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 (<1 year old) and the elderly (>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 (<15 years old), 15.4% occurred in adults (ages 15–59 years), and 53.9% occurred in patients more than 60 years old. Deaths were directly related to the cause of SE in seven cases, to complications of SE in two cases, and to other causes in four cases. The low case fatality in Switzerland could be explained in part by the quality of medical care in the area. A more likely reason for the low case fatality in Switzerland is the exclusion of patients with anoxic encephalopathy, a condition known to be associated with a high mortality. S-T M R F Etiology We found heterogeneity across etiologic subgroups in the Rochester study (Figure 4.2). Almost all early deaths (90%) occurred among those with acute symptomatic SE. There was one death (5%) among people with remote symptomatic SE and one death (5%) among people with progressive symptomatic SE. No deaths occurred in the first 30 days in those with idiopathic/cryptogenic SE. Concurrent illness is therefore the most important determinant of early mortality. Among the acute symptomatic cases, cerebrovascular disease and anoxia secondary to cardiac arrest were the two most frequent causes of SE for those dying in the first 30 days. Both of these conditions are characterized by
: , , ,
trolling for other factors. This is at variance from the finding in the population-based study in Richmond and may relate to differences in case classification, analytic methods, or ethnic heterogeneity (8).
F 4.2 Thirty-day mortality in people with status epilepticus according to cause. Charted are survival figures.
high mortality independent of the occurrence of SE or seizures, making it impossible to evaluate the independent contribution of SE to mortality in these conditions. Similarly, in the Richmond study, anoxia and hypoxia were associated with a very high mortality. Age In Rochester, almost 75% of deaths occurred in those over 65. Age was the single most important predictor of death following SE. Short-term mortality was increased nearly 20-fold in those older than 65 when compared with the reference group of persons ages 1–19. The Richmond study also noted a high mortality among the elderly (38%). Mortality was low in children in both Richmond and Rochester. Sex The risk of death for males in the first 30 days was twice that for females. This was true even after restriction of the analysis to cerebrovascular and anoxic encephalopathic SE in the elderly to account for possible confounding by age or etiology of SE. A difference in the short-term prognosis of SE associated with sex has not been previously described. Males may have a higher frequency of other comorbid conditions, such as cardiopathies, that are more likely to be fatal if associated with SE (1). There may also be a biological explanation. The GABA-sensitive region of substantia nigra associated with regulation of seizure threshold is under steroid hormone control. Female rats have a higher seizure threshold than male rats, and after castration, neonatal male rats experience upregulation of their seizure threshold (25). The incidence of SE in males is twice that in females (14). The mortality in males with epilepsy is also increased over that expected in the general population (9). All of these observations suggest that mechanisms controlling seizure suppression or termination or mechanisms protecting against neuronal damage induced by prolonged seizures may be under hormonal control. Duration In the Rochester studies, we did not find duration of SE to be a predictor of short-term mortality after con-
L-T M The majority of studies of mortality following SE have focused on short-term outcome. Our historical cohort study of the Rochester population allows evaluation of mortality at specific intervals following SE. We can also make external comparisons with other seizure disorders and with the general population, in addition to internal comparisons. Information regarding vital status (living or dead) was complete through 1996 (19). Case-fatality ratio More than 40% of those with SE who survived the first 30 days died in the next 10 years. The risk of death was increased threefold compared with the general population. As in short-term mortality, three out of four deaths occurred among the elderly. In contrast to short-term mortality, where deaths occurred almost exclusively in those with acute symptomatic SE, the case fatality was greatest in those with SE in association with progressive symptomatic SE (75%). The mortality was similar for those with acute symptomatic SE (41%) and with remote symptomatic SE (43%). This finding is not surprising, since causes of acute symptomatic SE are for the most part the same factors associated with remote symptomatic SE. As expected, the case fatality was lowest among those with idiopathic/cryptogenic SE (29%) when compared with the other etiologic subgroups. This case fatality was higher than that expected in the general population but is not clearly elevated when compared with mortality in people with idiopathic/cryptogenic epilepsy who never had an episode of SE. L-T M R F Predictors of longterm mortality differ from predictors of mortality in the first 30 days. Age Mortality among those over age 65 at the time of SE was increased more than 50-fold when compared with those ages 1–19 years. It is not surprising that older individuals are at increased risk for death. The magnitude is related to the inclusion of most of the progressive symptomatic cases in this age group. The elderly had a twofold increase in the risk of death compared with elderly in the general population. In contrast, subjects less than 65 years of age had a mortality rate fivefold greater than the rate in the general population. The excess risk was greater among the young because of the low mortality of the reference group. Sex Sex was not a predictor of long-term mortality. Etiology Using mortality in the idiopathic/cryptogenic cases as a referent, the mortality among those with remote
, , :
35
symptomatic SE was increased 1.5-fold and was doubled in those with progressive and acute symptomatic SE. None of these differences was significant. Seizure type We confirm the malignancy of myoclonic SE observed in previous studies (relative risk = 3.1 with generalized SE as a referent); the poor prognosis is largely attributable to the fact that the underlying cause of SE in all cases was anoxic encephalopathy following myocardial arrest. Future studies evaluating prognostic factors should segregate patients with myoclonic causes from patients with other causes of SE. Duration The duration of SE was a predictor of long-term mortality. After controlling for other factors, those with SE of more than 24 hours’ duration were more than twice as likely to die than those with SE of less than 2 hours’ duration. There was an interaction between duration and etiology. The effect was accounted for primarily through increased mortality in 30-day survivors of acute symptomatic SE. Duration may be an indicator of severity of the associated insult rather than an independent predictor of prognosis. T T M SE Although no studies have specifically examined the question, there is a general perception that mortality after SE has decreased in recent years. This decrease has been attributed to better recognition and thus more rapid treatment of SE, and to better management of those with SE (22). Our studies in Rochester failed to support this perception, and in fact, time trends were in the opposite direction: the mortality following SE increased over the 50-year study period (1935–1984) (21). The increase was caused by an increase in incidence and an unchanged summary case fatality. The increased incidence and increased mortality are due to the occurrence of myoclonic SE after cardiac arrest in the last decade of our study. The mortality in the elderly was twice that of the youngest group across the entire study period. Mortality decreased in children over time, particularly in those less than 1 year old. If myoclonic SE is excluded, survivorship in the last decade of the study shows an improvement. Changes in causes of SE over time, particularly the high frequency of SE associated with anoxic encephalopathy following cardiac arrest in recent years, suggest that overall mortality and case fatality can be expected to increase further in the future (18).
Morbidity There have been anecdotal reports that SE is associated with an increase in morbidity, including a risk for continuing epilepsy and for cognitive and neurologic dysfunction. Few
36
systematic studies of these issues have been conducted in humans, however. In our population-based study from Rochester, new neurologic findings after SE not obviously attributed to the precipitating insult included hemiparesis, encephalopathy, mental retardation, and aphasia. Such findings occurred in five of 146 patients who survived the first 30 days (3.4%) (4). These outcomes occurred predominantly in patients with acute or remote symptomatique SE and the association between the convulsive episode and these outcomes remains uncertain. Unprovoked seizures after a first episode of unprovoked SE Studies that address the relationship between SE and seizure recurrence following a first unprovoked seizure are somewhat conflicting. In adults, SE as a first unprovoked convulsive episode is associated with an increased risk for seizure recurrence, although on multivariable analysis, this observation is limited to those with a first unprovoked seizure associated with a prior neurologic insult (13). In children, this seems not to be the case (27). Unprovoked seizures after acute symptomatic SE We compared the risk for unprovoked seizures after a brief acute symptomatic seizure with the risk following acute symptomatic SE (15). By 10 years of follow-up, the risk of unprovoked seizure following an episode of acute symptomatic SE was 41%. By contrast, the risk of unprovoked seizures was 13% for those with brief acute symptomatic seizure. Controlling for age, sex, and cause, SE increased the risk for subsequent unprovoked seizure 3.3-fold (95% CI: 1.8–6.1) when compared with brief acute symptomatic seizures. Among patients with acute symptomatic SE, the risk of unprovoked seizure was increased 18.8-fold in patients with anoxic encephalopathy, 7.1-fold in patients with a structural brain lesion associated with the acute illness, and 3.6-fold in patients with a metabolic cause of the acute illness. The increased risk for unprovoked seizure after acute symptomatic SE when compared with shorter seizures may reflect a more severe injury or more extensive damage in those with SE. Other possible explanations include damage caused by SE, or the biological substrate associated with the tendency to experience SE. SE may also be associated with the development of intractable epilepsy in those with recurrent unprovoked seizures (2).
SE Recurrence Individuals who have experienced one episode of SE are at substantially increased risk for subsequent episodes of SE when compared with those with seizures who have never experienced SE (16). It seems this is more likely a result of the underlying substrate than a result of the SE. In the Rochester study, SE recurrence was highest (about 80%) in
: , , ,
those with progressive symptomatic SE. This observation is similar to the findings of Shinnar et al. (27, 28). Recurrence risk is lower in other etiologic subgroups.
Summary The short-term mortality following SE is substantial but occurs primarily in those with acute symptomatic SE associated with illnesses that are also associated with a high mortality. As yet, the contribution of SE to mortality has not yet been properly evaluated with a comparison group with similar insults but without SE, and it is inappropriate to attribute this mortality to SE without further study. Clearly, SE is associated with an increased long-term mortality, and this observation seems independent of etiologic considerations. SE is also associated with an increased morbidity in terms of recurrence of SE. In adults, there seems an increased risk for subsequent epilepsy in those with a first remote symptomatic episode of SE, although children may not be at the same risk. Acute symptomatic SE is associated with an increased risk for subsequent epilepsy when compared with those with brief acute symptomatic seizures. SE may also be associated with progression to intractable epilepsy, and with permanent neurologic deficits independent of the associated insult. The causal associations for these observations are as yet unclear. Based on recent studies, the prognosis for people with SE is mainly conditional on the nature of the underlying condition. Clinical trials of SE should separately evaluate patients with a clearly poor prognosis, such as those with myoclonic SE following cardiac arrest and an anoxic encephalopathy (21). REFERENCES 1. Anderson, K., P. Wilson, P. Odell, and W. Kannel. An updated coronary risk profile: A statement for health professionals. Circulation 1991;83:356–362. 2. Barry, E., and W. A. Hauser. Status epilepticus: The interaction of epilepsy and acute brain disease. Neurology 1993;43: 1473–1478. 3. 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. 4. Cascino, G. D., D. Hesdorffer, G. Logroscino, and W. A. Hauser. Morbidity of non-febrile status epileptius in Rochester, Minnesota. Epilepsia 1998;39:829–832. 5. Coeytaux, A., P. Jallon, B. Galobardes, and A. Morabia. Incidence of status epilepticus in French-speaking Switzerland: (EPISTAR). Neurology 2000;55:693–697. 6. 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.
7. Commission on Epidemiology and Prognosis, International League Against Epilepsy. Guidelines for epidemiologic studies on epilepsy. Epilepsia 1993;34(4):592–596. 8. 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. 9. Hauser, W. A., J. F. Annegers, and L. R. Elveback. Mortality in patients with epilepsy. Epilepsia 1980;21:399–412. 10. Hauser, W. A., J. F. Annegers, and L. T. Kurland. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984. Epilepsia 1993;34(3):453–468. 11. Hauser, W. A., J. F. Annegers, and L. T. Kurland. Prevalence of epilepsy in Rochester, Minnesota: 1940–1980. Epilepsia 1991;32:429–445. 12. Hauser, W. A., J. F. Annegers, and W. Rocca. Descriptive epidemiology of epilepsy: Contributions of population-based studies from Rochester, Minnesota. Mayo Clin. Proc. 1996; 71(6):576–586. 13. 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. 14. 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. 15. Hesdorffer, D. C., G. Logroscino, G. Cascino, J. F. Annegers, and W. A. Hauser. Risk of unprovoked seizure after acute symptomatic seizure: Effect of status epilepticus. Ann. Neurol. 1998;44(6):908–912. 16. Hesdorffer, D. C., G. Logroscino, W. A. Hauser, and G. D. Cascino. Risk of and predictors for recurrence in status epilepticus. Epilepsia 1995;36(Suppl. 4):149. 17. Knake, S., F. Rosenow, M. Vescovi, W. H. Oertel, H. H. Mueller, A. Wirbatz, N. Katsarou, H. M. Hamer, and the Status Epilepticus Study Group Hessen (SESGH). Incidence of status epilepticus in adults in Germany: A prospective, population-based study. Epilepsia 2001;42:714–718. 18. Krumholz, A., and A. T. Berg. Further evidence that for status epilepticus “one size fits all” doesn’t fit. Neurology 2002; 58(4):515–516. 19. Logroscino, G., D. C. Hesdorffer, G. D. Cascino, J. F. Annegers, E. Bagiella, and W. A. Hauser. Long-term mortality after a first episode of status epilepticus. Neurology 2002;58:537–541. 20. Logroscino, G., D. 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. 21. Logroscino, G., D. Hesdorffer, G. Cascino, J. F. Annegers, and W. A. Hauser. Time trends in incidence, mortality, and casefatality after first episode of status epilepticus. Epilepsia 2001;42:1031–1035. 22. 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. 23. 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. 24. Meldrum, B. S., and R. W. Horton. Physiology of status epilepticus in primates. Arch. Neurol. 1973;28:1–9. 25. Moshe, S. L., S. D. Garnt, E. Sperber, J. Veliskova, H. Kubova, and L. Brown. Ontogeny and topography of seizure regulation by the substantia nigra. Brain Dev. 1995:17(Suppl.): 61–72.
, , :
37
26. Scholtes, F. B., W. O. Renier, and H. Meinardi. Generalized convulsive status epilepticus: Causes, therapy and outcome in 346 patients. Epilepsia 1994;35:1104–1112. 27. Shinnar, S., A. T. Berg, S. L. Moshe, C. O’Dell, M. Alemany, D. Newstein, H. Kang, E. S. Goldensohn, and W. A. Hauser. The risk of seizure recurrence after a first unprovoked afebrile seizure in childhood: An extended follow-up. Pediatrics 1996;98:216–225. 28. Shinnar, S., J. Maytal, L. Krasnoff, and S. L. Moshe. Recurrent status epilepticus in children Ann. Neurol. 1992;31:598– 604. 29. 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(7):1070– 1076.
38
: , , ,
5
Epidemiology of Childhood Status Epilepticus
Introduction Status epilepticus (SE) is a common neurologic emergency that is associated with significant morbidity and mortality (36–38, 41, 61–63, 126). It occurs most commonly in children and can occur either as part of an established seizure disorder or in the context of an acute illness (22, 36–38, 41, 61–63). In more than 50% of cases there is no prior history of seizures (41, 62, 118). The incidence and etiology are highly age dependent (36–38, 87, 118). In the last 30 years there has been a dramatic decline in the morbidity and mortality from childhood SE. This chapter reviews the available epidemiologic data on childhood SE. The discussion includes the incidence of childhood SE, the causes and their age-dependent distributions, the specific populations at risk for an episode of SE, the morbidity and mortality from SE, and long-term sequelae of childhood SE. The long-term sequelae considered in the chapter include cognitive deficits in children who have an episode of SE. Finally, the chapter reviews what is known of the prognosis following SE as a first unprovoked seizure, febrile SE, and its association with subsequent epilepsy and recurrent SE.
of SE in the intensive care unit (ICU) in a critically ill child with a variety of acute complications may also go unreported. SE is most common in the very young and very old (36, 37, 62). The distribution of SE by age parallels that of all seizure disorders (13, 62, 65–67). Young children appear to be particularly susceptible. In the overall population, infants less than 1 year old have the highest incidence, but the elderly population has the highest number of cases (37). In an analysis of the two largest pediatric series, reported from Bronx, New York, and Richmond, Virginia (118), we found that 26% of cases occurred in the first year of life, 43% in the first 2 years of life, and 67% in the first 5 years of life. The distribution of cases from that study is shown in Figure 5.1. Figures reported in other series are comparable (5, 47, 132, 135). SE may occur in the setting of an acute insult, in patients with established epilepsy, or as a first unprovoked seizure in a patient without an acute insult or a prior history of seizures. The different causes and their relative frequency as a function of age in children are discussed below.
Etiology
Incidence SE is a not uncommon occurrence. Based on earlier studies, it was estimated that 50,000–60,000 cases of SE occur in the United States each year (62). More recent data from the prospective population-based study of SE in Richmond, Virginia, indicate an annual incidence of SE of 41 patients per 100,000 population per year and a total of 50 episodes of SE per 100,000 population per year (36–38). The higher number of episodes is due to the substantial proportion of cases with recurrent status. These numbers would correspond to 126,000–195,000 episodes of SE annually in the United States (37). The true incidence of SE is probably even higher, as not all cases are reported (36, 37, 62). Although convulsive SE usually presents to medical attention, it is not always recognized as such. In both children and adults, cases with two seizures without full recovery between seizures may be diagnosed as two seizures rather than as SE. The occurrence
The currently accepted etiologic classification of SE recognizes five etiologic categories of SE in childhood, as follows (34, 37, 41, 87): 1. Cryptogenic/idiopathic: SE occurring in the absence of an acute precipitating central nervous system (CNS) insult or systemic metabolic dysfunction. Included in this group are otherwise neurologically normal individuals with an established seizure disorder, as well as children who present with a first unprovoked seizure. The term idiopathic, which was previously used to classify all of these cases, is, under the new guidelines for epidemiologic research in epilepsy developed by the International League Against Epilepsy (ILAE), now reserved for children with genetically determined, agedependent epilepsy syndromes such as benign rolandic epilepsy and the primary generalized epilepsies (34). Using this definition, idiopathic SE is quite rare. Most of the cases referred to as idiopathic in the literature using the previous classification are in fact cryptogenic.
:
39
F 5.1 Age distribution of 394 children with status epilepticus in Bronx, New York, and Richmond, Virginia (n = 394). (Adapted from Shinnar et al. [121].)
2. Remote symptomatic: A seizure occurring without acute provocation in a patient with a prior history of CNS insult or abnormality known to be associated with an increased risk of convulsions. This category includes children with mental retardation or cerebral palsy of various causes, as well as children who have sustained a prior neurologic insult such as meningitis, head trauma, or intracerebral hemorrhage (34, 67). 3. Febrile: A febrile seizure is a seizure in association with a febrile illness in the absence of a CNS infection or acute electrolyte imbalance in children without prior afebrile seizures. The febrile illness must include a temperature greater than 38.4°C, although the temperature may not be evident until after the seizure (91). The child may be neurologically normal or abnormal. In the new guidelines for epidemiologic research, febrile seizures, and by extension febrile SE, are further divided into those without prior neonatal seizures and those with prior neonatal seizures (34). However, for purposes of this discussion, the two groups can be combined. Febrile SE, which represents the extreme end of complex febrile seizures (8, 15, 41, 49, 85), is really a form of acute symptomatic seizures. However, it is classified separately in children because it accounts for almost 25% of childhood SE and because it has a very different prognosis than other acute symptomatic seizures (49, 85, 118). 4. Acute symptomatic: SE occurring during an acute illness in which there was a known neurologic insult or systemic metabolic dysfunction. Insults include meningitis, hypoxia, and acute head trauma. Also included in this category are episodes of SE occurring within 1 week after the abrupt discontinuation of antiepileptic drugs (AEDs). However, a
40
clear history of abrupt discontinuation of AEDs rather than simply a measured subtherapeutic level, which may be longstanding, is required (42, 62, 87). 5. Progressive encephalopathy: SE occurring in association with a progressive neurologic disorder. Included in this category are patients with neurodegenerative diseases, malignancies not in remission, and neurocutaneous syndromes (41, 87). In many studies this group is included in the remote symptomatic group (5, 47). More recent studies have separated them (41, 89, 118) in recognition of the uniformly poor prognosis in this group, which reflects the prognosis of the underlying disease. Although this group represents less than 10% of children with SE, SE associated with a progressive neurologic disorder accounts for a significant proportion of the morbidity and mortality associated with childhood SE (87). The distribution of causes is different in children than in adults, with a higher proportion of acute symptomatic cases, particularly ones related to cerebrovascular disease (38). Febrile SE is seen only in childhood. Even in childhood, the distribution of causes is highly age dependent (118). The results from a study that analyzed the two largest pediatric series are summarized in Figure 5.2. In the first year of life, acute symptomatic seizures accounted for over 50% of the cases of SE. Febrile SE accounted for more than two-thirds of cases in the second year of life. In contrast, more than 60% of cases in children over age 4 were of cryptogenic and remote symptomatic etiology (118). The most common causes of acute symptomatic SE in childhood in the Bronx and Richmond cohorts were CNS infection, including both meningitis and encephalitis (29%); metabolic causes (25%);
: , , ,
F 5.2 Etiology of status epilepticus and age in 394 children with SE from Bronx, New York, and Richmond, Virginia. (Reprinted with permission from Shinnar et al. [118].)
trauma (17%); and anoxia (12%) (118). These different causes of acute symptomatic status were also age dependent. Other pediatric series show a similar distribution of causes (5, 41, 46, 47, 95, 132, 135).
Type of seizure The revised international classification of seizures separates seizures into those with generalized onset, including tonicclonic, tonic, absence, atonic, and myoclonic, and those with partial onset, including simple partial, complex partial, and partial with secondary generalization (33). In theory, all of these, with the exception of atonic, can occur as SE. SE can also be divided into convulsive and nonconvulsive types (41, 62, 87). Most cases of childhood SE are of the convulsive type. In a series of 193 children, only 13 (6.7%) had nonconvulsive SE (87). Other reports give similar results (47). In these series, convulsive SE included both generalized tonic-clonic and partial seizures with secondary generalization (38, 47, 87). Prior series reported that most cases of childhood SE were of generalized onset (5, 47, 87, 135). Thus, in the series of Maytal et al. (87), 133 of 193 cases (71%) were generalized, of which 130 were tonic-clonic and three were absence. Other prior series reported a rate of 50%–60% generalized cases (5, 47). These series were all based on clinical observation only, as electroencephalographic (EEG) data were not routinely available. Therefore, the true proportion of partial onset seizures was undoubtedly underestimated. The more recent greater Richmond SE study found that 71% of pediatric SE and 74% of adult SE episodes ended up as generalized seizures. However, with more intensive monitoring of
EEG data, it was felt that 64% of pediatric cases and 69% of adult cases were of partial onset (38). Generalized onset SE was most common in the first year of life, which is the age group in which SE is most likely to occur (38, 118). Although the precise frequency of partial onset SE in children remains unclear, it seems probable that for SE, the differences between pediatric and adult cases are less than was previously thought. In prior reports of pediatric SE, the vast majority were of partial onset status, secondarily generalized (5, 87, 135). Thus, in the series of Maytal and colleagues (87), the 56 cases with partial onset included 3 (5%) simple partial, 7 (13%) complex partial, and 46 (82%) partial with secondary generalization. The recent Richmond series reported a somewhat higher proportion of simple partial cases (38). Although nonconvulsive SE in childhood is uncommon, it certainly does occur. There have been reports limited to solely nonconvulsive SE in children (42, 57, 89, 99). Cases of nonconvulsive SE were also included in the larger series of SE (5, 38, 46, 47, 87). In a comparison with adult SE, DeLorenzo et al. reported that myoclonic SE and electrographic SE without clinical correlate, both of which are subtle forms of SE, were uncommon in childhood (38). Absence status was uncommon in all age groups. Seizure type is correlated with etiology. Febrile SE is more likely to be generalized, whereas remote symptomatic cases and acute symptomatic cases are more likely to be of partial onset (87). A breakdown of seizure type by etiology is not given in the other studies. It is hardly surprising that seizures associated with acute or remote brain injuries, many of which are focal, are more likely to be partial in origin.
:
41
Who gets SE?
P N A Both epilepsy in general and SE in particular are more common in neurologically abnormal children. Most series report that 14%–40% of children with SE have preexisting neurologic abnormalities (5, 21, 47, 84, 87, 95, 118, 122, 135). These numbers may underestimate the true incidence of neurologic abnormalities in this population. Moreover, many authors do not record the percentage of children with acute symptomatic or febrile seizures who have prior neurologic abnormalities. Also, in some studies, any child with SE and a low serum AED level was considered to have had acute symptomatic SE triggered by AED withdrawal or noncompliance (46), regardless of the child’s neurologic condition. In reports that do describe the rate of prior neurologic abnormalities in children who are not included in the remote symptomatic group (5, 84, 87, 118), the rates of prior abnormalities are high in both the febrile and acute symptomatic group (5, 86, 113). Recent data indicate that the proportion of children who are neurologically abnormal is age dependent. In an analysis of the data from Bronx, New York, and Richmond, Virginia (118), we found that 158 (40%) of 394 children with SE were known to be previously neurologically abnormal, including 35 (21%) of 169 under age 2 years and 123 (55%) of 225 older than 2 years (P < 0.001). Although it is possible that some of the children with SE at a young age who are subsequently found to have neurologic impairment had prior undiagnosed neurologic abnormalities, this does not appear to be the whole story.
order occurs primarily in the cryptogenic group. In a study of SE in children, more than 50% of subjects with cryptogenic SE had no prior history of seizures (87). In contrast, more than 80% of the subjects with remote symptomatic SE had had prior seizures. SE in children with no prior history of seizures occurs primarily in the young. In the analysis of the Bronx, New York, and Richmond, Virginia, data (118), 177 (45%) of 394 children had a history of prior seizures, including 142 (41%) of the 349 children with a first episode of status. A history of prior seizures was present in 34 (20%) of those under age 2 years, compared with 143 (64%) of those older than 2 years (P < 0.001). The effect of age remained significant even when the analysis was limited to those with SE of cryptogenic or remote symptomatic etiology. However, the older children were more likely to also be neurologically abnormal. Thus it appears that SE in young children occurs primarily in children who are neurologically normal and have no prior history of unprovoked seizure. In older children, SE occurs primarily in those who are known to have had prior unprovoked seizures and who are often also neurologically abnormal. SE also occurs as part of established seizure disorders. Between 10% and 27% of patients with epilepsy will experience at least one episode of SE (22, 41, 61–63, 70, 122). SE is particularly common in patients with remote symptomatic epilepsy. These patients account for 30% of cases of epilepsy but for 50% of cases of unprovoked status (5, 87, 99). Neurologically abnormal children with epilepsy are more likely to develop SE despite “therapeutic” AED levels (84, 115). They are also at high risk for recurrence of SE, which occurs in as many as 50% of the children (36, 37, 43, 115). SE is also very common in children with onset of seizures before 1 year of age (22, 26, 46, 56, 70, 83, 86, 122), a group that includes many children with static and progressive encephalopathies. Data from patients with intractable partial seizures suggest that the patients at risk for SE are the same patients who get seizure clusters. A recent community-based study of children with newly diagnosed epilepsy found a particularly high risk of SE in children who had undergone a craniotomy in the past (22). In adults, SE occurs more commonly in patients with partial seizure disorders, particularly those with frontal lobe epilepsy (41, 62).
P S SE is a common occurrence in both children and adults with seizure disorders. In studies of children and adults (64, 68, 111, 112) who presented with a first unprovoked seizure, approximately 8%–12% presented with SE. Similar numbers are expected in patients with epilepsy who first come to medical attention (22, 62, 122). These groups account for approximately one-third of the cases of SE (41, 62). SE as the initial presentation of a seizure dis-
R In the recent epidemiologic study of the incidence of SE in Richmond, Virginia (37, 38), an increased incidence was found in nonwhite population. In this geographic locale, this would reflect primarily an African-American population. The estimated incidence of SE in nonwhites was 57 per 100,000, compared with 20 per 100,000 in whites. Other studies of SE either do not contain incidence data by race or were done in racially homogeneous populations.
The majority of cases of SE occur in children who are neurologically normal and have no prior history of seizures (38, 41, 62, 87, 118). However, certain populations, such as the very young, those with prior neurologic abnormalities, and those with preexisting seizure disorders, are known to be at increased risk. The incidence by age was reviewed earlier. In addition, it seems that there is a subgroup of children with seizures with an inherent predisposition to prolonged seizures (15, 21, 35, 113, 114, 122); this situation is discussed later in the chapter (see Recurrent SE). This section reviews the other risk factors for experiencing an episode of SE.
42
: , , ,
There are data that indicate an increased incidence of seizure disorders in inner-city, predominantly nonwhite populations, though it is unclear whether this difference is based on ethnic or socioeconomic factors (62). As the incidence of SE tends to mirror the incidence of epilepsy, these data would be consistent with an increased rate of SE in innercity populations (13, 66).
Morbidity and mortality The morbidity and mortality of SE have decreased significantly over the past 30 years. Mortality from pediatric SE in two recent large series was 3% and was essentially limited to cases where the etiology was acute symptomatic or progressive encephalopathy (36, 87). This compares favorably with mortality in adults from the same Richmond series of 26% (36, 126). The decreased mortality in children is due both to a different distribution of causes, with fewer acute symptomatic cases and more cryptogenic and febrile cases, and to an apparent decreased morbidity and mortality in children compared with adults with similar insults (36, 61, 87). Other recent pediatric series report similar findings (46, 47, 88, 95, 132, 135). Older studies of SE in children reported a mortality of 11% (5). Approximately half of the deaths were associated with the acute event, and the remainder were the result of the disorders causing the episode of SE. Neurologic abnormalities were found in 45%–51% of the survivors. Even children with SE of cryptogenic or idiopathic etiology had a high rate (44%) of subsequent neurologic disabilities (4, 5, 56). Recent series paint a much more favorable picture. New cognitive or motor deficits are reported in 9%–28% of survivors (36, 46, 47, 62, 86–88, 95, 132, 135), with the great majority occurring in those with acute symptomatic or progressive encephalopathy etiology. In the series of Maytal et al. (87), 9% of the surviving children had neurologic deficit, but only 1.5% of the 137 children with cryptogenic, remote symptomatic, or febrile SE developed a new neurologic deficit. None of the 67 prospectively identified children with cryptogenic, remote symptomatic, or febrile SE developed a new neurologic deficit (87). Even Yager et al. (135), who reported a 28% incidence of sequelae in survivors, found only one child with cryptogenic SE who had neurologic sequelae. Their higher rate of sequelae can be attributed to the high proportion of acute symptomatic cases in their population. Similar results were reported by Dulac et al. (46). In a recent report of 172 prospectively identified children with febrile SE, none of the children had new cognitive or motor deficits following the episode of febrile status (94). Interestingly, the syndrome of hemiconvulsionshemiparesis-epilepsy, which was a commonly reported sequela of status in the older literature (3, 5, 56, 59), has
essentially disappeared and has not been reported in the more recent series. Earlier reports had emphasized the higher morbidity and mortality of SE occurring in the first year of life. Several studies have now reported that death and all types of sequelae are more common in younger children (5, 47, 87). As previously discussed, the incidence of SE is highest in the first year of life (36, 41, 62). However, the distribution of causes is also highly age dependent. While in general, the causes in children are more benign than in adults (36, 41), this is not true in the first year of life. In the Bronx, New York, and Richmond, Virginia, data (118), more than 50% of cases of SE in the first year of life were due to acute symptomatic causes, including CNS infection, metabolic causes, hypoxia, and trauma, all of which can be expected to have a high rate of sequelae (Figure 5.2). Thus the higher mortality and morbidity of status in this age group can be attributed to the higher proportion of acute symptomatic causes rather than to a particular vulnerability of the immature CNS to damage. This is confirmed by the data of Dulac et al. (46), who studied 79 children between 1 month and 2 years of age with SE and found only two children in whom the neurologic deficit could be attributed to sequelae of the seizure itself. We also note that cases of febrile SE occurring in the first year of life are not associated with an increased morbidity and mortality (85, 118). The precise reasons for the dramatic decline in the morbidity and mortality of convulsive SE in recent years, particularly in cryptogenic cases, are not fully understood. Although treatment has substantially improved, not just in terms of the availability of effective AED therapy but also in terms of supportive care for airway and circulation, the decline in pediatric morbidity and mortality has not been paralleled by a similar decline in morbidity and mortality in adult series (76). Perhaps the most dramatic impact of treatment was to drastically reduce morbidity and mortality in cases without an acute or progressive underlying neurologic insult. The more recent series, which report favorable outcomes of SE in children, are all based on children who were treated in modern emergency departments. It seems reasonable to speculate that the major reduction in morbidity and mortality has resulted from the availability of improved care. The disappearance of the hemiconvulsionshemiparesis-epilepsy syndrome (5, 56, 59) over this time period is most likely not a coincidence but a reflection of available effective treatment for these cases. Thus, while SE remains a neurological emergency, in properly treated cases in which effective treatment and supportive care are applied, the morbidity and mortality appear to be primarily a function of etiology. It should be noted that in the older series, a definition of SE of 60 minutes or longer was used (5, 56). The more recent series, which used the current definition of ≥30
:
43
minutes, include enough cases of status lasting ≥60 minutes to indicate that the decreased morbidity is not simply due to a less severe case mix (38, 46, 47, 87, 135). However, in the more recent series, in which children received appropriate treatment, the majority of episodes lasting more than an hour were associated with an acute or progressive underlying neurologic insult. In the series of Maytal et al. (87), acute symptomatic cases accounted for 23% of all cases but for 46% of episodes lasting longer than 1 hour. Most episodes of cryptogenic, febrile, or remote symptomatic SE are readily controlled with AED therapy. Only 18% of these episodes lasted longer than 60 minutes. Some of the differences in reported outcomes may be due to identification bias. The older series (5, 56) were primarily retrospective. Many of the affected patients were seen initially at smaller community hospitals and were not seen by the investigators until many years after the episodes of SE. This retrospective review would skew the results toward cases with a bad outcome, because patients with a favorable outcome would not require a referral to a specialist years later. This type of referral bias is particularly evident in the evaluation of subsequent seizures. When Fujiwara et al. (56) retrospectively identified the children at an epilepsy center who had previously had an episode of SE, they found that all had epilepsy. However, even in prospectively identified children from that era (2, 5), the morbidity and mortality were substantially higher than that reported today.
Long-term sequelae of SE in childhood C S In any entity associated with a significant morbidity and mortality, it is not surprising that cognitive impairment may occur as a sequela. Indeed, isolated case reports of cognitive impairment following SE abound (5, 42, 103, 107). However, much of the morbidity and mortality of SE is associated with the precipitating acute neurologic insult (5, 38, 40, 41, 46, 47, 61, 63, 87, 94, 132, 135). Also, the high rates of adverse sequelae reported in the older series are probably not representative of the current reality, as there has been a decline in the rate of all reported sequelae (38, 40, 41, 61, 62, 126). To address the issue of whether an episode of SE in childhood per se is associated with subsequent cognitive impairment, one must study the appropriate subjects. This is not a simple task, as SE often occurs in the context of an acute brain insult, in which setting it is difficult to separate the adverse effects of status from those of the acute insult (5, 40, 41, 87). In the cases of SE occurring as part of a chronic intractable seizure disorder, it is difficult to distinguish the effects of the isolated prolonged seizure from that of the repeated briefer seizures. In children, there is the additional difficulty that SE most often occurs in very young children, less than 2 years old (38, 41, 62, 118), an age where it is very
44
difficult to get an accurate estimate of premorbid intellectual function except in the setting of severe impairment. Children who present with SE as a first unprovoked seizure would seem to be an ideal population in which to study this issue. Although this is a not uncommon occurrence (9, 17, 62, 65, 66, 68, 85, 107, 108), very few such children have had prior neuropsychological testing and it is thus difficult to separate sequelae from premorbid deficits when one finds a subtle deficit. The data regarding cognitive impairment following SE were reviewed by Dodrill and Wilensky (39). Of the 14 studies reviewed (5, 6, 31, 39, 42, 46–49, 56, 63, 74, 87, 94, 99), the more recent and prospective ones were the ones that reported the lowest morbidity, including cognitive outcomes. However, few of the studies utilized any formal psychological testing. These same authors also performed a study on adults with refractory epilepsy in which serial neuropsychological testing was performed. They found that while SE tended to occur in more impaired individuals, there was little evidence of cognitive decline following an episode of SE in this population (40). The pediatric data also indicate that SE per se is rarely associated with long-term cognitive deficits. Ellenberg and Nelson examined 27 children from the National Collaborative Perinatal Project with febrile SE and found no differences in cognitive function at 7 years of age between them and their siblings (49). The British National Cohort Study also found no differences in intelligence, behavior, and academic achievement at age 10 between children with febrile seizures (including prolonged ones) and control subjects who were born in the same week and never had seizures (130). In children with epilepsy, the results are similar. Analysis of the data from the National Collaborative Perinatal Project also found no evidence of decline in cognitive function in children who had cognitive testing at 4 and 7 years of age as part of that study and who had onset of epilepsy between ages 4 and 7, including eight children who had experienced at least one episode of SE during that time (48). Dunn (47) and Maytal et al. (87) also found no long-term sequelae following SE in children, unless the episode of status was associated with an acute or progressive CNS insult, but those studies did not include formal psychological testing of the subjects. The available data indicate that the occurrence of cognitive deficits following an episode of SE not associated with an acute or progressive CNS insult is a rare event (107). SE F E The textbook definition of SE as “a seizure of such duration as to create a fixed epileptic condition” (58, 95) might lead one to assume that all cases of SE are inevitably associated with a subsequent chronic seizure disorder, but there is little evidence that this is the case. In this section we review the epidemiologic data on the risk of future seizures following an episode of SE in child-
: , , ,
hood in the setting of a first unprovoked seizure, febrile SE, and acute symptomatic status. SE as a first unprovoked seizure Approximately 10% of children and adults who come to medical attention with a first unprovoked seizure present with SE (9, 17, 41, 62, 64, 66, 68, 88, 111, 112, 122). In children, the risk of seizure recurrence following a cryptogenic or idiopathic first unprovoked seizure is not influenced by the duration of the initial seizure (9, 17, 56, 68, 109, 111–113). This is true whether one examines seizure duration as a continuous variable or compares those with SE as their first unprovoked seizure with those who presented with a brief first seizure. However, as discussed later (see the section, Recurrent SE), if a child with a prolonged first seizure does experience a seizure recurrence, the recurrent seizure is likely to be prolonged (112, 113). These studies, which include follow-up periods of over 10 years, provide the best evidence that SE per se does not create a permanent seizure disorder (68, 109, 111–113). When children present with SE as a first unprovoked seizure of remote symptomatic etiology, the risk of recurrence is increased (9, 17, 64, 68, 111, 112). These patients are at increased risk not just for recurrent seizures but also for recurrent SE (17, 43, 115). However, SE as the initial seizure is relatively uncommon in this group. In one study of childhood SE, 29 (63%) of 46 children with cryptogenic SE had no prior history of seizures, whereas 34 (75%) of 45 children with remote symptomatic status had a prior history of seizures (87). The fact that SE is a risk factor for subsequent seizures in remote symptomatic cases but not in cryptogenic ones suggests either that it is a marker for epilepsy in those cases or that the already compromised brain is more susceptible to injury as a result of SE (60, 106). The epidemiologic data in children also do not demonstrate an adverse impact of an isolated episode of SE on long-term outcome. The occurrence of SE does not influence long-term remission rates in children who present with SE as their first unprovoked cryptogenic seizure (109, 110). In a case-control study of predictors of intractability in children with newly diagnosed epilepsy, the occurrence of SE was found to be a marker for future intractability (14). The best predictor, however, was the presence of an underlying neurologic abnormality. Furthermore, of the four children thought to have cryptogenic epilepsy and whose presentation included an episode of SE, one was later diagnosed as having a brain tumor, one was later diagnosed as mentally retarded, and one was found to have a progressive neurologic disorder. Thus, the occurrence of SE in this population seems to be a marker for an abnormal brain, which is known to be a predictor of future intractability (14). In the prospective Connecticut study of newly diagnosed childhood-onset epilepsy, the occurrence of either febrile or unprovoked SE was not associated with the development of
intractable epilepsy (23). Similar results were reported in a population-based study of long-term outcomes of childhood-onset epilepsy from Finland (119–122). While the occurrence of SE was a predictor of future intractability on univariate analysis, it appeared to be a marker for the symptomatic cases, and in the multivariable analysis of outcome it had only a modest effect on remission rates and no effect on mortality or psychosocial outcomes (119–122). A recent imaging study found that SE, along with age at onset, etiology, and several other factors, was associated with decreased brain volume. The significance of these findings remains unclear, as status was but one of many factors associated with a decreased brain volume in this population of children with epilepsy. Febrile status epilepticus The morbidity and mortality of febrile SE in recent studies are low (7, 8, 37, 38, 41, 46, 47, 48, 62, 71, 85, 87, 93, 117, 127, 129–132, 135). In a group of 172 children with febrile SE prospectively identified between 1984 and 1994 in Bronx, New York, and Richmond, Virginia, only one child died due to malignant cerebral edema in association with presumed Shigella encephalopathy. There were no new motor or cognitive deficits in the 171 survivors (117). The risk of a subsequent febrile seizure is no different following a prolonged febrile seizure than following a brief one (15, 19, 93). However, if another febrile seizure does occur, it too is likely to be prolonged (15). This is very similar to the data in children with a first unprovoked seizure. The risk of subsequent epilepsy is increased following any complex febrile seizure, including febrile SE (7, 8, 15, 18, 41, 49, 71, 85, 91, 93, 129, 131). Risk factors for the development of epilepsy in the first few years following the febrile seizures include neurodevelopmental abnormality, complex febrile seizures, a family history of epilepsy, and the duration of fever prior to the febrile seizure (8, 18, 91, 93, 129, 131). Age at the time of febrile seizure and the height of the fever are not associated with a differential risk of subsequent epilepsy (18). The majority of children who develop epilepsy within a few years of their febrile seizure do not appear to have mesial temporal epilepsy. With long-term follow-up, the highest risk of subsequent epilepsy occurs in those whose febrile seizures were both prolonged and focal (8). In the Rochester, Minnesota, data, the cumulative risk for developing epilepsy in this small subgroup was 40%–50% (8). It is difficult to separate the effect of a prolonged febrile seizure from that of a focal one, as prolonged febrile seizures also tend to be focal (5, 8, 85, 117). One of the most controversial topics in epileptology is the issue of whether prolonged febrile seizures cause mesial temporal sclerosis. Retrospective studies from tertiary epilepsy centers report that many adults with intractable temporal
:
45
lobe epilepsy had a history of prolonged or atypical febrile seizures in childhood (1, 24, 27, 28, 29, 50–53, 55, 77–82, 99). However, population-based studies have failed to find this association, as have prospective studies of febrile seizures (7, 8, 16, 49, 71, 85, 93, 104, 105, 129, 131). In the Rochester, Minnesota, study, those with generalized febrile seizures were at increased risk for generalized epilepsies, particularly idiopathic epilepsies associated with generalized spike-and-wave abnormalities on EEG, whereas those who had focal seizures were at increased risk for partial epilepsy (8). This is precisely what one would expect if febrile seizures were an age-specific marker for future seizure susceptibility (119). Febrile SE is much more common in children who are already neurologically abnormal and are most likely to be focal suggesting prior focal pathology (8, 32, 49, 93, 106, 117, 118, 129, 131). Recent population- and community-based studies of children with new-onset seizures have not found an association between prior febrile seizures and temporal lobe epilepsy (21, 25). In addition, studies that have focused on treating febrile seizures have reduced the incidence of febrile seizures but have had no effect on the rate of subsequent epilepsy (16, 71–73, 97, 98, 104, 107, 133, 134). The epidemiological data do not support a causal relationship between prolonged febrile seizures and subsequent mesial temporal epilepsy. A fuller discussion of this issue can be found in several reviews focusing on this specific topic (16, 71, 104–108, 116). Very recently an association between very prolonged and focal febrile seizures and mesial temporal sclerosis has been demonstrated using MRI (52, 101, 102, 132). Van Landingham et al. (128) reported acute MRI changes in a few children with very prolonged (mean duration >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 (<20 years old) (83). The incidence of CPSE is difficult to estimate, for several reasons: (1) the difficulty of recognizing CPSE, (2) underreporting, and (3) the difficulty of differentiating CPSE from ASE. A few studies have attempted to estimate the incidence of CPSE and have placed the frequency at 35 persons per 1 million population, but as high as 100–200 per 1 million among the mentally handicapped population (104). Another study of a hospital-based population estimated the incidence of nonconvulsive SE to be 1.5 per 1 million population per year, and approximately half of these patients were thought to have CPSE (112). There are no population-based studies of simple partial SE. It is considered rare.
Etiology SE occurs in three broad settings in adult patients: (1) in patients who sustain an insult to the brain, such as hypoxia, head trauma, infection, drug intoxication, or metabolic disturbance; (2) in epileptic patients having an exacerbation of seizures; and (3) as a first unprovoked seizure, often heralding the onset of epilepsy. Each of the three groups accounts for approximately one-third of all cases of SE (19, 20). However, an important and frequent presentation in childhood is febrile SE. Gross-Tsur and Shinnar estimated 20%–28% of all cases of childhood SE to be triggered by
fever (36). In the more recent epidemiologic study by DeLorenzo et al. of the Richmond, Virginia, population, infections with fever accounted for 52% of cases of childhood SE (19). It is not clear in the published data what fraction of that represented CNS infections such as meningitis or encephalitis versus the classic syndrome of febrile convulsions. Even within the pediatric population, different causes are common in certain age groups. More than 80% of children less than 2 years old have a febrile or acute symptomatic cause of SE, while older children more commonly experience SE of remote symptomatic or cryptogenic causes (101). The genetic studies of familial fever-associated seizure syndromes revealed ion channel mutations involving the sodium channel or the GABA receptor in some pedigrees. In other cases the molecular basis is not yet clear (43). When SE is studied by adult and childhood onset, the precipitants of SE in these two age groups are found to be quite different (Table 10.3). Whereas fever/non-CNS infection represents the most frequent cause of SE in children, cerebrovascular events are the most common cause in adults. Of note, congenital malformations account for a considerable 7% of childhood SE cases. An additional etiologic consideration in ASE is carbamazepine, which has the potential to precipitate AES (11, 105). Among patients with CPSE, the anatomic site of seizure origin has been of interest. Previously thought to be synonymous with temporal lobe epilepsy, CPSE may be less temporal in origin, according to more recent studies. In one study with intracranial electrodes in patients undergoing evaluation for epilepsy surgery, all eight patients who had CPSE had extratemporal onset, four of those from the
T 10.3 Precipitants of status epilepticus
Precipitant Cerebrovascular Medication change Anoxia Ethanol-/drug-related Metabolic Unknown Fever/non-CNS infection Trauma Tumor CNS infection Congenital
Children (<16 yr), %
Adults (>16 yr), %
3.3 19.8 5.3 2.4 8.2 9.3 35.7 3.5 0.7 4.8 7.0
25.2 18.9 10.7 12.2 8.8 8.1 4.6 4.6 4.3 1.8 0.8
Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of America’s Working Group on Status Epilepticus. JAMA 1993;270:854–859.
, , :
115
frontal lobe (131). The clinical features that, in part, served to distinguish these seizures from complex partial seizures originating elsewhere included brief, frequent attacks, complex motor automatisms with kicking and thrashing, sexual automatisms, and vocalizations (129, 130). For patients with simple partial SE, specific causes should be considered, including Rasmussen’s encephalitis for epilepsia partialis continua, hypoxic-ischemic insult in the watershed territories, nonketotic hyperglycinemia, and uremia.
Imaging findings Multiple magnetic resonance imaging (MRI) studies have been performed in adults and children to elucidate the temporary changes during SE, mainly generalized SE. Most of these studies show some resolution of the lesions, although there may be atrophy or hippocampal sclerosis resulting from the status (52, 76, 122). However, not all patients with SE exhibit these focal changes, and not all children with hippocampal sclerosis have a history of SE (71). Hyperintense lesions on T2-weighted MRI are associated with decreased signal intensity on T1-weighted images in the same location or gyral contrast enhancement. These lesions eventually resolve in most cases (47). Hyperintense lesions can be confused with tumors, inflammatory disease, and dysmyelination processes. If serial MRI is performed, biopsies can sometimes be avoided, because the lesions are temporary in SE and permanent in other processes. In addition, the presence of the lesions suggests that the focus of the seizures arise from this area. Diffusion weighted MRI (DWI) has also been used in SE and shows temporary lesions (47). These lesions revealed increased T2 signals, increased signal on DWI, and a decrease in apparent diffusion coefficient. Four of the eight patients described by Kim et al. were pediatric patients (47). In one study of a 56-year-old patient with nonconvulsive status (NCS), hyperintensity with gyral swelling was seen, with no involvement of the brain stem, basal ganglia, thalamus, and white matter. This effect is probably caused by cytotoxic edema induced by excitotoxicity. The follow-up DWI showed marked atrophy and hypointensity of the corresponding area, which suggests that NCS results in lasting neuronal damage (12). However, it should be noted that the EEG and MRI findings in this case were suggestive of a focal process, and the patient was admitted after 3 days of mental status change. No such changes have been demonstrated in prolonged ASE. Single photon emission computed tomography shows reversible lesions (45), and one volumetric MRI study in adults showed no progressive volume loss of hippocampus after SE (92). Angiograms also show capillary blush and
116
early filling veins in the epileptogenic area caused by local hypoxia (53, 75, 79, 132).
EEG findings N S E EEG findings in neonatal SE were reviewed by Kellaway and Hrachovy (46) and more recently by Wical (127). Neonatal SE can present as a migrating and multifocal collection of seizures because of the unique combination of enhanced local network excitability with contributions from nonsynaptic mechanisms and the lack of maturation of projection circuits. Scher et al. (95, 96) demonstrated that ictal durations increase progressively with development, reflecting maturation of networks. Dissociation between the EEG findings and clinical manifestations is commonly encountered in neonates (77, 127). O C In older children, many aspects of the status-associated evolution of the EEG with the duration of seizures as described by Treiman (117) are probably relevant. In adults with generalized SE, Treiman has demonstrated a continuum of EEG changes that could be duplicated in a rat model of SE (117, 121): (1) discrete seizures, (2) waxing and waning of ictal discharges, (3) a continuous pattern of ictal activity, which is later interrupted by (4) periods of relative flattening, and then (5) periodic epileptiform discharges (PEDs), in which the PEDs occur on a flat background and are ictal or interictal (50). To our knowledge there are no published demonstrations of such a continuum of change specifically in the pediatric age group. About 70%–80% of cases of convulsive SE have a focal onset and secondary generalization (117). Generalized SE begins with localized epileptic activity, followed by generalized bursts of seizure activity, with normal EEG findings interspersed. The isolated ictal discharges merge and become a continuous discharge after 30 minutes. Discharges then fragment and are interspersed with flat periods. Eventually, periodic discharges emerge, which may reflect metabolic failure. In a semiologic description, recurrent seizures merge into continuous motor activity, followed by fragmentation of the motor activity and then myoclonus. If the seizure persists, then electromechanical dissociation will occur. The prognosis for recovery worsens the farther along the patient is on the continuum. Continuous epileptiform discharges have a worse prognosis than recurrent discrete electrographic seizures on the EEG (31, 117). A study by Nei et al. suggested that this continuum may not occur in a reliable sequence and that in some patients, a single EEG pattern may persist throughout the course of SE, no matter how long the duration (74). In addition, PEDs may not be seen late in the course only but may also occur earlier in the
:
course of SE (74). In some types of SE, such as EPC, there is an absence of EEG findings other than slowing, owing to the highly localized origin, which cannot be picked up by EEG electrodes (25). N S NCS is difficult to diagnose from the history and physical examination alone. Therefore, if a child is confused or in a coma, the EEG may reveal that the patient is in NCS (115). There are two types of NCS, CPSE and ASE. The EEG may be focal, generalized, or bihemispheric. Sometimes it is difficult to tell whether an EEG is truly interictal or whether the patient is having a seizure. At times, this can be determined if there is a sequence of progressive change in the EEG recording consistent with NCS rather than a static picture consistent with interictal background. Problems differentiating between ictal and interictal background most often occur when the EEG shows generalized spike-and-wave discharges rather than when the background is focal (8). Benzodiazepine administration may help distinguish an interictal state from an ictal state because SE would clear with benzodiazepine, compared to the interictal pattern. However, in some children with LennoxGastaut syndrome treatment with benzodiazepine worsens NCS (9, 56) or precipitates tonic seizures (7, 23, 81, 84, 109). In addition, benzodiazepine is not always helpful, because even triphasic waves resolve when benzodiazepines are given, owing to state changes (8). A S With absence status, the EEG shows continuous, generalized, bilaterally synchronous epileptic activity usually maximal anteriorly at a 3-Hz spike-and-wave discharge or less. In CPSE, the EEG is usually focal and often shows SE affecting temporal areas, although it can be generalized. Sometimes it is difficult to differentiate between the two, and there are overlaps. In NCS, 69% of patients have generalized discharges, 18% have a generalized pattern with frontal predominance, and 13% have focal discharges (34). Immediately after clinical SE stops, the EEG may show continued electrographic seizures, especially in neonates (22, 73). When the level of consciousness remains depressed in a patient after apparently successful treatment of SE, there needs to be a high suspicion that NCS may be occurring, and an EEG should be ordered; the treatment should be the same as that for refractory SE (71). This highlights the need for some of the children to remain on continuous EEG monitoring for a while after the generalized SE stops. In patients who are in SE, continuous EEG recording may also help determine that the abnormal movements and mental status changes seen after SE are not seizures (i.e., myoclonus), in which case anticonvulsants presumably would not be effective (88). Conditions associated with such
changes include acute dystonic reaction, paroxysmal dyskinesia, and tonic extensor spasms, seen in incipient tonsillar herniation. Critically ill, postoperative, or head injury patients with a need for paralysis and who have a high probability of seizures also should undergo continuous EEG monitoring to determine if there are subclinical seizures. If a patient with a head injury develops NCS, the prognosis worsens (124), either because the prognosis reflects the severity of the trauma or because of continuing damage from SE.
Laboratory markers of SE-associated injury The effect of neonatal seizures has been studied in rodent and primate models (28, 32, 125). These studies demonstrated an energy substrate crisis in the neonatal brain during prolonged seizures, which in turn could have played a role in the injury. Details of the cellular and network consequences of SE in the immature brain are covered in other chapters. Until recently, it was difficult in human neonates to differentiate the damage produced by SE from that caused by a common precipitant of the status, such as asphyxia. However, by comparing an MRS marker for neuronal integrity (N-acetyl aspartate) with choline, Miller et al. (70) have shown that the severity of seizures in human newborns with perinatal asphyxia is independently associated with brain injury and is not limited to structural damage detectable by MRI. Neuron-specific enolase (NSE) is a marker for neuronal damage that is found in the blood and CSF and is increased in different SE types such as CPSE, ASE, and subclinical SE (17, 18, 78). It is also elevated with hypoxic ischemic encephalopathy, cardiac arrest, or severe head trauma (71). NSE is a key enzyme for energy metabolism and is present in the cytoplasm of all cells (63, 97, 100, 134). NSE becomes measurable in blood owing to a leak across injured neuronal membranes and increased permeability of the blood-brain barrier (15). Animal models of SE confirm that elevated levels of NSE occur when there is histologic evidence of neuronal injury, and that such injury can be seen in developing animals as well (93, 94).
Medical complications Medical complications reflect the pathophysiology of SE. The systemic effects of convulsive SE result from the body’s attempt to maintain homeostasis. After 30 minutes, homeostasis fails and the patient needs systemic support. Symptoms may include tachycardia, hypertension, and hyperglycemia early in the status, then hypotension, hypoglycemia, pulmonary edema, hyperthermia, and hypoxia after 30 minutes (10, 31). Cerebral blood flow (CBF), blood glucose, and oxygen utilization increase in the initial phases of a seizure to maintain homeostasis, and all decrease later
, , :
117
in SE, which causes cell damage (86). As autoregulation fails, CBF becomes pressure dependent, which may contribute to irreversible cerebral damage if it fails to meet metabolic demands. Cardiovascular changes occur near death; the mean arterial pressure is elevated early in GCSE (111) because of elevated total peripheral resistance. With recurrent seizures, this may be associated with decreased cardiac output, although blood pressure may return to normal or decline later (5, 49). Continuous skeletal muscle contractions and impaired ventilation lead to lactic acidosis, hyperkalemia, hypoxia, hypercarbia, and hyperthermia. Fever is present in 80% of persons in early phases of GCSE (2) and is caused by extreme muscle activity rather than infection. Relative hypothermia prevents neuronal damage in some animals and decreases seizure duration, a finding that emphasizes the importance of treating fever (55). Severe myoglobinuria and hyperuricemia lead to rhabdomyolysis and kidney failure. The management of electrolyte imbalances can also cause problems, which medication-induced paralysis can prevent. However, paralysis may mask more seizure activity. With the use of muscle paralysis and artificial ventilation, brain damage can be prevented. If the epileptic activity continues for longer than 1 hour, then electromechanical dissociation may occur even when electrical discharges in the brain are not associated with a convulsive motor response. Treatment with drugs for SE such as phenobarbital and benzodiazepines may cause heart rate and blood pressure to drop (99). Factors contributing to a poor prognosis once patients are in pentobarbital coma include multi-organ failure before or during induction of the pentobarbital coma, older age (>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 (<2 months) and are considered ominous, reflecting some sort of underlying brain insult or metabolic abnormality. Benign forms exist, such as familial neonatal convulsion or hypocalcemia, vitamin B6 deficiency, and other treatable inborn errors, which have a good prognosis (71). Seizure duration is also an important factor contributing to mortality. GCSE with status lasting more than 60 minutes is associated with a higher mortality than GCSE with status lasting 30–50 minutes (114). Mortality is higher with continuous seizures than with intermittent seizures (126), but even seizures lasting 10–29 minutes are associated with a mortality of 4.4%, so it is felt that the definition of status should include these patients (62). The mortality is higher if caused by continuous rather than intermittent seizure activity because the ictal burden is greater during continuous seizure (126). In a study from Logroscino et al. (58), death occurred more frequently in myoclonic SE than in other seizure types, possibly because the etiology in myoclonic SE is associated with a poorer prognosis. CPSE is more likely to result in neuronal injury, similar to GCSE, while ASE is less likely to result in neuronal injury and complications (31). In NCS, outcome is generally poor, and several studies suggest that treatment may not be helpful (8, 26, 54). This is evident in a study of 48 patients with generalized electrographic SE: 88% died (most of these patients were comatose), and all 29 patients in coma died (27). PEDs, burst suppression, and post-SE ictal discharges (44) were associated with a worse prognosis. Patients whose
records normalized at the end did well. PEDs were associated with a poor outcome regardless of the etiology of the SE (74). Seizure duration and delay to diagnosis were also associated with increased mortality (133). In a study by Barnard and Wirrel of severe refractory SE, 23% of survivors were normal at follow-up, 34% showed developmental deterioration, and 36% had new-onset epilepsy (4). No deaths occurred in patients with SE of remote symptomatic etiology; a higher mortality and progressive encephalopathy were found in the acute symptomatic etiology group. Most children who died were younger than 3 (91). Another study showed that failure of seizure control after pentobarbital coma was associated with a poor prognosis and increased mortality (48).
Recurrence risk Recurrent convulsive SE occurs in about 17% of children after an initial episode of convulsive SE. Some 44% of children with recurrent convulsive SE have an underlying chronic brain disorder (99). Recurrence risk is closely associated with etiology. If the SE is due to remote symptomatic causes, then the patient is at a higher risk of recurrence than if the underlying etiology were hereditary (4, 6, 42, 66). Children with epilepsy caused by degenerative condition are at highest risk for recurrent SE. Noncompliance as an etiology has a lower risk (71).
Conclusion SE is an important childhood medical and neurologic emergency. The prevalence of SE is much greater during the neonatal period and early childhood than later in life. The improved outcome of childhood SE coincident with the redefinition of status to a shorter duration and the emergence of improved therapeutic interventions confirms the seriousness of this condition. Both in the laboratory and in the clinical situation, improved techniques are permitting us to understand the consequences of SE on the developing brain. Early intervention to treat prolonged seizures could contribute positively to improving morbidity and mortality as this approach is more widely adopted. REFERENCES 1. Aicardi, J., and J. Chevrie. Convulsive status epilepticus in infants and children: A study of 239 cases. Epilepsia 1970;11: 187–197. 2. Aminoff, M., and R. Simon. Status epilepticus: Causes, clinical features and consequences in 98 patients. Am. J. Med. 1980;69:657–666. 3. Andermann, F., and J. P. Robb. Absence status: A reappraisal following review of thirty-eight patients. Epilepsia 1972;13: 177–187.
, , :
119
4. Barnard, C., and E. Wirrel. Does status epilepticus in children cause developmental deterioration and exacerbation of epilepsy? J. Child Neurol. 1999;14:787–794. 5. Bayne, L., and R. Simon. Systemic and pulmonary vascular pressures during generalized seizures in sheep. Ann. Neurol. 1981;10:566–569. 6. Berg, A., S. Shinnar, S. R. Levy, and F. M. Testa. Status epilepticus in children with newly diagnosed epilepsy. Ann. Neurol. 1999;45:618–623. 7. Bittencourt, P., and A. Richens. Anticonvulsant-induced status epilepticus in Lennox-Gastaut syndrome. Epilepsia 1991;22:129–134. 8. Brenner, R. Is it status? Epilepsia 2002;43:103–113. 9. Brodtkorb, E., T. Sand, and A. Kristiansen. Nonconvulsive status epilepticus in the adult mentally retarded: Classification and role of benzodiazepines. Seizure 1993;2:115–123. 10. Brown, J., and I. Hussain. Status epilepticus. I. Pathogenesis. Dev. Med. Child Neurol. 1991;33:3–17. 11. Callahan, D. J., and M. J. Noetzel. Prolonged absence status epilepticus associated with carbamazepine therapy, increased intracranial pressure, and transient MRI abnormalities. Neurology 1992;42:2198–2201. 12. Chu, K., D. Kang, J. Kim, K. Chang, and S. Lee. Diffusion weighted magnetic resonance imaging in nonconvulsive status epilepticus. Arch. Neurol. 2001;58:993–998. 13. Cockerell, O. C., J. Rothwell, P. D. Thompson, C. D. Marsden, and S. D. Shorvon. Clinical and physiological features of epilepsia partialis continua: Cases ascertained in the UK. Brain 1996;119(Pt. 2):393–407. 14. 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. 15. Correale, J., A. Rabinowicz, and C. Heck. Status epilepticus increases CSF levels of neuron-specific enolase and alters the blood-brain barrier. Neurology 1998;50:1388–1391. 16. Dalby, M. A. Epilepsy and 3 per second spike and wave rhythms: A clinical, electroencephalographic and prognostic analysis of 346 patients. Acta Neurol. Scand. 1969;(Suppl. 40):3. 17. 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. 18. 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. 19. DeLorenzo, R. J., W. A. Hauser, A. R. Towne, J. G. Biggs, J. M. Pellock, L. Penberthy, et al. A prospective, populationbased epidemiologic study of status epilepticus in Richmond, Virginia. Neurology 1996;46:1029–1035. 20. DeLorenzo, R. J., J. M. Pellock, A. R. Towne, and J. G. Boggs. Epidemiology of status epilepticus. J. Clin. Neurophysiol. 1995;12:316–325. 21. 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. 22. 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. 23. Di Mario, F. J., Jr., and R. Clancy. Paradoxical precipitation of tonic seizures by lorazepam in a child with atypical absence seizures. Pediatr. Neurol. 1988;4:249–251.
120
24. Dodrill, C., and A. Wilensky. Intellectual impairment as an outcome of stauts epilepticus. Neurology 1990;40:23–27. 25. Drislane, F., A. Blum, and D. Schomer. Focal status epilepticus: Clinical features and significance of different EEG patterns. Epilepsia 1999;40:1254–1260. 26. Drislane, F., A. Blum, and D. Schomer. Unsuspected electrographic status epilepticus in an intensive care unit. Neurology 1998;50:A395–A396. 27. Drislane, F., and D. Schomer. Clinical implication of generalized electrographical status epilepticus. Epilepsy 1994;19: 111–121. 28. Dwyer, B. E., and C. G. Wasterlain. Neonatal seizures in monkeys and rabbits: Brain glucose depletion in the face of normoglycemia, prevention by glucose loads. Pediatr. Res. 1985;19:992–995. 29. Eriksson, K., and M. Koivikko. Status epilepticus in children: Aetiology, treatment and outcome. Dev. Med. Child Neurol. 1997;39:652–658. 30. Fountain, N. Status epilepticus: Risk factors and complications. Epilepsia 2000;41:S23–S30. 31. Fountain, N., and E. Lothman. Pathophysiology of status epilepticus. J. Clin. Neurophysiol. 1995;12:326–342. 32. Fujikawa, D. G., R. C. Vannucci, B. E. Dwyer, and C. G. Wasterlain. Generalized seizures deplete brain energy reserves in normoxemic newborn monkeys. Brain Res. 1988; 454:51–59. 33. Gastaut, H. Classification of status epilepticus. Adv. Neurol. 1983;34:15–35. 34. Granner, M., and S. Lee. Nonconvulsive status epilepticus: EEG analysis in a large series. Epilepsia 1994;35: 42–47. 35. Grin, J. M., and F. J. DiMario, Jr. Absence status epilepticus causing a prolonged acute confusional state. Clin. Pediatr. (Phila.) 1998;37:37–40. 36. Gross-Tsur, V., and S. Shinnar. Convulsive status epilepticus in children. Epilepsia 1993;34:S12–S20. 37. Haafiz, A., and N. Kissoon. Status epilepticus: Current concepts. Pediatr. Emerg. Care 1999;15:119–129. 38. Hallett, M. Myoclonus: Relation to epilepsy. Epilepsia 1985;26(Suppl. 1):S67–S77. 39. Harvey, A., J. Grattan Smith, P. Desmond, C. Chow, and S. F. Berkovic. Febrile seizures and hippocampal sclerosis: Frequent and related findings in intractable temporal lobe epilepsy of childhood. Pediatr. Neurol. 1995;12:201–206. 40. Hauser, W. A. Status epilepticus: Epidemiologic considerations. Neurology 1990;40:9–13. 41. Hauser, W. A. Status epilepticus: Frequency, etiology, and neurological sequelae. Adv. Neurol. 1983;34:3–14. 42. Hesdorffer, D., G. Logroscino, G. Cascino, J. F. Annegers, and W. A. Hauser. Risk of unprovoked seizure after acute symptomatic seizure: Effect of status epilepticus. Ann. Neurol. 1998; 44:908–912. 43. Hirose, S., R. P. Mohney, M. Okada, S. Kaneko, and A. Mitsudome. The genetics of febrile seizures and related epilepsy syndromes. Brain Dev. 2003;25:304–312. 44. Jaintly, R., J. Sgro, and A. Towne. Prognostic value of EEG monitoring after status epilepticus: A prospective adult study. J. Clin. Neurophysiol. 1997;14:326–334. 45. Juhasz, C., E. Scheidl, and I. Szirmai. Reversible focal MRI abnormalities due to status epilepticus: An EEG single photon emission computed tomography, transcranial Doppler follow-up study. Electroencephalogr. Clin. Neurophysiol. 1998;107:402–407.
:
46. Kellaway, P., and R. A. Hrachovy. Status epilepticus in newborns: A perspective on neonatal seizures. Adv. Neurol. 1983;34:93–99. 47. Kim, J., J. Chung, P. Yoon, D. Ki, T. Chung, E. Kim, et al. Transient MR signal changes in patients with generalized tonic clonic seizures or status epilepticus: Periictal diffusion weighted imaging. AJNR Am. J. Neuroradiol. 2001;22: 1149–1160. 48. Kim, S., D. Lee, and J. Kim. Neurologic outcomes of pediatric epileptic patients with pentobarbital coma. Pediatr. Neurol. 2001;25:217–220. 49. Kreisman, N., M. Gauthier-Lewis, S. Conklin, N. Voss, and R. Barbee. Cardiac output and regional hemodynamics during recurrent seizures in rats. Brain Res. 1993;626:295–302. 50. Krumholz, A. Epidemiology and evidence for morbidity of nonconvulsive status epilepticus. J. Clin. Neurophysiol. 1999;16: 314–323. 51. 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. 52. Lansberg, M., M. O’Brien, and A. Norbash. MRI abnormalities associated with partial status epilepticus. Neurology 1999;52:1021–1027. 53. Lee, B., O. Markand, H. Wellman, A. Siddiqui, H. Park, B. Mock, et al. HIPDM-SPECT in patients with medically intractable complex partial seizures: Ictal study. Arch. Neurol. 1988;45:397–402. 54. Litt, B., R. Wityk, and S. Hertz. Nonconvulsive status epilepticus in the critically ill elderly. Epilepsia 1998;39:1194–1202. 55. Liu, Z., A. Gatt, M. Mikati, and G. Holmes. Effect of temperature on kainic acid induced seizures. Brain Res. 1993;63: 51–58. 56. Livingston, J. H., A. Anderson, J. K. Brown, and A. McInnes. Benzodiazepine sensitivity testing in the management of intractable seizure disorders in childhood. Electroencephalogr. Clin. Neurophysiol. 1987;67:197–203. 57. Livingston, S., I. Torres, L. L. Pauli, and R. V. Rider. Petit mal epilepsy: Results of a prolonged follow-up study of 117 patients. JAMA 1965;194:227–232. 58. Logroscino, G., D. Hesdorffer, G. Cascino, J. Annegers, E. Bagiella, and W. Hauser. Long term mortality after a first episode of status epilepticus. Neurology 2002;58:537–541. 59. Lombroso, C. Prognosis in neonatal seizures. Adv. Neurol. 1983;34:101. 60. Lowenstein, D. H., and B. K. Alldredge. Status epilepticus. N. Engl. J. Med. 1998;338:970–976. 61. Lowenstein, D. H., and M. J. Aminoff. Clinical and EEG features of status epilepticus in comatose patients. Neurology 1992;42:100–104. 62. Lowenstein, D. H., T. Bleck, and R. L. Macdonald. It’s time to revise the definition of status epilepticus. Epilepsia 1999;40:120–122. 63. Marangos, P. J., A. P. Zis, R. L. Clak, 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. 64. Matsuoka, H., T. Okuma, T. Ueno, and H. Saito. Impairment of parietal cortical functions associated with episodic prolonged spike-and-wave discharges. Epilepsia 1986;27: 432–436. 65. Maytal, J. The management of status epilepticus in children. Children’s Hosp. Q. 1993;3:255–263.
66. Maytal, J., and S. Shinnar. Febrile status epilepticus. Pediatrics 1990;86:618–623. 67. 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. 68. Mesulam, M. M. Dissociative states with abnormal temporal lobe EEG: Multiple personality and the illusion of possession. Arch. Neurol. 1981;38:176–181. 69. 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. 70. Miller, S. P., J. Weiss, A. Barnwell, D. M. Ferriero, B. LatalHajnal, A. Ferrer-Rogers, et al. Seizure-associated brain injury in term newborns with perinatal asphyxia. Neurology 2002;58:542–548. 71. Mitchell, W. Status epilepticus and acute serial seizures in children. J. Child Neurol. 2002;17:S36–S43. 72. Mizrahi, E. Acute and chronic effects of seizures in the developing brain: Lessons from clinical experience. Epilepsia 1999;40:S42–S50. 73. Mizrahi, E., and P. Kellaway. Characterization and classification of neonatal seizures. Neurology 1987;37:1837–1844. 74. Nei, M., J. Lee, and V. Shanker. The EEG and prognosis in status epilepticus. Epilepsia 1999;40:157–163. 75. Nitsch, C., and I. Klatzo. Regional patterns of blood-brain barrier breakdown during epileptiform seizures induced by various convulsive agents. J. Neurol. Sci. 1983;59:305–322. 76. Nohria, V., N. Lee, and R. Tien. Magnetic resonance imaging evidence of hippocampal sclerosis in progression: A case report. Epilepsia 1994;35:1332–1336. 77. Olmos-Garcia de Alba, G., E. Udaeta Mora, J. Malagon Valdez, D. Villanueva Garcia, and F. Valarezo Crespo. Neonatal status epilepticus. II. Electroencephalographic aspects. Clin. Electroencephalogr. 1984;15:197–201. 78. O’Regan, M., and J. Brown. Serum neuron-specific enolase: A marker for neuronal dysfunction in children with continuous EEG epileptiform activity. Eur. J. Paediatr. Neurol. 1998; 2:193–197. 79. Patronas, N., and M. Argyropoulou. Intravascular thrombosis as a possible cause of transient cortical brain lesions: CT and MRI. J. Comput. Assist. Tomogr. 1992;16:849–855. 80. Pellock, J. M. Status epilepticus in children: Update and review. J. Child Neurol. 1994;9(Suppl. 2):27–35. 81. Perucca, E., L. Gram, and G. Avanzini. Antiepileptic drugs as a cause of worsening seizures. Epilepsia 1998;39:5–17. 82. Phillips, S., and R. Shanahan. Etiology and mortality of status epilepticus in children: A recent update. Arch. Neurol. 1989;46:74–76. 83. Porter, R., and J. Penry. Petit mal status. In A. DelgadoEscueta, C. Wasterlain, D. Treiman, and R. Porter, eds. Status Epilepticus. New York: Raven Press, 1983:61–67. 84. Prior, P., G. Maclaine, and D. Scott. Tonic status epilepticus precipiated by intravenous diazepam in a child with petit mal status. Epilepsia 1972;13:467–472. 85. Roberts, M. A., amd P. R. Humphrey. Prolonged complex partial status epilepticus: A case report. J. Neurol. Neurosurg. Psychiatry 1988;51:586–588. 86. Roberts, M. R., and J. Eng-Bourquin. Status epilepticus in children. Emerg. Med. Clin. North Am. 1995;13:489–507. 87. 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. The Epilepsies. New York: Elsevier, 1974: 1145–1188.
, , :
121
88. Ross, C., A. Blake, and W. Whitehouse. Status epilepticus on the paediatric intensive care unit: The role of EEG monitoring. Seizure 1999;8:335–338. 89. 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. 90. Sagduyu, A., S. Tarlaci, and H. Sirin. Generalized tonicclonic status epilepticus: Causes, treatment, complications and predictors of case fatality. J. Neurol. 1998;245:640–646. 91. Sahin, M., C. Menache, G. Holmes, and J. Riviello. Outcome of severe refractory status epilepticus in children. Epilepsia 2001;42:1461–1467. 92. Salmenpera, T., R. Kalviainen, and K. Paranen. MRI volumetry of the hippocampus, amygdala, entorhinal cortex, and perirhinal cortex after status epilepticus. Epilepsy Res. 2000;40:155–170. 93. Sankar, R., D. H. Shin, H. Liu, A. M. Mazarati, A. Pereira de Vasconcelos, and C. G. Wasterlain. Patterns of status epilepticus-induced neuronal injury during development and long-term consequences. J. Neurosci. 1998;18:8382–8393. 94. Sankar, R., D. H. Shin, and C. G. Wasterlain. Serum neuron specific enolase is a marker for neuronal damage following status epilepticus in the rat. Epilepsy Res. 1997;28: 129–136. 95. Scher, M. S., K. Aso, M. E. 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. 96. 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. 97. Schmechel, D., P. Marangos, A. Zis, M. Brightman, and F. Goodwin. Brain enolases as specfic markers of neuronal and glial cells. Science 1978;199:313–315. 98. Schulz, R., and A. Ebner. Prolonged febrile convulsions and mesial temporal lobe epilepsy in an identical twin. Neurology 2001;57:318–320. 99. Scott, R., R. Surtees, and B. Neville. Status epilepticus: Pathophysiology, epidemiology, and outcomes. Arch. Dis. Child. 1998;79:73–77. 100. 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 enolase (alpha gamma, beta gamma, and alpha beta) from homodimeric forms. Biochem. Biophys. Acta 1983;748: 278–284. 101. Shinnar, S., J. M. Pellock, A. T. Berg, C. O’Dell, S. M. Driscoll, J. Maytal, et al. Short-term outcomes of children with febrile status epilepticus. Epilepsia 2001;42:47–53. 102. Shinnar, S., J. M. Pellock, and S. Moshe. In whom does status epilepticus occur: Age-related differences in children. Epilepsia 1997;38:907–914. 103. Shorvon, S. The outcome of tonic clonic status epilepticus. Curr. Opin. Neurol. 1994;7:93–95. 104. Shorvon, S. Status Epilepticus: Its Clinical Features and Treatment in Adults and Children. Cambridge, U.K.: Cambridge University Press, 1994. 105. Snead, O. C. III, and L. C. Hosey. Exacerbation of seizures in children by carbamazepine. N. Engl. J. Med. 1985;313: 916–921.
122
106. Stewart, W., R. Harrison, and J. Dooley. Respiratory depression in the acute management of seizures. Arch. Dis. Child. 2002;87:225–226. 107. Sutula, T. P., and A. Pitkänen. More evidence for seizureinduced neuron loss: Is hippocampal sclerosis both cause and effect of epilepsy? Neurology 2001;57:169–170. 108. Takahashi, Y., H. Kubota, T. Fujiwara, K. Yagi, and M. Seino. Epilepsia partialis continua of childhood involving bilateral brain hemispheres. Acta Neurol. Scand. 1997;96: 345–352. 109. Tassinari, C., C. Dravet, and J. Roger. Tonic status epilepticus precipitated by intravenous benzodiazepine in five patients with Lennox-Gastaut syndrome. Epilepsia 1972;13: 421–435. 110. Tien, R., and G. 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. 111. Tomlinson, F., R. Anderson, and F. Meyer. Effect of arterial blood pressure and serum glucose on brain intracellular pH, cerebral and cortical blood flow during status epilepticus in the white New Zealand rabbit. Epilepsy Res. 1993;14:123–137. 112. 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. 113. Tomson, T., E. Svanborg, and J. E. Wedlund. Nonconvulsive status epilepticus: High incidence of complex partial status. Epilepsia 1986;27:276–285. 114. Towne, A., J. Pellock, D. Ko, and R. DeLorenzo. Determinants of mortality in status epilepticus. Epilepsia 1994;11: 187–197. 115. Towne, A., E. Waterhouse, and J. G. Boggs. Prevalence of nonconvulsive status epilepticus in comatose patients. Neurology 2000;54:340–345. 116. Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of America’s Working Group on Status Epilepticus. JAMA 1993;270:854–859. 117. Treiman, D. Electroclinical features of status epilepticus. J. Clin. Neurophysiol. 1995;12:343–362. 118. Treiman, D. M. The role of benzodiazepines in the management of status epilepticus. Neurology 1990;40:32–42. 119. Treiman, D. Status epilepticus. In J. Laidlaw, A. Richens, and D. Chadwick, eds. A Textbook of Epilepsy. Edinburgh: Churchill Livingstone, 1993. 120. Treiman, D. M., C. DeGiorgio, S. Salisbury, and C. Wickboldt. Subtle generalized convulsive status epilepticus. Epilepsia 1984;25:653. 121. Treiman, D. M., N. Walton, and C. Kendrick. A progressive sequence of electroencephalographic changes during generalized convulsive status epilepticus. Epilepsy Res. 1990;5: 49–60. 122. VanLandingham, K., E. Heinz, J. E. Cavazos, and D. V. Lewis. Magnetic resonance imaging evidence of hippocampal injury after prolonged, focal febrile convulsions. Ann. Neurol. 1998;43:411–412. 123. Verity, C., E. Ross, and J. Golding. Outcome of childhood status epilepticus and lengthy febrile convulsions: Findings of national cohort study. BMJ 1993;307:225–228. 124. Vespa, P., M. Nuwer, and V. Nenov. Increased incidence and impact of nonconvulsive and convulsive seizures after traumatic brain injury as detected by continuous electroencephalographic monitoring. J. Neurosurg. 1999;91:750–760.
:
125. Wasterlain, C. G. Effects of neonatal status epilepticus on rat brain development. Neurology 1976;26:975–986. 126. Waterhouse, E., L. Garnett, and A. Towne. Prospective population-based study of intermittent and continuous convulsive status epilepticus in Richmond, Virginia. Epilepsia 1999;40:752–758. 127. Wical, B. S. Neonatal seizures and electrographic analysis: Evaluation and outcomes. Pediatr. Neurol. 1994;10:271–275. 128. Wieschmann, U., F. Woermann, and L. Lemieux. Development of hippocampal atrophy: A serial magnetic resonance imaging study in a patient who developed epilepsy after generalized status epilepticus. Epilepsia 1997;38:1238–1241. 129. Wieser, H. G., B. E. Swartz, A. V. Delgado-Escueta, J. Bancaud, G. O. Walsh, H. Maldonado, et al. Differentiating frontal lobe seizures from temporal lobe seizures. Adv. Neurol. 1992;57:267–285. 130. Williamson, P. D., D. D. Spencer, S. S. Spencer, R. A. Novelly, and R. H. Mattson. Complex partial seizures of frontal lobe origin. Ann. Neurol. 1985;18:497–504. 131. Williamson, P. D., D. D. Spencer, S. S. Spencer, R. A. Novelly, and R. H. Mattson. Complex partial status epilepticus: A depth-electrode study. Ann. Neurol. 1985;18:647–654. 132. Yarnell, P., D. Burdich, B. Sanders, and J. Stears. Focal seizures, early veins and increased flow. Neurology 1974;24: 512–516. 133. Young, G., K. Jordan, and G. 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. 134. Zomzely-Neurath, C. Nervous system proteins: 14-3-2 protein, antigen alpha and neuron specific enolase. Scand. J. Immunol. 1982;9:1–40.
, , :
123
11
Nonconvulsive Status Epilepticus in Children: With Special Reference to Electrical Status Epilepticus During Slow-Wave Sleep Syndrome (ESES Syndrome)
, , , S (SE) is usually defined as any seizure lasting over 30 minutes, or recurrent seizures lasting a total of more than 30 minutes without full recovery of consciousness (2, 5, 6, 47), although there is still some disagreement over duration (2, 46). Etiologically, SE is divided into acute symptomatic SE due to acute brain insults or metabolic disorders and SE related to seizure disorders such as epilepsy and febrile seizures. The latter category of SE is further divided into symptomatic (remote symptomatic), cryptogenic (probably symptomatic), and idiopathic (46). The incidence of SE is high in the very young and in the elderly (25). In up to 10%–30% of cases, SE occur in the setting of chronic epilepsy (5, 46, 47), and most cases of SE are convulsive in epidemiologic studies, but 25%–35% of cases in hospital surveys are nonconvulsive (24). Although nonconvulsive SE (NCSE) may be underestimated, it is uncommon in children. Theoretically, there are as many types of SE as there are types of epileptic seizure (20). SE may be roughly classified into generalized and partial (focal), and further classified into convulsive and nonconvulsive (Table 11.1). Unilateral SE and neonatal SE are unique, and the dominant seizure side often alternates during seizures in infancy (2, 20). NCSE is heterogeneous and controversial (6, 27, 28). In epilepsy in children, it is also critical to consider SE, particularly NCSE, in the context of age and epileptic syndromes (46). After briefly discussing NCSE, this chapter takes up the syndrome of electrical SE during slow-wave sleep (ESES), which is a peculiar pathology in childhood characterized by the nearly continuous appearance of diffuse slow spike-andwave discharges during slow-wave sleep.
Nonconvulsive SE Although NCSE in childhood is receiving increasing attention, the classification of NCSE has not yet been fully clarified (6, 21, 27, 28, 46, 49, 56). NCSE is characterized clinically by subtle manifestations such as clouding of consciousness, pseudodementia, or ataxia, no overt motor (convulsive) manifestations, and electrically continuous or repetitive seizure patterns. It is often difficult to notice, and controversial in its definition and classification (6, 12, 20, 27, 49). Electroencephalographic (EEG) findings have decisive importance, showing continuous or nearly continuous electrographic seizure activity lasting at least 30 minutes (55). The EEG criteria for diagnosing NCSE include discrete electrographic seizures, continuous spike-and-wave activity, or rhythmic recurrent epileptiform activity that usually shows marked improvement with the injection of benzodiazepines. These EEG findings also differentiate generalized from focal-onset NCSE (21). Generalized NCSE (GNCSE), mainly absence status, is more often observed than partial SE in NCSE occurring in chronic epileptics. In acute symptomatic SE, however, nonconvulsive complex partial SE predominates, and its poor prognosis necessitates intensive emergency treatment (55). Accordingly, it is important to differentiate partial nonconvulsive SE from absence status, which has a better prognosis. After prolonged generalized convulsive SE (GCSE) or following incomplete treatment, convulsive symptoms become very subtle, and the residual persistent disturbance of consciousness and autonomic symptoms may be confused with transition to NCSE. A careful diagnosis of SE is important and should take into account the results of EEG monitoring (55).
.:
125
T 11.1 Classification of status epilepticus I. Generalized SE A. Convulsive generalized SE 1. Tonic-clonic SE (grand mal SE) 2. Tonic SE 3. Clonic SE 4. Myoclonic SE B. Nonconvulsive generalized SE 1. Absence status a. Typical absence status b. Atypical absence status c. Minor epileptic status d. Nonconvulsive SE in the age-dependent epileptic encephalopathy 2. Myoclonic status 3. Atonic and akinetic SE II. Unilateral SE 1. Hemiconvulsion-hemiplegia syndrome (HH syndrome) 2. Hemi-grand mal status III. Partial (focal) SE 1. Simple partial SE a. Convulsive simple partial SE i. Focal motor SE ii. Epilepsia partialis continua b. Nonconvulsive simple partial SE 2. Complex partial SE a. Convulsive complex partial SE b. Nonconvulsive complex partial SE IV. SE of undetermined whether partial or generalized 1. Convulsive SE 2. Nonconvulsive SE a. ESES syndrome b. Landau-Kleffner syndrome c. Obtundation status in severe myoclonic epilepsy in infancy V. SE in neonates (neonatal SE)
G N SE GNCSE is characterized by various degrees of clouding of mental processes, from simple slowing of ideation to complete unconsciousness, and by diffuse bilateral spike-and-wave activity on the EEG. Absence status Absence status (AS) is characterized by repetitive absences, either typical or atypical, or prolonged clouding of consciousness, which varies from light to profound stupor or confusion, together with diffuse spike-and-wave activity on the EEG. Complex mental testing may be needed to detect absence status with only mild mental slowing. Blinking, myoclonia of the upper extremities, or automatisms may occasionally occur but are not distinctive features of AS. This status, however, has terminologic and nosologic problems, being variously called petit mal status, epileptic twilight state, ictal stupor, spike-wave stupor, and minor epileptic status (2, 20, 39, 46). Electrographically, bilaterally synchronous spike-and-wave patterns are repeated at very
126
short intervals or continue without interruption. In atypical ASE and some time after the onset of typical AS, slow spikeand-wave patterns become predominant and somewhat irregular. Atypical AS associated with Lennox-Gastaut syndrome or myoclonic-astatic epilepsy is more often observed in childhood epilepsy (12, 20, 46). Petit mal status, typical AS, or spike-wave stupor. Formerly, we (39) proposed reserving the term petit mal status for cases with closely repeated 3-Hz spike-and-wave bursts corresponding to a series of petit mal absences and applying the term spikewave stupor exclusively to those cases with uninterrupted continuous 3-Hz spike-and-wave bursts and prolonged altered consciousness. Typical ASE rarely occurs in childhood absence epilepsy but is somewhat more frequent in other idiopathic forms of generalized epilepsy and in adults (20). Minor epileptic status. Reporting findings in 22 children, Brett (7) differentiated minor epiletic status from AS by the presence of myoclonus and less frequent spike-and-wave activity intermingled with slow waves on EEG, and by its poor prognosis. This syndrome is characterized clinically by periodic or fluctuating lowering of awareness and responsiveness and decreased speech, sometimes so severe as to simulate dementia (i.e., pseudodementia), and is often associated with lack of coordination and unsteadiness in walking that resembles ataxia (i.e., pseudoataxia) because of the intrusion of repeated small myoclonic jerks or twiches. Because both negative and positive myoclonus are observed, Brett’s cases (7) may include or be combined with some type of ESES syndrome or myoclonic status. Angelman’s syndrome is often accompanied by NCSE, which in most cases may be this kind of minor epileptic status (9, 33, 50). It is mainly observed from late infancy to early childhood. NCSE with hypsarrhythmia. The most typical continuous and longlasting epileptic EEG abnormality is hypsarrhythmia, observed in West syndrome. Infants with this condition become stuporous and apathetic, and their development stagnates or deteriorates. Thus, the twilight state in hypsarrhythmia may be regarded as a form of NCSE (12, 46). NCSE in myoclonic-astatic epilepsy and Lennox-Gastaut syndrome. NCSE is reported in 30%–40% of patients with myoclonicastatic epilepsy in childhood (12). It is characterized by apathy or stupor and slurred or decreased speech, and 2– 3 Hz spike-and-wave bursts on the EEG. There is palpable irregular twitching of the facial muscles and the extremities, and astatic seizures and head nodding can appear serially (12). This status of minor seizures may be a mixed type of atypical AS, myoclonic status, or myoclonic-astatic status. More than two-thirds of patients with Lennox-Gastaut syndrome experience SE (4), which usually consists of clouding of consciousness with or without intermixed serial tonic seizures of short or long duration.
:
Myoclonic status Myoclonic status is usually classified as a form of convulsive status (20) and subdivided into idiopathic and symptomatic generalized epilepsies. Rhythmic myoclonic jerks occur in the generalized forms and appear mainly in proximal muscles. The level of consciousness depends on the underlying disorders, and sometimes there is no clouding (20). Diffuse polyspike-and-wave discharges precede the myoclonic jerks. It may be reasonable to classify this status as NCSE when jerks or twiches are very small and clouding of consciousness is a more prominent feature (20). Myoclonic status in nonprogressive encephalopathies as described by Dalla Bernardina et al. (9) belongs to this kind of NCSE and probably overlaps with atypical ASE, minor epileptic status, or obtunded status. Nonconvulsive myoclonic status is also observed in eyelid myoclonia with absences. Atonic and akinetic SE This rare form of SE is peculiar to very young children during hyperthermia and is characterized by immobility (without or with tonus), sometimes with a few minor clonias, and unconsciousness. The EEG shows an epileptic recruiting rhythm progressively mixed with delta activity, forming some spike-and-wave patterns (20). P (F) N SE Simple partial SE Nonconvulsive simple partial SE (SPSE) by definition should not be associated with alterations of consciousness, and is more often neocortical and extratemporal in origin (46, 60). Rare cases with somatoinhibitory SE (ictal paralysis), somatosensory SE, visual SE (elementary visual phenomena, amaurotic, visual hallucination), auditory SE, dysphasic/aphasic SE, SE with pure transient amnesia (59), autonomic/vegetative SE, and SE with expression of fear, depression, and anxiety have been reported (46, 60). Complex partial SE Complex partial SE (CPSE) often originates from temporal or frontal lobe foci, but on rare occasions it originates from other cortical areas; an example is visual hallucinatory SE (46). Clinically, CPSE is characterized by recurrent or prolonged seizures involving some alteration of contact with the environment, of memory or of consciousness, but it usually stops short of coma. Automatisms may be observed, but not convulsive movement. Its fundamental characteristic, which enables differentiation of CPSE from other twilight states such as AS, is a cyclicity that alternates between total unresponsiveness with stereotyped automatisms and partial unresponsiveness with reactive automatisms (46, 56). N SE, U W P G ESES syndrome Among the NCSE conditions, ESES (26, 29, 42) is a peculiar pathologic condition that is observed only
in childhood epilepsy. Epilepsy with continuous spike waves during slow-wave sleep (CSWS) (8) characterized by ESES has many interesting electroclinical characteristics. However, its pathophysiology and the points of discriminating epilepsy with CSWS from related conditions, such as ESES syndrome (37), are still unclear (2, 10, 18, 19, 58). Some authors prefer to use the term CSWS syndrome (2, 19). ESES syndrome and its developmental aspects are discussed later in the chapter. Landau-Kleffner syndrome Active epileptic discharges appearing predominantly from the temporal areas can cause acquired aphasia, mainly due to auditory agnosia, in children ages 2–11 years (2, 48, 53). Epileptic seizures such as generalized tonic-clonic, focal motor seizures, or atypical absences usually appear before or after the onset of decreased speech, but there are no seizures in 17%–30% of cases (2). Intelligence usually is preserved, but behavior disorders are often observed. Epilepsy, aphasia, and epileptic EEG abnormalities disappear by the age of 15. This is understandable in the context of ESES syndrome (43, 48, 53), as ESES/CSWS is observed, but the spike-wave index during slow-ware sleep is relatively low, about 30% or more. Obtundation status in severe myoclonic epilepsy in infancy In this type of status, observed in 30%–40% of cases of Dravet syndrome, patients become obtunded and lose interest in their environment or do not answer (16). They may have erratic, small myoclonias, sometimes associated with increased muscular tone. The EEG shows diffuse dysrhythmia of slow waves, intermixed with focal and diffuse spikes, sharp waves, and spike-and-wave complexes, without correspondence between the spikes and the myoclonias (16). This status may belong to the category of ASE in a broad sense and may overlap minor epileptic status (7). Nearly the same atypical ASE is also observed in Lennox-Gastaut syndrome or myoclonic-astatic epilepsy (2, 4, 12).
ESES syndrome We propose that the rare, EEG-defined syndrome characterized by almost continuously appearing diffuse slow spikeand-wave activity during slow-wave sleep and subsequent brain dysfunction during awake periods be named ESES syndrome (37). It is very peculiar to have no or subtle clinical seizure manifestations corresponding to such continuous severe epileptic discharges (i.e., CSWS). For this reason, the entity is also called subclinical electrical SE. ESES syndrome includes epilepsy with CSWS (48, 53), nonconvulsive SE with epileptic negative myoclonus (37, 38, 40), atypical benign partial epilepsy (1, 2), and LandauKleffner syndrome (48, 53). Because Landau-Kleffner
.:
127
syndrome is semiologically independent, it will not be discussed further. E CSWS Epilepsy with CSWS, originally reported by Patry et al. (42) and Tassinari et al. (53), forms the core of ESES syndrome, with a mean age at onset of 4–5 years (48, 53). In the 1989 International League Against Epilepsy (ILAE) classification (8), this syndrome was placed under “epilepsies and syndromes undetermined whether focal or generalized,” with both generalized and focal seizures, but the classification does not define the time ratio occupied by spike-and-wave discharges during slow-wave sleep (the spike-wave index). A newly proposed diagnostic scheme for epilepsy (17) classifies epilepsy with CSWS and Landau-Kleffner syndrome into epileptic encephalopathies in which the epileptiform abnormalities may contribute to progressive dysfunction. Clinically, global deterioration detected with the appearance of CSWS is important. This deterioration rarely normalizes after the disappearance of CSWS, and neurologic, behavioral, and mental/cognitive dysfunctions often remain as sequelae (19, 48, 53). In two of our 15 patients (13.3%), peculiar EEG patterns characteristic of ESES (i.e., CSWS) were found after the patients visited the hospital complaining of mental slowing or behavior disorders not preceded by any epileptic seizures. But in the other 13 patients (86.7%) ESES appeared after other epileptic seizures, which belonged to the focal epilepsies in 11 cases (73.4%) and to the generalized epilepsies in two cases (13.3%) (35). A B P E Atypical benign partial epilepsy (ABPE) (1, 2), the concept proposed as a specific type of benign childhood epilepsy with centrotemporal spikes (BCECS) because of the presence of rolandic spikes on the waking EEG, is known to show CSWS. Clinically, focal motor seizures, absences, myoclonic, and particularly atonic seizures appear from 2 to 6 years of age. Clusters of frequent minor seizures lasting 1 to several weeks often repeat every several weeks or months. Although Aicardi and Chevrie (1) did not recognize this condition as a type of SE, it should be categorized as an NCSE (29, 30, 35, 37). We (37) and others (11) have proved that most of the episodes described as atonic seizures were negative myoclonus. A good prognosis without neuropsychiatric sequelae is considered to be a characteristic of ABPE (1), but there may be some exceptions (14, 18, 23). N SE E N M This, entity, NSENM, was reported as a peculiar type of nonconvulsive SE in childhood by Ohtahara et al. (37, 38, 40). It resembles epilepsy with CSWS but has some unique
128
clinical features: frequent brief atonic episodes without loss of consciousness, and transient hemiparesis. The age at onset of epileptic seizures, such as focal or generalized tonic-clonic seizures or atypical absences, is in early or school-age childhood, and NCSE with brief atonic episodes appears around the same time or several months or years later, around 4–8 years of age. Characteristically, such SE appears repeatedly, lasting a few days to several months, separated by remission intervals of several months. Brief atonic episodes are observed at all four extremities, the neck, and the upper half of the body. Sagging of the outstretched arms is often detected, usually with predominance on one side. Head nodding is sometimes noted. These episodes are not apparent when the child is lying down. Brief atonic episodes occur at most every few seconds, but there is no disturbance of consciousness. During SE, when frequent atonic episodes occur, the waking EEG shows focal spikes and diffuse spike-and-wave discharges, probably due to secondary generalization (30). The multifocal type is most often observed, but frontal, central or midtemporal single focus types may also be observed. The EEG during slow-wave sleep demonstrates CSWS, which often shows asymmetry or some focal features. In REM sleep, diffuse spike-and-wave discharges decrease, as in epilepsy with CSWS (48, 53). Because the atonic episodes do not necessarily correspond to spikes on the EEG, at first we considered them nonepileptic events (38, 40), but further investigation (37) revealed them to be negative myoclonus (36, 45). Figure 11.1 shows an EMG silent period during atonic episode corresponding to spikes. Accordingly, this type of epilepsy is reasonably named nonconvulsive SE with epileptic negative myoclonus (NSENM). Progressive mental slowing or behavior disorders appear and fluctuate with negative myoclonus (NM) and CSWS, just as in epilepsy with CSWS. In the remission periods of NM, continuous diffuse spike-and-wave patterns disappear or fragment in from the sleep EEG, and diffuse spike-and-wave discharges also decrease in the waking record. The clinicoelectrical course of this entity is age dependent, remitting by 15 years of age in all cases, but some mental deficiency often remains as a sequela (35, 37, 38, 40). NM ESES S NM is defined by mild irregular lapses of sustained posture associated with silent periods on the EMG (36, 45). The relationship between NM and epilepsy has been little studied, even a decade after Tassinari (51) first described epileptic negative myoclonus (ENM), and NM is not yet well known as an epileptic symptom, but it has recently been proposed as a seizure type (17). Although it seems to be relatively rare (22, 52), frequent NM is the major symptom of NSENM. In ABPE, most of the “atonic
:
F 11.1 Ictal polygram of “brief atonic episodes” or negative myoclonus (NM) in a patient with “nonconvulsive status epilepticus with NM,” recorded with the arms outstretched. The EMG is recorded from the right deltoid muscle, and the bottom trace is from an accelerometer (Nihon-Kohden MT 4111) placed on the right hand. NM (denoted by the arrows) occurred in clusters or isolation, in both arms, with predominance on the right side, and sometimes also in the head.
Most NM accompanied diffuse or almost diffuse slow spike-wave bursts in the EEG (A). However, NM occasionally occurred without any concomitant diffuse epileptic discharges (B, C ). In addition, many diffuse spike-wave bursts occurred without any overt NM. (Calibration: 1 second and 50 mV.)
seizures” indicated by Aicardi and Chevrie (1) may be NM in nature. A precise investigation of NM in a case with NSENM disclosed that the latency between the negative peak of spikes and the beginning of the EMG silent period is not always time-locked, as shown in Figure 11.1: it is broadly distributed from 20 msec to nearly 200 msec, with a peak distribution at 60–90 msec. EMG silent periods last 50–210 msec. Tassinari et al. (53) and Rubboli et al. (44) pointed out two types of NM, those time-locked with spikes by a latency of 20–40 msec and those unassociated with spikes. Using spike averaging and spike topography, Rubboli et al. (44) noticed a waveform difference between the spikes asociated with NM and those unassociated with it, and suggested frontal lobe involvement in the generation of epileptic NM. Baumgartner et al. (3), using a combined SPECT and EEG method, also estimated the generator of epileptic NM to be located in the premotor cortex of the middle frontal gyrus. Tassinari et al. (52) described variability of latency between the spike and the onset of the muscular inhibition and the variability of duration of the ENM itself (≥50– 400 msec), indicating that ENM could be the result of
inhibitory phenomena arising not only from a single cortical “inhibitory” area, but also from subcortical and pontine structures. In our series of NSENM and ABPE, ENM usually corresponded to the contralateral spikes that often appeared bilaterally, either synchronously or independently, but in no patient were spikes localized to only one hemisphere. Cases with ENM are extremely rare in partial epilepsy in general. Our experience, including a follow-up study, suggests that NM occurs in cases of combined focal cortical and diffuse pathology, but not in purely focal cortical epilepsy. On the other hand, NM was not observed in our cases of epilepsy with CSWS. Tassinari et al. (53) described atypical absences frequently associated with atonic and tonic components leading to a sudden fall in their group 3 of epilepsy with CSWS, but those may differ from NM. NM rarely occurs in this syndrome even if it exists, and it requires further investigation. These findings indicate that the manifestations of ENM probably require strong cortical involvement, as well as subcortical mechanisms responsible for ESES/CSWS. Interestingly, ENM is not observed in cases of epilepsy with CSWS, which have less cortical involvement. Future studies of
.:
129
T 11.2 Clinicoelectrical characteristics of three types of ESES syndrome
Epilepsy with CSWS
Atypical Benign Partial Epilepsy
Nonconvulsive SE with Negative Myoclonus
? (-) ~ (+) (-) ~ (+) (+) Good
(++) (+) (+) (-) Good
(+++) (-) (+) (+) Good
EEG Findings Awake
Rare spikes
Sleep
CSWS
Rolandic spikes, diffuse spike-waves Unilateral-dominant CSWS
Rolandic, F, mT, or multifocal spikes, sometimes generalized Unilateral-dominant CSWS
Clinical Symptoms Negative myoclonus Absences and myoclonic seizures Generalized tonic-clonic seizures Mental deterioration Seizure prognosis
Abbreviations: CSWS, continuous spike waves during slow-wave sleep; F, frontal; mT, midtemporal.
NSENM may contribute to a better understanding of the pathophysiology of NM. The diagnosis of NM is difficult to make (22). EEG-EMG polygraphy is necessary to detect EMG silent periods corresponding to atonic episodes. C R T T ESES S The characteristics of three types of ESES syndrome are shown in Table 11.2. Clinical and EEG findings suggest the important role of cortical pathology in NSENM and ABPE. NSENM in particular has a strong organic factor. In ABPE, presumed organic factors such as the existence of multiple seizure types may indicate this syndrome to be closer to NSENM than to benign childhood epilepsy with centrotemporal spikes (BCECS). Epilepsy with CSWS may have characteristics of a more diffuse encephalopathy. NM is observed in NSENM and ABPE and represents a major component of the former, but is not usually seen in epilepsy with CSWS. Mental regression, another important point of difference in these syndromes, is addressed later in the chapter. The spike-wave index is another difference. Tassinari et al. (53) require a spike-wave index above 85% to diagnose epilepsy with CSWS, but the 1989 ILAE classification of epileptic syndromes (8) did not address this point. The spikewave index is probably highest in epilepsy with CSWS, lowest in ABPE, and intermediate in NSENM. The three types probably have some overlap, as shown in Figure 11.2. In particular, a common pathophysiology is suggested for NSENM and the atypical form of ABPE. F- ESES The 29 cases in our series were classified into three groups according to the spike-wave index: group I, nine cases with a spike-wave index above 85%;
130
Sp-W INDEX
F 11.2 Relationship among three types of ESES syndrome. CSWS, continuous spike waves during slow-wave sleep; NSENM, nonconvulsive SE with negative myoclonus; ABPE, atypical benign partial epilepsy; BPE, benign partial epilepsy.
group II, 12 cases with a spike-wave index of 50%–84%; and group III, eight cases with a spike-wave index of 25%–49%. Long-term follow-up of mental status in 14 patients with a normal IQ (>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 <30 ng/mL) (32). Normal subjects were defined as subjects not suffering from a vascular or inflammatory process of the central nervous system (CNS), and therefore it is not clear if all subjects were indeed truly normal controls. The manufacturer of the commercial RIA (Pharmacia) states that NSE values less than 12.5 ng/mL represent the 95th percentile of NSE values in 112 normal individuals. In our laboratory the mean NSE level (based on measurements in 30 normal control subjects) is 5.02 ng/mL (SD 1.58 ng/nL; range, 2.0–8.8 ng/mL). The normal limit in our laboratory is 11 ng/mL, with normal limits in the published literature ranging from 10 to 12.5 ng/mL (4, 5, 7). The normal limit is typically calculated by adding 3.3 times the standard deviation to the mean NSE level. CSF NSE levels were originally reported in 1981 by Royds et al., who also used an RIA technique (30). Normal CSF was obtained by lumbar puncture in 40 subjects undergoing myelography, and values were reported in international units. The mean CSF NSE value was 0.72 IU/L ± 0.26 (range, 0.2–1.2 IU/L). Persson et al. reported CSF NSE levels in 16 subjects either undergoing routine lumbar puncture for headache or dizziness or undergoing myelography (25). CSF NSE values were less than 2 ng/mL in 15 control subjects and 2.4 ng/mL in one subject. Correale et al. also studied CSF NSE levels (19). They obtained CSF from 26 normal control subjects undergoing lumbar puncture for anesthesia for routine orthopedic procedures who had no evidence of epilepsy or active CNS disease. The mean CSF NSE for the 26 controls (13 men and 13 women, mean age 38.6 years [SD 11.3 years]) was 10.76 ng/mL ± 3.08 ng/mL (range, 4–18 ng/mL). We defined the abnormal range as >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 d 8d 0d 8d 2 wk 2d 0d 4 wk 0d 0d 2d * * 5d 2 wk 0d 1d 0d 7d 0d 0d 4d 1d
Timing of MRI Showing Resolution of T2 Signal Increases (from End of SE) 10 d 4 yr 8 wk 9 mo 7 wk 9d 9 wk 8 wk‡ 3.5 mo 4 wk 38 d 1 yr 2 mo 1 yr 3 mo‡ 3d 13 mo 9 mo 7 wk NR 5 wk NR 46 d
Abbreviations: CP, complex partial SE; SP, simple partial SE; NR, not reported. * These patients had MRI during CPSE, at about 24 hours following onset of CPSE. † Partial SE followed GCSE or frequent grand mal seizures. ‡ T2 signal increases were largely but not fully resolved, at the site of an astrocytoma (Young et al. [210], case 2) and of preceding brain biopsy (Soffer et al. [170], case 2).
These partial-SE-related signal alterations begin during CPSE, with no latent interval between termination of CPSE and development of the signal alterations. In several cases these signal alterations were present during electroclinical CPSE, when MRI was performed after CPSE failed to respond to initial therapy (26, 67, 88, 96, 117, 152, 179). The focal cerebral signal alterations can persist for as long as 4 weeks after the end of CPSE, but these changes also can resolve as early as 3 days after CPSE. The “intensity” of CPSE is variable across patients, in that ictal discharges may occupy a greater proportion of the total duration of CPSE in some cases than in others, or ictal discharges may propagate over a greater cerebral volume (even with occasional fully generalized discharges causing grand mal seizures intermixed with the predominantly complex partial seizures) in some cases than in others. It seems likely that longer duration and greater intensity of ictal discharges during CPSE would be associated with a greater volume of and a longer time course to resolution of CPSE-related T2 increases, but
this hypothesis cannot be assessed with currently available information. Based on these cases, it has been recommended that cerebral foci of signal alteration that appear on MRI after CPSE (and that have no significant mass effect or hemorrhagic component) should not be immediately resected or biopsied, but rather should be followed with serial MRI studies to full resolution of the focal signal changes (or to evolution to an appearance that makes neoplasm or other specific diagnoses likely, at which time any appropriate neurosurgical intervention is made). It is reasonable to perform MRI shortly after termination of CPSE. In my experience, most MRI studies performed after CPSE do not show these transitory signal alterations, perhaps because several days of SE are required for these changes to occur, and most cases of CPSE are diagnosed and treated earlier than this (when a neurologist is involved in patient care). Even when the transitory MR signal changes are present, they usually would not prevent recognition of most structural lesions that are associated with
:
187
CPSE, such as cavernous angiomas and hippocampal sclerosis. I have observed five cases of CPSE in which early post-SE MRI demonstrated focal T2 increases of the type that might represent transitory, noninflammatory cerebral edema of CPSE but in which detection of the MRI abnormalities led to lumbar puncture and diagnosis of herpes encephalitis; two of the patients were afebrile and had no specific indication for CSF examination other than the MR abnormalities (because the CPSE had been attributed to medication noncompliance in longstanding partial epilepsy in one instance and to a history of severe closed head injury in the other). I have also observed a case of CPSE with mesial temporal T2 increases that probably represented limbic encephalitis (see Figure 16.6) on the basis of a paraneoplastic syndrome, without a prior diagnosis of malignancy. Thus, in most cases there probably is little reason to postpone MRI following termination of CPSE and some reason to perform MRI urgently to exclude foci of cerebritis that may be caused by viral or other encephalitis. Brain CT can also demonstrate focal abnormalities attributable to cerebral edema after CPSE, although CT is less likely to demonstrate small regions of mild edema than is MRI. A new cerebral abnormality observed with CT following CPSE usually consists of focal white matter hypodensity, associated with focal enhancement following contrast administration but without mass effect; these focal abnormalities subsequently resolve (36, 54, 75, 157, 158, 160, 165, 212). Some cases of transitory focal white matter hypodensity on CT are not associated with SE, particularly in Indian patients (7). A case of Sturge-Weber syndrome was closely observed during new onset of CPSE with right hemispheric electrographic seizures, upon which CT showed severe right hemispheric edema underlying the leptomeningeal angioma; angiography showed no evidence of thrombosis in the angioma or arteries, but veins were occluded over the region of edema; follow-up MRI after resolution of cerebral edema showed right frontal infarction, associated with new sensorimotor deficits (24). A case of CPSE and prolonged hypoxia was associated with severe hemispheric edema causing transfalcal and uncal herniations, which were visible on CT (170). It is likely that the usually mild focal or multifocal cerebral edema of partial SE may be greatly exacerbated by anomalous cerebral vascular supply and by concomitant hypoxia or other metabolic encephalopathies. O N SE Other forms of nonconvulsive SE (NCSE), which clinically are manifested as globally altered awareness and diminished responsiveness, are not associated with definite electrographic seizures that are diagnostic of partial-onset seizures. During some episodes of NCSE, classic generalized 3-per-second spike-and-wave patterns occur in patients with established diagnoses of primary generalized epilepsies, and in other cases generalized slow
188
:
spike-and-wave patterns occur in patients with established diagnoses of symptomatic generalized epilepsies, supporting definitive diagnoses of absence SE (ASE) and atypical ASE, respectively. During some episodes of NCSE, ictal EEG recordings are indeterminate for partial-onset versus generalized-onset patterns. Some such cases of “spike-wave” stupor presumably began as well-defined electroclinical CPSE, but after hours or days without adequate treatment the ictal EEG patterns “degenerated” into more widespread discharges without clear differentiation of ictal and postictal periods. Other cases of spike-wave stupor probably began as ASE or atypical ASE, which when untreated demonstrates progressively lessening rhythmicity, and perhaps also waxing and waning focal or multifocal features on EEG. A previously established epilepsy diagnosis may be essential in classifying spike-wave stupor. De novo spike-wave stupor, with no prior history of seizures, may be more common in the elderly. Overall, CPSE probably is much more common than all other forms of NCSE, or at least more often recognized and reported. Detection of structural brain lesions in the diagnosis of ASE Absence SE, which occurs in the course of primary (idiopathic) generalized epilepsies, requires EEG for diagnosis, but rarely requires diagnostic neuroimaging. When ASE is prolonged over many hours or days, motor automatisms and confused behaviors become more common (3). Atypical features of ASE, in presumed primary generalized epilepsy, should lead to consideration of brain imaging, which may demonstrate evidence for rediagnosis as a secondary (symptomatic) generalized epilepsy, or may demonstrate an acute lesion that precipitated SE but was not related to the underlying primary epilepsy itself. Each of seven patients with ASE in adulthood was reported to have unilateral or bilateral frontal lobe atrophy or a frontal lobe lesion on CT (197). This early (1978) series used low-resolution CT, and review of the published images suggests that some of the patients may have had mild cortical volume loss that was within the normal range for age, with frontal accentuation due to supine positioning. One interesting report of apparent carbamazepine-induced ASE noted bilateral mesial frontal and right anterior insular T2 increases on MRI, which was performed several days after SE; signal changes had fully resolved on MRI performed 7 months later (12). Although this case was considered to represent primary generalized epilepsy, the ictal semiology and the slow rate (1–2 Hz) of interictal and ictal generalized spike-and-wave discharges must raise a question of symptomatic generalized epilepsy, which occasionally occurs in patients of normal intelligence and cryptogenic epileptogenesis. The MRI abnormalities in this case raise a question of CPSE of frontal origin. No comprehensive series of MRI in ASE with classic 3-Hz or faster generalized spike-and-wave discharges has been reported.
Detection of structural brain lesions in the diagnosis of atypical ASE Neuroimaging after atypical ASE, which occurs in the course of symptomatic generalized epilepsy, might well be considered analogous with CPSE in localization-related epilepsies. Urgent neurosurgical intervention may be required for acute intracranial hemorrhage, acute hydrocephalus, and other lesions that can trigger an episode of atypical ASE. Some such lesions may occur with increased frequency related to chronic lesions that cause these epilepsies. For example, progressive mass lesions in neurofibromatosis can acutely obstruct the cerebral aqueduct, causing acute hydrocephalus (associated with no sequelae following prompt ventriculostomy and shunting, or with new and permanent neurologic deficits, or death, if shunting is delayed). Bilateral perisylvian malformations of cortical development were detected with CT and fully characterized with MRI after the occurrence of atypical ASE in a patient with prior seizures and symptomatic generalized epilepsy (183). When brain MRI was performed before an episode of atypical ASE and did not show lesions of types that can progress, many neurologists likely would find little reason to repeat MRI after SE, with several possible exceptions. Such exceptional circumstances might include great difficulty in controlling SE and new neurologic deficits after SE. Such commonsense opinions are held in the absence of any published series of neuroimaging in patients with atypical ASE. Detection of structural brain lesions in the diagnosis of spike-wave stupor of the elderly Nonconvulsive SE can occur in adults who have no prior history of epilepsy, often in association with cerebral structural abnormalities. Among 24 elderly patients who presented with NCSE in the setting of unstable medical conditions and who had no history of anoxic encephalopathy, 20 had abnormal MRI or CT findings (with focal lesions, usually infarctions or tumors, in 15 and cerebral atrophy or leukoariosis in five patients) (101). These patients had generalized spike-and-wave discharges, unifocal ictal discharges, or bilateral independent ictal discharges. Brain MRI was normal in a middle-aged adult who had recurrent episodes of NCSE, with 3.5- to 4-Hz generalized spike-and-wave discharges during SE (199); the authors suspected frontal lobe epilepsy, based on report of an epigastric aura that preceded each prolonged period of SE, and anterior spikes on the interictal EEG. By contrast, a series of elderly adults with spike-wave stupor most often had generalized cerebral atrophy on CT, and did not include patients with infarcts or tumors (191). Generalized ictal EEG patterns during NCSE in the elderly may well represent a late stage of CPSE in which scalp EEG manifestations have become generalized and ictal discharges are more continuous than episodic. Alternatively, the seizures may have been of generalized onset from the start. In the absence of a clear assignment to a primary epilepsy category, it would be prudent to request neuroimaging studies in such individuals.
S P SE Structural brain imaging is highly useful for etiologic diagnosis in the acute presentation of SPSE. Acute lobar hemorrhage may be as likely to present with SPSE as it is to present with GCSE (182). When CT does not demonstrate a lesion after the first occurrence of SPSE, MRI should be considered in order to detect a lesion that was missed by CT. In some cases a second MRI study may be useful to document adequate therapy of infectious causes of cerebral lesions associated with SPSE (181). Detection of structural brain lesions in the diagnosis of epilepsia partialis continua Epilepsia partialis continua (EPC) may present acutely, subacutely, or chronically, as the motor form of SPSE. Both progressive EPC (with increasing motor involvement and increasing cognitive or other impairments) and nonprogressive EPC are often drug resistant. Among 14 patients with chronic nonprogressive EPC, structural imaging with MRI or CT demonstrated infarction in four, cortical atrophy in two, postoperative encephalomalacia in one, and normal cortex in seven cases (22). Subcortical MRI lesions occurred in two patients with continuous focal jerking of subcortical origin. Cortical neoplasia, vascular malformations, and other lesions also cause chronic nonprogressive EPC (80, 190, 192). Brain MRI sometimes demonstrates transitory focal cerebral edema following nonprogressive forms of SPSE, similar to its occurrence in CPSE, as discussed earlier (46, 77, 109, 180, 194). In some cases of refractory EPC that were successfully treated with resection, microscopic lesions were found in the surgical specimen despite normal findings on preoperative MRI; this may occur more often with multiple foci of microscopic focal cortical dysplasia (30, 109). Macroscopic malformations of cortical development are readily detectable with MRI in the setting of EPC (169). Thus, brain MRI is useful in the evaluation of EPC to detect foreign tissue lesions, which may require lesion-specific therapies, and also to determine drug therapies specific to EPC versus subcortical myoclonias. Chronic progressive EPC is highly associated with Rasmussen’s encephalitis, but can occur with other pathologies for which specific therapies may be indicated. In particular, chronic progressive EPC also can be caused by focal cortical dysplasia, which may be detected with MRI and in some cases responds fully to tailored cortical resection (30, 95). Both CT and MRI can demonstrate encephalomalacia of the involved hemisphere in Rasmussen’s encephalitis, and serial studies have shown progressive expansion of the encephalomalacic regions (93, 178). Bilateral, progressive cortical atrophy was detected with serial CT in three EPC patients who had bilateral epileptiform EEG abnormalities and bilateral motor dysfunction (184). Putative diagnostic role of functional imaging in nonmotor forms of SPSE The diagnosis of SPSE with purely sensory, psychic,
:
189
or autonomic symptoms can be quite difficult. Objective behavioral manifestations usually are nondiagnostic, and scalp EEG recordings often are nondiagnostic during brief or prolonged simple partial seizures, even when the recordings are performed during the paroxysmal symptoms (32, 84, 134, 176). Ictal SPECT may have a useful role in distinguishing SPSE from other causes of continuous, stereotyped sensory, psychic, or autonomic symptoms (77). Presumably, ictal [15O]H2O PET, fMRI, or lactate imaging with MRS also might be highly useful in the diagnosis of SPSE without motor manifestations, although these studies are less widely available than is SPECT. The finding of a structural lesion in a location appropriate to the type of subjective symptoms would increase the likelihood of SPSE, as would a subsequent good response to AED therapy. In general, epileptic phenomena often occur in the absence of a detectable structural lesion and resist medical therapy, while nonepileptic phenomena can occur in the presence of a cerebral lesion and may have a nonspecific positive response to AEDs. For these reasons, when ictal scalp EEG is unhelpful, appropriately located structural imaging abnormalities would not be as specific as would appropriately located foci of increased perfusion or lactate concentration for diagnosing nonmotor SPSE. When clinical evaluation suggests that nonmotor SPSE may be present, brain MRI is necessary to exclude neoplasm or other lesions requiring surgical therapy (18). Series of patients with differentiation of epileptic and nonepileptic causes of continuous, stereotyped sensory, psychic, or autonomic symptoms, based on diagnostic structural or functional neuroimaging, have yet to be reported. N SE The role of brain imaging in managing neonates with SE has been less explored than has its role in any form of SE in children and adults. Neonatal seizures and SE manifest quite differently from seizures and SE in children and adults, both clinically and electrographically (113, 161). Brain imaging may reveal congenital cerebral malformations, cerebral infection, cerebral infarction, and cerebral hemorrhage in neonates with SE, but more often perinatal asphyxia or other metabolic insults cause neonatal SE (161). In one case of neonatal SE that manifested with subtle bilateral myoclonias, staring, and bicycling movements associated with ictal EEG discharges, dwMRI showed bilateral frontoparietal water diffusibility decreases; it is not clear whether dwMRI abnormalities occurred due to perinatal asphyxia or to SE, or both, however (162). It may seem evident that brain imaging is indicated in every case of neonatal SE. Remarkably, this assumption cannot currently be supported by even a single published series of imaging in neonatal SE that is extant in the English language literature.
