAB-receptor-mediated processes in region CA1 in a chronic model of temporal lobe epilepsy. J. Neurophysiol. 1996;76:1282–1296. McBain, C. J., T. J. DiChiara, and J. A. Kauer. Activation of metabotropic glutamate receptors differentially affects two classes of hippocampal interneurons and potentiates excitatory synaptic transmission. J. Neurosci. 1994;14:4433– 4445. McCarren, M., and B. E. Alger. Use-dependent suppression of IPSPs in rat hippocampal pyramidal cells in vitro. J. Neurophysiol. 1985;53:557–571.
76. Morishita, W., and B. R. Sastry. Presynaptic actions of GABA and baclofen in CA1 region of the guinea-pig hippocampus in vitro. Neuroscience 1994;61:447–455. 77. Morrisett, R. A., D. D. Mott, D. V. Lewis, H. S. Swartzwelder, and W. A. Wilson. GABAB-receptor-mediated inhibition of the N-methyl--aspartate component of synaptic transmission in the rat hippocampus. J. Neurosci. 1991;11:203– 209. 78. Moss, S. J., G. H. Gorrie, A. Amato, and T. G. Smart. Modulation of GABAA receptors by tyrosine phosphorylation. Nature 1995;377:344–348. 79. Mtchedlishvili, Z., E. H. Bertram, and J. Kapur. Diminished allopregnanolone enhancement of GABAA receptor currents in a rat model of chronic temporal lobe epilepsy. J. Physiol. (Lond.) 2001;537:453–465. 80. Müeller, A. L., J. S. Taube, and P. A. Schwartzkroin. Development of hyperpolarizing inhibitory postsynaptic potentials and hyperpolarizing response to gamma-aminobutyric acid in rabbit hippocampus studied in vitro. J. Neurosci. 1984;4: 860–867. 81. Nusser, Z., and I. Mody. Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells. J. Neurophysiol. 2002;87:2624–2628. 82. Nusser, Z., J. D. B. Roberts, A. Baude, J. G. Richards, and P. Somogyi. Relative densities of synaptic and extrasynaptic GABAA receptors on cerebellar granule cells as determined by a quantitative immunogold method. J. Neurosci. 1995;15: 2948–2960. 83. Nusser, Z., W. Sieghart, and P. Somogyi. Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells. J. Neurosci. 1998;18: 1693–1703. 84. Obenaus, A., M. Esclapez, and C. R. Houser. Loss of glutamate decarboxylase mRNA-containing neurons in the rat dentate gyrus following pilocarpine-induced seizures. J. Neurosci. 1993;13:4470–4485. 85. Ohno-Shosaku, T., T. Maejima, and M. Kano. Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron 2001; 29:729–738. 86. Oliver, M. W., and J. J. Miller. Alterations of inhibitory processes in the dentate gyrus following kindling-induced epilepsy. Exp. Brain Res. 1985;57:443–447. 87 Olney, J. W., T. de Gubareff, and R. S. Sloviter. “Epileptic” brain damage in rats induced by sustained electrical stimulation of the perforant path. II. Ultrastructural analysis of acute hippocampal pathology. Brain Res. Bull. 1983;10:699– 712. 88 Otis, T. S., Y. De Koninck, and I. Mody. Lasting potentiation of inhibition is associated with an increased number of gamma-aminobutyric acid type A receptors activated during miniature inhibitory postsynaptic currents. Proc. Natl. Acad. Sci. U.S.A. 1994;91:7698–7702. 89. Otis, T. S., K. J. Staley, and I. Mody. Perpetual inhibitory activity in mammalian brain slices generated by spontaneous GABA release. Brain Res. 1991;545:142–150. 90. Patrylo, P. R., D. D. Spencer, and A. Williamson. GABA uptake and heterotransport are impaired in the dentate gyrus of epileptic rats and humans with temporal lobe sclerosis. J. Neurophysiol. 2001;85:1533–1542. 91. Pham, T. M., and J. C. Lacaille. Multiple postsynaptic actions of GABA via GABAB receptors on CA1 pyramidal cells of rat hippocampal slices. J. Neurophysiol. 1996;76:69–80.
:
291
92. Pham, T. M., S. Nurse, and J. C. Lacaille. Distinct GABAB actions via synaptic and extrasynaptic receptors in rat hippocampus in vitro. J. Neurophysiol. 1998;80:297–308. 93. Pitler, T. A., and B. E. Alger. Postsynaptic spike firing reduces synaptic GABAA responses in hippocampal pyramidal cells. J. Neurosci. 1992;12:4122– 4132. 94. Pitler, T. A., and B. E. Alger. Depolarization-induced suppression of GABAergic inhibition in rat hippocampal pyramidal cells: G protein involvement in a presynaptic mechanism. Neuron 1994;13:1447–1455. 95. Poorkhalkali, N., K. Juneblad, A. C. Jonsson, et al. Immunocytochemical distribution of the GABAB receptor splice variants GABAB R1a and R1b in the rat CNS and dorsal root ganglia. Anat. Embryol. (Berl.) 2000;201:1–13. 96. Ribak, C. E., P. H. Tran, I. Spigelman, M. M. Okazaki, and J. V. Nadler. Status epilepticus-induced hilar basal dendrites on rodent granule cells contribute to recurrent excitatory circuitry. J. Comp. Neurol. 2000;428:240 –253. 97. Robbins, M. J., A. R. Calver, A. K. Filippov, et al. GABAB2 is essential for g-protein coupling of the GABAB receptor heterodimer. J. Neurosci. 2001;21:8043–8052. 98. Robello, M., C. Amico, and A. Cupello. Evidence of two populations of GABAA receptors in cerebellar granule cells in culture: Different desensitization kinetics, pharmacology, serine/threonine kinase sensitivity, and localization. Biochem. Biophys. Res. Commun. 1999;266:603–608. 99. Salin, P. A., and D. A. Prince. Spontaneous GABAA receptormediated inhibitory currents in adult rat somatosensory cortex. J. Neurophysiol. 1996;75:1573–1588. 100. Scanziani, M., B. H. Gahwiler, and S. M. Thompson. Paroxysmal inhibitory potentials mediated by GABAB receptors in partially disinhibited rat hippocampal slice cultures. J. Physiol. (Lond.) 1991;444:375–396. 101. Scotti, A. L., and H. Reuter. Synaptic and extrasynaptic gaminobutyric acid type A receptor clusters in rat hippocampal cultures during development. Proc. Natl. Acad. Sci. U.S.A. 2001;98:3489–3494. 102. Shirasaka, Y., and C. G. Wasterlain. Chronic epileptogenicity following focal status epilepticus. Brain Res. 1994;655: 33– 44. 103. Sloviter, R. S. “Epileptic” brain damage in rats induced by sustained electrical stimulation of the perforant path. I. Acute electrophysiological and light microscopic studies. Brain Res. Bull. 1983;10:675–697. 104. Sloviter, R. S. Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat: The “dormant basket cell” hypothesis and its possible relevance to temporal lobe epilepsy. Hippocampus 1991;1:41–66. 105. Sloviter, R. S., and B. P. Diamano. Sustained electrical stimulation of the perforant path duplicates kainate-induced electrophysiological effects and hippocampal damage in rats. Neurosci. Lett. 1981;24:279–284. 106. Smith, S. S., Q. H. Gong, F. C. Hsu, R. S. Markowitz, J. M. French-Mullen, and X. Li. GABA(A) receptor alpha4 subunit suppression prevents withdrawal properties of an endogenous steroid. Nature 1998;392:926–930. 107. Smith, S. S., Q. H. Gong, X. Li, et al. Withdrawal from 3a-OH-5a-pregnan-20-One using a pseudopregnancy model alters the kinetics of hippocampal GABAA-gated current and increases the GABAA receptor a4 subunit in association with increased anxiety. J. Neurosci. 1998;18: 5275–5284.
292
:
108. Solís, J. M., and R. A. Nicoll. Pharmacological characterization of GABAB-mediated responses in the CA1 region of the rat hippocampal slice. J. Neurosci. 1992;12:3466–3472. 109. Soltesz, I., J. D. Roberts, H. Takagi, J. G. Richards, H. Mohler, and P. Somogyi. Synaptic and nonsynaptic localization of benzodiazepine/GABAA receptor/Cl- channel complex using monoclonal antibodies in the dorsal lateral geniculate nucleus of the cat. Eur. J. Neurosci. 1990;2:414–429. 110. Spigelman, I., X.-X. Yan, A. Obenaus, E. Y. Lee, C. G. Wasterlain, and C. E. Ribak. Dentate granule cells form novel basal dendrites in a rat model of temporal lobe epilepsy. Neuroscience 1998;86:109–120. 111. Staley, K. J., and W. R. Proctor. Modulation of mammalian dendritic GABAA receptor function by the kinetics of Cl- and HCO3- transport. J. Physiol. (Lond.) 1999;519(Pt. 3):693–712. 112. Staley, K. J., B. L. Soldo, and W. R. Proctor. Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors. Science 1995;269:977–981. 113. Stella, N., P. Schweitzer, and D. Piomelli. A second endogenous cannabinoid that modulates long-term potentiation. Nature 1997;388:773–778. 114. Stelzer, A., and H. Shi. Impairment of GABAA receptor function by N-methyl--aspartate-mediated calcium influx in isolated CA1 pyramidal cells. Neuroscience 1994;62:813– 828. 115. Strata, F., and E. Cherubini. Transient expression of a novel type of GABA response in rat CA3 hippocampal neurons during development. J. Physiol. (Lond.) 1994;480:493–503. 116. Stringer, J. L., and E. W. Lothman. Repetitive seizures cause an increase in paired-pulse inhibition in the dentate gyrus. Neurosci Lett. 1989;105:91–95. 117. Sundstrom, L. E., J. Mitchell, and H. V. Wheal. Bilateral reorganisation of mossy fibres in the rat hippocampus after a unilateral intracerebroventricular kainic acid injection. Brain Res. 1993;609:321–326. 118. Sutula, T., G. Cascino, J. Cavazos, I. Parada, and L. Ramirez. Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Ann. Neurol. 1989;26:321–330. 119. Swann, J. W., R. J. Brady, and D. L. Martin. Postnatal development of GABA-mediated synaptic inhibition in rat hippocampus. Neuroscience 1989;28:551–561. 120. Tauck, D. L., and J. V. Nadler. Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acid treated rats. J. Neurosci. 1985;5:1016–1022. 121. Thompson, S. M., R. A. Deisz, and D. A. Prince. Relative contributions of passive equilibrium and active transport to the distribution of chloride in mammalian cortical neurons. J. Neurophysiol. 1988;60:105–124. 122. Thompson, S. M., and B. H. Gähwiler. Activity-dependent disinhibition. II. Effects of extracellular potassium, furosemide, and membrane potential on ECl- in hippocampal CA3 neurons. J. Neurophysiol. 1989;61:512–523. 123. Titulaer, M. N. G., W. Kamphuis, and F. H. Lopes da Silva. Long-term and regional specific changes in [3H]flunitrazepam binding in kindled rat hippocampus. Neuroscience 1995;68:399–406. 124. Tossman, U., G. Jonsson, and U. Ungerstedt. Regional distribution and extracellular levels of amino acids in rat central nervous system. Acta Physiol. Scand. 1986;127:533–545. 125. Tsoo, K., K. Mackie, M. C. Sanudo-Pena, and W. M. Walker. Cannabinoid CB1 receptors are localized primarily on cholecystokinin-containing GABAergic interneurons in the rat hippocampal formation. Neuroscience 1999;93:969–975.
126. Tuff, L. P., R. J. Racine, and R. Adamec. The effects of kindling on GABA-mediated inhibition in the dentate gyrus of the rat. I. Paired-pulse depression. Brain Res. 1983;277:79– 90. 127. Tuff, L. P., R. J. Racine, and R. K. Mishra. The effects of kindling on GABA-mediated inhibition in the dentate gyrus of the rat. II. Receptor binding. Brain Res. 1983; 277:91–98. 128. Urban, L., P. G. Aitken, A. Friedman, and G. G. Somjen. An NMDA-mediated component of excitatory synaptic input to dentate granule cells in “epileptic” human hippocampus studied in vitro. Brain Res. 1990;515:319–322. 129. Uruno, K., M. J. O’Connor, and L. M. Masukawa. Alterations of inhibitory synaptic responses in the dentate gyrus of temporal lobe epileptic patients. Hippocampus 1994; 4:583–593. 130. Uruno, K., M. J. O’Connor, and L. M. Masukawa. Effects of bicuculline and baclofen on paired-pulse depression in the dentate gyrus of epileptic patients. Brain Res. 1995;695: 163–172. 131. Wallace, M. J., R. E. Blair, K. W. Falenski, B. R. Martin, and R. J. DeLorenzo. The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy. J. Pharmacol. Exp. Ther. 2003;307:129–137. 132. Wang, R. A., G. Cheng, M. Kolaj, and M. Randic. a-Subunit of calcium/calmodulin-dependent protein kinase II enhances gamma-aminobutyric acid and inhibitory synaptic responses of rat neurons in vitro. J. Neurophysiol. 1995;73: 2099–2106. 133. Wasterlain, C. G., C. F. Baxter, and R. A. Baldwin. GABA metabolism in the substantia nigra, cortex, and hippocampus during status epilepticus. Neurochem. Res. 1993;18:527–532. 134. Wasterlain, C. G., Y. Shirasaka, A. Mazarati, and I. Spigelman. Chronic epilepsy with damage restricted to the hippocampus: Possible mechanisms. Epilepsy Res. 1996;26: 255–265. 135. White, J. H., A. Wise, M. J. Main, et al. Heterodimerization is required for the formation of a functional GABAB receptor. Nature 1998;396:679–682. 136. Williamson, A., P. R. Patrylo, and D. D. Spencer. Decrease in inhibition in dentate granule cells from patients with medial temporal lobe epilepsy. Ann. Neurol. 1999;45:92–99. 137. Williamson, A., and D. D. Spencer. Impairment of the GABA transport system in epileptic patients is specific to the dentate gyrus. Epilepsia 1996;37(Suppl. 5):80. 138. Williamson, A., A. E. Telfeian, and D. D. Spencer. Prolonged GABA responses in dentate granule cells in slices isolated from patients with temporal lobe sclerosis. J. Neurophysiol. 1995;74:378–387. 139. Wilson, R. I., and R. A. Nicoll. Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 2001;410:588–592. 140. Wong, R. K. S., and D. J. Watkins. Cellular factors influencing GABA response in hippocampal pyramidal cells. J. Neurophysiol. 1982;48:938–951. 141. Wu, L.-G., and P. Saggau. GABAB receptor-mediated presynaptic inhibition in guinea-pig hippocampus is caused by reduction of presynaptic Ca2+ influx. J. Physiol. (Lond.) 1995; 485:649–657. 142. Zhang, L., I. Spigelman, and P. L. Carlen. Development of GABA-mediated, chloride-dependent inhibition in CA1 pyramidal neurons of immature rat hippocampal slices. J. Physiol. (Lond.) 1991;444:25– 49.
143. Zhang, L., I. Spigelman, and P. L. Carlen. Whole-cell patch study of GABA-ergic inhibition in CA1 neurons of the immature rat hippocampal slice. Dev. Brain Res. 1990;56:127–130. 144. Zhang, S. J., and M. B. Jackson. GABA-activated chloride channels in secretory nerve endings. Science 1993;259: 531–534.
:
293
22
Glutamate and Glutamate Receptors in Status Epilepticus
. .
Introduction Glutamate is the principal excitatory neurotransmitter in the brain and inevitably plays a key role in many of the phenomena of epilepsy and status epilepticus (SE). It acts on three families of ionotropic receptor—N-methyl--aspartate, or NMDA; a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, or AMPA; and kainate (22)—and on three families of metabotropic receptor—group I = mGlu1 and mGlu5, group II = mGlu2 and mGlu3, and group III = mGlu4, mGlu6, mGlu7, and mGlu8 (5, 18). This chapter addresses three questions that are the subject of current research and remain largely unresolved at present: 1. What role do glutamate and the different glutamate receptor subtypes play in the initiation and maintenance of SE? 2. Are there changes in glutamate receptor expression or function during the course of SE that influence its features and outcome? 3. Can drugs acting selectively on glutamate receptors influence the duration and outcome of SE?
Role of glutamate and glutamate receptors in initiation and maintenance of SE I S SE F I G R A That the focal injection of glutamate or aspartate into the cortex or certain brain nuclei could induce focal seizure activity was reported well before a neurotransmitter role for glutamate was proposed (45). Agonists that are specific for each of the subtypes of ionotropic glutamate receptor—that is, NMDA, AMPA, and kainate receptors—are also capable of inducing seizures on focal injection. In some regions there are clear differences between the effect of injecting kainate (or domoate), NMDA (or quinolinate or ibotenate), and AMPA (or quisqualate). The difference most often reported is observed with focal injections in the hippocampus: NMDA agonists produce local excitation and dense focal neurodegeneration, with little selectivity (50). Agonists acting on kainate or AMPA receptors tend to produce sustained seizure activity that
spreads to other regions, and selective patterns of neuronal loss both close to and distal to the injection site (9, 81, 82). The distal damage appears to involve synaptically released glutamate acting on NMDA receptors, and so can be prevented by systemic administration of diazepam or NMDA receptor antagonists (9, 50). These observations clearly establish that enhanced or excessive activation of glutamate receptors is a possible cause of epileptic activity. M SE The earliest microdialysis studies of SE were performed with the dialysis probe in the hippocampus in rabbits using bicuculline or kainate as the convulsant agent (61). Dialysate collection over 40 minutes of seizure activity (10-minute fractions) showed no change in extracellular glutamate but increases in alanine and phosphoethanolamine with both convulsants, and marked increases in taurine with kainate. Another early study (107) employed microdialysis probes in the piriform cortex of rats using soman or kainate as the convulsants, and analyzed fractions collected over 30 minutes. A slight increase in glutamate was seen 0–60 minutes after soman; a decrease in glutamine was seen 1–4 hours after soman. Taurine was markedly increased 30–90 minutes after kainate. Subsequent studies have tended to confirm that severe prolonged limbic seizures leading to selective patterns of brain damage can occur without a generalized increase in the extracellular concentration of glutamate. A modest increase in extracellular glutamate has been observed early in seizures induced by kainate (105) or pentylenetrazol (92). Using a sensitive assay with good time resolution, no change was seen in extracellular glutamate during seizures induced by systemic picrotoxin or focal bicuculline (76). In the presence of compounds blocking glutamate uptake, increases were observed in extracellular aspartate and glutamate prior to the onset of pilocarpine seizures (75). Decreases in extracellular glutamine are consistently reported in these experimental studies. A recent microdialysis study in the striatum of rats (57) receiving 4aminopyridine revealed elevations in extracellular glutamate 30–150 minutes following the treatment. Apartate showed transient increases (Table 22.1).
:
295
T 22.1 Microdialysis studies in experimental models of status epilepticus Convulsant Drug
Site of Microdialysis
Amino Acid Changes
Study
Pilocarpine Bicuculline Picrotoxin Pentylenetetrazol Kainate Kainate Kainate Folate (in amygdala) Soman 4-Aminopyridine
Rat hippocampus Rabbit hippocampus Rat hippocampus Rat amygdala Rabbit hippocampus Rat piriform cortex Rat hippocampus Rabbit hippocampus Rat piriform cortex Rat striatum
(ASP, GLUT, preseizure) Glutamate TAU Glutamate GLUT Glutamate ALA Glutamate GLUT GLUT ALA GLUT TAU GLUT ASP
Millan et al. (75) Lehmann et al. (61) Millan et al. (76) Rocha et al. (92) Lehmann et al. (61) Stafstrom et al. (100) Ueda et al. (105) Lehmann (60) Wade et al. (107) Kovacs et al. (57)
Note: Glutamate: no change in extracellular glutamate; ALA, TAU: marked increases in extracellular alanine or taurine; GLUT, ASP: modest increases in extracellular glutamate or aspartate.
Microdialysis data are not available for human SE. A study with bilateral chronically implanted hippocampal microdialysis probes in patients with drug-refractory temporal lobe epilepsy (24) has shown that extracellular glutamate is elevated in the epileptogenic hippocampus in the 3 minutes prior to seizure onset and bilaterally in the subsequent 3 minutes. This finding suggests that glutamate is potentially involved in seizure onset in patients with mesial temporal sclerosis. C G T One potential explanation for the onset or maintenance of seizure activity is the relative failure of glutamate reuptake. Glutamate is normally transported from the synaptic space into neurons and glia by specific Na+-dependent glutamate transporters. Four principal transporters have been identified in mammalian brain. These are known as GLAST, GLT-1, EAAC1, and EAAT4 in the rat, and as EAAT1, EAAT2, EAAT3, and EAAT4 in man, the first two being glial and the latter two neuronal (4, 7, 91). Homozygous mice deficient in GLT-1 show lethal spontaneous seizures (103). Epileptiform EEG activity is also seen in rats with a 70%–90% knockdown of EAAC1 (EAAT3) produced by antisense oligonucleotides (94). Thus, changes in the function of glutamate transporters could contribute to SE. Some transient changes in the expression of mRNA for the transporters have been observed in kindled rats (77). Changes in expression also occur in relation to glutamate agonist levels (kainate upregulates GLAST in astrocytic culture [35], mGluR agonists increase EAAC1 expression [80]) and in relation to brain injury (traumatic brain injury downregulates GLAST and GLT-1 [106]). After 4 hours of SE induced by kainate, expression of GLT-1 (as estimated by immunocyto-
296
:
chemistry) is modestly enhanced in the hippocampus, whereas expression of the neuronal transporter EAAC1 (EAAT3) is decreased (97). In astrocyte cultures, glutamate induces increased cell surface expression of GLAST (with an ED50 of 40 mM and an onset at 15 minutes) (23). Thus, enhanced glutamate uptake by astrocytes (involving GLAST or GLT-1) early in SE may be partly responsible for the lack of detectable increase in extracellular glutamate concentration. Spontaneous limbic seizures occurring after electrically induced SE provide a model of mesial temporal lobe epilepsy in man. In such epileptic rats, immunocytochemistry studies reveal upregulation of glial glutamate transporters but a decrease in the neuronal transporter EAAC1 in the inner molecular layer (38). Possibly the latter change could contribute to epileptogenesis.
Changes in glutamate receptors as a cause of seizures or SE The influence of changes in glutamate receptors on epileptogenesis has been studied in various direct and indirect ways. The most informative studies have involved either genetic manipulations in mice or studies of receptor expression and function in kindled rats. Other studies have concerned transient changes following experimental seizures or changes observed in human temporal lobectomy material. One mouse study that is relevant both to human syndromes of epilepsy and phenomena occurring in SE concerns the posttranslational editing of mRNA for the GluR2 (GluRB) subunit of the AMPA receptor (11, 28). The GluR2 subunit confers on homomeric or heteromeric AMPA receptors an extremely low Ca2+ conductance. Native AMPA receptors have variable expression of GluR2 and corre-
spondingly variable Ca2+ conductances (52). This phenomenon is dependent on having an arginine in position 586. The GluR2 DNA codes for a glutamine at this site, but posttranslational editing of the RNA (by an adenosine deaminase) converts the codon to an arginine codon. Interfering with this editing process in intron 11 in stem cells allows the creation of mice in which the total expression of GluR2 (GluRB) is reduced by about 25% and the RNA editing is similarly reduced. The Ca2+ currents produced by AMPA receptor activation in pyramidal neurons are markedly increased. Such mice show a variety of spontaneous seizures beginning around postnatal day 13 (P13) and leading to death around P20 (with significant hippocampal pathology). This provides clear evidence that altered AMPA receptor function can facilitate seizure activity and enhance epileptic pathology. Changes in either GluR2 subunit expression or RNA editing are possible during SE (37). In an in vitro model of SE in which hippocampal slices are chronically exposed to picrotoxin (36), mRNA levels for GluR1 and GluR2 fall to 50% of control levels, while GluR3 and GluR4 are unaltered (NR2A and NR2B levels are also reduced) (Table 22.2).
C G R K R A change in the function of NMDA receptors in dentate granule cells or in hippocampal pyramidal cell dendrites in amygdala or hippocampal kindled rats has been repeatedly reported (56, 78). This potentiates postsynaptic excitatory responses and enhances Ca2+ entry. It does not appear to be related to altered expression or subunit composition of the NMDA receptors, but is probably a consequence of altered phosphorylation (64). Because of changes in energy charge or availability of ATP during SE it is highly likely that altered phosphorylation of NMDA receptors will be seen during SE. A variety of changes in mGluR receptor function have been described in kindled rats. In particular, the effect of group I receptor activation is potentiated in the amygdala (3, 47). Group II and III receptor function has been reported to be potentiated in the contralateral amygdala (82). Group III receptor function is markedly reduced in the hippocampus (55). C G R H F E A variety of changes in glutamate receptor
T 22.2 Glutamate receptor changes in epilepsy and status epilepticus Species/SE Model
Change
Mice Spontaneous lethal seizures Rats Kindling/electroshock Lesion/status Lithium-pilocarpine Kainate Kindling Kindling Kindling Kindling Lithium-pilocarpine Kindling Kindling Kindling Kainate seizures Kainate seizures Man Rasmussen’s syndrome Refractory temporal lobe Refractory temporal lobe Refractory temporal lobe Refractory temporal lobe Refractory temporal lobe
epilepsy epilepsy epilepsy epilepsy epilepsy
Study
GluR2 editing
Brusa et al. (11), Feldmeyer et al. (28)
RNA GluR1 RNAs GluR1, GluR2 RNAs GluR1, GluR3 mRNAs GluR1, GluR2 Ionotropic mRNA GluR2 downregulation NMDAR1 alternate splicing NMDA function NMDA receptor trafficking Metabotropic group I potentiated Metabotropic groups II and III potentiated Metabotropic group III reduced Ionotropic Metabotropic
Wong et al. (110) Gold et al. (37) Condorelli et al. (17) Friedman et al. (30) Kamphuis et al. (53) Prince et al. (89) Kraus et al. (59) Köhr et al. (56) Neugebauer et al. (82) Akiyama et al. (3) Neugebauer et al. (82)
GluR3 antibodies GluR2 and GluR6 editing GluR1 (mRNA + protein) decreased Loss of NMDAR1 Ionotropic mRNA increased mGlu group III responses decreased
Rogers et al. (93) Grigorenko et al. (40) Grigorenko et al. (41) Bayer et al. (8) Mathern et al. (67) Dietrich et al. (21)
Klapstein et al. (55) Friedman et al. (31) Aronica et al. (6)
:
297
expression and function have been described in anterior temporal lobectomy specimens removed from patients with drug-refractory complex partial seizures with unilateral origin. Some of these changes reflect patterns of cell loss (34, 67), but many of them are similar to changes found in kindled animals and may be contributing to epileptogenicity (20, 66). This includes functional enhancement of NMDA receptor-mediated responses and also a reduction of the sensitivity of group III glutamate metabotropic receptors (58). There is immunolabeling evidence for an upregulation of mGlu4 in dentate granule cells in the hippocampus of patients with temporal lobe epilepsy (63); this change may be protective rather than epileptogenic. A study of editing of the Q/R site of the GluR2 subunit in AMPA receptors in hippocampi removed from patients with refractory epilepsy (40) found this to be normal (complete) in 14 of 16 cases, but abnormal (incomplete) in two children ages 2 and 10 years. This abnormality may be a consequence of seizures, but in light of the mouse data, it may well be a factor causing seizures.
Changes in glutamate receptors secondary to SE A variety of changes in ionotropic receptors occurring as a result of single seizures or electrical kindling have been described. Following a seizure induced by pentylenetetrazol in rats, there is an early (1-hour) upregulation of mRNA for NMDAR-1, the “universal” subunit of the NMDA receptor (51). The changes occurring secondary to SE in AMPA receptors have been studied by in situ hybridization and Northern blot techniques, and early and late changes in the mRNA for the GluR1, 2, and 3 subunits have been reported. We do not have matching functional data comparable to the functional changes in GABAA receptors occurring within 45 minutes of the onset of SE (54). The early changes reported in mRNA subunit expression are regionally selective and occur after 6–12 hours from the onset of lithiumpilocarpine- or kainate-induced SE (17, 30, 42). A reduction in the expression of GluR2 protein (30, 42) may contribute to the prolongation of SE or the later pathology, because the Ca2+ permeability of AMPA receptors is enhanced when the GluR2 subunit is not present. Experiments with antisense oligonucleotides targeted against GluR2 mRNA show that GluR2 deficiency facilitates cell death in CA1 and CA3 (85). C mGluR E S SE Using in situ hybridization to observe changes in mRNA for the various metabototropic glutamate receptors subsequent to sustained seizures induced by kainate Aronica et al. (6) found reduced levels of mGlu2 in the dentate granule cells 24 hours after seizure onset in rat pups (P10) and adults (P40). In pups, mGlu4 mRNA was enhanced in CA3 at 24 hours.
298
:
This change, if it is reflected in the presynaptc inhibitory function of mGlu4, could provide a protective mechanism against nerve cell loss in the neonatal rat brain. There is also evidence for long-term changes in mGluR function following limbic seizures induced by kainate. In particular, group I responses (enhanced PI hydrolysis) in hippocampal slices are enhanced after 7–92 days (68).
Glutamate antagonists as antiepileptics in SE It is clear that both AMPA and NMDA receptors contribute to the sustained seizure activity and the neuropathogic sequelae of SE (Table 22.3). Ionotropic glutamate receptor antagonists are powerful anticonvulsants in a wide range of animal models of acute epileptic seizures (13, 72). In particular, selective antagonists at the NMDA receptor are highly effective in blocking seizures in reflex epilepsy models in mice, rats, and baboons. They are also effective in a range of chemically and electrically induced seizures. They are relatively less effective against fully kindled seizures. They do, however, potently block the kindling process when given prior to each period of electrical stimulation (25, 79). Less information is available about the protective role of glutamate antagonists in SE compared with acute seizure models. The effects of NMDA antagonists have been studied in a wide range of prolonged seizures in rodents (Table 22.3). The main focus has been on the open channel, uncompetitive inhibitors dizocilpine (MK-801), N-[1-(2thienyl)cyclohexyl]-piperidine (TCP), and ketamine, but some studies have used competitive NMDA inhibitors, such as 4-(3-phosphonopropyl)piperazine-2-carboxylic acid (CPP) and (R)-(E)-2-amino-4-methyl-5-phosphono-3pentenoic acid (CGP 40116). The studies show variability in the effect on duration of EEG seizure activity, but protection against the pathologic consequences (hippocampal cell loss) of SE is commonly reported even when total seizure duration on the EEG is not reduced. The explanation for this finding is fairly straightforward. NMDA receptor antagonists block the late component of the paroxysmal depolarizing shift and the associated spikes (98). It is this late component that is primarily responsible for the entry of Ca2+. The increase in [Ca2+]i is the main determinant of selective neuronal degeneration (39, 44, 69, 71, 86, 102). The increase in [Ca2+]i activates numerous enzymes, including proteases, such as calpain I (96), phospholipases, nitric oxide synthases, endonucleases, protein kinases, and others (73). It also poisons the mitochondria and causes them to release cytochrome C, causing caspase 9 and caspase 3 activation (83). It is likely that the enhanced cerebral metabolic rate associated with the sustained seizure activity (12) also facilitates the neurotoxic effect of NMDA receptor activation (84, 101,
T 22.3 Studies showing neuroprotective effects of NMDA and AMPA antagonists in experimental status epilepticus in rats SE Model
EAA Antagonist
Lithium-pilocarpine
MK-801
Pilocarpine Kainate
Ketamine CGP 40116 MK-801 MK-801
Electrical stimulation (late)
Felbamate CPP TCP NBQX MK-801 CPP
Electrical stimulation (early) Perforant path stimulation
Ifenprodil MK-801 NBQX MK-801
Study Hughes et al. (49), Ormandy et al. (87), Walton and Treiman (108) Fujikawa (32) Fujikawa et al. (33) Rice and DeLorenzo (90) Clifford et al. (15), Fariello et al. (27), Stafstrom et al. (100) Chronopoulos et al. (14) Jarrard and Meldrum (50) Lerner-Natoli et al. (62) Mikati et al. (74) Bertram and Lothman (10), Yen et al. (111) Bertram and Lothman (10), Yen et al. (111) Yen et al. (111) Young and Dragunow (113) Young and Dragunow (112, 113) Thompson and Wasterlain (104)
Abbreviations: CPP, (2R)-4-(3-phosphonopropyl)piperazine-2-carboxylic acid; TCP, thienylcyclohexylpiperidine; NBQX, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulphonamide; MK 801, dizocilpine, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine; CGP 40116, (R)-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid.
114). This effect becomes more pronounced as the mitochondria become overloaded with Ca2+ (26, 39, 46) and form superoxide, leading to damage by free radical mechanisms. Thus, neuroprotection has been regularly observed when selective limbic system pathology is assessed in rat brains perfusion fixed 24 hours or longer after generalized or limbic SE when NMDA antagonists have been given prior to or after (commonly 15 minutes) the onset of SE (see Table 22.3). Protection is also seen against thalamic damage following prolonged focal cortical seizures (16). A few studies have concerned other species; for example, MK-801 protects against damage in hippocampus, amygdala, and piriform cortex in guinea pigs given soman (99). Some studies have used behavioral end-points. Thus, felbamate given 1 hour after kainate protects against performance deficits in the Morris water maze assessed 6 weeks later (14). Importantly, MK-801, 10 mg/kg IP, given as pretreatment to 25-day-old rats does not shorten SE but does prevent the later occurrence of spontaneous limbic seizures (100). It may also be possible to diminish epileptic brain damage due to NMDA receptor activation by blocking various downstream processes. In the postsynaptic density, many proteins contribute to NMDA receptor effects (95). It may be possible to decrease the neurotoxic effects of NMDA receptor
activation by acting on PSD-95 protein (1) or various kinase cascades. In particular, NMDA receptors containing NR2B subunits appear to be linked to a kinase pathway involving JNK1/2 and c-jun that facilitates cell death (43). Selectively blocking NR2B containing NMDA receptors might be beneficial. Blockade of AMPA receptors with NBQX in P35 rats undergoing SE induced by kainate prevents some hippocampal damage and some behavioral consequences (74). It may also be possible to produce neuroprotection during SE by actions involving metabotropic glutamate receptors (28). In particular, group I antagonists and group II or III agonists might be effective agents (see Meldrum, Chapter 23, this volume). Current approaches to neuroprotection in epilepsy have been reviewed by Meldrum (70) and Pitkänen (88).
Summary Activation of glutamate receptors contributes to the initiation and maintenance of seizure activity. Microdialysis commonly fails to reveal any increase in extracellular glutamate during experimental SE, possibly because astrocytic uptake is enhanced.
:
299
Altered expression or function of NMDA or AMPA glutamate receptors may contribute to SE. Reduced expression of the GluR2 subunit of the AMPA receptor (or impaired RNA editing of the Q/R site on GluR2) can be epileptogenic. Changes in GluR2 expression occur after some hours of SE. Activation of NMDA receptors during SE contributes to selective neuronal loss in the hippocampus. Selective NMDA antagonists prevent such selective neuronal loss even when they do not shorten total seizure duration. Glutamate receptor antagonists thus provide an important potential therapeutic approach in SE. REFERENCES 1. Aarts, M., Y. Liu, L. Liu, S. Besshoh, M. Arundine, J. W. Gurd, et al. Treatment of ischaemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions. Science 2002;298:846–850. 2. Akbar, M. T., R. Torp, N. C. Danbolt, L. M. Levy, B. S. Meldrum, and O. P. Ottersen. Expression of glial glutamate transporters GLT-1 and GLAST is unchanged in the hippocampus in fully kindled rats. Neuroscience 1997;78:351– 359. 3. Akiyama, K., A. Daigen, N. Yamada, T. Itoh, I. Kohira, H. Ujike, and S. Otsuki. Long-lasting enhancement of metabotropic excitatory amino-acid receptor-mediated polyphosphoinositide hydrolysis in the amygdala/pyriform cortex of deep prepiriform cortical kindled rats. Brain Res. 1992;569:71–77. 4. Amara, S. G., and M. J. Kuhar. Neurotransmitter transporters: Recent progress. Ann. Rev. Neurosci. 1993;16:73–93. 5. Anwyl, R. Metabotropic glutamate receptors: Electrophysiological properties and role in plasticity. Brain Res. Rev. 1999;29:83–120. 6. Aronica, E. M., J. A. Gorter, M. C. Paupard, S. Y. Grooms, M. V. L. Bennett, and R. S. Zukin. Status epilepticus-induced alterations in metabotropic glutamate receptor expression in young and adult rats. J. Neurosci. 1997;17:8588–8595. 7. Arriza, J. L., W. A. Fairman, J. I. Wadiche, G. H. Murdoch, M. P. Kavanaugh, and S. G. Amara. Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex. J. Neurosci. 1994;14:5559–5569. 8. Bayer, T. A., O. D. Wiestler, and H. K. Wolf. Hippocampal loss of N-methyl--aspartate receptor subunit 1 mRNA in chronic temporal lobe epilepsy. Acta Neuropathol. (Berl.) 1995;89:446–450. 9. Ben Ari, Y., E. Tremblay, O. P. Ottersen, and B. S. Meldrum. The role of epileptic activity in hippocampal and “remote” cerebral lesions induced by kainic acid. Brain Res. 1980; 191:79–97. 10. Bertram, E. H., and E. W. Lothman. NMDA receptor antagonists and limbic status epilepticus: A comparison with standard anticonvulsants. Epilepsy Res. 1990;5:177–184. 11. Brusa, R., F. Zimmermann, D. S. Koh, D. Feldmeyer, P. Gass, P. H. Seeburg, and R. Sprengel. Early-onset epilepsy and postnatal lethality associated with an editing-deficient GluRB allele in mice. Science 1995;270:1677–1680. 12. Chapman, A. G. Cerebral energy metabolism and seizures. In T. A. Pedley, and B. S. Meldrum, eds. Recent Advances in
300
:
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
Epilepsy. Vol. 2. Edinburgh: Churchill Livingstone, 1985: 19–63. Chapman, A. G., J. L. Graham, S. Patel, and B. S. Meldrum. Anticonvulsant activity of two orally active competitive NMDA-antagonists, CGP 37849 and CGP 39551, against sound-induced seizures in DBA/2 mice and photicallyinduced myoclonus in Papio papio. Epilepsia 1991;32:578– 587. Chronopoulos, A., C. Stafstrom, S. Thurber, P. Hyde, M. Mikati, and G. L. Holmes. Neuroprotective effect of felbamate after kainic acid-induced status epilepticus. Epilepsia 1993;34:359–366. Clifford, D. B., J. W. Olney, A. M. Benz, T. A. Fuller, and C. F. Zorumski. Ketamine, phencyclidine, and MK-801 protect against kainic acid-induced seizure-related brain damage. Epilepsia 1990;31:382–390. Clifford, D. B., C. F. Zorumski, and J. W. Olney. Ketamine and MK-801 prevent degeneration of thalamic neurons induced by focal cortical seizures. Exp. Neurol. 1989;105: 272–279. Condorelli, D. F., N. Belluardo, G. Mud, P. Dell’Albani, X. Jiang, and A. M. Giuffrida-Stella. Changes in gene expression of AMPA-selective glutamate receptor subunits induced by status epilepticus in rat brain. Neurochem. Int. 1994;25: 367–376. Conn, P. J., and J. P. Pin. Pharmacology and functions of metabotropic glutamate receptors. Annu. Rev. Pharmacol. Toxicol. 1997;37:205–237. Crino, P. B., H. Jin, M. D. Shumate, M. B. Robinson, D. A. Coulter, and A. R. Brooks-Kayal. Increased expression of the neuronal glutamate transporter (EAAT3/EAAC1) in hippocampal and neocortical epilepsy. Epilepsia 2002;43: 211–218. De Lanerolle, N. C., T. Eid, G. von Kampe, I. Kovacs, D. D. Spencer, and M. Brines. Glutamate receptor subunits GluR1 and GluR2/3 distribution shows reorganization in the human epileptogenic hippocampus. Eur. J. Neurosci. 1998;10: 1687–1703. Dietrich, D., T. Kral, H. Clusmann, M. Friedl, and J. Schramm. Reduced function of L-AP4 sensitive metabotropic glutamate receptors in human epileptic sclerotic hippocampus. Eur. J. Neurosci. 1999;11:1109–1113. Dingledine, R., K. Borges, D. Bowie, and S. F. Traynelis. The glutamate receptor ion channels. Pharmacol. Rev. 1999;51: 7–62. Duan, S., C. M. Anderson, B. A. Stein, and R. A. Swanson. Glutamate induces rapid upregulation of astrocyte glutamate transport and cell-surface expression of GLAST. J. Neurosci. 1999;19:10193–10200. During, M. J., and D. D. Spencer. Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet 1993;341:1607–1610. Dürmüller, N., M. Craggs, and B. Meldrum. The effect of the non-NMDA antagonists GYKI 52466 and NBQX and the competitive NMDA receptor antagonist D-CPPene on the development of amygdala kindling and on amygdala-kindled seizures. Epilepsy Res. 1994;17:167–174. Evans, M. C., T. Griffiths, and B. S. Meldrum. Kainic acid seizures and the reversibility of calcium loading in vulnerable neurons in the hippocampus. Neuropathol. Appl. Neurobiol. 1984;10:285–302. Fariello, R. G., G. T. Golden, G. G. Smith, and P. F. Reyes. Potentiation of kainic acid epileptogenicity and sparing from
28.
29.
30.
31.
32. 33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
neuronal damage by an NMDA receptor antagonist. Epilepsy Res. 1989;3:206–213. Feldmeyer, D., K. Kask, R. Brusa, H. C. Kornau, R. Kolhekar, A. Rozov, et al. Neurological dysfunctions in mice expressing different levels of the Q/R site-unedited AMPAR subunit GluR-B. Nat. Neurosci. 1999;2:57–64. Flor, P. J., G. Battaglia, F. Nicoletti, F. Gasparini, and V. Bruno. Neuroprotective activity of metabotropic glutamate receptor ligands. Adv. Exp. Med. Biol. 2002;513:197–223. Friedman, L. K., D. E. Pellegrini-Giampietro, E. F. Sperber, M. V. L. Bennett, S. L. Mosh‚ and R. S. Zukin. Kainateinduced status epilepticus alters glutamate and GABAA receptor gene expression in adult rat hippocampus: An in situ hybridization study. J. Neurosci. 1994;14:2697–2707. Friedman, L. K., E. F. Sperber, S. L. Mosh, M. V. Bennett, and R. S. Zukin. Developmental regulation of glutamate and GABAA receptor gene expression in rat hippocampus following kainate-induced status epilepticus. Dev. Neurosci. 1997;19:529–542. Fujikawa, D. G. Neuroprotective effect of ketamine administered after status epilepticus onset. Epilepsia 1995;36:186–195. Fujikawa, D. G., A. H. Daniels, and J. S. Kim. The competitive NMDA receptor antagonist CGP 40116 protects against status epilepticus-induced neuronal damage. Epilepsy Res. 1994;17:207–219. Geddes, J. W., L. D. Cahan, S. M. Cooper, R. C. Kim, B. H. Choi, and C. W. Cotman. Altered distribution of excitatory amino acid receptors in temporal lobe epilepsy. Exp. Neurol. 1990;108:214–220. Gegelashvili, G., G. Civenni, G. Racagni, N. C. Danbolt, I. Schousboe, and A. Scousboe. Glutamate receptor agonists up-regulate glutamate transporter GLAST in astrocytes. NeuroReport 1996;8:261–265. Gerfin-Moser, A., F. Grogg, L. Rietschin, S. M. Thompson, and P. Streit. Alterations in glutamate but not GABAA receptor subunit expression as a consequence of epileptiform activity in vitro. Neuroscience 1995;67:849–865. Gold, S. J., M. Hennegriff, G. Lynch, and C. M. Gall. Relative concentrations and seizure-induced changes in mRNAs encoding three AMPA receptor subunits in hippocampus and cortex. J. Comp. Neurol. 1996;365:541–555. Gorter, J. A., E. A. VanVliet, E. A. Proper, P. N. E. DeGraan, W. E. J. M. Ghijsen, F. Lopes daSilva, and E. Aronica. Glutamate transporters alterations in the reorganizing dentate gyrus are associated with progressive seizure activity in chronic epileptic rats. J. Comp. Neurol. 2002;442:365–377. Griffiths, T., M. C. Evans, and B. S. Meldrum. Intracellular calcium accumulation in rat hippocampus during seizures induced by bicuculline or -allylglycine. Neuroscience 1983; 10:385–395. Grigorenko, E. V., W. L. Bell, S. Glazier, T. Pons, and S. Deadwyler. Editing status at the Q/R site of the GluR2 and GluR6 glutamate receptor subunits in the surgically excised hippocampus of patients with refractory epilepsy. Neuroreport 1998;9:2219–2224. Grigorenko, E., S. Glazier, W. Bell, M. Tytell, E. Nosel, T. Pons, and S. A. Deadwyler. Changes in glutamate receptor subunit composition in hippocampus and cortex in patients with refractory epilepsy. J. Neurol. Sci. 1997;153:35–45. Grooms, S. Y., T. Opitz, M. V. Bennett, and R. S. Zukin. Status epilepticus decreases glutamate receptor 2 mRNA and protein expression in hippocampal pyramidal cells before neuronal death. Proc. Natl. Acad. Sci. 2000;97:3631–3636.
43. Hardingham, G. E., Y. Fukunaga, and H. Bading. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat. Neurosci. 2002;5:405–414. 44. Hartley, D. M., M. C. Kurth, L. Bjerkness, J. H. Weiss, and D. W. Choi. Glutamate receptor-induced 45Ca2+ accumulation in cortical cell culture correlates with subsequent neuronal degeneration. J. Neurosci. 1993;13:1993–2000. 45. Hayashi, T. A physiological study of epileptic seizures following cortical stimulation in animals and its application to human clinics. Jpn. J. Physiol. 1952;3:46–64. 46. Henshaw, R., B. G. Jenkins, J. B. Schulz, R. J. Ferrante, N. W. Kowall, B. R. Rosen, and M. F. Beal. Malonate produces striatal lesions by indirect NMDA receptor activation. Brain Res. 1994;647:161. 47. Holmes, K. H., N. B. Keele, and P. Shinnick-Gallagher. Loss of mGluR-mediated hyperpolarizations and increase in mGluR depolarizations in basolateral amygdala neurons in kindling-induced epilepsy. J. Neurophysiol. 1996;76:2808–2812. 48. Huang, Y., J. J. Doherty, and R. Dingledine. Altered histone acetylation at glutamate receptor 2 and brain-derived neurotrophic factor genes is an early event triggered by status epilepticus. J. Neurosci. 2002;22:8422–8428. 49. Hughes, P., D. Young, and M. Dragunow. MK-801 sensitizes rats to pilocarpine induced limbic seizures and status epilepticus. Neuroreport 1993;4:314–316. 50. Jarrard, L. E., and B. S. Meldrum. Selective excitotoxic pathology in the rat hippocampus. Neuropathol. Appl. Neurobiol. 1993;19:381–389. 51. Jensen, P. J., N. Millan, and K. J. Mack. Cortical NMDAR-1 gene expression is rapidly upregulated after seizure. Mol. Brain Res. 1997;44:157–162. 52. Jonas, P., C. Racca, B. Sakmann, P. H. Seeburg, and H. Monyer. Differences in Ca2+ permeability of AMPA-type glutamate receptor channels in neocortical neurons caused by differential GluR-B subunit expression. Neuron 1994;12: 1281–1289. 53. Kamphuis, W., T. C. De Rijk, L. M. Talamini, and F. H. Lopes da Silva. Rat hippocampal kindling induces changes in the glutamate receptor mRNA expression patterns in dentate granule neurons. Eur. J. Neurosci. 1994;6:1119–1127. 54. Kapur, J., and R. L. Macdonald. Rapid seizure-induced reduction of benzodiazepine and Zn2+ sensitivity of hippocampal dentate granule cell GABAA receptors. J. Neurosci. 1997;17:7532–7540. 55. Klapstein, G. J., B. S. Meldrum, and I. Mody. Decreased sensitivity to Group III mGluR agonists in the lateral perforant path following kindling. Neuropharmacology 1999;38:927–933. 56. Köhr, G., Y. De Koninck, and I. Mody. Properties of NMDA receptor channels in neurons acutely isolated from epileptic (kindled) rats. J. Neurosci. 1993;13:3612–3627. 57. Kovacs, A., A. Mihaly, A. Komaromi, E. Gyengesi, M. Szente, R. Weiczner, et al. Seizure, neurotransmitter release, and gene expression are closely related in the striatum of 4aminopyridine-treated rats. Epilepsy Res. 2003;55:117–129. 58. Kral, T., D. Dietrich, H. Clusmann, and J. Schramm. Mossy fibre sprouting correlates with loss of synaptic depression by Group III metabotropic glutamate receptors (mGluRs) in the area dentata of patients with temporal lobe epilepsy (TLE). Soc. Neurosci. Abstr. 1997;23:817. 59. Kraus, J. E., J. V. Nadler, and J. O. McNamara. Regulation of alternative splicing of NMDAR1 in the kindling model. Mol. Brain Res. 1996;41:97–104.
:
301
60. Lehmann, A. Alterations in hippocampal extracellular amino acids and purine catabolites during limbic seizures induced by folate injections into the rabbit amygdala. Neuroscience 1987;22:573–578. 61. Lehmann, A., H. Hagberg, I. Jacobson, and A. Hamberger. Effect of status epilepticus on extracellular amino acids in the hippocampus. Brain Res. 1985;359:147–151. 62. Lerner-Natoli, M., G. Rondouin, M. Belaidi, M. BaldyMoulinier, and J. M. Kamenka. N-[1-(2-thienyl)cyclohexyl]piperidine (TCP) does not block kainic acid-induced status epilepticus but reduces secondary hippocampal damage. Neurosci. Lett. 1991;122:174–178. 63. Lie, A. A., A. Becker, K. Behle, H. Beck, B. Malitschek, P. J. Conn, et al. Up-regulation of the metabotropic glutamate receptor mGluR4 in hippocampal neurons with reduced seizure vulnerability. Ann. Neurol. 2000;47:26–35. 64. Lieberman, D. N., and I. Mody, Regulation of NMDA channel function by endogenous Ca2+-dependent phosphatase. Nature 1994;369:235–239. 65. Lynd-Balta, E., W. H. Pilcher, and S. A. Joseph. Distribution of AMPA receptor subunits in the hippocampal formation of temporal lobe epilepsy patients. Neuroscience 1996;72:15–29. 66. McDonald, J. W., E. A. Garofalo, T. Hood, J. C. Sackellares, S. Gilman, P. E. McKeever, et al. Altered excitatory and inhibitory amino acid receptor binding in hippocampus of patients with temporal lobe epilepsy. Ann. Neurol. 1991; 29:529–541. 67. Mathern, G. W., J. K. Pretorius, H. I. Kornblum, D. Mendoza, A. Lozada, J. P. Leite, et al. Human hippocampal AMPA and NMDA mRNA levels in temporal lobe epilepsy patients. Brain 1997;120:1937–1959. 68. Mayat, E., M. Lerner-Natoli, G. Rondouin, F. Lebrun, I. R. Sassetti‚ and M. Casens. Kainate-induced status epilepticus leads to a delayed increase in various specific glutamate metabotropic receptor responses in the hippocampus. Brain Res. 1994;645:186–200. 69. Meldrum, B. S. First Alfred Meyer Memorial Lecture. Epileptic brain damage: A consequence and a cause of seizures. Neuropathol. Appl. Neurobiol. 1997;23:185–201. 70. Meldrum, B. S. Implications for neuroprotective treatments. In T. Sutula, and A. Pitkänen, eds. Do Seizures Damage the Brain? Prog. Brain Res. 2002;135:487–496. 71. Meldrum, B. S. Metabolic effects of prolonged epileptic seizures and the causation of epileptic brain damage. In F. C. Rose, ed. Metabolic Disorders of the Nervous System. London: Pitman, 1981:175–187. 72. Meldrum, B. S., and A. G. Chapman. Competitive NMDA antagonists as drugs. In J. C. Watkins, and G. L. Collingridge, eds. The NMDA Receptor. Oxford, U.K.: Oxford University Press, 1994:455–466. 73. Meldrum, B. S., and J. Garthwaite. Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Pharmacol. Sci. 1990;11:379–387. 74. Mikati, M. A., S. Werner, A. Gatt, Z. Liu, A. A. Rahmeh, R. A. Rachid, et al. Consequences of alpha-amino-3hydroxy-5-methyl-4-hydroxy-5-methyl-4-isoxazolepropionic acid receptor blockade during status epilepticus in the developing brain. Brain Res. Dev. Brain Res. 1999;113:139–142. 75. Millan, M. H., A. G. Chapman, and B. S. Meldrum. Extracellular amino acid levels in hippocampus during pilocarpineinduced seizures. Epilepsy Res. 1993;14:139–148. 76. Millan, M. H., T. P. Obrenovitch, G. S. Sarna, S. Y. Lok, L. Symon, and B. S. Meldrum. Changes in rat brain extracellu-
302
:
77.
78. 79.
80.
81.
82.
83.
84.
85.
86. 87.
88. 89.
90.
91.
92.
93.
lar glutamate concentration during seizures induced by systemic picrotoxin or focal bicuculline injection: An in vivo dialysis study with on-line enzymatic detection. Epilepsy Res. 1991;9:86–91. Miller, H. P., A. I. Levey, J. D. Rothstein, A. V. Tzingounis, and P. J. Conn. Alterations in glutamate transporter protein levels in kindling-induced epilepsy. J. Neurochem. 1997;68: 1564–1570. Mody, I. The molecular basis of kindling. Brain Pathol. 1993;3:395–403. Morimoto, K., K. Katayama, K. Inoue, and K. Sato. Effects of competitive and noncompetitive NMDA receptor antagonists on kindling and LTP. Pharmacol. Biochem. Behav. 1991;40:893–899. Munir, M., R. Rothstein, and M. B. Robinson. MGluR mediated increase in cell surface expression of the neuronal glutamate (Glu) transporter, EAAC1, a possible endogenous mechanism to limit excitotoxicity. Soc. Neurosci. Abstr. 1997; 23:585.9. Naylor, D. E., and C. G. Wasterlain. Synaptic NMDA receptor numbers increase in dentate granule cells during status epilepticus. Soc. Neurosci. Abstr. 2003;345.4. Neugebauer, V., N. B. Keele, and P. Shinnick-Gallagher. Epileptogenesis in vivo enhances the sensitivity of inhibitory presynaptic metabotropic glutamate receptors in basolateral amygdala neurons in vitro. J. Neurosci. 1997;17: 983–995. Niquet, J., R. A. Baldwin, S. G. Allen, D. G. Fujikawa, and C. G. Wasterlain. Hypoxic neuronal necrosis: Protein synthesis-independent activation of a cell death program. Proc. Natl. Acad. Sci. U.S.A. 2003;100:2825–2830. Novelli, A., J. A. Reilly, P. G. Lysko, and R. C. Henneberry. Glutamate becomes neurotoxic via the N-methyl--aspartate receptor when intracellular energy levels are reduced. Brain Res. 1988;451:205–212. Oguro, K., N. Oguro, T. Kojima, S. Y. Grooms, A. Calderone, X. Zheng, et al. Knockdown of AMPA receptor GluR2 expression causes delayed neurodegeneration and increases damage by sublethal ischemia in hippocampal CA1 and CA3 neurons. J. Neurosci. 1999;19:9218–9227. Olney, J. W. Excitatory transmitters and epilepsy-related brain damage. Int. Rev. Neurobiol. 1985;27:337–362. Ormandy, G. C., R. S. Jope, and O. C. Snead III. Anticonvulsant actions of MK-801 on the lithium-pilocarpine model of status epilepticus in rats. Exp. Neurol. 1989;106:172–180. Pitkänen, A. Drug mediated neuroprotection and antiepilkeptogenesis: Animal data. Neurology 2002;59:527–533. Prince, H. C., A. V. Tzingounis, A. I. Levey, and P. J. Conn. Functional downregulation of GluR2 in piriform cortex of kindled animals. Synapse 2000;38:489–498. Rice, A. C., and R. J. DeLorenzo. NMDA receptor activation during status epilepticus is required for the development of epilepsy. Brain Res. 1998;782:240–247. Robinson, M. B., and L. A. Dowd. Heterogeneity and functional properties of subtypes of sodium-dependent glutamate transporters in the mammalian central nervous system. Adv. Pharmacol. 1997;37:69–115. Rocha, L., M. Briones, R. F. Ackermann, B. Anton, N. T. Maidment, C. J. Evans, and J. Engel. Pentylenetrazol-induced kindling: Early involvement of excitatory and inhibitory systems. Epilepsy Res. 1996;26:105–113. Rogers, S. W., P. I. Andrews, L. C. Gahring, T. Whisenand, K. Cauley, B. Crain, et al. Autoantibodies to glutamate recep-
94.
95. 96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
tor GluR3 in Rasmussen’s encephalitis. Science 1994;265: 648–651. Sepukty, J., C. U. Eccles, R. P. Lesser, M. Dykes-Hoberg, and J. D. Rothstein. Molecular knockdown of neuronal glutamate transporter EAAT3 produces epilepsy and dysregulation of GABA metabolism. Soc. Neurosci. 1997;23:585.1. Sheng, M., and M. J. Kim. Postsynaptic signalling and plasticity mechanisms. Science 2002;298:776–780. Siman, R., J. C. Noszek, and C. Kegerise. Calpain I activation is specifically related to excitatory amino acid induction of hippocampal damage. J. Neurosci. 1989;9:1579–1590. Simantov, R., M. Crispino, W. Hoe, G. Broutman, G. Tocco, J. D. Rothstein, and M. Baudry. Changes in expression of neuronal and glial glutamate transporters in rat hippocampus following kainate-induced seizure activity. Brain Res. Mol. Brain Res. 1999;65:112–123. Simpson, L. H., H. V. Wheal, and R. Williamson. The contribution of non-NMDA and NMDA receptors to graded bursting activity in the CA1 region of the hippocampus in a chronic model of epilepsy. Can. J. Physiol. Pharmacol. 1991; 69:1091–1098. Sparenborg, S., L. H. Brennecke, N. K. Jaax, and D. J. Braitman. Dizocilpine (MK-801) arrests status epilepticus and prevents brain damage induced by soman. Neuropharmacology 1992;31:357–368. Stafstrom, C. E., G. L. Holmes, and J. L. Thompson. MK801 pretreatment reduces kainic acid-induced spontaneous seizures in prepubescent rats. Epilepsy Res. 1993;14:41–48. Tanaka, K., S. H. Graham, and R. P. Simon. Role of excitatory neurotransmitters in seizure-induced neuronal injury in rats. Brain Res. 1996;737:59–63. Tanaka, S., K. Sako, T. Tanaka, and Y. Yonemasu. Regional calcium accumulation and kainic acid (KA) induced limbic seizure status in rats. Brain Res. 1996;478:385–390. Tanaka, K., K. Watase, T. Manabe, K. Yamada, M. Watanabe, K. Takahashi, et al. Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 1997;276:1699–1702. Thompson, K., and C. Wasterlain. Partial protection of hippocampal neurons by MK-801 during perforant path stimulation in the immature brain. Brain Res. 1997;751:96–101. Ueda, Y., H. Yokoyama, A. Nakajima, J. Tokumaru, T. Doi, and Y. Mitsuyama. Glutamate excess and free radical formation during and following kainic acid-induced status epilepticus. Exp. Brain Res. 2002;147:219–226. Vemuganti, R., M. K. Baskaya, A. Dogan, A. M. Rao, J. D. Rothstein, and R. J. Dempsey. Traumatic brain injury downregulates glial glutamate transporters GLT-1 and GLAST. Soc. Neurosci. 1997;23:585.13. Wade, J. V., F. E. Samson, S. R. Nelson, and T. L. Pazdernik. Changes in extracellular amino acids during soman- and kainic acid-induced seizures. J. Neurochem. 1987;49:645–650. Walton, N. Y., and D. M. Treiman. Motor and electroencephalographic response of refractory experimental status epilepticus in rats to treatment with MK-801, diazepam, or MK-801 plus diazepam. Brain Res. 1991;553:97–104. Wasterlain, C. G., H. Liu, A. M. Mazarati, and R. Baldwin. NMDA receptor trafficking during the transition from single seizures to status epilepticus. Ann. Neurol. 2002;52(Suppl. 1):S16. Wong, M. L., M. A. Smith, J. Licinio, S. Q. Doi, S. R. B. Weiss, R. M. Post, and P. W. Gold. Differential effects of kindled and electrically induced seizures on a glutamate
111.
112.
113.
114.
receptor (GluR1) gene expression. Epilepsy Res. 1993;14: 221–227. Yen, W., J. Williamson, E. H. Bertram, and J. Kapur. A comparison of three NMDA receptor antagonists in the treatment of prolonged status epilepticus. Epilepsy Res. 2004;59: 43–50. Young, D., and M. Dragunow. MK-801 and NBQX prevent electrically induced status epilepticus. Neuroreport 1994;5: 1481–1484. Young, D., and M. Dragunow. Non-NMDA glutamate receptors are involved in the maintenance of status epilepticus. Neuroreport 1993;5:81–83. Zeevalk, G. D., and W. J. Nicklas. Evidence that the loss of the voltage-dependent Mg2+ block at the N-methyl-aspartate receptor underlies receptor activation during inhibition of neuronal metabolism. J. Neurochem. 1992;59: 1211–1220.
:
303
23
Metabotropic Receptors in Status Epilepticus
.
Introduction The involvement of ionotropic glutamate receptors in epilepsy has been much studied and is reviewed by Chapman and Meldrum in Chapter 22. In burst discharges, the early spikes and part of the paroxysmal depolarizing shift arise from AMPA (a-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid) receptor activation, and the later spikes and much of the depolarizing shift depend on NMDA (N-methyl--aspartate) receptor activation. The NMDA receptors also play a key role in selective neuronal degeneration after status epilepticus (SE). Glutamate metabotropic receptors are also involved in acute seizures and in the phenomena of SE. They may be responsible for some characteristic features of SE. Our present knowledge of their functional roles and their contribution to epileptic phenomena is, however, limited. This chapter reviews relevant aspects of glutamate metabotropic receptors and suggests ways in which they may be involved in sustained seizure activity and its aftermath.
Glutamate metabotropic receptors: Classification At present, eight glutamate metabotropic receptors, or mGluRs, have been sequenced and cloned. They fall into three families according to their transduction mechanisms, amino acid sequence homology, and agonist pharmacology (Table 23.1). Group I receptors (mGlu1 and mGlu5) are Gprotein-linked to activation of phospholipase C, with diacylglycerol and inositol triphosphate as second messengers. Receptors in groups II (mGlu2, mGlu3) and III (mGlu4, 6, 7, 8) are negatively coupled to adenylate cyclase, reducing the formation of cAMP. This influences the activity of various enzymes, including cAMP-dependent protein kinases. A number of splice variants have been detected in rat and man (mGlu1a–d; mGlu4a,b; mGlu5a,b; mGlu7a,b). In neonatal rats, activation of mGlu1 and mGlu5 leads to phospholipase D activation, with a pharmacology compatible with group I receptors (activation by 3,5dihydroxyphenylglycine [DHPG] and trans-azetidine-2,4dicarboxylate) (51, 52). In adult rat hippocampus, however, the pharmacology of mGluRs coupled to phospholipase
D is not consistent with group I receptor mediation, as three antagonists of group I responses (DHPG, amethyl-4-carboxyphenylglycine, and L(+)-2-amino-3phosphonopropionic acid) are all agonists (74). The glutamate metabotropic receptors have an enormous diversity of functional effects (for reviews, see 5, 27, 69, 72, 75, 82, and 96). They modify synaptic function by changing Ca2+ and K+ conductances. They modify the expression and effect of ionotropic glutamate receptors (5, 33, 94, 95). They may also modulate the expression and function of glutamate transporters: increases in cAMP regulate GLT-1 expression, and PKC activation increases Vmax of EAAC1 (35). mGluRs are involved in many behavioral phenomena; their roles in learning and memory, anxiety, and nociception are beginning to be defined. Each of the eight receptors has a specific regional pattern of expression in the brain or retina. mGlu6 is largely confined to the retina; mGlu8 is predominantly expressed in presynaptic terminals in the olfactory bulb (50, 72). Group III mGluRs occur presynaptically in the brain, whereas groups I and II mGluRs occur both presynaptically and postsynaptically in neurons (Table 23.2). EM-immunogold studies reveal crucial differences in the presynaptic locations of groups II and III mGluRs (85). In the rat hippocampus, mGlu1 and mGlu5 are postsynaptic; mGlu4, mGlu7a, and mGlu8 are concentrated at presynaptic zones, whereas mGlu2/3 receptors are on preterminals but remote from the synapse. Group III receptors are presumably activated during normal levels of synaptic activity, whereas group II receptors may require sustained synaptic activation and/or decreased glutamate uptake to be exposed to effective glutamate concentrations (81). The intrasynaptic (group III) and periterminal (group II) patterns of expression may be alternatives rather than functionally complementary. Thus, group III presynaptic effects predominate on the lateral perforant path, whereas group II receptors are functionally prominent on the medial perforant path (61). The postsynaptic neuron also determines the mGluR expression; thus, in the hippocampus, mGlu7 receptors are on pyramidal cell axon terminals presynaptic to interneurons expressing mGlu1a (84). Glia express mGlu1, mGlu3, and mGlu5. mGlu5 appears to be functionally significant in astrocytes (9, 67, 68).
:
305
T 23.1 Glutamate metabotropic receptors: Transduction, agonists, and antagonists Transduction
Antagonists (S)-4C3HPG AIDA LY 367385 SIB 1893 MPEP MCCG CPPG EGLU MTPG MSoPPE LY 341495 LY 379268 MAP4 MSOP CPPG MPPG MCPA
Group I mGlu1, mGlu5
PLC activation PI hydrolysis (DG, IP3) (PKC activation)
Quisqualate (S)-3,5-DHPG 1S,3R-ACPD CHPG
Group II mGlu2, mGlu3
Decrease in adenylyl cyclase activity (cAMP decrease)
Group III mGlu4, mGlu6 mGlu7, mGlu8
Decrease in adenylyl cyclase activity (cAMP decrease)
PLD-coupled
Phospholipase D activation
-CCGI (S)-4C3HPG 1S,3R-ACPD DCGIV NAAG 2R,4R-APDC LY354740 -AP4 -SOP Homo-AMPA 1S,3R-ACPD 4Cl-3,5-DHPG PPG ACPT-1 -CSA -AP3
Key: 1S,3R-ACPD ACPT-1 AIDA Homo-AMPA -AP3 2R,4R-APDC -CCG1 CHPG (S)-4C3HPG 4-Cl-3,5-DHPG CPPG -CSA 3,5-DHPG EGLU LY 367385 LY 354740 LY 379268 LY 341495 MAP4 MCCG MCPA MPEP MPPG MSOP MTPG NAAG PPG SIB 1893 -SOP
306
Agonists
3,5-DHPG
(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid (RS)-1-aminoindan-1,5-dicarboxylic acid 2-amino-4-(3-hydroxy-5-methyl-isoxazol-4-yl)butyric acid -(+)-2-amino-3-phosphonopropionic acid 2R,4R-aminopyrrolidine-2,4-dicarboxylic acid (2S,3S,4S)-2-carboxycyclopropylglycine (RS)-2-chloro-5-hydroxyphenylglycine (S)-4-carboxy-3-hydroxyphenylglycine 4-chloro-3,5-dihydroxyphenylglycine (RS)-a-cyclopropyl-4-phosphonophenylglycine -cysteine sulfinic acid 3,5-dihydroxyphenylglycine (2S)-a-ethylglutamic acid (+)-2-methyl-4-carboxyphenylglycine (1S,2S,5R,6S)-(+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxy (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylic acid (2S,1¢S,2¢S)-2-(9-xanthylmethyl)-2-(2¢carboxycyclopropyl)glycine (S)-2-amino-2-methyl-4-phosphonobutanoic acid a-methyl--CCG1 (S)-a-methyl-3-carboxyphenylalanine 2-methyl-6-phenylethynyl-pyridine (RS)-a-methyl-4-phosphonophenylglycine (RS)-a-methylserine-O-phosphate (RS)-a-methyl-4-tetrazoylphenylglycine N-acetylaspartylglutamate (RS)-4-phosphonophenylglycine (E)-6-methyl-2-styryl-pyridine -serine-O-phosphate
:
T 23.2 Glutamate metabotropic receptors: Synaptic locations and functions Presynaptic
Postsynaptic
Group I
Potentiate glutamate release Block GABAergic transmission
Group II
Block transmission (GABA, glutamate) Block transmission (GABA, glutamate) Inhibit P/Q Ca2+ channels
Depolarization Decrease Gk Promote Na+/Ca2+ exchange Enhance NMDA R responses Hyperpolarization (Ca2+-dependent Gk)
Group III
Oscillations in [Ca2+]i in astrocytes probably play an important role in cell signaling and network phenomena and are enhanced by mGlu5 activation (71) (Table 23.2). Immunohistochemical studies in man are rather limited. In the hippocampus, group I mGluRs are found in all neurons, with mGlu5 predominating in distal dendritic fields. mGlu2 and 3 are expressed in dentate granule cells and pyramidal neurons in CA2, 3, and 4 and in glial cells. mGlu4a is largely confined to the mossy fiber projection to stratum lucidum (11). It is commonly assumed that glutamate is the endogenous transmitter for mGluRs. Aspartate is relatively inactive. Some thio-analogues (homocysteine sulfinic acid, -cysteine sulfinic acid) are active at mGlu1 (49). N-acetylaspartylglutamate (NAAG) selectively inhibits forskolin-stimulated cAMP formation via mGlu3 (not mGlu4, 6, or 7) (97). The group III-selective agonist -phospho-O-serine occurs endogenously in the brain and is therefore a potential candidate for the endogenous transmitter at some or all of the group III receptors. -cysteine sulfinic acid is a more potent agonist for phospholipase D activation than is glutamate (12), and is therefore a candidate endogenous ligand. This chapter summarizes what is known about the influence of mGluRs on epileptic phenomena, and especially their contribution to sustained seizure activity.
Methods of investigation The role of mGluRs in epilepsy can be investigated from two aspects. One is primarily pharmacologic, testing the acute or chronic effects on seizure phenomena of activation or blockade of specific mGluRs. Similar information can be obtained by antisense technology decreasing the expression of particular mGluRs or by gene knockout techniques. The other aspect is the possibility that altered expression or function of mGluRs occurs as part of the process of epileptogenesis or as a consequence of seizures or SE. To date,
neither of these approaches has been extensively exploited. The following discussion emphasizes the opportunities available.
Pharmacologic approaches The development of selective agonists and antagonists for mGluRs is in a relatively early stage, although many active compounds have been studied (83). Some key features differentiating the three groups of metabotropic receptor are listed in Table 23.1. Although the members of each group are broadly similar, there are some intragroup differences, notably, for example, between mGlu1a and mGlu5. Among agonists, 3,5-dihydroxyphenylglycine is equi-active at mGlu1 and mGlu5, CPCCOEt is relatively selective for mGlu1, and CHPG is selective for mGlu5. LY 367385 is a selective antagonist for mGlu1 (26). (S)-4CPG and (S)4C3HPG are more effective antagonists for cells expressing mGlu1b than for cells expressing mGlu5a (60). MPEP (2-methyl-6-(phenylethynyl)pyridine) and SIB 1893 (2methyl-6-(phenylethenyl)pyridine) are noncompetitive group I antagonists with a high selectivity for mGlu5 (43, 93). (R,S)-PPG ((R,S)-4-phosphonophenylglycine) is a group III metabotropic antagonist with a 25-fold preference for mGlu8. mGlu8 shows some responses (high agonist sensitivity to LCCG1, antagonist sensitivity to MCPG) (80) that are more characteristic of a group II mGluR than of a group III mGluR. Thus it is appropriate to try to define agonist and antagonist specificity in terms of the individual receptor types, rather than the groups (Table 23.3).
Proconvulsant and anticonvulsant actions of selective agonists and antagonists in vivo G I A Group I agonists (such as 3,5dihydroxyphenyl glycine and 1S,3R-ACPD) are pro-
:
307
T 23.3 Anticonvulsant and proconvulsant effects of metabotropic agonists and antagonists in rodent models of epilepsy Group
Proconvulsant
Anticonvulsant
Group I
Agonists 3,5-DHPG 1S,3R-ACPD CHPG
Antagonists (S)4C3HPG MPEP SIB 1893 LY 367385 Agonists (S)4C3HPG 1S,3S-ACPD -CCGI LY 354740 LY 379268
Group II
Group III
Agonists 1S,3S-ACPD 2R,4R-APDC
Antagonists EGLU LY 341495 MTPG MPPG Agonists -AP4 -SOP
Agonists -AP4 -SOP PPG ACPT-1
Antagonists MCPA
Note: Abbreviations are as in Table 23.1. For 1S,3S-ACPD and the group III agonists (-AP4 and -SOP), the proconvulsant action is early (140 mg/mL) correlate better with thrombocytopenia than do high valproate doses (10). Thrombocytopenia has not been reported with IV use so far. Other hematologic abnormalities reported include platelet dysfunction, fibrinogen depletion, and coagulation abnormalities, which have been associated with altered bleeding time, bruising, and epistaxis (2, 30). H There are two published reports of symptomatic hypotension. In one, an 11-year-old girl with a varicella infection was postictal and febrile and had received 10 mg of diazepam and 1.6 mg of lorazepam prior to valproate therapy (42). Valproate was dosed at 30 mg/kg and infused IV over 1 hour. The hypotension was treated with IV fluids and vasopressor therapy. Kumar et al. (25) reported a case in a 5-year-old girl who was receiving vasopressor support and developed circulatory collapse after an IV injection of valproate at a dose of 480 mg over 20 minutes at
566
an infusion rate of 20 mg/min. An objective causality assessment performed using the Naranjo probability scale indicated a highly possible relationship between severe hypotension, cardiovascular collapse, and IV valproate therapy in this patient. The authors concluded that IV valproate should be used with caution, particularly in hemodynamically unstable patients. I S R A retrospective review compared the incidence of IV site reactions in neurotrauma patients receiving valproate and phenytoin. The authors found that all IV site reactions occurred at peripheral administration sites. The estimated incidence of site reactions was 21% and 30% for valproate and phenytoin, respectively (3).
Summary The recent literature suggests that IV valproate is fairly safe and well tolerated in the treatment of SE, but the data are limited. There is clearly a need for controlled studies of IV valproate to demonstrate its safety and efficacy in the treatment of SE. A major factor in determining whether patients with SE should be given IV valproate is refractoriness to other treatments and tolerance to drug-associated blood pressure changes. Currently, in view of its variable efficacy and limited experience, IV valproate cannot be recommended as a first-line agent in the treatment of SE. However, the low incidence of respiratory or circulatory depression reported is a very desirable feature, particularly in older patients. Its use as third- or fourth-line agent or as an adjunctive agent in SE appears justified, and in SE associated with primary generalized epilepsies, it may be an effective second- or third-line agent. Further studies are needed to assess its efficacy and dosing in SE. The favorable but limited experience accumulated to date justifies the use of IV valproate in refractory SE in children and adults, but the possibility of serious complications cannot be ruled out, and the exact indications have yet to be defined. REFERENCES 1. Abbott Laboratories, Abbott Park, Ill. Data on file. 2. Acharya, S., and J. B. Bussel. Hematologic toxicity of sodium valproate. J. Pediatr. Hematol. Oncol. 2000;22:62–65. 3. Altrup, U., G. Gerlach, H. Reith, M. N. Said, and E. J. Speckmann. Effects of valproate in a model nervous system (buccal ganglia of helix pomatia). I. Antiepileptic actions. Epilepsia 1992;33:743–752. 4. Anderson, G. D., Y. Lin, N. R. Temkin, et al. Incidence of intravenous site reactions in neurotrauma patients receiving valproate or phenytoin. Ann. Pharmacother. 2000;34:697–702. 5. Anderson, W. T., F. J. Ritter, M. D. Frost, and J. R. Gates. IV valproate induced pancreatitis during prolonged administration in dose exceeding 130 mg/kg/day (abstr. 2.288). Epilepsia 2003;44(Suppl. 9):274.
6. Bryant, A. E. III, and F. E. Dreifuss. Valproic acid hepatic fatalities. III. U.S. experience since 1986. Neurology 1996;46: 465–469. 7. Chapman, S. A., P. Wacksman, and B. D. Patterson. Pancreatitis associated with valproic acid: A review of the literature. Pharmacotherapy 2001;21:1549–1560. 8. Christian, N. A., C. N. Peters, and B. Pohlmann-Eden. Efficacy and safety of intravenous valproate in status epilepticus (abstr. 2.267). Epilepsia 1999;40(Suppl. 7):149–150. 9. Czapinski, P., and A. Terczynski. [Intravenous valproic acid administration in status epilepticus.] Neurol. Neurochir. Pol. 1998;32:11–22 (in Polish). 10. Delgado, M. R., A. R. Riela, P. A.-C. Janith Mills, et al. Thrombocytopenia secondary to high valproate levels in children with epilepsy. J. Child Neurol. 1994;9:311–314. 11. Devinsky, O., I. E. Leppik, L. J. Willmore, et al. Safety of intravenous valproate. Ann. Neurol. 1995;38:670–674. 12. Dreifuss, F. E., D. H. Langer, K. A. Moline, and J. E. Maxwell. Valproic acid hepatic fatalities. II. US experience since 1984. Neurology 1989;39(2 Pt. 1):201–207. 13. Dreifuss, F. E., N. Santilli, D. H. Langer, K. P. Sweeney, K. A. Moline, and K. B. Menander. Valproic acid hepatic fatalities: A retrospective review. Neurology 1987;37:379–385. 14. Giroud, M., D. Gras, A. Escousse, et al. Use of injectable valproic acid in status epilepticus. Drug Invest. 1993;5:154– 159. 15. Holle, L. M., B. E. Gidal, and D. M. Collins. Valproate in status epilepticus. Ann. Pharmacother. 1995;29:1042–1044. 16. Honack, D., and W. Löscher. Intravenous valproate: Onset and duration of anticonvulsant activity against a series of electroconvulsions in comparison with diazepam and phenytoin. Epilepsy Res. 1992;13:215–221. 17. Hovinga, C. A., M. F. Chicella, D. F. Rose, et al. Use of intravenous valproate in three pediatric patients with nonconvulsive or convulsive status epilepticus. Ann. Pharmacother. 1999;33: 579–584. 18. Isojarvi, J. I. T., T. J. Laatikainen, M. Knip, et al. Obesity and endocrine disorders in women taking valproate for epilepsy. Ann. Neurol. 1996;39:579–584. 19. Isojarvi, J. I. T., T. J. Laatikainen, A. J. Pakarinen, et al. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N. Engl. J. Med. 1993;329:1383–1388. 20. Isojarvi, J. I. T., E. Tauboll, A. J. Pakarinen, et al. Altered ovarian function and cardiovascular risk factors in valproatetreated women. Am. J. Med. 2001;111:290–296. 21. Kaplan, P. W. Intravenous valproate treatment of generalized nonconvulsive status epilepticus. Clin. Electroencephalogr. 1999; 30:1–4. 22. Kelly, T. E. Teratogenicity of anticonvulsant drugs. I. Review of the literature. Am. J. Med. Genet. 1984;19:413–434. 23. Knake, S., M. Vescovi, and H. H. Hamer. Intravenous sodium valproate in the treatment of status epilepticus (abstr. 2.269). Epilepsia 1999;40(Suppl. 7):150. 24. Konig, S. A., H. Siemes, F. Blaker, E. Boenigk, G. GrossSelbeck, F. Hanefeld, N. Haas, et al. Severe hepatotoxicity during valproate therapy: An update and report of eight new fatalities. Epilepsia 1994;35:1005–1015. 25. Kumar, P., C. J. Vallis, and C. M. Hall. Intravenous valproate associated with circulatory collapse. Ann. Pharmacother. 2003; 37:1797–1799. 26. Leniger, T., and A. Hufinagel. Nonconvulsive status epilepticus treated with intravenous valproate (abstr. 2.266). Epilepsia 1999;40(Suppl. 7):149–150.
27. Löscher, W. Correlation between alterations in brain GABA metabolism and seizure excitability following administration of GABA aminotransferase inhibitors and valproic acid: A re-evaluation. Neurochem. Int. 1981;3:397–404. 28. Löscher, W. Valproate: A reappraisal of its pharmacodynamic properties and mechanisms of action. Prog. Neurobiol. 1999;58: 31–59. 29. Naritoku, D. K., and S. Mueed. Intravenous loading of valproate for epilepsy. Clin. Neuropharmacol. 1999;22:102–106. 30. Perucca, E. Pharmacological and therapeutic properties of valporate: A summary after 35 years of clinical experience. CNS Drugs 2002;16:695–714. 31. Pohlmann-Eden, B., C. N. Peters, R. Wennberg, and C. E. Dempfle. Valproate induces reversible factor XIII deficiency with risk of perioperative bleeding. Acta Neurol. Scand. 2003; 108:142–145. 32. Price, D. J. Intravenous valproate: Experience in neurosurgery. In D. Chadwick, ed. Royal Society of Medicine Services International Symposium Series No. 152. London, U.K.: Royal Society of Medicine Services Limited, 1989:197–203. 33. Ramsay, R. E., D. Cantrell, S. D. Collins, et al. Safety and tolerance of rapidly infused Depacon: A randomized trial in subjects with epilepsy. Epilepsy Res. 2003;52:189–201. 34. Ramsay, R. E., B. Uthman, I. E. Leppik, et al. The tolerability and safety of valproate sodium given as an intravenous infusion. J. Epilepsy 1997;10:187–193. 35. Sheth, R. D., and B. E. Gidal. Intravenous valproic acid for myoclonic status epilepticus. Neurology 2000;54:1201. 36. Sinha, S., and D. K. Naritoku. Intravenous valproate is well tolerated in unstable patients with status epilepticus. Neurology 2000;55:722–724. 37. Snead, O. C., and M. V. Miles. Treatment of status epilepticus in children with rectal sodium valproate. J. Pediatr. 1985;106:323–325. 38. Thorpy, M. J. Rectal valporate syrup and status epilepticus. Neurology 1980;30:113–114. 39. Uberall, M. A., R. Trollmann, U. Wunsiedler, et al. Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus. Neurology 2000;54:2188–2189. 40. Vajda, F. J. E., G. W. Mihaly, J. L. Miles, G. A. Donnan, and P. F. Bladin. Rectal administration of sodium valproate in status epilepticus. Neurology 1978;28:897–899. 41. Venkataraman, V., and J. W. Wheless. Safety of rapid intravenous infusion of valproate loading doses in epilepsy patients. Epilepsy Res. 1999;35:147–153. 42. White, J. R. Intravenous valproate associated with significant hypotension in the treatment of status epilepticus. J. Child Neurol. 1999;14:822–823.
, , :
567
46
Other Pharmacologic Therapy for Refractory Status Epilepticus
. .
Introduction Most cases of status epilepticus (SE) remit with the first-line therapies discussed in this book. When status continues, however, doctors must turn to other therapies, the efficacies of which are less established. This chapter considers a miscellany of drug treatments not elsewhere described: propofol, inhaled anesthetics, etomidate, lidocaine, paraldehyde, magnesium, furosemide, and direct infusion of drugs at the seizure focus. The clinical characteristics of these drugs are described in Table 46.1. Midazolam is discussed in Chapter 49.
Propofol Propofol (2,6-di-isopropylphenol, Diprivan; Figure 46.1) is an alkyphenol that has been in use as an adjunct to anesthesia since 1989. It has a poor solubility in water and is therefore supplied as an emulsion in lipids, egg lecithin, and glycerol. Unlike inhalation anesthetics, the use of propofol does not always require intubation. For use as a sedative in the intensive care unit (ICU) setting, controlled trials have shown that propofol is better tolerated than midazolam and the opiates and is associated with a faster recovery (27, 145). Propofol has promise as a new agent for treatment of status, but under some circumstances, propofol can induce seizures or make them worse. B M Propofol appears to act on a wide variety of neuronal systems. Hara et al. (67) studied the effect of propofol on g-aminobutyric acid (GABA)-induced currents in dissociated rat hippocampal neurons. In concentrations higher than 1 millimolar (mM), propofol induces an inward hyperpolarizing current carried by chloride ions. This current cross-desensitizes with the GABAA-induced current and is blocked by bicuculline and strychnine. Although diazepam enhanced the propofol current, it was not blocked by the benzodiazepine receptor antagonist, flumazenil. In humans as well, flumazenil has no influence on recovery time or on the hemodynamic changes associated with propofol (47). In addition to a direct effect on chloride conductance (1), propofol potentiates the effect of GABA on neurons (65) by increasing the frequency of GABA-associated conductance events (130). GABAergic
recurrent inhibition in hippocampus is increased by 7–28 mmolar propofol, measured by paired-pulse inhibition (3). The net effect of these actions is to increase the potency of GABAergic inhibitory neurotransmission. Evidence is strong that propofol inhibits cellular excitation at the N-methyl--aspartate (NMDA) subtype of the glutamate receptor at clinically relevant concentrations of 35 mM (181). Patch-clamp study shows this to be a reversible, noncompetitive (possibly allosteric) action at the NMDAassociated channel to reduce the probability of channel opening (129). Propofol stimulates production and release of nitric oxide (NO) from endothelial cells (133). NO in turn attenuates seizures in animal models and prolongs the postictal state (74). Because NO is a vasodilator this also may account for some of the hypotension produced by propofol (143, 168). Propofol may be neuroprotective, especially in high concentrations. High concentrations of propofol protect against the toxicity of NMDA and glutamate, but not kainic acid or AMPA, on cultured rat fetal hippocampal neurons (64). Rats subjected to cerebral ischemia evidence more tissue protection and a better neurologic outcome when anesthetized with propofol compared to fentanyl (99). Propofol, 0.25 mg/ kg/min given intravenously (IV), was compared with a control vehicle for the acute and chronic period after a 10-minute cardiorespiratory arrest in cats (26). Hippocampal neuronal activity was less reduced with propofol, and neuronal deficit scores were similarly better after propofol treatment. Excitotoxicity in anoxic-ischemic events is believed to be mediated in part by extracellular increases in excitatory amino acids. It is therefore discouraging that propofol (200 mM) was far less effective than was halothane, enflurane, and pentothal in reducing glutamate release in anoxic brain slices (89). A M S Propofol has been found efficacious in several, but not all, animal seizure models (9). Propofol can either lower or increase the threshold for seizures produced by lidocaine in rats, depending on the propofol serum concentration (68). In the pentylenetetrazole (PTZ) model in the rabbit (6) and in the rat (70), propofol increased the seizure threshold. A nonsedating analogue
:
569
infusion. Approximate half-lives are 5 minutes following a 1hour infusion and 7 minutes following a 10-hour infusion. Tolerance and addiction appear minimal. Subjects lose eyelash reflex at serum concentrations of about 2.5 mg/mL and lose consciousness at serum concentrations at 3.4– 4.3 mg/mL (173), corresponding to infusion rates of 5.4– 8.8 mg/kg/hr (41). The volume of distribution is 3.6 L/kg, and the elimination half-life is 2–3 hours (179).
F 46.1
Chemical structure of propofol (Diprivan).
of propofol, 4-iodo-2,6-di-isopropylphenol, with similar GABA potentiation properties also demonstrated an increase in seizure threshold in a PTZ rat model (152). Propofol attenuates seizures in rat models with cortical penicillin (36), picrotoxin (69), and bupivacaine (72). In mice, propofol provided anticonvulsant protection against the GABA antagonists bicuculline and picrotoxin. In contrast, propofol worsened seizures provoked by strychnine and by the glutamate receptor subtype agonists kainate and quisqualate. The question arises as to whether propofol can serve as an anticonvulsant in subanesthetic doses. Hasan and Woolley (71) administered subanesthetic doses, ranging from 6.25 to 50 mg/kg, to rats undergoing maximal electroshock (MES) seizures. Partial inhibition of tonic hindlimb extension occurred at 12.5 mg/kg, and full inhibition occurred at 50 mg/kg. None of these doses produced major sedative effects, and none enhanced the MES seizures. Propofol therefore has a pattern of anticonvulsant action similar to that of the barbiturates, with some action against PTZ and MES seizures but not against strychnine- or NMDA-induced seizures. C P Propofol is an alkyphenol that was introduced in 1989 by Zeneca Pharmaceuticals after testing on 25,981 patients at 1,722 institutions by 1,819 anesthesiologists (5). Propofol has some advantages over benzodiazepines and opiates for sedation (10, 55), while the antiemetic and antipruritic effects of propofol set it above the more traditional anesthetics (23). Impediments to its use are cost and poor solubility in aqueous solutions; however, Astra Zeneca’s patent expired in 1999, and the drug has subsequently become significantly less expensive. Propofol has a quick onset of action, consistent with a first-pass effect on the brain. The offset of action is also rapid, and patients quickly return to full consciousness, even when infusions are prolonged. The drug is cleared from the serum by means of glucuronidation in the liver to inactive metabolites with secondary renal clearance, and also by rapid and slow equilibration into fatty tissues. The serum half-life is dependent on the amount of drug stored in tissues and is prolonged by approximately 50% after continuous
570
C U S SE The initial reports linking propofol and seizures were not encouraging and, in fact, described seizures provoked by propofol (49). As of 1993, seizures or involuntary movements had been reported in about 50 patients, one-third of whom had prior epilepsy (113). At least one of these patients with prior epilepsy developed SE after administration of propofol. The EEG correlates of these seizures remain largely unspecified, but one case showed generalized paroxysmal fast activity (126). In 1994, Sutherland and Burt (166) reviewed the subject of propofol and seizures. More recently Walder et al. (175) systematically reviewed all the literature reports of “seizure-like phenomena” associated with propofol. Seizure-like phenomena were classified as either generalized tonic-clonic seizure (GTCS), increased tone with twitching and rhythmic movements not perceived as GTCS, involuntary movements, opisthotonus, or focal motor seizures. Although they reviewed a total of 81 patient reports, it was unknown how many actual patient exposures this figure represented; the authors estimated approximately 2 million patient exposures to propofol occurred per year in France alone. In patients without a history of epilepsy, seizure-like phenomena primarily were of the GTCS (43%) variety or increased tone with twitching or rhythmic movements (29%), and occurred primarily during induction (34%) or emergence (40%) from propofol anesthesia. In patients with epilepsy, most events were characterized as GTCS (82%) and tended to occur during emergence from anesthesia (73%). Little is known of the mechanisms and predisposing risk factors other than the dose of propofol and the history of prior seizures. Propofol anesthesia for electroconvulsive therapy (ECT) for depression reduces the duration of the resultant seizure (48, 53, 117), which may not, however, reduce the efficacy of the ECT (96, 114, 115). Regardless of whether or not propofol carries with it some slight risk of inducing seizures, there are promising reports of its successful use in the treatment of SE. Some patients with SE resistant to conventional therapy are responsive to propofol. Borgeat et al. (19) described a patient with focal SE that began intraoperatively during drainage of a traumatic subdural hematoma. He was treated for 48 hours with propofol-induced burst suppression and had a good outcome. Mackenzie et al. (110) described two patients who were treated with propofol for 5 and 12 days, also with good
outcomes. Both of these patients had EEG evidence of seizures, together with very subtle motor activity in one and a delayed appearance of motor activity in the other. PittMiller (135) attempted treatment of nonconvulsive status epilepticus (NCSE) with subcoma dosages of propofol, but coma-inducing levels were needed to stop the seizure activity. One patient suffering SE from amoxapine stopped seizing with propofol, after demonstrating resistance to the usual SE therapies (120). Larger series are limited, but Kuisma and Roine (105) reported on the prehospital administration (in an ambulance) of propofol to eight individuals with SE. These patients ranged in age from 29 to 70 years. Four had had no prior seizures and four had had prior posttraumatic epilepsy. In patients whose SE did not respond to diazepam, propofol was given in stepwise fashion, with sequential boluses of 30 mg administered every 30 seconds until convulsions stopped. The total amount of propofol given ranged from 100 to 200 mg IV during the time of transport to an appropriate emergency department (ED). Patients remained unconscious for a mean of 3.25 hours (range, 2–41 hours). Only one patient required admission to an ICU. The only problems noted with the treatment were transient decreases in blood pressure. Another series (164) compared propofol to high-dose barbiturates and found a statistically significant reduction in time to initial control of seizures (2.6 minutes vs. 123 minutes). The propofol group had a smaller percentage of patients with continued control, but this difference did not meet statistical significance. It was the authors’ experience that abrupt cessation of propofol led to a higher risk of seizure recurrence. Prasad et al. (137) reviewed their retrospective, nonrandomized experience with propofol (n = 14) and midazolam (n = 6) and found no statistically significant differences in seizure suppression, either clinically or electrographically. There was a trend toward improved survival in the midazolam group; however, the propofol group had a larger percentage of patient with acute central nervous system (CNS) injuries and had a longer mean duration of SE prior to initiation of treatment, both factors potentially contributing to worsened outcome. Reviews of the literature concluded that “propofol has shown promising results in the management of refractory status epilepticus when traditional therapies have failed” (22) and that propofol and midazolam are of similar efficacy to pentobarbital in the treatment of refractory SE (29). Both reviews stated that controlled trials are needed to better define efficacy and toxicity. EEG E Propofol has variable effects on the electroencephalographic (EEG) recording of the awake patient, but in increasing doses the drug induces both slowing (170) and beta activity (97). Long-latency P300 cognitive evoked potentials are attenuated considerably by propofol (159).