190
:
Clinical and experimental pathophysiology of SE studied with ictal, postictal, and interictal neuroimaging P G C SE Imaging studies during and after experimental GCSE Systemic administration of the GABA antagonist bicuculline produces GCSE, which can be studied with brain imaging in rodents immobilized by neuromuscular blockade. In vivo [31P]MRS during bicuculline-induced GCSE confirmed earlier findings that had been made using in vitro biochemical assays. Both MRS and biochemical assay showed an initial decline in cerebral tissue concentration of phosphocreatine and a rise in cerebral inorganic phosphate concentration, preceding lowered intracellular pH, with little or no decline in adenosine triphosphate (ATP) stores during experimental GCSE (143, 149, 211), with a generalized cerebral distribution of these metabolic alterations. Further studies with [31P]MRS and proton MRS showed that early in bicuculline-induced GCSE, intracellular lactate levels rose before pH fell; after termination of SE, elevations in lactate concentrations outlasted pH alterations (144, 148). This evidence of compartmentalized chemical changes could not have been obtained with tissue-destructive techniques. Studies with dwMRI in experimental GCSE showed a generalized cerebral decline in the apparent diffusion coefficient (ADC) for water, which may be due to cerebral edema. During the generalized cerebral hyperperfusion of bicuculline-induced GCSE, the ADC fell 14%–18%, which is approximately half of the ADC decrease that occurs during the cerebral hypoperfusion of experimental infarction (214). Progressive decreases in the ADC for water began rapidly after onset of GCSE, persisted during ongoing GCSE (with greater decreases after more prolonged SE), and were rapidly reversed after early pentobarbital treatment, in dwMRI studies of the rodent flurothyl model, in which GCSE is produced by excessive, generalized opening of neuronal sodium ionophores (213). Diminished function of the blood-brain barrier may cause the generalized cerebral edema of GCSE, based on studies with high-field MRI and gadolinium in the systemic lithiumpilocarpine (muscarinic cholinergic agonism) model of GCSE in rodents (155). Thalamic edema preceded and also resolved earlier than did cortical edema, at least in this model of GCSE (155). Regional patterns of perfusion, glucose and lactate metabolism, and water diffusion could be determined with imaging during different electrographic stages of experimental GCSE. It is possible that particular tissue changes might be associated with particular stages in the progressive EEG changes of experimental GCSE. Given the apparent similarity of progressive EEG changes during human GCSE
and experimental GCSE (195), it is possible that particular EEG stages in human GCSE might specifically indicate periods in which neuronal injury is reversible versus periods of irreversible injury. Ultimately, since EEG can readily be performed during human GCSE while MRI cannot, EEG might be used to select neuroprotective or other therapies that are specific to overall levels of neuronal dysfunction based on previously established EEG-imaging correlations. Structural imaging studies after human GCSE The long-term sequelae of GCSE can be evaluated with various types of brain imaging. Grossly evident regions of encephalomalacia or porencephaly often are observed on CT or MRI after GCSE. Four children with partial epilepsy and a clinical picture of infantile autism were found to have bilateral hippocampal atrophy on MRI (28); each had a history of SE, presumably representing GCSE, in infancy or early childhood, and it was suspected the SE caused bilateral hippocampal injury. In most reported cases of brain lesions following GCSE, the lesions cannot be definitively attributed to effects of GCSE because baseline imaging was not performed before SE. In exceptional case reports, however, baseline imaging was performed shortly before the onset of GCSE. Severe bilateral, multifocal gray and white matter encephalomalacia was noted on CT after GCSE of 5 days’ duration in a patient who had a normal CT scan on the day before SE (136). After several isolated grand mal seizures, a young woman had a normal brain MRI and occasional generalized spike-and-wave complexes on EEG; 2 days after the MRI she entered 5 days of GCSE; after these 5 days she was paralyzed and ventilated and underwent MRI, which showed mild diffuse cerebral edema and severe mesial temporal edema bilaterally. Brain MRI performed 3 weeks after SE showed resolution of mesial temporal edema but new, bilateral hippocampal atrophy, and 2 months after SE, a fourth MRI study showed increased severity of bilateral hippocampal atrophy that was associated clinically with severe memory and naming deficits and the new onset of complex partial seizures. Infectious and paraneoplastic etiologies of a limbic encephalitis appear unlikely in this case of GCSE that was preceded by isolated grand mal seizures and interictal generalized spike-and-wave discharges (109). Another patient was shown to have increased hippocampal T2 intensity, no hippocampal atrophy, and no extrahippocampal abnormalities on MRI performed immediately after GCSE, but after 2 months, bilateral hippocampal atrophy was present. The patient had ongoing seizures but no recurrence of SE over the next 5 years, during which time three more MRI scans showed progression in the severity of the bilateral hippocampal atrophy (207). Thus, GCSE can cause the new onset of hippocampal sclerosis with or without more
widespread encephalomalacia. Nonetheless, when a single CT or MRI study shows new atrophy or encephalomalacia following GCSE, it should not be assumed that the new lesion began immediately following recovery from SE. In another intensively studied case, a patient with longstanding temporal lobe epilepsy had mild left hippocampal atrophy on MRI. He had two to three complex partial seizures and two to three grand mal seizures per month for 4 years, after which volumetry demonstrated an 11% loss of left hippocampal volume, representing a statistically quite significant volume decline. The patient never had any clinical form of SE (128). Only the most severe of GCSE-induced brain injuries will be detected with CT and even with structural MRI. More subtle sequelae of GCSE might be detected with measures of neuronal density or of glial density. Regional density of viable neurons might be determined with NAA signal density on MRS, as an indirect measure of neuronal loss following SE (94). Regional density of glia might be determined with [3H]L-deprenyl PET for glia-specific monoamine oxidase B binding or with [11C]PK-11195 PET for glia-specific peripheral benzodiazepine receptor binding (which is most strongly expressed in activated microglia), as an indirect measure of regional gliosis following SE (65, 91, 151). Each of these measures would ideally be performed in the same individual both before and after GCSE, which is easily arranged with experimental GCSE, but only structural MRI is likely to be performed (as part of routine clinical evaluation of epilepsy) before clinical GCSE. Functional imaging studies after human GCSE Diagnostic brain imaging must be performed only after GCSE has been fully controlled. Overwhelming evidence of increased mortality and permanent brain injury during prolonged GCSE militates against delaying therapy in order to perform imaging studies during SE. Although refractory GCSE may occasionally be treated with parenteral agents during emergency CT, most cases of GCSE will be controlled before any imaging is performed, and certainly before research with functional imaging. Thus, ethical considerations prevent neuroimaging study of cerebral blood flow (CBF) and metabolic changes during GCSE in humans. Functional imaging studies could be performed immediately following termination of human GCSE, however. Such studies could use three different nuclear magnetic resonance techniques, with repeated measurements following SE. Proton MRS can be used to map the relative brain concentrations of lactate, of the neuronal marker NAA, of g-aminobutyric acid (GABA), and of glutamate-glutamine (16, 25, 94, 142). Phosphorus 31 MRS ([31P]MRS) can be used to map intracellular pH and the relative concentrations of ATP and phosphocreatine (25, 97). The diffusibility of tissue water can be mapped
:
191
with dwMRI (150). Reports of such studies following GCSE are not currently available. P C P SE Brain imaging has to a considerable extent clarified the distribution and types of dysfunctions that occur during clinical and experimental CPSE. It is now clear that prolonged CPSE can cause permanent, structural brain injury. Future imaging investigations also may clarify whether permanent neuronal loss or other residua are caused by all cases of clinical CPSE, an area of intense speculation and great clinical relevance that has yet to be adequately addressed (82). Focal atrophy on MRI is a nonspecific sign of neuronal loss due to partial SE, but MRS maps neuronal markers that may permit specific determination of SE-associated neuronal losses in humans, as it has in animal models. In the future, neuroprotective and other therapies of SE may be assessed noninvasively with MRS or other forms of neuroimaging. Blood flow mapping of onset and propagation sites in experimental CPSE Experimental CPSE has been studied with fMRI, using the ovine intracerebral penicillin model (73). Sites of MR signal increases (relative CBF increases) during electrographic seizures included the frontal cortex where penicillin was injected, and ipsilateral and contralateral subcortical gray matter regions. Early in SE, multifocal CBF increases occurred during electrographic seizures, and MR signals remained approximately at pre-SE baseline during the electrophysiologically abnormal periods between ictal discharges. The same sites that had MR signal increases during electrographic seizures early in the course of SE continued to have MR signal increases during electrographic seizures later in this model of CPSE (73). By contrast, later in the overall period of electroclinical SE, during the electrophysiologically abnormal periods between ictal discharges, sites in the penicillin-injected hemisphere showed progressive declines in MR signals (relative CBF decreases at sites that had no such changes early in CPSE), but no such changes were observed contralaterally. These prolonged periods of fMRI acquisition demonstrated relative regional CBF patterns that changed with increasing duration of experimental CPSE. This effect of SE duration might account for the variety of differing regional CBF patterns that have been reported with clinical imaging, given that clinical studies typically are performed only at a single point in time during clinical CPSE. Blood flow and glucose uptake mapping of onset and propagation sites in human CPSE Functional brain imaging can detect regional changes in glucose metabolism and blood flow during clinical CPSE, and these changes are generated by regional increases and decreases in regional synaptic activity levels, without specificity for excitatory or inhibitory
192
:
synapses (76). Some of these changes resolve rapidly after termination of SE. Each of five applicable imaging modalities has unique advantages and disadvantages in studying CPSE. Ictal [15O]H2O PET studies are difficult to perform, in part due to the short half-life of oxygen 15 (2.1 minutes), but can provide fully quantitative measurement of CBF (200). Ictal [18F]FDG PET studies are less difficult to perform, but the cerebral metabolic rate for glucose cannot be fully quantified because glucose metabolism is not at steady state, and FDG uptake is averaged over greater than 10 minutes (55). Ictal [99mTc]HMPAO (or ECD) SPECT is practical during CPSE, and is especially sensitive when ictal-minus-interictal CBF differences are superimposed on the patient’s own MRI, but SPECT cannot fully quantify CBF or temporally resolve CBF to better than about 1 minute (9, 127). Ictal fMRI and ictal MR angiography (MRA) also can be performed during CPSE and offer superior temporal resolution (to less than 1 second), but CBF is not quantified, and patients must have little or no cranial motion during CPSE (173). Functional neuroimaging with [18F]FDG PET, SPECT, fMRI, and MRA cannot determine whether global (whole-brain) metabolism and blood flow are increased or decreased during CPSE compared with the interictal state, and cannot determine whether a particular brain region has increased or decreased CBF and glucose metabolism during CPSE versus the interictal state. These modalities do permit comparison of relative CBF and CMRGlc, averaged over a single epoch of time, among different regions of the same brain during CPSE. Scalp EEG monitoring of SE can be recorded during image acquisition, easily for PET and SPECT, but only with special techniques for fMRI and MRA (47, 71). In general, functional imaging during clinical CPSE shows complex patterns of relatively increased and decreased CBF and glucose metabolic activity at the site of ictal onset, and in multiple ipsilateral or bilateral regions, based on studies with [18F]FDG PET (40, 41, 53), with SPECT (52, 70, 186), with perfusion MRI (203), and with MRA (96). Sometimes a region of relative hyperperfusion can persist for days following electroclinically defined termination of CPSE, although it is more common for hyperperfusion to end when clinical CPSE ends (186, 203). Among five patients with definite CPSE of frontal lobe origin who had SPECT during SE, four patients had unilateral frontal hyperperfusion and one had bilateral frontal hyperperfusion, but none had temporal lobe CBF increases (193). On the other hand, Engel et al. described a patient with established limbic temporal lobe epilepsy whose [18F]FDG scan showed frontal and thalamic hypermetabolism ipsilateral to the hypermetabolic temporal lobe during CPSE (41). Another patient in this series had marked hypermetabolism of the right occipital lobe and the adjacent temporal lobe, with hypometabolism elsewhere, during CPSE of
right occipital origin. Patterns of metabolic activity on FDG PET studies in which a single complex partial seizure occurred are different from those of scans during CPSE. A single complex partial seizure usually is much briefer than the duration of cerebral FDG uptake, so a cerebral region of steady-state interictal hypometabolism may not be qualitatively altered on PET images by averaging of a brief period of ictal hypermetabolism into a longer period of hypometabolism. Averaging of brief ictal hypermetabolism occurring early in the FDG uptake period together with subsequent hypometabolism can result in “normalization” of regional FDG activity, however (as exemplified in Figure 2 of Henry et al. [66]). Imaging of cerebral water diffusibility, edema, and neuronal injury during and after experimental CPSE Focal cerebral decreases in water mobility are detected with dwMRI almost immediately at the onset of CPS, before focal increases in T2 signal are detected with structural MRI, in experimental CPSE (121, 201, 202). The rodent kainate model of CPSE also demonstrated (1) that focal decreases in the ADC of water occur in areas of expected maximal ictal involvement (the amygdala and the piriform cortex, and to a lesser extent the hippocampus), (2) that these water diffusibility decreases become progressively more severe with increasing duration of CPSE, and (3) that focal diffusibility decreases outlast CPSE (121, 153, 202). In a rodent kainate experiment that used both dwMRI and [23Na]MRS, the sites of water diffusibility decrease also had significantly increased sodium concentration (probably due to SE-induced increases in neuronal Na,K-ATPase activity), but the focal sodium signal increases began later and lasted longer than did the water diffusibility decreases (202). Foci of neuronal pyknosis coincided with premortem sites of diffusibility decrease in these experiments. A further study of sequelae of systemic kainate-induced CPSE in rodents found that in the hippocampus and several other mesial temporal regions, the degree of T2 hyperintensity on post-SE MRI (at up to 8 weeks) was highly correlated with the severity of neuronal loss (145). On the other hand, when serial MRI was performed early and late (1 hour to 120 days) following intrahippocampal kainate injection in rodents, focal T2 increases in that hippocampus and adjacent amygdala occurred at times associated with vasogenic edema (earliest), with cytotoxic edema (slightly later), and with neuronal loss (latest) (10). Thus, mesial temporal T2 hyperintensity is not specific to various effects of CPSE in general but with delayed imaging is highly associated with neuronal loss, at least in rodent kainate models. Focal cerebral alterations in NAA concentration and lactate have been measured with proton MRS in experimental CPSE (38, 112, 119, 120). During kainate-induced CPSE in rodents, the hippocampi have increased NAA/
creatine ratios, compared with prekainate measurements (119, 120). Subsequently NAA/creatine ratios decline, and by 24 hours later the hippocampal NAA/creatine ratio is significantly lower than the baseline prekainate ratio; the hippocampal NAA/creatine ratio remains at this same depressed level 6 days later (38, 119, 120). A different course of lactate changes has been observed, in that hippocampal lactate/creatine ratios are elevated during and at 24 hours following CPSE, but have returned to baseline prekainate values by 6 days later (112, 119, 120). (This prolonged but not permanent elevation in post-CPSE hippocampal lactate in the rodent kainate model is not observed with postictal MRS of single seizures in the rodent kindling model [119]; after each limited seizure or secondarily generalized seizure, postictal elevations in lactate have declined to baseline interictal values within 3 hours, and late NAA decreases do not occur during kindling.) Late NAA decreases also occur in other areas of expected maximal ictal involvement in kainate SE, in addition to late decreases in hippocampal NAA (38). Some sites of post-SE NAA decrease were not associated with T2 increases on structural MRI. Following MRS acquisition, histologica examinations have revealed neuronal injury or loss at all sites of NAA decrease (38, 119, 120). In this model, pretreatment with the protein synthesis inhibitor cycloheximide blocked rises in lactate and late decreases in NAA (but did not alter the early increases in NAA), and prevented hippocampal neuronal loss (119). Based in part on these findings, it appears that prolonged focal elevations in lactate and late focal decreases in NAA might serve as markers of neuronal populations that have been severely injured by clinical CPSE, and both might serve as efficacy measures in clinical trials of SE therapies. Imaging of cerebral water diffusibility, edema, and neuronal injury during and after human CPSE Reports of clinical CPSE indicate that foci of dwMRI signal increase (i.e., foci of decreased water diffusibility) coincide with the sites of hyperperfusion during CPSE (48, 96). In clinical CPSE, it would be predicted that SE-induced foci of diffusibility decreases in cortical gray matter will be detected with dwMRI much earlier, and perhaps more sensitively (during briefer or less intense episodes of CPSE), than will foci of gray matter edema with structural MRI. Three cases of clinical CPSE were studied with both MRI and dwMRI, and in each case imaging was performed during CPSE, in a single session after about 24 hours of ongoing CPSE; all three patients had coinciding foci of T2 increase and water diffusibility decrease at this time, associated with local vascular hyperpermeability (contrast enhancement) and hyperperfusion. After 2 months or longer, two of the patients had only focal cortical atrophy, which was confined to a smaller volume of tissue within the previous region of cerebral edema and
:
193
water hypodiffusibility (96). It remains to be seen whether MR imaging after briefer CPSE might demonstrate focal water diffusibility decreases in patients who do not have evidence of focal cerebral edema in the form of T2 increases. In TLE it appears that focal temporal lobe water diffusibility decreases are not detected after single complex partial seizures, using imaging sequences that detected such changes after CPSE (35). In one case of CPSE, early water diffusibility decreases and T2 increases were widespread over cortex bilaterally, but late imaging showed evidence of widespread bilateral cortical atrophy corresponding to earlier dwMRI abnormalities (20). In another case of CPSE, early water diffusibility decreases and T2 increases were localized only to the region of electroclinical seizure activity, which also showed localized hyperperfusion on fMRI and localized lactate increases and NAA decreases on proton MRS. Three months after cessation of CPSE, the patient had NAA decreases in the same region as previously, but all other abnormalities on MRI, dwMRI, fMRI, and MRS had resolved (98). Empirical evidence of a high sensitivity and specificity of dwMRI for cellular injury in SE would support the use of dwMRI to study the distribution, severity, and permanence of cerebral injury due to clinical CPSE, and also to objectively evaluate the relative efficacies of various therapies for CPSE. Focal cerebral edema often is detected by brain MRI, as regional increases in cerebral water density (T2 signal increases), during and for some time following clinical CPSE, as discussed earlier. Not all patients with CPSE are found to have focal T2 increases on MRI that is performed during or shortly after the end of CPSE. Further, patients who have never had seizures or CPSE may nonetheless have focal cerebral edema caused by a wide variety of lesions. Therefore, CPSE can cause focal cerebral edema with or without an associated cerebral lesion, but MRI-detected focal cerebral edema is neither sensitive nor specific to the ictal state of CPSE itself. The pathophysiologic basis of acute CPSE-induced focal cerebral edema probably is locally increased vascular permeability (vasogenic cerebral edema) in all cases, with additional neuroglial injury (cytotoxic cerebral edema) in some cases. Regional hyperperfusion and increased vascular permeability accompany single partial seizures in experimental models, but perfusion and vascular permeability increase in proportion to the frequency and duration of seizures (102, 103, 123, 141, 204). Evidence of focal increases in vascular permeability induced by clinical CPSE is provided by the contrast enhancement observed at sites of transitory white matter hypodensities on CT and T2 increases on MRI, as discussed previously. Other factors in addition to SE itself can modify the distribution of focal edema and cerebrovascular hyperpermeability that occur transiently after SE. In fact, when associated with significant toxic or metabolic insults (such as renal failure,
194
:
hepatic failure, or intrathecal methotrexate), a single generalized tonic-clonic seizure can induce transient focal or multifocal sites of edema and cerebrovascular hyperpermeability, which have CT or MRI signal alterations and a time course of resolution similar to the focal abnormalities that are induced by CPSE (168, 208). Prolonged experimental CPSE can cause focal neuronal and glial injury, as discussed previously. In clinical CPSE, vasogenic cerebral edema may be associated with less intense or prolonged SE, causing the commonly observed T2 increases that are confined to subcortical white matter on MRI, and combined vasogenic and cytotoxic cerebral edema may be associated with more intense or prolonged SE, causing the less often observed T2 increases that extend over cerebral gray and white matter on MRI. Imaging of human CPSE due to excitotoxin ingestion Clinical domoate intoxication in humans bears considerable similarity to the rodent kainate model with respect to features of behavioral, EEG, imaging, and histopathologic sequelae. The excitotoxin domoic acid can be absorbed systemically after ingestion of contaminated mussels, as occurred in a cluster of cases in western Canada in 1987 (187). Domoate is structurally similar to kainate. Systemically administered domoate produces a rodent limbic SE highly similar to that induced by kainate, in terms of both seizures and histopathologic findings (196). One closely observed victim of domoate poisoning had electroclinically defined CPSE during acute intoxication, with a normal brain CT. He recovered except for severe, new memory deficits, but after a year he began to have occasional complex partial seizures, at which time brain MRI showed bilateral hippocampal atrophy and T2 signal increase. Three years after domoate poisoning he died of pneumonia, and autopsy revealed neuronal loss in the hippocampi, amygdalae, septal nuclei, and other limbic system structures bilaterally, with little or no damage outside of limbic structures (14). In this and several cases of domoate poisoning, interictal FDG PET showed bilateral mesial temporal hypometabolism (14, 187). S C E T M B C G C SE C P SE Mesial TLE with hippocampal sclerosis following GCSE or CPSE Hippocampal gliosis and neuronal loss are detected histopathologically in animals that develop hippocampal atrophy and other imaging abnormalities after experimental GCSE or CPSE. In the rodent pilocarpine model, delayed neuronal degeneration is predominantly localized to the hippocampus and medial thalamus, even though abnormalities of decreased water diffusibility (dwMRI) and edema (T2-weighted MRI) are distributed rather equally among cortex, hippocampus, amygdala, and thalamus during the first day after SE (45). Post-SE hippocampal atrophy is bilat-
eral after GCSE induced by systemic lithium-pilocarpine (155), but the resulting hippocampal atrophy is exclusively ipsilateral to focal infusion of bicuculline into area tempestas or into entorhinal cortex (60, 79), and to amygdalar electrostimulation (146). Combined imaging and histopathologic studies of experimental SE also show variable distributions of extrahippocampal limbic injury. In one study a systemic lithium-pilocarpine treatment induced GCSE in all rat pups. Among rats with mesial temporal T2 signal prolongation by 1–3 days post SE, all went on to develop chronic seizures. No rats with normal post-MRI developed late seizures (156). Thus, early post-SE imaging abnormalities may have some specificity for limbic epileptogenesis. Human imaging and clinical studies strongly suggest that hippocampal sclerosis can be caused by GCSE, but that GCSE is neither necessary nor sufficient to cause hippocampal sclerosis and mesial TLE. Brain MRI is sensitive to atrophy and signal changes of hippocampal sclerosis. MRI is now so widely available that some patients undergo brain MRI before SE unexpectedly occurs. The strongest evidence for SE causing hippocampal sclerosis in humans must be post-SE imaging showing hippocampal atrophy that was not present on pre-SE imaging. Alternatively, MRI can be repeated serially after SE in patients who did not have MRI before SE, to provide evidence of evolving post-SE hippocampal injury (in patients for whom hippocampal sclerosis appears unlikely to have preceded SE based on absence of seizures and of neurologic deficits before SE). In a series of children imaged once within the first week after GCSE, those with febrile SE had increased hippocampal volumes and T2 signal (consistent with focal edema), while those with afebrile SE had normal hippocampal imaging (164). Early post-SE hippocampal volume increase and T2 increase have later evolved into hippocampal atrophy with T2 increase, in individual patients (86, 172). These studies also reported focal hippocampal decreases in water diffusibility on early post-SE dwMRI. Idiopathic GCSE apparently caused the new onset of hippocampal gliosis and neuronal death in a man who had normal MRI scan before SE but had bilateral hippocampal T2 increases after 4 days of SE. The patient’s death during SE precluded any possible observation of newonset complex partial seizures, which might have occurred if new hippocampal sclerosis was associated with new mesial TLE (124). Multifocal, extrahippocampal T2 signal abnormalities of cortical gray matter and subcortical white matter are often observed shortly after termination of GCSE, in association with hippocampal imaging abnormalities; there is interesting but limited evidence that early hippocampal imaging abnormalities more often progress to atrophic lesions than do the extrahippocampal imaging abnormalities (39). Careful observations with serial MRI also make it clear that GCSE does not always cause hippocampal sclerosis, and that new cases of mesial TLE-hippocampal scle-
rosis can arise in the absence of GCSE or CPSE (11, 128, 195). In some cases of hippocampal sclerosis and mesial TLE following SE, subtle malformations of cortical development may be detected near the affected hippocampus (140). Viral and other encephalitides can trigger SE, and hippocampal injury may be intensified by the combined insults of encephalitis and SE (81). Hippocampal sclerosis may be a final common pathway in limbic system injury, to which GCSE and partial SE may contribute. Syndrome of hemiconvulsion-hemiparesis-encephalomalacia following GCSE or CPSE Imaging and clinical observations also suggest that some cases of the hemiconvulsion-hemiparesisencephalomalacia (HHE) syndrome may be caused at least in part by GCSE or partial SE. In a few cases, serial imaging demonstrated progressive cerebral hemiatrophy after SE in patients who developed the HHE syndrome (50). One patient reportedly had unilateral cortical-thalamic and contralateral cerebellar T2 increases and water diffusibility decreases acutely after SE, but died before manifesting the clinical signs of HHE; postmortem histopathology revealed extensive neuronal necrosis in areas of imaging abnormality (111). Several reported cases feature a temporal sequence of GCSE or partial SE preceding widespread but unilateral hemispheric atrophy, with contralateral hemiparesis and epilepsy (19, 115, 130). Obviously, it is rare for SE to be associated with subsequent HHE. The experimentally observed, SE-triggered necrotic and apoptotic neuronal insults, and the clinically observed acute post-SE hemispheric imaging changes of cytotoxic edema preceding chronic hemispheric encephalomalacia, suggest an etiologic role of SE in the HHE syndrome. P O N SE Absence SE can be imaged during the ictal state in humans more safely and conveniently than can any other form of SE, by using hyperventilation to induce repetitive absence seizures. Interictal FDG PET scans usually are normal in absence epilepsies (42, 44, 129, 189). Relative increases in generalized cerebral FDG activity were of modest degree interictally in one patient whose EEG showed frequent generalized spike-and-wave discharges (129). Marked relative, generalized cerebral FDG activity increases and CBF increases occur during frequent absence seizures when studied with FDG PET and [15O]H2O PET (42, 147, 189). No significant metabolic asymmetries and no trends toward relatively greater increases or decreases between cortical and subcortical cerebral gray matter metabolism were observed, during interictal or ictal FDG studies of absence epilepsies (42). On the other hand, thalamic CBF is increased to a greater extent than is cortical CBF during absence seizures (147). One must exercise caution in equating hyperventilation-induced absence SE with “spontaneous” ASE. Both states feature
:
195
generalized spike-and-wave discharges that persist longer than 30 minutes and are associated with more or less continuous alteration of awareness. Spontaneously occurring ASE is associated with greater degrees of altered responsiveness and cannot be controlled simply by instructing the subject to cease overbreathing, however. Despite obvious differences between these states, findings on imaging during hyperventilation-induced ASE (or “near SE”) are different from those that are found interictally and may reflect part, if not the entirety, of the pathophysiologic changes that occur during spontaneous ASE. In general, localized increases in synaptic activity drive commensurate increases in CBF and glucose metabolism (76). The apparent “mismatch” of CBF and glucose metabolic increases in thalamus but not cortex suggests a pathologic state of thalamic function in which increases in synaptic activity are not the sole generators of CBF and glucose metabolic increases. Spike-wave stupor of adults that occurs in the absence of any history of isolated seizures or SE must be considered differently from other ASE. Such de novo spike-wave stupor may in fact represent a localization-related phenomenon, similar to the generalized topography of secondary bilateral synchrony observed with interictal epileptiform abnormalities in some individuals with partial epilepsy, or might represent a generalized-onset (thalamocortically driven) phenomenon, similar to that of an idiopathic or a cryptogenic-symptomatic generalized epilepsy. Acute benzodiazepine withdrawal and other acute metabolic or nonmetabolic generalized cerebral insults must also be considered in such cases. Generalized insults in many such cases have caused cerebral atrophy (191). An older series of brain CT in adults with ASE probably included patients with de novo spike-wave stupor, among patients who had established histories of primary generalized epilepsy since childhood, and reported a high rate of unilateral or bilateral frontal lobe abnormalities (197). Presumably ictal functional neuroimaging (fMRI, lactate imaging with MRS, PET, or SPECT) studies might be used to differentiate atypical spike-wave stupor of frontal lobe epilepsies from atypical spike-wave stupor of the generalized epilepsies. P S P SE The distribution of increased synaptic activity during SPSE can be mapped with FDG PET, [15O]H2O PET, SPECT, and fMRI. Among these modalities, only [15O]H2O PET permits fully quantitative CBF measurements during the non-steady-state conditions of SPSE (200), and best temporal resolution is provided by fMRI (173). During EPC, fMRI in sequential 10-second epochs showed relative hyperperfusion focally over regions of the precentral gyrus continuously, with an increasing volume of hyperperfusion spreading into adjacent cortex during focal motor seizures, in a young boy with Rasmussen’s encephalitis (72). The same patient also had
196
:
SPECT during EPC, which showed focal hyperperfusion of the perisylvian cortex, with decreased perfusion of ipsilateral cortical regions (72). Multiple other investigations of EPC with FDG PET, [15O]H2O PET, and SPECT showed focal perisylvian hypermetabolism/hyperperfusion or hypometabolism/hypoperfusion when the ictal discharge remained limited, or more diffuse unilateral cortical hypermetabolism/hyperperfusion or hypometabolism/hypoperfusion when intrahemispheric spread occurred; in some cases, ipsilateral thalamic or contralateral cerebellar hypermetabolism also occurred (21, 40, 41, 49, 61, 65, 85, 125, 186). In some cases, hyperperfusion of the site of maximal ictal discharges can outlast the duration of EPC for up to a day (87), similar to the prolonged post-SE hyperperfusion that has been observed following CPSE. Right frontal hypermetabolism and other bilateral regions of hypermetabolism were present during left arm-leg EPC in one patient (41). Fully quantitative functional imaging of EPC, with [15O]O2 PET, demonstrated hyperperfusion, increased oxygen metabolism, and decreased oxygen extraction fraction in widespread areas of the involved cerebral hemisphere; frontal lobe abnormalities were quantitatively more severe than those of other regions (49). Studies of Rasmussen’s encephalitis using MR techniques demonstrate progressive hemispheric injury in gray and white matter that is more extensive than the site of ictal discharges and progresses even after clinical seizures have been controlled. Rasmussen’s encephalitis causes focal lactate accumulation during EPC but not interictally, and causes widespread hemispheric loss of NAA that is present during EPC and interictally, based on studies with proton MRS (168). Lactate concentration was increased at the cortical site of maximal ictal involvement in patients who had EPC during MRS, but lactate concentrations were normal in patients who were imaged 48 hours or longer after termination of EPC. Loss of NAA signal was more widespread in the involved hemisphere than were structural MRI changes of encephalomalacia, but NAA/creatine ratios were normal over the contralateral hemisphere. Lateralized loss of NAA signal was increased 1 year later, on comparison of the same patients’ initial scans (15). In two patients with histologically proven Rasmussen’s encephalitis, only the encephalomalacic regions had marked increases in [11C](R)-PK11195 activity on PET, suggesting increased density of activated microglia (6); this finding might be used to differentiate Rasmussen’s encephalitis from noninflammatory causes of EPC and to evaluate anti-inflammatory therapies of encephalitis. Studies of noninflammatory EPC using MR techniques suggest that a single episode of EPC can cause a small focus of neuronal loss or severe dysfunction that involves the site of ictal discharges and persists long after EPC is controlled. Nonprogressive EPC can cause focal decreases in water diffusibility that are detectable using dwMRI (34, 206), and
transitory focal cerebral edema on MRI (46, 109, 194), as discussed previously. A case report suggests that proton MRS may be able to detect foci of increased excitatory amino acid neurotransmitter concentration during EPC in the absence of Rasmussen’s encephalitis (46). (Current techniques for chemical shift imaging do not permit separation of the proton spectra peaks that are associated with glutamate and glutamine, so proton MRS cannot resolve a signal that is specific to glutamate.) This patient had an increased glutamateglutamine peak, decreased NAA/creatine ratio, and increased T2 signal at the cortical site associated with seizure generation during EPC. During EPC the patient also had additional sites of T2 signal increase in the thalamus ipsilateral to and in the cerebellum contralateral to this cortical site. Three months after EPC was controlled, the structural MRI had returned to normal, but focal decreases in NAA persisted (46). The more extensive and severe neuroglial injury that occurs in EPC with Rasmussen’s encephalitis causes grossly evident encephalomalacia on structural MRI, as discussed earlier. Decreases in NAA can reflect transitory insults that may not give rise to fixed lesions in SPSE, as demonstrated by a patient who had locally increased perfusion (SPECT) and increased lactate and decreased NAA (proton MRS) during SPSE, but milder NAA decreases (and normal lactate) 3 weeks after SPSE (116). P S (E) SE Subclinical SE can be diagnosed when EEG recordings show electrographic SE but observable behaviors and patient-reported function are at baseline (on comparison of behavior during periods of electrographic SE with behavior during periods of baseline interictal EEG recordings) (176). Ictal EEG discharges during subclinical SE can consist of partial or generalized ictal patterns, and the frequency and waveforms of the ictal discharges themselves are similar to those recorded during clinically evident CPSE, SPSE, ASE, or atypical ASE. In the case of subclinical partial SE, behavior and consciousness probably are not altered because SE discharges are confined to cerebral regions that are clinically silent during waking or sleep. In the case of subclinical generalized SE, behavior and consciousness probably are not altered because SE discharges occur during sleep, or in rare cases because a small proportion of all cortical pyramidal neurons are generating the recorded ictal discharges and the majority of cortical neurons are processing information normally during waking. Subclinical partial SE usually has been recorded during intracranial EEG monitoring, although scalp EEG rarely records electrographic SE without clinical seizures (31, 69, 167, 175, 176). Focal hippocampal hypermetabolism was surrounded by relatively depressed metabolism (compared with [18F]FDG activity over the rest of the cortex) in a seemingly interictal [18F]FDG PET study; after the PET
study, the patient’s intracerebral EEG recordings showed highly focal, subclinical SE of the same hippocampus (175). Episodic left frontal neocortical hyperperfusion alternated with periods of normal relative perfusion during a seemingly interictal fMRI study; after the fMRI study, the patient’s intracerebral EEG recordings showed highly focal, subclinical seizures over a small region of left frontal neocortex (31). Focal occipital hypermetabolism occurred during focal electrographic SE of the overlying scalp electrodes in a patient with no clinical signs (167). These observations suggest that subclinical SE might be detected with [18F]FDG PET, with SPECT, or with fMRI, similar to possible imaging roles in the diagnosis of nonmotor SPSE. Further work is necessary to validate functional imaging in these diagnostic roles, since pathophysiologies other than focal SE may explain prolonged periods of focal increases in CBF and FDG activity, and potential imaging artifacts also must be assessed. P E A E SE Several electroclinical syndromes feature both diffuse or focal cerebral dysfunction and ongoing diffuse or focal epileptiform EEG discharges, which represent either definite ictal discharges or seemingly interictal discharges that are much more frequent and persistent than are typical interictal spikes. In these syndromes the “negative” clinical phenomena might be explained by causes of cerebral dysfunction other than seizures (unlike the “positive” clinical signs of limbic auras, focal motor seizures, and generalized convulsions). These syndromes might best be considered as possible SE, and perhaps imaging findings might contribute to defining them as SE or not SE, or as subclinical SE versus SE causing clinically evident dysfunction. Electrographic SE during slow-wave sleep Electrographic SE during slow-wave sleep (ESES) may or may not represent subclinical SE. The occurrence of ESES does not have a time-locked behavioral correlate—that is, patients do not awaken or demonstrate paroxysmal motor phenomena during the ictal generalized spike-and-wave discharges—but nocturnal ESES is variably associated with diurnal seizures and other phenomena (137). The diurnal phenomena include mental retardation, progressive or static language dysfunction (the Landau-Kleffner syndrome of acquired epileptic aphasia), and progressive apraxias (including the acquired epileptiform opercular syndrome) (23, 166). It is possible that ESES is in itself a symptom of the underlying brain injury that also has caused the global or specific cognitive deficits. Alternatively, cerebral dysfunction due to nocturnal ESES might actually cause the diurnal, global or specific, cognitive deficits; this has in particular been suspected in patients who had progressive cognitive deficits that began during periods of life in which ESES was evident. It
:
197
therefore is not clear whether or not the phenomenon of ESES truly is subclinical. In one case of ESES studied with PET, generalized cerebral increases in FDG activity occurred during periods of continuous generalized spikeand-wave discharges in sleep, and focal right temporal decreases in FDG activity occurred during periods of interictal right temporal spikes in sleep (51). In another child with ESES, focal right parietotemporal increases in FDG activity occurred during periods of continuous generalized spikeand-wave discharges in sleep, but focal right parietotemporal increases in FDG activity also occurred without EEG spikes in the awake state (135). In two children with both ESES and acquired aphasia, FDG activity during asymptomatic nocturnal generalized spiking showed a focal right temporal increase in one child and a focal left frontotemporal decrease in the other (105). An adult with ESES had normal MRI findings and right parietal hypometabolism on FDG PET (107). Further studies confirmed that regional metabolic dysfunction is variable and sometimes bilateral in patients with acquired epileptic aphasia (106, 154). Similarly, multifocal FDG activity increases occurred during ESES in a girl who did not have new aphasia but rather had new oral apraxia and dysarthria (166). In fact, the Landau-Kleffner syndrome is as often associated with focal and multifocal EEG spikes as it is with ESES (23). The FDG PET findings probably confirm the heterogeneously focal, multifocal, and generalized cortical and subcortical dysfunction suggested by the EEG findings, and neither PET nor EEG findings suggest that a single critical zone of dysfunction underlies this heterogeneity of localization. In a series of nine patients with ESES and with unilateral or bilateral perisylvian polymicrogyria on MRI, eight of nine patients were mentally retarded and had atonic seizures, while one patient was of normal intelligence and had only focal motor seizures (59). Most series of ESES have not included high-resolution MRI data, and it would be premature to conclude that malformations of cortical development are requisite for ESES. This report does suggest that mental retardation may be due to lifelong malformations of cortical development, and that ESES did not generate the chronic encephalopathy in these patients. Early epileptic encephalopathy with suppression bursts The Ohtahara syndrome of early epileptic encephalopathy with suppression bursts may constitute another example of pseudosubclinical SE in which the clinical manifestation of SE is encephalopathy rather than time-locked electrographic and clinical seizure activity. Generalized tonic seizures occur in this syndrome but are not temporally associated with changes in the ongoing burst-suppression EEG pattern (131). In one such child, MRI showed right frontoparietal cortical malformation and SPECT showed right hemispheric hyperperfusion; contrary to the usual course of
198
:
severe developmental delay and early death, this child underwent resection of the dysplastic cortex, followed by mild developmental delay and a single febrile convulsion over the next 2 years (139). Persistent pseudoperiodic epileptiform discharges Electrographic SE during periods of encephalopathy caused by metabolic or other apparent nonepileptic etiology poses a conceptually difficult problem. When nonepileptic brain insults are sufficient to cause stupor or coma but the EEG shows epileptiform discharges that are diagnostic of electrographic SE or are persistent and very frequent, it is unclear whether the epileptiform activities are significant and potentially treatable contributors to the encephalopathy. Additional multifactorial confounding of these problems is posed by the high potential for toxic encephalopathy of barbiturates, benzodiazepines, propofol, and other agents used to treat refractory SE. Examples of these clinical situations include myoclonic SE with coma, and (unilateral, or bilateral independent) pseudoperiodic lateralized epileptiform discharges (PLEDs). Functional imaging might offer data that can distinguish epileptic and nonepileptic factors in the pathogenesis of encephalopathy. The variable association of generalized spike-and-wave discharges with periods of myoclonus in myoclonic SE with coma (78, 210), and the widespread spinal cord neuronal loss, as well as brain injury, in reported cases (210), raise questions as to whether this myoclonic SE is in fact epileptic, or whether agonal, nonepileptic motor neuron dysfunction might cause the jerks. To date, structural and functional imaging studies have not been reported in this syndrome. The question of whether PLEDs should be considered a form of SE has been addressed, but not conclusively answered, using functional imaging in individual patients. A case report of focal right temporal hypermetabolism on FDG PET during continuous right hemispheric PLEDs, with resolution of hypermetabolism after PLEDs ceased, was interpreted to support the concept of PLEDs as a form of partial electrographic SE (63). An early report of PLEDs that was associated with lateralized hyperperfusion on SPECT imaging (100) was confirmed in multiple later cases (1, 5). These later reports also noted some individuals in whom aggressive AED therapy was associated with cessation of PLEDs and resolution of hyperperfusion. An alternative interpretation of these observations is that focal interictal spikes might generate brief periods of increased synaptic activity within a region of severely decreased synaptic activity, which is detected on PET or SPECT as regional hypometabolism or hypoperfusion, and only when interictal spikes occur so frequently as do PLEDs can the spike-generated bursts of synaptic activity be detected with PET or SPECT as increased FDG or HMPAO activity. The latter interpretation is consistent with concurrent scalp EEG-fMRI studies
that have demonstrated localized perfusion increases during typical interictal spikes (47, 71). These elegant techniques of concurrent EEG-fMRI acquisition might also be applied to PLEDs. Mapping of the intensity and distribution of perfusion, lactate, or other functional signals might be performed during typical interictal spikes, during PLEDs, during simple partial seizures, and during SPSE within the same individuals, using concurrent EEG-fMRI and EEG-MRS techniques. If such investigations found that typical interictal spikes and PLEDs are functionally similar to each other but not to seizures and SE, the concept of PLEDs as interictal phenomena would be supported. If such investigations found that PLEDs, seizures, and SE are functionally similar to each other but not to typical interictal spikes, the concept of PLEDs as ictal phenomena would be supported. (Alternatively, PLED-related imaging characteristics might be found sometimes to be similar to imaging during spikes and at other times to imaging during seizures, or PLED-related imaging characteristics might be entirely different from those of interictal spikes or electrographic seizures.)
Summary Brain imaging is an essential clinical tool in the diagnosis and therapy of SE. After a first episode of GCSE is controlled, emergency cranial X-ray CT is indicated to exclude conditions that require immediate neurosurgical intervention. CPSE and SPSE also require structural brain imaging. Brain MRI detects some lesions missed by CT, and brain MRI usually adds diagnostic specificity to CT findings. Brain CT detects many types of lesions that are associated with SE, including acute or chronic intracranial hemorrhage, subacute or chronic cerebral infarction, hypertensive encephalopathy (including eclampsia), cerebral abscess, cerebral cysticercosis, many primary and metastatic neoplasms, arteriovenous malformation, and acute hydrocephalus. Brain MRI detects many types of lesions that are associated with SE and that rarely if ever are detected with CT. Such lesions include limbic encephalitis due to herpesvirus infection or to a paraneoplastic syndrome, cerebritis or meningeal inflammation due to diffuse encephalitis (of infectious and noninfectious causes, during acute and chronic stages), early stages of Rasmussen’s encephalitis, cavernous angioma, focal cortical dysplasia and other malformations of cortical development, and small or inferiorly located neoplasms and foreign tissue or encephalomalacic lesions of any type. Thus, MRI should be performed when CT findings are normal or nondiagnostic following medical therapy for a first episode of GCSE and partial forms of SE. When GCSE recurs in a patient who had a technically satisfactory MRI study after the first episode of SE, emergency CT is indicated to exclude new hemorrhage or other pathology, but a second MRI study usually will be unnecessary.
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 most of these series. Partial SE often causes localized cerebral edema, detectable as T2 signal increases in gray and white matter on MRI. These MRI abnormalities may persist for up to several weeks following partial SE, but ultimately prove to be transitory. Such changes may be misdiagnosed as neoplasia and subjected to inappropriate surgical treatment, but re-imaging is indicated on follow-up because such changes can also occur in conjunction with cerebral neoplasm. Experimental and clinical evidence indicates that vasogenic edema underlies some of these transitory changes, but that cytotoxic edema also occurs in partial SE. Thus, clinical MRI can demonstrate the anatomic locations of processes that cause focal or multifocal neuronal loss, which is useful information in individual patients, but other imaging studies have provided considerable additional information on the metabolic dysfunctions and sequelae of various forms of SE. The pathophysiology of various forms of SE has been elucidated with human imaging studies, in correlation with animal imaging and tissue-destructive investigations in experimental SE. Focal, multifocal, or generalized alterations in many functions can be mapped with brain imaging during SE. Although it is not ethical to delay therapy of GCSE to perform such imaging in humans, imaging can be performed during partial SE and ASE. During ASE in humans, global cerebral synaptic activity is increased, but thalamic activity is increased to a relatively greater extent than is cortical activity (as demonstrated by regional CBF changes). During and following partial SE, brain imaging of patients has shown the following alterations in regions of ictal onset and propagation of partial SE: (1) increased synaptic activity at sites of ictal onset and maximal ictal propagation during SE, which in some instances continues briefly after the end of electrographic SE and in some instances is combined with sites of decreased synaptic activity, (2) vasogenic and cytotoxic cerebral edema during and following SE, (3) decreased water diffusibility during and following SE, (4) vascular hyperpermeability during SE, (5) increased lactate concentration during SE, (6) decreased concentration of the neuronal marker NAA following SE, and (7) focal cerebral atrophy following SE (in patients who did not have atrophy on MRI before SE). Each of these pathologic alterations also has been detected with neuroimaging in experimental partial SE. At this time, ictal SPECT and other functional imaging techniques do not have a clinical role in diagnosis of nonconvulsive SE, in part because electroclinical diagnosis often appears to be sufficient and in part because functional imaging has not been shown to fully distinguish SE from other epileptic states (including single seizures, early postictal states, and perhaps
:
199
periods of extremely frequent interictal spiking, which also can be associated with focal or widespread increases in perfusion). Thus, in GCSE, ASE, and partial SE, imaging is not required for the diagnosis of SE itself, but imaging is required to determine the etiology of the SE. Brain imaging also has elucidated the pathophysiology of the early and late, structural and metabolic sequelae of various forms of SE. Permanent brain injury due to GCSE, and possibly also to CPSE or SPSE, can be demonstrated with MRI and studied with a variety of imaging techniques. In general, the imaging-detectable causes of neuronal death that are associated with SE might be split into immediate and direct neuronal insults during SE (such as hypoxia and excitotoxic injuries) and delayed neuronal insults due to gliovascular dysfunction persisting after SE (in particular, injury due to cerebral edema). These types of insults may not be temporally and biochemically distinguishable, however, and particularly not when SE is prolonged, such that focal or widespread cerebral edema begins during SE and causes vascular compromise with resulting hypoxia that is additive to non-edema-related mechanisms of SE-induced hypoxia. Significant SE-induced alterations in neuronal metabolism can be mapped with functional imaging during experimental GCSE, including elevated glucose utilization, elevated lactate and inorganic phosphate concentrations, decreased intracellular pH and phosphocreatine concentration, decreased NAA concentration, and decreased water diffusibility. The severity and distribution of some metabolic changes induced by SE can be measured in humans, by performing lactate imaging with MRS or water mobility mapping with dwMRI, soon after GCSE is terminated. Hyperperfusion during SE may contribute to brain injury in patients with cerebrovascular anomalies. Vasogenic and cytotoxic cerebral edema in single or multiple foci can be detected with MRI during or immediately following experimental convulsive SE. Severe cerebral edema in itself can cause neuronal necrosis. Further, SE-induced cerebral edema occurs in the presence of SE-induced neuronal metabolic alterations, and presumably, sublethal “doses” of edema and of metabolic dysfunction might interact with each other to cause neuronal necrosis or apoptosis. Sequential imaging studies suggest that partial SE of early childhood is the cause of the HHE syndrome, and that partial SE and GCSE are sufficient but not necessary to cause the syndrome of mesial TLE with hippocampal sclerosis.
3. 4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17. REFERENCES 1. 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. 2. Amato, C., M. Elia, S. A. Musumeci, P. Bisceglie, and M. Moschini. Transient MRI abnormalities associated with
200
:
18.
partial status epilepticus: A case report. Eur. J. Radiol. 2001; 38:50–54. Andermann, F., and J. P. Robb. Absence status. Neurology 1972;13:177–187. Antoniuk, S. A., I. Bruck, R. L. Morais, F. B. Navolar, E. Meister, and A. Spessatto. Hypertensive encephalopathy associated to repetitive seizures: Case report. Arq. Neuro-Psiquiatr. 2000;58:351–355. Assal, F., J. P. Papazyan, D. O. Slosman, P. Jallon, and G. W. Goerres. SPECT in periodic lateralized epileptiform discharges (PLEDs): A form of partial status epilepticus? Seizure 2001;10:260–265. Banati, R. B., G. W. Goerres, R. Myers, et al. [11C] (R)PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen’s encephalitis. Neurology 1999;53:2199–2203. Bansal, B. C., A. Dua, R. Gupta, and M. S. Gupta. Appearing and disappearing CT scan abnormalities in epilepsy in India: An enigma. J. Neurol. Neurosurg. Psychiatry 1989;52: 1185–1187. 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. Berkovic, S. F. SPECT: Neurobiology of periictal blood flow alterations. In T. R. Henry, J. S. Duncan, and S. F. Berkovic, eds. Functional Imaging in the Epilepsies. Philadelphia: Lippincott Williams & Wilkins, 2000:33–39. Bouilleret, V., A. Nehlig, C. Marescaux, and I. J. Namer. Magnetic resonance imaging follow-up of progressive hippocampal changes in a mouse model of mesial temporal lobe epilepsy. Epilepsia 2000;41:642–650. Briellmann, R. S., S. F. Berkovic, A. Syngeniotis, M. A. King, and G. D. Jackson. Seizure-associated hippocampal volume loss: A longitudinal magnetic resonance study of temporal lobe epilepsy. Ann. Neurol. 2002;51:641–644. Callahan, D. J., and M. J. Noetzel. Prolonged absence status epilepticus associated with carbamazepine therapy, increased intracranial pressure, and transient MRI abnormalities. Neurology 1992;42:2198–2201. Cascino, G. D., and C. R. Jack, Jr., eds. Neuroimaging in Epilepsy: Principles and Practice. Boston: Butterworth & Heinemann, 1996. Cendes, F., F. Andermann, S. Carpenter, R. J. Zatorre, and N. R. Cashman. Temporal lobe epilepsy caused by domoic acid intoxication: Evidence for glutamate receptor-mediated excitotoxicity in humans. Ann. Neurol. 1995;37:123–126. 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. Cendes, F. Proton MRS: Lactate. In T. R. Henry, J. S. Duncan, and S. F. Berkovic, eds. Functional Imaging in the Epilepsies. Philadelphia: Lippincott Williams & Wilkins, 2000: 249–253. Chan, S., S. S. Chin, K. Kartha, D. R. Nordli, R. R. Goodman, T. A. Pedley, et al. Reversible signal abnormalities in the hippocampus and neocortex after prolonged seizures. AJNR Am. J. Neuroradiol. 1996;17:1725–1731. Chang, J. W., J. H. Chang, S. C. Park, T. S. Kim, Y. G. Park, and S. S. Chung. Radiologically confirmed de novo glioblastoma multiforme and hippocampal sclerosis associated with the first onset of nonconvulsive simple partial status epilepticus. Acta Neurochirurg. 2001;143:297–300.
19. Christiaens, F. J., L. D. Mewasingh, C. Christophe, S. Goldman, and B. Dan. Unilateral cortical necrosis following status epilepticus with hypoglycemia. Brain Dev. 2003;25: 107–112. 20. Chu, K., D. W. Kang, J. Y. Kim, K. H. Chang, and S. K. Lee. Diffusion-weighted magnetic resonance imaging in nonconvulsive status epilepticus. Arch. Neurol. 2001;58:993–998. 21. Chugani, H. T., P. J. Rintahaka, and D. A. Shewmon. Ictal patterns of cerebral glucose utilization in children with epilepsy. Epilepsia 1994;35:813–822. 22. Cockerell, O. C., J. Rothwell, P. D. Thompson, C. D. Marsden, and S. D. Shorvon. Clinical and physiological features of epilepsia partialis continua: Cases ascertained in the UK. Brain 1996;119:393–407. 23. Cole, A. J., F. Andermann, L. Taylor, et al. The LandauKleffner syndrome of acquired epileptic aphasia: Unusual clinical outcome, surgical experience, and absence of encephalitis. Neurology 1988;38:31–38. 24. Coley, S. C., J. Britton, and A. Clarke. Status epilepticus and venous infarction in Sturge-Weber syndrome. Child. Nerv. Syst. 1998;14:693–696. 25. Constantinidis, I. MRS: Methodology. In T. R. Henry, J. S. Duncan, and S. F. Berkovic, eds. Functional Imaging in the Epilepsies. Philadelphia: Lippincott Williams & Wilkins, 2000: 237–248. 26. Cox, J. E., V. P. Matthews, C. C. Santos, and A. D. Elster. Seizure-induced transient hippocampal abnormalities on MR: Correlation with positron emission tomography and electroencephalography. AJNR Am. J. Neuroradiol. 1995;16: 1736–1738. 27. De Carolis, P., M. Crisci, S. Laudadio, A. Baldrati, and T. Sacquegna. Transient abnormalities on magnetic resonance imaging after partial status epilepticus. Ital. J. Neurol. Sci. 1992;13:267–269. 28. DeLong, G. R., and E. R. Heinz. The clinical syndrome of early-life bilateral hippocampal sclerosis. Ann. Neurol. 1997;42: 11–17. 29. 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. 30. Desbiens, R., S. F. Berkovic, F. Dubeau, et al. Lifethreatening focal status epilepticus due to occult cortical dysplasia. Arch. Neurol. 1993;50:695–700. 31. Detre, J. A., J. I. Sirven, D. C. Alsop, M. J. O’Connor, and J. A. French. Localization of subclinical ictal activity by functional magnetic resonance imaging: Correlation with invasive monitoring. Ann. Neurol. 1995;38:618–624. 32. Devinsky, O., S. Sato, C. V. Kufta, et al. Electroencephalographic studies of simple partial seizures with subdural electrode recordings. Neurology 1989;39:527–533. 33. D’Giano, C. H., M. Del C. Garcia, H. Pomata, and A. L. Rabinowicz. Treatment of refractory partial status epilepticus with multiple subpial transection: Case report. Seizure 2001;10:382–385. 34. Diehl, B., I. Najm, P. Ruggieri, et al. Periictal diffusionweighted imaging in a case of lesional epilepsy. Epilepsia 1999;40:1667–1671. 35. Diehl, B., I. Najm, P. Ruggieri, et al. Postictal diffusionweighted imaging for the localization of focal epileptic areas in temporal lobe epilepsy. Epilepsia 2001;42:21–28. 36. Dillon, W., M. Brant-Zawadzki, and R. G. Sherry. Transient computed tomographic abnormalities after focal seizures. Am. J. Nucl. Radiat. 1984;5:107–109.
37. Dodson, W. E., R. J. DeLorenzo, T. A. Pedley, S. Shinnar, D. M. Treiman, and B. B. Wannamaker. Treatment of convulsive status epilepticus: Recommendations of the Epilepsy Foundation of America’s Working Group on Status Epilepticus. JAMA 1993;270:854–859. 38. Ebisu, T., W. D. Rooney, S. H. Graham, M. W. Weiner, and A. A. Maudsley. N-acetylaspartate as an in vivo marker of neuronal viability in kainate-induced status epilepticus: 1H magnetic resonance spectroscopic imaging. J. Cereb. Blood Flow Metab. 1994;14:373–382. 39. El-Koussy, M., J. Mathis, K. O. Lovblad, F. Stepper, C. Kiefer, and G. Schroth. Focal status epilepticus: Follow-up by perfusion- and diffusion MRI. Eur. Radiol. 2002;12:568–574. 40. Engel, J., Jr., D. E. Kuhl, and M. E. Phelps. Patterns of human local cerebral glucose metabolism during epileptic seizures. Science 1982;218:64–66. 41. Engel, J., Jr., D. E. Kuhl, M. E. Phelps, R. Rausch, and M. Nuwer. Local cerebral metabolism during partial seizures. Neurology 1983;33:400–413. 42. Engel, J., Jr., P. Lubens, D. E. Kuhl, and M. E. Phelps. Local cerebral metabolic rate for glucose during petit mal absences. Ann. Neurol. 1985;17:121–128. 43. Engel, J., Jr., B. I. Ludwig, and M. Fetell. Prolonged complex partial status epilepticus: EEG and behavioral observations. Neurology 1978;28:863–869. 44. Engel, J., Jr., R. F. Ochs, and P. Gloor. Metabolic studies of generalized epilepsy. In M. Avoli, P. Gloor, G. Kostopoulos, and R. Naguet, eds. Generalized Epilepsy. Cambridge, Mass.: Birkhauser, 1990:387–396. 45. Fabene, P. F., P. Marzola, A. Sbarbati, and M. Bentivoglio. Magnetic resonance imaging of changes elicited by status epilepticus in the rat brain: Diffusion-weighted and T2weighted images, regional blood volume maps, and direct correlation with tissue and cell damage. NeuroImage 2003; 18:375–389. 46. Fazekas, F., P. Kapeller, R. Schmidt, et al. Magnetic resonance imaging and spectroscopy findings after focal status epilepticus. Epilepsia 1995;36:946–999. 47. Fish, D. R., K. Krakow, P. J. Allen, L. Lemieux, and M. R. Symms. Methodology: EEG-correlated fMRI. In T. R. Henry, J. S. Duncan, and S. F. Berkovic, eds. Functional Imaging in the Epilepsies. Philadelphia: Lippincott Williams & Wilkins, 2000:187–201. 48. Flacke, S., U. Wullner, E. Keller, F. Hamzei, and H. Urbach. Reversible changes in echo planar perfusion- and diffusionweighted MRI in status epilepticus. Neuroradiology 2000;42: 92–95. 49. Franck, G., B. Sadzot, E. Salmon, et al. Regional cerebral blood flow and metabolic rates in human focal epilepsy and status epilepticus. In A. V. Delgado-Escueta, A. A. Ward, Jr., D. M. Woodbury, and R. D. Porter, eds. Basic Mechanisms of the Epilepsies: Molecular and Cellular Approaches. New York: Raven Press, 1985:935–948. 50. Freeman, J. L., L. T. Coleman, L. J. Smith, and L. K. Shield. Hemiconvulsion-hemiplegia-epilepsy syndrome: characteristic early magnetic resonance imaging findings. J. Child Neurol. 2002;17:10–16. 51. Fueki, N., K. Iinuma, A. Kojima, et al. Alteration of regional cerebral metabolic rate for glucose at interictal and ictal stages in a case of epilepsy with electrical status epilepticus during slow sleep. Jpn. J. Psychiatr. Neurol. 1988;42:611–612. 52. Fugiwara, T., M. Watanabe, K. Matsuda, M. Senbongi, K. Yagi, and M. Seino. Complex partial status epilepticus
:
201
53.
54.
55.
56.
57. 58.
59.
60.
61.
62.
63.
64. 65.
66.
67.
68.
69.
70.
202
provoked by ingestion of alcohol: A case report. Epilepsia 1999;32:650–656. Gorman, D. G., W. D. Shields, D. A. Shewmon, et al. Neurosurgical treatment of refractory status epilepticus. Epilepsia 1992;33:546–549. Goulatia, R. K., A. Verma, N. K. Mishra, and G. K. Ahiya. Disappearing CT lesions in epilepsy. Epilepsia 1987;28: 523–527. Grafton, S. T. PET: Activation of cerebral blood flow and glucose metabolism. In T. R. Henry, J. S. Duncan, and S. F. Berkovic, eds. Functional Imaging in the Epilepsies. Philadelphia: Lippincott Williams & Wilkins, 2000:87–103. Granger, N., P. Convers, O. Beauchet, et al. First epileptic seizure in the elderly: Electroclinical and etiological data in 341 patients. Rev. Neurol. 2002;158:1088–1095. Granner, M. A., and S. I. Lee. Nonconvulsive status epilepticus: EEG analysis in a larger series. Epilepsia 1994;35:42–47. Greenfield, L. J., Jr., M. Blaivas, and I. Drury. De novo status epilepticus due to multiple cerebral hamartomas. Neurology 1999;53:237–238. Guerrini, R., P. Genton, M. Bureau, et al. Multilobar polymicrogyria, intractable drop attack seizures, and sleep-related electrical status epilepticus. Neurology 1998;512:504–512. Gunderson, V. M., M. Dubach, P. Szot, et al. Development of a model of status epilepticus in pigtailed macaque infant monkeys. Dev. Neurosci. 1999;21:352–364. Hajek, M., A. Antonini, K. L. Leenders, and H.-G. Wieser. Epilepsia partialis continua studied with PET. Epilepsy Res. 1991;9:44–48. Handforth, A., and R. F. Ackermann. Mapping of limbic seizure progressions utilizing the electrogenic status epilepticus model and the 14C-2-deoxyglucose method. Brain Res. Rev. 1995;20:1–23. 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. Hauser, W. A. Status epilepticus: Epidemiologic considerations. Neurology 1990;40(Suppl. 2):9–13. Henry, T. R. Progress in epilepsy research: Functional neuroimaging with positron emission tomography. Epilepsia 1996; 37:1141–1154. Henry, T. R., H. T. Chugani, B. W. Abou-Khalil, W. H. Theodore, and B. E. Swartz. Positron emission tomography in presurgical evaluation of epilepsy. In J. Engel, Jr., ed. Surgical Treatment of the Epilepsies. 2nd ed. New York: Raven Press, 1993:211–232. 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. Henry, T. R., J. S. Duncan, and S. F. Berkovic, eds. Functional Imaging in the Epilepsies. Philadelphia: Lippincott Williams & Wilkins, 2000. Henry, T. R., D. A. Ross, L. A. Schuh, and I. Drury. Indications and outcome of ictal recording with intracerebral and subdural electrodes in refractory complex partial seizures. J. Clin. Neurophysiol. 1999;16:426–438. Ichiseki, H., M. Hamamoto, T. Miyazaki, and A. Terashi. Regional cerebral blood flow in status epileptics measured by single photon emission computed tomography. J. Nippon Med. School 1995;62:605–614.
:
71. Ives, J. R., S. Warach, F. Schmitt, et al. Monitoring the patient’s EEG during echoplanar MRI. Electroencephalogr. Clin. Neurophysiol. 1993;87:417–420. 72. Jackson, G. D., A. Connelly, J. H. Cross, I. Gordon, and D. G. Gadian. Functional magnetic resonance imaging of focal seizures. Neurology 1994;44:850–856. 73. Jackson, G. D., and H. I. Opdam. Ictal fMRI: Methods and models. In T. R. Henry, J. S. Duncan, and S. F. Berkovic, eds. Functional Imaging in the Epilepsies. Philadelphia: Lippincott Williams & Wilkins, 2000:203–211. 74. Jan, M., B. G. Neville, T. C. Cox, and R. C. Scott. Convulsive status epilepticus in children with intractable epilepsy is frequently focal in origin. Can. J. Neurol. Sci. 2002; 29:65–67. 75. Jayakumar, P. N., A. B. Taly, and P. K. Mohan. Transient computerized tomographic abnormalities following partial seizures. Acta Neurol. Scand. 1985;72:26–29. 76. Jueptner, M., and C. Weiller. Review: Does measurement of regional cerebral blood flow reflect synaptic activity? NeuroImage 1995;2:148–156. 77. Juhasz, C., E. Scheidl, and I. Szirmai. Reversible focal MRI abnormalities due to status epilepticus. An EEG, single photon emission computed tomography, transcranial Doppler follow-up study. Electroencephalogr. Clin. Neurophysiol. 1998;107:402–407. 78. Jumao-As, A., and R. P. Brenner. Myoclonic status epilepticus: A clinical and electrographic study. Neurology 1990; 40:1199–1202. 79. Jurgen Wenzel, H., D. E. Born, M. F. Dubach, et al. Morphological plasticity in an infant monkey model of temporal lobe epilepsy. Epilepsia 2000;41(Suppl. 6):S70–S75. 80. Juul-Jensen, P., and D. Denny-Brown. Epilepsia partialis continua. Arch. Neurol. 1966;15:563–578. 81. Kaiboriboon, K., and R. E. Hogan. Hippocampal shape analysis in status epilepticus associated with acute encephalitis. AJNR Am. J. Neuroradiol. 2002;23:1003–1006. 82. 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. 83. Kapur, J., and R. L. Macdonald. Status epilepticus: A proposed pathophysiology. In S. Shorvon, F. Dreifuss, D. Fish, and D. Thomas, eds. The Treatment of Epilepsy. Oxford, U. K.: Blackwell Science, 1996:258–268. 84. Kapur, J., A. Pillai, and T. R. Henry. Psychogenic elaboration of simple partial seizures. Epilepsia 1995;36:1126–1130. 85. Katz, A., A. Bose, S. J. Lind, and S. S. Spencer. SPECT in patients with epilepsia partialis continua. Neurology 1990;40: 1848–1850. 86. Kim, J. A., J. I. Chung, P. H. Yoon, et al. Transient MR signal changes in patients with generalized tonicoclonic seizure or status epilepticus: Periictal diffusion-weighted imaging. AJNR Am. J. Neuroradiol. 2001;22:1149–1160. 87. Kimura, M., H. Sejima, H. Ozasa, and S. Yamaguchi. Technetium-99m-HMPAO SPECT in patients with hemiconvulsions followed by Todd’s paralysis. Pediatr. Radiol. 1998;28:92–94. 88. 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. 89. Klopstock, T., M. Jaksch, and T. Gasser. Age and cause of death in mitochondrial diseases. Neurology 1999;53:855– 857.
90. Kramer, R. E., H. Lüders, R. P. Lesser, et al. Transient focal abnormalities of neuroimaging studies during focal status epilepticus. Epilepsia 1987;28:528–532. 91. Kumlien, E., M. Bergstrom, A. Lilja, et al. Positron emission tomography with [11C]deuterium-deprenyl in temporal lobe epilepsy. Epilepsia 1995;36:712–721. 92. Kumpfel, T., C. Lechner, D. Auer, E. Kraft, H. Lydtin, and C. Trenkwalder. Non-convulsive status epilepticus with marked neuropsychiatric manifestations and MRI changes after treatment of hypercalcaemia. Acta Neurol. Scand. 2000; 102:337–339. 93. Kuzniecky, R. I., and G. D. Jackson, eds. Magnetic resonance in Epilepsy. New York: Raven Press, 1995. 94. Kuzniecky, R. I., and B. M. Maton. Proton MRS: N-acetyl aspartate, creatine, and choline. In T. R. Henry, J. S. Duncan, and S. F. Berkovic, eds. Functional Imaging in the Epilepsies. Philadelphia: Lippincott Williams & Wilkins, 2000:255– 261. 95. Kuzniecky, R. I., and R. Powers. Epilepsia partialis continua due to cortical dysplasia. J. Child Neurol. 1993;8:386–388. 96. 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. 97. Laxer, K. D. Phosphorus MRS: pH, ATP, PCr. In T. R. Henry, J. S. Duncan, and S. F. Berkovic, eds. Functional Imaging in the Epilepsies. Philadelphia: Lippincott Williams & Wilkins, 2000:275–279. 98. Lazeyras, F., O. Blanke, I. Zimine, J. Delavelle, S. H. Perrig, and M. Seeck. MRI, (1)H-MRS, and functional MRI during and after prolonged nonconvulsive seizure activity. Neurology 2000;55:1677–1682. 99. 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. 100. Lee, B. I., and D. S. Schauwecker. Regional cerebral perfusion in PLEDs: A case report. Epilepsia 1988;29:607–611. 101. Litt, B., R. Wityk, S. Hertz, P. Mullen, D. Ryan, and T. R. Henry. Outcome of nonconvulsive status epilepticus in the critically ill elderly. Epilepsia 1998;39:1194–1202. 102. Loiseau, H., N. Averet, E. Arrigoni, and F. Cohadon. Relation between epileptic activities and edema formation after cryogenic injury in the rabbit. In D. M. Long, ed. Brain Edema: Pathogenesis, Imaging and Therapy. New York: Raven Press, 1990: 257–267. 103. Lorenzo, A. V., I. Shirahige, M. Liang, and C. F. Barlow. Temporary alteration of cerebrovascular permeability to plasma protein during drug-induced seizures. Am. J. Physiol. 1972;223:268–277. 104. Ma, X., J. Liporace, M. J. O’Connor, and M. R. Sperling. Neurosurgical treatment of medically intractable status epilepticus. Epilepsy Res. 2001;46:33–38. 105. Maquet, P., E. Hirsch, D. Dive, et al. Cerebral glucose utilization during sleep in Landau-Kleffner syndrome: A PET study. Epilepsia 1990;31:778–783. 106. Maquet, P., E. Hirsch, M. N. Metz-Lutz, J. Motte, D. Dive, C. Marescaux, et al. 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. 107. Mariotti, P., G. Della Marca, L. Iuvone, et al. Is ESES/CSWS a strictly age-related disorder? Clin. Neurophysiol. 2000;111: 452–456.
108. Mazziotta, J. C., and S. Gilman, eds. Clinical Brain Imaging: Principles and Applications. Philadelphia: F. A. Davis, 1992. 109. Meierkord, H., U. Wieshmann, L. Niehaus, and R. Lehmann. Structural consequences of status epilepticus demonstrated with serial magnetic resonance imaging. Acta Neurol. Scand. 1997;96:127–132. 110. Meldrum, B. S., and R. W. Horton. Physiology of status epilepticus in primates. Arch. Neurol. 1973;28:1–9. 111. Men, S., D. H. Lee, J. R. Barron, and D. G. Munoz. Selective neuronal necrosis associated with status epilepticus: MR findings. AJNR Am. J. Neuroradiol. 2000;21:1837–1840. 112. Meric, B., B. Barrere, M. Peres, et al. Effects of kainateinduced seizures on brain metabolism: A combined 1H and 31P NMR study in rat. Brain Res. 1994;638:53–60. 113. Mizrahi, E. M., and P. Kellaway. Diagnosis and Management of Neonatal Seizures. New York: Lippincott-Raven, 1998. 114. Montagna, P., R. Gallassi, R. Medori, et al. MELAS syndrome: Characteristic migrainous and epileptic features and maternal transmission. Neurology 1988;38:751–754. 115. 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. 116. 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. 117. Murchison, J. T., R. J. Sellar, and A. J. Steers. Status epilepticus presenting as progressive dysphasia. Neuroradiology 1995; 37:438–439. 118. Nagasaka, T., K. Shindo, M. Hiraide, T. Sugimoto, and Z. Shiozawa. Ipsilateral thalamic MRI abnormality in an epilepsy patient. Neurology 2002;58:641–644. 119. Najm, I., Y. Wang, S. C. Hong, H. O. Lüders, T. Ng, and Y. Comair. Temporal changes in proton MRS metabolites after kainic acid-induced seizures in rat brain. Epilepsia 1997;38: 87–94. 120. Najm, I. M., Y. Wang, D. Shedid, H. O. Lüders, T. Ng, and Y. Comair. MRS metabolic markers of seizures and seizureinduced neuronal damage. Epilepsia 1998;39:244–250. 121. Nakasu, Y., S. Nakasu, S. Morikawa, S. Uemura, T. Inubushi, and J. Handa. Diffusion-weighted MR in experimental sustained seizures elicited with kainic acid. Am. J. Neuroradiol. 1995;16:1185–1192. 122. Ng, Y. T., H. L. Kim, and J. W. Wheless. Successful neurosurgical treatment of childhood complex partial status epilepticus with focal resection. Epilepsia 2003;44:468–471. 123. Nitsch, C., and I. Klatzo. Regional patterns of blood-brain barrier breakdown during epileptiform seizures induced by various convulsive agents. J. Neurol. Sci. 1983;59:305–322. 124. Nixon, J., D. Bateman, and T. Moss. An MRI and neuropathological study of a case of fatal status epilepticus. Seizure 2001;10:588–591. 125. Noachtar, S., A. Ebner, O. Witte, and R. Seitz. Palatal tremor of cortical origin presenting as epilepsia partialis continua. Epilepsia 1995;36:207–209. 126. 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. 127. O’Brien, T. J. SPECT methodology. In T. R. Henry, J. S. Duncan, and S. F. Berkovic, eds. Functional Imaging in the Epilepsies. Philadelphia: Lippincott Williams & Wilkins, 2000: 11–32.
:
203
128. O’Brien, T. J., E. L. So, F. B. Meyer, J. E. Parisi, and C. R. Jack. Progressive hippocampal atrophy in chronic intractable temporal lobe epilepsy. Ann. Neurol. 1999;45:526–529. 129. Ochs, R. F., P. Gloor, J. L. Tyler, et al. Effect of generalized spike-and-wave discharge on glucose metabolism measured by positron emission tomography. Ann. Neurol. 1987;21: 458–464. 130. Oe, H., R. Yuasa, M. Tsuchiyama, and K. Kitamura. Neuroimaging findings of hemiconvulsions, hemiplegia, epilepsy (HHE) syndrome. Clin. Neurol. 1999;39:485–488. 131. Ohtahara, S. Clinico-electrical delineation of epileptic encephalopathy in childhood. Asian Med. J. 1978;21:499–509. 132. Ortega, M. D., M. Tintore, X. Montalban, A. Codina, and A. Rovira. Intracranial involvement in neurosarcoidosis: A report of 4 cases as initial manifestation of the disease. Rev. Neurol. 1999;28:491–494. 133. Ou, S. F., C. S. Chi, W. J. Shian, S. C. Mak, and T. T. Wong. Dural arteriovenous malformation with symmetrical calcification of the basal ganglia: A case report. Chin. Med. J. 1994;54:204–208. 134. Palmini, A. L., P. Gloor, and M. Jones-Gotman. Pure amnestic seizures in temporal lobe epilepsy: Definition, clinical symptomatology and functional anatomical considerations. Brain 1992;115:749–769. 135. 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. 136. Pascal-Castroviejo, I., S. I. Pacual-Pacual, W. Pena, and M. Talavera. Status-epilepticus-induced brain damage and opercular syndrome in childhood. Dev. Med. Child Neurol. 1999;41:420–423. 137. Patry, G., S. Lyagoubi, and C. A. Tassinari. Subclinical “electrical status epilepticus” induced by sleep in children. Arch. Neurol. 1971;24:242–252. 138. Pavlakis, S. G., P. C. Phillips, S. DiMauro, D. C. DeVivo, and L. P. Rowland. Mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike episodes: A distinctive clinical syndrome. Ann. Neurol. 1984;16:481–488. 139. Pedespan, J. M., H. Loiseau, A. Vital, C. Marchal, D. Fontan, and A. Rougier. Surgical treatment of an early epileptic encephalopathy with suppression-bursts and focal cortical dysplasia. Epilepsia 1995;36:37–40. 140. Perez, E. R., P. Maeder, K. M. Villemure, V. C. Vischer, J. G. Villemure, and T. Deonna. Acquired hippocampal damage after temporal lobe seizures in 2 infants. Ann. Neurol. 2000;48: 384–387. 141. Petito, C. K., J. A. Schaefer, and F. Plum. The blood-brain barrier in experimental seizures. In H. M. Pappius and W. Feindel, eds. Dynamics of Brain Edema. Berlin: Springer-Verlag, 1976:38–42. 142. Petroff, O. A. C., R. H. Mattson, and D. L. Rothman. Proton MRS: GABA and glutamate. In T. R. Henry, J. S. Duncan, and S. F. Berkovic, eds. Functional Imaging in the Epilepsies. Philadelphia: Lippincott Williams & Wilkins, 2000:263–273. 143. Petroff, O. A. C., J. W. Prichard, K. L. Behar, J. R. Alger, and R. G. Shulman. In vivo phosphorus nuclear magnetic resonance spectroscopy in status epilepticus. Ann. Neurol. 1984;16: 169–177. 144. Petroff, O. A. C., J. W. Prichard, T. Ogino, M. J. Avison, J. R. Alger, and R. G. Shulman. Combined 1H and 31P nuclear magnetic resonance studies of bicuculline-induced seizures in vivo. Ann. Neurol. 1986;20:185–193.
204
:
145. Pirttila, T. R., A. Pitkanen, J. Tuunanen, and R. A. Kauppinen. Ex vivo MR microimaging of neuronal damage after kainate-induced status epilepticus in rat: Correlation with quantitative histology. Magn. Res. Med. 2001;46:946– 954. 146. Pitkanen, A., J. Nissinen, J. Nairismagi, et al. Progression of neuronal damage after status epilepticus and during spontaneous seizures in a rat model of temporal lobe epilepsy. Prog. Brain Res. 2002;135:67–83. 147. Prevett, M. C., J. S. Duncan, T. Jones, D. R. Fish, and D. J. Brooks. Demonstration of thalamic activation during typical absence seizures using H2(15)O and PET. Neurology 1995;45: 1396–1402. 148. Prichard, J. W. Nuclear magnetic resonance spectroscopy of seizure states. Epilepsia 1994;35(Suppl. 6):S14–S20. 149. Prichard, J. W., J. R. Alger, K. L. Behar, O. A. C. Petroff, and R. G. Shulman. Cerebral metabolic studies in vivo by 31P NMR. Proc. Natl. Acad. Sci. U.S.A. 1983;80:2748–2751. 150. Prichard, J. W., and J. J. Neil. Diffusion-weighted MRI: periictal studies. In T. R. Henry, J. S. Duncan, and S. F. Berkovic, eds. Functional Imaging in the Epilepsies. Philadelphia: Lippincott Williams & Wilkins, 2000:281–286. 151. Reutens, D. C. Imaging monoamine oxidase B receptor mapping. In T. R. Henry, J. S. Duncan, and S. F. Berkovic, eds. Functional Imaging in the Epilepsies. Philadelphia: Lippincott Williams & Wilkins, 2000:173–176. 152. Riela, A. R., B. P. Sires, and J. K. Penry. Transient magnetic resonance imaging abnormalities during partial status epilepticus. J. Child Neurol. 1991;6:143–145. 153. Righini, A., C. Pierpaoli, J. R. Alger, and G. Di Chiro. Brain parenchyma apparent diffusion coefficient alterations associated with experimental complex partial status epilepticus. Magn. Res. Imag. 1994;12:865–871. 154. Rintahaka, P. J., H. T. Chugani, and R. Sankar. LandauKleffner syndrome with continuous spikes and waves during slow-wave sleep. J. Child Neurol. 1995;10:127–133. 155. Roch, C., C. Leroy, A. Nehlig, and I. J. Namer. Magnetic resonance imaging in the study of the lithium-pilocarpine model of temporal lobe epilepsy in adult rats. Epilepsia 2002;43: 325–335. 156. Roch, C., C. Leroy, A. Nehlig, and I. J. Namer. Predictive value of cortical injury for the development of temporal lobe epilepsy in 21-day-old rats: An MRI approach using the lithium-pilocarpine model. Epilepsia 2002;43:1129–1136. 157. Rougier, A., P. Loiseau, J. Rivel, F. Cohadon, and J. M. Orgogozo. Partial epileptic seizures in four adolescents with abnormal CT scan, focal gliosis and spontaneous regression. Rev. Neurol. 1984;140:171–178. 158. Rumack, C. M., M. A. Guggenheim, J. W. Fasules, and D. Burdick. Transient positive post-ictal computed tomographic scan. J. Pediatr. 1980;97:263–264. 159. Salmenpera, T., R. Kalviainen, K. Partanen, E. Mervaala, and A. Pitkanen. MRI volumetry of the hippocampus, amygdala, entorhinal cortex, and perirhinal cortex after status epilepticus. Epilepsy Res. 2000;40:155–170. 160. Sammaritano, M., F. A. Andermann, D. Melanson, H. M. Papprus, P. Camfield, J. Aicardi, et al. Prolonged focal cerebral edema associated with partial status epilepticus. Epilepsia 1985;26:334–335. 161. 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: 284–289.
162. Scher, M. S., R. W. Redline, and B. A. Bangert. Delayed onset of status epilepticus after transient asphyxia in an asymptomatic full-term neonate. J. Child Neurol. 2002;17:780– 783. 163. Schuelke, M., M. Bakker, G. Stoltenburg, J. Sperner, and A. von Moers. Epilepsia partialis continua associated with a homoplasmic mitochondrial tRNA(Ser(UCN)) mutation. Ann. Neurol. 1998;44:700–704. 164. Scott, R. C., D. G. Gadian, M. D. King, et al. Magnetic resonance imaging findings within 5 days of status epilepticus in childhood. Brain 2002;125:1951–1959. 165. Sethi, P. K., B. R. Kumar, V. S. Madan, and V. Mohan. Appearing and disappearing CT scan abnormalities and seizures. J. Neurol. Neurosurg. Psychiatry 1985;48:866–869. 166. Shafrir, Y., and A. L. Prensky. Acquired epileptiform opercular syndrome: A second case report, review of the literature, and comparison to the Landau-Kleffner syndrome. Epilepsia 1995;36:1050–1057. 167. Sheth, R. D., and J. E. Riggs. Persistent occipital electrographic status epilepticus. J. Child Neurol. 1999;14:334–336. 168. Silverstein, A. M., and J. A. Alexander. Acute postictal cerebral imaging. AJNR Am. J. Neuroradiol. 1998;19:1485–1488. 169. Singh, G., A. K. Dhanuka, H. S. Bains, and D. Singh. Febrile status epilepticus as the first presentation of cortical developmental malformation: Report of 2 cases. Neurol. India 2001; 49:287–290. 170. Soffer, D., E. Melamed, Y. Assaf, and S. Cotev. Hemispheric brain damage in unilateral status epilepticus. Ann. Neurol. 1986;20:737–740. 171. Sokic, D. V., N. Stojsavljevic, J. Drulovic, et al. Seizures in multiple sclerosis. Epilepsia 2001;42:72–79. 172. Sokol, D. K., W. E. Demyer, M. Edwards-Brown, S. Sanders, and B. Garg. From swelling to sclerosis: Acute change in mesial hippocampus after prolonged febrile seizure. Seizure 2003;12:237–240. 173. Song, A. W., C. A. Popp, J. Mao, and W. T. Dixon. fMRI: Methodology: acquisition and processing. In T. R. Henry, J. S. Duncan, and S. F. Berkovic, eds. Functional Imaging in the Epilepsies. Philadelphia: Lippincott Williams & Wilkins, 2000: 177–185. 174. Spencer, S. S., and R. E. D. Bautista. Functional neuroimaging in localization of the ictal onset zone. In T. R. Henry, J. S. Duncan, and S. F. Berkovic, eds. Functional Imaging in the Epilepsies. Philadelphia: Lippincott Williams & Wilkins, 2000: 287–298. 175. Sperling, M. R., A. Alavi, M. Reivich, J. A. French, and M. J. O’Connor. False lateralization of temporal lobe epilepsy with FDG positron emission tomography. Epilepsia 1995;36: 722–727. 176. Sperling, M. R., and M. J. O’Connor. Auras and subclinical seizures: Characteristics and prognostic significance. Ann. Neurol. 1990;28:320–328. 177. Sperner, J., B. Sander, S. Lau, H. Krude, and D. Scheffner. Severe transitory encephalopathy with reversible lesions of the claustrum. Pediatr. Radiol. 1996;26:769–771. 178. Stephen, L. J., and M. J. Brodie. An islander with seizures. Scott. Med. J. 1998;43:183–184. 179. Stone, J. L., J. R. Hughes, A. Barr, W. Tan, E. Russell, and R. M. Crowell. Neuroradiological and electroencephalographic features in a case of temporal lobe status epilepticus. Neurosurgery 1986;18:212–216. 180. Stübchen, J.-P. Crossed cerebellar diaschisis related to recurrent focal seizures. Epilepsia 1995;36:316–318.
181. Suarez, J. I., D. Mlakar, and S. M. Snodgrass. Cerebral syphilitic gumma in an HIV-negative patient presenting as prolonged focal motor status epilepticus. N. Engl. J. Med. 1996;335:1159–1160. 182. Sung, C.-Y., and N.-S. Chu. Epileptic seizures in intracerebral hemorrhage. J. Neurol. Neurosurg. Psychiatry 1989;52: 1273–1276. 183. 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. 184. Takahashi, Y., H. Kubota, T. Fujiwara, K. Yagi, and M. Seino. Epilepsia partialis continua of childhood involving bilateral brain hemispheres. Acta Neurol. Scand. 1997;96:345–352. 185. Takamatsu, K., T. Takizawa, S. Sato, et al. [Transient focal abnormalities of MRI and angiographic neuroimaging in status epilepticus: Case report.] No To Shinkei 1991;43: 289–294 (in Japanese). 186. Tatum, W. O., A. Alavi, and M. M. Stecker. Technetium99m-HMPAO SPECT in partial status epilepticus. J. Nucl. Med. 1994;35:1087–1094. 187. Teitelbaum, J. S., R. J. Zatorre, S. Carpenter, et al. Neurologic sequelae of domoic acid intoxication due to the ingestion of contaminated mussels. N. Engl. J. Med. 1990;322: 1781–1787. 188. Thebaud, B., B. Husson, Y. Navelet, et al. Haemorrhagic shock and encephalopathy syndrome: Neurological course and predictors of outcome. Intensive Care Med. 1999;25: 293–299. 189. Theodore, W. H., R. Brooks, R. Margolin, et al. Positron emission tomography in generalized seizures. Neurology 1985; 35:684–690. 190. Thomas, J. E., T. J. Reagan, and D. W. Klass. Epilepsia partialis continua: A review of 32 cases. Arch. Neurol. 1977;34: 266–275. 191. Thomas, P., A. Beaumanoir, P. Genton, C. Dolisi, and M. Chatel. “De novo” absence status epilepticus of late onset: Report of 11 cases. Neurology 1992;42:104–110. 192. Thomas, P., M. Borg, G. Suisse, and M. Chatel. Opercular myoclonic-anarthric status epilepticus. Epilepsia 1995;36: 281–289. 193. Thomas, P., B. Zifkin, O. Migneco, et al. Nonconvulsive status epilepticus of frontal origin. Neurology 1999;52:1174– 1183. 194. 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. 195. 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. 196. Tryphonas, L., J. Truelove, E. Nera, and F. Iverson. Acute neurotoxicity of domoic acid in the rat. Toxicol. Pathol. 1990; 18:1–9. 197. van Gall, M., G. Scollo-Lavizzari, and H. Becker. Absence status in the adult: New results including computerized transverse axial tomography. Eur. Neurol. 1978;17:121–128. 198. Veltkamp, R., A. Kupsch, J. Polasek, T. A. Yousry, and H. W. Pfister. Late onset postpartum eclampsia without preeclamptic prodromi: Clinical and neuroradiological presentation in two patients. J. Neurol. Neurosurg. Psychiatry 2000;69: 824–827.
:
205
199. Villeumier, 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. 200. Votaw, J. R. PET image acquisition and analysis. In T. R. Henry, J. S. Duncan, and S. F. Berkovic, eds. Functional Imaging in the Epilepsies. Philadelphia: Lippincott Williams & Wilkins, 2000:69–86. 201. Wall, C. J., E. J. Kendall, and A. Obenaus. Rapid alterations in diffusion-weighted images with anatomic correlates in a rodent model of status epilepticus. Am. J. Neuroradiol. 2000;21: 1841–1852. 202. Wang, Y., A. Majors, I. Najm, et al. Postictal alteration of sodium content and apparent diffusion coefficient in epileptic rat brain induced by kainic acid. Epilepsia 1996;37: 1000–1006. 203. Warach, S., J. M. Levin, D. L. Schomer, B. L. Holman, and R. R. Edelman. Hyperperfusion of ictal seizure focus demonstrated by MR perfusion imaging. AJNR Am. J. Neuroradiol. 1994;15:965–968. 204. Wasterlain, C. G. Mortality and morbidity from serial seizures. Epilepsia 1974;15:155–176. 205. 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. 206. Wieshmann, U. C., M. R. Symms, and S. D. Shorvon. Diffusion changes in status epilepticus. Lancet 1997;350: 493–494. 207. 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 after generalized status epilepticus. Epilepsia 1997;38:1238– 1241. 208. Yaffe, K., D. Ferriero, D. A. Barkovich, and H. Rowley. Reversible MRI abnormalities following seizures. Neurology 1995;45:104–108. 209. Yoshimura, K. A case of nonconvulsive status epilepticus associated with focal cortical dysplasia. Brain Dev. 2003;25: 207–210. 210. Young, G. B., J. J. Gilbert, and D. W. Zochodne. The significance of myoclonic status epilepticus in postanoxic coma. Neurology 1990;40:1843–1848. 211. Young, R. S., M. D. Osbakken, R. W. Briggs, S. K. Yagel, D. W. Rice, and S. Goldberg. 31P NMR study of cerebral metabolism during prolonged seizures in the neonatal dog. Ann. Neurol. 1985;18:14–21. 212. Zegers De Beyl, D., N. Hermanus, H. Colle, and S. Goldman. Focal seizures with reversible hypodensity on the CT scan. J. Neurol. Neurosurg. Psychiatry 1985;48:187–188. 213. Zhong, J., O. A. Petroff, J. W. Prichard, and J. C. Gore. Barbiturate-reversible reduction of water diffusion coefficient in fluorothyl-induced status epilepticus in rats. Magn. Res. Med. 1995;33:253–256. 214. Zhong, J., O. A. Petroff, J. W. Prichard, and J. C. Gore. Changes in water diffusion and relaxation properties of rat cerebrum during status epilepticus. Magn. Res. Med. 1993; 30:241–246.
206
:
IV BASIC MECHANISMS: PATHOPHYSIOLOGY
17
Self-Sustaining Status Epilepticus
. , , . , , . , , , , .
T status epilepticus (SE) to become selfperpetuating, and the fact that it is more than a series of severe seizures, were recognized as early as the nineteenth century (64). It is also reflected in the many animal models of SE that are now available. In a few models of SE, usually created under anesthesia, seizure response is tightly coupled with the epileptogenic stimulus (46). However, in awake, free-running animals, SE tends to become selfsustaining and to continue for hours if the epileptogenic stimulus is withdrawn. This is true regardless of the nature of the initial cause of the seizures, which can be chemical (6, 46, 60) or electrical stimulation (31–33, 36–42). This independence of continuing seizures from their initial trigger makes self-sustaining SE (SSSE) a convenient model for studying basic mechanisms underlying SE. Understanding the conditions critical for the transition from stimulus-bound seizures to SSSE may help us to understand at what point SE becomes intractable and brain damaging, and how to prevent these consequences. Our studies of SSSE addressed the question of the type and minimal duration of epileptogenic stimulation sufficient to induce SSSE, the mechanisms of transition from stimulus-bound SE to SSSE, the mechanisms of the initiation phase and the maintenance phase of SSSE, and the interventions that can terminate SSSE and perhaps improve treatment outcome.
Models of SSSE The first model of SSSE was derived from the observation that, when rats were paralyzed, ventilated with oxygen, and kept in good metabolic balance, repetitive application of electroconvulsive shocks (ECS) for more than 25 minutes resulted in seizures that continued after stimulation stopped (Figure 17.1). The duration and severity of these selfsustaining seizures directly correlated with the duration of stimulation (71, 72). Animals exposed to repeated ECS for 25 minutes had self-sustaining seizures for a few minutes, whereas animals subjected to ECS for 50 minutes continued to seize for up to an hour, and rats stimulated for 100 minutes remained in SSSE for hours and usually died, even though their oxygenation, acid-base balance, and other metabolic parameters remained stable.
Following the discovery of the kindling phenomenon by Goddard et al. (15), Taber et al. (61) and de Campos and Cavalheiro (8) modified the method of stimulation to obtain SE. McIntyre et al. (43, 44) showed that continuous stimulation (for 60 minutes) of the basolateral amygdala of kindled animals with high-frequency current induced SSSE in about 60% of animals, thus demonstrating that the kindled state predisposes to the development of SSSE. Buterbaugh et al. (1982) showed that small amounts of pilocarpine would also induce SSSE in kindled animals. Seeking a model in which SE could be induced in naive animals, Turski et al. (65) developed the pilocarpine model of SE. Buterbaugh et al. (6) and Morrisset et al. (46) showed that, in these chemical models, seizures become independent of the initial trigger and self-sustaining, as they do in electrical stimulation models. Later it was shown that both continuous high- (45) and low-frequency (7) stimulation of limbic structures can induce SSSE. Inoue et al. (23, 24) reproduced SSSE in naive rats by electrical stimulation of prepiriform cortex. Handforth and Ackerman (18, 19) used a similar approach, with continuous high-frequency stimulation of hippocampus or amygdala, and analyzed the functional anatomy of SSSE, correlating metabolic (14C-deoxyglucose) mapping with the behavioral pattern of seizures. They delineated several types of SSSE of differing severity, ranging from a very restricted limbic pattern with regional involvement around the site of stimulation and mild behavioral manifestations (motor arrest) to bilateral extensive involvement of limbic and extralimbic structures accompanied by widespread clonic seizures. This approach was later used by a number of investigators, notably Lothman and colleagues (32), who showed that stimulation of dorsal hippocampus for 60 minutes with high-frequency trains with very short intertrain intervals, a protocol they called continuous hippocampal stimulation (CHS), resulted in the development, in many animals, of SSSE characterized by nonconvulsive or mild convulsive seizures that lasted for hours after the end of CHS (29). Metabolic activity was increased in many brain structures (maximal in CA1, dentate gyrus, presubiculum, and subiculum) (67); these seizures led to loss of GABAergic hippocampal inhibition, to hippocampal interictal spiking, and to delayed (1 month after CHS) spontaneous seizures (31, 33).
.: -
209
F 17.1 Repeated electroconvulsive shock induces SSSE in rats. Representative electrographic recordings from skull screw electrodes in paralyzed and oxygen-ventilated rats. Animals shocked repeatedly for 25 minutes (50 shocks) or longer showed
self-sustaining seizure activity after the end of electrical stimulation. Increasing the number of shocks resulted in longer lasting selfsustaining seizures (Reprinted with permission from Wasterlain [71].)
Vicedomini and Nadler (68, 69) reevaluated the importance of the site of stimulation for induction of SSSE. Repeated application of high-frequency trains to the perforant path, which induced afterdischarges from the dentate gyrus, a key structure in the propagation of seizure activity (21), resulted in the build-up of self-sustaining seizure activity, which lasted for hours. SSSE developed in each animal that showed 10 consecutive afterdischarges. Morissett et al. (46) modified the pilocarpine model of SE by administering atropine sulfate, which removed the cholinergic stimulus. Although it was effective in blocking SE when given before the onset of behavioral seizures, administration of atropine sulfate after overt seizures occurred was unable to stop seizures. This finding clearly showed that different mechanisms are responsible for initiation and maintenance of SE, and that SSSE can be triggered by chemical as well as by electrical stimulation. These results were extended to juvenile animals by Suchomelova et al. (60). We used a protocol derived from those of Vicedomini and Nadler (68, 69) and Sloviter (57). We stimulated the perforant path in awake rats with 10-second, 20-Hz trains (1-msec square wave, 20 V) delivered every minute, and with 2-Hz continuous stimulation. Recording was made from the dentate gyrus (42). Nissinen et al. (50) developed a similar
model based on amygdala stimulation. Space limitations preclude discussion here of the very nice work done with the amygdala model or with variations of the perforant path model (16, 66).
210
:
T P P S M SSSE Threshold for initiation of SSSE Our initial studies derived from the need to eliminate the potentially confounding effect of anesthesia in our studies of seizure-induced brain damage in immature animals (62). In free-running adult rats, intermittent perforant path stimulation (PPS) easily triggered SSSE. With 7 minutes of PPS, animals (n = 5) showed epileptiform discharges in response to stimulation, but none of the animals showed any seizures after the end of stimulation. During 15-minute PPS, four of six rats showed ictal behavior, which stopped when stimulation ended. However, the two remaining rats displayed prolonged seizures during PPS (total time, 900 and 700 seconds), and after the end of stimulation they developed SSSE, which lasted for 2 and 16 hours, respectively. The animal with 6-hour SSSE died during SSSE. During 30-minute PPS, discrete spikes or spike-and-wave complexes or organized electrographic seizures appeared independently of stimuli, after 7–20 minutes of stimulation (Figure 17.1). As PPS continued,
seizure duration increased, and the interval between the seizures decreased. After 20–25 minutes of PPS, all animals were displaying repetitive stage 3 to 4 seizures. The time spent in seizures during PPS was 12 ± 1.4 minutes (mean ± SEM). After the end of PPS, seizures continued in all animals (Figure 17.1). The severity of seizures varied from stage 1 (facial clonus) to stage 5 (clonus, rearing and falling). Electrographically, either discrete spikes or spike-and-wave complexes (recognized as spikes by the software), associated with stage 1–3 convulsions, or organized seizures lasting for up to 2 minutes and accompanied by stage 4–5 convulsions were observed (Figure 17.1). They merged into nearly continuous polyspike activity, which later became interrupted by postictal low-voltage periods. The time spent in seizure after 30-minute PPS averaged 490 ± 128 minutes in this series of animals. As SSSE continued, the incidence of overt seizures decreased (Figure 17.2). Starting at 3–6 hours, postictal episodes lengthened, and ictal activity evolved toward a pattern of periodic epileptiform discharges (PEDs), with a frequency of 1.5 Hz, accompanied by stage 3 seizures. In the final hours of SSSE the amplitude of PEDs decreased
and slow waves appeared. However, interictal spikes occurring at irregular intervals (sometimes 1 per minute) were observed even 24 hours after PPS. After 60-minute PPS, seizures occurred with higher frequency, and the duration of individual seizures was longer. Indeed, although the time of the last seizure after 30-minute and 60-minute PPS did not differ significantly (644 ± 134 and 730 ± 147 minutes, respectively), 60-minute PPS resulted in a significantly longer time spent in seizures (510 ± 71 vs. 352 ± 801 minutes, P < 0.05). These results show that SSSE has a threshold for duration of epileptogenic stimulation that is critical for transition from stimulus-bound to self-sustaining seizures, and that this threshold lies between 7 and 30 minutes, which is close to the time needed to induce 10 afterdischarges in the studies of Vicedomini and Nadler (68). In this paradigm, the duration of seizure-like stimulation needed to induce SSSE was very short: 5 minutes of high-frequency trains (30-minute PPS) induced SSSE in 100% of rats, and behavioral and electroencephalographic (EEG) patterns were stereotypical from animal to animal.
F 17.2 EEG during SSSE induced by 30 minutes of perforant path stimulation (PPS). (A) Representative course of spikes. (B) The 24-hour distribution of seizures (black bars). PPS is indicated by the gray bar at top. Each line represents 2 hours of
monitoring. (C) Sample electrographic activity in the dentate gyrus during SSSE. (Modified with permission from Mazarati et al. [42]. © 1998 by Elsevier Publishing.)
.: -
211
SSSE maintained by an underlying change in excitability not dependent on continuous seizure activity Perihilar injection of the AMPA/kainate receptor blocker CNQX 10 minutes after 30-minute PPS produced only transient effects: there was strong suppression of both electrographic (Figure 17.3E) and behavioral seizures. However, 4–5 hours after injection of CNQX, electrographic spikes and seizures reappeared, and soon after that behavioral convulsions recurred. Despite the effective seizure suppression for hours, total time spent in seizures over 24 hours (253 + 60 minutes vs. 352 + 80 minutes in controls) and the time of occurrence of the last seizure (627 + 40 minutes vs. 644 + 95 minutes in controls) did not significantly differ from controls (41). It seems that the change in excitability triggered by SE outlasted the drug and did not depend on continuous seizure activity in limbic circuits.
We discuss some possible substrates for this change in excitability. The two phases of SE are pharmacologically distinct Pharmacologically, a large number of agents are able to induce SSSE (Table 17.1), suggesting that the circuit that maintains selfsustaining seizures has many potential points of entry. However, pharmacologic responsiveness during initiation of SSSE and during established SSSE are strikingly different. Minute amounts of many agents that enhance inhibitory transmission or reduce excitatory transmission easily block the development of SSSE (Table 17.1), suggesting that brain circuits are biased against it and that all systems must be “go” in order for the phenomenon to develop. This is hardly surprising, insofar as SSSE is a rare, life-threatening event. However, once seizures are self-sustaining, few agents are
A. Control D. Ketamine
500 400
Spikes / 30 min
Spikes / 30 min
600
300 200 100 0
600 500 400 300 200 100 0 2 4 6 8 10 12 14 16 18 20 22 24 hours of monitoring
B. MK-801 400
E. CNQX Spikes / 30 min
300
300
200
200 100
100
0 2 4 6 8 10 12 14 16 18 20 22 24 hours of monitoring
0 2 4 6 8 10 12 14 16 18 20 22 24
C. 5,7-DCK Spikes / 30 min
Spikes / 30 min
2 4 6 8 10 12 14 16 18 20 22 24 hours of monitoring
300 200 100 0 2 4 6 8 10 12 14 16 18 20 22 24 hours of monitoring
F 17.3 The effects of NMDA (A–D) and AMPA/kainate (E) receptor blockers on SSSE induced by 60-minute PPS (A–D) or 30minute PPS (E). Each graph shows the frequency of spikes (number of spikes per 30-minute epoch) plotted against time during the course of SSSE. PPS is indicated by the dotted gray bar on each graph. Representative time course of seizures detected by the software is shown next to the graphs. Each line represents 2 hours of monitoring, and each seizure is indicated by a black bar. Arrows
212
:
indicate time of drug administration. NMDA receptor blockers MK-801 (0.5 mg/kg IP), 2,5-DCK (10 nmol into the hilus), and ketamine (10 mg/kg IP) administered 10 minutes after the end of PPS irreversibly aborted SSSE soon after injection. CNQX (10 nmol into the hilus) injected after 30-minute PPS induced only transient suppression of seizures, which reappeared within 2–4 hours after CNQX injection. (Modified with permission from Mazarati et al. [41]. © 1998 by Elsevier Publishing.)
T 17.1 Agents capable of initiating and blocking self-sustaining status epilepticus
Initiators
Blockers of initiation phase
Blockers of maintenance phase
Low Nao+, high Ko+ GABAA antagonists Glutamate agonists: NMDA, AMPA, kainate, low Mgo2+, low Cao2+, stimulation of glutamatergic pathways Cholinergic muscarinic agonists, stimulation of muscarinic pathways Tachykinins (SP, NKB) Galanin antagonists Opiate delta agonists Opiate kappa antagonists
Na+ channel blockers GABAA agonists NMDA antagonists, high Mgo2+ AMPA/kainate antagonists Cholinergic muscarinic antagonists SP, neurokinin B antagonists Galanin Somatostatin NPY Opiate d antagonists Dynorphin (k agonist)
NMDA antagonists Tachykinin antagonists Galanin Dynorphin
effective in terminating them, and they usually work only in large concentration. The most efficacious agents are blockers of NMDA synapses, or presynaptic inhibitors of glutamate release (Table 17.1).
available for intravenous use in the U.S. Pharmacopeia, when administered after either 30- or 60-minute PPS, stopped both behavioral and electrographic seizures within 10 minutes after drug injection.
Initiation is accompanied by a loss of GABA inhibition Prolonged loss of paired-pulse inhibition occurs after brief (<5 minutes) perforant path stimulation in vitro (in hippocampal slices), as well as in vivo, with the paired-pulse population-spike amplitude ratio (P2/P1) increasing from a baseline of 0.53 ± 0.29 to 1.17 ± 0.09 after PPS (P < 0.05). After perfusion with the GABAA antagonist bicuculline, the P2/P1 ratio increases from a baseline of 0.52 ± 0.16 to 1.15 ± 0.26 (P < 0.05). After 1–2 minutes of PPS, a 22% ± 6% (P < 0.05) decrease occurs in the P2/P1 amplitude ratio of pairedpulse-evoked inhibitory postsynaptic currents, consistent with the involvement of GABAA synaptic receptors. The findings suggest that loss of inhibition at GABAA synapses may be an important early event in the initiation of SE.
Time-dependent development of pharmacoresistance Diazepam and phenytoin (or their analogues, lorazepam and fosphenytoin) are the two anticonvulsants most often used for treatment of SE in humans (34, 35, 59, 70). We examined the effects of these two antiepileptic drugs with regard to dose and time of injection. Pretreatment with diazepam in doses of 0.5 mg/kg, 5 mg/kg (not shown), 10 mg/kg (Figure 17.4), or phenytoin (50 mg/kg), before initiation of stimulation, effectively prevented the development of SSSE. Even for the lower doses, the cumulative time spent in seizures after the end of PPS did not exceed 5 minutes, and the last seizure occurred within 10 minutes after treatment. When administered 10 minutes after the end of 30-minute PPS, diazepam in doses of 0.5 and 5 mg/kg had no seizure-protective effects. After injection of 10 mg/kg, motor seizures stopped within 10 minutes. At this dose, diazepam induced strong muscle relaxation and ataxia. However, despite the absence or mild character of behavioral seizures, electrographic seizures continued. Total time spent in seizures was 95 ± 22 minutes, and the last seizure was observed at 140 ± 32 minutes after the administration of diazepam, a significantly longer period than in the group pretreated with diazepam before PPS. Phenytoin (50 mg/kg) effectively aborted SSSE when injected 10 minutes after 30minute PPS: animals spent 6.3 ± 2.5 minutes in seizures, and the last seizure occurred within 30 minutes after drug administration (Figure 17.4). When injected 10 minutes after 60minute PPS, both diazepam (10 mg/kg, Figure 17.4) and phenytoin (50 mg/kg) failed to stop established SSSE. Time spent in seizures was 204 ± 30 and 216 ± 27 minutes, and the
Maintenance of SSSE depends on the activation of NMDA receptors Intraperitoneal administration of the NMDA receptor blocker MK801 (0.5 mg/kg) after 60-minute PPS effectively aborted SSSE. Suppression of electrographic seizure activity was reflected in a decrease in spike frequency (Figure 17.3), in the total time spent in seizures (9.8 + 3 minutes vs. 510 + 70 minutes in controls), and in the time of occurrence of the last seizure (28 + 6 minutes vs. 730 + 148 minutes in controls). Another NMDA receptor blocker, 5,7dichlorokinurenic acid (10 nmoles injected into the hilus of the dentate gyrus), quickly and irreversibly stopped both electrographic and behavioral manifestations of SSSE (Figure 17.3) without inducing behavioral depression. Ketamine (10 mg/kg IP) and felbamate, two NMDA antagonists
.: -
213
A. Injections before 60 min PPS
C. Control
800
minutes
600 400
D. Diazepam
200 0
CON
**
**
DZP
PHT
B. Injections after 60 min PPS
800
minutes
600
#
400
*
#
*
200
#
E. Diazepam
*
#
*
0
CON
DZP
PHT
F 17.4 Time-dependent development of pharmacoresistance in SSSE induced by 60-minute PPS. (A) When administered before PPS, both diazepam (DZP) and phenytoin (PHT) prevented the development of SSSE. (B) When injected 10 minutes after the end of PPS, neither diazepam nor phenytoin aborted SSSE, although they shortened its duration (*P < 0.05 vs. control; #P < 0.05 vs. diazepam and phenytoin as shown in A [pretreatment]). Open bars indicate cumulative seizure time; solid bars indicate the duration of SSSE (time of occurrence of the last seizure during SSSE). (C–E) Representative time course of seizures in a control animal (C), an animal pretreated with diazepam (D), or an animal
with diazepam injected 10 minutes after PPS (E). Each line represents 2 hours of EEG monitoring. Each software-recognized seizure is shown by a small black bar. PPS is indicated by gray dotted bars at the top of each graph. Time of injection of diazepam is indicated by an arrow in D and E. In the control animal, self-sustaining seizures were observed for 17 hours. In diazepam-pretreated rats, seizures occurred during PPS, but only a few seizures were observed after PPS and only within the first 20 minutes. In the diazepam-post-treated animal, self-sustaining seizures continued for 8 hours. (Modified with permission from Mazarati et al. [36]. © 1998 by Elsevier Publishing.)
last seizure occurred 366 ± 65 and 300 ± 93 minutes after injection of diazepam and phenytoin, respectively (P < 0.05 vs. control). All of these measurements were significantly higher than in the pretreatment protocol (36). In other words, the same dose that was very effective when given as pretreatment failed when administered after SSSE was established. The reduction through endocytosis of the number of GABAA receptors available at the synapse may explain the loss of benzodiazepine potency: the clathrin-binding site, which is the mediator of endocytosis, is located on the benzodiazepinebinding g2 subunit of GABAA receptors, and this could make that subunit particularly prone to internalization.
Mechanisms of the transition from isolated seizures to SE
214
:
Endocytosis of synaptic GABAA receptors may play a part in the transition from stimulus-bound to self-sustaining seizures, and in the development of benzodiazepine pharmacoresistance. GABAergic agents lose their therapeutic effectiveness as SE proceeds, and brief convulsant stimuli result in a diminished inhibitory tone of hippocampal circuits (as indicated by loss of paired-pulse inhibition in vivo). To examine the effects on GABAA synapses, whole-cell patch-clamp recordings of miniature inhibitory postsynap-
tic currents (mIPSCs) were obtained from dentate gyrus granule cells in hippocampal slices from 4- to 8-week-old Wistar rats after 1 hour of lithium-pilocarpine SE, and compared with controls. mIPSCs recorded from granule cells in slices prepared 1 hour into SE showed a decreased peak amplitude (PA), to 61.8% ± 11.9% of controls (-31.5 ± 6.1 pA for SE vs. -51.0 ± 17.0 pA for controls; P < 0.001) (Figure 17.5) and an increase in decay time to 127.9% ± 27.6% of controls (7.75 ± 1.67 msec for SE vs. 6.06 ± 1.17 msec for controls; P < 0.001). Unlike mIPSCs, tonic currents increased in amplitude to a mean of -130.0 (±73.6) pA in SE versus -44.8 (±19.2) pA in controls (P < 0.05), and the increase in baseline holding current standard deviation prior to application of the GABAA antagonist SR95531 was 11.05 ± 2.31 pA for SE and 6.10 ± 1.53 pA for controls (P < 0.001). Tonic currents are thought to be mediated by extrasynaptic receptors containing d subunits, which are known to display low levels of desensitization and internalization. The persistence of tonic currents during SE might suggest the use of drugs with o strong affinity for extrasynaptic receptors, such as neurosteroids (which prefer d-containing receptors) or THIP (which prefers a4-containing receptors). Possible explanations for the pA decrease of mIPSCs include GABAA receptor internalization, changes in receptor kinetics, and/or alteration of GABA release/uptake during SE. Exposing hippocampal slices to micromolar GABA resulted in a rapid reduction of mIPSCs, suggesting that the changes observed in SE may be triggered by the massive GABA release during seizures. Mathematical modeling of GABAA synapses using mean variance fluctuation analysis and seven-state GABAA receptor models suggested that SE involves a 47% reduction in postsynaptic receptor number (from 34 ± 7 [control] to 22 ± 5 [SE] receptors per synapse; P < 0.001). This may underestimate the acute changes, since slices collected from animals in SE were examined after 1–2 seizure-free hours in vitro. Modeling of tonic GABAA currents suggests that the difference between SE and control animals can be accounted for by a 5–10 mM increase in extracellular GABA during SE. Immunocytochemistry was performed in rats perfused after 30 or 60 minutes of seizures induced by lithiumpilocarpine, PPS, or intrahippocampal injection of neurokinin B. Sections through hippocampus were double-labeled with antibodies for the b2/b3 subunits (which are among the most abundant subunits of those receptors) and for the presynaptic marker synaptophysin, and viewed by confocal microscopy. These anatomic studies indicate that the decrease in number of synaptic receptors observed physiologically reflects, at least in part, receptor internalization (Figure 17.6). They show colocalization of the b2/b3 subunits with the presynaptic marker synaptophysin on the surface of soma and proximal dendrites of dentate granule
cells and CA3a pyramids in controls, with internalization of those subunits in SE: in the lithium-pilocarpine model at 60 minutes, 12% ± 17% of b2/b3 subunits are internalized in control CA3, compared with 54% ± 15% in slices from rats in SE (P < 0.001). When cell bodies immunoreactive for GABAA b2/b3 subunits were counted (average, 21 per section in dentate gyrus; 18 per section in the CA1 region), there were few control neurons with more than five b2/b3 subunit-immunoreactive endosomes per cell body. A cell body with more than 15 b2/b3 subunit-immunoreactive endosomes was considered to have internalized receptors. In the dentate gyrus granule cells, control slices had 9.7% ± 0.3% of neurons showing receptor internalization, while in slices from SE rats, 70.7% ± 0.9% of neurons showed GABAA receptor internalization by these criteria. Numbers in CA1 were similar, with 7.3% of control neurons showing receptor internalization compared with 70% ± 1.5% in slices from rats in SE. We also found that the g2 subunits are internalized during SE: because of the high cell packing density and relatively low g2 subunit concentration on their soma, those measurements were difficult in granule cells, but the proportion of internalized endosome-like structures with b2like immunoreactivity in the soma of basket cells at the edge of the granule cell layer increased from 19% ± 4% to 86% ± 23% after 1 hour of lithium-pilocarpine SE (47–49). Finally, an adaptation of the model for mIPSCs was used to fit perforant path–evoked IPSCs obtained from granule cells in the slice. When parameters obtained for mIPSCs from SE animals are entered, this model predicted the loss of paired-pulse inhibition (40 msec interstimulus interval) seen after brief convulsant stimulation. The model suggests that a basis for loss of paired-pulse inhibition during seizures is an increase in extracellular GABA resulting in GABAA postsynaptic receptor desensitization and (mostly) endocytosis. It does not preclude a role for chloride influx into neurons during SE, reducing the hyperpolarization that results from opening of GABAA receptor channels, or even causing depolarization (26), although the latter has not been demonstrated in vivo. Changes in extracellular space volume could also modify excitability by changing potassium or other ionic concentration (12). In conclusion, a decrease in synaptic GABAA currents and an increase in extrasynaptic tonic currents are observed with SE. An increase in extracellular GABA during SE can explain the tonic current increase (as these receptors do not desentitize significantly), while desensitization/internalization of postsynaptic GABAA receptors (possibly from increased GABA exposure) can explain the decrease amplitude of synaptic mIPSCs, although an increase in intracellular chloride concentration may also play a role. These changes at GABAergic synapses may represent important events in the transition from single seizures to SSSE (Figure 17.8). Because internalized receptors are not functional, this
.: -
215
F 17.5 Comparison of mIPSCs from dentate gyrus granule cells of SE animals and controls. (a) mIPSC mean traces from a typical granule cell from a control animal (solid line) and an SE animal (dotted line), demonstrating smaller amplitude and prolonged decay in the latter. (b) Optimized computer model fits
216
:
(dashed line) to mean and standard deviation traces of mIPSCs (solid line) from a control and an SE cell. (c) Histogram for peak amplitudes of individual mIPSC events recorded from a control (left) and an SE (right) granule cell, with the superimposed predicted distribution (bullet) from model fits of b.
GABAA receptor
Synaptophysin
Overlay
sg h CTL CA3 sg LiPC
h
CA3 F 17.6 Intracellular distribution of GABAA subunits in hippocampal neurons from SE and control rats. Double-labeled immunocytochemistry was performed in dentate and CA3 of control and SE animals using antibodies to GABAA g2 subunits (red) and synaptophysin (green). Note the colocalization
(yellow) of receptor subunits with presynaptic sites in controls and the greater internalization of receptor subunits relative to synaptophysin during SE. (Scale bar = 10 mm.) The neuron illustrated is located close to the inner surface of the granule cell layer. (See Color Plate 3.)
internalization may reduce the response of inhibitory synapses to additional seizures and may in part explain the failure of inhibitory GABAergic mechanisms, which characterizes the initiation phase of SSSE. Internalized receptors may be recycled to the synaptic membrane through the Golgi apparatus or may be destroyed in lysosomes (Figure 17.8). The reduced synaptic receptor numbers may also explain the diminished effect of benzodiazepines and other GABAergic drugs as SE proceeds (27, 36).
loss of GABA inhibition, which occurs at a very early stage of stimulation, may contribute to facilitation of LTP. However, direct changes affecting excitatory NMDA receptors also seem to be involved. We compared findings in 4- to 8-week-old rats in SSSE for 1 hour induced by lithium (3 mEq/kg IP) plus pilocarpine (40 mg/kg IP) with findings in controls. Physiologic measurements included NMDA miniature EPSCs (mEPSCs) recorded from granule cells in the hippocampal slice with visualized whole-cell patchclamp (-60 mV holding potential) using tetrodotoxin (TTX) (1 mM), DNQX (10 mM), picrotoxin (30 mM), -serine (10 mM), and 0 Mg2+ in the CSF. The mEPSCs showed an increased pA from -16.2 ± 0.4 for controls to -19.5 ± 2.4 for SE (P < 0.001). No significant changes in event decay time were noted, although there was a slight trend toward increased decay of mEPSCs during SE (23.9 ± 2.9 msec vs. 21.7 ± 6.1 msec for controls; 0.05 < P < 0.1). A slight increase in mEPSC frequency was noted for SE cells (1.15 ± 0.51 Hz vs. 0.73 ± 0.37 Hz; 0.05 < P < 0.01). Mean variance analysis of the mEPSCs showed an increase from 5.2 ± 1.2 receptors per synapse in controls to 7.8 ± 1.2 receptors during SE (50% increase; P < 0.001).
NMDA receptor trafficking, synaptic potentiation, and the maintenance phase of SSSE The self-perpetuating nature of SSSE suggests that synaptic potentiation, such as a form of long-term potentiation (LTP) and/or posttetanic potentiation, may account for some of the maintenance mechanisms of SSSE. Indeed, we found that SSSE is accompanied by increased LTP in the perforant path-dentate gyrus pathway (40). Several mechanisms may underlie facilitation of LTP during SSSE. The first is impaired GABAergic inhibition, as discussed previously. Lack of GABA inhibition facilitates LTP. Thus, SE-induced
.: -
217
F 17.7 On the left, in this control CA3 pyramidal neuron, the NR1-LI (red) is in large part internal to synaptophysin-LI, but on the right, after 1 hour of SE, NR1-LI outlines the neuronal membrane of another CA3 neuron much more clearly, and the
number of colocalizations with synaptophysin-LI is markedly increased, suggesting trafficking of NR1 subunits of NMDA receptors toward the synapses. (See Color Plate 4.)
Immunocytochemical analysis of this phenomenon was carried out with antibodies to the NR1 subunit of NMDA receptors. It showed a movement of NR1 subunits from cytoplasmic sites to the neuronal surface, and an increase in colocalization with the presynaptic marker synaptophysin, suggesting a mobilization of “spare” subunits to the synapse (Figure 17.9). In conclusion, during SE, endocytosis/internalization of GABAA postsynaptic receptors is accompanied by an increase in excitatory NMDA synaptic receptors. Receptor trafficking may regulate the balance between excitatory and inhibitory postsynaptic receptor numbers and may be an important element in the transition to and maintenance of SE. Another possible mechanism of facilitation of LTP during SSSE is presynaptic changes in calcium-dependent calmodulin kinase II (CaMKII). Wasterlain et al. (73) examined this phenomenon in the bicuculline and lithium-pilocarpine models of SE. They showed that after SE, the calciumindependent fraction of CaMKII increased, while the calcium-dependent fraction decreased. During SE, repeated depolarization of neurons removes the magnesium block in the ionic channel associated with NMDA receptors. Since at the same time glutamate is liberated, binding to those receptors, the NMDA-associated ionic channels open, at the same
time that depolarization opens the voltage-gated calcium channels, resulting in an increase in free intracellular calcium. This increased intraneuronal calcium causes autophosphorylation of CaMKII II, greatly increasing its calcium-independent kinase activity. This continues to phosphorylate proteins even when the cell is not firing and intracellular calcium is not elevated. This increases the rate of phosphorylation of synapsin I, resulting in separation of phosphosynapsin I from the vesicle wall and increasing the likelihood of transmitter release. The increased transmitter release may play a role in the transition from stimulus-bound seizures to SSSE. Many other factors undoubtedly intervene in the transition to SSSE, including the changes in neuropeptides described later in this chapter.
218
:
Studies of the neuronal circuitry subserving SSSE Three major approaches have been used to examine these circuits: electrographic mapping, metabolic mapping with 2deoxyglucose (2-DG) or c-fos, and morphologic examination of brain damage after SSSE. E M Electrographic mapping employs multiple deep electrode recordings during SSSE
F 17.8 Model summarizing our hypothesis on the role of receptor trafficking in the transition from single seizures to SE. After repeated seizures, the synaptic membrane of GABAA receptors forms clathrin-coated pits (Cl), which internalize as clathrin-coated vesicles, thus inactivating the receptors because they are no longer within reach of the neurotransmitter. These vesicles evolve into endosomes, which can deliver the receptors to lyso-
somes (L), where they are destroyed, or to the Golgi apparatus (G), from where they are recycled to the membrane. By contrast, in NMDA synapses subunits are mobilized to the synaptic membrane and assemble into additional receptors. As a result of this trafficking, the number of functional NMDA receptors per synapse increases while the number of functional GABAA receptors decreases (60). (See Color Plate 5.)
.: -
219
A
B
F 17.9 Representative coronal sections showing 2-DG autoradiographs from a control animal (A) and an animal killed 45 minutes after the end of 30-minute PPS, during SSSE (B). Abbreviations: SEPT, septum; PIR, piriform cortex; CAU, caudateputamen; HI, hippocampus; HY, hypothalamus; AMY, amygdala;
SN, substantia nigra pars reticulata; ENT, entorhinal cortex; MOT, motor; PAR, parietal; AUD, auditory cortices; THAL, thalamic nuclei. Glucose utilization increased in all the mentioned structures during SSSE. (Reprinted with permission from Pereira et al. [51]. © 1999 by Elsevier Publishing.)
and examination of the time sequence of the involvement of various structures in seizure activity. Despite the obvious advantages of the method, since the events are detected “on line,” only a few reports described the electrographic characteristics of SSSE. Bertram (4), using Lothman’s continuous hippocampal stimulation model, defined several types of onset and propagation of seizures: with hippocampal, extrahippocampal (e.g., piriform, amygdala), and diffuse onset. Diffuse onset of seizures was the most common type; in these cases seizures appeared to start simultaneously from the stimulated hippocampus and other structures, such as amygdala, entorhinal cortex, piriform cortex, amygdala, and contralateral hippocampus. Bertram suggested that no single primary focus or single functional perturbation is responsible for the expression and maintenance of limbic SSSE, but rather that SSSE is subserved by a distributed network of large epileptogenic circuits. However, one could interpret those data as reflecting the well-known difficulty
of timing methods for analyzing central circuits, and the variability of the point of stimulation, since simple stereotaxic methods without physiologic feedback were used for implantation.
220
:
I P Immunostaining for fos protein, or the detection of c-fos mRNA by in situ hybridization, maps gene activation in brain structures. During SE induced by lithium-pilocarpine, fos immunostaining was increased in the limbic circuit: the olfactory tubercle, piriform cortex, amygdala, septum, and dentate gyrus, as well as in nucleus accumbens and caudateputamen, probably reflecting involvement of the structures responsible for motor expression of seizures (1). Surprisingly, no staining was observed in substantia nigra reticulata, which showed high metabolic activity. This shows a limitation of the method, since some brain structures may not express the required biochemical messengers (10).
A S U 2-DG Autoradiographic studies using 2-DG allows mapping of seizurerelated metabolic activation (most intense in presynaptic terminals). 2-DG autoradiography performed in a model of continuous hippocampal or amygdalal stimulation by Handforth and Ackerman (18, 19) showed increased 2-DG uptake throughout limbic, extralimbic, and nonlimbic structures. The distribution of 2-DG uptake in this model was variable but correlated nicely with the behavioral patterns of SSSE, and clearly showed that nonconvulsive seizures involved a limbic circuit, whereas motor seizures consistently displayed extrahippocampal spread. In our PPS model of SSSE, increased utilization of 2-DG at the peak of seizure activity (1 hour after the end of PPS) was observed in the hippocampus (three- to fourfold increase compared with controls in the dentate gyrus, hilus, CA3, and CA1; Figure 17.9), other limbic structures (fourfold increase in olfactory nucleus, lateral septum, amygdala, and piriform and entorhinal cortices), as well as in structures related to motor components of seizures: nucleus accumbens, caudateputamen, endopeduncular nucleus, and substantia nigra reticulata (8). The distribution of SSSE-induced neuronal injury overlaps with the map of metabolic activation. The importance of recruitment of extrahippocampal structures in SSSE becomes evident if one compares two models of SE: SSSE induced by brief PPS in awake animals, and focal SE induced by 24-hour PPS under urethane anesthesia. In these models, parameters of stimulation are similar, except for duration. However, under urethane, metabolic changes remain local (increased 2-DG uptake confined to the stimulated hippocampus, with minimal increases in contralateral hippocampus and no extrahippocampal spread), neuronal injury is strictly hippocampal and predominantly in the stimulated hilus, and seizures never become self-sustaining (55). This pattern indicates that SSSE is associated with the metabolic activation of a limbic circuit that may be similar in diverse forms of SE, and that includes hippocampus, amygdala, medial thalamus, septum, nucleus accumbens, entorhinal and piriform cortices, and some parts of caudate/putamen, cingulate cortex, and dorsal neocortex. We speculate that this map represents the anatomic substrate of SSSE and that it is shared by many types of SE, with additional areas of activation reflecting model-specific spread to motor cortex and to other less eloquent areas involved in specific subtypes of SE.
Role of neuropeptides in SSSE E M T R C SSSE Bioactive peptides may be powerful modulators of brain excitability, often through presyn-
aptic control of the release of classical neurotransmitter, and therefore may act as endogenous “anticonvulsants” or “convulsants” that contribute to self-perpetuation of seizure activity. In our model of SSSE induced by PPS, we examined the involvement of several neuropeptides in SSSE. E O P Both acute seizures and chronic epilepsy induce changes in the functioning of opioid peptidergic mechanisms in the brain. Changes in endogenous opioid peptide content and in their mRNA expression have been shown in SE induced by kainic acid (9, 22, 25), pilocarpine (2), and protracted hippocampal stimulation (16). Further, exogenously applied peptides were shown either to attenuate or to facilitate seizures, depending on their affinity for a subtype of opiate receptors, their dose, and the epilepsy model used (5, 14, 54). Physiologically, endogenous opioid peptides interplay with the classical neurotransmitters and modulate their action via pre- or postsynaptic mechanisms. For example, dynorphin may inhibit glutamate release from perforant path and mossy fiber terminals (11). Changes in endogenous opioid peptide immunoreactivity during SSSE In animals killed 3 hours after the end of PPS, during continuous seizure activity, we found a dramatic bilateral decrease in dynorphin-like and enkephalin-like immunoreactivity in both CA3 and hilus. Twenty-four hours after PPS, as seizures stopped, immunoreactivity for both peptides recovered to near basal levels (39). Effects of endogenous opioid peptid receptor ligands on SSSE To reveal possible facilitating effects of peptides on SSSE, we examined the effects of pretreatment followed by 7-minute PPS, a duration of stimulation that in control rats is not sufficient to induce SSSE. Under these conditions, animals pretreated with the delta opioid receptor agonist [DSer2]Leu-enkephalin-Thr6 (DSLET) or the kappa opioid receptor antagonist norbinaltorphimine (NBNI) developed self-sustaining seizures lasting 2–3 hours (Figure 17.10). Thus, activation of delta receptors or blocking of kappa receptors in the hippocampus facilitated the establishment of SSSE (39). To examine possible anticonvulsant effects of endogenous opioid peptides, we administered them 10 minutes after the end of 30-minute PPS. The kappa agonist dynorphin (A) 1–13, when injected into the hilus of the dentate gyrus of seizing animals, effectively stopped SSSE. Manipulation with both delta and mu receptors did not affect the course of SSSE. Therefore, selective activation of kappa receptors is able to stop established SE in this animal model.
.: -
221
200 SSSE duration, min
A
*
Injected before 7 min PPS
150
*
100 50 0 CON
DSLET
NBNI
DAMGO
600
B
Injected after 30 min PPS
SSSE duration, min
500 400 300 200 100 * 0 CON
NAX
NAD
ICI-174864
DYN
F 17.10 The effects of opiate receptor ligands on the induction and maintenance of SSSE. (A) Drugs were administered prior to 7-minute PPS, a treatment that does not normally induce SSSE (as indicated by the bar labeled CON [control]). The d agonist DSLET and the k antagonist NBNI, injected prior to PPS, facilitated the establishment of self-sustaining seizures, which lasted for
more than 2 hours, while the m agonist DAMGO had no effect. (B) Ligands were injected 10 minutes after the end of 30-minute PPS, a time when SSSE is established. Although the m/d agonist naloxone (NAX), and the d antagonists naltrindole (NAD) and ICI174864 did not affect SSSE, the k agonist dynorphin-A(1–13) (DYN) aborted SSSE. *P < 0.05 versus control.
G Galanin, a bioactive peptide containing 29 or 30 amino acid residues, is widely distributed throughout the CNS. Physiologic studies suggest that galanin’s action in the hippocampus is predominantly inhibitory (3, 13, 52, 75) and associated with a reduction in glutamate release. In animals killed 3 hours after the end of PPS, during steady-state SSSE, Gal-ir fibers were absent in all hippocampal areas (Figure 17.9), suggesting a loss of this inhibitory neuromodulator during SSSE. Gal-ir fibers were still absent 12 hours after PPS, as well as 1 and 3 days later. Six hours after PPS, on the plateau of SSSE, galanin concentration as measured by ELISA in both stimulated and contralateral hippocampi was significantly lower than in controls (38).
behavioral seizure was seen. 2-Ala-galanin, a putative agonist for GalR2 receptors, did not affect the course of SSSE when given before PPS in a dose of 0.5 nmol, although a dose of 5 nmol significantly decreased the duration of selfsustaining seizures, which lasted for 2–4 hours. Perihilar administration of galanin (0.5 nmol but not 0.05 nmol) 10 minutes after the end of PPS stopped selfsustaining seizures within 25 minutes. The seizure-blocking effects of galanin were canceled by coadministration with any of three galanin receptor antagonists (Figure 17.11). Since galanin displayed anticonvulsant effects, we examined the consequences of administration of galanin receptor antagonists on the initiation of SSSE. In this set of experiments, the animals received PPS for 7 minutes after the intrahippocampal administration of placebos or of galanin antagonists. As shown earlier, 7-minute PPS never induced SSSE in control animals. Animals (n = 4) that received 5 nmol of the galanin type 1 receptor antagonist M35 developed SSSE and continued to seize for 180–250 minutes after PPS (39) (Figure 17.11).