The effects of propofol on the EEG in patients with epilepsy was investigated during dental surgery (127). A sedative dose averaging 5.5 mg/kg/hr reduced paroxysmal EEG discharges in five of 11 patients. The Cleveland Clinic group (44) evaluated the effect of propofol, 2 mg/kg, during surgery to remove implanted subdural grids. All 17 studied patients had intractable epilepsy. Mean spike frequency decreased from two to zero spikes per minute before and after propofol, respectively, concomitant with EEG burst suppression and increased beta activity. Parameters needed to achieve an EEG burst-suppression pattern were documented by Illievich and colleagues (88). Propofol was given in an initial bolus of 1 mg/kg, followed by continuous infusion at a rate of 20 mg/kg/hr for 30 minutes, then 15 mg/kg/hr for 30 minutes. The infusion was stopped after a total of 1 hour. The cumulated propofol dose was 1,926 ± 346 mg (mean ± SD), with maximal serum concentrations of 0.92 ± 0.29 mg/mL. Burst suppression was evident after 15.7 ± 3.2 minutes and persisted for a mean of 10.9 ± 2.6 minutes after cessation of propofol infusion. With these rates and dosages, about 20% of the patients had a significant decline in heart rate, arterial pressure cardiac index, and cardiac work. These adverse events were treated with infusion of lactated Ringer’s solution, with no lasting consequences. In otherwise healthy adults, therefore, propofol can reduce the EEG to a burst-suppression pattern, with a small but definite risk of hemodynamic compromise. More than 93% of patients awaken within 15 minutes of cessation of propofol infusion (5). EEGs recover after 1–2 mg/kg propofol induction over a time course similar to that of clinical recovery (141). A E Propofol appears safe but is certainly not free from potential adverse events. These events include bradycardia and hypotension, transient movement disorders, and hyperlipidemia. Local irritation at the injection site is also seen in a significant proportion of patients. In use for anesthesia, propofol can cause significant respiratory depression with induction doses of 2.5 mg/kg, although subsequent maintenance at 12 mg/kg/hr has little effect on ventilation (84). Propofol causes hypotension, with systolic blood pressure levels falling below 90 mm Hg in about 15% of cases, usually within 10 minutes of induction. Bradycardia, with pulse rates falling to less than 50 beats per minute, occurs in about 5% of patients; however, less than 0.2% of 25,981 patients required drug therapy to counteract hemodynamic problems caused by propofol (86). Because propofol is poorly soluble in water, it is supplied as a lipid-egg emulsion. This mixture is a good source of nutrition for bacterial contamination, and therefore strict adherence to aseptic technique is required, with unused portions discarded within 12 hours of breaking the seal. Rare cases of sepsis have been thought to be secondary to
:
571
contamination of the emulsion. The emulsion also can raise serum triglyceride levels (10). Propofol is not indicated during pregnancy and has little clear advantage over inhalation agents in this setting, but it “does give satisfactory results and should be available as an alternative” (58). D R In adult patients with refractory SE, treatment with propofol should be instituted with an initial bolus of 1–2 mg/kg, followed by continuous infusion at approximately 2–10 mg/kg/hr, with EEG monitoring and titration to burst suppression. At these doses the patient is expected to become comatose, and standard supportive care should be instituted as for all patients in a drug-induced coma. This care includes adequate support of respiratory function, nutritional support, and frequent turning, with the use of special mattresses to prevent pressure sores. If an attempt is to be made to control the seizures with subcoma doses of propofol, then a continuous infusion may be started at 0.1 mg/kg/hr, with rapid titration upward until seizure activity stops or sedative side effects become too severe for continued escalation. On a cautionary note, a MedLine search found only a single article that reported the treatment of SE with subcoma doses of propofol, and this dosage level was unsuccessful. The patient’s seizures did, however, eventually respond to full-coma-level doses of propofol. Propofol is an expensive medication, but faster recovery times for brief procedures in children undergoing magnetic resonance imaging (93) and in women undergoing gynecologic surgery (174) may allow total savings. A dissenting study in adults found no appreciable cost saving (147). Since the time of those studies, however, the drug’s cost has dropped significantly, as it is no longer under patent protection. No such cost analysis has been done for epilepsy.
Inhaled anesthetics The inhaled anesthetics halothane (Fluothane) and isoflurane (Forane) have been in clinical use for many years (Figure 46.2). Halothane was first introduced in 1956, when it was popular because of its lack of flammability in a breathing mixture and its relatively quick offset of action compared with other anesthetics of the day. Isoflurane was introduced in 1981. It is associated with fewer toxic side effects and is not corrosive. They are administered by means of drug vaporization into the breathing mixture. Because they depress respiration, they must be administered by means of endotracheal intubation. B M Like many anesthetic agents, including those reviewed earlier in this chapter, the inhalation agents are potentiators of GABA. At clinically relevant concentrations, both halothane and isoflurane increase the peak amplitude and duration of GABAA-induced current (92).
572
F 46.2 Chemical structure of the inhaled anesthetics halothane and isoflurane.
Isoflurane produces no increase in chloride conductance in the absence of GABA (62). Enhancement of chloride conductance with inhaled anesthetics can be blocked by the GABAA antagonists, bicuculline and picrotoxin (182). The electrical response of mouse cortical wedges to NMDA and AMPA is decreased in the presence of isoflurane, while halothane more preferentially affects AMPAmediated response (25). These changes occur in a noncompetitive fashion. In rat cerebellar granule cells, the response to kainic acid was inhibited by halothane and isoflurane but not by enflurane, and none of these anesthetic agents had any effect on NMDA-mediated glutamate release (184). Again, the halothane inhibition of kainate-induced glutamate release was noncompetitive. Numerous studies have shown that the inhaled anesthetics have a significant effect on NO-mediated vascular relaxation (16). A M S Limited data exist on the anticonvulsant properties of the inhaled anesthetics. High concentrations of sevoflurane and isoflurane reduced lidocaine-induced seizures in rats; however, halothane had no anticonvulsant effect (124). C P All the inhaled anesthetics in clinical use today are halogenated hydrocarbons. They are delivered by vaporization into a breathing mixture. The maximum vapor concentration for both halothane and isoflurane is greater than 30%, far exceeding the concentrations used clinically. Halothane is absorbed in the lung bed and is largely eliminated unchanged in exhaled air. Approximately 20%–40% of the absorbed drug is metabolized in the liver by mixed function oxidase or cytochrome P450 systems. Cytochromeinducing medications may increase the rate of breakdown of halothane. Isoflurane is almost entirely eliminated via exhalation, with only 0.2% of the drug undergoing metabolic degradation. C U S SE The most commonly cited paper in the recent literature regarding the use of halothane in SE is that by Opitz et al. in Advances in Neurology
(128). In this article, three cases of SE in children were treated successfully with halothane or enflurane plus muscle relaxants. The authors concluded that inhaled anesthetics “can and should be used in the treatment of severe status epilepticus that does not respond to intravenous antiepileptic agents.” In 1985, Kofke et al. reported on the use of prolonged low-flow isoflurane in the control of SE in a 10-year-old girl (100). The cause of the SE was unknown, and the SE was resistant to multiple trials of pentobarbital coma, with seizures recurring after each attempt to wean the patient off barbiturates. In this case, isoflurane was administered in O2 + N2O and the inhaled concentration was increased until the EEG demonstrated obliteration of ictal activity, which largely meant a burst-suppression pattern. After 24 hours and again after 48 hours of anesthesia, isoflurane was turned off, with a return of electrographic seizures. After 48 hours the electrographic seizures were unaccompanied by clinical seizure activity, and the isoflurane was discontinued. The electrographic spiking was replaced by delta activity, and the patient did not regain consciousness. IV fluid and pressure support were required. An anesthetist was present during the entire treatment, and additional difficulties arose in trying to maintain prolonged anesthesia outside the operating room without exposing personnel to anesthetic. The following year the same group reported on the use of halothane and isoflurane on a patient who had been in SE resistant to conventional medications (146). They found that halothane alone did not suppress the seizures, whereas halothane with N2O was effective for a 30-minute period. Isoflurane alone was able to abolish electrographic seizure activity for a 5-hour period. The patient eventually died. The authors concluded that isoflurane was more efficacious at suppressing EEG activity than halothane and that this, plus the improved adverse effect profile, made isoflurane the preferable agent for the treatment of refractory SE. Several other authors have reported individual cases of SE treated with isoflurane (80, 87). Two reports in the literature discussed the treatment multiple patients with isoflurane. Sakaki et al. (151) reported four cases of postsurgical SE unresponsive to multiple other agents. In all cases, isoflurane was administered for less than 24 hours, and the patients had good outcomes. Kofke et al. (101) reported isoflurane treatment of 11 cases of SE occurring in nine patients (one of these patients was described above). Anesthesia was administered for between 1 and 55 hours, with adequate suppression of the EEG pattern. All patients required pressure support during the period of administration. Upon cessation of isoflurane, seizures recurred in eight cases, and six of the nine patients died. All surviving patients had significant neurologic sequelae. EEG E Halothane inhalation results in a predictable sequence of EEG changes. The first of these is
development of a low-voltage, fast activity in place of the alpha rhythm. This is followed by 12–15 Hz spindle activity (8). If anesthetic levels are pushed higher, a burstsuppression pattern ensues. The EEG effects of isoflurane and desflurane have been studied in neurosurgical patients (83). In that study, patients received increasing concentrations of anesthetic until a burst-suppression pattern of greater than 40% suppression appeared. The investigators found that with increasing concentrations of end-tidal anesthetic, the EEG first slowed and then developed a burstsuppression pattern. In patients with a baseline EEG showing greater than 80% power in the delta range, there was no appreciable further slowing prior to the onset of burst suppression. The degree of burst suppression at a given concentration of isoflurane is variable and age dependent, with a greater degree of suppression in elderly patients (153). Spectral edge frequency (SEF) has been discussed as a way to monitor degree of anesthesia; however, Spencer et al. could not find a correlation between SEF and either level of sedation or serum drug concentration using isoflurane (161). Electrocorticographic (ECoG) studies of isoflurane in patients with epilepsy have shown no reduction in spike frequency with increasing levels of isoflurane from 0.25% to 1.25% (50). A prior study with fewer patients had suggested that isoflurane reduced spike frequency (91). A E The circulatory side effects of halothane are dose dependent, and predictable. Halothane is a myocardial depressant, and cardiac output may be decreased up to 50%. The use of halothane also obtunds the normal baroceptor mechanisms, and therefore reflexive tachycardia does not ensue following a drop in blood pressure. With prolonged administration of several hours or more, these effects may gradually diminish. Halothane slows cardiac conduction and sensitizes the heart to catecholamines. Patients may develop both tachyarrhythmias and bradyarrhythmias. Halothane also diminishes circulatory autoregulation at many sites, including the brain. Because of this, halothane elevates intracerebral pressure (ICP) and should not be used in patients with significant ICP elevation. Halothane is especially known for its side effect of hepatitis progressing to hepatic necrosis. This syndrome occurs following approximately 1 in 10,000 administrations of halothane and is more likely to occur in a patient previously exposed to halothane. This raises the question of whether the syndrome is an immunologically mediated response to halothane or to one of its metabolites. Halothane is corrosive to most metals and may also dissolve plastic tubing during prolonged exposure. Appropriate equipment must therefore be utilized if halothane is to be used for prolonged control of SE. Like halothane, the administration of isoflurane causes a drop in systemic blood pressure. Unlike halothane, this effect
:
573
is not because of myocardial depressant effect but because of a drop in systemic vascular resistance. Cardiac output is well maintained with isoflurane. Cardiac arrhythmias are not precipitated by isoflurane. Isoflurane does not cause an elevation in ICP. Isoflurane does not cause hepatic necrosis. Given the increased risk of side effects with halothane, including fatal hepatic necrosis and an elevation in ICP, there is little to recommend its use in the treatment of SE over the more benign drug, isoflurane. D R Anesthetic induction dosages usually run from 1.5% to 3.0%, with lower concentrations for maintenance. In the studies reviewed, anesthetic concentration was titrated to burst suppression on EEG and generally ran in the range of 0.8%–2.0% inhaled isoflurane concentration. Halothane may be given at similar concentrations but may not be tolerated at dosages sufficient to induce EEG suppression. This limitation may be overcome by concomitant administration of N2O in the breathing mixture. Administration requires special equipment not usually available in an ICU setting and should be regulated by a qualified anesthetist. Halothane is mixed with a small amount of thymol as a stabilizing agent. Because thymol does not vaporize with the halothane, continuous administration of halothane from the same vaporization chamber may result in a build-up of thymol. If the anesthetic fluid becomes yellowed, the chamber should be emptied and cleaned appropriately.
Etomidate Etomidate (Amidate) is an injectable hypnotic used for induction of, and in brief cases maintenance of, anesthesia. Etomidate allows relative preservation of central synaptic transmission and evoked potentials. Although it has been tried in the treatment of SE, the results have not been impressive. B M Etomidate potentiates GABAA-induced chloride currents. Experiments with patch-clamp techniques suggest that the potentiation of the GABA current is dependent on the presence of the g2 subunit of the GABA receptor (171). This activity is not blocked by the benzodiazepine antagonist, flumazenil. Albertson et al. (2) showed that etomidate reduced the amplitude of spikes in hippocampal dentate gyrus by up to 30% following single perforant pathway stimulation. With paired stimulatory pulses to dentate gyrus, etomidate decreased the relative amplitude of the second pulse in a dose-related and reversible manner, consistent with an enhancement of the IPSP. A M S In an animal model of absence epilepsy, etomidate increased spike-and-wave discharges in a dose-dependent fashion (42). At dosages
574
one-half that required to achieve surgical anesthesia, spikeand-wave discharges were continuous and the animals were unresponsive. At lower dosages, spike-and-wave discharges changed in morphology and frequency and were correlated with clinically evident changes in behavior. Other investigators, however, have shown etomidate to be anticonvulsive in a mouse PTZ model (108). C P Etomidate has a rapid onset of action, usually within 1 minute, and a brief period of time for recovery of consciousness. At the typical doses used for anesthesia, the recovery time is within 5 minutes. Etomidate may also be used in the operating room to potentiate somatosensory-evoked potentials during intraoperative monitoring. Etomidate undergoes rapid metabolism in the liver, with approximately 80% of the drug being metabolized via hydrolyzation. Metabolites are excreted in the urine. Following cessation of injection, the serum levels fall rapidly in the first 30 minutes and then more slowly, with a half-life of approximately 75 minutes. In patients with hepatic dysfunction, the serum half-life may be prolonged up to twofold. C U S SE In 1995, Avramov et al. (7) reported on the duration of EEG and clinical seizures following ECT with a variety of anesthetic agents. Of those tested, etomidate was associated with the longest seizure duration, whereas propofol was associated with the shortest duration of seizure activity in a dose-dependent fashion. Similar findings were found by Saffer and Berk when they compared etomidate, propofol, and thiopentene (150) as anesthestic induction agents for ECT. A more recent article by Stadtland et al. (162) noted that in patients undergoing ECT using propofol anesthesia, approximately 12% did not achieve seizure duration in excess of 30 seconds and were therefore switched to etomidate for future ECT sessions. Mean electrographic seizure duration in these select patients increased from 18.6 to 43.4 seconds (P < 0.001) and retained this increase throughout further sessions. There is one report in the literature of the use of etomidate in the control of refractory SE (183). In this series, etomidate was used in eight patients at doses to achieve a 5 mV mean EEG amplitude. Burst suppression was avoided when possible. Patients were mechanically ventilated, and corticosteroid replacement was provided. Although all patients demonstrated rapid control of seizure activity, tolerance developed in a number of patients, with return of seizure activity in half. Weaning from the drug was difficult in half of the patients due to seizure recurrence. Long-term outcome was poor: Two patients died and two others survived with significant neurologic impairment. EEG E The effects of etomidate on the EEG have largely been reported to be excitatory. Reddy et al. (140)
reported spike activity in more than 20% of patients receiving etomidate anesthesia. Numerous authors have reported increases in epileptiform activity in epileptic patients undergoing surgery (43, 56, 85). Hsieh et al., in fact, suggest that this proepileptic effect makes the drug useful in mapping epileptic foci during ablative epilepsy surgery (85). A E The side effects of etomidate are minimal during the brief periods of use as an anesthetic, but prolonged use may cause adrenal insufficiency. Commonly reported side effects are pain at the infusion site, nausea, and vomiting. Musculoskeletal movements, often bilateral and occasionally confused with seizure activity, may be seen in up to two-thirds of patients. EEG monitoring has shown spikes in up to 20% of these cases (140), but the report does not state the movements are ictal. With large doses, respiratory depression or upper airway dysfunction may occur. Cardiovascular side effects are rare, although a case of circulatory collapse has been reported, likely as an anaphylactic reaction to the medication. There is an approximately 30% decrease in cerebral blood flow during the administration of etomidate which closely parallels the decrease in CNS oxygen utilization during this time. Etomidate blocks 11b-hydroxylation in the adrenal cortex. This results in transient adrenocortical insufficiency, which cannot be overcome with adrenocorticotropin stimulation. Although this is of little consequence during short surgical procedures, it may become important during prolonged administration, such as in cases of SE (40). D R The available literature gives little dosage guidance for the treatment of SE. Of the drugs reviewed in this chapter, etomidate would not be our first choice, owing to the probable proconvulsive effect and the poor outcomes in the one reported series. If, however, etomidate is chosen, then dosage recommendations are as follows: The initial bolus used in the study by Yeoman et al. (183) was 300 mg/kg, followed by 25 mg/kg/min constant infusion. Because of tachyphylaxis, the maintenance dose had to be escalated in several patients, and continuous EEG monitoring was required. Other regimens that may be followed can be derived from the experiences with etomidate as an anesthetic agent. Because of the inhibition of 11b-hydroxylation in the adrenal cortex, corticosteroids (e.g., hydrocortisone, 100 mg every 8 hours) should be supplemented during prolonged administration.
Lidocaine Lidocaine was first introduced in 1948. Internists have in the past been comfortable with the use of lidocaine in the treatment of SE because they are very familiar with the drug as
a cardiac antiarrhythmic agent. Nevertheless, lidocaine has a narrow therapeutic ratio in this setting, and few controlled trials of efficacy exist. B M Lidocaine enhances the GABAinduced chloride current but has little effect on the excitatory glutamate current (66). A M S Lidocaine traditionally has been used as a means of inducing seizures in animal models. The mechanism by which this occurs is not well understood. Ingvar and Shapiro (90) demonstrated an increase in hippocampal glucose utilization during infusion of lidocaine at levels that induced a “pre-ictal” pattern on the EEG. This increase in glucose metabolism in limbic structures was in contrast to decreased utilization in most other areas of brain. Follow-up studies in lidocaine-kindled rats show similar findings (136). As an antiepileptic drug (AED), lidocaine was found to have a biphasic action in a penicillin-induced seizure model in cats. Lidocaine was administered either by local cutaneous injections into wound margins or by slow IV infusion. With either route of administration, antiepileptic activity was well documented at serum concentrations of lidocaine of greater than 1.0 mg/mL. When lidocaine levels fell below this level, epileptiform activity reappeared on the EEG. It was thought that levels tended to be smoother and more easily maintained with cutaneous and intramuscular (IM) injections than with the IV infusions. When levels reached greater than 7.5 mg/mL, the EEG demonstrated greater irritability, with return of ictal discharges. In a rat model of bicuculline-induced focal epilepsy, local perfusion of lidocaine directly on the seizure focus stopped the seizures (158). C P Lidocaine is a type 1b antiarrhythmic, as is phenytoin. It is used extensively as a local anesthetic, both by local injection and less so by topical administration. It has been in use as a cardiac antiarrhythmic since the early 1960s. Its cardiac electrophysiologic effects include a decrease in the slope of depolarization of Purkinje fibers of the conduction pathway. Lidocaine inhibits recovery of the sodium channel, inhibiting repetitive firing of neurons. Lidocaine is nearly completely cleared through renal excretion of hepatic metabolites, some of which are active. The serum half-life is prolonged in patients with liver disease. Lidocaine is readily absorbed by oral administration; however, it undergoes approximately 70% first-pass clearance, rendering it unusable as an oral agent. Absorption following injection is nearly 100%, but the rate of absorption depends on the site of injection and on such factors as the presence of local vasoconstriction. The lowest peak levels are seen after subcutaneous injection.
:
575
Drug distribution has been studied in acute myocardial infarction. In this setting, lidocaine undergoes rapid initial distribution into the brain, heart, kidneys, and liver (125). It is then rapidly redistributed into other tissues, yielding an initial serum half-life of only 4–8 minutes. Its overall elimination half-life is much longer, on the order of 1.5–2 hours. The drug passes both blood-brain and placental barriers by passive diffusion. Protein binding is dependent on plasma concentration and in the ranges generally used for cardiac arrhythmias is in the 60%–80% range. C U S SE Lidocaine toxicity as a cause of seizures is a well-known phenomenon. There are numerous reports of seizures secondary to excessive drug levels in patients treated for cardiac arrhythmias, wound anesthesia, or even oral ingestion of viscous lidocaine (57, 78, 148). Reports of the use of lidocaine for controlling SE date back to 1955 (14). In 1988, Pascual et al. reported the successful use of lidocaine in eight elderly patients with chronic obstructive pulmonary disease who were not responsive to safe doses of diazepam (132). A follow-up study was performed in which 42 episodes of SE were treated prospectively with lidocaine (131). Inclusion criteria included unresponsiveness to diazepam or pulmonary problems precluding the use of diazepam without intubation. In this study, 31 of 42 cases responded immediately to the initial bolus of 1.5–2 mg/kg of lidocaine with cessation of clinical seizures. Unfortunately, seizure recurrence was noted in 19 of these patients, usually within 30 minutes. Most responded again to further doses of lidocaine. All of the patients unresponsive to the initial bolus of lidocaine were unresponsive to a subsequent bolus. Interpretation of the study is complicated by polypharmacy. Subsequent to receiving lidocaine as a bolus, all patients also received phenytoin, 18 mg/kg IV. The initial responses can therefore be attributed to lidocaine, but the long-term control of SE may have been due to phenytoin. Lidocaine given by continuous infusion, as opposed to bolus therapy, has also been efficacious in the management of SE refractory to multiple first-line agents. DeGiorgio et al. (35) described two patients with partial SE confirmed by EEG who had been refractory for days to various combinations of lorazepam, diazepam, phenytoin, and phenobarbital. Despite prolonged seizure activity in both patients, lidocaine stopped the SE within 1 hour. Lidocaine has also been used with good efficacy and safety in infants unresponsive to more conventional methods of treatment (73). EEG E Seo et al. (154) documented a series of EEG changes during the incremental intoxication of a cat with lidocaine. The earliest manifestations were of generalized slowing, followed by low-voltage, fast activity, recurrence of slowing, and finally by an epileptiform EEG. Crampton (32)
576
gave healthy volunteers infusions of 6–9 mg/kg of lidocaine, provoking seizures. He observed epileptic spikes during all seizures, and also apnea outlasting the electrographic seizures in half. The duration of the seizure was 105–125 seconds. A E Systemic side effects from lidocaine include bradycardia, hypotension, and occasional allergic reactions. CNS side effects tend to be dose dependent and include confusion, drowsiness, tinnitus, diplopia or blurred vision, tremors, and convulsions. CNS depression may progress to respiratory depression, with subsequent respiratory arrest. CNS side effects are usually seen at serum drug concentrations of approximately 6 mg/mL, and therefore serum levels may need to be monitored during continuous infusion. D R The recommended initial bolus is 0.7–3 mg/kg (17), more typically 1.5–2 mg/kg (131), or about 100 mg for the average-sized adult. If the first injection is ineffective, then a second bolus may be given; however, it is rarely of benefit. Because the therapeutic response following a single bolus tends to be short-lived, consideration should be given to the use of an additional agent or to prolonged lidocaine infusion. Continuous infusion may be given at doses of 0.01–0.15 mg/kg/min (0.6–9.0 mg/kg/hr). Caution must be used with doses greater than approximately 0.06 mg/kg/min (3.5 mg/ kg/hr), as they are associated with significant CNS toxic effects. The maximum dose recommended by the manufacturer is 300 mg/hr. CNS side effects generally appear at serum levels in excess of 6 mg/mL. Lidocaine is not currently approved for use by the U.S. Food and Drug Administration (FDA) in the management of SE.
Paraldehyde Paraldehyde is a cyclic polymer of acetaldehyde that has been in clinical use since the late nineteenth century (Figure 46.3). Paraldehyde has been particularly favored in past years for treatment of alcohol withdrawal syndromes and the treatment of SE in children. Paraldehyde is currently unavailable in the United States because of its narrow safety margin, its tendency to decompose when exposed to light, and its tendency to dissolve plastic. B M The mechanism of action of paraldehyde is unknown. It appears to induce widespread neuronal depression, particularly of cortical activity, and leads to sedation, followed by anesthesia. Its effects on neurotransmitters and receptors have not been systematically studied. A M of S Morrisett et al. (122) reported the use of paraldehyde and other AEDs in the initiation and maintenance of SE in the lithium-pilocarpine
metabolism is dependent on the P450 enzyme system, and the half-life is thus prolonged during concomitant administration of phenobarbital, which competes for these enzymes. In the absence of phenobarbital, the serum half-life is approximately 6 hours, but it is longer in children and infants.
F 46.3 Chemical structure of paraldehyde and its breakdown products.
model. Although most of the tested drugs prevented the initiation of SE in this model, only paraldehyde was able to rapidly abolish the episodes and increase survival of the animals. This suggests that paraldehyde may be useful clinically in situations in which other drugs have failed. C P Paraldehyde is miscible with oil but poorly soluble in water. Because its solubility in water is greater at room temperature than at body temperature, droplets of pure paraldehyde can precipitate during IV infusion of inadequately diluted drug. These droplets can become paraldehyde pulmonary emboli, resulting in pulmonary edema, one of the well-known complications of paraldehyde infusion. Paraldehyde readily degrades to acetaldehyde and acetic acid in the presence of air or light. Improperly stored paraldehyde may contain a high concentration of acetic acid, the administration of which may be fatal. Paraldehyde can dissolve plastic or vinyl IV tubing, bags, or syringes (178). Proper storage, handling, and delivery of paraldehyde are therefore of utmost importance. Paraldehyde may be given by IV infusion of a dilute solution, ideally directly with glass syringes or with short lengths of IV tubing. The IV solution concentration must be 5% or less because of the reduced solubility (7.8%) at body temperature. IM injection has been attempted but runs the risk of sterile abscesses or peripheral nerve injury. With IM injection, peak levels are seen within 30–60 minutes. Paraldehyde may be given by oral or rectal administration. Oral administration is difficult because of the disagreeable odor and taste. This may not be an issue in cases of SE, but the substance is caustic and may result in severe esophageal irritation. Rectal administration of paraldehyde in vegetable or mineral oil provides 80% bioavailability and peak levels in 90–120 minutes. Paraldehyde undergoes metabolism in the liver, first to acetaldehyde and then to acetic acid. Approximately 70% of the drug is eliminated via hepatic pathways, with the remaining 30% excreted via exhalation from the lungs. Hepatic
C U S SE Paraldehyde as a treatment for SE has never been compared with other medications in well-designed trials. Several uncontrolled studies were performed in the 1940s and early 1950s. In 1983 Curless et al. (34) reported the use of paraldehyde in 13 pediatric patients. Two patients received multiple trials, for a total of 16 trials of paraldehyde for these 13 patients. Three patients experienced pulmonary arrest with an IV loading dose of a 20%–25% paraldehyde solution, fourfold more than the currently recommended concentration of 5%. Seven of the 16 trials resulted in no improvement in seizures; three patients experienced a fair improvement (seizures stopped in 1–8 hours), and six achieved good seizure control (seizures stopped within 1 hour). A E Paraldehyde use is complicated by many adverse reactions depending on the route of administration. IV use is most often complicated by pulmonary side effects, which are likely secondary to pulmonary emboli of pure paraldehyde. These side effects include cough, pulmonary edema, right-sided heart failure, and pulmonary hemorrhage. Pulmonary side effects can be minimized by infusing only diluted mixtures of paraldehyde of 5% or less. If the drug has been stored improperly, administration may inadvertently deliver a large load of acetic acid. This can result in acidosis and has been reported to be the cause of at least one fatality. IM administration has been associated with sterile abscess formation and local nerve damage due to the highly irritative nature of the undiluted drug. Oral and rectal administrations may cause local mucosal irritation. In the case of rectal administration, large bowel perforation has been reported, while severe esophagitis has been reported with oral administration. Regardless of the route of administration, a significant percentage of drug is excreted by exhalation of volatilized paraldehyde. This causes an unpleasant odor to be excreted. D R Paraldehyde levels are not easily monitored, and the levels required for anticonvulsant activity have not been well established. Benefit against seizures seems to begin following administration of approximately 100– 200 mg/kg as a loading dose. This dose can be delivered by nasogastric tube, rectal administration, deep IM injection (not recommended), or IV. Dilution is necessary. With IV administration, peak levels are achieved immediately, but with other routes there is a delay of 30–120 minutes, depending on the route of administration. Therefore, although we
:
577
discuss various routes of administration of paraldehyde which may be of use in some types of seizures, IV administration is by far the route of choice in SE. For IV administration the solution should be diluted to a maximum of 5% paraldehyde. This can be done by mixing 25 mL (equivalent to 25 grams of paraldehyde) into 475 mL of saline to yield a total of 500 mL of diluted mixture. The initial bolus of 100–200 mg/kg should result in administration of 7–14 grams for a 70-kg person (140–280 mL of a 5% solution). Reports vary as to how fast it can safely be given, but an infusion over a 1-hour period should be safe. Following the loading dose, a continuous infusion may be given at a rate of 20 mg/kg/hr (0.4 mL/kg/hr of a 5% solution). Similar dosages have been used in infants (103). The dose should be titrated to the lowest dose necessary to control the seizures. Special care must be taken in patients with hepatic dysfunction. Oral and rectal routes also require dilution. In the case of oral or nasogastric administration, the paraldehyde should again be diluted in saline and dosages should be the same as for IV administration. At concentrations greater than 5% there is a risk of dissolving the plastic nasogastric tube or causing significant mucosal burns. In the case of rectal administration, the paraldehyde should be diluted 2 : 1 in vegetable or mineral oil. The bioavailability of rectally administered drug is approximately 80%, and therefore a higher dose of 125–250 mg/kg may be necessary. In order to maintain adequate blood levels, repeated doses of 50– 100 mg/kg will be necessary approximately every 2–4 hours. As a last resort, paraldehyde has been given IM, in doses of 100–200 mg/kg initially, followed by 50–100 mg/kg every 2–4 hours. Because of severe local irritation, this route is not recommended.
Magnesium Magnesium is an important endogenous divalent cation with wide influence on the excitability of nervous tissue. Deficiencies and excesses of magnesium produce important and often urgent clinical disorders, including seizures (60). B M Magnesium has significant effects on several receptors and ion channels. Magnesium collaborates with calcium and other divalent cations in maintenance of electrical stability of excitable neuronal membrane. Calcium and magnesium, however, have opposite effects on the synaptic release of neurotransmitters, with calcium facilitating such release and magnesium inhibiting release (37). This block of synaptic activity can either be excitatory or inhibitory, depending on the nature of the synapse. Normal function of the magnesium ion includes voltage-dependent blockade of excitatory NMDA-induced currents (176). Because this blockade largely disappears at depolarized levels of the membrane potential, it is not at all certain that
578
magnesium will block NMDA channels in depolarized neurons of the seizure focus. In general, the mechanism of magnesium’s anticonvulsant action is not known. A M S Low levels of magnesium can induce epileptiform-like ictal events in the hippocampal slice (4). Mice fed a magnesium-deficient diet are more susceptible to audiogenic seizures (112), and intraventricular administration of magnesium can lessen the seizures (24). These observations do not, however, mean that magnesium will be therapeutic in seizures produced by stimuli other than low magnesium levels. Such studies have found effects in some models but not others, sometimes depending on the routes of magnesium administration (31). Barbiturate withdrawal seizures in C57bl/6J mice can be reduced by parenteral administration of magnesium sulfate (13). Magnesium delays time to behavioral and EEG epileptiform changes in the hyperbaric rat seizure model (95). The NMDA seizure model is improved by magnesium sulfate (116, 118), more so than by phenytoin, which is known to be poorly efficacious in the NMDA model. In contrast, amygdala-kindled seizures in rats are inhibited by phenytoin but not by magnesium (163). Seizures and brain injury produced by the neurotoxin quinolinic acid also are improved by magnesium sulfate given subcutaneously prior to the toxin (180). Borges and Gücer (20) initially reported that parenteral injection of magnesium in cats, dogs, and primates attenuated the epileptiform EEG spiking produced by a penicillin focus. These authors did not, however, provide data on control injections, raising the possibility that the spikes were declining over time as the penicillin effect diminished. This explanation was supported by Koontz and Reid (102), who used control groups to show that the EEG of penicillin foci of anesthetized cats was not altered by parenteral magnesium. Magnesium sulfate did not differ from saline in altering either brain levels of magnesium in pregnant rats or the threshold for lidocaineinduced seizures (28). Finally, hypomagnesemia itself does not always exert a proconvulsant effect; mice lines bred for low magnesium levels were actually less susceptible to audiogenic seizures than were similar strains of mice bred for high magnesium levels (123). The two preeminent screening models for AEDs are maximal electroshock and pentylenetetrazole (51). Parenteral magnesium sulfate, given to levels sufficient to produce neuromuscular blockade, failed to alter thresholds for MES in mice or PTZ seizures in mice and rats (104, 107) (Figure 46.4). A subsequent study in rats reported a 34% increase in MES seizure threshold (63). C P Magnesium homeostasis is poorly understood, but it is known to be linked to calcium homeostasis. Excretion is renal. In rabbits, IV magnesium distributes four to six times more readily to muscle than
F 46.4 Effect of magnesium on pentylenetetrazole-induced seizures in mice. (Reprinted with permission from Krauss et al. [104].)
to brain (79). In humans, complete neuromuscular blockade without loss of consciousness can be accomplished with IV administration of magnesium chloride or sulfate (160). This phenomenon probably occurs because magnesium poorly penetrates the blood-brain barrier. One patient treated with magnesium sulfate for SE (52) had a serum magnesium level of 14.2 mEq/L, with a CSF level of only 3.5 mEq/L. Even though the serum-CSF gradient is high, magnesium sulfate does raise CSF magnesium from its baseline (169). EEG E Magnesium infusion in clinically relevant dosages does not significantly alter the spontaneous EEG of rats (18). In the setting of preeclampsia and eclampsia, abnormal EEG slowing and spiking is not altered by parenteral magnesium sulfate (157). Very high serum levels of magnesium sulfate can convert generalized spikes to blunter sharp waves, but at the same frequency (52). C U S SE Magnesium-deficient seizures (11) are the only types of seizures for which magnesium therapy is not controversial. Magnesium sulfate has been recommended for alcohol withdrawal symptoms (46), but serum magnesium levels tend to be low in alcohol abusers whether or not they present with seizures (121). Magnesium sulfate was said to be useful in the treatment of seizures from porphyria (141), a condition in which most of the traditional AEDs are contraindicated. Considerable attention has been given to use of magnesium sulfate in the treatment of eclamptic seizures or in preeclampsia. The pathophysiology of eclampsia is unknown (155, 156). Preeclampsia is associated with high peripheral vascular resistance (106), and an effect of magnesium to relax the peripheral or central (12) vessels could account for part of its action. Magnesium may also have beneficial effects on prostaglandin formation in eclampsia (177). The efficacy of magnesium sulfate in the treatment of eclamptic seizures has been vigorously debated (94). In the United States, magnesium sulfate, supplemented with antihy-
pertensive medications (e.g., hydralazine), has been the standard therapy for preeclampsia (119). Elsewhere in the world, obstetricians have tended to use other therapies. This disparity generated several studies of magnesium sulfate versus phenytoin or diazepam in the treatment of eclampsia. In one study, 50 hypertensive pregnant women were randomly assigned to either magnesium sulfate therapy or phenytoin (6). One patient in the magnesium group and two in the phenytoin group withdrew because of adverse effects. No patients suffered from seizures. The conclusion was that phenytoin and magnesium are both well tolerated in pregnancy. Another small study (39) of phenytoin versus magnesium sulfate in 22 women with eclampsia observed seizures in four of 11 patients in the phenytoin group and none of 11 in the magnesium group. Therapeutic serum levels were achieved in both agents. A group of 51 eclamptic women were randomized to therapy with diazepam or magnesium sulfate (33). Convulsions ensued in 26% in the diazepam group and 21% of the magnesium group. One death occurred in the magnesium group and none in the diazepam group, but otherwise magnesium was better tolerated in terms of cardiopulmonary problems and urine flow than was the benzodiazepine. None of these studies was large enough to be conclusive, and multicenter studies therefore were established. In a study published in the Lancet (30), a total of 1,680 women with eclampsia were studied with a multicenter randomized protocol comparing magnesium sulfate (n = 841) to phenytoin (n = 387) or diazepam (n = 452). One arm of the study compared magnesium sulfate to diazepam, and the other compared magnesium sulfate to phenytoin. In the diazepam arm, magnesium was superior, with 13% having seizures, compared to 28% given diazepam. In the phenytoin arm, magnesium was again superior, with 6% in the magnesium group having seizures, versus 17% in the phenytoin group. These differences reflected a mean 52% and 67% reduction, respectively, in risk for recurrent convulsions. The differences were highly significant. Fewer mothers and infants in the magnesium sulfate arm required intensive care. A second study appeared at the same time in the New England Journal of Medicine (109). This study randomized 1,089 pregnant and hypertensive women to phenytoin, 1,000 mg given IV over 1 hour, followed by 500 mg given orally 10 hours later. The comparison group was 1,049 women given magnesium sulfate, 10 grams IM (sometimes with an additional 4-gram load IV), followed by 5 grams given IM every 4 hours. Ten patients in the phenytoin group had convulsions, compared with none of the magnesium group (P = 0.004). Maternal and fetal outcomes were similar in the two groups. Despite some issues about fixed doses of phenytoin and small numbers of patients with therapeutic phenytoin levels, these two multicenter studies provided the first compelling evidence for the efficacy of magnesium sulfate in the treatment of
:
579
eclampsia. Although the two studies showed the utility of magnesium over phenytoin or diazepam, neither study had a true placebo arm. In 2002, the results of the Magpie study were published (111), documenting the utility of magnesium in more than 10,000 preeclamptic women. This study was carried out in approximately 40 countries, including both affluent countries and countries with extreme poverty and developing world status. Magnesium reduced the risk of eclamptic seizures by 58% when compared with placebo, with a calculated 11 fewer women with eclampsia per 1,000 treated. Although there were no maternal deaths in the countries with overall low rates of perinatal mortality, there was an approximate 50% reduction in maternal deaths in countries with either moderate or high baseline perinatal mortality rates. There was no appreciable difference in infant mortality. The pathophysiology of eclampsia is likely not the same as that of other seizures, so the role of magnesium in the treatment of other forms of status remains uncertain. As noted earlier, results in animal models of epilepsy remain mixed, although that is not unusual for most of the existing AEDs. In 1931, magnesium sulfate was shown to be effective in uremic convulsions in two children (15). Two years later, Storchheim advised use of magnesium sulfate for SE in place of the standard therapy with sodium amytal, morphine, atropine, chloral hydrate, ether, or chloroform. In eight treated cases, none ended fatally, in contrast to the author’s expectation of universal fatality in such cases. Little else was written subsequently about the clinical use of magnesium in the treatment of SE. Fisher and colleagues (52) showed that magnesium sulfate sufficient to increase serum magnesium levels to 14.2 mEq/L did not suppress EEG spikes or lead to clinical improvement in a patient with myoclonic SE. Epileptologists have yet to emulate the obstetricians in committing to a controlled trial of magnesium for SE. A E Magnesium sulfate rarely can produce hypotension (21), but commonly reduces quantitatively determined pulmonary function (75, 139). During pregnancy, magnesium sulfate prolongs bleeding time (54). Magnesium sulfate may be beneficial for ventricular arrhythmias (98); however, overdose of magnesium sulfate can cause cardiac conduction problems, asystole, and cardiac arrest (172). In addition to inhibitory actions on skeletal and cardiac neuromuscular junctions, magnesium can also block parasympathetic neurotransmission. One patient with a serum level of magnesium of 9.85 mEq/L from iatrogenic administration of magnesium had fixed and dilated pupils (144). Transient accommodation paresis and diplopia are common during therapy with magnesium sulfate (38). Parasympathetic block may also be evident in the form of paralytic ileus (59). D R Magnesium sulfate infusion is supported by evidence in the case of hypomagnesemic seizures
580
and eclamptic seizures. Its use in other types of seizures remains speculative and is not recommended unless all other reasonable therapies have failed. Magnesium serum concentrations in the United States are usually reported in units of mEq/L. Normal serum magnesium levels are in the range of 1.8–2.8 mEq/L, and target levels of serum magnesium in eclampsia are 3.5–6.0 mEq/L (138). This level may be achieved by infusion of 5 grams of magnesium sulfate over 5–30 minutes, followed by 1 g/hr continuous infusion (30, 134). A multicenter study (109) used the IM route for treating eclampsia, with 10 grams injected IM, followed by 5 grams every 4 hours. A target level for SE is not known, but in SE the infusion rate has been increased to 3 g/hr (52). Above serum levels of 6.0 mEq/L, neuromuscular block and hypotension become significant risks. These problems should be anticipated.
Furosemide Furosemide (Lasix) is a chloride cotransport inhibitor in wide use as a loop diuretic. Furosemide has never been considered an anticonvulsant; however, experiments have shown furosemide to block kainic acid–induced synchronized bursting in hippocampal slice preparations (81), suggesting the possibility that it may be of use in seizure control. Followup studies have further suggested that furosemide blockade of chloride cotransport may be the mechanism of action (82). Animal studies have also found that agents (including furosemide) that block potassium chloride cotransport may limit audiogenic seizures in susceptible rat populations (142). Evidence of antiseizure properties in humans was found rather serendipitously during a case-control evaluation of the risk of hypertension in the development of seizures (76). This study noted that diuretics were associated with a reduced risk of seizures compared with matched controls; however, this was not a primary end-point, and the results may have been questionable. A follow-up study by the same group (77) found use of either furosemide or thiazide diuretics reduced the odds of seizure development in adults. The same paper also found efficacy in animal models of epilepsy with both MES and PTZ models in rats and mice. Although significant preliminary evidence exists that furosemide or similar agents may have antiseizure properties, there is no literature at this time to suggest it is ready for clinical trials for this purpose.
Focal perfusion of antiepileptic drugs Although never used clinically for seizure control, there is a fair amount of experience with local perfusion of medications for other purposes such as chemotherapy. Local perfusion of antispasticity drugs such as baclofen into portions of
brain or spinal cord has been done in humans with programmable infusion pumps. As an investigational therapy only, the perfusion of AED directly on a cortical focus has shown considerable promise. In a study of the “seizure trigger area,” the area tempestas, Gale and associates blocked bicuculline-induced seizures in rats by treating the area of injection with local muscimol. Smith et al. (158) induced a focal seizure model in rats by deep prepiriform cortex microinfusion of bicuculline. The seizures that ensued were treated by microinfusion of lidocaine directly on the lesion. Tamargo et al. (167) applied
a matrix containing phenytoin onto a cobalt chloride seizure focus and found reduced rates of seizures and spiking. Eder et al. found similar results with infusion of diazepam in both a bicuculline as well as cobalt chloride–pilocarpine model (45). Diazepam induced an almost immediate cessation of focal seizure activity with localized infusion delivered to the zone of seizure origination. Animals treated with control vehicle progress to (often fatal) SE. Our laboratory has shown similar outcomes with focal perfusion of diazepam to control partial SE in rat hippocampus (165) (Figure 46.5).
T 46.1 Summary of clinical characteristics of the “miscellany treatments” for status epilepticus Drug
Safe and Efficacious
Special Considerations
Propofol
Yes
Probable need to push to coma-inducing doses
Inhaled anesthetics
Mixed reports
Need special apparatus for delivery; requires skilled anesthetist in attendance
Etomidate
Probably not
Inhibition of adrenocorticoid synthesis; requires exogenous supplementation
Lidocaine
Yes
Short period of efficacy, epileptogenic at high serum concentrations
Paraldehyde
Yes (efficacy) Mixed reports (safety)
Not available in the United States; need to use dilute mixture to avoid dangerous adverse effects
Magnesium
Yes: hypomagnesemia Yes: eclampsia No: other causes of SE
Useful in seizures due to eclampsia and hypomagnesemia, but not other causes
Dosage and Regimen Loading dose: 1–2 mg/kg. Maintenance dose: Start at 2 mg/kg/hr. Requires EEG monitoring with titration to burst suppression. Subcoma doses: Continuous infusion. Start at 0.1 mg/ kg/hr; titrate upward until seizure activity stops. Induction: Inhaled concentration of 1.5%–3.0%. Maintenance dose: Dose should be titrated to burst suppression on EEG (generally will be in range of 0.8%–2.0% inhaled isoflurane concentration). Halothane may require mixing with N2O to achieve burst suppression without loss of cardiac output. Loading dose (optional): 300 mg/kg. Maintenance dose: Start at 25 mg/kg/min. May require escalation due to tachyphylaxis. Continuous EEG monitoring should be used with titration to burst suppression. Loading dose: 0.7–3 mg/kg (typically 100 mg total). May repeat if first bolus is ineffective. Maintenance dose: Continuous infusion up to 0.06 mg/kg/min. The maximum recommended dose is 300 mg/hr (although higher dosages have been reported in past). IV or PO administration: Loading dose: 100–200 mg/kg (over 1 hr if given IV). Maintenance dose: Continuous infusion of 20 mg/kg/hr or sequential bolus every 2–4 hr of 40–80 mg/kg. Rectal administration: Loading dose: 125–250 mg/kg; then 50–100 mg/kg every 2–4 hr. IM administration: Not recommended. Titrate paraldehyde to the lowest dose necessary to control seizures. In hypomagnesemia: Replete to serum concentration 1.8–2.8 mEq/L. In eclampsia: 5 g IV over 5–30 min; then 1 g/hr infusion. Intramuscular injection may be substituted with 10 g bolus; then 5 g every 4 hr. Goal of 3.5–6.0 mEq/L.
Note: None of the drugs listed in the table has been studied in a well-controlled clinical trial, and doses and regimens (if used) must be individualized for each patient.