Effects of galanin receptor ligands on SSSE Perihilar injection of galanin (0.05 nmol [n = 5] and 0.5 nmol [n = 6]) prior to 30minute PPS significantly shortened the duration of selfsustaining seizures (Figure 17.11). After PPS, stage 4 seizures continued for only minutes, and spikes were observed for another 10–20 minutes, after which no electrographic or
222
:
B. Injected before 30’ PPS
2 1.5
668+107’
1
*
0.5
* 0.01
0.05 Galanin
0.5
0.5 5 nmol 2-Ala-Galanin
C. Injected after 30’ PPS
2.5 2 1.5 1 0.5 0
633+83’
M40 + Gal
M40, 5
M35 + Gal
M35, 0.5
M15, 5
Gal, 0.5
2-Ala-Gal, 5
* Gal, 0.05
D
Peptide/ control seizure duration
0
*
M15 + Gal
Peptide/ control seizure duration
C
D. Injected before 7’ PPS
F
60 Peptide/ control seizure duration
E
*
40 20 4+2’
1
0.5 5 M15
0.5 5 M35
0.5 5 nmol M40
WT, 30 min PPS
30 min after PPS
GalKO, 30 min PPS * WT, 60 min PPS
GalOE, 60 min * 0.5 mV 0.5 s
0
F 17.11 Galanin-like immunoreactivity in the hippocampus of a control rat (A) and of an animal killed 3 hours after the end of 30-minute PPS, during SSSE (B). There is a dense, fine network of galanin-immunoreactive fibers in the control rat that disappears in the animal in SSSE. Scale bar = 200 mm. (C–E) Effects of galanin receptor ligands on SSSE. Galanin is a nonselective GalR1 and GalR2 receptor agonist. 2-Ala-galanin is a selective GalR2 receptor agonist. M15 and M40 are peptides that preferentially block GalR2, and M35 is a preferential blocker of GalR1. (C) Effects of peptides injected prior to 30-minute PPS. (D) Effects of peptides injected after the end of PPS. Galanin, but not 2-Ala-galanin, stopped established SSSE. These effects were abolished by all three galanin receptor antagonists. (E) Effects of galanin receptor antagonists injected prior to 7-minute PPS. M35, but not the two other galanin receptor antagonists, facilitated the establishment of SSSE when given prior to 7-minute PPS. Bars
100
200
300
indicate mean ± SD of the ratio of SSSE durations in the peptidetreated animals to control animals. SSSE duration in controls is indicated by the dashed line. Absolute values (mean + SD, in minutes) of SSSE duration in control rats are indicated above the dashed line. *P < 0.05 versus control values. (Modified with permission from Lothman et al. [33]. © 1998 by the Society for Neuroscience.) (F) Galanin transgenic mice show altered ability to establish SSSE. At left are EEG tracings recorded from the dentate gyrus 30 minutes after the end of PPS. At right, the time in seizures after PPS (mean ± SEM) is graphed. PPS for 30 minutes was insufficient to induce SSSE in wild-type mice (WT), but induced SSSE in galanin knockout mice. (GalKO). PPS for 60 minutes induced SSSE in wild-type controls, but had no effect on galanin-overexpressing animals (GalOE). *P < 0.05 versus respective wild-type control values. (Reprinted with permission from Mazarati et al. [37, 38]. ©1998, 2000 by the Society for Neuroscience.)
.: -
223
Further evidence for the role of galanin in SSSE came from the studies on galanin knockout (GalKO) and galaninoverexpressing (GalOE) mice. Although 30 minutes of PPS was not sufficient to induce SSSE in any of the wild-type controls, all of the GalKO mice developed SSSE, with the last seizure observed 345 ± 45 minutes after PPS. In contrast, 60-minute PPS induced SSSE in wild-type mice, but only brief seizure activity was observed in GalOE mice (37). These data imply that endogenous galanin plays an active role in controlling induction of seizure activity during SSSE. Based on these results, a nonpeptidic galanin agonist was synthesized (55) that crosses the blood-brain barrier. It is an effective, broad-spectrum anticonvulsant. Transfection of the galanin gene also has anticonvulsant effects (18, 55). T Substance P (SP) increases excitatory transmission, in part by presynaptic facilitation of glutamate release. Agonists are proconvulsants, and antagonists are anticonvulsants in several models. A combination of intrahippocampal injection of SP and a very brief period of PPS (7 minutes), which is insufficient to induce SE by itself, resulted in the establishment of SE (Figure 17.12). This effect was receptor mediated, since it was blocked by neurokinin 1 receptor antagonists such as spantide II. Mice lacking SP showed a greatly reduced predisposition to development of SE on systemic administration of kainic acid (29). Surprisingly, SSSE increases the expression of this endogenous proconvulsant (and its message) in the dentate mossy fibers, and this maladaptive change may contribute to out-of-control excitation in SSSE (Figure 17.12) and in lithium-pilocarpine SE. These data suggest that SP may be an endogenous convulsant that promotes seizures (30). Neurokinin B, another tachykinin closely
related to SP, has similar effects. It also enhances glutamate release presynaptically and potentiates glutamate actions postsynaptically; agonists at its specific (neurokinin 3) receptor enhance seizures, and antagonists are anticonvulsants.
Ontogeny of SSSE The ability to develop SSSE after PPS is age dependent. Rat pups at postnatal day 15 and younger do not develop SSSE even after several hours of stimulation. About 25% of the 3-week-old animals tested established SSSE. At postnatal day 30, SSSE was observed in 60% of animals. By age 35 days, the ability to develop SSSE fully matures, and all animals readily show self-sustaining seizures. Why the ability to establish SSSE is a function of age is not clear. The phenomenon is not model dependent, since it is seen in 2-weekold pups that develop SE after lithium-pilocarpine (53). When given atropine to block the muscarinic effects of pilocarpine, postnatal day 15 rats stop seizing, while postnatal day 28 rats continue to seize over many hours (after a transient depression), showing that seizures have become self-sustaining (60). These differences may reflect the maturation of neuronal circuits responsible for propagation of seizure activity from dentate gyrus (a prime target of PPS) and elsewhere.
Mechanisms of SSSE Based on these data, we suggest the following key features of SSSE: 1. SSSE is different from ordinary epileptic seizures. Repetitive seizures do something that enhances excitability and begets further seizures.
Seizure duration (min)
*
100
10
1
B
C F 17.12 Substance P in SE. (A and B) In situ hybridization of substance P mRNA in a control animal (A) and in an animal killed during SSSE, 6 hours after 30-minute PPS (B). (C) The SP antagonist spantide II (50 nmol injected into the hilus 10 minutes
224
*
:
S PP S in m PP 7 in + m SP , 7 I l SI ro + nt Sl Co PPS PP in in m m 30 30 l, ro nt Co
A
1000
after the end of 30-minute PPS) aborted SSSE. Substance P (SP, 10 pmol) injected into the hilus prior to 7-minute PPS facilitated the establishment of SSSE. *P < 0.05 versus control. (Reprinted with permission from Liu et al. [30].)
F 17.13 Hippocampal circuitry of SSSE. This putative circuit is limited to the hippocampus and its close cortical connections. Autoradiographic studies suggest involvement of a number of other regions, such as amygdala, medial thalamus, and substantia nigra. A small arrow next to the name of a peptide indicates the direction of change induced by SE. An asterisk indicates
a late change. SUB, subiculum; LS, lateral septum; MS, medial septum; GC, dentate granule cells; IN, hilar interneurons; LC, locus ceruleus; PRC, perirhinal cortex; ERC, entorhinal cortex; CTX, neocortex; OFR, olfactory cortex; CIN, cingulated cortex; PYR, piriform cortex; INS, insula. (Reprinted with permission from Wasterlain et al. [74]. © 2002 by Blackwell Publishing.)
2. The anatomic substrate of that change is limbic. During SSSE, the balance between excitation and inhibition in that circuit is compromised, resulting in limbic hyperexcitability (Figure 17.13). 3. Access to that limbic circuit can involve many entry points and many pathways. All systems must be “go” for SSSE to develop; therefore, many pharmacologic agents can block the initiation of SSSE (Figure 17.10), either by reducing excitation or by increasing inhibition at any point of the circuit. 4. The limbic circuit that maintains SSSE, however, is very similar (but not identical) in many models and types of SE: once it gets going, it is self-sustaining, stereotyped, and no longer dependent on the original stimulus. During the maintenance phase of SSSE, both loss of inhibition and enhancement of excitation are observed (40); the latter seems key, because only drugs that reverse it can easily terminate SSSE. 5. Once SSSE gets going, standard anticonvulsants lose their effectiveness, for reasons that are complex. A prominent component is a decrease in the number of synaptic GABAA receptors, due mainly to GABAA receptor endocytosis. The g2- benzodiazepine-binding subunit, which bears the clathrin-binding site, may be particularly prone to internalization into endosomes, where the receptor no longer behaves as a functional ion channel, greatly reducing the response to benzodiazepines. There is also a decrease in
GABAA receptor effectiveness owing to desensitization and to a chloride shift into neurons, making the opening of chloride channels less effective (26, 27, 58). 6. The potentiation of NMDA synaptic responses, due principally to receptor trafficking, which increases the number of active receptors at the synapse, may play a large role in maintaining SSSE, insofar as the agents most effective in blocking established SSSE are presynaptic blockers of glutamate release or postsynaptic blockers of NMDA receptors. The experimental data suggest that those agents (e.g., ketamine, notwithstanding its effects on intracranial pressure) that are currently available and safe should be evaluated for the treatment of refractory SSSE. Other compounds (e.g., peptide agonists or antagonists) should be evaluated experimentally, and may become the drugs of choice for the future treatment of SE (52). This work was supported by grants Nos. NS043409 (A.M.) and NS 11315 (C.W.) from the National Institute of Neurological Disorders and Stroke, by the Research Service of Veterans Health Administration, and by the James and Debbie Cho Foundation.
REFERENCES 1. Barone, P., M. Morelli, G. Cicarelli, A. Cozzolino, G. DeJoanna, G. Campanella, et al. Expression of c-fos protein in the experimental epilepsy induced by pilocarpine. Synapse 1993;14:1–9.
.: -
225
2. Bausch, S. B., and C. Chavkin. Changes in hippocampal circuitry after pilocarpine-induced seizures as revealed by opioid receptor distribution and activation. J. Neurosci. 1997;17: 477–492. 3. Ben-Ari, Y., and M. Lazdunski. Galanin protects hippocampal neurons from the functional effects of anoxia. Eur. J. Pharmacol. 1989;165:331–332. 4. Bertram, E. H. Functional anatomy of spontaneous seizures in a rat model of limbic epilepsy. Epilepsia 1997;38:95–105. 5. Bonhaus, D. W., L. C. Rigsbee, and J. O. McNamara. Intranigral dynorphin-1-13 suppresses kindled seizures by a naloxone-insensitive mechanism. Brain Res. 1987;405:358–363. 6. Buterbaugh G. G., H. B. Michelson, and D. O. Keyser. Status epilepticus facilitated by pilocarpine in amygdala-kindled rats. Exp. Neurol. 1986;94(1):91–102. 7. Cain, D. P., D. J. McKitrick, and F. Boon. Rapid and reliable induction of partial status epilepticus in naive rats by lowfrequency (3-Hz) stimulation of the amygdala. Epilepsy Res. 1992;12:51–55. 8. de Campos, C. J., and E. A. Cavalheiro. Modification of the “kindling” method for obtaining experimental status epilepticus in rats. Arq. Neuropsiquiatr. 1980;38(1):81–88. 9. Douglass, J., L. Grimes, J. Shook, P. H. Lee, and J. S. Hong. Systemic administration of kainic acid differentially regulates the levels of prodynorphin and proenkephalin mRNA and peptides in the rat hippocampus. Brain Res. Mol. Brain Res. 1991; 9:79–86. 10. Dragunow, M., and R. L. M. Faull. The use of c-fos as a metabolic marker in neuronal pathway tracing. J. Neurosci. Methods 1990;29:261–265. 11. Drake, C. T., G. W. Terman, M. L. Simmons, T. A. Milner, D. D. Kunkel, P. A. Schwartzkroin, and C. Chavkin. Dynorphin opioids present in dentate granule cells may function as retrograde inhibitory neurotransmitters. J. Neurosci. 1994;14:3736–3750. 12. Dudek, F. E., T. Yasumura, and J. E. Rash. “Non-synaptic” mechanisms in seizures and epileptogenesis. Cell Biol. Int. 1998;22(11–12):793–805. 13. Dutar, P., Y. Lamour, and R. A. Nicoll. Galanin blocks the slow cholinergic EPSP in CA1 pyramidal neurons from ventral hippocampus. Eur. J. Pharmacol. 1989;164:355–360. 14. Garant, D. S., and K. Gale. Infusion of opiates into substantia nigra protects against maximal electroshock seizures in rats. J. Pharmacol. Exp. Ther. 1985;234:45–48. 15. Goddard, G. V., D. C. McIntyre, and C. K. Leech. A permanent change in brain function resulting from daily electrical stimulation. Exp. Neurol. 1969;25:295–330. 16. Gorter, J. A., P. M. Goncalves Pereira, E. A. van Vliet, E. Aronica, F. H. Lopes da Silva, and P. J. Lucassen. Neuronal cell death in a rat model for mesial temporal lobe epilepsy is induced by the initial status epilepticus and not by later repeated spontaneous seizures. Epilepsia 2003;44(5):647– 658. 17. Haberman, R. P., R. J. Samulski, and T. J. McCown. Attenuation of seizures and neuronal death by adeno-associated virus vector galanin expression and secretion. Nat. Med. 2003;9(8): 1076–1080. Epub 2003. 18. Handforth, A., and R. F. Ackermann. Hierarchy of seizure states in the electrogenic limbic status epilepticus model: Behavioral and electrographic observations of initial states and temporal progression. Epilepsia 1992;33:589–600. 19. Handforth, A., and R. F. Ackermann. Mapping of limbic seizure progressions utilizing the electrogenic status epilepticus
226
:
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31. 32.
33.
34. 35.
model and the 14C-2-deoxyglucose method. Brain Res. Rev. 1995;20:1–23. Harrison, M. B., M. D. Shumate, and E. W. Lothman. Opioid peptide expression in models of chronic temporal lobe epilepsy. Neuroscience 1995;65:785–795. Heinemann, U., J. P. Beck, J. P. Dreier, E. Ficjer, J. Stabel, and C. L. Zhang. The dentate gyrus as a regulated gate for the propagation of epileptiform activity. In C. E. Ribak, C. M. Gall, and I. Mody, eds. The Dentate Gyrus and Its Role in Seizures. Amsterdam: Elsevier, 1992:273–280. Hong, J. S., L. Grimes, T. Kanamatsu, and J. F. McGinty. Kainic acid as a tool to study the regulation and function of opioid peptides in the hippocampus. Toxicology 1987;46: 141–157. Inoue, K., K. Morimoto, K. Sato, H. Ishizu, K. Kawai, N. Yamada, et al. A model of status epilepticus induced by intermittent electrical stimulation of the deep prepyriform cortex in rats. Jpn. J. Psychiatry Neurol. 1992;46:361–367. Inoue, K., K. Morimoto, K. Sato, N. Yamada, and S. Otsuki. Mechanisms in the development of limbic status epilepticus and hippocampal neuron loss: An experimental study in a model of status epilepticus induced by kindling-like electrical stimulation of the deep prepyriform cortex in rats. Acta Med. Okayama 1992;46:129–139. Kanamatsu, T., J. Obie, L. Grimes, J. F. McGinty, K. Yoshikawa, S. Sabol, et al. Kainic acid alters the metabolism of Met5-enkephalin and the level of dynorphin A in the rat hippocampus. J. Neurosci. 1986;6:3094–3102. 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 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. Lin, E. J., C. Richichi, D. Young, K. Baer, A. Vezzani, and M. J. During. Recombinant AAV-mediated expression of galanin in rat hippocampus suppresses seizure development. Eur. J. Neurosci. 2003;18(7):2087. Liu, H., Y. Cao, A. I. Basbaum, A. M. Mazarati, R. Sankar, and C. G. Wasterlain. Resistance to excitotoxin-induced seizures and neuronal death in mice lacking the preprotachykinin A gene. Proc. Natl. Acad. Sci. U.S.A. 1999;96:12096– 12101. 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. Lothman, E. W., and E. H. Bertram. Epileptogenic effects of status epilepticus. Epilepsia 1993;34(Suppl. 1):S59–S70. 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. 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; 6:110–118. MacDonald, R. L., and K. M. Kelly. Antiepileptic drug mechanisms of action. Epilepsia 1995;36:S2–S12. MacDonald, R. L., and B. S. Meldrum. General principles: Principles of antiepileptic drugs action. In R. H. Levy, R. H.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
Mattson, and B. S. Meldrum, eds. Antiepileptic Drugs. 4th ed. New York: Raven Press, 1995:61–77. 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. Mazarati, A. M., J. G. Hohmann, A. Bacon, H. Liu, R. Sankar, R. A. Steiner, et al. Modulation of hippocampal excitability and seizures by galanin. J. Neurosci. 2000;20:6276–6281. Mazarati, A., H. Liu, U. Soomets, R. Sankar, D. Shin, H. Katsumori, U. Langel, and C. G. Wasterlain. Galanin modulation of seizures and seizure modulation of hippocampal galanin in animal models of status epilepticus. J. Neurosci. 1998;18:10070–10077. Mazarati, A. M., H. Liu, and C. G. Wasterlain. Opioid peptide pharmacology and immunochemistry in an animal model of self-sustaining status epileptocus. Neuroscience 1999;89:167–173. Mazarati, A. M., and C. G. Wasterlain. Loss of hippocampal inhibition and enhanced LTP after self-sustaining status epilepticus. Epilepsia 1997;38(Suppl. 3):178. Mazarati, A. M., and C. G. Wasterlain. NMDA receptors antagonists abolish the maintenance phase of self-sustaining status epilepticus. Neurosci. Lett. 1999;65:187–190. 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;801:251–253. McIntyre, D. C., D. Nathanson, and N. Edson. A new model of partial status epilepticus based on kindling. Brain Res. 1982;250:53–63. McIntyre, D. C., K. A. Stokes, and N. Edson. Status epilepticus following stimulation of a kindled hippocampal focus in intact and commissurotomized rats. Exp. Neurol. 1986;94: 554–570. Milgram, N. W., I. Green, M. Liberman, K. Riexinger, and T. L. Petit. Establishment of status epilepticus by limbic system stimulation in previously unstimulated rats. Exp. Neurol. 1985;88:253–264. 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 lithium-pretreated rats. Exp. Neurol. 1987;97:193–200. Naylor, D. E., H. Liu, and C. G. Wasterlain. Trafficking of GABAA receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. J. Neurosci., in press. Naylor, D. E., and C. G. Wasterlain. GABA synapses and the rapid loss of inhibition to dentate gyrus granule cells after brief perforant path stimulation. Epilepsia, 2005;46(Suppl. 5): 142–147. Naylor, D. E., and C. G. Wasterlain. Status epilepticus has differential effects on phasic and tonic GABAA currents (abstr). Soc. Neurosci. 2002;32:603.2. Nissinen, J., T. Halonen, E. Koivisto, and A. Pitkanen. A new model of chronic temporal lobe epilepsy induced by electrical stimulation of the amygdala in rat. Epilepsy Res. 2000;38(2–3): 177–205. Pereira de Vasconcelos, A. P., A. M. Mazarati, C. G. Wasterlain, and A. Nehlig. Self-sustaining status epilepticus after a brief electrical stimulation of the perforant path: A 2-deoxyglucose study. Brain Res. 1999;838:110–118. Saar, K., A. M. Mazarati, R. Mahlapuu, G. Hallnemo, U. Soomets, K. Kilk, et al. Anticonvulsant activity of a nonpeptide galanin agonist. Proc. Natl. Acad. Sci. U.S.A. 2002;99: 7136–7141.
53. Sakurai, E., T. Maeda, S. Kaneko, A. Akaike, and M. Satoh. Galanin inhibits long-term potentiation at Schaffer collateralCA1 synapses in guinea-pig hippocampal slices. Neurosci. Lett. 1996;212:21–24. 54. Sankar, R., D. H. Shin, H. Liu, A. M. Mazarati, A. de Vasconselos, and C. G. Wasterlain. Patterns of status epilepticus-induced neuronal injury during development and longterm consequences. J. Neurosci. 1998;18:8382–8393. 55. Schwark, W. S., H. H. Frey, and S. J. Czuczwar. Effect of opiates on the parameters of seizures in rats with full amygdaloid-kindled convulsions. Neuropharmacology 1986;25:839– 844. 56. Shirasaka, Y., and C. G. Wasterlain. Chronic epileptogenicity following focal status epilepticus. Brain Res. 1994;655: 33–44. 57. Sloviter, R. S. Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. Science 1987; 235:73–76. 58. 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: 41–46. 59. Staley, K. J., B. L. Soldo, and W. R. Proctor. Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors. Science 1995;269:977–981. 60. Suchomelova, L., R. A. Baldwin, and C. G. Wasterlain. SE in the immature brain is not self-sustaining nor benzodiazepineresistant. Neurology 2003;60:A517–A518. 61. Taber, K. H., J. J. McNamera, and S. F. Zornetzer. Status epilepticus: A new rodent model. Electroencephalogr. Clin. Neurophysiol. 1977;43(5):707–724. 62. Thompson, K., A. M. Holm, A. Schousboe, P. Popper, P. Micevych, and C. G. Wasterlain. Hippocampal stimulation produces neuronal death in the immature brain. Neuroscience 1998;82:337–348. 63. Treiman, D. M., N. Y. Walton, C. Wielboldt, and C. M. DeGiorgio. Predictable sequence of EEG changes during generalized convulsive status epilepticus in man and three experimental models of status epilepticus in rat. Neurology 1987; 37:244–255. 64. Trousseau, A. Lectures on Clinical Medicine Delivered at the Hotel Dieu, Paris. Vol. 1 (P. V. Bazire, trans.). London: New Sydenham Society, 1868. 65. Turski, W. A., E. A. Cavalheiro, M. Schwarz, S. J. Czuczwar, Z. Kleinrok, and L. Turski. Limbic seizures produced by pilocarpine in rats: Behavioural, electroencephalographic and neuropathological study. Behav. Brain. Res. 1983;9:315– 335. 66. Van Vliet, E. A., E. Aronica, E. A. Tolner, F. H. Lopes da Silva, and J. A. Gorter. Progression of temporal lobe epilepsy in the rat is associated with immunocytochemical changes in inhibitory interneurons in specific regions of the hippocampal formation. Exp. Neurol. 2004;187(2):367–379. 67. VanLandingham, K. E., and E. W. Lothman. Self-sustaining status limbic status epilepticus. I. Acute and chronic cerebral metabolic studies: Limbic hypermetabolism and neocortical hypometabolism. Neurology 1991;41:1942–1956. 68. 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. 69. Vicedomini, J. P., and J. V. Nadler. Stimulation-induced status epilepticus: Role of the hippocampal mossy fibers in the
.: -
227
70.
71. 72. 73.
74.
75.
seizures and associated neuropathology. Brain Res. 1990;512: 70–74. Walton, N. Y., and D. M. Treiman. Rational polytherapy in the treatment of status epilepticus. In I. E. Leppik, ed. Rational Polypharmacy. Amsterdam: Elsevier, 1996:123–139. Wasterlain, C. G. Breakdown in brain polysomes in status epilepticus. Brain Res. 1972;39:278–284. Wasterlain, C. G. Mortality and morbidity from serial seizures: An experimental study. Epilepsia 1974;15:155–176. Wasterlain, C. G., J. M. Bronstein, A. M. Morin, B. E. Dwyer, and R. Sankar. Translocation and autophosphorylation of brain calmodulin kinase II in status epilepticus. Epilepsy Res. 1992;Suppl. 9:231–238. Wasterlain, C. G., A. M. Mazarati, D. Naylor, J. Niquet, H. Liu, L. Suchomelova, et al. Short-term plasticity of hippocampal neuropeptides and neuronal circuitry in experimental status epilepticus. Epilepsia 2002;43(Suppl. 5):20–29. Zini, S., M. Roisin, U. Langel, T. Bartfai, and Y. Ben-Ari. Galanin reduces release of endogenous excitatory amino acids in the rat hippocampus. Eur. J. Pharmacol. 1993;245:1–7.
228
:
18
Pathophysiology of Seizure Circuitry in Status Epilepticus
. , , . T types of status epilepticus as there are types of seizures described in the international classification of epileptic seizures. —Henri Gastaut, 1983
As Henri Gastaut pointed out in 1983, there appear to be as many forms of status epilepticus (SE) as there are forms of epileptic seizures (13). Although this point went unrecognized for many years—most neurologists and scientists considered significant only the severe form of convulsive generalized SE—it is now recognized that many other forms of SE should be considered neurologically dangerous and treated aggressively (9, 22, 23, 39, 47). Because of the high morbidity and mortality associated with generalized convulsive SE, a good deal has been learned about this condition, including the progression of its encephalographic presentation (11, 27, 46, 48) and the distribution of brain damage that ensues in adults when the attacks are prolonged (4, 5, 41). There are now several animal models that mimic both the electrographic presentation and the pathologic aspects of generalized SE (2, 24, 48, 49). On the other hand, the many forms of SE with milder presentation, such as complex partial SE, are far less well studied, despite the serious morbidity and mortality they produce (9, 21, 22, 40, 44, 45). This chapter describes a number of distinct forms of SE in the rat that develop in an unpredictable fashion from a single induction procedure. These isoforms of SE vary from severe convulsive secondarily generalized SE to mild nonconvulsive partial SE, and all are derived initially from focal origin. In the description of these isoforms, we briefly summarize their electrographic and [14C]2-deoxyglucose (2-DG) correlates, the neuroanatomic site for most reliable initiation, and the time course in development of brain damage that each engenders. The point of the last part of the description is to draw attention to those areas of the forebrain damaged in SE that are also proving to be significant in the development of kindled convulsive seizures and that, by analogy, might prove to be important in the development of temporal lobe epilepsy.
The basic model The model of SE that we describe was based first on the antecedent development of a kindled site in each rat. We originally defined kindling as the progressive and permanent increase in triggered afterdischarge activity and associated behavioral correlates that resulted from discrete, daily electrical stimulation of certain forebrain sites, particularly limbic sites (15). In the majority of kindling studies, most researchers develop their triggered kindled seizures to the level of stage 5, rearing-and-falling convulsive responses (38), and with protracted kindling, spontaneous seizures also begin to appear (31, 37). A decade or so after presenting the initial kindling studies, we reported that protracted, low-intensity electrical stimulation of a kindled focus would trigger SE in many of the kindled rats, but in only a few of the nonkindled controls (30). The development of SE usually occurred only in rats that expressed numerous (more than six) stage 5 seizures during the 60-minute stimulation procedure. During that same stimulation period, some rats did not develop SE and became relatively refractory to the stimulation, both behaviorally and electrographically. SE did develop in most rats, but it presented in a variety of isoforms. In an individual rat, one isoform ultimately and invariably predominated. In the model we describe here, rats underwent amygdala kindling to six stage 5 seizures, followed by 3 weeks of rest. To induce SE, they were subsequently reexposed to the kindling stimulus but in a near-continous form for 60 minutes.
Varieties of SE: Behavior, EEG, and 2-DG correlates I SE The mildest presentation, involving only lowfrequency electrographic SE, was behaviorally nonconvulsive. The rat was usually inactive during the SE but could engage in activities that appeared environmentally appropriate and normal. Like Handforth and Ackermann (16), who develop SE in nonkindled rats using high-intensity square stimulation of the amygdala, we have called this isoform of SE immobile SE (27), whereas White and Price (51), who induced SE by electrical stimulation in one of a variety of limbic sites, have called it type I SE.
, , :
229
The electroencephalogram (EEG) during the first 1–2 hours of immobile SE showed low-frequency spiking, of 0.5 Hz or less, and predominantly unilateral. This lowfrequency spiking pattern slowly waned over a period of 24–48 hours; the baseline EEG amplitude decreased for a few additional days before recovering. To determine which brain regions were hypermetabolic during SE, the radioactive compound 2-DG was injected 1, 5, or 10 hours after the onset of SE, and the rats were killed 45 minutes later. Sectioning the brains of these rats and exposing the sections to X-ray film indicated a consistent pattern of metabolic activity concentrated in the ipsilateral medial amygdalohippocampal area and the adjacent dorsal portion of the posterior cortical nucleus. This pattern of 2DG accumulation was nearly identical to that reported by Handforth and Ackermann (16) and by White and Price (51), who developed SE by more intense focal electrical stimulation in nonkindled rats. A SE A behaviorally more severe form of SE was typified by continuous front-to-back or side-to-side rocking movements of the torso while the animal shuffled about the chamber, with slight drooling. We have called this ambulatory SE (27); Handforth and Ackermann (16) have called it exploratory SE and White and Price (51), type II SE. The behavioral stereotypies exhibited in this state have no homologue with the traditional kindling stages and might be a consequence of sustained, unilateral activity in limbic structures (ipsilateral to the triggering stimulus). This unilateral activation can be seen in the 2-DG results described below, even though the electrographic discharge activity was clearly bilateral. Such observations suggest that electrographic recordings provide a more sensitive index of low-intensity seizure activity than 2-DG records (27). The bilaterally symmetric EEG seizure discharge displayed a frequency of 1.0 Hz in both amygdalae during the first few hours and decreased in amplitude over time in the kindled hemisphere compared with the contralateral hemisphere. Ultimately, the EEG activity in the ipsilateral amygdala became isoelectric (which is consistent with the brain damage reported later in the discussion). Conversely, the metabolic activity, reflected by 2-DG accumulation at 1–2 hours of ambulatory SE, was predominantly unilateral. It was found within the basolateral and central amygdala nuclei, the endopiriform nucleus, and the deep perirhinal and entorhinal cortices ipsilateral to the kindled amygdala (Figure 18.1). In thalamic areas, the dorsomedial and reuniens nuclei showed high metabolic activity ipsilateral to the kindled amygdala (see 27 for details). After 5 hours of ambulatory SE, the metabolic activity became much more bilaterally symmetric in the structures mentioned, while the EEG discharges paradoxically became
230
:
F 18.1 Computer enhancement of a [14C]-2-DG radiograph taken from a rat during ambulatory SE. High metabolic activity was stricted to the basolateral and central nuclei of the amygdala (adjacent to the tip of the kindling electrode), the ipsilateral deep piriform and perirhinal cortices, and the endopiriform nucleus. High metabolic activity was also observed in the dorsal medial thalamus and reuniens nuclei, and in the ipsilateral hypothalamus. In the contralateral hemisphere, only the basolateral amygdala nucleus was strongly hypermetabolic. This section is similar to Swanson’s (42) section 29.
more lateralized, presumably with the loss of cells in many of the ipsilateral limbic structures. By 10 hours the 2-DG index of activity had weakened substantially and had become more localized to the ipsilateral amygdalohippocampal area and the posterior cortical and medial amygdala nuclei. Interestingly, this is the same neuroanatomic area that showed 2-DG activity in the milder isoform of immobile SE. In addition, the final behavioral profile of the 10-hour ambulatory SE rats was consistent with this new restricted metabolic pattern, that is, quiet immobility. Again, similar patterns of activity were seen by Handforth and Ackermann (16) and by White and Price (51). M SE Some animals displayed a behavioral outcome more severe than ambulatory SE. This form of SE was mildly convulsive and involved little ambulation but extensive drooling, head bobbing, and continuous stage 2 (38) mastication. We (27) and others (16, 51) have called this form masticatory SE. The seizure discharge in this form was bilaterally symmetric at about 4–5 Hz, with bursts of discharges at 5–8 Hz and brief periods of stage 3 forelimb clonus. The 2-DG results from these rats after 1 hour of SE indicated a more widespread pattern of metabolic activity than that seen with the ambulatory SE rats. It was now bilateral and included the hippocampus, but was otherwise congruent with the pattern shown in Figure 18.1. After 5 hours of masticatory SE, both EEG and 2-DG activity were reduced bilaterally, again, presumably because of the progressive
bilateral loss of neurons in the amygdala/piriform cortex recording area. G SE Our most severe isoform of SE (27), as in many other generalized models (e.g., 17), was strongly convulsive. In these cases the rats presented behaviorally with near-continuous clonic forelimb responses that alternated between milder stage 3 and stronger stage 5 convulsions. The EEG correlates of this isoform of SE were high-amplitude and high-frequency spiking at about 5–10 Hz, which diminished in amplitude but not in frequency by the 1-hour interval. The 2-DG index of hyperactivity associated with this condition at 1 hour included a marked increase (compared with the other forms of SE) in most neocortical structures, particularly in the frontal cortex, as well as in the striatum and thalamus; yet in concert with this increased activity there was decreased activity in the septum, diagonal band, globus pallidus, and subthalamic nuclei. This form of SE was extremely life-threatening and, when untreated, could result in the death of the rat within 3–5 hours. A few rats whose seizures were slightly less severe than others’ in this group survived beyond this time window and were assessed for brain damage in later time periods.
F 18.2 Kindling rate (measured by the number of stimulations to the first stage 5 convulsion) of the perirhinal (Prh) and piriform (Pir) cortices, compared with the central (Ce), basolateral (BL), and medial (Med) amygdala nuclei. *P < 0.05 versus the BL and Med groups.
SE initiation site Based on our 2-DG results (27) and those of others (16, 51), several neuroanatomic sites become hyperactive early in most isoforms of SE. In the ambulatory SE model, the active structures are the basolateral and central amygdala, the laterally adjacent deep piriform/endopiriform cortices, and the dorsally adjacent perirhinal cortex (Figure 18.1). Because these same neuroanatomic sites all show relatively rapid kindling characteristics (28) but important differences in convulsion latencies, we assessed their individual abilities to trigger SE following previous kindling (34). In this neuroanatomic assessment, we included the relatively slowly kindling medial nucleus of the amygdala for comparison. The procedure used in this experiment involved, first, kindling one of these five neuroanatomic sites. Three weeks later, SE induction was attempted using the stimulation protocol previously described (30). Electrical stimulation was applied to the kindled site for 60 minutes at the threshold intensity for triggering an AD. By using very low intensity stimulation, we believed that we could minimally activate the epileptic network and discriminate between the five structures in their “ease” of provoking SE. As expected from previous results (28, 34), the fastest kindling structures were the perirhinal and piriform cortices and the central amygdala. Significantly slower were the basolateral and medial amygdalae (Figure 18.2). Important differences between structures were apparent in the latencies
F 18.3 Average latency from stimulus onset to forelimb clonus onset during the six stage 5 convulsions triggered from the five different neuroanatomic groups. Abbreviations are as in Figure 18.2. *P < 0.001 compared with the Pir, BL, and Med groups; **P < 0.05 compared with the Ce group.
from stimulus onset to the initiation of forelimb clonus during the stage 5 seizures; the perirhinal cortex and central amygdala showed a uniquely facile access to the motor systems controlling clonic convulsions (Figure 18.3). Surprisingly, the ease of SE induction for each of these five structures (measured by the probability of SE developing during the protracted stimulation procedure) did not parallel the kindling results. Instead, the basolateral amygdala nucleus was clearly the site from which SE was most easily triggered, promoting SE in 100% of the rats, while the piriform cortex was notably dormant, promoting SE in 0% of the rats (Figure 18.4). Thus, one of the fastest kindling
, , :
231
regions recruited during SE, as revealed by 2-DG autoradiography. As a consequence, one might expect each isoform to be associated with a characteristic pattern of hyperactivity-induced brain damage and each, perhaps, with a unique time course. In the next experiment, we examined the brains of rats at several time periods (3, 6, 24, and 72 hours) after the induction of different forms of SE, triggered from a kindled amygdala. In this analysis, damaged cells were identified using the silver impregnation, argyrophilic technique of Nadler and Evenson (35), which was a modification of the procedure used by Gallyas et al. (12). The extensive damage to thalamic and hypothalmic structures that is associated with ambulatory, masticatory, and generalized SE is not described here. F 18.4 Percentage of rats in each kindled group developing one of the four isoforms of SE during protracted, low-intensity electrical stimulation of the kindled site. Abbreviations are as in Figure 18.2. *P < 0.05 compared with the Prh and Pir groups.
sites did not promote SE and one of the slowest kindling sites promoted maximal SE development. Furthermore, the isoforms of SE induced by the stimulation bore no relationship to the anatomic structure that had been kindled. For example, three of the four isoforms of SE were seen in rats receiving basolateral nucleus stimulation (34). Facile induction of SE following basolateral amygdala nucleus kindling is consistent with the results of White and Price (52), who showed that SE induced in nonkindled rats by protracted, relatively high-intensity electrical stimulation of several different limbic structures could be terminated by lidocaine cannulated into the basolateral amygdala, but not the anterior piriform cortex, amygdalohippocampal area, or ventral hippocampus. These data, and our own, point to a special importance of the basolateral amygdala in SE. In this same experiment (52), the ventral hippocampal injection of lidocaine deactivated the ventral hippocampus and subiculum, encroaching on the adjacent deep entorhinal and perirhinal cortices. As a result, the behavioral presentation changed in form from an ongoing convulsive masticatory SE with forelimb clonus (type III) into nonconvulsive ambulatory SE (type II). This outcome fits well with our previous kindling and anatomic observations (28, 29, 34) that indicate that the perirhinal cortex is an important anatomic substrate for clonic convulsive movements during intense limbic seizures. We return to this point later in the chapter.
Time course of brain damage following SE Although the neuroanatomic site of initiation influences the propensity to trigger SE, it does not predict which behavioral and electrographic isoform of SE will be expressed. This is, however, well predicted by the pattern of brain
232
:
I SE At 24 hours, 72 hours, or 5 days after the onset of mild, nonconvulsive immobile SE, argyrophilic cells were observed in a limited area in the hemisphere ipsilateral to the kindled amygdala. This area included layer 3 (42) of the lateral portion of the posterior cortical amygdala nucleus, subjacent to the amygdalohippocampal area (AHA), and a few cells in the posterior accessory basal amygdala nucleus (Figure 18.5C). These damaged cells were observed in part of the hyperactive area seen in our 2-DG experiments, however, intense 2-DG accumulation within the dorsal and medial aspects of the AHA was not correlated with argyrophilic cell damage. The dorsal and medial portions of the AHA have been shown by fos immunoreactivity and 2-DG uptake to be the most active areas during SE induced in nonkindled rats (51). This comparative result suggests that the most active neurons (assessed by fos and 2-DG) do not necessarily die during SE, although in many cases the areas of strongest 2-DG accumulation are those that also show the greatest brain damage. A SE Within 3 hours of the onset of ambulatory SE, much of the full pattern of neuronal damage (defined by an argyrophilic response) was already apparent. At the level of the stimulation site, the ambulatory pattern was similar to the immobile SE pattern but was far more extensive. Damage additional to that seen in immobile SE involved many cells in the ventral subiculum and the laterally adjacent layers 5/6 of the entorhinal and perirhinal/ insular cortices. In the perirhinal cortex, the damage was located more specifically in layers 6B, 5A, and parts of layer 3 (Figure 18.6). This pattern of cortical damage extended anteriorly throughout the entire perirhinal cortex, throughout the agranular insular cortex, and into the orbital cortex. Ventral to the perirhinal cortex, considerable early damage was evident throughout the entire anteroposterior extent of deep layer 3 in the piriform cortex and lateral entorhinal cortex, as well as much of the adjacent endopiriform nucleus.
F 18.5 Summary schematic diagram of the areas showing a strong argyrophilic response 24 hours after the onset of immobile (I-SE), ambulatory (A-SE), or generalized (G-SE) SE. The uni-
lateral argyrophilic responses associated with immobile and ambulatory SE are indicated in the right hemisphere; the bilateral deposition in generalized SE is indicated in the left hemisphere.
Argyrophilic damage at 3 hours was also observed in the amygdala. This damage involved the lateral nucleus, the parvocellular but not magnocellular parts of the basal nucleus, the accessory basal nucleus, and scattered cells in the medial and intercalated amygdala nuclei. The central and anterior cortical nuclei were little affected. This pattern of amygdala damage was very similar to that described recently by others (49, 50) after SE induced by systemic injection of kainic acid. The most anterior cortical damage was evident in layers 6B and 5A in the prelimbic cortex. It was continuous ventrally through the infralimbic cortex into layer 3 of taenea tecta. At this early period, there was no obvious damage in the hippocampus or dentate gyrus. These patterns of neuronal damage continued to evolve over time (6 and 24 hours), as witnessed by increasing numbers of argyrophilic cells in these same areas (see Figure 18.5). However, by 24 hours, a clear qualitative difference in the brain damage became apparent. In the piriform cortex, the argyrophilia in layer 3 expanded considerably to include
all of layer 2B, while in the medial entorhinal cortex, the damage now included nearly all of layer 3 (see Figures 18.5B–D). This latter finding is consistent with the observations of Du et al. (7, 8), both in their rat models of SE and in their tissue surgically excised from patients with temporal lobe epilepsy. Also, in some of our rats at 24 hours, argyrophilic cells were now often seen bilaterally in the hippocampal CA1–3 fields, and in a few cells in the posterior dentate gyrus granule cell field. By 72 hours, in about half of the ambulatory SE rats, a strong argyrophilic response was observed bilaterally in the dorsal CA1 hippocampal field. Beyond this bilateral damage to the hippocampal formation and some limited bilateral damage in the deep layers of the posterior perirhinal and entorhinal cortices, all of the other argyrophilic cells observed in the ambulatory SE model were unilateral and ipsilateral to the kindled triggering site. M SE The pattern and time course of damage in masticatory SE were much the same as for ambulatory SE,
, , :
233
F 18.6 (A) Photomicrograph montage of a cresyl violet–stained section of the anterior perirhinal cortex and its laminae. (B) Schematic representation of the average argyrophilic response (shaded areas) in the perirhinal sublaminae following 3
hours of ambulatory SE. The section in A and B is similar to plate 27 in Swanson (42). Abbreviations: Prh, perirhinal cortex; Par2, parietal cortex, area 2; Pir, piriform cortex; DEn, dorsal endopiriform nucleus; ec, external capsule.
except for being bilateral in all structures. Although this bilateral damage pattern is consistent with the increase in severity of electrographic indices, 2-DG measurements of hyperactivity, and behavioral seizure manifestations compared with the milder ambulatory SE, there is a paradox, which is simply that the extent of the hippocampal damage seen in rats following masticatory (more intense) SE was always less than in ambulatory (milder) SE. Previously, we observed (19) a similar correlation between SE form (ambulatory vs. masticatory SE) and hippocampal brain damage in nonkindled rats during SE induced by systemic injection of kainic acid. In the latter cases where masticatory SE developed, relatively little hippocampal damage was recorded several weeks later, compared with the extensive hippocampal damage seen at that time following either ambulatory or generalized SE. Therefore, different patterns of brain damage following SE appeared to be related either to different mechanisms or to the involvement of different neuronal circuits associated with the different forms of SE, but not to the means (electrical vs. chemical) of SE induction.
rophilic response in the neocortex. The latter was represented as moderate damage to layer 5A cells in the medial frontal cortex and extensive damage to layer 3 cells in the posterior parietal, temporal, and perirhinal cortices. By 24 hours, new and substantial damage was evident throughout layer 4 of the entire parietal cortex, extending posterodorsally into the visual cortex. Medially there was damage in layer 5A of the retrosplenial cingulate cortex. At this time, nearly all CA1 neurons in the entire hippocampus were argyrophilic (see Figure 18.5). Finally, by 72 hours, the globus pallidus exhibited extensive silver impregnation. The patterns of damage described in our severe generalized SE model are very similar to those reported by Meldrum (32) in adolescent baboons intravenously infused with bicuculline, and in other rat models using either focal intra-amygdala kainic acid injections (1), systemic injections of pilocarpine or kainic acid (2, 6, 11, 17, 18, 50), or high-intensity stimulation of the lateral nucleus of the amygdala (36).
G C SE This severe form of SE was associated with all of the same patterns of brain damage that were seen in the milder forms, but with several substantial additions. These additions, at 3 hours, included complete cell loss (i.e., extensive argyrophilia) in the substantia nigra reticulata, similar degenerative changes within a few cells in the hippocampal CA1 field and posterior dorsal dentate gyrus granule cell field, and a much broader argy-
234
:
S V T S Following spontaneous offset of protracted SE (ambulatory, masticatory, or generalized forms) and the development of associated brain damage, a great deal of reorganization in the nervous system is evident. This reorganization has been most thoroughly documented within the hippocampus, where the mossy fibers of the dentate granule cells develop collateral axons, many of which enter the inner molecular layer of the dentate gyrus and bifurcate recursively to form a dense plexus that can be visualized using the Timm stain for zinc.
Thus, sprouting in the dentate gyrus, both in rats and in humans, leads to large numbers of mossy fiber terminals appearing in an area of the dentate gyrus that was previously only weakly innervated by them. Because zinc in the brain is reported to colocalize with glutamate, such innervation patterns are thought to represent an approximate presynaptic distribution of the excitatory transmitter glutamate. It has been suggested that sprouting of glutamate terminals in the dentate gyrus provides the granule cells with an enhanced epileptic potential (24–26, 43, 53). Although this is possibly true, many other structures also exhibit glutamatergic terminal sprouting (measured by the Timm stain) as a consequence of SE. If such sprouting occurs in areas of the brain that have been shown previously to be very important for seizure genesis or convulsive expression, they should be identified. From data presented earlier, we identified the perirhinal cortex as the fastest kindling structure known in the forebrain, kindling at a rate about 10 times faster than the hippocampus. Also, the convulsive seizures triggered from the perirhinal cortex exhibited latencies to clonic movements that were nearly immediate, which suggested an intimate connection between it and the requisite motor structures (28, 34). In addition to these results, we have observed (20) that if the perirhinal/insular cortex is destroyed, along with the piriform cortex, convulsive kindling from the dorsal hippocampus as a secondary or transfer site is largely preempted, whereas a similar loss of the posterior perirhinal cortex alone (3) and/or the entire piriform cortex (20) has no such impact. These results suggest that the hippocampus may develop its convulsive seizure expression by recruiting the combined output to the forebrain motor systems of the perirhinal/insular and piriform cortices. The damage to the perirhinal/insular and entorhinal cortices following SE was somewhat variable between animals, but it always included layers 6B, 5A, and much of 3. Many of the surviving cells in those structures, particular in layer 5B, appear to be cells that project to the frontal motor cortex (29). With this in mind, we suspect that such surviving cells in the perirhinal/insular (and entorhinal) cortex might become hyperexcitable after SE-induced neuronal reorganization. As such, they could facilitate or cause the spontaneous motor convulsions that develop in the days or weeks following SE. If, however, SE destroyed all of the perirhinal/insular cortex in a given animal, spontaneous convulsive seizures might not subsequently develop at all. We have observed this outcome recently in two rats in the pilocarpine model of SE; by contrast, 10 other rats in the same treatment group sustained minimal damage to the perirhinal cortex, and they all exhibited spontaneous convulsive seizures within 2 weeks of pilocarpine SE (D. C. McIntyre and M. E. Kelly, unpublished observations).
What effect does SE-based damage have on the excitability of the perirhinal or entorhinal cortex? These questions have not yet been examined. However, we do know that the normally high thresholds for triggering local seizures in the perirhinal cortex dramatically decrease following perirhinal kindling (10). As such, one might predict a similar outcome following SE. This outcome has been reported in the amygdala following SE (41). Like the perirhinal cortex, the amygdala also kindles quite rapidly, and is well connected anatomically to provide wide recruitment of seizure activity and to generate significant behavioral disturbances. In fact, Gloor (14) has argued that the amygdala is critically important in human temporal lobe epilepsy because the amygdala, or the adjacent neocortices, generate most of the auras in the patients, and because amygdalectomies provide relief from intractable temporal lobe epilepsy equal to hippocampectomies; it should be noted, however, that both resection procedures also remove significant parts of the perirhinal and entorhinal cortices. With these various facts in mind, we report a reorganization of the perirhinal/insular cortex following SE—that is, a well-defined cell loss and a considerable sprouting in the surviving laminae—as evinced by an increase in Timm staining. This increase is particularly easily recognized in the ambulatory SE model, where damage to the perirhinal/ insular cortex occurs only on one side of the brain, while the other side serves as an internal control. In Figure 18.7, the perirhinal area on the SE-damaged side of the brain has reduced volume (with the loss of many cells in layers 6B, 5A, and 3) but an increased density of staining compared with the intact, contralateral perirhinal cortex. In all masticatory and generalized SE rats, these anatomic changes in the perirhinal cortex are bilateral. If such anatomic changes translate electrophysiologically into hyperexcitability, then this likely impacts strongly on convulsive seizure expression. Indeed, recently Mello et al. (33) observed that, following exposure to pilocarpine SE and the subsequent development of spontaneous convulsive seizures, c-fos expression 1 hour after a spontaneous convulsive seizure was evident only in the perirhinal and piriform cortices (“and to a very small tip of the [adjacent] ventral dentate gyrus”), but not in the sprouted hippocampus or any other location. This result strongly suggests that the level of depolarization that is necessary to activated the immediate early gene, c-fos, during spontaneous convulsive seizures, is being expressed in only a very limited part of the brain, particularly the surviving portions of the perirhinal and piriform cortices. Presumably other structures are also involved in the seizure expression, but their activity might occur via currents in other channels, such as AMPA channels, rather than NMDA channels. Regardless of the mechanism, the perirhinal cortex has distinguished itself in a model of SE (pilocarpine) that produces
, , :
235
F 18.7 (A and B) Photomicrographs of Timm staining in both perirhinal cortices of a rat 2 months after the offset of ambulatory SE that was triggered from a kindled focus in the right amygdala (B). The left perirhinal and piriform cortices (A) are intact and show normal staining, while the right piriform cortex has com-
pletely degenerated and the associated perirhinal cortex has compressed. With the loss of specific sublaminae in the right dorsal perirhinal (area 36) and parietal cortices, the increased Timm staining in the surviving tissue is readily observable.
the most rapid expression of spontaneous convulsive seizures.
SE results, all forms of SE should be considered a medical emergency. Because each form of SE was characterized by a specific pattern of brain damage, damage to the hippocampus was not the earliest or most severe pattern of damage in all of the milder forms of SE. Indeed, certain cellular laminae in many of the structures in the parahippocampal gyrus, including the perirhinal, insular, piriform, entorhinal, and prelimbic cortices, were early casualties in SE. This is an important observation, because many of these same structures rapidly relay seizure activity to other brain sites in animal models, and therefore their reorganization after strong activation or damage may prove to be central in the development of the clinical symptoms in human temporal lob epilepsy.
Summary Many isoforms of SE can be produced and studied experimentally, ranging in severity from mild partial nonconvulsive SE to strong generalized convulsive SE. We were able to develop all of these isoforms from a single neuroanatomic induction site. Although the several forms of SE described here appear to be behaviorally discontinuous, their electrographic, metabolic, and neuropathologic representations seem to be continuous. Each progressively stronger form represents a significant quantitive or qualitative (or both) increase over the milder form on each of these three measures. With this in mind, we have emphasized the progressive increase in brain damage that accrued during or following SE. The pattern and the extent of damage associated with generalized convulsive SE were expected. However, an unexpected observation was that in the mildest form of SE, a specific, if limited, pattern of brain damage also developed. If this latter observation relates as well to the human condition as do the generalized
236
:
REFERENCES 1. 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. 2. Ben-Ari, Y., E. Tremblay, D. Riche, G. Ghilini, and R. Naquet. Electrographic, clinical and pathological alterations following
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
systemic administration of kainic acid, bicuculline or penetetrazole: Metabolic mapping using the deoxyglucose method and special reference to the pathology of epilepsy. Neuroscience 1981;6:1361–1391. Bureau, Y. Perirhinal or postrhinal cortex lesions: Effects on spatial versus fear learning and kindling. Ph.D. diss., Carleton University, Ottawa, Ontario, 2001. Celesia, G. G. Prognosis in convulsive 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;34:55–59. Corsellis, J. A. N., and C. J. Bruton. Neuropathology of status epilepticus in humans. 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;34:129–139. Covolan, L., and L. E. Mello. Temporal profile of neuronal injury following pilocarpine or kainic acid-induced status epilepticus. Epilepsy Res. 2000:133–152. Du, F., T. Eid, E. W. Lothman, C. Kohler, and R. Schwarcz. Preferential neuronal loss in layer III of the medial entorhinal cortex in rat models of temporal lobe epilepsy. J. Neurosci. 1995;15:6301–6313. Du, F., W. O. Whetsell, Jr., B. Abou-Khalil, B. Blumenkopf, E. W. Lothman, and R. Schwarcz. Preferential neuronal loss in layer III of the entorhinal cortex in patients with temporal lobe epilepsy. Epilepsy Res. 1993;16:223–233. Engel, J., Jr., B. Ludwig, and M. Fetell. Prolonged partial complex status epilepticus: EEG and behavioral observations. Neurology 1978;28:863–869. Felstead, L. L., M. E. Kelly, and D. C. McIntyre. Laminar and topographical analysis of perirhinal cortex kindling in the rat. Soc. Neurosci. Abstr. 1995;25:1971. Fujikawa, D. G. The temporal evolution of neuronal damage from pilocarpine-induced status epilepticus. Brain Res. 1996; 725:11–22. Gallyas, F., J. R. Wolff, H. Bottcher, and L. Zaborsky. A reliable and sensitive method to localize terminal degeneration and lysosomes in the central nervous system. Stain Technol. 1980;55:299–306. Gastaut, H. Classification of 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;34:15–35. Gloor, P. Role of the amygdala in temporal lobe epilepsy. In J. P. Aggleton, ed. The Amygdala: Neurobiological Aspects of Emotion, Memory and Mental Dysfunction. New York: Wiley-Liss, 1992: 505–538. Goddard, G. V., D. C. McIntyre, and C. K. Leech. A permanent change in brain function resulting from daily electrical stimulation. Exp. Neurol. 1969;25:295–330. Handforth, A., and R. F. Ackermann. Functional [14C]2deoxyglucose mapping of progressive states of status epilepticus induced by amygdala stimulation in the rat. Brain Res. 1988;460:94–102. Handforth, A., and D. M. Treiman. Functional mapping of the early stages of status epilepticus: A 14C-2-deoxyglucose study in the lithium-pilocarpine model in rat. Neuroscience 1995;64: 1057–1073. Hopkins, K. J., G. Wang, and L. C. Schmued. Temporal progression of kainic acid induced neuronal and myelin degeneration in the rat forebrain. Brain Res. 2000;864: 69–80.
19. Kelly, M. E., and D. C. McIntyre. Hippocampal kindling protects several structures from the neuronal damage resulting from kainic acid-induced status epilepticus. Brain Res. 1994; 634:245–256. 20. Kelly, M. E., W. A. Staines, and D. C. McIntyre. Secondary generalization of hippocampal kindled seizures in rats: Examining the role of the piriform cortex. Brain Res. 2002;957: 152–161. 21. Knopman, D., G. Margolis, and A. Reeves. Prolonged focal epilepsy and hypoxemia as a case of focal brain damage: A case study. Ann. Neurol. 1977;1:195–198. 22. 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. 23. Leifer, D., D. G. Cole, and N. W. Kowall. Neuropathologic asymmetries in the brain of a patient with a unilateral status epilepticus. J. Neurol. Sci. 1991;103:127–135. 24. 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. 25. Masukawa, L. M., W. M. O’Connor, and J. Lynott, et al. Longitudinal variation in cell density and mossy fiber reorganization in the dentate gyrus from temporal lobe epileptic patients. Brain Res. 1995;678:65–75. 26. Mathern, G. W., T. L. Babb, P. S. Mischel, et al. Childhood generalized and mesial temporal epilepsies demonstrate different amounts and patterns of hippocampal neuron loss and mossy fibre synaptic reorganization. Brain 1996;119: 965–987. 27. McIntyre, D. C., J. C. Don, and N. Edson. Distribution of [14C]2-deoxyglucose after various forms and durations of status epilepticus induced by stimulation of a kindled amygdala focus in rats. Epilepsy Res. 1991;10:119–133. 28. McIntyre, D. C., M. E. Kelly, and J. N. Armstrong. Kindling in the perirhinal cortex. Brain Res. 1993;615:1–6. 29. McIntyre, D. C., M. E. Kelly, and W. A. Staines. Efferent projections of the anterior perirhinal cortex of the rat. J. Comp. Neurol. 1996;369:302–318. 30. McIntyre, D. C., D. Nathanson, and N. Edson. A new model of partial status epilepticus based on kindling. Brain Res. 1982;250:53–63. 31. McIntyre, D. C., M. O. Poulter, and K. Gilby. Kindling: Some old and some new. Epilepsy Res. 2002;50:79–92. 32. Meldrum, B. S. Metabolic factors during prolonged seizures and their relation to nerve cell damage. 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. 33. Mello, L. E. A. M., C. M. Kohman, A. M. Tan, E. A. Cavalheiro, and D. M. Finch. Lack of Fos-like immunoreactivity after spontaneous seizures or reinduction of status epilepticus by pilocarpine in rats. Neurosci. Lett. 1996;208: 133–137. 34. Mohapel, P., C. Dufresne, M. E. Kelly, and D. C. McIntyre. Differential sensitivity of various temporal lobe structures in the rat to kindling and status epilepticus induction. Epilespy Res. 1996;23:179–187. 35. Nadler, J. V., and D. A. Evenson. Use of excitatory amino acids to make axon-sparing lesions of hypothalamus. Methods Enzymol. 1983;103:393–400.
, , :
237
36. Nissinen, J., T. Halonen, E. Koivisto, and A. Pitkanen. A new model of chronic temporal lobe epilepsy induced by electrical stimulation of the amygdala in rat. Epilepsy Res. 2000; 38(2–3):177–205. 37. Pinel, J. P. J., R. F. Mucha, and A. G. Phillips. Spontaneous seizures generated in rats by kindling: A preliminary report. Physiol. Psychol. 1975;3:127–129. 38. Racine, R. J. Modification of seizure activity by electrical stimulation: Motor seizure. Electroencephalogr. Clin. Neurophysiol. 1972;32:281–294. 39. Scholtes, F. B., W. O. Renier, and H. Meinardi. Generalized convulsive status epilepticus: Pathophysiology and treatment. Pharmacy World Sci. 1993;15:17–28. 40. Scholtes, F. B., W. O. Renier, and H. Meinardi. Simple partial status epilepticus: Causes, treatment, and outcome in 47 patients. J. Neurol. Neurosurg. Psychiatry 1996;61:90–92. 41. Smith, B. N., and F. E. Dudek. Enhanced population responses in the basolateral amygdala of kainate-treated rats in vitro. Neurosci. Lett. 1997;222:1–4. 42. Swanson, L. W. Brain maps: Structure of the Rat Brain. Amsterdam: Elsevier, 1992. 43. Tauck, D. L., and J. V. Nadler. Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acidtreated rats. J. Neurosci. 1985;5:1016–1022. 44. Tomson, T., E. Svanborg, and J.-E. Wedlund. Nonconvulsive status epilepticus: High incidence of complex partial status. Epilepsia 1986;27:276–285. 45. Treiman, D. M. Electroclinical features of status epilepticus. J. Clin. Neurophysiol. 1995;12:343–362. 46. 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. 47. 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. 48. Turski, W. A., E. A. Cavalheiro, M. Schwarz, S. J. Czuczwar, Z. Kleinrok, and L. Turski. Limbic seizures produced by pilocarpine: Behavioural, electroencephalographic and neuropathological study. Behav. Brain Res. 1983;9:315–335. 49. Tuunanen, J., T. Halonen, and A. Pitkanen. Status epilepticus causes selective regional damage and loss of GABAergic neurons in the rat amygdaloid complex. Eur. J. Neurosci. 1996;8:2711–2725. 50. Tuunanen, J., K. Lukasiuk, T. Halonen, and A. Pitkanen. Status epilepticus-induced neuronal damage in the rat amygdala complex: Distribution, time-course and mechanisms. Neuroscience 1999;94:473–495. 51. White, L. E., and J. L. Price. The functional anatomy of limbic status epilepticus in the rat. I. Patterns of [14C]2-deoxyglucose uptake and Fos immunocytochemistry. J. Neurosci. 1993;13: 4787–4809. 52. White, L. E., and J. L. Price. The functional anatomy of limbic status epilepticus in the rat. II. The effects of focal deactivation. J. Neurosci. 1993;13:4810–4830. 53. Wuarin, J.-P., and F. E. Dudek. Electrographic seizures and new recurrent excitatory circuits in the dentate gyrus of hippocampal slices from kainate-treated epileptic rats. J. Neurosci. 1996;15:4438–4448.
238
:
19
Neuroanatomy of Status Epilepticus
C (SE) anatomy are useful to the clinician faced with problems of diagnosis and treatment. Knowledge of SE anatomy is invaluable to the investigator in guiding the selection of cerebral areas in which to study SE mechanisms. This chapter emphasizes concepts of seizure spread, focusing on partial-onset SE. The objective is to provide a perspective that can be integrated with recent advances in the clinical and physiologic understanding of SE.
Status epilepticus originating from limbic sites Concepts of SE anatomy and behavior-anatomic parallelism emerge from animal SE models, in which SE can be generated under controlled conditions and mapped with functional tracers such as [14C]2-deoxyglucose (2-DG). In electrogenic limbic SE models, for example, a portion of cerebrum is stimulated continuously or intermittently via an implanted electrode until the animal enters SE (3, 71, 110, 125, 186). In this process, parts of the cerebrum can be converted from normal physiologic activity to self-sustaining continuous ictus within 30–90 minutes, despite the absence of physical or chemical derangements, exogenous chemicals, or a past history of seizures. During the SE induction process, electroencephalographic (EEG) recordings reveal that whereas seizures are initially discrete and intermittent, with seizure repetition ictal discharges develop that eventually become continuous. This intriguing observation indicates that cerebral circuits may be persuaded to engage in the physiologically inappropriate process of incessant seizure activity without the formation of new connections. Just as the normally structured brain can undergo rapid kindling, so it can also enter SE. Similarly, the focal injection of kainate or bicuculline into susceptible areas results in progressive seizure intensification and SE. The mechanism of SE induction is the central mystery of the field; results of investigations on this issue are described in other chapters of this book. A frequent and sometimes underappreciated clinical counterpart of experimental de novo SE is that patients may present with SE without a prior history of seizures or of previous cerebral damage. Medical personnel may be caught
off guard by the unresponsive patient who entered SE in the stress of a medical illness. SE elicited by electrical stimulation of a focal limbic structure can result in various SE behavioral states that differ in severity. Several laboratories have made comparable observations of mild to severe SE behavioral states with SE induced from amygdala, hippocampus, or other limbic sites in rat (70, 71, 110, 121, 186, 208). In addition, gradations of SE severity can be produced by focal cerebral injections of convulsants such as kainate or bicuculline into amygdala, hippocampus, or olfactory bulb (4, 9, 192, 193), or by systemic administration of kainate (111). Not all of the following behaviors are elicited from each of these models, but with each model usually three of the following behaviors are elicited. In the mildest SE state, immobile or staring SE, the rat is virtually immobile, while maintaining posture. The next SE state, exploratory or ambulatory SE, is characterized by relatively normal-appearing behavior, but incessant exploration-like activity with irritable hyperreactivity on attempted handling. The next stage of SE severity has been termed minor convulsive or masticatory SE. Animals in this stage display oral/facial movements and/or head twitches. Best known is clonic convulsive SE, in which clonic head and forelimb jerking occurs. This behavioral spectrum of severity appears to correlate roughly with some human SE states, such as spike-wave stupor, complex partial SE, and generalized convulsive status. When 2-DG autoradiography is performed in order to map the SE cerebral anatomic substrates in these animals, the results are highly informative and indicate parallelism between SE behavioral severity and extent of cerebrum hyperactivated by SE. A caveat is that this parallelism applies to acute SE in intact brain; the problem of subtle convulsive SE is discussed in a separate section. Another caveat in the interpretation of 2-DG autoradiographs is that they represent average cerebral glucose utilization during a 30- to 45minute experiment, with weighting on the early minutes. If an animal in masticatory SE has three convulsions during the experiment, accounting for a total of 4 out of 40 minutes, the autoradiographs will mainly correspond to masticatory SE rather than clonic convulsive SE. If 2-DG is used in an attempt to map one or more discrete seizures in
:
239
an animal not in SE, the autoradiographs will map seizures incompletely; with such discrete events, c-fos protein staining is preferable. In reviewing the progression of SE from limbic origins, we shall consider for purposes of discussion four stages: (1) highly restricted patterns of cerebral involvement by SE, (2) restricted patterns, in which multiple nuclei are involved by SE, (3) extensive limbic patterns, in which limbic cortical regions are contiguously involved, along with their subcortical connections, and (4) neocortical patterns, in which extensive neocortical involvement is added to extensive limbic participation in SE. H R SE The most restricted 2-DG activation patterns tend to be associated with staring or immobile SE behavior; the animal may also be described as having normal behavior. Several corresponding highly restricted 2-DG-mapped SE activation anatomic patterns have been recognized: 1. The basolateral amygdala nucleus. The basolateral amygdala nucleus is capable of autonomous SE, with secondary metabolic activation of only a few first-order projection sites (72, 121, 157), as illustrated in Figure 19.1. The basolateral amygdala is well known to constitute a rapid kindling site. 2. Amygdalohippocampal nucleus. Another nucleus that can be highly activated by seizure activity in virtual isolation is the amygdalohippocampal nucleus of amygdala (AHA) (72, 208). This nucleus receives input from olfactory structures, hippocampus, and amygdala subnuclei; it projects to areas of hypothalamus involved in sexual behavior. Dendritic alterations in AHA have been reported after amygdala kindling in mice (92). 3. Hippocampus. A number of investigators have documented SE activation of the hippocampus alone (112, 191) or in combination with the septum, as mapped with 2-DG (10, 30, 72, 111, 206). 4. Olfactory bulb. The olfactory bulb, along with the anterior olfactory nucleus, can also support restricted SE (4). 5. Entorhinal cortex. The medial entorhinal cortex has also been shown capable of supporting sustained focal seizure activity (30). Interestingly, the entorhinal cortex may be atrophic without hippocampal atrophy in some patients with temporal lobe epilepsy (13). Pyramidal neurons of layers III and V, but not II, possess recurrent glutamatemediated excitatory connections (41), a property that may predispose to epileptogenicity. Layer III of the medial entorhinal cortex is selectively damaged in specimens from some patients with temporal lobe epilepsy. Injections of excitatory amino acids into this layer induce seizure activity in animals (173).
240
:
A
B
F 19.1 2-DG cerebral autoradiographs of a rat in SE induced by amygdala stimulation. At the time 2-DG was infused, the EEG showed slow spiking and the animal was immobile. In B, there is intense hypermetabolism of the posterior basolateral amygdala nucleus. Only one other nucleus showed comparable hyperactivation, the lateral bed nucleus of stria terminalis (A), which receives a direct projection from the basolateral amygdala.
Discussion These examples demonstrate that single nuclei or very small anatomically connected networks may contain sufficient circuity to sustain SE. The concept that SE may be highly restricted has clinical implications. Well recognized are focal convulsive manifestations, such as eye deviation or hand twitching in an alert patient with a frontal SE focus. Less well recognized by many clinicians is the fact that some nonconvulsive or deficit symptoms, such as aphasia (96), panic attacks (168), or nose wiping (23), may be a manifestation of focal cortical status. In view of the relative inaccessibility of the medial temporal lobe to EEG, the local occurrence of focal SE is probably underestimated, particularly in children. An interesting case report documented electrographic SE with 1-Hz sharp waves in the anterior hippocampus, involving tissue less than 1 cm in diameter. Seizure activity occasionally spread to posterior hippocampus, amygdala, or temporobasal cortex, but was generally subclinical (52). We reported an example of medial temporal lobe SE, associated with lethargy and periodic lateralized epilepti-
form discharges (PLEDs) on EEG, in which 18F-2-DG positron emission tomography (PET) revealed intense focal hypermetabolism (72). A focal increase in blood flow on single-photon emission computed tomography (SPECT) has been reported in a patient with complex partial SE and PLEDs (2) and in a series of 18 patients with PLEDs (5), supporting the interpretation that PLEDs signify partial SE. It may be noted that PLEDs are comparable to the slow periodic complexes associated with highly restricted or restricted patterns of SE in rat (e.g., Figure 19.8). E S S H R R R P Beyond the highly restricted focal involvement of one or more structures, the next line of recruitment involves synaptically linked structures that become activated in restricted patterns, as revealed by 2-DG. The corresponding behaviors may be immobile (staring), normal, or exploratory-like (Figure 19.2). We now consider recruitment from three focal limbic SE sites. Recruitment from the basolateral amygdala The basolateral amygdala nucleus projects to ventral subiculum, lateral entorhinal cortex, endopiriform nucleus, nucleus centralis of amygdala, prelimbic and infralimbic (areas 32 and 25) medial prefrontal cortex, insular cortex, perirhinal cortex, bed nucleus of stria terminalis, nucleus accumbens, and dorsomedial thalamus (102, 103). 2-DG studies of SE induced by electrical stimulation reveal that the bed nucleus of stria terminalis, dorsomedial thalamus, nucleus accumbens, medial prefrontal cortex, and nucleus centralis of amygdala are all prone to be activated early in restricted SE patterns. Thus, not all of the projections of basolateral amygdala are initially recruited, but with further amplification of seizure activity by deep olfactory cortical regions and hippocampal formation, the amygdala is well positioned to play an important role in seizure and SE propagation. Recruitment from the hippocampal-entorhinal complex The precisely organized anatomic relationship within Ammon’s horn and subiculum (98) provides circuitry that is vulnerable to epileptogenesis and SE. Seizure discharges from medial entorhinal cortex do not propagate well to CA3/CA1 in slices from normal adult rats, but do so with recurrent discharges in entorhinal cortex if slices are taken from kindled rats (66). The recurrent ictal discharge may involve a projection from presubiculum, as interruption of the projection from presubiculum to entorhinal cortex has been reported to attenuate seizure-induced layer III damage in entorhinal cortex (173). Patients with temporal lobe epilepsy commonly display entorhinal cortical as well as hippocampal-amygdala atrophy on volumetric magnetic resonance imaging (MRI) (12).
A
E
B
F
C
G
D
H
F 19.2 2-DG autoradiographs from two rats in exploratory SE. (A–D) In the first animal, intense hypermetabolism occurred in several amygdala nuclei (D), dorsomedial and reuniens thalamic nuclei (C), nucleus accumbens (B), and infralimbic and prelimbic cortex (A). In addition, a contiguous band of hyperactivated deep limbic cortex connects the medial prefrontal cortex (A) and the deep entorhinal/perirhinal cortex (D), involving deep insular cortex and endopiriform nucleus (B, C). These areas are anatomically connected. (E–H) A similar seizure activation pattern was seen in the second animal, but with more involvement of the insular cortex (E, F), posterior piriform cortex (G), entorhinal cortex, and ventral hippocampus (H).
It is thus not surprising that the hippocampus can be driven into SE by epileptiform activation of entorhinal afferents. Injection of kainate into the entorhinal cortex causes SE with consistent CA1 damage (130). Intermittent stimulation of the perforant path over 30 minutes reliably elicits self-sustained SE with hippocampal involvement (157), a model described more fully elsewhere in this book. Conversely, seizures and SE readily propagate externally from hippocampus via projections of CA1 and subiculum. CA1 projects to entorhinal, perirhinal, and subicular cortices, as well as to lateral septum. The temporal CA1 also projects to amygdala, olfactory bulb, anterior olfactory nucleus, and nucleus accumbens (197). In addition to projections to entorhinal cortex, the subicular complex has extensive limbic projections to the anterior olfactory nucleus, the prelimbic cortex, retrosplenial cortex, hypothalamus (mamillary complex, dorsomedial, medial preoptic, and
:
241
other nuclei), the anterior thalamic complex, nucleus reuniens, nucleus accumbens and portions of caudate, and amygdala (basomedial, basolateral, amygdalohippocampal, and other cortical amygdala structures) (20, 67, 87, 185, 214). 2-DG studies have amply documented that perirhinal/ entorhinal cortex may be recruited by SE initiated in the hippocampus (72, 97, 206). As depicted in Figure 19.3, the initial spread of discharges from the hippocampal formation may propagate to entorhinal cortex and one or more specific first-order projection sites. Once fully engaged by ictus, the entorhinal cortex, with extrahippocampal projections that arise mainly in the deep layers of the lateral entorhinal cortex, is well-positioned to propagate seizure discharges to periamygdala cortex, basolateral and lateral amygdala, piriform cortex, endopiriform nucleus, anterior olfactory nucleus and olfactory bulb, medial prefrontal cortex, nucleus accumbens, and ventral
A
B
C
F 19.3 Bilateral hippocampal activation in a rat in immobile SE. Intense activation of the lateral septal nuclei (A), the hippocampus, and the right amydalohippocampal nucleus (B) is evident, as is partial activation of the entorhinal cortex (C).
242
:
pallidum, and to limbic thalamic nuclei (210, 211, 213). Entorhinal seizure discharges to these projection sites may be reinforced by similar projections from seizure-activated CA1, subiculum, and basolateral amygdala, as described earlier. Some of the distal sites, such as medial prefrontal cortex, nucleus reuniens, and anterior olfactory nucleus, have reciprocating projections, potentially further reinforcing seizure activity. Recruitment from rostral limbic regions Induction of SE from limbic prefrontal regions has not been well studied. Given the prelimbic/infralimbic early activation with restricted SE patterns associated with amygdala or hippocampal induction and the rich connections of the medial prefrontal region with insular, entorhinal, and perirhinal cortex, ventral hippocampal formation, amygdala, and dorsomedial and reuniens thalamus (31), the medial prefrontal cortex should exhibit proclivity for status induction. The left column of Figure 19.2 shows images from a rat with SE induced by electrical stimulation of this region. All activated areas are known to receive projections from prelimbic or infralimbic cortex (162). The activation pattern overlaps that seen with restricted patterns from posterior limbic regions. In addition, this example displays activation of deep insular layers and endopiriform nucleus that courses in a continuous band into entorhinal cortex, suggesting that this zone is prone to SE activity. Araki et al. (4) described sequential recruitment of structures, as shown with 2-DG after injection of kainate into the olfactory bulb. After initial activation of the olfactory bulb and anterior olfactory nucleus, additional structures to show hypermetabolism included the entorhinal cortex, endopiriform nucleus, nucleus accumbens, and ventral pallidum. In the most advanced pattern, the dorsomedial, centromedian, and ventromedial thalamus, entopeduncular nucleus (equivalent to internal globus pallidus), substantia nigra reticulata, and sensory cortex were activated. Discussion Studies of the highly restricted and less restricted patterns of SE activation suggest that within a network, one nucleus may serve as a generator, which then activates other nuclei via efferent projections. This is suggested when a small network of hypermetabolic nuclei are known to receive projections from a single nucleus, particularly when the highly restricted patterns have shown that nucleus to be activated in virtual isolation. The interpretation that a specific structure is an SE generator is additionally supported by observations that that nucleus is the one most activated metabolically, whereas other nuclei are only partly activated. Examples encountered earlier in this chapter included the basolateral amygdala, hippocampus, entorhinal cortex, medial prefrontal cortex, and olfactory bulb.
Another inference that can be made from studies of SE 2DG patterns is that some structures are more prone to engage in SE than others. In the electrogenic limbic SE model in rat, although there is clearly some nonoverlap between restricted activation patterns corresponding to focal SE induced from different sites, the basolateral nucleus of amygdala, AHA, and the ventral hippocampal formation are highly prone to be involved, even when SE is evoked from amygdala, hippocampus, or medial prefrontal cortex (72). The tendency of temporal lobe seizures to spread to frontal lobe regions is well known to clinicians. For example, a case study showed that when a young epileptic patient with a medial temporal onset engaged in disturbed affective behavior, a seizure network involved the amygdala, orbitofrontal cortex, and frontal operculum in coupled activity (6). One potential clinical implication is that, after SE has originated and spread from one site, such as a neocortical focus, other nuclei, for example amygdaloid or hippocampal, may become intensely engaged and thereby liable to damage. S SE E L R After restricted patterns of limbic SE involvement are attained, the next most common stage is that of extensive limbic involvement, in which the entire limbic cortex below the rhinal sulcus is activated, along with medial prefrontal cortex, limbic thalamus, and limbic basal ganglia. Extensive limbic activation can be unilateral, as indicated in Figure 19.4, and associated with exploratory-like behaviors. Unilateral extensive limbic activation has been described by several authors (4, 72, 121, 192, 207, 208). Bilateral extensive limbic activation corresponds to minor convulsive/masticatory SE manifestations (10, 30, 72, 111, 199, 206), as shown in Figure 19.5. In this section we consider candidate structures that may be instrumental in furthering SE spread to extensive cerebral regions. In some instances a potential role is suggested by models of seizures rather than models of SE. From amygdala The basolateral amygdala is connected with hippocampus, entorhinal cortex, perirhinal cortex, insular, prefrontal, and piriform/endopiriform regions, all of which might play a role in seizure generalization and propagation. In an interesting study by Imamura et al. (84), intraamygdala kainate injection induced SE with mastication and clonic convulsions; histologic examination showed extensive amygdala and hippocampal damage. If a cut was made to separate the dorsal and ventral hippocampus, a less severe form of SE was induced by intra-amygdala kainite, and histologic examination revealed pronounced damage to the amygdala but not the hippocampus. This study suggests that the intact hippocampus plays an important role in promot-
A
B
C
F 19.4 In this animal in exploratory SE, unilateral extensive limbic activation is present, including olfactory, orbital, insular, and medial prefrontal cortices (A), olfactory tubercle and lateral septum (B), entorhinal, periamygdala, and perirhinal cortex, and substantia nigra (C). In addition, several structures are partly activated contralaterally, compatible with intermittent spread of seizures to these sites. The contralateral hippocampus is particularly involved (C).
ing SE spread from the amygdala. Similarly, lidocaine injection of CA1 has been reported to reduce seizure activity and retard kindling from the amygdala (139). From perirhinal cortex and adjacent structures Perirhinal cortex. McIntyre et al. (124) demonstrated that layer V projects dense efferents to the frontal cortex. In
:
243
A
D
B
E
C
F
F 19.5 (A–C) 2-DG pattern of a rat in minor convulsive SE. Bilateral extensive limbic activation is present, with dorsal encroachment in medial frontal areas (A) and ventral temporal cortex (C). Mid- and dorsal caudate-putamen (B) and lateral thalamic areas (C) remain spared. (D–F) 2-DG pattern of a rat in severe
clonic convulsive SE. The neocortical mantle has been captured by SE hypermetabolism, as well as all striatal (E) and thalamic areas (F). The patterns shown in Figures 19.1 to 19.5 depict a parallel behavior-anatomic progression.
addition, the anterior perirhinal cortex projects to insular cortex, claustrum, entorhinal and posterior piriform cortex, infralimbic cortex, basal amygdala, and nucleus accumbens. Convulsive seizures can be kindled very rapidly from the anterior perirhinal cortex (94, 144). Kainate injections of this structure trigger motor seizures (85). Lesions of the perirhinal cortex attenuate intra-amygdala kainate-induced mastication, facial twitching, and forelimb clonus (57), but lesions or local microinjection with procaine or glutamate blockers do not interfere with amygdala kindling (99, 170). Nonetheless, the available observations suggest that the perirhinal cortex could contribute to the spread of seizure activity from limbic regions to convulsive networks in SE. Claustrum. Mohapel et al. (144) kindled the perirhinal cortex, adjacent insular cortex, or posterior claustrum and concluded that all three sites were highly epileptogenic, with very rapid kindling and short latency to convulsions. Zhang et al. (219) similarly described the anterior claustrum as highly kindling sensitive. Lesions of the anterior and posterior claustrum delay amygdala kindling to clonic convulsions (143) but do not prevent convulsions that have already been kindled (174). The anterior claustrum is connected to
the frontal and motor cortex, amygdala, endopiriform nucleus, midline thalamus, nucleus accumbens, and substantia nigra. It is postulated that the claustrum participates in the development of limbic-onset generalized seizures (174, 219).
244
:
From piriform cortex and endopiriform nucleus Piriform cortex. Kindling studies have shown that the piriform cortex kindles very rapidly, is recruited early when kindling is conducted at other sites, and is prone to interictal discharges. Injections of GABA-promoting drugs or NMDA antagonists into the piriform cortex block amygdala-kindled seizures (108). In 2-DG studies of SE propagation from amygdala, we have observed transitional forms between restricted and extensive limbic patterns in which deep piriform layers are selectively activated. Consistent with this observation, it has been shown in vitro and in vivo that epileptiform potentials can be evoked from deep piriform layers on stimulation of the basolateral amygdala (108). Bicuculline microinjections into the deep layers of piriform cortex have revealed that all regions of the piriform cortex are highly susceptible to seizures (46).
Central piriform cortex. Bilateral lesions of the central piriform cortex, but not of the anterior or of the posterior piriform cortex, retard kindling of convulsive seizures from the amygdala (169). Injection of vigabatrin into the central piriform cortex retards amygdala kindling (172) and is more successful than anterior or posterior piriform injections in blocking kindled convulsions (171). GABA-secreting cells implanted in the central piriform cortex increase the latency to convulsions but do not retard amygdala kindling (63). It is speculated that the central piriform cortex is especially important among the piriform areas in generalizing amygdala-onset seizures owing to its denser connections with all piriform regions, including contralaterally, orbitofrontal cortex, and rich connections with the entorhinal cortex and amygdala (171). Endopiriform nucleus. Studies of the endopiriform nucleus indicate that this structure is highly epileptiform (reviewed by Behan and Haberly [7]). The endopiriform nucleus lies deep to the piriform cortex along its rostral-caudal axis. Figure 19.2 shows involvement of the endopiriform nucleus by SE. The endopiriform nucleus has dense intrinsic connections and projects to the piriform, insular, and amygdaloid cortical regions. It provides a massive caudal to rostral pathway that is lacking in piriform cortex. This structure is thus well positioned to promote seizure spread within olfactory cortex and related regions (7). Deep anterior piriform cortex (area tempestas). Piredda and Gale (160) observed that injection of a low dose of bicuculline or other proconvulsant into the deep layers of a small region of the rostral piriform cortex readily produced limbicoriginated clonic convulsions. The area of greatest predilection for producing convulsions was found to be quite circumscribed. Seizure activity elicited in the deep layer readily propagates to the cell body layer of overlying piriform cortex, which then participates in seizure propagation (43). Injection of a non-NMDA glutamate antagonist into the anterior piriform cortex reduces CA3 cell loss in systemic kainate-induced SE (93). Examination of this area with standard histologic stains does not suggest why this region should differ functionally from other regions of piriform cortex that, as discussed above, are also seizure prone. However, Ekstrand et al. (49) have provided connectional and immunohistochemical evidence that this region is indeed distinctive. They term the cortex the rostroventral anterior piriform cortex (APCrv) and the underlying deep layer the preendopiriform nucleus (pEn). The pEn corresponds to the zone of greatest sensitivity to the seizure-producing effect of bicuculline. The APCrv directly and the pEn indirectly project to the ventrolateral orbital cortex. The pEn also projects to the submedial thalamic nucleus. Immunostaining indicates a paucity of GABA terminals on axon initial segments.
The model of forebrain seizures elicited by focal chemoconvulsants injected into the deep anterior piriform cortex has provided considerable utility for the study of anatomic networks regulating seizure spread, as noted in other sections of this chapter. Potential role of thalamic nuclei in SE spread 2-DG studies of restricted and extensive limbic activation patterns associated with SE display activation of parataenial, dorsomedial, reuniens, and rhomboid nuclei (Figures 19.1 to 19.5). In addition, the medial portions of the anterior thalamus and the ventromedial thalamus may be involved. Dorsomedial thalamus. In rat, topographic afferents to dorsomedial subnuclei arrive from medial prefrontal, orbital, cingulate, and agranular insular cortex regions, amygdala, substantia innominata, hypothalamus, and midbrain (32). Portions of the dorsomedial thalamus and the adjacent parataenial nuclei project topographically to medial precentral, cingulate, prelimbic, medial and lateral orbital, dorsal and ventral agranular insular cortical regions and to the basolateral amygdala nucleus (101). In the primate, the dorsomedial thalamus is reciprocally and topographically connected with prefrontal fields (64) and has received considerable attention for a potential role in memory functions and neurobehavioral disorders. The dorsomedial thalamus projects to the nucleus accumbens and ventral striatum, which also receive afferents from numerous structures connected with the dorsomedial thalamus. Thus the dorsomedial thalamus, as part of the limbic thalamus, is interconnected with selective regions of limbic/ prefrontal cortex and basolateral amygdala, with these structures sending converging projections to the limbic striatum. The limbic striatum in turn projects to the ventral pallidum. Neuron loss in the dorsomedial nucleus is prominent after prolonged SE in humans (56). Experimentally, Bertram et al. (14) found that afterdischarges propagate early to midline thalamic nuclei during kindling and that the dorsomedial, reuniens, and rhomboid nuclei show neuronal loss during kindling. Lidocaine microinjections shortened afterdischarge duration. Noting that dorsomedial thalamus is damaged in SE induced from anterior piriform cortex (area tempestas), Cassidy and Gale found that intradorsomedial thalamic injection of the GABA agonist muscimol, the AMPA antagonist NBQX, or the GABA transaminase inhibitor vigabatrin protected against seizures induced by intrapiriform bicuculline injection (22). Injection of an NMDA antagonist into the dorsomedial thalamus had no effect. Cassidy and Gale (22) concluded that the dorsomedial thalamus plays a critical role in seizure generalization from the piriform cortex, and that AMPA and GABA receptors are crucial in this process.
:
245
Anterior thalamus. The subnuclei of the anterior thalamus receive topographically organized projections from the mammillary complex nuclei (180). The anteromedial subnucleus has complex topographic projections to area 2 of frontal lobe, anterior cingulate, and entorhinal cortex in the rat (181). The anteroventral and anterodorsal nuclei project to the retrosplenial cortex and parts of the subicular complex (198). From these connections it may be surmised that the anterior nucleus may serve as a conduit of hippocampal formation activity to recruit via excitatory projections important regions of the frontal lobe and limbic cortex, as well as amplifying limbic seizure activity by its projections back to the subicular complex and entorhinal cortex. The anterior thalamus has received considerable recent interest as a therapeutic target. Mirski and Ferrendelli reported that muscimol microinjection into the anterior thalamus blocked pentylenetetrazol (PTZ)-induced seizure activity (140). Lesions of the mamillothalamic tracts also protected against PTZ-induced convulsions, while lesions of the fornices or mamillary bodies exerted efficacy but were not as effective (141). Miller et al. (137) found that injection of vigabatrin into the anteromedial thalamus blocked PTZ seizures without producing behavioral effects. These observations provided justification for preliminary clinical trials of deep brain stimulation of the anterior thalamus in the United States and Canada (80, 95). Preliminary observations include reductions in total seizures, convulsions, and seizurerelated falls, with good tolerance. Indeed, patients could not tell whether they were receiving stimulation. In an interesting experiment, Hamani et al. (68) report that rats receiving bilateral anterior thalamus DBS had delayed onset of SE induced by pilocarpine. However bilateral anterior thalamotomy was more effective, preventing entry into SE. If this finding is confirmed in other models, a potential therapeutic role of anterior thalamotomy might warrant consideration. Anterior midline thalamus. Miller et al. (137) reported the interesting observation that microinjection of muscimol into anterior midline nuclei, namely, the interanteromedial, intermediodorsal, centromedial, and paraventricular, produced sedation and enhanced susceptibility to PTZ seizures. This finding suggests that normally this system promotes alertness and resistance to seizures. Conceivably, encephalopathies that impair this system could thereby promote susceptibility to seizures and SE. Ventromedial thalamus. The principal ventromedial thalamic nucleus receives afferents from prefrontal cortex, rostral agranular cortex, and premotor cortex. It also receives significant extrapyramidal inputs from the internal globus pallidus, substantia nigra reticulata, and deep cerebellar nuclei (89). The ventromedial thalamic complex projects to the granular insular cortex and to the frontal cortical pole (101). Few studies have examined the role of ventromedial
246
:
thalamus in seizures. Moshe et al. (145) found that lesions of this nucleus did not affect susceptibility to flurothyl-induced seizures. Discussion An interesting feature of the unilateral extensive pattern is that despite its capture of a large cerebral territory, the associated behavior is merely exploratory-like. Thus, even when SE is nonconvulsive, large limbic territories may be engaged by seizure activity. A comparable and not infrequent clinical situation is the EEG finding of extensive continuous ictus over temporal lobe regions, often bilateral, in complex partial SE. Such patients may have moment-to-moment cycling or continuous alteration in behavior. The altered behavior may range from frank psychomotor automatisms to subtle deficits in conversational patients. The latter has been termed subtle complex partial status by Treiman. (The “nonconvulsive SE” of complex partial SE must not be confused with that of absence SE or with the “nonconvulsive SE” of moribund patients in subtle generalized convulsive SE.) Another interesting concept is that even extensive patterns of ictal involvement may depend on the involvement of one or a few nuclei acting as generators to drive the entire network. Few experiments have been performed to address this issue in limbic-onset SE; thus the experimental evidence for this concept is tentative. White and Price (209) showed that inactivation of the basolateral amygdala with focal lidocaine microinjection during limbic SE in the rat promptly abolishes unilateral extensive limbic SE. Lidocaine injection within anterior piriform cortex or hippocampus did not have this effect. Microinjection of the amygdala with the GABA agonist muscimol was also ineffective, likely because the GABA receptor becomes unresponsive in SE. In a comparable study, Hirsch et al. (79) found that lidocaine injections of the amygdala prevent seizure spread from brain stem to forebrain, whereas hippocampal injections are ineffective. Complex partial SE is recognized as a cause of neuronal damage to temporal lobe structures such as the hippocampus in patients (50, 105). Fujikawa et al. (56) studied the brains of three patients who presented with focal motor SE and had EEG evidence of epileptiform activity in one or both temporal lobes during SE. None of the patients had systemic complications that could cause neuronal loss. SE lasted 9 hours to 3 days, and death occurred 11–27 days after SE onset. Neuronal loss occurred in the hippocampus, amygdala, dorsomedial thalamus, piriform and entorhinal cortex, and in Purkinje cells. These findings are comparable to the regions of damage occurring after electrogenic limbic SE in the rat (82). F G L SE Upon attainment of the more severe stage of clonic convulsive SE, SEinduced intense metabolic activation expands to neocortical
regions in the rat (72). Comparison of autoradiographic patterns with the degree of clonic convulsive severity in the electrogenic limbic SE model suggests that the initial recruitment of the neocortical mantle occurs in frontal neocortex. With more severe clonus, more caudal neocortex is also recruited. In clonic convulsive SE, pronounced activation of lateral and posterior thalamic structures now occurs, basal ganglia recruitment is complete, and the hypothalamus is activated. The brain stem, aside from the substantia nigra, is relatively spared marked hypermetabolism, but partial increases, corresponding to physiological activation, have been noted by investigators in midbrain, pons, and cerebellum (see Figure 19.5). In this capture of telencephalon by severe SE, innumerable connections serve to reinforce ongoing seizure activity. The anatomic interest is in the identification of structures that influence the susceptibility to generalized seizures. Such potential regions include portions of the thalamus, the basal ganglia, and the brain stem. Thalamic modulation of seizure susceptibility Because of the role of the anterior thalamus in influencing frontal lobe and hippocampal formation activity, bilateral inactivation of this nucleus may be expected to impede limbic propagation of seizures and the recruitment of frontal cortex for convulsive activity. The centromedian-parafascicular thalamic complex is of interest, as it projects extensively to the neocortex, the entire striatum, the globus pallidus, subthalamus, and substantia nigra. The centromedian nucleus in particular projects to motor regions (163, 165). Velasco’s group has described the beneficial effects of centromedian deep brain stimulation on seizure control and EEG discharges in patients with primarily and secondarily generalized convulsions, and atypical absences. However, they concluded that complex partial seizures and temporal lobe EEG discharges were not suppressed by centromedian stimulation (200, 201). Fisher et al. (55) performed a controlled clinical study of centromedian stimulation (2 hours per day) and found a trend toward reduction of tonic-clonic convulsions that was not statistically significant. On open follow-up, stimulation 24 hours per day appeared to be more effective. Further controlled studies are required to assess the efficacy of centromedian deep brain stimulation, but these preliminary results suggest that generalized convulsions, which require motor cortical involvement, may be ameliorated, whereas the complex partial seizures of limbic origination are not suppressed. Basal ganglia modulation of seizure susceptibility In a simplified version of basal ganglia circuitry, the substantia nigra reticulata and the globus pallidus interna (GPi, corresponding to the entopeduncular nucleus in rodents) are output
structures, with inhibitory projections to the thalamus and brain stem. These nuclei receive excitatory afferents from the subthalamus that release glutamate, and GABAcontaining afferents from the striatum. They also receive afferents from the globus pallidus externa. The dorsal and limbic striatum project respectively to the globus pallidus and ventral pallidus, which send GABA-containing efferents to the subthalamus. The striatum receives topographically organized convergent excitatory inputs from cortical, thalamic, and limbic regions. This circuit scheme is greatly simplified and does not explain well some problems, such as why GPi lesions ameliorate dyskinesias or dystonia. Nonetheless, it has proved useful in the development of surgical and pharmacologic therapies for movement disorders. Substantia nigra reticulata. The discovery two decades ago that lesions or muscimol injection into the substantia nigra reticulata suppressed full generalization of seizures in maximal electroshock and chemoconvulsant models in the rat (59, 83) spurred great interest. Lesions or muscimol injections into substantia nigra also block kindled seizures (127) and convulsions elicited by bicuculline injected into the anterior piriform cortex (115). Since these original observations, it has become recognized that the effect of nigral manipulations is a function of age, sex, and nigral topography (62, 179, 203). In addition, it has been reported that although GABAergic inhibition of substantia nigra reticulata suppresses absence and clonic seizures in rats, which depend on forebrain circuits, this intervention fails to suppress audiogenic seizure-induced tonic seizures, which depend on brain stem circuits (36). Bonhaus et al. (16) determined that nigral cells fire in bursts during generalized seizures in kindled rats but not in amygdala-induced seizures in unkindled rats. This observation corresponds with 2-DG evidence that the substantia nigra is not activated in highly restricted limbic SE patterns but becomes involved as seizure activity becomes anatomically more extensive (see Figure 19.4). Deransart et al. (34) similarly recorded substantia nigra reticulata bursting in association with cortical spike-wave discharges during absence seizures in GAERS rats. Chronically increased firing of posterior but not anterior reticulata neurons has been reported after amygdala kindling in response to generalized convulsions (61). Such chronic and seizure-associated nigral reticulata increases in firing would be expected to promote seizure generalization. Intranigral blockade of glutamate receptors also blocks generalized seizures in a genetic model (37), and electroshock- and pilocarpine-induced seizures (33). Intranigral fluoxetine also suppresses anterior piriform cortexelicited seizures, an action that depends on endogenous serotonin and is exerted through multiple serotonin receptor subtypes (153).
:
247
The above evidence is compatible with the notion that reticular nigral neurons normally fire tonically, with the downstream effect of facilitating forebrain generalized seizures. During seizures, nigral cells fire more, tending to promote seizure propagation. Maneuvers that suppress nigral neuronal firing, such as injection of GABA agonists or blockade of glutamate receptors, have an anticonvulsant effect. Recently, innovative approaches have shown seizure inhibition with intranigral GABA-releasing implants (109, 187) and deep brain stimulation in the rat (202) to suppress evoked or spontaneous seizures (188). Dorsal midbrain and pontine reticular formation. On anatomic grounds, nigral efferents to the thalamus appeared to be the logical route of downstream effects on seizures. However, lesioning experiments indicated this was not the case (60, 145). Instead, the nigral target for seizure modulation was within the dorsal midbrain (60, 177). The nigrotectal target zone comprises an anticonvulsant zone that includes the deep superior colliculus, the adjacent mesencephalic reticular formation, and the intercolliculus. Bicuculline injections into this region protect against tonic hindleg extension in electroshock seizures (177) and against clonic convulsions elicited by focal injections of bicuculline into the deep anterior piriform cortex (58). Electrical stimulation of the superior colliculus suppresses absense seizures in the GAERS rat, as do picrotoxin injections into the superficial and intermediate caudal superior colliculus (147). Knife cuts of efferent pathways from this region suggest that the descending pathway, which projects to pontine reticular structures, is essential for the dorsal midbrain anticonvulsant effect (175, 178). It was further shown that bicuculline microinjection into the ventrolateral pontine reticular formation, a projection site of the dorsal midbrain anticonvulsant zone, protected against electroshock-induced hindleg extension (176). Entopeduncular nucleus/globus pallidus interna. The GPi (entopeduncular nucleus) has similar connections as substantia nigra reticulata. Injection of muscimol or a glutamate blocker suppresses electroshock- and pilocarpine-induced seizures in rat (33, 81, 154). Some investigators have found microinjections in the entopeduncular nucleus to be less effective than in the substantia nigra (33, 81). Subthalamus. Intrasubthalamic injections of muscimol suppress generalized seizures in the genetic absence model in the rat, motor seizures elicited by focal bicuculline injected into the anterior piriform cortex, flurothyl-induced convulsions, and convulsive seizures, but not afterdischarges in amygdala-kindled rats (35, 37, 45, 204). The therapeutic application of subthalamic deep brain stimulation for refractory clinical epilepsy has been examined in pilot studies (8, 24, 42, 107). The premise of subthalamic deep brain stimulation is that it may suppress its pro-seizure excitatory output to the substantia nigra reticulata and GPi,
248
:
and also may block epileptic discharge excitation of the subthalamus, propagated by direct corticosubthalamic projections (42). Globus pallidus externa and ventral pallidum. The globus pallidus receives afferents from sensorimotor striatum, whereas the ventral pallidum receives afferents from the limbic striatum, including nucleus accumbens. Tonically firing neurons of these pallidal structures project inhibitory fibers to the subthalamus. Disinhibition of pallidal neurons with local injection of a GABA antagonist, which causes these neurons to fire more, suppresses absence seizures in a genetic rat model, presumably by inhibiting the subthalamus and preventing it from exerting its normal pro-seizure effect on substantia nigra reticulata and entopeduncular/GPi nucleus. Indeed, this seizure suppression is associated with a fall in extracellular glutamate levels in the substantia nigra, as expected. Moreover, injection of a GABA agonist into pallidal structures aggravates absence seizures, as predicted (38). Despite the coherence of these results, other evidence suggests that labeling the globus pallidus externa as an antiseizure nucleus may be an oversimplification. Chen et al. (26) found no effect of local zolpidem on systemic PTZ-induced tonic seizures and mortality in rats, but intrapallidal injection of the GABAB receptor agonist baclofen completely blocked tonic seizures and mortality. Intrapallidal injections of picrotoxin cause lethal seizures that are prevented by injecting amphetamine into the striatum (215). Injection of kainate into the rat globus pallidus externa induces multiple seizures over hours, including clonic convulsions. The 2-DG shows mainly unilateral activation of limbic, cortical, basal ganglia, and thalamic structures (167). Striatum. Striatal output neurons project GABAergic efferents directly to the GPi/entopeduncular nucleus and substantia nigra; activation of this direct pathway would be expected to suppress seizures. On the other hand, the striatum also projects to these output nuclei indirectly via GABAergic projections to the globus pallidus and ventral pallidum, which inhibit the subthalamus. Activation of the striatum’s effect on the indirect pathway would be expected to be proconvulsant, as the pro-seizure effect of the subthalamus would be disinhibited. Experimentation indicates that of these two outcomes, the action of the direct pathway generally prevails. Injection of NMDA or bicuculline into caudate-putamen in rat suppresses pilocarpine-induced seizures (194, 195), and similar findings have been reported in other models (39). Discussion of basal ganglia role. The preponderance of experimental evidence indicates that activated striatal neurons inhibit GPi and substantia nigra reticulata via a direct projection, thereby disinhibiting antiseizure neurons in the dorsal midbrain, which may act by exciting the ventrolateral pontine reticular formation. Activation of the subthalamus,
by striatal inhibition of GPe or ventral pallidum, thereby causing subthalamus disinhibition, or direct excitation by afferents from cortex or thalamus has a pro-seizure effect, mediated by increased inhibitory outflow from nigral or GPi neurons. Although this body of evidence is already leading to exploration of new therapies, such as GABAergic implants or deep brain stimulation, there are several gaps in our knowledge. Because the work has been conducted with rats, it is not clear whether the GPi may be more or less important than substantia nigra for seizure control in primates. Much needs to be learned about the downstream effector pathways. 2-DG autoradiographs reveal intense metabolic activation of parts of striatum, the globus pallidus, the ventral pallidum, and the substantia nigra reticulata when extensive regions of cerebrum are involved in SE. Damage to the substantia nigra reticulata is a well-known consequence of experimental SE, likely reflecting excessive glutamate release from subthalamic afferents. Interesting questions are whether the dominant effect of striatal activation by seizure activity shifts toward the pro-seizure indirect pathway during the development of SE, and whether the subthalamus loses its inhibitory response to direct striatal afferents while retaining excitatory responses to cortical afferents. Brain stem and basal forebrain modulation of forebrain generalized seizures A number of brain stem structures have been studied with regard to their role in modulating forebrain seizures, and thus may be important in influencing SE. In addition, brain stem structures themselves may be involved by seizure activity. The latter issue is considered in a separate section. Periaqueductal gray. The PAG receives afferents from the lateral reticular, oral and caudal pontine reticular, raphe magnus and pallidus, zona incerta, thalamic parafascicular, and several hypothalamic nuclei (116). The dorsolateral PAG projects efferents mainly to the locus ceruleus, subceruleus, A5 cell group, parts of the paragigantocellular and gigantocellular nuclei, the centrolateral and paraventricular thalamus, and anterior hypothalamus. The ventrolateral PAG projects mainly to the nucleus magnus, caudal paragigantocellularis, rostroventrolateral reticular formation, centromedian and parafascicular thalamus, lateral hypothalamus, and lateral bed nucleus of stria terminalis (18, 19). Peterson et al. (158) elicited seizures of the forebrain type on carbachol microinjection into the PAG, associated with forebrain electrographic discharges. Thus the PAG may, on excitation by forebrain or brain stem afferents, promote forebrain seizure activity. Cerebellum and deep cerebellar nuclei. Electrical stimulation of the cerebellum cortical surface was initially felt to be effective for intractable epilepsy in open treatment, but it did not prove to be effective in a controlled trial (212).
Studies of the role of cerebellar regions in relation to seizures have yielded conflicting results. Here we cite several studies and do not attempt to review this field, which has not received thorough investigation with modern techniques. Electrolytic lesions of the fastigial or of the dentate nucleus lead to accelerated amygdaloid kindling, suggesting that these nuclei inhibit seizures (138). Such lesions may transect axons of passage, but these results partly confirm the findings of Miller et al. (135), who employed the microinjection technique, which avoids affecting passing axons. Injections of GABA agonists into the fastigial nuclei increase susceptibility to systemic bicuculline-induced seizures in the rat, suggesting that the fastigial nucleus outflow normally is seizure-inhibitory. Injection of GABA agonists into the dentate nuclei had no effect (135). On the other hand, transection of the cerebellar peduncles retards amygdaloid kindling, suggesting that the cerebellar output is normally pro-convulsive (155). In partial support of this notion, Rubio et al. (164) stimulated the superior cerebellar peduncle with 100-Hz pulses during amygdala kindling in the rat and found facilitation of the early stages of limbic kindling, but shortening of the kindled clonic convulsion. Kandel and Buzsaki (90) recorded unit bursting in cerebellar cortex and deep nuclei in synchrony with spike-and-wave discharges in a rat model of absence seizures and suggested that the cerebellum contributes to generalized spike-and-wave activity of absence seizures. Clinical case reports have described motor seizures and simple partial motor SE in patients with isolated cerebellar lesions, with propagation of discharges to the cerebral cortex (129, 196). In the case described by Mesiwala et al., ictal activity was recorded from a cerebellar ganglioglioma, and all seizures ceased with resection of the cerebellar lesion. Laterodorsal tegmental reticular nucleus. The brain stem contains structures with neurons that release specific neurotransmitters within the forebrain. Miller and colleagues studied the laterodorsal tegmental nucleus of the pons/ midbrain, which contains cholinergic neurons, and found that microinjection of a GABA or GABAB agonist lowered the threshold to clonic but not tonic seizures produced by systemic bicuculline or PTZ in the rat (132). In another experiment it was determined that microinjection of a neurotoxin specific for cholinergic neurons resulted in a lower threshold for PTZ-induced face and forelimb clonic seizures, which are forebrain-mediated. It was thus suggested that the laterodorsal tegmental nucleus exerts an important antiseizure effect on the forebrain (134). Further studies indicated that the target site is the centromedial thalamic nucleus, which receives cholinergic projection from the laterodorsal tegmental nucleus. Injection of inhibitory substances into either site suppresses behavioral arousal and exacerbates forebrain convulsive seizures (133, 136).
:
249
Cholinergic basal forebrain. Ferencz et al. (53) lesioned select regions of cholinergic neurons by microinjecting an immunotoxin into basal forebrain structures and were able to show that depletion of cholinergic neurons in the nucleus basalis facilitates the late stages of amygdala kindling. By contrast, depletion of cholinergic neurons in the medial septum and vertical limb of the diagonal band facilitates the early stages of hippocampal kindling (54). Depletion of basal forebrain cholinergic neurons with saporin also shortens the latency to generalized convulsions in rats exposed to flurothyl or PTZ (182). These results suggest that basal forebrain cholinergic neurons exert suppressive effects on seizure spread and generalization. Locus ceruleus. Neurons of this nucleus project norepinephrine-releasing terminals to widespread regions of forebrain. Depletion of norepinephrine within the amygdala by local injection with 6-hydroxydopamine accelerates amygdala kindling (120). Because the locus ceruleus (LC) projects fibers to the amygdala and other parts of the limbic system, this finding implies a role for LC in controlling seizures. Transection of ascending noradrenergic pathways accelerates kindling (48), as does administration of 6-hydroxydopamine or DSP-4 so as to deplete norepinephrine terminals or LC cell bodies (21, 54, 122, 151). These lesions promote both focal and generalized forebrain seizures. Mishra et al. (142) demonstrated that lesions of LC with a selective neurotoxin lowered the threshold to corneal electroshock seizures in rat. LC lesions also increase the frequency of absence seizures in the genetic rat model, but the effect is transient (106). In addition, LC lesions confer greater susceptibility to audiogenic seizures, supporting a role in regulating brain stem seizure susceptibility (88). Krahl et al. (100) demonstrated that the LC is an essential relay in vagus nerve stimulation seizure suppression. When the LC was lesioned, vagus nerve stimulation no longer suppressed electroshock-elicited seizures. Attempted kindling at short intervals is blocked by endogenous seizure-induced seizure-suppressive mechanisms (69, 126). McIntyre et al. (126) showed that short-term suppression could be ameliorated by norepinephrine depletion, suggesting that norepinephrine plays a role in seizureactivated seizure suppression. This notion is compatible with evidence that in reaction to activation by a seizure, the LC markedly increases forebrain norepinephrine release; a response lasting approximately 8 minutes in the rat (11). These characteristics of the LC system would thus suggest that it is important for preventing repeated discrete seizures from occurring and merging into continuous SE. Contrary to expectations, McIntyre and Edson (123) did not find that norepinephrine depletion affected entry into SE after 1 hour of amygdala stimulation. However, Giorgi et al. (65) described experimental results that suggest that LC-released norepinephrine may play an important role in preventing
250
:
the conversion from discrete seizures to continuous SE. They found that when low-dose bicuculline is injected into the anterior piriform cortex, the normal response is self-limited sporadic seizures. If the animal previously received systemic DSP-4 to lesion LC neurons, the same dose of bicuculline elicited self-sustained, continuous, long-lasting SE. Nucleus of solitary tract. The vagus nerve terminates predominantly on the nucleus of the solitary tract. Muscimol injection of the caudal medial subdivision, but not of other subdivisions, suppresses seizures elicited by bicuculline methiodide injection into anterior piriform cortex, or by systemic bicuculline or PTZ. Microinjection of kynurenate, a glutamate receptor blocker, or the local anesthetic procaine has similar effects. Injection of bicuculline methiodide into the medial nucleus of the solitary tract has no effect. These results were interpreted as suggesting that inhibition of medial nucleus of solitary tract outflow leads to resistance to forebrain limbic motor seizures (205). Magdaleno-Madrigal et al. (114) electrically stimulated the medial nucleus of solitary tract with 30-Hz pulses just prior to amygdala kindling stimuli in cats and observed prevention of kindling to the stages of secondary seizure generalization. Stimulation of the nearby nucleus intercalatus or the lateral tegmental field had no effect. The effect of solitary nucleus stimulation on preventing kindling progression was striking, and the authors speculated that the LC may in part mediate this action. Dorsal raphe nucleus. Racine and Coscina (161) found that lesions of the dorsal and median raphe facilitated amygdala kindling, but concluded the effect was not robust. Neuman and Thompson (148) found that the suppressive effects of peripheral noxious stimulation on a penicillin cortical focus could be abolished by drugs that lowered the firing rate of raphe neurons. Injection of drugs directly into the dorsal raphe, which reduces neuronal firing, also blocks the effect of peripheral stimuli in producing cortical desynchronization and suppression of focal cortical epileptiform activity (189). Parallel observations were made by Moyanova et al. (146) after lesions of the dorsal raphe. These observations suggest that the suppressive effect of serotoninergic dorsal raphe neurons on seizure spread is more apparent when the dorsal raphe is activated. Discussion Examination of 2-DG autoradiographs indicates that once limbic-onset SE has captured extensive domains of the cerebrum, the originating SE site can no longer be identified, because the anatomic SE substrate and behavioral correlate become the same for different originating sites. Experimentally, the same 2-DG activation pattern and ictal behavior can occur with a variety of originating SE sites in rats with exploratory SE, minor convulsive SE, or clonic convulsive SE, so that an observer would be unable to deter-
mine from where within the forebrain the SE had originated. Similarly, the clinician may be unable to assess where seizure activity originated in a patient presenting with secondarily generalized convulsive SE. In this section we provided a survey of thalamic, basal ganglia, and brain stem structures that could potentially modulate the occurrence of generalized convulsive SE. This evidence is based mainly on animal seizure models that range from single seizures to SE. Kindled rats are not usually epileptic, yet prior kindling facilitates SE entry in rat (70, 125). Few studies of SE have been performed in epileptic animals, although many patients with clinical SE have prior epilepsy. Prior epilepsy may alter the ease of SE entry, the severity of SE, and the portions of cerebrum affected.
Status epilepticus originating from neocortex The EEG of patients with simple partial SE may reveal focal epileptiform activity corresponding to a cortical focus. With worsening SE, the seizure activity involves more extensive regions of the ipsilateral hemisphere, or of both hemispheres if generalized SE occurs. Neocortical foci, such as those induced by local application of penicillin, kainate, or other convulsants (29, 78), are associated with marked focal hypermetabolism during focal SE. The neostriatal sector and the thalamic nuclei receiving direct projections from the focus become activated early. With application of more convulsant the focus enlarges, and seizure activity may expand within the ipsilateral hemisphere cortex, and partially within the contralateral hemisphere. Subcortical structures become increasingly involved by intense hypermetabolism and include thalamic projection sites, the striatum, substantia nigra, and cerebellum. With the development of generalized convulsive seizures, the involvement of these regions becomes bilateral. Immunocytochemical studies of cortex after induction of focal seizure activity with 4-aminopyridine suggest that a considerable number of inhibitory neurons are activated, especially in the contralateral (mirror) cortex (131). Hashizume and Tanaka (78) performed subpial cortical transections on each side of a kainate neocortical focus in rat and found that this maneuver reduced the severity of convulsive activity, although it was not completely abolished. 2-DG mapping revealed that ipsilateral cortical spread of seizure activity from the focus was successfully restricted by the cuts. However, there was still spread to the contralateral hemisphere and to the striatum and thalamus. These authors concluded that subpial transections were effective in interrupting local cortical spread but not vertical seizure spread, which utilized white matter pathways to the opposite hemisphere and to relay nuclei. In a clinical correlate of this experiment, the use of multiple subpial transections to treat refractory SE has been reported (40).
Surgery for intractable SE can be lifesaving and has been recommended if medical therapies have failed, including three courses of cerebral suppression over a 2-week period. Where a focal lesion or spiking source can be identified, local resection or multiple subpial transection may be employed. If the SE is generalized with no localizable source, a callosotomy may be performed. Resections may be local (see, e.g., reference 149 for complex partial SE), regional (104), or may require hemispherectomy (44, 113). The concept that intractable seizures are often driven by a discrete focus has led to attempts to develop therapies directed at the focus. Cooling suppresses neuronal network synchrony that is needed for epileptiform activity (86). Local cortical cooling suppresses focal seizure activity induced by 4-aminopyridine in a rat model (217, 218). Another experimental approach has been to inject diazepam with an infusion pump into a focus to suppress spiking and seizures in the cobalt-pilocarpine and focal bicuculline models. The infusion can be automated by linkage to a computerized seizure detection system (47, 184). Although such approaches have been envisaged as potential treatments for epilepsy, they could play a useful role in controlling intractable SE, and have the advantage of reversibility. Local cortical cooling has been reported to be clinically successful for SE (91).
Status epilepticus and the brain stem B A B S S R S M In rat seizure models, the clonic movements of the upper body depend on seizure circuits within the forebrain, whereas hindleg clonus, tonic seizures, and wild-running seizures depend on seizure-activated circuits in the brain stem (17). Stimulation, microperfusion, and functional mapping experiments indicate that seizure activity in the brain stem involves mainly midbrain and pontine areas, including inferior colliculus, PAG, and reticular formation (117, 119). McCown et al. (117) showed that electrical stimulation of the inferior colliculus could elicit seizures, with associated marked 2-DG uptake in the peripeduncular nucleus, dorsal PAG, and medial geniculate. The genetically epilepsy-prone rat (GEPR-9) has proved a useful model to study brain stem seizure networks. The inferior colliculus is essential for elicitation of audiogenic seizures. The first phase, wild-running seizure, is preceded by tonic firing within the deep layers of the superior colliculus, suggesting that this structure mediates this behavior (51, 216). The next seizure stage is clonic-tonic, preceded by tonic firing in the PAG and pontine reticular formation (51). Injections of NMDA or bicuculline into the PAG provoke clonic-tonic seizures (158), whereas injection of an NMDA
:
251
blocker or GABA agonist into PAG suppresses audiogenic seizures in GEPR-9 rats (150). Electrical stimulation of PAG can also produce running and tonic-clonic seizures (152). With cessation of clonic-tonic seizures, postictal depression occurs, with neuronal quiescence (51). In contrast to some of these inferences, Merrill et al. (128) found that electrolytic lesions of the superior colliculus abolished tone-induced clonic and tonic seizures in GEPR-9 rats, with sparing of wild running, while bicuculline microinjections elicited seizures similar to audiogenic seizures. S P B F B S Animals kindled from forebrain structures generally display only clonic seizures. If the rat is highly overkindled, the kindling stimulus may elicit clonic, then tonic or wild-running behaviors in the same fit, suggesting a rostral-to-caudal spread of seizure activity from forebrain to brain stem (159). Conversely, the reverse has been demonstrated: repeated elicitation of seizures from brain stem structures, by electrical or audiogenic stimuli, results in the progressive propagation of seizures in the caudal-to-rostral direction, so that forebrain structures become kindled by brain stem seizures (79, 118, 157). Chemical or electrical stimulation of the PAG can produce seizure activity in both forebrain and brain stem (152, 158), leading to suggestions that the PAG may be an important link between forebrain and brain stem seizure territories. McCown et al. (118) demonstrated 2-DG uptake in numerous midbrain and forebrain areas with kindled inferior collicular seizures, including dorsal PAG, peripeduncular nucleus, substantia nigra, entopeduncular nucleus, centromedian thalamus, and perirhinal, parietal, and frontal cortical regions. This group found that tonic-clonic convulsions could be suppressed by procaine microinjections into the pontine reticular formation, dorsal PAG, peripeduncular nucleus, substantia nigra, entopeduncular nucleus, amygdala, or perirhinal cortex, but did not abolish the wildrunning seizure response to inferior colliculus stimulation. Procaine microinjection into the cuneiform/pedunculopontine region did suppress wild-running but not convulsive seizure responses to collicular stimulation. The results of the studies by McCown et al. support the notion that the neural networks for wild-running and tonic-clonic behaviors differ. Interestingly, structures identified as essential for propagation to forebrain structures have usually been implicated as important in modulating intraforebrain seizure spread, including the basal ganglia output nuclei, as discussed in a previous section of this chapter. Simler et al. (183) employed c-fos staining to study the spread of seizures into the forebrain with repeated audiogenic seizures in the Wister model of generalized epilepsy. They concluded that the initial forebrain targets were the amygdala and perirhinal cortex. With further audiogenic
252
:
seizure kindling, the motor cortex was recruited, then the piriform cortex, hippocampus, and entorhinal cortex. Hirsch et al. (79) showed that injection of the amygdala with lidocaine inhibited audiogenic seizure-induced cortical epileptiform activity in this model. These findings suggest the amygdala plays an important role in brain stem-to-forebrain seizure propagation. D B S SE S A O H? Paroxysmal clonic convulsive-like movements can occur in patients with brain stem strokes (166). Although the absence of epileptiform activity on EEG is interpreted as evidence that these events are not seizures, it should be borne in mind that the cortical EEG is also not epileptiform in rats with brain stem seizures. It is thus uncertain whether these clinical events could represent focal brain stem seizure activity. Another situation that may be considered is the postcardiac arrest patient with short bursts of rapid bilateral body jerks every few seconds, correlated on EEG with ictal burst suppression. Such patients have clinical evidence of diffuse cortical injury and relative preservation of brain stem function. The anatomic substrate of this SE state is presently unknown, but the intriguing possibility arises that it may encompass thalamic-midbrain-pontine circuitry.
Temporal dynamics of SE territorial spread The preceding section discussed SE anatomic substrates as if they were static. Clinically, however, patients with SE commonly change from moment to moment in seizure severity. Some patients in simple partial motor SE, complex partial SE, or generalized convulsive SE have discrete seizures, in which individual ictal events are separated by seizure-free intervals. Patients with more severe involvement have waxing-and-waning status, in which some degree of seizure activity is continuous but fluctuates in severity. In continuous SE, the behavioral ictus is invariant. Patients may progress from the first to the last of these presentations as stages in worsening SE. The EEG in generalized convulsive SE may show in the discrete seizures stage corresponding individual electrographic ictal events, which may have an initial focal onset. The EEG of waxing-and-waning SE displays crescendodecrescendo changes in spike amplitude and frequency. A frequent observation in such cases is that, when electrographic ictus is at a nadir, it may be localizable to a discrete cerebral focus, then it expands over both hemispheres in the crescendo phase. These EEG observations suggest momentto-moment variation in the size of cerebral SE territories. Corroborating clinical observations, several animal SE models display a progression from discrete seizures to continuous convulsive SE (74, 190). I studied 2-DG patterns in
the lithium-pilocarpine model and found that, in the initial stages, rostral cortical and olfactory cortical areas were maximally activated, whereas other regions were only partially activated. With progression into invariant continuous SE, maximal activation was attained within most of the telencephalon (75), as shown in Figure 19.6. These clinical and experimental observations led to the conceptualization depicted in Figure 19.7, in which the brain is divided into compartments at each stage of partialonset SE. The conceptualization is discussed in the following paragraphs. Discrete seizures; two compartments. At this stage, an intermittently active focus fires and recruits a given territorial extent. This compartment is engaged in intermittent seizures but retains the capacity to terminate individual seizures. The size of this compartment determines whether the behavioral expression of the seizure is simple partial, complex partial, or secondarily generalized. The second brain compartment is simply that CNS component that does not at any time engage in ictus. Components of this compartment receive physiologic inputs from the ictal compartment, so that autonomic or behavioral ictal manifestations are expressed. Waxing-and-waning seizures; three to four components. In this stage, a generator focus is continually engaged in ictus, forming a continuous SE compartment. If one or more focal
generators succeed in driving captured territory into continuous SE, this captured territory can be considered a second compartment, insofar as it cannot sustain SE independently of the generator. Regions engaged in continual seizure activity have presumably lost innate mechanisms that normally terminate seizures. The region of continuous SE thus comprises a generator or a generator plus captured territory. Outside this is a penumbra in which seizure activity occurs intermittently. This third compartment is periodically recruited by the continuous ictus substrate whenever seizure activity transiently expands to greater domains. This third compartment retains the capacity for seizure termination, and in effect is engaged in discrete seizures. The fourth compartment is the CNS portion uninvolved by seizure activity. Continuous SE; three compartments. If ictal activity becomes invariant, with no expansions or contractions of cerebral territories, the brain can be conceptualized as three compartments: within that continually involved by seizure activity is the generator and the captured territory; the remainder of the CNS is not directly involved by ictus. Discussion In clinical cases or animal models where stages of SE entry can be observed and the ictus is of the partialonset type, the progressive worsening of SE reflects an inexorable failure of seizure-terminating mechanisms. The role
A
C
B
D
F 19.6 Lithium-pilocarpine model of SE. The animal on the left was displaying discrete and waxing-and-waning seizures during 2-DG exposure. Pronounced activation of orbital and rostral insular cortex (A), entorhinal cortex, and substantia nigra (B) is present. Partial activation of neocortical areas and hip-
pocampus is apparent. The autoradiographs in C and D are from an animal in continuous convulsion with invariant continuous fast spiking. Those cerebral structures partly involved by intermittent seizure activity in early SE (A, B) are now maximally activated in intense SE (C, D).
:
253
254 : F 19.7 Conceptual depiction of cerebral compartments defined according to their degree of involvement by partial-onset SE. The white compartment does not participate in SE activity. The lined compartment is intermittently involved by discrete ictal
events. The gray zone is in continuous SE. The black area represents an SE generator focus. The extent of cerebrum involved by seizure activity determines whether the SE is simple partial SE, complex partial SE, or generalized convulsive SE.
of glutamate and GABA receptor responses is the subject of other chapters in this book. Other neurotransmitters or neuromodulators likely play an important role as well. For example, we found that in the electrogenic limbic SE model, a nonconvulsant dose of theophylline converts nonconvulsive SE into convulsive SE. The EEG and 2-DG autoradiographs demonstrate that this event is associated with an anatomic expansion of SE (75), as shown in Figure 19.8. This observation suggests that endogenous cerebral adenosine plays a role in limiting SE spread, as has been shown with kindled seizures (1). The antiseizure potency of adenosine is shown in the block of hippocampus-kindled seizures after lateral ventricle grafts of adenosine-releasing cells (15). The notion that the cerebrum in SE can be divided into compartments according to the degree to which SE has engaged them provides a useful conceptual framework. These compartments should differ in the extent to which underlying SE-associated derangements have proceeded, with the generator site most affected and the discreteseizures compartment least so. Correspondingly, patients with continuous SE are harder to treat than those with discrete seizures. Finally, this concept is consistent with the observation that drug treatment may progressively constrict the zone of SE involvement, as discussed in the next section.
The effect of anticonvulsants on SE anatomy Among some patients in generalized convulsive SE, anticonvulsant administration leads to a gratifyingly quick halt in behavioral and electrographic seizure activity. All too often, however, the first drug does not result in complete suppression of SE, so that additional drugs are sequentially infused. During this ordeal, the clinician may observe lessening and disappearance of clonus and a gradual transformation of the EEG status record. Spiking may become asymmetric, then regional within one hemisphere. In the final stages, the spiking can be so focal as to be revealed by only a few leads, yet it can be remarkably difficult to quench with drug treatment. Often the location of the focus corresponds to a known lesion, such as ischemic infarct, traumatic injury, tumor, abscess, subdural hematoma, a biopsy site, or a previously documented epileptic focus. In these cases the ictal focus revealed by anticonvulsant drug treatment of SE may represent the same inciting focus that precipitated SE. The concept that anticonvulsant drug treatment may contract SE ictus to smaller territories has important clinical implications. It provides one explanation why behavioral assessment alone is inadequate in judging whether SE has stopped in response to treatment. It may provide an explanation why SE recurs following treatment in some patients; SE at the generator focus actually may not have stopped. Persistent firing by a generator SE focus may be not only behaviorally invisible but also electrographically
inapparent if remote from surface electrodes. Since residual ictus at a focus is frequently refractory to drug treatment and poses the danger of reengaging the cerebrum once cerebral suppressants are withdrawn, it would be logical to develop therapies directed toward the offending generator focus. Some potential interventions were discussed earlier in this chapter and are more thoroughly discussed by A. G. Stein and R. S. Fisher in Chapter 46. The constriction of the SE anatomic substrate by anticonvulsants can readily be demonstrated in animal models. For example, the administration of diazepam to rats with kainate-induced SE will suppress convulsive activity and prevent recruitment of the piriform cortex, so that the main site of seizure-induced hypermetabolism is the hippocampus (25). A concern of uncertain clinical relevance is that SE might create new generators unrelated to the original inciting focus, so that when SE is submaximally suppressed with anticonvulsants, the new generators may continue to be active, even when the original focus has been suppressed. If such new generators occurred in limbic structures, damage could ensue. We have found that even when SE is elicited from different sites within rat cerebrum and then treated with anticonvulsant drugs, 2-DG autoradiography reveals residual ictus within temporal lobe nuclei (Figure 19.9). The extent to which a similar phenomenon occurs clinically in adult or pediatric SE is uncertain.