:
581
F 46.5 EEG recording showing immediate suppression of ictal activity in a rat bicuculline seizure model treated with focal diazepam infusion. Each line represents a contiguous 10-second
tracing from the same lead (left posterior). Diazepam infusion began at the single arrow and continued until the double arrows.
Summary
limited clinical information and must be individualized for each patient. None of the therapies discussed in this chapter has yet been the subject of a properly controlled clinical trial. None has been compared to therapies studied in the VA Status Epilepticus Cooperative Trial. Until such work is completed, the use of these medications is likely to remain limited to instances in which better documented therapies have failed or are believed to be unsafe in a particular circumstance.
Although most cases of SE resolve with standard therapies, a small portion do not. In these cases the treatment options are of less proven safety and efficacy. Propofol may be the most promising of this miscellaneous group, but experience with it remains quite limited, and it is an expensive medication. Inhaled anesthetics are occasionally of value in treating SE but are usually not practical, and most of the reported cases had a poor outcome. Etomidate is potentially a convulsant or an anticonvulsant and has not reliably been of use as a seizure therapy. The use of magnesium sulfate has engendered considerable controversy over the past decades. In animal models of SE and in a least one clinical case report, it produced neuromuscular blockade without eliminating EEG spiking. Magnesium sulfate may, however, have special value in the treatment of eclamptic seizures. Paraldehyde (currently difficult to obtain in the United States) and lidocaine are old medications well known to the medical community, but they have narrow therapeutic windows and only anecdotal successes in the treatment of refractory SE. Furosemide is another “old friend” with theoretical and in vitro evidence, but little clinical evidence, of effectiveness. Laboratory work has raised the possibility of designing new treatments for partial SE by targeted delivery of AEDs directly to the seizure focus. Table 46.1 summarizes clinical characteristics of the agents discussed in this chapter. Note should be taken that the dosages and regimens for therapy of SE are based on
582
REFERENCES 1. Adodra, S., and T. G. Hales. Potentiation, activation and blockade of GABAA receptors of clonal murine hypothalamic GT1–7 neurones by propofol. Br. J. Pharmacol. 1995;115: 953–960. 2. Albertson, T. E., W. F. Walby, and R. M. Joy. Modification of GABA-mediated inhibition by various injectable anesthetics. Anesthesiology 1992;77:488–499. 3. Albertson, T. E., W. F. Walby, L. G. Stark, and R. M. Joy. The effect of propofol on CA1 pyramidal cell excitability and GABAA-mediated inhibition in the rat hippocampal slice. Life Sci. 1996;58:2397–2407. 4. Anderson, W. W., D. V. Lewis, H. S. Swartzwelder, and W. A. Wilson. Magnesium-free medium activates seizure-like events in the rat hippocampal slice. Brain Res. 1986;398:215–219. 5. Apfelbaum, J. L., T. H. Grasela, C. C. Hug, et al. The initial clinical experience of 1819 physicians in maintaining anesthesia with propofol: Characteristics associated with prolonged time to awakening. Anesth. Analg. 1993;77:S10–S14. 6. Appleton, M. P., T. J. Kuehl, M. A. Raebel, et al. Magnesium sulfate versus phenytoin for seizure prophylaxis in pregnancy-
7.
8.
9.
10. 11.
12.
13.
14.
15. 16.
17. 18.
19.
20. 21.
22. 23. 24.
25.
26.
induced hypertension. Am. J. Obstet. Gynecol. 1991;165: 907–913. Avramov, M. N., M. M. Husain, and P. F. White. The comparative effects of methohexital, propofol, and etomidate for electroconvulsive therapy: An update of its use in anaesthesia and conscious sedation. Anesth. Analg. 1995;81:596–602. Avramov, M. N., T. Murayama, K. Shingu, and K. Mori. Electroencephalographic changes during vital capacity breath induction with halothane. Br. J. Anaesth. 1991;66: 212–215. Bansinath, M., V. K. Shukla, and H. Turndorf. Propofol modulates the effects of chemoconvulsants acting at GABAergic, glycinergic, and glutamate receptor subtypes. Anesthesiology 1995;83:809–815. Barr, J. Propofol: A new drug for sedation in the intensive care unit. Int. Anesthesiol. Clin. 1995;33:131–154. Becker, K., I. Lombeck, and H. J. Bremer. Primary hypomagnesemia: Clinical, diagnostic and therapeutic studies in three children. Monatsschr. Kinderheilkd. 1979;127:37–42. Belfort, M. A., and K. J. Moise, Jr. Effect of magnesium sulfate on maternal brain blood flow in preeclampsia: A randomized, placebo-controlled study. Am. J. Obstet. Gynecol. 1992;167:661–666. Belknap, J. K., J. H. Berg, G. Ondrusek, and S. Waddingham. Barbiturate withdrawal and magnesium deficiency in mice. Psychopharmacology 1978;59:299–303. Bernhard, C. G., E. Bohm, and M. L. Hojeberg. A new treatment of status epilepticus. Archi. Neurol. Psychiatry 1955;74: 208–214. Blackfan, K. D., and C. F. McKhann. Acute glomerular nephritis in children. JAMA 1931;97:1052–1055. Blaise, G., Q. To, M. Parent, et al. Does halothane interfere with the release, action, or stability of endothelium-derived relaxing factor/nitric oxide? Anesthesiology 1994;80:417–426. Bleck, T. P. Therapy for status epilepticus. Clin. Neuropharmacol. 1983;6:255–269. Bohdanecky, Z., and T. Weiss. The electrophysiological manifestation of the narcotic state evoked by magnesium sulfate. Activ Nerv. 1964;6(Suppl.):42. Borgeat, A., O. H. Wilder Smith, P. Jallon, and P. M. Suter. Propofol in the management of refractory status epilepticus: A case report. Intensive Care Med. 1994;20:148–149. Borges, L. F., and G. Gücer. Effect of magnesium on epileptic foci. Epilepsia 1978;19:81–89. Bourgeois, F. J., S. Thiagarajah, G. M. Harbert, Jr., and C. DiFazio. Profound hypotension complicating magnesium therapy. Am. J. Obstet. Gynecol. 1986;154:919–920. Brown, L. A., and G. M. Levin. Role of propofol in refractory status epilepticus. Ann. Pharmacother. 1998;32:1053–1059. Bryson, H. M., B. R. Fulton, and D. Faulds. Propofol. Drugs 1995;50:513–559. Buck, D. R., A. W. Mahoney, and D. G. Hendricks. Effects of cerebral intraventricular magnesium injections and a low magnesium diet on nonspecific excitability level, audiogenic seizure susceptibility and serotonin. Pharmacol. Biochem. Behav. 1979;10:487–491. Carla, V., and F. Moroni. General anaesthetics inhibit the responses induced by glutamate receptor agonists in the mouse cortex. Neurosci. Lett. 1992;146:21–24. Cervantes, M., R. Ruelas, I. Chavez Carrillo, and A. Contreras Gomez. Effects of propofol on alterations of multineuronal activity of limbic and mesencephalic structures and
27.
28.
29.
30.
31.
32. 33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
neurological deficit elicited by acute global cerebral ischemia. Arch. Med. Res. 1995;26:385–395. Chamorro, C., F. J. de Latorre, A. Montero, et al. Comparative study of propofol versus midazolam in the sedation of critically ill patients: Results of a prospective, randomized, multicenter trial. Crit. Care Med. 1996;24:932–939. Choi, W. W., D. S. Warner, D. J. Monahan, and M. M. Todd. Effects of acute hypermagnesemia on the threshold for lidocaine-induced seizures in the rat. Am. J. Obstet. Gynecol. 1991;164:693–697. Claassen, J., L. J. Hirsch, R. G. Emerson, and S. A. Mayer. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: A systematic review. Epilepsia 2002; 43:146–153. [The Collaborative Eclampsia Trialists]: Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet 1995;345:1455–1463. Cotton, D. B., C. A. Janusz, and R. F. Berman. Anticonvulsant effects of magnesium sulfate on hippocampal seizures: Therapeutic implications in preeclampsia eclampsia. Am. J. Obstet. Gynecol. 1992;166:1127–1134. Crampton, R. S. EEG evaluation of lidocaine convulsions. JAMA 1968;205:803. Crowther, C. Magnesium sulphate versus diazepam in the management of eclampsia: A randomized controlled trial. Br. J. Obstet. Gynaecol. 1990;97:110–117. Curless, R. G., B. H. Holzman, and R. E. Ramsay. Paraldehyde therapy in childhood status epilepticus. Arch. Neurol. 1983;40:477–480. DeGiorgio, C. M., K. Altman, E. Hamilton Byrd, and A. L. Rabinowicz. Lidocaine in refractory status epilepticus: Confirmation of efficacy with continuous EEG monitoring. Epilepsia 1992;33:913–916. De Riu, P. L., V. Petruzzi, C. Testa, et al. Propofol anticonvulsant activity in experimental epileptic status. Br. J. Anaesth. 1992;69:177–181. Del Castillo, J., and L. Engback. The nature of the neuromuscular block produced by magnesium. J. Physiol. (Lond.) 1954;124:370–384. Digre, K. B., M. W. Varner, and J. S. Schiffman. Neuroophthalmologic effects of intravenous magnesium sulfate. Am. J. Obstet. Gynecol. 1990;163:1848–1852. Dommisse, J. Phenytoin sodium and magnesium sulphate in the management of eclampsia. Br. J. Obstet. Gynaecol. 1990;97: 104–109. Dorr, H. G., U. Kuhnle, H. Holthausen, et al. Etomidate: A selective adrenocortical 11beta-hydroxylase inhibitor. Klini. Wochenschr. 1984;62:1011–1013. Dunnet, J. M., C. Prys Roberts, D. E. Holland, and B. L. Browne. Propofol infusion and the suppression of consciousness: Dose requirements to induce loss of consciousness and to suppress response to noxious and non noxious stimuli. Br. J. Anaesth. 1994;72:29–34. Duysens, J., M. Inoue, E. L. Van Luijtelaar, et al. Facilitation of spike-wave activity by the hypnotic etomidate in a rat model for absence epilepsy. Int. J. Neurosci. 1991;57:213–217. Ebrahim, Z. Y., G. E. DeBoer, H. Luders, et al. Effect of etomidate on the electroencephalogram of patients with epilepsy. Anesth. Analg. 1986;65:1004–1006. Ebrahim, Z. Y., A. Schubert, P. Van Ness, et al. The effect of propofol on the electroencephalogram of patients with epilepsy. Anesth. Analg. 1994;78:275–279.
:
583
45. Eder, H. G., D. B. Jones, and R. S. Fisher. Localized epidural perfusion of diazepam attenuates epileptiform activity in the rat bicuculline model of epilepsy. Epilepsia 1996; 37(Suppl. 5):67. 46. Embry, C. K., and S. Lippmann. Use of magnesium sulfate in alcohol withdrawal. Am. Fam. Physician. 1987;35:167–170. 47. Fan, S. Z., C. C. Liu, H. Y. Yu, et al. Lack of effect of flumazenil on the reversal of propofol anaesthesia. Acta Anesthesiol. Scand. 1995;39:299–301. 48. Fear, C. F., C. S. Littlejohns, E. Rouse, and P. McQuail. Propofol anaesthesia in electroconvulsive therapy. Reduced seizure duration may not be relevant. Br. J. Psychiatry 1994;165:506–509. 49. Finley, G. A., B. MacManus, S. E. Sampson, et al. Delayed seizures following sedation with propofol. Can. J. Anaesth. 1993;40:863–865. 50. Fiol, M. E., J. A. Boening, R. Cruz Rodriguez, and R. Maxwell. Effect of isoflurane (Forane) on intraoperative electrocorticogram. Epilepsia 1993;34:897–900. 51. Fisher, R. S. Animal models of the epilepsies. Brain Res. Rev. 1989;14:245–278. 52. Fisher, R. S., P. W. Kaplan, A. Krumholz, et al. Failure of high-dose intravenous magnesium sulfate to control myoclonic status epilepticus. Clin. Neuropharmacol. 1988;11: 537–544. 53. Fredman, B., M. M. Husain, and P. F. White. Anaesthesia for electroconvulsive therapy: Use of propofol revisited. Eur. J. Anaesthesiol. 1994;11:423–425. 54. Fuentes, A., A. Rojas, K. B. Porter, et al. The effect of magnesium sulfate on bleeding time in pregnancy. Am. J. Obstet. Gynecol. 1995;173:1246–1249. 55. Fulton, B., and E. M. Sorkin. Propofol: An overview of its pharmacology and a review of its clinical efficacy in intensive care sedation. Drugs 1995;50:636–657. 56. Gancher, S., K. D. Laxer, and W. Krieger. Activation of epileptogenic activity by etomidate. Anesthesiology 1984;61: 616–618. 57. Garrettson, L. K., and E. B. McGee. Rapid onset of seizures following aspiration of viscous lidocaine. J. Toxicol. Clin. Toxicol. 1992;30:413–422. 58. Gin, T. Propofol during pregnancy. Acta Anaesthesiol. Sin. 1994;32:127–132. 59. Golzarian, J., H. W. Scott, Jr., and W. O. Richards. Hypermagnesemia-induced paralytic ileus. Dig. Dis. Sci. 1994; 39:1138–1142. 60. Graber, T. W., A. S. Yee, and F. J. Baker. Magnesium: Physiology, clinical disorders, and therapy. Ann. Emerg. Med. 1981; 10:49–57. 61. al Hader, A., M. Hasan, and Z. Hasan. The comparative effects of propofol, thiopental, and diazepam, administered intravenously, on pentylenetetrazol seizure threshold in the rabbit. Life Sci. 1992;51:779–786. 62. Hall, A. C., W. R. Lieb, and N. P. Franks. Stereoselective and non stereoselective actions of isoflurane on the GABAA receptor. Br. J. Pharmacol. 1994;112:906–910. 63. Hallak, M., R. F. Berman, S. M. Irtenkauf, et al. Peripheral magnesium sulfate enters the brain and increases the threshold for hippocampal seizures in rats. Am. J. Obstet. Gynecol. 1992;167:1605–1610. 64. Hans, P., V. Bonhomme, J. Collette, et al. Propofol protects cultured rat hippocampal neurons against N-methyl-aspartate receptor-mediated glutamate toxicity. J. Neurosurg. Anesthesiol. 1994;6:249–253.
584
65. Hara, M., Y. Kai, and Y. Ikemoto. Enhancement by propofol of the gamma-aminobutyric acid response in dissociated hippocampal pyramidal neurons of the rat. Anesthesiology 1994;81:988–994. 66. Hara, M., Y. Kai, and Y. Ikemoto. Local anesthetics reduce the inhibitory neurotransmitter-induced current in dissociated hippocampal neurons of the rat. Eur. J. Pharmacol. 1995;283:83–89. 67. Hara, M., Y. Kai, and Y. Ikemoto. Propofol activates GABAA receptor chloride ionophore complex in dissociated hippocampal pyramidal neurons of the rat. Anesthesiology 1993; 79:781–788. 68. Hartung, J., H. Ying, J. Weinberger, and J. E. Cottrell. Propofol prevents or elevates the threshold for lidocaine-induced seizures in rats. J. Neurosurg. Anesthesiol. 1994;6:254–259. 69. Hasan, M. M., Z. A. Hasan, A. F. al-Hader, and M. S. Takrouri. The anticonvulsant effects of propofol, diazepam, and thiopental against picrotoxin-induced seizure in the rat. Middle East J. Anesthesiol. 1993;12:113–121. 70. Hasan, Z. A., M. M. Hasan, A. A. al Hader, and M. S. Takrouri. The effect of propofol and thiopentone on pentylenetetrazol seizure threshold in the rat. Middle East J. Anesthesiol. 1992;11:359–367. 71. Hasan, Z. A., and D. E. Woolley. Comparison of the effects of propofol and thiopental on the pattern of maximal electroshock seizures in the rat. Pharmacol. Toxicol. 1994;74:50– 53. 72. Heavner, J. E., J. Arthur, J. Zou, et al. Comparison of propofol with thiopentone for treatment of bupivacaine-induced seizures in rats. Br. J. Anaesth. 1993;71:715–719. 73. Hellstrom Westas, L., U. Westgren, I. Rosen, and N. W. Svenningsen. Lidocaine for treatment of severe seizures in newborn infants. I. Clinical effects and cerebral electrical activity monitoring. Acta Paediatr. Scand. 1988;77:79–84. 74. Herberg, L. J., A. Grottick, and I. C. Rose. Nitric oxide synthesis, epileptic seizures and kindling. Psychopharmacology 1995; 119:115–123. 75. Herpolsheimer, A., K. Brady, M. K. Yancey, et al. Pulmonary function of preeclamptic women receiving intravenous magnesium sulfate seizure prophylaxis. Obstet. Gynecol. 1991;78: 241–244. 76. Hesdorffer, D. C., W. A. Hauser, J. F. Annegers, and W. A. Rocca. Severe, uncontrolled hypertension and adult-onset seizures: A case-control study in Rochester, Minnesota. Epilepsia 1996;37:736–741. 77. Hesdorffer, D. C., J. P. Stables, W. A. Hauser, et al. Are certain diuretics also anticonvulsants? Ann. Neurol. 2001;50:458–462. 78. Hess, G. P., and P. D. Walson. Seizures secondary to oral viscous lidocaine. Ann. Emerg. Med. 1988;17:725–727. 79. Hilmy, M. I., and G. G. Somjen. Distribution and tissue uptake of magnesium related to pharmacological effects. Am. J. Physiol. 1968;214:406–413. 80. Hilz, M. J., J. Bauer, D. Claus, et al. Isoflurane anesthesia in the treatment of convulsive status epilepticus. J. Neurol. 1992;239:135–137. 81. Hochman, D. W., S. C. Baraban, J. W. Owens, and P. A. Schwartzkroin. Dissociation of synchronization and excitability in furosemide blockade of epileptiform activity. Science 1995;270:99–102. 82. Hochman, D. W., and P. A. Schwartzkroin. Chloridecotransport blockade desynchronizes neuronal discharge in the “epileptic” hippocampal slice. J. Neurophysiol. 2000;83: 406–417.
83. Hoffman, W. E., and G. Edelman. Comparison of isoflurane and desflurane anesthetic depth using burst suppression of the electroencephalogram in neurosurgical patients. Anesth. Analg. 1995;81:811–816. 84. Hou, W. Y., F. Y. Huang, W. Z. Sun, et al. The effect of total intravenous propofol on spontaneous respiration during anesthesia for minor surgery. Ma Tsui Hsueh Tsa Chi 1992;30:7–11. 85. Hsieh, J. C., Y. S. Shih, L. D. Hwang, et al. Activation of epileptogenic activities by etomidate in electrocorticoencephalography (ECoG) during operation for epilepsy. Ma Tsui Hsueh Tsa Chi 1990;28:127–135. 86. Hug, C. C., Jr., C. H. McLeskey, M. L. Nahrwold, et al. Hemodynamic effects of propofol: Data from over 25,000 patients. Anesth. Analg. 1993;77:S21–S29. 87. Hughes, D. R., and M. D. Sharpe. Control of epilepsia partialis continua and secondarily generalized status epilepticus with isoflurane. J. Neurol. Neurosurg. Psychiatry 1992;55: 739–740. 88. Illievich, U. M., W. Petricek, W. Schamm, et al. Electroencephalographic burst suppression by propofol infusion in humans: Hemodynamic consequences. Anesth. Analg. 1993;77: 155–160. 89. Illievich, U. M., M. H. Zornow, K. T. Choi, et al. Effects of hypothermia or anesthetics on hippocampal glutamate and glycine concentrations after repeated transient global cerebral ischemia. Anesthesiology 1994;80:177–186. 90. Ingvar, M., and H. M. Shapiro. Selective metabolic activation of the hippocampus during lidocaine-induced preseizure activity. Anesthesiology 1981;54:33–37. 91. Ito, B. M., S. Sato, C. V. Kufta, and D. Tran. Effect of isoflurane and enflurane on the electrocorticogram of epileptic patients. Neurology 1988;38:924–928. 92. Jones, M. V., P. A. Brooks, and N. L. Harrison. Enhancement of gamma-aminobutyric acid-activated Cl currents in cultured rat hippocampal neurones by three volatile anaesthetics. J. Physiol. (Lond.) 1992;449:279–293. 93. Kain, Z. N., D. J. Gaal, T. S. Kain, et al. A first-pass cost analysis of propofol versus barbiturates for children undergoing magnetic resonance imaging. Anesth. Analg. 1994;79: 1102–1106. 94. Kaplan, P. W., R. P. Lesser, R. S. Fisher, et al. A continuing controversy: Magnesium sulfate in the treatment of eclamptic seizures. Arch. Neurol. 1990;47:1031–1032. 95. Katz, A., D. Kerem, and D. Sherman. Magnesium sulfate suppresses electroencephalographic manifestations of CNS oxygen toxicity. Undersea Biomed. Res. 1990;17:45–49. 96. Kirkby, K. C., W. G. Beckett, R. M. Matters, and T. E. King. Comparison of propofol and methohexitone in anaesthesia for ECT: Effect on seizure duration and outcome. Aust. N. Z. J. Psychiatry 1995;29:299–303. 97. Kishimoto, T., C. Kadoya, R. Sneyd, et al. Topographic electroencephalogram of propofol-induced conscious sedation. Clin. Pharmacol. Ther. 1995;58:666–674. 98. Knudsen, K., and J. Abrahamsson. Antiarrhythmic effects of magnesium sulphate: Report of three cases. Acta Anesthesiol. Scand. 1995;39:850–854. 99. Kochs, E., W. E. Hoffman, C. Werner, et al. The effects of propofol on brain electrical activity, neurologic outcome, and neuronal damage following incomplete ischemia in rats. Anesthesiology 1992;76:245–252. 100. Kofke, W. A., M. T. Snider, R. S. K. Young, and J. C. Ramer. Prolonged low-flow isoflurane anesthesia for status epilepticus. Anesthesiology 1985;62:653–656.
101. Kofke, W. A., R. S. K. Young, P. Davis, et al. Isoflurane for refractory status epilepticus: A clinical series. Anesthesiology 1989;71:653–659. 102. Koontz, W. L., and K. H. Reid. Effect of parenteral magnesium sulfate on penicillin-induced seizure foci in anesthetized cats. Am. J. Obst. Gynecol. 1985;153:96–99. 103. Koren, G., W. Butt, P. Rajchgot, et al. Intravenous paraldehyde for seizure control in newborn infants. Neurology 1986;36:108–111. 104. Krauss, G. L., P. Kaplan, and R. S. Fisher. Parenteral magnesium sulfate fails to control electroshock and pentylenetetrazol seizures in mice. Epilepsy Res. 1989;4: 201–206. 105. Kuisma, M., and R. O. Roine. Propofol in prehospital treatment of convulsive status epilepticus. Epilepsia 1995;36: 1241–1243. 106. Lindheimer, M. D., and A. I. Katz. Preeclampsia: Pathophysiology, diagnosis, and management. Annu. Rev. Med. 1989; 40:233–250. 107. Link, M. J., R. E. Anderson, and F. B. Meyer. Effects of magnesium sulfate on pentylenetetrazol-induced status epilepticus. Epilepsia 1991;32:543–549. 108. Lowson, S., J. P. Gent, and C. S. Goodchild. Convulsive thresholds in mice during the recovery phase from anaesthesia induced by propofol, thiopentone, methohexitone and etomidate. Br. J. Pharmacol. 1991;102:879–882. 109. Lucas, M. J., K. J. Leveno, and F. G. Cunningham. A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N. Engl. J. Med. 1995;333:201– 205. 110. Mackenzie, S. J., F. Kapadia, and I. S. Grant. Propofol infusion for control of status epilepticus. Anaesthesia 1990;45: 1043–1045. 111. Magpie Trial Collaborative Group. Do women with preeclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: A randomised placebo-controlled trial. Lancet 2002;359:1877–1890. 112. Mahoney, A. W., D. G. Hendricks, N. Bernhard, and D. V. Sisson. Fasting and ketogenic diet effects on audiogenic seizure susceptibility of magnesium-deficient rats. Pharmacol. Biochem. Behav. 1983;18:683–687. 113. Makela, J. P., M. Iivanainen, I. P. Pieninkeroinen, et al. Seizures associated with propofol anesthesia. Epilepsia 1993; 34:832–835. 114. Malsch, E., I. Gratz, S. Mani, et al. Efficacy of electroconvulsive therapy after propofol and methohexital anesthesia. Convuls. Ther. 1994;10:212–219. 115. Martensson, B., A. Bartfai, B. Hallen, et al. A comparison of propofol and methohexital as anesthetic agents for ECT: Effects on seizure duration, therapeutic outcome, and memory. Biol. Psychiatry 1994;35:179–189. 116. Mason, B. A., C. A. Standley, S. M. Irtenkauf, et al. Magnesium is more efficacious than phenytoin in reducing Nmethyl--aspartate seizures in rats. Am. J. Obstet. Gynecol. 1994;171:999–1002. 117. Matters, R. M., W. G. Beckett, K. C. Kirkby, and T. E. King. Recovery after electroconvulsive therapy: Comparison of propofol with methohexitone anesthesia. Br. J. Anaesth. 1995; 75:297–300. 118. McCaslin, P. P., and W. W. Morgan. Anticonvulsive activity of several excitatory amino acid antagonists against barbital withdrawal–induced spontaneous convulsions. Eur. J. Pharmacol. 1988;147:381–386.
:
585
119. McCombs, J. Treatment of preeclampsia and eclampsia. Clin. Pharm. 1992;11:236–245. 120. Merigian, K. S., R. G. Browning, and K. V. Leeper. Successful treatment of amoxapine-induced refractory status epilepticus with propofol (Diprivan). Acad. Emerg. Med. 1995;2: 128–133. 121. Meyer, J. G., and K. Urban. Electrolyte changes and acidbase balance after alcohol withdrawal, with special reference to rum fits and magnesium depletion. J. Neurol. 1977;215: 135–140. 122. Morrisett, R. A., R. S. Jope, and O. C. Snead. Effects of drugs on the initiation and maintenance of status epilepticus induced by administration of pilocarpine to lithiumpretreated rats. Exp. Neurol. 1987;97:193–200. 123. Motta, R., and J. P. Louis. Audiogenic seizure sensitivity in mouse lines genetically selected for high versus low blood magnesium levels. Behav. Genet. 1999;29:125–130. 124. Murao, K., K. Shingu, K. Tsushima, K. Takahira, S. Ikeda, and S. Nakao. The anticonvulsant effects of volatile anesthetics on lidocaine-induced seizures in cats. Anesth. Analg. 2000;90:148–155. 125. Nattel, S., G. Gagné, and M. Pineau. The pharmacoknetics of lignocaine and beta-adrenoceptor antagonists in patients with acute myocardial infarction. Clin. Pharmacokinet. 1987; 13:293–316. 126. Nowack, W. J., and R. Jordan. Propofol, seizures and generalized paroxysmal fast activity in the EEG. Clin. Electroencephalogr. 1994;25:110–114. 127. Oei Lim, V. L., C. J. Kalkman, E. C. Bouvy Berends, et al. A comparison of the effects of propofol and nitrous oxide on the electroencephalogram in epileptic patients during conscious sedation. Anesth. Analg. 1992;75:708–714. 128. Opitz, A., M. Marschall, R. Degen, and D. Koch. General anesthesia in patients with epilepsy and status epilepticus. In A. V. Delgado Escueta, C. G. Wasterlain, D. M. Treiman, and R. J. Porter, eds. Status Epilepticus. Adv. Neurol. 1983;34: 531–536. 129. Orser, B. A., M. Bertlik, L. Y. Wang, and J. F. MacDonald. Inhibition by propofol (2,6-di-isopropylphenol) of the Nmethyl--aspartate subtype of glutamate receptor in cultured hippocampal neurones. Br. J. Pharmacol. 1995;116:1761– 1768. 130. Orser, B. A., L. Y. Wang, P. S. Pennefather, and J. F. MacDonald. Propofol modulates activation and desensitization of GABAA receptors in cultured murine hippocampal neurons. J. Neurosci. 1994;14:7747–7760. 131. Pascual, J., J. Ciudad, and J. Berciano. Role of lidocaine (lignocaine) in managing status epilepticus. J. Neurol. Neurosurg. Psychiatry 1992;55:49–51. 132. Pascual, J., M. J. Sedano, J. M. Polo, and J. Bercano. Intravenous lidocaine for status epilepticus. Epilepsia 1988;29: 584–589. 133. Petros, A. J., R. G. Bogle, and J. D. Pearson. Propofol stimulates nitric oxide release from cultured porcine aortic endothelial cells. Br. J. Pharmacol. 1993;109:6–7. 134. Phuapradit. W., N. Saropala, S. Haruvasin, and P. Thuvasethakul. Serum level of magnesium attained in magnesium sulfate therapy for severe preeclampsia. Asia Oceania J. Obstet. Gynaecol. 1993;19:387–390. 135. Pitt-Miller, P. L., B. J. Elcock, and M. Maharaj. The management of status epilepticus with a continuous propofol infusion. Anesth. Analg. 1994;78:1193–1194.
586
136. Post, R. M., C. Kennedy, M. Shinohara, et al. Metabolic and behavioral consequences of lidocaine kindled seizures. Brain Res. 1984;324:295–303. 137. Prasad, A., B. B. Worrall, E. H. Bertram, and T. P. Bleck. Propofol and midazolam in the treatment of refractory status epilepticus. Epilepsia 2001;42:380–386. 138. Pritchard, S. A. The Parkland Memorial Hospital protocol for treatment of eclampsia: Evaluation of 245 cases. Am. J. Obstet. Gynecol. 1984;152:951–963. 139. Ramanathan, J., B. M. Sibai, V. Duggirala, and A. L. Maduska. Pulmonary function in preeclamptic women receiving MgSO4. J. Reprod. Med. 1988;33:432–435. 140. Reddy, R. V., S. S. Moorthy, S. F. Dierdorf, et al. Excitatory effects and electroencephalographic correlation of etomidate, thiopental, methohexital, and propofol. Anesth. Analg. 1993;77: 1008–1011. 141. Reddy, R. V., S. S. Moorthy, T. Mattice, et al. An electroencephalographic comparison of effects of propofol and methohexital. Electroencephalogr. Clin. Neurophysiol. 1992;83:162–168. 142. Reid, K. H., S. Z. Guo, and V. G. Iyer. Agents which block potassium-chloride cotransport prevent sound-triggered seizures in post-ischemic audiogenic seizure-prone rats. Brain Res. 2000;864:134–137. 143. Rigaud Monnet, A. S., E. Pinard, J. Borredon, and J. Seylaz. Blockade of nitric oxide synthesis inhibits hippocampal hyperemia in kainic acid–induced seizures. J. Cereb. Blood Flow Metab. 1994;14:581–590. 144. Rizzo, M. A., M. Fisher, and J. P. Lock. Hypermagnesemic pseudocoma. Arch. Intern. Med. 1993;153:1130–1132. 145. Ronan, K. P., T. J. Gallagher, B. George, and B. Hamby. Comparison of propofol and midazolam for sedation in intensive care unit patients. Crit. Care Med. 1995;23:286–293. 146. Ropper, A. H., A. Kofke, E. B. Bromfield, and S. K. Kennedy. Comparison of isoflurane, halothane, and nitrous oxide in status epilepticus. Ann. Neurol. 1986;19:98–99. 147. Rosenberg, M. K., P. Bridge, and M. Brown. Cost comparison: A desflurane versus a propofol based general anesthetic technique. Anesth. Analg. 1994;79:852–855. 148. Rothstein, P., J. Dornbusch, and B. A. Shaywitz. Prolonged seizures associated with the use of viscous lidocaine. J. Pediatr. 1982;101:461–463. 149. Sadeh, M., I. Blatt, G. Martonovits, et al. Treatment of porphyric convulsions with magnesium sulfate. Epilepsia 1991; 32:712–715. 150. Saffer, S., and M. Berk. Anesthetic induction for ECT with etomidate is associated with longer seizure duration than theiopentone. J. ECT 1998;14:89–93. 151. Sakaki, T., K. Abe, T. Hoshida, et al. Isoflurane in the management of status epilepticus after surgery for lesion around the motor area. Acta Neurochir. 1992;116:38–43. 152. Sanna, E., C. Motzo, M. Usala, et al. Characterization of the electrophysiological and pharmacological effects of 4iodo-2,6-diisopropylphenol, a propofol analogue devoid of sedative-anaesthetic properties. Br. J. Pharmacol. 1999;126: 1444–1450. 153. Schwartz, A. E., R. H. Tuttle, and P. J. Poppers. Electroencephalographic burst suppression in elderly and young patients anesthetized with isoflurane. Anesth. Analg. 1989;68:9–12. 154. Seo, N., E. Oshima, J. Stevens, and K. Mori. The tetraphasic action of lidocaine on CNS electrical activity and behavior in cats. Anesthesiology 1982;57:451–457.
155. Sibai, B. M. Magnesium sulfate is the ideal anticonvulsant in preeclampsia eclampsia. Am. J. Obstet. Gynecol. 1990;162: 1141–1145. 156. Sibai, B. M. Medical disorders in pregnancy, including hypertensive diseases. Curr. Opin. Obstet. Gynecol. 1990;2:13–22. 157. Sibai, B. M., J. A. Spinnato, D. L. Watson, et al. Effect of magnesium sulfate on electroencephalographic findings in preeclampsia eclampsia. Obstet. Gynecol. 1984;64:261–266. 158. Smith, D. C., S. E. Krahl, R. A. Browning, and E. J. Barea. Rapid cessation of focally induced generalized seizures in rats through microinfusion of lidocaine hydrochloride into the focus. Epilepsia 1993;34:43–53. 159. Sneyd, J. R., S. K. Samra, B. Davidson, et al. Electrophysiologic effects of propofol sedation. Anesth. Analg. 1994;79: 1151–1158. 160. Somjen, G. G., M. Hilmy, and C. R. Stephen. Failure to anesthetize human subjects by intravenous administration of magnesium sulfate. J. Pharmacol. Exp. Ther. 1966;154:652– 659. 161. Spencer, E. M., J. L. Green, and S. M. Willatts. Continuous monitoring of depth of sedation by EEG spectral analysis in patients requiring mechanical ventilation. Br. J. Anaesth. 1994;73:649–654. 162. Stadtland, C., A. Erfurth, U. Ruta, and N. Michael. A switch from propofol to etomidate during an ECT course increases EEG and motor seizure duration. J. ECT 2002; 18:22–25. 163. Standley, C. A., S. M. Irtenkauf, L. Stewart, et al. Magnesium sulfate versus phenytoin for seizure prevention in amygdala kindled rats. Am. J. Obstet. Gynecol. 1994;171: 948–951. 164. Stecker, M. M., T. H. Kramer, E. C. Raps, et al. Treatment of refractory status epilepticus with propofol: Clinical and pharmacokinetic findings. Epilepsia 1998;39:18–26. 165. Stein, A. G., H. G. Eder, D. E. Blum, et al. An automated drug delivery system for focal epilepsy. Epilepsy Res. 2000;39: 103–114. 166. Sutherland, M. J., and P. Burt. Propofol and seizures. Anaesth. Intensive Care 1994;22:733–737. 167. Tamargo, R. J., L. A. Rossell, E. H. Kossoff, et al. The intracerebral administration of phenytoin using controlled-release polymers reduces experimental seizures in rats. Epilepsy Res. 2002;48:145–155. 168. Theard, M. A., V. L. Baughman, Q. Wang, et al. The role of nitric oxide in modulating brain activity and blood flow during seizure. Neuroreport 1995;6:921–924. 169. Thurnau, G. R., D. B. Kemp, and A. Jarvis. Cerebrospinal fluid levels of magnesium in patients with preeclampsia after treatment with intravenous magnesium sulfate: A preliminary report. Am. J. Obstet. Gynecol. 1987;157:1435–1438. 170. Traast, H. S., and C. J. Kalkman. Electroencephalographic characteristics of emergence from propofol/ sufentanil total intravenous anesthesia. Anesth. Analg. 1995; 81:366–371. 171. Uchida, I., G. Kamatchi, D. Burt, and J. Yang. Etomidate potentiation of GABAA receptor-gated current depends on the subunit composition. Neurosci Lett. 1995;185:203–206. 172. Vissers, R. J., and R. Purssell. Iatrogenic magnesium overdose: Two case reports. J. Emerg. Med. 1996;14:187–191. 173. Vuyk, J., F. H. Engbers, H. J. Lemmens, et al. Pharmacodynamics of propofol in female patients. Anesthesiology 1992;77: 3–9.
174. Wagner, B. K., and D. A. O’Hara. Cost analysis of propofol versus thiopental induction anesthesia in outpatient laparoscopic gynecologic surgery. Clin. Ther. 1995;17:770–776. 175. Walder, B., M. R. Tramer, and M. Seeck. Seizure-like phenomena and propofol: A systematic review. Neurology 2002;58: 1327–1332. 176. Wang, L. Y., and J. F. MacDonald. Modulation by magnesium of the affinity of NMDA receptors for glycine in murine hippocampal neurones. J. Physiol. (Lond.) 1995; 486(Pt. 1):83–95. 177. Watson, K. V., C. F. Moldow, P. L. Ogburn, and H. S. Jacob. Magnesium sulfate: Rationale for its use in preeclampsia. Proc. Natl. Acad. Sci. U.S.A. 1986;83:1075–1078. 178. Welty, T. E., J. C. Cloyd, and M. M. Abdel Monem. Delivery of paraldehyde in 5% dextrose and 0.9% sodium chloride injections through polyvinyl chloride i.v. sets and burettes. Am. J. Hosp. Pharm. 1988;45:131–135. 179. Wessen, A., P. M. Persson, A. Nilsson, and P. Hartvig. Clinical pharmacokinetics of propofol given as a constant-rate infusion and in combination with epidural blockade. J. Clin. Anesth. 1994;6:193–198. 180. Wolf, G., G. Keilhoff, S. Fischer, and P. Hass. Subcutaneously applied magnesium protects reliably against quinolinateinduced N-methyl--aspartate (NMDA)-mediated neurodegeneration and convulsions in rats: Are there therapeutical implications? Neurosci Lett. 1990;117:207–211. 181. Yamakura, T., K. Sakimura, K. Shimoji, and M. Mishina. Effects of propofol on various AMPA, kainate and NMDA selective glutamate receptor channels expressed in Xenopus oocytes. Neurosci Lett. 1995;188:187–190. 182. Yang, J., K. E. Isenberg, and C. F. Zorumski. Volatile anesthetics gate a chloride current in postnatal rat hippocampal neurons. FASEB J. 1992;6:914–918. 183. Yeoman, P., A. Hutchinson, A. Byrne, et al. Etomidate infusions for the control of refractory status epilepticus. Intensive Care Med. 1989;15:255–259. 184. Zhu, S., and R. C. Baker. Effects of inhalation anesthetics on kainate-induced glutamate release from cerebellar granule cells. Life Sci. 1996;58:1359–1366.
:
587
IX THERAPEUTIC MANAGEMENT
47
Approaches to Treating Status Epilepticus Outside the Hospital
. .
Introduction Status epilepticus (SE) often begins outside the hospital (1, 44). Overall, SE is similar in this setting, but there is a higher incidence of cases resulting from drug withdrawal and acute toxic and metabolic derangements than in the hospital (1, 12, 44). Although the goal of rapid seizure termination is still key outside of the hospital, a number of practical issues, particularly the absence of physicians and difficulties in rapidly obtaining access for intravenous (IV) drug administration, often mandate a different treatment approach. Early treatment of SE has been shown not only to reduce seizure duration but also to improve the response to medication (32, 33). Most treatment protocols and randomized studies of the treatment of generalized SE have been in hospitalized patients (30, 50, 53). SE, however, often begins in homes, public places, and residential care facilities, with the patients then transported to the hospital, imposing a significant treatment delay. Rapidly acting agents such as benzodiazepines can be administered by nonphysicians. Concerns over nonphysician administration include the potential for respiratory depression, hypotension, and inappropriate administration due to misdiagnosis of SE (32). Route of administration is also a key issue; IV administration may lead to a quicker onset of drug action but a higher risk of respiratory compromise. In addition, delay due to difficulty in obtaining IV access by inexperienced medical support staff may negate the advantages of this route. Rectal, intranasal, buccal, intramuscular (IM), and subcutaneous routes have been used as alternatives, particularly when the drug is administered by the patient’s family or by staff at long-term care facilities.
Pharmacology of agents used to treat out-of-hospital SE The benzodiazepines are the drugs of choice for treating SE because they are effective for many types of seizures, are relatively safe, and have a rapid onset of action. Diazepam, midazolam, and lorazepam are the benzodiazepines used. The effect of the benzodiazepines is due to their interaction with the g-aminobutyric acid (GABA) subtype A receptor,
the major inhibitory neurotransmitter in the central nervous system (CNS) (45). Benzodiazepines can be administered by IV, IM, oral, rectal, sublingual, or intranasal routes (5). However, animal studies suggest that benzodiazepines rapidly lose their potency with increasing duration of seizures (25, 35), probably because seizures induce endocytosis, resulting in a loss of GABAA receptors from synapses (40). D The onset and duration of antiseizure effect of diazepam are dependent on the rate of absorption (for nonIV formulations) and the rate of distribution into and out of the CNS. The duration of antiseizure effect is not dependent on the elimination half-life (30). In animal studies, after IV administration, peak brain and plasma concentrations were reached within 1 minute. Within an hour, brain concentrations have declined to subtherapeutic levels (43). The time to initial effect of non-IV formulations depends on the time course of absorption. After oral administration, doses are completely absorbed, with peak concentrations occurring within 30–90 minutes (23). Rectal administration of diazepam solution results in peak concentrations within 60 minutes (36). The rectal gel formulation (Diastat) is rapidly and completely absorbed within 30–60 minutes, with an estimated bioavailability of 90% (11). Diazepam rectal suppositories exhibit slow and variable absorption and therefore are not suitable for the treatment of acute seizures (47). In contrast to the antiseizure effect, the duration of adverse effects depends on the elimination of diazepam and its active metabolite, desmethyldiazepam. Both diazepam and desmethyldiazepam are extensively metabolized, with elimination half-lives of 1–2 days and 2–5 days, respectively (20). Therefore, CNS adverse effects can continue for several days after diazepam administration. M Midazolam is water soluble in commercially available solution at acidic pH but is very lipid soluble at neutral, physiologic pH and is rapidly absorbed. Therefore, it is suitable for administration by a variety of routes. It has a shorter duration of action than diazepam and lorazepam, with the potential for less prolonged sedation but also briefer protection against seizure recurrence. Peak sedation is
:
591
achieved within 3 minutes in healthy adults after IV infusion (24). After IM administration, peak levels are reached in 20–30 minutes, with 91% bioavailability (24). The parenteral formulation can be administered by the oral, rectal, buccal, and intranasal routes (26). Midazolam undergoes extensive first-pass metabolism, resulting in only 20%–40% of the dose reaching systemic circulations after oral administrations, with a peak concentration occurring in 20–50 minutes (4). When a solution of midazolam was administered by the intranasal route, the bioavailability of midazolam was 50% and peak concentrations occurred with 30 minutes (7). In a recent study of a more concentrated nasal spray, bioavailability was greater than 80% and peak concentrations occurred within 15–20 minutes, possibly due to decreased swallowing of the midazolam. Rectal administration results in bioavailability of approximately 50% with peak concentrations at 20–50 minutes (10). Peak concentrations occur within 30 minutes after buccal administration, with approximately 75% of the midazolam dose reaching the systemic circulation (46). Unlike diazepam, midazolam is eliminated rapidly, with an elimination half-life of 1–4 hours, resulting in a relatively short duration of adverse effects compared to diazepam and lorazepam (4, 52). L Lorazepam is less lipophilic than diazepam, which results in a slower distribution into and out of the CNS than diazepam. Therefore, lorazepam has a longer distribution half-life than diazepam and a prolonged duration of action of 12–24 hours (2). After oral, IM, and sublingual administration, the bioavailability of lorazepam is greater than 90%, with peak concentrations reached within 1–2 hours (21). Lorazepam is extensively metabolized, with an elimination half-life of 17–56 hours (5). F The parenteral formulation of phenytoin is not suitable for IM injection due to high pH and propylene glycol formulation. In contrast, fosphenytoin, the phosphate ester of phenytoin, is water soluble, is used at pH 8.5, and can be given successfully by IM administration. IM administration of a 10 mg/kg dose results in a maximum phenytoin concentration in the upper therapeutic range within 1–2 hours, with 50% of subjects having therapeutic phenytoin plasma concentrations by 30 minutes (13). Therefore, IM fosphenytoin is a viable option in the treatment of out-ofhospital SE. P Propofol is a rapidly acting, highly lipophilic anesthetic that has antiseizure properties (34). The anticonvulsant activity is thought to be mediated by multiple mechanisms, including effects on GABAA receptors and a decrease in the release of excitatory amino acids, -
592
glutamate and -aspartate (6). After IV administration, the distribution into the brain occurs within minutes, with a blood-brain equilibrium half-life of less than 3 minutes. Propofol is extensively metabolized, with an elimination halflife of 3–6 hours. Unlike the other drugs, propofol use is limited to IV administration for the treatment of out-ofhospital SE.
Clinical studies of out-of-hospital treatment of SE Administration of IV benzodiazepines by emergency paramedics to treat SE has been implemented in many places in recent years. It is reasonable to assume that properly trained staff can perform this safely. It is also plausible that this intervention could lead to improved outcome, not only because of fewer sequelae with attenuation of convulsive SE but also because the seizures might respond better with earlier treatment. These assumptions have only recently been tested in a randomized, prospective, double-blind clinical trial (1). In this study, adults with prolonged (>5 minutes) or repetitive seizures were treated by IV diazepam (5 mg, 68 patients), lorazepam (2 mg, 66 patients), or placebo (71 patients), and the dose was repeated if the seizures recurred or lasted more than 4 minutes. Patients with bradycardia, hypotension, cardiac arrhythmia, a history of asthma, chronic obstructive pulmonary disease, or known benzodiazepine sensitivity or chronic use were excluded. Only 3%–7% of the treatment groups had nonepileptic seizures. Patients who received benzodiazepine were less likely to be seizing on arrival at the ED (lorazepam, 59.1%; diazepam, 42.6%; placebo, 21.1%) and also were less likely to have respiratory or circulatory complications (lorazepam, 10.6%; diazepam, 10.3%; placebo, 22.5%). This study therefore demonstrates the safety and efficacy of IV benzodiazepines in this situation and suggests possible better efficacy for lorazepam (1). Even with the large number of patients in this study, however, a significant difference in neurologic outcome and mortality was not demonstrated, although there was a trend (P = 0.08) toward a higher in-hospital mortality in the placebo group. Further investigation is needed to determine whether higher benzodiazepine doses might be more effective. Alternative routes of benzodiazepine administration have been investigated in situations where the IV route is not practical. One place is the home of patients with a past history of episodes of severe seizures or SE. Another setting is the long-term residential care facility serving, for example, developmentally delayed children or adults or geriatric patients with neurologic diseases, with a high incidence of seizures and SE. Instituting on-site treatment with benzodiazpines not only might improve outcome but also might make transportation to the hospital unnecessary. Because
placement of IV catheters may be an unusual occurrence in long-term care facilities and because residents often have poor peripheral veins, the delay in obtaining IV access may negate any advantage of that method of administration (19). Of course, it is rarely possible to use the IV route in the home before the arrival of emergency medical technicians. For these reasons, alternative administration routes are needed. An early approach was administration of the standard diazepam IV solution into the rectum by means of a syringe (8, 31). This is unquestionably an effective treatment for SE and severe repetitive seizures. It was shown to have similar efficacy to the IV agent in stopping seizures when administered by emergency paramedics (15) and was found to decrease ED visits with home use (27). When diazepam was compounded into rectal suppositories for more convenient use, however, absorption was found to be slow and unreliable (14, 37, 39). A better approach has been the use of diazepam gel, which is marketed in a rectal delivery system for convenient and rapid administration (9, 16). This product comes in premeasured units for immediate use and is stable for many months at room temperature (3). In a randomized, double-blind study of home use (16), this agent was superior to placebo in reducing seizure frequency in patients with clusters of acute repetitive seizures. The most common side effect of rectal diazepam gel was somnolence, but respiratory depression was not reported (9, 16, 38, 51). In a longterm care facility for developmentally disabled adults, 15– 20 mg of rectal diazepam gel was compared to 4 mg of IV lorazepam in an open-label study (19). The diazepam gel resulted in a significantly shorter total seizure time because of a shorter mean time to begin administration; additionally, successful administration of IV lorazepam was possible only 30% of the time. This suggests that the time to begin administration of the agent, rather than the route, may be the main determinant of seizure time, and that a non-IV route may be preferable in long-term care facilities. Other routes of benzodiazepine administration have also been used successfully. Midazolam has been most investigated. Nasal midazolam (17, 18, 22, 29, 41) was studied to treat acute pediatric seizures at home and was effective for most patients, terminating 122 of 125 seizures within 10 minutes in the largest study (17). Some parents found nasal midazolam easier to use and felt that it caused less postictal sedation. Buccal midazolam, where the agent is injected by syringe between the cheeks and the teeth, results in rapid absorption (48) and may be easier to use than the nasal route (49) and less affected by breathing and congestion. This was studied in 79 seizures in 42 patients with severe epilepsy at a residential treatment school in a randomized, open-label protocol (49). When seizures lasted more than 5 minutes, 10 mg of buccal midazolam or rectal diazepam was admin-
istered. These two methods appeared to be comparable in efficacy, as time to administration and time to seizure cessation were similar in the two groups, and midazolam successfully stopped seizures in 75% of patients and diazepam in 59% (P = 0.16). These studies raise the possibility that several different benzodiazepines and several different routes of administration may be effective for treating severe seizures and SE outside the hospital. The most important issue may be the practical one of which preparation can most easily be kept on hand with a patient’s particular living situation and lifestyle, and which can be administered the quickest. Rectal diazepam gel has the advantage of being the best-studied and documented treatment and of coming in stable, premeasured, commercially available units. Buccal midazolam is less expensive and avoids the potential embarrassment of rectal administration. Other benzodiazepines, such as lorazepam, and other routes, such as IM and subcutaneous administration, are sometimes used in clinical practice but require validation in clinical trials outside the hospital. In addition to the benzodiazepines, other agents, including phenytoin, fosphenytoin, phenobarbital, pentobarbital, profofol, and valproate, have been used to treat SE in the hospital (42). Profofol in particular is rapidly acting in a fashion similar to benzodiazepines and has been safely used out of the hospital in a pilot study in eight patients (28). Valproate phenytoin and barbiturates have properties less favorable for out-of-hospital administration because they require slower administration and have a higher risk of circulatory and respiratory compromise. In addition, in one controlled trial of treatment of in-hospital SE (53), initial treatment with IV lorazepam was more effective than initial treatment with IV phenytoin. Nonetheless, fosphenytoin has the advantage that it can be given IM (54), so it might have a limited role in the treatment of benzodiazepine-resistant SE, particularly in situations in which it is not possible to rapidly transport the patient to the hospital.
Summary If treatment for SE is initiated earlier, the seizures are more likely to respond, and it is probable that treatment costs and overall outcome may be improved. For many episodes of SE, this requires beginning treatment outside the hospital—in the ambulance, at home, or at a care facility. There is now ample evidence that benzodiazepines are safe and effective in these settings. The IV administration of lorazepam or diazepam by paramedics and rectal administration of diazepam by family and caregivers are the best-documented approaches in these situations, but it is likely that with further investigation, a variety of other benzodiazepines and administration routes may prove useful.
:
593
REFERENCES 1. Alldredge, B. K., A. M. Gelb, S. M. Isaacs, M. D. Corry, F. Allen, S. K. Ulrich, et al. A comparison of lorazepam, diazepam and placebo for the treatment of out-of-hospital status epilepticus. N. Engl. J. Med. 2001;345:631–637. 2. Alldredge, B. K., and D. H. Lowenstein. Status epilepticus: New concepts. Curr. Opin. Neurol. 1999;12:183–190. 3. Alldredge, B. K., R. Venteicher, and T. S. Calderwood. Stability of diazepam rectal gel in ambulance-like environments. Am. J. Emerg. Med. 2002;20:88–91. 4. Allonen, H., G. Ziegler, and U. Klotz. Midazolam kinetics. Clin. Pharmacol. Ther. 1981;30:653–661. 5. Anderson, G. D., and J. W. Miller. Benzodiazepine: Chemistry, biotransformation and pharmacokinetics. In R. Levy, R. Mattson, B. Meldrum, and E. Perucca, eds. Antiepileptic Drugs. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2002: 187–205. 6. Borgeat, A., O. H. G. Wilder-Smith, and P. M. Suter. The nonhypnotic therapeutic applications of propofol. Anesthesiology 1994;80:642–646. 7. Burstein, A. H., R. Modica, M. Hatton, and F. M. Gengo. Intranasal midazolam plasma concentration profile and its effect on anxiety associated with dental procedures. Anesth. Prog. 1996;43:52–57. 8. Camfield, C. S., P. R. Camfield, E. Smith, and J. M. Dooley. Home use of rectal diazepam to prevent status epilepticus in children with convulsive disorders. J. Child Neurol. 1989;4: 125–126. 9. Cereghino, J. J., W. G. Mitchell, J. Murphy, et al. Treating repetitive seizures with a rectal diazepam formulation. Neurology 1998;51:1274–1282. 10. Clausen, T. G., J. Wolff, P. B. Hansen, et al. Pharmacokinetics of midazolam and alpha-hydroxy-midazolam following rectal and intravenous administration. Br. J. Clin. Pharmacol. 1988; 25:457–463. 11. Cloyd, J. C., R. L. Lalonde, T. E. Beniak, and G. D. Novack. A single-blind, crossover comparison of the pharmacokinetics and cognitive effects of a new diazepam rectal gel with intravenous diazepam. Epilepsia 1998;39:520–526. 12. DeLorenzo, R. J., J. M. Pellock, A. R. Towne, et al. Epidemiology of status epilepticus. J. Clin. Neurophysiol. 1995;12: 316–325. 13. DeToledo, J. C., and R. E. Ramsay. Fosphenytoin and phenytoin in patients with status epilepticus: Improved tolerability versus increased costs. Drug Safety 2000;22:459–466. 14. Dhillon, S., J. Oxley, and A. Richens. Bioavailability of diazepam after intravenous, oral and rectal administration in adult epileptic patients. Br. J. Clin. Pharmacol. 1982;13:427–432. 15. Dieckmann, R. A. Rectal diazepam for prehospital pediatric status epilepticus. Ann. Emerg. Med. 1994;23:216–224. 16. Dreifuss, F. E., N. P. Rosman, J. C. Cloyd, et al. A comparison of rectal diazepam gel and placebo for acute repetitive seizures. N. Engl. J. Med. 1998;338:1869–1975. 17. Fisgin, T., Y. Gurer, N. Senbil, et al. Nasal midazolam effects on childhood acute seizures. J. Child Neurol. 2000;15:833–835. 18. Fisgin, T., Y. Gurer, T. Tahsin, et al. Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: Prospective randomized study. J. Child Neurol. 2002;17: 123–126. 19. Fitzgerald, B. J., A. J. Okos, and J. W. Miller. Treatment of outof-hospital status epilepticus with diazepam rectal gel. Seizure 2003;12:52–55.
594
20. Greenblatt, D. J., M. K. Divoll, M. H. Soong, H. G. Boxenbaum, J. S. Harmatz, and R. I. Shader. Desmethyldiazepam pharmacokinetics: Studies following intravenous and oral desmethyldiazepam, oral clorazepate, and intravenous diazepam. J. Clin. Pharmacol. 1988;28:853–859. 21. Greenblatt, D. J., R. I. Shader, K. Franke, et al. Pharmacokinetics and bioavailability of intravenous, intramuscular, and oral lorazepam in humans. J. Pharm. Sci. 1979;68:57–63. 22. Jeannet, P. Y., E. Roulet, M. Maeder-Ingvar, M. Gehri, A. Jutzi, and T. Deonna. Home and hospital treatment of acute seizures in children with nasal midazolam. Eur. J. Paediatr. Neurol. 1999;3:73–77. 23. Kaplan, S. A., M. L. Jack, K. Alexander, and R. E. Weinfeld. Pharmacokinetic profile of diazepam in man following single intravenous and oral and chronic oral administration. J. Pharm. Sci. 1973;62:1789–1796. 24. Kanto, J. H. Midazolam: The first water-soluble benzodiazepine. Pharmacology, pharmacokinetics and efficacy in insomnia and anesthesia. Pharmacotherapy 1985;5:138–154. 25. Kapur, J., and R. L. Macdonald. Rapid seizure-induced reduction of benzodiazepine and Zn2+ sensitivity of hippocampal dentate granule cell GABAA receptors. J. Neurosci. 1997; 17:7532–7540. 26. Knoester, P. D., D. M. Jonker, R. T. Van Der Hoeven, et al. Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray: A study in healthy volunteers. Br. J. Clin. Pharmacol. 2002;53:501–507. 27. Kriel, R. L., J. C. Cloyd, R. S. Hadsall, A. M. Carlson, K. L. Floren, and C. M. Jones-Seate. Home use of rectal diazepam for cluster and prolonged seizures: Efficacy, adverse reactions, quality of life, and cost analysis. Pediatr. Neurol 1991;7:13–17. 28. Kuisma, M., and R. O. Roine. Propofol in prehospital treatment of convulsive status epilepticus. Epilepsia 1995;36: 1241–1243. 29. Lahat, E., M. Goldman, J. Barr, G. Eshel, and M. Berkovitch. Intranasal midazolam for childhood seizures. Lancet 1998;352: 224. 30. Leppik, I. E., A. T. Derivan, R. W. Homan, J. Walker, R. E. Ramsay, and B. Patrick. Double-blind study of lorazepam and diazepam in status epilepticus. JAMA 1983;249:1452–1454. 31. Lombroso, C. T. Intermittent home treatment of status and clusters of seizures. Epilepsia 1989;30(Suppl. 2):S11–S14. 32. Lowenstein, D. H., and B. K. Aldridge. Status epilepticus. N. Engl. J. Med. 1998;338:970–976. 33. Lowenstein, D. H., and B. K. Alldredge. Status epilepticus at an urban public hospital in the 1980s. Neurology 1993;43: 483–488. 34. Lowson, S., J. P. Gent, and C. S. Goodchild. Anticonvulsant properties of propofol and thiopentone: Comparison using two tests in laboratory mice. Br. J. Anaesth. 1990;64:59–63. 35. Mazarati, A. M., R. A. Baldwin, R. Sankar, and C. G. Wasterlain. Time-dependent decrease in the effectiveness of antiepileptic drugs during the course of self-sustaining status epilepticus. Brain Res. 1998;814:179–185. 36. Meberg, A., A. Langslet, J. E. Bredesen, and P. K. M. Lunde. Plasma concentration of diazepam and N-desmethyldiazepam in children after a single rectal or intramuscular dose of diazepam. Eur. J. Clin. Pharmacol. 1978;14:272–276. 37. Milligan, N., S. Dhillon, J. Oxley, and A. Richens. Absorption of diazepam from the rectum and its effect on interictal spikes in the EEG. Epilepsia 1982;23:323–331. 38. Mitchell, W. G., J. A. Conry, P. K. Crumrine, R. L. Kriel, J. J. Cereghino, L. Groves, et al. An open-label study of repeated
39.
40.
41.
42. 43.
44.
45. 46.
47.
48.
49.
50.
51.
52.
53.
54.
use of diazepam rectal gel (Diastat) for episodes of acute breakthrough seizures and clusters: Safety, efficacy, and tolerance. North American Diastat Group. Epilepsia 1999;40:1610–1617. Moolenaar, E., S. Bakker, J. Visser, and T. Huizinga. Biopharmaceutics of rectal administration of drugs in man. IX. Comparative biopharmaceutics of diazepam after single rectal, oral, intramuscular and intravenous administration in man. Int. J. Pharm. 1980;5:127–137. Naylor, D. E., H. Liu, and C. G. Wasterlain. Alterations in inhibition occur early during status epilepticus and include internalization of GABA subtype A receptors. Epilepsia 2002; 43(Suppl. 1):141. O’Regan, M. E., J. K. Brown, and M. Clarke. Nasal rather than rectal benzodiazepines in the management of acute childhood seizures? Dev. Med. Child Neurol. 1996;38:1037–1045. Pellock, J. M. Management of acute seizure episodes. Epilepsia 1998;39(Suppl. 1):S28–S35. Ramsay, R. E., E. J. Hammond, R. J. Perchalski, and B. J. Wilder. Brain uptake of phenytoin, phenobarbital and diazepam. Arch. Neurol. 1979;36:535–539. Reuber, M., L. Hattingh, and P. J. Goulding. Epileptological Emergencies in Accident and Emergency: A survey at St. James’s University Hospital, Leeds. Seizure 2000;9:216–220. Rho, J. M., and R. Sankar. The pharmacologic basis of antiepileptic drug action. Epilepsia 1999;40:1471–1483. Schwagmeier, R., S. Alincic, and H. W. Striebel. Midazolam pharmacokinetics following intravenous and buccal administration. Br. J. Clin. Pharmacol. 1998;46:203–206. Schwartz, D. E., M. Vecchi, A. Ronco, and K. Kaiser. Blood levels after administration of 7-chloror-1,3 dihydro-1-methyl5-phenyl-2H-1,4-benzodiazepine-2-one (diazepam) in various forms. Arzneim. Forsch. 1966;16:1109–1110. Scott, R. C., G. M. Besag, S. G. Boyd, D. Berry, and B. G. Neville. Buccal absorption of midazolam: Pharmacokinetics and pharmacodynamics. Epilepsia 1998;39:290–294. Scott, R. C., F. M. C. Besag, and B. G. R. Neville. Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: A randomized trial. Lancet 1999;353:623–626. Shaner, D. M., S. A. McCurdy, M. O. Herring, and A. J. Gabor. Treatment of status epilepticus: A prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin. Neurology 1988;38:202–207. Shellenberger, K., L. Groves, J. Franklin, and D. Carson. Diastat (diazepam rectal gel) therapy of acute epileptic seizures does not compromise respiratory function. Epilepsia 1997; 38(Suppl. 8):57–58. Smith, M. T., M. J. Eadie, and T. O. Brophy. The pharmacokinetics of midazolam in man. Eur. J. Clin. Pharmacol. 1981;19:271–278. Treiman, D. M., P. D. Meyers, N. Y. Walton, et al. A comparison of four treatments for generalized convulsive status epilepticus. N. Engl. J. Med. 1998;339:792–798. Uthman, B. M., B. J. Wilder, and R. E. Ramsay. Intramuscular use of fosphenytoin: An overview. Neurology 1996;46: S24–S28.
:
595
48
The Treatment of Status Epilepticus Patients in the Emergency Setting
. *
Introduction Status epilepticus (SE) is a neurologic emergency that requires prompt diagnosis and treatment to maximize patient outcome. The rapid termination of seizures and SE both in locations outside the hospital and in the emergency department (ED) prevents acute complications and minimizes the risk of long-term morbidity and mortality. This chapter discusses the optimal diagnostic and management strategies employed by paramedics, nurses, and emergency physicians for patients who are diagnosed with SE in the emergency setting, including a review of information from the American College of Emergency Physicians’ 2004 seizure clinical policy.
Epidemiology There are an estimated 2.5 million patients with epilepsy in the United States, a prevalence of about 6.6 per 1,000 Americans (41). Up to 28% of these epilepsy patients receive treatment in an ED annually (72). An additional 150,000 persons are newly diagnosed with seizures each year, most of whom will be initially managed in the ED (9). Recent studies show that 1%–2% of all ED visits are seizure related, suggesting that more than 8 million seizure patients were treated during the years 1997–2000 (44, 69, 87). SE occurs in 50,000–150,000 patients per year, with an estimated mortality of 5%–31% (28, 29, 40, 101). The incidence of SE in the United States is 41 per 100,000 population per year, with the greatest incidence being at the extremes of age (28). SE is seen in up to 7% of ED seizure patients, and most emergency physicians report treating five or more cases of SE per year (33, 44). The etiology of SE seen in the ED is similar to that of non-SE seizures, with
*Disclosure: Dr. Sloan has been an advisor to and is part of the speakers’ bureau for Eisai Inc., has provided consultation and lectures for Abbott Laboratories, and has been an advisor to King Pharmaceuticals.
alcohol, drugs, or low antiepileptic drug (AED) levels causing more than 50% of SE episodes treated (63). In 1995, 160,000 hospitalizations for seizures or SE occurred in nonfederal hospitals (6). Up to 38% of patients seen in the ED for seizures are admitted, with higher hospital admission rates occurring in adults and at tertiary care hospitals, where a greater number of patients with difficult to manage seizure disorders are treated (44, 87). Total direct costs for treating seizures in 1991 were estimated to be at least $609 million (9).
Status epilepticus in the out-of-hospital setting Seizures that occur outside of a medical facility need to be terminated quickly to minimize secondary injury and prevent the development of SE prior to hospital arrival. Seizures account for about 6% of all prehospital emergency medical services (EMS) encounters and are second only to acute alcohol intoxication as a cause of repetitive ambulance use (14). Seizure patients, because of this repetitive use of EMS care, account for 7% of patients with a medical complaint who refuse EMS transport to the hospital (67). The prehospital treatment of pediatric SE with diazepam reduces seizure duration by 47% and reduces the seizure recurrence rate by 32% (3). In adults, the use of benzodiazepines in the treatment of SE has been shown to be safe and superior to deferral of prehospital SE treatment, with lorazepam exhibiting a twofold greater effectiveness than diazepam in terminating SE (2). The data from this study, although important, perhaps cannot be generalized to all populations, because there was an observed 41%–79% rate of ongoing SE at the time of ED arrival. This rate is significantly different from the rate seen in most ED seizure patients, in whom seizures refractory to prehospital therapies occur in less than 5% of cases (44, 99). It has been shown that prehospital advanced life support care (intravenous [IV] line, oxygen, monitoring) may be necessary only in the 25% of EMS seizure patients with abnormal vital signs, serious comorbid conditions or neurologic
:
597
compromise, including the presence of SE (1). Spinal immobilization with a backboard or collar may not be an absolute requirement for the prehospital treatment of patients who are in SE, insofar as the incidence of fractures in seizure patients is only 0.2%, and no spinal fractures were noted in one series of 1,656 consecutive seizure patients (65). In patients who present in SE as a result of traumatic brain injury, however, such precautions may be prudent, in light of the greater likelihood of cervical spine injuries in this subset of SE patients. Most seizure/SE standing medical orders (SMOs) emphasize the need to control the patient’s airway, prevent secondary injury, and treat hypoglycemia and cardiac dysrhythmias when detected. Diazepam is the benzodiazepine most often used by paramedics in EMS SMOs because of its prior prehospital use, safety profile, the possibility of rectal administration, and the ability to store it without refrigeration. The Chicago EMS seizure SMOs recommend multiple 5 mg IV adult doses or 0.1 mg/kg diazepam doses in children in the prehospital setting (21). Rectal diazepam, dosed at 0.3–0.5 mg/kg, has been shown to be safe and effective in seizing children when IV diazepam cannot be given and is often listed as an SMO alternative when IV access is not available (33). Midazolam is now being used more often in EMS SMOs because it can be used effectively when administered either IV or intramuscularly (IM), precluding the need for diazepam, which must be given rectally when IV access is not possible (20). EMS systems that utilize midazolam recommend multiple 2 mg/kg adult doses and 0.1 mg/kg doses in children. Propofol, which has been shown to be effective in treating refractory SE, also has been used successfully to treat SE in one prehospital case series from Finland (55, 89). The prehospital use of midazolam and propofol may be limited, however, because they require refrigeration in the out-ofhospital environment, where temperatures can fluctuate greatly.
Emergency department status epilepticus I M SE etiology and duration are important predictors of patient outcome. Thirty-day mortality is 10-fold higher (32% vs. 2.7%) for patients who seize for longer than 60 minutes, a finding related both to high morbidity seizure causes such as anoxia and central nervous system (CNS) infection and to the irreversible CNS injury that occurs with sustained seizure activity (18, 27, 28). It is therefore the job of the ED team to terminate SE as quickly as possible, before complications develop. Although most generalized seizures are self-limited, it is impossible for the emergency physician to know prospectively which seizing patients will develop refractory seizures and SE. For that reason most emergency physicians elect to
598
treat seizures that last more than 1–2 minutes. Practically speaking, this corresponds to the amount of time it takes to recognize the generalized seizure and deliver a medication to the bedside for administration. Patients who arrive in the ED with seizures that have not responded to prehospital therapy are practically defined as having SE, since most prehospital times exceed 10–15 minutes. Most emergency physicians determine the initial vital signs, perform pulse oximetry, determine initial glucose concentrations, provide hemodynamic monitoring and support, and administer diazepam or lorazepam, glucose, and/or thiamine as part of the initial SE management, when indicated. C D Once the emergency physician has terminated the acute, generalized seizure, efforts are directed toward determining the SE etiology and the patient disposition. Although the ED diagnosis most often simply reads “seizure disorder” or “status epilepticus,” it may be helpful to the neurologist who will be providing ongoing care to document any prior seizure or SE episodes, the type and cause of the current seizure episode, the onset of the generalized seizure (primarily or secondarily generalized), and on what basis the diagnosis of SE was made (66). Many emergency physicians and neurologists now believe that any two seizures that occur without a lucid interval or a single seizure that lasts for longer than 5–10 minutes should be classified as SE (43, 62). This more aggressive SE definition shortens the seizure duration criteria from 30 minutes and is consistent with the treatment philosophy that prompts paramedics, nurses, and emergency physicians to treat seizures early, regardless of duration (38, 91, 104). Besides early, aggressive, and consistent treatment, SE patient outcome can be improved if two important types of SE that are easily overlooked can be diagnosed by the emergency physician. Complex partial SE may be present in patients with altered mental status or intermittent bizarre or unusual behaviors that can ultimately transition into a generalized tonic-clonic seizure. Another important type of SE is subtle SE, which is a late manifestation of prolonged generalized, convulsive SE (GCSE) and is suggestive of profound encephalopathy. This subtle SE often presents as coma with minimal or no focal motor activity, requiring prompt electroencephalography (EEG) diagnosis (35, 46, 49, 76). In two series, between 8% and 14% of comatose patients whose generalized seizures had been terminated clinically continued to have ictal discharges on EEG, suggesting persistent, subtle status epilepticus (31, 90). In the Veterans Affairs Status Epilepticus Cooperative Study, a similar proportion of patients whose GCSE had resolved at 20 minutes were noted to have EEG findings consistent with ongoing seizure activity (94). In the past, a patient with altered mental status and only a twitching eyelid or hand may have been considered less sick than a patient with GCSE because of the
absence of generalized tonic-clonic seizure activity. This now appears not to be the case. Patients who present with or who develop subtle SE as a late complication of GCSE are more refractory to initial therapies, resulting in a higher mortality rate, up to 65% at 30 days (7). D T Laboratory testing A complete laboratory evaluation, including AED levels and toxicology screening, is required in all SE patients, in light of the need to determine the cause of the prolonged seizure episode. Because a cardiac dysrhythmia often is a suspected cause or complication of SE, an ECG most often is obtained. In patients who seize for prolonged periods, up to 50% may present with a temperature above 100.5°, suggesting a CNS infection as the SE etiology, prompting a lumbar puncture to be considered. When a fever is present in an SE patient, a lumbar puncture should be performed unless a clear source of infection is identified and it is believed, based other clinical findings, that there is a very low likelihood of a CNS infection. Fever, leukocytosis, and cerebrospinal fluid pleocytosis may accompany SE even in the absence of a CNS infection, complicating the ability to determine the cause of a prolonged seizure (7). Emergency physicians most often will presumptively treat bacterial meningitis in this setting, such that the only treatment decision relates to the use of antiviral therapy for presumed viral meningitis or encephalitis. Neuroimaging Neuroimaging is indicated for seizures that are of new onset, are complicated by SE, and occur in patients with comorbid conditions that impart a greater risk of seizure-related complications (5). Non-contrast-enhanced computed tomopaphy (CT) of the head, performed in the ED, is a reasonable first imaging study, since it reliably identifies space-occupying lesions that are associated with significant mass effect and midline shift. A non-contrast-enhanced CT study also can identify other causes of SE, including trauma, hemorrhage, and cerebral ischemia or infarction. Contrast-enhanced CT often is necessary only when the initial non-contrast-enhanced CT suggests lesions that require further clarification with the aid of a contrast agent, such as a vascular abnormality or an isodense subdural hematoma. Magnetic resonance (MR) neuroimaging is deferred acutely in SE patients, because many MRI suites are too distant from the ED and because acute treatment and disposition decisions can most often be made without the supplemental information that MRI provides. MRI can be performed after ED disposition and is especially useful in patients with intractable epilepsy, since it can detect relevant findings twice as often as CT does (50% vs. 25%) (15). EEG monitoring The use of EEG in the ED has been limited, despite its ability to indicate nonconvulsive or subtle
SE in seizure patients with persistent alterations in mental status with or without the occurrence of a generalized tonicclonic seizure (46, 49, 76, 77). Only 12% of emergency physicians report having access to EEG in the ED, and only 15% have used it in the evaluation of suspected nonconvulsive SE (33). An EEG should be obtained whenever nonconvulsive or subtle SE is suspected, as well as in patients in whom neuromuscular paralysis, continuous midazolam, pentobarbital, or propofol infusions, or general anesthesia are used to manage the SE. It may also be of value in patient populations at high risk for subtle SE because of diffuse cerebral insult, including those with significant cerebral ischemia, post-SAH vasospasm, and traumatic brain injury (76, 97). Two-channel EEG monitors are available for use in ED cardiac monitors that include changeable modular units. Although limited, this technology could allow the emergency physician to quickly determine if persistent seizure activity is occurring, necessitating additional seizure therapies to be administered. At a minimum, even if an EEG cannot be done in the ED, it is reasonable for the emergency physician to arrange for EEG testing to be performed on SE patients who remain comatose at the time of ICU arrival so that subtle or nonconvulsive SE can be expeditiously diagnosed and treated (81). S E T There are many therapies available to assist the emergency physician in terminating SE. Although most seizure patients will respond to the first therapy provided (up to 80% of cases), patients in SE may require multiple treatments in order to stop the seizure activity (8, 25, 39, 60, 83, 93). In the VA study, SE patients who required more than one therapy in order to terminate seizure activity had a twofold greater mortality than those who responded favorably to the first drug administered (94). More than the use of specific drug or a specific drug order, the most important factors in SE termination are the rapid use of effective drugs in adequate doses, based on estimated weights and mg/kg requirements (104). Therapy can be optimized, therefore, by the use of guidelines that include rational, sequential drug therapies that are provided in adequate doses before any individual therapy is considered to be ineffective. The classes of therapeutics that can be utilized in the management of patients in SE are described next. Benzodiazepines The benzodiazepines, which work through enhancing the g-aminobutyric acid (GABA) inhibition of repetitive neuronal firing, are easy to administer and rapidly acting, with efficacy of at least 79% in the treatment of SE (60, 92, 93). Over the past 10 years, many emergency physicians and neurologists have advocated the use of lorazepam in the treatment of SE, since its longer half-life (13–15 hours)
:
599
affords extended protection against recurrent seizures and SE. Although no clinical trials in adults have definitively established the superiority of lorazepam over diazepam in SE, several studies have suggested that it may be more effective in treating SE, in both out-of-hospital and in-hospital settings (2, 60, 94). In children, lorazepam is less frequently associated with the need for intubation than is diazepam, so that lorazepam is often the recommended IV benzodiazepine in children with seizures or SE (22). In general, because patients with multiple or prolonged seizures are at greater risk for developing SE, it is reasonable to utilize lorazepam to treat most ED seizure patients, given its likely greater efficacy and longer duration of action. Although lorazepam protects against recurrent seizures and SE for a longer period of time than does diazepam, the prolonged mental status depression seen with lorazepam may prolong the ED observation period or require hospital admission to a higher level of care. If diazepam is preferred because of a briefer period of CNS depression and is used to terminate SE in the emergency setting, the emergency physician must quickly protect against recurrent seizures and SE with the use of longer-acting therapies that can be rapidly infused, such as fosphenytoin or valproate, both of which can be repeatedly infused during diazepam’s short period of effectiveness (20–40 minutes) (80, 102). Five alternative benzodiazepine administration routes are currently available or are being studied for clinical use: the IM, intranasal, or buccal administration of midazolam, the rectal administration of diazepam gel, and IM auto-injection of diazepam. These alternative benzodiazepine routes make it unnecessary to infuse benzodiazepines via the interosseous route in SE patients (98). Midazolam is the most reliably absorbed IM benzodiazepine for use in seizures and SE, and is effective within minutes of IM administration (59, 79). When IV access is yet to be established, IM midazolam is comparable to IV diazepam because it can be administered more rapidly (20). Intranasal midazolam has also been shown to be effective in treating seizures when no IV access is available (50). The buccal administration of liquid midazolam has been shown to be comparable in efficacy to rectal diazepam, and neither therapy has been shown to cause significant cardiorespiratory complications (82). Rectal diazepam has also been used successfully when IV access is not available (33). The rectal diazepam gel is formulated and prepackaged so that it can be given rectally without the need to draw up the diazepam in a tuberculin syringe or to tape or hold the buttocks together while the drug is being absorbed. This rectal preparation is quickly absorbed and effective in the termination and prevention of acute repetitive seizures and can be useful for home use, in the prehospital setting, or in instances when IV access is not available in the acute setting (19). Diazepam can also be
600
injected IM using an auto-injector system, which makes outof-hospital use possible. This system, however, is currently available only for military and EMS use and cannot be prescribed for individual use. Midazolam has most often been studied as a continuous IV infusion in the setting of refractory SE (56–58). In one series, the infusions of diazepam and midazolam were shown to be comparable in terminating SE, although midazolam was associated with a higher seizure recurrence rate and complication rate. Midazolam was also found to be comparable in efficacy to propofol and pentobarbital infusions, suggesting that the use of continuous benzodiazepine infusion in the ED is a reasonable treatment option (23, 24, 75). Phenytoins Extensive experience, limited respiratory depression, and minimal effect on consciousness have for many years made phenytoin an ideal AED for ED use (25). Phenytoin works though membrane Na+ and Ca+ channel stabilization, reducing the likelihood of repetitive neuronal firing. The standard phenytoin dose of 18–20 mg/kg is rarely exceeded in the treatment of SE, even though high dose (30 mg/kg) phenytoin therapy is recommended for SE that is refractory to standard phenytoin loading doses (104). Few emergency physicians utilize this treatment option, mostly owing to unawareness that the suggested therapeutic level can be exceeded in instances of refractory SE. Besides the cardiac and soft tissue toxicity associated with the diluents in parenteral phenytoin, the greatest limitation in its use in the ED is the fact that it is most often used once the seizure episode has been terminated or after benzodiazepines have been administered in the treatment of SE (10, 47, 88). Fosphenytoin, the water-soluble prodrug of phenytoin, is dosed in phenytoin equivalents, making dosing comparable to that of phenytoin (16). It can be infused more rapidly than phenytoin and with less pain, fewer injection site reactions, and fewer adverse events, and it can also be dosed IM with rapid attainment of a therapeutic phenytoin level (4, 32, 54, 64, 70, 80). Although therapeutic free phenytoin levels are achieved in a similar amount of time with rapid fosphenytoin and phenytoin infusions, the rapid infusion of fosphenytoin at 150 mg/min (in phenytoin equivalents) may still be of benefit in patients with SE refractory to initial benzodiazepine therapy (53, 100). The potential benefit of fosphenytoin is derived from the fact that a fosphenytoin infusion can be completed three times more quickly than can an equimolar infusion of phenytoin, allowing for the more rapid decision to infuse an additional seizure therapy if the SE has not been terminated (36). IV fosphenytoin therapy may also be useful when IV access is tenuous, when significant cardiac comorbidity exists, in children, and in the setting of SE, since comatose SE patients cannot effectively declare pain if extravasation of phenytoin were to occur.
Fosphenytoin IM injections as large as 20 mL can be given with only minimal pain or irritation, allowing for its parenteral use in SE patients in the prehospital setting (26, 37, 103). IM fosphenytoin could be used in the prehospital setting either after the initial seizure has been terminated by a benzodiazepine or in addition to a benzodiazepine in patients with refractory seizures and SE. If IM fosphenytoin, which provides a therapeutic level within 20–30 minutes, were used by paramedics in the out-of-hospital setting, phenytoin levels often would be therapeutic by the time of the initial ED evaluation, even in EMS systems with short transport times (26). As was the case with the benzodiazepines, the ability to deliver fosphenytoin IM should obviate the need to deliver a phenytoin intraosseously (51). Barbiturates The barbiturates are an effective class of AEDs that work through the enhancement of GABA inhibition of neuronal firing. Phenobarbital is effectively used to terminate SE and is an option for ED SE patients who fail to respond to therapeutic doses of a benzodiazepine or a phenytoin (71, 83, 94). Phenobarbital must be slowly dosed because of the risk of respiratory depression and hypotension, and as such it requires continued cardio-pulmonary monitoring. Refractory SE, which is operationally defined as SE nonresponsive to initial therapy with benzodiazepines, phenytoins, and/or phenobarbital, occurs in up to 22,000 patients per year (11, 12, 45). Pentobarbital is an effective barbiturate in refractory SE, but because it requires extensive airway, cardiovascular, and EEG monitoring, its use is mainly in the ICU setting (45, 95). Pentobarbital use in the ED is also less common because infusions of midazolam and propofol are more likely to be used in patients with refractory SE, owing to greater emergency physician familiarity with these therapies (24, 52, 89). Valproate Although the exact mechanism of valproate action in SE in unknown, it is thought to work via enhancing neuronal GABA inhibition. IV valproate may be optimal for ED SE patients who require rapid restoration of a therapeutic serum valproate level and for patients with new-onset SE, in whom valproate is preferred because of its ability to be infused quickly with minimal adverse cardiorespiratory effects (61, 68, 78, 86). IV valproate has been shown to be safe when infused in high doses (up to 44 mg/kg) and at high rates (up to 3 mg/kg/min in children or 6 mg/kg/min in adults, to a maximum infusion rate of 300 mg/min) (96, 102, 106). IV valproate has also been shown to be effective in a several case series of SE patients, including those with generalized convulsive, nonconvulsive, and myoclonic SE (17, 39, 42, 48, 84, 105). In general, IV valproate may be useful in patients who do not respond to a
benzodiazepine or a phenytoin, and it can be administered prior to the use of phenobarbital or continuous infusion seizure therapies. Propofol Propofol, like pentobarbital, is an anesthetic agent that provides burst suppression through GABA inhibition. It is provided to SE patients in the ED as a continuous infusion following the use of a benzodiazepine, a phenytoin, valproate, or phenobarbital (13, 74, 75, 89). Propofol, in fact, has been successfully used to treat SE in the prehospital setting in Finland (55). Propofol is potentially useful because of emergency physician familiarity with the drug, ease of administration, and because its effects resolve quickly if discontinued, which makes it possible to rapidly determine the clinical status of the patient, when necessary.
Status epilepticus patient management guidelines The Working Group on Status Epilepticus recommendations, which were published in 1993, provide a framework for optimizing the management of SE patients in the ED (104). These guidelines, which were developed as a minimum standard for SE management, outline the initial diagnostic and treatment paradigm in SE patients, including the time course over which the therapies should be provided. Important aspects of this treatment guideline for emergency physicians include the rapid implementation of an established treatment protocol, adequate mg/kg dosing, and the use of high-dose phenytoin in cases of nonresponsive SE. These guidelines are currently being updated in conjunction with the Epilepsy Foundation of America and several specialty societies, including the American Academy of Neurology, the American College of Emergency Physicians, and the American Epilepsy Society. The American College of Emergency Physicians has published a clinical policy that addresses critical issues in the evaluation and management of adult patients who present to the ED with seizures and SE (Table 48.1) (5a). This policy includes level C recommendations regarding the treatment of SE patients who fail to respond to initial therapy with a benzodiazepine and a phenytoin preparation. In these SE patients, the recommended possible treatment strategies include the IV administration of one of the following: highdose fosphenytoin or phenytoin, phenobarbital, valproate, or the continuous infusions of midazolam, pentobarbital, or propofol. Regarding the use of EEG monitoring in the ED, the policy again provides a level C recommendation that emergency EEG monitoring should be considered in patients suspected of being in nonconvulsive or subtle convulsive SE, and in patients who have received a long-acting paralytic agent or who are in a drug-induced coma. Both of these settings reflect a situation in which a prolonged
:
601
T 48.1 Recommendations from the 2004 ACEP clinical policy, “critical issues in the evaluation and management of adult patients presenting to the emergency department with seizures” What agent(s) should be administered to a patient in status epilepticus who continues to seize after having received a benzodiazepine and a phenytoin? Level A Recommendations. None specified. Level B Recommendations. None specified. Level C Recommendations. Administer one of the following agents intravenously: high-dose fosphenytoin or phenytoin, phenobarbital, valproic acid, or infusions of midazolam, pentobarbital, and/or propofol. When should EEG testing be performed in the ED? Level A Recommendations. None specified. Level B Recommendations. None specified. Level C Recommendations. Consider an emergency EEG in patients suspected of being in nonconvulsive status epilepticus or in subtle convulsive status epilepticus, and in patients who have received a long-acting paralytic, or who are in a druginduced coma.
T 48.2 A proposed timeline and activities in the management of status epilepticus patients seen in the emergency department Total Time
Emergency Department Activity
0–30 min
30–60 min 60–90 min 90–120 min
Address ABCs. Establish IV access and hemodynamic monitoring. Provide glucose and thiamine, as needed. Provide repeated benzodiazepine injections. Provide fosphenytoin or phenytoin up to 30 mg/kg. Provide phenobarbital and/or valproate infusions. Obtain CT neuroimaging and neurology consultation. Initiate a continuous infusion of midazolam, propofol, or pentobarbital. Arrange ICU disposition for EEG monitoring.
comatose state could be the result of ongoing ictal activity despite the absence of seizure-related motor manifestations. Optimal SE patient management includes an aggressive approach to identifying and terminating the SE episode in order to minimize the risk of irreversible hippocampus injury (Table 48.2). Within 30 minutes of ED arrival, the emergency physician should be able to manage the patient’s airway, provide hemodynamic monitoring and support, and deliver glucose, thiamine, and repeated benzodiazepine injections as indicated. Over the next 30 minutes, rapid IV fosphenytoin or phenytoin infusions up to 30 mg/kg can be initiated using 500–1,000 mg unit doses. During the next 30
602
minutes, infusions of phenobarbital or valproate can be provided, taking the total time to declaring the patient to be in refractory SE to be 90 minutes. At this point, continuous infusions of propofol, midazolam, or pentobarbital should be considered in consultation with a neurologist. Additionally, CT neuroimaging and disposition to the ICU arranged for ongoing EEG monitoring should be quickly arranged once refractory SE has been diagnosed. All of these treatment and diagnostic modalities should optimally be provided within 120–150 minutes of ED arrival in order to minimize morbidity and mortality in these critically ill SE patients.
Research horizons: SE in the emergency setting Despite the logistical difficulties associated with emergency research for disease states that require immediate therapy, such as SE, research that would further clarify the optimal management of SE patients in the emergency setting can be conducted because of the option to use an exception to informed consent. Four specific clinical questions could be addressed in controlled clinical trials: (1) What is the role of the various parenteral AEDs, such as midazolam, rectal diazepam gel, auto-injector diazepam, IM fosphenytoin, valproate, and propofol in the out-of-hospital treatment of SE? (2) How can the use of these and other therapeutics be optimally used in the ED to treat SE patients? (3) What is the best treatment strategy in SE patients who do not have IV access? (4) How can the use of EEG monitoring in the ED be optimized to increase the diagnosis of nonconvulsive SE and hopefully enhance SE patient outcome? If these questions can be successfully answered, clinical practice in the emergency setting will be enhanced, as will SE patient outcomes.
Conclusion Status epilepticus is a neurologic emergency that requires prompt and effective treatment by emergency care providers. Although the causes of SE in patients who present to the ED in SE vary greatly, the outcome can be enhanced for all of these SE patients by providing consistent care that follows a standardized protocol that requires the use of effective drugs in adequate doses. Future research will continue to establish how patient outcome can be improved through better use of current diagnostic treatment modalities and the development of new therapies that can be effectively used in the emergency setting. REFERENCES 1. Abarbanell, N. R. Prehospital seizure management: Triage criteria for the advanced life support rescue team. Am. J. Emerg. Med. 1993;11:210–212.
2. Alldredge, B. K., A. M. Gelb, S. M. Isaacs, M. D. Corry, F. Allen, S. Ulrich, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N. Engl. J. Med. 2001;345:631–637. 3. Alldredge, B. K., D. B. Wall, and D. M. Ferriero. Effect of prehospital treatment on the outcome of status epilepticus in children. Pediatr. Neurol. 1995;12:213–216. 4. Allen, F. H., J. W. Runge, and S. Legarda. Safety, tolerance, and pharmacokinetis of intravenous fosphenytoin (Cerebyx) in status epilepticus. Epilepsia 1993;36:90. 5. American College of Emergency Physicians, American Academy of Neurology, American Association of Neurological Surgeons, American Society of Neuroradiology. Practice parameter: Neuroimaging in the emergency patient presenting with seizure (summary statement). Ann. Emerg. Med. 1996; 27:114–118. 5a. American College of Emergency Physicians. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with seizures. Ann. Emerg. Med. 2004;43:605–625. 6. American Hospital Association. Acute care hospital discharge data. Chicago: Author, 1995. 7. Aminoff, M. J., and R. P. Simon. Status epilepticus: Causes, clinical features and consequences in 98 patients. Am. J. Med. 1980;69:657–666. 8. Appleton, R., A. Sweeney, I. Choonara, J. Robson, and E. Molyneux. Lorazepam versus diazepam in the acute treatment of epileptic seizures and status epilepticus. Dev. Med. Child Neurol. 1995;37:682–688. 9. Begley, C. E., J. F. Annegers, D. R. Lairson, T. F. Reynolds, and W. A. Hauser. Cost of epilepsy in the United States: A model based on incidence and prognosis. Epilepsia 1994;35: 1230–1243. 10. Binder, L., J. Trujillo, D. Parker, and A. Cuetter. Association of intravenous phenytoin toxicity with demographic, clinical, and dosing parameters. Am. J. Emerg. Med. 1996;14:398– 401. 11. Bleck, T. P. Refractory status epilepticus. Neurol. Chronicle 1992; 2:1–4. 12. Bleck, T. P. Refractory status epilepticus in 2001. Arch. Neurol. 2002;59:188–189. 13. Borgeat, A., O. H. Wilder-Smith, P. Jallon, and P. M. Suter. Propofol in the management of refractory status epilepticus: A case report. Intensive Care Med. 1994;20:148–149. 14. Brokaw, J., L. Olson, L. Fullerton, D. Tandberg, and D. Sklar. Repeated ambulance use by patients with acute alcohol intoxication, seizure disorder, and respiratory illness. Am. J. Emerg. Med. 1998;16:141–144. 15. Bronen, R. A. Epilepsy: The role of MR imaging. AJR Am. J. Roentgenol. 1992;159:1165–1174. 16. Browne, T. R., A. R. Kugler, and M. A. Eldon. Pharmacology and pharmacokinetics of fosphenytoin. Neurology 1996; 46(Suppl. 1):S3–S7. 17. Campistol, J., A. Fernandez, and J. Ortega. Status epilepticus in children: Experience with intravenous valproate. Update of treatment guidelines. Rev. Neurol. 1999;29:359–365. 18. Cascino, G. D. Generalized convulsive status epilepticus. Mayo Clin. Proc. 1996;71:787–792. 19. Cereghino, J. J., W. G. Mitchell, J. Murphy, R. L. Kriel, W. E. Rosenfeld, and E. Trevathan. Treating repetitive seizures with a rectal diazepam formulation: A randomized study. The North American Diastat Study Group. Neurology 1998;51:1274–1282.