The puzzle of subtle generalized SE The parallelism between the behavioral seizure severity and the anatomic SE substrate extent, discussed in the initial sections of this chapter, breaks down when subtle generalized convulsive SE is considered. Subtle generalized SE is characterized by ambiguous or inapparent convulsive activity in the context of electrographic generalized SE. There is thus a discrepancy between the vigor of SE on the EEG and the feeble behavioral expression. In some patients discovered to be in subtle convulsive SE, the early stages of generalized convulsive SE have occurred, but for a variety of reasons no anticonvulsant was administered, so that the patient progressed to subtle generalized convulsive SE. In these patients, clonic seizure activity has lessened with time to unimpressive or absent twitches, yet the EEG shows ictus to a degree out of proportion to the behavioral alteration. Patients in this stage are profoundly sedated; subtle SE thus should be considered in cases of unexplained coma. This progression from overt to subtle generalized convulsive SE was observed in epilepsy asylums at the turn of the twentieth century (28) and has been well documented to occur in animal models (76, 77, 190, 199). Despite the common occurrence of subtle SE, little work has been performed investigating the underlying mechanisms.
:
255
A
C
E
B
D
F
F 19.8 Effect of adenosine antagonist or agonist on SE. Rats received amygdala stimulation according to an SE induction protocol that produces longlasting exploratory SE (74); 2-DG in such animals displays the unilateral extensive limbic SE activation pattern. After 15 minutes of exploratory SE, animals received drug IP, followed 30 minutes later by 2-DG. The EEG was recorded via epidural screws from left frontal cortex (LFC) and right parietal cortex (RPC), and via intracerebral electrodes from left and right amygdala (RA, LA). (A and B) EEG and 2-DG pattern of a control saline-administered exploratory SE animal. (C and D) Effect of a subconvulsive dose of the adenosine antagonist theophylline, 25 mg/kg, on an exploratory
SE animal. The behavioral manifestations changed from exploratory to minor convulsive SE. The EEG displays generalization of spiking to cortex, while the corresponding 2-DG autoradiograph confirms enlargement of the SE anatomic substrate. (E and F) Effect of an adenosine agonist, 2-chloroadenosine, 20 mg/kg, on a rat in exploratory SE. The animal became sedated and the EEG was suppressed. 2-DG autoradiography revealed constriction of SE hypermetabolism to the amygdalohippocampal area (F), and the known projection of this nucleus to the medial preoptic hypothalamus (E).
A
B
C
D
E
F
F 19.9 Effect of diazepam on SE anatomy, as mapped by 2-DG. (A–C) 2-DG patterns in lithium-pilocarpine generalized continuous convulsive SE in an untreated animal (A) and in an animal treated with diazepam, 25 mg/kg (B, C). The generalized hyperactivation of cortical, thalamic, basal ganglia, and limbic areas is characteristically associated with continuous fast spiking in the lithium-pilocarpine model (A). The administration of diazepam to such an animal is successful in abolishing most of the hyperactivation, but the basolateral amygdala remains active on one side (B), as well as the posterior cingulate (C). That the latter nucleus is engaged in seizure activity is indicated by laterodorsal thalamus hypermetabolism (B), known to receive a projection from the cingulate cortex. (D–F) 2-DG patterns in electrogenic
generalized continuous convulsive SE in an untreated animal (D) and in an animal treated with diazepam, 5 mg/kg (E, F). The pattern of hypermetabolism shown in D is characteristic of animals with electrogenic convulsive SE of intermediate severity. Treatment of such an animal with diazepam is successful in abolishing most of the SE-associated hypermetabolism, but the bed nucleus of the stria terminalis remains hypermetabolic (E), especially the lateral portion, which receives a specific projection from basolateral amygdala, intensely activated in this example (F). In addition, the amygdalohippocampal area also remains intensely hypermetabolic. These examples indicate that after diazepam treatment of generalized SE, residual seizure activity may persist in discrete circuits.
Another explanation for the EEG/behavior dissociation of subtle generalized SE is that a diffuse compromise of neural function accumulates during SE due to the elaboration of inhibitory or toxic substances, widespread alterations in cell membrane polarization, exhaustion of energy stores, or progressive diffuse cortical damage. Compatible with this general notion, we found that, in a late stage of the lithiumpilocarpine model in rat, a reduction in hypermetabolism occurred within SE territories prior to the later constriction of SE anatomic substrate (76). Chu et al. (27) reported a case of a 56-year-old man in subtle generalized SE in whom MRI revealed extensive gyriform diffusion-weighted imaging hyperintensity and T2 hyperintensity. The cortex was later found to have become atrophic. Subcortical regions were not affected. The findings were compatible with SE-associated cortical cytotoxic edema and neuronal loss. This case suggests that some cases of subtle generalized SE have extensive cortical damage. Finally, some patients present with subtle SE without any preceding overt convulsions. These patients have extensive cerebral compromise from anoxic encephalopathy, head trauma, multiple embolic infarcts, or other insults. It may be conjectured that, in these patients, pervasive damage prevents the cortical engagement of subcortical structures that is necessary for expressing overt convulsive behaviors.
A
B
F 19.10 Two examples of rats with subtle convulsive SE in late lithium-pilocarpine SE. Both animals had periodic epileptiform discharges on EEG, with slight twitches (A) or no motor manifestations (B). In comparison with the earlier stage of continuous convulsive SE (see Figure 19.6, right column), these patterns suggest that at this late stage of SE, the SE anatomic substrate has spontaneously constricted to selective limbic areas, especially the hippocampus.
Very little is known about the SE anatomic substrate in such patients. Several animal studies have shown that very late in convulsive SE, only a few cerebral structures may continue to reveal hypermetabolism (76, 199) (Figure 19.10), indicating that SE has constricted to smaller cerebral territories. A similar process may occur in patients with lower amplitude, highly asymmetric spiking in subtle SE. Anticonvulsant drugs frequently suppress the behavioral expression of SE before successfully quenching electrographic SE. One well-known presentation of subtle SE is the patient who was treated with incremental doses of a benzodiazepine or phenytoin hours to days earlier without EEG confirmation of successful treatment, and now has clonic twitches. In such cases, the unwary clinician may have temporarily reduced the SE anatomic substrate to territories that are behaviorally ineloquent, as described earlier in this chapter. Alternatively, the sedative effects of the drug may have suppressed the behavioral manifestation of an unaltered seizure substrate.
258
:
Summary This chapter has reviewed anatomic concepts about partialonset SE. Notions of cerebral compartments engaged in SE initiation, recruitment, and spread, each compartment differing in the extent to which seizure termination mechanisms have been lost, provide a conceptual framework for the clinician treating SE and for the investigator attempting to understand SE mechanisms or devise better therapies. To solve the problem of refractory partial-onset SE, investigations should logically be directed to the refractory SE generator focus. With regard to subtle generalized status, little is understood about the underlying mechanisms; animal evidence suggests that multifactorial processes contribute to this state. This work was supported by the Department of Veterans Affairs and by the Epilepsy Foundation of America.
REFERENCES 1. Albertson, T. E. Effect of aminophylline on amygdaloidkindled postictal inhibition. Pharmacol. Biochem. Behav. 1986; 24:1599–1603. 2. 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.
3. Alonso-DeFlorida, F., and J. M. R. Delgado. Lasting behavioral and EEG changes in cats induced by prolonged stimulation of amygdala. Am. J. Physiol. 1958;193:223–229. 4. Araki, T., M. Kato, and T. Kobayashi. Limbic seizures originating in the olfactory bulb: An electro-behavioral and glucose metabolism study. Brain Res. 1995;693:207–216. 5. Assal, F., J. P. Papazyan, D. O. Slosman, P. Jallon, and G. W. Goerres. SPECT in periodic lateralized epileptiform discharges (PLEDs): A form of partial status epilepticus? Seizure 2001;10:260–265. 6. Bartolomeil, F., M. Guye, F. Wendling, et al. Fear, anger and compulsive behavior during seizure: Involvement of large scale fronto-temporal neural networks. Epileptic Disord. 2002; 4:235–241. 7. Behan, M., and L. B. Haberly. Intrinsic and efferent connections of the endopiriform nucleus in rat. J. Comp. Neurol. 1999;408:532–548. 8. Benabid, A. L., L. Minotti, A. Koudsie, A. de Saint Martin, and E. Hirsch. Antiepileptic effect of high-frequency stimulation of the subthalamic nucleus (corpus luysi) in a case of medically intractable epilepsy caused by focal dysplasia: A 30month follow-up. Technical case report. Neurosurgery 2002;50: 1385–1391. 9. Ben-Ari, Y., E. Tremblay, and O. P. Ottersen. Injections of kainic acid into the amygdaloid complex of the rat: An electrographic, clinical and histological study in relation to the pathology of epilepsy. Neuroscience 1980;5:515–528. 10. Ben-Ari, Y., E. Tremblay, D. Riche, G. Ghilini, and R. Naquet. Electrographic, clinical and pathological alterations following systemic administration of kainic acid, bicuculline and pentetrazole: Metabolic mapping using the deoxyglucose method with special reference to the pathology of epilepsy. Neuroscience 1981;6:1361–1391. 11. Bengzon, J., I. Kikvadze, M. Kokaia, and O. Lindvall. Regional forebrain noradrenalin release in response to focal and generalized seizures induced by hippocampal kindling stimulation. Eur. J. Neurosci. 1992;4:278–288. 12. Bernasconi, N., A. Bernasconi, F. Andermann, F. Dubeau, W. Feindel, and D. C. Reutens. Entorhinal cortex in temporal lobe epilepsy: A quantitative MRI study. Neurology 1999; 52:1870–1876. 13. Bernasconi, N., A. Bernasconi, Z. Caramanos, F. Dubeau, J. Richardson, F. Andermann, and D. L. Arnold. Entorhinal cortex atrophy in epilepsy patients exhibiting normal hippocampal volumes. Neurology 2001;56:1335–1339. 14. Bertram, E. H., P. S. Mangan, D. Zhang, C. A. Scott, and J. M. Williamson. The midline thalamus: alterations and a potential role in limbic epilepsy. Epilepsia 2001;42:967–978. 15. Boison, D., A. Huber, V. Padrun, N. Deglon, P. Aebischer, and H. Mohler. Seizure suppression by adenosine-releasing cells is independent of seizure frequency. Epilepsia 2002;43: 788–796. 16. Bonhaus, D. W., J. R. Walters, and J. O. McNamara. Activation of substantia nigra neurons: Role in the propagation of seizures in kindled rats. J. Neurosci. 1986;6:3024–3030. 17. Browning, R. A., and D. K. Nelson. Modification of electroshock and pentylenetetrazol seizure patterns in rats after precollicular transections. Exp. Neurol. 1986;93:546–556. 18. Cameron, A. A., I. A. Khan, K. N. Westlund, K. D. Cliffer, and W. D. Willis. The efferent projections of the periaqueductal gray in the rat: A Phaseolus vulgaris-leucoagglutinin study. I. Ascending projections. J. Comp. Neurol. 1995;351: 568–584.
19. Cameron, A. A., I. A. Khan, K. N. Westlund, and W. D. Willis. The efferent projections of the periaqueductal gray in the rat: A Phaseolus vulgaris-leucoagglutinin study. II. Descending projections. J. Comp. Neurol. 1995;351:585–601. 20. Canteras, N. S., and L. W. Swanson. Projections of the ventral subiculum to the amygdala, septum, and hypothalamus: A PHAL anterograde tract-tracing study in the rat. J. Comp. Neurol. 1992;324:180–194. 21. Carre, G., and C. Harley. DSP-4 treatment accelerates kindling. Exp. Neurol. 1986;94:812–816. 22. Cassidy, R. M., and K. Gale. Mediodorsal thalamus plays a critical role in the development of limbic motor seizures. J. Neurosci. 1998;18:9002–9009. 23. Catenoix, H., M. Guenot, J. Isnard, C. Fischer, F. Mauguiere, and P. Ryvlin. Intracranial, EEG study of seizure-associated nose wiping. Neurology 2004;63:1127–1129. 24. Chabardes, S., P. Kahane, L. Minotti, A. Koudsie, E. Hirsch, and A. L. Benabid. Deep brain stimulation in epilepsy with particular reference to the subthalamic nucleus. Epileptic Disord. 2002;4(Suppl 3):S83–S93. 25. Chastain, J. E., Jr., F. Samson, S. R. Nelson, and T. L. Pazdernik. Attenuation of cerebral glucose use in kainic acid-treated rats by diazepam. Eur. J. Pharmacol. 1987;142: 215–224. 26. Chen, L., Y. S. Chan, and W. H. Yung. GABAB receptor activation in the rat globus pallidus potently suppresses pentylenetetrazol-induced tonic seizures. J. Biomed. Sci. 2004; 11:457–464. 27. Chu, K., D. W. Kang, J. Y. Kim, K. H. Chang, and S. K. Lee. Diffusion-weighted magnetic resonance imaging in nonconvulsive status epilepticus. Arch. Neurol. 2001;58:993–998. 28. Clark, L. P. A clinical contribution to the irregular and unusual forms of status epilepticus. Am. J. Insanity. 1913–1914; 70:334–410. 29. Collins, R. C., C. Kennedy, L. Sokoloff, and F. Plum. Metabolic anatomy of focal motor seizures. Arch. Neurol. 1976;33: 536–542. 30. Collins, R. C., R. G. Tearse, and E. W. Lothman. Functional anatomy of limbic seizures: Focal discharges from medial entorhinal cortex in rat. Brain Res. 1983;280:25–40. 31. Conde, F., E. Maire-Lepoivre, E. Audinat, and F. Crepel. Afferent connections of the medial frontal cortex of the rat. II. Cortical and subcortical afferents. J. Comp. Neurol. 1995; 352:567–593. 32. Cornwall, J., and O. T. Phillipson. Afferent projections to the dorsal thalamus of the rat as shown by retrograde lectin transport. I. The mediodorsal nucleus. Neuroscience 1988;24: 1035–1049. 33. De Sarro, G., S. Patel, and B. S. Meldrum. Anticonvulsant action of a kainate antagonist gamma-D-glutamyl aminomethylsulphonic acid injected focally into the substantia nigra and entopeduncular nucleus. Eur. J. Pharmacol. 1986; 132:229–236. 34. Deransart, C., B. Hellwig, M. Heupel-Reuter, J. F. Leger, D. Heck, and C. H. Lucking. Single-unit analysis of substantia nigra pars reticulata neurons in freely behaving rats with genetic absence epilepsy. Epilepsia 2003;44:1513–1520. 35. Deransart, C., B. T. Le, C. Marescaux, and A. Depaulis. Role of the subthalamo-nigral input in the control of amygdalakindled seizures in the rat. Brain Res. 1998;807:78–83. 36. Deransart, C., B. T. Le-Pham, E. Hirsch, C. Marescaux, and A. Depaulis. Inhibition of the substantia nigra suppresses absences and clonic seizures in audiogenic rats, but not tonic
:
259
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51. 52.
53.
260
seizures: Evidence for seizure specificity of the nigral control. Neuroscience 2001;105:203–211. Deransart, C., C. Marescaux, and A. Depaulis. Involvement of nigral glutamatergic inputs in the control of seizures in a genetic model of absence epilepsy in the rat. Neuroscience 1996; 71:721–728. Deransart, C., V. Riban, B. T. Le, V. Hechler, C. Marescaux, and A. Depaulis. Evidence for the involvement of the pallidum in the modulation of seizures in a genetic model of absence epilepsy in the rat. Neurosci. Lett. 1999;265:131– 134. Deransart, C., L. Vercueil, C. Marescaux, and A. Depaulis. The role of basal ganglia in the control of generalized absence seizures. Epilepsy Res. 1998;32:213–223. D’Giano, C. H., C. Del, M. Garcia, H. Pomata, and A. L. Rabinowicz. Treatment of refractory partial status epilepticus with multiple subpial transection: Case report. Seizure 2001;10:382–385. Dhillon, A., and R. S. Jones. Laminar differences in recurrent excitatory transmission in the rat entorhinal cortex in vitro. Neuroscience 2000;99:413–422. Dinner, D. S., S. Neme, D. Nair, E. B. Montgomery, Jr., K. B. Baker, A. Rezai, et al. EEG and evoked potential recording from the subthalamic nucleus for deep brain stimulation of intractable epilepsy. Clin. Neurophysiol. 2002;113: 1391–1402. Doherty, J., K. Gale, and D. A. Eagles. Evoked epileptiform discharges in the rat anterior piriform cortex: Generation and local propagation. Brain Res. 2000;861:77–87. Duane, D. C., Y. T. Ng, H. L. Rekate, S. Chung, J. B. Bodensteiner, and J. F. Kerrigan. Treatment of refractory status epilepticus with hemispherectomy. Epilepsia 2004;45: 1001–1004. Dybdal, D., and K. Gale. Postural and anticonvulsant effects of inhibition of the rat subthalamic nucleus. J. Neurosci. 2000;20:6728–6733. Ebert, U., P. Wlaz, and W. Loscher. High susceptibility of the anterior and posterior piriform cortex to induction of convulsions by bicuculline. Eur. J. Neurosci. 2000;12:4195– 4205. Eder, H. G., A. Stein, and R. S. Fisher. Interictal and ictal activity in the rat cobalt/pilocarpine model of epilepsy decreased by local perfusion of diazepam. Epilepsy Res. 1997;29:17–24. Ehlers, C. L., D. K. Clifton, and C. H. Sawyer. Facilitation of amygdala kindling in the rat by transecting ascending noradrenergic pathways. Brain Res. 1980;189:274–278. Ekstrand, J. J., M. E. Domroese, D. M. Johnson, S. L. Feig, S. M. Knodel, M. Behan, et al. A new subdivision of anterior piriform cortex and associated deep nucleus with novel features of interest for olfaction and epilepsy. J. Comp. Neurol. 2001;434:289–307. El-Koussy, M., J. Mathis, K. O. Lovblad, F. Stepper, C. Kiefer, and G. Schroth. Focal status epilepticus: Follow-up by perfusion- and diffusion MRI. Eur. Radiol. 2002;12:568–574. Faingold, C. L. Neuronal networks in the genetically epilepsyprone rat. Adv. Neurol. 1999;79:311–321. Fauser, S., and A. Schulze-Bonhage. How large must an epileptic focus be to cause an electrographic status epilepticus: A case report. Clin. Neurophysiol. 2004;115:2274– 2279. Ferencz, I., G. Leanza, A. Nanobashvili, M. Kokaia, and O. Lindvall. Basal forebrain neurons suppress amygdala kindling
:
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
via cortical but not hippocampal cholinergic projections in rats. Eur. J. Neurosci. 2000;12:2107–2116. Ferencz, I., G. Leanza, A. Nanobashvili, Z. Kokaia, M. Kokaia, and O. Lindvall. Septal cholinergic neurons suppress seizure development in hippocampal kindling in rats: Comparison with noradrenergic neurons. Neuroscience 2001;102: 819–832. Fisher, R. S., S. Uematsu, G. L. Krauss, B. J. Cysyk, R. McPherson, R. P. Lesser, et al. Placebo-controlled pilot study of centromedian thalamic stimulation in treatment of intractable seizures. Epilepsia 1992;33:841–851. Fujikawa, D. G., H. H. Itabashi, A. Wu, and S. S. Shinmei. Status epilepticus-induced neuronal loss in humans without systemic complications or epilepsy. Epilepsia 2000;41:981– 991. Fukumoto, S., S. Tanaka, H. Tojo, K. Akaike, and M. Takigawa. Perirhinal cortical lesion suppresses the secondary generalization in kainic acid-induced limbic seizure. Psychiatry Clin. Neurosci. 2002;56:561–567. Gale, K., A. Pazos, R. Maggio, K. Japikse, and P. Pritchard. Blockade of GABA receptors in superior colliculus protects against focally evoked limbic motor seizures. Brain Res. 1993; 603:279–283. Garant, D. S., and K. Gale. Lesions of substantia nigra protect against experimentally induced seizures. Brain Res. 1983;273:156–161. Garant, D. S., and K. Gale. Substantia nigra-mediated anticonvulsant actions: Role of nigral output pathways. Exp. Neurol. 1987;97:143–159. Gernert, M., M. Fedrowitz, P. Wlaz, and W. Loscher. Subregional changes in discharge rate, pattern, and drug sensitivity of putative GABAergic nigral neurons in the kindling model of epilepsy. Eur. J. Neurosci. 2004;20:2377–2386. Gernert, M., and W. Loscher. Lack of robust anticonvulsant effects of muscimol microinfusions in the anterior substantia nigra of kindled rats. Eur. J. Pharmacol. 2001;432:35–41. Gernert, M., K. W. Thompson, W. Loscher, and A. J. Tobin. Genetically engineered GABA-producing cells demonstrate anticonvulsant effects and long-term transgene expression when transplanted into the central piriform cortex of rats. Exp. Neurol. 2002;176:183–192. Giguere, M., and P. S. Goldman-Rakic. Mediodorsal nucleus: areal, laminar, and tangential distribution of afferents and efferents in the frontal lobe of rhesus monkeys. J. Comp. Neurol. 1988;277:195–213. Giorgi, F. S., M. Ferrucci, G. Lazzeri, C. Pizzanelli, P. Lenzi, M. G. Alessandrl, et al. A damage to locus coeruleus neurons converts sporadic seizures into self-sustaining limbic status epilepticus. Eur. J. Neurosci. 2003;17:2593–2601. Gloveli, T., D. Schmitz, and U. Heinemann. Interaction between superficial layers of the entorhinal cortex and the hippocampus in normal and epileptic temporal lobe. Epilepsy Res. 1998;32:83–93. Groenewegen, H. J., E. Vermeulen-Van der Zee, A. te Kortschot, and M. P. Witter. Organization of the projections from the subiculum to the ventral striatum in the rat: A study using anterograde transport of Phaseolus vulgaris leucoagglutinin. Neuroscience 1987;23:103–120. Hamani, C., F. I. Ewerton, S. M. Bonilha, G. Ballester, L. E. Mello, and A. M. Lozano. Bilateral anterior thalamic nucleus lesions and high-frequency stimulation are protective against pilocarpine-induced seizures and status epilepticus. Neurosurgery 2004;54:191–195.
69. Handforth, A. Postseizure inhibition of kindled seizures by electroconvulsive shock. Exp. Neurol. 1982;78:483–491. 70. Handforth, A., and R. F. Ackermann. Electrogenic status epilepticus induced from numerous limbic sites. Epilepsy Res. 1993;15:21–26. 71. Handforth, A., and R. F. Ackermann. A hierarchy of seizure states in the electrogenic limbic status epilepticus model: Behavioral and electrographic observations of initial states and temporal progression. Epilepsia 1992;33:589–600. 72. Handforth, A., and R. F. Ackermann. Mapping of limbic seizure progressions utilizing the electrogenic status model and the 14C-2-deoxyglucose method. Brain Res. Rev. 1995;20: 1–23. 73. Handforth, A., J. Cheng, M. A. Mandelkern, and D. M. Treiman. Markedly increased metabolism of mesial temporal lobe in a case with PLEDs: Further evidence that PLEDs are a manifestation of partial status epilepticus. Epilepsia 1994;35:876–881. 74. Handforth, A., and D. M. Treiman. Effect of an adenosine antagonist and an adenosine agonist on status entry and severity in a model of limbic status epilepticus. Epilepsy Res. 1994;18:29–42. 75. Handforth, A., and D. M. Treiman. Functional mapping of the early stages of status epilepticus: A 14C-2-deoxyglucose study in the lithium-pilocarpine model in rat. Neuroscience 1995;64:1057–1073. 76. 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. 77. Handforth, A., and D. M. Treiman. A new, nonpharmacologic model of convulsive status epilepticus induced by electrical stimulation: Behavioral/electrographic observations and response to phenytoin and phenobarbital. Epilepsy Res. 1994;19:15–25. 78. Hashizume, K., and T. Tanaka. Multiple subpial transection in kainic acid-induced focal cortical seizure. Epilepsy Res. 1998;32:389–399. 79. Hirsch, E., L. Danober, S. Simler, A. Pereira de Vasconcelos, B. Maton, A. Nehlig, et al. The amygdala is critical for seizure propagation from brainstem to forebrain. Neuroscience 1997; 77:975–984. 80. Hodaie, M., R. A. Wennberg, J. O. Dostrovsky, and A. M. Lozano. Chronic anterior thalamus stimulation for intractable epilepsy. Epilepsia 2002;43:603–608. 81. Hosford, D. A., and J. O. McNamara. Microinjection of muscimol into entopeduncular nucleus suppresses pilocarpine but not maximal electroshock seizures in rats. Brain Res. 1988; 462:205–210. 82. Hsieh, P. F. Neuropathology of limbic status epilepticus induced by electrical stimulation of naive rats. Neurol. Res. 1999;21:399–403. 83. Iadarola, M. J., and K. Gale. Substantia nigra: site of anticonvulsant activity mediated by gamma-aminobutyric acid. Science 1982;218:1237–1240. 84. Imamura, S., S. Tanaka, K. Akaike, H. Tojo, M. Takigawa, and J. Kuratsu. Hippocampal transection attenuates kainic acid-induced amygdalar seizures in rats. Brain Res. 2001;897: 93–103. 85. Imamura, S., S. Tanaka, H. Tojo, S. Fukumoto, K. Uetsuhara, J. Kuratsu, and M. Takigawa. Kainic acidinduced perirhinal cortical seizures in rats. Brain Res. 1998; 800:323–327.
86. Javedan, S. P., R. S. Fisher, H. G. Eder, K. Smith, and J. Wu. Cooling abolishes neuronal network synchronization in rat hippocampal slices. Epilepsia 2002;43:574–580. 87. Jay, T. M., and M. P. Witter. Distribution of hippocampal CA1 and subicular efferents in the prefrontal cortex of the rat studied by means of anterograde transport of Phaseolus vulgaris-leucoagglutinin. J. Comp. Neurol. 1991;313:574–586. 88. Jerlicz, M., W. Kostowski, A. Bidzinski, M. Hauptman, and J. Dymecki. Audiogenic seizures in rats: Relation to noradrenergic neurons of the locus coeruleus. Acta Physiol. Pol. 1978;29:409–412. 89. Jimenez-Castellanos, J., Jr., and F. Reinoso-Suarez. Topographical organization of the afferent connections of the principal ventromedial thalamic nucleus in the cat. J. Comp. Neurol. 1985;236:297–314. 90. Kandel, A., and G. Buzsaki. Cerebellar neuronal activity correlates with spike and wave EEG patterns in the rat. Epilepsy Res. 1993;16:1–9. 91. Karlov, V. A. Focal cooling suppresses continued activity of epileptic focus in patients with partial status epilepticus. Epilepsia 2003;44:1605. 92. Kato, K., T. Masa, Y. Tawara, K. Kobayashi, T. Oka, A. Okabe, and S. Shiosaka. Dendritic aberrations in the hippocampal granular layer and the amygdalohippocampal area following kindled-seizures. Brain Res. 2001;901:281–295. 93. Kawaguchi, K., and R. P. Simon. Non-NMDA but not NMDA blockade at deep prepiriform cortex protects against hippocampal cell death in status epilepticus. Brain Res. 1997; 753:152–156. 94. Kelly, M. E., and D. C. McIntyre. Perirhinal cortex involvement in limbic kindled seizures. Epilepsy Res. 1996;26:233– 243. 95. Kerrigan, J. F., B. Litt, R. S. Fisher, S. Cranstoun, J. A. French, D. E. Blum, et al. Electrical stimulation of the anterior nucleus of the thalamus for the treatment of intractable epilepsy. Epilepsia 2004;45:346–354. 96. 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. 97. Kliot, M., and C. E. Poletti. Hippocampal afterdischarge: Differential spread of activity shown by the [14C]deoxyglucose technique. Science 1979;204:641–643. 98. Knowles, W. D. Normal anatomy and neurophysiology of the hippocampal formation. J. Clin. Neurophysiol. 1992;9:252–263. 99. Kodama, M., N. Yamada, K. Sato, T. Sato, K. Morimoto, and S. Kuroda. The insular but not the perirhinal cortex is involved in the expression of fully-kindled amygdaloid seizures in rats. Epilepsy Res. 2001;46:169–178. 100. Krahl, S. E., K. B. Clark, D. C. Smith, and R. A. Browning. Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulation. Epilepsia 1998;39:709–714. 101. Krettek, J. E., and J. L. Price. The cortical projections of the mediodorsal nucleus and adjacent thalamic nuclei in the rat. J. Comp. Neurol. 1977;171:157–191. 102. Krettek, J. E., and J. L. Price. Projections from the amygdaloid complex to the cerebral cortex and thalamus in the rat and cat. J. Comp. Neurol. 1977;172:687–722. 103. Krettek, J. E., and J. L. Price. Projections from the amygdaloid complex and adjacent olfactory structures to the entorhinal cortex and to the subiculum in the rat and cat. J. Comp. Neurol. 1977;172:723–752. 104. Krsek, P., M. Tichy, T. Belsan, J. Zamecnik, L. Paulas, L. Faladova, et al. Life-saving epilepsy surgery for status
:
261
105.
106.
107.
108. 109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
262
epilepticus caused by cortical dysplasia. Epileptic Disord. 2002; 4:203–208. Krumholz, A. Epidemiology and evidence for morbidity of nonconvulsive status epilepticus. J. Clin. Neurophysiol. 1999; 16:314–322 [discussion 353]. Lannes, B., M. Vergnes, C. Marescaux, A. Depaulis, G. Micheletti, J. M. Warter, and E. Kempf. Lesions of noradrenergic neurons in rats with spontaneous generalized nonconvulsive epilepsy. Epilepsy Res. 1991;9:79–85. Loddenkemper, T., A. Pan, S. Neme, K. B. Baker, A. R. Rezai, D. S. Dinner, et al. Deep brain stimulation in epilepsy. J. Clin. Neurophysiol. 2001;18:514–532. Loscher, W., and U. Ebert. The role of the piriform cortex in kindling. Prog. Neurobiol. 1996;50:427–481. Loscher, W., U. Ebert, H. Lehmann, C. Rosenthal, and G. Nikkhah. Seizure suppression in kindling epilepsy by grafts of fetal GABAergic neurons in rat substantia nigra. J. Neurosci. Res. 1998;51:196–209. 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. Lothman, E. W., and R. C. Collins. Kainic acid induced seizures: Metabolic, behavioral, electroencephalographic and neuropathological correlates. Brain Res. 1981;218:299– 318. Lothman, E. W., J. M. Hatlelid, and C. F. Zorumski. Functional mapping of limbic seizures originating in the hippocampus: A combined 2-deoxyglucose and electrophysiologic study. Brain Res. 1985;360:92–100. Ma, X., J. Liporace, M. J. O’Connor, and M. R. Sperling. Neurosurgical treatment of medically intractable status epilepticus. Epilepsy Res. 2001;46:33–38. Magdaleno-Madrigal, V. M., A. Valdes-Cruz, D. MartinezVargas, A. Martinez, S. Almazan, R. Fernandez-Mas, et al. Effect of electrical stimulation of the nucleus of the solitary tract on the development of electrical amygdaloid kindling in the cat. Epilepsia 2002;43:964–969. Maggio, R., and K. Gale. Seizures evoked from area tempestas are subject to control by GABA and glutamate receptors in substantia nigra. Exp. Neurol. 1989;105:184–188. Marchand, J. E., and N. Hagino. Afferents to the periaqueductal gray in the rat: A horseradish peroxidase study. Neuroscience 1983;9:95–106. McCown, T. J., G. E. Duncan, and G. R. Breese. Neuroanatomical characterization of inferior collicular seizure genesis: 2-deoxyglucose and stimulation mapping. Brain Res. 1991;567:25–32. McCown, T. J., G. E. Duncan, K. B. Johnson, and G. R. Breese. Metabolic and functional mapping of the neural network subserving inferior collicular seizure generalization. Brain Res. 1995;701:117–128. McCown, T. J., R. S. Greenwood, G. D. Frye, and G. R. Breese. Electrically elicited seizures from the inferior colliculus: A potential site for the genesis of epilepsy. Exp. Neurol. 1984;86:527–542. McIntyre, D. C. Amygdala kindling in rats: Facilitation after local amygdala norepinephrine depletion with 6hydroxydopamine. Exp. Neurol. 1980;69:395–407. McIntyre, D. C., J. C. Don, and N. Edson. Distribution of [14C]2-deoxyglucose after various forms and durations of status epilepticus induced by stimulation of a kindled amygdala focus in rats. Epilepsy Res. 1992;10:119–133.
:
122. McIntyre, D. C., and N. Edson. Facilitation of amygdala kindling after norepinephrine depletion with 6-hydroxydopamine in rats. Exp. Neurol. 1981;74:748–757. 123. McIntyre, D. C., and N. Edson. Kindling-based status epilepticus: Effect of norepinephrine depletion with 6hydroxydopamine. Exp. Neurol. 1989;104:10–14. 124. McIntyre, D. C., M. E. Kelly, and W. A. Staines. Efferent projections of the anterior perirhinal cortex in the rat. J. Comp. Neurol. 1996;369:302–318. 125. McIntyre, D. C., D. Nathanson, and N. Edson. A new model of partial status epilepticus based on kindling. Brain Res. 1982; 250:53–63. 126. McIntyre, D. C., J. Rajala, and N. Edson. Suppression of amygdala kindling with short interstimulus intervals: Effect of norepinephrine depletion. Exp. Neurol. 1987;95:391–402. 127. McNamara, J. O., M. T. Galloway, L. C. Rigsbee, and C. Shin. Evidence implicating substantia nigra in regulation of kindled seizure threshold. J. Neurosci. 1984;4:2410–2417. 128. Merrill, M. A., R. W. Clough, P. C. Jobe, and R. A. Browning. Role of the superior colliculus and the intercollicular nucleus in the brainstem seizure circuitry of the genetically epilepsy-prone rat. Epilepsia 2003;44:305–314. 129. Mesiwala, A. H., J. D. Kuratani, A. M. Avellino, T. S. Roberts, M. A. Sotero, and R. G. Ellenbogen. Focal motor seizures with secondary generalization arising in the cerebellum: Case report and review of the literature. J. Neurosurg. 2002;97: 190–196. 130. Miettinen, R., T. Kotti, J. Tuunanen, A. Toppinen, P. Riekkinen, Sr., and T. Halonen. Hippocampal damage after injection of kainic acid into the rat entorhinal cortex. Brain Res. 1998;813:9–17. 131. Mihaly, A., M. Szente, Z. Dubravcsik, B. Boda, E. Kiraly, T. Nagy, and A. Domonkos. Parvalbumin- and calbindincontaining neurons express c-fos protein in primary and secondary (mirror) epileptic foci of the rat neocortex. Brain Res. 1997;761:135–145. 132. Miller, J. W., M. E. Bardgett, and B. C. Gray. The role of the laterodorsal tegmental nucleus of the rat in experimental seizures. Neuroscience 1991;43:41–49. 133. Miller, J. W., B. C. Gray, and M. E. Bardgett. Characterization of cholinergic regulation of seizures by the midline thalamus. Neuropharmacology 1992;31:349–356. 134. Miller, J. W., B. C. Gray, and M. E. Bardgett. Effects of selective toxic lesions of cholinergic neurons of the laterodorsal tegmental nucleus on experimental seizures. Brain Res. 1992; 579:161–164. 135. Miller, J. W., B. C. Gray, and G. M. Turner. Role of the fastigial nucleus in generalized seizures as demonstrated by GABA agonist microinjections. Epilepsia 1993;34:973–978. 136. Miller, J. W., B. C. Gray, G. M. Turner, and M. E. Bardgett. An ascending seizure-controlling pathway in the medial brainstem and thalamus. Exp. Neurol. 1993;121:106–112. 137. Miller, J. W., C. M. Hall, K. D. Holland, and J. A. Ferrendelli. Identification of a median thalamic system regulating seizures and arousal. Epilepsia 1989;30:493–500. 138. Min, J. K., P. A. Valentine, and G. C. Teskey. Effect of complete and partial bilateral lesions of the deep cerebellar nuclei on amygdaloid kindling in rats. Epilepsia 1998;39:692–699. 139. Mirnajafi-Zadeh, J., M. Mortazavi, Y. Fathollahi, M. Alasvand Zarasvand, and M. Reza Palizvan. Effect of transient hippocampal inhibition on amygdaloid kindled seizures and amygdaloid kindling rate. Brain Res. 2002;954:220– 226.
140. Mirski, M. A., and J. A. Ferrendelli. Anterior thalamic mediation of generalized pentylenetetrazol seizures. Brain Res. 1986;399:212–223. 141. Mirski, M. A., and J. A. Ferrendelli. Interruption of the connections of the mammillary bodies protects against generalized pentylenetetrazol seizures in guinea pigs. J. Neurosci. 1987;7:662–670. 142. Mishra, P. K., R. L. Burger, A. F. Bettendorf, R. A. Browning, and P. C. Jobe. Role of norepinephrine in forebrain and brainstem seizures: Chemical lesioning of locus ceruleus with DSP4. Exp. Neurol. 1994;125:58–64. 143. Mohapel, P., D. K. Hannesson, L. L. Armitage, G. W. Gillespie, and M. E. Corcoran. Claustral lesions delay amygdaloid kindling in the rat. Epilepsia 2000;41:1095– 1101. 144. Mohapel, P., X. Zhang, G. W. Gillespie, J. Chlan-Fourney, D. K. Hannesson, S. M. Corley, et al. Kindling of claustrum and insular cortex: comparison to perirhinal cortex in the rat. Eur. J. Neurosci. 2001;13:1501–1519. 145. Moshe, S. L., R. Okada, and B. J. Albala. Ventromedial thalamic lesions and seizure susceptibility. Brain Res. 1985; 337:368–372. 146. Moyanova, S., S. Rousseva, and S. Dimov. Changes in the EEG-reactions to repetitive peripheral and central electrical stimulation by intraraphedorsal kainic acid in the cat. Methods Find. Exp. Clin. Pharmacol. 1987;9:39–47. 147. Nail-Boucherie, K., B. T. Le-Pham, C. Marescaux, and A. Depaulis. Suppression of absence seizures by electrical and pharmacological activation of the caudal superior colliculus in a genetic model of absence epilepsy in the rat. Exp. Neurol. 2002;177:503–514. 148. Neuman, R. S., and P. M. Thompson. Serotonin mediates suppression of focal epileptiform activity induced by noxious stimulation. Epilepsia 1989;30:307–313. 149. Ng, Y. T., H. L. Kim, and J. W. Wheless. Successful neurosurgical treatment of childhood complex partial status epilepticus with focal resection. Epilepsia 2003;44:468–471. 150. N’Gouemo, P., and C. L. Faingold. The periaqueductal grey is a critical site in the neuronal network for audiogenic seizures: Modulation by GABAA, NMDA and opioid receptors. Epilepsy Res. 1999;35:39–46. 151. N’Gouemo, P., M. Lerner-Natoli, G. Rondouin, K. Watanabe, F. Sandillon, A. Privat, and M. Baldy-Moulinier. Catecholaminergic systems and amygdala kindling development: Effects of bilateral lesions of substantia nigra dopaminergic or locus coeruleus noradrenergic neurones. Epilepsy Res. 1990;5:92–102. 152. Omori, N., T. Ishimoto, F. Mutoh, and S. Chiba. Kindling of the midbrain periaqueductal gray in rats. Brain Res. 2001;903: 162–167. 153. Pasini, A., A. Tortorella, and K. Gale. The anticonvulsant action of fluoxetine in substantia nigra is dependent upon endogenous serotonin. Brain Res. 1996;724:84–88. 154. Patel, S., M. H. Millan, L. M. Mello, and B. S. Meldrum. 2Amino-7-phosphonoheptanoic acid (2-APH) infusion into entopeduncular nucleus protects against limbic seizures in rats. Neurosci. Lett. 1986;64:226–230. 155. Paz, C., F. Gutierrez-Baeza, and B. Bazan-Perkins. Transection of the superior cerebellar peduncle interferes with the onset and duration of generalized seizures induced by amygdaloid kindling. Brain Res. 1991;558:90–92. 156. Pereira de Vasconcelos, A., A. M. Mazarati, C. G. Wasterlain, and A. Nehlig. Self-sustaining status epilepticus
157.
158.
159.
160. 161.
162.
163.
164.
165.
166. 167.
168.
169.
170.
171.
172.
173.
174.
after a brief electrical stimulation of the perforant path: A 2deoxyglucose study. Brain Res. 1999;838:110–118. Pereira de Vasconcelos, A., M. Vergnes, S. Boyet, C. Marescaux, and A. Nehlig. Forebrain metabolic activation induced by the repetition of audiogenic seizures in Wistar rats. Brain Res. 1997;762:114–120. Peterson, S. L., J. J. Armstrong, and M. K. Walker. Focal microinjection of carbachol into the periaqueductal gray induces seizures in the forebrain of the rat. Epilepsy Res. 2000;42:169–181. Pinel, J. P. J., and L. J. Rovner. Experimental epileptogenesis: Kindling-induced epilepsy in rat. Exp. Neurol. 1978;58:190– 202. Piredda, S., and K. Gale. A crucial epileptogenic site in the deep prepiriform cortex. Nature 1985;317:623–625. Racine, R., and D. V. Coscina. Effects of midbrain raphe lesions or systemic p-chlorophenylalanine on the development of kindled seizures in rats. Brain Res. Bull. 1979;4: 1–7. Room, P., F. T. Russchen, H. J. Groenewegen, and A. H. Lohman. Efferent connections of the prelimbic (area 32) and the infralimbic (area 25) cortices: An anterograde tracing study in the cat. J. Comp. Neurol. 1985;242:40–55. Royce, G. J., and R. J. Mourey. Efferent connections of the centromedian and parafascicular thalamic nuclei: An autoradiographic investigation in the cat. J. Comp. Neurol. 1985; 235:277–300. Rubio, C., V. Custodio, F. Juarez, and C. Paz. Stimulation of the superior cerebellar peduncle during the development of amygdaloid kindling in rats. Brain Res. 2004;1010:151–155. Sadikot, A. F., A. Parent, and C. Francois. Efferent connections of the centromedian and parafascicular thalamic nuclei in the squirrel monkey: A PHA-L study of subcortical projections. J. Comp. Neurol. 1992;315:137–159. Saposnik, G., and L. R. Caplan. Convulsive-like movements in brainstem stroke. Arch. Neurol. 2001;58(4):654–657. Sawamura, A., K. Hashizume, and T. Tanaka. Electrophysiological, behavioral and metabolical features of globus pallidus seizures induced by a microinjection of kainic acid in rats. Brian Res. 2002;935:1–8. Sazgar, M., P. L. Carlen, and R. Wennberg. Panic attack semiology in right temporal lobe epilepsy. Epileptic Disord. 2003;5:93–100. Schwabe, K., U. Ebert, and W. Loscher. Bilateral lesions of the central but not anterior or posterior parts of the piriform cortex retard amygdala kindling in rats. Neuroscience 2000; 101:513–521. Schwabe, K., U. Ebert, and W. Loscher. Bilateral microinjections of vigabatrin in the central piriform cortex retard amygdala kindling in rats. Neuroscience 2004;129:425–429. Schwabe, K., U. Ebert, and W. Loscher. The central piriform cortex: Anatomical connections and anticonvulsant effect of GABA elevation in the kindling model. Neuroscience 2004; 126:727–741. Schwabe, K., U. Ebert, and W. Loscher. Effects of lesions of the perirhinal cortex on amygdala kindling in rats. Epilepsy Res. 2000;42:33–41. Schwarcz, R., T. Eid, and F. Du. Neurons in layer III of the entorhinal cortex: A role in epileptogenesis and epilepsy? Ann. N.Y. Acad. Sci. 2000;911:328–342. Sheerin, A. H., K. Nylen, X. Zhang, D. M. Saucier, and M. E. Corcoran. Further evidence for a role of the anterior claustrum in epileptogenesis. Neuroscience 2004;125:57–62.
:
263
175. Shehab, S., P. Dean, and P. Redgrave. The dorsal midbrain anticonvulsant zone–II. Efferent connections revealed by the anterograde transport of wheatgerm agglutinin-horseradish peroxidase from injections centred on the intercollicular area in the rat. Neuroscience 1995;65:681–695. 176. Shehab, S., J. Guadagno, K. Ferguson, and P. Redgrave. Regional distribution of the anticonvulsant and behavioural effects of bicuculline injected into the pontine reticular formation of rats. Eur. J. Neurosci. 1997;9:1875–1884. 177. Shehab, S., M. Simkins, P. Dean, and P. Redgrave. The dorsal midbrain anticonvulsant zone–I. Effects of locally administered excitatory amino acids or bicuculline on maximal electroshock seizures. Neuroscience 1995;65:671–679. 178. Shehab, S., M. Simkins, P. Dean, and P. Redgrave. The dorsal midbrain anticonvulsant zone–III. Effects of efferent pathway transections on suppression of electroshock seizures and defence-like reactions produced by local injections of bicuculline. Neuroscience 1995;65:697–708. 179. Shehab, S., M. Simkins, P. Dean, and P. Redgrave. Regional distribution of the anticonvulsant and behavioural effects of muscimol injected into the substantia nigra of rats. Eur. J. Neurosci. 1996;8:749–757. 180. Shibata, H. Topographic organization of subcortical projections to the anterior thalamic nuclei in the rat. J. Comp. Neurol. 1992;323:117–127. 181. Shibata, H., and A. Kato. Topographic relationship between anteromedial thalamic nucleus neurons and their cortical terminal fields in the rat. Neurosci. Res. 1993;17:63– 69. 182. Silveira, D. C., G. L. Holmes, S. C. Schachter, C. Geula, and D. L. Schomer. Increased susceptibility to generalized seizures after immunolesions of the basal forebrain cholinergic neurons in rats. Brain Res. 2000;878:223–227. 183. Simler, S., M. Vergnes, and C. Marescaux. Spatial and temporal relationships between C-Fos expression and kindling of audiogenic seizures in Wistar rats. Exp. Neurol. 1999;157: 106–119. 184. Stein, A. G., H. G. Eder, D. E. Blum, A. Drachev, and R. S. Fisher. An automated drug delivery system for focal epilepsy. Epilepsy Res. 2000;39:103–114. 185. Swanson, L. W., and W. M. Cowan. An autoradiographic study of the organization of the efferent connections of the hippocampal formation in the rat. J. Comp. Neurol. 1977;172: 49–84. 186. Taber, K. H., J. J. McNamara, and S. F. Zornetzer. Status epilepticus: A new rodent model. Electroencephalogr. Clin. Neurophysiol. 1977;43:707–724. 187. Thompson, K., V. Anantharam, S. Behrstock, E. Bongarzone, A. Campagnoni, and A. J. Tobin. Conditionally immortalized cell lines, engineered to produce and release GABA, modulate the development of behavioral seizures. Exp. Neurol. 2000;161:481–489. 188. Thompson, K. W., and L. M. Suchomelova. Transplants of cells engineered to produce GABA suppress spontaneous seizures. Epilepsia 2004;45:4–12. 189. Thompson, P. M., G. Zebrowski, and R. S. Neuman. Alteration of neocortical activity in response to noxious stimulation: Participation of the dorsal raphe. Neuropharmacology 1991;30:135–141. 190. 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.
264
:
191. Tremblay, E., L. N. Nitecka, M. L. Berger, and Y. Ben-Ari. Maturation of kainic acid seizure-brain damage syndrome in the rat. I. Clinical, electrographic and metabolic observations. Neuroscience 1984;13:1051–1072. 192. Tremblay, E., O. P. Ottersen, C. Rovira, and Y. Ben-Ari. Intra-amygdaloid injections of kainic acid: Regional metabolic changes and their relation to the pathological alterations. Neuroscience 1983;8:299–315. 193. Turski, W. A., E. A. Cavalheiro, L. S. Calderazzo-Filho, Z. Kleinrok, S. J. Czuczwar, and L. Turski. Injections of picrotoxin and bicuculline into the amygdaloid complex of the rat: An electroencephalographic, behavioral and morphological analysis. Neuroscience 1985;14:37–53. 194. Turski, L., S. Diedrichs, T. Klockgether, M. Schwarz, W. A. Turski, K. H. Sontag, et al. Paradoxical anticonvulsant activity of the gamma-aminobutyrate antagonist bicuculline methiodide in the rat striatum. Synapse 1991;7:14–20. 195. Turski, L., B. S. Meldrum, E. A. Cavalheiro, L. S. CalderazzoFilho, Z. A. Bortolotto, C. Ikonomidou-Turski, and W. A. Turski. Paradoxical anticonvulsant activity of the excitatory amino acid N-methyl--aspartate in the rat caudate-putamen. Proc. Natl. Acad. Sci. U.S.A. 1987;84:1689–1693. 196. Van Groen, T., and J. M. Wyss. Extrinsic projections from area CA1 of the rat hippocampus: Olfactory, cortical, subcortical, and bilateral hippocampal formation projections. J. Comp. Neurol. 1990;302:515–528. 197. Van Groen, T., and J. M. Wyss. Projections from the anterodorsal and anteroventral nucleus of the thalamus to the limbic cortex in the rat. J. Comp. Neurol. 1995;358:584–604. 198. Vander, T., M. Medvedovsky, and Y. Herishanu. Epilepsia partialis continua possibly caused by cerebellar lesion. Cerebellum 2004;3:126–128. 199. VanLandingham, K. E., and E. W. Lothman. Self-sustaining limbic status epilepticus. I. Acute and chronic cerebral metabolic studies: Limbic hypermetabolism and neocortical hypometabolism. Neurology 1991;41:1942–1949. 200. Velasco, F., M. Velasco, A. L. Velasco, F. Jimenez, I. Marquez, and M. Rise. Electrical stimulation of the centromedian thalamic nucleus in control of seizures: Long-term studies. Epilepsia 1995;36:63–71. 201. Velasco, M., F. Velasco, A. L. Velasco, F. Jimenez, F. Brito, and I. Marquez. Acute and chronic electrical stimulation of the centromedian thalamic nucleus: Modulation of reticulocortical systems and predictor factors for generalized seizure control. Arch. Med. Res. 2000;31:304–315. 202. Velisek, L., J. Veliskova, and S. L. Moshe. Electrical stimulation of substantia nigra pars reticulata is anticonvulsant in adult and young male rats. Exp. Neurol. 2002;173:145–152. 203. Veliskova, J., and S. L. Moshe. Sexual dimorphism and developmental regulation of substantia nigra function. Ann. Neurol. 2001;50:596–601. 204. Veliskova, J., L. Velsek, and S. L. Moshe. Subthalamic nucleus: A new anticonvulsant site in the brain. Neuroreport 1996;7:1786–1788. 205. Walker, B. R., A. Easton, and K. Gale. Regulation of limbic motor seizures by GABA and glutamate transmission in nucleus tractus solitarius. Epilepsia 1999;40:1051–1057. 206. Watson, R. E., Jr., H. M. Edinger, and A. Siegel. A [14C]2deoxyglucose analysis of the functional neural pathways of the limbic forebrain in the rat. III. The hippocampal formation. Brain Res. Rev. 1983;5:133–176. 207. Watson, R. E., Jr., R. Troiano, J. Poulakos, S. Weiner, C. H. Block, and A. Siegel. A [14C]2-deoxyglucose analysis of the
208.
209.
210.
211.
212.
213.
214.
215.
216.
217.
218.
219.
functional neural pathways of the limbic pathways of the limbic forebrain in the rat. I. The amygdala. Brain Res. Rev. 1983;5:1–44. White, L. E., and J. L. Price. The functional anatomy of limbic status epilepticus in the rat. I. Patterns of 14C-2deoxyglucose uptake and fos immunocytochemistry. J. Neurosci. 1993;13:4787–4809. White, L. E., and J. L. Price. The functional anatomy of limbic status epilepticus in the rat. II. The effects of focal deactivation. J. Neurosci. 1993;13:4810–4830. Witter, M. P., and H. J. Groenewegen. Connections of the parahippocampal cortex in the cat. III. Cortical and thalamic efferents. J. Comp. Neurol. 1986;252:1–31. Witter, M. P., and H. J. Groenewegen. Connections of the parahippocampal cortex in the cat. IV. Subcortical efferents. J. Comp. Neurol. 1986;252:51–77. Wright, G. D., D. L. McLellan, and J. G. Brice. A doubleblind trial of chronic cerebellar stimulation in twelve patients with severe epilepsy. J. Neurol. Neurosurg. Psychiatry 1984;47: 769–774. Wyss, J. M. An autoradiographic study of the efferent connections of the entorhinal cortex in the rat. J. Comp. Neurol. 1981;199:495–512. Wyss, J. M., and T. Van Groen. Connections between the retrosplenial cortex and the hippocampal formation in the rat: A review. Hippocampus 1992;2:1–11. Yakimovskii, A. Activation of neostriatal dopaminergic system in rats prevents toxic effects of picrotoxin administered into globus pallidus. Bull. Exp. Biol. Med. 2000;130: 737–738. Yang, L., C. Long, and C. L. Faingold. Neurons in the deep layers of superior colliculus are a requisite component of the neuronal network for seizures during ethanol withdrawal. Brain Res. 2001;920:134–141. Yang, X. F., D. W. Duffy, R. E. Morley, and S. M. Rothman. Neocortical seizure termination by focal cooling: Temperature dependence and automated seizure detection. Epilepsia 2002;43:240–245. Yang, X. F., and S. M. Rothman. Focal cooling rapidly terminates experimental neocortical seizures. Ann. Neurol. 2001;49:721–726. Zhang, X., D. K. Hannesson, D. M. Saucier, A. E. Wallace, J. Howland, and M. E. Corcoran. Susceptibility to kindling and neuronal connections of the anterior claustrum. J. Neurosci. 2001;21:3674–3687.
:
265
20
Role of GABAA Receptors in Status Epilepticus
.
Introduction Most seizures are relatively brief and self-terminating. During some seizures, however, early termination fails and status epilepticus (SE) ensues. One hypothesis for the development of SE is that activation of g-aminobutyric acid (GABA) receptor-mediated inhibition is responsible for normal termination of a seizure. If the GABAergic inhibition fails to terminate the seizure, a progressive reduction of GABAA receptor-mediated inhibition develops that, when severe enough, results in a prolonged self-sustained seizure (24). There is experimental support for this hypothesis. Prolonged hippocampal seizures reduce GABA receptormediated inhibition (20), and this reduction of inhibition can reliably predict the occurrence of SE (20). The treatment of SE in humans also suggests a role for GABA receptors, since SE is treated with the benzodiazepines diazepam, lorazepam, and midazolam and the barbiturates phenobarbital and pentobarbital, all of which exert their anticonvulsant effect by enhancing GABA-mediated inhibition (65). The GABA receptor is the site of action of many of the antiepileptic drugs used to treat SE in humans, and there is direct evidence of altered properties of hippocampal GABA receptors during SE. Thus, it is important to characterize the functional properties of GABA receptors and the effect of SE on these properties in order to understand the pathogenesis and treatment of SE.
Recombinant and native GABA receptors P S R GABA R GABA is the major inhibitory neurotransmitter in the central nervous system (CNS). GABA is released from GABAergic neurons and binds to several types of GABA receptors, including GABAA, GABAB, and GABAC receptors. GABAA receptors mediate most fast inhibition in the CNS and are macromolecular proteins that contain specific binding sites for GABA and for multiple allosteric regulators, including picrotoxin, barbiturates, benzodiazepines, and the anesthetic steroids, and form a chloride ion-selective channel. Based on sequence similarity, eight different GABAA receptor subunit families have been identified, the a, b, g, d,
e, p, q, and r subunits. There is 30%–40% sequence identity among the subunit families. About 20%–30% sequence homology exists among all GABAA receptor subunit candidates and other gene products of the superfamily (13, 47, 56). Most of the subunit families have multiple members (a1–6, b1–4, g1–4, and r1–3), and all of the sequences within each subunit family are homologous, with about 70%–80% amino acid sequence identity (Table 20.1). Additional diversity arises from splice variants, described so far for g2, b2, and b4 subtypes subunits (1, 28, 29, 72). Each GABAA receptor subunit cDNA encodes for a polypeptide of about 50 kd, with putative N-glycosylation sites and four a-helical hydrophobic membrane-spanning regions (47, 56). Between the third and fourth membrane-spanning region is a hydrophilic putative cytoplasmic region of highly variable sequence involved in intracellular regulatory mechanisms such as phosphorylation. The current understanding of the molecular structure of the GABAA receptor-ion channel complex is that it is a heteropentameric glycoprotein of about 275 kd, composed of combinations of multiple polypeptide subunits. The subunits form a quasi-symmetric structure around the ion channel, with each subunit contributing to the wall of the channel (47). The model is based on the nicotinic acetylcholine receptor, another member of the ligand-gated ion channel gene superfamily, and on electron microscopic image analysis of the native GABAA receptors (42). However, the number of each subtype and their stoichiometry remain uncertain. The GABAA receptor is generally thought to be composed of combinations of a, b, g, d, and possibly e subunits. The r subunit forms homopentameric GABAC receptors in the retina. The role of the q and p subunits remain uncertain. P R GABAA R The pharmacologic properties of GABAA receptors depend on subunit subtype composition. Benzodiazepine sensitivity of GABAA receptors differs when different a subtypes are combined with b and g subunits (27, 50, 51, 68, 69) (Table 20.2). The a1bg subunits produce diazepam- and zolpidemsensitive BZ 1 GABAA receptors, a2bg and a3bg subunits produce BZ 2a,b GABAA receptors with high diazepam and
:
267
low zolpidem sensitivity, a5bg subunits produce BZ 2c GABAA receptors with high diazepam sensitivity that are zolpidem insensitive, and a4 or a6bg subunits produce BZ 3 GABAA receptors that are benzodiazepine insensitive. Barbiturates bind to an allosteric regulatory site on the GABAA receptor, but the subunit location of the barbituratebinding site is unknown. There is growing evidence of the structural diversity of native GABAA receptors derived from whole brain. The distribution of mRNAs in the CNS as determined by in situ hybridization is very different for each subunit subtype. For example, the r subunit is expressed primarily in the retina (9), while various a, b, and g subtypes and the one d subtype show very different regional as well as developmental distributions (e.g., 30, 31, 73). Immunoprecipitation studies have shown that different specific combinations of GABAA receptor subtypes occur in the different regions of the brain. McKernan et al. (37) found that a majority of native GABAA
T 20.1 GABAA receptor subunit subtypes Subunit
No. of subtypes No. of splice variants Size range (kd) % AA homology intrafamily % AA homology interfamily
a
b
g
d
e
6 0 48–64 70–80
4 2 51 70–80
4 1 48 70–80
1 0 48 NA
1 0 ? ?
30–40
30–40
30–40
30–40
?
receptors contain only a single a subtype, and that a1, a2, a3, or a5 subtypes exist in combination with a b and a g2 subtype. d Subunit-specific serum was found to precipitate a specific set of GABAA receptors that contained a1, a3b2/3g2 subtypes, but not the a5 subtype (41). Partial colocalization suggests some tentative major oligomeric assemblies: for example, Wisden et al. (73) propose the likely existence of at least five combinations: a1b2g2, a2b3gx, a5b1gx, a1a4b2d, and a1a6b2d. They also note that the g1 subunit is limited to the limbic regions of amygdala, hypothalamus, and septum.
Hippocampal GABAA receptors It is likely that multiple specific GABAA receptor isoforms are expressed in the hippocampus. The existence of GABAA receptor isoforms has been demonstrated by in vivo and in vitro pharmacologic studies. Immunopurification and in situ hybridization studies have shown that the subtypes display a heterogeneous distribution in the CNS. Experiments using subunit-specific antibodies for quantitative immunopurification of GABAA receptors from specific regions of the CNS and comparison of the identified subunit combinations with the localization of the corresponding mRNA has allowed initial identification of the subunit composition of some GABAA receptor isoforms. Hippocampal dentate granule cells can potentially express GABAA receptors with distinct properties, since they express high levels of specific GABAA receptor subtype mRNAs. In situ hybridization studies have demonstrated that dentate granule cells primarily express mRNAs for a1,2,4, b1,3, g1,2, and d1 GABAA receptor subunit subtypes. Which subtypes assemble to form native granule cell GABAA receptor(s) is unknown. a4, b1, g1, and d1 subtype mRNAs have a restricted distribution in the
T 20.2 Subunit-specific pharmacologic properties of GABAA receptors Pharmacologic Property Benzodiazepine sensitivity High benzodiazepine affinity (nM BZ affinity) BZ 1 pharmacology (high zolpidem affinity) BZ 2a,b pharmacology (low zolpidem affinity) BZ 2c pharmacology (zolpidem insensitive) BZ 3 pharmacology (BZR agonist insensitive) High zinc sensitivity (IC50 < 10 mM) Low zinc sensitivity (IC50 > 100 mM) Moderate zinc sensitivity (IC50 10–100 mM) Enhancement by loreclezole High furosemide sensitivity (IC50 < 10 mM) Moderate furosemide sensitivity (IC50 0.1–1 mM) Low furosemide sensitivity (IC50 > 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 (<30 minutes) and the anticonvulsant action is late (6–24 hours and 1–48 hours, respectively).
convulsant with a short latency when given intracerebroventricularly (1CV) in mice or injected focally into the brain in rats (44, 90, 91). They induce a broad range of seizure phenomena, including limbic seizures when injected in limbic structures. In neonatal rats, systemically administered 1S,3R-ACPD (16 mg/kg IP) is convulsant (62). There are multiple mechanisms by which group I receptor activation can facilitate seizure activity. Some of those that have been identified using intracellular recording techniques are listed in Table 23.4. Blockade of accommodation is an effect seen at low agonist concentration that is likely to favor a wide range of seizure phenomena. Potentiation of NMDA responses (38, 46, 53) is also a powerful effect that seems to depend on two mechanisms, one of which involves phosphorylation by PKC (76, 92). 1S,3R ACPD and other group I agonists can act presynaptically to potentiate excitatory postsynaptic potentials (63). Adenosine A1 receptor activation acts presynaptically to decrease excitatory transmission in the hippocampus. This effect is attenuated by group I agonists such as 3,5-DHPG, apparently by activating PKC (31). Such an effect might come into play during SE because of the concomitant release of adenosine and glutamate. The concentrations of agonists that have been injected focally in many experiments (79, 90, 91) are, however, sufficiently high to cause widespread depolarization (59). It is clear that a facilitation of mGlu1 and mGlu5 responses during seizure activity could contribute to the activity becoming sustained and refractory to treatment.
308
:
T 23.4 Mechanisms of convulsant action of group I agonists 1. Block accommodation to sustained current 2. Depolarize neuronal membrane a. Decrease potassium currents b. Promote Na+/Ca2+ exchange 3. Enhance NMDA receptor responses 4. Enhance AMPA receptor responses 5. Enhance glutamate release 6. Presynaptic block of GABAergic transmission 7. Decrease in inhibitory effect of adenosine A1 receptor activation
G I A (S)-4C3HPG ((S)4-carboxy-3hydroxyphenylglycine) is a potent group I antagonist (but also a group II agonist) that has an immediate transient anticonvulsant action when injected ICV in DBA/2 mice or focally in GEP rats (29, 44, 89). Other group I antagonists that do not act as group II agonists, such as AIDA (1aminoindan-1,5-dicarboxylic acid) (70) and LY 367385 (2methyl-4-carboxyphenylglycine) (26) are also acutely anticonvulsant when injected ICV in mice or focally intracerebrally in rats (21). Two noncompetitive antagonists that are highly selective for mGlu5, MPEP and SIB1893, are also anticonvulsant in a wide range of seizure models when given intracerebrally or systemically (23). These observations suggest that activation of group I mGluRs occurs during a
wide variety of seizures and contributes significantly to the progression and maintenance of seizure activity. G II G III A A Agonists of group II (L-CCG-I, 1S,3S-ACPD) and group III (LAP4, L-SOP) receptors can produce an early transient proconvulsant effect following ICV injection in mice or focal intracerebral injection in rats. Group III agonists can also produce, with a delayed onset, prolonged anticonvulsant effects following ICV injection in mice or focal injection in rats (87). L-AP4 delivered into the rat amygdala 20 minutes prior to amygdala stimulation can block both epileptogenesis and fully kindled seizures (1). PPG, a group III agonist with preferential action on mGlu8, is anticonvulsant when given intracerebrally in mouse epilepsy models (22). One group III antagonist with a limited spectrum of activity, MCPA, also has acute anticonvulsant effects when given ICV in mice (44).
mGluRs in in vitro models of epilepsy and SE The effects of mGluR agonists and antagonists on interictal and ictal activity induced in hippocampal slice preparations by a variety of convulsive agents have been reported (8, 78). Trans-1-aminocyclopentane-1,3-dicarboxylic acid (TransACPD) enhances the rate of interictal spiking induced by bicuculline or 4-aminopyridine (78). The transition from interictal spiking to ictal discharges in the presence of 4aminopyridine is prevented by the nonspecific mGluR antagonist MCPG (8). The frequency of repetitive bursting induced by picrotoxin in CA3 is decreased by MCPG (66). The frequency is increased by the preferential group II agonists L-CCGI, 1S,3R-ACPD, (S)-4CPG, and RS-4C3HPG. These data have been interpreted as showing that released glutamate is activating mGluRs during seizure activity.
Changes in metabotropic responses associated with amygdaloid kindling in the rat A variety of changes have been described in glutamate metabotropic receptor–mediated responses in the amygdala and hippocampus during and after the process of kindling induced by unilateral electrical stimulation of the amygdala. These changes may participate in the process of epileptogenesis or they may be a response to events that are secondary to seizure activity. Similar events may occur as a consequence of status, and may contribute to epileptogenesis after SE. A potentiation of group I–mediated responses has been repeatedly described in amygdala-kindled rats. Increases in phosphoinositide hydrolysis induced by quisqualate or ibotenate are seen in both the hippocampus and the amygdala, but are sustained only in the amygdala (3, 4). Electrophysi-
ologic studies in basolateral amygdala neurons contralateral to the kindling site reveal a variety of changes. The depolarization associated with mGlu1 or mGlu5 activation is potentiated in the kindled animal (48). This depolarization is at least partially dependent on potentiation of Na+/Ca2+ exchange. A hyperpolarizing response evoked by activation of group II receptors by L-CCG-1 ((2S,3S,4S)-a(carboxycyclopropyl)glycine-1) or 1S,3R-ACPD is decreased in the basolateral amygdala contralateral to the kindled amygdala (48). The presynaptic inhibitory effect of group II and group III receptors is, however, potentiated in the kindled amygdala (73). In contrast, in hippocampal-kindled rats, the inhibitory action of a group III agonist, L-SOP, on dentate responses to lateral perforant path stimulation (PPS) is diminished (53). A change of this sort could contribute to the enhanced excitability in the fully kindled state. Interestingly, a similar reduction in group III effects has been observed with lateral PPS in hippocampal slices from temporal lobectomies in patients with complex partial seizures and Ammon’s horn sclerosis (31, 32). Studies utilizing in situ hybridization to measure changes in mRNA show altered expression of mGlu1 and mGlu5 in the hippocampus associated with the process of kindling (2). Whereas mGlu1 mRNA is increased in dentate granule cells and CA3 pyramidal cells 24 hours after the last fully kindled seizure, mGlu5 mRNA is decreased in these structures at this time. These changes are not sustained at later time points and would appear to be a consequence of the seizure or a transient phenomenon related to kindling rather than the basis of the kindled state.
Actions on excitotoxic brain damage, in vitro and in vivo A variety of studies suggest that group II and group III metabotropic receptor agonists tend both to suppress SE and to prevent neuronal damage secondary to status. For example, NMDA receptor activation and the associated entry of Ca2+ contribute critically to loss of CA1 and CA3 pyramidal neurons in experimental models of SE (65). Drugs that block the postsynaptic excitatory effect of NMDA receptor activation, such as dizocilpine, protect against hippocampal pyramidal cell loss in limbic status induced by kainate (37, 58). In cortical cultures, the excitotoxic action of NMDA is attenuated by the broad-spectrum mGlu agonist trans-ACPD (55). This effect can be reproduced with compounds that act preferentially as agonists on group II receptors, such as (S)-4-carboxy-3-hydroxy-phenylglycine and (2s,1¢r,2¢r)-2-(2,3-dicarboxy cyclopropyl)glycine (DCGIV) (14, 15, 18, 19, 78). A similar effect has recently been reported for group III agonists (16). The most probable explanation for this effect is that NMDA receptor activation enhances the formation of cAMP (through
:
309
calcium-calmodulin activation of adenylyl cyclase) (25). Activation of cAMP-dependent tyrosine kinases leads to the phosphorylation (and potentiation) of NMDA receptors and the activation of voltage-dependent Ca2+ channels such that more Ca2+ enters the neurons (24, 46). The presynaptic effects of group II and III agonists apparently depend on a decreased entry of Ca2+ through voltagedependent channels and consequent reduction of glutamate and GABA release (86).
Transition from interictal to ictal state and from seizures to SE The in vivo pharmacologic data indicate that the three groups of mGluR all play significant roles in seizure activity. A key question that is not yet answered is whether they play a determining role in the key transitions from interictal to ictal activity and from seizures that are self-limiting to SE. That they might play a critical role in the transition to the ictal state is suggested, for example, by evidence that extracellular glutamate concentration rises in the human hippocampus prior to the onset of complex partial seizures (36). This is consistent with a reduction in the effectiveness of presynaptic mGluRs in reducing glutamate release (as observed in hippocampal kindling) (20, 53) contributing to seizure onset. Similarly, the reduction in expression of mGluR2 occurring as a result of sustained seizure activity (6) could contribute to its persistence. Attempts have been made to address these issues in slice preparations by measuring changes in the frequency or duration of burst discharges (induced by GABAergic blocking agents or 4-aminopyridine) in the presence of drugs acting on subsets of mGluRs (see, e.g., 60, 71). However, the data are complex and difficult to interpret in the in vivo context.
Changes in mGluRs as a consequence of SE Published studies on changes in glutamate metabotropic receptors following SE concern three rodent models: prolonged seizures induced by kainic acid (6, 45, 60), by pilocarpine (57, 87, 88), or by electrical stimulation (7) (Table 23.5). Functional changes in mGluRs were studied by Mayat et al. (62). These authors induced limbic SE lasting about 12 hours in adult Sprague-Dawley rats by unilateral intraamygdaloid injection of kainic acid. Inositol phosphate (IP) formation following stimulation by ibotenate or trans-ACPD was measured in synaptoneurosomes from hippocampus or entorhinal cortex and in hippocampal slices. IP formation was increased in hippocampal slices 7, 14, and 42 days after the limbic status (but not in synaptoneurosomal preparations, or at other times [1 day and 92 days] in hippocampal slices). The cellular location and significance of this finding are not known. The change presumably involves mGlu1 and
310
:
T 23.5 Long-term changes in glutamate metabotropic receptors found in the limbic system following status epilepticus in rodents, electrical kindling in rodents, and in mesial temporal sclerosis in man Rats: Kainate status Group I responses potentiated (62) Rats: Pilocarpine status Group II effects potentiated (34) Decreased effect of group III agonists (? on mGlu8) (57) Reduced presynaptic inhibition by mGluR7 (13) Rats: Electrical status Astrocytic mGlu2/3 and mGlu5 upregulated (7) Rats: Electrical kindling Group I excitatory effects potentiated (3, 4, 48) Inhibitory effects of group II receptors potentiated in amygdala (73) Group III responses decreased in molecular layer (hippocampal kindling) (53) Group III responses unchanged in molecular layer (amygdala kindling) (39) Humans: Mesial temporal sclerosis Group III responses decreased in hippocampus (31, 32)
mGlu5, and may occur predominantly in glial cells. It may be related to the occurrence of spontaneous seizures. There is some similarity to the enhanced PI formation seen in the amygdala and hippocampus after kindling (3). A study of the mossy fiber pathway 2 weeks after kainate-induced SE (45) showed a loss of paired-pulse facilitation and of long-term potentiation. The releasable pool of glutamate was enhanced. An in situ hybridization study of mRNA for the mGluRs revealed changes in mGlu2 and mGlu4 mRNA in the rat hippocampus 24 hours after the onset of kainic acid seizures (6). mGlu2 expression is reduced in the dentate granule cell layer in rat pups (10 days) and adults (40 days). mGlu4 expression is enhanced in CA3 pyramidal neurons in pups. It is possible that this latter change, by enhancing the presynaptic inhibitory action of glutamate, contributes to the relative lack of vulnerability of CA3 neurons to epileptic brain damage at this developmental stage in the rat. Long-term changes in mGluRs have been studied after seizures induced by pilocarpine. This model is of particular interest because it has been possible to correlate functional changes with the occurrence of spontaneous seizures by comparing field excitatory postsynaptic potentials in hippocampal slices from rats showing, or not showing, spontaneous seizures (57). The depressant effect of the group III agonists -AP4 (-2-amino-4-phosphonic acid) and PPG ((R,S)-4-phosphonophenylglycine) was much reduced in the rats with spontaneous seizures. This is interpreted as indicating a downregulation of presynaptic mGlu8, which reduces the normal negative feedback provided following
glutamate release, and thus facilitates excessive excitatory transmission. Surprisingly, a study employing immunohistochemistry and immunoelectron microscopy has found an upregulation of mGlu8 in all layers of CA1 7–31 days after SE induced by pilocarpine (89). This effect, however, appears to be due to an abnormal expression of mGlu8 in reactive astrocytes, the functional significance of which is unknown. In the same model, immunoreactivity for mGluR1a showed a complex pattern of changes at 1–31 days (87). A potentiation of group II presynaptic receptors on the excitatory input to hilar border interneurons of the dentate gyrus in rats having experienced pilocarpine-induced SE was postulated by Doherty and Dingledine (34) on the basis of alterations in short-term depression of granule cell inputs induced by selective agonists and antagonists. Study of field excitatory postsynaptic potentials (EPSPs) in the medial and lateral perforant path in mouse hippocampal slices showed that the presynaptic inhibitory effect of mGluR7 activation (by AP4) was reduced in the latent period (3–9 days) after pilocarpine-induced SE (13). The mediation by mGluR7 was shown by the similar changes in wild-type and mGluR4/mGluR8 knockout mice. The effects of mGluR8 activation on lateral perforant path EPSPs were not changed after pilocarpine-induced SE (13). Chronic spontaneous seizures are also observed subsequent to SE induced by 1 hour of electrical angular bundle stimulation (7). Immunolabeling studies show a marked upregulation in the expression of mGlu2/3 and mGlu5 that corresponds to astrocytic activation, as shown by vimentin or GFAP colocalization. There is a particular mechanism by which metabotropic receptor expression can be modified following seizures that may be responsible for some of the long-term consequences of SE. A prominent consequence of severe or sustained seizure activity is enhanced expression of immediate early genes, followed by an increased expression of some neurotrophins, such as NGF, bFGF, and BDNF (10, 40–42, 56). This in turn leads to an increased expression of mGlu5 (68).
Summary Glutamate metabotropic receptors participate in acute seizures and in the process of epileptogenesis. Their expression and function is modified during and after SE. Group I receptor activation is epileptogenic, and enhanced group I function may contribute to epileptogenesis in kindling and in temporal lobe epilepsy. Diminished group III receptor function, with a reduction in presynaptic inhibition of glutamatergic inputs, may contribute to epileptogenesis in kindling, in limbic seizures following SE in rodents, and in complex partial seizures associated with Ammon’s horn sclerosis. Drugs acting as antagonists at
group I receptors are anticonvulsant, as are some agonists for group II and III receptors. These compounds provide potential therapies for epilepsy and for SE. REFERENCES 1. Abdul-Ghani, A.-S., P. J. E. Attwell, N. S. Kent, H. F. Bradford, M. J. Croucher, and D. E. Jane. Antiepileptogenic and anticonvulsant activity of -2-amino-4-phosphonobutyrate, a presynaptic glutamate receptor agonist. Brain Res. 1997;755: 202–212. 2. Akbar, M. T., M. Rattray, J. F. Powell, and B. S. Meldrum. Altered expression of group I metabotropic glutamate receptors in the hippocampus of amygdala-kindled rats. Brain Res. Mol. Biol. 1996;43:105–116. 3. Akiyama, K., A. Daigen, N. Yamada, T. Itoh, 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. Akiyama, K., N. Yamada, and S. Otsuki. Lasting increase in excitatory amino acid receptor–mediated polyphosphoinositide hydrolysis in the amygdala/pyriform cortex of amygdalakindled rats. Brain Res. 1989;485:95–101. 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. Aronica, E., E. A. van Vliet, O. A. Mayboroda, D. Troost, F. H. da Silva, and J. A. Gorter. Upregulation of metabotropic glutamate receptor subtype mGlu3 and mGlu5 in reactive astrocytes in a rat model of mesial temporal lobe epilepsy. Eur J. Neurosci. 2000;12:2333–2344. 8. Arvanov, V. L., K. H. Holmes, N. B. Keele, and P. ShinnickGallagher. The functional role of metabotropic glutamate receptors in epileptiform activity induced by 4-aminopyridine in the rat amygdala slice. Brain Res. 1995;669:140–144. 9. Balázs, R., S. Miller, C. Romano, A. de Vries, Y. Chun, and C. Cotman. Metabotropic glutamate receptor mGluR5 in astrocytes: Pharmacological properties and agonist regulation. J. Neurochem. 1997;69:151–163. 10. Bengzon, J., S. Söderström, Z. Kokaia, et al. Widespread increase of nerve growth factor protein in the rat forebrain after kindling-induced seizures. Brain Res. 1992;587: 338–342. 11. Blümcke, I., K. Behle, B. Malitshek, R. Kuhn, T. Knöpfel, H. K. Wolf, and O. D. Wiestler. Immunohistochemical distribution of metabotropic glutamate receptor subtypes mGluR1b, mGluR2/3, mGluR4a and mGluR5 in human hippocampus. Brain Res. 1996;736:217–226. 12. Boss, V., K. M. Nutt, and P. J. Conn. L-cysteine sulfinic acid as an endogenous agonist of a novel metabotropic receptor coupled to stimulation of phospholipase D activation. Mol. Pharmacol. 1994;45:1177–1182. 13. Bough, K. J., D. D. Mott, and R. J. Dingledine. Medial perforant path inhibition mediated by mGluR7 is reduced after status epilepticus. J. Neurophysiol. 2004;92:1549–1557. 14. Bruno, V., G. Battaglia, A. Copani, et al. Activation of class II or III metabotropic glutamate receptors protects cultured
:
311
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
cortical neurons against excitotoxic degeneration. Eur. J. Neurosci. 1995;7:1906–1913. Bruno, V., A. Copani, G. Battaglia, R. Raffaele, H. Shinozaki, and F. Nicoletti. Protective effect of the metabotropic glutamate receptor agonist, DCG-IV, against excitotoxic neuronal death. Eur. J. Pharmacol. 1994;256:109–112. Bruno, V., A. Copani, L. Bonanno, et al. Activation of group III metabotropic glutamate receptors is neuroprotective in cortical cultures. Eur. J. Pharmacol. 1996;310:61–66. Bruno, V., A. Copani, T. Knöpfel, et al. Activation of metabotropic glutamate receptors coupled to inositol phospholipid hydrolysis amplifies NMDA-induced neuronal degeneration in cultured cortical cells. Neuropharmacology 1995;34: 1089–1098. Buisson, A., and D. W. Choi. The inhibitory mGluR agonist, S-4-carboxy-3-hydroxy-phenylglycine selectively attenuates NMDA neurotoxicity and oxygen glucose deprivation–induced neuronal death. Neuropharmacology 1995;34:1081–1087. Buisson, A., S. P. Yu, and D. W. Choi. DCG-IV selectively attenuates rapidly triggered NMDA-induced neurotoxicity in cortical neurons. Eur. J. Neurosci. 1996;8:138–143. Bushell, T. J., D. E. Jane, H. W. Tse, J. C. Watkins, J. Garthwaite, and G. L. Collingridge. Pharmacological antagonism of the actions of group II and group III mGluR agonists in the lateral perforant path of rat hippocampal slices. Br. J. Pharmacol. 1996;117:1457–1462. Chapman, A. G., K. Nanan, M. Williams, and B. S. Meldrum. Anticonvulsant activity of two metabotropic glutamate group I antagonists selective for the mGlu5 receptor, 2-methyl6-(phenylethynyl)-pyridine (MPEP), and (E)-6-methyl-2styryl-pyridine (SIB 1893). Neuropharmacology 2000;39: 1567–1574. Chapman, A. G., K. Nanan, P. Yip, and B. S. Meldrum. Anticonvulsant activity of a metabotropic glutamate receptor 8 preferential agonist, (R,S)-4-phosphonophenylglycine. Eur. J. Pharmacol. 1999;383:23–27. Chapman, A. G., P. K. Yip, J. S. Yap, L. P. Quinn, E. Tang, J. R. Harris, and B. S. Meldrum. Anticonvulsant actions of LY 367385 ((+)-2-methyl-4-carboxyphenylglycine) and AIDA (R,S)-1-aminoindan-1,5-dicarboxylic acid. Eur. J. Pharmacol. 1999;368:17–24. Chetkovich, D. M., R. Gray, D. Johnston, and J. D. Sweatt. Nmethyl--aspartate receptor activation increases cAMP levels and voltage-gated Ca++ channel activity in CA1 of hippocampus. Proc. Natl. Acad. Sci. U.S.A. 1991;88:6467–6471. Chetkovich, D. M., and J. D. Sweatt. NMDA receptor activation increases cyclic AMP in area CA1 of the hippocampus via calcium/calmodulin stimulation of adenylyl cyclase. J. Neurochem. 1993;61:1933–1942. Clark, B. P., S. R. Baker, J. Goldsworthy, J. R. Harris, and A. E. Kingston. 2-Methyl-4-carboxy-phenylglycine (LY367385) selectively antagonises metabotropic glutamate mGluR1 receptors. Bioorg. Med. Chem. Lett. 1997;7:2777–2780. Conn, P. J., and J. P. Pin. Pharmacology and functions of metabotropic glutamate receptors. Annu. Rev. Pharmacol. Toxicol. 1997;37:205–237. Copani, A., V. M. G. Bruno, V. Barresi, G. Battaglia, D. F. Condorelli, and F. Nicoletti. Activation of metabotropic glutamate receptors prevents neuronal apoptosis in culture. J. Neurochem. 1995;64:101–108. Dalby, N. O., and C. Thomsen. Modulation of seizure activity in mice by metabotropic glutamate receptor ligands. J. Pharmacol. Exp. Ther. 1996;276:516–522.
312
:
30. De Mendonça, A., and J. A. Ribeiro. Influence of metabotropic glutamate receptor agonists on the inhibitory effects of adenosine A1 receptor activation in the rat hippocampus. Br. J. Pharmacol. 1997;121:1541–1548. 31. Dietrich, D., H. Clusmann, T. Kral, C. Steinhauser, I. Blümcke, U. Heinemann, and J. Schramm. Two electrophysiologically distinct types of granule cells in epileptic human hippocampus. Neuroscience 1999;90:1197–1206. 32. 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. 33. Doherty, A. J., M. J. Palmer, J. M. Henley, G. L. Collingridge, and D. E. Jane. (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) activates mGlu5, but not mGlu1, receptors expressed in CHO cells and potentiates NMDA responses in rat hippocampal slices. Neuropharmacology 1997;36:265–267. 34. Doherty, J., and R. Dingledine. Reduced excitatory drive onto interneurons in the dentate gyrus after status epilepticus. J. Neurosci. 2001;21:2048–2057. 35. Dowd, L. A., and M. B. Robinson. Rapid stimulation of EAAC-1 mediated Na+-dependent -glutamate transport activity in C6 Glioma cells by phorbol ester. J. Neurochem. 1996;67:508–516. 36. During, M. J., and D. D. Spencer. Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet 1993;341:1607–1610. 37. Fariello, R. G., G. T. Golden, G. G. Smith, and P. F. Reyes. Potentiation of kainic acid epileptogenicity and sparing from neuronal damage by an NMDA receptor antagonist. Epilepsy Res. 1989;3:206–213. 38. Fitzjohn, S. M., A. J. Irving, M. J. Palmer, J. Harvey, D. Lodge, and G. L. Collingridge. Activation of Group I mGluRs potentiates NMDA responses in rat hippocampal slices. Neurosci. Lett. 1996;203:211–213. 39. Friedl, M., H. Clusmann, T. Kral, D. Doetrich, and J. Schramm. Analysing metabotropic glutamate group III receptor mediated modulation of synaptic transmission in the amygdala-kindled dentate gyrus of the rat. Brain Res. 1999; 821:117–123. 40. Gall, C. M. Seizure-induced changes in neurotrophin expression: Implications for epilepsy. Exp. Neurol. 1993;124:150–166. 41. Gall, C. M., R. Berschauer, and P. J. Isackson. Seizures increase basic fibroblast growth factor mRNA in adult rat forebrain neurons and glia. Mol. Brain Res. 1994;21:190–205. 42. Gall, C., K. Murray, and P. J. Isackson. Kainic acid–induced seizures stimulate increased expression of nerve growth factor mRNA in rat hippocampus. Mol. Brain Res. 1991;9:113–123. 43. Gasparini, F., K. Lingenhöhl, N. Stoehr, P. J. Flor, M. Heinrich, I. Vranesic, et al. 2-Methyl-6-(phenylethynyl)pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 1999;38: 1493–1504. 44. Ghauri, M., A. G. Chapman, and B. S. Meldrum. Convulsant and anticonvulsant actions of agonists and antagonists of group III mGluRs. Neuroreport 1996;7:1469–1474. 45. Goussakov, I. V., K. Fink, C. E. Elger, and H. Beck. Metaplasticity of mossy fiber synaptic transmission involves altered release probability. J. Neurosci. 2000;20:3434–3441. 46. Greengard, P., J. Jen, A. C. Nairn, and C. F. Stevens. Enhancement of the glutamate response by cAMP-dependent protein kinase in hippocampal neurons. Science 1991;253: 1135–1138.
47. Harvey, J., and G. L. Collingridge. Signal transduction pathways involved in the acute potentiation of NMDA responses by (1S,3R)-ACPD in rat hippocampal slices. Br. J. Pharmacol. 1993;109(10):85–1090. 48. 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. 49. Kingston, A. E., J. Lowndes, N. Evans, B. Clark, R. Tomlinson, J. P. Burnett, et al. Sulfur-containing amino acids are agonists for group 1 metabotropic receptors expressed in clonal RGT cell lines. Neuropharmacology 1998;37:277–287. 50. Kinoshita, A., H. Ohishi, A. Neki, S. Nomura, R. Shigemoto, M. Takada, et al. Presynaptic localization of a metabotropic glutamate receptor, mGluR8, in the rhinencephalic areas: A light and electron microscope study in the rat. Neurosci. Lett. 1996;207:61–64. 51. Klein, J., M. Iovino, M. Vakil, H. Shinozaki, and K. Löffelholz. Ontogentic and pharmacological studies on metabotropic receptors coupled to phospholipase D activation. Neuropharmacology 1997;36:305–311. 52. Klein, J., K. G. Reymann, and G. Riedel. Activation of phospholipases C and D by the novel metabotropic glutamate receptor agonist tADA. Neuropharmacology 1997;36:261–263. 53. Klapstein, G. J., B. S. Meldrum, and I. Mody. Decreased sensitivity to group III mGluR agonists in the rat lateral perforant path following kindling. Neuropharmacology 1999;38:927–934. 54. Klitgaard, H., and P. Laudrup. Metabotropic excitatory amino acid receptor agonists selectively potentiate behavioural effects induced by ionotropic excitatory amino acid receptor agonists in mice. Eur. J. Pharmacol. 1993;250:9–13. 55. Koh, J., E. Palmer, and C. W. Cotman. Activation of the metabotropic glutamate receptor attenuates N-methyl-aspartate neurotoxicity in cortical cultures. Proc. Natl. Acad. Sci. U.S.A. 1991;88:9431–9435. 56. Kornblum, H. I., R. Sankar, D. H. Shin, C. G. Wasterlain, and C. M. Gall. Induction of brain derived neurotrophic factor mRNA by seizures in neonatal and juvenile rat brain. Mol. Brain Res. 1997;44:219–228. 57. Kral, T., E. Erdmann, D. Sochivko, H. Clusmann, J. Schramm, and D. Dietrich. Down-regulation of mGluR8 in pilocarpine epileptic rats. Synapse 2003;47:278–284. 58. Lerner-Natoli, M., G. Rondouin, M. Belaidi, M. BaldyMoulinier, and J. M. Kamenka. N-[1-(2-thienyl)cyclohexyl] piperidine (TCP) does not block kaininc acid–induced status epilepticus but reduces secondary hippocampal damage. Neurosci. Lett. 1991;122:174–178. 59. Libri, V., A. Constanti, M. Zibetti, and M. Postlethwaite. Metabotropic glutamate receptor subtypes mediating slow inward tail current (Iadp) induction and inhibition of synaptic transmission in olfactory cortical neurones. Br. J. Pharmacol. 1997;120:1083–1095. 60. Lin, F. F., M. Varney, A. I. Sacaan, et al. Cloning and stable expression of the mGluR1b subtype of human metabotropic receptors and pharmacological comparison with the mGluR5a subtype. Neuropharmacology 1997;36:917–931. 61. Macek, T. A., D. G. Winder, R. W. Gereau, C. O. Ladd, and P. J. Conn. Differential involvement of group II and group III mGluRs as autoreceptors at lateral and medial perforant path synapses. J. Neurophysiol. 1996;76:3798–3806. 62. Mayat, E., M. Lerner-Natoli, G. Rondouin, F. Lebrun, I. Sasetti, and M. Recasens. Kainate-induced status epilepticus leads to a delayed increase in various specific glutamate
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75. 76.
77.
78.
79.
80.
metabotropic receptor responses in the hippocampus. Brain Res. 1994;645:186–200. McBain, C. J., T. J. CiChiara, 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. McDonald, J. W., A. S. Fix, J. P. Tizzano, and D. D. Schoepp. Seizures and brain injury in neonatal rats induced by 1S, 3RACPD, a metabotropic glutamate receptor agonist. J. Neurosci. 1993;13:4445–4455. Meldrum, B. S. Epileptic brain damage: A consequence and a cause of seizures. First Alfred Meyer Lecture. Neuropathol. Appl. Neurobiol. 1997;23:185–201. Merlin, L. R., G. W. Taylor, and R. K. Wong. Role of metabotropic glutamate receptor subtypes in the pattern of epileptic activity in vitro. J. Neurophysiol. 1995;74:896–900. Miller, S., C. Romano, and C. W. Cotman. Growth factor upregulation of a phosphoinositide-coupled metabotropic glutamate receptor in cortical astrocytes. J. Neurosci. 1995;15: 6103–6109. Miller, S., N. Sehati, C. Romano, and C. W. Cotman. Exposure to thrombin reduces levels of the metabotropic glutamate receptor mGluR5. J. Neurochem. 1996;67:1435–1447. Moldrich, R. X., and P. M. Beart. Emerging signalling and protein interaction mediated via metabotropic glutamate receptors. Curr. Drug Targets CNS Neurol. Disord. 2003;2:593–602. Moroni, F., G. Lombardi, C. Thomsen, P. Leonardi, S. Attucci, F. Peruginelli, et al. Pharmacological characterization of 1aminoindan-1,5-dicarboxylic acid. J. Pharmacol. Exp. Ther. 1997;281:721–729. Nakahara, K., M. Okada, and S. Nakanishi. The metabotropic glutamate receptor mGluR5 induces calcium oscillations in cultured astrocytes via protein kinase C phosphorylation. J. Neurochem. 1997;69:1467–1475. Nakanishi, S. Metabotropic glutamate receptors: Synaptic transmission, modulation and plasticity. Neuron 1994;13: 1031–1037. 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. Pellegrini-Giampietro, D. E., S. A. Torregrossa, and F. Moroni. Pharmacological characterization of metabotropic glutamate receptors coupled to phospholipase D in the rat hippocampus. Br. J. Pharmacol. 1996;118:1035–1043. Pin, J.-P., and R. Duvoisin. The metabotropic glutamate receptors: Structure and functions. Neuropharmacology 1995;34:1–26. Pisani, A., P. Calabresi, D. Centonze, and G. Bernardi. Enhancement of NMDA responses by group I metabotropic glutamate receptor activation in striatal neurones. Br. J. Pharmacol. 1997;120:1007–1014. Renaud, J., M. Emond, S. Meilleur, C. Psarropoulou, and L. Carmant. AIDA, a class I metabotropic glutamate-receptor antagonist limits kainite-induced hippocampal dysfunction. Epilepsia 2002;43:1306–1317. Rutecki, P. A., and Y. Yang. Metabotropic glutamate receptor activation modulates epileptiform activity in the hippocampus. Neuroscience 1997;81:927–935. Sacaan, A. I., and D. D. Schoepp. Activation of hippocampal metabotropic excitatory amino acid receptors leads to seizures and neuronal damage. Neurosci. Lett. 1992;139:77–81. Saugstad, J. A., J. M. Kinzie, M. M. Shinohara, T. P. Segerson, and G. L. Westbrook. Cloning and expression of rat
:
313
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
metabotropic glutamate receptor 8 reveals a distinct pharmacological profile. Molec. Pharmacol. 1997;51:119–125. Scanziani, M., P. A. Salin, K. E. Vogt, R. C. Malenka, and R. A. Nicoll. Use-dependent increases in glutamate concentration activate presynaptic metabotropic glutamate receptors. Nature 1997;385:630–634. Schoepp, D. D., and P. J. Conn. Metabotropic glutamate receptors in brain function and pathology. Trends Pharmacol. Sci. 1993;14:13–20. Schoepp, D. D., D. E. Jane, and J. A. Monn. Pharmacological agents acting at subtypes of metabotropic glutamate receptors. Neuropharmacology 1999;38:1431–1476. Shigemoto, R., A. Kulik, J. D. B. Roberts, H. Ohishi, Z. Nusse, T. Kaneko, and P. Somogyi. Target-cell-specific concentration of a metbotropic glutamate receptor in the presynaptic active zone. Nature 1996;381:523–525. Shigemoto, R., A. Kinoshita, E. Wada, S. Nomura, H. Ohishi, M. Takada, et al. Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus. J. Neurosci. 1997;17:7503–7522. Takahashi, T., I. D. Forsythe, T. Tsujimoto, M. Barnes-Davies, and K. Onodera. Presynaptic calcium current modulation by a metabotropic glutamate receptor. Science 1996;274:594–597. Tang, E., P. K. Yip, A. G. Chapman, D. E. Jane, and B. S. Meldrum. Prolonged anticonvulsant action of glutamate metabotropic agonists in inferior colliculus of GEP rats. Eur. J. Pharmacol. 1997;327:109–115. Tang, F. R., W. L. Lee, J. Yang, M. K. Sim, and E. A. Ling. Expression of metabotropic glutamate receptor 1 alpha in the hippocampus of rat pilocarpine model of status epilepticus. Epilepsy Res. 2001;46:179–189. Tang, F. R., W. L. Lee, J. Yang, M. K. Sim, and E. A. Ling. Metabotropic glutamate receptor 8 in the rat hippocampus after pilocarpine induced status epilepticus. Neurosci. Lett. 2001;300:137–140. Tizzano, J. P., K. I. Griffey, J. A. Johnson, A. S. Fix, D. R. Helton, and D. D. Schoepp. Intracerebral 1S,3R-1aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) produces limbic seizures that are not blocked by ionotropic glutamate receptor antagonists. Neurosci. Lett. 1993;162:12–16. Tizzano, J. P., K. I. Griffey, and D. D. Schoepp. Induction or protection of limbic seizures in mice by mGluR subtype selective agonists. Neuropharmacology 1995;34:1063–1067. Ugolini, A., M. Corsi, and F. Bordi. Potentiation of NMDA and AMPA responses by group I mGluR in spinal cord motoneurons. Neuropharmacology 1997;35:1047–1055. Varney, M. A., N. D. P. Cosford, C. Jachec, S. P. Rao, A. Sacaan, F. F. Lin, et al. SIB-1757 and SIB-1893: Selective, noncompetitive antagonists of metabotropic glutamate receptor type 5. J. Pharmacol. Exp. Ther. 1999;290:170–181. Wang, L.-Y., M. W. Salter, and J. F. Macdonald. Regulation of kainate receptors by cAMP-dependent protein kinase and phosphatases. Science 1991;253:1132–1135. Wang, Y. T., and M. W. Salter. Regulation of NMDA receptors by tyrosine kinases and phosphatases. Nature 1994;369: 233–235. Winder, D. G., and P. J. Conn. Roles of metabotropic glutamate receptors in glial function and glial-neuronal communication. J. Neurosci. Res. 1996;46:131–137. Wroblewska, B., J. T. Wroblewski, S. Pshenichkin, A. Surin, S. E. Sullivan, and J. H. Neale. N-acetylaspartylglutamate selectively activates mGluR3 receptors in transfected cells. J. Neurochem. 1997;69:174–181.
314
:
24
The Role of Adenosine in Status Epilepticus
T the prolonged seizure disorder status epilepticus (SE) has long been subject to intensive research. Extensive experimental evidence using animal models of SE implicate an imbalance in excitatory glutamatergic and inhibitory GABAergic neurotransmission underlying SE development, yet no general consensus for either mechanism exists. It is now increasingly evident that a defect solely in one or the other is too simplistic. An alternative approach to investigating the underlying mechanisms of SE generation may involve asking whether SE represents a continuum of brief seizures or a distinct form of seizure activity. In various animal models (9, 58, 78, 79), SE does not begin as an unlimited seizure but builds up gradually, starting with discrete seizures that become more frequent, eventually merging into self-sustaining and continuous or cyclic epileptiform activity. Electrographic seizure activity and the stereotypic progression through various motor seizure behaviours during the initial stages of experimental SE resemble that observed with brief seizures and during kindling development (102). This supports the view that early SE does not represent a new type of seizure activity but may result from a prolongation of brief seizures. The link between a defect in seizure termination mechanisms and SE is supported by the finding that pilocarpine administered to kindled animals immediately following a seizure that would normally terminate spontaneously causes the spontaneous resumption of seizures and SE (15). In addition, aminophylline and the A1-adenosine receptor antagonist 8-cyclopentyl 1,3-dimethylxanthine (8-CPT) abolishes ictal-interictal cycling induced by penicillin (47). Therefore, an alternative approach to unraveling the cause of SE may be to investigate the brain’s own capacity to terminate seizures and protect against further seizure episodes.
Failure of seizure termination mechanisms Epileptic seizures are typically brief (1–2 minutes) and selflimiting, even in the absence of anticonvulsant medication, and the brain remains refractory to further seizure attacks for a period of time after the seizure (the postictal refractory period). GABAergic mechanisms are likely to be involved in
seizure termination mechanisms and there is some support for this contention. Stringer and Lothman (113) have characterized a stereotyped form of paroxysmal event in the dentate gyrus that can be used as a marker for reverberatory seizure activity in the hippocampal formation called maximal dentate activation (MDA). MDA has the propensity to lengthen when repeatedly elicited and has quantifiable parameters. The time to onset of MDA is used as an indicator of the ease with which seizure activity can be initiated, while the duration of MDA is an indicator of the ability of the system to terminate seizures (113). The GABAA receptor antagonists bicuculline and picrotoxin lengthen MDA, and conversely, muscimol, a GABAA agonist, and baclofen, a GABAB agonist, shorten MDA but have little effect on the time to onset of MDA (114). This suggests that GABAergic mechanisms are more important in seizure termination than seizure initiation mechanisms. However, if GABAergic mechanisms played a significant role in seizure termination, then administration of GABA receptor antagonists should prolong the duration of brief seizures. Although there is some evidence to support this conjecture, the majority of studies show that subconvulsant doses of GABA antagonists have no effect on kindled seizures, suggesting that endogenous GABA is not involved in seizure termination. For example, the GABAA antagonists bicuculline and picrotoxin do enhance secondary generalization after amygdaloid kindling (87), yet norharmane, a benzodiazepine inverse agonist, failed to promote secondary generalization. Similarly, other studies have found that picrotoxin does not affect the duration of amygdala-kindled seizures (68). In addition, GABAA antagonists also do not augment pilocarpineinduced seizures to cause SE (120), nor does bicuculline alter either the ictal or interictal phases of penicillin-induced SE (47), suggesting that activation of GABAA receptors is probably not involved in seizure arrest mechanisms (28). A more favourable hypothesis has been proposed (26, 28). It has been postulated that the seizure-induced liberation of endogenous anticonvulsant substances is involved in seizure termination and postictal protection from further seizure episodes, as shown in Figure 24.1 (26, 28). These early studies in our laboratory led us to ask (132), if there is a failure in the ability of the brain to terminate brief
:
315
the strongest support is for the purine neuromodulator adenosine.
Adenosine as an endogenous anticonvulsant
F 24.1 Endogenous anticonvulsant substances. Brief seizures lead to the production of seizure terminators, which are responsible for arresting brief seizures. Levels of adenosine (128) and perhaps nitric oxide (NO) (12, 124) rise rapidly during the brief seizure, may reach some threshold and then terminate the seizure. The potent inhibitory effects of adenosine, mediated by A1-adenosine receptors, on the release of excitatory amino acid neurotransmitters, as well as its direct hyperpolarizing action, may mediate its anticonvulsant effects (38, 39). Postseizure anticonvulsants are produced in the brain and these account for the postseizure refractory period. Adenosine levels return to baseline slowly after seizure arrest (44), and therefore may also provide postseizure anticonvulsant effects (126). However, the main substances that appear to exert postseizure anticonvulsant effects are opioids and prostaglandins, because interfering with their production or effects reduces postseizure refractoriness (28).
epileptic seizures, then do seizures continue unabated, and does SE develop? The following discussion reviews some of the processes proposed in the spontaneous arrest of brief seizures.
Endogenous anticonvulsant neurochemicals Initial studies postulated that a nonspecific “running down” of the nervous system caused by the rapid utilization of available metabolic substrates or a reduction in local oxygen availability contributed to seizure termination. However, subsequent studies suggested that neither appeared to be an answer, because cerebral blood flow increases dramatically to meet increased metabolic demands and hypoxic and hypercapnic conditions do not reach critical levels until after 20 minutes of repeated seizures (16, 74, 86). Furthermore, at the cellular level, seizure termination coincides with neuronal hyperpolarization, whereas hypoxic and hypercapnic conditions cause neuronal depolarisation (16). A more favorable explanation is that seizures induce an elevation in the concentrations of inhibitory neurochemicals that can modulate excitatory synaptic transmission. These neurochemicals include opioids (116), prostaglandins (49, 50), adenosine (14, 32), and nitric oxide (NO) (12, 124), although the contribution of NO is controversial (67), and of these,
316
:
Several lines of evidence have led to the proposal that adenosine is the brain’s endogenous anticonvulsant (18, 26, 29, 32). Within 10 seconds of the onset of bicuculline-induced (97, 128) and electroshock-induced seizures (106), extracellular adenosine levels in the brain rise dramatically to peak and remain stable for 20–60 seconds, a time that also coincides with seizure termination (26, 105). If the seizure termination hypothesis is correct, then adenosine receptor agonists should shorten seizure duration, whereas adenosine receptor antagonists should prolong seizure duration without affecting processes involved in seizure initiation. The adenosine receptor antagonists theophylline and caffeine facilitate seizure spread and generalization and greatly prolong seizure duration without affecting seizure initiation in the rat (3, 27, 31, 32). Furthermore, adenosine receptor agonists and adenosine uptake blockers have anticonvulsant effects in several in vivo and in vitro seizure models (1, 7, 14, 23, 32, 40, 75, 90, 134). Adenosine levels in the brain remain elevated for a time after seizures and may have a role in postictal protection from further seizure episodes, because adenosine agonists such as -phenylisopropyladenosine (L-PIA) and 5¢N-ethylcarboxamidoadenosine (NECA) can prolong the duration of the postictal refractory period (105, 126). This postseizure period may reflect the activity of an inhibitory system that serves to terminate seizures or prevents their recurrence. The rank order of potency of these compounds for specific adenosine receptor subtypes suggests that the anticonvulsant effects may be mediated by the A1-adenosine receptor. However, an alternative theory based on in vitro evidence also suggests that tonically released adenosine maintains a high anticonvulsant threshold (18, 37, 75), although whether this tonic inhibitory purinergic tone exists is controversial. The extracellular concentration of adenosine under resting conditions has been estimated to be 1–2 mM, based on dialysis studies in rat and human hippocampi (44, 133), which is in excess of that required to activate adenosine receptors. However, whether adenosine at these levels exerts a physiologic influence is controversial, with the supporting evidence largely derived from in vitro experiments, where basal adenosine levels may be abnormally enhanced. Adenosine levels rise approximately 30-fold higher (65 mM) than basal levels in the human epileptic hippocampus following seizure onset and remain elevated postictally (44). However, in that study there appeared to be no lowering of adenosine levels immediately preceding seizure onset, suggesting that a reduction in tonically released adenosine does not trigger
seizures. However, while microdialysis techniques allow a crude approximation of extracellular adenosine levels, again, this may not reflect changes at the synaptic level. If endogenous adenosine does maintain a high anticonvulsant threshold, then we would predict that administration of adenosine agonists would augment this seizure suppressive effect and raise the threshold required to initiate a seizure, while adenosine antagonists would have the converse effect. Murray et al. (90) have demonstrated that adenosine agonists can increase the threshold dose required for elicitation of pentylenetetrazol-induced seizures, a finding that provides support for this concept. However, although adenosine receptor agonists raise the threshold for initiation of electrically induced afterdischarges in kindled animals, blocking these receptors with adenosine receptor antagonists does not lower the threshold stimulus but only affects seizure duration (3, 32, 33). In support of this finding, adenosine agonists reduce the duration of MDA without affecting the time to onset of MDA, a measure of seizure initiation processes (112). However, it may be that both tonic influences and seizureinduced increases in adenosine may be important for seizure generation and termination. In hippocampal slice cultures, the A1-adenosine receptor antagonist 8-cyclopentyl-1,3dipropylxanthine (DPCPX) has no effect on the membrane potential or amplitude of synaptic potentials in pyramidal cells in a saline bathing medium, which argues against significant tonic activation of adenosine receptors under resting conditions (115). But in the presence of bicuculline, which generates spontaneous epileptiform discharges, DPCPX increases the frequency of spontaneous epileptiform events and repetitive ictal-like events. In addition, high concentrations of adenosine (50 mM) are required to block stimulus-evoked epileptiform activity, whereas spontaneous epileptiform discharges in the hippocampus are particularly sensitive to low concentrations of adenosine (115). Consistent with this finding, White et al. (127) suggest that low-level stimulation of NMDA receptors leads to release of endogenous adenosine, which provides an inhibitory threshold against normal NMDA-mediated neurotransmission in the cortex but is unlikely to protect against the excessive NMDA receptor stimulation that might occur with seizures. Therefore, a low-level purinergic tone exists, but higher levels of adenosine such as that induced by seizures are required to terminate seizures. The key point of these findings is that they suggest that adenosine has more significant effects on seizure termination mechanisms than on seizure initiation processes. These studies have led to the conjecture that loss of adenosine-mediated anticonvulsant effects may lead to seizure prolongation and SE.
Adenosine and adenosine receptors There are several sources for adenosine in the brain (53). Intracellular adenosine is derived from two pathways, either as a 5¢nucleotidase-catalyzed breakdown product from 5¢AMP or synthesis from S-adenosyl homocysteine (SAH) through the action of SAH hydrolase. Adenosine degradation occurs mainly through the action of adenosine kinase and adenosine deaminase (53). Neurons and glia have an active transport system that recognizes adenosine, enabling rapid uptake of extracellular adenosine (22, 60, 129). Although facilitated diffusion processes also exist, they are of negligible importance at low extracellular concentrations of adenosine. In addition, adenosine is formed by the action of membrane bound 5¢nucleotidase (ecto 5¢nucleotidase), which generates the most important source of extracellularly synthesized adenosine (81). The effects of adenosine are mediated by the adenosine receptors, one of a family of membrane receptors that elicit their cellular responses via guanine-nucleotide-binding protein (G protein) coupling to their effector systems. Four adenosine receptor subtypes exist. The A1- and the A2a,2badenosine receptors are negatively and positively coupled to Gi and Gs proteins, respectively, resulting in the inhibition or stimulation of adenylate cyclase and corresponding changes in intracellular cAMP levels (46, 51, 101, 121). The role of the A3-adenosine receptor in the CNS remains unclear, although mRNA transcripts have been found in cortex, striatum, and olfactory bulb regions (77). In addition, the A1adenosine receptor is Gi protein-coupled to a subset of K+ channels (118, 119). Although the A1 and A2 subtypes mediate the central actions of adenosine, the suppression of neural activity in the hippocampus is predominantly mediated by the A1-adenosine receptor through postsynaptic K+ channel activation and presynaptic inhibition of Ca2+ conductances (38, 39). This is also supported by the differential distribution in rat brain of A1 and A2 receptors: A1adenosine receptors are found in high levels in hippocampal regions (particularly in CA1), cortex, thalamus, striatum, and cerebellum, whereas A2a-adenosine receptors are only localized in the caudate putamen, nucleus accumbens, and olfactory tubercle (34, 56, 66). Furthermore, A1-adenosine receptor-specific agonists are more potent in terminating seizure activity in animal seizure models and in vitro hippocampal slice preparations. This observation has led to the suggestion that the anticonvulsant effects of adenosine are likely to be mediated by the A1-receptor-mediated activation of postsynaptic K+ channels to produce neuronal hyperpolarization (39, 40, 73). There is now substantial electrophysiologic and biochemical evidence to suggest that other receptor subtypes, including the GABAB, and 5-HT1A receptors, are coupled to
:
317
the same set of K+ channels by a common pool of Gi proteins (91). This convergence of A1-adenosine, GABAB, and 5-HT1A receptors coupled to the same subset of K+ channels has been observed in a single cell, for example, in CA1 pyramidal neurons (5, 134).
Role of adenosine in SE Could SE be a result of an alteration in endogenous seizure termination mechanisms? It seems reasonable to propose that if this hypothesis is correct, and if these endogenous anticonvulsants are essential for seizure termination, then blockade of their effects should lead to SE. What effect does blocking opioid receptors, prostaglandin production, or NO, neurochemicals postulated to have an endogenous anticonvulsant role, have? Antagonism of opioid receptors with naloxone or blocking prostaglandin production does not prolong seizures or promote the conversion of seizures to SE (28, 47). Similarly, blocking NO production with the NO synthesis inhibitor -nitro-arginine (L-NOARG) fails to produce SE following amygdala-kindled seizures, although SE generalizes more quickly, suggesting NO has an important role in seizure spread (102, 104). Of all the neurochemicals listed above, only blockade of adenosine receptors can cause SE. In early studies, low doses of theophylline and caffeine were shown to have proconvulsant effects (3, 27, 126) and could transform brief, partial, electrically and chemically induced seizures into SE in rats (2, 47, 89, 120), whereas high doses caused spontaneous SE in animals (117). These effects can be blocked by the adenosine agonists 2-chloroadenosine (2-CLA) and L-PIA (3, 120). Theophylline treatment can also increase the risk for development of SE in humans, and a number of SE cases have been documented in patients administered theophylline for the treatment of obstructive airway disease (20, 36, 88, 122, 136). There has also been a report of a patient administered theophylline who developed SE following electroshock treatment (98). Cerebrospinal fluid levels of adenosine metabolites are also elevated after SE in humans (19), and hippocampal levels of adenosine metabolites are elevated in experimentally induced seizures (10). However, high doses of caffeine and theophylline have other neurochemical effects, including inhibition of phosphodiesterase activity (4, 62, 99, 110), inhibitory effects on benzodiazepine receptor binding (84, 85), and effects on Ca2+ mobilization (99), which could contribute to their seizure-prolonging action. This lack of specificity of these compounds has made it difficult to conclusively ascribe the seizure-prolonging effects of caffeine and theophylline to adenosine receptor antagonism. Interfering with other aspects of adenosine pharmacology can also cause SE. Administration of dipyridamole, an adenosine uptake blocker, to rats during recycling SE pro-
318
:
longs the interictal phase (47). Homocysteine, a drug that can cause SE at high doses in rodents, may be a proconvulsant by depleting adenosine through the SAH hydrolase–catalyzed formation of SAH (57, 83, 123). Humans with the genetic disorder homocysteinuria, which is characterized by elevated serum levels of homocysteine due to a defect in the degradative enzyme cystathionine b-synthase, often exhibit convulsive episodes (52). More recent in vitro evidence suggests that deletion of cellular ATP levels and consequently a key source of adenosine production removes an inhibitory brake, resulting in the progression of seizure-like events to SE-like activity (6). The more recent development of specific A1- and A2adenosine receptor-selective compounds has provided an opportunity for isolation of the receptor subtype involved and extensive characterization of the effect of these compounds on seizures and SE. The selective A1-adenosine receptor antagonist 8-CPT prolongs hippocampal seizures (35), and Eldridge et al. (47) reported that theophylline and 8-CPT both prolong ictal discharges and alter the cycling pattern of ictal-interictal spiking such that sometimes an ictal spiking period can be as long as 30 minutes. However, 8-CPT has no effect on the duration of the interictal period. This finding suggests that adenosine, endogenously generated and released to the extracellular space during an ictal discharge, is involved in its cessation. We have extended these studies and shown that pretreatment of rats with 8-CPT can transform a brief hippocampal seizure elicited by electrical stimulation into SE, dramatically in some cases after only one stimulus (130). This effect is centrally mediated because the selective A1adenosine receptor antagonist 8-sulfophenyl-theophylline (8SPT), which has limited brain penetration following systemic administration (8, 48), failed to induce SE when administered peripherally but induced SE when administered intraventricularly (130). Further, coadministration with selective A1-adenosine receptor agonists such as N6-cyclohexyladenosine (CHA) or N6-cyclopentyladenosine (CPA) could block these proconvulsant effects, but not coadministration with the A2-adenosine receptor agonist CGS 21680C, even though animals exhibited reduced locomotor activity, an effect principally mediated by central A2-adenosine receptors (42, 43, 93). A1-adenosine receptor selective agonists also have potent anticonvulsant effects against electrically induced SE induced by continuous hippocampal stimulation. Pretreatment with CHA, CPA, or 5¢-(N-cyclopropyl)-carboxamidoadenosine (CPCA) could prevent the initiation of electrically induced SE, which was also reversed with 8-CPT but not with peripherally administered 8-SPT (131), which blocks the potential anticonvulsant contribution of peripheral hypotensive and hypothermic effects of these compounds (40, 59, 71, 94, 109). Interestingly, only one-tenth the
dose of 8-CPT required to transform a brief seizure into SE was required to reduce the latency to development of electrically induced SE, suggesting that perhaps the mechanism by which SE develops in this model also involves a collapse of adenosinergic mechanisms. Indeed, in preliminary studies we have observed that an animal pretreated with 1 mg/kg of 8-CPT alone developed SE after only 15 minutes of continuous stimulation, compared with the 30–70 minutes normally required. Intraperitoneal administration of CHA after progression of SE for 20 minutes was also successful in terminating SE, particularly partial SE. However, additional doses of CHA were often required, especially for generalized SE, which may reflect a higher proportion of receptor sites to be activated to achieve the same anticonvulsant response, and also the wider anatomic spread of seizure activity (58). Consistent with the findings in this study, in a repeated electrical stimulation paradigm involving the amygdala, Handforth and Treiman (58) found that aminophylline hastens the entry into SE development, whereas the adenosine agonist 2chloroadenosine resists SE entry. These investigators concluded that endogenous adenosine mechanisms may operate to prevent the development of SE and also to restrict the anatomic spread of seizure activity. These results strongly support the concept that SE results from a failure of adenosine-mediated seizure termination mechanisms. However, the finding that intraventricular administration of 8-SPT was able to induce SE in two animals in our study (132) without additional electrical stimuli also suggests that tonically release adenosine may also influence SE initiation. The pattern of seizure activity evoked was characteristic of seizures of hippocampal origin, consisting of a primary afterdischarge followed by an intervening period of EEG silence and a second period of seizure activity developing into SE. This pattern would be consistent with blockade of A1-adenosine receptors, which are found in high density in the hippocampus (34, 56, 66). Murray et al. (90) have similarly shown that theophylline can reduce the seizure threshold for pentylenetetrazol-induced seizures, and that high doses of aminophylline can induce SE in adult rats without additional electrical or chemical stimuli (3, 20, 117). However, aminophylline levels reach as high as 1,000 mM in the blood, far in excess of the concentration required to block adenosine receptors, and it may be that additional mechanisms not related to adenosine receptors are involved. Indirect evidence suggesting the involvement of A1adenosine receptors in SE has also been obtained. Pretreatment of rats with the Gi protein inactivator pertussis toxin (PTX) 3 days prior to stimulation can transform a brief electrically induced seizure into generalized SE (132). This proconvulsant effect is consistent with the reported potentiation of NMDA, pilocarpine, and kainic acid seizure activity fol-
lowing PTX (42, 72, 95, 96) and suggests that inactivation of G-protein-linked receptors is involved in SE development. High-dose PTX such as that used in our study (132) has been reported to cause spontaneous seizure occurrences after a 4-day delay (55, 111). However, a dose of the adenosine agonist L-PIA that is fully protective against lithiumpilocarpine-induced SE has only partial anticonvulsant effects against lithium-pilocarpine-induced SE in rats that have undergone a 72-hour pretreatment with PTX (96), suggesting a significant attenuation in functional PTX-sensitive adenosine receptor numbers at this time. These results suggest that at least part of the proconvulsant effects of PTX treatment may be attributable to the suppression of inhibitory pre- and postsynaptic A1-adenosine receptors (119), although the data are inconsistent as to whether presynaptic receptors are PTX sensitive (23, 53, 92, 111). In addition, inactivation of GABAB receptor responses may also contribute to SE development (76). Although these studies strongly implicate PTX-mediated inactivation of adenosinergic and GABAB systems that are involved in producing SE, not all the convulsant effects of PTX can be specifically ascribed to inactivation of these systems. Many other neurotransmitter systems including, the dopamine D2, muscarinic M2, enkephalin m, a2-norepinephrine and somatostatin receptors (92), are also associated with PTXsensitive G proteins. Inactivation of these systems could possibly also promote some of the convulsant effects observed. Interestingly, phorbol esters, which activate protein kinase C, block adenosine, baclofen, and serotonin responses by phosphorylating and inactivating certain PTX-sensitive G proteins (5, 64). These compounds also have proconvulsant effects when administered to animals (108).
A possible mechanism for SE development The A1-adenosine receptor-mediated modulation of neurotransmitter release, specifically that of glutamate, GABA, and acetylcholine, has been fairly well characterized (21, 22, 61). Adenosine release is also NMDA receptor mediated, creating in effect a negative feedback system that may modulate hippocampal excitability (13, 17, 21, 24, 61, 65, 82, 100). Thus, a postulated mechanism for SE generation could involve block or loss of adenosine’s modulatory effects on glutamatergic neurotransmission. Initially, a reduction in adenosine-mediated neuromodulation and a possible contribution by reduced GABAergic inhibition (71, 72) leads to an increase in extracellular glutamate concentration. The elevated glutamate levels that precede seizure onset in epileptic hippocampi (45) activate NMDA and possibly non-NMDA receptors to induce seizure activity (130). Involvement of these glutamatergic receptor subtypes is also supported by findings that the noncompetitive NMDA receptor antagonist MK-801 can suppress the
:
319
induction of 8-CPT-induced SE (unpublished observations). Although these seizures would normally be terminated by the seizure-induced release of extracellular adenosine, loss or alteration in adenosine release or receptor function may also lead to prolongation of seizures and hence to SE. SE is then propagated by activation of both NMDA and nonNMDA ionotropic glutamate receptors (131). Manzoni et al. (82) have reported that at least one of the sources of the glutamate-induced NMDA-mediated adenosine released is from interneurons, which then act at a presynaptic site distant from its release to inhibit the release of glutamate. Perhaps loss of these interneurons, which are highly vulnerable to brain insults (80), may form the underlying cellular basis for the reduced source of adenosine, in addition to loss of GABAergic inhibition. Could these results have relevance for the development of SE in humans? Extracellular glutamate levels are elevated immediately prior to seizure onset (45), while adenosine levels rise immediately following seizure onset in the epileptic hippocampus of patients with temporal lobe epilepsy (44). Further, Chin et al. (19) have reported an increase in CSF levels of adenosine metabolites shortly after SE. The results of these studies suggest that perhaps similar mechanisms observed in the rat may be applicable to humans.
Future studies Future studies may involve determining whether a reduction in adenosine levels occurs immediately prior to the induction of spontaneous SE. In addition, we would want to know whether a loss of adenosine-mediated neuromodulation of glutamate release lead to an elevation in extracellular glutamate concentration, which triggers the seizure, in much the same way that seizures are initiated in human epileptic hippocampi (45). It would also be interesting to compare the time profile of the seizure-induced release of adenosine at the precise times that coincide with seizure termination. Microdialysis studies in humans show that increases in adenosine levels in epileptic hippocampi peak at a time that coincides with seizure termination and remain elevated for about 20 minutes after the seizure, leading to the contention that adenosine may be involved in seizure termination and postictal protection mechanisms (44). However, it would be interesting to evaluate whether the elevation and decline of adenosine levels observed for brief seizures show a similar profile for SE development, or whether adenosine levels decline rapidly, leading to continuation of seizures. Even if these projected studies show no significant changes, the results must be interpreted cautiously. In experimental SE models, SE is induced in essentially naive animals that have no underlying neuropathology. Although a subpopulation of patients experience SE as their first
320
:
seizure event, most patients who develop SE have some predisposition to SE, in some cases due to some underlying neuropathology that may have resulted in a reduction in GABAergic inhibition (107). In these patients, it may be that only a slight loss of adenosine-mediated anticonvulsant systems, precipitated by a compromise in GABAergic inhibition, is sufficient to tilt the balance in favor of excitation, leading to the development of SE. Thus, dramatic changes in adenosine levels or blockade may not be observed prior to the development of SE in humans. It would be interesting to determine the effect of 8-CPT and other related compounds in animals with similar neuropathology to that observed in, for example, patients with temporal lobe epilepsy. With some underlying neuropathology resulting in reduced GABAergic inhibition, is only a slight reduction in adenosinergic modulation sufficient to induce SE, and would low doses of 8-CPT therefore be sufficient, with or without stimulation, to convert spontaneous seizures into SE? Whether adenosine agonists may be good candidates as future anticonvulsant drugs is unclear because of the extensive peripheral hypotensive and sedative actions of these compounds. However, new adenosine kinase inhibitors (73, 125) that have improved side effect profiles and controlled release of adenosine from an adenosine-releasing synthetic polymer (11) may eliminate these problems. Adenosinereleasing cells grafted into the ventricles of electrically kindled rats showed nearly complete protection from behavioral seizures and afterdischarges, suggesting promise of an ex vivo gene therapy approach for the treatment of drugresistant partial epilepsies (63). Activation of brain adenosine receptors may also provide another novel approach to SE management, since A1-adenosine receptor agonists may stop seizures and also reduce SE-induced brain damage (30). However, whether this therapeutic approach will be useful is uncertain, because there is some evidence that A1-adenosine receptor numbers are significantly reduced in the temporal cortex and hippocampus of patients with complex partial seizures (54). Therefore, this strategy may not be useful in this group of individuals with a possible predisposition toward developing SE. Of potentially greater therapeutic value may be drugs that block processes involved in SE initiation and maintenance, and we have recently highlighted the importance of AMPA receptors in this regard (131).
Conclusions These results suggest that SE could develop as a result of impairment of the seizure-terminating effects mediated by the action of adenosine on CNS A1-adenosine receptors and that the presence of endogenous adenosine or exogenous CHA can prevent SE development. A failure of adenosinemediated seizure termination mechanisms, possibly com-
bined with a reduction in GABA-mediated inhibition, may underlie SE generation and provides an attractive hypothesis that may ultimately lead to alternative treatment strategies targeted at these mechanisms. This work was supported by grants from the New Zealand Health Research Council, New Zealand Neurological Foundation, and Auckland Medical Research Foundation and Lotteries Health (M.D.).