20. Chamberlain, J. M., M. A. Altieri, C. Futterman, G. M. Young, D. W. Ochsenschlager, and Y. Waisman. A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Pediatr. Emerg. Care 1997;13:92–94. 21. Chicago Project Medical Directors’ Consortium. Chicago Fire Department Standing Medical Orders, 1998. 22. Chiulli, D. A., T. E. Terndrup, and R. K. Kanter. The influence of diazepam or lorazepam on the frequency of endotracheal intubation in childhood status epilepticus. J. Emerg. Med. 1991;9:13–17. 23. Claassen, J., L. J. Hirsch, R. G. Emerson, J. E. Bates, T. B. Thompson, and S. A. Mayer. Continuous EEG monitoring and midazolam infusion for refractory nonconvulsive status epilepticus. Neurology 2001;57:1036–1042. 24. Claassen, J., L. J. Hirsch, R. G. Emerson, and S. A. Mayer. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: A systematic review. Epilepsia 2002; 43:146–153. 25. Cloyd, J. C., R. J. Gumnit, and L. W. McLain, Jr. Status epilepticus: The role of intravenous phenytoin. JAMA 1980; 244:1479–1481. 26. Dean, J. C., K. R. J. Smith, B. A. Boucher, D. D. Michie, A. R. Kugler, and J. Marriott. Safety, tolerance, and pharmacokinetics of intramuscular fosphenytoin, a phenytoin prodrug, in neurosurgery patients. Epilepsia 1993;34(Suppl. 6):S111. 27. DeGiorgio, C. M., U. Tomiyasu, P. S. Gott, and D. M. Treiman. Hippocampal pyramidal cell loss in human status epilepticus. Epilepsia 1992;33:23–27. 28. DeLorenzo, R. J., W. A. Hauser, A. R. Towne, J. G. Boggs, J. M. Pellock, L. Penberthy, et al. A prospective, populationbased epidemiologic study of status epilepticus in Richmond, Virginia. Neurology 1996;46:1029–1035. 29. DeLorenzo, R. J., J. M. Pellock, A. R. Towne, and J. G. Boggs. Epidemiology of status epilepticus. J. Clin. Neurophysiol. 1995; 12:316–325. 30. DeLorenzo, R. J., A. R. Towne, J. M. Pellock, and D. Ko. Status epilepticus in children, adults, and the elderly. Epilepsia 1992;33(Suppl. 4):S15–S25. 31. DeLorenzo, R. J., E. J. Waterhouse, A. R. Towne, J. G. Boggs, D. Ko, G. A. DeLorenzo, et al. Persistent nonconvulsive status epilepticus after the control of convulsive status epilepticus. Epilepsia 1998;39:833–840. 32. DeToledo, J. C., M. R. Lowe, A. Rabinstein, and N. Villaviza. Cardiac arrest after fast intravenous infusion of phenytoin mistaken for fosphenytoin. Epilepsia 2001;42:288. 33. Dieckmann, R. A. Rectal diazepam for prehospital pediatric status epilepticus. Ann. Emerg. Med. 1994;23:216–224. 34. Emergency Medicine Physician Survey: The Management of Acute Seizure Emergencies. ACEP Satellite Symposium, San Francisco, Calif., 1997. 35. Faught, E. Seizure classification. Neurology 1994;44:1555. 36. Fischer, J. H., T. V. Patel, and P. A. Fischer. Fosphenytoin: Clinical pharmacokinetics and comparative advantages in the acute treatment of seizures. Clin. Pharmacokinet. 2003;42: 33–58. 37. Garnett, W. R., A. R. Kugler, K. A. O’Hara, S. M. Driscoll, and J. M. Pellock. Pharmacokinetics of fosphenytoin and phenytoin following intramuscular administration of fosphenytoin substituted for oral phenytoin in epileptic patients. Neurology 1995;45(Suppl. 4):A248. 38. Gastaut, H. Classification of status epilepticus. Adv. Neurol. 1983;34:15–35.
:
603
39. Giroud, M., D. Gras, A. Escousse, R. Dumas, and G. Venaud. Use of injectable valproic acid in status epilepticus. Drug Invest. 1993;5:154–159. 40. Hauser, W. A. Status epilepticus: Epidemiologic considerations. Neurology 1990;40:9–13. 41. Hauser, W. A., and L. T. Kurland. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia 1975;16:1–66. 42. Hovinga, C. A., M. F. Chicella, D. F. Rose, S. K. Eades, J. T. Dalton, and S. J. Phelps. Use of intravenous valproate in three pediatric patients with nonconvulsive or convulsive status epilepticus. Ann. Pharmacother. 1999;33:579–584. 43. Huff, J. S. Status epilepticus: A systematic approach to assessment, differential diagnosis, and outcome-effective management. Emerg. Med. Rep. 1997;18:137–148. 44. Huff, J. S., D. L. Morris, R. U. Kothari, and M. A. Gibbs. Emergency department management of patients with seizures: A multicenter study. Acad. Emerg. Med. 2001;8: 622–628. 45. Jagoda, A., and S. Riggio. Refractory status epilepticus in adults. Ann. Emerg. Med. 1993;22:1337–1348. 46. Jordan, K. G. Continuous EEG monitoring in the neuroscience intensive care unit and emergency department. J. Clin. Neurophysiol. 1999;16:14–39. 47. Jordan, K. G. Status epilepticus: A perspective from the neuroscience intensive care unit. Neurosurg. Clin. North Am. 1994;5: 671–686. 48. Kaplan, P. W. Intravenous valproate treatment of generalized nonconvulsive status epilepticus. Clin. Electroencephalogr. 1999; 30:1–4. 49. Kaplan, P. W. Nonconvulsive status epilepticus in the emergency room. Epilepsia 1996;37:643–650. 50. Kendall, J. L., M. Reynolds, and R. Goldberg. Intranasal midazolam in patients with status epilepticus. Ann. Emerg. Med. 1997;29:415–417. 51. Khan, T. M., N. Kissoon, M. Y. Hasan, V. Saldajeno, S. P. Murphy, and J. J. Lima. Comparison of plasma levels and pharmacodynamics after intraosseous and intravenous administration of fosphenytoin and phenytoin in piglets. Pediatr. Crit. Care Med. 2000;1:60–64. 52. Krishnamurthy, K. B., and F. W. Drislane. Relapse and survival after barbiturate anesthetic treatment of refractory status epilepticus. Epilepsia 1996;37:863–867. 53. Kugler, A. R., L. E. Knapp, and M. A. Eldon. Attainment of therapeutic phenytoin concentrations following administration of loading doses of fosphenytoin: A meta-analysis. Neurology 1996;46(Suppl.):A176. 54. Kugler, A. R., S. C. Olson, C. L. Webb, and T. M. Annesley. Cross-reactivity of fosphenytoin (Cerebyx) in 2 human phenytoin immunoassays. Pharm. Res. 1994;11:S102. 55. Kuisma, M., and R. O. Roine. Propofol in prehospital treatment of convulsive status epilepticus. Epilepsia 1995;36: 1241–1243. 56. Kumar, A., and T. P. Bleck. Intravenous midazolam for the treatment of refractory status epilepticus. Crit. Care Med. 1992; 20:483–488. 57. Labar, D. R., A. Ali, and J. Root. High-dose intravenous lorazepam for the treatment of refractory status epilepticus. Neurology 1994;44:1400–1403. 58. Lal, K. R., A. G. Raj, A. Chacko, R. Joshi, and E. M. Seif. Continuous midazolam infusion as treatment of status epilepticus. Arch. Dis. Child 1997;76:445–448.
604
59. LeDuc, T. J., W. E. Goellner, and N. el-Sanadi. Out-of-hospital midazolam for status epilepticus. Ann. Emerg. Med. 1996;28:377. 60. Leppik, I. E., A. T. Derivan, R. W. Homan, J. Walker, R. E. Ramsay, and B. Patrick. Double-blind study of lorazepam and diazepam in status epilepticus. JAMA 1983;249:1452–1454. 61. Limdi, N. A., and E. Faught. The safety of rapid valproic acid infusion. Epilepsia 2000;41:1342–1345. 62. Lowenstein, D. H. Status epilepticus. West. J. Med. 1998; 168:263. 63. Lowenstein, D. H., and B. K. Alldredge. Status epilepticus at an urban public hospital in the 1980s. Neurology 1993;43: 483–488. 64. Magar, R., A. Marchetti, J. Fischer, E. P. Sloan, and P. Fischer. A pharmacoeconomic evaluation of intravenous posphenytoin versus intravenous phenytoin in emergency departments. Clin. Ther. 1996;18:953–966. 65. McArthur, C. L., and C. T. Rooke. Are spinal precautions necessary in all seizure patients? Am. J. Emerg. Med. 1995;13: 512–513. 66. Mosewich, R. K., and E. L. So. A clinical approach to the classification of seizures and epileptic syndromes. Mayo Clin. Proc. 1996;71:405–414. 67. Moss, S. T., T. C. Chan, J. Buchanan, J. V. Dunford, and G. M. Vilke. Outcome study of prehospital patients signed out against medical advice by field paramedics. Ann. Emerg. Med. 1998;31:247–250. 68. Naritoku, D. K., and S. Mueed. Intravenous loading of valproate for epilepsy. Clin. Neuropharmacol. 1999;22:102– 106. 69. National Center for Health Statistics. The National Hospital Ambulatory Medical Care Survey (NHAMCS). Author, 2004:5–17. 70. Ogutu, B. R., C. R. Newton, S. N. Muchohi, G. O. Otieno, G. Edwards, W. M. Watkins, et al. Pharmacokinetics and clinical effects of phenytoin and fosphenytoin in children with severe malaria and status epilepticus. Br. J. Clin. Pharmacol. 2003;56:112–119. 71. Painter, M. J., M. S. Scher, A. D. Stein, S. Armatti, Z. Wang, J. C. Gardiner, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N. Engl. J. Med. 1999;341:485–489. 72. Pashko, S., A. McCord, and M. M. Sena. The cost of epilepsy and seizures in a cohort of Pennsylvania Medicaid patients. Med. Interface 1993;Nov.:79–84. 73. Patrias, J. M., J. R. Gates, and F. J. Ritter. Safety of intravenous valproate. Epilepsia 1993;34(Suppl. 6):111. 74. Pitt-Miller, P. L., B. J. Elcock, and M. Maharaj. The management of status epilepticus with a continuous propofol infusion. Anesth. Analg. 1994;78:1193–1194. 75. Prasad, A., B. B. Worrall, E. H. Bertram, and T. P. Bleck. Propofol and midazolam in the treatment of refractory status epilepticus. Epilepsia 2001;42:380–386. 76. Privitera, M., M. Hoffman, J. L. Moore, and D. Jester. EEG detection of nontonic-clonic status epilepticus in patients with altered consciousness. Epilepsy Res. 1994;18:155–166. 77. Privitera, M. D., and R. H. Strawsburg. Electroencephalographic monitoring in the emergency department. Emerg. Med. Clin. North Am. 1994;12:1089–1100. 78. Pryor, F. M., B. Gidal, R. E. Ramsay, J. DeToledo, and R. O. Morgan. Fosphenytoin: Pharmacokinetics and tolerance of intramuscular loading doses. Epilepsia 2001;42:245–250.
79. Raines, A., T. R. Henderson, E. A. Swinyard, and K. L. Dretchen. Comparison of midazolam and diazepam by the intramuscular route for the control of seizures in a mouse model of status epilepticus. Epilepsia 1990;31:313–317. 80. Ramsay, R. E., and J. DeToledo. Intravenous administration of fosphenytoin: Options for the management of seizures. Neurology 1996;46:S17–S19. 81. Ruegg, S. J., and M. A. Dichter. Diagnosis and treatment of nonconvulsive status epilepticus in an intensive care unit setting. Curr. Treat. Options Neurol. 2003;5:93–110. 82. Scott, R. C., F. M. Besag, and B. G. Neville. Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: A randomised trial. Lancet 1999;353:623–626. 83. Shaner, D. M., S. A. McCurdy, M. O. Herring, and A. J. Gabor. Treatment of status epilepticus: A prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin. Neurology 1988;38:202–207. 84. Sheth, R. D., and B. E. Gidal. Intravenous valproic acid for myoclonic status epilepticus. Neurology 2000;54:1201. 85. Singhi, S., A. Murthy, P. Singhi, and M. Jayashree. Continuous midazolam versus diazepam infusion for refractory convulsive status epilepticus. J. Child. Neurol. 2002;17:106– 110. 86. Sinha, S., and D. K. Naritoku. Intravenous valproate is well tolerated in unstable patients with status epilepticus. Neurology 2000;55:722–724. 87. Sloan, E. P., J. C. Silva, and M. S. Rosenberg. Outcome in adult seizure patients treated in the emergency setting. Ann. Emerg. Med. 1999;34:S101. 88. Spengler, R. F., J. B. Arrowsmith, D. J. Kilarski, C. Buchanan, L. Von Behren, and D. R. Graham. Severe soft-tissue injury following intravenous infusion of phenytoin: Patient and drug administration risk factors. Arch. Intern. Med. 1988;148: 1329–1333. 89. Stecker, M. M., T. H. Kramer, E. C. Raps, R. O’Meeghan, E. Dulaney, and D. J. Skaar. Treatment of refractory status epilepticus with propofol: Clinical and pharmacokinetic findings. Epilepsia 1998;39:18–26. 90. Towne, A. R., E. J. Waterhouse, J. G. Boggs, L. K. Garnett, A. J. Brown, J. R. Smith, Jr., et al. Prevalence of nonconvulsive status epilepticus in comatose patients. Neurology 2000;54: 340–345. 91. Treiman, D. M. Generalized convulsive status epilepticus in the adult. Epilepsia 1993;34(Suppl. 1):S2–S11. 92. Treiman, D. M. Pharmacokinetics and clinical use of benzodiazepines in the management of status epilepticus. Epilepsia 1989;30(Suppl. 2):S4–S10. 93. Treiman, D. M. The role of benzodiazepines in the management of status epilepticus. Neurology 1990;40:32–42. 94. Treiman, D. M., P. D. Meyers, N. Y. Walton, J. F. Collins, C. Colling, A. J. Rowan, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N. Engl. J. Med. 1998;339:792–798. 95. Van Ness, P. C. Pentobarbital and EEG burst suppression in treatment of status epilepticus refractory to benzodiazepines and phenytoin. Epilepsia 1990;31:61–67. 96. Venkataraman, V., and J. W. Wheless. Safety of rapid intravenous infusion of valproate loading doses in epilepsy patients. Epilepsy Res. 1999;35:147–153. 97. Vespa, P. M., M. R. Nuwer, V. Nenov, E. Ronne-Engstrom, D. A. Hovda, M. Bergsneider, et al. Increased incidence and
98.
99.
100.
101.
102.
103.
104.
105.
106.
impact of nonconvulsive and convulsive seizures after traumatic brain injury as detected by continuous electroencephalographic monitoring. J. Neurosurg. 1999;91:750–760. Walsh-Kelly, C. M., R. J. Berens, P. W. Glaeser, and J. D. Losek. Intraosseous infusion of phenytoin. Am. J. Emerg. Med. 1986;4:523–524. Wang, R. S., E. P. Sloan, M. Koenigsberg, L. Dorsi, and M. Rosenberg. Seizure therapy in the prehospital setting. Prehosp. Emerg. Care 1998;2:231. Wang, X., and P. N. Patsalos. A comparison of central brain (cerebrospinal and extracellular fluids) and peripheral blood kinetics of phenytoin after intravenous phenytoin and fosphenytoin. Seizure 2003;12:330–336. Waterhouse, E. J., L. K. Garnett, A. R. Towne, L. D. Morton, T. Barnes, D. Ko, et al. Prospective population-based study of intermittent and continuous convulsive status epilepticus in Richmond, Virginia. Epilepsia 1999;40:752–758. Wheless, J., and V. Venkataraman. Safety of high intravenous valproate loading doses in epilepsy patients. J. Epilepsy 1998;11:319–324. Wilder, B. J., K. Campbell, R. E. Ramsay, W. R. Garnett, J. M. Pellock, S. A. Henkin, et al. Safety and tolerance of multiple doses of intramuscular fosphenytoin substituted for oral phenytoin in epilepsy or neurosurgery. Arch. Neurol. 1996;53:764–768. Working Group on Status Epilepticus. Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of America’s Working Group on Status Epilepticus. JAMA 1993;270:854–859. Yamamoto, L. G., and G. K. Yim. The role of intravenous valproic acid in status epilepticus. Pediatr. Emerg. Care 2000;16: 296–298. Yu, K. T., S. Mills, N. Thompson, and C. Cunanan. Safety and efficacy of intravenous valproate in pediatric status epilepticus and acute repetitive seizures. Epilepsia 2003;44: 724–726.
:
605
49
Critical Care of the Status Epilepticus Patient
. S (SE) represents one of the defining disorders of critical care. The patient in SE often requires endotracheal intubation, mechanical ventilation, nutritional support, and prophylaxis or treatment of the numerous complications that can befall the critically ill. Anticonvulsant therapy for SE, especially refractory SE, requires knowledge and experience with drugs seldom used by neurologists outside of this disorder, with a substantial risk of adverse effects and drug interactions (5). Finally, the concern and distress of family members and friends of a patient who may need days or weeks of pharmacologic coma, with an uncertain prognosis, are important to consider. The modern era of critical care dates to the poliomyelitis epidemics of the 1950s, during which physicians learned to provide prolonged mechanical ventilation. Patients with SE often need mechanical ventilation, hemodynamic support, and the rest of the accoutrements of the intensive care unit. This chapter addresses the critical care aspects of the management of patients with SE, as well as the pharmacologic management of patients with refractory SE.
Airway management As with any critically ill patient, the initial approach to the patient in SE involves the basics of airway, respiration, and circulation. Often, the best way to obtain control of the airway is to terminate SE pharmacologically; this should proceed concurrently with the elements of life support. Many patients will need intubation for airway protection and to maintain ventilation during SE treatment. The choice of techniques and medications for intubation depends on several factors; in SE patients, the most important ones include the possibilities of increased intracranial pressure (ICP) and of neuromuscular dysfunction. The act of laryngoscopy and intubation raises the ICP, which is especially problematic in patients with preexisting intracranial lesions. Premedication with intravenous (IV) lidocaine or thiopental, or probably with etomidate, blunts the rise in ICP and thereby lessens the risks of intubation (4, 25). All three of these drugs probably lower cerebral oxygen demand transiently, resulting in an appropriate decrease in cerebral blood flow; thus, ICP falls without producing an
oxygen deficit. Thiopental (1.5 mg/kg) and etomidate (0.3 mg/kg) are also useful, if only briefly effective, anticonvulsants, and will often cause convulsive activity to cease for several minutes; this facilitates intubation. Lidocaine (1 mg/kg) has been suggested as an anticonvulsant as well (11), but in my experience it has not been effective for this purpose. However, lidocaine and etomidate are useful agents to consider in the patient with hypotension or marginal cardiovascular reserve, as they are less likely to cause hypotension than thiopental. Topical or regional anesthesia of the larynx with lidocaine does not confer the same ICP control advantage as an IV dose. A single dose of etomidate is well tolerated, but because of its adrenal suppressant effects it should not be used as a continuous infusion. Whether to employ neuromuscular junction (NMJ) blockade in a patient with SE remains the subject of debate. Those favoring NMJ blockade suggest that complete relaxation increases the likelihood of successful intubation on the first attempt. The counter argument suggests that NMJ blockade allows SE to continue or recur while the patient is paralyzed (and thus unable to manifest seizure activity, except via the autonomic responses of pupillary dilation and tachycardia), and also leaves the patient in whom intubation is unsuccessful without spontaneous respiratory capabilities for the duration of the blockade. It is my preference to use NMJ blockade. In any case, once one is committed to intubating the patient, appropriate personnel and equipment should be available to accomplish this maneuver expeditiously, to maintain the patient’s airway by proper head and jaw positioning, and to provide ventilation via a bag-valvemask system, regardless of whether NMJ blockade is employed. The choice of the NMJ blocking agent is also contentious. Some prefer to use succinylcholine (1.5 mg/kg), since it provides the shortest latency to intubating conditions (60–90 seconds) and the briefest recovery time (5–8 minutes) of the currently available agents. However, as a depolarizing agent, it carries the risk of profound, sometimes fatal hyperkalemia in patients who have dysfunction of the neuromuscular system, including spinal cord injuries and sometimes hemiparesis of cerebral origin. Thus, unless the patient was known to be neurologically intact until the
:
607
present episode of SE, a different drug should be considered. With the withdrawal of rapacuronium from the market, the major choices for a nondepolarizing NMJ blocking agent include vecuronium, rocuronium, and cisatracurium. Vecuronium (0.1 mg/kg), the least expensive member of this class, has a somewhat longer latency than succinylcholine and lasts about 20–30 minutes. During this time physical findings in the patient cannot be used as evidence regarding the presence of seizure activity; thus, unless electroencephalographic (EEG) monitoring is in progress, one must assume that the patient is continuing to seize despite the lack of motor activity. Although these drugs are usually considered to be cleared quickly in patients with normal renal function, there is considerable variability in the normal population in the rate of excretion (10). High-dose rocuronium (0.6 mg/kg) has a latency similar to that of succinylcholine, but its duration of blockade at this dose is about 30–60 minutes. In contrast to the other NMJ blocking agents discussed here, cisatracurium (0.2 mg/kg, latency 2–4 minutes, duration 30–60 minutes) does not depend on renal (or hepatic) clearance mechanisms. However, it does have a potentially epileptogenic metabolite (laudanosine), which is probably of minimal import in humans (20). The end of NMJ blockade is typically apparent from the return of spontaneous respiratory efforts and other muscle movements, unless they have been suppressed by the medications being used to terminate SE. One can also use a train-of-four nerve stimulator to determine the extent of residual blockade. To speed recovery from these drugs, consider using neostigmine (50–70 mg/kg), usually given once two twitches are present on train-of-four stimulation. This will permit examination of the patient sooner; however, its duration of action is shorter than that at some of the NMJ blockers, so caution should be used when extubating patients whose blocking agents were reversed with neostigmine, as its effect may wane before the patient is strong enough for airway protection and breathing. The choice of a route for intubation is similarly contentious. I favor orotracheal intubation under direct laryngoscopy, even though it often involves NMJ blockade. Blind nasal intubation has been proffered as an alternative that may not require NMJ blocking agents. The risks of sinusitis, and secondarily nosocomial pneumonia, as a consequence of nasal intubation argue against its use (33).
Mechanical ventilation The SE patient who is intubated will require mechanical ventilation at least for the duration of the NMJ blockade and the sedative effects of the anticonvulsants used. During this period, the patient may be maintained on an assist/control or SIMV mode with 8–10 mL/kg tidal volume at a rate of
608
12 breaths per minute and 5 cm H2O PEEP. The current trend toward using lower tidal volumes for patients with acute lung injury (8) is not applicable to the SE patient without severe lung disease. As the effects of medications wear off, the patient in whom SE has been terminated may be weaned either with pressure support ventilation (with progressively decreasing pressures) or with SIMV with trials of spontaneous breathing. I prefer the former, but it is probably more important to have a protocol that directs weaning than it is to use choose a particular mode of ventilatory support.
Initial circulatory support and basic critical care management Placing the patient on mechanical ventilation involves a reversal of the usual negative intrathoracic pressure— atmospheric pressure gradient of spontaneous ventilation. The positive intrathoracic pressure developed throughout the respiratory cycle decreased venous return, lowering cardiac output and sometimes producing hypotension. Most of the drugs used to control SE have potentially deleterious cardiovascular effects. Diminution of preload is a common side effect and is amplified by positive intrathoracic pressure. Many of the antistatus drugs are also negative inotropes, further impairing cardiac output and blood pressure. Unless there is concern for preexisting volume overload or heart failure, one should consider giving normal saline as a bolus (5–10 mL/kg) near the time of intubation to help counteract the combined effects of positive pressure ventilation and drugs on preload. Some patients will need more intravascular volume expansion, and inotropic or vasopressor support as well. Patients in whom SE is rapidly controlled seldom need prolonged mechanical ventilation or circulatory support. However, those with refractory SE may require days or weeks of mechanical ventilation. These patients require careful attention to nutrition (preferably enteral, started as soon as possible), prophylaxis against deep venous thrombosis, body positioning to decrease the risk of aspiration (30–45 degree elevation of the trunk with reference to the floor; simply elevating the head of the bed to a given angle does not mean that the patient is actually elevated to that angle) (15), and passive physical therapy. If the cause of the refractory SE involves a process that increases ICP, then one should consider measuring that pressure and attempting to keep the cerebral perfusion pressure (CPP) greater than 60 mm Hg. CPP is the difference between mean arterial pressure and ICP. In this circumstance, ICP is usually measured with a parenchymal monitor or (if needed for some other purpose) a ventriculostomy. If pharmacologic blood pressure augmentation is required, an arterial line is typically placed to get a reliable, continuous monitor so that
the lowest dose of the agents chosen can be employed. If the ICP cannot be measured continuously, a single measurement from the opening pressure of a lumbar puncture can be used as an estimate. The details of pharmacologic support of blood pressure and cardiac function are beyond the scope of this chapter; only the broad outline can be sketched here. To the extent that positive pressure ventilation and medications have decreased right ventricular preload, volume loading (usually with normal saline) is the appropriate response. To counteract arterial vasodilation, vasopressor agents (norepinephrine and epinephrine) are used. If diminished cardiac contractility is the major problem, then dobutamine, epinephrine, or smaller doses of dopamine are typically employed.
Drug therapy for refractory SE From the moment of presentation or initial diagnosis of SE, therapy should proceed along three fronts: termination of SE, prevention of its recurrence, and management of its complications. T SE Many different approaches to the termination of SE have been advocated. However, the Veterans Affairs Cooperative Trial on Status Epilepticus provides the best evidence to guide therapy of generalized convulsive SE (40). Patients enrolled in this study were initially classified as having “overt” and “subtle” status, depending on the nature of their convulsive activity. For those classified as having overt SE, lorazepam was most likely to terminate SE. Phenobarbital was the next most likely, diazepam followed by phenytoin was next, and phenytoin alone was least likely. However, the only statistically significant difference was between lorazepam and phenytoin. The doses used and their success rates are summarized in Table 49.1. For subtle SE, none of these conventional antiseizure agents was particularly effective. In this trial, SE had to be terminated within 20 minutes and had to not recur within 60 minutes from the start of the
T 49.1 Summary of VA Status Epilepticus Cooperative Study: Main results
Regimen
Dose(s) (mg/kg)
% Overt SE Cases Terminated
% Subtle SE Cases Terminated
Lorazepam Phenobarbital Diazepam/phenytoin Phenytoin
0.10 15 0.15/15 16
65 58 56 43
18 24 8 8
infusion. Success required both clinical and EEG cessation of seizure. The four regimens did not differ statistically in respiratory or cardiovascular adverse effects or in the incidence of sedation. The choice of agents is probably of secondary import compared with the alacrity of treatment. If therapy was initiated during the first EEG stage of SE (discrete seizures), the aggregate response rate (all drugs averaged over all patients) for overt SE was 75%. During the next stage (waxing and waning seizure activity) it was 30%; for a continuous seizure pattern, 24%; for seizures interrupted by brief suppressions, 8%; and for a background of periodic discharges, 7%. This steep decline in efficacy with time argues for the most expeditious treatment possible. Other parenteral agents have been advocated for the initial attempt to terminate SE. For example, a few case series suggest the utility of sodium valproate (20–30 mg/kg) (48). At this time, however, there is no direct comparison of the efficacy of valproate to that of these other agents. Since none of these agents is overwhelmingly effective in terminating SE, the treating physician must be familiar with a selection of other strategies. In the past, a common choice was the use of a second conventional anticonvulsant if the first failed. However, preliminary data from the VA cooperative trial, presented in abstract form, indicate that this is an ineffective strategy (41). The aggregate response rate to all first agents was 56%. The order of subsequent agents was not randomized (so that a patient who had received phenytoin would not receive another dose of this drug) but was predetermined. The aggregate response rate to all second agents was only 7%, and to all third agents, 2%. Data for each arm are presented in Table 49.2. Patients in subtle SE again fared poorly, with 15% responding to the first agent, 3% to the second, and 5% to the third. Again, this argues that the speed of treatment is more important than the particular agent chosen. R SE The definition of refractory SE varies among studies. Most contemporary authors require failure of a benzodiazepine and phenytoin; others require failure of a third agent, usually phenobarbital. The data suggest that failure of any reasonable first agent portends a low likelihood of response to other conventional agents. Thus, one might legitimately define refractory SE as failure to respond to one accepted anti-SE drug. The incidence of refractory SE in the United States appears to have declined over the past decade (43). Although it is tempting to attribute this decline to dissemination of the data from the VA cooperative trial, the actual reason is not known. It is also tempting to credit an increase in prehospital treatment (2). However, refractory SE continues to account for one-fifth to one-third of all SE cases, or up to
:
609
T 49.2 Response rates for subsequent agents in each arm of the VA Status Epilepticus Cooperative Study (overt SE patients only) Drug
Response Rate (%)
A. Initial drug: lorazepam Lorazepam Phenytoin Phenobarbital
65 7 2
B. Initial drug: phenobarbital Phenobarbital Phenytoin Lorazepam
58 3 2
C. Initial drugs: diazepam/phenytoin Diazepam/phenytoin Lorazepam Phenobarbital
56 3 2
D. Initial drug: phenytoin Phenytoin Lorazepam Phenobarbital
44 14 3
Note: Rates do not sum to 100% because not all patients responded.
65,000 cases per year. It is thus incumbent on everyone who treats SE to have a plan for terminating refractory SE, including transfer to another facility if more sophisticated services should become necessary. The majority of drugs used to terminate refractory SE are GABAA agonists given in exceptionally large doses (22). They include the barbiturates, benzodiazepines, and propofol. Barbiturates Barbiturates are commonly used for the treatment of refractory SE despite the high rates of associated hypotension (18). Barbiturates in general prolong the open time of the chloride channel coupled to the GABAA receptor without affecting the affinity of the receptor for GABA (21). The anesthetic barbiturates may have an advantage over phenobarbital in that they are direct GABA mimetics at very high serum concentrations (47). Although there are no data to prove greater efficacy of one barbiturate over another in the treatment of refractory SE, pentobarbital is often used; it has a shorter half-life than phenobarbital and is less cardiotoxic than thiopental (28). Of 40 patients with refractory SE who were treated with pentobarbital, 39 achieved clinical and electrographic control of seizures (18). Twenty-six were successfully treated; nine had relapses and five died during initial treatment. Although pentobarbital administration was delayed by more than 12 hours after seizure onset in 21 patients, the delay was not associated with
610
a worse outcome. Despite the long half-life, tapering pentobarbital appears to be associated with fewer relapses than does abrupt withdrawal. Although the EEG goal of treatment has not been established with certainty, those treated with pentobarbital with flat EEGs had slightly better outcomes than those with a burst-suppression EEG pattern (17). Hypotension was not associated with the dose of pentobarbital or the degree of EEG suppression. Measurement of serum concentrations does not appear to be useful. Pentobarbital can be detected in serum up to 8 days after administration, and patients can develop reversible side effects, including diffuse weakness, confusion, and ataxia, after recovering consciousness (28, 32). A common recommendation is to administer a loading dose of 12–15 mg/kg over 1 hour, followed by an infusion of 0.5–2 mg/kg/hr. Yaffe and colleagues assessed the prognosis of seventeen patients with refractory SE who were treated with pentobarbital for 13.5 hours to 29 days (44). Approximately half died of apparent complications of the underlying disorder responsible for the refractory SE. Of the eight who survived, two had a severe decline in neurologic status. The other six had no or minimal change from neurologic baseline at hospital discharge. In a series of 10 patients with refractory SE treated with thiopental, successful seizure control was achieved in all (29). Four needed vasopressors and all needed extra IV fluids to maintain blood pressure. The protocol used included thiopental, 5 mg/kg in 1–2 mg/kg boluses, until a burstsuppression pattern was achieved, followed by an infusion of 5 mg/kg/hr. A wide range of doses was required to achieve burst suppression. ICU care was prolonged due to sedation from the thiopental. Some advocate the addition of phenobarbital to the treatment of those patients with SE that remains refractory to treatment (24). Because there is apparently no ceiling to the anticonvulsant effect of barbiturates, increasing doses can be used. Despite high doses, tolerance develops to their respiratory depressant action and sedative properties. Very high doses of pentobarbital and phenobarbital may be accompanied by a higher risk of propylene glycol toxicity, including metabolic acidosis, because their vehicles contain propylene glycol (46). Midazolam Midazolam is a short-acting benzodiazepine that is popular for the treatment of SE. It enhances chloride entry through the channel coupled to the GABAA receptor by increasing the affinity of the receptor for GABA. In seven patients in whom lorazepam, diazepam, and phenytoin all failed to suppress seizure activity, cessation of clinical seizures or electrographic seizures occurred in all after initiation of midazolam (19). Only one patient developed hypotension. Because of its short duration of action, midazolam may
decrease the time required in the intensive care setting after discontinuation of use, although even in those without renal or hepatic function it may have a prolonged effect after sustained infusion (26). This effect may be due to accumulation in adipose tissue. The effective dose required to treat refractory SE varies widely. We use a bolus of 0.2 mg/kg, followed by an infusion of 0.04–4.0 mg/kg/hr; a similar dose was used in a study from Columbia University (9). In a small retrospective analysis, midazolam and propofol were found to have similarly high rates of seizure cessation, but those treated with midazolam had a lower mortality rate that was not statistically significant (31). In a retrospective analysis of 33 episodes of refractory SE (17 convulsive and 16 nonconvulsive SE cases at onset), continuous midazolam infusions led to seizure cessation within 1 hour of treatment initiation in 82%, without recurrence between 1 and 6 hours (9). Of the 33 episodes, 18% could not eventually be controlled with the infusion. Propofol Propofol is an IV general anesthetic agent that has been used to treat refractory SE. As with benzodiazepines and barbiturates, it enhances GABAergic transmission through the GABAA receptor, and in addition has effects on other receptor systems and cell membranes that may be relevant to its antistatus effect (3, 39). In a series comparing eight patients treated with propofol with eight treated with barbiturates (primarily pentobarbital), control of seizures was attained in five of the propofol-treated patients and nine of 11 treatments with the barbiturate (after propofol failed, barbiturates were used) (37). The mean time to seizure control in the patients who responded to propofol was 2.6 minutes; the mean time in those who responded to barbiturates was 123 minutes. Propofol concentrations decreased rapidly even after prolonged infusion. Consequently, when propofol was abruptly stopped, seizures recurred more commonly than when it was slowly discontinued. The protocol involved a bolus of 1–2 mg/kg, followed by a maintenance dosage of 1–15 mg/kg/hr. This protocol yielded plasma levels greater than that required for sedation but lower than that needed for maintenance of general anesthesia with propofol alone. Propofol has the advantages of rapid onset and offset. It causes cardiosuppression and hypotension, and can lead to metabolic acidosis. Its lipid vehicle must be factored into the patient’s nutrition. The safety of high doses for long periods is uncertain in pediatric ICU practice because of occasional hypoxia and rhabdomyolysis (14). Inhaled anesthetics Kofke et al. reported the use of isoflurane in treating refractory SE in nine patients (16). Each had been unsuccessfully treated with benzodiazepines, phenytoin, and phenobarbital before general anesthesia was initiated. There was at least an attenuation of seizure activity in all patients.
A burst-suppression pattern was the most common EEG pattern attained. All required IV fluids or vasopressors to maintain an adequate mean arterial pressure. Of the nine patients, six died; two had multiple organ failure. Prolonged use can be associated with release of fluoride ions, which in this series did not reach nephrotoxic levels. There may be less of an increase in cerebral blood flow and associated increased ICP with isoflurane than with halothane. Isoflurane also carries a lower risk of hepatotoxicity (23). Desflurane is pharmacodynamically and pharmacokinetically similar to isoflurane but is probably even more resistant to biotransformation and is a reasonable alternative to isoflurane (34). All of the volatile anesthetics share the difficulties of anesthetic gas administration outside of the operating room, including the need for a gas scavenging system. Etomidate Yeoman and colleagues treated eight refractory SE patients with etomidate (45). Each had been seizing for longer than 6 hours despite several anticonvulsants. Etomidate terminated seizures in all patients. There was minimal hypotension on initiation of treatment, but five patients had episodes of hypotension during maintenance infusions. Of the eight patients treated, two died, four returned to their premorbid conditions, and two were debilitated at 6 months. Steroid replacement must be used with etomidate, as this drug reversibly inhibits cortisol synthesis. Ketamine Ketamine is metabolized by the cytochrome P450 system to its active metabolite nor-ketamine. Unlike most general anesthetic agents, ketamine does not have a significant effect on the GABAA receptor. Instead, it inhibits the NMDA receptor by binding to its phencyclidine site, making it a good candidate when GABAergic drugs have failed. Another important distinction is that it is associated with a rise in blood pressure, heart rate, and cardiac output, which can be useful when treating a patient in refractory SE. In an animal model, it was useful in controlling seizures after an hour, but not earlier, supporting the theory that early in SE, lack of inhibition predominates, but later there is an excess of excitatory amino acid transmission (7). In one case report, ketamine was used to control seizures in a 13-year-old who was unable to be weaned from pentobarbital after coma was induced, despite trials of lorazepam, valproate, lidocaine, and propofol (35). In a retrospectively collected case series of seven patients with refractory SE, two had seizure cessation after a loading dose and another three patients gained seizure control with an infusion (6). In this series, loading doses were 0.9–3 mg/kg, and infusions varied from 0.3 to 5.8 mg/kg/hr. Lidocaine Although at higher doses lidocaine may be associated with seizures, lower-dose lidocaine infusions can be
:
611
used to treat refractory SE. A loading dose of 1 mg/kg, followed by an infusion of 1 mg/min, has been reported to control refractory SE (11). Of four patients in another series, three had immediate cessation of seizures after a single bolus of 100 mg of IV lidocaine (1). Repeat boluses followed by infusions have been used with relapses (30). The mechanism of action of lidocaine may be membrane stabilization and the limitation of neuronal recruitment secondary to lower extracellular potassium (1). Lidocaine is not associated with the same risk of hypotension and sedation as many of the other choices for refractory SE. However, brain concentrations of lidocaine are increased by seizures, raising concern for lidocaine toxicity, which may exacerbate seizures (36). Lidocaine increased seizures and the mortality associated with cocaine in experimental animals (12). Valproate In a series of 41 children (neonates to 16 years) with refractory SE, IV valproate stopped clinical and electrographic seizures in 78% (42). The treatment consisted of a 20–40 mg/kg loading dose for 1–5 minutes, followed by an infusion of 5 mg/kg/hr. Valproate concentrations 4–6 minutes after the loading dose suggested that those with higher initial levels were more likely to respond. The most successful loading doses were between 30 and 40 mg/kg. IV valproate was well tolerated, without the hypotension and cardiac toxicity of many other treatments for refractory SE. In a retrospective review of 18 children treated with parenteral valproate, all had resolution of SE with resumption of mental state within an hour of treatment (48). Topiramate Due to its several likely modes of action, topiramate is a good candidate for the treatment of refractory SE. Additionally, in animal models topiramate attenuated hippocampal damage in experimental SE (27). It must be crushed, mixed with water, and administered through a gastric tube. Towne and colleagues successfully treated six patients with 300–1600 mg in less than a day in refractory SE (38). The only side effect noted was lethargy. Vagal nerve stimulation Zimmerman and colleagues used vagal nerve stimulation (VNS) to treat three patients with partial seizures who developed refractory SE during anticonvulsant withdrawal (49). The duration of refractory SE prior to VNS implantation was 1–5 weeks. Each patient had the VNS device escalated to the maximum current with rapid cycling (3 mA, signal frequency 30 Hz, pulse width 500 msec, on time 60 sec, off time 60 sec), with cessation of seizures 3–5 days after implantation. Neurosurgical treatment Gorman and colleagues reported a patient with refractory SE who was successfully treated with seizure focus resection (13).
612
Maintenance of seizure control Once refractory SE is controlled, the clinician needs a strategy to prevent seizure recurrence. This will typically be dictated by the etiology of the refractory SE. Patients who developed refractory SE as a consequence of drug or alcohol withdrawal can often be managed with a tapering dose of a benzodiazepine. Those with preexisting epilepsy will need reconsideration of their prior regimens. The most difficult cases to control are in patients with apparent encephalitis, based on spinal fluid findings, but in whom an etiologic agent is rarely demonstrated. They may have had weeks or months of refractory SE before the treatment can be successfully withdrawn. In order to accomplish this, they may need to be maintained on more than one conventional antiseizure agent, often at high serum concentrations (e.g., phenobarbital at concentrations of 150 mg/mL). REFERENCES 1. Aggarwal, P., and J. P. Wali. Lidocaine in refractory status epilepticus: A forgotten drug in the emergency department. Am. J. Emerg. Med. 1993;11:243–244. 2. Alldredge, B. K., A. M. Gelb, S. M. Isaacs, M. D. Corry, F. Allen, S. Ulrich, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N. Engl. J. Med. 2001;345:631–637. 3. Balasubramanian, S. V., R. B. Campbell, and R. M. Straubinger. Propofol, a general anesthetic, promotes the formation of fluid phase domains in model membranes. Chem. Phys. Lipids 2002;114:35–44. 4. Bedford, R. F., J. A. Persing, L. Pobereskin, and A. Butler. Lidocaine or thiopental for rapid control of intracranial hypertension? Anesth. Analg. 1980;59:435–437. 5. Bleck, T. P. Management approaches to prolonged seizures and status epilepticus. Epilepsia 1999;40(Suppl. 1):S59–S63. 6. Bleck, T. P., M. Quigg, B. R. Nathan, T. L. Smith, and J. Kapur. Electroencephalographic effects of ketamine treatment for refractory status epilepticus. Epilepsia 2002;43(Suppl. 7): 282. 7. Borris, D. J., E. H. Bertram, and J. Kapur. Ketamine controls prolonged status epilepticus. Epilepsy Res. 2000;42(2–3): 117–122. 8. Brower, R. G., and G. D. Rubenfeld. Lung-protective ventilation strategies in acute lung injury. Crit. Care Med. 2003;31(4 Suppl.):S312–S316. 9. Claassen, J., L. J. Hirsch, R. G. Emerson, J. E. Bates, T. B. Thompson, and S. A. Mayer. Continuous EEG monitoring and midazolam infusion for refractory nonconvulsive status epilepticus. Neurology 2001;57:1036–1042. 10. Debaene, B., B. Plaud, M. P. Dilly, and F. Donati. Residual paralysis in the PACU after a single intubating dose of nondepolarizing muscle relaxant with an intermediate duration of action. Anesthesiology 2003;98:1042–1048. 11. DeGiorgio, C. M., K. Altman, E. Hamilton-Byrd, and A. L. Rabinowicz. Lidocaine in refractory status epilepticus: Confirmation of efficacy with continuous EEG monitoring. Epilepsia 1992;33:913–916.
12. Derlet, R. W., T. E. Albertson, and R. S. Tharratt. Lidocaine potentiation of cocaine toxicity. Ann. Emerg. Med. 1991;20: 135–138. 13. Gorman, D. G., W. D. Shields, D. A. Shewmon, H. T. Chugani, R. Finkel, Y. G. Comair, et al. Neurosurgical treatment of refractory status epilepticus. Epilepsia 1992;33:546–549. 14. Hanna, J. P., and M. L. Ramundo. Rhabdomyolysis and hypoxia associated with prolonged propofol infusion in children. Neurology 1998;50:301–303. 15. Helman, D. L., Jr., J. H. Sherner, III, T. M. Fitzpatrick, M. E. Callender, and A. F. Shorr. Effect of standardized orders and provider education on head-of-bed positioning in mechanically ventilated patients. Crit. Care Med. 2003;31:2285–2290. 16. Kofke, W. A., R. S. Young, P. Davis, S. K. Woelfel, L. Gray, D. Johnson, et al. Isoflurane for refractory status epilepticus: A clinical series. Anesthesiology 1989;71:653–659. 17. Krishnamurthy, K. B., and F. W. Drislane. Depth of EEG suppression and outcome in barbiturate anesthetic treatment for refractory status epilepticus. Epilepsia 1999;40:759–762. 18. Krishnamurthy, K. B., and F. W. Drislane. Relapse and survival after barbiturate anesthetic treatment of refractory status epilepticus. Epilepsia 1996;37:863–867. 19. Kumar, A., and T. P. Bleck. Intravenous midazolam for the treatment of refractory status epilepticus. Crit. Care Med. 1992;20:483–488. 20. Lefrant, J. Y., C. Farenc, J. E. De la Coussaye, L. Muller, J. Ripart, P. Cuvillon, et al. Pharmacodynamics and atracurium and laudanosine concentrations during a fixed continuous infusion of atracurium in mechanically ventilated patients with acute respiratory distress syndrome. Anaesth. Intensive Care 2002; 30:422–427. 21. Macdonald, R. L. Antiepileptic drug actions. Epilepsia 1989;30(Suppl. 1):S19–S28. 22. Manno, E. M. New management strategies in the treatment of status epilepticus. Mayo Clin. Proc. 2003;78:508–518. 23. Meeke, R. I., B. E. Soifer, A. W. Gelb. Isoflurane for the management of status epilepticus. Drug Intell. Clin. Pharmacol. 1989; 23:579–581. 24. Mirski, M. A., M. A. Williams, and D. F. Hanley. Prolonged pentobarbital and phenobarbital coma for refractory generalized status epilepticus. Crit. Care Med. 1995;23:400– 404. 25. Modica, P. A., and R. Tempelhoff. Intracranial pressure during induction of anaesthesia and tracheal intubation with etomidate-induced EEG burst suppression. Can. J. Anaesth. 1992;39:236–241. 26. Naritoku, D. K., and S. Sinha. Prolongation of midazolam half-life after sustained infusion for status epilepticus. Neurology 2000;54:1366–1368. 27. Niebauer, M., and M. Gruenthal. Topiramate reduces neuronal injury after experimental status epilepticus. Brain Res. 1999;837:263–269. 28. Osorio, I., and R. C. Reed. Treatment of refractory generalized tonic-clonic status epilepticus with pentobarbital anesthesia after high-dose phenytoin. Epilepsia 1989;30: 464–471. 29. Parviainen, I., A. Uusaro, R. Kalviainen, E. Kaukanen, E. Mervaala, and E. Ruokonen. High-dose thiopental in the treatment of refractory status epilepticus in intensive care unit. Neurology 2002;59:1249–1251. 30. Pascual, J., M. J. Sedano, J. M. Polo, and J. Berciano. Intravenous lidocaine for status epilepticus. Epilepsia 1988;29: 584–589.