REFERENCES 1. Alasvand Zarasvand, M., J. Mirnajafi-Zadeh, Y. Fathollahi, and M. R. Palizvan. Anticonvulsant effect of bilateral injection of N6-cyclohexyladenosine into the CA1 region of the hippocampus in amygdala-kindled rats. Epilepsy Res. 2001; 47(1–2):141–149. 2. Albertson, T. E. Effect of aminophylline on amygdaloidkindled postictal inhibition. Pharmacol. Biochem. Behav. 1986; 24:1599–1603. 3. Albertson, T. E., L. G. Stark, R. M. Joy, and J. F. Bowyer. Aminophylline and kindled seizures. Exp. Neurol. 1983;81: 703–713. 4. Amer, M. S., and W. E. Kreighbaum. Cyclic nucleotide phosphodiesterases: Properties, activators, inhibitors, structureactivity relationships, and possible role in drug development. J. Pharmacol. Sci. 1985;64:1–37. 5. Andrade, R., R. C. Malenka, and R. A. Nicoll. A G-protein couples serotonin and GABAB receptors to the same channels in hippocampus. Science 1986;234:1261–1265. 6. Avsar, E., and R. M. Empson. Adenosine acting via A1 receptors, controls the transition to status epilepticus-like behaviour in an in vitro model of epilepsy. Neuropharmacology 2004:47: 427–437. 7. Barraco, R. A., T. H. Swanson, J. W. Phillis, and R. F. Berman. Anticonvulsant effects of adenosine analogues on amygdaloid-kindled seizures in rats. Neurosci. Lett. 1984;46: 317–322. 8. Baumgold, J., O. Nikodijevic, and K. A. Jacobson. Penetration of adenosine antagonists into mouse brain as determined by ex vivo binding. Biochem. Pharmacol. 1992;43(4): 889–894. 9. Ben-Ari, Y., E. Tremblay, and O. P. Ottersen. Injections of kainic acid into the amygdaloid complex of the rat: An electrographic, clinical and histological study in relation to the pathology of epilepsy. Neuroscience 1980;5:515–528. 10. Berman, R. F., B. B. Fredholm, U. Aden, and W. T. O’Connor. Evidence for increased dorsal hippocampal adenosine release and metabolism during pharmacologically induced seizures in rats. Brain Res. 2000;872(1–2):44–53. 11. Boison, D., L. Scheurer, J. L. Tseng, P. Aebischer, and H. Mohler. Seizure suppression in kindled rats by intraventricular grafting of an adenosine releasing synthetic polymer. Exp. Neurol. 1999;160:164–174. 12. Buisson, A., N. Lakhmeche, C. Verrecchia, M. Plotkine, and R. G. Boulu. Nitric oxide: An endogenous anticonvulsant substance. Neuroreport 1993;4:444–446. 13. Burke, S. P., and J. V. Nadler. Regulation of glutamate and aspartate release from slices of the hippocampal CA1 area: Effects of adenosine and baclofen. J. Neurochem. 1988;51: 1541–1551.
14. Burley, E. S., and J. A. Ferendelli. Regulatory effects of neurotransmitters on electroshock and pentylenetetrazol seizures. Fed. Proc. 1984;43:2521–2524. 15. Buterbaugh, G. G., H. B. Michelson, and D. O. Keyser. Status epilepticus facilitated by pilocarpine in amygdala-kindled rats. Exp. Neurol. 1986;94:91–102. 16. Caspers, H., and E.-J. Speckmann. Cerebral P2, P2 and pH: Changes during convulsive activity and their significance for spontaneous arrest of seizures, Epilepsia 1972;13:699–725. 17. Chen, Y., D. J. Graham, and T. W. Stone. Release of endogenous adenosine and its metabolites by the activation of NMDA receptors in the rat hippocampus in vivo. Br. J. Pharmacol. 1992;106:632–638. 18. Chin, J. H. Adenosine receptors in brain: Neuromodulation and role in epilepsy. Ann. Neurol. 1989;26:695–698. 19. Chin, J. H., J. B. Wiesner, and J. Fujitaki. Increase in adenosine metabolites in human cerebrospinal fluid after status epilepticus. J. Neurol. Neurosurg. Psychiatry 1995;58:513–514. 20. Chu, N. S. Caffeine- and aminophylline-induced seizures. Epilepsia 1981;22:85–94. 21. Corradetti, R., G. LoConte, F. Moroni, M. B. Passani, and G. Pepeu. Adenosine decreases aspartate and glutamate release from rat hippocampal slices. Eur. J. Pharmacol. 1984;104:19–26. 22. Deckert, J., P. F. Morgan, and P. J. Marangos. Adenosine uptake site heterogeneity in the mammalian CNS: Uptake inhibitors as probes and potential neuropharmaceuticals. Life Sci. 1988;42:1331–1345. 23. DeSarro, G., A. DeSarro, and B. S. Meldrum. Anticonvulsant action of 2-chloroadenosine injected focally into the inferior colliculus and substantia nigra. Eur. J. Pharmacol. 1991;194:145–152. 24. Dolphin, A. C., and E. R. Archer. An adenosine agonist inhibits and a cyclic AMP analogue enhances the release of glutamate but not GABA from slices of rat dentate gyrus. Neurosci. Lett. 1983;43:49–54. 25. Dolphin, A. C., and S. A. Prestwich. Pertussis toxin reverses adenosine inhibition of neuronal glutamate release. Nature 1985;316:148–150. 26. Dragunow, M. Adenosine: The brain’s natural anticonvulsant. Trends Pharmacol. Sci. 1986:128–130. 27. Dragunow, M. Adenosine receptor antagonism accounts for the seizure-prolonging effects of aminophylline. Pharmacol. Biochem. Behav. 1990;36:751–755. 28. Dragunow, M. Endogenous anticonvulsant substances. Neurosci. Biobehav. Rev. 1986;10:229–244. 29. Dragunow, M. Purinergic mechanisms in epilepsy. Prog. Neurobiol. 1988;31:85–108. 30. Dragunow, M., and R. L. M. Faull. Neuroprotective effects of adenosine. Trends Pharmacol. Sci. 1988;9:193–194. 31. Dragunow, M., and G. V. Goddard. Adenosine modulation of amygdala kindling. Exp. Neurol. 1984;84:654–665. 32. Dragunow, M., G. V. Goddard, and R. Laverty. Is adenosine an endogenous anticonvulsant? Epilepsia 1985;26:480–487. 33. Dragunow, M., G. V. Goddard, and R. Laverty. Proconvulsant effects of theophylline on hippocampal afterdischarges. Exp. Neurol. 1987;96:732–735. 34. Dragunow, M., K. Murphy, R. A. Leslie, and H. A. Robertson. Localization of adenosine A1-receptors to the terminals of the perforant path. Brain Res. 1988;462:252–257. 35. Dragunow, M., and H. A. Robertson. 8-Cyclopentyl 1,3dimethylxanthine prolongs epileptic seizures in rats. Brain Res. 1987;417:377–379.
:
321
36. Dunn, D. W., and H. U. Parekh. Theophylline and status epilepticus in children. Neuropaediatrics 1991;22:24–26. 37. Dunwiddie, T. V. Endogenously released adenosine regulates excitability in the in vitro hippocampus. Epilepsia 1980;21: 541–548. 38. Dunwiddie, T. V., and B. B. Fredholm. Adenosine receptors mediating inhibitory electrophysiological responses in rat hippocampus are different from receptors mediating cyclic AMP accumulation. Arch. Pharmacol. 1984;326:294–301. 39. Dunwiddie, T. V., and B. B. Fredholm. Adenosine A1 receptors inhibit adenylate cyclase activity and neurotransmitter release and hyperpolarise pyramidal neurons in rat hippocampus. J. Pharmacol. Exp. Ther. 1989;249:31–37. 40. Dunwiddie, T. V., and T. Worth. Sedative and anticonvulsant effects of adenosine analogs in mouse and rat. J. Pharmacol. Exp. Ther. 1982;220:70–76. 41. Durcan, M. J., and P. F. Morgan. Evidence for adenosine A2 receptor involvement in the hypomobility effects of adenosine analogues in mice. Eur. J. Pharmacol. 1989;168:285–290. 42. Durcan, M. J., and P. F. Morgan. Intracerebroventricular pertussis toxin enhances sensitivity to N-methyl--aspartateinduced seizures in mice. Eur. J. Pharmacol. 1991;197:209–211. 43. Durcan, M. J., and P. F. Morgan. NECA-induced hypomotility in mice: Evidence for a predominantly central site of action. Pharmacol. Biochem. Behav. 1989;32:487–490. 44. During, M. J., and D. D. Spencer. Adenosine: A potential mediator of seizure arrest and postictal refractoriness. Ann. Neurol. 1992;32:618–624. 45. During, M. J., and D. D. Spencer. Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet 1993;41:1607–1610. 46. Ebersolt, C., J. Premont, A. Prochiantz, M. Perez, and J. Bockaert. Inhibition of brain adenylate cyclase by A1 adenosine receptors: Pharmacological characteristics and locations. Brain Res. 1983;267:123–129. 47. Eldridge, F. L., D. Paydarfar, S. C. Scott, and R. T. Dowell. Role of endogenous adenosine in recurrent generalized seizures. Exp. Neurol. 1989;103:179–185. 48. Evoniuk, G., R. W. Von Borstel, and R. J. Wurtman. Antagonism of the cardiovascular effects of adenosine by caffeine or 8-(p-sulfophenyl)theophylline. J. Pharmacol. Exp. Ther. 1987;240:428–432. 49. Forstermann, U., R. Heldt, F. Knappen, and G. Hertting. Potential anticonvulsive properties of endogenous prostaglandins formed in mouse brain. Brain Res. 1982;240: 303–310. 50. Forstermann, U., A. Seregi, and G. Hertting. Anticonvulsive effects of endogenous prostaglandin formed in brain of spontaneously convulsive gerbils. Prostaglandins 1984;27:913–923. 51. Fredholm, B. B., B. Jonzon, G. Lindgren, and K. Lindstrom. Adenosine receptors mediating cyclic AMP production in the rat hippocampus. J. Neurochem. 1982;39:165–175. 52. Gaull, G. E. Homocysteinuria and other disorders of sulphur metabolism. In E. Goldensohn, and S. Appel, eds. Scientific Approaches to Clinical Neurology. Philadelphia: Lea & Febiger, 1977:46–54. 53. Geiger, J. D., R. A. Padua, and J. I. Nagy. Adenosine deaminase regulation of purine actions. In J. W. Phillis, ed. Adenosine and Adenine Nucleotides as Regulators of Cellular Function. Boca Raton, FL: CRC Press, 1991:71–84. 54. Glass, M., R. L. M. Faull, J. Y. Bullock, K. Jansen, E. W. Mee, E. B. Walker, et al. Loss of A1 adenosine receptors in human temporal lobe epilepsy. Brain Res. 1996;710:56–68.
322
:
55. Goh, J. W., and P. S. Pennefather. Pertussis toxin prevents induction of hippocampal long-term potentiation in the stratum radiatum and stratum oriens inputs to CA1 neurons. Brain Res. 1990;511:345–348. 56. Goodman, R. R., and S. H. Snyder. Autoradiographic localisation of adenosine receptors in rat brain using [3H]cyclohexyladenosine. J. Neurosci. 1982;2:1230–1241. 57. Hammond, E. J., R. W. Hurd, B. J. Wilder, and F. J. Thompson. Focal and generalized experimental seizures induced by homocysteine. Electroencephalogr. Clin. Neurophysiol. 1980;49:184–186. 58. Handforth, A., and D. M. Treiman. Effect of an adenosine antagonist and an adenosine agonist on status entry and severity in a model of limbic status epilepticus. Epilepsy Res. 1994;18:29–42. 59. Heffner, T. G., J. N. Wiley, A. E. Williams, R. F. Bruns, L. L. Coughenour, and D. A. Downs. Comparison of the behavioral effects of adenosine agonists and dopamine antagonists in mice. Psychopharmacology 1989;98:31–37. 60. Hertz, L. Nucleoside transport in cells: Kinetics and inhibitor effects. In J. W. Phillis, ed. Adenosine and Adenine Nucleotides as Regulators of Cellular Function. Boca Raton, FL: CRC Press, 1991:85–107. 61. Hoehn, K., and T. D. White. Role of excitatory amino acid receptors in K+- and glutamate-evoked release of endogenous adenosine from rat cortical slices. J. Neurochem. 1990;54: 256–265. 62. Horrobin, D. F., M. S. Manku, D. J. Franks, and P. Hamet. Methylxanthine phosphodiesterase inhibitors behave as prostaglandin antagonists in a perfused rat mesenteric artery preparation. Prostaglandins 1977;13:33–40. 63. Huber, A., V. Padrun, N. Deglon, P. Aebischer, H. Mohler, and D. Boison. Grafts of adenosine-releasing cells suppress seizures in kindling epilepsy. Proc. Natl. Acad. Sci. U.S.A. 2001;98(13):7611–7616. 64. Jacobs, K. H., S. Bauer, and Y. Watanabe. Modulation of adenylate cyclase of human platelets by phorbol ester: Impairment of the hormone-sensitive inhibitory pathway. Eur. J. Biochem. 1985;151:425–430. 65. Jakisch, R., H. Strittmatter, L. Kasakov, and G. Hertting. Endogenous adenosine as a modulator of hippocampal acetylcholine release. Arch. Pharmacol. 1984;327: 319–325. 66. Jarvis, M. F., and M. Williams. Direct autoradiographic localisation of adenosine A2 receptors in the rat brain using the A2 selective agonist [3H]-CGS 21680. Eur. J. Pharmacol. 1989;168:243–246. 67. Kaku, T., M. H. Jiang, J. Hada, K. Morimoto, and Y. Hayashi. Sodium nitroprusside-induced seizures and adenosine release in rat hippocampus. Eur. J. Pharmacol. 2001;413(2–3):199–205. 68. Kalichman, M. W., W. M. Burnham, and K. E. Livingston. Pharmacological investigation of GABA and fully-developed generalised seizures in the amygdala-kindled rat. Neuropharmacology 1982;21:127–131. 69. 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. 70. 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.
71. Katims, J. J., Z. Annau, and S. H. Snyder. Interactions in the behavioral effects of methylxanthines and adenosine derivatives. J. Pharmacol. Exp. Ther. 1983;227:167–173. 72. Korolkiewicz, R., Z. Kleinrok, and M. Mylnarcyzyk. Intracerebroventricular pertussis toxin enhances sensitivity to chemical convulsants an decreases protective efficacy of carbamazepine in mice. Pharmacol. Res. 1996;33:211–215. 73. Kowaluk, E. A., S. S. Bhagwat, and M. F. Jarvis. Adenosine kinase inhibitors. Curr. Pharmacol. Des. 1998;4:403–416. 74. Kreisman, N. R., M. Rosenthal, J. C. LaManna, and T. J. Sick. Cerebral oxygenation during recurrent seizures. In A. V. Delgado-Escueta, C. G. Wasterlain, D. M. Treiman, R. J. Porter, eds. Status Epilepticus: Mechanisms of Brain Damage and Treatment. Adv. Neurol. 1983;34:231–239. 75. Lee, K. S., P. Schubert, and U. Heinemann. The anticonvulsant action of adenosine: A postsynaptic, dendritic action by a possible endogenous anticonvulsant. Brain Res. 1984;321: 160–164. 76. Lewis, D. V., L. S. Jones, and H. Swartzwelder. The effects of baclofen and pertussis toxin on epileptiform activity induced in the hippocampal slice by magnesium depletion. Epilepsy Res. 1989;4:109–118. 77. Linden, J. Cloned adenosine A3 receptors: Pharmacological properties, species differences and receptor functions. Trends Pharmacol. Sci. 1994;15:298–306. 78. 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. 79. Lothman, E. W., and R. C. Collins. Kainic acid-induced limbic motor seizures: Metabolic, behavioral, electroencephalographic and neuropathological correlates. Brain Res. 1981;218:299–318. 80. Lowenstein, D. H., M. J. Thomas, D. H. Smith, and T. K. MacIntosh. Selective vulnerability of dentate hilar neurons following traumatic brain injury: A potential mechanistic link between head trauma and disorders of the hippocampus. J. Neurosci. 1992;12:4846–4853. 81. MacDonald, W. F., and T. D. White. Nature of extrasynaptosomal accumulation of endogenous adenosine evoked by K+ and veratridine. J. Neurochem. 1985;45:791–797. 82. Manzoni, O. J., T. Manabe, and R. A. Nicoll. Release of adenosine by activation of NMDA receptors in the hippocampus. Science 1994;265:2098–2101. 83. Marangos, P. J., T. Loftus, J. Wiesner, T. Lowe, E. Rossi, C. E. Browne, and H. E. Gruber. Adenosinergic modulation of homocysteine-induced seizures in mice. Epilepsia 1990;31: 239–246. 84. Marangos, P. J., A. M. Martino, S. M. Paul, and P. Skolnick. The benzodiazepines and inosine antagonize caffeineinduced seizures. Psychopharmacology 1981;72:269–273. 85. Marangos, P. J., S. M. Paul, A. M. Parma, F. K. Goodwin, P. Syapin, and P. Skolnick. Purinergic inhibition of diazepam binding to rat brain (in vitro). Life Sci. 1979;24:851–858. 86. 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. 87. Mingo, N. S., and W. M. Burnham. Secondary generalization in non-kindled rats following acute administration of GABA-complex and adenosine antagonists. Electroencephalogr. Clin. Neurophysiol. 1990;75:444–451. 88. Mori, H., T. Mizutani, M. Yoshimura, H. Yamanouchi, and H. Shimada. Unilateral brain damage after prolonged hemi-
89.
90.
91. 92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
convulsions in the elderly associated with theophylline administration. J. Neurol. Neurosurg. Psychiatry 1992;55:466–469. Morrisett, R. A., R. S. Jope, and O. Carter Snead III. 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. Murray, T. F., D. Sylvester, C. S. Schultz, and P. Szot. Purinergic modulation of the seizure threshold for pentylenetetrazol in the rat. Neuropharmacology 1985;24:761–766. Nicoll, R. A. The coupling of neurotransmitter receptors to ion channels in the brain. Science 1988;242:545–551. Nicoll, R. A., R. C. Malenka, and J. Kauer. Functional comparison of neurotransmitter receptor subtypes in the mammalian central nervous system. Physiol. Rev. 1990;70:513–565. Nikodijevic, O., J. W. Daly, and K. A. Jacobson. Characterisation of the locomotor depression produced by an A2selective adenosine agonist. FEBS Lett. 1990;261:67–70. Nikodijevic, O., R. Sarges, J. W. Daly, and K. A. Jacobson. Behavioral effects of A1- and A2-selective adenosine agonists and antagonists: Evidence for synergism and antagonism. J. Pharmacol. Exp. Ther. 1991;259:286–294. O’Regan, M. H., and J. W. Phillis. Pertussis toxin blocks the inhibitory effects of adenosine on rat cerebral cortical neurons. Brain Res. 1987;436:380–383. Ormandy, G. C., and R. S. Jope. Pertussis toxin potentiates seizures induced by pilocarpine, kainic acid and N-methyl-aspartate. Brain Res. 1991;553:51–57. Park, T. S., D. G. L. Van Wylen, R. Rubio, and R. M. Berne. Interstitial fluid adenosine and saggital sinus blood flow during bicuculline seizures in newborn piglets. J. Cereb. Blood Flow Metab. 1987;6:633–639. Peters, S. G., D. N. Wochos, and G. C. Peterson. Status epilepticus as a complication of concurrent electroconvulsive and theophylline therapy. Mayo Clin. Proc. 1984;59:568–570. Phillis, J. W., and P. H. Wu. The role of adenosine and its nucleotides in central synaptic transmission. Prog. Neurobiol. 1981;16:187–239. Poli, A., R. Lucchi, M. Vibio, and O. Barnabei. Adenosine and glutamate modulate each other’s release from rat hippocampal synaptosomes. J. Neurochem. 1991;57:298–306. Premont, J., M. Perez, and J. Bockaert. Adenosine-sensitive adenylate cyclase in rat striatal homogenates and its relationship to dopamine and calcium-sensitive adenylate cyclase. Mol. Pharmacol. 1977;13:662–670. Racine, R. J. Modification of seizure activity by electrical stimulation. II. Motor seizure, Electroencephalogr. Clin. Neurophysiol. 1978;32:281–294. Rondouin, G., J. Bockaert, and M. Lerner-Natoli. -Nitroarginine, an inhibitor of NO synthase, dramatically worsens limbic epilepsy in rats. Neuroreport 1993;4:1187–1190. Rondouin, G., M. Lerner-Natoli, O. Manzoni, M. Lafon-Cazal, and J. Bockaert. A nitric oxide (NO) inhibitor accelerates amygdala kindling. Neuroreport 1992;3:805–808. Rosen, J. B., and R. F. Berman. Prolonged postictal depression in amygdala kindled rats by the adenosine analog, phenylisopropyladenosine. Exp. Neurol. 1985;90:549–557. Schultz, V., and J. M. Lowenstein. The purine nucleotide cycle: Studies of ammonia production and interconversions of adenosine and hypoxanthine nucleotides and nucleosides by rat brain in situ. J. Biol. Chem. 1978;253:1938–1943. Sloviter, R. S. Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. Science 1987;235:73–76.
:
323
108. Smith, S. E., and B. S. Meldrum. The protein kinase C activators, phorbol 12-myristate,13-acetate and phorbol 12,13dibutyrate, are convulsant in the piconanomolar range in mice. Eur. J. Pharmacol. 1992;213:133–135. 109. Snyder, S. H., J. S. Katims, Z. Annau, R. F. Bruns, and J. W. Daly. Adenosine receptors and the actions of the methylxanthines. Proc. Natl. Acad. Sci. U.S.A. 1981;78:3260–3264. 110. Stephanovich, V. Influence of theophylline on concentrations of cyclic 3¢,5¢5-adenosine monophosphate and cyclic 3¢5¢guanosine monophosphate of rat brain. Neurochem. Res. 1979;4:587–594. 111. Stratton, K. R., A. J. Cole, J. Pritchett, C. U. Eccles, P. F. Worley, and J. M. Baraban. Intrahippocampal injection of pertussis toxin blocks adenosine suppression of synaptic responses. Brain Res. 1989;494:359–364. 112. Stringer, J. L., and E. W. Lothman. A1-Adenosinergic modulation alters the duration of maximal dentate activation. Neurosci. Lett. 1990;118:231–234. 113. Stringer, J. L., and E. W. Lothman. Maximal dentate gyrus activation: Characteristics and alterations after repeated seizures. J. Neurophysiol. 1989;62:136–143. 114. Stringer, J. L., and E. W. Lothman. Pharmacological evidence indicating a role of GABAergic systems in termination of limbic seizures. Epilepsy Res. 1990;7:197–204. 115. Thompson, S. M., H. L. Haas, and B. H. Gähwiler. Comparison of the actions of adenosine at pre- and postsynaptic receptors in the rat hippocampus in vitro. J. Physiol. 1992;451:347–363. 116. Tortella, F. C., and J. B. Long. Endogenous anticonvulsant substance in rat cerebrospinal fluid after a generalised seizure. Science 1985;228:1106–1108. 117. Trommer, B. L., J. F. Pasternak, and G. M. Suyeoka. Proconvulsant effects of aminophylline during amygdala kindling in developing rats. Dev. Brain Res. 1989;46:169–172. 118. Trussell, L. O., and M. B. Jackson. Adenosine-activated potassium conductance in cultured striatal neurons. Proc. Natl. Acad. Sci. U.S.A. 1985;82:4857–4861. 119. Trussell, L. O., and M. B. Jackson. Dependence of an adenosine-activated potassium current on a GTP-binding protein in mammalian central neurons. J. Neurosci. 1987;7: 3306–3316. 120. Turski, W. A., E. A. Cavalheiro, C. Ikonomidou, L. E. A. Moraes Mello, Z. A. Bortolotto, and L. Turski. Effects of aminophylline and 2-chloroadenosine on seizures produced by pilocarpine in rats: Morphological and electroencephalographic correlates. Brain Res. 1985;361:309–323. 121. van Calker, D., M. Muller, and B. Hamprecht. Adenosine regulates via two different types of receptors, the accumulation of cyclic AMP in cultured brain cells. J. Neurochem. 1979;33:999–1005. 122. Walker, J. E. Aminophylline seizures in the rat. J. Pharm. Pharmacol. 1981;33:479–480. 123. Walton, N. Y., and D. M. Treiman. Experimental secondarily generalized convulsive status epilepticus induced by ,-homocysteine thiolactone. Epilepsy Res. 1988;2: 79–86. 124. Wang, Q., M. A. Theard, D. A. Pelligrino, V. L. Baughman, W. E. Hoffman, R. F. Albrecht, et al. Nitric oxide (NO) is an endogenous anticonvulsant but not a mediator of the increase in cerebral blood flow accompanying bicuculline-induced seizures in rats. Brain Res. 1994;658:192–198. 125. Wiesner, J. B., B. G. Ugarkar, A. J. Castellino, J. Barankiewicz, D. P. Dumas, H. E. Gruber, et al. Adenosine kinase inhibitors
324
:
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
as a novel approach to anticonvulsant therapy. J. Pharmacol. Exp. Ther. 1999;289:1669–1677. Whitcomb, K., C. R. Lupica, J. B. Rosen, and R. F. Berman. Adenosine involvement in postictal events in amygdalakindled rats. Epilepsy Res. 1990;6:171–179. White, T. D., C. G. Craig, and K. Hoehn. Extracellular adenosine, formed during low level NMDA receptor activation, provides an inhibitory threshold against further NMDA receptor–mediated neurotransmission in the cortex. Drug Dev. Res. 1993;28:406–409. Winn, H. R., J. E. Welsh, C. Bryner, R. Rubio, and R. M. Berne. Brain adenosine production during the initial 60 seconds of bicuculline seizures in rats. Acta Neurol. Scand. 1979;60(Suppl. 72):536–537. Wu, P. H., and J. W. Phillis. Uptake by central neuron tissues as a mechanism for the regulation of extracellular adenosine concentrations. Neurochem. Int. 1984;6:613–632. Young, D., and M. Dragunow. MK801 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. Young, D., and M. Dragunow. Status epilepticus may be caused by loss of adenosine anticonvulsant mechanisms. Neuroscience 1994;58:245–261. Zetterstrom, T., L. Vernet, U. Ungerstedt, U. Tossman, B. Jonzon, and B. B. Fredholm. Purine levels in the intact rat brain: Studies with an implanted perfused hollow fibre. Neurosci. Lett. 1982;29:111–115. Zgodzinski, W., A. Rubaj, Z. Kleinrok, and M. SiekluckaDziuba. Effect of adenosine A1 and A2 receptor stimulation on hypoxia-induced convulsions in adult mice. Pol. J. Pharmacol. 2001;53(1):83–92. Zgombick, J. M., S. G. Beck, C. D. Mahle, B. CraddockRoyal, and S. Maayani. Pertussis toxin-sensitive guanine nucleotide-binding protein(s) couple adenosine A1 and 5hydroxytryptamine1A receptors to the same effector systems in rat hippocampus: Biochemical and electrophysiological studies. Mol. Pharmacol. 1989;35:484–494. Zwillich, C. W., F. D. Sutton, T. A. Neff, W. M. Cohn, R. A. Matthay, and M. M. Weinberger. Theophylline-induced seizures in adults. Ann. Intern. Med. 1975;82:784–787.
V BASIC MECHANISMS: BRAIN DAMAGE
25
Excitotoxicity in Status Epilepticus
. . . , , ,
Excitotoxic hypothesis Excitotoxicity, or the “excitotoxic hypothesis,” to use the term coined by John Olney in 1978, suggests that a cell firing mechanism underlies glutamate neurotoxicity and that the toxic action may be mediated through glutamatergic or aspartergic neurotransmission (64). As a concept, excitotoxicity has gained wide acceptance and was long suggested to play a role in neuronal cell death associated with status epilepticus (SE) (8, 65). Glutamate and calcium play pivotal roles in the cascade of events leading to excitotoxic cell death (44, 55). Electron microscopy studies have helped establish at the ultrastructural level the involvement of mitochondria (18, 28) and changes in chromatin and cytoplasm that characterize excitotoxic cell death as a necrotic process (9). A lesser level of excessive excitation can also initiate molecular events leading to a delayed type of cell death, apoptosis. Several mechanisms have been implicated as partially responsible for the neurochemical cellular alterations that supervene after excitotoxic stimuli (80). These events, when longlasting, lead the cell into a state of energy imbalance, with deterioration of the membrane potential, and cause neuronal and glial depolarization (37). Decreases in highenergy phosphate stores prevent glutamate reuptake, with consequent activation of N-methyl--aspartate (NMDA), aamino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and metabotropic glutamate receptors, the first two contributing to Ca2+ overload (74, 88). Mitochondrial depolarization after glutamate exposure has been reported to be an early event associated with intracellular Ca2+ loading (1, 31, 38, 40, 77). This event, suggested to be neuroprotective if acute and of moderate intensity (7, 86), seems to trigger necrotic cell death when longlasting and intense. Increases in mitochondrial Ca2+ contents may cause disruption of the inner membrane, disturbing electron chain transport and adenosine triphosphate (ATP) production (17). The distinction between a reversible, physiologic response to increased energy demand and a pathologic depolarization after mitochondrial damage is not always easy to make. It has recently been demonstrated that physiologic increases in conductance of mitochondrial membranes might develop as a response to increased synaptic activity (35). More important, this calcium-dependent change in mitochondrial conductance outlasts the period of stimulation by tens of seconds, and has been suggested to contribute to synaptic plasticity
(35). During SE, however, such increases in conductance would presumably contribute to an earlier failure of mitochondrial activity. In addition, elevated cytosol Ca2+ leads to an increase in the activity of various proteases, phospholipases, and endonucleases (5). Caspases are aspartate-specific cysteine proteases normally existing as zymogens in cells. When cytochrome C is released from the inner mitochondrial membrane, it activates caspases, which might kill the cells (27). Although free radicals and arachidonic acid metabolites have been implicated as fundamental players in diverse processes of cell degeneration (16), they are not addressed further in this chapter.
Status epilepticus–induced cell damage The clinical relevance of SE has been stressed by many investigators (for review, see 91). It has been postulated that SE-induced cell death might be at the root of epileptogenesis, and many animal models have supported such a hypothesis (43, 49, 58). There is considerable evidence that prolonged SE produces neuronal damage, even in welloxygenated animals (56). Several brain structures, among them the hippocampus, cerebellar and cerebral cortices, certain thalamic and amygdaloid nuclei, and piriform cortex, appear to be selectively vulnerable to excitotoxic stimuli (52, 55), and death involves both necrotic and apoptotic processes (70, 83, 93). A crucial issue relating to the genesis of this neuropathologic picture has to do with the duration of SE needed for epilepsy to ensue. Experimental evidence suggests that the longer the SE duration, the more intense the excitotoxic neuronal damage and the more likely it is that epilepsy will develop. Thus, clinical SE is considered a major neurologic emergency requiring immediate effective treatment. Conversely, SE discharges of only 30 minutes’ duration do not lead to supragranular mossy fiber sprouting or cell damage in some animal models of epilepsy (43, 70, 83, 93). Similarly, infantile febrile convulsions of short duration do not carry greatly increased chances of progressing to temporal lobe epilepsy (51, 79). Thus, what are the real consequences of a brief period of continuous seizures for patients? Is there a borderline period during which irreversible damage occurs in more vulnerable cell populations? Is the irreversible cell damage more deleterious to neuronal circuitry than to partially injured, surviving cells?
.:
327
Silver impregnation methods have long been used to identify which cell populations are vulnerable to excessive cell excitation (15, 62). Such techniques however, in contrast to the relative effortlessness of immunohistochemical procedures aimed at identifying cell damage, are technically difficult and have not gained wide acceptance. In the early nineties, Gallyas and colleagues (23, 24, 92) described a silver impregnation method in which, after an insult, vulnerable neurons were suggested to suffer a breakdown of polymeric cytoskeletal elements. Exposure of electrical charges of the monomers would allow a process of silver accumulation, which would then permit visualization. This procedure allows the identification of black-stained injured neurons against a yellowish background, in a Golgi-like fashion, therefore allowing morphologic characterization of specific neuronal populations. More recently this technique has been suggested to stain not only neurons that are destined to die or that have already suffered early death but also injured neurons that suffered reversible damage (30, 90). Accordingly, the Gallyas technique allows the detection of neuronal damage and neuronal death. Using the silver staining procedure, we recently undertook a comparative study of the temporal pattern of neuronal damage after kainic acid– or pilocarpine-induced SE (10). That study, however, did not address the question of neuronal damage following a very brief, and thus more clinically relevant, episode of SE. To do so, we used a technique that allows complete control over the electroencephalographic (EEG) and behavioral epileptic activity that characterizes pilocarpine-induced SE (43). Complete control over SE duration was necessary because many pathologic processes (e.g., mitochondrial swelling, cytoplasmic changes, dark cell changes) might take place many minutes or hours after an event (16). Hence, sacrificing an animal 5 minutes after SE onset might not allow the observation of damaged cells, even though such processes might already have started (Figures 25.1 and 25.2).
F 25.1 Schematic representation of the experimental design. SE duration could be either 5 minutes (as represented) or 10, 20, 30, 60, or 120 minutes. Perfusion for each SE duration could be performed either 2 hours or 24 hours later (n = 3 or 4 for each SE duration and perfusion time). Pilo, pilocarpine; Thio, thiopembutal; Bzd, benzodiazepine.
328
:
Pilocarpine-induced SE of only 5 minutes’ duration was sufficient to cause neuronal damage, even though mild, in several areas. Such damage, which was not readily visible with silver staining 2 hours after SE termination, was rather clear at 24 hours. Previous studies using light microscopy and cell counts either had not looked at such short SE durations or had failed to show any damage after even longer durations (22, 43, 56, 80). Perfusion of the animals 2 hours after a 5-minute episode of SE showed neuronal damage in the hippocampal hilus, primary sensory neocortex layers II and III, endopiriform cortex, piriform cortex, and cortical and basomedial amygdaloid nuclei. Amygdaloid complex, perirhinal cortex (mainly deep layers), and piriform cortex neurons were the most vulnerable neuronal cell types after short SE durations. For animals that experienced similar SE durations but were perfused at a later time (24 hours), there was a clear progression of the damage with seizure duration, as a larger number of neurons became silver-stained in various brain areas (Figures 25.3 to 25.5). However, this process was not homogeneous throughout the brain. Perfusion of the animals 24 hours after a 5-minute episode of SE allowed neuronal damage to be seen at approximately the same intensity in the same areas as for shorter SE durations with earlier perfusion, and also in retrosplenial cortex layers II–IV and in perirhinal cortical layers III–IV (a marked number of stained neurons). As expected, longer SE times led to more pronounced damage and to neuronal staining in additional brain areas. SE durations of 10–15 minutes did not further increase the number of damaged neurons in cortical areas but allowed dark cells to be seen in some thalamic (reuniens, medial geniculate, and suprageniculate) and hypothalamic (ventral and dorsal premammillary) nuclei as well. For some areas— the hippocampal formation, perirhinal and entorhinal cortices—cell damage remained relatively stable from 10 to 30 minutes of SE duration. SE duration of more than 30 minutes was necessary to induce neuronal damage in CA1 and CA3 pyramidal cells, CA1 stratum oriens, and perirhinal cortical layers III and IV. Further, many neuronal processes in the stratum oriens-alveus of the CA1 region were visualized after 30 minutes of SE. The robust axonal projections of single CA3 pyramidal cells to these areas (CA1 stratum oriens-alveus) suggest that these degenerating fibers could be the axons of the few injured CA3 pyramidal cells. For the hippocampal dentate granule cells and CA1 and CA3 pyramidal cells areas, a similar number of neurons was stained at either 2 or 24 hours after 30 minutes of SE. The opposite was true for the hippocampal hilus and perirhinal and entorhinal cortices, where distinct staining patterns were found, depending on whether animals were perfused 2 hours or 24 hours after a 30-minute SE event. In
F 25.2 EE recordings obtained from an animal before and during pilocarpine (Pilo)-induced SE and after SE termination. Fifteen minutes after pilocarpine injection (320 mg/kg IP), a kindling stage III seizure lasting 55 seconds was recorded. Thirty minutes after pilocarpine administration, cortical and hippocam-
pal electrical activities were characteristic of SE. Ten minutes after BDZ+PB injection (10 and 30 mg/kg IP, respectively), EEG activity was not different from that of control recordings, evidencing complete control over SE.
general, 30 minutes of SE could be considered a threshold for cell damage in most brain areas. From then on, there was a dramatic increase in both the number of stained cells and additional brain areas affected. In comparison with 30 minutes of SE, additional areas that showed intense damage after either 1 or 2 hours of SE were the lateral septum, bed nuclei of stria terminalis, thalamic nuclei (paraventricular, parafascicular, reuniens, centromedial), hypothalamic nuclei (medial preoptic area, dorsal and ventral premamillary, lateral area), caudate-putamen, and cortical neurons (layers IV and VI). One or two hours of SE induced damage in similar brain areas. Dentate granule cells and hilar cells were conspicuously stained after 1–2 hours of SE (see Figures 25.3 and 25.4). Using relative rather than absolute numbers would still identify the hippocampal hilus as the most injured area at all time points (10). For CA1 pyramidal neurons, an SE duration of 2 hours yielded dramatically different results, whether assessed right at 2 hours or at 24 hours. Perfusion of the animals 24 hours
after the end of a 2-hour SE episode resulted in a 10-fold increase in the number of silver-stained neurons in CA1. For the amygdala, piriform, entorhinal, and perirhinal cortices, a severe edema and often a disrupted neuropil (pale) were present 24 hours after a 2-hour SE episode. Graphs quantifying these results after different SE durations and different perfusion times are shown in Figures 25.4 and 25.5. One major conclusion that can be drawn from these results is that cell loss for each brain area has remarkably specific profiles. The intensity of cell damage does not vary linearly with SE duration. After a given insult, cell damage may progress with time, but it does not necessarily do so. Another interesting issue arises from the experimental data of models of temporal lobe epilepsy (43) that set at more than 30 minutes (but less than 60 minutes) the minimum duration of SE necessary for spontaneous recurrent seizures to ensue afterward. Accordingly, it could be speculated that if cell damage or loss is indeed necessary for
.:
329
F 25.3 Photomicrographs of silver-stained (degenerating) cells in the hippocampal formation. (A and B) The dorsal hippocampal complex of animals submitted to 30 minutes of pilocarpine-induced SE but perfused at either 2 hours (A) or 24 hours (B) after SE onset. There is a higher density of stained cells in the hilus in B compared with A, with a relative absence of stained cells in other fields. (C and D) Silver-stained dentate cells after 120
minutes of pilocarpine-induced SE. In C, besides the extensive staining of hilar cells, there was also an initial staining of cells with the morphology of CA3 pyramids (arrow). In D (a higher magnification of C), cells with the morphology of dentate granule cells can be seen in the lower blade of the dentate gyrus. Calibration bar = 200 mm for A, B, and C; 150 mm for D.
F 25.4 Graphic representation of the number of stained (degenerating) neurons in the hippocampal complex after different SE durations and perfusion times. Open symbols represent animals perfused at 2 hours; closed symbols represent animals perfused at 24 hours after SE onset. Damage to pyramidal CA3 cells was not
readily visible in any of the experimental groups. Damage to CA1 pyramidal cells was clear only after 2 hours of SE and a late perfusion interval (24 hours). Dentate hilar and granule cells were the most frequently injured cells in the hippocampal complex at any SE duration and perfusion interval.
F 25.5 Graphic representation of the number of stained (degenerating) neurons in the piriform cortex, amygdala, and perirhinal (layers IV–V) and entorhinal cortices after different SE durations and perfusion times. Dotted bars represent animals perfused at 2 hours; and solid bars represent animals perfused at 24 hours after SE onset. In general, most noticeably for the 2-hour perfusion interval, there was a sharp distinction in cell damage for SE durations £30 minutes or ≥60 minutes. A 24-hour delay
between SE onset and perfusion usually did not allow cell damage to be quantified after SE durations of more than 60 minutes because of the disappearance of specific brain areas. Liquefaction necrosis (indicated by double asterisks) was present in these brain areas (but not in hippocampus; see Figure 25.4) for every animal perfused 24 hours after a 2-hour-duration SE episode. For the entorhinal cortex, liquefaction necrosis was already present after a 1-hour SE duration.
spontaneous seizures to develop, then either cell damage induced after 30 minutes of SE is not intense enough or it does not affect brain areas critical for the development of spontaneous seizures. On the other hand, it is not totally clear that cell loss is necessary for epileptogenesis. In their review, Lothman and Bertram (49) addressed this issue in both human epilepsy and animal models. Their final statement was that data obtained from adult patients and animals support, but do not prove, the concept of a two-step process in which SE leads to brain damage and brain damage leads to active epilepsy. In agreement with Lemos and Cavalheiro’s findings (43), there was a sharp distinction between cell damage induced
after 30 and 60 minutes of SE for most brain areas. Among the notable exceptions, the CA1 and CA3 hippocampal subfields did not show a significant increase in silver-stained neurons from 30 to 60 minutes. Overall, the fundamental difference between 30 and 60 minutes of SE is not damage to new areas but a significant increase in damage to already damaged areas.
Apoptosis versus necrosis Apoptosis, a term coined to describe a specific type of cell death, usually associated with early embryonic events (39), has a broader use today. A number of studies have reported
.:
331
that some cells suffer apoptosis after continuous epileptic activity (70, 83, 93). Whether a cell undergoes necrosis or apoptosis after SE seems to be associated with at least two main factors, the severity of the SE (6) and the specific features of the target cells (83). Therefore, cell death induced by excitotoxicity might be mainly postsynaptically determined by the way in which different target cells interpret an excitatory insult (83).
Our current and previous findings (12), based on the ultrastructural analysis of dentate granule cells, show both apoptotic and necrotic features of cell death at various time intervals (2–48 hours) after pilocarpine-induced SE. We did not find any clear-cut evidence of apoptosis (Figure 25.6). However, cell death in the CNS following injury can occur in hybrid forms. NMDA receptor and non-NMDA receptormediated excitotoxic injury results in neurodegeneration
F 25.6 Electron photomicrographs of degenerating granule cells. (A) A degenerating granule cell shown next to an apparently normal cell. The degenerating cell presents a pathologic alteration of the lysosomes and swelling of mitochondria (small arrows) besides a convoluted nuclear membrane (arrowheads). (B) A degen-
erating granule cell (large arrow) in an animal perfused 48 hours after pilocarpine-induced SE. Note the high electron density of the degenerating cell and the vacuolization of its cytoplasm. Magnification: ¥10,000 in A and ¥3,000 in B.
332
:
along an apoptosis–necrosis continuum. The distinction between the two is relevant for determining which pharmacologic compound should be used to prevent degeneration after an insult. The perspective of a continuum between the two processes suggests that drugs targeting both necrosis and apoptosis or even a combination of various specific drugs might be preferable (14).
Long-term changes In recent years, a number of plastic morphologic changes ensuing after SE have been described in animal models of epilepsy (11, 59, 68, 85), but none of these changes has yet been adequately evaluated regarding its possible contribution to epileptogenesis. It is thus possible that SE-related excitotoxicity induces not only cell loss and axonal changes but also permanent dendritic distortion, cell dispersion, and neurogenesis. The description of supragranular mossy fiber sprouting in the dentate gyrus of kainate-treated rats (89) followed searches for neuronal reorganizations and long-term changes that would follow SE or brain insults in general. Supragranular mossy fiber sprouting in particular has been suggested to be a major anatomic change that could lead to temporal lobe epilepsy in both humans and animal models (3, 13, 58, 87). This interpretation, however, has been questioned in a series of papers from our laboratory in which blockade of the supragranular mossy fiber sprouting induced after SE did not alter the later development of epilepsy (45–48, 81). Subsequent studies by different laboratories have further refuted a causative role for supragranular mossy fiber sprouting in temporal lobe epilepsy (60, 63), although some have taken the obverse position (95). It has been suggested that a key event necessary for mossy fibers to sprout after an insult would be the loss of hilar mossy cells (4, 82). Selective loss of hilar cells in temporal lobe epilepsy, a condition termed endfolium sclerosis (2, 52, 53, 57), might occur in the absence of any additional hippocampal cell loss, thus underscoring the view of hillar cells as one of the most vulnerable cell populations in the hippocampus. Indeed, hilar cell loss, especially mossy cell loss, has been considered a key event to explain hippocampal hyperexcitability in the dormant basket cell hypothesis as well as the mossy fiber sprouting hypothesis. Recent studies, however, have suggested that hilar mossy cells might not be as vulnerable as initially suggested and in fact might themselves become “epileptic” after an insult such as SE (71, 73, 75), thus leading to the “mossy cell irritable cell” hypothesis (73). In addition of the morphologic changes noted earlier, a previously overlooked observation is that of distorted cell bodies and dendrites in the hippocampus and temporal lobe of epileptic patients (69, 76) and animals (94). Scheibel’s observations tended to be dismissed on the basis of possible
fixation artifacts (even though they were not present in his control cases). Using the pilocarpine model of temporal lobe epilepsy, we have reported similar findings for both dentate granule cells and hippocampal pyramidal cells (19, 33). However, it is possible that the dendritic and cell body distortions encountered were induced by the micropipet used for the intracellular injections of the dyes (even though distortions were not present in our control animals). The crucial experiments were done by Müller and colleagues in organotypic hippocampal slice culture (61). In their experiment, addition of picrotoxin and or bicuculline (GABAA antagonists and convulsant agents) to the culture led to profound dendritic alterations in hippocampal pyramidal and dentate granule cells, and removal of convulsants led to subsequent recovery of the normal dendritic profile. This elegant experimental design demonstrates the potential for excitation (blockade of inhibition, in this case) to induce dendritic alterations. The mechanisms by which altered synaptic activity induces changes in dendritic spines are unknown. Recent findings have suggested that mature neurons are able to regulate total spine number according to the level of activity (41). A reduction in postsynaptic calcium levels permits enhanced actin polymerization (21, 34), thereby supporting outgrowth of spinelike protusions. More recent studies in the pilocarpine model and in material from patients with temporal lobe epilepsy suggest that initial acute seizures (SE) do not cause permanent damage in dendrites and spines and that dendritic spines of epileptic neurons can respond to changes in the local cellular environment, including newly formed afferents, in a plastic manner (32). In addition, basal dendrites growing into the hilar region of the dentate gyrus and synapsing with mossy fibers have been shown to occur after the onset of pilocarpine-induced SE (72). The relationship of these changes, triggered by an initial acute insult (e.g., SE), to the later ensuing epilepsy is not clear. An increased rate of neurogenesis of the dentate granule cells after an ictal event has been described in many animal models of temporal lobe epilepsy (26, 66, 78). Although this finding initially suggested a direct relationship between the newly formed dentate granule cells and aberrant mossy fiber sprouting and hippocampal hyperexcitability (68), later studies dismissed an association between SE-induced neurogenesis and mossy fiber sprouting (11, 67). In addition, earlier studies measuring dentate granule cell dispersion in epileptic tissue, which might occur as a consequence of the increased rate of neurogenesis, in the pilocarpine model as well as in epileptic patients, did not find an association between the level of dispersion and the frequency of spontaneous seizures (50, 59). Finally, even though this discussion has been concerned mostly with changes in the hilus and dentate gyrus, it is clear that other areas of the hippocampal complex and of the
.:
333
forebrain might undergo plastic changes as a consequence of SE. Sprouting of CA1 pyramidal cell axons and changes in the intrinsic membrane properties of those neurons have been reported in humans and in rodent models of SE (20, 25, 42, 84). Altered patterns of excitability were also decribed within different elements of the intracortical network in the entorhinal cortex (36) and could play a role in predisposing this area to epileptogenesis. Overexpression of NADPHd by remaining neurons of the deep layers of the entorhinal cortex, suggested to be an adaptative process providing seizure blockade, is another plastic change that has been reported in rats many months after the induction of SE (29).
Comment
4.
5.
6.
7.
8.
To date, most studies on the excitotoxic effects of SE have concentrated on a time window from 30 minutes to 2 hours of SE duration. We found that even a short episode of SE (5 minutes) might damage a significant number of hilar neurons. On the other hand, in rats, pilocarpine-induced SE shorter than 30 minutes is not sufficient to evoke a chronic epileptic condition (43). It is yet not clear what SE-related factors lead to the eventual development of epilepsy. SE-induced neuronal damage is presumably only one such factor. Finally, we must consider that cell damage is not limited to acute or delayed cell loss but may also take the form of chronic impairment of surviving neurons. Evidence from both humans and experimental animal studies supports the notion that excitotoxicity may lead to morphologically deformed and functionally impaired neurons, which in turn could contribute to epilepsy (19, 33, 76). In this respect, excitotoxicity might be regarded as an excellent concept from its inception, since it is not restricted to cell death but encompasses damage to both dying cells and surviving cells. Financial support was provided by PRONEX (118/96), FAPESP-CEPID, and Instituto do Milênio-CNPq (L.C. was a FAPESP fellow). Ultrastructural work was developed at CEME-UNIFESP. Dr. Edna Freymüller Haapalainen made available the electron microscope, and Ivone de Paulo and Marcia F.A. Tanakai provided technical assistance.
9.
10.
11.
12.
13.
14.
15.
16.
17. 18.
19. REFERENCES 1. Ankarcrona, M., J. M. Dypbukt, S. Orrenius, and P. Nicotera. Calcineurin and mitochondrial function in glutamate-induced neuronal cell death. FEBS Lett. 1996;394:321–324. 2. Babb, T. L., and W. J. Brown. Pathological findings in epilepsy. In J. Engel, Jr., ed. Surgical Treatment of the Epilepsies. New York: Raven Press, 1987:511–512. 3. Babb, T. L., W. R. Kupfer, and J. K. Pretorius. Recurrent excitatory circuits by “sprouted” mossy fibers into the fascia
334
:
20.
21.
dentata of human hippocampal epilepsy. Epilepsia 1988;29: 674. 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 dentata. Neuroscience 1991;42:351– 363. Beal, M. F., B. T. Hyman, and W. Koroshetz. Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? Trends Neurosci. 1993;16:125–131. Bonfoco, E., D. Krainc, M. Ankarcrona, P. Nicotera, and S. A. Lipton. Apoptosis and necrosis: Two distinct events induced, respectively, by mild and intense insults with N-methyl-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc. Natl. Acad. Sci. U.S.A. 1995;92:7162–7166. Budd, S. L., and D. G. Nicholls. Mitochondrial calcium regulation and acute glutamate excitotoxicity in cultured cerebellar granule cells. J. Neurochem. 1996;67:2282–2291. Choi, D. W. Ionic dependence of glutamate neurotoxicity. J. Neurosci. 1987;7:369–379. Colbourne, F., G. R. Sutherland, and R. N. Auer. Electron microscopic evidence against apoptosis as the mechanism of neuronal death in global ischemia. J. Neurosci. 1999;19: 4200–4210. Covolan, L., and L. E. Mello. Temporal profile of neuronal injury following pilocarpine or kainic acid–induced status epilepticus. Epilepsy Res. 2000;39:133–152. Covolan, L., L. T. Ribeiro, B. M. Longo, and L. E. Mello. Cell damage and neurogenesis in the dentate granule cell layer of adult rats after pilocarpine- or kainate-induced status epilepticus. Hippocampus 2000;10:169–180. Covolan, L., R. L. Smith, and L. E. Mello. Ultrastructural identification of dentate granule cell death from pilocarpineinduced seizures. Epilepsy Res. 2000;41:9–21. Cronin, J., and F. E. Dudek. Chronic seizures and collateral sprouting of dentate mossy fibers after kainic acid treatment in rats. Brain Res. 1988;474:181–184. De Keyser, J., G. Sulter, and P. G. Luiten. Clinical trials with neuroprotective drugs in acute ischaemic stroke: Are we doing the right thing? Trends Neurosci. 1999;22:535–540. de Olmos, J. S., S. O. E. Ebbesson, and L. Heimer. Silver methods for impregnation of degenerating axoplasm. In L. Heimer, and M. Robards, eds. Anatomical Methods for Tract Tracing. New York: Plenum Press, 1980. Dirnagl, U., C. Iadecola, and M. A. Moskowitz. Pathobiology of ischaemic stroke: An integrated view. Trends Neurosci. 1999;22:391–397. Dugan, L. L., and D. W. Choi. Excitotoxicity, free radicals, and cell membrane changes. Ann. Neurol. 1994;35:S17–S21. Dugan, L. L., S. L. Sensi, L. M. Canzoniero, S. D. Handran, S. M. Rothman, T. S. Lin, et al. Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl--aspartate. J. Neurosci. 1995;15:6377–6388. Duran, R. V., D. M. Finch, A. M. Tan, and L. E. A. M. Mello. Laminar analysis of neuronal reorganization in the hippocampus of pilocarpine chronic rats. Presented at a Society for Neuroscience meeting, Miami Beach, FL, 1994; abstract book p. 1456. Esclapez, M., J. C. Hirsch, Y. Ben-Ari, and C. Bernard. Newly formed excitatory pathways provide a substrate for hyperexcitability in experimental temporal lobe epilepsy. J. Comp. Neurol. 1999;408:449–460. Fifkova, E. Actin in the nervous system. Brain Res. 1985;356: 187–215.
22. Fujikawa, D. G. The temporal evolution of neuronal damage from pilocarpine-induced status epilepticus. Brain Res. 1996; 725:11–22. 23. Gallyas, F., M. Hsu, and G. Buzsaki. Four modified silver methods for thick sections of formaldehyde-fixed mammalian central nervous tissue: “Dark” neurons, perikarya of all neurons, microglial cells and capillaries. J. Neurosci. Methods 1993;50:159–164. 24. Gallyas, F., G. Zoltay, and W. Dames. Formation of “dark” (argyrophilic) neurons of various origin proceeds with a common mechanism of biophysical nature (a novel hypothesis). Acta Neuropathol. 1993;83:504–509. 25. Gorter, J. A., E. A. van Vliet, E. Aronica, and F. H. Lopes da Silva. Long-lasting increased excitability differs in dentate gyrus vs. CA1 in freely moving chronic epileptic rats after electrically induced status epilepticus. Hippocampus 2002;12: 311–324. 26. Gray, W. P., and L. E. Sundstrom. Kainic acid increases the proliferation of granule cell progenitors in the dentate gyrus of the adult rat. Brain Res. 1998;790:52–59. 27. Green, D. R., and J. C. Reed. Mitochondria and apoptosis. Science 1998;281:1309–1312. 28. 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. 29. Hamani, C., F. Tenorio, R. Mendez-Otero, and L. E. Mello. Loss of NADPH diaphorase-positive neurons in the hippocampal formation of chronic pilocarpine-epileptic rats. Hippocampus 1999;9:303–313. 30. Horváth, Z. C., J. Czopf, and G. Buzsaki. MK-801-induced neuronal damage in rats. Brain Res. 1997;753:181–195. 31. Isaev, N. K., D. B. Zorov, E. V. Stelmashook, R. E. Uzbekov, M. B. Kozhemyakin, and I. V. Victorov. Neurotoxic glutamate treatment of cultured cerebellar granule cells induces Ca2+dependent collapse of mitochondrial membrane potential and ultrastructural alterations of mitochondria. FEBS Lett. 1996; 392:143–147. 32. Isokawa, M. Remodeling dendritic spines of dentate granule cells in temporal lobe epilepsy patients and the rat pilocarpine model. Epilepsia 2000;41:S14–S17. 33. Isokawa, M., and L. E. Mello. NMDA receptor-mediated excitability in dendritically deformed dentate granule cells in pilocarpine-treated rats. Neurosci. Lett. 1991;129:69–73. 34. Janmey, P. A. Phosphoinositides and calcium as regulators of cellular actin assembly and disassembly. Annu. Rev. Physiol. 1994;56:169–191. 35. Jonas, E. A., J. Buchanan, and L. K. Kaczmarek. Prolonged activation of mitochondrial conductances during synaptic transmission. Science 1999;286:1347–1350. 36. Jones, R. S. Short- and long-term alterations in glutamate transmission in the entorhinal cortex: Relevance to epileptogenesis. Epilepsy Res. Suppl. 1996;12:229–237. 37. Katsura, K., T. Kristian, and B. K. Siesjo. Energy metabolism, ion homeostasis, and cell damage in the brain. Biochem. Soc. Trans. 1994;22:991–996. 38. Keelan, J., O. Vergun, B. I. Khodorov, and M. R. Duchen. Calcium-dependent mitochondrial depolarization specific to toxic glutamate depolarization in cultured rat hippocampal neurons. J. Physiol. 1998;506:75P. 39. Kerr, J. F., and B. V. Harmon. Definition and incidence of apoptosis: An historical perspective. In L. D. Tomei, and F. O. Cope, eds. Current Communications in Cell and Molecular Biology.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49. 50.
51.
52.
53.
54.
55.
56.
Vol. 3. Apoptosis: The Molecular Basis of Cell Death. New York: Cold Spring Harbor Laboratory Press, 1991:5–29. Khodorov, B., V. Pinelis, O. Vergun, T. Storozhevykh, and N. Vinskaya. Mitochondrial deenergization underlies neuronal calcium overload following a prolonged glutamate challenge. FEBS Lett. 1996;397:230–234. Kirov, S. A., and K. M. Harris. Dendrites are more spiny on mature hippocampal neurons when synapses are inactivated. Nat. Neurosci. 1999;2:878–883. Lehmann, T. N., S. Gabriel, R. Kovacs, A. Eilers, A. Kivi, K. Schulze, et al. Alterations of neuronal connectivity in area CA1 of hippocampal slices from temporal lobe epilepsy patients and from pilocarpine-treated epileptic rats. Epilepsia 2000;41:S190–S194. Lemos, T., and E. A. Cavalheiro. Suppression of pilocarpineinduced status epilepticus and the late development of epilepsy in rats. Exp. Brain. Res. 1995;102:423–428. Lipton, S. A., and P. A. Rosenberg. Mechanisms of disease: Excitatory amino acids as a final common pathway for neurological disorders. N. Engl. J. Med. 1994;330:613–622. Longo, B. M., and L. E. Mello. Blockade of pilocarpine- or kainate-induced mossy fiber sprouting by cycloheximide does not prevent subsequent epileptogenesis in rats. Neurosci. Lett. 1997;226:163–166. Longo, B. M., and L. E. Mello. Effect of long-term spontaneous recurrent seizures or reinduction of status epilepticus on the development of supragranular mossy fiber sprouting. Epilepsy Res. 1999;36:233–241. Longo, B. M., and L. E. Mello. Supragranular mossy fiber sprouting is not necessary for spontaneous seizures in the intrahippocampal kainate model of epilepsy in the rat. Epilepsy Res. 1998;32:172–182. Longo, B. M., E. R. Sanabria, S. Gabriel, E. A. Cavalheiro, and L. E. A. M. Mello. Electrophysiologic abnormalities of the hippocampus in the pilocarpine/cycloheximide model of chronic spontaneous seizures. Epilepsia 2002;43 (in press). Lothman, E. W., and E. H. Bertram III. Epileptogenic effects of status epilepticus. Epilepsia 1993;34:S59–S70. Lurton, D., B. El Bahh, L. Sundstrom, and A. Rougier. Granule cell dispersion is correlated with early epileptic events in human temporal lobe epilepsy. J. Neurol. Sci. 1998;154:133–136. Maher, J., and R. S. McLachlan. Febrile convulsions: Is seizure duration the most important predictor of temporal lobe epilepsy? Brain 1995;118:1521–1528. Margerison, J. H., and J. A. Corsellis. Epilepsy and the temporal lobes: A clinical, electroencephalographic and neuropathological study of the brain in epilepsy, with particular reference to the temporal lobes. Brain 1966;89:499–530. Mathern, G. W., T. L. Babb, and D. L. Armstrong. Hippocampal sclerosis. In J. Engel, Jr., and T. A. Pedley, eds. Epilepsy: A Comprehensive Textbook. New York: Lippincott-Raven, 1997;133–156. Meldrum, B. S. Cell damage in epilepsy and the role of calcium in citotoxicity. In A. V. Delgado-Escueta, A. A. Ward, Jr., D. M. Woodbury, and R. J. Porter, eds. Basic Mechanisms of Epilepsies: Molecular and Cellular Approaches. Adv. Neurol. 1986;44:849–855. Meldrum, B. S. Epilepsy. In W. Blackwood, and J. A. N. Corsellis, eds. Greenfield’s Neuropathology. London: Arnold, 1984: 921–950. 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.
.:
335
57. Meldrum, B. S., and C. J. Bruton. Epilepsy. In J. H. Adams, and M. R. Duchen, eds. Greensfield’s Neuropathology. New York: Oxford University Press, 1992:1246–1283. 58. Mello, L. E., E. A. Cavalheiro, A. M. Tan, W. R. Kupfer, J. K. Pretorius, T. L. Babb, and D. M. Finch. Circuit mechanisms of seizures in the pilocarpine model of chronic epilepsy: Cell loss and mossy fiber sprouting. Epilepsia 1993;34:985–995. 59. Mello, L. E. A. M., E. A. Cavalheiro, A. M. Tan, J. K. Pretorius, W. R. Kupfer, T. L. Babb, and D. M. Finch. Granule cell dispersion in relation to mossy fiber sprouting, hippocampal cell loss, silent period and seizure frequency in the pilocarpine model of epilepsy. In J. Engel, Jr., G. Avanzini, E. A. Cavalheiro, U. Heinemann, and C. G. Wasterlain, eds. Molecular Neurobiology of Epilepsy. Amsterdam: Elsevier, 1992:51–60. 60. Mohapel, P., L. L. Armitage, T. H. Gilbert, D. K. Hannesson, G. C. Teskey, and M. E. Corcoran. Mossy fiber sprouting is dissociated from kindling of generalized seizures in the guineapig. Neuroreport 2000;11:2897–2901. 61. Müller, M., B. H. Gähwiler, L. Rietschin, and S. M. Thompson. Reversible loss of dendritic spines and altered excitability after chronic epilepsy in hippocampal slice cultures. Proc. Natl. Acad. Sci. U.S.A. 1993;90:257–261. 62. Nadler, J. V., and D. A. Evenson. Use of excitatory amino acids to make axon-sparing lesions of hypothalamus. Methods Enzymol. 1983;103:393–400. 63. Nissinen, J., K. Lukasiuk, and A. Pitkänen. Is mossy fiber sprouting present at the time of the first spontaneous seizures in rat experimental temporal lobe epilepsy? Hippocampus 2001;11:299–310. 64. Olney, J. W. Neurotoxicity of excitatory amino acids. In E. McGeer, J. W. Olney, and P. McGeer, eds. Kainic Acid as a Tool in Neurobiology. New York: Raven Press, 1978:95–102. 65. Olney, J. W., R. C. Collins, and R. S. Sloviter. Excitotoxic mechanisms of epileptic brain damage. In A. V. DelgadoEscueta, A. A. Ward, Jr., D. M. Woodbury, and R. J. Porter, eds. Basic Mechanisms of Epilepsies: Molecular and Cellular Approaches. Adv. Neurol. 1986;44:857–877. 66. Parent, J. M., S. Janumpalli, J. O. McNamara, and D. H. Lowenstein. Increased dentate granule cell neurogenesis following amygdala kindling in the adult rat. Neurosci. Lett. 1998;247:9–12. 67. Parent, J. M., E. Tada, J. R. Fike, and D. H. Lowenstein. Inhibition of dentate granule cell neurogenesis with brain irradiation does not prevent seizure-induced mossy fiber synaptic reorganization in the rat. J. Neurosci. 1999;19:4508–4519. 68. Parent, J. M., T. W. Yu, R. T. Leibowitz, D. H. Geschwind, R. S. Sloviter, and D. H. Lowenstein. Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J. Neurosci. 1997;17:3727–3738. 69. Paul, L. A., and A. B. Scheibel. Structural substrates of epilepsy. In A. V. Delgado-Escueta, A. A. Ward, Jr., D. M. Woodbury, and R. J. Porter, eds. Basic Mechanisms of Epilepsies: Molecular and Cellular Approaches. Adv. Neurol. 1986;44:775–786. 70. Pollard, H., C. Charriaut-Marlangue, S. Cantagrel, A. Represa, O. Robain, J. Moreau, and Y. Ben-Ari. Kainateinduced apoptotic cell death in hippocampal neurons. Neuroscience 1994;63:7–18. 71. Ratzliff, A. H., V. Santhakumar, A. Howard, and I. Soltesz. Mossy cells in epilepsy: Rigor mortis or vigor mortis? Trends Neurosci. 2002;25:140–144. 72. Ribak, C. E., P. H. Tran, I. Spigelman, M. M. Okazaki, and J. V. Nadler. Status epilepticus-induced hilar basal dendrites on
336
:
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
rodent granule cells contribute to recurrent excitatory circuitry. J. Comp. Neurol. 2002;428:240–253. Santhakumar, V., R. Bender, M. Frotscher, S. T. Ross, G. S. Hollrigel, Z. Toth, and I. Soltesz. Granule cell hyperexcitability in the early post-traumatic rat dentate gyrus: The “irritable mossy cell” hypothesis. J. Physiol. 2000;524(Pt. 1):117–134. Scharfman, H. E., and P. A. Schwartzkroin. Protection of dentate hilar cells from prolonged stimulation by intracellular calcium chelation. Science 1989;246:257–260. Scharfman, H. E., K. L. Smith, J. H. Goodman, and A. L. Sollas. Survival of dentate hilar mossy cells after pilocarpineinduced seizures and their synchronized burst discharges with area CA3 pyramidal cells. Neuroscience 2001;104:741–759. Scheibel, M. E., P. H. Crandall, and A. B. Scheibel. The hippocampal-dentate complex in temporal lobe epilepsy: A Golgi study. Epilepsia 1974;15:55–80. Schinder, A. F., E. C. Olson, N. C. Spitzer, and M. Montal. Mitochondrial dysfunction is a primary event in glutamate neurotoxicity. J. Neurosci. 1996;16:6125–6133. Scott, B. W., S. Wang, W. M. Burnham, U. De Boni, and J. M. Wojtowicz. Kindling-induced neurogenesis in the dentate gyrus of the rat. Neurosci. Lett. 1998;248:73–76. Shinnar, S., A. T. Berg, S. L. Moshe, C. O’Dell, M. Alemany, D. Newstein, et al. The risk of seizure recurrence after a first unprovoked afebrile seizure in childhood: An extended followup. Pediatrics 1996;98:216–225. Siesjö, B. K., and T. Wieloch. Epileptic brain damage: Pathophysiology and neurochemical pathology. In A. V. DelgadoEscueta, A. A. Ward, Jr., D. M. Woodbury, and R. J. Porter, eds. Basic Mechanisms of the Epilepsies: Molecular and Cellular Approaches. Adv. Neurol. 1986;44:813–848. Silva, J. G., and L. E. Mello. The role of mossy cell death and activation of protein synthesis in the sprouting of dentate mossy fibers: Evidence from calretinin and neo- Timm staining in pilocarpine-epileptic mice. Epilepsia 2000;41: S18–S23. Sloviter, R. S. Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. Science 1987;235:73–76. 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. Smith, B. N., and F. E. Dudek. Network interactions mediated by new excitatory connections between CA1 pyramidal cells in rats with kainate-induced epilepsy. J. Neurophysiol. 2002; 87:1655–1658. 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. Stout, A. K., H. M. Raphael, B. I. Kanterewicz, E. Klann, and I. J. Reynolds. Glutamate-induced neuron death requires mitochondrial calcium uptake. Nat. Neurosci. 1998;1:366–373. 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. Tanaka, S., K. Sako, T. Tanaka, and Y. Yonemasu. Regional calcium accumulation and kainic acid (KA)-induced limbic seizure status in rats. Brain Res. 1989;478:385–390. Tauck, D. L., and J. V. Nadler. Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acidtreated rats. J. Neurosci. 1985;5:1016–1022.
90. Toth, Z., G. S. Hollrigel, T. Gorcs, and I. Soltesz. Instantaneous perturbation of dentate interneuronal networks by a pressure wave-transient delivered to the neocortex. J. Neurosci. 1997;17:8106–8117. 91. Treiman, D. M. General principles of treatment: Responsive and intractable status epilepticus in adults. 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;34:377–384. 92. van den Pol, A. N., and F. Gallyas. Trauma-induced Golgi-like staining of neurons: A new approach to neuronal organization and response to injury. J. Comp. Neurol. 1990;296:654–673. 93. Wasterlain, C. G., D. G. Fujikawa, L. Penix, and R. Sankar. Pathophysiological mechanisms of brain damage from status epilepticus. Epilepsia 1993;34:S37–S53. 94. Westrum, L. E., L. E. J. White, and A. A. Ward, Jr. Morpholgy of the experimental epileptic focus. J. Neurosurg. 1964;21: 1033–1046. 95. Williams, P. A., J. P. Wuarin, P. Dou, D. J. Ferraro, and F. E. Dudek. Reassessment of the effects of cycloheximide on mossy fiber sprouting and epileptogenesis in the pilocarpine model of temporal lobe epilepsy. J. Neurophysiol. 2002;88(4):2075–2087.
.:
337
26
Seizure-Induced Damage in the Immature Brain: Overcoming the Burden of Proof
.
Introduction Status epilepticus (SE) occurs much more frequently in infants and children than in adults. In the Richmond study by DeLorenzo and collaborators (16, 17), the incidence of SE in infants during the first year of life was 156 per 100,000, compared with 38 per 100,000 in children and 27 per 100,000 in adults. This heightened propensity of the developing brain to undergo SE has been demonstrated in the laboratory by in vitro (12, 28, 72) and in vivo (1, 49, 51) experiments. The consequences of repeated seizures and/or SE on the developing brain continues to be a subject of debate (8, 83), owing to conflicting clinical reports. Although some studies have associated seizures in childhood with neuronal damage comparable to that seen in the adult (13, 42, 44, 58), extended febrile seizures occur relatively frequently in children, and many seemingly with no apparent association with brain injury, as evidenced by the lack of subsequent neurologic deficits (19, 81). Studies in the latter population have attempted to resolve the controversy surrounding the effects of prolonged seizures on the developing brain. As noted, several studies have reported a benign course in children after febrile convulsions (19, 56, 80) or SE (45). Other reports have found measurable consequences. For example, Schiottz-Christensen and Bruhn (65) found mild deficits in intellectual performance in monozygotic twins who had sustained febrile seizures compared with their twin siblings who had not, and van Esch et al. (78) reported sequelae after a first episode of febrile SE in 24% of a cohort with no previous seizures or neurologic abnormalities. Mahar and McLachlan (41) described a strong association between febrile convulsions and temporal lobe epilepsy (TLE) with mesial temporal sclerosis in families with febrile seizures. These families had been selected in order to reduce genetic and phenotypic heterogeneity in studying the connection between febrile convulsions and TLE. A prolonged febrile convulsion was the most important determinant of this association.
Radiologic studies in children with complex partial seizures found that 57% of these children had magnetic resonance imaging evidence of hippocampal sclerosis (30). This finding was associated with a history of neurologic insults, including idiopathic febrile seizures, prior to the onset of complex partial seizures. More recent imaging studies found a strong association between prolonged febrile convulsions, acute edema, and the subsequent development of medial temporal lobe sclerosis (39, 79). These findings are supported by a number of related studies (48, 66, 67). Because of the different causes, duration, and severity of the epileptic condition and the physiologic impacts of medical treatment (which are particularly important in the developing nervous system [7, 33]), human studies are not likely to provide unambiguous answers as to whether seizureinduced brain damage can occur in the immature brain, and when such vulnerability begins in the course of maturation. For this reason we turn to animal models to study the relevant phenomena in reduced, and well-controlled, conditions. Several animal models of SE have been developed in many animal species. In mature animals, these models replicate many of the pathophysiologic and neuropathologic changes seen in the brains of humans with intractable temporal lobe epilepsy, or of people experiencing fatal episodes of SE (24). The use of chemical convulsants such as kainate and pilocarpine, in vivo electrical stimulation of excitatory pathways, and the induction of ischemia- and traumainduced seizures has increased our basic understanding of how the mature brain responds to seizure events and prolonged seizure-like discharges. Interestingly, when some wellestablished models of SE were tried in immature animals, none of them reliably produced damage in the immature rat brain (1, 6, 49–51, 77). These basic data supported the idea that very young children were resistant, or immune, to brain damage produced by febrile seizures or even SE, and that the pathologies observed were produced by factors unrelated to seizure activity per se (e.g., birth trauma, idiopathic lesions, or systemic changes produced by severe seizures).
: -
339
Despite the pioneering work of Meldrum and colleagues (47), which showed that seizure-induced damage could occur in the adolescent brain in the absence of hypoxia, only within the past decade, following the development of several new models of SE in the young, has a new, broader perspective emerged. These new models (generally involving an adaptation of an existing model to make it appropriate for the immature nervous system) have been combined with sensitive indicators of cell death and markers of synaptic rearrangement (26, 27, 36, 62, 73, 74). Analysis of these studies leads to the major conclusion that the immature brain can sustain significant damage as a result of severe seizures (85). Another major conclusion from these studies is that the severity and the phenotype of seizure-induced brain damage are model-specific. Deeply embedded in the issue of model specificity are the complicating factors of comparisons between species that may be more or less altricial or precocial at birth, as well as the significant influence of genetic (strain) differences within species (21, 23, 57). We explore these points by reviewing a number of studies that demonstrate model-specific vulnerabilities of the immature brain to seizure-induced damage, with an emphasis on the developing hippocampal region.
Review of experimental data The rat is an extremely useful subject for study because it develops altricially, thus enabling relatively easy postnatal manipulations during the brain growth spurt. Although other species have provided valuable data, much of the discussion that follows relies on data derived from rat studies, and therefore a few relevant caveats must be discussed in advance. The hippocampus, the most epileptogenic region of the brain, begins development in the rat on embryonic day 15 (Ammon’s horn) but does not approach a mature cellular complement (i.e., dentate granule cells [21, 23, 57]) or synaptic functioning (i.e., maximal long-term potentiation [29]) until the third postnatal week (ca. postnatal day 18). Glutamatergic receptors, which are known to be important in seizure-induced damage, have very different distributions in the immature brain (9, 59). The hippocampal inhibitory circuits develop asynchronously between subfields, with area CA1 lagging compared to area CA3 (71) or the dentate gyrus (5). Finally, the electrographic and behavioral progression of seizures in the immature rat are qualitatively different from what is seen in more mature rats (i.e., postnatal day 18 and later) within a given model (6, 50, 77). Damage to the nervous system can be measured indirectly by measuring the serum concentrations of neuron-specific enolase (s-NSE). This metabolic enzyme has been shown to correlate with the duration and outcome of SE in humans (15, 54) and has proved to be a sensitive measure for the existence of brain damage in the neonate. Rats were treated
340
:
F 26.1 Seizure-associated elevation in serum neuronspecific enolase levels as a function of age in rats.
with lithium followed by pilocarpine at 1, 2, 3, and 4 weeks and in adulthood to produce SE. Lithium pretreatment lowers the seizure threshold and greatly reduces the mortality from that seen in earlier studies, which used high doses of pilocarpine alone. One day later, s-NSE levels were compared with those of age-matched controls, and by week 2, clear differences had emerged (64). The differences in s-NSE levels were found to be proportional to the histologic damage shown by hematoxylin-eosin staining in the same animals (Figure 26.1). Hippocampal and extrahippocampal neuronal damage, produced by seizures induced by lithium-pilocarpine, is clearly seen in the rat 2 weeks after birth. A comparison of hippocampal cell death between the different age groups in the lithium-pilocarpine model revealed an extreme vulnerability of CA1 neurons that abated as the hippocampus matured (62). This vulnerability is likely related to the high levels of expression of Ca2+-permeant AMPA receptors in this region in the very young (59). Our laboratory has also noted a parallel phenomenon of very high levels of seizureinduced substance P expression, which modulates synaptic excitability, in CA1 of 2-week-old rats (40). On the other hand, cell death of CA3 and of hilar neurons, in this model, shows a different temporal profile. Damage in these areas was not obvious at 2 weeks but was severe by 3 weeks of age and beyond (Figure 26.2). Reasoned explanations for the ontologic course of the damage have been presented elsewhere (60, 63, 86), but it is prudent not to take these data to mean that the 2-week-old rat is immune to seizure-induced CA3 or hilar cell damage. Several studies using different models suggest otherwise, as discussed before. Even the same lithium-pilocarpine model, when used in a different species at a relatively similar development stage to the 2-week-old rat, provides a different picture. We have shown that 10-day-old rabbits treated with lithium-
F 26.2 Histologic lesions in lithium-pretreated rats 24 hours after the onset of pilocarpine-induced SE. (A–D) Hematoxylineosin-stained sections of CA1 from a 2-week-old pup (A), a 3-weekold pup (B), and a 4-week-old pup (C) show a large number of eosinophilic cells that fluoresce brightly, whereas the CA1 of a mature rat (D) has scattered damage. Dentate granule cells and hilar interneurons are damaged after pilocarpine seizures in rats pretreated with lithium. (E) Scattered eosin fluorescence is seen in a 2-week-old pup 24 hours after SE. (F) Section from a 3-week-old pup shows extensive damage to the hilar and outer granule cells. (G and H) Damaged hilar cells are also visible in a 4-week-old pup (G) and an adult rat (H). Scale bar = 100 mm.
pilocarpine show severe cell loss in all hippocampal subfields, as well as extrahippocampal damage. The CA1 subfield of the hippocampus, similar to what is seen in the rat, was most severely affected, but substantial cell death in the hilus, CA3, and the subiculum was also demonstrated (74). Measurement of blood gases in that experiment ruled out a hypoxic component to the insult, supporting the interpretation that neuronal loss was the direct result of seizure activity. There were interesting parallels with the damage reported by Franck and Schwartzkroin (22) after kainate administration (a model that has been reported not to produce damage in immature rats) in still younger rabbits. That study showed CA1 and CA3 hippocampal damage, with CA1 neurons being most vulnerable. Nonhuman primates, which are far more mature at birth than rodents or humans, show a different pattern of cell death after lithium-pilocarpine administration. A group of
four marmoset monkeys aged 2–4 weeks were preinjected with lithium (3 mEq/kg), followed 18 hours later by pilocarpine (100 mg/kg), and kept on a 37°C warming pad throughout the 8- to 32-hour period of SE. The marmosets showed widespread neuronal injury characterized by eosinophilic cytoplasm and fragmented or pyknotic nuclei with evidence of DNA damage. Damage was severe in the nucleus accumbens and in the reticular nucleus of the thalamus. Damage was moderate in the basolateral amygdala, the medial septum, and the medial caudate nucleus. Damage was mild in the lateral caudate, the dorsal and dorsomedial thalamus, in layers 4–5 of neocortex, in the entorhinal and basal frontal cortices, in Ammon’s horn, the hilus, the amygdala, the lateral septum, and in the olfactory cortex. Other regions were spared (Figure 26.3). As early as 10 days after birth, rat hippocampal pyramidal cells outside of the CA1 subfield have been shown to undergo seizure-induced damage. Baram and Schultz (4) showed that the convulsant corticotropin-releasing hormone (CRH), when delivered to the cerebral ventricles via an implanted cannula, produces selective death of the CA3 pyramidal cells that have mossy fiber afferents. The cell loss also produces synaptic reorganization in the hippocampus (mossy fiber sprouting) (3) that commonly follows severe hippocampal cell loss. Sprouting of mossy fibers is widely believed to be pathologic and potentially epileptogenic. High doses of CRH produce seizures in the adult rat without producing neuronal damage. These data show that the immature hippocampus (subfield CA3 in this case) is not generally protected from seizure-induced damage and that, in this model, the immature hippocampus has a selective vulnerability that involves cell loss and major synaptic rearrangement. Conclusive evidence that the immature brain can sustain damage as a result of prolonged seizure (or seizure-like) activity comes from a series of studies we performed in 14to 16-day-old rats using an adapted version of the perforant path stimulation (PPS) model developed by Sloviter (68, 69). We necessarily abandoned the use of urethane anesthesia because we found that the longlasting anesthetic induced cell death in the piriform cortex (76). Electrode implantation and physiologic tests were performed under metafane anesthesia, and the long-term PPS was delivered in the awake, freely moving animal, while granule cell discharges were monitored continuously. Unlike older animals, which show self-sustaining spontaneous seizures with PPS in the awake state, young rats typically show frequent “wet dog shakes” and hindlimb scratching movements. Only two of 24 animals displayed brief periods of limbic seizure-like behaviors, with forelimb clonic activity and rearing during the stimulation period; however, the behavior of the animals was not monitored continuously throughout stimulation. Granule cells
: -
341
DOUBLESTRANDED DNA BREAKS
F 26.3 Parietal cortex of a 14-day-old marmoset 24 hours after SE induction by lithium (3 mEq/kg infused IM 16 hours prior to pilocarpine) and pilocarpine (60 mg/kg IM). TUNEL staining
(brighter cells in this gray-scale image) showed double-stranded DNA breaks distributed in a laminar fashion.
continued to respond to each train throughout the stimulation period, but the responses decreased in amplitude by 12 hours in two of the three animals monitored every hour during the stimulation period. Perforant path stimulation, in this adapted model, produces unilateral hilar cell damage and bilateral granule cell and pyramidal cell damage in young rats. The cell loss is associated with a significant loss of frequency-dependent paired-pulse inhibition (Figure 26.4). Extrahippocampal lesions are found in the piriform cortex. The ipsilateral hilar cell death strongly suggests that it is the seizure-like discharges rather than systemic complications that cause the neuronal damage. It is interesting to note that prolonged focal seizures in children have also been associated with bilateral temporal lobe cell loss (39). The specific cell losses in the dentate gyrus produced by PPS in the young were studied in detail. The hilar cell losses were evaluated using Nissl cell counts and immunohistochemical methods. It was shown that large interneurons throughout the hilus, and somatostatin- and neuropeptide Ypositive interneurons within the polymorphic area, were particularly vulnerable to the seizure-induced damage (Figure 26.4). These populations have been shown to be affected in humans with intractable temporal lobe epilepsy (14). The dentate granule cells are affected early (the injury is obvious at the end of stimulation), and the degenerating cells disappear early (not obvious 24 hours after stimulation). The granule cells affected are primarily in the inner granule cells. They label with TdT dUTP-mediated nick end labeling, antibodies to cleaved poly-ADP-ribose polymerase, and they have nuclear features compatible with apoptosis (Figure 26.5). The inner granule cell layer has been shown to be vul-
nerable to seizures caused by ventricular homocysteic acid at earlier ages (38) and lithium-pilocarpine at later ages, also with evidence of apoptosis (63). Granule cell neogenesis has also been reported, however (61), although McCabe et al. present a different view (46). Granule cell loss has been seen in resected tissue from children with intractable epilepsy (43). The noncompetitive N-methyl--aspartate (NMDA) receptor blocker MK-801 was used to investigate NMDA receptor involvement in the observed hippocampal damage induced by PPS in the young rat. MK-801-injected animals showed reduced hilar damage and no lesion of pyramidal cells, or dentate granule cells, that were affected in all salinetreated animals. Cell counts confirmed MK-801 protection. There were reduced numbers of necrotic hilar cells in the MK-801 injected group (11.7 ± 12.1; range, 0–21.7) compared to the unmedicated group (29.3 ± 6.2; range, 23.7–36.0; P < 0.05) and preserved paired-pulse inhibition was shown (75). These data strongly implicate excitotoxic mechanisms working through the NMDA glutamate receptor in producing seizure-induced cell death in the immature hippocampus. Detailed reviews of the effects of seizures on brain growth and synaptic connections are available elsewhere (70, 84, 85). Severe or repeated seizures can impair brain growth in an age-specific manner (82), and can reduce cell-cell communications (34, 70), including white matter and synaptic markers in experimental SE (34) and white matter in humans with uncontrolled seizures (31, 32). They can modify growth factor expression (35), and they can also prevent pruning of some cells or connections, with potentially adverse consequences (70). Seizures, or anomalies of synaptic activity, can also distort neuronal anatomy, spine
342
:
percent of first spike (S2/S1)
1 mV
A
10 ms
160 120 S2
S1
80
B
40
before after week month
and synaptic morphology, and specific neuronal connections (25, 52). These effects can have a profound influence on the brain and its development, and have seen only limited exploration in human.
Discussion We have highlighted the data that reveal the sensitivity of the developing brain to seizure-induced injury by identifying models where that phenomenon can be demonstrated. Supporting evidence continues to mount for this (36, 37, 63,
F 26.4 Graphs at top show losses in frequency-dependent paired-pulse inhibition following perforant path stimulation (PPS) in 14- to 15-day-old rats. Paired pulses were delivered 50 msec apart, and at 2 Hz (dark bars) and 3 Hz (open bars). Paired-pulse test responses were recorded before, immediately after, 1 week after, and 1 month after stimulation. In the left graph, the percentages are expressed as the ratio of second spike (S2)/first spike (S1) ¥ 100 (Top left side). Statistical significance was demonstrated using oneway ANOVA. Symbols indicate significance (P < 0.05). The right graph shows an example of the 2-Hz paired-pulse inhibition test. Before stimulation (A), the first spike activates inhibitory mechanisms that suppress the second granule cell spike. Immediately after stimulation (B), the first spike (S1) no longer inhibits the second spike (S2). Black circles indicate the stimulus artifact. Histologic lesions 24 hours after the end of PPS are shown below the physiologic data. At 24 hours, sections were processed for a standard hematoxylin-eosin stain. (A and B) In the stimulated hilus, cells viewed under light microscopy showed shrunken and pyknotic nuclei and eosinophilic cytoplasm (A), while under ultraviolet light, necrotic cells showed bright eosin fluorescence (B). This pattern of damage was seen in all stimulated animals. (C–E) Many animals had additional damage in areas CA3, CA1, and the subiculum. Control animals showed no hippocampal lesions. (F) A fluorescent view of one unstimulated control animal shows the electrode track through the pyramidal cell layer, but no hilar or pyramidal cell damage resembling stimulated animals.
85). These basic data are consistent with historical (20, 42) and recent clinical data (11, 39, 79) (obtained with advanced imaging technology) showing a relationship between early seizures and brain damage. Using these (and other, yet-tobe-described) basic models to discover the molecular mechanisms of seizure-induced damage in order to advance the treatment and care of children experiencing seizures should now be the primary goal. The integration of results of studies that show seizureinduced cell losses with studies that do not show cell losses can provide insight into, and a platform for, the needed translation of basic findings into improved clinical care of children experiencing seizures. A thorough exploration of the differences between studies is warranted. The level of discordance between the findings is reduced with the realization that metrics and the time of analysis figure prominently in comparisons between studies. Whereas the earlier, negative studies tended to compare healthy cells at later time points (1, 10, 50), more recent studies have included sensitive indicators of acutely dying cells (36, 55, 62, 73, 74), which allowed detection of injured cells that would have been missed entirely at later time points (i.e., dentate granule cells in the PPS model). The use of specific stains and electron microscopy, which can detect different types of cell death (apoptosis vs. necrosis, both of which contribute to seizure-induced damage in the immature brain [60, 85]), also provides certain advantages. Finally, a deeper understanding of the model itself provides a clearer picture of why some models produce damage and others do not. In a
: -
343
F 26.5 Damage is evident in the dentate gyrus 2 hours after PPS in the immature rat. (A–F) In situ end-labeled nuclei were seen in cells located within the inner layer of the granule cells bilaterally, in unstimulated hippocampus (A, C, and E) and in stimulated hippocampus (B, D, and F). The cells within the hippocampus that contained labeled nuclei were eosinophilic (A–D) and fluorescent (E and F). Injured ISEL-positive cells in the granule cell layer were seen concomitantly with ISEL-negative injured cells within the hilus (D and F). (G–J) Immunohistochemistry for cleaved PARP showed positive staining in the inner granule cell layer bilaterally (G and H), and semi-thin sections showed condensed nuclear profiles bilaterally in the granule cell layer (I and J) (inset in I shows higher magnification of cells in granule cell layer), but only cytoplasmic staining of injured cells within the stimulated hilus ( J).
detailed study of SE-induced damage in the kainate model, Nitecka et al. (50) documented progressive damage to limbic structures from postnatal day 18 on. The development of vulnerability to seizure-induced damage to the hilus and CA3 was attributed to the maturation of the mossy fiber terminals and the maturation of kainic acid receptors in the amygdala toward the end of the third postnatal week (6). The major differences in observations seem to be a consequence of the model that is employed. In fact, the same
344
:
model applied to different species at similar developmental stages shows different patterns of damage. Although the rat exhibits primarily CA1 damage at 2 weeks, and the immature rabbit shows severe damage throughout the hippocampus with extrahippocampal damage, the extrahippocampal damage is greater still in the nonhuman primate after lithium-pilocarpine-induced seizures. Differences in pathology within a single model are an indication of the differences to be expected between models. That is why overgeneralization from a result in one model, at a particular developmental stage, can be dangerous and counterproductive. Controversy persists, and debate emerges in the literature, only when results from one model or one clinical finding are overextended. An important question is what type of seizure is being modeled, and what is the analogous period in human development of the relevant anatomic structures (not the complete organism) that show seizure-induced damage. Both questions are difficult to answer and may be additional sources of debate, but it is likely to be a productive debate. The general relevance of particular models to seizure types seen in children, such as CRH-induced seizures to infantile spasms (2), heat-induced seizures to febrile convulsions (18), and PPS to extended focal seizures in the temporal lobe, may be obvious in some cases. Finding the specific relevance of a model to the clinical picture is more challenging. A child in SE may have several structures synaptically involved, and the clinical features may change during the course of a seizure. So the results of several models may be relevant to a single clinical case. For example, an overlapping feature of several of the models is granule cell loss, and it is interesting that granule cell neuronal densities are significantly reduced in tissue from children with poorly controlled seizures, regardless of the anatomic focus of the seizures (43). A deeper understanding of the model specificity of seizure-induced damage will give insight into the relationship between the model and the clinical scenario. Accepting a model for what it is (and understanding what it is not) should focus the search for molecular mechanisms of seizure-induced damage, which would increase the potential for the development of protective agents. Integrating positive and negative study findings to understand what elements of a particular seizure model are clinically relevant, and the developmental stage being studied, could form the basis for a decision to treat or not treat a child with anticonvulsants. The dangers of drugs that may induce cell death by themselves during some periods of the brain growth spurt (53) are becoming known and are another key factor in the treatment decision. As the developmental seizure models advance our understanding of the molecular mechanisms in seizureinduced neuronal death, and as diagnostic and imaging capabilities advance, so too should our ability to shield children from seizure-induced cell/synapse losses, to better
enable them to proceed along a normal course of development and growth. This work was supported by grant No. NS13515 from the National Institute of Neurological Disorders and Stroke (NINDS) and by the Research Service of the Veterans Health Affairs (K.T.); also by NINDS grants Nos. NS046516 and NS045911, and support from the DAPA Foundation (R.S.).
REFERENCES 1. Albala, B. J., S. L. Moshé, and R. Okada. Kainic-acid-induced seizures: A developmental study. Brain Res. 1984;315:139–148. 2. Baram, T. Z. Pathophysiology of massive infantile spasms: Perspective on the putative role of the brain adrenal axis. Ann. Neurol. 1993;33:231–236. 3. Baram, T. Z., and C. E. Ribak. Peptide-induced infant status epilepticus causes neuronal death and synaptic reorganization. Neuroreport 1995;6:277–280. 4. Baram, T. Z., and L. Schultz. Corticotropin-releasing hormone is a rapid and potent convulsant in the infant rat. Brain Res. Dev. Brain Res. 1991;61:97–101. 5. Bekenstein, J. W., and E. W. Lothman. A comparison of the ontogeny of excitatory and inhibitory neurotransmission in the CA1 region and dentate gyrus of the rat hippocampal formation. Brain Res. Dev. Brain Res. 1991;63:237–243. 6. Berger, M. L., E. Tremblay, L. Nitecka, and Y. Ben-Ari. Maturation of kainic acid seizure-brain damage syndrome in the rat. III. Postnatal development of kainic acid binding sites in the limbic system. Neuroscience 1984;13:1095–1104. 7. Bittigau, P., K. Genz, S. V. Engelbrechten, et al. Antiepileptics which enhance GABAergic inhibition cause neuronal apoptosis in the developing CNS. Soc. Neurosci. Abstr. 2000;26:323. 8. Camfield, P. R. Recurrent seizures in the developing brain are not harmful [see comment]. Epilepsia 1997;38:735–737. 9. Campochiaro, P., and J. T. Coyle. Ontogenetic development of kainate neurotoxicity: Correlates with glutamatergic innervation. Proc. Natl. Acad. Sci. U.S.A. 1978;75:2025–2029. 10. Cavalheiro, E. A., D. F. Silva, W. A. Turski, L. S. CalderazzoFilho, Z. A. Bortolotto, and L. Turski. The susceptibility of rats to pilocarpine-induced seizures is age-dependent. Brain Res. 1987;465:43–58. 11. Cendes, F., F. Andermann, 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. 12. Connors, B. W., L. S. Benardo, and D. A. Prince. Coupling between neurons of the developing rat neocortex. J. Neurosci. 1983;3:773–782. 13. Corsellis, J. A., and C. J. Bruton. Neuropathology of status epilepticus in humans. Adv. Neurol. 1983;34:129–139. 14. 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. 15. 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. 16. 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.
17. DeLorenzo, R. J., J. M. Pellock, A. R. Towne, and J. G. Boggs. Epidemiology of status epilepticus [see comment]. J. Clin. Neurophysiol. 1995;12:316–325. 18. 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. 19. Ellenberg, J. H., and K. B. Nelson. Febrile seizures and later intellectual performance. Arch. Neurol. 1978;35:17–21. 20. Falconer, M. A., E. A. Serafetinides, and J. A. N. Corsellis. Etiology and pathogenesis of temporal lobe epilepsy. Arch. Neurol. 1964;10:233–248. 21. Ferraro, T. N., G. T. Golden, G. G. Smith, and W. H. Berrettini. Differential susceptibility to seizures induced by systemic kainic acid treatment in mature DBA/2J and C57BL/ 6J mice. Epilepsia 1995;36:301–307. 22. Franck, J. E., and P. A. Schwartzkroin. Immature rabbit hippocampus is damaged by systemic but not intraventricular kainic acid. Brain Res. 1984;315:219–227. 23. Freund, R. K., R. J. Marley, and J. M. Wehner. Differential sensitivity to bicuculline in three inbred mouse strains. Brain Res. Bull. 1987;18:657–662. 24. Fujikawa, D. G., H. H. Itabashi, A. Wu, and S. S. Shinmei. Status epilepticus–induced neuronal loss in humans without systemic complications or epilepsy. Epilepsia 2000;41:981–991. 25. Galvan, C. D., J. H. Wenzel, K. T. Dineley, et al. Postsynaptic contributions to hippocampal network hyperexcitability induced by chronic activity blockade in vivo. Eur. J. Neurosci. 2003;18:1861–1872. 26. Germano, I. M., E. F. Sperber, S. Ahuja, and S. L. Moshe. Evidence of enhanced kindling and hippocampal neuronal injury in immature rats with neuronal migration disorders. Epilepsia 1998;39:1253–1260. 27. Germano, I. M., Y. F. Zhang, E. F. Sperber, and S. L. Moshé. Neuronal migration disorders increase susceptibility to hyperthermia-induced seizures in developing rats. Epilepsia 1996; 37:902–910. 28. Hablitz, J. J., and U. Heinemann. Extracellular K+ and Ca2+ changes during epileptiform discharges in the immature rat neocortex. Brain Res. 1987;433:299–303. 29. Harris, K. M., and T. J. Teyler. Developmental onset of longterm potentiation in area CA1 of the rat hippocampus. J. Physiol. 1984;346:27–48. 30. Harvey, A. S., J. D. Grattan-Smith, P. M. Desmond, C. W. Chow, and S. F. Berkovic. Febrile seizures and hippocampal sclerosis: Frequent and related findings in intractable temporal lobe epilepsy of childhood. Pediatr. Neurol. 1995;12:201–206. 31. Hermann, B., R. Hansen, M. Seidenberg, V. Magnotta, and D. O’Leary. Neurodevelopmental vulnerability of the corpus callosum to childhood onset localization-related epilepsy. Neuroimage 2003;18:284–292. 32. Hermann, B., M. Seidenberg, B. Bell, et al. The neurodevelopmental impact of childhood-onset temporal lobe epilepsy on brain structure and function. Epilepsia 2002;43:1062–1071. 33. Jevtovic-Todorovic, V., N. Benshoff, and J. W. Olney. GABAergic agents (isoflurane and barbituates) trigger widespread apoptotic neurodegeneration in the infant rat brain. Soc. Neurosci. Abstr. 2000;26:323. 34. Jorgensen, O. S., B. Dwyer, and C. G. Wasterlain. Synaptic proteins after electroconvulsive seizures in immature rats. J. Neurochem. 1980;35:1235–1237. 35. Kornblum, H. I., R. Sankar, D. H. Shin, C. G. Wasterlain, and C. M. Gall. Induction of brain derived neurotrophic factor
: -
345
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
mRNA by seizures in neonatal and juvenile rat brain. Brain Res. Mol. Brain Res. 1997;44:219–228. Kubova, H., R. Druga, K. Lukasiuk, et al. Status epilepticus causes necrotic damage in the mediodorsal nucleus of the thalamus in immature rats. J. Neurosci. 2001;21:3593–3599. Lado, F. A., E. C. Laureta, and S. L. Moshé. Seizure-induced hippocampal damage in the mature and immature brain. Epileptic Disord. 2002;4:83–97. Langmeier, M., J. Folbergrova, R. Haugvicova, J. Pokorny, and P. Mares. Neuronal cell death in hippocampus induced by homocysteic acid in immature rats. Epilepsia 2003;44:299–304. Lewis, D. V., D. P. Barboriak, J. R. MacFall, J. M. Provenzale, T. V. Mitchell, and K. E. VanLandingham. Do prolonged febrile seizures produce medial temporal sclerosis? Hypotheses, MRI evidence and unanswered questions. Prog. Brain Res. 2002;135:263–278. Liu, H., R. Sankar, D. H. Shin, A. M. Mazarati, and C. G. Wasterlain. Patterns of status epilepticus–induced substance P expression during development. Neuroscience 2000;101: 297–304. Maher, J., and R. S. McLachlan. Febrile convulsions: Is seizure duration the most important predictor of temporal lobe epilepsy? Brain 1995;118:1521–1528. Margerison, J. H., and J. A. Corsellis. Epilepsy and the temporal lobes: A clinical, electroencephalographic and neuropathological study of the brain in epilepsy, with particular reference to the temporal lobes. Brain 1966;89:499–530. Mathern, G. W., J. P. Leite, J. K. Pretorius, B. Quinn, W. J. Peacock, and T. L. Babb. Children with severe epilepsy: Evidence of hippocampal neuron losses and aberrant mossy fiber sprouting during postnatal granule cell migration and differentiation. Brain Res. Dev. Brain Res. 1994;78:70–80. Mathern, G. W., J. P. Leite, J. K. Pretorius, B. Quinn, W. J. Peacock, and T. L. Babb. Severe seizures in young children are associated with hippocampal neuron losses and aberrant mossy fiber sprouting during fascia dentata postnatal development. Epilepsy Res. Suppl. 1996;12:33–43. Maytal, J., S. Shinnar, S. L. Moshé, and L. A. Alvarez. Low morbidity and mortality of status epilepticus in children. Pediatrics 1989;83:323–331. McCabe, B. K., D. C. Silveira, M. R. Cilio, et al. Reduced neurogenesis after neonatal seizures. J. Neurosci. 2001;21: 2094–2103. 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. 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. Moshé, S. L., B. J. Albala, R. F. Ackermann, and J. Engel, Jr. Increased seizure susceptibility of the immature brain. Brain Res. 1983;283:81–85. 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. Okada, R., S. L. Moshé, and B. J. Albala. Infantile status epilepticus and future seizure susceptibility in the rat. Brain Res. 1984;317:177–183. Oliva, A. A., Jr., T. T. Lam, and J. W. Swann. Distally directed dendrotoxicity induced by kainic acid in hippocampal
346
:
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
interneurons of green fluorescent protein-expressing transgenic mice. J. Neurosci. 2002;22:8052–8062. Olney, J. W., N. B. Farber, D. F. Wozniak, V. JevtovicTodorovic, and C. Ikonomidou. Environmental agents that have the potential to trigger massive apoptotic neurodegeneration in the developing brain. Environ. Health Perspect. 2000; 108(Suppl. 3):383–388. O’Regan, M. E., and J. K. Brown. Serum neuron specific enolase: A marker for neuronal dysfunction in children with continuous EEG epileptiform activity. Eur. J. Paediatr. Neurol. 1998;2:193–197. Ribak, C. E., and T. Z. Baram. Selective death of hippocampal CA3 pyramidal cells with mossy fiber afferents after CRHinduced status epilepticus in infant rats. Brain Res. Dev. Brain Res. 1996;91:245–251. Ross, E. M., C. S. Peckham, P. B. West, and N. R. Butler. Epilepsy in childhood: Findings from the National Child Development Study. BMJ 1980;280:207–210. Royle, S. J., F. C. Collins, H. T. Rupniak, J. C. Barnes, and R. Anderson. Behavioural analysis and susceptibility to CNS injury of four inbred strains of mice. Brain Res. 1999;816: 337–349. 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. Sanchez, R. M., S. Koh, C. Rio, et al. Decreased glutamate receptor 2 expression and enhanced epileptogenesis in immature rat hippocampus after perinatal hypoxia-induced seizures. J. Neurosci. 2001;21:8154–8163. Sankar, R. Seizure-induced apoptosis and necrosis in the developing rat brain. In A. Nehlig, J. Motte, S. L. Moshé, and P. Plouin, eds. Childhood Epilepsies and Brain Development. London: John Libbey, 1999:199–210. Sankar, R., D. Shin, H. Liu, H. Katsumori, and C. G. Wasterlain. Granule cell neurogenesis after status epilepticus in the immature rat brain. Epilepsia 2000;41(Suppl. 6): S53–S56. Sankar, R., D. H. Shin, H. Liu, A. Mazarati, A. Pereira de Vasconcelos, and C. G. Wasterlain. Patterns of status epilepticus–induced neuronal injury during development and longterm consequences. J. Neurosci. 1998;18:8382–8393. Sankar, R., D. Shin, H. Liu, C. Wasterlain, and A. Mazarati. Epileptogenesis during development: Injury, circuit recruitment, and plasticity. Epilepsia 2002;43(Suppl. 5):47–53. 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. Schiottz-Christensen, E., and P. Bruhn. Intelligence, behaviour and scholastic achievement subsequent to febrile convulsions: An analysis of discordant twin-pairs. Dev. Med. Child Neurol. 1973;15:565–575. Scott, R. C., D. G. Gadian, M. D. King, et al. Magnetic resonance imaging findings within 5 days of status epilepticus in childhood [see comment] [erratum appears in Brain 2002 125(Pt. 12):2792]. Brain 2002;125:1951–1959. Scott, R. C., M. D. King, D. G. Gadian, B. G. Neville, and A. Connelly. Hippocampal abnormalities after prolonged febrile convulsion: A longitudinal MRI study. Brain 2003;126: 2551–2557. Sloviter, R. S. Feedforward and feedback inhibition of hippocampal principal cell activity evoked by perforant path stimulation: GABA-mediated mechanisms that regulate excitability in vivo. Hippocampus 1991;1:31–40.
69. 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. 70. Swann, J. W. Recent experimental studies of the effects of seizures on brain development. Prog. Brain Res. 2002;135: 391–393. 71. 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. 72. Swann, J. W., K. L. Smith, and R. J. Brady. Age-dependent alterations in the operations of hippocampal neural networks. Ann. N.Y. Acad. Sci. 1991;627:264–276. 73. 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. 74. Thompson, K., and C. Wasterlain. Lithium-pilocarpine status epilepticus in the immature rabbit. Brain Res. Dev. Brain Res. 1997;100:1–4. 75. 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. 76. Thompson, K. W., and C. G. Wasterlain. Urethane anesthesia produces selective damage in the piriform cortex of the developing brain. Brain Res. Dev. Brain Res. 2001;130:167–171. 77. Tremblay, E., L. Nitecka, M. L. Berger, and Y. Ben-Ari. Maturation of kainic acid seizure-brain damage syndrome in the rat. I. Clinical, electrographic and metabolic observations. Neuroscience 1984;13:1051–1072. 78. van Esch, A., I. R. Ramlal, H. A. van Steensel-Moll, E. W. Steyerberg, and G. Derksen-Lubsen. Outcome after febrile status epilepticus. Dev. Med. Child Neurol. 1996;38:19–24. 79. VanLandingham, K. E., E. R. Heinz, J. E. Cavazos, and D. V. Lewis. Magnetic resonance imaging evidence of hippocampal injury after prolonged focal febrile convulsions [see comment]. Ann. Neurol. 1998;43:413–426. 80. Verity, C. M., N. R. Butler, and J. Golding. Febrile convulsions in a national cohort followed up from birth. II. Medical history and intellectual ability at 5 years of age. Br. Med. J. Clin. Res. Ed. 1985;290:1311–1315. 81. Verity, C. M., R. Greenwood, and J. Golding. Long-term intellectual and behavioral outcomes of children with febrile convulsions [see comment]. N. Engl. J. Med. 1998;338: 1723–1728. 82. Wasterlain, C. G. Effects of neonatal status epilepticus on rat brain development. Neurology 1976;26:975–986. 83. Wasterlain, C. G. Recurrent seizures in the developing brain are harmful. Epilepsia 1997;38:728–734. 84. Wasterlain, C. G., and D. B. Farber. Kindling alters the calcium/calmodulin-dependent phosphorylation of synaptic plasma membrane proteins in rat hippocampus. Proc. Natl. Acad. Sci. U.S.A. 1984;81:1253–1257. 85. Wasterlain, C. G., J. Niquet, K. W. Thompson, et al. Seizureinduced neuronal death in the immature brain. Prog. Brain Res. 2002;135:335–353. 86. Wasterlain, C. G., K. W. Thompson, H. I. Kornblum, A. M. Mazarati, Y. Shirasaka, H. Katsumori, et al. Long-term effects of recurrent seizures on the developing brain. In A. Nehlig, J. Motte, S. L. Moshé, and P. Plouin, eds. Childhood Epilepsies and Brain Development. London: John Libbey, 1999:237–254.
: -
347
27
Metabolic and Circulatory Adaptations to Status Epilepticus in the Immature Brain
T brain is quite prone to develop seizures. In humans, the incidence of seizures is highest during the first years of life (34); in rats, there is an increased susceptibility to seizures during the second and third postnatal weeks (3, 19, 61, 100, 101, 111). Several features may underlie the high epileptogenicity of the developing brain. There is a temporary increase in excitability related to the overproduction of excitory synapses in the CA3 pyramidal neurons (95), accompanied by a transient increased density in NMDA receptors in the immature hippocampus (96). Moreover, the excitatory pathways mature before the inhibitory ones, and g-aminobutyric acid (GABA) is excitatory early in life (11). On the other hand, in the immature rat brain, seizures usually do not induce brain damage (84, 93), probably because of the high degree of plasticity and the possibility of repair of the actively growing brain. The metabolic and circulatory responses of the immature brain to various pathophysiologic situations exhibit specific patterns that are quite different from those of mature individuals. This is particularly true during status epilepticus (SE), which requires metabolic and circulatory adaptations that are often close to or beyond the possible limits of the immature brain. This chapter focuses on the postnatal changes in brain energy metabolism, blood flow, and glucose transport to the brain during the period of high susceptibility to seizures, a period that is also characterized by very active maturation processes. Thereafter the discussion concentrates on the effects of seizures on brain energy metabolism and blood flow during SE in relation to potential neuronal damage in the immature brain.
Maturation of brain energy metabolism under normal conditions T H B In human neonates, cerebral glucose utilization, measured by positron emission tomography with [18F]fluorodeoxyglucose, is at 71%–93% of the adult level in most brain regions, with values ranging from 13 to 25 mmol/100 g/min (13, 14, 43, 98). Adult cerebral meta-
bolic rates for glucose (LCMRglcs, 19–33 mmol/100 g/min) are reached by 2 years. Thereafter, LCMRglcs continue to rise until 3–4 years to values ranging from 49 to 65 mmol/ 100 g/min that are maintained at that high level until approximately 9 years. Then LCMRglcs start to decline and reach adult levels by the end of the second decade of life. The high levels of brain energy metabolism in children during the first decade of life underwrite the basal energetic and biosynthetic needs required by the very active maturational processes occurring during that period. T R B In contradistinction to what is seen in the human brain, glucose consumption in the whole rat brain is very low at birth, about 2–4 mmol/100 g/min. It undergoes a sigmoidal rise from birth to adulthood, reaching 65– 72 mmol/100 g/min in the adult rat brain (67, 92). The measurement of LCMRglcs in the developing rat brain assessed by the quantitative autoradiographic [14C]2deoxyglucose (2-DG) method (86) adapted to the immature rat in our laboratory shows that LCMRglcs are low and quite homogeneous between postnatal day 10 (P10) and P17, with the exception of higher rates in some posterior regions (67). Most of the significant increases in LCMRglcs occurring between P10 and P17 correlate with the acquisition of specific functions, such as audition, vision, and locomotion (64, 67). LCMRglcs undergo a widespread increase of about 50% between P17 and P21, then further increase until the adult stage is reached (67). Conversely to the human brain, LCMRglcs do not exhibit a peak during maturation in the rat and are never higher in pups than in the adult brain. However, the postnatal evolution of LCMRglcs in the rat parallels that of the cerebral metabolic rate of oxygen and the activity of the enzymes of oxidative glucose breakdown (9, 49, 50). Simultaneously, because of the high lipid and low carbohydrate content of maternal milk, shortly after birth the rat pup develops a nutritional ketosis that lasts throughout the suckling period (for a review, see ref 64). During that period, ketone bodies constitute up to 22%–76% of the total energy
:
349
metabolism balance of the brain, and positive cerebral arteriovenous differences for b-hydroxybutyrate and acetoacetate proportional to their concentration in arterial blood are recorded (16, 35, 44, 45). The uptake of b-hydroxybutyrate by the immature rat brain as measured by autoradiography is high during suckling, reaching peak levels at P14 and P17 (21, 62, 63). Between P17 and P21, regional rates of bhydroxybutyrate uptake largely decrease in all brain regions (62, 63), concurrently with the marked increase in LCMRglcs (67). In the immature rat brain, which is dependent on glucose and b-hydroxybutyrate for its energy metabolism and biosynthesis needs, changes in LCMRglcs are region-specific and underlie functional changes (67), as in the human brain (13, 14), whereas ketone bodies appear to be oriented toward more general purposes shared by all brain regions, namely, cellular build-up (62). Conversely, in the human brain, active growth occurs mainly between 3 and 9 years of age, when glucose is the sole cerebral substrate under normal conditions.
Correlation between cerebral energy metabolism and blood flow in the developing brain under normal conditions In the human infant, the postnatal evolution of local cerebral blood flow (LCBF) rates is similar to that of LCMRglcs. At birth, cortical CBF rates are lower than those of adults, then increase until 5–6 years to values 50%–85% higher than adult rates. The adult level is reached by age 15–19 years (6, 12, 71). Thus, the highest rates of LCBF occur in all brain regions at the period when the highest LCMRglcs are recorded (6, 12, 14, 71, 87). In the rat, the postnatal evolution of LCBF rates differs from the maturation of LCMRglcs. Rates of LCBF measured by the quantitative autoradiographic [14C]iodoantipyrine (IAP) technique (88) adapted to the immature rat (66) remain low and homogeneous until P14, at 18%–35% of the adult levels. Between P14 and P17, LCBF rates dramatically increase to reach values similar to those recorded at P35. Between P17 and P21, rates of LCBF decrease by 15%–40%. After P21 and until adulthood, changes in LCBF again parallel LCMRglcs changes (66). The apparent mismatch between LCMRglcs and LCBF rates at P17 is related to the active utilization of ketone bodies by the suckling rat brain. Indeed, when glucose and b-hydroxybutyrate utilization are summed to represent the whole supply of metabolic substrates, the peak level of energy metabolism occurs at P17 (62), at the same age as the peak of LCBF (66). Thus, in human and rat infants, rates of cerebral energy metabolism and blood flow remain coupled during development, with the highest rates in both species occurring during the period of active brain growth.
350
:
Transport of glucose to the brain Glucose enters the brain via a carrier-mediated, facilitated diffusion process, saturable and stereospecific, energy-, Na+-, and insulin-independent (53, 72). This process is mediated by the facilitative glucose transporter proteins, GLUT1 and GLUT3 (54, 73). GLUT1 is located at the blood-brain barrier and GLUT3 allows the transport of glucose across the neuronal membrane (74, 89). In rodent brain, the density of GLUT1 is low at birth, about 15% of the adult level, and relatively homogeneously distributed in the different brain areas. It increases fourfold between P14 and the adult stage (8, 20, 99). These data are in agreement with the postnatal maturation of the capacity of glucose uptake from blood to brain. GLUT3, the specific neuronal carrier, has a very low density in the rat brain at birth and increases concurrently with LCMRglcs (67) to reach a regional heterogeneous distribution in the mature brain (99). In the human brain, the density of GLUT3 at birth is two to three times lower than in the adult (55). The regulation of the neuronal GLUT3 is tightly coupled to the maturation of functional activity in neurons and directly reflects postnatal changes in LCMRglcs, while GLUT1 expression is less heterogeneous and is regulated instead by the growth and nutritional state of the animal (67, 99).
Cerebral energy metabolism during seizures E S B E R M Seizures induced by various chemoconvulsants, such as flurothyl, bicuculline, or pentylenetetrazol, in neonates from different species (rats, mice, dogs, rabbits, marmoset monkeys) lead to changes in cerebral energy metabolism that occur within minutes of seizure activity and last for several hours. These changes are characterized by an increase in glycolytic flux concurrent with a reduction in brain glycogen (25%) and glucose (80%–95%) concentrations and with a two- to sixfold increase in lactate concentration (27, 28, 33, 87, 102, 103, 106, 107). These metabolic changes are accompanied by a decrease in tissue phosphocreatine (PCr, 50%–75%) and adenosine triphosphate (ATP) (15%–45%) levels (33, 87, 102, 106, 107). Brain and blood lactate concentrations are closely related during the initial phase of the seizure, suggesting a rapid efflux of lactate from brain (28, 103, 108). Indeed, the accumulation of lactate in the brain, which may play a key role in hypermetabolic necrosis during SE in adults, never reaches toxic levels in the immature brain because of the high concentration of the lactate carrier in the blood-brain barrier of suckling rats (17, 18, 74). However, in immature animals, the new steady state for PCr and lactate during seizures is achieved more slowly than in adults, while the modest decrease in brain ATP levels during SE indicates that brain energy state is not
radically altered if oxygenation is maintained (108). It must be noted that cerebral energy metabolism and oxidative perturbations recorded in newborn monkeys are more severe than in other species and could indicate that primates are especially prone to SE-induced brain damage (33). This interspecies difference could be related to the more advanced maturity of newborn monkeys at birth compared with humans or rats. In human neonates, nuclear magnetic resonance (NMR) spectroscopy measurements show that early postnatal seizures induce a 33% decrease in brain PCr concentration and a 45% increase in oxidative metabolism, lateralized for focal seizures and bilateral with generalized seizures. Large decreases in PCr levels during seizures are related to the development of long-term neurologic sequelae, probably by increasing cerebral metabolic demands above possible energy supply (110). E SE LCMR I A The quantification of LCMRglcs requires the IV administration of the radiolabeled tracer, 2-DG, and uptake of timed arterial samples through indwelling catheters. Moreover, since most seizures lower plasma and brain glucose, the lumped constant of the operational equation of the method needs to be recalculated for the quantification of LCMRglcs, which requires knowledge of brain and plasma glucose concentrations (94). For these reasons, most measurements of LCMRglcs are semiquantitative, using IP 2-DG injections and determination of cerebral optical density ratios in brain regions activated by the seizures (1, 3, 26, 36, 96, 104). Semiquantitative measurements of LCMRglcs The semiquantitative 2-DG technique has been used to map the structures involved in seizure circuitry at various ages. In P16 rats, repeated unilateral stimulations of the amygdala spaced 15–20 minutes apart lead to enhanced 2-DG accumulation in most forebrain limbic structures connected to the amygdala—the piriform and entorhinal cortices, ventral hippocampus, and lateral septum (1, 2). However, unlike in adult animals, increased 2-DG accumulation is not observed in the neocortex, the thalamus, or the substantia nigra. The immaturity of the circuitry in suckling rat pups was also reported after kainic acid–induced seizures. When the toxin is administered to P3–P16 rats, tonic-clonic seizures occur, while 2-DG uptake is limited to the hippocampus and the lateral septum (1, 2). After the third week of life, when rats are able to exhibit limbic seizures, 2-DG accumulation spreads to the areas closely associated with the limbic system—the amygdala and midline thalamic nuclei, piriform and entorhinal cortices, anterior olfactory nuclei, and olfactory tubercles—and to the deep layers of the neocortex, the ventral tegmental area, and the substantia nigra. At
P28–P35, metabolic maps are similar to those recorded in adults (3, 96). Since the substantia nigra is a crucial site involved in the propagation and arrest of seizure activity in adult animals (38, 71), the lack of 2-DG uptake in the substantia nigra, thereby limiting the involvement of seizureterminating systems in rat pups, may account for the early generalization, the increased severity of seizures, and the lack of postictal seizure refractoriness during rapid kindling in suckling rats (1–3, 96). By means of the semiquantitative technique, there were also attemps to correlate 2-DG accumulation rates in the immature brain and seizure-induced neuropathologic damage. Thus, in rat pups, kainic acid induces only brain damage once it causes limbic seizures and metabolic increases in the amygdala, that is, from P18. Between P18 and P35 there is a progressive increase in the severity of the damage, the adult pattern being reached by P35 (68). In infant marmoset monkeys (4–15 days) subjected to bicuculline, large increases in 2-DG uptake are recorded in the neocortex and hippocampus, while moderate increases are noted in the cerebellum, corpus callosum, brain stem, and basal ganglia. These increases in 2-DG uptake are inversely correlated with rates of inhibition of protein synthesis measured with the flooding technique using [1-14C]valine. The largest decreases in protein synthesis occur in hippocampus and cerebral cortex, and normal rates of protein synthesis are recorded in the regions where 2-DG is not affected by seizures (104). Thus, large metabolic increases associated with profound depression of protein synthesis could be involved in the pathogenesis of seizure-induced brain damage, since they occur in regions of high vulnerability (15, 56, 104). Conversely, in P3–P5 rats subjected to pentylenetetrazol (PTZ), maximal 2-DG uptake rates are recorded in the septum and related areas, midbrain, inner cortical layers, and thalamus, except ventral nuclei. However, these metabolic changes are not paralleled by similar alterations in brain protein synthesis, as assessed by regional [1-14C]leucine accumulation (36), conversely to the marmoset monkey (104). However, the data are presently too sparse to understand the relation between cerebral metabolic increases, protein synthesis decreases, and potential brain damage in the immature brain. Quantitative measurements of LCMRglcs To date, there are only three quantitative studies of the effects of seizures on LCMRglcs in immature animals. The first study relates to the cerebral metabolic consequences of bicuculline-induced SE in newborn marmoset monkeys (30). The studies performed in rats concern the effects of PTZ- (78) and lithiumpilocarpine-induced SE in immature rats (29). LCMRglcs in newborn marmoset monkeys. In 2-week-old marmoset monkeys subjected to bicuculline, LCMRglc measurement was initiated at the onset of the first tonic seizure
:
351
(i.e., at 2–3 minutes after bicuculline administration) and continued for 45 minutes. In that study, the lumped constant necessary for the calculation of LCMRglcs and correcting for the slight structural difference between 2-DG and glucose increased by 120%–150% during seizures in three cortical areas and in thalamus. LCMRglcs calculated with the control lumped constant increased 160%–700% over control values. When corrected for the increase in lumped constant, LCMRglcs remained significantly increased by 49%–95% in cortical regions but were similar to control values in the thalamus (30). Thus, this study shows the importance of measuring the lumped constant when assessing LCMRglcs during seizures. Measurement of LCMRglcs during seizures in immature rats. The quantitative 2-DG method was also applied to the measurement of LCMRglcs during PTZ-induced SE (28, 78) and lithium-pilocarpine-induced SE in rats between P10 and P21 (29). SE was induced by the repetitive administration of subconvulsive doses of PTZ (28) or by the administration of 60 or 30 mg/kg of pilocarpine to P10 and P21 rats, respectively, about 20 hours after the injection of 3 mEq/kg of lithium chloride. These two protocols led to continuous seizures at both ages that lasted for at least 60–80 minutes for PTZ (28) and 4–6 hours with lithium-pilocarpine, allowing use of the fully quantitative 2-DG method, which requires a steady-state situation for LCMRglc measurements over 45 minutes (92). Because of the severe hypoglycemia induced by PTZ seizures, the lumped constant was measured during SE in that model (28). Conversely, lithiumpilocarpine-induced seizures did not lead to hypoglycemia in P10 and P21 rats. Thus, LCMRglcs could be calculated with the normal lumped constant during lithiumpilocarpine-induced SE (29). Acute and long-term effects of PTZ-induced SE on LCMRglcs in immature rats. The PTZ model of seizures is a widely used model of generalized myoclonic, tonic, and clonic seizures that originate in brain stem structures (59). This model has been commonly used for the screening of anticonvulsant drugs (51, 52). During PTZ-induced SE in P10 rats, LCMRglcs measured between 10 and 55 minutes after the onset of SE (i.e., over the first hour of SE) increased by 100%–400% in almost all cerebral regions with the exception of all hippocampal areas, inferior colliculus, cochlear nucleus, and cerebellar cortex, where LCMRglcs were similar to control levels. The highest metabolic increases were recorded in brain stem regions involved in the circuitry of these seizures and in the control of autonomic functions essential for the survival of the animals (Figure 27.1). Conversely, at P21, PTZ-induced seizures led to metabolic increases, decreases, or no change compared with control levels. LCMRglcs remained increased (25%–100%) in most brain stem regions but were similar to control values in anterior limbic areas, motor regions, and some thalamic regions.
352
:
LCMRglcs were lower than control rates at P21 in cerebral cortex, some thalamic nuclei, sensory regions, and white matter fiber tracts, as well as in regions in which LCMRglcs were not increased by PTZ-induced seizures at P10, that is, the hippocampus, inferior colliculus, and cerebellar cortex (Figures 27.2 and 27.3). Interestingly, in the P10 and P21 rat subjected to PTZ-induced SE, the greatest increases in LCMRglcs occurred in nonvulnerable areas, such as the brain stem, conversely to the newborn marmoset monkey (30) and to adult animals subjected to seizures (40, 41, 57). It has been shown that during prolonged epileptic seizures in adult animals, LCMRglcs first increase, then return to control levels after longer periods of convulsive activity. If seizures last even longer, LCMRglcs may decrease to less than control values concurrently with the occurrence of neuropathologic damage (68). In P21 rats, the metabolic decreases recorded at P21 after prolonged seizure activity related to repeated PTZ injections that induce progressive electroencephalographic (EEG) and behavioral convulsive manifestations occur in highly vulnerable structures such as cerebral cortex, hippocampus, sensory regions, and thalamus (15, 56, 78). However, these metabolic decreases occur at P10 and P21 without any neuropathologic damage as assessed by staining with acid fuchsin and hematoxylineosin, as well as with TUNEL staining for DNA fragmentation (65, 83). We also measured the long-term effects of PTZ-induced SE at P10 or P21 on LCMRglcs in young adult rats (P60) (37). At P60, LCMRglcs were significantly reduced compared to control levels in 10 regions of rats exposed to PTZ at P10 and in 29 structures out of 60 in rats subjected to PTZ at P21. These regions were sensory, cortical, and hippocampal areas, and some thalamic and hypothalamic regions (Figure 27.4), that is those considered most vulnerable in various epilepsy models (57). Because there is no visible neuronal damage, these long-term metabolic decreases may reflect changes in the final synaptic organization and dendritic arborization in these animals. Effects of lithium-pilocarpine-induced SE on LCMRglcs during the acute, latent, and chronic phase in immature rats. The pilocarpine model of epilepsy shares many features with human temporal lobe epilepsy. This is especially true for the temporal development of the epilepsy, as the type of seizures and localization of the damage (10). Thus, the acute period of SE is followed by a latent phase lasting for a mean duration of 14 days in the adult and 37–75 days in the 18- to 24-dayold rat, during which there are no behavioral or EEG signs of seizures (10, 84). After that period, the onset of the chronic phase is characterized by the occurrence of recurrent seizures that last for the whole life of the animal. However, while 100% of adult and 30% of P21 rats become chronically epileptic, no animal subjected to seizures before
F 27.1 (A–D) Acute effects of PTZ-induced SE on LCMRglc and LCBF in P10 rats. Values expressed as percentage of control rates. Show representative structures of four groups, defined according to their metabolic response to PTZ-induced seizures (78): A, structures showing no change in LCMRglcs at P10 and decreases at P21; B, structures showing an increase in LCMRglcs at P10 and decreases at P21; C, structures showing an increase in LCMRglcs at P10 and no change compared to control rates at P21; and D, areas showing increases in LCMRglcs during seizures at P10 and P21. Abbreviations: DHIP, dorsal hippocampus; DGYR, dentate gyrus; MB, mammillary body; ICOL, inferior colliculus; COCHL, cochlear nucleus; CBCX, cerebellar cortex;
PFCX, prefrontal cortex; MOTCX, motor cortex; AUDCX, auditory cortex; GENU, genu of corpus callosum; AVTHAL, anteroventral thalamus; LGEN, lateral geniculate body; MEAMY, medial amygdala; AHYP, anterior hypothalamus; VLTHAL, ventrolateral thalamus; MDTHAL, mediodorsal thalamus; SNPR, substantia nigra pars reticulata; DENT, dentate nucleus; DMHYP, dorsomedian hypothalamus; CMTHAL, centromedian thalamus; MRF, mesencephalic reticular formation; MRAPH, median raphe; AMB, ambiguus nucleus; NTS, nucleus of the tractus solitarius. *P < 0.05, **P < 0.01, ***P < 0.001 versus controls (Student t test). (Redrawn with permission from Pereira de Vasconcelos et al. [77, 78].)
:
353
F 27.2 (A–D) Acute effects of PTZ-induced SE on LCMRglcs and LCBF rates in P21 rats. Values are expressed as a percentage of control rates. Groups and abbreviations are as defined in Figure 27.1.
*P < 0.05, **P < 0.01, ***P < 0.001 versus controls (Student t test). (Redrawn with permission from Pereira de Vasconcelos et al. [77, 78].)
P18 is able to develop spontaneous recurrent seizures (10, 84, 89). Many authors use the lithium-pilocarpine model instead of the pilocarpine model originally described. The main differences between these models have to do with the dose of pilocarpine necessary to induce seizures, which is decreased by a factor of 10–12 when combined with lithium, and with the better reproducibility of seizure induction after pretreatment with lithium. T A P. Lithium-pilocarpine-induced seizures lead to generalized increases in LCMRglcs measured during
the second hour of SE in both P10 and P21 rats (29). In P10 animals, increases in LCMRglcs ranged from about 30% to 130% in most cortical, hypothalamic, thalamic, and brain stem areas. Conversely, LCMRglcs largely increased (200%–600%) in the olfactory, piriform, and entorhinal cortices, the substantia nigra, and in most forebrain limbic areas (anterior olfactory nuclei, septum, amygdala, and hippocampus) (Figure 27.5). In P21 rats, LCMRglc increases were rather moderate (55%–230%) in most brain stem areas, cerebellar cortex, nuclei, and white matter, and in mammil-
354
:
F 27.3 [14C]2-Deoxyglucose autoradiographs of rat brain sections taken at the level of caudate nucleus (CAU), dorsal hippocampus (HI) and median thalamus (THAL), and inferior colliculus (IC) in P10 and P21 control and PTZ-treated rats. Note the low and homogeneous level of grain density in control P10 rats, except for the ventromedian thalamus and hippocampus. In P21 control rats, the optical density is more heterogeneous than at P10 and is increased mainly in the cerebral cortex, hypothalamus (HY),
inferior colliculus, and superior olive (SO). During PTZ-induced SE, grain density is markedly increased over control levels in all subcortical areas of P10 rats and more moderately in cortical regions. At P21, PTZ seizures lead to high increases in grain density in brain stem, septum, certain thalamic nuclei, and the habenula (HB). Increases are strikingly heterogeneous in the thalamus and the inferior colliculus, while decreases in grain density can be seen in cortical regions.
lary body, that is, in regions where no neuronal damage was recorded. Conversely, dramatic increases in LCMRglcs (415%–875%) occurred in the cerebral cortex, hippocampus, amygdala, septum, and thalamus (Figures 27.5 and 27.6), but neuronal damage did not develop in all of these brain regions (23, 24). Thus, in the lithium-pilocarpine model of epilepsy, the largest increases in LCMRglcs during acute seizures at P21 are not clearly associated with the later
appearance of neuronal damage, as distinct from the data reported previously in other models of prolonged seizures in the adult brain (40, 42, 57). It is also interesting to note that the largest increases in LCMRglcs during lithiumpilocarpine-induced seizures at P10 also occurred in areas that are vulnerable in adult animals but are of lesser magnitude than at P21 and are not associated with subsequent damage.
:
355
F 27.4 Long-term effects of PTZ-induced SE at P10 and P21 on LCMRglcs measured in P60 rats. Values are expressed as a percentage of control rates. Abbreviations: PARCX, parietal cortex; PIRCX, piriform cortex; DHIP, dorsal hippocampus; LS,
lateral septum; AMY, amygdala; MDTH, mediodorsal thalamus; ICOL, inferior colliculus; LG, lateral geniculate body. *P < 0.05, **P < 0.01 versus controls (Student t test). (Redrawn with permission from Hussenet et al. [37].)
T L P. We also measured LCMRglcs at 14 and 60 days after acute lithium-pilocarpine treatment in P10 or P21 rats, during which period the animals returned to their normal environment (22). Indeed, the latent phase in P21 rats has a mean duration of 74 days at that age (23, 24). When rats were subjected to SE at P10, LCMRglcs measured 14 and 60 days after the induction of seizures were similar in rats injected with lithium-pilocarpine and in saline-treated controls in all brain regions. Conversely, when SE was induced at P21, LCMRglcs measured at 14 days were significantly reduced in lithium-pilocarpine-exposed rats compared to controls in cortical regions, such as entorhinal cortex, in basolateral amygdala, dentate gyrus hilus, and most thalamic nuclei. These metabolic decreases occurred in regions where LCMRglcs increased the most during the acute phase of SE (see Figure 27.4). Conversely, at 60 days
after SE, LCMRglcs returned to normal levels. No damage was recorded in adjacent sections of rats subjected to lithium-pilocarpine SE at P10, while damage was limited to the hilus of the dentate gyrus, lateral thalamus, and basal cortices in rats subjected to SE at P21. However, the extent of damage recorded in P21 rats was quite variable among animals, ranging from almost control-like cellular distribution to extensive damage. The variability in the damage may relate to the limited number of P21 rats (30%) that develop spontaneous recurrent seizures (22–24, 84). T C P. At 6 months after SE, cerebral metabolism and number of neurons are identical in control rats and in rats subjected to lithium-pilocarpine SE at P10 (22–24). When rats were subjected to SE at P21, 33% of the population became spontaneously epileptic and 24% did not develop seizures, while the remainder of the population had
356
:
F 27.5 Acute effects of Li-PILO-induced SE on LCMRglcs and LCBF rates in P21 rats. Values are expressed as a percentage of control values. (A) Representative areas in the group of structures resistant to neuronal damage. (B) Representative areas in the group of vulnerable structures showing neuronal damage after lithium-pilocarpine-induced SE (84). Abbreviations: MRF, mesencephalic reticular formation; MRAPH, medial raphe; LC, locus ceruleus; ICOL, inferior colliculus; CBCX, cerebellar cortex;
DENT, dentate nucleus; PFCX, prefrontal cortex; OLFCX, olfactory cortex; LSEPT, lateral septum; BLAMY, basolateral amygdala; HILUS, hilus of the dentate gyrus; MDTHAL, mediodorsal thalamus. *P < 0.05, **P < 0.01 versus controls (Student t test). (Redrawn with permission from Fernandes et al. [29] and Pereira de Vasconcelos et al. [79].)
:
357
F 27.6 [14C]2-Deoxyglucose autoradiographs of rat brain sections taken at the level of the caudate nucleus (CAU), dorsal hippocampus (HI) and median thalamus (THAL), and inferior colliculus (IC) in P21 control and lithium-pilocarpine-treated rats. Note the low and homogeneous level of grain density in control P10 rats. In P21 control rats, the optical density is increased in all brain areas compared with P10 control rats. A heterogeneous distribution of grain density is visible, with highest levels in the thalamus, the amygdala (AMY), inferior colliculus and lateral lemniscus (LL).
Conversely, during lithium-pilocarpine-induced SE, grain density is largely increased over control levels in many cortices such as sensorimotor (SM), piriform (PIR), parietal (PAR), and entorhinal cortex (ENT), as well as in the thalamus, amygdala, and certain layers of the hippocampus and superior olive. At P21, lithium-pilocarpineinduced seizures lead to very high increases in grain density all over the brain, especially marked in cortical areas, including anterior cingulate (CING) and visual cortex (VIS) and in septum (SEPT), that are only moderately activated during seizures at P10.
seizures when stressed or handled. In P21 rats, brain metabolism in the chronic phase was measured 2 months after the occurrence of the first spontaneous or provoked seizure, or after an equivalent time in nonepileptic rats. The animals were recorded to make sure that brain metabolism would be measured at least 5 hours after the last seizure, that is, during the interictal period. In rats that did not become epileptic, the levels of cerebral metabolism were lower than in control
animals in all forebrain areas that represent the structures of generation and spread of the seizure (hippocampus, entorhinal and piriform cortices, amygdala, thalamus) and that are also subjected to neuronal loss in adult animals. In nonepileptic P21 rats, only the hilus of the dentate gyrus, medial amygdala, and layer II of the entorhinal cortex underwent minimal cell loss. In animals that became spontaneously epileptic, damage was recorded in the hilus and
358
:
lateral thalamus; levels of brain energy metabolism were in the normal range (22–24). Thus, in P21 rats, there does not appear to be a direct correlation between the areas involved in the circuit of the seizures and neuronal loss. The most prominent feature of the chronic phase, a feature that is also present but to a more moderate extent during the latent phase, is the relative hypermetabolism recorded in the hilus of the dentate gyrus, which is normometabolic in animals with seizures, although they experience a 60% cell loss. This mismatch is indicative of the quite important role played by the hilus of the dentate gyrus in the genesis and maintenance of spontaneous recurrent seizures. This feature of the epileptic brain is confirmed by similar but even more amplified data we obtained in adult rats subjected to lithium-pilocarpine SE (22–24). Altogether, these data also confirm the relative resistance of the immature brain to seizure-induced damage (3, 93), and that brain damage appears mainly during the third postnatal week (89), with the apparent exception of the thalamus, in which injured cells can be detected after lithium-pilocarpine SE in P12 rats (46). E SE LCBF R I B In adult humans and animals, LCBF rises severalfold in the early part of a seizure. This increase occurs within seconds of the onset of seizure activity, peaks in the first 4 minutes (up to 900% of control values), then subsides to about 300% of control values after 2 hours (for review, see 25 and 58). To date, there have been few experimental studies on the effects of generalized seizures on LCBF in developing brain. Most studies concern newborns of different species studied at a single age (32, 75, 109). Because of the technical difficulties linked to blood sampling for quantitative LCBF measurements, most of these studies used a semiquantitative or qualitative approach. Qualitative or semiquantitative measurement of LCBF during SE Sagittal sinus blood flow, which primarily represents cortical blood flow (58), measured by an ultrasonic blood flowmeter using the venous outflow technique, increased by 50%–70% in paralyzed and artificially ventilated piglets subjected to bicuculline. This increase was accompanied by a 40%–60% increase in cortical oxygen consumption and a 20%–30% decrease in cerebrovascular resistance and occurred whether mean arterial blood pressure was allowed to rise spontaneously or was kept constant at the preictal level (75). With [123I]- or [131I]-isopropyliodoamphetamine as an indicator of LCBF, ratios of blood flow in pons-medulla over the other brain structures increased 1.5- to 2.5-fold in cortical regions, putamen, thalamus, and cerebellum during bicucullineinduced seizures in P7–P18 marmoset monkeys (32). These seizures led to a redistribution of local blood flow in favor of posterior areas, occurring only in newborn but not in 4- to 8-
week-old animals. The increase in LCBF in brain stem compared with forebrain was not due to systemic changes such as hypoxemia, or hypotension, hypoglycemia, or hyper- or hypocapnia but could be related to the advanced maturation of the brain stem compared with the forebrain, leading to a greater vasodilatory capacity of the former region (31, 32). Quantitative measurement of LCBF in immature animals during SE There are to date only three quantitative studies of LCBF during sustained seizure activity in developing animals. Young et al. (109) measured LCBF with [14C]IAP in P1–P10 mongrel dogs subjected to bicuculline. In normoxic conditions, 5-minute seizure activity induced a 50%–300% increase in LCBF rates in all structures except the cerebellum. These changes were concurrent with significant hypertension, acidosis, hyperoxia, hyperglycemia, and increased plasma lactate and adrenaline levels. The quantitative [14C]IAP method (88), adapted to the immature rat (66), was applied to the measurement of LCBF during PTZ-induced SE in rats from P10 to P21 (77) and during lithium-pilocarpine-induced SE at P21 (79). In the two models, SE was initiated as described in the previous section on the effects of seizures on LCMRglcs. Acute effects of PTZ-induced SE on LCBF in immature rats. During PTZ-induced SE in P10 rats, rates of LCBF measured 30 minutes after the onset of SE showed a 32%–184% increase, affecting all structures studied. The greatest increases were recorded in the accumbens and septal nuclei, amygdala, reticular formation, and all thalamic and hypothalamic structures (Figures 27.1 and 27.7). Moderate increases occurred in sensory and limbic structures such as hippocampus and parietal cortex (Figures 27.1 and 27.7). At P21, rates of LCBF had increased (30%–120%) in twothirds of the structures, including posterior limbic areas, substantia nigra, and some thalamic nuclei; decreased by 29%–43% in most cortical areas, hippocampus, and dentate gyrus of PTZ-treated rats; and were not affected by SE in one-third of the structures (Figures 27.2 and 27.7). At both ages, as previously shown for LCMRglcs, highest increases in LCBF were recorded in posterior and midbrain structures and all thalamic and hypothalamic nuclei (Figures 27.1, 27.2, and 27.7). As in newborn marmoset monkeys subjected to bicuculline seizures (32), greater increases in LCBF occurred in brain stem than in forebrain in rats subjected to PTZ. However, conversely to marmoset monkeys, in which this redistribution occurs only in newborns, it is present in both P10 and P21 rats, possibly because of the less advanced brain development of the rat at birth compared with the marmoset monkey. This redistribution phenomenon could reflect the role of posterior regions in the control of cardiorespiratory functions, and could represent a protective mechanism to autonomic functions (4, 7). Finally, in the PTZ
:
359
F 27.7 [14C]-Iodoantipyrine autoradiographs of rat brain sections taken at the level of the dorsal hippocampus and median thalamus, substantia nigra, and inferior colliculus in P10 and P21 control and PTZ-treated rats. Note the heterogeneous grain density in P10 control rats with higher optical densities in ventromedian thalamus, medial geniculate body, inferior colliculus, and superior
olive. Grain density is increased all over the brain in P21 control rats compared with P10 animals. PTZ-induced SE leads to marked increases in grain density in the thalamus, hippocampus, midbrain, and brain stem regions of P10 rats. At P21, increases in grain density are very marked in subcortical areas, while decreases occur in cerebral cortex.
model of SE, the increase in LCBF rates in the brain stem, thalamus, and hypothalamus at all ages might also be related to involvement of the subcortical areas in this type of seizure (59, 77). Acute effects of lithium-pilocarpine-induced SE on LCBF in immature rats. Conversely to LCMRglcs, LCBF rates measured at 70 minutes of lithium-pilocarpine-induced SE in P10 animals show only moderate and restricted changes in a limited number of limbic areas, such as slight increases in the septum and hippocampus and a decrease in the piriform
cortex. No change in LCBF rates was noticed in the other brain areas (Figures 27.5 and 27.8). In P21 rats, rates of LCBF increased by 70%–330% over control levels during lithium-pilocarpine-induced SE. These increases were of lesser amplitude than those of LCMRglcs, occurring in 75% of the 24 structures studied (Figures 27.5 and 27.8). The greatest LCBF increases were recorded in thalamus, entorhinal cortex, amygdala, and a few posterior areas. More moderate increases were seen in hippocampus and brain stem regions, while in anterior limbic structures
360
:
F 27.8 [14C]2-deoxyglucose and [14C]iodoantipyrine autoradiograms of rat brain sections taken at the level of the dorsal hippocampus and median thalamus in P10 and P21 rats, both in control conditions (lithium-saline) and during lithium-pilocarpine SE. Radioactive tracers were injected 50 and 70 minutes after the beginning of SE for metabolic and blood flow studies, respectively. Note the relatively lower density and more homogeneous tracer distribution in blood flow images compared with the higher densities and heterogeneous distribution of the radioactive tracer in meta-
bolic images in the two age groups. In LCMRglc studies, there appears to be a large activation of hippocampus, entorhinal cortex, and amygdala at P10 that spreads to the whole cortex and thalamus at P21. Conversely, there is no difference in the densities of blood flow autoradiographic images of control and seizing P10 rats. In P21 animals, SE induces a generalized increase in the density of LCBF images. Moreover, there is no regional heterogeneity in tracer densities on blood flow images of lithiumpilocarpine exposed rats at both P10 and P21.
such as prefrontal and olfactory cortices and in the septum, LCBF rates were similar in both control and lithiumpilocarpine-treated animals (79). Age-related LCBF response to SE in immature animals. The circulatory response of the immature rat brain to SE varies with age and is characterized by the appearance of a heterogeneous LCBF response to SE during the third week of life, with specific decreases in areas that are shown to be sensitive to seizure-induced damage in various models of SE in adults (10, 15, 39, 57). In adult animals, however, LCBF rates, although markedly heterogeneous during SE, usually remain above control levels (41). The factors involved in regionally and age-dependent vascular response to sustained seizure activity are still unknown. During PTZ-induced SE in immature rats, hypertension, hyperoxia, hypocapnia, and acidosis occur but are probably not the main factors involved
in the age-related variation in LCBF response to seizures, because changes in these parameters are of the same amplitude at both P10 and P21 (77). Nitric oxide (NO), which participates in the reactive hyperemia associated with focal (76) and limbic seizures in adult rats (60, 85), is a potential candidate for the age-dependent effects of seizures. Indeed, at P10, NO synthase (NOS) inhibitors aggravate PTZ-induced seizures and increase the mortality rate, while -arginine, the endogenous NOS substrate, has no effect. The absence of beneficial effects of -arginine in P10 rats may reflect a high availability of the substrate that could be linked to specific developmental features at that age, such as a great amino acid influx through the blood-brain barrier, active transport systems, and transient expression of specific isoforms of NOS during the first 2 weeks of postnatal life in the rat (80, 81). Conversely, at P21, -arginine protects against
:
361
mortality after PTZ-induced SE, while NOS inhibitors have no effect, reflecting changes in the mechanisms of regulation of seizure activity that might be less dependent on NO at that age. In addition, the protective role of -arginine at P21 could be linked to beneficial vascular effects of the NOS substrate or to the modulation of seizure type—clonic in arginine-treated rats versus tonic-clonic in control animals receiving PTZ only (80, 81). Thus, NO appears to be involved in the age-dependent regulation of seizures and their consequences in the immature brain. Whether the protection against SE-induced deleterious effects in the very immature rat is linked to beneficial cerebrovascular effects of NO, however, remains to be elucidated. Relationship among LCMRglc, LCBF, and neuronal damage during SE in immature animals In adult and immature animals and humans, LCMRglcs and LCBF are tightly coupled in most physiologic and pharmacologic states (5, 12, 47, 48, 66). In adult animals, LCBF rates and LCMRglcs usually increase to a similar degree during the early phase of seizures. However, in vulnerable structures, such as hippocampus, cerebral cortex and thalamus, this early LCBF increase is followed by a mismatch between flow and metabolism: there is a pronounced decrease in LCBF rates that is accompanied by still high LCMRglcs at 2 hours of SE (15, 39, 90). This prolonged hypermetabolism and relative hyperfusion lasting for at least 25–30 minutes have been shown to be related to seizure-induced neuronal damage in adult animals (39). In immature animals, the relationship between circulatory and metabolic changes during SE and subsequent cerebral damage is less clear. The immature rat brain is quite resistant to seizure-induced brain damage, which usually is not seen until the age of P20–P30 (10, 69, 93, 102). In lithiumpilocarpine-induced SE in P21 rats, there is a marked mismatch between LCBF and LCMRglcs that is restricted to structures known to experience neuronal damage (22, 29) (see Figure 27.5), as seen in adult animals (15, 39, 90). In these structures—the entorhinal and piriform cortices, hippocampus, amygdala, anterior olfactory nuclei, and thalamus—metabolic increases in P21 rats subjected to lithiumpilocarpine-induced SE are highest (610%–875%), while LCBF rates increase much less (0%–265%). On the other hand, at P21, no mismatch between LCBF and LCMRglcs could be evidenced in structures where no damage occurred after lithium-pilocarpine-induced seizures. The latter structures are mainly in posterior and midbrain areas, cerebellar regions, and sensory areas, such as the superior and inferior colliculi (79) (see Figure 27.5). At P10, no mismatch or only a moderate hyper- or hypoperfusion is seen in structures resistant to seizure-induced brain damage in adults (see Figure 27.5). Even at P10, however, a clear mismatch appears in structures susceptible to lithium-pilocarpine-
362
:
induced damage in adult rats, such as the piriform cortex, hippocampus, septum, and amygdala (29, 79) (see Figure 27.5). In newborn marmoset monkeys subjected to bicuculline, a clear mismatch was shown in vulnerable areas such as cerebral cortex and hippocampus, with relative LCMRglc increases greater than those of LCBF. This hypoperfusion was accompanied by a severe energy depletion and a decrease in protein synthesis in cerebral cortex. In the brain stem, by contrast the increase in 2-DG uptake matched the LCBF increase, and no inhibition of protein inhibition was observed (32, 103–105). Despite a flow-metabolism mismatch, however, no neuronal damage was seen in marmoset monkeys even after 4 hours 30 minutes of SE. Only minimal neuropathologic changes, such as potentially reversible perivascular edema and mitochondrial swelling in a few neurons of the cerebral cortex and hippocampus, were reported (91). However, these studies were conducted under ketamine anesthesia, which could have been neuroprotective, and survival was brief, so that delayed neuronal death would have been missed. In the rat PTZ model of SE, LCBF and LCMRglc increased in almost all brain regions at P10. At that age, in most areas, metabolic increases were greater than blood flow increases. The most marked differences occurred in some cortical areas, white matter, and posterior regions, where LCBF increased by 80%–100% over control levels, while LCMRglcs increased up to 300% (see Figure 27.1). At P21, LCBF and LCMRglc responses to PTZ-induced SE remained coupled, were region-specific, and increased, decreased, or did not change compared with control levels. At P21, a slight hyperperfusion but no clear mismatch occurred in a few areas, such as inferior colliculus, mediodorsal thalamus, and substantia nigra pars reticulata (see Figure 27.2). In the PTZ model of SE, no damage was seen at any age, except for a transient staining of hippocampal, thalamic, and cortical neurons by acid fuchsin, possibly indicative of neuronal suffering (65).
Conclusion It appears that the P21 rat has achieved a cerebral maturity that renders it partly sensitive to seizure-induced cerebral metabolism-blood flow mismatch, which leads to subsequent neuronal damage; however, damage is not as extended as in adult animals. Thus, although the mismatch between LCMRglcs and LCBF rates is as extensive as in adult animals, not all areas will develop damage, as is the case in the adult brain. Conversely, in younger animals, such as P10 rats or newborn marmoset monkeys, large metabolic increases and mismatches between LCBF and LCMRglcs occur during SE without having clear neuropathologic consequences. The reasons underlying the lack of vulnerability
of the very immature brain, as well as the partial protection of the P21 rat brain, to large metabolic increases and LCBFLCMRglc mismatch during SE require further clarification. REFERENCES 1. Ackerman, R. F., S. L. Moshé, and B. J. Albala. Restriction of enhanced [2–14C]deoxyglucose utilization to rhinencephalic structures in immature amygdala-kindled rats. Exp. Neurol. 1989;104:73–81. 2. Ackerman, R. F., S. L. Moshé, B. J. Albala, and J. Engel, Jr. Anatomical substrates of amygdala kindling in immature rats demonstrated by 2-deoxyglucose autoradiography. Epilepsia 1982;23:494–495. 3. Albala, B. J., S. L. Moshé, and R. Okada. Kainic acid–induced seizures: A developmental study. Dev. Brain Res. 1984;13:139–148. 4. Ashwal, S., P. S. Dale, and L. D. Longo. Regional cerebral blood flow: Studies in the fetal lamb during hypoxia, hypercapnia, acidosis, and hypotension. Pediatr. Res. 1984;18: 1309–1315. 5. Baron, J. C., D. Rougemont, F. Soussaline, P. Bustany, C. Crouzel, M. G. Bousser, et al. Local interrelationship of cerebral oxygen consumption and glucose utilization in normal subjects and in ischaemic stroke patients: A positron tomography study. J. Cereb. Blood Flow Metabol. 1984;4: 140–149. 6. Barthel, H., M. Wiener, C. Dannenberg, S. Bettin, B. Sattler, and W. H. Knapp. Age-specific cerebral perfusion in 4- to 15year-old children: A high resolution brain SPECT using 99m Tc-ECD. Eur. J. Nucl. Med. 1997;24:1245–1252. 7. Bilger, A., and A. Nehlig. Regional cerebral blood flow response to acute hypoxia changes with postnatal age in the rat. Dev. Brain Res. 1993;76:197–205. 8. Bondy, C. A., W. H. Lee, and J. Zhou. Ontogeny and cellular distribution of brain glucose transporter gene expression. Mol. Cell Neurosci. 1992;3:305–314. 9. Booth, R. F. G., T. B. Patel, and J. B. Clark. The development of enzymes of energy metabolism in the brain of a precocial (guinea pig) and non-precocial (rat) species. J. Neurochem. 1980;34:17–25. 10. Cavalheiro, E. A. The pilocarpine model of epilepsy. Ital. J. Neurosci. 1995;16:33–37. 11. Cherubini, E., C. Rovira, J. L. Gaiarsa, R. Corradetti, and Y. Ben-Ari. GABA mediated excitation in immature CA3 hippocampal neurons. Int. J. Dev. Neurosci. 1990;8: 481–490. 12. Chiron, C., C. Raynaud, B. Mazière, et al. Changes in regional cerebral blood flow during brain maturation in children and adolescents. J. Nucl. Med. 1992;33:696–703. 13. Chugani, H. T., and M. E. Phelps. Maturational changes in cerebral function in infants determined by 18FDG positron emission tomography. Science 1986;231:840–843. 14. Chugani, H. T., M. E. Phelps, and J. C. Mazziotta. Positron emission tomography study of human brain functional development. Ann. Neurol. 1987;22:487–497. 15. Corsellis, J. A. N., and B. S. Meldrum. The pathology of epilepsy. In W. Blackwood, and J. A. N. Corsellis, eds. Greenfield’s Neuropathology. 3rd ed. London: Edward Arnold, 1976:71–795. 16. Cremer, J. E. Substrate utilization and brain development. J. Cereb. Blood Flow Metab. 1982;2:394–407.
17. Cremer, J. E., L. D. Braun, and W. H. Oldendorf. Changes during development in transport processes of the blood-brain barrier. Biochim. Biophys. Acta 1976;448:633–637. 18. Cremer, J. E., V. J. Cunningham, W. M. Pardridge, et al. Kinetics of blood-brain barrier transport of pyruvate, lactate and glucose in suckling, weanling and adult rats. J. Neurochem. 1979;33:439–445. 19. De Feo, M., O. Mecarello, and G. Ricci. Bicuculline- and allylglycine-induced epilepsy in developing rats. Exp. Neurol. 1985;90:411–421. 20. Devaskar, S., D. S. Zahm, L. Holtzclaw, K. Chundu, and B. E. Wadzinski. Developmental regulation of the distribution of rat brain insulin-insensitive (Glut 1) glucose transporter. Endocrinology 1991;129:1530–1540. 21. DeVivo, D. C., M. P. Leckie, and H. C. Agrawal. -bHydroxybutyrate: A major precursor of amino acids in the developing rat brain. J. Neurochem. 1975;25:161–170. 22. Dubé, C., S. Boyet, C. Marescaux, and A. Nehlig. Progressive metabolic changes underlying the chronic reorganization of brain circuits during the silent phase of the lithium-pilocarpine model of epilepsy in the immature and adult rat. Exp. Neurol. 2000;162:146–157. 23. Dubé, C., C. Marescaux, and A. Nehlig. A metabolic and neuropathological approach to the understanding of plastic changes occurring in the immature and adult rat brain during lithium-pilocarpine-induced epileptogenesis. Epilepsia 2000; 41(Suppl. 6):S36–S43. 24. Dubé, C., C. Marescaux, and A. Nehlig. Relationship between neuronal loss and interictal metabolism during the chronic phase of the lithium-pilocarpine model of epilepsy in the immature and adult rat. Exp. Neurol. 2001;167:227–241. 25. Duncan, R. Epilepsy, cerebral blood flow, and cerebral metabolic rate. Cerebrovasc. Brain Metab. Rev. 1992;4:105–121. 26. Dwyer, B. E., and C. G. Wasterlain. Metabolic consequences of seizures in the immature brain (abstr.). J. Neurochem. 1983;41(Suppl.):S161. 27. Dwyer, B. E., and C. G. Wasterlain. Neonatal seizures in monkeys and rabbits: Brain glucose depletion in the face of normoglycemia, prevention by glucose loads. Pediatr. Res. 1985;19:992–995. 28. El Hamdi, G., A. Pereira de Vasconcelos, P. Vert, and A. Nehlig. An experimental model of generalized seizures for the measurement of local cerebral glucose utilization in the immature rat. I. Behavioral characterization and determination of lumped constant. Dev. Brain Res. 1992;69:233–242. 29. Fernandes, M. J. S., C. Dubé, S. Boyet, C. Marescaux, and A. Nehlig. Correlation between hypermetabolism and neuronal damage during status epilepticus induced by lithium and pilocarpine in immature and adult rats. J. Cereb. Blood Flow Metab. 1999;19:195–209. 30. Fujikawa, D. G., B. E. Dwyer, R. R. Lake, and C. G. Wasterlain. Local cerebral glucose utilization during status epilepticus in newborn primates. Am. J. Physiol. 1989;256 (6 pt. 1):C1160–C1167. 31. Fujikawa, D. G., B. E. Dwyer, R. R. Lake, and C. G. Wasterlain. Cerebral blood flow and metabolism during neonatal seizures. In C. G. Wasterlain, and P. Vert, eds. Neonatal Seizures. New York: Raven Press, 1990:143–158. 32. Fujikawa, D. G., B. E. Dwyer, and C. G. Wasterlain. Preferential blood flow to brainstem during generalized seizures in the newborn marmoset monkey. Brain Res. 1986;397:61–72. 33. Fujikawa, D. G., R. C. Vannucci, B. E. Dwyer, and C. G. Wasterlain. Generalized seizures deplete brain energy
:
363
34. 35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
364
reserves in normoxemic newborn monkeys. Brain Res. 1988; 454:51–59. Hauser, W. A. Seizure disorders: The changes with age. Epilepsia 1992;33(Suppl. 4):S6–S14. Hawkins, R. A., D. H. Williamson, and H. A. Krebs. Ketonebody utilization by adult and suckling rat brain in vivo. Biochem. J. 1971;122:13–18. Howse, D. C. Regional glucose and leucine metabolism during status epilepticus in the newborn rat. In M. BaldyMoulinier, D. H. Ingvar, and B. S. Meldrum, eds. Cerebral Blood Flow, Metabolism and Epilepsy. London: John Libbey, 1984:150–154. Hussenet, F., S. Boyet, and A. Nehlig. Long-term metabolic effects of pentylenetetrazol-induced status epilepticus in the immature rat. Neuroscience 1995;67:455–461. Iadarola, M. J., and K. Gale. Substantia nigra: Site of anticonvulsant activity mediated by g-aminobutyric acid. Science 1982;218:1237–1240. Ingvar, M. Cerebral blood flow and metabolic rate during seizures: Relationship to epileptic brain damage. Ann. N. Y. Acad. Sci. 1986;462:194–206. Ingvar, M., J. Folbergrova, and B. K. Siesjö. Metabolic alterations underlying the development of hypermetabolic necrosis in the substantia nigra in status epilepticus. J. Cereb. Blood Flow Metab. 1987;7:103–108. Ingvar, M., and B. K. Siesjö. Local blood flow and glucose consumption in the rat brain during sustained bicucullineinduced seizures. Acta Neurol. Scand. 1983;68:129–144. Ingvar, M., and B. K. Siesjö. Pathophysiology of epileptic brain damage. In C. G. Wasterlain, and P. Vert, eds. Neonatal Seizures: Pathophysiology and Pharmacological Management. New York: Raven Press, 1990:113–122. Kinnala, A., H. Suhonen-Polvi, T. Aorimaa, P. Kero, H. Korvenranta, et al. Cerebral metabolic rate for glucose during the first six months of life: A FDG positron emission tomography study. Arch. Dis. Child. 1996;74:F153–F157. Kraus, H., S. Schlenker, and D. Schwedesky. Developmental changes of cerebral ketone body utilization in human infants. Hoppe Seylers Z. Physiol. Chem. 1974;355:164–170. Krebs, H. A., D. H. Williamson, M. W. Bates, M. A. Page, and R. A. Hawkins. The role of ketone bodies in caloric homeostasis. Adv. Enzyme Regul. 1971;9:387–409. Kubova, H., R. Druga, K. Lukasiak, L. Suchomelová, R. Haugvicova, I. Jirmanova, and A. Pitkänen. Status epilepticus causes necrotic damage in the mediodorsal nucleus of the thalamus in immature rats. J. Neurosci. 2001;21: 3593–3599. Kuschinski, W. Regulation of cerebral blood flow: An overview. In S. Marovitch, and R. Sercombe, eds. Neurophysiological Basis of Cerebral Blood Flow Control: An Introduction. London: John Libbey, 1996:245–262. Kuschinski, W., S. Suda, and L. Sokoloff. Local cerebral glucose utilization and blood flow during metabolic acidosis. Am. J. Physiol. 1981;241:H772–H777. Leong, S. F., and J. B. Clark. Regional enzyme development in rat brain: Enzymes associated with glucose utilization. Biochem. J. 1984;218:131–138. Leong, S. F., and J. B. Clark. Regional enzyme development in rat brain: Enzymes of energy metabolism. Biochem. J. 1984;218:139–145. Löscher, W., D. Honack, C. P. Fassbender, and B. Nolting. The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. III.
:
52.
53. 54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
Pentylenetetrazole seizure models. Epilepsy Res. 1991;8: 171–189. Löscher, W., and D. Schmidt. Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations. Epilepsy Res. 1988;2:145–181. Lund-Andersen, H. Transport of glucose from blood to brain. Physiol. Rev. 1979;59:305–352. Maher, F., S. J. Vannucci, and I. A. Simpson. Glucose transporter isoforms in brain: Absence of GLUT3 from the blood-brain barrier. J. Cereb. Blood Flow Metab. 1993;13: 342–345. Mantych, G. J., D. E. James, H. D. Chung, and S. U. Devaskar. Cellular localization and characterization of Glut 3 glucose transporter isoform in human brain. Endocrinology 1992;131:1270–1278. Meldrum, B. S. First Alfred Meyer Memorial Lecture. Epilpetic brain damage: A consequence and a cause of seizures. Neuropathol. Appl. Neurol. 1997;23:185–202. 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;34:261–270. 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. Miller, J. W., and J. A. Ferrendelli. Brain stem and diencephalic structures regulating experimental generalized (pentylentetrazol) seizures in rodents. In B. S. Meldrum, J. A. Ferrendelli, and H. G. Wieser, eds. Anatomy of Epileptogenesis. London: John Libbey, 1991:57–69. Montecot, C., J. Borredon, J. Seylaz, and E. Pinard. Nitric oxide of neuronal origin is involved in cerebral blood flow incresae during seizures induced by kainate. J. Cereb. Blood Flow Metab. 1997;17:94–99. Moshé, S. L., B. J. Albala, R. F. Ackerman, and J. Engel, Jr. Increased seizure susceptibility of the immature brain. Dev. Brain Res. 1983;7:81–85. Nehlig, A. Respective roles of glucose and ketone bodies as substrates for cerebral energy metabolism in the suckling rat. Dev. Neurosci. 1996;18:426–433. Nehlig, A., S. Boyet, and A. Pereira de Vasconcelos. Autoradiographic measurement of local cerebral b-hydroxybutyrate uptake in the rat during postnatal development. Neuroscience 1991;40:871–878. Nehlig, A., and A. Pereira de Vasconcelos. Glucose and ketone body metabolism in the neonatal rat brain. Prog. Neurobiol. 1993;40:163–221. Nehlig, A., and A. Pereira de Vasconcelos. The model of pentylenetetrazol-induced status epilepticus in the immature rat: Short- and long-term effects. Epilepsy Res. 1996;26: 93–103. Nehlig, A., A. Pereira de Vasconcelos, and S. Boyet. Postnatal changes in local cerebral blood flow measured by the quantitative autoradiographic [14C]iodoantipyrine technique in freely moving rats. J. Cereb. Blood Flow Metab. 1989;9: 579–588. Nehlig, A., A. Pereira de Vasconcelos, and S. Boyet. Quantitative autoradiographic measurement of local cerebral glucose utilization in freely moving rats during postnatal development. J. Neurosci. 1988;8:2321–2333.
68. Nevander, G., M. Ingvar, R. N. Auer, and B. K. Siesjö. Status epilepticus in well-oxygenated rats causes neuronal necrosis. Ann. Neurol. 1985;18:281–290. 69. 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. 70. Ogawa, A., Y. Sakurai, T. Kayama, and T. Yoshimoto. Regional cerebral blood flow with age: Changes in rCBF in childhood. Neurol. Res. 1989;11:173–176. 71. Okada, R., S. L. Moshé, B. Y. Wong, E. Sperber, and D. Zhao. Age-related substantia nigra–mediated seizure facilitation. Exp. Neurol. 1986;93:180–187. 72. Pardridge, W. M. Brain metabolism: A perspective from the blood-brain barrier. Physiol. Rev. 1983;63:1481–1535. 73. Pardridge, W. M., R. J. Boado, and C. R. Farrell. Braintype glucose transporter (GLUT-1) is selectively localized to the blood-brain barrier. J. Biol. Chem. 1990;265: 18035–18040. 74. Pardridge, W. M., and W. H. Oldendorf. Transport of metabolic substrates through the blood-brain barrier. J. Neurochem. 1977;28:5–12. 75. Park, T. S., D. G. L. Van Wylen, R. Rubio, and R. M. Berne. Interstitial fluid adenosine and sagittal sinus blood flow during bicuculline-seizures in newborn piglets. J. Cereb. Blood Flow Metabol. 1987;7:633–639. 76. Pereira de Vasconcelos, A., R. A. Baldwin, and C. G. Wasterlain. Nitric oxide mediates the increase in local cerebral blood flow during focal seizures. Proc. Natl. Acad. Sci. U.S.A. 1995;92:3175–3179. 77. Pereira de Vasconcelos, A., S. Boyet, V. Koziel, and A. Nehlig. Effects of pentylenetetrazol-induced status epilepticus on local cerebral blood flow in the developing rat. J. Cereb. Blood Flow Metabol. 1995;15:270–283. 78. Pereira de Vasconcelos, A., G. El Hamdi, P. Vert, and A. Nehlig. An experimental model of generalized seizures for the measurement of local cerebral glucose utilization in the immature rat. II. Mapping of brain metabolism using the quantitative [14C]2-deoxyglucose technique. Dev. Brain Res. 1992;69:243–259. 79. Pereira de Vasconcelos, A., A. Ferrandon, and A. Nehlig. Local cerebral blood flow during lithium-pilocarpine seizures in the developing and adult rat: Role of coupling between blood flow and metabolism in the genesis of neuronal damage. J. Cereb. Blood Flow Metab. 2002;22:196–205. 80. Pereira de Vasconcelos, A., F. Gizard, C. Marescaux, and A. Nehlig. Role of nitric oxide in pentylenetetrazol-induced seizures: Age-dependent effects in the immature rat. Epilepsia 2000;41:363–371. 81. Pereira de Vasconcelos, A., C. Marescaux, and A. Nehlig. Age-dependent regulation of seizure activity by nitric oxide in the developing rat. Dev. Brain Res. 1998;107:315–319. 82. Pessin, J. E., and G. I. Bell. Mammalian facilitative glucose transporter family: Structure and molecular regulation. Annu. Rev. Physiol. 1992;54:911–930. 83. Pineau, N., C. Charriaut-Marlangue, J. Motte, and A. Nehlig. Pentylenetetrazol seizures induce cell suffering but not death in the immature rat brain. Dev. Brain Res. 1999;112:139–144. 84. Priel, M. R., N. F. Santos, and E. A. Cavalheiro. Developmental aspects of the pilocarpine model of epilepsy. Epilepsy Res. 1996;26:115–121. 85. Rigaud-Monnet, A. S., E. Pinard, J. Borredon, and J. Seylaz. Blockade of nitric oxide synthesis inhibits hippocampal
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
hyperemia in kainic acid–induced seizures. J. Cereb. Blood Flow Metabol. 1994;14:581–590. Rubinstein, M., R. Denays, H. R. Ham, et al. Functional imaging of brain maturation in human using iodine-123iodoamphetamine and SPECT. J. Nucl. Med. 1989;30: 1982–1985. Sacktor, B., J. E. Wilson, and C. G. Tiekert. Regulation of glycolysis in brain, in situ, during convulsions. J. Biol. Chem. 1966;241:5071–5075. Sakurada, O., C. Kennedy, J. Jehle, J. D. Brown, and L. Sokoloff. Measurement of local cerebral blood flow with [14C]iodoantipyrine. Am. J. Physiol. 1978;234:H59–H66. Sankar, R., D. H. Shin, H. Liu, A. Mazarati, A. Pereira de Vasconcelos, and C. G. Wasterlain. Patterns of status epilepticus–induced neuronal injury during development and long-term consequences. J. Neurosci. 1998;18:8382–8393. Siesjö, B. K., M. Ingvar, J. Folbergrova, and A. G. Chapman. Local cerebral circulation and metabolism in bicucullineinduced status epilepticus: Relevance for development of cell damage. 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; 34:217–231. Söderfeldt, B., D. G. Fujikawa, and C. G. Wasterlain. Neuropathology of status epilepticus in the neonatal marmoset monkey. In C. G. Wasterlain, and P. Vert, eds. Neonatal Seizures. New York: Raven Press, 1990:91–98. Sokoloff, L., M. Reivich, C. Kennedy, et al. The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: Theory, procedure, and normal values in the conscious and anesthetized albino rat. J. Neurochem. 1977;28:897–916. Sperber, E. F., K. Z. Haas, P. K. Stanton, and S. L. Moshé. Resistance of the immature brain to seizure-induced synaptic reorganization. Dev. Brain Res. 1991;60:88–93. Suda, S., M. Shinohara, M. Miyaoka, G. Lucignani, C. Kennedy, and L. Sokoloff. The lumped constant of the deoxyglucose method in hypoglycemia: Effects of moderate hypoglycemia on local cerebral glucose utilization in the rat. J. Cereb. Blood Flow Metab. 1990;10:499–509. Swann, J. W., R. J. Brady, and D. L. Martin. Postnatal development of GABA-mediated synaptic inhibition in rat hippocampus. Neuroscience 1988;28:551–562. Tremblay, E., L. Nitecka, M. L. Berger, and Y. Ben-Ari. Maturation of kainic acid seizure-brain damage syndrome in the rat. I. Clinical, electrographic and metabolic observations. Neuroscience 1984;13:1051–1072. Tremblay, E., M. P. Roisin, A. Represa, C. CharriautMarlangue, and Y. Ben-Ari. Transient increased density of NMDA binding sites in the developing rat hippocampus. Brain Res. 1988;461:393–396. Van Bogaert, P., D. Wilker, P. Damhaut, H. B. Szliwowski, and S. Goldman. Regional changes in glucose metabolism during brain development from the age of 6 years. Neuroimage 1998;8:62–68. Vannucci, S. J. Developmental expression of GLUT1 and GLUT3 glucose transporters in rat brain. J. Neurochem. 1994;62:240–246. Velisek, L., H. Kubova, M. Pohl, et al. Pentylenetetrazolinduced seizures in rats: An ontogenetic study. NaunynSchmiedebergs Arch. Pharmacol. 1992;346:588–591. Velisek, L., and P. Mares. Increased epileptogenesis in the immature hippocampus. Exp. Brain Res. 1991;20:183–185.
:
365
102. Wasterlain, C. G., and T. E. Duffy. Status epilepticus in immature rats: Protective effects of glucose on survival and brain development. Arch. Neurol. 1976;33:821–827. 103. Wasterlain, C. G., and B. E. Dwyer. Brain metabolism during prolonged seizures in neonates. 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;34:241–260. 104. Wasterlain, C. G., B. E. Dwyer, and D. Fujikawa. Metabolic studies of neonatal seizures in newborn marmoset monkeys: A possible role in the pathogenesis of brain damage for mismatch between flow and metabolism. In M. BaldyMoulinier, D. H. Ingvar, and B. S. Meldrum, eds. Cerebral Blood Flow, Metabolism and Epilepsy. London: John Libbey, 1984:121–129. 105. Wasterlain, C. G., and Y. Shirasaka. Seizures, brain damage and brain development. Brain Dev. 1994;16:279–295. 106. Young, R. S. K., B. E. Cowan, O. A. C. Petroff, E. Novotny, S. L. Dunham, and R. W. Briggs. In vivo 31P and in vitro 1H nuclear magnetic resonance study of hypoglycemia during neonatal seizures. Ann. Neurol. 1987;22:622–628. 107. Young, R. S. K., M. D. Osbakken, R. W. Briggs, S. K. Yagel, D. W. Rice, and S. Goldberg. 31P NMR study of cerebral metabolism during prolonged seizures in the neonatal dog. Ann. Neurol. 1985;18:14–20. 108. Young, R. S. K., O. A. C. Petroff, B. Chen, J. C. Gore, and W. J. Aquila. Brain energy state and lactate metabolism during status epilepticus in the neonatal dog: In vivo 31P and 1 H nuclear magnetic resonance study. Pediatr. Res. 1991; 29:191–195. 109. Young, R. S. K., S. Yagel, and T. Gonya-Magee. Physiologic and metabolic alterations associated with seizures in normoxic and asphyxiated neonatal dogs. Epilepsia 1984;25: 569–573. 110. Younkin, D. P., M. Delivoria-Papadopoulos, J. Maris, E. Donlon, R. Clancy, and B. Chance. Cerebral metabolic effects of neonatal seizures measured with in vivo 31P NMR spectroscopy. Ann. Neurol. 1986;20:513–519. 111. Zouhar, A., P. Mares, K. Liskova-Bernaskova, and M. Mudrochova. Motor and electrographic epileptic activity induced by bicuculline in developing rats. Epilepsia 1989; 30:501–510.
366
:
28
Excitotoxicity and Seizures in the Immature Brain
ˇ T effects of glutamate have been known for years (11, 45). The neuromediator function of glutamate and aspartate was proven later, and now these transmitters are regarded as the main excitatory transmitters, achieving their effects through ionotropic as well as metabotropic receptors. Putting together these two basic physiologic observations, McDonald et al. formulated the excitotoxic hypothesis: “accumulation of the excitatory amino acid transmitters, glutamate and aspartate, in the extracellular space, as the result of increased synaptic release and reduced cellular uptake, produces excitotoxic injury through excessive activation of excitatory amino acid receptors” (40). The excitotoxic mechanism plays a role in hypoxia-ischemia injury in mature (6) as well as immature brain (23). Another field where excitotoxicity is of primary importance is epilepsy (18, 41, 42, 53). Agonists of all types of ionotropic excitatory amino acid receptors—NMDA, AMPA, kainate—are able to induce neuronal injury in the central nervous system. This effect was originally demonstrated for kainic acid (44, 46, 54) and later for NMDA (58) and AMPA (43). The sensitivity of immature brain to the excitotoxic effects of agonists of the three ionotropic receptors develops differentially. Intrahippocampal kainate injection resulted in neuronal death in 1week-old rats (13, 14), but when administered systemically it does not induce immediate neuronal damage in rats up to the third postnatal week (striatum [8] and hippocampus [5, 56]). In contrast, neuronal damage may be seen after a long latent period (a few months) even in rats injected with kainate systemically as well as intrahippocampally at the age of 7 or 12 postnatal days (2, 31). Unlike this specific response of the immature brain to kainate, the excitotoxic action of NMDA, AMPA, and quisqualate, resulting in neuronal death, can be demonstrated even in the first week of life, and the sensitivity of rat pups is higher than that of adult animals (17, 19, 22, 24, 37, 67). This hypersensitivity peaks around postnatal day 10, with a small difference in sensitivity to NMDA and AMPA (36, 40). Brain injury was also demonstrated after administration of the type I metabotropic glutamate receptor agonist 1S,3R-ACPD (38). Excitatory amino acids represent a common pathway of neuronal destruction in immature animals after various pathologic
changes (hypoxia-ischemia [47], epileptic seizures [42, 64], and administration of aminooxyacetic acid [39] or malonate [16]). The temporal evolution of brain damage is very fast; nuclear magnetic resonance imaging demonstrates changes 15 minutes after intracerebroventricular NMDA injection (63). The administration of agonists of all types of ionotropic receptors and of type I metabotropic receptors elicits seizures in immature rats. With repeated administration, kainic acid elicited seizures even in 7-day-old rat pups, an age when immediate morphologic damage in the hippocampal field CA3 is absent (1, 4, 10, 62). The sensitivity to kainic acid induction of seizures was highest in 7-day-old rats and decreased moderately with age (62). NMDA is also active during very early stages of development (35, 52), and sensitivity to its convulsant action decreases dramatically with age—the effective doses in 7-day-old rats are 100 times lower than those for adult animals (35). ,-Homocysteic acid, producing its excitatory action mainly by means of NMDA receptors (but not exclusively [61], and unpublished data from our laboratory), reliably elicits seizures after postnatal day 7 when administered systemically (33). The epileptogenic action of ,-homocysteic acid also decreases during development, but the decline is not so steep as with NMDA (33). Homocysteine also elicits seizures from postnatal day 7, but there is no simple relationship between efficacy and age (29), probably because the roles of NMDA and non-NMDA receptors in the convulsant action of homocysteine vary during development (15). AMPA is also effective at an early age (10 days), but quantitative data are lacking (52). Similarly, a convulsant action of the type I metabotropic glutamate receptor agonist 1S,3R-ACPD was demonstrated in 7-day-old rats (39). Excitatory amino acid agonists did not induce the same pattern of seizures, and they may have a different influence on models of electrically induced of epileptic seizures in developing rats (34). Kainic acid elicts a sequence of automatisms (“wet-dog shakes” are the most conspicuous behavior in adult rodents, whereas scratching is the principal behavioral symptom in rat pups), minimal seizures (clonic seizures involving head and forelimb muscles, with preservation of righting reflexes), and generalized tonic-clonic
ˇ:
367
seizures, with a loss of righting ability at the beginning of the tonic phase (62). NMDA never elicits minimal seizures. Its action starts with a period of immobility, then a hyperlocomotion appears, and after a somewhat longer latency (if the dose is high enough) seizures characterized by violent generalized clonic-tonic convulsions are observed. Generalized seizures invariably lead to death. Rat pups up to the age of 18 days exhibit an age-specific phenomenon consisting of flexion, emprosthotonic seizures. The animals are curled up into a ball for some seconds or maximally some tens of seconds during these seizures (35). The seizure pattern induced by homocysteic acid is practically the same as that elicited by NMDA (33). On the other hand, homocysteine is able to induce a mixture of both patterns, that induced by NMDA and that induced by kainic acid, again indicating the possibility of multiple mechanisms of action of this drug on excitatory amino acid receptors (29). These observations might reflect the actions of kainic acid and NMDA on different brain structures, with minimal seizures taken as forebrain seizures and generalized tonic-clonic seizures (and, with a high probability, also clonic-tonic seizures) generated in the brain stem (7). Unfortunately, no data on the generation of flexion seizures are available. The age dependence of flexion seizures may reflect either an increased sensitivity of immature brain to NMDA (as has been repeatedly noted in the literature) or, less probably, an uneven maturation of different brain structures, which would allow the generator of flexion seizures to express the seizure pattern up to the moment when another brain structure (or structures) is set into action. The data for kainic acid indicate that immediate neuronal death is not always connected with seizures but may reflect the toxicity of kainate. Seizures and neuronal death might represent two parallel phenomena induced by excitatory amino acids. Excitatory amino acids are the main agents responsible for neuronal destruction after severe seizures elicited by other mechanisms. Status epilepticus (SE) induced by the cholinomimetic pilocarpine (in two modifications, the highdose model and the lithium-pilocarpine model) leads to extensive neuronal damage in adult brain (12). The role of NMDA receptors in pilocarpine-induced seizures has been demonstrated (55). Pilocarpine-induced SE and its morphologic consequences have also been described in developing rats (9, 20). There are marked differences in the structures compromised, as well as in the extent of neuronal damage, in SE induced at different developmental stages (9, 25, 49). Acute changes evaluated in Nissl-stained sections are much more expressed in animals undergoing SE as adults than in rats seizing at an early age, and the same is true for kainic acid–induced seizures. On the other hand, histochemical (25) or immunohistochemical methods (28) are able to show
368
:
specific changes even in rats seizing at the age of 12 days. We are at the beginning of exact mapping of the morphologic consequences of SE induced at different stages of maturation, because attention is usually focused on the hippocampus (21, 26, 27, 49, 51, 65). Neuronal death may be induced also by electrically induced models of SE (51, 60). Even less is known about the functional consequences of SE that might be connected to excitotoxic damage. The studies reported here demonstrate that even the youngest rats exhibit longlasting consequences of SE in motor performance and spontaneous behavior, but the impact of these changes on brain development is far from being understood (30, 48, 57, 59, 66). Another open question is the role of neuronal death in chronic epileptogenesis in immature brain (3, 50). Ongoing work from our laboratory is addressing these questions. This work was supported by the Center for Neuropsychiatric Studies as a research project of the Ministry of Education of the Czech Republic, No. LN00B122.
REFERENCES 1. Albala, B. J., S. L. Moshé, and R. Okada. Kainic acid–induced seizures: A developmental study. Dev. Brain Res. 1984;13: 139–148. 2. Babb, T. L., J. Pereira-Leite, G. W. Mathern, and J. K. Pretorius. Kainic acid induced hippocampal seizures in rats: Comparisons of acute and chronic seizures using intrahippocampal versus systemic injections. Ital. J. Neurol. Sci. 1995;16:39–44. 3. Baram, T. Z., M. Eghbal-Ahmadi, and R. A. Bender. Is neuronal death required for seizure-induced epileptogenesis in the immature brain? In T. Sutula, and A. Pitkänen, eds. Do Seizures Damage the Brain. Prog. Brain Res. 2002;135:365–375. 4. Ben-Ari, Y., E. Tremblay, M. Berger, and L. Nitecka. Kainic acid seizure syndrome and binding sites in developing rats. Dev. Brain Res. 1984;14:284–288. 5. Ben-Ari, Y., E. Tremblay, D. Riche, G. Ghilini, and R. Naquet. Electrographic, clinical and pathological alterations following systemic administration of kainic acid, bicuculline or pentylenetetrazole: Metabolic mapping using the deoxyglucose method with special reference to pathophysiology of epilepsy. Neuroscience 1981;6:1361–1391. 6. Beneviste, H., J. Drejer, A. Schousboe, and N. H. Diemer. Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by cerebral microdialysis. J. Neurochem. 1984;43:1369–1374. 7. Browning, R. A., and D. K. Nelson. Modification of electroshock and pentylenetetrazol seizure patterns in rats after precollicular transsection. Exp. Neurol. 1986;93:546– 556. 8. Capochiaro, P., and J. T. Coyle. Ontogenetic development of kainate neurotoxicity: Correlates with glutamatergic innervation. Proc. Natl. Acad. Sci. U.S.A. 1978;75:2025–2029. 9. Cavalheiro, E. A., D. F. Silva, W. A. Turski, L. S. CalderazzoFilho, Z. A. Bortolotto, and L. Turski. The susceptibility of rats
10.
11. 12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24. 25.
26.
to pilocarpine-induced seizures is age-dependent. Dev. Brain Res. 1987;37:43–58. Cherubini, E., M. R. De Feo, O. Mecarelli, and G. F. Ricci. Behavioral and electrographic patterns induced by systemic administration of kainic acid in developing rats. Dev. Brain Res. 1983;9:69–77. Choi, D. W. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1988;1:623–634. Clifford, D. B., J. W. Olney, A. Maniotis, R. C. Collins, and C. F. Zerumski. The functional anatomy and pathology of lithium-pilocarpine and high-dose pilocarpine seizures. Neuroscience 1987;23:953–968. Cook, T. M., and K. A. Crutcher. Extensive target cell loss during development results in mossy fibers in the regio superior (CA1) of the rat hippocampal formation. Brain Res. 1985;353:19–30. Cook, T. M., and K. A. Crutcher. Intrahippocampal injection of kainic acid produces significant pyramidal cell loss in neonatal rats. Neuroscience 1986;18:79–92. Folbergrová, J. Anticonvulsant action of both NMDA and non-NMDA receptor antagonists against seizures induced by homocysteine in immature rats. Exp. Neurol. 1997;145: 442–450. Greene, J. G., and J. T. Greenamyre. Characterization of the excitotoxic potential of the reversible succinate dehydrogenase inhibitor malonate. J. Neurochem. 1995;64:430–436. Guiramand, J., I. Sassetti, and M. Recasens. Developmental changes in the chemosensitivity of rat brain synaptosomes to excitatory amino acids, estimated by inositol phosphate formation. Int. J. Dev. Neurosci. 1989;7:257–266. Haglid, K. G., S. Wang, Y. Qiner, and A. Hamberger. Excitotoxicity: Experimental correlates to human epilepsy. Mol. Neurobiol. 1994;9:259–263. Hattori, H., and C. G. Wasterlain. Excitatory amino acids in the developing brain: Ontogeny, plasticity, and excitotoxicity. Pediatr. Neurol. 1990;6:219–228. Hirsch, E., T. Z. Baram, and O. C. Snead, III. Ontogenic study of lithium-pilocarpine-induced status epilepticus in rats. Brain Res. 1992;583:120–126. Holmes, G. L., R. Khazipov, and Y. Ben-Ari. Seizure-induced damage in the developing human: Relevance of experimental models. In T. Sutula, and A. Pitkänen, eds. Do Seizures Damage the Brain. Prog. Brain Res. 2002;135:321–334. Ikonomidou, C., J. L. Mosinger, K. S. Salles, J. Labruyere, and J. W. Olney. Sensitivity of the developing rat brain to hypobaric/ischemic damage parallels sensitivity to Nmethyl-aspartate neurotoxicity. J. Neurosci. 1989;9:2809– 2818. Ikonomidou, C., M. T. Price, J. L. Mosinger, G. Frierdich, J. Labruyere, K. Shahid Salles, and J. W. Olney. Hypobaricischemic conditions produce glutamate-like cytopathology in infant rat brain. J. Neurosci. 1989;9:1693–1700. Johnston, M. V. Neurotransmitters and vulnerability of the developing brain. Brain Dev. 1995;17:301–306. Kubová, H., R. Druga, R. Haugvicová, M. Sˇkutová, and P. Maresˇ. Changes in NADPH-diaphorase positivity induced by status epilepticus in allocortical structures of the immature rat brain. Brain Res. Bull. 1999;48:39–47. Kubová, H., R. Druga, R. Haugvicová, L. Suchomelová, and A. Pitkänen. Dynamic changes of status epilepticus-induced neuronal degeneration in the mediodorsal nucleus of the thal-
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41. 42. 43. 44.
amus during postnatal development of the rat. Epilepsia 2002;43(Suppl. 5):54–60. Kubová, H., R. Druga, K. Lukasiuk, 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. Kubová, H., R. Druga, L. Suchomelová, and R. Haugvicová. Status epilepticus in immature rats leads to a decrease of calcium-binding protein-containing cells in motor cortex, striatum, and piriform cortex. Epilepsia 1998;39(Suppl. 6): 16. Kubová, H., J. Folbergrová, and P. Maresˇ. Seizures induced by homocysteine in rats during ontogenesis. Epilepsia 1995;36: 750–756. Kubová, H., R. Haugvicová, L. Suchomelová, and P. Maresˇ. Does status epilepticus influence motor development of immature rats? Epilepsia 2000;41(Suppl. 6):S64–S69. Leite, J. P., T. L. Babb, J. K. Pretorius, P. A. Kuhlman, K. M. Yeoman, and G. W. Mathern. Neuron loss, mossy fiber sprouting, and interictal spikes after intrahippocampal kainate in developing rats. Epilepsy Res. 1996;26:219–231. Lynch, M., U. Sayin, J. Bownds, S. Jampalli, and T. Sutula. Long-term consequences of early postnatal seizures on hippocampal learning and plasticity. Eur. J. Neurosci. 2000;12: 2252–2264. Maresˇ, P., J. Folbergrová, J. Langmeier, R. Haugvicová, and H. Kubová. Convulsant action of ,-homocysteic acid and its stereoisomers in immature rats. Epilepsia 1997;38:767–776. Maresˇ, P., R. Haugvicová, and H. Kubová. Interaction of excitatory amino acid agonists with cortical afterdischarges in developing rats. Epilepsia 2002;43(Suppl. 5):61–67. Maresˇ, P., and L. Velísˇek. N-Methyl--aspartate (NMDA)induced seizures in developing rats. Dev. Brain Res. 1992;65: 185–189. McDonald, J. F., F. S. Silverstein, and M. V. Johnston. Neurotoxicity of N-methyl--aspartate is markedly enhanced in developing rat central nervous system. Brain Res. 1988;459: 200–203. McDonald, J. F., and M. V. Johnston. Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res. Rev. 1990;15:41–70. McDonald, J. F., A. S. Fix, J. P. Tizzano, and D. D. Schoepp. Seizures and brain injury in neonatal rats induced by 1S,3RACPD, a metabotropic glutamate receptor agonist. J. Neurosci. 1993;13:4445–4455. McDonald, J. F., and D. D. Schoepp. Aminooxyacetic acid produces excitotoxic brain injury in neonatal rats. Brain Res. 1993;624:239–244. McDonald, J. F., W. H. Trescher, and M. V. Johnston. Susceptibility of brain to AMPA induced excitotoxicity transiently peaks during early postnatal development. Brain Res. 1992;583: 54–70. Meldrum, B. Excitotoxicity and epileptic brain damage. Epilepsy Res. 1991;10:55–61. Meldrum, B. S. Excitotoxicity and selective neuronal loss in epilepsy. Brain Pathol. 1993;3:405–412. Morgan, I. G. AMPA is a powerful neurotoxin in the chicken retina. Neurosci. Lett. 1987;79:267–271. Nadler, J. V., B. W. Perry, and C. W. Cotman. Intraventricular kainic acid preferentially destroys hippocampal pyramidal cells. Nature 1978;271:676–677.
ˇ:
369
45. Olney, J. W. Glutamate-induced neuronal necrosis in the infant mouse hypothalamus: An electron microscopic study. J. Neuropathol. Exp. Neurol. 1971;30:75–90. 46. Olney, J. W., V. Rhee, and O. L. Ho. Kainic acid: A powerful neurotoxic analogue of glutamate. Brain Res. 1974;77:507–512. 47. Puka-Sundvall M, E. Gilland, E. Bona, A. Lehmann, M. Sandberg, and H. Hagberg. Development of brain damage after neonatal hypoxia-ischemia: Excitatory amino acids and cysteine. Metab. Brain Dis. 1996;11:109–123. 48. Rutten, A., M. van Albada, D. C. Silveira, B. H. Cha, X. Liu, Y. N. Hu, et al. Memory impairment following status epilepticus in immature rats: Time course and environmental effects. Eur. J. Neurosci. 2002;16:501–513. 49. Sankar, R., D. H. Shin, H. Liu, A. Mazarati, A. Pereira de Vasconcelos, and C. G. Wasterlain. Patterns of status epilepticusinduced neuronal injury during development and long-term consequences. J. Neurosci. 1998;18:8382–8393. 50. Sankar, R., D. Shin, H. Liu, C. Wasterlain, and A. Mazarati. Epileptogenesis during development: Injury, circuit recruitment, and plasticity. Epilepsia 2002;43(Suppl. 5):47–53. 51. Sankar, R., D. Shin, A. M. Mazarati, H. Liu, H. Katsumori, R. Lezama, and C. G. Wasterlain. Epileptogenesis after status epilepticus reflects age- and model-dependent plasticity. Ann. Neurol. 2000;48:580–589. 52. Schoepp, D. D., A. Y. Gamble, C. R. Salhoff, B. G. Johnson, and P. L. Ornstein. Excitatory amino acid-induced convulsions in neonatal rats mediated by distinct receptor subtypes. Eur. J. Pharmacol. 1990;182:421–427. 53. Sloviter, R. S. “Epileptic” brain damage in rats induced by sustained electrical stimulation of perforant path. I. Acute electrophysiological and light microscopic studies. Brain Res. Bull. 1983;10:675–697. 54. Shinozaki, H., and S. Konishi. Action of several anthelmintics and insecticides on rat cortical neurons. Brain Res. 1970;24: 368–371. 55. Smolders, I., G. M. Khan, J. Manil, G. Ebinger, and Y. Michotte. NMDA receptor-mediated pilocarpine-induced seizures: Characterization in freely moving rats by microdialysis. Br. J. Pharmacol. 1997;121:1171–1179. 56. Sperber, E. F., P. K. Stanton, K. Haas, R. F. Ackermann, and S. L. Moshé. Developmental differences in the neurobiology of epileptic brain damage. Epilepsy Res. 1992;Suppl. 9:67–81. 57. Stafstrom, C. E. Assessing the behavioral and cognitive effects of seizures on the developing brain. In T. Sutula, and A. Pitkänen, eds. Do Seizures Damage the Brain. Prog. Brain Res. 2002;135:377–390. 58. Stewart, G. R., M. T. Price, J. W. Olney, B. K. Hartman, and C. Cozzari. N-methylaspartate: An effective tool for lesioning basal forebrain cholinergic neurons of the rat. Brain Res. 1986;3369:377–382. 59. Sutula, T., and A. Pitkanen. Summary: Seizure-induced damage in development and functional consequences. In T. Sutula, and A. Pitkänen, eds. Do Seizures Damage the Brain. Prog. Brain Res. 2002;135:395–396. 60. Thompson, K., A. M. Holm, A. Schousboe, P. Popper, P. Micevych, and C. G. Wasterlain. Hippocampal stimulation produces neuronal death in immature brain. Neuroscience 1998;82:337–348. 61. Turski, W. A. Homocysteic acid: Convulsant actions of stereoisomers in mice. Brain Res. 1989;479:371–373. 62. Velísˇková, J., L. Velísˇek, and P. Maresˇ. Epileptic phenomena produced by kainic acid in laboratory rats during ontogenesis. Physiol. Bohemoslov. 1988;37:395–405.
370
:
63. Verheul, H. B., R. Palazs, J. W. Berkelbach van der Srenkel, C. A. F. Tulleken, K. Nicolay, and M. van Lookeren Campagne. Temporal evolution of NMDA-induced excitotoxicity in the neonate rat brain measured with 1H nuclear magnetic resonance imaging. Brain Res. 1993;618:203–212. 64. Wasterlain, C. G., and R. Sankar. Excitotoxicity and the developing brain. In G. Avanzini, R. Fariello, U. Heinemann, and R. Mutani, eds. Epileptogenic and Excitotoxic Mechanisms. London: John Libbey, 1993:135–151. 65. Wasterlain, C. G., J. Niquet, K. W. Thompson, R. Baldwin, H. Liu, R. Sankar, et al. Seizure-induced neuronal death in the immature brain. In T. Sutula, and A. Pitkänen, eds. Do Seizures Damage the Brain. Prog. Brain Res. 2002;135:335–353. 66. Wu, C. L., L. T. Huang, C. W. Liou, T. J. Wang, Y. R. Tung, H. Y. Hsu, and M. C. Lai. Lithium-pilocarpine-induced status epilepticus in immature rats result in long-term deficits in spatial learning and hippocampal cell loss. Neurosci. Lett. 2001;312:113–117. 67. Young, R. S. K., O. A. C. Petroff, E. J. Novotny, Jr., and M. Wong. Neonatal excitotoxic brain injury. Dev. Neurosci. 1990; 12:210–220.
29
Age-Specific Mechanisms of Status Epilepticus
ˇ, , . C indicate that children have a greater propensity to develop status epilepticus (SE) than adults (13, 14, 34, 35, 55) (see Shinnar, Chapter 5, this volume). Infants less than 1 year old have the highest incidence of SE (12). Studies in different epilepsy models provide further evidence that the immature brain is more susceptible to seizures than the mature brain. Differences in seizure thresholds and patterns as a function of age have been observed in seizures induced by kainic acid, pilocarpine, and flurothyl. In kainic acid- and pilocarpine-induced seizures, rat pups have a lower convulsive threshold, more rapid onset of SE, and a higher mortality than adult rats (3, 8). The seizure thresholds following exposure to flurothyl are also shorter in rat pups than in adults (84). Studies with the kindling model indicate that in the immature brain, focal afterdischarges are not easily confined to the stimulated focus, with the rapid development of kindled seizures that recur at short time intervals (60, 61, 63). Alternating stimulations of two sites led to the development of seizures from both sites (31, 32). This is not the case in adult rats (7). These kindling data suggest that in the immature brain, the refractory period that follows a seizure is very short compared with the refractory period observed in adulthood. The decreased refractory period may underlie the propensity of the immature brain to develop SE. Certain brain structures participate in the propagation and eventually in the arrest of seizures, and [14C]2deoxyglucose (2-DG) autoradiographic studies have been used to identify these structures in different seizure models. In the adult rat, increased glucose uptake was identified in different brain structures during various stages of kindling in the amygdala kindling seizure model. During partial seizures (stages 1 and 2), enhanced 2-DG utilization was limited to certain primary projection areas of the stimulated amygdala. After the appearance of generalized seizures (stages 3, 4, and 5), enhanced 2-DG utilization was noted in more distant extralimbic structures, including the substantia nigra pars reticulata (SNR), thalamus, and neocortex (20). Studies of regional glucose metabolism in pentylenetetrazole (PTZ)-induced SE in adult rats showed increased 2-DG utilization in the SNR, hippocampus, most areas of the cerebral cortex, striatum, and the reticular formation of the
brain stem (38). The increases in metabolic activity in the SNR were especially striking. A marked increase in adult rat SNR 2-DG uptake has also been observed with SE induced by kainic acid (3, 5, 50), flurothyl (83), bicuculline, PTZ (5), and penicillin (73). Although the patterns of 2-DG uptake vary across different seizure models, the SNR appears to be a structure always activated in fully generalized seizures. Therefore, the adult rat SNR seems to play a crucial role in the expression of generalized seizures. However, unlike in adult rats, in rat pups there is no qualitative change in 2-DG utilization of the SNR in several seizure models, regardless of seizure severity (1, 3, 83). In addition, in rat pups, the pattern of 2-DG metabolic changes of SNR in PTZinduced SE varies greatly as a function of postnatal age (74). These results suggest that SNR involvement in seizures is different in rat pups, and this difference may account for the early generalization of seizures, increased seizure severity, and quick onset of SE. This chapter discusses the role of the SNR in seizure control as a function of age.
Anatomy and connectivity of the SNR The substantia nigra (SN) is divided into three parts, the pars compacta (SNC), SNR, and pars lateralis (SNL) (33). The SNC contains the majority of dopaminergic neurons that project to the striatum via the nigrostriatal pathway and release dopamine in the striatum. The SNC dopaminergic neurons receive tonic inhibitory g-aminobutyric acid (GABA) input from SNR cells (30). The SNR contains mainly GABAergic neurons (70, 72), which receive GABA inputs from the striatum (18, 43, 44, 67) and the globus pallidus (44, 82) and send inhibitory GABAergic projections to the thalamus (17, 42, 53), superior colliculus (10, 17, 96), tegmental reticular formation (11), and SNC (30). The SNR neurons projecting to the tectum are concentrated in the anterior part of the SNR (22, 54). The nigrotegmental cells are located in the posterior part of the SNR (15). The nigrothalamic cells are scattered throughout the SNR and consequently are intermixed with the other groups (15, 16, 22). There is also a set of neurons in the SNR projecting to the striatum; these cells are found within the ventromedial region of the posterior SNR. They correspond in their
ˇ, , : -
371
topographic distribution to the SNR dopamine-containing neurons (68). The neurons in the SNR, which exert an inhibitory influence on SNC cells, are located just ventral to the SNC (30). In addition, the SNL neurons project mainly to the superior colliculus (54). Early electrophysiologic studies indicated that in adult rats, electrographic seizure activity propagates into the SNR (36, 97). Pharmacologic studies using site-specific drug microinjections have offered significant insight into the role of the SNR in seizures in adult rats. Initial studies by Iadarola and Gale (39) demonstrated that the SNR is a key site of GABA-mediated anticonvulsant action, since microinjections of muscimol (an agonist of GABA receptor site) into the SNR decreased susceptibility to electroshock and chemically induced seizures (39). Later studies in other experimental seizure models demonstrated that intranigral infusions of GABAA agonists can suppress motor and electrographic seizures (25, 28, 62, 70, 85). In amygdala kindling seizures, bilateral infusions of muscimol into rat SNR markedly reduced the duration of motor seizures and decreased the duration of electrical afterdischarges (46, 57, 58). During prolonged SE in rats, extensive lesions may develop in the SNR, whereas the SNC remains intact (4, 38, 66, 89). These lesions may arise from a massive metabolic derangement and hyperexcitation in the activated SNR. Therefore, within the SN the SNR plays a critical role in the control of seizures (24). The neurons in the SNR have a much greater sensitivity to muscimol than neurons in the SNC (100). Because dopaminergic agents have no effect on a variety of experimental seizures (41), it has been suggested that the anticonvulsant effect induced by GABAA agonist infusions into the SNR is not mediated by the nigral dopaminergic pathway (2, 24), although the evidence is still inconclusive (64, 65). The SNR receives GABA inputs, which have been demonstrated to inhibit the SNR projection sites, based on both electrophysiologic (30, 53, 100) and biochemical studies (59). Because the projections of SNR are also GABAergic, the net effect of GABA activity in nigral synapses is disinhibition of SNR target neurons. The infusion studies just discussed indicate that the increased GABA activity in the SNR inhibits nigral outflow pathways and has anticonvulsant effects. Destruction of the SNR neurons should also block the nigral output systems and thus reduce seizure susceptibility. However, the findings of SNR lesion studies are contradictory. Bilateral destruction of the SNR suppressed seizures induced by bicuculline, electroshock (25), and kindling (57). Nevertheless, more selective and specific SNR lesions either had no effect or facilitated rather than inhibited kindling development in rats (80, 98, 99). It is possible that the extent of the SNR lesion may account for the different effects. Within the adult SNR, there are two functional regions that mediate opposite effects on seizures
372
:
(88, 92–94). In our original study, we found that infusions of muscimol in the anterior SNR (SNRanterior) have anticonvulsant effects, whereas infusions of muscimol in the posterior SNR (SNRposterior) have proconvulsant effects on flurothyl seizures (64). This finding may provide another hint to explain the contradictory results from SNR lesion studies. Lesions of different regions of the SNR or lesions of only a part rather than the entire SNR may have different effects on seizures.
Role of the SNR in seizures in adult animals Based on the SNR infusion and lesion studies, we hypothesized that, in adult rats, the GABA-sensitive system of the SNR is able to control the propagation of seizures. To identify the GABA receptor types that affect the nigral influences on seizures in adult rats, we microinfused different GABA agents into SNRanterior and SNRposterior regions to test their effect on flurothyl seizure threshold (Table 29.1). In the central nervous system (CNS), there are two major classes of GABA receptor, GABAA and GABAB. The distinction between these two receptors is based on numerous criteria, including pharmacologic, biochemical, and electrophysiologic data. GABAA receptors are ionotropic receptors with hetero-oligomeric structure (9). GABAB receptors are metabotropic receptors with hetero-oligomeric structure (9, 41). GABAA receptors are bicuculline sensitive and GABAB receptors are bicuculline insensitive, but sensitive to baclofen (37, 40). In addition, GABAA receptors have high- and lowaffinity binding sites (21). Infusions of g-vinyl GABA (GVG) into the adult SNRanterior have anticonvulsant effects (94, 104), while infusions into the SNRposterior have proconvulsant effects on flurothyl-induced seizures (94). GVG increases the concentration of endogenous GABA, which can bind to GABAA and GABAB receptors. To determine which SNR GABA receptors affect flurothyl-induced seizures, agonists and antagonists of GABAA and GABAB receptors were microinfused into the SNR. Microinfusions of GABAA agonists {muscimol, THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) and ZAPA [(Z)-3-[(aminoiminomethyl)thio] prop-2-enoic acid]} have anticonvulsant effects (62, 71, 87, 94, 105), while microinfusions of the GABAA antagonist (bicuculline) have proconvulsant effects on flurothyl-induced seizures (85). In the adult SNRanterior, microinfusions of a GABAB agonist (baclofen) and antagonist (CGP 35348) do not have any effect on flurothyl-induced seizures (87, 90). These data suggest that in adult rats, the effects of SNRanterior on seizures are mediated by GABAA receptors. GABAB receptors do not appear to participate in the control of seizures at this age. Which GABAA receptors mediate SNRanterior effects on seizures? ZAPA is an agonist and bicuculline is an antagonist of the GABAA receptor low-affinity site. In the adult
T 29.1 Effects of intranigral microinfusions of GABA agents on flurothyl-induced seizure thresholds in adult and P15 rats Adult Drugs
GABA Receptor Action
SNRanterior
SNRposterior
P15 SNR
Muscimol 100 ng/0.25 mL
GABAA agonist of both lowand high-affinity sites
Anticonvulsant
Proconvulsant
Proconvulsant
THIP 500 ng ZAPA 2 mg/0.25 mL 8 mg/0.25 mL
GABAA agonist of highaffinity sites GABAA agonist: potent agonist of low-affinity sites, weak agonist of high-affinity sites GABAA antagonist of lowaffinity sites GABA-transaminase inhibitor
Anticonvulsant
Not tested
Proconvulsant
Okada et al., 1986; Moshé and Albala, 1984; Moshé et al., 1994 Xu et al., 1992
No effect
No effect
Anticonvulsant
Velísˇková et al., 1996
Anticonvulsant
Proconvulsant
Proconvulsant
Proconvulsant
No effect
Proconvulsant
Anticonvulsant
Proconvulsant
Anticonvulsant
GABAB agonist
No effect
Not tested
Anticonvulsant
Sperber et al., 1987; Velísˇková et al., 1996 Velísˇková et al., 1996; Xu et al., 1991 Sperber et al., 1989
GABAB antagonist
No effect
Not tested
Proconvulsant
Velísˇková, 1994
Bicuculline 100 ng/0.25 mL GVG 20 mg/0.25 mL Baclofen 100 ng/0.25 m CGP 35348 2 mg/0.25 m
Study
Abbreviations: THIP, 4,5,6,7-tetrahydroisoxazolo{5,4-c}pyridin-3-ol; ZAPA, (Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid; GVG, gvinyl GABA.
SNRanterior, the effects of ZAPA and bicuculline are in the opposite direction (94). ZAPA has anticonvulsant effects, bicuculline has proconvulsant effects. The role of SNRanterior low-affinity GABAA receptors on seizures is supported by data showing that the anticonvulsant effect of GVG infusions in this part of SNR can be blocked by nigral bicuculline infusions (104). THIP is an agonist of the GABAA receptor high-affinity site. It has anticonvulsant effects on flurothyl-induced seizures when infused into SNRanterior (105). Combining these data, we propose that in adult rats, in the SNRanterior, both low- and high-affinity GABAA receptors are involved in seizure control. In the SNRposterior, muscimol and ZAPA have proconvulsant effects on flurothyl-induced seizures (64, 93, 94). In the adult SNRposterior, bicuculline does not alter the seizure threshold, while ZAPA has proconvulsant effects. Therefore, the low-affinity GABAA receptor may not be involved in the adult SNRposterior, since the proconvulsant effect of ZAPA could be due to its effect on the high-affinity GABAA receptor sites (94). The role of GABAB receptors in SNRposterior in flurothyl-induced seizures remains to be explored. It has been shown that the affinity of GABA agents and functional properties of GABAA receptors depend on subunit composition of GABAA receptors (48, 49, 51, 78, 81, 95). The GABAA receptor is a pentamer comprised of
several subunits (to date, 16 subunits has been cloned) (9). The neuronal responsiveness to GABAergic input is influenced by differential expression of various subunit genes (48, 49). In situ hybridization and immunohistochemistry studies have revealed that the different subunits have a characteristic topographic distribution in the brain (19, 23, 45, 52, 102). In adult rat brain, a1, b2, and g2 subunits predominantly contribute to form the receptor (101). To date, the detailed distribution of the different subunits of GABAA receptor in the SNR has not been reported. We studied the distribution of a1 and g2L subunits of GABAA receptor, the most abundant subunits in the adult rat SNR. The data show that the two SNR regions, which mediate opposite effects on seizures, also differ in the amount of the mRNA expression of both subunits. Our in situ hybridization study using a a1 and g2L cDNA probes was performed in the sagittal plane. The distributional patterns of both subunits were similar (91). At the level of the subthalamic nucleus, the emulsions revealed two hybridization patterns at the cellular level in SNRanterior and SNRposterior. In SNRanterior, the labeled cells tended to be arranged in clusters, and the size of clusters was larger than in SNRposterior. The number of hybridization grains per cell was generally higher, but fewer cells were labeled in SNRanterior than in SNRposterior. The two different patterns of
ˇ, , : -
373
a1 and g2L expression in the SNR provide a possible molecular basis for the infusion studies, which show different effects on seizures following GABAergic drug infusions in the SNRanterior and SNRposterior regions. The SNR effects on seizures may depend on (1) the site of microinfusions, (2) the subunit composition of the GABAA receptor, and (3) the anatomic connections of the subdivisions of the SNR. Therefore, the site-dependent effects in the SNR on seizures can also be the result of the different functional network involved. To test the functional networks that mediate the effects on SNRanterior and SNRposterior, we used 2-DG mapping to identify which regions of brain were metabolically altered by unilateral muscimol infusions in SNRanterior and SNRposterior (64). Muscimol infusions in the SNR produced specific regional metabolic changes compared to saline controls. In adults, muscimol infusions in SNRanterior decreased glucose utilization in the ipsilateral striatum, sensorimotor cortex, and ventromedial thalamus. However, muscimol infusions in SNRposterior produced a different pattern of metabolism. Glucose utilization was increased in the ipsilateral dorsal striatum and not changed in the sensorimotor cortex. Glucose utilization was also increased in the globus pallidus. Thus, two separate functional networks were demonstrated. Interestingly, both SNRanterior and SNRposterior infusions activated the deep layer of the superior colliculus, a site that may be involved in control of seizures (26, 76, 77, 79). However, there is still debate on the role of each SNR output system in seizure control. In summary, the data indicate that the anticonvulsant and proconvulsant effects of GABAergic infusions in SNRanterior and SNRposterior on flurothyl-induced seizures may be mediated through distinct groups of neurons with GABAA receptors composed of different subunits. These neurons may use different projection networks to mediate the regional SNR effect on seizures.
Role of the SNR in seizures in young animals In postnatal day 15 (P15) rats, the effects of bilateral nigral infusions of GABA agents do not show any regional specificity (64, 93, 94) (see Table 29.1). Intranigral microinfusions of muscimol, an agonist of low- and high-affinity GABAA receptor sites, and THIP, an agonist of the high-affinity GABAA receptor sites, have proconvulsant effects on flurothyl-induced seizures (62, 105). Intranigral infusions of bicuculline, an antagonist of low-affinity GABAA receptor sites, also have proconvulsant effects (85, 94). An intermediate dose of ZAPA (2 mg per site) has anticonvulsant effects, but a large dose (8 mg per site) is proconvulsant (94). ZAPA is an agonist of low-affinity GABAA receptor sites that also has a weak affinity for high-affinity GABAA receptor sites. We speculate that the low-affinity GABAA receptor site may
374
:
mediate the anticonvulsant action of ZAPA and that the proconvulsant action may be due to activation of the highaffinity GABAA receptor sites. Thus, both low- and highaffinity GABAA receptor sites play a role in seizures in P15 rats, but their activation leads to opposite effects on seizures. Infusions of GVG in P15 SNR have anticonvulsant effects on seizures (94). This anticonvulsant effect is mediated by both GABAA receptor sites and GABAB receptors. Indeed, microinfusions of baclofen (an agonist of GABAB receptors) have anticonvulsant effects, while microinfusions of CGP 35348 (an antagonist of GABAB receptors) have proconvulsant effects on flurothyl-induced seizures (86, 90). Therefore, the nigral GABAB receptors play a role in control of seizures in P15 rats. The results of these pharmacologic studies correlate with the findings in receptor-binding studies of GABA receptors in the SN. In these studies, the GABAB receptor density is three to five times higher in P15 SNR than in adult SNR (27). The densities of low-affinity GABAA receptors in P15 rat SNR are slightly higher (130%) than in the adult SNR; however, the density of the high-affinity GABAA receptors is only 13% of the adult level (103). In situ hybridization and immunohistochemistry studies showed that the expression of different subunits of GABAA receptors is developmentally regulated (19, 23, 45, 52, 102). Our in situ hybridization studies indicate that the expression of a1 and g2L subunit mRNAs of GABAA receptor in the SNR is generally lower in P15 rats than in adults. At the cellular level, the hybridization grains are clustered in the SNR and evenly distributed (91). This is not the case in the adult SNR, where two regions with different hybridization patterns have been observed. The hybridization pattern in the SNR of P15 rats is similar to the pattern in the SNRposterior of adult rats. The 2-DG study revealed that the metabolic changes observed after unilateral SNR infusions in P15 pups resemble the patterns observed in adults with muscimol infusions into SNRposterior. Glucose utilization is increased in the globus pallidus. However, changes in glucose utilization were observed in the ventromedial thalamus (decreased), as well as in the superior colliculus (64). Thus, the immature SNR appears to have certain features that resemble adult SNRposterior, which may account for the propensity of the immature CNS to experience SE. This propensity diminishes with age as SNRanterior matures and begins exerting (via its GABAergic neurotransmission) anticonvulsant effects.
Developmental profile of the “anticonvulsant” SNR region We determined the developmental profile of the SNR with respect to the effects of muscimol infusions on flurothyl-
induced seizures. In P15 and P21 rats, muscimol infusions have uniform proconvulsant effects compared to salineinfused controls, irrespective of the site of infusion. At P25, the SNR starts to differentiate; infusions of muscimol into SNRanterior have no effect on flurothyl-induced seizures, while infusions into SNRposterior have proconvulsant effects. In P30 and older rats, there is a clear difference between muscimol infusions into SNRanterior and SNRposterior. Muscimol infusions into SNRanterior have anticonvulsant effects and muscimol infusions into SNRposterior retain proconvulsant effects (93). The maturation of the “anticonvulsant” SNR region strikingly coincides with the sexual maturation (69). This observation raises the possibility that the appearance of the anticonvulsant SNRanterior may be under the influence of gonadal hormones. In male rats, there is a sudden drop in plasma testosterone levels (P20–25) (47, 75) just prior to the age when SNRanterior assumes its anticonvulsant characteristics. Thus, we speculate that the functional maturation of the SNR regions may be under the influence of testosterone. Gonadal steroid hormones interact with intracellular receptors in the CNS and trigger genomically directed alterations in protein synthesis (56). Testosterone, as well as other gonadal steroids, plays a significant role in the formation of neuronal circuits, as well as in the modulation of neuronal development (6, 29). To test our hypothesis that testosterone may play a role in formation of anticonvulsant SNRanterior, we castrated male rats on the day of birth. The rats were tested at age P15 and P25. In neonatally castrated male rats, muscimol infusions into SNRanterior at P15 had no effect on seizures; at P25, muscimol infusions into SNRanterior already achieved anticonvulsant effects compared with results in saline-infused neonatally castrated controls (93). Thus, in neonatally castrated male rats, the emergence of the anticonvulsant SNRanterior shifts to an earlier time point. These data suggest that the depletion of postnatal testosterone may accelerate the appearance of the anticonvulsant SNRanterior. Better knowledge of the influence of the endocrine system on brain development and neuronal activity may bring new insights into therapy for age-dependent seizure disorders, including SE.
Summary The immature brain has greater propensity to develop SE than mature brain. The SNR is an important structure involved in generalized seizures and SE in adult rats. Activation of the SNR during the SE shows differences in adult rats and rat pups. Intranigral infusion studies provide further evidence that the GABA system in the SNR is involved in the control of seizures and that the role of the SNR changes as a function of age. In adult rats, the GABA system in SNRanterior and SNRposterior mediates opposite effects on
seizures. The different distribution of GABAA and GABAB receptors and of GABAA receptor low- and high-affinity sites in SNRanterior and SNRposterior may account for the site-specific effects of the SNR. The mRNA distribution of a1 and g2L subunits for the GABAA receptor within the adult SNR is different, and these two regions are using divergent networks as well. In contrast, infusion studies in rat pups show that the effects of the SNR on seizures are not region specific, and only the proconvulsant network is present. In the immature SNR, the mRNA expression of the a1 and g2L subunits of the GABAA receptor does not display the regional topographic organization as it is in the adult SNR, and only one output network is activated by muscimol infusions. SNRanterior becomes functional later than SNRposterior. Intranigral infusion studies indicate that SNRanterior anticonvulsant effects on flurothyl-induced seizures emerge at the age of P30 in male rats. Castration shifts the emergence of the SNRanterior anticonvulsant effects to P25. Therefore, testosterone may play a role in the maturation of the SNR. The age-specific mechanisms of the SNR in controlling seizures may underlie the greater susceptibility of SE in immature brain. This work was supported by grants No. NS20253 (S.L.M.) and No. NS-36238 (J.V.) from the National Institute of Neurological Disorders and Stroke.
REFERENCES 1. Ackermann, R. F., S. L. Moshé, and B. J. Albala. Restriction of enhanced 14C-2-deoxyglucose utilization to rhinencephalic structures in immature amygdala-kindled rats. Exp. Neurol. 1989;104:73–81. 2. Albala, B. J., S. L. Moshé, J. F. Cubells, N. S. Sharpless, and M. H. Makman. Unilateral perisubstantia nigra catecholaminergic lesion and amygdala kindling. Brain Res. 1986; 370:388–392. 3. Albala, B. J., S. L. Moshé, and R. Okada. Kainicacid-induced seizures: A developmental study. Dev. Brain Res. 1984;13:139–148. 4. Auer, R. N., M. Ingvar, G. Nevander, Y. Olsson, and B. K. Siesjo. Early axonal lesion and preserved microvasculature in epilepsy-induced hypermetabolic necrosis of the substantia nigra. Acta Neuropathol. 1986;71:207–215. 5. Ben-Ari, Y., E. Tremblay, D. Riche, G. Ghilini, and R. Naquet. Electrographic, clinical and pathological alterations following systemic administration of kainic acid, bicuculline or pentetetrazole: Metabolic mapping using the deoxyglucose method with special reference to the pathology of epilepsy. Neuroscience 1981;6:1361–1391. 6. Breedlove, S. M. Steroid influences on the development and function of a neuromuscular system. Prog. Brain Res. 1984; 61:147–170. 7. Burchfiel, J. L., C. D. Applegate, and R. J. Konkol. Kindling antagonism: A role for norepinephrine in seizure suppression. In J. A. Wada, ed. Kindling 3. New York: Raven Press, 1986:213–229.
ˇ, , : -
375
8. Cavalheiro, E. A., D. F. Silva, W. A. Turski, L. S. CalderazzoFilho, Z. A. Bortolotto, and L. Turski. The susceptibility of rats to pilocarpine-induced seizures is age-dependent. Dev. Brain Res. 1987;465:43–58. 9. Chebib, M., and G. A. Johnston. The “ABC” of GABA receptors: A brief review. Clin. Exp. Pharmacol. Physiol. 1999;26: 937–940. 10. Chevalier, G., T. Thierry, T. Shibazaki, and J. Féger. Evidence for a GABAergic inhibitory nigrotectal pathway in the rat. Neurosci. Lett. 1981;21:67–70. 11. Childs, J. A., and K. Gale. Neurochemical evidence for a nigrotegmental GABAergic projection. Brain Res. 1983;258: 109–114. 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. DeLorenzo, R. J., J. M. Pellock, A. R. Towne, and J. G. Boggs. Epidemiology of status epilepticus. J. Clin. Neurophysiol. 1995;12:316–325. 14. 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. 15. Deniau, J. M., and G. Chevalier. The lamellar organization of the rat substantia nigra pars reticulata: Distribution of projection neurons. Neuroscience 1992;46:361–377. 16. Deniau, J. M., A. Menetrey, and S. Charpier. The lamellar organization of the rat substantia nigra pars reticulata: Segregated patterns of striatal afferents and relationship to the topography of corticostriatal projections. Neuroscience 1996; 73:761–781. 17. Di Chiara, G., M. L. Porceddu, M. Morelli, M. L. Mulas, and G. L. Gessa. Evidence for a GABAergic projection from the substantia nigra to the ventromedial thalamus and to the superior colliculus of the rat. Brain Res. 1979;176: 273–284. 18. Dray, A. The physiology and pharmacology of mammalian basal ganglia. Prog. Neurobiol. 1980;14:211–335. 19. Dunn, S. J., A. N. Bateson, and I. L. Martin. Molecular neurobiology of the GABAA receptor. Int. Rev. Neurobiol. 1994; 36:51–98. 20. Engel, J., Jr., L. Wolfson, and L. Brown. Anatomical correlates of electrical and behavioral events related to amygdaloid kindling. Ann. Neurol. 1978;3:538–544. 21. Enna, S. J. GABA A receptors. In R. F. Squires, ed. GABA and Benzodiazepine Receptors. Boca Raton, FL: CRC Press, 1988:91–106. 22. Faull, R. L. M., and W. R. Mehler. The cells of origin of nigrotectal, nigrothalamic and nigrostriatal projections in the rat. Neuroscience 1978;3:989–1002. 23. Fritschy, J.-M., J. Paysan, A. Enna, and H. Mohler. Switch in the expression of rat GABAA-receptor subtypes during postnatal development: An immunohistochemical study. J. Neurosci. 1994;14:5302–5324. 24. Gale, K. Progression and generalization of seizure discharge: Anatomical and neurochemical substrates. Epilepsia 1988; 29:S15–S34. 25. Garant, D., and K. Gale. Lesions of substantia nigra protect against experimentally induced seizures. Brain Res. 1983; 273:156–161. 26. Garant, D. S., and K. Gale. Substantia nigra-mediated anticonvulsant actions: Role of nigral output pathways. Exp. Neurol. 1987;97:143–159.
376
:
27. Garant, D. S., E. F. Sperber, and S. L. Moshé. The density of GABAB binding sites in the substantia nigra is greater in rat pups than in adults. Eur. J. Pharmacol. 1992;214:75–78. 28. Gonzalez, L. P., and M. K. Hettinger. Intranigral muscimol suppresses ethanol withdrawal seizures. Brain Res. 1984;298: 163–166. 29. Goy, R. W., and B. S. McEwen. Sexual Differentiation of the Brain. Cambridge, Mass.: MIT Press, 1980. 30. Grace, A. A., and B. S. Bunney. Paradoxical GABA excitation of nigral dopaminergic cell: Indirect mediation through reticulata inhibitory neurons. Eur. J. Pharmacol. 1979;59: 211–218. 31. Haas, K., E. F. Sperber, and S. L. Moshé. Kindling in developing animals: Expression of severe seizures and enhanced development of bilateral foci. Dev. Brain Res. 1990;56: 275–280. 32. Haas, K. Z., E. F. Sperber, and S. L. Moshé. Kindling in developing animals: Interactions between ipsilateral foci. Dev. Brain Res. 1992;68:140–143. 33. Hanaway, J., J. A. McConnel, and M. G. Netsky. Cytoarchitecture of the substantia nigra in the rat. Am. J. Anat. 1970; 129:417–438. 34. Hauser, W. A. Status epilepticus: Epidemiologic considerations. Neurology 1990;40:9–13. 35. Hauser, W. A. Status epilepticus: Frequency, etiology, and neurological sequelae. Adv. Neurol. 1983;34:3–14. 36. Heath, R. G. Brain function in epilepsy: Midbrain, medullary, and cerebellar interaction with the rostral forebrain. J. Neurol. Neurosurg. Psychiatry 1976;39:1037–1051. 37. Hill, D. R., and N. G. Bowery. 3H-baclofen and 3H-GABA bind to bicuculline insensitive GABAB sites in rat brain. Nature 1981;290:149–152. 38. Howse, D. C. Cerebral energy metabolism during experimental status epilepticus. In A. Delgado-Escueta, C. G. Wasterlain, D. M. Treiman, et al., eds. Status Epilepticus: Mechanisms of Brain Damage and Treatment. Adv. Neurol. 1983:209–216. 39. Iadarola, M. J., and K. Gale. Substantia nigra: Site of anticonvulsant activity mediated by g-aminobutyric acid. Science 1982;218:1237–1240. 40. Johnston G. A. R. Multiplicity of GABA receptors. In R. W. Olsen, and J. G. Venter, eds. Benzodiazepine/GABA Receptors and Chloride Channels. New York: Alan R. Liss, 1986:55–71. 41. Kammerer, R. A., S. Frank, T. Schulthess, R. Landwehr, A. Lustig, and J. Engel. Heterodimerization of a functional GABAB receptor is mediated by parallel coiled-coil alphahelices. Biochemistry 1999;38:13263–13269. 42. Kilpatrick, I. C., M. S. Starr, A. Fletcher, T. A. James, and N. K. MacLeod. Evidence for a GABAergic nigrothalamic pathway in the rat. I. Behavioural and biochemical studies. Exp. Brain Res. 1980;40:45–54. 43. Kim, J. S., I. J. Bak, R. Hassler, and Y. Okada. Role of g-aminobutyric acid (GABA) in the extrapyramidal motor system. 2. Some evidence for the existence of a type of GABA-rich strio-nigral neurons. Exp. Brain Res. 1971;14: 95–104. 44. Kondo, Y., and K. Iwatsubo. Increased release of preloaded [3H]GABA from substantia nigra in vivo following stimulation of caudate nucleus and globus pallidus. Brain Res. 1978;154:395–400. 45. Laurie, D. J., W. Wisden, and P. H. Seeburg. The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. J. Neurosci. 1992;12:4151–4172.
46. Le Gal La Salle, G., M. Kaijima, and S. Feldblum. Abortive amygdaloid kindled seizures following microinjection of g-vinyl-GABA in the vicinity of substantia nigra in rats. Neurosci. Lett. 1983;36:69–74. 47. Lee, V. W. K., D. M. de Kretser, B. Hudson, and C. Wang. Variations in serum FSH, LH and testosterone levels in male rats from birth to sexual maturity. J. Reprod. Fertil. 1975; 42:121–126. 48. Levitan, E. S., L. A. C. Blair, V. E. Dionne, and E. A. Barnard. Biophysical and pharmacological properties of cloned GABAA receptor subunits expressed in Xenopus oocytes. Neuron 1988;1:773–781. 49. Levitan, E. S., P. R. Schofield, D. R. Burt, L. M. Rhee, W. Wisden, M. Köhler, et al. Structural and functional basis for GABAA receptor heterogeneity. Nature 1988;335: 76–79. 50. Lothman, E. W., and R. C. Collins. Kainic acid induced limbic seizures: Metabolic, behavioral, electroencephalographic and neuropathological correlates. Brain Res. 1981; 218:299–318. 51. Lüddens, H., P. H. Seeburg, and E. R. Korpi. Impact of b and g variants on ligand-binding properties of g-aminobutyric acid type A receptors. Mol. Pharmacol. 1994;45:810–814. 52. MacLennan, A. J., N. Brecha, M. Khrestchatisky, C. Sternini, N. J. K. Tillakaratne, M. Y. Chiang, et al. Independent cellular and ontogenetic expression of mRNAs encoding three polypeptides of the rat GABAA receptor. Neuroscience 1991;43:369–380. 53. MacLeod, N. K., T. A. James, I. C. Kilpatrick, and M. S. Starr. Evidence for a GABAergic nigrothalamic pathway in the rat. II. Electrophysiological studies. Brain Res. 1980;40: 55–61. 54. May, P. J., and W. C. Hall. The sources of the nigrotectal pathway. Neuroscience 1986;19:159–180. 55. Maytal, J., and S. Shinnar. Status epilepticus in children. In S. Shinnar, N. Amir, and D. Branski, eds. Child Seizures. Basel: S. Krager, 1995:111–122. 56. McEwen, B. S. Non-genomic and genomic effects of steroids on neural activity. Trends Pharmacol. Sci. 1991;12:141–144. 57. McNamara, J. O., M. T. Galloway, L. C. Rigsbee, and C. Shin. Evidence implicating substantia nigra in regulation of kindled seizure threshold. J. Neurosci. 1984;4:2410–2417. 58. McNamara, J. O., L. C. Rigsbee, and M. T. Galloway. Evidence that the substantia nigra is crucial to the network of kindled seizures. Eur. J. Pharmacol. 1983;86:485–486. 59. Melis, M. R., and K. Gale. Effect of dopamine agonists on gamma-aminobutyric acid (GABA) turnover in the superior colliculus: Evidence that nigrotectal GABA projections are under the influence of dopaminergic transmission. J. Pharmacol. Exp. Ther. 1983;226:425–431. 60. Moshé, S. L. The effects of age on the kindling phenomenon. Dev. Psychobiol. 1981;14:75–81. 61. Moshé, S. L., and B. J. Albala. Maturational changes in postictal refractoriness and seizure susceptibility in developing rats. Ann. Neurol. 1983;13:552–557. 62. Moshé, S. L., and B. J. Albala. Nigral muscimol infusions facilitate the development of seizures in immature rats. Dev. Brain Res. 1984;13:305–308. 63. Moshé, S. L., B. J. Albala, R. F. Ackermann, and J. J. Engel. Increased seizure susceptibility of the immature brain. Dev. Brain Res. 1983;7:81–85. 64. Moshé, S. L., L. L. Brown, H. Kubová, J. Velísˇková, R. S. Zukin, and E. F. Sperber. Maturation and segregation of
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
brain networks that modify seizures. Brain Res. 1994;665: 141–146. Moshé, S. L., and E. F. Sperber. Substantia nigra-mediated control of generalized seizures. In G. Gloor, R. Kostopoulos, M. Naquet, et al., eds. Generalized Epilepsy: Cellular, Molecular and Pharmacological Approaches. Boston: Birkhauser, 1990: 355–367. 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. Nitsch, C., and R. Riesenberg. Immunocytochemical demonstration of GABAergic synaptic connections in rat substantia nigra after different lesions of the striatonigral projection. Brain Res. 1988;461:127–142. Oertel, W. H., M. L. Tappaz, A. Berod, and I. Mugnaini. Two-color immunohistochemistry for dopamine and GABA neurons in rat substantia nigra and zona incerta. Brain Res. Bull. 1982;9:463–474. Ojeda, S. R., and H. F. Urbanski. Puberty in the rat. In E. Knobil, and J. Neil, eds. The Physiology of Reproduction. 2nd ed. New York: Raven Press, 1994:363–409. Okada, Y. The role of GABA in the substantia nigra. In E. Roberts, T. N. Chase, and D. B. Tower, eds. GABA in Nervous System Function. New York: Raven Press, 1976:235–243. Okada, R., S. L. Moshé, B. Y. Wong, E. F. Sperber, and D. Zhao. Age-related substantia nigra–mediated seizure facilitation. Exp. Neurol. 1986;93:180–187. Okada, Y., C. Nitsch-Hassler, J. S. Kim, I. J. Bak, and R. Hassler. Role of gamma-aminobutyric acid (GABA) in the extrapyramidal motor system. 1. Regional distribution of GABA in rabbit, rat, guinea pig and baboon CNS. Exp. Brain Res. 1971;13:514–518. Pazdernik, T. L., R. S. Cross, M. Giesler, F. E. Samson, and S. R. Nelson. Changes in local cerebral glucose utilization induced by convulsants. Neuroscience 1985;14:823–835. Pereira de Vasconcelos, A., G. el Hamdi, P. Vert, and A. Nehlig. An experimental model of generalized seizures for the measurement of local cerebral glucose utilization in the immature rat. II. Mapping of the brain metabolism using quantitative [14C]-2-deoxyglucose technique. Dev. Brain Res. 1992;69:243–259. Piacsek, B. E., and M. P. Goodspeed. Maturation of the pituitary-gonadal system in the male rat., J. Reprod. Fertil. 1978;52:29–35. Redgrave, P., L. Marrow, and P. Dean. Anticonvulsant role of nigrotectal projection in the maximal electroshock model of epilepsy. II. Pathways from substantia nigra pars lateralis and adjacent peripeduncular area to the dorsal midbrain. Neuroscience 1992;46:391–406. Redgrave, P., M. Simkins, P. Overton, and P. Dean. Anticonvulsant role of nigrotectal projection in the maximal electroshock model of epilepsy. I. Mapping of dorsal midbrain with bicuculline. Neuroscience 1992;46:379–390. Saxena, N. C., and R. L. Macdonald. Properties of putative cerebellar gamma-aminobutyric acid A receptor isoforms. Mol. Pharmacol. 1996;49:567–579. Shehab, S., P. Dean, and P. Redgrave. The dorsal midbrain anticonvulsant zone. II. Efferent connections revealed by the anterograde transport of wheatgerm agglutinin–horseradish peroxidase from injections centered on the intercollicular area in the rat. Neuroscience 1995;65:681–695. Shin, C., J. M. Silver, D. W. Bonhaus, and J. O. McNamara. The role of substantia nigra in the development of kindling:
ˇ, , : -
377
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
378
Pharmacologic and lesion studies. Brain Res. 1987;412: 311–317. Sigel, E., R. Baur, G. Trube, H. Mohler, and P. Malherbe. The effect of subunit composition of rat brain GABAA receptors on channel function. Neuron 1990;5:703–711. Smith, Y., and J. P. Bolam. Neurons of the substantia nigra reticulata receive a dense GABA–containing input from the globus pallidus in the rat. Brain Res. 1989;493: 160–167. Sperber, E. F., L. L. Brown, and S. L. Moshé. Functional mapping of different seizure states in the immature rat using 14 C-2-deoxyglucose. Epilepsia 1992;33:44. Sperber, E. F., and S. L. Moshé. Age-related differences in seizure susceptibility to flurothyl. Dev. Brain Res. 1988;39: 295–297. Sperber, E. F., B. Y. Wong, J. N. Wurpel, and S. L. Moshé. Nigral infusions of muscimol or bicuculline facilitate seizures in developing rats. Brain Res. 1987;465:243–250. Sperber, E. F., J. N. D. Wurpel, and S. L. Moshé. Evidence for the involvement of nigral GABAB receptors in seizures in rat pups. Dev. Brain Res. 1989;47:143–146. Sperber, E. F., J. N. D. Wurpel, D. Y. Zhao, and S. L. Moshé. Evidence for the involvement of nigral GABAA receptors in seizures of adult rats. Brain Res. 1989;480:378–382. Thompson, K., V. Anantharam, S. Behrstock, E. Bongarzone, A. Campagnoni, and A. J. Tobin. Conditionally immortalized cell lines, engineered to produce and release GABA, modulate the development of behavioral seizures. Exp. Neurol. 2000;161:481–489. Turski, L., E. A. Cavalheiro, M. Sieklucka-Dziuba, C. Ikonomidou-Turski, S. J. Czuczwar, and W. A. Turski. Seizures produced by pilocarpine: Neuropathological sequelae and activity of glutamate decarboxylase in the rat forebrain. Brain Res. 1986;398:37–48. Velísˇková, J., D. S. Garant, S.-G. Xu, and S. L. Moshé. Further evidence of involvement of substantia nigra GABAB receptors in seizure suppression in developing rats. Dev. Brain Res. 1994;79:297–300. Velísˇková, J., H. Kubová, L. K. Friedman, R. Wu, E. F. Sperber, R. S. Zukin, and S. L. Moshé. The expression of GABAA receptor subunits in the substantia nigra is developmentally regulated and region-specific. Ital. J. Neurol. Sci. 1998;19:205–210. Velísˇková, J., W. Löscher, and S. L. Moshé. Regional and age specific effects of zolpidem microinfusions in the substantia nigra on seizures. Epilepsy Res. 1998;30:107–114. Velísˇková, J., and S. L. Moshé. Sexual dimorphism and developmental regulation of substantia nigra function. Ann. Neurol. 2001;50:596–601. Velísˇková, J., L. Velísˇek, M. L. Nunes, and S. L. Moshé. Developmental regulation of regional functionality of substantia nigra GABAA receptors involved in seizures. Eur. J. Pharmacol. 1996;309:167–173. Verdoorn, A., A. Draguhn, S. Ymer, P. H. Seeburg, and B. Sakmann. Functional properties of recombinant rat GABAA receptors depend upon subunit composition. Neuron 1990;4: 919–928. Vincent, S. R., T. Hattori, and E. G. McGeer. The nigrotectal projection: A biochemical and ultrastructural characterization. Brain Res. 1978;151:159–164. Wada, J. A., and M. Sato. Generalized convulsive seizures induced by daily stimulation of the amygdala in cats. Neurology 1974;24:565–574.
:
98. Wahnschaffe, U., and W. Löscher. Effect of selective bilateral destruction of the substantia nigra on antiepileptic drug actions in kindled rats. Eur. J. Pharmacol. 1990;186:157–167. 99. Wahnschaffe, U., and W. Löscher. Selective bilateral destruction of substantia nigra has no effect on kindled seizures induced from stimulation of amygdala or piriform cortex in rats. Neurosci. Lett. 1990;113:205–210. 100. Waszczak, B. L., N. Eng, and J. R. Walters. Effects of muscimol and picrotoxin on single unit activity of substantia nigra neurons. Brain Res. 1980;188:185–197. 101. 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. 102. Wisden, W., and P. Seeburg. GABAA receptor channels: from subunits to functional entities. Curr. Opin. Neurobiol. 1992;2: 263–269. 103. Wurpel, J. N. D., A. Tempel, E. F. Sperber, and S. L. Moshé. Age-related changes of muscimol binding in the substantia nigra. Dev. Brain Res. 1988;43:305–308. 104. Xu, S. G., D. S. Garant, E. F. Sperber, and S. L. Moshé. Effects of substantia nigra g-vinyl-GABA infusions on flurothyl seizures in adult rats. Brain Res. 1991;566:108–114. 105. Xu, S. G., D. S. Garant, E. F. Sperber, and S. L. Moshé. The proconvulsant effect of nigral infusions of THIP on flurothylinduced seizures in rat pups. Dev. Brain Res. 1992;68:275–277.
30
Developmental Differences in Seizure Susceptibility and Hippocampal Vulnerability: Molecular Correlates
. .
Increased seizure susceptibility in the immature brain Epilepsy is the third most common neurologic disorder and the one with the highest incidence of seizures occurring early in life (41). In experimental epilepsy, a seizure results from an imbalance between excitation and inhibition (5). A possible explanation is that the excitatory postsynaptic potentials (EPSPs) are dominant, leaving the countereffect of inhibitory postsynaptic potentials (IPSPs) relatively inoperable (60, 83, 84). Another possibility, suggested by Sloviter (84), is that inhibitory synaptic inputs are impeded or nonfunctional during a seizure because of dormancy of interneurons and their disconnection from glutamatergic afferents. However, it has since been directly demonstrated that GABAergic inhibition in hippocampal interneurons is operative and only partly reduced in two seizure models of temporal lobe epilepsy (20). Moreover, lack of inhibitory drive cannot be the only explanation for elicitation of asynchronous activity. This is because the period of maximal seizure susceptibility does not coincide with the first postnatal week, when inhibition is minimal or lacking, but instead occurs just prior to the second week and continuing on into the third week of postnatal life, when inhibitory events are reaching maturity (6, 15, 49, 51, 54, 93). In contrast to the mature brain, the immature brain is highly susceptible to epileptiform activity (2, 62, 68) and status epilepticus (SE) (1, 13, 43, 86, 101, 104). Early studies in neonatal kittens showed that increased seizure susceptibility occurs during a critical window of development, because immature neocortical neurons have high input resistance and hence larger currents (68). Other factors that may lead to developmentally regulated changes in seizure susceptibility include (1) the extent of axonal myelination, which affects communication among cells (78); (2) the existence of electrotonic junctions or ephaptic influences to facilitate neuronal synchronization (78); and (3) the delayed
maturation of glia, which may result in accumulation of potassium in the extracellular space and lead to general hyperexcitability (62). Studies of the immature hippocampus show that expression of inhibitory events in CA1 neurons is delayed. During the first 2 weeks of life, both orthodromic and antidromic stimulation produce only EPSPs, whereas hyperpolarizing IPSPs first appear at 10–14 days of age (78, 79, 94, 96, 97). The apical dendrites of CA1 pyramidal neurons are most sensitive to N-methyl--aspartate (NMDA), expressed by large influxes of calcium, during the same critical window for epileptogenesis (second to third postnatal weeks) (39). As the brain matures, the sensitivity of CA1 apical dendrites to NMDA decreases and is similar to responses elicited by dendrites before this critical window. Lowering extracellular calcium levels in young animals can also induce spontaneous paroxysmal activity (2). In accordance with neurophysiologic observations, electron microscopy of the CA1 subregion in rabbit brain reveals few or no symmetric synapses, which have been associated with inhibition in adult animals, until the second and third weeks of development (80). The developmental window of increased epileptogenesis is also evident within CA3 neurons. For example, IPSPs in CA3 develop by the end of the first postnatal week, 1 week earlier than in the CA1 area. Between the second and third postnatal weeks, CA3 is also more prone to epileptiform discharges relative to CA1 (78, 79, 96). Physiologic experiments in slices prepared from the immature hippocampus show that excitation is predominantly mediated by GABAA receptors (6, 15). In contrast, in adult slices, application of GABA antagonists (such as penicillin) produce prolonged interictal but not ictal activities (92, 93, 95). It has also been postulated that increased seizure susceptibility during the critical window reflects a transitory enhancement of excitation rather than a lack of inhibition (96). These in vitro studies support the conjecture that epileptic activity is developmentally regulated.
:
379
To determine whether brain damage early in life increases seizure susceptibility later in life, Sperber and colleagues produced bilateral CA3 lesions in 14-day-old rat pups by radiofrequency stimulation (unpublished observations). After rats matured, they were kindled using a rapid kindling procedure (stimulated at 20-minute intervals). This resulted in a higher kindling stage in lesioned rats than in nonlesioned rats. Similarly, longer afterdischarge durations were observed with increasing stimulation trials (88). A higher susceptibility to seizures and damage was also found in immature rats with hippocampal and cortical neuronal migration disorders, experimentally induced by prenatal exposure to methylazoxymethanol acetate (3, 36). Therefore, if brain damage occurs postnatally, either by direct injury or by in utero chemomanipulation, young rats are more prone to seizures and premature damage.
age 2–3 weeks (74, 75), but other studies suggest that these reported changes in morphology may be transitory (14, 63) or may depend on the severity or number of seizure episodes. Hence, despite severe experimental conditions, damage still emerges according to a developmental profile in which damage increases with age. Thus, the immature brain is still resistant to seizure-induced damage even under highly adverse seizure conditions. Interestingly, seizures induced by more than one injection of kainate at different maturational stages may either exacerbate injury (50, 76) or protect neurons from dying (48). Protection appears to depend on the timing and extent of the first seizure episode (48; Liu et al., unpublished observations).
Resistance of the immature brain to seizure-induced neuronal cell loss
A number of factors may lead to periods of reduced or increased neuronal vulnerability during development. Maturation of postnatal synaptic connections and synaptic reorganization of glutamatergic and GABAergic anatomic pathways may result in age-dependent differences. In the hippocampus, glutamatergic afferents between the dentate gyrus and CA3 (67) and between the entorhinal cortex and the molecular layer of the dentate gyrus (22) reach maturity after the second postnatal week. SE-induced CA3 damage first appears following maturation of these connections (63, 101). The adult pattern of neurodegeneration is not reached until the end of the third postnatal week. Synaptic reorganization and sprouting of mossy fibers are also first detectable only after 3 weeks of postnatal development and seizures (70). In addition, excitatory and inhibitory amino acid receptor expression significantly alters with age (55, 56). [3H]Kainate and [3H]AMPA (a-amino-3-hydroxy-5-methyl4-isoxazole-propionic acid) binding-site densities increase from birth to the second to third postnatal week, after which they decline to adult levels, further indicating an agedependent sensitivity to glutamate (7, 8, 57). The genes encoding AMPA, NMDA, and GABA receptors are also developmentally regulated. GluR1 and GluR2 mRNA is expressed at near adult levels early in development, rises steadily until the third postnatal week, then declines to adult levels. GluR3 is below adult levels at birth, rises to a peak during the second to third postnatal week, and then declines to adult levels (59, 66, 89). GABAA a1 is low at birth, then rises gradually to adult levels by 12 days of age (31). RNA editing of the GluR2 subunit is not significantly altered with development (12). Taken together, these observations further support the existence of critical periods of elevated receptor numbers with various subunit combinations that presumably can influence glutamate neurotoxicity.
After a single injection of kainic acid (28, 43, 63, 86) or pilocarpine (13, 73) and flurothyl vapor exposure (87, 105), pups are resistant to cell loss until the postnatal weeks 3–4. For example, 24 hours after a single kainate injection, silver impregnation assay showed that pyramidal neurons of 1and 2-week-old rat pups had regular-shaped cell bodies and nuclei without argyrophilia (28, 34) (Figure 30.1). In contrast, in adult brains, intense silver deposits had accumulated within many CA3 neurons after kainate-induced seizures at the same time point. Silver-stained neurons were dystrophic, shrunken, and irregularly shaped, with intense labeling of proximal and distal dendritic processes. Mossy fiber synaptic reorganization is also age-related (69, 90, 91). In adult rats, new mossy fiber collaterals are observed after kainateinduced SE (17, 86, 98), kindling (90), and pentylenetetrazole administration (37). In 2-week-old rat pups, synaptic reorganization is absent following kainate (86) or flurothyl (87, 88) injections. Timm staining is not observed in the supragranular layer, a further demonstration of the resistance of the immature brain to seizure-induced hippocampal damage and sprouting. Similarly, repeated kindling in P16 rats results in no cell loss or detectable synaptic rearrangement (39). If, however, seizure conditions are very severe in the immature brain, such as prolonged electrical stimulation of the perforant path (for 16 hours) (100), or if SE is maintained by corticotropin release hormone (4) or lithium-pilocarpine (74, 75), neuronal injury, usually within the CA1 subfield, is readily detectable. Injury and cell loss have been observed after kainate infusion in the developing brain after a longer delay, but much less so than in adults (39). Different types of acute neuronal injury can occur after pilocarpine infusion at
380
:
Potential factors involved in age-dependent seizure-induced damage
F 30.1 Photomicrographs of silver impregnation stains (left) and Timm stain (right) of postnatal (P)14 and adult CA3 pyramidal neurons 24 hours after induction of kainate SE. (A and B) In pups, silver impregnation stains revealed no detectable neuronal damage (clear arrows in A), whereas many CA3 neurons in adult sections exhibited intense silver labeling (arrows in B), indicative of neurodegeneration. (C and D) In pups, the Timm stain revealed no
detectable synaptic reorganization (arrowheads in C), whereas heavy Timm staining was apparent in the supragranular layer of adult sections (small arrowheads in D), indicative of mossy fiber sprouting. Scale bar = 50 mm. (Modified with permission from Friedman et al. [28] and Sperber et al. [86], © 1997 by S. Karger and © 1991 by Elsevier Science, respectively.)
The role of AMPA receptors in delayed cell death
delayed reduction in GluR2 subunit expression may enhance glutamate excitotoxicity within a given population of cells due to rises in cytosolic Ca2+ mediated through AMPA receptor homomeric or heteromeric assemblies (e.g., GluR1, GluR3, or GluR4)—the GluR2 hypothesis (24–26, 28, 29, 102). This hypothesis was supported by our earlier molecular studies. In adult rats, kainate-induced SE resulted in pronounced decreases in GluR2 mRNA (29) (Figure 30.2) and protein within the vulnerable CA3 subregion but prior to cell loss (24). Our study of kainate-induced seizures in development also supported the GluR2 hypothesis, because at young
It is widely accepted that sustained increases in intracellular Ca2+ after prolonged seizures initiate a series of events that will lead to neuronal cell loss (16, 18, 72, 82). NMDA-type glutamate receptors were thought to be responsible for the delayed neuronal injury due to rises in Ca2+ permeability conductance properties. Now, however, AMPA receptors (encoded by a gene family designated GluR1 to GluR4) (9, 103) are also thought to be involved in the pathology because AMPA-type glutamate receptors that lack the GluR2 subunit are highly permeable to Ca2+ (11, 35, 42, 99, 103). Thus, a
:
381
382 : F 30.2 (A–F, left) In situ hybridization autoradiographs of P14 rat pups depicting GluR1, GluR2, and GluR3 receptor RNA probes to coronal sections. GluR1 (A, B) and GluR2 (C, D) mRNAs were unchanged in the CA3 but markedly increased in the dentate gyrus 24 hours after SE induction. GluR3 (E, F), receptor mRNA was unchanged throughout the hippocampus. (A–F, right) Autoradiographs of GluR1, GluR2, and GluR3 mRNAs in control and SE adult rats 24 hours after the onset of SE. Autoradiographs were obtained at the level of the hippocampus. GluR1, GluR2, and
GluR3 mRNA levels are shown from the same experimental animal. (A and B) GluR1 mRNA levels were not detectably altered in any region. (C–F) GluR2 and GluR3 expression were markedly increased in the dentate gyrus and were decreased in CA3 (between left two arrows) and further decreased in CA4 (between second and third arrows). Control sections are shown on the left, experimental SE sections on the right. (Modified with permission from Friedman et al. [26, 28], © 1994 by the Society for Neuroscience and © 1997 by S. Karger, respectively.)
ages, rat pups that are relatively resistant to CA3 damage do not show decreases in GluR2 mRNA or protein expression (28) (Figure 30.2). In keeping with this observation, unilateral hippocampal knockdown of the GluR2 subunit in young rats results in electrographic paroxysmal activity and CA3 neurodegeneration during a period of high seizure susceptibility but at an age when they are still resistant to seizure-induced cell death (25, 29). However, it should also be noted that neurons of CA1 and the dentate gyrus were spared, and CA3 cell loss was observed only in animals exhibiting spontaneous seizures. In adult rats, in the absence of seizures, knockdown of the GluR2 subunit within a single hippocampus is insufficient to induce neuronal cell death (25, 30). In addition, in adult rats, kainic acid administered after GluR2 knockdown only accentuated the already known pattern of CA3/hilar injury; CA1 and DG regions were spared (30). Thus, the attempt to abolish regional differences in hippocampal vulnerability before induction of seizures in the mature animal was unsuccessful, suggesting that loss of GluR2 subunits may not be responsible for the delayed injury or that loss of GluR2 subunits may have a regional effect on CA3 neurotoxicity. Accordingly, Seeburg and co-workers (1995 and 1997) showed that mutation of the GluR2 RNA editing mechanism (but not the overall level of GluR2 mRNA expressed) increases AMPA-mediated Ca2+ influx throughout the brain. However, only selective CA3 hippocampal neurodegeneration results after mutant mice develop spontaneous seizures (10, 21). Similarly, the GluR2 editing-deficient mutant mice (neo/neo) with the highest Ca2+ permeability were lethargic and developmentally retarded, but they did not exhibit seizures or neurodegeneration, suggesting that high Ca2+ concentrations were not responsible for the damage (21). In addition, GluR2 mutants with only 30% GluR2 editing deficiency and twofold increases in AMPAmediated Ca2+ influx did not exhibit hippocampal pathophysiology (47). Thus, a functional role for the GluR2 subunit in excitotoxicity appears to depend on the age of the animal and the population of neurons that is involved in the epileptic seizure. It is suggested that changes in Ca2+ permeability may not be the critical component causing selective cell death. To directly test the effects of shifting the GluR1/GluR2 subunit ratio on Ca2+ permeability and excitotoxicity, GluR2 antisense deoxyoligonucleotides (AS-ODNs) were applied to dissociated hippocampal cultures. Immunocytochemistry showed that exposure of the GluR2 AS-ODNs for 2–3 days was sufficient to significantly reduce GluR2 but not GluR1 protein expression, and the neurons looked healthy, with normal morphology (Figure 30.3A). In AS-ODN controls after 3 days of GluR2 AS-ODN exposure, GluR1 immunoreactive neurons were intensely labeled and had healthy, long, matured processes (Figure 30.3A). These findings
were indistinguishable from those of control untreated cultures that were changed to defined medium. Intracellular Ca2+ imaging was carried out to determine whether a transient decrease in GluR2 synthesis induced by GluR2 AS-ODNs would cause a detectable increase in AMPA receptor-mediated Ca2+ permeability alone or in response to brief excitotoxin applications (27). Basal Ca2+ levels were unchanged, but [Ca2+]i was selectively increased by agonist stimulation of AMPA receptors (27). However, contrary to our expectations, little difference in cell viability was observed with kainate (100 mM) (Figure 30.3B) or with the other excitotoxins at any concentration, despite loss of GluR2 subunits. In addition, delayed neurotoxicity was unaltered at low doses and attenuated at saturating doses of glutamate (Figure 30.3C). Therefore, rises in AMPA receptor-mediated Ca2+ influx were not associated with neurotoxicity, despite marked decreases in GluR2 immunoreactivity. Thus, under certain conditions, a modification of AMPA receptor stochiometry that raises agonist-stimulated Ca2+ influx during an excitotoxic insult may have eventual neuroprotective effects.