31. Prasad, A., B. B. Worrall, E. H. Bertram, and T. P. Bleck. Propofol and midazolam in the treatment of refractory status epilepticus. Epilepsia 2001;42:380–386. 32. Rashkin, M. C., C. Youngs, and P. Penovich. Pentobarbital treatment of refractory status epilepticus. Neurology 1987;37: 500–503. 33. Rouby, J. J., P. Laurent, M. Gosnach, E. Cambau, G. Lamas, A. Zouaoui, et al. Risk factors and clinical relevance of nosocomial maxillary sinusitis in the critically ill. Am. J. Respir. Crit. Care Med. 1994;150:776–783. 34. Sharpe, M. D., G. B. Young, S. Mirsattari, and C. Harris. Prolonged desflurane administration for refractory status epilepticus. Anesthesiology 2002;97:261–264. 35. Sheth, R. D., and B. E. Gidal. Refractory status epilepticus: Response to ketamine. Neurology 1998;51:1765–1766. 36. Simon, R. P., N. L. Benowitz, J. Bronstein, and P. Jacob, III. Increased brain uptake of lidocaine during bicucullineinduced status epilepticus in rats. Neurology 1982;32:196–199. 37. Stecker, M. M., T. H. Kramer, E. C. Raps, R. O’Meeghan, E. Dulaney, and D. J. Skaar. Treatment of refractory status epilepticus with propofol: Clinical and pharmacokinetic findings. Epilepsia 1998;39:18–26. 38. Towne, A. R., L. K. Garnett, E. J. Waterhouse, L. D. Morton, and R. J. DeLorenzo. The use of topiramate in refractory status epilepticus. Neurology 2003;60:332–334. 39. Trapani, G., C. Altomare, G. Liso, E. Sanna, and G. Biggio. Propofol in anesthesia: Mechanism of action, structureactivity relationships, and drug delivery. Curr. Med. Chem. 2000; 7:249–271. 40. Treiman, D. M., P. D. Meyers, N. Y. Walton, J. F. Collins, C. Colling, A. J. Rowan, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N. Engl. J. Med. 1998;339:792–798. 41. Treiman, D. M., N. Y. Walton, J. F. Collins, and the VSECS Group. Treatment of status epilepticus if first drug fails. Epilepsia 1999;40(Suppl. 7):243. 42. Uberall, M. A., R. Trollmann, U. Wunsiedler, and D. Wenzel. Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus. Neurology 2000;54:2188–2189. 43. Wu, Y. W., D. W. Shek, P. A. Garcia, S. Zhao, and S. C. Johnston. Incidence and mortality of generalized convulsive status epilepticus in California. Neurology 2002;58:1070–1076. 44. Yaffe, K., and D. H. Lowenstein. Prognostic factors of pentobarbital therapy for refractory generalized status epilepticus. Neurology 1993;43:895–900. 45. Yeoman, P., A. Hutchinson, A. Byrne, J. Smith, and S. Durham. Etomidate infusions for the control of refractory status epilepticus. Intensive Care Med. 1989;15:255–259. 46. Yorgin, P. D., A. A. Theodorou, A. Al-Uzri, K. Davenport, L. V. Boyer-Hassen, and M. I. Johnson. Propylene glycolinduced proximal renal tubular cell injury. Am. J. Kidney Dis. 1997;30:134–139. 47. Young, G. B., W. T. Blume, C. F. Bolton, and K. G. Warren. Anesthetic barbiturates in refractory status epilepticus. Can. J. Neurol. Sci. 1980;7:291–292. 48. Yu, K. T., S. Mills, N. Thompson, and C. Cunanan. Safety and efficacy of intravenous valproate in pediatric status epilepticus and acute repetitive seizures. Epilepsia 2003;44:724–726. 49. Zimmerman, R. S., J. L. Sirven, J. F. Drazkowski, et al. High-output current/rapid cycling vagus never stimulation for refractory status epilepticus: preliminary results. Epilepsia 2002;43(Suppl. 7):286.
:
613
50
The Impact of Status Epilepticus on Health Care Delivery Systems: Quality of Care and Access
.
Introduction In response to dramatic increases in health care costs in the 1980s, the health care systems in many developed countries were restructured in an effort to constrain this growth. Some of these changes in the organizational systems and reimbursement mechanisms for delivering health care, as exemplified by the managed care industry in the United States, have raised concerns that cost-containment strategies may adversely affect the quality of medical care being delivered. To collect objective information on quality, indicators of quality of care must be developed and validated (2). In addition to quality of care, the debate over optimal systems for delivering health care has also focused on questions of ensuring adequate access to care (22) and reducing disparities in the receipt of health care services. This chapter addresses the conceptualization of quality of care and quality-of-care assessment for status epilepticus (SE). A framework for disseminating and evaluating the impact of established quality-of-care standards for the management of SE is presented, using examples from published research for another condition. Emergency department (ED) visits and hospitalizations for SE can serve as indicators of decreased access to health care, especially if SE is included among the conditions recently conceptualized as ambulatory-sensitive conditions. Additional research is needed to assess the goals of improving quality of care for SE and access to care for this population.
Assessing quality of care Quality of care has been defined by the Institute of Medicine as “the degree to which health services for individuals and populations increase the likelihood of desired health outcomes and are consistent with current professional knowledge” (13). Over the past two decades, a conceptual framework for quality of care has led to the development of methods for measuring quality of care. With the exception of stroke, however, this research has infrequently been
applied to evaluating care for neurologic conditions such as epilepsy. Donabedian (7) defined the interrelated dimensions of quality in health care as structure, process, and outcomes. Examples of structure measures of quality of care are whether a hospital facility meets certain standards or codes, or the proportion of physicians in a health plan who are board certified. Over the past decade, however, the emphasis has turned to assessing outcomes, such as mortality, disease symptoms, or health status, and assessing processes of care. An example of a process of care is a physician’s recommendation (or not) for a diagnostic test, a surgical procedure, or a pharmacologic or rehabilitation treatment in a given clinical situation. Processes of care that best serve as markers of quality of care are those that, when adhered to, result in improved health outcomes, based on currently available scientific evidence or on formally derived consensus among experts in a field. One method for assessing processes of care is to measure the extent of adherence to established standards of care or guidelines. An example is the measurement of childhood immunization rates in a health insurance plan. This particular process-of-care measure must be collected by health plans that desire to be assessed by the National Committee on Quality Assurance (NCQA), because it is one of the quality-of-care indicators in the NCQA’s Health Plan Employer Data and Information Set (HEDIS) (4). These data are now made available to consumers and to purchasers of care (i.e., employers), so that information about the quality of care provided by different health plans can be used to guide decisions about the choice of plans (8). Such information can also be used to drive quality improvement efforts when deficiencies in care are identified. A few studies have assessed the quality of epilepsy care, primarily in the United Kingdom (18). An example of an ongoing quality-of-care initiative that assesses outcomes is the evaluation of mortality rates for cardiovascular surgery across different hospitals in New York State (10). In this case, considerable attention is paid to
:
615
adjusting for differences in case mix or severity of the condition across patients seen at different hospitals before interpreting these comparative data on quality of care. Otherwise, conclusions about different levels of quality of care could be invalid, since tertiary hospitals may be treating sicker or more high-risk patients and thus may have higher crude or unadjusted mortality rates than community hospitals. Once these statistical adjustments have been made, appraisals of quality can be made based on mortality rates: hospitals having lower adjusted mortality rates for the procedure are judged to have higher quality of care, while hospitals with higher adjusted mortality rates have lower quality of care.
Assessing quality of care for SE With respect to convulsive SE, standards of care (i.e., process measures of care) for evaluation and management have been established by a group of experts and codified by endorsement of the Professional Advisory Board of the Epilepsy Foundation of America. These standards were developed based both on literature review, where links between the prescribed recommendations for management (i.e., the processes of care) and better outcomes were identified, and on expert consensus. The recommendations described in this document are fairly explicit, a characteristic that makes it more feasible to translate these recommendations into quality indicators. Quality indicators allow one to determine whether or not processes of care were followed; they make operational the guidelines for measurement of quality of care. As an example, an indicator could be developed that assessed whether or not glucose and thiamine were administered (in eligible patients, i.e., those with documented hypoglycemia or where a blood glucose measurement was unavailable) within the first 9 minutes after seizure onset (24). A standardized assessment form could be developed using this and other key indicators, and the forms could be used to abstract documentation of the key processes of care from medical records. A set of medical records could be identified from ICD codes of ED visits or hospitalizations for all cases seen within a health plan over a specified period of time. Proportions of records concordant with different key indicators could be calculated and reported. In one published study, researchers measured quality of care at a community hospital for the management of SE in children (16). A consecutive series of pediatric admissions over 5 years was reviewed. All admissions for seizures were identified; among those, there were 59 episodes of SE. The researchers developed criteria for appropriate antiepileptic drug (AED) treatment based on existing recommendations, including Canadian Pediatric Society guidelines (3), abstracted the medical records of those SE episodes, and
616
determined the proportion of episodes managed with appropriate drug therapy. In their series, only 30% of these episodes—based on these explicit criteria—were found to have received appropriate AED therapy. The researchers were able to conduct exploratory analyses to identify factors related to treatment rated as not meeting criteria for appropriate therapy. Another study of quality of care for SE also focused on measurement of processes of care (17). Approximately onequarter of all consecutive pediatric emergencies over a 1year period in one region of Germany were seizures in children. Before the study observation period, guidelines on management of the three pediatric emergency conditions that were evaluated (seizures, trauma, and obstructive airway disease) were distributed to emergency physicians in the region. The study found that some aspects of care were excellent, including appropriate airway management in 85% of cases and documentation of appropriate clinical evaluation (i.e., neurologic status) in 75% of cases. However, appropriate medication use occurred in only 50% of cases, and overall management was evaluated as appropriate only 52% of the time. The Epilepsy Foundation Working Group’s guidelines for managing SE have been disseminated through publication in the Journal of the American Medical Association (24) and through mailings to physicians. However, there has been no formal evaluation of the impact of this dissemination strategy. Furthermore, there are only rare published data on patterns of care for SE, the level of adherence to these care standards, or where gaps exist in quality of care for SE. Gaps in care refer to aspects of actual care provision that reflect low adherence to established standards. In addition, it is useful to ascertain what aspects of care potentially provide the greatest return in improving outcomes compared with other aspects of care. As an example, would it be of greater overall health benefit to be able to deliver appropriate drugs within minutes of the onset of status or to have sophisticated electrophysiologic monitoring available at a hospital for instances of SE refractory to initial treatment? Should the target audience for maximally improving quality of care be physicians or nonphysicians, such as paramedics? Having data on the epidemiology of care for SE is critical for answering these questions and for planning guideline dissemination and implementation strategies that can measurably improve quality of care. Without such information, quality improvement efforts may be misdirected and have a limited impact.
Intervention research to improve quality of care for SE Target audiences for guideline dissemination efforts need to be identified before such efforts are undertaken. One target audience for SE standards will be physicians, most likely
emergency physicians. There is a body of literature on the kinds of dissemination strategies that are effective in actually changing physician behavior. In general, the literature has shown that it takes more than passive educational methods, such as traditional lectures or written texts, to change behavior. Instead, one or more intensive interventions, such as face-to-face interactions with individual physicians (“academic detailing”), or use of a reminder system, are needed to produce a measurable impact on practice patterns (5). An example of a study that compared several methods for implementing practice guidelines was that of Lomas and colleagues (14). They randomly assigned 16 hospitals in Ontario, with a total of 76 physicians at these hospitals, to three guideline dissemination strategies. The guideline was the recommendation to offer women who had undergone a previous cesarian section a trial of labor for their subsequent pregnancy. (This national guideline was developed in conjunction with the Society of Obstetricians and Gynecologists of Canada.) There were three randomization arms in the study: (1) physicians within the control group of hospitals, who received a single mailing of the practice guideline, (2) physicians within an “audit and feedback” group of hospitals, whose charts were regularly audited, with data aggregated across physicians for feedback at regular department meetings, and (3) physicians within an “opinion leader” group of hospitals. These physicians were surveyed using a standardized questionnaire to nominate a local colleague who best demonstrated the characteristics of an influential physician. Each opinion leader hosted a meeting regarding the guide-
line, endorsed multiple mailings of the guidelines to study physicians, and informally maintained contacts with these physicians and recorded those contacts. Study outcomes were the proportion of patients in each of the three arms of the trial who were managed in a way that reflected adherence to the guideline. The most effective intervention strategy was use of the opinion leaders; there was evidence of a modest effect using audit and feedback. Both strategies were more effective than simply mailing the guideline to the target group of physicians (Figure 50.1). A cluster randomized controlled trial of implementation of an epilepsy guideline in primary care compared usual care (mailing of a guideline) to an intermediate intervention (mailing of a guideline, plus a workshop) and a more intensive intervention (mailing of a guideline, a workshop, and a nurse specialist to support and promote use of the guideline and assist clinics in setting up programs to review their epilepsy care) (6). Sixty-eight clinics in one region of the United Kingdom were randomized to one of these three arms. Although the trial showed no differences in epilepsy care processes or outcomes across the three study arms, a significant barrier to assessing the efficacy of the interventions per se was low implementation of these interventions within the intermediate and intensive arms. For example, only a small minority of physicians participated in the workshops that were offered, and fewer than a third of clinics randomized to the intensive intervention arm set up a system to review their epilepsy care. This study illustrates the difficulty of implementing change in health care delivery systems and underscores the importance of publishing negative quality of care intervention trials, so that future intervention trials
F 50.1 Study of intervention strategies. The lowest level of intervention, mailing of a guideline to physians (control), was
significantly less effective than either the audit and feedback or opinion leader intervention strategies. See text for details.
:
617
can be designed to overcome barriers, obstacles, and other “lessons learned” from such studies. No examples of intervention research to improve the quality of care for SE were found in a recent literature review; thus, research in this area is highly needed. To disseminate and implement guidelines for the management of SE, the key steps are (1) to identify the target audiences and key aspects of care for which quality improvement efforts would produce the most benefit, (2) to design and incorporate intensive implementation efforts, relying on the literature for methods shown to be most effective in disseminating guidelines, and (3) to plan an evaluation of the impact of the dissemination and implementation efforts.
SE as a possible indicator of access to care For the subgroup of individuals with established epilepsy who develop SE, some experts hypothesize that many such episodes are preventable or avoidable. A review of the reasons for admission of a consecutive series of patients with epilepsy to an inner-city hospital in the United Kingdom found that many of the admissions appeared attributable to potentially modifiable factors rather than reflecting cases of severe, refractory epilepsy (11). Research on access to care has identified a set of “ambulatory-sensitive conditions,” or conditions for which some proportion of hospitalizations is avoidable in certain settings and for which higher hospitalization rates can be linked to decreased access to ambulatory care (23). The concept of ambulatory-sensitive conditions is that these are chronic conditions that can be managed primarily in the outpatient setting, and most or a significant proportion of hospitalizations for that condition can be avoided if there is adequate access to outpatient care.
F 50.2 Hypothetical relationships between admission rates and access to outpatient care for an ambulatory-sensitive condition
618
The concept of ambulatory-sensitive conditions is shown in Figure 50.2. If measures of access are collected in a population and admission rates for a given condition are plotted against these access ratings, access and admission rates for ambulatory-sensitive conditions such as asthma, diabetes, and congestive heart failure are found to be related, with better access associated with lower admission rates and worse access associated with higher admission rates. Hospitalization for an acute, self-limiting condition such as appendicitis, which intuitively would not have an association with admission rates across varying degrees of access (1, 19), is an essentially horizontal line (see Figure 50.2). Several studies have included seizures as an ambulatory caresensitive condition in children (20) and adults (12). One study of consecutive pediatric admissions to an urban hospital found that seizure disorder was the fourth most common condition for which hospitalization was considered potentially avoidable, yet it accounted for 8% of all hospitalizations (9). Analogous to asthma and other conditions, epilepsy may represent an indicator neurologic condition where access to appropriate ambulatory care can prevent some proportion of hospitalizations or ED visits for episodes of SE, as well as for episodes of breakthrough or clusters of seizures, drug withdrawal, or drug toxicity. In support of this hypothesis, one series of consecutive cases of SE at an urban hospital in the 1980s (15) found that 56% of cases of SE were in patients with established epilepsy (and thus potentially avoidable). In this series, 45% of those cases were probably a consequence of AED withdrawal that was not part of a medical plan for drug discontinuation, providing some support for the hypothesis that better access to care may result in lower rates of hospitalizations for SE.
and for an acute condition (i.e., appendicitis) with an assumed R 2 = 0.50, p < 0.001.
Agenda for quality of care and access to care research Key health policy issues of quality of care and access to care are relevant to people with epilepsy. Without scientific research in these areas, there can be no assurance that the most advanced, efficacious management strategies are actually being delivered to this population. Areas of high priority for future research are (1) development of quality of care indicators, (2) dissemination, implementation, and evaluation of the impact of guidelines for SE management, and (3) assessment of access to care for people with epilepsy and potential disparities in access due to ethnicity or socioeconomic factors. A potential focus for this research on access is investigation of whether or not epilepsy is an ambulatorysensitive condition, one in which the rate of hospitalizations and ED visits for SE and acute exacerbations of seizures is an indicator of access to care. REFERENCES 1. Bindman, A. B., K. Grumbach, D. Osmond, M. Komaromy, K. Vranzan, N. Lurie, et al. Preventable hospitalizations and access to health care. JAMA 1995;274:305–311. 2. Brook, R. H., E. A. McGlynn, and P. D. Cleary. Quality of health care. Part 2. Measuring quality of care (editorial). N. Engl. J. Med. 1996;335:966–970. 3. Canadian Pediatric Society. Management of the paediatric patient with generalized convulsive status epilepticus in the emergency department. CPS Statement EP 95-01. Ottawa: Author, 1995. 4. Corrigan, J. M., and D. M. Nielsen. Toward the development of uniform reporting standards for managed care organizations: The Health Plan Employer Data and Information Set (Version 2.0). Jt. Commi. J. Qual. Improv. 1993;19:566–575. 5. Davis, D. A., M. A. Thomson, A. D. Oxman, and R. B. Haynes. Changing physician performance: A systematic review of the effect of continuing medical education strategies. JAMA 1995;274:700–705. 6. Davis, J., R. Roberts, D. L. Davidson, A. Norman, S. Ogston, J. M. Grimshaw, et al. Implementation strategies for a Scottish national epilepsy guideline in primary care: Results of the Tayside Implementation of Guidelines in Epilepsy Randomized (TIGER) Trial. Epilepsia 2004;45:28–34. 7. Donabedian, A. Explorations in Quality Assessment and Monitoring. Vol. 1. The Definition of Quality and Approaches to its Assessment. Ann Arbor: Health Administration Press, 1980. 8. Epstein, A. Performance reports on quality: Prototypes, problems, and prospects. N. Engl. J. Med. 1995;333:57–61. 9. Flores, G., M. Abreu, C. E. Chaisson, and D. Sun. Keeping children out of hospitals: Parents’ and physicians’ perspectives on how pediatric hospitalizations for ambulatory care-sensitive conditions can be avoided. Pediatrics 2003;112:1021–1030. 10. Hannan, E. L., H. Kilburn, Jr., M. Racz, E. Shields, and M. R. Chassin. Improving the outcomes of coronary artery bypass surgery in New York State. JAMA 1994;271:761– 766. 11. Irving, P., A. Al Dahma, A. Srinivasan, and R. Greenwood. An audit of admissions of patients with epilepsy to a district general hospital. Seizure 1999;8:166–169.
12. Laditka J. N., S. B. Laditka, and M. P. Mastanduno. Hospital utilization for ambulatory care sensitive conditions: Health outcome disparities associated with race and ethnicity. Soc. Sci. Med. 2003;57:1429–1441. 13. Lohr, K. N., ed. Medicare: A Strategy for Quality Assurance. Vol. 1. Washington, D.C.: National Academy Press, 1990. 14. Lomas, J., M. Enkin, G. M. Anderson, W. J. Hannah, E. Vayda, and J. Singer. Opinion leaders vs. audit and feedback to implement practice guidelines: Delivery after previous cesarean section. JAMA 1991;265:2202–2207. 15. Lowenstein, D. H., and B. K. Alldredge. Status epilepticus at an urban public hospital in the 1980s. Neurology 1993;43: 483–488. 16. Mah, J. K., and M. W. Mah. Pediatric status epilepticus: Perspective from Saudi Arabia. Pediatr. Neurol. 1999;20:364–369. 17. Moller, J. C., S. Ballnus, M. Kohl, W. Gopel, M. Barthel, U. Kruger, et al. Evaluation of the performance of general emergency physicians in pediatric emergencies: Obstructive airway diseases, seizures, and trauma. Pediatr. Emerg. Care 2002; 18:424–428. 18. Muir, T. M., A. Bradley, S. F. Wood, G. D. Murray, and M. J. Brodie. An audit of treated epilepsy in Glasgow. West of Scotland Epilepsy Research Group. Seizure 1996;5:41–46. 19. Oster, A., and A. B. Bindman. Emergency department visits for ambulatory care sensitive conditions: Insights into preventable hospitalizations. Medi. Care 2003;41:198–207. 20. Parker, J. D., and K. C. Schoendorf. Variation in hospital discharges for ambulatory care-sensitive conditions among children. Pediatrics 2000;106(4 Suppl.):942–948. 21. Soumerai, S., and J. Avorn. Principles of educational outreach (“academic detailing”) to improve clinical decision making. JAMA 1990;263:549–556. 22. Starfield, B. Access: Perceived or real, and to what? JAMA 1995;274:346–347. 23. Weissman, J. S., C. Gatsonis, and A. M. Epstein. Rates of avoidable hospitalization by insurance status in Massachusetts and Maryland. JAMA 1992;268:2388–2394. 24. Working Group on Status Epilepticus. Treatment of convulsive status epilepticus: Recommendations of the Epilepsy Foundation of America’s Working Group on status epilepticus. JAMA 1993;270:854–859.
:
619
51
Status Epilepticus: The Future Or: The Status of Status Gives Me Fits
. . What does the future hold? The high level of interest in status epilepticus (SE), reflected in a flood of publications on this topic in the past 5 years, shows no sign of abating, and we can expect further progress in the next few years. However, there are significant barriers to progress: the federal funding for epilepsy research is decreasing, the number of people trained in epilepsy research is on the wane, the pharmaceutical industry is reducing its investments in basic and drug discovery research, the already formidable regulatory and legal barriers that limit translation of new discoveries into practical treatments are mushrooming out of control, and the few practical treatments that are developed remain available only to a privileged few in the most developed countries. There is significant progress in basic science. In our basic understanding of SE and its complications, we are just scratching the surface, but these few scratches are already quite revealing. We have developed a concept of what SE really is, and this has already altered our therapeutic attitudes. The proof that SE is more than an aggregate of seizures (since we can transiently suppress the seizures without altering the course of status; see Chapter 17) only confirms the observations of Trousseau (1867), but the devil is in the details. The role of receptor trafficking in the minute-to-minute evolution and of neuropeptide modulators in the hour-to-hour evolution of status suggest novel approaches (how to get GABA receptors back into synapses, how to develop peptide-like drugs that cross the blood-brain barrier), as does the role of changes in gene expression in its long-term consequences (can we switch back the expression ratios of GABA or AMPA receptor subunits?). If the “nature of the beast” really reflects massive potentiation of glutamate receptors that does not get consolidated, could epileptogeny represent residual consolidation, and is this why NMDA blockers are antiepileptogenic in experimental SE? The demonstration of time-dependent pharmacoresistance, of the rapid development of self-sustaining seizures, and of neuronal injury gives the treating physician a sense of urgency that is reflected in the shrinking of the temporal criteria used to define status and in the use of an operational definition for treatment purposes. Indeed, the treatment of
this life-threatening condition should not be delayed until we are sure that every patient is in full-blown SE. The broad acceptance of the concept of subtle status aligns our therapeutic practice (it’s about time) with the concept of Bourneville (1876) that status progresses from a convulsive to a “meningitic” phase, and directs us to treat that condition vigorously, if not always successfully (see Treiman, Chapter 6 in this volume). We have also made considerable progress in understanding the complications of SE. The development of many reliable models of status-induced epileptogenesis gives us an important tool for screening antiepileptogenic drugs, and prompts us to reexamine the human relevance of those models. Our understanding of neuronal apoptosis and necrosis has taken giant steps and should lead to more effective prevention of brain damage, a goal that is already partially feasible in animal models. The effects of experimental SE on the immature brain are now relatively well understood: seizure-induced neuronal necrosis and apoptosis have both been demonstrated. Damage is highly species- and model-dependent. For example, kainate-induced SE massively damages the rabbit’s but not the rat’s brain. By contrast, lithium-lipocarpineinduced SE damages both, and shows high epileptogenicity. This recognition of the diversity of outcomes in experimental SE parallels the recognition of the complexity and diversity of SE in humans. What is still very muddy is the extent to which experimental lessons apply to the human animal, and the implications of those facts for our therapeutic decisions. The dangers of drugs for the immature brain are significant, and the recent discovery of druginduced developmental apoptosis, in which drugs that block GABA or other synapses may cause massive neuronal death at very specific ages in discrete brain regions, has raised that issue and placed it in the forefront of our current concerns. Preclinical research in SE: Where will the support come from? Federal agencies have seen a reduction of the proportion of funds devoted to epilepsy research, and the pharmaceutical industry has recently reduced its efforts in basic research and
: :
621
drug discovery, although this has been compensated to some extent by the efforts of small biotechnology companies. Now that we have good animal models of SE and epileptogenesis, many of the questions that traditionally are resolved in human trials can be asked in experimental animal studies at a much lower cost. Comparisons between drugs in conditions such as SE should be made in animals first, but at present no mechanism exists for funding such “routine” studies (with minor exceptions in the form of limited NIH initiatives), and industry does not usually fund comparative studies of uncertain outcome. Yet such studies would make many human trials unnecessary, and would pinpoint the direction that should be taken by human studies. At the molecular level, we need to explore in much greater detail the practical implications of changes in synaptic function, and we need expanded support for drug discovery and other therapeutic investments.
through an industry-sponsored double-blind trial proving its efficacy and safety. Yet increasing restrictions from the FDA, HMOs, the VHA, and so on are trying to prevent the offlabel use of drugs without type I evidence for the very specific application being considered. At the same time, the increasing practice of gigantic awards in the courts for the complications caused by novel drugs have enormously increased the financial risk that industry (and eventually the patient) is made to bear. The mathematics are clear: the current system offers strong financial disincentives to rational drug development in small markets such as SE. Unless that changes, it is unlikely that physicians will have additional therapeutic options when the next treatise on SE is published. This bleak picture applies only to the most fortunate populations. For the majority of human beings on this planet, the situation is far worse: they cannot afford the majority of established drugs, and sometimes they have no access to any injectable drug at all.
New treatments are few and far between. This book offers a striking contrast between rapid progress in our understanding of a disease and the snail-like progress in developing tools to treat it. The only new treatments that have become available since the publication of Shorvon’s monograph are fosphenytoin and valproic acid. They are based on active compounds discovered 40 to 70 years ago. Furthermore, fosphenytoin might not be allowed to be marketed for SE if it were released today. Neither drug was ever evaluated for its efficacy or safety in the treatment of SE. Only three controlled trials and one major double-blind study of the treatment of SE have ever been published. None is planned. None of the newer antiepileptic drugs is available in IV form (although one is under development), and none of them can boast type I evidence for treating SE. Most of the progress in treating SE has come through a better understanding of the use of existing agents (e.g., of the need for early, high-dose IV intervention) rather than through the scientific development of new agents using double-blind trials. Lack of translation of basic advances into clinical practice is often assumed to reflect a lack of education of the medical public, but that may not be the case here (see Chapter 38). The problem is not that physicians are unaware of recent progress or are not using this knowledge. It is that structural, regulatory, and medicolegal barriers discourage new therapeutic applications. There are an estimated 100,000–150,000 cases of SE yearly in the United States. Given the size of that market, no profit-seeking company can afford to spend the $800 million (estimated) cost of bringing a drug to market through the front door (with type I evidence and FDA approval). As a matter of fact, none of the agents of choice for the treatment of SE has ever gone
622
Is there a solution to these structural problems? Since the purpose of the law in a democratic society is to make it profitable to achieve socially desirable goals, such as safe and effective new treatments, we should consider how we can make it profitable to develop new treatments for SE. One option would be to redefine orphan drugs to include SE and many other conditions that have limited markets and as a result limited profitability. Another option would be to redefine the contribution of evidence-based medicine in fields that cannot bear the economic burden of large-scale clinical trials. A third and highly desirable option is to shield industry from very large awards in fields with limited economic potential (e.g., since sales and profit figures for specific drugs are available to the public, one could limit the penalties or awards in proportion to the size of the profits). A desirable but expensive and probably unrealistic option would be to provide federal funding for clinical trials of drugs with limited market potential. The Antiepileptic Drug Development program at NIH is a good example of a successful attempt to encourage industry to take an interest in a field by assuming some of the initial (and very small) risks, but it remains to be seen how this approach can apply to the (inherently expensive) translational phase of drug development. Any or all of the other methods proposed, however, would restore some balance to the risk-benefit ratio for small markets, and might be worth some serious thought.
INDEX
A ABPE (atypical benign partial epilepsy), 128 Abscesses, cerebral, neuroimaging features of, 181 Absence status epilepticus (ASE), 91–104, 109, 113, 126 atypical, 92, 93, 96 diagnostic neuroimaging in, detection of structural brain lesions in diagnosis and, 188–189 treatment of, 518 clinical classification of, 13, 15, 93–94 clinical features of, 95–99 de novo, of late onset, 93, 97 diagnosis of, 99 neuroimaging in, 188–189 EEG in, 99–100, 117 epidemiology of, 94–95, 115 etiology of, 102–103 with focal features, 94, 98 historical background of, 91 natural history of, 103 neuroimaging in, 188–189 detection of structural brain lesions in diagnosis and, 188 pathophysiology and, 195–196 neuronal injury due to, 119 new cases of uncertain classification, 92–93 pathophysiology of, neuroimaging studies of, 195–196 petit mal, 91–92 situation-related, 93 treatment of, 100–102, 517–518 long-term, 103–104 typical, 92, 93, 95 Access to care, 618–619 research agenda for, 619 N-Acetylaspartate (NAA) in CPSE, 193, 194 in EPC, 197 as marker of neuronal injury, 174 Acidemia, isovaleric, neonatal SE and, 507 Acidosis, 153–156 Acute symptomatic status epilepticus, sequelae of, 46 Adenosine, 315–321 as endogenous anticonvulsant, 316–317 formation of, 317 future research directions for, 320 mechanism for SE development and, 319–320 mediation of effects by adenosine receptors, 317–318 role in SE, 318–319 Adenosine agonists, as endogenous anticonvulsants, 320 Adenosine receptors, 317–318 AEDs. See Antiepileptic drugs (AEDs); specific drugs Affective symptoms, nonconvulsive SPSE with, 75 Age CPSE and, 76 epileptogenesis and, 426 mortality related to, 35 AIDs (anti-inflammatory drugs), epileptogenesis prevention by, 414–415 Airway management, in critical care, 607–608 Akinetic status epilepticus, 127
Ambulatory patients, electrographic SE in, 109–110 Ambulatory status epilepticus, 230 time course of brain damage following, 232–233, 234 Amidate. See Etomidate Amino acid disturbances, neonatal SE and, 506 a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). See AMPA entries Amnesia, in CPSE, 78 AMPA, inhaled anesthetics and, 572 AMPA receptor(s), 295 changes in, secondary to SE, 298 excitotoxicity and, 367 neuronal death related to, 466, 468 posttranslational editing for mRNA for GluR2 subunit of, 296–297 reactive synaptogenesis and, 450 role in delayed cell death, 381–383, 384 AMPA receptor antagonists, neuroprotection by, 472 Amygdala basolateral recruitment from, 241 status epilepticus originating from, 240 as kindling structure, 235 spread of SE to extensive limbic regions from, 243 Amygdalohippocampal nucleus, status epilepticus originating from, 240 Anesthesia, general, 498, 500. See also Inhaled anesthetics for convulsive SE, 516 for GCSE, 486, 495 Angelmann’s syndrome, NCSE associated with, 126 Angiomas, cavernous, neuroimaging features of, 182 Anoxic encephalopathy, acute, neuroimaging features of, 181 Anterograde amnesia, in CPSE, 78 Anticonvulsant(s), endogenous, 316 adenosine agonists as, 320 adenosine as, 316–317 Anticonvulsant agents. See Antiepileptic drugs (AEDs); specific drugs Antiepileptic drugs (AEDs). See also specific drugs adverse effects of, 484–485 anatomical effects of, 255, 257 ASE associated with, 103 controversies regarding antiepileptogenic effects of, 414 dosing of. See also specific drugs inadequate, 482 focal perfusion of, 580–581, 582 glutamate antagonists as, 298–299 historical background of, 6 for neonatal seizures, 140–141 in subtle GCSE, 258 Anti-inflammatory drugs (AIDs), epileptogenesis prevention by, 414–415 Aphasic status epilepticus, 82–83 Apoptosis, 468–470. See also Neuronal death bcl-2 gene family and, 158–159 necrosis versus, 331–333 Apraxia, in CPSE, 78 Area tempestas, spread of SE to extensive limbic regions from, 246–251 Arteriovenous malformations, neuroimaging features of, 182 ASE. See Absence status epilepticus (ASE)
623
Astrocytomas, neuroimaging features of, 181–182 Atonic status epilepticus, 127 Atypical benign partial epilepsy (ABPE), 128 Auditory hallucinations, in CPSE, 78 Auditory nonconvulsive simple partial status epilepticus, 74 Automatisms in ASE, 97–98 in CPSE, 77 Axon sprouting. See Mossy fiber sprouting; Reactive synaptogenesis
B Baclofen, seizure threshold and, 372, 373 BAPTA (1,2-bis-[2-amino-phenoxy]ethane-Nt Nt N ¢N ¢-tetraacetic acid), 472 Barbiturates. See also Pentobarbital; Phenobarbital for emergency department treatment of SE, 601 for refractory SE, 610 Barbituric acid, 553 Basal forebrain, modulation of seizure susceptibility by, 249, 250 Basal ganglia, modulation of seizure susceptibility by, 247, 248–249 Basic model of status epilepticus, 229 Basolateral amygdala, recruitment from, 241 BCECS (benign childhood epilepsy with centrotemporal spikes), 128 bcl-2 gene family, apoptosis and, 158–159 BDNF (brain derived neurotrophic factor), 389, 391–392, 395–396 epileptogenesis and, 414 BDNF mRNA (brain derived neurotropic factor mRNA), SE induction of expression in developing brain, 393, 394, 395 Behavioral consequences of status epilepticus, 399–404 animal studies of, 400–404 cognitive deficits and, 403–404 mechanisms responsible for age-related differences in vulnerability to SE and, 401–403 morphologic, 400–401 clinical studies of, 399–400 Benign childhood epilepsy with centrotemporal spikes (BCECS), 128 Benzodiazepines, 525–533. See also specific drugs for ASE, therapeutic trial of, 100–102 buccal/sublingual administration of, 530–531 chemistry of, 525, 526, 527 choice of, 495 for CPSE, 79 for emergency department treatment of SE, 599–600 as initial intravenous therapy, clinical efficacy of, 528–529 intramuscular administration of, 531–532 intranasal administration of, 532 pharmacokinetics and pharmacodynamics of, 526–528 pharmacology of, 525–526 prehospital treatment using, 532–533 rectal administration of, 530, 531 resistance to, 272–273 Bicuculline, seizure threshold and, 372, 373 Birth trauma, neonatal SE and, 504 1,2-bis-[2-amino-phenoxy]ethane-Nt Nt N ¢N ¢-tetraacetic acid (BAPTA), 472 Blood-brain barrier, transient breakdown of, CSF pleocytosis and, 153 Blood pressure. See Hypertension; Hypotension BMPs (bone morphogenetic proteins), 390 Bone morphogenetic proteins (BMPs), 390 Brain. See also Neuronal entries adenosine sources in, 317 consequences of generalized status epilepticus and, 3–4 energy metabolism in. See Cerebral energy metabolism imaging of. See Neuroimaging; specific imaging modalities
624
neurotrophic factors in. See Neurotrophic factors SE effects on growth of, 342 structural changes in, SE-induced, 391 synaptic plasticity in, 400 Brain derived neurotrophic factor (BDNF), 389, 391–392, 395–396 epileptogenesis and, 414 Brain derived neurotropic factor (BDNF) mRNA, SE induction of expression in developing brain, 393, 394, 395 Brain stem, 251–252 anatomy in rat seizure models, 251–252 modulation of seizure susceptibility by, 249 seizure propagation between forebrain and, 252 SE or seizure activity in humans and, 252 Brainstem release phenomena, 136
C CAD (caspase-activated DNase), apoptosis and, 470 Caffeine, proconvulsant effects of, 318 Calcium channel antagonists, L-type, neuroprotective effect of, 472 Calcium chelators, cell-permeant, neuroprotective effect of, 472 Calpains apoptosis and, 470 inhibition of, 472–473 Carbamazepine for neonatal SE, 510 to reduce incidence or severity of chronic epilepsy following SE, 434 (S)4-Carboxy-3-hydroxyphenylglycine [(S)-4C3HPG], proconvulsant and anticonvulsant actions of, 308–309 Cardiac arrhythmias, drug-induced, 485 with phenytoin, 542 Caspase-3, apoptosis and, 469–470 Caspase-activated DNase (CAD), apoptosis and, 470 Catecholamines, in SE, 149, 151–154 Cathepsins, lysosomal, inhibition of, 472–473 Cell death delayed role of AMPA receptors in, 381–383, 384 role of enkephalins in, 383–384, 385 prevention of, by neurotrophins, 390 seizure-induced, resistance of immature brain to, 380, 381 Cerebellar nuclei, deep, modulation of seizure susceptibility by, 249 Cerebellum, modulation of seizure susceptibility by, 249 Cerebral abscess, neuroimaging features of, 181 Cerebral blood flow, local, SE effects on, in immature brains, 359–362 Cerebral edema, focal, foreign tissue lesions versus, neuroimaging for detection in CPSE, 186–188 Cerebral energy metabolism, 349–363 correlation with blood flow in developing brain under normal conditions, 350 glucose transport to brain and, 350 maturation under normal conditions, 349–350 in human brain, 349 in rat brain, 349–350 during seizures, 350–362 cerebral metabolic rates for glucose and, 351–359 SE effects on LCBF in immature brains and, 359–362 seizure effects on brain energy reserves and metabolites and, 350–351 Cerebral infarction, acute, neuroimaging features of, 181 Cerebrospinal fluid lactate in, as marker of neuronal injury, 174 pleocytosis and, status-induced, 152–153 Cerebrovascular accident, as cause of SE, 28–29
Cerebyx. See Fosphenytoin CGP35348, seizure threshold and, 372, 373 CHA (N6-Cyclohexyladenosine), 318, 319 Chlormethiazide, for GCSE, 495 Chlormethiazole for convulsive SE, 516 as second-line agent, 496 (S)-4C3HPG ([S]4-Carboxy-3-hydroxyphenylglycine), proconvulsant and anticonvulsant actions of, 308–309 Ciliary neurotrophic factor (CNTF), 390 Circulatory support, in critical care, 608–609 Cisatracurium, for critical care, 608 Classification of status epilepticus, 13–15 clinical, 13–14 historical background of, 4 semiologic, 13, 14–15 description of seizure type and, 14–15 description of type of SE and, 14 Claustrum, spread of SE to extensive limbic regions from, 244 Clinical features of status epilepticus, 17 Clobazam, for ASE, 101–102 Clonazepam, 525. See also Benzodiazepines chemical structure of, 525, 527 for convulsive SE, 516 intranasal administration of, 532 for neonatal SE, 510 pharmacokinetics of, 527, 528 rectal administration of, 531 Clonic convulsive status epilepticus, 239 CNTF (ciliary neurotrophic factor), 390 Cocaine, maternal use of, neonatal SE and, 507 Cognitive function deficits following SE, 403–404 in ESES, 130 following febrile seizures, 339 nonconvulsive SPSE and, 74–75 sequelae of SE and, 44 Comatose patients, electrographic SE in, 110–112 Complex motor seizures, 14 Complex partial status epilepticus (CPSE), 75–82, 109, 113–114, 127 age and, 76 blood flow mapping of onset and propagation sites in in experimental CPSE, 192 in human CPSE, 192–193 cerebral water diffusibility, edema, and neuronal injury imaging in in experimental CPSE, 193 in human CPSE, 193–194 clinical characteristics of, 77–78 clinical classification of, 13, 15 clinical forms intermediate between SPSE and, 82–83 definition of, 75–76 diagnostic neuroimaging in, 185–190 detection of focal cerebral edema versus foreign tissue lesions and, 186–188 detection of structural brain lesions in diagnosis and, 185–186 emergency treatment of, 79 epidemiology of, 115 etiology of, 77, 115–116 following domoate intoxication, neuroimaging in, 194 frequency of cases of, 75 incidence of, 77 laboratory evaluation in, 78–79 neuronal injury due to, 119 NSE in, 172–173 pathophysiology of, neuroimaging studies of, 192–194
phenomenologic classification of, 75–76 prognosis of, 80–82 syndromes following, pathophysiology of, neuroimaging studies of, 194–195 terminology related to, 75 triggering factors for, 77 Computed tomography in ASE, 196 in CPSE, 194 in GCSE, 191 etiologic diagnosis using, 183–184 pathophysiological studies using, 177 structural brain lesion detection using, 178, 179, 181–185, 189 in GCSE, 178, 179, 183–185 in spike-wave stupor of the elderly, 189 Consciousness, clouding of in ASE, 95–98 in CPSE, 77 Continuous spike-and-wave discharges during slow-wave sleep (CSWS) syndrome, 127, 128 pathophysiology of, 131–132 Continuous status epilepticus, 252, 253 Convulsive status epilepticus (CSE), 163–167 clinical features of, 163–166, 167 hippocampal sclerosis in, 163, 165, 166 ischemic lesions in, 163 parenchymal necrosis in, 163, 166 refractory, treatment of, 517 treatment of, 515–517 Cortical dysplasia, neuroimaging features of, 182 Cortical lesions, epileptogenicity of, 423 Cortisol, serum, as marker of neuronal injury, 173–174 CPA (N6-Cyclopentyladenosine), 318 CPSE. See Complex partial status epilepticus (CPSE) Critical care, 607–612 airway management in, 607–608 circulatory support and basic critical care management in, 608–609 drug therapy for refractory SE in, 609–612 maintenance of seizure control and, 612 mechanical ventilation in, 608 CSE. See Convulsive status epilepticus (CSE) CSWS (continuous spike-and-wave discharges during slow-wave sleep) syndrome, 127, 128 pathophysiology of, 131–132 8-Cyclopentyl 1,3-dimethylxanthine (8-CPT), 315, 318–319 Cysticercosis, cerebral, neuroimaging features of, 181 Cytochrome c, translocation from mitochondria to cytosol, apoptosis and, 470