Role of enkephalins in delayed cell death Endogenous opioid neuropeptides, such as the enkephalins, are thought to function as neurotransmitters or neuromodulators in the central nervous system (CNS) and are involved in a number of physiologic functions such as pain and analgesia, stress, anxiety, and sexual behavior (45, 46). In young and adult animals, the putative opioid precursor mRNA, preproenkephalin (PPE), is predominantly expressed in the striatum, whereas relatively low mRNA levels are detected in the hippocampus (106–108). The distribution of enkephalin pentapeptides is different from that of PPE mRNA expression such that enkephalin-like immunoreactivity is moderately expressed in (1) the mossy fiber axons of the dentate granule cells, which predominantly innervate CA3 pyramidal cells, and (2) perforant path axons, which arise from entorhinal and piriform cortex and innervate both dentate granule and pyramidal neurons (31). In adult rats, several models of limbic seizures result in a rapid increase in PPE mRNA expression in the dentate gyrus (19, 40, 52, 58, 71). Mossy fiber enkephalin-like immunoreactivity also rises early after SE (33). Opioids are thought to modulate neurotransmission predominantly by presynaptic actions, resulting in reduced excitatory neurotransmitter release and suppressed neuronal firing (44, 61, 64, 65). To investigate another molecular mechanism that may contribute to the resiliency of immature brain to seizureinduced damage, the regional distribution of PPE mRNA expression was compared at two ages (P14 pups and adult rats) (23). In contrast to adults, pups exhibited pronounced increases in the expression of PPE mRNA in CA3 and in
:
383
F 30.3 Photomicrographs depicting GluR2 knockdown in dissociated hippocampal neurons. (A) After 3 days of sense application, GluR2 immunolabeled protein was intense and uniform (A). After 3 days of GluR2 antisense application, GluR2 protein was significantly decreased (B), whereas GluR1 protein was sustained at control levels (C). (B) Cell viability counting with trypan blue showed that no change in neurotoxicity after GluR2 (B) knockdown
and 100 mM kainate injection. (C) Neurotoxicity was reduced at high but not low doses of glutamate after GluR2 knockdown. Data represent means ± SEM of MTT mean values at 570 nm, quantified from control and experimental hippocampal cultures. *P < 0.05, **P < 0.01 by one-way ANOVA. (Adapted with permission from Friedman et al. [27].) (See Color Plate 7.)
interneurons of CA1 and the dentate gyrus, as determined by in situ hybridization (Figure 30.4). Marked increases in enkephalin neuropeptide synthesis in immature CA3 neurons may reduce glutamate release presynaptically and also prevent voltage-gated Ca2+ uptake into these neurons despite recurrent seizure activity. Since mature CA3 neurons do not upregulate PPE mRNA after SE, a reduction in presynaptic release of glutamate would not be sufficient to protect against postsynaptic mechanisms involved in the CA3 delayed cell death process. Because rat pups do synthesize extraordinary amounts of PPE mRNA in CA3 and moderate amounts in dentate gyrus, it is possible that the combined effects of presynaptic inhibition of glutamate release from granule cells and direct block of voltagedependent Ca2+ conductance on CA3 neurons postsynaptically may be required to protect neurons from seizure-induced damage that may result from overaccumu-
lations of Ca2+. Thus, opioid-mediated inhibition may also provide an explanation for the resistance of the immature CA3 region to seizure-induced damage.
384
:
Summary Although the immature brain is highly susceptible to seizures, it is relatively resistant to seizure-induced neuronal cell loss. Possible explanations for this paradox implicate a number of endogenous physiologic and biological mechanisms that emerge during development. Furthermore, a number of genes from the AMPA receptor and opioid systems may influence seizure-induced cell death due to cellspecific and age-dependent alterations consequent on SE. This work was supported by the Epilepsy Foundation of America (grant No. 9526-2431) and March of Dimes (grant No. FY 950097-2469), and by grants No. NS-38069
F 30.4 Autoradiographs of PPE mRNA expression at the level of the hippocampus 5–6 hours after SE induction in P14 and adult rats. (A) PPE expression in control pup brain. (B) In pups, a striking rise in PPE mRNA was observed in CA3a-c and in interneurons (arrows) of CA1 stratum radiatum and
pyramidale; increased expression was also noted in P14 dentate gyrus. (C) PPE expression in control adult hippocampus. (D) Increased phenotypic expression of PPE mRNA in adult dentate granule cells. (Reprinted with permission from Friedman [23], © 1997 by Elsevier Science.)
(L.K.F.) and No. NS 30387 (E.F.S.) from the National Institutes of Health. Earlier studies were also supported by grant No. NS 20253 (Solomon L. Moshé).
7. Berger, M. L., and Y. Ben-Ari. Autoradiographic visualization of [3H] kainic acid receptor subtypes in the rat hippocampus. Neurosci. Lett. 1983;39:237–240. 8. Berger, M. L., E. Tremblay, L. Nitecka, and Y. Ben-Ari. Maturation of kainic acid seizure brain damage syndrome in the rat. III. Postnatal development of kainic acid binding sites. Neuroscience 1984;13:1095–1104. 9. Bettler, B., and C. Mulle. Review: Neurotransmitter receptors. II. AMPA and kainate receptors. Neuropharmacology 1995; 34:123–139. 10. Brusa, R. F., 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 GluR-B allele in mice. Science 1995;270:1677–1680. 11. Burnashev, N., A. Khodorova, P. Jonas, P. J. Helm, W. Wisden, H. Monyer, et al. Calcium-permeable AMPA-kainate receptors in fusiform cerebellar glial cells. Science 1992;256: 1566–1570. 12. Burnashev, N., H. Monyer, P. H. Seeburg, and B. Sakmann. Divalent ion permeability of AMPA receptor channels is dominated by the edited form of a single subunit. Neuron 1992;8:189–198. 13. Cavalheiro, E. A., D. F. Silva, W. A. Turski, L. S. CalderazzoFilho, Z. Bartolotto, and L. Turski. The susceptibility of rats to pilocarpine-induced seizures is age dependent. Dev. Brain Res. 1987;37:43–58.
REFERENCES 1. Albala, B. J., S. L. Moshé, and R. Okada. Kainic-acidinduced seizures: A developmental study. Dev. Brain Res. 1984; 13:139–148. 2. Albrecht, D., and U. Heinemann. Low calcium–induced epileptiform activity in hippocampus slices from infant rats. Dev. Brain Res. 1989;48:316–320. 3. Baraban, S. C., and P. A. Schwartzkroin. Flurothyl seizure susceptibility in rats following prenatal methylazoxymethanol treatment. Epilepsy Res. 1996;23:189–194. 4. Baram, T. Z., and C. E. Ribak. Peptide-induced infant status epilepticus causes neuronal death and synaptic organization. Neuroreport 1995;6:277–280. 5. Ben-Ari, Y., K. Krnjevic, and W. Reinhardt. Hippocampal seizures and failure of inhibition. Can. J. Physiol. Pharmacol. 1979;57:1462–1466. 6. Ben-Ari, Y., R. Khazipov, X. Leinekugel, O. Caillard, and J. L. Gaiarsa. GABAA, NMDA and AMPA receptors: A developmentally regulated “ménage à trois.” Trends Neurosci. 1997;20:523–529.
:
385
14. Chang, D., and T. Z. Baram. Status epilepticus results in reversible neuronal injury in infant rat hippocampus: Novel use of a marker. Dev. Brain Res. 1994;77:133–136. 15. Cherubini, E., C. Rovira, J. L. Gaiarsa, R. Corradetti, and Y. Ben-Ari. GABA mediated excitation in immature rat CA3 hippocampal neurons. Int. J. Dev. Neurosci. 1990;8:481–490. 16. Choi, D. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1988;1:623–634. 17. Cronin, J., and F. E. Dudek. Chronic seizure and collateral sprouting of dentate mossy fibers after kainic acid treatment in rats. Brain Res. 1988;474:181–184. 18. Dingledine, R., C. J. McBain, and J. O. McNamara. Excitatory amino acid receptors in epilepsy. Trends. Pharmacol 1990; 11:334–338. 19. Douglass, J., L. Grimes, J. Shook, P. Lee, and J. S. Hong. Systemic administration of kainic acid differentially regulates the levels of prodynorphin and proenkephalin mRNA and peptides in the rat hippocampus. Mol. Brain Res. 1991;9: 79–86. 20. Esclapez, M., J. C. Hirsch, R. Khazipov, Y. Ben-Ari, and C. Bernard. Operative GABAergic inhibition in hippocampal CA1 pyramidal neurons in experimental epilepsy. Proc. Natl. Acad. Sci. U.S.A. 1997;94:12151–12156. 21. Feldmeyer, D., K. Kask, R. Brusa, H. C. Kornau, R. Kolhekar, N. Burnashev, 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. 22. Fricke, R., and W. M. Cowan. An autoradiographic study of the development of the entorhinal and commissural afferents to the dentate gyrus of the rat. J. Comp. Neurol. 1977;173: 231–250. 23. Friedman, L. K. Developmental switch in phenotypic expression of preproenkephalin mRNA and 45Ca2+ accumulation following kainate-induced status epilepticus. Dev. Brain Res. 1997;101:287–293. 24. Friedman, L. K. Selective reduction of GluR2 protein in adult hippocampal CA3 neurons following status epilepticus but prior to cell loss. Hippocampus 1998;8:511–525. 25. Friedman, L. K., and A. R. Koudinov. Unilateral GluR2(B) hippocampal knockdown: A novel partial seizure model in the developing rat. J. Neurosci. 1999;19:9412–9425. 26. Friedman, L. K., D. E. Pellegrini-Giampietro, E. F. Sperber, M. V. L. Bennett, S. L. Moshé, and R. S. Zukin. Kainateinduced status epilecticus alters glutamate and GABAA receptor gene expression in adult rat hippocampus: An in situ hybridization study. J. Neurosci. 1994;14:2697–2707. 27. Friedman, L. K., M. Segal, and J. Velísˇková. GluR2(B) knockdown reveals a dissociation between [Ca2+]i surge and neurotoxicity. Neurochem. Int. 2003;1318:1–11. 28. Friedman, L. K., E. F. Sperber, S. L. Moshé, M. V. L. 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. 29. Friedman, L. K., and J. Velísˇková. GluR2 hippocampal knockdown reveals developmental regulation of epileptogenicity and neurodegeneration. Mol. Brain Res. 1998;61: 224–231. 30. Friedman, L. K., J. Velísˇková, J. Kaur, D. W. Magrys, and H. Liu. GluR2(B) knockdown accelerates CA3 injury after status epilepticus. J. Exp. Neurol. Neuropathol. 2003;62:733–750. 31. Fritschy, J. M., J. Paysan, A. Enna, and H. Mohler. Switch in the expression of rat GABAA-receptor subtypes during post-
386
:
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
natal development: An immunohistochemical study. J. Neurosci. 1994;14:5302–5324. Gall, C. M. Localization of enkephalin immunoreactivity to identified axonal and neuronal populations in the rat hippocampus. J. Comp. Neurol. 1981;198:335–350. Gall, C. M. Seizures induce dramatic and distinctly different changes in enkephalin, dynorphin and CCK immunoreactivities in mouse hippocampal mossy fibers. J. Neurosci. 1988;8:1852–1862. Gallyas, F., J. R. Wolff, W. H. Böttcher, and L. Zaborszky. A reliable and sensitive method to localize terminal degeneration and lysosomes in the central nervous system. Stain Technol. 1980;55:299–306. Geiger, J. R., T. Melcher, D. S. Koh, B. Sackmann, P. H. Seeburg, P. Jonas, and H. Monyer. Relative abundance of subunit mRNAs determines gating and Ca2+ permeability of AMPA receptors in principal neurons and interneurons. Neuron 1995;15:193–204. Germano, I. M., and E. F. Sperber. Transplacentally induced neuronal migration disorders: An animal model for the study of the epilepsies. J. Neurosci. Res. 1998;51:473–488. Golarai, G., J. E. Cavazos, and T. P. Sutula. Activation of the dentate gyrus by pentylenetetrazol-evoked seizures induces mossy fiber synaptic reorganization. Brain Res. 1992;593: 257–264. Haas, K. Z., E. F. Sperber, L. A. Opanashuk, P. K. Stanton, and S. L. Moshé. Resistance of immature hippocampus to morphologic and physiologic alterations following status epilepticus or kindling. Hippocampus 2001;11:615–625. Hamon, B., and U. Heinemann. Developmental changes in neuronal sensitivity to excitatory amino acids in area CA1 of the rat hippocampus. Brain Res. 1988;466:286–290. Harrison, M. B., M. D. Shumate, and E. W. Lothman. Opioid peptide expression in models of chronic temporal lobe epilepsy. Neuroscience 1995;65:785–795. Hauser, W. A., and L. T. Kurland. The epidemiology of epilepsy in Rochester, Minnesota, 1935–1967. Epilepsia 1975; 16:1–66. Hollman, M., M. Hartley, and S. Heinemann Ca2+ permeability of KA-AMPA-gated glutamate receptor channels depends on subunit composition. Science 1991;253:1028– 1031. Holmes, G. L., and J. L. Thompson. Effects of kainic acid on seizure susceptibility in the developing brain. Dev. Brain Res. 1988;39:51–59. Hori, Y., E. Katsuaki, and T. Takahashi. Presynaptic inhibitory action of enkephalin excitatory transmission in superficial dorsal horn of rat spinal cord. J. Physiol. 1992;450: 673–685. Howlette, T. H., and L. H. Rees. Endogenous opioid peptides and hypothalamo-pituitary function. Annu. Rev. Physiol. 1986; 48:527–536. Imura, I., Y. Kato, Y. Naki, K. Nako, and I. Tanaka. Endogenous peptides and related peptides: From molecular biology to clinical psychology. J. Endocrinol. 1985;107:147–157. Kask, K., D. Zamanillo, N. Burnashev, R. Sprengel, and P. H. Seeburg. The AMPA receptor subunit GluR-B in its Q/R site-unedited form is not essential for brain development and function. Proc. Natl. Acad. Sci. U.S.A. 1998; 95:13777–13782. Kelly, M. E., and D. C. McIntyre. Hippocampal kindling protects several structures from the neuronal damage resulting from kainic acid–induced status epilepticus. Brain Res. 1994;634:245–256.
49. Khazipov, R., X. Leinekugel, I. Khalailov, J. L. Gaiarsa, and Y. Ben-Ari. Synchronization of GABAergic interneuron network in CA3 subfield of neonatal rat hippocampus. J. Physiol. 1997;498:763–772. 50. Koh, S., T. W. Storey, T. C. Santos, A. Y. Mian, and A. J. Cole. Early-life seizures in rats increase susceptibility to seizureinduced brain injury in adulthood. Neurology 1999;53: 915–921. 51. Kriegstein, A. R., T. Suppes, and D. A. Prince. Cellular and synaptic physiology and epileptogenesis of the developing rat neocortical neurons in vitro. Dev. Brain Res. 1987;34:161–171. 52. Lasón, W., B. Przewlocka, and R. Przewlocki. The effects of excitatory amino acids on proenkephalin and prodynorphin mRNA levels in the hippocampal dentate gyrus of the rat: An in situ hybridization study. Mol. Brain Res. 1992;12: 243–247. 53. Laurie, D. J., W. Wisden, and P. H. Seeburg. The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. J. Neurosci. 1992;12:4151–4172. 54. Leinekugel, X., I. Medina, I. Khalailov, 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. 55. McDonald, J. W., and M. V. Johnston. Excitatory amino acid neurotoxicity in the developing brain. Res. Monogr. 1993;133: 185–205. 56. McDonald, J. W., and M. V. Johnston. Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res. Rev. 1990;15: 41–70. 57. Miller, L. P., A. E. Johnson, R. E. Gelhard, and T. R. Insel. The ontogeny of excitatory amino acid receptors in the rat forebrain. II. Kainic acid receptors. Neuroscience 1990;35: 45–51. 58. Moneta, M. E., and V. Hölt. Perforant path kindling induces differential alterations in the mRNA levels coding for prodynorphin and proenkephalin in the rat hippocampus. Neurosci. Lett. 1990;110:273–278. 59. Monyer, H., P. H. Seeburg, and W. Wisden. Glutamateoperated channels: Developmentally early and mature forms arise by alternative splicing. Neuron 1991;6:799–810. 60. Moshé, S. L., S. Koszer, S. Wolf, and M. Cornblath. Developmental aspects of epileptogenesis. In E. Wyllie, ed. The treatment of Epilepsy: Principles and Practice. 2nd ed. Baltimore: Williams & Willcins, 1997:139–150. 61. Mudge, A. W., S. E. Leeman, and G. D. Fischbach. Enkephalin inhibits release of substance P from sensory neurons in culture and decreases action potential duration. Proc. Natl. Acad. Sci. U.S.A. 1979;76:526–530. 62. Mutani, R., K. J. Futamachi, and D. A. Prince. Potassium activity in immature cortex. Brain Res. 1984;75:27–39. 63. 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. 64. North, R. A. Opioid actions on membrane ion channels. In A. Hertz, H. Akil, and E. J. Simon, eds. Handbook of Experimental Pharmacology. Berlin: Springer, 1993:773–797. 65. North, W., and J. T. Williams. How do opiates inhibit neurotransmitter release? Trends Neurosci. 1983;6:337–339. 66. Pellegrini, D. E., M. V. L. Bennett, and R. S. Zukin. Differential expression of three glutamate receptor genes in devel-
67.
68.
69.
70.
71.
72.
73. 74.
75.
76.
77.
78. 79.
80.
81.
82.
83.
84.
85.
oping brain: An in situ hybridization study. Proc. Natl. Acad. Sci. U.S.A. 1991;88:4157–4161. Pokorny, J., and T. Yamamoto. Postnatal ontogenesis of hippocampal CA1 area in rats. II. Development of ultrastructure in stratum lacunosum and moleculare. Brain Res. Bull. 1981;7:121–130. Purpura, D., R. Schoffer, and T. Scarff. Properties of synaptic activities and spike potential in immature neocortex. J. Neurophysiol. 1965;28:925–942. Repressa, A., E. Tremblay, and Y. Ben-Ari. Kainate binding sites in the hippocampal mossy fibers: Localization and plasticity. Neuroscience 1987;20:739–748. Ribak, C. E., and M. S. Navetta. An immature mossy fiber innervation of hilar neurons may explain their resistance to kainate-induced cell death in 15-day-old rats. Dev. Brain Res. 1994;79:47–62. Rosen, J. B., C. J. Cain, S. R. B. Weiss, and R. M. Post. Alterations in mRNA of enkephalin, dynorphin and thyrotropin release hormone during amygdala kindling: An in situ hybridization study. Mol. Brain Res. 1992;15:247–255. Rothman, S. M., and J. W. Olney. Delayed neurotoxicity of excitatory amino acids in vitro. Trends Neurosci. 1987;10: 290–302. Rothstein, J. D. Excitotoxicty hypothesis. Neurology 1996; 47(Suppl. 2):S19–S25. Sankar, R., D. H. Shin, H. Liu, A. Mazarati, A. Pereira de Vasconcelos, and C. G. Wasterlain. Patterns of status epilepticus–induced neuronal injury during development and longterm consequences. J. Neurosci. 1998;18:8383–8393. 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;282:129–136. Schmid, R., P. Tandon, C. E. Stafstrom, and G. L. Holmes. Effects of neonatal seizures on subsequent seizure-induced brain injury. Neurology 1999;53:1754–1761. Schreiber, S. S., and M. Baudry. Selective neuronal vulnerability in the hippocampus: A role for gene expression? Trends Neurosci. 1995;18:446–450. Schwartzkroin, P. A. Development of rabbit hippocamus: Physiology. Dev. Brain Res. 1982;2:469–486. Schwartzkroin, P. A. Epileptogenesis in the immature CNS. In P. A. Schwartzkroin, and H. V. Wheal, eds. Electrophysiology of Epilepsy. London: Academic Press, 1984:389–412. Schwartzkroin, P. A., D. D. Kunkel, and L. H. Mathers. Development of rabbit hippocampus: Anatomy. Dev. Brain Res. 1982;2:452–468. Shaw, P. J., and P. G. Ince. Glutamate excitotoxicity and amyotrophic lateral sclerosis. J. Neurol. 1997;244(Suppl. 2): S3–S14. Siesjö, B. K., and F. Bengtsson. Ca2+ fluxes, Ca2+ antagonists, and Ca2+-mediated pathology in brain ischemia, hypoglycemia, and spreading depression. J. Cereb. Blood Flow Metab. 1989;9:127–140. Sloviter, R. S. Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. Science 1987;253:73–76. Sloviter, R. S. Permanantly 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;1:44–66. Sperber, E. F., K. Z. Haas, M. T. Romero, and P. K. Stanton. Flurothyl status epilepticus in developing rats: Behavioral,
:
387
electrographic, histological, and electrophysiological studies. Brain Res. Dev. Brain Res. 1999;116:59–68. 86 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;60:88–93. 87. Sperber, E. F., and S. L. Moshé. Age-related differences in seizure susceptibility to flurothyl. Dev. Brain Res. 1988;39: 295–297. 88. Sperber, E. F., J. Velísˇková, I. M. Germano, L. K. Friedman, and S. Moshé. Age-dependent vulnerability to seizures. In A. V. Delgado, R. W. Olsen, and R. J. Wilson, eds. Basic Mechanisms for the Epilepsies. Third International Symposium. Adv. Neurol. 1999:161–169. 89. Standley, S., G. Tocco, M. F. Tourigny, G. Massicotte, R. F. Thompson, and M. Baudry. Developmental changes in aamino-3-hydroxy-5-methyl-4-isoxazole propionate receptor properties and expression in the rat hippocampal formation. Neuroscience 1995;67:881–892. 90. Sutula, T., H. Xiao-Xian, J. Cavazos, and S. Grayson. Synaptic reorganization in the hippocampus induced by abnormal functional activity. Science 1988;239:1147–1150. 91. Sutula, T., P. Zhand, M. Lynch, U. Sayin, G. Golarai, and R. Rod. Synaptic and axonal remodeling of mossy fibers in the hilus and supragranular region of the dentate gyrus in kainate-treated rats. J. Comp. Neurol. 1998;390: 578–594. 92. Swann, J. W., and R. J. Brady. Penicillin-induced epileptogenesis in immature rats CA3 hippocampal pyramidal cells. Dev. Brain Res. 1984;12:243–254. 93. Swann, J. W., R. J. Brady, R. J. Friedman, and E. J. Smith. The dendritic origins of penicillin-induced epileptogenesis in CA3 hippocampal pyramidal cells. J. Neurophysiol. 1986;56:1718–1738. 94. Swann, J. W., R. J. Brady, and D. L. Martin. Postnatal development of GABA mediated synaptic inhibition in rat hippocampus. Neuroscience 1989;28:551–562. 95. Swann, J. W., K. L. Smith, and R. J. Brady. Extracellular K+ accumulation during penicillin-induced epileptogenesis in the CA3 region of immature rat hippocampus. Dev. Brain Res. 1986;395:243–255. 96. 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. 97. Swann, J. W., K. L. Smith, and R. Brady. Neural networks and synaptic transmissions in immature hippocampus. In Y. Ben-Ari, ed. Excitatory Amino Acids and Neuronal Plasticity. Advances in Experimental Medicine and Biology. Putnam Press, 1990;161–171. 98. 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. 99. Tempia, F., K. Masanobu, R. Schneggenburger, C. Schirra, O. Garaschuk, T. Plant, and A. Konnerth. Fractional calcium current through neuronal AMPA-receptor channels with a low calcium permeability. J. Neurosci. 1996;16:456–466. 100. Thompson, K., and C. Wasterlain. Lithium-pilocarpine status epilepticus in the immature rabbit. Dev. Brain Res. 1997;100:1–4. 101. Tremblay, E., L. Nitecka, M. L. Berger, and Y. Ben-Ari. Maturation of kainic acid seizure-brain damage syndrome in
388
:
102.
103.
104. 105.
106.
107.
108.
the rat: Clinical, electrographic and metabolic observations. Neuroscience 1984;13:1051–1072. Vandenberghe, W., W. Robberecht, and J. R. Brorson. AMPA receptor calcium permeability, GluR2 expression, and selective motorneuron vulnerability. J. Neurosci. 2000;20:123–132. Verdoorn, T. A., N. Burnashev, H. Monyer, P. H. Seeburg, and B. Sakmann. Structural determinants of ion flow through recombinant glutamate receptor channels. Science 1991;252:1715–1718. Wasterlain, C. G. Effects of neonatal status epilepticus on rat brain development. Neurology 1976;26:975–986. Wasterlain, C. G., Y. Shirasaka, A. M. Mazarati, and I. Spigelman. Chronic epilepsy with damage restricted to the hippocampus: Possible mechanism. Epilepsy Res. 1996;26: 255–265. Yang, H. Y. T., J. S. Hong, and E. Costa. Regional distribution of Leu- and Met-enkephalin in rat brain. Neuropharmacology 1977;16:303–307. Yoshikawa, K., C. Williams, and L. S. Sabol. Rat brain preproenkephalin mRNA: cDNA cloning, primary structure, and distribution in the central nervous system. J. Biol. Chem. 1984;259:14301–14308. Zagon, I. S., T. Isayama, and P. J. McLaughlin. Preproenkephalin mRNA expression in the developing brain. Mol. Brain Res. 1994;21:85–98.
31
Seizures and Neurotrophic Factor Expression
. . I suspected that seizures influence the likelihood of further seizure activity, or, as Sir William Gowers is alleged to have said, “seizures beget seizures” (31). Clearly, with kindling, recurrent seizure discharges play a role in epileptogenesis, and therefore the identification of neurochemical-functional changes induced by seizures may reveal processes that contribute to epilepsy. Numerous studies, including our own, have shown that seizures lead to dramatic changes in neuronal gene expression. These changes may underlie the differences in neuronal vulnerability to seizures, the likelihood of experiencing additional seizures, and the development of epilepsy. Among these changes in gene expression, influences on neurotrophic factor expression are particularly interesting, for several reasons. First, although all changes in gene expression described to date are transient in nature (with changes in mRNA content lasting for about a week at most), the structural and cell-survival effects of neurotrophic factors could far outlive the seizure-induced genomic event. Second, the neurotrophin class of neurotrophic factors influences the strength of glutamatergic transmission, suggesting that acute effects of the neurotrophins can potentiate other processes contributing to the development of epilepsy. Third, despite many years of interest and investigation, the basis of differences in neuronal vulnerability to seizure remains a mystery. Neurotrophic factors are known to influence cell survival and to regulate factors that influence the level of neuronal vulnerability to a variety of experimental insults; regional differences in the expression and action of these agents may indeed contribute to differences in the vulnerability to seizure, seizure-induced cell death, and epileptogenesis. Many studies have shown that seizures dramatically and differentially regulate the expression of genes encoding the neurotrophins in the central nervous system (CNS). Although originally thought to be a phenomenon that occurred predominantly in association with seizures in the adult brain, neurotrophin regulation by seizures is now believed to build during development, but it is already evident in the early postnatal period and could be of consequence to childhood seizures and epilepsy. To put these data into context, the discussion in this chapter first provides some
background information on the neurotrophic factors influenced by seizure.
Neurotrophic factors Neurotrophic factors are a heterogeneous group of molecules that have, as a common feature, the ability to promote neuronal survival and/or differentiation. The prototypic neurotrophic factor, nerve growth factor (NGF), was first isolated by Levi-Montalcini. At first, NGF was thought to play a role only in the development of the peripheral nervous system, responsible for the maintenance of sympathetic and dorsal root ganglion neurons (29, 37). Initial investigations of a possible role for NGF in brain development failed to demonstrate its expression in brain. With the advent of modern molecular techniques, however, NGF was found to be expressed in the developing and adult rodent brain (48). Additionally, the low-affinity NGF receptor (a.k.a. P75) was shown to be produced by CNS cholinergic neurons (41, 79). Culture and in vivo studies established that NGF was capable of promoting the survival and process outgrowth of basal forebrain and striatal cholinergic neurons (11, 21, 32). Given the wide variety of CNS neuronal phenotypes and the restricted spectrum of NGF activity in the CNS, it was considered likely that other neurotrophic factors must exist that affected noncholinergic neurons. In the mid-1980s, small quantities of such a factor were isolated from brain. This factor, which had neurotrophic activity in vitro and was clearly not NGF, was called brain-derived neurotrophic factor (BDNF) (6). When BDNF was cloned and sequenced, there were clear homologies to NGF, making it part of the same molecular family, the neurotrophins. Subsequently other neurotrophins have been identified, including neurotrophin 3 (NT-3) (56), neurotrophin 4/5 (NT-4/5) (20) and neurotrophin 6 (NT-6) (30). There is further complexity to the neurotrophin story. NGF, BDNF, and NT-3 all have multiple splice variants that arise, at least in part, through differential regulation of multiple promoter regions (45, 52, 76). The functional significance of these variants is not known, but it appears that the multiple promoters provide a basis for region- and cell-specific differences in transcriptional regulation (50, 51).
:
389
The primary functional receptors for the neurotrophins have been identified as members of the trk family of tyrosine kinases. There is a selectivity in the response characteristics of the trks for the different neurotrophins (for a review, see 57). Trk (or trkA) responds preferentially to NGF, trkB responds to BDNF and NT-4/5, and trkC responds to NT3. These response characteristics are not absolute, and there is some overlap in receptor responsiveness (e.g., NT-3 has some activity at the trkA receptor). All three trks are expressed in mammalian CNS. Expression of the appropriate trk receptor is required for most of the neurotrophic functions of neurotrophins, although each can bind the lowaffinity P75 receptor and may thereby influence apoptotic activity. Like the neurotrophins, the trks also have numerous splice variants, including forms with deletions, or severe truncation, of the cytoplasmic domain (3, 16, 61, 84). The function of these splice variants is unknown, but the predominant expression of truncated forms by glial and ventricle epithelial cells has suggested that these receptors, which lack full signal transduction capacity, may serve to limit diffusion of active factor through the neuropil (87). The interaction of neurotrophins with the trk receptors induces a biochemical cascade of events, many steps of which are now known (for review, see 40). Neurotrophin binding to the homodimeric trk receptor induces tyrosine autophosphorylation and an activation of the kinase activities of the receptor. This leads to the phosphorylation and activation of latent second messengers and transcription factors that modulate the transcription of a variety of immediate early genes (IEGs). The IEG products include other transcription factors that regulate the expression of a range of genes that in turn regulate biochemical and morphologic differentiation, such as the production of neurotransmitters or elaboration of neurites. Several of these gene products are of particular interest in regard to epilepsy, although those playing the most important role have yet to be identified. For example, the neurotrophins have been demonstrated to regulate the expression of calcium-binding proteins, long suspected to buffer intracellular calcium levels and to protect cells from excitotoxic insult (2). Moreover, BDNF can induce the expression of neuropeptide Y (NPY) and may indeed be responsible for the induction of NPY synthesis in response to seizures (63). NPY, in turn, has a strong antiepileptic effect (42, 71, 78). A less well understood but equally important function of neurotrophins is the prevention of cell death. It has long been known that peripheral sympathetic neurons cultured in the absence of NGF undergo programmed, or apoptotic, cell death (58)—a cell death program that depends on both RNA and protein synthesis leading to DNA fragmentation prior to neuronal lysis. Neurotrophins signaling through the trk family of receptors may prevent apoptosis by enhancing transcription of protective factors (e.g., b-cl2) that inhibit
390
:
apoptosis or by inhibiting the transcription of genes within the cell death program. An exciting discovery in the field of neurotrophin signaling is that the P75 receptor, which binds all of the neurotrophins but was for a time thought to play little role in signal transduction, actually does play a role in the regulation of cell death (70). Neurotrophins enhance cell death when they interact with the P75 receptor in the absence of trk expression, but in other cases neurotrophins can prevent cell death by interacting with the P75 receptors. Additionally, under hypoxic-ischemic or excitotoxic conditions, neurotrophins may enhance the necrotic death of neurons that normally respond to neurotrophins in a trophic manner. It is not known if these effects are mediated by trk or P75 receptors (43). Several recent experiments have documented novel, rather surprising neuromodulatory functions of neurotrophins. As was first shown in electrophysiologic studies of acute hippocampal slices in culture, BDNF and NT-3 potentiate glutamatergic transmission within hippocampus (38, 39). This effect builds over a period of about 30 minutes, can be longlasting, and is reported to depend on new protein synthesis. Subsequent studies demonstrated the potentiating effects of neurotrophins within the neocortex, as well (1). Together with evidence that seizures stimulate neurotrophin synthesis and increases in neurotrophin content within axons and terminal boutons (14), these findings further suggest that the contribution of the neurotrophins to synaptic physiology may be potentiated in the wake of seizures; as a consequence, these factors may make a particularly large contribution to postictal events. Beyond the neurotrophins, the expression and activities of several additional families of central neurotrophic factors are of interest in relation to the effects of seizures. The cytokine superfamily includes glial-cell-line-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), leukemia inhibitory factor, and the bone morphogenetic proteins (BMPs). GDNF and CNTF have both been studied in clinical trials to test their therapeutic value in the treatment of neurodegenerative diseases. These factors interact with the serine-threonine protein kinase receptors (53). Another large family of fibroblast growth factors (FGFs) includes several members that are expressed in the CNS and, like the neurotrophins, are thought to play roles in neuronal and glial differentiation, protein synthesis, and survival. The FGFs interact with at least three tyrosine kinase receptors (7). The epidermal growth factor (EGF) family contains several members, the prototype of which is EGF, that interact with the 170-kd tyrosine kinase EGF receptor (EGF-R). These peptides also have numerous actions on CNS cells. Interestingly, members of both the EGF and FGF family can induce the proliferation of pluripotent CNS stem cells (73, 86). These cells are capable of producing neurons, astro-
cytes, and oligodendrocytes. Members of another family of peptide growth factors, the heregulins, interact with a group of receptors that share sequence homology with EGF-R but do not bind the EGF family of peptides (69). The functions of these peptides are not yet well understood, but they appear to be important for some aspects of brain development (15, 27, 47). Additionally, numerous other compounds have been reported to have neurotrophic activities.
Status epilepticus results in structural changes in the brain Studies in experimental animals and in humans have demonstrated that status epilepticus (SE) results in several potentially related structural changes in the brain. First and foremost, seizures can cause region-specific neuronal cell death. This point is dramatically demonstrated by cell loss occurring after pilocarpine- or kainic acid–induced seizures in the adult rat (8). Areas particularly affected are the hippocampus, especially pyramidal cell region CA3, amygdala, piriform cortex, thalamus, and some neocortical regions. Other models of SE also result in cell death, with somewhat different topographies of loss, depending on the mode of seizure induction and the animal model being used. Both apoptotic (programmed) and necrotic cell death result from prolonged seizures (77). Young animals do not appear to suffer the same degree of cellular loss after SE as do adults. Kainic acid and pilocarpine are both capable of producing SE in very young animals. Although these seizures had not been previously thought to produce any neuronal death at early ages, recent data suggest that the very young brain is subject to at least some cellular degeneration. As described by Sankar et al. (74), lithium-pilocarpine-induced SE does appear to result in both apoptotic cell and necrotic neuronal death in the CA1 region of animals as young as postnatal day 14 (P14). Intense, afterdischarge-inducing, perforant path stimulation results in cell death as early as P14 in the rat hippocampus (82). Moreover, corticotropin-releasing hormone (CRH)-induced SE results in cellular damage in the CA3 region of P12 rats (5). Perhaps more pertinent to seizure-induced trophic factor activities, seizures also result in the growth of new axonal connections. The most well-characterized example of this is the sprouting of the mossy fiber axons of the dentate gyrus granule cells. These intrinsic hippocampal axons are normally distributed within the dentate hilus and stratum lucidum of region CA3 and, in these regions, innervate hilar neurons and the CA3 pyramidal cells, respectively. However, in a number of models involving recurrent limbic seizures (e.g., pilocarpine- or kainic acid–induced seizures, limbic kindling), the mossy fiber axons sprout to form an aberrant axonal plexus in the dentate gyrus inner molecular layer and
recurrent innervation of the dentate gyrus granule cells themselves (81), and exuberant innervation of the basal dendrites of the CA3 pyramidal cells (72). Studies by Bundman et al. (12) have demonstrated that recurrent limbic seizures also induce the elaboration of spines on the somata of the dentate gyrus granule cells. These spines appear to be associated with preexisting excitatory (i.e., asymmetric) synaptic contacts and, like the exuberant mossy fiber collaterals, far outlive the period of seizures. Both mossy fiber sprouting and spine formation suggest that seizures effect changes in the distribution and configuration of excitatory innervation within the hippocampus, which may influence both the relative balance of excitatory and inhibitory activities and seizure threshold. Finally, many recent studies, including the pioneering one of Parent et al. (68), have demonstrated that seizures stimulate mitotic activity within hippocampus in a manner suggesting that seizures induce the formation of new granule cells from undifferentiated precursors known to reside at the granule cell–hilar interface.
Status epilepticus induces neurotrophic factor expression in the adult brain The mechanisms through which seizures induce morphologic changes in the brain are not known, but there is good reason to believe that seizure-induced trophic activities are involved. In 1989, Gall and Isackson (24) reported that recurrent limbic seizures induced by lesions in the dentate hilus resulted in dramatic elevations in NGF mRNA in as little as 30 minutes (Figure 31.1). The time course of this induction of NGF mRNA is biphasic, with peaks at approximately 2 and 24 hours. Areas of enhanced NGF mRNA expression include dentate gyrus granule cells, neurons of the neocortex and piriform and entorhinal cortices, and the lateral and cortical nuclei of the amygdala. These brain areas all exhibit some degree of NGF expression under baseline conditions. Not all NGF-expressing neurons are subject to induction of NGF mRNA by seizures. Interneurons of the hippocampus show no changes in NGF mRNA following seizures (Figure 31.1). Seizure-induced NGF mRNA expression has been subsequently demonstrated in a variety of experimental paradigms, including seizures induced by kainic acid, bicuculline, pentylenetetrazole (PTZ), pilocarpine, and kindling (22). Acute seizures also induce dramatic elevations in BDNF mRNA levels in the adult rat brain. In virtually all models that have been investigated, seizures rapidly result in elevated levels of BDNF mRNA in numerous brain regions, including neocortcial and allocortical areas, the amygdala, and some thalamic nuclei (17, 36, 46). Elevated expression occurs as rapidly as 30 minutes after seizure onset, peaks at around 4 hours, and subsequently declines to near baseline
:
391
F 31.1 Limbic seizures markedly upregulate NGF mRNA expression. Hybridization studies were performed using [35S]-NGF cRNA in control (top) or hilus-lesioned (seizure) animal. Intense hybridization occurred in the dentate gyrus of the lesioned animal. Levels of mRNA in the interneuron (scattered cells) remained the same.
levels by 24 hours. Seizures appear to induce all four splice variants of BDNF (83). However, the mechanisms controlling production of the different transcripts appear to be different. Just two of the BDNF transcripts are induced by activity as IEGs (51); the expression of the remaining two splice variants is positively and negatively correlated by neuronal activity and the adrenal hormones, respectively (50). The elevations in BDNF and NGF mRNA induced by seizures are accompanied by changes in protein content. Sun et al. (80) found that bicuculline-induced SE resulted in an increase of NGF protein levels as measured by radioimmunoassay. NGF protein levels were also found to be elevated after kindling-induced seizures (9). Humpel et al. (35) demonstrated an acute decrease in dentate and hilar BDNF immunoreactivity (ir) following PTZ-induced seizures, while PTZ kindling-induced seizures resulted in elevations in BDNF-ir. The decrease in BDNF protein levels after acute seizures may be interpreted as a result of protein release. The same group (75) demonstrated increased BDNF-ir in the dentate gyrus granule cells after lithium-pilocarpineinduced SE but did not describe changes in other brain areas, such as neocortex, in which BDNF mRNA is elevated
392
:
as a result of seizures. However, using a sensitive two-site immunoassay technique, Nawa et al. (64) did observe elevations in BDNF-ir in numerous brain regions after hilus lesion-induced seizures. Immunoreactivity was increased in all areas exhibiting increases in BDNF mRNA in this same paradigm. Surprisingly, seizure-induced increases in BDNFir lagged behind the increase in BDNF mRNA by just 4 hours but were far more enduring; whereas BDNF mRNA had largely returned to control levels by 24 hours after seizure onset, BDNF-ir was still well elevated as long as 4 days after seizure. In one study on BDNF-ir using immunocytochemical techniques (23), we found that seizures induced a rapid increase in perikaryal BDNF-ir in all areas exhibiting increases in BDNF mRNA content. Perikaryal immunostaining is maximal 6–12 hours after seizure onset. After this time there appears to be a shift in immunostaining from the perikarya to the axonal (as opposed to dendritic) arbors of the BDNF-producing cells. Although BDNF-ir dissipates slowly with time, immunostaining is still well elevated within the entorhinal cortex as long as 1 week after a single recurrent seizure episode. Finally, seizure-induced increases in neurotrophin transcription and translation are associated with the expected increases in neurotrophin bioactivity. Lowenstein et al. (55) showed that hippocampal extracts supported the survival of chick dorsal root ganglion neurons for up to 2 months after a seizure. Chick DRG neurons have long been used as a bioassay for neurotrophin function. Studies in other laboratories have demonstrated that, in addition to effects on the neurotrophins, seizures influence expression of the trk neurotrophin receptors. Most particularly, in the hippocampus, mRNA and protein for trkB and trkC are increased by acute and kindled seizure activity (9, 65). These increases may indicate that seizures can increase cellular responsiveness to BDNF. However, it appears that in some cell groups, such as the neocortex, seizures may induce only the mRNA for the truncated form of trkB, which lacks the tyrosine kinase domain and therefore would not be expected to transduce BDNF (or NT-4/5) signal (9). Although the seizures induce rather similar increases in NGF and BDNF expression in hippocampus and cortex, these response profiles are truly neurotrophin-specific and cannot be considered representative of effects on other neurotrophins of other neurotrophic factors in general. This point is illustrated by the very different effects of seizures on NT-3 mRNA. This neurotrophin is normally expressed by the dentate gyrus granule cells and, in low levels, by cells of the caudal neocortex and the cortical regions of amygdala. Single epileptiform afterdischarges and recurrent seizures result in a dramatic decrease in NT-3 mRNA in each of these areas, and this decrease in mRNA content persists through at least 4 days after seizure (25).
Although there is evidence that neurotrophin expression is particularly vulnerable to levels of neuronal activity in comparison to many of the other neurotrophic factors produced in the CNS, seizures, and in particular recurrent limbic seizures, elicit changes in the expression of members of other trophic families (24). Basic fibroblast growth factor (FGF-2) mRNA is elevated as a result of bicuculline-, kainite-, hilus lesion-, and electroshock-induced seizures. This elevation occurs in both neurons and glia in numerous brain regions. The expression of other members of the FGF gene family, FGF-5 and FGF-1, is also induced by seizures, as is the expression of at least one of the FGF receptors, FGF-R1. Other trophic factors whose expression is induced by seizures include GDNF (35) transforming growth factor-alpha, and heparin-binding epidermal growth factor (67).
Status epilepticus induces BDNF mRNA expression in the developing brain One of the critical theories on the development of epilepsy is that prolonged convulsions occurring during childhood predispose the brain to changes that subsequently result in the epileptic condition. Thus, numerous investigators have sought to define how seizures affect the developing brain and how these effects may lead to epilepsy. One might postulate that neurotrophic factors play a role in this process. Dugich-Djordjevic et al. (18), in the first study of the expression of neurotrophins following seizures in the developing brain, found that in Sprague-Dawley rats, kainateinduced seizures increased BDNF mRNA levels in the dentate gyrus on P13. They did not observe increases prior to P13, and the level of expression induced by seizures at this age was well below that induced by similar treatment on P21. Furthermore, the widespread induction of BDNF mRNA observed in older animals was not seen on P13. Da Penha Berzaghi et al. (15) studied the effects of pilocarpine administration on BDNF mRNA in the developing Wistar rat and found elevated expression in the dentate granule cells as early as P7, without significant elevations elsewhere in hippocampus at this age. These investigators hypothesized that this effect was secondary to activation of NMDA receptors, because it was prevented by administration of MK801. Of note, da Penha Berzaghi et al. did not attribute these effects to pilocarpine-generated seizures, and no electrographic recordings were performed during this study. They also found elevated hippocampal expression of NGF but no change in NT-4 expression after pilocarpine administration on P7. Kainate, on the other hand, did not induce changes in neurotrophin expression at these early ages, although behavioral seizures were observed after treatment. Because of the potential importance of neurotrophin expression in the developing brain, we examined the effects of
cholinergic and kainate-induced seizures on BDNF expression in young Wistar rats (46). Seizures were induced by treatment with lithium-pilocarpine in rats from P7 to P21 (Figure 31.2). As early as P7, the convulsants increased BDNF mRNA within the hippocampus, but our results differed from those of da Penha Berzaghi et al. in several ways. First, in rats treated on P7, BDNF mRNA was maximally increased in hippocampal CA1 stratum pyramidale, but it was also clearly increased in other cortical limbic structures (e.g., piriform, entorhinal, and cingulate cortices). Second, increases in BDNF mRNA were accompanied by seizures, and prevention of seizures with diazepam prevented the rise in expression. Third, in rats treated with lithium-pilocarpine on P12, dramatic elevations in extrahippocampal BDNF expression were present in the limbic and neocortices. Finally, kainic acid treatment resulted in elevations in BDNF mRNA as early as P7, but at this early age, elevated expression was limited to the CA3 region of hippocampus (Figure 31.3). Treatment at later ages produced a more widespread pattern of induction. The reasons for the discrepancies between the studies cited probably stems from the different treatment paradigms and rat strains used. However, it seems clear that neuronal activation in the form of seizure activity does result in elevated BDNF mRNA expression at early stages of brain development, but there is also a maturation of the response profile over the first 2–3 weeks of life in the rat, leading to greater and more widespread increases with postnatal age. Nevertheless, seizures clearly influence BDNF expression in the developing brain, and this may be of serious consequence to ongoing process outgrowth, synaptogenesis, and proliferative activity occurring at these ages.
Potential functions of seizure-induced neurotrophic factor expression As is evident from the preceding discussion, there is little doubt that acute seizures result in enhanced expression of several neurotrophic factors, but the effect of this expression on the brain and on the further development of seizures is not known. Neurotrophins may function in adaptive and maladaptive ways. Moreover, whether altered neurotrophin expression is beneficial or not may depend on the developmental stage during which seizures occur. One potential functional role of seizure-induced neurotrophic factor expression is the protection of neurons from cell death. In numerous in vitro systems, neurotrophins and FGFs are capable of increasing the viability of cultured neurons and diminishing the effects of excitotoxic insults, including a reduction in apoptosis (54). Additionally, BDNF is required for the positive effects of activity on neuronal survival by cortical neurons in vitro (28). It is conceivable, then, that seizures in the absence of neurotrophic factor
:
393
F 31.2 Pilocarpine-induced seizures upregulate BDNF mRNA expression in developing brain. (A) Neonatal (P7) and (B) P14 rats were pretreated with lithium, followed 16 hours later by pilocarpine hydrochloride (100 mg/kg), and killed 2 hours after seizure onset. (C and D) Control animals were treated with normal
394
:
saline injection. The pattern of BDNF hybridization in the treated P7 animal, while still elevated over control, is different from that found on P14 (at which age the adult pattern of activation is observed). Scale bar = 1 mm.
F 31.3 Kainic acid seizures induce BDNF mRNA expression in neonatal rat brain. Shown are autoradiographs of hippocampal BDNF mRNA expression in a control P7 rat and kainic
acid–treated P7 rat (which resulted in SE). Note intense hybridization in CA3 of the kainate-treated animal. Scale bar = 0.5 mm.
expression would yield an even greater degree of cell death than that observed. One might wonder, however, why there is both less cell death and lower levels of seizure-induced neurotrophin expression in the developing brain. Several explanations are possible. First, the lower levels of neurotrophin production may still be sufficient to support the survival of developing neurons, which may be expected to be more sensitive to neurotrophic effects. Second, other neurotrophic factors, as yet unexplored, may be produced in the developing brain after seizures and may account for neuronal survival. Third, the basic mechanisms of excitotoxininduced cell death may not be mature in the developing brain, thus making the young brain relatively resistant to excitotoxic damage. However, neurotrophins may not be protective in all circumstances. Koh et al. (43) showed that neurotrophins can induce necrotic neuronal death under hypoxic-ischemic conditions, conditions that may prevail during prolonged SE (87). One possible mechanism by which seizure-induced neurotrophic factor expression may influence the development of future seizures is by participating in the reorganization of neuronal circuitry. As discussed in other chapters, seizures can result in aberrant synaptogenesis, and this phenomenon may contribute to epilepsy by creating reverberating excitatory circuits. As neurotrophic factors induce process outgrowth of sensitive neurons, it seems reasonable to propose that they do something similar after SE. Studies are now beginning to address this issue, although the results are not entirely consistent. In one study, Van der Zee et al. (85) demonstrated that intraventricular administration of anti-NGF antibodies blocked sprouting of mossy fiber to CA3 pyramidal cells during kindling. Additionally, the development of kindling was retarded by the administration of these antibodies. These data imply that seizure-induced NGF expression is involved in the development of seizures and that one mech-
anism may be mossy fiber sprouting. It must be cautioned, however, that dentate gyrus granule cells have not been shown to express the receptor for NGF, trkA. In another study, Holtzman and Lowenstein (33) demonstrated that anti-NGF antibodies blocked sprouting of the septohippocampal cholinergic pathway but did not affect mossy fiber sprouting after pilocarpine-induced seizures. Thus, the role of NGF in sprouting and the development of epilepsy is not clear. The role of BDNF in epileptogenesis is also not well understood, although it has been intensively studied (10). Some studies point to seizure-induced expression of BDNF as contributing to the development of seizures. Thus, mice heterozygous for the BDNF null mutation and that express low levels of BDNF protein have a slower rate of kindling than do wild-type mice (45). On the other hand, the chronic administration of exogenous BDNF has been shown to inhibit kindling as well as PTZ-induced seizures. This result was obtained even though BDNF did not alter mossy fiber sprouting, suggesting that the degree of mossy fiber sprouting may not correlate with secondary epileptogenesis (49). One mechanism by which BDNF may influence epileptogenesis is through its effects on the expression of other neuromodulatory peptides. As stated earlier, elevated BDNF levels may induce neuropeptide Y expression. Neuropeptide Y in turn may reduce susceptibility to seizures (4, 42). Studies over the last several years have demonstrated that neurotrophins may have a more immediate impact on seizure development and propagation. Both BDNF and NT-3, but not NGF, have been shown to enhance synaptic efficacy at CA3 to CA1 synapses in hippocampal slice preparations (38, 39). These effects are probably not by direct modulation of ion channels, because they require receptor phosphorylation and protein synthesis to occur. BDNF also enhances glutamate and aspartate release in cultured neurons (60, 66) and appears to act in an antegrade
:
395
fashion (19), so that a granule cell or pyramidal cell that synthesizes BDNF will release the BDNF on appropriate excitation. The BDNF in turn will act on the postsynaptic neuron to facilitate the release of excitatory amino acids. Glial-cell-line-derived neurotrophic factor is released during SE, as mentioned earlier. Although fewer studies have focused on the role of this trophic factor in epileptogenesis, the ones that have been performed are also seemingly contradictory. Exogenous GDNF admininstration inhibits seizures induced by kainic acid (59), while mice lacking one of the GDNF receptor components are resistant to kindling, suggesting that GDNF signaling has a net proconvulsive effect (62). The data introduced here underscore that the cumulative effects of neurotrophic release in humans during SE on subsequent seizure development are not known and are difficult to predict. Factors such as location and duration of seizures, the anticonvulsants used, and the age of the patient undoubtedly play a role. Finally, one of the most intriguing possibilities is that neurotrophic factors promote the formation of new neurons after seizures. Both FGF-2 and factors that activate the epidermal growth factor receptor induce the proliferation of CNS stem cells from the subventricular zone (73, 86), as well as the hippocampus (20). In the hippocampus, these cells may then go on to form new granule cell neurons that participate in the functional circuitry of the hippocampus. Acute seizures induce the proliferation of dentate granule cell precursors, and these new granule cells participate in the formation of connections in the adult rat hippocampus (68). The hypothesis that it is seizure-induced FGF that regulates this neurogenesis has yet to be tested. It is also unclear whether the formation of new granule cells is an adaptive or maladaptive response.
Summary A large body of evidence shows that seizures result in the enhanced expression of several neurotrophic factors, including BDNF, NGF, GDNF, and FGF-1 and FGF-2 in the adult brain. The expression of at least one neurotrophic factor, NT-3, is inhibited by seizures. Furthermore, seizures induce the expression of at least one neurotrophic factor, BDNF, at relatively early stages of development. The implications of these alterations in neurotrophic factor expression for the ultimate function of the CNS and the development of epilepsy are only beginning to be explored. REFERENCES 1. Akaneya, Y., T. Tsumoto, S. Kinoshita, and H. Hatanaka. Brain-derived neurotrophic factor enhances long-term potentiation in rat visual cortex. J. Neurosci. 1997;17:6707–6716.
396
:
2. Alexi, T., J. L. Venero, and F. Hefti. Protective effects of neurotrophin-4/5 and transforming growth factor-alpha on striatal neuronal phenotypic degeneration after excitotoxic lesioning with quinolinic acid. Neuroscience 1997;78:73–86. 3. Allen, S. J., D. Dawbarn, S. D. Eckford, G. K. Wilcock, M. Ashcroft, S. M. Colebrook, et al. Cloning of a non-catalytic form of human trkB and distribution of messenger RNA for trkB in human brain. Neuroscience 1994;60:825–834. 4. 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. 5. Baram, T. Z., and C. E. Ribak. Peptide-induced infant status epilepticus causes neuronal death and synaptic reorganization. Neuroreport 1995;6:277–280. 6. Barde, Y. A., A. M. Davies, J. E. Johnson, R. M. Lindsay, and H. Thoenen. Brain-derived neurotrophic factor. Prog. Brain Res. 1987;71:185–189. 7. Belluardo, N., G. Wu, G. Mudo, A. C. Hansson, R. Pettersson, and K. Fuxe. Comparative localization of fibroblast growth factor receptor-1, -2, and -3 mRNAs in the rat brain: In situ hybridization analysis. J. Comp. Neurol. 1997;379:226–246. 8. 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. 9. Bengzon, J., Z. Kokaia, P. Ernfors, M. Kokaia, G. Leanza, O. G. Nilsson, et al. Regulation of neurotrophin and trkA, trkB and trkC tyrosine kinase receptor messenger RNA expression in kindling. Neuroscience 1993;53:433–446. 10. Binder, D. K., S. D. Croll, C. M. Gall, and H. E. Scharfman. BDNF and epilepsy: Too much of a good thing? Trends Neurosci. 2001;24:47–53. 11. Bostwick, J. R., S. H. Appel, and J. R. Perez-Polo. Distinct influences of nerve growth factor and a central cholinergic trophic factor on medial septal explants. Brain Res. 1987;422:92–98. 12. Bundman, M., and C. Gall. Ultrastructural plasticity of the dentate gyrus granule cells following recurrent limbic seizures. II. Alterations in somatic synapses. Hippocampus 1994;4:611– 622. 13. Conner, J. M., J. C. Lauterborn, Q. Yan, C. M. Gall, and S. Varon. Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: Evidence for anterograde axonal transport. J. Neurosci. 1997; 17:2295–2313. 14. Corfas, G., K. M. Rosen, H. Aratake, R. Krauss, and G. D. Fischbach. Differential expression of ARIA isoforms in the rat brain. Neuron 1995;14:103–115. 15. da Penha Berzaghi, M., J. Cooper, E. Castren, F. Zafra, M. Sofroniew, H. Thoenen, and D. Lindholm. Cholinergic regulation of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) but not neurotrophin-3 (NT-3) mRNA levels in the developing rat hippocampus. J. Neurosci. 1993;13: 3818–3826. 16. DiStefano, P. S., and E. M. Johnson, Jr. Identification of a truncated form of the nerve growth factor receptor. Proc. Natl. Acad. Sci. U. S. A. 1988;85:270–274. 17. Dugich-Djordjevic, M. M., G. Tocco, P. A. Lapchak, G. M. Pasinetti, I. Najm, M. Baudry, and F. Hefti. Regionally specific and rapid increases in brain-derived neurotrophic factor messenger RNA in the adult rat brain following seizures induced by systemic administration of kainic acid. Neuroscience 1992;47:303–315.
18. Dugich-Djordjevic, M. M., G. Tocco, D. A. Willoughby, I. Najm, G. Pasinetti, R. F. Thompson, et al. BDNF mRNA expression in the developing rat brain following kainic acid– induced seizure activity. Neuron 1992;8:1127–1138. 19. Fawcett, J. P., S. Bamji, C. Causing, R. Aloyz, A. Ase, T. Reader, et al. Functional evidence that BDNF is an anterograde neuronal trophic factor in the CNS. J. Neurosci. 1998;18:2808–2821. 20. Gage, F. H., P. W. Coates, T. D. Palmer, H. G. Kuhn, L. J. Fisher, J. O. Suhonen, et al. Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc. Natl. Acad. Sci. U. S. A. 1995;92:11879–11883. 21. Gähwiler, B. H., A. Enz, and F. Hefti. Nerve growth factor promotes development of the rat septo-hippocampal cholinergic projection in vitro. Neurosci. Lett. 1987;75:6–10. 22. Gall, C. M. Regulation of brain neurotrophin expression by physiological activity. Trends Pharmacol. Sci. 1992;13:401–403. 23. Gall, C. M., J. Cooper, J. C. Lauterborn, Q. Yan, and S. Varon. Cellular localization of BDNF protein after recurrent seizures in rat: Evidence for axonal transport of the newly synthesized factor. Epilepsia 1994;37(Suppl. 5):47. 24. Gall, C. M., and P. J. Isackson. Limbic seizures increase neuronal production of messenger RNA for nerve growth factor. Science 1989;245:758–761. 25. Gall, C., and J. Lauterborn. The dentate gyrus: A model system for studies of neurotrophin regulation. Epilepsy Res. Suppl. 1992;7:171–185. 26. Gall, C., J. Lauterborn, M. Bundman, K. Murray, and P. Isackson. Seizures and the regulation of neurotrophic factor and neuropeptide gene expression in brain. Epilepsy Res. Suppl. 1991;4:225–245. 27. Gassmann, M., F. Casagranda, D. Orioli, H. Simon, C. Lai, R. Klein, and G. Lemke. Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 1995;378:390–394. 28. Ghosh, A., J. Carnahan, and M. E. Greenberg. Requirement for BDNF in activity-dependent survival of cortical neurons. Science 1994;263:1618–1623. 29. Gorin, P. D., and E. M. Johnson, Jr. Effects of exposure to nerve growth factor antibodies on the developing nervous system of the rat: An experimental autoimmune approach. Dev. Biol. 1980;80:313–323. 30. Gotz, R., R. Koster, C. Winkler, F. Raulf, F. Lottspeich, M. Schartl, and H. Thoenen. Neurotrophin-6 is a new member of the nerve growth factor family. Nature 1994;372:266–269. 31. Gowers, W. R. Epilepsy and Other Chronic Convulsive Diseases. London, Churchill, 1881. 32. Hartikka, J., and F. Hefti. Comparison of nerve growth factor’s effects on development of septum, striatum, and nucleus basalis cholinergic neurons in vitro. J. Neurosci. Res. 1988;21:352–364. 33. Holtzman, D. M., and D. H. Lowenstein. Selective inhibition of axon outgrowth by antibodies to NGF in a model of temporal lobe epilepsy. J. Neurosci. 1995;15:7062–7070. 34. Humpel, C., B. Hoffer, I. Stromberg, S. Bektesh, F. Collins, and L. Olson. Neurons of the hippocampal formation express glial cell line-derived neurotrophic factor messenger RNA in response to kainate-induced excitation. Neuroscience 1994;59:791–795. 35. Humpel, C., C. Wetmore, and L. Olson. Regulation of brainderived neurotrophic factor messenger RNA and protein at the cellular level in pentylenetetrazol-induced epileptic seizures. Neuroscience 1993;53:909–918. 36. Isackson, P. J., M. M. Huntsman, K. D. Murray, and C. M. Gall. BDNF mRNA expression is increased in adult rat fore-
37.
38.
39.
40. 41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53. 54.
brain after limbic seizures: Temporal patterns of induction distinct from NGF. Neuron 1991;6:937–948. Johnson, E. M., Jr., P. D. Gorin, L. D. Brandeis, and J. Pearson. Dorsal root ganglion neurons are destroyed by exposure in utero to maternal antibody to nerve growth factor. Science 1980;210:916–918. Kang, H., and E. M. Schuman. Long-lasting neurotrophininduced enhancement of synaptic transmission in the adult hippocampus. Science 1995a;267:1658–1662. Kang, H. J., and E. M. Schuman. Neurotrophin-induced modulation of synaptic transmission in the adult hippocampus. J. Physiol. (Paris) 1995b;89:11–22. Kaplan, D. R., and R. M. Stephens. Neurotrophin signal transduction by the Trk receptor. J. Neurobiol. 1994;25:1404–1417. Kiss, J., J. McGovern, and A. J. Patel. Immunohistochemical localization of cells containing nerve growth factor receptors in the different regions of the adult rat forebrain. Neuroscience 1988;27:731–748. Klapstein, G. J., and W. F. Colmers. Neuropeptide Y suppresses epileptiform activity in rat hippocampus in vitro. J. Neurophysiol. 1997;78:1651–1661. Koh, J. Y., B. J. Gwag, D. Lobner, and D. W. Choi. Potentiated necrosis of cultured cortical neurons by neurotrophins. Science 1995;268:573–575. Kokaia, M., P. Ernfors, Z. Kokaia, E. Elmer, R. Jaenisch, and O. Lindvall. Suppressed epileptogenesis in BDNF mutant mice. Exp. Neurol. 1995;133:215–224. Kokaia, Z., M. Metsis, M. Kokaia, J. Bengzon, E. Elmer, M. L. Smith, et al. Brain insults in rats induce increased expression of the BDNF gene through differential use of multiple promoters. Eur. J. Neurosci. 1994;6:587–596. Kornblum, H. I., R. Sankar, D. H. Shin, C. G. Wasterlain, and C. M. Gall. Induction of brain derived neurotrophic factor mRNA by seizures in neonatal and juvenile rat brain. Brain Res. Mol. Brain Res. 1997;44:219–228. Kramer, R., N. Bucay, D. J. Kane, L. E. Martin, J. E. Tarpley, and L. E. Theill. Neuregulins with an Ig-like domain are essential for mouse myocardial and neuronal development. Proc. Natl. Acad. Sci. U.S.A. 1996;93:4833–4838. Large, T. H., S. C. Bodary, D. O. Clegg, G. Weskamp, U. Otten, and L. F. Reichardt. Nerve growth factor gene expression in the developing rat brain. Science 1986;234:352–355. Larmet, Y., S. Reibel, J. Carnahan, H. Nawa, C. Marescaux, and A. Depaulis. Protective effects of brain-derived neurotrophic factor on the development of hippocampal kindling in the rat. Neuroreport 1995;6:1937–1941. Lauterborn, J. C., F. R. Poulsen, C. T. Stinis, P. J. Isackson, and C. M. Gall. Transcript-specific effects of adrenalectomy on seizure-induced BDNF expression in rat hippocampus. Brain Res. Mol. Brain Res. 1998;55:81–91. Lauterborn, J. C., S. Rivera, C. T. Stinis, V. Y. Hayes, P. J. Isackson, and C. M. Gall. Differential effects of protein synthesis inhibition on the activity-dependent expression of BDNF transcripts: Evidence for immediate-early gene responses from specific promoters. J. Neurosci. 1996;16:7428–7436. Leingartner, A., and D. Lindholm. Two promoters direct transcription of the mouse NT-3 gene. Eur. J. Neurosci. 1994;6: 1149–1159. Lin, H. Y., and A. Moustakas. TGF-beta receptors: Structure and function. Cell. Mol. Biol. (Noisy-le-grand) 1994;40:337–349. Lindvall, O., Z. Kokaia, J. Bengzon, E. Elmer, and M. Kokaia. Neurotrophins and brain insults. Trends Neurosci. 1994;17: 490–496.
:
397
55. Lowenstein, D. H., M. S. Seren, and F. M. Longo. Prolonged increases in neurotrophic activity associated with kainateinduced hippocampal synaptic reorganization. Neuroscience 1993;56:597–604. 56. Maisonpierre, P. C., L. Belluscio, S. Squinto, N. Y. Ip, M. E. Furth, R. M. Lindsay, and G. D. Yancopoulos. Neurotrophin3: A neurotrophic factor related to NGF and BDNF. Science 1990;247:1446–1451. 57. Maness, L. M., A. J. Kastin, J. T. Weber, W. A. Banks, B. S. Beckman, and J. E. Zadina. The neurotrophins and their receptors: Structure, function, and neuropathology. Neurosci. Biobehav. Rev. 1994;18:143–159. 58. Martin, D. P., A. Ito, K. Horigome, P. A. Lampe, and E. M. Johnson, Jr. Biochemical characterization of programmed cell death in NGF-deprived sympathetic neurons. J. Neurobiol. 1992;23:1205–1220. 59. Martin, D., G. Miller, M. Rosendahl, and D. A. Russell. Potent inhibitory effects of glial-derived neurotrophic factor against kainic acid–mediated seizures in the rat. Brain Res. 1995;683: 172–178. 60. Matsumoto, T., T. Numakawa, N. Adachi, D. Yokomaku, S. Yamagashi, N. Takei, and H. Hatanaka. Brain-derived neurotrophic factor enhances depolarization-evoked glutamate receptor release in cultured cortical neurons. J. Neurochem. 2001;79:522–530. 61. Middlemas, D. S., R. A. Lindberg, and T. Hunter. trkB, a neural receptor protein-tyrosine kinase: Evidence for a full-length and two truncated receptors. Mol. Cell. Biol. 1991;11:143–153. 62. Nanobashvili, A., Z. Kokaia, and O. Lindvall. Generalization of rapidly recurring seizures is suppressed in mice lacking glial cell line-derived neurotrophic factor family receptor alpha2. Neuroscience 2003;118:845–852. 63. Nawa, H., Y. Bessho, J. Carnahan, S. Nakanishi, and K. Mizuno. Regulation of neuropeptide expression in cultured cerebral cortical neurons by brain-derived neurotrophic factor. J. Neurochem. 1993;60:772–775. 64. Nawa, H., J. Carnahan, and C. Gall. BDNF protein measured by a novel enzyme immunoassay in normal brain and after seizure: Partial disagreement with mRNA levels. Eur. J. Neurosci. 1995;7:1527–1535. 65. Nibuya, M., S. Morinobu, and R. S. Duman. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J. Neurosci. 1995;15:7539–7547. 66. Numakawa, T., N. Takei, and H. Hatanaka. BDNF rapidly induces aspartate release from cultured CNS neurons. J. Neurosci. Res. 2000;37:59–65. 67. Opanashuk, L. A., R. J. Mark, J. Porter, D. Damm, M. P. Mattson, and K. B. Seroogy. Heparin-binding epidermal growth factor-like growth factor in hippocampus: modulation of expression by seizures and anti-excitotoxic action. J. Neurosci. 1999;19:133–146. 68. Parent, J. M., T. W. Yu, R. T. Leibowitz, D. H. Geschwind, R. S. Sloviter, and D. H. Lowenstein. Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J. Neurosci. 1997;17:3727–3738. 69. Prigent, S. A., and N. R. Lemoine. The type 1 (EGFR-related) family of growth factor receptors and their ligands. Prog. Growth Factor Res. 1992;4:1–24. 70. Rabizadeh, S., J. Oh, L. T. Zhong, J. Yang, C. M. Bitler, L. L. Butcher, and D. E. Bredesen. Induction of apoptosis by the low-affinity NGF receptor. Science 1993;261:345–348.
398
:
71. Reibel, S., R. Benmaamar, B. T. Le, Y. Larmet, S. P. Kalra, C. Marescaux, and A. Depaulis. Neuropeptide Y delays hippocampal kindling in the rat. Hippocampus 2003;13:557–560. 72. Represa, A., and Y. Ben-Ari. Long-term potentiation and sprouting of mossy fibers produced by brief episodes of hyperactivity. Epilepsy Res. Suppl. 1992;7:261–269. 73. Reynolds, B. A., W. Tetzlaff, and S. Weiss. A multipotent EGFresponsive striatal embryonic progenitor cell produces neurons and astrocytes. J. Neurosci. 1992;12:4565–4574. 74. Sankar, R., D. H. Shin, H. Liu, A. Mazarati, A. Pereira de Vasconcelos, and C. G. Wasterlain. Patterns of status epilepticus–induced neuronal injury during development and long-term consequences. J. Neurosci. 1998;18:8382–8393. 75. Schmidt-Kastner, R., C. Humpel, C. Wetmore, and L. Olson. Cellular hybridization for BDNF, trkB, and NGF mRNAs and BDNF-immunoreactivity in rat forebrain after pilocarpineinduced status epilepticus. Exp. Brain Res. 1996;107:331–347. 76. Selby, M. J., R. Edwards, F. Sharp, and W. J. Rutter. Mouse nerve growth factor gene: Structure and expression. Mol. Cell. Biol. 1987;7:3057–3064. 77. 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. 78. 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. 79. Springer, J. E., S. Koh, M. W. Tayrien, and R. Loy. Basal forebrain magnocellular neurons stain for nerve growth factor receptor: Correlation with cholinergic cell bodies and effects of axotomy. J. Neurosci. Res. 1987;17:111–118. 80. Sun, F. Y., E. Costa, and I. Mocchetti. Adrenal steroids mediate the increase of hippocampal nerve growth factor biosynthesis following bicuculline convulsions. Neuropsychopharmacology 1993; 8:219–225. 81. Sutula, T., X. X. He, J. Cavazos, and G. Scott. Synaptic reorganization in the hippocampus induced by abnormal functional activity. Science 1988;239:1147–1150. 82. 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. 83. Timmusk, T., K. Palm, M. Metsis, T. Reintam, V. Paalme, M. Saarma, and H. Persson. Multiple promoters direct tissuespecific expression of the rat BDNF gene. Neuron 1993;10: 475–489. 84. Valenzuela, D. M., P. C. Maisonpierre, D. J. Glass, E. Rojas, L. Nuñez, Y. Kong, et al. Alternative forms of rat TrkC with different functional capabilities. Neuron 1993;10:963–974. 85. Van der Zee, C. E., K. Rashid, K. Le, K. A. Moore, J. Stanisz, J. Diamond, et al. Intraventricular administration of antibodies to nerve growth factor retards kindling and blocks mossy fiber sprouting in adult rats. J. Neurosci. 1995;15:5316–5323. 86. Vescovi, A. L., B. A. Reynolds, D. D. Fraser, and S. Weiss. bFGF regulates the proliferative fate of unipotent (neuronal) and bipotent (neuronal/astroglial) EGF-generated CNS progenitor cells. Neuron 1993;11:951–966. 87. Wasterlain, C. G., and T. E. Duffy. Status epilepticus in immature rats: Protective effects of glucose on survival and brain development. Arch. Neurol. 1976;33:831–837.
32
Behavioral Consequences of Status Epilepticus in the Immature Brain
. , , , . , .
Introduction
Effects of prolonged seizures on the developing brain
It is well recognized that children are at higher risk for seizures than adults (23, 24). In addition to the higher incidence of epilepsy in children than in adults, precipitating factors such as fever are far more likely to induce a seizure in a young child than in an adult. Children also have a significantly higher likelihood of entering remission than adults (8), further suggesting that the brain becomes less excitable with age. The results of animal studies parallel the results of clinical studies, with both indicating that the immature brain is more susceptible to seizures than the adult brain. Kindling, a process in which recurrent electrical stimulations initially produce only in brief electrical discharges and mild behavioral changes but, as the stimulations continue, result in more prolonged and intense electrical and behavioral seizures, occurs at all ages. Kindling occurs more rapidly in young animals than in mature animals (55). In addition, a shorter period of postictal refractoriness in young animals leads to a quick progression through the early stages of kindling and results in rapid generalization of seizures (26). Immature rats are also more likely to develop seizures with hypoxia than are mature rats (31). Although the threshold for seizure generation is lower in immature than in adult brains, developing neurons are less vulnerable, in terms of neuronal damage and cell loss, than adult neurons to a wide variety of pathologic insults. For example, immature hippocampal neurons continue responding to synaptic stimuli in a fully anoxic environment for longer durations than adult ones (14). Similarly, longer anoxic episodes are required to irreversibly destroy the circuit in young animals (79). This reduced vulnerability is also reflected in the consequences of status epilepticus (SE). The pathophysiologic effects of SE are age-related, with both the morphologic and the behavioral consequences dependent on the age at SE onset.
C S SE has been associated with a high incidence of neurologic sequelae (1, 2). In a study of 239 cases of SE in children, acquired neurologic deficits were found after the episode of SE in 47 (20%), and mental retardation was found in 78 (33%) (10). The combined incidence of new mental and neurologic abnormalities after SE was 34%. In a study by Aicardi and Chevrie (2), the duration of SE was defined as greater than 60 minutes, substantially longer than the more recently used criterion of 30 minutes. The incidence of neurologic deficits after SE was much lower in a later study reported by Maytal et al. (48). New neurologic deficits were found in 17 (9%) of the 186 survivors. All of the deaths and almost all of the neurologic sequelae (15 of 17 cases) occurred in the 56 children with an acute or progressive neurologic disorder. Neurologic sequelae were age dependent, occurring in 29% of infants less than 1 year old, 11% of children ages 1–3 years, and 6% of children older than 3 years. However, these results reflected the greater incidence of acute neurologic disease in the younger age groups. It is likely that the improved mortality and morbidity rates associated with SE are due to earlier and better methods of treatment. The results of Maytal et al. (48) also suggest that the prognosis of SE in children is more favorable than in adults. Although their overall outcome after SE is generally favorable, children sometimes do incur neurologic sequelae, even when appropriately managed (40, 76, 77). Van Esch and colleagues (76) retrospectively studied 57 children (ages 6–57 months) who had SE secondary to fever. None of the children had had previous seizures or neurologic abnormalities. Twelve children (21%) had subsequent neurologic sequelae that varied from speech deficits in nine children to severe neurologic deficits and epilepsy in three children. In this study, the most important predictors of adverse sequelae were the number of drugs needed for seizure termination and the duration of the seizures.
.:
399
Children with refractory SE have a very high risk of neurologic sequelae. Sahin et al. (63) operationally defined refractory SE as a seizure lasting more than 60 minutes despite initial therapy with a benzodiazepine (diazepam or lorazepam) followed by treatment with phenobarbital or phenytoin, with therapeutic levels achieved. Of the 22 children they described, seven died, eight developed new neurologic deficits, including seizures, and the condition of seven returned to baseline. None of the eight children with normal premorbid neurologic status saw a return to baseline condition. Although SE is associated with a wide variety of neuropsychological problems, memory deficits, including impairment of episodic memory, are especially prominent (34, 38, 76). In animal models, impairment of spatial memory is a common finding after SE (20, 62, 84, 85) and is discussed later in the chapter. A S In assessing the effects of SE on subsequent cognitive development in children, it is often difficult to differentiate between the effects of the cause of the SE, the effects of seizure duration, and adverse cognitive effects of the antiepileptic drugs used. Animal models are quite useful in controlling for these and other variables. An example of the value of animal experimentation is the pioneering work of Meldrum and colleagues (50, 51) on seizureinduced brain damage. These investigators found that adolescent baboons subjected to 1.5–5 hours of SE induced by bicuculline sustained neuronal cell loss in the neocortex, hippocampus, and cerebellum. To determine whether the cell loss was due to systemic derangements such as hypoxia, hypercapnia, hypoglycemia, or hyperthermia, baboons were paralyzed and maintained in metabolic homeostasis with maintenance of normal blood pressure, oxygen and carbon dioxide pressures, glucose concentration, and body temperature. These baboons also sustained cell loss in the neocortex, in the hippocampus (involving Sommer’s sector and the end folium), and in the thalamus, clearly demonstrating that SE, even in the absence of systemic metabolic derangements, can lead to brain damage. In rodent studies, there are clear differences in the consequences of SE in immature and mature rats. The morphologic and behavioral consequences of SE as a function of age are reviewed next. Morphologic studies Although seizures can induce changes in multiple areas of the brain, the hippocampus has been particularly well studied, because this is the brain area that is most vulnerable to seizure-induced injury. In the adult animal, SE causes neuronal loss in hippocampal fields CA1, CA3, the dentate granule cell layer, and the dentate hilus (5, 7, 56, 57, 67). Cellular damage results from excessive excitatory neurotransmitter release, which activates
400
:
N-methyl--aspartate (NMDA) receptors and voltageactivated Ca2+ channels, allowing Ca2+ to enter the cell. Increased intracellular Ca2+ and other ionic changes result in a cascade of biochemical changes that eventually result in cell death (42). A high Ca2+ concentration leads to the generation of reactive oxygen species via activation of nitric oxide synthase, uncouples oxidative phosphorylation in mitochondria, and activates a large range of enzymes, such as lipases, proteases, endonucleases, and other catabolic enzymes, that collectively have adverse consequences for cell function (17). Seizures in the adult brain lead to various forms of synaptic plasticity, including long-term potentiation of synaptic responses, a process that is reminiscent of that occurring in memory processes (6). This is followed by alterations in the cortical network that result in a reduction of seizure threshold. Thus, prolonged seizures can cause synaptic reorganization with aberrant growth (sprouting) of granule cell axons (the so-called mossy fibers) in the supragranular zone of the fascia dentata (60, 72) and infrapyramidale region of CA3 (60). Since glutamate is the neurotransmitter of the mossy fibers, it is likely that this sprouting results in an excessive degree of excitation of dentate granule cells and CA3 pyramidal neurons. A further indication of the role of excitability in the generation of synaptic plasticity is the observation that blocking one of the glutamate receptor subtypes (NMDA) retards the development of mossy fiber development (49, 72). Sprouting and neosynapse formation occur in other brain regions, notably the CA1 pyramidal neurons, where newly formed synapses produce an enhanced frequency of glutamatergic spontaneous synaptic currents (19). Therefore, these alterations appear to be a general response of cortical networks to neuronal hyperexcitability, the consequences of the seizures far outlasting the effects of the initiating event. Compared with SE in the mature brain, SE in the immature rodent brain is associated with far less damage. A single prolonged seizure in very young rats (<14 days old) results in no discernible hippocampal cell loss (3, 12, 15, 68, 71) or sprouting (4, 68). However, the rat pup is not totally resistant to seizure-induced brain damage (15, 65, 75, 81, 83). Kubová et al. (39) demonstrated that SE results in necrotic damage in the mediodorsal nucleus of the thalamus in rat pups. Hippocampal cell injury elicited by seizures occurs later, beginning between the second and third postnatal weeks (15, 65). Figure 32.1 shows cell loss and supragranular sprouting in a rat subjected to SE on postnatal day 20 (P20). In addition, although rat studies are very useful in helping researchers understand the neurobiology of SEinduced injury, there are good indications that the degree of seizure-related damage is related to the species studied (21, 74). Unlike in rats, kainate-induced seizures in immature rabbits reliably induce neuronal injury (21).
F 32.1 Examples of cell loss (A, B) and supragranular sprouting (C, D) in control rat (A, C) and a rat with SE (B, D). Note cell loss in CA3 of SE rat (B, arrow) compared to control (A, arrow). Although cell loss was seen in other areas of the hippocampus, including CA1 and the hilus, it was most pronounced in CA3.
Supragranular Timm staining (arrow) is seen in the animals with SE (D) but not in the control animal (C, arrow). The staining was prominent in the inner molecular layer (IML) of the dentate gyrus (DG) (arrowheads). Calibration mark = 50 mm. (See Color Plate 8.)
Although overt cell loss and synaptic organization appear to be minimal during the first weeks of life, SE can result in changes in the developing brain that increase the risk for subsequent damage with a second insult. Koh et al. (37) studied the effects of SE in the second week of life on subsequent seizure-induced neuronal damage and behavior. Systemic kainate was used to induce seizures on P15 and again in adolescence, on P45. Although kainate-induced seizures on P15 did not result in any detectable injury or cell death, it predisposed animals to more extensive neuronal injury after the second seizure in adulthood. Moreover, although early life kainate-induced seizures caused no impairment of spatial learning, animals that had kainate-induced seizures in both early life and adulthood performed significantly worse than those who had seizures only as adults. This study demonstrated that early life seizures, without causing overt cellular
injury, predisposed the brain to the damaging effects of seizures later in life. Likewise, Schmid et al. (66) reported that SE in adolescent rats with a history of neonatal seizures caused substantially more damage than in animals without a history of neonatal seizures. The authors found no cell loss in animals that had neonatal seizures only. Although the mechanism for the enhanced susceptibility to injury is not known, the study provides further evidence that seizures can alter the developing brain by means other than cell loss. Mechanisms responsible for age-related differences in vulnerability to SE It is likely that SE, if severe and prolonged, can result in damage at any age. The preponderance of evidence, however, shows that the immature brain is less vulnerable to SE-induced injury than the mature brain is. There are a number of anatomic and physiologic differences between
.:
401
the immature and mature brain that may render the immature brain less vulnerable to injury (64). A few of the major differences relevant to SE are briefly discussed here. Differences in metabolic needs in the mature and immature brain likely account for some of the age-related responses to SE. There is considerable evidence that seizureevoked neuronal necrosis results from energy failure (82). Seizures are associated with a sharp increase in brain energy debt to restore the ionic gradients, which are strongly disturbed during seizure activity. Although there are augmented metabolic attempts to compensate for the increased demand (58, 59), energy reserves become depleted after prolonged seizures (22). From studies of the effects of hypoxia, it is known that as soon as the intracellular depots of energy are exhausted and the level of adenosine triphosphate (ATP) drops below 10% of control value, the activity of Na,KATPase ceases, resulting in major changes in the ionic gradients and rapid depolarization to nearly 0 mV (32, 78). In the case of hypoxia, rapid depolarization is the key phenomenon that marks the beginning of the phase when irreversible damage occurs to neurons (41). Rapid depolarization also develops after severe seizures, terminating the epileptic discharge and resulting in underlying postictal depression (10). It is likely that neuronal death evoked by seizure also occurs during postictal depolarization, as in the case of hypoxia. Immature neurons have lower metabolic demand and in particular are capable of maintaining energy production via anaerobic glycolysis. Therefore, their metabolic state during SE is less compromised compared with mature neurons. Studies using the intact hippocampus from neonatal rats in vitro fail to reveal any spreading depression-like phenomenon at the end of the sustained ictal discharges induced by bicuculline, kainate, or high K+ (33–36), also suggesting a different mechanism for postictal depression in the immature hippocampus. It has been argued that the decreased vulnerability of the immature brain may simply reflect the immaturity of excitatory pathways, with an insufficient amount of glutamate released during seizures to cause neuronal damage (61). Counterposed to this argument is the finding that similar elevations in extracellular glutamate occur in immature and mature rats during pilocarpine- or kainate-induced SE (66). The issue of age-related changes in glutamate release during seizures requires more study. Microdialysis probes provide only a gross measure of changes in neurotransmitters, and little is known about changes in glutamate and other neurotransmitters at the synapse level. The immature brain does appear to be more “resistant” to the toxic effects of glutamate than the mature brain (9, 44, 47). Bickler et al. (9) noted an increase in intracellular Ca2+ of 240% from ages P1–P2 to age P28 after application
402
:
of 500 mM glutamate in rat cerebral cortex slices. When the effects of hypoxia, aglycemia, and hypoxia-aglycemia on synaptosomal free Ca2+ were studied, it was found that neither aglycemia or hypoxia-aglycemia caused a rise in Ca2+ in rats that were P20 or younger, whereas significant increases in Ca2+ occurred in older rats. These ontogenetic differences in intracellular Ca2+ accumulation could not be attributed to differences in ATP levels, since the decline in ATP levels was similar in all age groups. Likewise, the degree of Ca2+ entry into CA1 neurons is directly related to age; in P1–P3 neurons glutamate minimally increases intracellular Ca2+, whereas in P21–P25 neurons glutamate results in marked increases in intracellular Ca2+ and causes neuronal swelling and retraction of dendrites into the soma (47). This relative resistance is thought to be due to the smaller density of active synapses, lower energy consumption, and, in general, the relative immaturity of the biochemical cascades that lead to cell death. Carmant and colleagues (11) measured inositol 1,4,5 trisphosphate (IP3), one of the intermediates in the complex cascade of phosphoinositide hydrolysis, following kainate infusion in immature and mature rats. IP3 is of particular interest in seizures and seizure-induced brain damage because of its role in direct regulation of intracellular Ca2+ stores and its possible role, with IP4, in promoting influx of external Ca2+ in conjunction with IP4 (29, 52). Despite kainate causing more severe seizures in the immature animals, there was no hippocampal damage or induction of phosphoinositide hydrolysis. In mature animals, seizures were mild, but severe hippocampal damage was seen and was associated with a marked and sustained release of IP3. Intracellular Ca2+ buffering capabilities may also differ as a function of age. The age-related effects of glutamate on hippocampal neurons were directly measured through injections of glutamate in vivo (44). When equal amounts of glutamate (0.5 mmol) were injected unilaterally into the CA1 subfield of the hippocampus, the size of the resultant hippocampal lesion was highly age dependent. Minimal cell loss was noted in P10 rats; lesions in P20 rats were smaller than those in P30 and P60 rats, which were similar in extent. This study, in which the same volumes and concentrations of glutamate were given to each age group, argues against the hypothesis that the age differences in seizure-induced brain damage are due solely to reduced release of glutamate during seizures in the immature brain. Rather, the results suggest that glutamate is less toxic in the immature brain than in the mature brain. The factors responsible for the age-related differences in brain damage after SE are likely to be multifactorial and complex. A better understanding of the biological processes that differ in the immature and mature brain will be
instrumental in designing novel therapeutic approaches to SE. Behavior studies Like the studies evaluating morphology, behavioral studies have shown age-related effects on cognitive deficits after SE (15, 18, 43, 69, 70). In general, there is a reasonable correlation between morphologic changes in the brain—that is, cell loss or mossy fiber sprouting—and cognitive impairment after SE. As with histologic damage, cognitive dysfunction after SE is greater in mature than in immature animals. Stafstrom and colleagues (70) found that the long-term behavioral sequelae of kainate-induced SE are determined by the age at which the kainate is given. Rats of P5, P10, P20, P30, and P60 days were administered kainate in doses that caused SE but little or no mortality. For several months after the episode of SE, rats were monitored by videotape for spontaneous seizure recurrence. Rats also underwent behavioral testing to examine the effects of SE on cognitive function. Behavioral tests included the Morris water maze (a test of visuospatial learning and memory), the open field test (a measure of responsiveness to a novel environment), and the handling test (to assess emotional responses to stressful or painful stimuli). Behavioral testing began on P80, well into adulthood. A separate group of rats were subjected to kainate-induced SE on P60 and then began behavioral testing on P120, to ensure that results were not confounded by the length of time since SE occurred. The water maze tests visual-spatial abilities by requiring the rat to find the location of a submerged platform in a pool of water using only visual cues from the room’s environment (53, 54). Normally a rat will quickly learn the platform’s location and on subsequent trials will quickly swim to the platform and mount it. A reduction in the time needed to find the escape platform with multiple trials is a measure of spatial memory. After several days of training, the platform is removed from the tank and the rat is placed in the pool for an additional trial to test its ability to remember the platform’s previous position (spatial bias or “probe” test). The amount of time spent in each quadrant is then calculated. Typically a rat will spend most of the time swimming in the quadrant of the tank where the platform had been previously located. Rats with hippocampal lesions are impaired in their ability to find and remember the location of the platform. The open field test assesses motor activity in a novel environment. Normal rats explore an open field with caution, whereas those with various brain lesions are “disinhibited” and show hyperactive behavior in the open field (80). In the handling test, rats with cerebral dysfunction become unusually aggressive on routine handling or in response to mildly painful stimuli (25, 27, 28).
Rats in all age groups developed severe kainate-induced seizures, although younger animals required less kainate on a milligram-per-kilogram basis. In addition, the latency time to seizures was shorter in the younger rats and the seizure mortality was higher, suggesting that the seizures in the immature rats were at least as severe as, if not more so than, the seizures in the adult rats. Nevertheless, rats that received kainate on P5 or P10 did not develop spontaneous seizures. In addition, when rats that received kainate on P5 or P10 were challenged as adults with the convulsant inhalant flurothyl, there was no significant difference between control and kainate-treated rats in latency time to flurothyl-induced seizures. Taken together, these results suggest that there is no increase in subsequent seizure susceptibility after SE at these young ages. In contrast, rats that received kainate at age P20 or older developed recurrent seizures, with the incidence and frequency of spontaneous seizures increasing with age. Kainate-treated P5 and P10 rats had no demonstrable deficits on any behavioral test compared with controls. Kainate-treated P20 rats differed from controls only on the water maze spatial bias test. Kainate-treated P30 rats had deficits in spatial bias, were more active in the open field, and were more aggressive when handled. Kainate-treated P60 rats, whether tested on P80 or on P120, had deficits in learning platform position and spatial bias on the water maze test, were more active in the open field test, and were more aggressive when handled. In a somewhat similar study, Cilio et al. (15) used lithium and pilocarpine to induce SE in P12, P16, and P20 rats and then studied visual-spatial memory in the water maze when the animals were adults (P55). The authors demonstrated that rats undergoing SE at age P12 had no histologic lesions and performed similarly to controls in the water maze when studied as adults. SE at P16 and P20 elicited cell loss, mossy fiber sprouting, and water maze impairment when animals were tested as adults. Cell damage and cognitive deficits have now been demonstrated by a number of investigators when the SE occurs at P20 or later (20, 62). Whether cognitive dysfunction is detected after SE in rodents may be task dependent. Rat pups (P1–P14) subjected to kainate-induced seizures had long-term impairment on the radial arm maze, a hippocampal-dependent spatial memory task (46). Rats receiving kainate on P10 were also found to have impairment in righting responses and a prolonged reaction time in an active avoidance task when studied during adolescence (16). As with the case of SE-induced histologic damage, it is likely that SE at any age can result in cognitive deficits when the animals are studied later in life. The type and extent of cognitive impairment are related to the test chosen and how it is performed (69). The preponderance of studies have demonstrated a clear age-related effect of SE on cognitive
.:
403
function, with younger animals faring better than mature ones.
10.
Summary Although children are at high risk for SE, both clinical and experimental data suggest that the immature brain is less vulnerable to the adverse effects of prolonged seizures. Although the reasons for this age-related phenomenon are not clear, there is increasing evidence that the decreased vulnerability of the immature brain to glutamate relates to differences in the postsynaptic action of glutamate. These observations may lead to the development of age-specific therapeutic approaches to SE. The reduced vulnerability to seizure-induced brain injury does not mean that the immature brain is completely resistant to seizure-induced injury. Children who have had SE need to be followed closely for the development of cognitive effects. Although animal studies indicate potential mechanisms and trends in age-related consequences of seizures, extrapolation of animal findings to children should be done with great caution. This research was supported by grant No. NS27984 from the National Institute of Neurological Disorders and Stroke.
11.
12.
13.
14.
15.
16.
17.
18. REFERENCES 1. 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: Mechanisms of Brain Damage and Treatment. Adv. Neurol. 1983;34:115–125. 2. Aicardi, J., and J. J. Chevrie. Convulsive status epilepticus in infants and children. Epilepsia 1990;11:187–197. 3. Albala, B. J., S. L. Moshé, and R. Okada. Kainic-acid-induced seizures: A developmental study. Dev. Brain Res. 1984;13: 139–148. 4. Baram, T. Z., and C. E. Ribak. Peptide-induced infant status epilepticus causes neuronal death and synaptic reorganization. Neuroreport 1995;6:277–280. 5. Ben-Ari, Y. Limbic seizure and brain damage produced by kainic acid: Mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 1985;14:375–403. 6. Ben-Ari, Y., and M. Gho. Long-lasting modification of the synaptic properties of rat CA3 hippocampal neurones induced by kainic acid. J. Physiol. 1988;404:365–384. 7. Ben-Ari, Y., E. Tremblay, and O. P. Ottersen. Injections of kainic acid into the amygdaloid complex of the rat: An electrographic, clinical and histological study in relation to the pathology of epilepsy. Neuroscience 1980;5:515–528. 8. Berg, A. T., S. Shinnar, S. R. Levy, F. M. Testa, S. SmithRapaport, B. Beckerman, et al. Two-year remission and subsequent relapse in children with newly diagnosed epilepsy. Epilepsia 2001;42:1553–1562. 9. Bickler, P. E., S. M. Gallego, and B. M. Hansen. Developmental changes in intracellular calcium regulation in rat
404
:
19.
20.
21.
22.
23. 24. 25.
26. 27.
cerebral cortex during hypoxia. J. Cereb. Blood Flow Metab. 1993; 13:811–819. Bragin, A., M. Penttonen, and G. Buzsaki. Termination of epileptic afterdischarge in the hippocampus. J. Neurosci. 1997;17:2567–2579. Carmant, L., Z. Liu, S. Werner, M. A. Mikati, and G. L. Holmes. Role of inositol-trisphosphate and intracellular calcium stores in kainic acid–induced hippocampal damage. Ann. Neurol. 1994;36:526–527. Cavalheiro, E. A., D. F. Silva, W. A. Turski, L. S. CalderazzoFilho, Z. A. Bortolotto, and L. Turski. The susceptibility of rats to pilocarpine-induced seizures is age-dependent. Brain Res. 1987;465:43–58. Chen, K., T. Z. Baram, and I. Soltesz. Febrile seizures in the immature rat model modify neuronal excitability long-term. Nat. Med. 1999;5:888–894. Cherubini, E., Y. Ben-Ari, and K. Krnjevic. Anoxia produces smaller changes in synaptic transmission, membrane potential and input resistance in immature rat hippocampus. J. Neurophysiol. 1989;62:882–895. Cilio, M. R., Y. Sogawa, B. H. Cha, Z. Liu, L.-T. Huang, and G. L. Holmes. Long-term effects of status epilepticus in the immature brain are specific for age and model. Epilepsia 2003;44:518–528. De Feo, M. R., O. Mecarelli, G. Palladini, and G. F. Ricci. Long-term effects of early status epilepticus on the acquisition of conditioned avoidance behavior in rats. Epilepsia 1986;27:476–482. De Keyser, J., G. Sulter, and P. G. Luiten. Clinical trials with neuroprotective drugs in acute ischaemic stroke: Are we doing the right thing? Trends Neurosci. 1999;22:535–540. dos Santos, N. F., R. M. Arida, E. M. Filho, M. R. Priel, and E. A. Cavalheiro. Epileptogenesis in immature rats following recurrent status epilepticus. Brain Res. Brain Res. Rev. 2000;32: 269–276. Esclapez, M., J. Hirsch, Y. Ben-Ari, and C. Bernard. Newly formed excitatory pathways provide a substrate for hyperexcitability in experimental temporal lobe epilepsy. J. Comp. Neurol. 1999;408:449–460. Faverjon, S., D. C. Silveira, D. D. Fu, B. H. Cha, C. Akman, Y. Hu, et al. Beneficial effects of enriched environment following status epilepticus in immature rats. Neurology 2002;59: 1356–1364. Franck, J. E., and P. A. Schwartzkroin. Immature rabbit hippocampus is damaged by systemic but not intraventricular kainic acid. Dev. Brain Res. 1984;13:219–227. Fujikawa, D. G., R. C. Vannucci, B. E. Dwyer, and C. G. Wasterlain. Generalized seizures deplete brain energy reserves in normoxemic newborn monkeys. Brain Res. 1988;454:51–59. Hauser, W. A. Seizure disorders: The changes with age. Epilepsia 1992;33(Suppl. 4):S6–S14. Hauser, W. A., and D. C. Hersdorffer. Epilepsy: Frequency, Causes and Consequences. New York: Demos, 1990. 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. Dev. Brain Res. 1993;73:71–77. Holmes, G. L., and J. L. Thompson. Rapid kindling in the prepubescent rat. Brain Res. 1987;433:281–284. Holmes, G. L., J. L. Thompson, T. A. Marchi, P. S. Gabriel, M. A. Hogan, F. G. Carl, et al. Effects of seizures on learning, memory, and behavior in the genetically epilepsy-prone rat. Ann. Neurol. 1990;27:24–32.
28. Holmes, G. L., S. T. Thurber, Z. Liu, C. E. Stafstrom, A. M. 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. 29. Irvine, R. F. Inositol tetrakisphosphate as a second messenger: Confusions, contradictions and a potential resolution. BioEssays 1991;13:419–427. 30. Jambaque, I., G. Dellatolas, O. Dulac, G. Ponsot, and J. L. Signoret. Verbal and visual memory impairment in children with epilepsy. Neuropsychologia 1993;31:1321–1337. 31. Jensen, F. E., C. D. Applegate, D. Holzman, T. R. Belin, and J. L. Burchfiel. Epileptogenic effect of hypoxia in the immature rodent brain. Ann. Neurol. 1991;29:629–637. 32. Katsura, K., E. B. Rodriguez de Turco, J. Folbergrova, N. G. Bazan, and B. K. Siesjö. Coupling among energy failure, loss of ion homeostasis, and phospholipase A2 and C activation during ischemia. J. Neurochem. 1993;61:1677–1684. 33. Khalilov, I., V. Dzhala, Y. Ben-Ari, and R. Khazipov. Dual role of GABA in the neonatal rat hippocampus. Dev. Neurosci. 1999;21:310–319. 34. Khalilov, I., V. Dzhala, I. Medina, X. Leinekugel, Z. Melyan, K. Lamsa, et al. Maturation of kainate-induced epileptiform activities in interconnected intact neonatal limbic structures in vitro. Eur. J. Neurosci. 1999;11:3468–3480. 35. Khalilov, I., M. Esclapez, I. Medina, D. Aggoun, K. Lamsa, X. Leinekugel, et al. A novel in vitro preparation: The intact hippocampal formation. Neuron 1997;19:743–749. 36. Khalilov, I., R. Khazipov, M. Esclapez, and Y. Ben-Ari. Bicuculline induces ictal seizures in the intact hippocampus recorded in vitro. Eur. J. Pharmacol. 1997;319:R5–R6. 37. Koh, S., T. W. Storey, T. C. Santos, A. Y. Mian, and A. J. Cole. Early-life seizures in rats increase susceptibility to seizureinduced brain injury in adulthood. Neurology 1999;53: 915–921. 38. 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. 39. Kubová, H., R. Druga, K. Lukasiuk, L. Suchomelová, R. Haugvicová, I. Jirmanová, et al. Status epilepticus causes necrotic damage in the mediodorsal nucleus of the thalamus in immature rats. J. Neurosci. 2001;21:3593–3599. 40. Kwong, K. L., S. L. Lee, A. Yung, and V. C. Wong. Status epilepticus in 37 Chinese children: Aetiology and outcome. J. Paediatr. Child Health. 1995;31:395–398. 41. Lipton, P. Ischemic cell death in brain neurons. Physiol. Rev. 1999;79:1431–1568. 42. Lipton, S. A., and P. A. Rosenberg. Excitatory amino acids as a final common pathway for neurologic disorders. N. Engl. J. Med. 1994;330:613–622. 43. Liu, Z., A. Gatt, M. Mikati, and G. L. Holmes. Long-term behavioral deficits following pilocarpine seizures in immature rats. Epilepsy Res. 1995;19:191–204. 44. Liu, Z., C. E. Stafstrom, M. Sarkisian, P. Tandon, Y. Yang, A. Hori, et al. Age-dependent effects of glutamate toxicity in the hippocampus. Dev. Brain Res. 1996;97:178–184. 45. Liu, Z., C. E. Stafstrom, M. R. Sarkisian, Y. Yang, A. Hori, P. Tandon, et al. Seizure-induced glutamate release in mature and immature animals: An in vivo microdialysis study. Neuroreport 1997;8:2019–2023. 46. Lynch, M., U. Sayin, J. Bownds, S. Janumpalli, and T. Sutula. Long-term consequences of early postnatal seizures on
47.
48.
49.
50.
51.
52.
53.
54.
55. 56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
hippocampal learning and plasticity. Eur. J. Neurosci. 2000;12: 2252–2264. Marks, J. D., J. E. Friedman, and G. G. Haddad. Vulnerability of CA1 neurons to glutamate is developmentally regulated. Brain Res. Dev. Brain Res. 1996;97:194–206. Maytal, J., S. Shinnar, S. L. Moshé, and L. A. Alvarez. Low morbidity and mortality of status epilepticus in children. Pediatrics 1989;83:323–331. McNamara, R. K., and A. Routtenberg. NMDA receptor blockade prevents kainate induction of protein F1/GAP-43 mRNA in hippocampal granule cells and subsequent mossy fiber sprouting in the rat. Mol. Brain Res. 1995;33:22–28. 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. Meldrum, B. S., R. W. Horton, and J. B. Brierley. Epileptic brain damage in adolescent baboons following seizures induced by allylglycine. Brain Res. 1974;97:417–428. Mitani, A., H. Yanase, K. Sakai, Y. Wake, and K. Kataoka. Origin of intracellular calcium elevation induced by in vitro ischemia-like condition in hippocampal slices. Brain Res. 1993; 601:103–110. Morris, R. Development of a water maze procedure for studying spatial learning in the rat. J. Neurosci. Meth. 1984; 11:47–60. Morris, R. G., P. Garrud, J. N. Rawlins, and J. O’Keefe. Place navigation impaired in rats with hippocampal lesions. Nature 1982;297(5868):681–683. Moshé, S. L. The effects of age on the kindling phenomenon. Dev. Psychobiol. 1981;14:75–81. Nadler, J. V., B. W. Perry, and C. W. Cotman. Intraventricular kainic acid preferentially destroys hippocampal pyramidal cells. Nature 1978;271:676–677. Olney, J. W., T. Fuller, and T. De Gubareff. Acute dendrotoxic changes in the hippocampus of kainate-treated rats. Brain Res. 1979;176:91–100. Petroff, O. A., J. W. Prichard, K. L. Behar, J. R. Alger, and R. G. Shulman. In vivo phosphorus nuclear magnetic resonance spectroscopy in status epilepticus. Ann. Neurol. 1984;16: 169–177. Pinard, E., 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;13:1051–1072. Represa, A., E. Tremblay, and Y. Ben-Ari. Kainate binding sites in the hippocampal mossy fibers: Localization and plasticity. Neuroscience 1987;20:739–748. Ribak, C. E., and M. S. Navetta. An immature mossy fiber innervation of hilar neurons may explain their resistance to kainate-induced cell death in 15-day-old rats. Dev. Brain Res. 1994;79:47–62. Rutten, A., M. van Albada, D. C. Silveira, B. H. Cha, X. Liu, Y. N. Hu, et al. Memory impairment following status epilepticus in immature rats: Time-course and environmental effects. Eur. J. Neurosci. 2002;16:501–513. Sahin, M., C. C. Menache, G. L. Holmes, and J. J. Riviello. Outcome of severe refractory status epilepticus in children. Epilepsia 2001;42:1461–1467. Sanchez, R. M., and F. E. Jensen. Maturational aspects of epilepsy mechanisms and consequences for the immature brain. Epilepsia 2001;42:577–585. Sankar, R., D. H. Shin, H. Liu, A. Mazarati, A. Pereira de Vasconcelos, and C. G. Wasterlain. Patterns of status
.:
405
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80. 81. 82.
83. 84.
epilepticus–induced neuronal injury during development and long-term consequences. J. Neurosci. 1998;18:8382–8393. Schmid, R., P. Tandon, C. E. Stafstrom, and G. L. Holmes. Effects of neonatal seizures on subsequent seizure-induced brain injury. Neurology 1999;53:1754 –1761. Sloviter, R. S., E. Dean, A. I. 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. 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;60:88–93. Stafstrom, C. E. Assessing the behavioral and cognitive effects of seizures on the developing brain. Prog. Brain Res. 2002; 135:377–390. Stafstrom, C. E., A. Chronopoulos, S. Thurber, J. L. Thompson, and G. L. Holmes. Age-dependent cognitive and behavioral deficits following kainic acid–induced seizures. Epilepsia 1993;34:420–432. Stafstrom, C. E., J. L. Thompson, and G. L. Holmes. Kainic acid seizures in the developing brain: Status epilepticus and spontaneous recurrent seizures. Dev. Brain Res. 1992;65: 227–236. Sutula, T., J. Koch, G. Golarai, Y. Watanabe, and J. O. McNamara. NMDA receptor dependence of kindling and mossy fiber sprouting: Evidence that the NMDA receptor regulates patterning of hippocampal circuits in the adult brain. J. Neurosci. 1996;16:7398–7406. Tauck, D., and J. V. Nadler. Evidence of functional mossy fiber sprouting in the hippocampal formation of kainic acid–treated rats. J. Neurosci. 1985;5:1016–1022. Thompson, K., and C. Wasterlain. Lithium-pilocarpine status epilepticus in the immature rabbit. Dev. Brain Res. 1997; 100:1–4. Toth, Z., X.-X. Yan, S. Haftoglou, C. E. Ribak, and T. Z. Baram. Seizure-induced neuronal injury: Vulnerability to febrile seizures in an immature rat model. J. Neurosci. 1998; 18:4285–4294. van Esch, A., I. R. Ramlal, H. A. van Steensel-Moll, and E. W. Steyerberg. Outcome after febrile status epilepticus. Dev. Med. Child Neurol. 1996;38:19–24. VanLandingham, K. E., E. R. Heinze, J. E. Cavazos, and D. V. Lewis. Magnetic resonance imaging evidence of hippocampal injury after prolonged focal febrile convulsions. Ann. Neurol. 1998;43:413– 426. Verhaegen, M., P. A. Iaizzo, and M. M. Todd. A comparison of the effects of hypothermia, pentobarbital, and isoflurane on cerebral energy stores at the time of ischemic depolarization. Anesthesiology 1995;82:1209–1215. Volpe, J. J. Hypoxic-ischemic encephalopathy: Biochemical and physiological aspects. In Joseph J. Volpe, ed. Neurology of the Newborn. Philadelphia: W. B. Saunders, 2001:217–276. Walsh, R. N., and R. A. Cummins. The open field test: A critical review. Psychol. Bull. 1976;83:482–504. Wasterlain, C. G. Effects of neonatal status epilepticus on rat brain development. Neurology 1975;26:975–979. Wasterlain, C. G., J. Niquet, K. W. Thompson, R. Baldwin, H. Liu, R. Sankar, et al. Seizure–induced neuronal death in the immature brain. Prog. Brain Res. 2002;135:335–353. Wasterlain, C. G., and F. Plum. Vulnerability of developing rat brain to electroconvulsive seizures. Arch. Neurol. 1973;29:38–45. Wu, C. L., L. T. Huang, C. W. Liou, T. J. Wang, Y. R. Tung, H. Y. Hsu, et al. Lithium-pilocarpine-induced status
406
:
epilepticus in immature rats result in long-term deficits in spatial learning and hippocampal cell loss. Neurosci. Lett. 2001; 312:113–117. 85. Yang, Y., Z. Liu, J. M. Cermak, P. Tandon, M. R. Sarkisian, C. E. Stafstrom, et al. Protective effects of prenatal choline supplementation on seizure-induced memory impairment. J. Neurosci. 2000;20(22):RC109.
VI BASIC MECHANISMS: EPILEPTOGENESIS
33
Late Consequences of Status Epilepticus
, , .
Introduction Status epilepticus (SE) is defined as an epileptic seizure lasting more than 30 minutes or intermittent seizures lasting more than 30 minutes during which the patient does not regain consciousness between repeated episodes (47, 48). SE represents a major medical and neurological emergency and can be the basis for fixed and lasting neurologic conditions (34). Approximately 10% of patients with previous epilepsy can be expected to experience SE in their lifetime (48); however, SE can be the first epileptic manifestation in a subgroup of patients. SE occurs mainly in the early years of life (47), a period in which SE and other epileptic events can be more detrimental to further brain development (100). The main neurologic sequelae of SE reported in the literature include cognitive impairment, brain damage–related deficits, and the long-term development of recurrent seizures. The occurrence of SE without a previous history of epilepsy is not rare and seems to be a function of age at the time of SE (66). The occurrence of SE as the first ictal episode varies from 50% to 80% in several studies of patients with SE (1, 3, 66, 73), and approximately 20% of these patients develop epilepsy later in life (1, 66). SE has also been a strong predictor of seizure intractability in patients with histories of epileptic seizures refractory to antiepileptic drug treatment (87). In humans, the causal relation linking SE and the further development of epilepsy seems to be related to the cause of SE and has serious implications for the subsequent treatment of these patients (44). Using a simplistic classification, and taking together studies in both adults and children, idiopathic SE does not seem to increase the risk for epilepsy (83, 85), while symptomatic SE is able to facilitate the development of seizure disorders at some time in the future (4, 5, 13, 47, 50, 70). Retrospective studies in patients with partial epilepsy who underwent surgery for temporal lobe epilepsy showed that approximately 50% of the patients reported a history of “severe” or “prolonged” infantile convulsions (38, 39, 61). In a recent study in which only patients with medial temporal lobe epilepsy were evaluated (those with mass lesions were excluded), 81% of patients gave a history of
convulsions during early childhood or infancy. Complicated febrile seizures were described by 94% of the patients from whom detailed descriptions of the febrile seizures were obtained (42). On the other hand, prospective studies have shown that the risk for the development of epilepsy is similar for those presenting with SE and for those presenting with an isolated seizure as the first unprovoked ictal event (47, 49, 82–84). Once again, the etiology of SE seems to be determinant, and substantial evidence indicates that febrile or symptomatic SE (26, 65) are most likely to induce later epilepsy. A common problem for all clinical studies in addressing the issue of whether neurologic sequelae and chronic epilepsy can be accounted for by a previous episode of SE is that of prior unrecognized brain dysfunction or damage that preceded both the SE and the presumed SE-induced neurologic deficit (58). In temporal lobe epilepsy, for example, it has been suggested that mesial temporal sclerosis may represent a sequela of disturbed embryogenesis (80). Another limitation of human clinical-pathologic studies of patients with refractory epilepsy is that surgically resected specimens give only a frozen picture of an “endpoint” process of epileptogenesis. For these reasons, experimental preparations are particularly useful because they allow the study of SE-induced epileptogenesis starting from a “nonpathologic” brain, and the course of neuropathologic changes can be assessed more dynamically. Over the past decade, the development of new animal models close to human temporal lobe epilepsy has helped investigators assess the problem of whether SE causes later epilepsy. This chapter considers the experimental evidence hypothesizing that epilepsy with spontaneous recurrent seizures following SE implies that the massive epileptic activation during SE and the subsequent neuronal damage may induce plastic changes that underlie the ensuing epileptogenesis (20).
Animal models of temporal lobe epilepsy Among the various experimental models developed in recent years we can find those induced by chemoconvulsants applied systemically or intracerebrally, such as kainic acid,
.:
409
pilocarpine, and cholera or tetanus toxin (10, 11, 21, 22, 54, 56, 64, 95), and those elicited by electrical stimulation of limbic structures (58, 59, 86, 88). Acute induction is characterized by longlasting limbic SE associated with sustained electrographic discharges in limbic structures. In these preparations, several parameters have been used to assess chronic epileptogenicity after the acute induction, such as thresholds for flurothyl-induced seizures (99), kindling facilitation (40), and response to paired electrical pulses (86, 88). However, the best criterion for the epileptic condition is the occurrence of actual spontaneous seizures. As in temporal lobe epilepsy patients with prolonged febrile convulsions, spontaneous recurrent seizures occur after a seizure-free interval or apparently normal behavior and electrographic activity. Accordingly, the phenomenologic descriptions and pathologic changes after SE-induced damage are critical for understanding the process of epileptogenesis. N H The administration of kainic acid or pilocarpine to rodents induces ictal and interictal epileptic activity in hippocampal and cortical electrographic recordings that are correlated with a sequence of behavioral alterations that includes akinesia, ataxic lurching, and facial automatisms, progressing to motor seizures and SE. After a single application of these drugs, SE can last from 6 to 12 hours. After spontaneous remission of SE, animals are comatose and both hippocampal and cortical recordings are depressed, with high-voltage spiking activity (11, 22, 60, 96). The electrical stimulation of afferent hippocampal pathways for approximately 90 minutes induces a self-sustained SE that lasts up to 12 hours (59). These events have been called the “acute period” of these models, and metabolic studies performed during this period have revealed increased glucose utilization mainly in the hippocampus and other limbic structures, thalamus, and substantia nigra (12, 45, 46, 98) (Figure 33.1). The pattern of neuronal loss observed in these animals closely matches the areas that are metabolically activated during SE (12, 21, 22, 28, 59); however, the occurrence of spontaneous seizures seems unrelated to the extent of brain damage in the tetanus toxin model (54). More recently, magnetic resonance imaging (MRI) has been used to explore changes during pilocarpine- and kainateinduced SE. MRI findings indicate acute cortical and hippocampal edema that can be observed days or weeks after SE (17, 77). Animals surviving the acute period of SE proceed to a latent, seizure-free period with apparently normal behavior except for some aggressivity on manipulation and toward other rats if they are maintained in groups (21, 22). This period lasts 1–8 weeks, depending on animal strain and method used to induce SE, and ends with the occurrence of the first spontaneous seizure. The recurrence of spontaneous seizures during the “chronic period” may vary according to
410
:
the model, ranging from one seizure per month to several seizures per day (7, 14, 15, 21, 22, 29, 56, 64, 86). The evolution of spontaneous seizures follows the behavioral and electrographic stages of kindling. Although this aspect has been better characterized for the pilocarpine model (22), the progression from an initial brief limbic event to a more generalized motor seizure has also been described for the kainic acid and electrical stimulation of the perforant path models (62). In the majority of Wistar rats injected with pilocarpine, the first seizure is normally characterized by paroxysmal discharges localized in the hippocampal or amygdala leads, without changes in cortical recordings. Behavioral correlates of this seizure comprise an arrest reaction, followed by eye blinking, chewing, and head nodding, resembling kindling stages 1 or 2. The following seizures show gradual synchronization of cortical and hippocampal records and longer duration of ictal events. Clonus of the forelimbs and rearing-with-falling, as in kindling stages 4 or 5, are the hallmarks of such seizures (Figure 33.2). However, the progression of spontaneous seizures is variable in terms of duration of paroxysmal discharges and the sequence of behavioral stages in every individual animal. Several seizure stages of similar or lesser intensity can be observed before a generalized motor convulsion is reached. Once the generalized convulsion similar to stage 5 kindled seizures occurs, then the vast majority of the following seizures are also generalized (Figure 33.3). These observations made in the pilocarpine model of epilepsy (22, 56) suggest that the development of epilepsy as a consequence of SE follows the stages of kindling.
Mechanisms of SE-induced epileptogenesis: Current hypotheses The massive and self-sustained epileptic activity that occurs during SE induces a cascade of molecular and cellular changes that seem to be fundamental steps in the development of an “epileptic” brain. Since the hippocampus has a central role in temporal lobe epilepsy, most neuropathologic, neurochemical, and electrophysiologic studies in experimental epilepsy have been concerned with this structure. These studies indicate that hippocampal damage seems to be a primary prerequisite for chronic limbic seizures (21, 22, 58, 59, 86, 88). Some hypotheses have been proposed to explain how neuronal death and the ensuing morphologic changes might lead to focal hyperexcitability in the hippocampus (67). The death of GABAergic interneurons in the alumina cream model led to the idea that decreased GABA-mediated inhibition would result in pathologic hyperexcitability of remaining neurons (75, 76). This hypothesis has been challenged by immunocytochemical studies of the sclerotic hippocampus from experimental animals and humans that demonstrated that GABAergic
F 33.1 14C-2-deoxyglucose (2-DG) autoradiograms (left) corresponding to diagrams (right) of the brain of a representative animal subjected to pilocarpine-induced SE. 2-DG injection was
done 3 hours after the beginning of SE. There is increased labeling in the striatum, septum, hippocampal formation, thalamus, substantia nigra, and cortex.
neurons are more resistant to seizure-induced neuron loss (9, 19, 32, 88). More recent studies, however, have redeemed this suspicion by showing that a subset of the GABAergicpositive neurons are in fact damaged after pilocarpineinduced SE (71) (Figure 33.4). Sloviter (88, 89) has proposed the “dormant basket cell” hypothesis to reconcile the apparently paradoxical findings of preserved GABAergic interneurons and loss of GABA-mediated inhibition in the perforant path model. This hypothesis proposes that the SEinduced death of excitatory neurons (i.e., the mossy cells) denervates the excitatory input to GABAergic basket cells, which become “dormant” without their usual activation by
mossy cells. The disconnection of GABAergic basket cells would reduce the level of inhibition of granule cells, and the decreased granule cell inhibition would facilitate the development of seizures (88, 89). The author concluded that reduced inhibition would be the hallmark of hippocampal epileptogenesis and that the plastic changes that occur after hippocampal damage (i.e., mossy fiber sprouting) would represent only a compensatory mechanism to restore dentate inhibition (90). Several points, however, remain unanswered under this scenario. First, the vast majority of mossy cell synaptic contacts in the ipsilateral hippocampus are normally onto
.:
411
F 33.2 Electrographic recordings obtained during the latent period (A) and the subsequent progression to a full stage 5 seizure (B and C) in the pilocarpine model of epilepsy, evincing a kindling-
like evolution of the spontaneous seizures. HPC, hippocampus; CX, cortex.
F 33.3 (A–C) Electrographic recordings of a spontaneous seizure observed in a rat 63 days after pilocarpine-induced SE. HPC, hippocampus; CX, cortex.
412
:
F 33.4 Morphologic changes in the pilocarpine model of epilepsy. (A and B) The hippocampus (A) and dentate gyrus (B) of a normal rat. (C and D) The same areas from an epileptic rat. (A
and C, Nissl staining; B and D, Timm staining.) Neuronal loss in CA1, CA3, and hilar regions is evident, as is mossy fiber sprouting in the epileptic brain.
proximal dendrites of granule cells (18). Second, aberrant mossy fibers after hippocampal damage do form functional excitatory synapses with granule cells (30). These findings are confirmed with ultrastructural studies showing asymmetric contacts of mossy fiber with granule cell dendrites (7, 72). Third, what do the abnormal electrophysiologic responses of paired-pulse stimuli represent in the context of chronic epilepsy? In the kainate model, paired perforant path stimulation shows loss of recurrent GABA-mediated inhibition 7 days after kainate-induced SE (90), at a time when usually no spontaneous seizures are observed in this model (22, 63). Paired-pulse responses return to normal after 2 months of kainate, indicating recovery of inhibition; however, at this time kainate-injected animals usually show spontaneous seizures. An alternative hypothesis, the synaptic reorganization of mossy fiber, suggests that the granule cell excitatory collaterals are the anatomic substrate of a positive feedback that results in hippocampal excitability and seizures. After mossy cell death and elimination of mossy cell axons, granule cells would display vacant postsynaptic sites in the inner molecular layer that would be occupied by their own mossy fiber axon collaterals (Figure 33.5). Several studies have indicated the occurrence of mossy fiber sprouting in response to lesions in the hippocampal formation in some animal models of epilepsy, as well as in human epilepsy (6, 24, 25, 68, 90, 93, 94). Such reorganization can be readily observed through the use of Timm staining, in which mossy fiber
buttons are recognized by their characteristically black staining, which is indicative of the high content of metal cations, mainly zinc (31). Evidence that mossy fiber sprouting is probably functional was brought by Tauck and Nadler (94), who demonstrated in slices from kainic acid–treated rats that antidromic stimulation resulted in multiple population spikes of granule cells. In vitro electrophysiologic studies in both humans and rats have provided additional information that is consistent with the association of abnormal granule cell responses and mossy fiber sprouting (30, 41). If mossy fiber aberrant axon collaterals are functional, one might expect that the postsynaptic domain of this circuitry would also undergo plastic changes. Immunocytochemical studies for antibodies against postsynaptic excitatory receptors have indicated increased NMDA and AMPA expression in association with mossy fiber sprouting (8, 63). More recently, three-dimensional reconstruction techniques and electrophysiologic recordings in CA1 have demonstrated that neosynapse formation is not restricted to the mossy fibers (37). In an attempt to support or refute these hypotheses, some experiments have been designed using pharmacologic agents that could interfere with axonal sprouting, then looking for the occurrence of spontaneous seizures on long-term follow-up. E A P E If we accept the premise that mossy fiber sprouting is directly
.:
413
F 33.5 Schematic representation of the synaptic reorganization of the mossy fiber after SE-induced mossy cell loss. (A)
Normal situation. (B) SE-induced death of the mossy cells. (C) Sprouting of the mossy fibers toward the granular cell layer.
dependent on hilar (mossy cell) damage, it seems conceivable that preventing SE-induced neuronal loss would prevent the course of events culminating in epilepsy. However, understanding the molecular mechanisms that control fascia dentata axon sprouting after neuronal damage may also suggest new therapeutic interventions aimed at halting epileptogenesis. It has been postulated that axon sprouting may be controlled or modulated by neurotrophins. For example, increased expression of neurotrophins and neurotrophin receptors can be induced in granule cells by seizure activity and may be part of the molecular events responsible for abnormal synaptic rearrangements (43, 67). Intraventricular infusions of anti-nerve growth factor (NGF) antibodies induced a selective inhibition of one type of sprouting (cholinergic) without hindering fascia dentata mossy fiber sprouting (52). Using intraventricular administrations of anti-NGF antibodies, Van der Zee et al. (97) were able to inhibit kindling-induced mossy fiber sprouting in the stratum oriens of CA3 and retard the rate of kindling. Moreover, various studies have shown that brain-derived neurotrophic factor (BDNF) increases neuronal excitability and is localized and upregulated in areas implicated in epileptogenesis. Seizure activity increases the expression of BDNF mRNA and protein, and recent studies have shown that interfering with BDNF signal transduction inhibits the development of the epileptic state in vivo. These results suggest that BDNF contributes to epileptogenesis (16). Besides NGF and BDNF, more than a dozen additional cytokines, growth factors, and neurotrophins have been examined in different animal models of epilepsy (53). There are some controversies regarding the antiepileptogenic effects of antiepileptic drugs (AEDs). In a recent publication, Shinnar and Berg (81), reviewing this aspect, concluded that AEDs do not alter the course of epilepsy. On
the other hand, experimental studies have used AEDs with the intent of altering the underlying epileptogenic process. AEDs or other agents with primary action on neurotransmitters, mainly GABA and glutamate receptors, have been used during or after kainate- or pilocarpineinduced SE in rats to determine whether these drugs could prevent the later development of epilepsy (69, 92). One of these experiments was carried out in our laboratory (69). Twenty-four hours after pilocarpine-induced SE, rats were treated with diazepam, phenobarbital, or ketamine for the next 30 days. During this period, animals were continuously observed for the assessment of spontaneous seizures. After that, their brains were analyzed for neuronal counting and Timm staining. We observed that the frequency of spontaneous seizures, neuronal loss, and mossy fiber sprouting were significantly reduced in rats treated with diazepam or phenobarbital. Although supragranular staining and spontaneous seizures were not significantly reduced in ketamine-treated rats, this drug was more powerful than diazepam or phenobarbital in preventing neuronal loss. These results indicate that the use of drugs that increase GABA-mediated inhibition can interfere with or at least retard the development of chronic epilepsy in the pilocarpine model of epilepsy. Other research groups have recently studied the effect of anti-inflammatory drugs (AIDs) in different models of epilepsy (27, 33, 35). Kainate-treated rats showed increased COX-2 and PGE synthase mRNA levels, with increased PGE2, PGF2, and PGD2 production during SE (27). Treatment with dexamethasone or celecoxib, a selective COX-2 inhibitor, reduced the expression of both COX-2 and PGEs in kainate-treated animals. If COX-2 plays a role in neuronal cell death, AIDs could be useful in preventing SEinduced brain damage. In another study, transcripts of
414
:
One question that always arises is the relationship between the duration of SE and the late development of epilepsy. We have addressed this topic by studying the duration of SE induced by pilocarpine and its relation to latency to the appearance of the first spontaneous seizure, the frequency of such seizures, the cell density in the hippocampal formation, and the intensity of reactive synaptogenesis observed through the Timm method (57). After the administration of pilocarpine to adult rats, SE was blocked 30 minutes or 1, 2, or 6 hours after its beginning using diazepam and phenobarbital (Figure 33.6). In this experiment we observed that animals subjected to 30 minutes of SE did not progress to the chronic period of the pilocarpine model and did not show any seizure in the long-term period of observation. A significant increase in the mean latency to the first spontaneous seizure and a significant decrease in seizure frequency were observed in animals with a short duration of SE (1 and
2 hours). Brain morphologic analysis did not reveal any difference between animals subjected to 30 minutes of SE and control rats. On the other hand, extensive neuropathologic alterations were found in the hippocampus, basal amygdaloid nucleus, dorsomedial thalamic nucleus, substantia nigra, parietal and temporal neocortex, and piriform and entorhinal cortices of animals with SE that did not receive any pharmacologic intervention. A similar pattern of neuropathologic changes was observed in the brain of animals treated 6 hours after the beginning of SE. The severity of the neuropathologic changes decreased with earlier treatment of the animals with diazepam and pentobarbital (Figure 33.6). The pattern of Timm staining was clearly altered in pilocarpine-treated rats and could be related to the duration of SE. Control animals and those subjected to 30 minutes of SE showed a similar pattern of staining in the hippocampal formation. Timm-positive granules, normally absent in the supragranular layer, could be detected in the dentate gyrus of rats treated 1 and 2 hours after SE. In animals treated 6 hours after the beginning of pilocarpine-induced SE, and similarly in the untreated group, the granular cell layer showed zones of widening and retraction, which gave a characteristic undulating aspect to this layer. In these animals, Timm-positive granules were distributed in a dense and continuous band throughout the inner third of the molecular layer (Figures 33.7 and 33.8). These results clearly showed that the blockade of pilocarpine-induced SE modifies the development of later epilepsy. Neuropathologic changes and the late development of spontaneous seizures were completely prevented in animals subjected to SE of less than 1 hour. The results also show a positive association among SE duration, hippocampal cell loss, and intensity of Timm staining in pilocarpinetreated rats. The suppression of SE (<1 hour) reduced or prevented the sprouting and avoided later epilepsy.