D Definition of status epilepticus, 11–15, 125, 409 classification and, 13–15 conceptual basis for, 11 for impending SE, 11, 12, 13 need for reexamination of, 18 operational, for therapeutic purposes, 493–494 risk of overtreatment and, 13 seizure duration as basis of clinical basis for, 11–12 experimental basis for, 12–13 Dendritic sprouting. See also Reactive synaptogenesis epileptogenesis and, 431 Dentate granule cell GABA receptors. See Hippocampal GABAA receptors
625
Dentate gyrus cell loss in, in PPS model, 342 mossy fiber sprouting in, 333, 391. See also Reactive synaptogenesis, in fascia dentata neurogenesis of, increase after ictal events, 333 Desflurane, for refractory SE, 611 Development factors, neurologic sequelae of SE and, 417–419 DFF40 (DNA fragmentation factor 40), apoptosis and, 470 Diazepam, 495, 498. See also Benzodiazepines chemical structure of, 525, 527 for convulsive SE, 516 for CPSE, 79 for emergency department treatment of SE, 600 GABAA receptor current enhancement by, 269, 270, 274–275 for GCSE, 486 as initial treatment, 483, 484 prehospital, 482 historical background of, 525 intranasal administration of, 532 lorazepam compared with, 496–497 for neonatal SE, 510 for out-of-hospital treatment of status epilepticus, 592–593 pharmacokinetics of, 527, 528 pharmacology of, 591 pharmacoresistance in SSSE and, 213–214 rectal administration of, 530, 531 for GCSE, 481–482 to reduce incidence or severity of chronic epilepsy following SE, 434 resistance to, 272–273, 276–277 Diazepam-phenytoin, 497 adverse effects of, 484 for GCSE, 485 as initial treatment, 483 Diffusion-weighted magnetic resonance imaging, 116 in CPSE, 193, 194 in GCSE, 190, 192, 195 structural brain lesion detection using, in neonates, 190 Dilantin. See Phenytoin Discrete seizures, 252, 253 DNA fragmentation factor 40 (DFF40), apoptosis and, 470 Domoate intoxication, epilepsy following, 425 neuroimaging in CPSE and, 194 Dopamine, for critical care, 609 Dormant basket cell hypothesis, 411, 428 Dorsomedial thalamus, role in SE spread, 245 Dosing. See also specific drugs inadequate, 482 Drug kinetics, in SE, 156 Duration of status epilepticus. See also Seizure duration late development of epilepsy and, 415, 416 mortality related to, 36 Dysembryoplastic neuroepithelial tumors, neuroimaging features of, 182
E EGF (epidermal growth factor), 390–391 Electroencephalogram, 599 in ASE, 99–100, 117 emergency, 99 spike-and-wave activity on, 99–100 in clinical diagnosis, 598 in CPSE, paroxysmal activity on, 78, 79 in CSWS, 131–132 etomidate and, 574–575
626
in GCSE, 62, 190–191 ictal discharges on, 58–61 inhaled anesthetics and, 573 lidocaine and, 576 with magnesium, 579 in NCSE, 117 in neonatal SE, 116 neonatal seizures and, 503 in neonates, 141–142 in older children, 116–117 propofol and, 571 Electrographic nonconvulsive status epilepticus, 109–112 in ambulatory patients, 109–110 in comatose inpatients, 110–112 Electrographic status epilepticus clinical classification of, 13 encephalopathies associated with, pathophysiology of, neuroimaging studies of, 197–199 pathophysiology of, neuroimaging studies of, 197 Electrographic status epilepticus during slow-wave sleep (ESES) syndrome, 127–132 ABPE in, 128 comparison and relation of types of, 130 CSWS in, 128 pathophysiology of, 131–132 follow-up of, 130–131 negative myoclonus and, 128–130 NSENM in, 128 pathophysiology of, neuroimaging studies of, 197–198 prognosis of, 131, 132 Emergency department treatment, 597–606 clinical diagnosis and, 598–599 diagnostic testing and, 599–601 epidemiology of SE and, 597 initial management for, 598 patient management guidelines for, 601–602 prehospital treatment and, 597–598 research directions for, 602 therapies for, 599–601 Emotional disturbances, in CPSE, 78 Encephalitis bihemispheric, acute, neuroimaging features of, 181 limbic acute, neuroimaging features of, 181 paraneoplastic, neuroimaging features of, 183 Rasmussen’s, 72–73 neuroimaging features of, 181 pathophysiology of, neuroimaging studies of, 196 Encephalitis syndrome, historical background of, 3 Encephalomalacia, neuroimaging features of, 181 Encephalopathy anoxic, acute, neuroimaging features of, 181 epileptic, with suppression bursts. See Ohtahara syndrome hypertensive, neuroimaging features of, 181 hypoxic-ischemic, neonatal SE and, 503–504 EndoG, apoptosis and, 470 Endopiriform nucleus, spread of SE to extensive limbic regions from, 245 Energy metabolism, cerebral. See Cerebral energy metabolism Enkephalins, role in delayed cell death, 383–384, 385 Entopeduncular nucleus, modulation of seizure susceptibility by, 248 Entorhinal cortex recruitment from, 241–242 status epilepticus originating from, 240 EPC. See Epilepsia partialis continua (EPC)
Epidemiology of status epilepticus, 17–29, 39–47, 114–115, 597 of ASE, 94–95, 115 clinical features and, 17 of CPSE, 115 etiology and, 24–26, 39–41 ethnic origin and, 24–25 past history of epilepsy and, 26 first population-based study of, 18–20 of GCSE, 56, 115 importance of prospective data collection for study of, 19–20 incidence and, 20–23, 34, 39, 40 genetic predisposition and, 29 occurrence of SE in United States and the world and, 21–23 recurrence of SE and, 23 long-term sequelae of SE in childhood and, 44–46 morbidity and, 43–44 mortality and, 26, 27, 43 of myoclonic SE, 115 of NCSE, 41 new advances through studies of, 28–29 outcome of SE and, 27–28 recurrence of SE and, 47 of recurrent SE, 47 risk for status epilepticus and, 42–43 seizure types and, 23–24, 41 Epidermal growth factor (EGF), 390–391 Epilepsia partialis continua (EPC), 70–73, 114 diagnostic neuroimaging in, detection of structural brain lesions in diagnosis and, 189 of nonspecific etiology, 70–72 pathophysiology of, neuroimaging studies of, 196–197 Rasmussen’s encephalitis, 72–73 Epilepsy, future development of, with SE, 44–46 Epileptiform discharges, pseudoperiodic, persistent, neuroimaging studies of, 198–199 Epileptogenesis, SE-induced, 409, 423–436. See also Neurologic sequelae of status epilepticus experimental attempts to prevent, 413–415 experimental evidence for, 423–424 neuropathology associated with, 424, 425 extrapolation of experimental evidence to humans, 425 in immature brain, 426 mechanisms of, 410–411, 413–415, 426–436 evidence for new excitatory connections and, 429, 431, 432 location of epileptogenic focus and, 426–427 loss of inhibition and, 428–429, 430, 431 patterns of neuronal injury resembling mesial temporal sclerosis and, 427–428 prevention, mitigation, or reversal of epileptogenesis and, 431, 434–436 neuropathology associated with clinical evidence of, 425–426 experimental evidence of, 424, 425 EPSPs (excitatory postsynaptic potentials), 379 ESES. See Electrographic status epilepticus during slow-wave sleep (ESES) syndrome Ethnic origin in status epilepticus, 24–25 Etiology of status epilepticus, 24–26, 39–41, 115–116 acute symptomatic, 40 of ASE, 102–103 cerebrovascular accident as cause and, 28–29 of CPSE, 77, 115–116 cryptogenic/idiopathic, 39 ethnic origin and, 24–25 febrile, 40 of GCSE, 56
genetic predisposition and, 29 mortality related to, 35–36 progressive encephalopathy and, 40 remote symptomatic, 40 seizure type correlated with, 41 Etomidate for critical care, 607 for refractory SE, 574–575, 581, 611 adverse effects of, 575 animal models of seizures and, 574 clinical pharmacokinetics of, 574 clinical use of, 574 dosage and regimens for, 575 EEG effects of, 574–575 mechanisms of action of, 574 Excitatory postsynaptic potentials (EPSPs), 379 Excitotoxicity, 327–334. See also Neuronal damage apoptosis versus necrosis and, 331–333 excitotoxic hypothesis and, 327 long-term changes and, 333–334 SE-induced, 327–331 silver impregnation methods to identify cell populations vulnerable to, 328 temporal pattern of, 328–331 Extravasation, of phenytoin, 541
F Familial seizures, neonatal SE and, 507 Fascia dentata, reactive synaptogenesis in. See Reactive synaptogenesis, in fascia dentata Febrile seizures, consequences of, 339 Febrile status epilepticus, 45–46 Felbamate, to reduce incidence or severity of chronic epilepsy following SE, 434 FGFs (fibroblast growth factors), 390 Fibroblast growth factors (FGFs), 390 Filter hypothesis, 429 Fluorofelbamate, to reduce incidence or severity of chronic epilepsy following SE, 434 Fluothane. See Halothane Focal motor disturbances, in CPSE, 78 Focal neurologic deficits, in CPSE, 78 Foix-Chavany-Marie syndrome, 71 Forane. See Isoflurane Forebrain basal, modulation of seizure susceptibility by, 249, 250 generalization of limbic SE and, 246–251 seizure propagation between brain stem and, 252 Fosphenytoin, 495 adverse effects of, 484, 485 as alternative to phenytoin, 494–495, 542 animal studies of, 550 for convulsive SE, 516 for emergency department treatment of SE, 600–601 for GCSE, 485, 486, 497, 499 for continuing care, 487 intramuscular, 546–548 intravenous, clinical trials of, 548–550 for out-of-hospital treatment of status epilepticus, 593 parenteral, 545–546 pharmacoeconomic studies of, 550–551 pharmacology of, 592 phenytoin compared with, 498 to reduce incidence or severity of chronic epilepsy following SE, 435
627
Free radicals, postsynaptic generation of, reduction of, 472 Functional magnetic resonance imaging in CPSE, 192, 194 pathophysiological studies using, 177 in PLEDs, 198–199 Furosemide, for refractory SE, 580, 581
G GABA, potentiation of, by inhaled anesthetics, 572 GABAA antagonists, seizure duration and, 315 GABAA receptors benzodiazepines and, 525–526 SE-induced decreases in function of, 285–286 SNR effects on seizures and, 372–373 GABAB receptors, SNR effects on seizures and, 372, 373 GABAergic basket cells, 411, 413 GABAergic inhibition, 281–289 development of, 282, 284 loss of, 428–429, 430, 431 mechanisms contributing to decreased release of GABA and, 284–285, 287 physiology of, 281–282 postsynaptic, 281–282, 283 presynaptic, 282, 283 propofol and, 569 SE-induced decreases in GABAA receptor function and, 285–286 SE-induced early changes in, 284, 285, 286 SE-induced long-term changes in, 286–289 GABAergic mechanisms, in seizure termination, 315 GABAergic system, reactive synaptogenesis and, 445, 448–449, 450, 452 Gabapentin, to reduce incidence or severity of chronic epilepsy following SE, 434 GABA receptors, 267–278 in GCSE, 57–58 hippocampal. See Hippocampal GABAA receptors molecular mechanisms for altered function of, 277–278 plasticity of function during SE, 277 recombinant pharmacology of, 267–268 properties and structure of, 267, 268 in SSSE, 213, 214–217, 219 Galanin, endogenous, 222–224 Gamma-aminobutyric acid (GABA). See also GABA entries potentiation of, by inhaled anesthetics, 572 t-Vinyl GABA (GVG), seizure threshold and, 372, 373 Gangliocytomas, neuroimaging features of, 182 Gangliogliomas, neuroimaging features of, 182 GCSE. See Generalized convulsive status epilepticus (GCSE) GDNF (glial-cell-line-derived neurotrophic factor), 390 General anesthesia, 498, 500. See also Inhaled anesthetics for convulsive SE, 516 for GCSE, 486, 495 Generalized convulsive status epilepticus (GCSE), 55–63, 113 clinical classification of, 13, 14 clinical diagnosis of, 598–599 clinical features of, 58–61 clonic, 113 definition of, 55–56 diagnosis of, 62 diagnostic neuroimaging in, 178–185 detection of structural brain lesions in diagnosis and, 178–183
628
etiologic diagnosis with CT versus MRI and, 183–184 myoclonic and subtle, 184–185 EEG in, 58–61 epidemiology of, 56, 115 etiology of, 56 functional neuroimaging studies after, in human GCSE, 191– 192 historical background of, 3 mortality in, 62–63 myoclonic, 113 neuroimaging studies during and after, in experimental GCSE, 190–191 overt, 55 clinical features of, 58 pathology related to, 62 pathophysiology of, 56–58 neuroimaging studies of, 190–192 refractory, treatment of, 487–489 structural neuroimaging studies after, in human GCSE, 191 subtle, 55, 58, 113 neuroanatomy of, 255, 258 syndromes following, pathophysiology of, neuroimaging studies of, 194–195 time course of brain damage following, 234 tonic, 113 tonic-clonic, 113 treatment of, 481–489, 495, 497, 499, 500 adverse effects of drugs used for, 484–485 continuing care for, 487 environment of care and, 481 initial, 494–495 initiation of, 482–484 prehospital, 481–482 prevention of recurrence and, 487 for refractory SE, 487–489 sequences and protocols for, 485–486 types of, 13–14 Generalized nonconvulsive status epilepticus (GNCSE), 125, 126–127 akinetic, 127 ASE, 126 atonic, 127 with hypsarrhythmia, 126 minor epileptic SE, 126 myoclonic, 127 in myoclonic-astatic epilepsy and Lennox-Gastaut syndrome, 126 petit mal, 126 Generalized periodic eplileptiform discharges (GPEDs), in electrographic SE, 112 Generalized status epilepticus, 231 Genetic predisposition for status epilepticus, 29 Glial-cell-line-derived neurotrophic factor (GDNF), 390 Globus pallidus externa, modulation of seizure susceptibility by, 248 Globus pallidus interna, modulation of seizure susceptibility by, 248 Glucose cerebral metabolic rates for, 351–359 SE effects on, in immature animals, 351–359 plasma levels of, elevation in SE, 151 transport to brain, 350 Glutamate excitotoxicity and. See Neuronal damage induction of seizures or SE by, 295
microdialysis and, 295–296 release of calcium-dependent, blockade of, 473 sodium-dependent, reduction of, 473 resistance of immature brain to effects of, 402 Glutamate receptor(s), 295 changes in, as cause of seizures or SE, 296–298 in human focal epilepsy, 297–298 in kindled rats, 297 changes in, secondary to SE, 298 metabotropic. See Metabotropic receptors neuronal death related to, 464, 466 Glutamate receptor antagonists as antiepileptics, 298–299 neuroprotection by, 472 Glutamate transporters, change in, onset or maintenance of seizure activity and, 296 GNCSE. See Generalized nonconvulsive status epilepticus (GNCSE) GPEDs (generalized periodic eplileptiform discharges), in electrographic SE, 112 G protein-coupled receptors, neuronal death related to, 466 Grand mal status epilepticus. See Generalized convulsive status epilepticus (GCSE) Granule cell(s) damage to, in PPS model, 342 hyperexcitability of, mossy fiber sprouting and, 452–454 loss of, in PPS model, 342 Granule cell GABA receptors. See Hippocampal GABAA receptors Growth factors, neuroprotective effect of, 473 GVG (t-vinyl GABA), seizure threshold and, 372, 373
H Hallucinations, in CPSE, 78 Halothane, 572. See also Inhaled anesthetics for refractory SE, 611 Hamartomas, glial, neuroimaging features of, 182 Handling test, 403 HEE (hemiconvulsion-hemiparesis-encephalomalacia) syndrome, following GCSE or CPSE, neuroimaging studies in, 194–195 Hemiconvulsion-hemiparesis-encephalomalacia (HHE) syndrome, following GCSE or CPSE, neuroimaging studies in, 194–195 Hemiconvulsion-hemiplegia-epilepsy syndrome, neuroimaging features of, 183 Hemimegalencephaly, neuroimaging features of, 182 Hepatotoxicity, of valproate, 565–566 Heterotopia band, neuroimaging features of, 182 regional, neuroimaging features of, 182 Hilar cells damage to, in PPS model, 342 loss of, in PPS model, 342 Hippocampal GABAA receptors, 268–270 different effects of SE and TLE on, 277 involvement in SE, 273–276 dentate granule cell GABAA receptor currents from rats undergoing SE and, 273–274 diminished diazepam enhancement of GABAA receptor currents in granule cells from rats undergoing SE and, 274–275, 276–277 diminished zinc sensitivity of GABAA receptor currents in granule cells from rats undergoing SE and, 275, 276
pentobarbital enhancement of GABAA receptor current cells from rats undergoing SE and, 275–276 pharmacology of, 269–270 Hippocampal sclerosis, 4, 118–119 in CSE, 163, 165, 166 following febrile seizures, 339 mesial TLE with, following GCSE or CPSE, neuroimaging studies in, 194–195 neuroimaging features of, 183 Hippocampus epileptogenicity and, 423 lesions in, epileptogenesis and, 425, 426 neuronal damage in, 340 neuronal death in, 424, 425 recruitment from, 241–242 SE-induced epilepsy and, 410–411, 413–415 status epilepticus originating from, 240 time course following SE, sprouting visualized with Timm stain and, 234–236 vulnerability of, 379 History of status epilepticus, 3–6 of centralized conceptual issue, 4–5 of classification of types, 4 clinical, 3 of experimental studies, 5–6 of pathological consequences, 3–4 of therapy, 6 Hydrocephalus, acute, neuroimaging features of, 183 Hyperglycemia, nonketotic, EPC and, 71 Hyperglycinemia ketotic, neonatal SE and, 506–507 nonketotic, neonatal SE and, 506 Hyperpyrexia, in GCSE, 61 Hypertension, in SE, 156–158 Hypertensive encephalopathy, neuroimaging features of, 181 Hyperthermia historical background of, 3 with SE, 149, 150, 151 Hypnotics, withdrawal from, neonatal SE and, 507 Hypocalcemia, neonatal SE and, 505 Hypoglycemia, neonatal SE and, 505 Hypotension avoiding, 497 drug-induced, 484–485 inhaled anesthetics and, 573 with phenobarbital, 558 phenytoin-induced, 541–542 with valproate, 566 Hypoventilation, drug-induced, 484 Hypoxic-ischemic encephalopathy, neonatal SE and, 503–504 Hypsarrhythmia, NCSE with, 126
I Ictal activity, transition from interictal activity to, metabotropic receptors and, 310 Ideational apraxia, in CPSE, 78 Ideomotor apraxia, in CPSE, 78 Imaging studies. See Neuroimaging; specific imaging modalities Immobile status epilepticus, 229–230, 239 time course of brain damage following, 232, 233 Impending status epilepticus, 11, 12, 13 Incidence of status epilepticus. See Epidemiology of status epilepticus Infants. See also Neonatal entries myoclonic epilepsy in, obtundation status epilepticus in, 127
629
Infections, neonatal SE and, 507 Inhaled anesthetics. See also Halothane; Isoflurane for refractory SE, 572–574, 581, 611 adverse effects of, 573–574 animal models of seizures and, 572 clinical pharmacokinetics of, 572 clinical use of, 572–573 dosage and regimens for, 574 EEG effects of, 573 mechanisms of action of, 572 Inhibition. See GABAergic inhibition Inhibitory postsynaptic potentials (IPSPs), 379 Initiation sites, 231–232 Injection site reactions, with valproate, 566 Interictal activity, transition to ictal activity from, metabotropic receptors and, 310 Intracranial hemorrhage, neuroimaging features of, 181 IPSPs (inhibitory postsynaptic potentials), 379 Isoflurane, 572. See also Inhaled anesthetics for refractory SE, 611 Isovaleric acidemia, neonatal SE and, 507
K Kainate receptors, 295 Kainic acid receptors, neuronal death related to, 367–368, 466 Kernicterus, neonatal SE and, 507 Ketamine, 496, 500 for convulsive SE, 516 neuroprotective effect of, 474 for refractory SE, 499, 611 Ketotic hyperglycinemia, neonatal SE and, 506–507 Kindling, 231–232, 399 in amygdala, 235 in perirhinal cortex, 235 in SSSE, 209 Kojewnikow syndrome. See Epilepsia partialis continua (EPC) Kufs’ disease, in EPC, 71
L Laboratory markers CSF lactate as, 174 of SE-associated injury, 117, 173–174 cortisol as, 173–174 NAA as, 174 NSE as. See Neuron-specific enolase (NSE) Laboratory testing, 599 Lactate, in CSF, as marker of neuronal injury, 174 Lamotrigine, to reduce incidence or severity of chronic epilepsy following SE, 434 Landau-Kleffner syndrome, 127 Language disturbances, in CPSE, 78 Lennox-Gastaut syndrome hippocampal sclerosis in, 166 NCSE in, 126 tonic SE associated with, 14 Lethargic stupor, in ASE, 98 Leukemoid reactions, in SE, 151–152 Leukocyte demargination, in SE, 151–152 Levetiracetam, to reduce incidence or severity of chronic epilepsy following SE, 434 Lidocaine, 496 for convulsive SE, 516 for critical care, 607 for neonatal SE, 511
630
for refractory SE, 575–576, 581, 611–612 adverse effects of, 576 animal models of seizures and, 575 clinical pharmacokinetics of, 575–576 clinical use of, 576 EEG effects of, 576 mechanisms of action of, 575 Limbic encephalitis, paraneoplastic, neuroimaging features of, 183 Limbic regions, rostral, recruitment from, 242 Limbic status epilepticus, 239–251. See also Complex partial status epilepticus (CPSE) early spread from highly restricted regions to restricted patterns, 241–243 epileptogenesis and, 426 forebrain generalization of, 246–251 highly restricted, 240–241 historical background of, 3 neuronal death and, 424, 425 spread to extensive limbic regions, 243–246 Lissencephaly, neuroimaging features of, 182 Local cerebral blood flow, SE effects on, in immature brains, 359–362 Locus ceruleus, modulation of seizure susceptibility by, 250 Long-term complications of status epilepticus, 118 Lorazepam, 495, 497, 498, 525. See also Benzodiazepines chemical structure of, 525, 527 for convulsive SE, 516 for CPSE, 79 diazepam compared with, 496–497 for emergency department treatment of SE, 599–600 for GCSE, 485, 486 as initial treatment-6, 483 prehospital, 482 for neonatal SE, 510 neuroprotective effect of, 474–475 for out-of-hospital treatment of status epilepticus, 592, 593 pharmacokinetics of, 527, 528 pharmacology of, 592 rectal administration of, 531
M Magnesium, for refractory SE, 578–580, 581 adverse effects of, 580 animal models of seizures and, 578, 579 clinical pharmacokinetics of, 578–579 clinical use of, 579–580 dosage and regimens for, 580 EEG effects of, 579 mechanisms of action of, 578 Magnetic resonance angiography, in CPSE, 192 Magnetic resonance imaging, 116 in ASE, 188, 189 in CPSE, 185–188, 194 in EPC, 189, 196–197 in ESES, 198 in GCSE, 178–179, 180, 183–184, 191, 195 in NCSE, 188, 189 in Ohtahara syndrome, 198 pathophysiological studies using, 177 structural brain lesion detection using, 178–179, 180, 181–184, 185–188, 189, 190 Magnetic resonance spectroscopy in CPSE, 194 in EPC, 196, 197
in GCSE, 190, 191 in PLEDs, 199 Maple syrup urine disease, neonatal SE and, 506 Masticatory status epilepticus, 230–231, 239 time course of brain damage following, 233–234 Maximal dentate activation (MDA), 315 Mechanical ventilation, in critical care, 608 Medical complications, 117–118 MELAS syndrome in EPC, 71 in GCSE, 178–179 Meningiomas, neuroimaging features of, 182 Meningitis, neuroimaging features of, 181 Mental regression, in ESES, 130 Metabotropic receptors, 295, 305–311 actions on excitotoxic brain damage, 309–310 agonists for, proconvulsant and anticonvulsant actions of, 307–308, 309 amygdaloid kindling in rat and, 309 antagonists for, proconvulsant and anticonvulsant actions of, 308–309 changes in, as consequence of SE, 310–311 classification of, 305–307 neuronal death related to, 466 pharmacologic approaches and, 307, 308 study methods for, 307 transition from interictal to ictal state and from seizures to SE and, 310 in in vitro models of epilepsy and SE, 309 Metastasis, cerebral, neuroimaging features of, 182 N-Methyl-D-aspartate (NMDA). See NMDA entries Metrizamide, ASE associated with, 103 mGluRs. See Metabotropic receptors Midazolam, 495, 498, 525. See also Benzodiazepines buccal/sublingual administration of, 530–531 chemical structure of, 525, 527 for convulsive SE, 516 for emergency department treatment of SE, 600 for GCSE, 485, 486, 495, 497, 499 as initial treatment, 484 refractory, 488 intramuscular administration of, 531–532 intranasal administration of, 532 for neonatal SE, 510 for out-of-hospital treatment of status epilepticus, 593 pharmacokinetics of, 527, 528 pharmacology of, 591–592 rectal administration of, 531 for refractory SE, 610–611 as second-line agent, 496 Midbrain, dorsal, modulation of seizure susceptibility by, 248 Minor convulsive status epilepticus. See Masticatory status epilepticus Minor epileptic status epilepticus, 126 MK-801, to reduce incidence or severity of chronic epilepsy following SE, 434–435 Morbidity, 36, 43–44 Morris water maze, 403 Mortality, 26, 27, 28, 34–36, 43, 118 with GCSE, 62–63 risk factors for long-term, 35–36 short-term, 34–35 seizure duration related to, 119 short-term, 34
sudden death and, in SE, 158 time trends in, 36 Mossy fiber sprouting, 333, 413. See also Reactive synaptogenesis electrophysiologic changes and, 452–454 epileptogenesis and, 429, 431, 432 neurotrophic factors and, 391, 395 visualized with Timm stain, time course following SE, 234–236 mRNA BDNF, SE induction of expression in developing brain, 393, 394, 395 posttranslational editing for glutamate receptors, 296–297 Muscimol, seizure threshold and, 372, 373 Myoclonic-astatic epilepsy, NCSE in, 126 Myoclonic epilepsy, obtundation status epilepticus in, in infancy, 127 Myoclonic jerks, in EPC, 71–72 Myoclonic status epilepticus, 56, 127 diagnostic neuroimaging in, 184–185 epidemiology of, 115 treatment of, 564 Myoclonus in ASE, 98 negative ESES syndrome and, 128–130 NCSE with, 128
N NAA. See N-Acetylaspartate (NAA) NADH-coenzyme Q reductase deficiency, EPC and, 71 Narcotic withdrawal, neonatal SE and, 507 NCSE. See Nonconvulsive status epilepticus (NCSE) N6-Cyclohexyladenosine (CHA), 318, 319 N6-Cyclopentyladenosine (CPA), 318 Necrosis, 468. See also Neuronal death apoptosis versus, 331–333 Negative myoclonus ESES syndrome and, 128–130 NCSE with, 128 Neocortex, SE originating from, 251 Neocortical status epilepticus, 251 Neonatal seizures, 135–142 classification of, 136–138 definition of SE and, 135 EEG and, 141–142 epidemiology of, 136 etiology of, 138–139 impact on prognosis, 139–140 predisposition to SE in, 135–136 treatment of, AEDs for, 140–141 Neonatal status epilepticus, 503–512 diagnosis of, 503, 508 EEG in, 503 neuroimaging in, 190 EEG in, 116 etiology of, 503–508 birth trauma and, 504 familial seizures and, 507 hypoxic-ischemic encephalopathy and, 503–504 kernicterus and, 507 metabolic, 505–507 toxins and, 507–508 outcome in, 511–512 prognosis of, 119 treatment of, 508–511 recommendation for, 511 Nerve growth factor (NGF), 389, 392. See also Neurotrophic factors
631
Neuroanatomy of status epilepticus, 239–258 anticonvulsant effects on, 255, 257 brain stem and, 251–252 status epilepticus originating from limbic sites and. See Limbic status epilepticus status epilepticus originating from neocortex and, 251 subtle generalized status epilepticus and, 255, 258 temporal dynamics of territorial spread and, 252–255 Neurofibromatosis, neuroimaging features of, 182 Neurogenesis, of dentate gyrus, increase after ictal events, 333 Neuroimaging, 116, 177–200, 599 in CPSE, 78–79, 80 diagnostic in CPSE, 185–190 in EPC, detection of structural brain lesions in diagnosis and, 189 in GCSE, 178–185 in myoclonic SE, 184–185 in NCSE, in elderly persons, 189 in neonatal SE, 190 in SPSE, nonmotor, putative diagnostic role of, 189–190 pathophysiology studied with, 190–199 in ASE, 195–196 in CPSE, 192–194 in encephalopathies associated with subclinical (electographic) SE, 197–199 in GCSE, 190–192 in SPSE, 196–197 in subclinical (electrographic) SE, 197 in syndromes following GCSE or CPSE, 194–195 Neurological abnormalities, as risk factor for status epilepticus, 42 Neurologic sequelae of status epilepticus, 399–400, 409–419. See also specific sequelae animal models of TLE and, 409–410 developmental factors and, 417–419 mechanisms of SE-induced epileptogenesis and, 410–411, 413–415 SE duration and late development of epilepsy and, 415, 416 Neuromuscular junction blockade, for critical care, 607–608 Neuronal circuitry, neurotrophic factors and, 395 Neuronal damage, 339–345, 367–368, 400–401, 424, 425, 466 experimental data on, 340–344 extrahippocampal, 340 hippocampal, 340 markers of, 117 cortisol as, 173–174 CSF lactate as, 174 NAA as, 174 NSE as. See Neuron-specific enolase (NSE) metabotropic receptor agonist actions on, 309–310 modulation during seizures, 158, 159 resembling mesial temporal sclerosis, 427–428 time course following SE, 232–236 in ambulatory SE, 232–233, 234 in GCSE, 234 in immobile SE, 232, 233 in masticatory SE, 233–234 sprouting visualized with Timm stain and, 234–236 Neuronal death. See also Apoptosis; Necrosis axon sprouting as consequence of, 447 bcl-2 gene family and, 158–159 evidence for, 463–464 manipulation of cell-death-promoting or cell-death-inhibiting proteins and, 474
632
mechanisms of, 464, 466–468 AMPA receptor antagonists and, 468 excitotoxic hypothesis and, 466 NMDA receptor antagonists and, 466–468 neuroprotective strategies and, 470–475 blockade of pre- and postsynaptic neuronal depolarization with sodium channel blockers as, 473 blockade of presynaptic calcium-dependent, vesicular glutamate release as, 473 brief antecedent seizures as neuroprotectants and, 474 cell-permeant calcium chelators as, 472 growth factors as, 473 inhibition of calcium-sensitive proteases and lysosomal cathepsins as, 472–473 inhibition of poly (ADP-ribose) polymerase-1 as, 474 manipulation of cell-death-promoting or cell-death-inhibiting proteins as, 474 platelet-activating factor antagonists as, 473 postsynaptic blockade of calcium influx as, 472 postsynaptic glutamate receptor blockade as, 472 reduction of calcium-independent, sodium-dependent glutamate release as, 473 reduction of postsynaptic free radical generation as, 472 suggested first approach for, 474–475 region-specific, 391 time course of, 464, 465 types of, 468–470 Neuron-specific enolase (NSE), 169–173 detection of, 169 epileptic control values for, 170 in individual seizures, 171 limitations of, 174 as marker for neuronal injury, 117, 170–171 measurement of neurologic damage by, 340 mechanism of release of, 173 normal values of, 169–170 in SE, 171–173 in CPSE-5, 172 in NCSE, 172 Neuropeptides, in SSSE, 221–224 Neuroprotection. See also Neuronal death, neuroprotective strategies and by glutamate antagonists, 298–299 by neurotrophic factors, 393, 395 by phenobarbital, 557 Neuropsychological testing, in ASE, 96–97 Neurosurgery, for refractory SE, 612 Neurotrophic factors, 389–396 neuromodulatory functions of, 390 to prevent axon sprouting, 414 receptors for, 390 seizure-induced expression of in adult brain, 391–393 in developing brain, 393, 394, 395 functions of, 393, 395–396 structural changes in brain following SE and, 391 NGF (nerve growth factor), 389, 392. See also Neurotrophic factors Nimodipine, neuroprotective effect of, 472 Nitrous oxide (NO), 318 NMDA, inhaled anesthetics and, 572 NMDA receptor(s), 295, 305 antagonists of, protective role of, 298–299 excitotoxicity and, 367, 368 hippocampal damage and, in PPS model, 342 neuronal death related to, 466–468 propofol and, 569
reactive synaptogenesis and, 450, 451 in SSSE, 213, 217–218, 220 NMDA receptor antagonists neuroprotection by, 472 neuroprotective effect of, 473, 474 NO (nitrous oxide), 318 Nonconvulsive simple partial status epilepticus. See Simple partial status epilepticus (SPSE), nonconvulsive Nonconvulsive status epilepticus (NCSE), 24, 55–56, 125–132 absence. See Absence status epilepticus (ASE) clinical manifestations of, 125 complex partial. See Complex partial status epilepticus (CPSE) confusional, 91 diagnostic neuroimaging in, 188–190 in elderly persons, 189 EEG in, 117 electrographic, 109–112 in ambulatory patients, 109–110 in comatose inpatients, 110–112 epidemiology of, 41 ESES syndrome. See Electrographic status epilepticus during slow-wave sleep (ESES) syndrome frontal, 82, 83, 84 generalized. See Generalized nonconvulsive status epilepticus (GNCSE) with hypsarrhythmia, 126 Landau-Kleffner syndrome, 127 nonconfusional, 91 NSE in, 172 obtundation, in severe myoclonic epilepsy in infancy, 127 partial complex (focal). See Complex partial status epilepticus (CPSE) simple. See Simple partial status epilepticus (SPSE), nonconvulsive treatment of, 518–519 treatment of, 517–519, 564 Nonketotic hyperglycinemia, neonatal SE and, 506 Norepinephrine, elevation of, vasoconstriction and, 151 NSE. See Neuron-specific enolase (NSE)
O Obtundation status epilepticus, in severe myoclonic epilepsy, in infancy, 127 Ohtahara syndrome, 507 neuroimaging studies of, 198 Olfactory bulb, status epilepticus originating from, 240 Oligodendromas, neuroimaging features of, 182 Open field test, 403 Opioid peptides, endogenous, in SSSE, 221, 222 Opioid receptors, 318 Outcome of status epilepticus, 27–28 Out-of-hospital treatment, 591–593 clinical studies of, 592–593 pharmacology of agents used for, 591–592
P Pallidum, ventral, modulation of seizure susceptibility by, 248 Pancreatitis, with valproate, 566 Paraldehyde for convulsive SE, 516 for GCSE, 495 for refractory SE, 576–578, 581 adverse effects of, 577 animal models of seizures and, 576–577
clinical pharmacokinetics of, 577 clinical use of, 577 dosage and regimens for, 577–578 mechanisms of action of, 576 as second-line agent, 496 Past history of epilepsy, as etiologic factor, 26 PEDs. See Periodic eplileptiform discharges (PEDs) Pentobarbital, 500 for emergency department treatment of SE, 601 enhancement of GABAA receptor currents from rats undergoing SE, 275–276 for GCSE, 485, 486, 495 as initial treatment, 484 refractory, 487 for refractory SE, 499, 610 as second-line agent, 496 Pentothal, as second-line agent, 496 Perforant path stimulation (PPS) model circuit modifications resulting from SE in, 428–429 epileptogenicity and, 423 neuronal damage and, 341–342, 343, 344 of SSSE, 210–214 Periaqueductal gray, modulation of seizure susceptibility by, 249 Periodic eplileptiform discharges (PEDs) in GCSE, 58, 61 generalized, in electrographic SE, 112 Perirhinal cortex as kindling structure, 235 spread of SE to extensive limbic regions from, 243–244 Perisylvian malformation, bilateral, neuroimaging features of, 182 Pertussis toxin (PTX), 318 Petit mal status epilepticus, 91–92, 126. See also Absence status epilepticus (ASE) historical background of, 3 Pharmacoresistance, development of, 272–273 Phenobarbital, 496–497, 553–559 adverse effects of, 484, 558–559 chemistry of, 553–554 for convulsive SE, 516 dosage and clinical use of, 556–557 efficacy in SE, 555–556, 557 for emergency department treatment of SE, 601 for GCSE, 485, 486, 495, 497, 499 as initial treatment, 6, 483 mechanism of action of, 553, 554 for neonatal SE, 509 neuroprotective effects of, 557 pharmacokinetics of, 554–555 to reduce incidence or severity of chronic epilepsy following SE, 435 for refractory SE, 610 as second-line agent, 496 Phenytoin, 496, 539–542. See also Diazepam-phenytoin adverse effects of, 484, 485 animal studies of, 550 for convulsive SE, 516 dosing for, 541 for emergency department treatment of SE, 600 fosphenytoin as alternative to, 494–495, 498, 542 for GCSE, 485, 486, 497 for continuing care, 487 as initial treatment, 6, 483 mechanism of action of, 539 for neonatal SE, 509–510 for out-of-hospital treatment of status epilepticus, 593 parenteral, 540–541, 545
633
Phenytoin (continued ) pharmacoeconomic studies of, 550–551 pharmacoresistance in SSSE and, 213–214 to reduce incidence or severity of chronic epilepsy following SE, 435 as second-line drug, 495–496 time course of action of, 539–540 toxicity of, 541–542 Phlebitis, drug-induced, 485 Physiologic responses to status epilepticus, 149–159. See also specific responses Piriform cortex central, spread of SE to extensive limbic regions from, 245 deep anterior, spread of SE to extensive limbic regions from, 245 spread of SE to extensive limbic regions from, 244–245 Platelet-activating factor (PAF) antagonists, neuroprotective effect of, 473 PLEDs (pseudoperiodic lateralized epileptiform discharges), neuroimaging studies of, 198–199 Polymicrogyria, focal, neuroimaging features of, 182 Poly(ADP-ribose) polymerase-1, inhibition of, neuroprotective effect of, 474 Pontine reticular formation, modulation of seizure susceptibility by, 248 Porencephaly, neuroimaging features of, 181 Positron-emission tomography in ASE, 195–196 in CPSE, 192, 193, 194 in electrographic SE, 196 in EPC, 196 in ESES, 198 pathophysiological studies using, 177 in PLEDs, 198 in SPSE, 196 Postsynaptic receptors, reactive synaptogenesis and, 449–452 PPE (preproenkephalin), 383–384, 385 PPS model. See Perforant path stimulation (PPS) model P75 receptors, in cell death regulation, 390 Precipitating factors, for CPSE, 77 Pregabalin, to reduce incidence or severity of chronic epilepsy following SE, 435 Prehospital treatment, 597–598 Preproenkephalin (PPE), 383–384, 385 Primates, nonhuman, cell death in, 341 Primidone, for neonatal SE, 510–511 Procaine derivatives, neonatal SE and, 507 Prognosis of status epilepticus, 118–119 of CPSE, 80–82 of ESES, 131, 132 after first episode, 33–37 incidence of SE and, 34 morbidity and, 36 mortality and, 34–36 recurrence of SE and, 36–37 Rochester, Minnesota study of, 33 impact of neonatal seizures on, 139–140 neonatal, 119 Propofol for convulsive SE, 516 for CPSE, 79 for emergency department treatment of SE, 601 for GCSE, 485, 486, 495 as initial treatment, 484 refractory, 488–489 for out-of-hospital treatment of status epilepticus, 593 pharmacology of, 592
634
for refractory SE, 499, 569–572, 581, 611 adverse effects of, 571–572 animal models of seizures and, 569–570 clinical pharmacokinetics of, 570 clinical use of, 570–571 dosage and regimens for, 571–572 EEG effects of, 571 mechanisms of action of, 569 as second-line agent, 496 Propofol infusion syndrome, 498, 500 Propylene glycol, phenytoin toxicity due to, 541 Pseudoperiodic lateralized epileptiform discharges (PLEDs), neuroimaging studies of, 198–199 Psychiatric manifestations, in ASE, 99 Psychotropic medications, ASE associated with, 102–103 p53 tumor-suppressor gene, apoptosis and, 469 PTX (pertussis toxin), 318 Pulmonary vascular hypertension, in SE, 156–158 Purple glove syndrome, 485, 494, 541 Pyramidal cell damage, in PPS model, 342 Pyridoxine for convulsive SE, 516 dependency of, neonatal SE and, 505–506
Q Quality of care, 615–618 assessment of, 615–616 intervention research to improve, 616–618 research agenda for, 619
R Race, as risk factor for status epilepticus, 42–43 Radioimmunoassay (RIA), for NSE detection, 169 Raphe nucleus, dorsal, modulation of seizure susceptibility by, 250 Rasmussen’s encephalitis, 72–73 neuroimaging features of, 181 pathophysiology of, neuroimaging studies of, 196 Rat, as subject for study, 340 Reactive synaptogenesis, 441–454 axon and dendritic responses to partial synaptic loss and, 441–443 collateral sprouting and, 442 denervation-renervation process and, 443 in fascia dentata, 443–454 axon sprouting as consequence of SE-induced neuronal loss and, 447–449 functional consequences of, 449–454 loss of neuron following SE and, 447 mechanisms influencing axon sprouting and, 448, 449, 450 normal anatomy and, 443–447 paraterminal sprouting and, 443 Recurrent status epilepticus, 23, 36–37 convulsive, 119 epidemiology of, 47 prevention of, in GCSE, 487 Refractory status epilepticus critical care for, 609–612 treatment of, 498, 499, 569–582 etomidate for, 570, 574–575, 581 focal perfusion of antiepileptic drugs and, 580–581, 582 furosemide for, 580, 581 inhaled anesthetics for, 572–574, 581 lidocaine for, 575–576, 581 magnesium for, 578–580, 581
paraldehyde for, 576–578, 581 propofol for, 569–572, 581 Research on adenosine, future directions for, 320 on emergency department treatment, future directions for, 602 future directions for, 621–622 intervention, to improve quality of care, 616–618 on quality of care, agenda for, 618–619 Respiratory depression phenobarbital and, 558 propofol and, 571 Retrograde amnesia, in CPSE, 78 RIA (radioimmunoassay), for NSE detection, 169 Rocuronium, for critical care, 608
S Schizencephaly, neuroimaging features of, 181 Seizure(s) antecedent, as neuroprotectants, 474 first, SE as, 45 prior, as risk factor for status epilepticus, 42 Seizure duration definition of status epilepticus based on clinical basis for, 11–12 experimental basis for, 12–13 GABAA antagonists and, 315 mortality related to, 119 Seizure susceptibility, 379–384 age-related differences in, mechanisms responsible for, 401–403 delayed cell death and. See Cell death, delayed factors involved in age-dependent seizure-induced damage and, 380 increased, in immature brain, 379–380 resistance of immature brain to seizure-induced neuronal cell loss and, 380, 381 Seizure termination in critical care, 609, 610 GABAergic mechanisms in, 315 Seizure types, 23–24, 28, 41 correlation with etiology, 41 mortality related to, 36 Self-sustaining status epilepticus (SSSE), 209–225 GABA receptors and, 213, 214–217, 219 maintenance of, 212 mechanism of transition from isolated seizures to SE and, 214–217, 219 mechanisms of, 224–225 models of, 209–214 neuronal circuitry subserving, 218, 220–221 autoradiographic studies using 2-DG and, 221 electrographic mapping of, 218, 220 immunostaining for fos protein and, 220 neuropeptides in, 221–224 NMDA receptors and, 213, 217–218, 220 NMDA receptor trafficking, synaptic potentiation, and maintenance phase of, 217–218, 220 ontogeny of, 224 pharmacologic distinctiveness of two phases of, 212–213 threshold for initiation of, 210–212 time-dependent development of pharmacoresistance and, 213–214 Semiologic classification of status epilepticus, 13, 14–15 description of seizure type and, 14–15 description of type of SE and, 14 Sensory seizures, 14–15
Simple partial status epilepticus (SPSE), 69–75, 114, 127 clinical forms intermediate between CPSE and, 82–83 convulsive, 69–73 epilepsia partialis continua, 70–73 somatomotor, 69–70, 71 nonconvulsive, 73–75 with affective symptoms, 75 auditory, 74 with cognitive symptoms, 74–75 somatosensory, 74 with vegetative symptoms, 74 visual, 74 nonmotor, diagnostic neuroimaging in, putative diagnostic role of, 189–190 pathophysiology of, neuroimaging studies of, 196–197 Single-photon emission computed tomography, 116 in CPSE, 192 in Ohtahara syndrome, 198 pathophysiological studies using, 177 in PLEDs, 198 in SPSE, 196 structural brain lesion detection using, 190 SNC (substantia nigra pars compacta), 371, 372 SNL (substantia nigra pars lateralis), 371 SNR. See Substantia nigra pars reticulata (SNR) Sodium channel blockers, blockade of pre- and postsynaptic neuronal depolarization with, 473 Solitary tract, nucleus of, modulation of seizure susceptibility by, 250 Somatomotor simple partial status epilepticus, 69–70, 71 Somatosensory nonconvulsive simple partial status epilepticus, 74 SP (substance P), endogenous, 224 Spike-wave index, in ESES, 130 Spike-wave stupor, 91, 126. See also Absence status epilepticus (ASE) pathophysiology of, neuroimaging studies of, 196 Spontaneous seizures, fascia dentata synaptic reorganization and, 452 Spread of status epilepticus to extensive limbic regions, 243–246 from amygdala, 243 from claustrum, 244 from endopiriform nucleus, 245 from perirhinal cortex, 243–244 from piriform cortex, 244–245 role of thalamic nuclei in, 245–246 between forebrain and brain stem, 252 temporal dynamics of, 252–255 SPSE. See Simple partial status epilepticus (SPSE) SSSE. See Self-sustaining status epilepticus (SSSE) Staring status epilepticus. See Immobile status epilepticus Striatum, modulation of seizure susceptibility by, 248 Stupor, lethargic, in ASE, 98 Sturge-Weber syndrome, neuroimaging features of, 182 Substance P (SP), endogenous, 224 Substantia nigra pars compacta (SNC), 371, 372 Substantia nigra pars lateralis (SNL), 371 Substantia nigra pars reticulata (SNR), 371–375 anatomy and connectivity of, 371–372 developmental profile of “anticonvulsant” region of, 374–375 modulation of seizure susceptibility by, 247–248 role in seizures in adult animals, 372–374 role in seizures in young animals, 374 Subthalamus, modulation of seizure susceptibility by, 248 Succinylcholine, for critical care, 607–608 Sudden death, in SE, 158 Synaptic connections, SE effects on, 342–343 Synaptic plasticity, in adult brain, 400 Synaptogenesis, reactive. See Reactive synaptogenesis
635
T Tachykinins, endogenous, 224 Tegmental reticular nucleus, laterodorsal, modulation of seizure susceptibility by, 249 Temporal lobe epilepsy (TLE) animal models of, 409–410 hippocampal GABAA receptors and, 277 mesial evolution to, 119 with hippocampal sclerosis, following GCSE or CPSE, neuroimaging studies in, 194–195 with mesial temporal sclerosis, following febrile seizures, 339 natural history of, 410, 411, 412 SE in, 166, 167 Temporal sclerosis, mesial following SE, 425–426 patterns of neuronal injury resembling, 427–428 with prolonged febrile seizures, 45–46 temporal lobe epilepsy with. See Temporal lobe epilepsy (TLE), with mesial temporal sclerosis 4,5,6,7-Tetrahydroisoxazolo[5,5-c]pyridin-3-ol (THIP), seizure threshold and, 372, 373 Thalamic nuclei, role in SE spread, 245–246 Thalamus, modulation of seizure susceptibility by, 247 Theophylline, proconvulsant effects of, 318 Thiopental for convulsive SE, 516 for critical care, 607 for GCSE, 495 refractory, 487 for neonatal SE, 511 for refractory SE, 610 as second-line agent, 496 THIP (4,5,6,7-tetrahydroisoxazolo[5,5-c]pyridin-3-ol), seizure threshold and, 372, 373 Thrombocytopenia, with valproate, 566 Tiagabine, nonconvulsive SE associated with, 518 Tissue necrosis, drug-induced, 485 TLE. See Temporal lobe epilepsy (TLE) Todd’s paresis, 82 Tonic status epilepticus associated with Lennox-Gastaut syndrome, 14 treatment of, 518 Topiramate to reduce incidence or severity of chronic epilepsy following SE, 435 for refractory SE, 612 Toxicity. See also specific drugs of valproate, 565–566 Treatment of status epilepticus, 515–520. See also specific drugs and types of status epilepticus acute changes in, 270, 272–273 during acute period, 436 benzodiazepines for, choice of, 495, 497–498 for convulsive SE, 515–517 critical care and. See Critical care emergency, for CPSE, 79 in emergency department. See Emergency department treatment future of, 622 general anesthesia for, choice of, 498, 500 hydantoins for, comparison of, 498 initial choice of benzodiazepine for, 495, 497–498 fosphenytoin versus phenytoin for, 494–495
636
one versus two drugs for, 494, 497 protocols for, 495 initiation of, 482–484 dosing considerations for, 482 in hospital, controlled clinical trials of, 482–483 uncontrolled case studies of, 483–484 VA cooperative study of, 483 during latent period, 436 for neonatal seizures, AEDs for, 140–141 in neonates, 508–511 for nonconvulsive SE, 517–519 out-of-hospital, 591–593 clinical studies of, 592–593 pharmacology of agents used for, 591–592 prehospital, 532–533, 597–598 for refractory SE, 609–612 therapeutic algorithms for, 496–500 therapeutic attitudes and, 493–496 initial treatment of GCSE and, 494–495 management of treatment failures and, 495–496 operational definition of SE for therapeutic purposes and, 493–494 timing of, 515 for treatment failures, 495–496 second-line drugs for, 495–496 vigor of, 496 Tuberous sclerosis, neuroimaging features of, 183 Tyrosine kinases, as neurotrophic factor receptors, 390
U Ulegyria, neuroimaging features of, 181 Unilateral status epilepticus, clinical classification of, 13 Urea cycle abnormalities, neonatal SE and, 506
V Vagal nerve stimulation, for refractory SE, 612 Valproate, 496, 561–566 ASE associated with, 103 for convulsive SE, 516 dosage and administration of, 565 efficacy in SE, 562–565 adult studies of, 562–564 pediatric studies of, 564–565 for emergency department treatment of SE, 601 for GCSE, 485, 497, 499 refractory, 489 indications for, 561 mechanism of action of, 561 for myoclonic SE, 564 for nonconvulsive SE, 564 for out-of-hospital treatment of status epilepticus, 593 rapid infusions of, tolerability of, 562 to reduce incidence or severity of chronic epilepsy following SE, 435 for refractory SE, 498, 499, 612 safety trials of, 561–562 side effects of, 565–566 Valproic acid, for neonatal SE, 511 Vasoconstriction, in SE, 151 Vecuronium, for critical care, 608 Vegetative signs, in CPSE, 78 Vegetative symptoms, nonconvulsive SPSE with, 74 Ventromedial thalamus, role in SE spread, 246
Vigabatrin, to reduce incidence or severity of chronic epilepsy following SE, 435 t-Vinyl GABA (GVG), seizure threshold and, 372, 373 Visual hallucinations, in CPSE, 78 Visual nonconvulsive simple partial status epilepticus, 74
W Waxing-and-waning seizures, 252, 253 West’s syndrome, historical background of, 3
Z ZAPA ([Z]-3-[(aminoiminomethyl)thio] prop-2-enoic acid), seizure threshold and, 372, 373 Zinc diminished sensitivity of GABAA receptor currents from rats undergoing SE, 275, 276 GABAA receptor current reduction by, 270, 271 Zolpidem, GABAA receptor current enhancement by, 269–270, 271
637