F 33.6 Electrographic recordings demonstrating the effects of diazepam (DZ) plus pentobarbital (PB) administered 30 minutes or 1, 2, or 6 hours after pilocarpine-induced SE in rats. The control recording (A) was obtained before pilocarpine administration. The
remaining recordings shown were made after 15 minutes of SE (B), 30 minutes of SE (C ), 1 hour of SE (D), 2 hours of SE (E), 6 hours of SE (F), and 24 hours after DZ + PB. Arrows indicate the moment of DZ + PB administration. HPC, hippocampus; CX, cortex.
interleukin-1b, interleukin-6, interleukin-1 receptor antagonist, and inducible nitric oxide synthase were demonstrated to be dramatically increased during limbic SE induced by unilateral electrical stimulation of the hippocampus (34). Interleukin-1b mRNA was still higher during the chronic period in rats with spontaneous seizures. Interestingly, multiple intracerebroventricular injections of interleukin-1 receptor antagonist (0.5 mg/3 mL) significantly decreased the severity of behavioral convulsions during electrical stimulation and selectively reduced tumor necrosis factor-a content in the hippocampus measured 18 hours after SE. Thus, the induction of spontaneously recurring seizures in rats involves the activation of inflammatory factors and related pro- and anti-inflammatory genes that can be modified by anti-inflammatory therapy.
Status epilepticus duration and the late development of epilepsy
.:
415
F 33.7 Graphs showing latency to the first spontaneous seizures (A), seizure frequency (B), number of CA1 pyramidal neurons/mm3 (three sections per rat) (C), and Timm stain grading
(D) in rats subjected to 30 minutes or 1, 2, or 6 hours of pilocarpine-induced SE (see text for details).
F 33.8 Percentage of normal-appearing neurons in the dentate hilus of rats subjected to pilocarpine-induced SE at different periods of postnatal development and that manifested sponta-
neous seizures later in life. The hilar cell count in animals subjected to SE that did not progress to chronic epilepsy was similar to that observed in control rats.
416
:
T 33.1 Number of rats surviving pilocarpine-induced status epilepticus over the number of injected animals, number of animals that developed spontaneous recurrent seizures (SRS) later in life, and latency to the appearance of the first spontaneous seizure (latent period) according to age
Age (days) 7–11 12–17 18–24 25–35 36–45 50–60 90–120
Dose (mg/kg)
Surviving Animals/Total
Animals with SRS
Latent Period (days)*
380 170–380 170–225 230–320 320–350 350 350
29/35 61/70 36/95 26/66 42/74 45/62 32/41
0 0 8 14 39 45 32
0 0 36.5 ± 24.8 23.2 ± 10.3 19.1 ± 7.4 17.8 ± 6.4 14.2 ± 4.6
* Data are expressed as mean ± SD.
Developmental aspects The majority of cases of SE occur in young children, particularly in the first years of life (2, 36, 66, 73). In these studies, the incidence of neurologic sequelae after an episode of SE varies from 10% to 48%, suggesting that the more immature brain is particularly susceptible to the effects of SE. On the other hand, several authors have shown the absence of epileptic brain damage in young animals subjected to SE (23, 51, 91). At least two considerations arise when we contemplate the differences between the susceptibility to brain damage and long-term sequelae after SE in experimental and human studies. The first is related to what postnatal age in the rat corresponds to human brain development (55). The second points to the maturational time course of certain brain mechanisms and circuits (metabolism, receptors, pathways, etc.) that could be relevant or even determinant for the different SE-inducing methods (kainic acid, pilocarpine, electrical stimulation) used in experimental animals. In accordance with these observations, we investigated whether pilocarpine-induced SE in developing rats would lead to the appearance of spontaneous seizures later in life. Wistar rats aged 7–120 days received an intraperitoneal injection of pilocarpine and were continuously observed by video monitoring for the next 120 days. After this period their brains were processed for cell counting and supragranular Timm staining. The results indicated that chronic seizures after pilocarpine-induced SE could be observed if the SE was induced after the 18th day of life (P18) (Table 33.1), even if some degree of brain damage could already be detected when SE was induced in earlier stages of life (P12–P15). In contrast to adult rats, the latency (silent period) to the appearance of the first spontaneous seizure was longer and the seizure frequency during the chronic
T 33.2 Frequency of spontaneous recurrent seizures during 4 months of observation in rats subjected to pilocarpine-induced status epilepticus at different periods of postnatal development Developmental Period When SE Induced Age (days)
Month 1
Month 2
Month 3
Month 4
7–11 12–17 18–24 25–35 36–45 50–60 90–120
— — 0.5 ± 0.5 1.3 ± 0.8 2.7 ± 2.1 4.5 ± 3.8 6.6 ± 4.5
— — 1.6 ± 0.7 2.6 ± 1.3 4.6 ± 3.1 8.7 ± 4.1 10.5 ± 8.3
— — 1.8 ± 0.8 3.5 ± 1.9 7.3 ± 5.2 9.2 ± 3.8 12.3 ± 5.8
— — 2.5 ± 1.3 3.6 ± 2.0 7.7 ± 4.1 9.1 ± 4.2 10.2 ± 6.2
Note: Frequency data are expressed as mean ± SD.
period was lower in P18–P24 rats (Table 33.2). In addition, hilar cell loss and density of Timm staining were less prominent in these animals, suggesting a positive association among mossy fiber sprouting, de novo recurrent excitation of granule cells (30, 63, 101) (Figure 33.9), and the development of spontaneous seizures in this epilepsy model (74). Since animals younger than 18 days do not develop spontaneous seizures as a consequence of SE (although they exhibit electrographic and behavioral alterations of long duration associated with the administration of pilocarpine), we decided to investigate the long-term effects of three consecutive episodes of SE in developing rats (P7, P8, and P9) (78, 79). Although some SE characteristics, such as duration and mortality, did not change significantly with the repeated administration of pilocarpine, these animals developed longlasting changes in hippocampal and cortical recordings, with episodes of complex spiking activity (Figure 33.10), and
.:
417
F 33.9 Supragranular Timm staining in the dentate gyrus of rats subjected to pilocarpine-induced SE at different ages. (A) Control animal. (B) SE at P10. (C) SE at P18. (D) SE at P28. (E)
SE at P36. (F) SE at P90. Animals were killed at least 120 days after SE.
F 33.10 Electrographic recordings from adult rats. (A) Control. (B) Experimental animal subjected to 3 consecutive episodes of SE at P7, P8 and P9.
418
:
F 33.11 Coronal sections of the sensorimotor cortex of adult rats (P35) submitted to pilocarpine-induced SE at P7, P8, and P9. Double-labeling experiments using the antibodies antiparval-
bumin (green) and anticalbindin (red) revealed longlasting changes in neocortical circuitries. (A and C) Control rats. (B and D) Treated rats. Scale bar = 150 mm (A, B), 50 mm (C, D). (See Color Plate 9.)
a small percentage (10%–15%) of the rats had spontaneous seizures when they became adults. The seizures observed in those animals differed substantially from those observed in the model of pilocarpine-induced SE in adult rats. In that model the animals had complex partial seizures (limbic seizures), whereas rats treated on P7, P8, and P9 develop generalized seizures associated with cognitive impairment. The occurrence of consecutive episodes of SE on P7, P8, and P9 alters cortical maturation, and animals develop progressive alterations of intracortical circuitry, which could explain the epileptic discharges and cognitive deficits observed later in life (Figure 33.11).
epileptic focus. Experimental data indicate that therapeutic interventions controlling the duration of SE or administered during the latent, seizure-free period can modify the formation of such a focus, with the later occurrence of epilepsy thus avoided or retarded.
Conclusion Severe and long-duration SE, capable of inducing neuronal loss and subsequent synaptic reorganization in the hippocampal formation, might lead to the development of an
This work was supported by research grants from FAPESP, CNPq, and PRONEX (Brazil).
REFERENCES 1. Aicardi, J., and J. J. Chevrie. Consequences of status epilepticus in infants and children. In A. V. Delgado-Escueta, C. G. Wasterlain, D. W. Treiman, and R. J. Porter, eds. Status Epilepticus: Mechanisms of Brain Damage and Treatment. Adv. Neurol. 1983;34:115–125. 2. Aicardi, J., and J. J. Chevrie. Convulsive status epilepticus in infants and children: A study of 239 cases. Epilepsia 1970; 11:187–197.
.:
419
3. Aminoff, M. J., and R. P. Simon. Status epilepticus: Causes, clinical features and consequences in 98 patients. Am. J. Med. 1980;69:657–666. 4. Annegers, J. F., S. A. Blakely, W. A. Hauser, and L. T. Kurland. Recurrence of febrile convulsions in a populationbased cohort. Epilepsy Res. 1990;5:209–216. 5. Annegers, J. F., W. A. Hauser, S. B. Sirts, and L. T. Kurland. Factors prognostic of unprovoked seizures after febrile convulsions. N. Engl. J. Med. 1987;316:493–498. 6. Arida, R. M., F. A. Scorza, C. A. Peres, and E. A. Cavalheiro. The course of untreated seizures in the pilocarpine model of epilepsy. Epilepsy Res. 1999;34:99–107. 7. Babb, T. L., W. R. Kupfer, J. K. Pretorius, P. H. Crandall, and M. F. Lévesque. Synaptic reorganization by mossy fibers in human fascia dentata. Neuroscience 1991;42:351–362. 8. Babb, T. L., G. W. Mathern, J. P. Leite, J. K. Pretorius, K. M. Yeoman, and P. A. Kuhlman. Glutamate AMPA receptors in the fascia dentata of human and kainate rat hippocampal epilepsy. Epilepsy Res. 1996;26:193–205. 9. Babb, T. L., J. K. Pretorius, W. R. Kupfer, and P. H. Crandall. Glutamate decarboxylase-immunoreactive neurons are preserved in human epileptic hippocampus. J. Neurosci. 1989;9:2562–2574. 10. Ben-Ari, Y. Limbic seizure and brain damage produced by kainic acid: Mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 1985;14:375–403. 11. Ben-Ari, Y., E. Tremblay, O. P. Ottersen, and R. Naquet. Evidence suggesting secondary epileptogenic lesions after kainic acid: Pre-treatment with diazepam reduces distant but not local damage. Brain Res. 1979;165:632–635. 12. Ben-Ari, Y., E. Tremblay, D. Riche, G. Ghilini, and R. Naquet. Electrographic, clinical and pathological alterations following systemic administration of kainic acid, bicuculline or pentetrazole: Metabolic mapping using the deoxyglucose method with special reference to the pathology of epilepsy. Neuroscience 1981;6:1361–1391. 13. Berg, A. T., and S. Shinnar. The risk of seizure recurrence following a first unprovoked seizure: A quantitative review. Neurology 1991;41:965–972. 14. Bertram, E. H., and J. F. Cornett. The evolution of a rat model of chronic spontaneous limbic seizures. Brain Res. 1994;661:157–162. 15. Bertram, E. H., and J. F. Cornett. The ontogeny of seizures in a rat model of limbic epilepsy: Evidence for the kindling development of chronic spontaneous seizures. Brain Res. 1993;625:295–300. 16. Binder, D. K., S. D. Croll, C. M. Gall, and H. E. Scharfman. BDNF and epilepsy: Too much of a good thing? Trends Neurosci. 2001;24:47–53. 17. Bouilleret, V., A. Nehlig, C. Marescaux, and I. J. Namer. Magnetic resonance imaging follow-up of progressive hippocampal changes in a mouse model of mesial temporal lobe epilepsy. Epilepsia 2000;41:642–650. 18. Buckmaster, P. S., and P. A. Schwartzkroin. Hippocampal mossy cell function: A speculative view. Hippocampus 1994;4: 393–402. 19. Cavalheiro, E. A. GAD-immunoreactive neurons are preserved in the hippocampus of rats with spontaneous recurrent seizures. Braz. J. Med. Biol. Res. 1990;23:555–558. 20. Cavalheiro, E. A. Status epilepticus and secondary epileptogenesis in the pilocarpine model of epilepsy. In P. Wolf, ed. Epileptic Seizures and Syndromes. London: John Libbey, 1994: 523–532.
420
:
21. 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. 22. Cavalheiro, E. A., D. A. Riche, and G. Le Gal La Salle. Longterm effects of intrahippocampal kainic acid injection in rats: A method for inducing spontaneous recurrent seizures. Electroencephalogr. Clin. Neurophysiol. 1982;53:581–589. 23. Cavalheiro, E. A., D. F. Silva, W. A. Turski, L. S. CalderazzoFilho, Z. A. Bortolotto, and L. Turski. The susceptibility of rats to pilocarpine-induced seizures is age-dependent. Dev. Brain Res. 1987;37:43–58. 24. Cavazos, J. E., G. Golarai, and T. P. Sutula. Mossy fiber synaptic reorganization induced by kindling: Time course of development, progression and permanence. J. Neurosci. 1991;11:2795–2803. 25. 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;527:1–6. 26. Cendes, F., F. Andermann, F. Dubeau, P. Gloor, A. Evans, and M. Jones-Gotman, et al. Early childhood prolonged febrile convulsions, atrophy and sclerosis of mesial structures, and temporal lobe epilepsy. Neurology 1993;43:1083–1087. 27. Ciceri, P., Y. Zhang, A. F. Shaffer, K. M. Leahy, M. B. Woerner, and W. G. Smith, et al. Pharmacology of celecoxib in rat brain after kainate administration. J. Pharmacol Exp. Ther. 2002;302:846–852. 28. 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. 29. Cronin, J., and F. E. Dudek. Chronic seizures and collateral sprouting of dentate mossy fiber after kainic acid treatment in rats. Brain Res. 1988;474:181–184. 30. Cronin, J., A. Obenaus, C. R. Houser, and F. E. Dudek. Electrophysiology of dentate granule cells after kainate-induced synaptic reorganization of mossy fiber. Brain Res. 1992; 573:305–310. 31. Danscher, G. Histochemical demonstration of heavy metals: A revised version of the silver sulphide method suitable for both light and electron microscopy. Histochemistry 1981;71: 1–16. 32. 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. 33. De Simoni, M. G., C. Perego, T. Ravizza, D. Moneta, M. Conti, and F. Marchesi, et al. Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus. Eur. J. Neurosci. 2000;12:2623–2633. 34. DeLorenzo, R. J., J. M. Pellock, S. R. Towne, and J. G. Boggs. Epidemiology of status epilepticus. J. Clin. Neurophysiol. 1995;12:316–325. 35. Doretto, M. C., N. Garcia-Cairasco, N. J. Pimenta, D. A. Souza, and M. A. Tatsuo. Dipyrone, a novel anticonvulsant agent? Insights from three experimental epilepsy models. Neuroreport 1998;9:2415–2421. 36. Dunn, D. W. Status epilepticus in children: Etiology, clinical features and outcome. J. Child Neurol. 1988;3:167–173. 37. Esclapez, M., J. C. Hirsch, Y. Ben-Ari, and C. Bernard. Newly formed excitatory pathways provide a substrate for
38.
39.
40.
41.
42.
43.
44. 45.
46.
47. 48.
49.
50.
51.
52.
53.
54.
55. 56.
hyperexcitability in experimental temporal lobe epilepsy. J. Comp. Neurol. 1999;408:449–460. Falconer, M. A. Genetic and related aetiological factors in temporal lobe epilepsy: A review. Epilepsia 1971;12: 13–21. Falconer, M. A., E. A. Serafetinides, and J. A. N. Corsellis. Etiology and pathogenesis of temporal lobe epilepsy. Arch. Neurol. 1964;10:233–248. Feldblum, S., and R. F. Ackermann. Increased susceptibility to hippocampal and amygdala kindling following intrahippocampal KA. Exp. Neurol. 1987;2:255–269. Franck, J. E., J. Pokorny, D. D. Kunkel, and P. A. Schwartzkroin. Physiologic and morphologic characteristics of granule cell circuitry in human epileptic hippocampus. Epilepsia 1995;36:543–558. French, J. A., P. D. Williamson, V. M. Thadani, T. M. Darcey, R. H. Mattson, S. S. Spencer, and D. D. Spencer. Characteristics of medial temporal lobe epilepsy. I. Results of history and physical examination. Ann. Neurol. 1993;34: 774–780. Gall, C. M., and P. J. Isackson. Limbic seizures increase neuronal production of messenger RNA for nerve growth factor. Science 1989;245:758–761. Gross-Tsur, V., and S. Shinnar. Convulsive status epilepticus in children. Epilepsia 1993;34:S12–S20. Handforth, A., and D. M. Treiman. Functional mapping of the early stages of status epilepticus: A 14C-2-deoxyglucose study in the lithium-pilocarpine model in rat. Neuroscience 1995a;64:1057–1073. 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 1995b;64:1075–1089. Hauser, W. A. Status epilepticus: Epidemiological considerations. Neurology 1990;40:13–22. Hauser, W. A. Status epilepticus: Frequency, etiology, and neurological sequelae. In A. V. Delgado-Escueta, C. G. Wasterlain, D. G. Treiman, and R. J. Porter, eds. Status Epilepticus: Mechanisms of Brain Damage and Treatment. Adv. Neurol. 1983;34:3–14. Hauser, W. A., V. E. Anderson, and R. B. Lowenson. Seizure recurrence after a first unprovoked seizure. N. Engl. J. Med. 1982;307:522–528. Hauser, W. A., and L. T. Kurland. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia 1975;16:1–66. Holmes, G. L., and J. L. Thompson. Effects of kainic acid on seizure susceptibility in the developing brain. Dev. Brain Res. 1988;39:51–59. Holtzman, D. M., and D. H. Lowenstein. Selective inhibition of axon outgrowth by antibodies to NGF in a model of temporal lobe epilepsy. J. Neurosci. 1995;15:7062–7070. Jankowsky, J. L., and P. H. Patterson. The role of cytokines and growth factors in seizures and their sequelae. Prog. Neurobiol. 2001;63:125–149. Jefferys, J. G. R., C. Borck, and J. Mellanby. Chronic focal epilepsy induced by intracerebral tetanus toxin. Ital. J. Neurol. Sci. 1995;16:27–32. Knowles, W. D. Aspects of epileptogenesis: Maturation of neuronal circuits. Cleve. Clin. J. Med. 1989;56:S221–S225. Leite, J. P., Z. A. Bortolotto, and E. A. Cavalheiro. Spontaneous recurrent seizures in rats: An experimental model of partial epilepsy. Neurosci. Biobehav. Rev. 1990;14:511–517.
57. Lemos, T., and E. A. Cavalheiro. Suppression of pilocarpineinduced status epilepticus and the late development of epilepsy in rats. Exp. Brain Res. 1995;102:423–428. 58. Lothman, E. W., and E. H. Bertram. Epileptogenic effects of status epilepticus. Epilepsia 1993;34:S59–S70. 59. 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. 60. Lothman, E. W., and R. C. Collins. Kainic acid induced limbic seizures: Metabolic, behavioral, electroencephalographic and neuropathological correlates. Brain Res. 1981; 218:299–318. 61. Margerison, J. H., and J. A. N. Corsellis. Epilepsy and the temporal lobes: A clinical, electroencephalographic and neuropathological study of the brain in epilepsy with particular reference to the temporal lobes. Brain 1966;89:499–530. 62. Mathern, G. W. Hippocampal pathophysiology in experimental models. In P. Kotagal and H. Lüders, eds. The Epilepsies: Etiologies and Prevention. San Diego: Academic Press, 1999:149–166. 63. Mathern, G. W., T. L. Babb, J. P. Leite, J. K. Pretorius, K. M. Yeoman, and P. A. Kuhlman. The pathogenic and progressive features of chronic human hippocampal epilepsy. Epilepsy Res. 1996;26:151–161. 64. Mathern, G. W., F. Cifuentes, J. P. Leite, J. K. Pretorius, and T. L. Babb. Hippocampal EEG excitability and chronic spontaneous seizures are associated with aberrant synaptic reorganization in the rat intrahippocampal kainate model. Electroencephalogr. Clin. Neurophysiol. 1993;87:326–339. 65. 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. 66. Maytal, J., S. Shinnar, S. L. Moshé, and L. A. Alvarez. Low morbidity and mortality of status epilepticus in children. Pediatrics 1989;83:323–331. 67. McNamara, J. O. Cellular and molecular basis of epilepsy. J. Neurosci. 1994;14:3413–3425. 68. Mello, L. E. A. M. M., E. A. Cavalheiro, A. M. Tan, W. R. Kupfer, J. K. Pretorius, and T. L. Babb, et al. Circuit mechanisms of seizures in the pilocarpine model of chronic epilepsy: Cell loss and mossy fiber sprouting. Epilepsia 1993;39:985–995. 69. Moraes, W. A. S., and E. A. Cavalheiro. Pharmacological treatment inhibits status epilepticus–induced supragranular sprouting. Epilepsia 1997;36(Suppl. 3):S47–S48. 70. Nelson, K. B., and J. H. Ellenberg. Prognosis in children with febrile seizures. Pediatrics 1978;61:720–727. 71. 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. 72. Okazaki, M. M., D. A. Evenson, and J. V. Nadler. Hippocampal mossy fiber sprouting and synapse formation after status epilepticus in rats: Visualization after retrograde transport of biocytin. J. Comp. Neurol. 1995;352:515–534. 73. Phillips, S. A., and R. J. Shanahan. Etiology and mortality of status epilepticus in children: A recent update. Arch. Neurol. 1989;46:74–76. 74. Priel, M. R., N. F. Santos, and E. A. Cavalheiro. Developmental aspects of the pilocarpine model of epilepsy. Epilepsy Res. 1996;26:115–121.
.:
421
75. Ribak, C. E., R. M. Bradurne, and A. B. Harris. A preferential loss of GABAergic, symmetric synapses in epileptic foci: A quantitative ultrastructural analysis of monkey neocortex. J. Neurosci. 1982;2:1725–1735. 76. Ribak, C. E., A. B. Harris, J. E. Vaughn, and E. Roberts. Inhibitory, GABAergic nerve terminals decrease at sites of focal epilepsy. Science 1979;205:211–214. 77. Roch, C., C. Leroy, A. Nehlig, and I. J. Namer. Predictive value of cortical injury for the development of temporal lobe epilepsy in 21-day-old rats: An MRI approach using the lithium-pilocarpine model. Epilepsia 2002;43:1129–1136. 78. Santos, N. F., R. M. Arida, E. M. Trindade Filho, M. R. Priel, and E. A. Cavalheiro. Epileptogenesis in immature rats following recurrent status epilepticus. Brain Res. Rev. 2000;32: 269–276. 79. Santos, N. F., R. H. Marques, L. Correia, R. SinigagliaCoimbra, L. Calderazzo, and E. R. G. Sanabria, et al. Multiple pilocarpina-induced status epilepticus in developing rats: A long-term behavioral and electrophysiological study. Epilepsia 2000;41(Suppl. 6):S57–S63. 80. Scheibel, A. B. Are complex partial seizures a sequela of temporal lobe dysgenesis? Adv. Neurol. 1991;55:59–77. 81. Shinnar, S., and A. T. Berg. Does antiepileptic drug therapy prevent the development of “chronic epilepsy”? Epilepsia 1996;37:701–708. 82. Shinnar, S., A. T. Berg, and S. L. Moshé. Recurrence risk after a first unprovoked seizure in childhood. Ann. Neurol. 1988;24: 315–317. 83. Shinnar, S., A. T. Berg, and S. L. Moshé. The risk of seizure recurrence following a first unprovoked seizure in childhood: A prospective study. Pediatrics 1990;85:1076–1085. 84. Shinnar, S., A. T. Berg, S. L. Moshé, C. O’Dell, M. Alemany, D. Newstein, et al. The risk of seizure recurrence after a first unprovoked afebrile seizure in childhood: An extended follow-up. Pediatrics 1996;98:216–225. 85. Shinnar, S., A. T. Berg, Y. Ptachewich, and M. Alemany. Sleep state and the risk of seizure recurrence following a first unprovoked seizure in childhood. Neurology 1993;43:701–706. 86. Shirasaka, Y., and C. G. Wasterlain. Chronic epileptogenicity following focal status epilepticus. Brain Res. 1994;655: 33–44. 87. Sillanpää, M. Remission of seizures and predictors of intractability in long-term follow-up. Epilepsia 1993;34: 930–936. 88. Sloviter, R. S. Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. Science 1987;235:73–76. 89. 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. 90. Sloviter, R. S. Possible functional consequences of synaptic reorganization in the dentate gyrus of kainate-treated rats. Neurosci. Lett. 1992;137:91–96. 91. Sperber, E. F., K. Z. Hass, P. K. Stanton, and S. L. Moshé. Resistance of the immature hippocampus to seizure induced synaptic reorganization. Dev. Brain Res. 1991;60:88–93. 92. Sutula, T., J. Cavazos, and G. Golarai. Alteration of longlasting structural and functional effects of kainic acid in the hippocampus by brief treatment with phenobarbital. J. Neurosci. 1992;12:4173–4187.
422
:
93. Sutula, T., H. Xiao-Xian, J. Cavazos, and G. Scott. Synaptic reorganization in the hippocampus induced by abnormal functional activity. Science 1988;239:1147–1150. 94. 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. 95. 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. 96. Turski, W. A., E. A. Cavalheiro, M. Schwarz, S. J. Czuczwar, Z. Kleinrok, and L. Turski. Limbic seizures produced by pilocarpine in rats: Behavioral, electroencephalographic and neuropathological study. Behav. Brain Res. 1983;9:315–335. 97. Van der Zee, C. E. E. M., K. Rashid, K. Le, K. A. Moore, J. Stanisz, J. Diamond, et al. Intraventricular administration of antibodies to nerve growth factor retards kindling and blocks mossy fiber sprouting in adult rats. J. Neurosci. 1995;15:5316–5323. 98. VanLandingham, K. E., and E. W. Lothman. Self-sustaining limbic status epilepticus. I. Acute and chronic metabolic studies: Limbic hypermetabolism and neocortical hypometabolism. Neurology 1991;41:1942–1949. 99. Wasterlain, C. G. Effects of neonatal status epilepticus on rat brain development. Neurology 1976;26:975–986. 100. Wasterlain, C. G., and Y. Shirasaka. Seizures, brain damage and brain development. Brain Dev. 1994;16:279–285. 101. Williams, S., P. Vachon, and J. C. Lacaille. Monosynaptic GABA-mediated inhibitory postsynaptic potential in CA1 pyramidal cells of hyperexcitable hippocampal slices from kainic acid-treated rats. Neuroscience 1993;52:541–554.
34
Epileptogenic Effects of Status Epilepticus
, , . , .
Introduction Over the past few years, we have gone from having no animal models of acquired epilepsy (defined as an illness characterized by the occurrence of spontaneous epileptic seizures) to having a plethora of animal models with a clinical course and a neuropathology that often closely mimic some forms of the human illness. In most of those models, chronic epilepsy is the long-term sequela of a bout of status epilepticus (SE) and is associated with hippocampal neuronal loss and hippocampal synaptic reorganization. Thus, SE-induced epileptogenesis is a widespread phenomenon induced by many different types of SE in several animal species. Human evidence of the same phenomenon, however, is surprisingly scarce and indirect. In this chapter we briefly review the phenomenon of SE-induced epileptogenesis and make a few points derived from our own research observations using the Sloviter model of perforant path stimulation (PPS) under anesthesia, which has the unique advantage that its lesions are restricted to the hippocampus. Cortical lesions are often found in epilepsy patients, and there is considerable circumstantial evidence of their epileptogenicity (1, 51, 102). Palecortical foci, such as those associated with hippocampal lesions, are associated with one of the most common types of focal (localization-related) epilepsy (40, 50). Hippocampal lesions show the strongest association with intractable epilepsy and have been extensively studied. In the hippocampus of patients with temporal lobe epilepsy, intractable seizures and/or SE are associated with selective injury to Sommer’s sector (prosubiculum and CA1) and CA3 (43); somatostatin- and neuropeptide Y-immunoreactive (ir) neurons are selectively lost in the dentate hilus (44, 69); and GAD-immunoreactive (ir) basket cells are relatively preserved (10, 69). Neuronal loss in the dentate hilus has been postulated to induce the aberrant mossy fiber sprouting also observed in these patients (9, 55, 66, 68, 124). In addition to these morphologic alterations, surgically resected hippocampi from patients with intractable epilepsy show enhanced N-methyl--aspartate (NMDA) receptor-mediated responses (57, 68, 138) and sometimes decreased g-aminobutyric acid (GABA)-mediated inhibition (139). Consequently, these hippocampal lesions exhibit
enhanced excitability, which may play a role in their epileptogenicity. Additional evidence for the epileptogenicity of hippocampal lesions is provided by human cases of domoic acid intoxication, which induced hippocampal sclerosis and caused temporal lobe epilepsy in humans (28), just as kainic acid does in experimental animals. Several animal models of SE show neuronal damage in the hippocampus similar to that seen in patients with temporal lobe epilepsy, and also show spontaneous epileptic seizures after SE. Chemical convulsant–induced SE models are easy to induce and have been the most extensively studied. However, in these models there are many extrahippocampal lesions. Cholinergic drugs such as pilocarpine induce widespread brain damage (31, 47, 90) that is sometimes greater in neocortex than in hippocampus (31), and kainic acid, despite some selectivity for the hippocampus (13), still produces extensive extrahippocampal lesions (14, 107). Therefore, in these models we have no assurance that the seizures come from the hippocampus. Sustained stimulation of the perforant path induced neuronal injury morphologically similar to that caused by kainic acid (92, 111, 126). Light microscopic analysis showed a highly reproducible pattern of hippocampal damage to a selected population of ipsilateral dentate hilar interneurons (110, 112, 114) and bilateral CA1 and CA3 pyramidal neurons (111). Presumably because the 24-hour stimulation is performed under urethane anesthesia (109), this model shows more restricted lesions than other types of experimental SE, and it is free from the direct effects of convulsant drugs on neurons. We carried out a detailed study of epileptogenicity in this model, where the lack of extrahippocampal lesions is a major asset, in the PPS model in awake rats, which is a good model of self-sustaining SE, and in the lithiumpilocarpine model, which is convenient for pharmacotherapy.
Long-term consequences of SE SE-I E: E E Systemic administration of kainic acid, pilocarpine, or lithium-pilocarpine (13, 54, 90, 137), intracerebral injection of kainic acid (132) or other toxins (131), continuous electrical stimulation of the hippocampus (16, 64), or
.:
423
Implantation
Seizure onset
SE
LATENT PERIOD FACTS
4-12 weeks: spikes, fast ripples, loss of paired pulse inhibition, no seizures
Hilar lesions Hypothesis Loss of inh. Loss of filter
Potentiation of excitatory synapses
CHRONIC EPILEPSY
May last a lifetime: spontaneous recurrent seizures, recovery of paired pulse inhibition, sprouting of excitatory and inh. axons/dendrites Return of inhibition but potentiated/sprouted excitatory circuits maintain intermittent excitation/ inhibition imbalance
F 34.1 Typical evolution of SE-induced epileptogenesis (above the time line) and hypothetical key events according to the filter hypothesis (below the line).
intermittent stimulation of the perforant path (75), piriform cortex (56), or amygdala (86) in awake animals can all induce SE that spreads through limbic structures with partial secondary generalization. This SE becomes self-sustaining (75, 79, 122) and causes clonic seizures resembling those from kindling that last many hours. Although behavioral, electrographic, and anatomic features vary from model to model, studies of metabolic anatomy using 2-deoxyglucose (2-DG) and studies of gene activation using c-fos show that, in all those models, seizures potently activate the limbic system. They are models of focal or complex partial SE rather than models of generalized SE. In the models in which SE is induced by systemic injection of chemical convulsants, secondary generalization with tonic seizures often results in a high mortality, but for unknown reasons such spread is rare in some of the electrical stimulation models, and as a result, mortality is quite low (75, 83). The lack of hypoxemia, apnea, and other systemic complications in these models is an asset in studying long-term complications that are the direct result of seizure activity. Stimulation of the perforant path under anesthesia (110) does not produce self-sustaining seizures, but when it is continued for a sufficient period of time, it does cause neuronal injury (in a more restricted distribution) and has similar longterm epileptogenic and anatomic consequences (141). After a latent period of weeks to months, during which no behavioral seizures are evident (Figure 34.1), all of those models cause the appearance of spontaneous recurrent seizures. These seizures are behaviorally and electrographically similar to kindled seizures and activate the same limbic circuits that were activated and lesioned during SE (94). Figure 34.2 shows a spontaneous seizure originating from the ventral hippocampus in a rat in which SE was generated by stimulating the perforant path in the dorsal hippocampus. A N: E E Meldrum and Brierley (77) showed that convulsive SE rapidly leads to brain damage in rats and baboons, and that nonconvulsive SE in the absence of systemic complications also causes brain damage (although more slowly). Focal
424
:
A. L VHipp L EC R VHipp REC 0.5 mV
0.5 s B.
L Pir R Pir L DHipp R DHipp L VHipp R VHipp
L EC REC
F 34.2 (A) Interictal spikes recorded from entorhinal cortex and ventral hippocampus. (B) Onset of a seizure from ventral hippocampus in a rat subjected to perforant path stimulation several months earlier. In our limited sample, seizures originated from the contralateral hippocampus as often as from the stimulated hippocampus. VHipp, ventral hippocampus; EC, entorhinal cortex; Pir, piriform cortex. (Reprinted with permission from Mazarati, A. M., A. Bragin, R. Baldwin, et al. Epileptogenesis after selfsustaining status epilepticus. Epilepsia 2002;43(Suppl. 5):74–80.)
seizures were shown to induce neuronal death in synaptically connected sites (32). Limbic seizures (induced chemically or by stimulation) by themselves cause neuronal death in hippocampus and other regions (13, 16, 54, 64, 75, 85, 90, 91, 131, 132, 135). In fact, vigorous synaptic stimulation, even if it does not trigger seizures, can cause neuronal injury (110). Figure 34.3 illustrates the localized nature of neuronal injury associated with PPS under urethane anesthesia (110). Lesions are restricted to the hippocampus, with hilar lesions that are exclusively ipsilateral to stimulation and CA1/CA3 lesions that are bilateral but strongly predominate on the stimulated side.
F 34.3 Injured neurons stand out because of their eosin fluorescence in the stimulated dentate gyrus after perforant path stim-
ulation under urethane anesthesia. (Reprinted with permission from Wasterlain et al. [142].)
C W E E E S-I E H? SEinduced epileptogenesis is common and easily induced in many (but not all) animal models of SE, at many if not all ages (42). Human evidence of seizure-induced epileptogenesis, however, is remarkably sparse and subject to different interpretations. For example, in population-based statistics from Rochester, Minnesota, the risk of an unprovoked seizure was 3.3-fold higher after acute symptomatic SE (41%) than after single seizures (54). In a population-based cohort study in the United Kingdom, the risk of developing afebrile seizures was vastly increased after SE compared to simple febrile convulsions (89, 103, 106). Of course, these differences might reflect a more severe illness in patients with SE rather than SE-induced epileptogenesis. The closest approximation to animal models is probably the patient who survived SE induced by domoic acid, a toxin closely related to kainic acid, and who subsequently developed chronic epilepsy. Cendes et al. (28) followed up this patient, who had been intoxicated by domoic acid from dietary mussels. One year after SE triggered by the acute intoxication, this patient developed spontaneous recurrent seizures, and hippocampal sclerosis was confirmed by MRI and autopsy. This is the human counterpart of the kainic acid model of SE and suggests that the human response to nonNMDA ionotropic glutamate receptor agonists is very similar to that of animals, and includes epileptogenicity. Of course,
no treated controls were available to separate toxin-induced from seizure-induced epileptogenesis in this patient (5). A N: C E There is no doubt that human SE is associated with a neuropathology very similar to that seen after SE in experimental animals. However, the complexity of clinical situations in a severe, acute illness such as SE is such that cause-and-effect relationships are rarely clear-cut. Norman (87) autopsied 11 children (ages 1–6 years) after episodes of SE. Most of them showed Spielmeyer’s “ischemic cell change” in neurons in CA1, CA3, the “end-folium” (hilus plus CA3c), and thalamus, amygdala, striatum, and cerebellum. Corsellis et al. (33, 65) found acute hippocampal lesions in the brains of six children who died after SE. In a 3-year-old boy who died after 6 weeks of SE but who never experienced significant metabolic abnormalities, including hypotension, hypoxemia, hypoglycemia, or hyperpyrexia, magnetic resonance imaging (MRI) showed progressive increases in hippocampal T2 hyperintensity during that period, and autopsy showed neuronal loss and gliosis in dentate hilus, CA1, CA3, amygdala, neocortex, and cerebellar Purkinje cells. Even in that case, however, the possibility that both seizures and neuropathology were independent results of some unknown illness cannot be ruled out. The development of mesial temporal sclerosis with chronic epilepsy following SE has been documented by MRI
.:
425
multiple times (89, 140), but this does not prove a causeand-effect relationship. DeGiorgio et al. (43, 44) found an increase in the serum level of neuron-specific enolase, a marker of neuronal injury, following various types of SE, including complex partial SE without convulsive activity, strongly supporting the view that severe, repetitive seizure activity causes neuronal injury (43). SE-I E I B Chapter 26 reviews the experimental evidence that SE in the immature brain can cause neuronal necrosis and apoptosis. Epileptogenicity is highly age and model dependent: In P15 rats, lithium-pilocarpine-induced SE is far more epileptogenic than PPS-induced SE (105). However, there is no doubt that at ages P12 and above in the rat, some types of SE are epileptogenic (61). Below that age, local injection of tetanus toxin can be epileptogenic (129), and this may depend on seizure activity rather than on a direct effect of the toxin, but no model of SE-induced epileptogenesis is currently available. However, preliminary results (L. Suchomelová, personal communication) show spontaneous recurrent seizures after lithium-pilocarpine-induced SE in P10 rats. In humans, many types of neonatal seizures or SE are not associated with an increased risk of epilepsy (106), but childhood SE shows such an association. As in adults, it is subject to diverse interpretations. Of the 184 patients without prior epilepsy studied by Aicardi and Chevrie (4), 77% developed chronic epilepsy. The incidence of epilepsy was similar among patients who developed hemiplegia during unilateral SE (2–4, 49, 103, 104). However, the cause of the SE played a major role in its prognosis: The incidence of neurologic sequelae was 64% among children with symptomatic SE, versus 25% among those with idiopathic SE (3). The duration of SE also played a major role, similar to what is seen in experimental animals: Barois et al. (11) found that SE lasting more than 24 hours had a much higher morbidity than SE of shorter duration. More recent epidemiologic studies have shown a far lower incidence of post-SE epilepsy (see Chapters 4 and 5). Whether the more benign prognosis of recent reports and the near disappearance of hemiconvulsions-hemiplegia-epilepsy syndrome are the result of better treatment or reflect the fact that older studies were retrospective and biased in favor of severe cases of SE is the subject of active debate.
Mechanism of epileptogenesis A S: W I E F? Where is the lesion? Limbic SE induced in rodents by kainic acid, pilocarpine, or stimulation of excitatory pathways produces neuronal loss in hilar, CA3, and CA1 hippocampal regions, a pattern similar to that seen in human mesial tem-
426
:
poral sclerosis (13, 80, 113, 118, 137). There is a positive correlation between the extent of damage and SE duration (13, 37, 56). Extrahippocampal structures are extensively damaged in most models (67, 74, 96, 97). Neuronal damage can occur as early as 1 hour after SE (47), and neurons continue to die for up to 2 months (66). In the Sloviter model, lesions are restricted to the hippocampus (109), and chronic epilepsy with spontaneous recurrent seizures follows SE. Surprisingly, this model has rarely been used to study epileptogenesis. Three days after PPS, many neurons in the polymorph layer at the center of the ipsilateral dentate hilus were necrotic (see Figure 34.3), while CA3, CA1, and interneurons at the edge of the granule cell layer (presumably basket cells) were selectively spared. There were no extrahippocampal lesions except for a few cells in layer 2 of entorhinal cortex in two of 24 rats. One month after PPS, the population of hilar neurons immunoreactive for somatostation or for neuropeptide Y was reduced by about half. The mechanism of neuronal injury was probably excitotoxic, since neuropeptide Y neurons were protected by administration of the nonNMDA receptor antagonist NBQX, while somatostatin-ir hilar neurons were partially protected by both NBQX and the NMDA receptor antagonist MK-801 (93). Several neuroimaging techniques have been used to detect neuropathologic changes during and after SE. Diffusionweighted imaging shows changes during or immediately after primary generalized or limbic SE in structures with histopathologic damage (82, 102, 107, 147); this is before T2-weighted images show changes (107). Alterations in Nacetylaspartate and lactate, which correlate with a degree of neuronal loss (81), were present before any evidence of histologic damage was present (46). Where do the seizures come from? Here, human evidence is often much clearer than experimental evidence. In intractable human epilepsy, seizures often originate in the vicinity of an area of mesial temporal sclerosis. Sampling limitations often preclude a more precise source localization, but the results of surgery clearly point to the importance of mesial temporal sclerosis in seizure expression. In animals, seizure onset is usually recorded close to areas of histologic damage, but precise localization of ictal origin has proved elusive in post-SE epilepsy, as well as in the kindling phenomenon. In the PPS model, seizures often are first detected in ventral hippocampus and spread from there to limbic and neocortical sites (see Figure 34.2). Can we equate lesion location and seizure origin? It is not proven that spontaneous seizures originate in an area of histologic damage. We cannot rule out the possibility that structurally intact neurons with acquired biochemical abnormalities might be epileptogenic. Many biochemical abnormalities
have been described in mesial temporal sclerosis, and in post-SE brains, major changes in gene expression modify the composition of key receptors (22) and are sufficient to explain changes in excitability of hippocampal networks (34–36). In fact, the kindling model seemed to support that interpretation, until careful measures showed that it is associated with hilar neuronal loss (25, 26). Reports of neuroprotective treatments that reduced histologic lesions without preventing epileptogenesis (6) could also support that view, but they have not completely ruled out a mild, residual neuronal loss that might be sufficient for epileptogenicity (as in kindling). B H and E SE P P N I T R M T S Human evidence Pfleger (95) autopsied patients who died during SE. Their hippocampi showed extensive neuronal necrosis in a distribution similar to that described the same year by Sommer (118). These lesions appeared acute, and some of them were hemorrhagic; he therefore concluded that they must have been the result of seizure activity. In their autopsy series of 18 patients with epileptic seizures, Bouchet and Cazauvielh in 1825 found six with hippocampal hardening/sclerosis and two with hippocampal softening (20). Corsellis and Bruton (33) found hippocampal lesions resembling sclerosis in most of their patients with SE, including children. DeGiorgio et al. (44) examined the brains of five patients who died in SE, five controls, and five patients matched for age, epilepsy, and ethanol intake. They found that SE patients had a significant neuronal loss in CA1, CA3, and prosubiculum. Fujikawa et al. (48) examined the brains of three patients with “subtle” SE who had no tonic-clonic seizures and no hypotension, anoxemia, hypoglycemia, or significant hyperthermia. Two had no underlying brain pathology. They found widespread neuronal loss in hippocampus, amygdala, dorsomedial thalamus, entorhinal and perirhinal cortices, and Purkinje cells. The hippocampal damage involved dentate hilus, CA1, and CA3, and spared
F 34.4 Fast spin-echo oblique coronal section through the head of the hippocampi of a child who had a 72-minute-long complex febrile convulsion with left-sided jerking. (A) MRI performed 2 days after the event shows increased sign and signal in
dentate granule cells and CA2. They did not comment on the fate of basket cells. The four victims of domoic acid poisoning studied by Teitelbaum et al. (134) showed a similar picture, with loss of CA1 and CA3 neurons, sparing of CA2, some loss of dentate granule cells, severe lesions in amygdala, and damage in claustrum, olfactory areas, septum, nucleus accumbens, insular and subfrontal cortex, and mediodorsal thalamus. The one patient who survived SE but developed chronic epilepsy and died 31/2 years later had extensive neuronal loss in CA1, CA3, dentate hilus, amygdala, overlying cortex, septum, and nucleus accumbens. Again, the hippocampal pathology was strikingly similar to hippocampal sclerosis. Only about a third of patients with hippocampal sclerosis have a history of SE, so other causes are at work, but in those patients with a history of SE, the likelihood of SE contributing to hippocampal sclerosis is high. In fact, the development of the MRI picture of hippocampal atrophy and mesial temporal sclerosis has been observed following SE in children (76) (Figure 34.4). Experimental evidence Despite some variations, all experimental models of “limbic” SE produce a histologic picture resembling mesial temporal sclerosis. Intracerebral or systemic administration of kainic acid (14, 92), pilocarpine (137), lithium and pilocarpine, PPS (72), amygdala stimulation (86), and ventral hippocampal stimulation (17, 18) all produce extensive neuronal loss in the hilus, CA1, and CA3, with relative sparing of dentate granule cells, CA2, and basket cells. However, they also induce multiple extrahippocampal lesions in piriform and entorhinal cortex and thalamus, and to a lesser extent in caudate/putamen and other neocortical sites. Despite the common hippocampal pathology and its similarity to the most common substrate of human epilepsy, there is no solid evidence that, in these models, spontaneous seizures originate in the hippocampus. However, the Sloviter (110) model, created under anesthesia, causes cell loss in ipsilateral hilar neurons, in pyramidal neurons on both sides (142), and is devoid of extrahippocampal lesions. It is likely that seizures in that model are of hippocampal origin. It represents the
the right hippocampal head (arrow). (B) Follow-up MRI performed 9 months later shows a subsequent decrease in the size but persistently increased signal in the right hippocampus (arrow). (Reprinted with permission from VanLandingham et al. [140].)
.:
427
closest experimental approximation of human epilepsy associated with mesial temporal sclerosis. C M: E for L of I SE-induced loss of selective subpopulations of GABAergic neurons Both in mesial temporal sclerosis and in the postexperimental SE hippocampus, specific hilar populations of GABAergic interneurons (e.g., those colocalizing somatostatin or neuropeptide Y; see references 88, 93, and 110) are lost, but this loss alone is not sufficient to explain the development of chronic epilepsy: This loss is immediate, whereas spontaneous recurrent seizures appear only 3–4 weeks later. By contrast, the basket cells, which represent the main population of GABAergic recurrent inhibitors of granule cell firing, are selectively preserved after SE (10). Is dentate GABAergic inhibition fully connected to the network? Sloviter’s dormant basket cell hypothesis proposed that mossy cells innervate and excite basket cells in distant hippocampal lamellae. Mossy cells are very vulnerable to seizure-related injury and are massively lost in mesial temporal sclerosis or in post-SE brains, so that their loss might make basket cells less active due to a reduced excitatory input (12, 110, 116). Previous studies had failed to confirm the low level of activity predicted for basket cells (15), the existence of long mossy fiber projections (23), or the loss of inhibition in lamellae 1 mm removed from a localized (bicuculline) stimulus in hippocampi isolated from epileptic rats several months after kainate-induced SE (23). Furthermore, Ratzliff et al. (100) have been able to ablate 5%–20% of mossy cells in hippocampal slices from a healthy rat, and they observed a reduction in perforant path–evoked granule cell responses in interconnected and distant hippocampal lamellae. This would suggest that the net role of mossy cells is predominantly excitatory and that their loss could not be epileptogenic. However, Zappone and Sloviter (146) found translamellar inhibition at a greater distance (2.5–4 mm) from the stimulus than examined previously, and this inhibition was compromised in rats examined 3 days after kainate- or PPS-induced SE. This loss of inhibition was seen only when more than 40% of mossy cells were injured and so might not be detectable in the mossy cell ablation studies described earlier, which removed only 20% or less of those cells. Mossy cells picked up fluorogold from distant lamellae, supporting the existence of a direct projection, as postulated in the dormant basket cell hypothesis. Additional studies are needed to resolve some of those issues. A clue to the circuit modifications resulting from SE in the perforant path model is the striking reversal of the loss of inhibition by NMDA antagonists (73). Systemic injection of low quantities (0.5 mg/kg IP) of the NMDA blocker MK801, or intrahilar injection of nanomolar amounts of one of the NMDA antagonists MK-801, dichlorokinurenic acid, or
428
:
AP5, completely and transiently reversed granule cell disinhibition as measured with paired pulses (Figure 34.5), suggesting that excitatory drive to basket cells was not disconnected but was actively suppressed through an NMDA synapse. The complete and transient return of short interstimulus interval (ISI)- and frequency-dependent pairedpulse inhibition in dentate gyrus injected with NMDA blockers suggests that GABAergic inhibition (presumably mediated by the basket cells of the subgranular zone, which are known to survive SE) is not anatomically deafferented but is actively suppressed through an NMDA synapse. Although we cannot rule out a plastic change in synaptic function, it
F 34.5 Effects of NMDA receptor antagonists on the SEinduced loss of paired pulse inhibition. (A) Before PPS-induced SE, the feedback and/or feedforward inhibition triggered by the first population spike blocks any population spike in response to the second stimulation, 40 msec later (top trace). After PPS, this inhibition is lost, and the second pulse triggers a population spike equal to the first. After intraperitoneal injection of 0.5 mg/kg of the NMDA blocker MK-801, inhibition is restored, and only a minimal population spike is generated by the second stimulation. When MK-801 is eliminated (bottom trace), this effect disappears. (B) Paired-pulse inhibition after injection of NMDA receptor blockers into the dentate gyrus. +1 h and +24 h indicate time after administration of a compound. MK-801 acts inside the channel, while 2,7 DCK and AP5 block the glycine and glutamate site, respectively. White bars indicate short ISI-dependent inhibition (at 40 msec); black bars indicate long ISI-dependent inhibition (at 700 msec); gray bars indicate frequency-dependent inhibition (40 msec, 2 Hz). P2/P1 is the ratio of the second to the first population spike. ISI, interstimulus interval. Data are presented as means ± SEM. *P < 0.05 versus before PPS (repeated-measures ANOVA followed by Newman–Keuls post hoc test). (Reprinted with permission from Mazarati and Wasterlain [73].)
appears more likely that this change would result from the loss of one or several cell populations in the lesioned hilus (e.g., mossy cells, GABAergic interneurons). Figure 34.6 proposes various putative circuits that could explain these experimental results. In each circuit, SEinduced loss of inhibitory or excitatory neurons results in suppression of GABAergic inhibition in the dentate gyrus. Since inhibition of basket cells by other GABAergic neurons has been demonstrated within the dentate gyrus, these schemes postulating inhibition of inhibition are compatible with the known organization of hippocampal circuitry. Time course of the loss of inhibition In many SE models, disinhibition is maximal immediately after SE, weeks before spontaneous recurrent seizures occur, and then slowly recovers. However, this transient loss of inhibition could play a role in epileptogenesis, by generating plastic changes which might help to transform interictal spikes (present right after SE in many models) into full-blown seizures. For example, in our studies with the model of PPS enacted under anesthesia (110), naive rats showed marked paired-pulse inhibition in response to pairs of perforant path volleys at short (10–60 msec) ISIs, a process that is thought to be GABAA-mediated (8, 136). In PPS rats, 30 minutes after the end of stimulation, short-ISI paired-pulse inhibition was completely lost. Two weeks after stimulation, some inhibition returned, but short-ISI pairedpulse inhibition was still reduced significantly. Four weeks after stimulation, the inhibition scores increased further and had fully recovered in some animals (108). This is the time when spontaneous seizures first appeared. Our studies showed evidence for a progression of hippocampal hyperexcitability (similar to that seen during kindling; see references 43, 108, and 142) during the latent period, at the same time that dentate paired-pulse inhibition was recovering: first, hippocampal hyperexcitability, as indicated by input-output curves of the granule cell response to PPS and by the occurrence of generalized seizures in response to 2-Hz stimulation, was not seen immediately after SE but was present 4 weeks after SE. A similar increase takes place during kindling (Figure 34.7A). Second, after PPS, the long-term potentiation (LTP) of granule cell responses to perforant path volleys by trains of impulses delivered through the perforant path was markedly enhanced (Figure 34.7B) in both amplitude and duration. Third, the kindling rate was massively accelerated (Figure 34.7C), not only in response to PPS but also in response to stimulation of the contralateral amygdala (108). Progression of excitability may also occur in other SE models: in pilocarpine-treated rats, spontaneous seizure frequency increased 20–30 days after SE (57, 58). Kainic acid–injected rats began to shown spontaneous amygdaloid seizures 20–40 days and generalized convulsions 30–60 days
after injection (130). Therefore, it seems that lesions caused by SE cannot induce spontaneous recurrent epileptic seizures directly but a second hit is needed—in other words, these lesions permit the activation of some process that induces a chronic epileptic state over a period of weeks. Summary: The filter hypothesis revisited In previous work, we suggested that the hippocampus may have a frequency or intensity “filter” that prevents physiologic neuronal firing from kindling the limbic system (142), that this filter function may, in part, reflect the activity of hilar interneurons, and that this filter may be damaged by SE. In the Sloviter model of focal SE, seizures caused lesions only in the hippocampus, with the most severe damage occurring in the dentate hilus. The SE-lesioned hippocampus showed an immediate and profound loss of GABAA inhibition that recovered slowly over several weeks. Perforant path-granule cell LTP and kindling were enhanced, possibly because a decrease in recurrent GABAergic inhibition made it easier to depolarize granule cells and to relieve the magnesium block of NMDA receptors. Kindling-like increases in granule cell excitability occurred spontaneously over the next month. The appearance of a chronic epileptic state was delayed by several weeks after SE. These changes suggest that SE leads to chronic epilepsy by a two-step process. In the first step, SE-induced lesions generate an abnormal hippocampal circuit in which dentate GABAergic inhibition is actively suppressed through an NMDA-dependent step. However, that suppression of inhibition alone is not sufficient to cause chronic epilepsy, since no spontaneous seizures are seen. But SE-induced loss of inhibition may have removed the “filter” that normally prevents physiological stimuli from kindling the hippocampus. In the second step, dentate gyrus disinhibition facilitates LTP of excitatory synapses, which may spread progressively through the brain and eventually lead to chronic epilepsy. At the same time, sprouting of inhibitory fibers leads to recovery of dentate GABAergic inhibition, but this recovery comes too late to stop spontaneous recurrent seizures, since the potentiation of excitatory circuits is already established. Many investigators have previously suggested a two-step process of SE-induced epileptogenesis (17). It is supported by the antiepileptogenic effect of kindling inhibitors given during the latent period (70, 120). C M: E for N E C Axonal sprouting Extensive neuronal loss is associated with synaptic reorganization in the hippocampus (80, 124, 133, 145). Mossy fibers, which are easily visualized with the Timm stain because of their zinc content, sprout into the inner molecular layer of the dentate gyrus after epileptogenic insults (Figure 34.8), and have been shown to form
.:
429
F 34.6 Putative circuits explaining the SE-induced loss of inhibition in dentate gyrus, based on (A) loss of mossy cells that innervate and excite basket cells (the dormant basket cell hypothesis); (B) loss of mossy cells that compete with an inhibitory cell for the same basket cell targets, the mossy cell input being normally dominant. Loss of the mossy cells will leave the basket cells suppressed by the unopposed inhibitory input, but if this inhibitory cell is driven by granule cells through an NMDA synapse, blocking
that synapse will restore inhibition (the “suppressed basket cell” hypothesis). (C) The basket cell is inhibited by cell x, which is itself inhibited by cell y, and both cell x and cell y are driven by excitatory perforant path input. Loss of cell y during SE releases from inhibition cell x, which inhibits the basket cell. Blockage of perforant path excitation of cell x by NMDA blockers or presynaptic inhibitors of glutamate release restores inhibition. (Reprinted with permission from Wasterlain et al. [141].)
PS ratio (at 250 µA)
A
100
F 34.7 (A) Sequential changes of population spike (PS) ratio [(PS amplitude at 250 mA stimulus intensity)/(maximal PS amplitude in the same experiment) ¥ 100] in stimulated rats and control rats. The PS ratio increased during the latent period. When both groups of rats were kindled through the perforant path (arrows), the control rats’ PS ratio increased but that of SE rats remained at a plateau, as if they were already kindled. Abbreviations: PfPS or Kindling with arrows, the time point at which PPS or kindling stimulation was given; stimulated, rats given PfPS; control, nonstimulated control rats. Before, after, 30 min, 2 weeks, and 4 weeks after refer to PPS in stimulated rats and to 24-hour anesthesia in control rats, respectively. *, †: Significantly different from before (P < 0.05) **P < 0.01. (Reprinted with permission from Shirasaka et al. [108].) (B) The long-term potentiation of granule cell responses to perforant path stimulation was enhanced in amplitude and duration, when tested 24 hours after perforant path stimulation-induced SE. (Reprinted with permission from Wasterlain et al. [141.]) (C) In rats subjected to PPS-induced SE, afterdischarge threshold of granule cell responses to PPS is decreased, afterdischarge duration is increased, and the number of stimulations needed to reach stage 5 seizures is markedly reduced compared to sham-stimulated controls. (Reprinted with permission from Wasterlain et al. [141].)
Kindling
80 †
** ‡
PfPS
60
*
40
†
†
20 stimulus control
0 D –20 before 30 min 2 wks 4 wks after after after
B
Before PPS
after Kindling 1 wk 4 wks
After PPS 1/2 max PS
Before tetanus
4 3 2 30’ after tetanus
1 0
20 40 60 90 120 180
reproduced by other investigators (143), and this issue remains quite controversial. Since the kainate model produces widespread extrahippocampal lesions that might well be epileptogenic, it would be surprising if all spontaneous recurrent seizures in that model were of hippocampal origin, and the presence of chronic epilepsy in the absence of mossy fiber sprouting in kainate-treated animals does not rule out an epileptogenic role for sprouting of excitatory fibers.
90’ after tetanus
C 600
400 *
300 C 200
E
0
75 50 25 0
E C
Number of Trials to First C5
100 AD Duration (s)
AD Threshold (mA)
500
100
15
125
12 9 6
C **
3 E 0
functional asymmetric excitatory connections with granule cell dendrites (27, 144), suggesting the formation of a novel recurrent excitatory circuit. Such recurrent excitation is, of course, potentially epileptogenic. Mossy fiber reorganization has been proposed to play a key role in epileptogenicity in kainic acid models (38, 39, 133, 144), pilocarpine models (58), or kindling models (53, 99, 125, 127), as well as in the human epileptic temporal lobe (67). A correlation between timing and extent of sprouting and epileptogenicity is controversial, but often poor (38, 85, 115). There is good physiologic evidence that sprouted mossy fibers form functional synapses onto granule cells (144). However, profound inhibition of mossy fiber sprouting has been reported to be associated with fully intact epileptogenesis (62, 63), although these results have not been
Dendritic sprouting Sprouting is not restricted to mossy fibers. Dendritic sprouting is prominent in the dentate gyrus after SE (119), and the new synaptic connections made on these dendrites modify the physiology of dentate granule cells. Sprouting of inhibitory fibers has also been documented, and indeed, inhibition returns progressively to the post-SE hippocampus, and in chronic animals may exceed the levels seen in untreated controls (115). There is also evidence for sprouting of excitatory fibers outside the dentate gyrus. Increased excitatory responses in CA1 minislices from kainate SE rats bathed in bicuculline suggest the existence of abnormal axonal sprouting generating synaptic connections between CA1 cells (117). C SE-I E P, M, R? A number of studies have reported attempts to reduce the incidence or the severity of epilepsy by treating during SE, during the latent period, or during both. Unfortunately, these efforts have been haphazard, without any systematic attempt to compare the effects of different drugs in the same model, dose, and age (Table 34.1). Moreover, seizure susceptibility varies with genetic background and with developmental age, and this is likely
.:
431
F 34.8 Mossy fiber sprouting shown by use of the Timm method, which stains zinc present in mossy fibers. (A) Cresyl violet–stained normal human hippocampus. (B) Magnification of the boxed area in A. The Timm-stained area is clearly limited to the polymorph layer (PM). (C) Similar display of a hippocampus surgically resected from a patient with mesial temporal lobe epilepsy with hippocampal sclerosis. There is a second Timmstained band in the inner molecular layer (IML) due to the sprouted
432
:
recurrent collaterals from granule axons. (D and E) Timm-stained puncta (presumed mossy fiber terminals) in the IML (D) and supragranular layer (SG) (E) from the boxed area in C. OML, outer molecular layer; MML, middle molecular layer; g, granule cell; hf, hippocampal fissure. (Reprinted with permission from Isokawa, M., M. Levesque, I. Fried, and J. Engel, Jr. Glutamate currents in morphologically identified human dentate granule cells in temporal lobe epilepsy. J. Neurophysiol. 1997;77:3355–3369.)
F 34.9 (A and B) Low magnification of the dentate gyrus in control (A) and PPS rats (B), illustrating the axons (arrowheads) emerging from the base of control granule cells in A, and basal
dendrites (arrows) at the base of the cells from a stimulated rat in B. Scale bar = 10 mm. ML, molecular layer; GL, granule cell layer; H, hilus. (Reprinted with permission from Spigelman et al. [119].)
.:
433
434
T 34.1 Results of experimental studies seeking to reduce the incidence or severity of chronic epilepsy following status epilepticus
:
AED
Age
SE Model
Carbamazepine
Adult
Pilocarpine
Diazepam
Adult
Amygdaloid stimulation
Diazepam
P15, P28
Lithiumpilocarpine
Felbamate
P30
Kainate
Fluorofelbamate
Adult
PPS
Fosphenytoin
Lithiumpilocarpine
P28
Gabapentin
P35
Kainate
Lamotrigine
Adult
Levetiracetam
Adult
Amygdaloid stimulation Pilocarpine
Levetiracetam
Adult
PPS
Levetiracetam
Adult
PPS
Levetiracetam (200 mg/kg)
P28
Lithiumpilocarpine
Levetiracetam (1,000 mg/kg)
P28
Lithiumpilocarpine
Levetiracetam (200 mg/kg) + diazepam (5 mg/kg)
P28
Lithiumpilocarpine
Time of Treatment
Effect on Epileptogenesis
For 56 days (started 24 hr after pilocarpine) Two doses (started 3 hr after onset of SE) Single dose (20, 40, or 70 min after pilocarpine)
~0 effect on incidence of epilepsy ±0 effect on latency ~0 effect on incidence of epilepsy
Single dose (1 hr after kainate) Single dose (10 or 40 min after onset of SE) Single dose (20, 40, or 70 min after pilocarpine) For 40 days (started 24 hr after SE) For 11 weeks (started 2 hr after SE) For 21 days (started 30 min after onset of SE) Single dose (10 min after onset of SE) For 29 days (started 1 hr after onset of SE) Single dose (20, 40, or 70 min after pilocarpine) Single dose (20, 40, or 70 min after pilocarpine) Single dose (20, 40, or 70 min after pilocarpine)
≠ latency to fluorothyl seizures ~0 effect on latency
20 min Ø incidence of SRS (P15, P28)
~0 effect on incidence
Ø incidence (just visual, before drug washout) ~0 effect on incidence ~0 effect on incidence
Disease-modifying Effect
Study
Ø seizure frequency, duration. No EEG
Capella and Lemos (24)
Ø seizure frequency ~0 effect on seizure duration 40, 70 min ±0 seizure frequency, duration, Ø spike frequency (P15) 40, 70 min Ø seizure frequency, ~0 effect on spike frequency, duration (P28) n.d.
Nissinen et al. (85)
10 min Ø seizure and spike frequency, remission of SRS ~0 effect on seizure and spike frequency, duration n.d.
Mazarati et al. (72)
~0 effect on seizure frequency, duration ~0 effect on seizure frequency
Nissinen et al. (84)
Suchomelová et al. (120, 122)
Chronopoulos et al. (29)
Suchomelová et al. (123)
Cilio et al. (30)
Klitgaard et al. (59)
≠ latency ~0 effect on incidence ~0 effect on incidence
Ø seizure frequency
Mazarati et al. (70)
Ø seizure frequency
Mazarati et al. (70)
~0 effect on incidence
Ø seizure frequency, ±0 spike frequency, duration 20, 70 min seizure frequency, ±0 spike frequency, duration 70 min Ø seizure frequency, ±0 spike frequency, duration
Suchomelová et al. (121)
~0 effect on incidence
20, 40 min Ø incidence of epilepsy
Suchomelová et al. (121)
Suchomelová et al. (121)
.:
MK-801
Adult
Hippocampal stimulation Kainate
MK-801
Adult
MK-801
P28
Lithiumpilocarpine
Phenobarbital
Adult
Kainate
Phenobarbital
P35
Kainate
Phenobarbital
P35
Kainate
Phenobarbital
Adult
Phenytoin
Adult
Pregabalin
P21
Hippocampal stimulation Hippocampal stimulation Lithiumpilocarpine
Pregabalin
Adult
Lithiumpilocarpine
Topiramate
Adult
Topiramate
Adult
Lithiumpilocarpine Pilocarpine
Topiramate
P15, P28
Lithiumpilocarpine
Valproate
P35
Kainate
Valproate
Adult
Pilocarpine
Vigabatrin
Adult
Vigabatrin
Adult
Amygdaloid stimulation Lithiumpilocarpine
Single dose (1–4 hr after onset of SE) Single dose (90 min after onset of SE) Single dose (20, 40, or 70 min after pilocarpine) For 5 days (started immediately after kainate) For 40 days (started 24 hr after onset of SE) For 118 days (started 24 hr after onset of SE) Single dose (1–4 hr after onset of SE) Single dose (1–4 hr after onset of SE) For 13 days (started 20 min after pilocarpine) For 13 days (started 20 min after pilocarpine) For 7 days (started 1 hr after onset of SE) For 4 days (started 1 hr after onset of SE) Single dose (20, 40, or 70 min after pilocarpine) For 40 days (started 24 hr after onset of SE) For 21 days (started 30 min after onset of SE) For 10 weeks (started 2 days after SE) For 45 days (started 10 min after pilocarpine)
1 or 2 hr Ø incidence of epilepsy ~0 effect on incidence of epilepsy Ø incidence of epilepsy
n.d.
Prasad et al. (98)
~0 effect on seizure frequency
Brandt et al. (21) Suchomelová and Wasterlain (123)
Ø susceptibility to kindling
n.d.
Sutula et al. (125)
~0 effect on incidence (during drug taper, just video) n.d.
~0 effect on seizure frequency (video only)
Bolanos et al. (19)
~0 effect on seizure frequency (video only)
Mikati et al. (78)
1 hr – Ø incidence
n.d.
Prasad et al. (98)
~0 effect on incidence
n.d.
Prasad et al. (98)
~0 effect on incidence ≠ latency (visual)
n.d.
Andre et al. (7)
~0 effect on incidence ≠ latency (visual)
n.d.
Andre et al. (7)
~0 effect on incidence ~0 effect on latency Ø incidence of epilepsy
~0 effect on seizure frequency (video only) n.d.
Rigoulet et al. (101)
Ø incidence of epilepsy (P15) 20 min Ø incidence of epilepsy (P28) Ø no animals with SRS (during drug taper, video) ~0 effect on incidence
40, 70 min Ø seizure frequency, ±0 spike frequency, duration (P28) n.d.
Suchomelová et al. (120, 122)
~0 effect on seizure frequency
Klitgaard et al. (59)
~0 effect on seizure frequency, duration n.d.
Halonen et al. (52)
~0 effect on incidence ±0 latency ~0 effect on latency
435
Abbreviations: PPS, perforant path stimulation; SRS, spontaneous recurrent seizures; n.d., no data.
DeLorenzo et al. (45)
Bolanos et al. (19)
Andre et al. (6)
to be true for SE as well, yet there has been no systematic comparison of genetic or developmental factors. Treatment during acute SE The effect of treatment on the duration of SE stands out as the most conspicuous factor in altering epileptogenesis (60). Most drugs given early (e.g., after 20 minutes of SE) are antiepileptogenic, but those that do not stop seizures (e.g., fosphenytoin on lithium/ pilocarpine SE) have no effect even if given early. Treatment given more than 2 hours into SE is rarely antiepileptogenic. However, there is a suggestion that anticonvulsant and antiepileptogenic effects can be dissociated. For the same time of treatment, some agents are much more antiepileptogenic than others, at the doses studied: MK-801 was not very effective against acute SE but was highly effective in reducing the incidence of spontaneous recurrent seizures (98) (Table 34.1). In P15 rats, topiramate was less effective than diazepam against acute SE, but was more effective than diazepam in reducing spontaneous recurrent seizures (Table 34.1). Surprisingly, the antiepileptogenicity of an agent could depend on the age of the subject: the same dose of topiramate was more antiepileptogenic at P15 than at P28 (Table 34.1). Treatment during the latent period Three studies found treatment started 24 hours or more after SE to reduce seizure frequency (19, 24, 30). The valproate study (19) reported a decreased incidence of epilepsy but used only video, so that electrographic seizures with minimal or nonspecific behavioral manifestations could have been missed. Furthermore, recordings were carried out close to the time of drug withdrawal, without drug serum level measurements, casting a doubt on its conclusions. Another valproate study was negative but used a different model (59). Surprisingly, the other successful drugs (carbamazepine [24] and gabapentin [30]) were not studied again. Other attempts to treat during the latent period failed to alter epileptogenesis (6, 7, 19, 52, 59, 78, 84, 101). We found that levetiracetam given during the latent period reduced the severity of SE-induced chronic epilepsy in the perforant path model, but treatment was started before SE was terminated, and also shortened the duration of SE (70). This work was supported by the Veterans Administration Research Service, by research grant No. NS13515 from the National Institute of Neurological Disorders and Stroke, and by a fellowship from the Epilepsy Foundation of America (Y. S.).
REFERENCES 1. Aicardi, J. Epilepsy in Children. 2nd ed. New York: Raven Press, 1994.
436
:
2. Aicardi, J., J. Amsili, and J. J. Chevrie. Acute hemiplegia in infancy and childhood. Dev. Med. Child Neurol. 1969;11: 162–173. 3. Aicardi, J., and J. J. Chevrie. Consequences of status epilepticus in infants and children. Adv. Neurol. 1983;34:115–125. 4. Aicardi, J., and J. J. Chevrie. Convulsive status epilepticus in infants and children: A study of 239 cases. Epilepsia 1970; 11:187–197. 5. Anderson, W. M., H. S. Swartzwelder, and W. A. Wilson. The NMDA receptor antagonist 2-amino-5-phosphonovalerate blocks stimulus train–induced epileptogensis but not epileptiform bursting in the rat hippocampal slice. J. Neurophysiol. 1987;57:1–21. 6. Andre, V., A. Ferrandon, C. Marescaux, and A. Nehlig. Vigabatrin protects against hippocampal damage but is not antiepileptogenic in the lithium-pilocarpine model of temporal lobe epilepsy. Epilepsy Res. 2001;47:99–117. 7. Andre, V., M. A. Rigoulot, E. Koning, A. Ferrandon, and A. Nehlig. Long-term pregabalin treatment protects basal cortices and delays the occurrence of spontaneous seizures in the lithium-pilocarpine model in the rat. Epilepsia 2003;44: 893–903. 8. Austin, K. B., J. D. Bronzino, and P. J. Morgane. Paired-pulse facilitation and inhibition in the dentate gyrus is dependent on behavioral state. Exp. Brain Res. 1989;77:595–604. 9. 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 dentata. Neuroscience 1991;42:351–363. 10. Babb, T. L., J. K. Pretorius, W. R. Kupger, and P. H. Crandall. Glutamate decarboxylase-immunoreactive neurons are preserved in human epileptic hippocampus. J. Neurosci. 1989;9:2562–2574. 11. Barois, A., B. Estournet, S. Baron, and M. Levy-Alcover. Long-term prognosis of states of prolonged convulsive disorders: apropos of 29 cases of states of convulsive disorders in excess of 24 hours. Ann. Pediatr. (Paris) 1985;32:621–626. 12. Bekenstein, J. W., and E. W. Lothman. Dormancy of inhibitory interneurons in a model of temporal lobe epilepsy. Science 1993;259:97–100. 13. Ben-Ari, Y. Limbic seizure and brain damage produced by kainic acid: Mechanism and relevance to human temporal lobe epilepsy. Neuroscience 1985;14:375–403. 14. Ben-Ari, Y., E. Tremblay, D. P. Ottersen, and R. Naquet. Evidence suggesting secondary epileptogenic lesions after kainic acid: Pretreatment with diazepam reduces distant but not local brain damage. Brain Res. 1979;165:362–365. 15. Bernard, C., M. Esclapez, J. C. Hirsch, and Y. Ben-Ari. Interneurones are not so dormant in temporal lobe epilepsy: A critical reappraisal of the dormant basket cell hypothesis. Epilepsy Res. 1998;32:93–103. 16. Bertram, E. H. Functional anatomy of spontaneous seizures in a rat model of limbic epilepsy. Epilepsia 1997;38:95–105. 17. Bertram, E. H., and J. Cornett. The ontogeny of seizures in a rat model of limbic epilepsy: Evidence for a kindling process in the development of chronic spontaneous seizures. Brain Res. 1993;625:295–300. 18. Bertram, E. H., III, 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. 19. Bolanos, A. R., M. Sarkisian, Y. Yang, et al. Comparison of valproate and phenobarbital treatment after status epilepticus in rats. Neurology 1998;51:10–11.
20. Bouchet, Cazauvieilh. De l’epilepsie considerée dans ses rapports avec l’alienation mentale: Recherche sur la nature et le siege de ces deux maladies. Arch. Gen. Med. 1825/6;9: 510–542, 10:5–50. 21. Brandt, C., H. Potschka, W. Loscher, and U. Ebert. N-methyl-aspartate receptor blockade after status epilepticus protects against limbic brain damage but not against epilepsy in the kainate model of temporal lobe epilepsy. Neuroscience 2004; 118:727–740. 22. Brooks-Kayal, A. R., M. D. Shumate, H. Jin, T. Y. Rikhter, and D. A. Coulter. Selective changes in single cell GABAA receptor subunit expression and function in temporal lobe epilepsy. Nat. Med. 1998;4:1166–1172. 23. Buckmaster, P. S., and F. E. Dudek. Neuron loss, granule cell axon reorganization, and functional changes in the dentate gyrus of epileptic kainate-treated rats. J. Comp. Neurol. 1997; 385:385–404. 24. Capella, H., and T. Lemos. Effect on epileptogenesis of carbamazepine treatment during the silent period of the pilocarpine model of epilepsy. Epilepsia 2002;43:110–111. 25. 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;14:3106–3121. 26. Cavazos, J. E., G. Golarai, and T. P. Sutula. Mossy fiber synaptic reorganization induced by kindling: Time course of development, progression, and permanence. J. Neurosci. 1991; 11:2795–2803. 27. Cavazos, J. E., P. Zhang, R. Qazi, and T. P. Sutula. Ultrastructural features of sprouted mossy fiber synapses in kindled and kainic acid-treated rats. J. Comp. Neurol. 2003;458:272–292. 28. Cendes, F., F. Andermann, S. Carpenter, R. J. Zatorre, and N. R. Cashmen. Temporal lobe epilepsy caused by domoic acid intoxication. Ann. Neurol. 1995;37:123–126. 29. 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. 30. Cilio, M. R., A. R. Bolanos, Z. Liu, et al. Anticonvulsant action and long-term effects of gabapentin in the immature brain. Neuropharmacology 2001;40:139–147. 31. 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. 32. Collins, R. C., and J. W. Olney. Focal cortical seizures cause distant thalamic lesions. Science 1982;218:177–179. 33. Corsellis, J. A. N., and C. J. Bruton. Neuropathology of status epilepticus in humans. In Advances in Neurology, vol. 34: A. V. Delgado-Escueta, C. G. Wasterlain, D. M. Treiman, and R. J. Porter, eds. Status Epilepticus. New York: Raven Press, 1983;129–139. 34. Cossart, R., C. Dinocourt, J. C. Hirsch, A. Merchan-Perez, J. De Felipe, Y. Ben-Ari, et al. Dendritic but not somatic GABAergic inhibition is decreased in experimental epilepsy. Nat. Neurosci. 2001;4:52–62. 35. Coulter, D. A. Chronic epileptogenic cellular alterations in the limbic system after status epilepticus. Epilepsia 1999; 40(Suppl. 1):S23–S33. 36. Coulter, D. A. Epilepsy-associated plasticity in gammaaminobutyric acid receptor expression, function, and inhibitory synaptic properties. Int. Rev. Neurobiol. 2001;45: 237–252.
37. Covolan, L., and L. E. Mello. Temporal profile of neuronal injury following pilocarpine or kainic acid–induced status epilepticus. Epilepsy Res. 2000;39:133–152. 38. Cronin, J., and F. E. Dudek. Chronic seizures and collateral sprouting of dentate mossy fibers after kainic acid treatment in rats. Brain Res. 1988;474:181–184. 39. Cronin, J., A. Obenhaus, C. R. Houser, and F. E. Dudek. Electrophysiology of dentate granule cells after kainateinduced synaptic reorganization of the mossy fibers. Brain Res. 1992;573:305–310. 40. Dam, A. M. Hippocampal neuron loss in epilepsy and after experimental seizures. Acta Neurol. Scand. 1982;66:601–642. 41. 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. 42. 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. 43. DeGiorgio, C. M., C. N. Heck, A. L. Rabinowicz, P. S. Gott, T. Smith, and J. Correale. Serum non-specific enolase in the major subtypes of status epilepticus. Neurology 1999;52: 746–749. 44. 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. 45. DeLorenzo, R. J., T. A. Morris, R. E. Blair, M. Wallace, and B. Razvi. Topiramate is both neuroprotective and antiepileptogenic in the pilocarpine model of status epilepticus. Epilepsia 2002;43:S15p. 46. Ebisu, T., W. D. Rooney, S. H. Graham, A. Mancuso, M. W. Weiner, and A. A. Maudsley. MR spectroscopic imaging and diffusion-weighted MRI for early detection of kainateinduced status epilepticus in the rat. Magn. Reson. Med. 1996; 36:821–828. 47. Fujikawa, D. The temporal evolution of neuronal damage from pilocarpine-induced status epilepticus. Brain Res. 1996; 725:11–22. 48. Fujikawa, D. G., H. H. Itabashi, A. Wu, and S. S. Shinmei. Status epilepticus–induced neuronal loss in humans without systemic complications or epilepsy. Epilepsia 2000;41:981– 991. 49. Gastaut, H., J. Faidherbe, and J. Roger. 5 case reports of unusual development of the hemiconvulsion-hemiplegiaepilepsy syndrome (HHE syndrome) in children. Acta Neurol. Belg. 1962;62:177–192. 50. Glass, M., and M. Dragunow. Neurochemical and morphological changes associated with human epilepsy. Brain Res. Rev. 1995;21:29–41. 51. Goldensohn, E. Structural lesions of the frontal lobe. In P. Chauvel, A. V. Delgado-Escueta, E. Halgren, and J. Bancaude, eds. Frontal Lobe Seizures and Epilepsies. Adv. Neurol. 1992;57:435–447. 52. Halonen, T., J. Nissinen, and A. Pitkanen. Chronic elevation of brain GABA levels beginning two days after status epilepticus does not prevent epileptogenesis in rats. Neuropharmacology 2001;40:536–550. 53. Heinemann, U., H. Clussmann, J. Dreier, and J. Stabel. Changes in synaptic transmission in the kindled hippocampus. Adv. Exp. Med. Biol. 1990;268:445–450. 54. Hesdorffer, D. C., G. Logroscino, G. Cascino, J. F. Annegers, and W. A. Hauser. Risk of unprovoked seizure after acute symptomatic seizure: Effect of status epilepticus. Ann. Neurol. 1998;44:908–912.
.:
437
55. Houser, C. R., J. E. Miyashire, 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. 56. Inoue, K., K. Morimoto, K. Sato, N. Yamada, and S. Otsuki. Mechanisms in the development of limbic status epilepticus and hippocampal neuron loss: An experimental study in a model of status epilepticus induced by kindling-like electrical stimulation of the deep prepyriform cortex in rats. Acta Med. Okayama 1992;46:129–139. 57. Isokawa, M., and I. Fried. Exocellular slow negative transient in the dentate gyrus of human epileptic hippocampus in vitro. Neuroscience 1996;72:31–37. 58. Isokawa, M. Decreased time constant in hippocampal dentate granule cells in pilocarpine-treated rats with progressive seizure frequencies. Brain Res. 1996;718:169–175. 59. Klitgaard, H. V., A. C. Matagne, and J. Vanneste-Goemaere. Effect of prolonged administration of levetiracetam on pilocarpine-induced epileptogenesis in rat. Epilepsia 2001;42: S114–S115. 60. Klitgaard, H., A. Matagne, J. Vanneste-Goemaere, and D. G. Margineanu. Pilocarpine-induced epileptogenesis in the rat: Impact of initial duration of status epilepticus on electrophysiological and neuropathological alterations. Epilepsy Res. 2002;51:93–107. 61. Kubová, H., P. Maresˇ, L. Suchomelová, G. Brozek, R. Druga, and A. Pitkänen. Status epilepticus in immature rats leads to behavioural and cognitive impairment and epileptogenesis. Eur. J. Neurosci. 2004;19:3255–3265. 62. Longo, B. M., and L. E. Mello. Blockade of pilocarpine- or kainate-induced mossy fiber sprouting by cycloheximide does not prevent subsequent epileptogenesis in rats. Neurosci. Lett. 1997;226:163–166. 63. Longo, B. M., and L. E. Mello. Supragranular mossy fiber sprouting is not necessary for spontaneous seizures in the intrahippocampal kainate model of epilepsy in the rat. Epilepsy Res. 1998;32:172–182. 64. 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;6:110–118. 65. Margerison, J. H., and J. A. N. Corsellis. Epilepsy and the temporal lobes: A clinical, electroencephalographic and neuropathological study of the brain with particular reference to the temporal lobes. Brain 1996;89:680–708. 66. Masukawa, L. M., W. M. O’Connor, J. Lynott, et al. Longitudinal variation in cell density and mossy fiver reorganization in the dentate gyrus from temporal lobe epileptic patients. Brain Res. 1996;678:65–75. 67. Masukawa, L. M., K. Uruno, M. Sperling, M. J. O’Connor, and L. J. Burdette. The functional relationship between antidromically evoked field response of the dentate gyrus and mossy fiber reorganization in temporal lobe epileptic patients. Brain Res. 1992;579:119–127. 68. Masukawa, L. M., H. Wang, M. J. O’Connor, and K. Uruno. Prolonged field potentials evoked by 1 Hz stimulation in the dentate gyrus of temporal lobe epileptic human brain slices. Brain Res. 1996;721:132–139. 69. Mathern, G. W., T. L. Babb, J. K. Pretorius, and J. P. Leite. Reactive synaptogensis and neuron densities for neuropeptide Y, somatostatin and glutamate decaboxylase immuno-
438
:
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80. 81.
82.
83.
84.
85.
86.
reactivity in the epileptogenic human fascia dentata. J. Neurosci. 1995;15:3990–4004. Mazarati, A., R. A. Baldwin, H. Klitgaard, A. Matagne, and C. G. Wasterlain. Treatment with levetiracetam during latent period after experimental status epilepticus reduces chronic spontaneous seizures. Epilepsia 2003;44:223. Mazarati, A. M., R. A. Baldwin, R. D. Sofia, and C. G. Wasterlain. Felbamate in experimental model of status epilepticus. Epilepsia 2000;41:123–127. Mazarati, A. M., R. D. Sofia, and C. G. Wasterlain. Anticonvulsant and antiepileptogenic effects of fluorofelbamate in experimental status epilepticus. Seizure 2002;11:423–430. Mazarati, A. M., and C. G. Wasterlain. Blockers of NMDA receptors restore paired-pulse inhibition in the rat dentate gyrus lesioned by perforant path stimulation. Neurosci. Lett. 1997;234:135–138. Mazarati, A. M., and C. G. Wasterlain. Selective facilitation of kindled seizures from the amygala after hippocampal lesions induced by perforant path stimulation. Neurosci. Lett. 1997;224:165–168. 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;801:251– 253. Meierkord, H., U. Wieshmann, L. Niehaus, and R. Lehmann. Structural consequences of status epilepticus demonstrated with serial magnetic resonance imaging. Acta Neurol. Scand. 1997;96:127–132. 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. Mikati, M., G. L. Holmes, A. Chronopoulos, P. Hyde, S. Thurber, A. Gatt, et al. Phenobarbital modifies seizurerelated brain injury in the developing brain. Ann. Neurol. 1994; 36:425–433. Morrisett, R. A., R. S. Jope, and O. C. Snead, III. 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. Nadler, J. V. Minireview: Kainic acid as a tool for the study of temporal lobe epilepsy. Life Sci. 1981;29:2031–2042. Najm, I. M., Y. Wang, D. Shedid, H. O. Luders, T. C. Ng, and Y. G. Comair. MRS metabolic markers of seizures and seizure-induced neuronal damage. Epilepsia 1998;39:244– 250. Nakasu, Y., S. Nakasu, S. Morikawa, S. Uemura, T. Inubushi, and J. Handa. Diffusion-weighted MR in experimental sustained seizures elicited with kainic acid. AJNR Am. J. Neuroradiol. 1995;16:1185–1192. 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. Nissinen, J., C. H. Large, S. C. Stratton, and A. Pitkänen. Effect of lamotrigine treatment on epileptogenesis: An experimental study in rat. Epilepsy Res. 2004;58:119–132. Nissinen, J., K. Lukasiuk, and A. Pitkänen. Is mossy fiber sprouting present at the time of the first spontaneous seizures in rat experimental temporal lobe epilepsy? Hippocampus 2001;11:299–310. Nissinen, J., S. Narkilahti, K. Lukasiuk, and A. Pitkänen. Diazepam treatment has a disease-modifying effect on the
87. 88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
developing epilepsy after status epileticus in rat. Epilepsia 2001;42:S131. Norman, R. M. The neuropathology of status epilepticus. Med. Sci. Law 1964;14:46–51. Obenhaus, A., M. Esciapez, 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. Ohtsu, M., H. Oguni, Y. Awaya, and M. Osawa. Clinical and EEG analysis of initial status epilepticus during infancy in patients with mesial temporal lobe epilepsy. Brain Dev. 2002; 24:231–238. Olney, J. W., T. de Gubareff, and J. Labruyere. Seizure-related brain damage induced by cholinergic agents. Nature 1983;301: 520–522. Olney, J. W., T. de Gubareff, and R. S. Sloviter. “Epileptic” brain damage in rats induced by sustained electrical stimulation of perforant path. II. Ultrastructural analysis of acute hippocampal pathology. Brain Res. Bull. 1983;10:699–712. Olney, J. W., V. Rhee, and O. L. Ho. Kainic acid: A powerful neurotoxic analogue of glutamate. Brain Res. 1974;77:507– 512. Penix, L. R., and C. G. Wasterlain. Selective protection of neuropeptide-containing dentate hilar interneurons by nonNMDA receptor blockade in an animal model of status epilepticus. Brain Res. 1994;644:19–24. Pereira de Vasconcelos, A., A. M. Mazarati, C. G. Wasterlain, and A. Nehlig. Self-sustaining status epilepticus after a brief electrical stimulation of the perforant path: A 2-deoxyglucose study. Brain Res. 1999;838:110–118. Pfleger, L. Beobachtungen über Schrumpfung und Sklerose des Ammonshorn bei Epilepsie. Allg. Z. Psychiatrie 1880;35: 359–365. Pitkänen, A. Drug-mediated neuroprotection and antiepileptogenesis: Animal data. Neurology 2002;59(Suppl. 5): S27–S33. Pitkänen, A., J. Nissinen, J. Nairismagi, et al. Progression of neuronal damage after status epilepticus and during spontaneous seizures in a rat model of temporal lobe epilepsy. Prog. Brain Res. 2002;135:67–83. Prasad, A., J. M. Williamson, and E. H. Bertram. Phenobarbital and MK-801, but not phenytoin, improve the long-term outcome of status epilepticus. Ann. Neurol. 2002;51:175–181. Rashid, K., C. E. E. M. Van der Zee, G. M. Ross, et al. A nerve growth factor peptide retards seizure development and inhibits neuronal sprouting in a rat model of epilepsy. Proc Natl. Acad. Sci. U.S.A. 1995;92:9495–9499. Ratzliff, A. H., A. L. Howard, V. Santhakumar, L. Osapay, and I. Soltesz. Rapid deletion of mossy cells does not result in a hyperexcitable dentate gyrus: Implications for epileptogenesis. J. Neurosci. 2004;24:2259–2269. Rigoulot, M. A., E. Koning, A. Ferrandon, and A. Nehlig. Neuroprotective effect of topiramate in the lithium- pilocarpine model of epilepsy. J. Pharmacol. Exp. Ther. 2003; 308:787–795. Robitalle, Y., T. Rasmussen, F. Dubeau, D. Tampieri, and K. Kemball. Histopathology of nonneoplastic lesionsin frontal lobe epilepsy. In P. Chauvel, A. V. Delgado-Escueta, E. Halgren, and J. Bancaude, eds. Frontal Lobe Seizures and Epilepsies. Adv. Neurol. 1992;57:499–513. Roger, J., M. Bureau, C. Dravet, B. Dalla Bernardina, C. A. Tassinari, M. Revol, et al. Cerebral hemiplegias in children:
104.
105.
106. 107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
EEG data and epileptic manifestations related to childhood cerebral hemiplegia in children. Rev. EEG Neurophysiol. Clin. 1972;2:5–28. Roger, J., C. Dravet, and M. Bureau. Unilateral seizures: Hemiconvulsions-hemiplegia syndrome (HH) and hemiconvulsions-hemiplegia-epilepsy syndrome (HHE). Electroencephalogr. Clin. Neurophysiol. Suppl. 1982;35:211–221. Sankar, R., D. Shin, A. M. Mazarati, H. Liu, H. Katsumori, R. Lezama, and C. G. Wasterlain. Epileptogenesis after status epilepticus reflects age- and model-dependent plasticity. Ann. Neurol. 2000;48:580–589. Scher, M. S. Neonatal seizures and brain damage. Pediatr. Neurol. 2003;29:381–390. Schwob, J. E., T. E. Fuller, J. L. Price, and J. W. Olney. Widespread patterns of neuronal damage following systemic or intracerebral injection of kainic acid: A histological study. Neuroscience 1980;5:991–1014. Shirasaka, Y., and C. G. Wasterlain. Chronic epileptogenicity following focal status epilepticus. Brain Res. 1994;655: 33–44. Shirasaka, Y., and C. G. Wasterlain. The effect of urethane anesthesia on evoked potentials in dentate gyrus. Eur. J. Pharmacol. 1995;282:11–17. Sloviter, R. S. Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. Science 1987;235:73–76. Sloviter, R. S. “Epileptic” brain damage in rats induced by sustained electrical stimulation of the perforant path. I. Acute electophysiological and light microscopic studies. Brain Res. Bull. 1983;10:675–697. Sloviter, R. S. Feedforward and feedback inhibition of hippocampal principal cell activity evoked by perforant path stimulation: GABA-mediated mechanisms that regulate excitability in vivo. Hippocampus 1991;1:31–40. 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;1:41–48. Sloviter, R. S. Possible functional consequences of synaptic reorganization in the dentate gyrus of kainate-treated rats. Neurosci. Lett. 1992;137:91–96. Sloviter, R. S, C. A. Zappone, B. D. Harvey, A. V. Bumanglag, R. A. Bender, and M. Frotscher. “Dormant basket cell” hypothesis revisited: Relative vulnerabilities of dentate gyrus mossy cells and inhibitory interneurons after hippocampal status epilepticus in the rat. J. Comp. Neurol. 2003;459:44– 76. Smith, B. N., and F. E. Dudek. Network interactions mediated by new excitatory connections between CA1 pyramidal cells in rats with kainate-induced epilepsy. J. Neurophysiol. 2003;87:1655–1658. Sommer, W. Erkrankung des Ammonhornes als aetiologisches Moment des Epilepsie. Arch. Psychiatr. Nervenkr. 1880; 10:631–675. 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.
.:
439
120. Suchomelová, L., R. A. Baldwin, A. M. Mazarati, and C. G. Wasterlain. Efficacy of topiramate in blocking epileptogenesis after lithium-pilocarpine status epilepticus depends on time of treatment. Epilepsia 2002;43(Suppl. 1):33. 121. Suchomelová, L., R. A. Baldwin, and C. G. Wasterlain. Levetiracetam/diazepam combination improves long-term outcome of status epilepticus. Abstr. Soc. Neurosci. 2004:47. 122. Suchomelová, L., R. A. Baldwin, and C. G. Wasterlain. Topiramate improves the long-term outcome of status epilepticus in immature rats. Epilepsia 2003;44(Suppl. 9):209. 123. Suchomelová, L., and C. G. Wasterlain. MK-801 and topiramate, but not phenytoin, improve the long-term outcome of status epilepticus in juvenile rats. Neurology 2004; 62(Suppl. 5):A252–A253. 124. 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. 125. Sutula, T., J. Cavazos, and G. Golarai. Alteration of longlasting structural and functional effects of kainic acid in the hippocampus by brief treatment with phenobarbital. J. Neurosci. 1992;12:4173–4187. 126. Sutula, T., and B. P. Dimiano. Sustained electrical stimulation of the perforant path duplicates kainite-induced electrophysiological effects and hippocampal damage in rats. Neurosci. Lett. 1981;24:279–284. 127. Sutula, T., J. Koch, G. Golarai, Y. Watanabe, and J. O. McNamara. NMDA receptor dependence of kindling and mossy fiber sprouting: Evidence that the NMDA receptor regulates patterning of hippocampal circuits in the adult brain. J. Neurosci. 1996;16:7389–7406. 128. Sutula, T., H. Xiao-Xan, J. Cavazos, and G. Scott. Synaptic reorganization in the hippocampus induced by abnormal functional activity. Science 1988;239:1147–1150. 129. Swann, J. W., M. G. Pierson, K. L. Smith, and C. L. Lee. Developmental neuroplasticity: Roles in early life seizures and chronic epilepsy. Adv. Neurol. 1999;79:203–216. 130. Tanaka, T., M. Kaijima, Y. Yonemasu, and C. Cepeda. Spontaneous secondarily generalized seizures induced by a single microinjection of kainic acid into unilateral amygdale in cats. Electroencephalogr. Clin. Neurophysiol. 1985;61:422– 429. 131. Tanaka, T., S. Kondo, T. Hori, S. Tanaka, and Y. Yonemasu. Various hippocampal lesions induced by multi-fractional ibotenic acid injections and amygdala kindling in rats. Brain Res. 1991;559:154–158. 132. Tanaka, T., S. Tanaka, T. Fujita, K. Takano, H. Fukuda, K. Sako, and Y. Yonemasu. Experimental complex partial seizures induced by a microinjection of kainic acid into limbic structures. Prog. Neurobiol. 1992;38:317–334. 133. 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. 134. Teitelbaum, J. S., R. J. Zatorre, S. Carpenter, D. Gendron, A. C. Evans, A. Gjedde, et al. Neurologic sequelae of domoic acid intoxication due to the ingestion of contaminated mussels. N. Engl. J. Med. 1990;322:1781–1787. 135. 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. 136. 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.
440
:
137. Turski, L., E. A. Cavalheiro, M. Sieklucka-Dziuba, C. Ikonomidou-Turski, S. J. Czuczwar, and W. A. Turski. Seizures produced by pilocarpine: Neuropathological sequelae and activity of glutamate decarboxylase in the rat forebrain. Brain Res. 1986;398:37–48. 138. 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. 139. Uruno, K., M. J. O’Connor, and L. M. Masukawa. Effects of bicuculline and baclotein on paird-pulse depression in the dentate gyrus of epileptic patient. Brain Res. 1995;695:163– 172. 140. VanLandingham, K. E., E. R. Heinz, J. E. Cavazos, and D. V. Lewis. Magnetic resonance imaging evidence of hippocampal injury after prolonged focal febrile convulsions. Ann. Neurol. 1998;43:413–426. 141. Wasterlain, C. G., D. B. Farber, and M. D. Fairchild. Hippocampal lesions and lesional epilepsies: A Hebbian theory of epileptogenesis. In A. V. Delgado-Escueta, W. Wilson, R. Olsen, and R. J. Porter, eds. Jasper’s Basic Mechanisms of the Epilepsies. Baltimore: Lippincott Williams & Wilkins, 1999: 829–844. 142. Wasterlain, C. G., Y. Shirasaka, A. M. Mazarati, and I. Spigelman. Chronic epilepsy with damage restricted to the hippocampus: Possible mechanisms. Epilepsy Res. 1996;26: 255–265. 143. Williams, P. A., J. P. Wuarin, P. Dou, D. J. Ferraro, and F. E. Dudek. Reassessment of the effects of cycloheximide on mossy fiber sprouting and epileptogenesis in the pilocarpine model of temporal lobe epilepsy. J. Neurophysiol. 2002;88: 2075–2087. 144. Wuarin, J.-P., and F. E. Dudek. Electrographic seizures and new recurrent excitatory circuits in the dentate gyrus of hippocampal slices from kainate-treated epileptic rats. J. Neurosci. 1996;16:4438–4448. 145. Yang, Y., P. Tandon, Z. Liu, M. R. Sarkisian, C. E. Stafstrom, and G. L. Holmes. Synaptic reorganization following kainic acid-induced seizures during development. Dev. Brain Res. 1998;107:169–177. 146. Zappone, C. A., and R. S. Sloviter. Translamellar disinhibition in the rat hippocampal dentate gyrus after seizureinduced degeneration of vulnerable hilar neurons. J. Neurosci. 2004;24:853–864. 147. Zhong, J., O. A. Petroff, J. W. Prichard, and J. C. Gore. Barbiturate-reversible reduction of water diffusion coefficient in flurothyl-induced status epilepticus in rats. Magn. Reson. Med. 1995;33:253–256.
35
Hippocampal Reactive Synaptogenesis from Status Epilepticus
.
Introduction Nerve and muscle cells that partially lose their synaptic inputs experience one of the following: (1) postsynaptic transcellular degeneration, if the differentiation is severe; (2) cellular survival, but with fewer synaptic inputs than before; or (3) selected denervated sites becoming renervated from “new” axon connections (185). The process whereby axons and corresponding synapses are replaced after partial differentiation is termed reactive synaptogenesis (35). The concept that after partial synaptic loss, nearby undamaged axons sprout new branches to reform synaptic contacts has existed for years. It originated in studies of the peripheral nervous system. Haighton, in 1795, was perhaps the earliest to suggest that after denervation, surviving peripheral motor nerves could reform functional connections and might even hyperinnervate organs such as the stomach and vocal cords, thus explaining postinjury dysfunctional physical signs (68). After incomplete proximal motor nerve transection, Exner (51) in 1885 observed that muscular contraction appeared prior to nerve fiber regeneration, and concluded that this was from “new” local collateral nerve growth. Likewise, Kennedy (85) in 1897 cautioned that one explanation for studies purporting to show peripheral nerve regeneration might be that local undamaged nerves sprouted into denervated sites. Subsequently, studies by Lugaro (104), Ramón y Cajal (161), Van Harrelveld (202), Edds (49), and Hoffman (72) provided anatomic and physiologic evidence that intact fibers from partially cut peripheral nerves can generate axon sprouts that renervate muscles. These studies were followed by Murray and Thompson’s (146) 1957 report showing that axonal sprouting also occurred in partially denervated sympathetic ganglion, and Liu and Chambers’s (95) 1958 paper indicating that after dorsal spinal root transection there was subsequent axonal sprouting of caudal nerve root fibers into the dorsal spinal cord. Within a short time other studies demonstrated injuryinduced axonal sprouting in the central nervous system (CNS) (66, 158, 167). Anatomically, one of the most con-
vincing was Raisman’s 1969 study, which used light and electron microscopy (159). In his experiment, the medial forebrain bundle and/or the fimbria were sectioned, and several weeks later septal neurons were examined for signs of axon degeneration and renervation. After a fimbria lesion, the medial forebrain fibers extended axonal branches into zones once occupied by prior fimbria axons. Likewise, after medial forebrain lesions, fimbria fibers occupied terminals closer to the septal somata that were presumably vacated by medial forebrain fibers. Raisman concluded that after partial nerve fiber injury, deafferented synapses on septal neurons were reoccupied, in time, by surviving axonal branches. Since these early reports there have been numerous experimental and human studies on the CNS showing injuryinduced reactive synaptogenesis (34, 105). This chapter focuses on reactive synaptogenesis and epileptogenesis as it pertains to denervation after status epilepticus (SE) in the hippocampus. The goals are to (1) review the general principles of reactive synaptogenesis in the CNS, (2) discuss the anatomic and physiologic findings of SE-induced hippocampal neuronal loss and axonal sprouting, (3) present experimental evidence supporting the view that “new” aberrant excitatory and inhibitory axon fibers form functional and probably abnormal circuit connections that contribute to spontaneous recurrent seizures, and (4) present the possible molecular mechanisms that may govern the initiation and regulation of SE-induced aberrant axon growth.
General principles of axon and dendritic responses to partial synaptic loss By definition, reactive synaptogenesis entails the replacement of vacated synapses by new ones, and one possible consequence of reactive sprouting is to alter the brain’s hard wiring (32). Although there may be mechanistic and physiologic similarities, reactive synaptogenesis is different from normal neuronal development and axogenesis because it is a reparative process (35, 185). It is also important to emphasize that reactive sprouting is most likely initiated by
:
441
the presence of empty synapses. Neuronal loss itself is less important than denervated synapses, and cutting axon connections is just as affective as neuronal damage with secondary axon loss in initiating axon sprouting. Likewise, following neuron and axon injury, renervation seems to be the rule rather than the exception. However, not every axon system seems capable of reactive sprouting (i.e., the process is selective). When multiple axons have the opportunity to sprout, one fiber type often predominates within a denervated zone (44, 45, 58, 214). Conceptually, one purpose of reactive synaptogenesis might be to facilitate functional recovery after brain injury (53). However, an alternative hypothesis is that sprouting alters excitatory and inhibitory axon connections onto surviving neurons in such
a way that the resulting circuit is abnormal and may depress or overexpress synaptic responses. Hence, reformed axon circuits after injury are most likely maladaptive and pathologic (52). In the brain, not all axonal sprouting is the same, and there are several types, as illustrated in Figure 35.1. The first, termed collateral sprouting, involves the growth of new axon branches from areas outside the denervated zone. In collateral sprouting, axon branches grow into sites that they normally would not innervate. The new collateral branches cross traditional laminar borders, and the likely consequence is an abnormal axon circuit and synapse, which may have a different neurotransmitter and alter the postsynaptic receptor subunit composition or functional properties. The second
F 35.1 Possible axon reactive responses to denervation. Normal: This drawing shows a postsynaptic dendrite receiving two different axon inputs and synaptic transmitters (marked A, B, A¢, and B¢, respectively). In the subsequent illustrations the B axons are lost. Collateral: In this form of reactive synaptogenesis, axons from outside the denervated zone and from different neurons than B sprout axon branches to form synapses in place of the lost B fibers (fiber C and synapse C¢). With collateral sprouting there may be a substantial change in the resulting axon circuitry and neurotransmitters used in the new synapse (marked C¢). Paraterminal: In this
type of sprouting, existing axons along the same dendrite sprout new branches to occupy the lost B fibers. The resulting axon circuit and synaptic transmitters are similar to those already existing on this dendrite. However, the total number of A-type synapses are now increased compared to normal (i.e., hyperinnervation). No Sprouting: One other consequence of denervation may be that no axons sprout, in which case the dendritic segment that lost its synapses atrophies. The net effect is a shorter dendrite, and the remaining axon fibers are in closer proximity to the cell body than before.
442
:
type, referred to as paraterminal sprouting, differs from collateral sprouting in that new fibers branch off existing axons within the denervated region. The new fibers renervate synapses in relatively close proximity to their normal targets, there is minimal translaminar growth, and the resulting axon connections are only slightly different than normal. In paraterminal sprouting, one might expect only slight differences in axonal connections, synapses, and neurotransmitters compared with collateral sprouting. However, one probable consequence of paraterminal sprouting is that there might be a relative increase in the number of axon contacts per dendrite (i.e., hyperinnervation). Therefore, in paraterminal sprouting, the resulting synaptic response may be increased or may show greater synchrony than normally expected. Collateral and paraterminal sprouting are therefore distinguished by the location of the axon branch point, by the distance and translaminar direction the new fibers grow before establishing synaptic contacts, and by the aberrant nature of the resulting axonal connections and synaptic circuitry. In the fascia dentata, examples of both sprouting types after SE-induced injury occur and will be illustrated later in this chapter. Finally, another possible response to synaptic denervation is that sprouting may not occur, in which case the portion of the dendrite that lost its synaptic contacts shortens accordingly. All of these different possibilities are illustrated in Figure 35.1. Reactive synaptogenesis depends on the presence of a viable postsynaptic cell in which to form new synapses. In addition, dendrites are not passive participants in the denervation-renervation process but adjust their length and number of postsynaptic spines accordingly (185). For example, within 2–10 days after axon loss, there is a rapid disappearance of postsynaptic spines, and at the same time atrophy (i.e., shortening) of the denervated dendritic segments occurs (40). The change in dendritic lengths and spine formation can be modified by renervation and synaptic activity. Increased synaptic activity maintains synaptic spines and dendritic lengths, while reduced activity promotes dendritic atrophy (24, 25). In rodents, reactive axonal growth begins within 4–5 days after injury. Reactive synaptogenesis is greatest between 9 and 30 days and continues at a reduced rate for more than 6 months (35). When new sprouted axons come in close proximity to dendrites, the postsynaptic spines reform, but the spines are initially small and increase in size with time (2, 62, 155). Reinervated dendrites are then partially restored, with lengths, to about 80% of normal. Equally important is that the denervation-renervation process changes the final dendritic architecture of the neuron. In the fascia dentata, after reactive synaptogenesis distal dendrites shorten more than proximal segments do. For most normal dendrites the first branch point is usually very near the somata. After denervation-renervation the
dendrites changes such that (1) the distance from the cell body to the first branch point may be three times longer than normal; (2) there are fewer branch points near the cell body and more distally; and (3) the distal dendritic segments are often shorter than expected (216). The anatomic and physiologic consequences of these changes are a relative increase in synaptic densities closer to the neuron and an accompanying increase in somal excitatory and inhibitory synaptic efficiency (73, 74, 76, 79, 209–211). Of note, these denervation-renervation dendritic architectural changes have been observed in granule cell dendrites of human temporal lobe epilepsy patients with hippocampal sclerosis (75, 203).
Sprouting after SE: The fascia dentata as an example With these basic principles of reactive synaptogenesis now outlined, the following discussion examines the process of denervation and renervation in the fascia dentata that follows prolonged SE in rodents. The axon fibers that sprout after SE-induced neuronal injury fill in regions expected to have vacated synapses. For a better understanding of the areas of denervation and subsequent axonal sprouting, this section first presents the normal neuronal and axonal circuit anatomy of the fascia dentata. There follows a description of neuron loss in animal models after SE and the expected denervation of granule cell dendrites. The sprouting of new axon systems after SE and the molecular layer regions they reinnervate are brought into the picture, then studies showing changes in growth-related proteins observed in areas undergoing reactive synaptogenesis are discussed. It is important to remember that the fascia dentata represents only one anatomic site for which we have experimental evidence regarding SE-induced neuronal damage and reactive synaptogenesis (other hippocampal and neocortical sites have been less extensively studied), and that sprouting occurs in many regions of the damaged CNS as a consequence of SE (157, 169). N F D A The hippocampus lies in the mesial aspect of the temporal lobe and structurally consists of the dentate gyrus, Ammon’s horn, and the subiculum. In comparison with other neocortical and subcortical anatomic structures, the fascia dentata and Ammon’s horn have a relatively simple architecture and laminar organization (2, 162). In transverse sections, the mammalian hippocampus is composed of two parallel neuronal populations that form juxtaposed C-shaped layers. One layer consists of tightly packed Ammon’s horn pyramidal cells, the second layer is dentate gyrus granule cells, and each layer is segregated, with dendrites lying on one side of the neurons and axons on the other (i.e., a three-layer cortex; Figure 35.2). The pyramidal cell layer is divided into four
:
443
F 35.2 Low-power micrographs of Nissl-stained hippocampal sections from normal rat and a kainite-induced SE rat, and a bar graph showing the estimated percent hippocampal neuronal loss in different rat models of limbic status. (A) Contralateral dorsal hippocampus in a rat that received intrahippocampal kainic acid (0.4 mg/0.2 mL), showing normal hippocampal anatomy. The following hippocampal subfields are labeled: The dentate gyrus (DG) granule cells, hilus (H), and CA3 and CA1 stratum pyramidale. (B) Ispilateral kainite-injured rat hippocampus. The end folium shows severe hilar and CA3 neuronal loss (arrows). However,
444
:
the CA1 region (arrowhead) shows minimal neuronal damage. (C) Bar graph illustrating the percent hippocampal neuron loss in different SE rat models. Models include the self-sustained limbic epilepsy (SSLE), pilocarpine, and intraperitoneal kainate (IP-KA). The data are similar for dentate gyrus granule cells, CA3, and CA1 pyramids. The area of greatest variability between models was the hilar neuron count. Data were compiled from the author’s laboratory with the collaboration of Luiz Mello and Edward Bertram. Calibration bar = 0.5 mm.
cornu ammonis (CA) subfields termed CA1–CA4, with areas CA3 and CA2 a part of the Ammon’s horn regio inferior (i.e., near the granule cells) and CA1 the regio superior (98). The subiculum is a transitional cortex found immediately distal to CA1. Intermixed within all hippocampal subfields, but especially in the fascia dentata hilus, are inhibitory GABAergic interneurons (Figure 35.2). Principal neurons greatly outnumber GABAergic cells. The fascia dentata, also known as the dentate gyrus, consists of granule cells and hilar neurons (Figures 35.2 and 35.3). The layer of tightly packed granule cells, termed the stratum granulosum, forms an arch enclosing the regio inferior end of the cornu ammonis subfields (i.e., CA4-3c). The region within the enclosed granule cell arch is termed the hilus and contains the aforementioned extension of CA4-3 pyramidal neurons, and between the pyramids and granule cells a population of variously shaped, loosely packed interneurons and mossy cells in the polymorph layer. CA4 neurons are generally considered to be the pyramids between the granule cell blades that are an extension of CA3c, and hilar neurons are the polymorph cells between the subgranular zone and CA4 pyramids (115, 123). The granule cell apical dendrites project into the molecular layer (stratum moleculare). This is perpendicular to their somata on the outside fascia dentata arch, and granule cell axons, the mossy fibers, project into the hilus and regio inferior, where they form multiple synaptic connections onto hilar neurons and proximal dendrites of CA3 pyramids (Figure 35.3, left panel). For most anatomists, the fascia dentata is assumed to include the stratum moleculare, granulosum, and hilar polymorph layers, but not necessarily the CA4 pyramids (14). The major extrinsic and intrinsic axonal connections into the fascia dentata center on granule cell dendrites, and the inputs are organized into discrete laminae (30, 197). For granule cells, the major extrinsic cortical connections are from perforant path fibers that originate from the entorhinal cortex. The entorhinal cortex consists of six layers, with layers I–III classified as superficial and layers IV–VI as deep. The perforant path axons arise mostly from layer II stellate neurons. The fibers pass into the underlying white matter, termed the angular bundle, cross the subiculum and hippocampal fissure, branch, and form boutons en passent on small spines in the outer two-thirds to three-fourths of the molecular layer. These fibers form synapses on granule cell and inhibitory interneuron dendrites (70, 71, 151, 160, 184, 186). In rodents, approximately 86% of the outer molecular layer (OML) synaptic boutons are from perforant path fibers; they are mostly excitatory and glutamatergic, and only a small proportion are GABAergic (64, 133, 134). Neurons from the medial entorhinal cortex project to the deepest portion of the OML, and more lateral entorhinal cells terminate in the superficial molecular layers (184). In
primates and humans compared with rodents, the perforant pathway becomes phylogenetically and physiologically more important. The second major afferent axon system onto granule dendrites is fibers from the ipsilateral associational and contralateral commissural projections (Figure 35.3, left panel). The fibers originate from hilar mossy cells, some hilar interneurons, and regio inferior pyramids, and their axons project into the proximal one-third of the molecular layer (IML) (67, 187). These fibers are a combination of excitatory axons from mossy cells, some GABAergic fibers, and other axons that contain transmitters thought to modulate synaptic efficiency (somatostatin, neuropeptide Y, enkephalin, and so on) (8). In the rodent molecular layer, there is virtually no overlap between OML perforant path fibers and IML associational axons (i.e., a molecular layer translaminar boundary). In humans and monkeys, studies support the idea that the ipsilateral associational system is anatomically more prominent and physiologically more functional than the contralateral commissural fibers (59, 174, 212, 213). Compared with the perforant path and associationalcommissural projections, the other extrinsic fibers from the septum and brain stem are less numerous and probably functionally less important, especially in humans (not illustrated in Figure 35.3). These fibers consist of (1) cholinergic fibers from the medial septal nucleus, nucleus of the diagonal band, and intermediolateral septum (137), (2) noradrenergic fibers from the locus ceruleus (82), and (3) serotonergic raphe projections (173). These axons pass into the fascia dentata from the fimbria-fornix and innervate mostly hilar and other interneurons (88, 145, 191). The intrinsic fascia dentata GABAergic connections are also highly organized and can be roughly separated into two main fiber systems (56). One GABAergic system consists of chandelier (axo-axonal) and basket cells, and their cell bodies are found within or just beneath the stratum granulosum. Also termed parasomal inhibitory cells, they receive inputs from perforant path fibers (feedforward), mossy fibers, and other intrinsic hilar associational axons (feedback), and project onto hundreds of granule cells near their cell bodies or initial axon segments (7, 87). Because parasomal GABAergic axons terminate close to the somata and initial axon segments, these interneurons constitute an important inhibitory circuit that significantly modulates granule cell activity (149, 150, 185). The second major fascia dentata GABAergic system consists of fibers from hilar neurons termed dendritic inhibitory interneurons. These consist of cells in the hilus and molecular layer that, like the parasomal interneurons, receive perforant path and mossy fiber inputs, but unlike parasomal cells send their axons into the molecular layer, where they terminate on distal granule cell
:
445
446 : F 35.3 Scheme summarizing the fascia dentata neuronal losses and axon sprouting after SE-induced neuronal injury. The normal fascia dentata anatomy and axon circuitry are shown in the left panel (see text for details). After SE, there is preferential loss of hilar mossy cells and somatostatin neurons, along with some neuropeptide Y neurons, as shown in the middle panel. The regions of lost molecular layer synapses are indicated by dashed lines. The reorganized excitatory and inhibitory axon circuits (bold lines) and postsynaptic receptor changes are illustrated in the right panel (see text for descriptions). Abbreviations: GC, granule cells; BC, basket cells; MC mossy cell; SS, somatostatin; NYP, neuropeptide Y; GAD, glutamate decarboxylase. Ovals denote AMPA GluR1 postsynaptic receptors, rectangles denote NMDAR2 receptors, and triangles denote GABA-A receptors.
dendrites in a distribution similar to perforant path fibers. This is also a feedforward and feedback inhibitory system, and because of its axon organization, dendritic inhibitory interneurons are thought to modulate and fine-tune granule cell dendritic synaptic responses without significantly affecting granule cell somata. L F D N F SE In adult animal and human studies, prolonged SE is associated with a fairly consistent pattern of hippocampal neuron loss. The pathophysiologic mechanisms probably responsible for selective neuronal injury are covered in several excellent reviews and will not be addressed here (9, 139, 140, 152, 204, 205). Instead, it is important to note that neuronal damage following lethal SE in humans or rats involves not just the hippocampus but also diffuse areas of the brain, including amygdala, piriform and entorhinal cortices, septum, substantia nigra, thalamus, and neocortex (11, 12, 15, 17, 20, 47, 48, 54, 108, 153, 178, 193, 198, 219). SE-induced fascia dentata damage often preferentially involves certain neuronal subtypes (see Figures 35.2B and C). After SE in rodents, there is loss of hilar mossy cells, subtypes of hilar interneurons, and regio inferior pyramids (CA4, CA3c) compared with granule cells and regio superior Ammon’s horn pyramids (CA1; see Figures 35.2B and C). This pattern of fascia dentata neuron loss is observed whether SE is induced by application of neurotoxins like pilocarpine or kainic acid or by continuous electrical stimulation (see Figure 35.2C). By knowing the normal fascia dentata anatomy and afferent axonal connections, one can predict which molecular layer postsynaptic sites will lose their synaptic contacts as a consequence of SE-induced cell loss (see Figure 35.3, middle panel). Specifically, the IML becomes vacated from loss of mossy cells and CA3 pyramidal axons, and the OML loses synaptic contacts from loss of hilar dendritic inhibitory interneurons that are immunoreactive (ir) for somatostatin, and neuropeptide Y. By contrast, GABAergic basket and chandelier cells of the parasomal inhibitory interneuron system do not seem to be selectively damaged after SE-induced hippocampal injury (4, 38, 119, 126, 181). F D A S C SEI N L After loss of synaptic inputs into the molecular layer, the remaining fibers from several fascia dentata neurons respond by sprouting axon collaterals or paraterminal branches. The best-studied axons have been the mossy fibers from granule cells, which show collateral sprouting into the IML in rat SE models and in patients with mesial temporal lobe epilepsy (36, 37, 41, 42, 55, 89, 127, 148, 164, 189, 194, 217). One reason mossy fiber sprouting has been so extensively studied is because these axons can be easily identified by the neo-Timm histochemical stain,
and new fiber growth into the IML occurs in a region where mossy fibers do not normally exist. This stain uses a low concentration of sodium sulfide that binds to free zinc within mossy fibers and their terminals. The zinc-sulfide complex is developed with silver intensification, much as a photograph is developed. Normally, neo-Timm-stained mossy fibers form a dark brown to black set of fibers and puncta within the hilus and proximal dendrites of CA3 (Figures 35.4B and D). There is no staining or only light brown coloration without puncta in the normal fascia dentata IML. Beginning a few days after SE-induced hippocampal hilar injury and proceeding for many weeks thereafter, the IML shows dark, neo-Timm-stained puncta consistent with aberrant mossy fiber sprouting (Figures 35.5B and D). The histochemical findings have been confirmed by filling single granule cells with tracers in slices and by electron microscopy (57, 75, 80, 154, 155, 166). These findings demonstrate that mossy fibers sprout to occupy the deafferented IML granule cell dendrites left vacant most likely from loss of associational fibers from hilar and CA3 cell loss (see Figure 35.3, right panel). Because mossy fibers normally do not exist in the IML, supragranular mossy fiber sprouting represents a form of collateral reactive synaptogenesis (see Figure 35.1). Studies in rats using neo-Timm staining demonstrate several features that one would expect for the time course of mossy fiber reactive synaptogenesis. For example, after SEinduced injury, the first signs of sprouting are observed as early as 4–7 days. The greatest progression of neoTimm-stained puncta density occurs in the first 30–60 days and continues to slowly increase for the next several months (114, 141, 155). Likewise, the first neo-Timm-stained puncta are small, and they eventually increase in size with time (84, 116, 132). Reactive synaptogenesis in the fascia dentata after SE is not limited to excitatory mossy fibers but also includes GABAergic fibers and other fiber systems (see Figure 35.3, right panel). For example, animal and human studies have shown differences in the pattern and amount of immunoreactivity for GABA, somatostatin, neuropeptide Y, and so on that is most consistent with the notion of molecular layer axon sprouting (15, 29, 38, 39, 171, 175, 218). These studies agree with biochemical and in situ hybridization experiments showing that after SE-induced denervation, fascia dentata interneurons increase synthetic GABA enzymes and the amount of GABA released with electrical stimulation (50, 126, 147). In entorhinal-lesioned rats, Deller et al. (43) found anatomic evidence that hilar neurons sprout GABAergic axons to occupy OML sites previously receiving mostly glutamatergic perforant path axons. Of interest, there is more IML GABA-ir in patients with hippocampal sclerosis than in tumor patients with temporal lobe epilepsy (119). Such findings support the concept that the remaining
:
447
F 35.4 In a control animal, photomicrographs of Nisslstained (A and C) and neo-Timm-stained (B and D) horizontal hippocampal sections from two sample sites. Figures 35.4 to 35.6 are similarly organized, and the rats were perfused and processed in the same batch. The normal, Nissl-stained sections show numer-
ous CA3 and hilar neurons, and the neo-Timm-stained section shows a slight amount of light brown stain of the inner molecular layer, but no dark puncta. All photomicrographs in Figures 35.4 to 35.6 are of equal magnification. Calibration bar = 500 mm.
F 35.5 (A–D) Photomicrographs of a rat hippocampus 2 weeks after kainate-induced SE. Compared to the control sections (Figure 35.4), the Nissl-stained sections show loss of CA3 pyramids and some hilar damage in the middle and dorsal sections (A and C). However, the hilar cell loss was greater in the middle section
than in the dorsal section. The neo-Timm-stained sections show dark puncta in the IML both sections, consistent with aberrant mossy fiber sprouting. However, the staining was increased in the middle section, where the hilar damage was greater than in the dorsal section.
inhibitory axons probably sprout fibers to replace lost axonal contacts and may hyperinnervate IML granule cell dendrites. Because molecular layer GABAergic sprouting most likely originates from parasomal and surviving dendritic inhibitory interneurons that normally innervate the granule cell and molecular layer, the new axons likely represent a form of paraterminal sprouting (see Figure 35.1C). The functional consequence is likely an increase in GABAmediated innervation that may suppress hyperexcitability, or it may help to synchronize granule cell synaptic activity and be epileptogenetic (15, 31, 168). Not every fascia dentata axon system sprouts after SE. One of the principles of reactive synaptogenesis is that the renervation process is often selective (34). There is currently little evidence to show that perforant path or locus ceruleus fibers sprout toward the IML after SE-induced neuronal loss, even though they are in much closer proximity to denervated IML synapses than granule cell mossy fibers (35). Why only certain axons seem capable of reactive synaptogenesis is not clearly understood, but the resulting pattern of new aberrant axon connections is often as rigidly laminated as the normal pattern was before SE-related injury.
Mechanisms that influence axon sprouting Animal studies indicate that at least two factors significantly influence the amount of aberrant fascia dentata mossy fiber sprouting after SE. One is the amount of initial IML denervation, and the second is the time after injury that the animals are studied (28, 90, 99, 100, 102, 122, 188, 198). In rats, we have illustrated these anatomic features in Figures 35.4 to 35.6. For example, Figure 35.4 shows normal Nissland neo-Timm-stained horizontal sections from the dorsal and middle portions of the hippocampus of a control rat. Figure 35.5 shows similar sections in a rat 2 weeks after SEinduced hilar injury. In a comparison of dorsal to middle sections between the control rat and the hilar-injured rat, there is visibly greater hilar damage in the middle section and greater IML neo-Timm staining. Figure 35.6 shows hippocampal sections from a rat 2 months after SE; similar amounts of hilar and CA3 neuronal loss are apparent as in the animal studied 2 weeks after SE (Figure 35.5). However, one difference between the 2-month and the 2-week surviving rat is that there is greater supragranular mossy fiber sprouting. In rats, the greater ventral than dorsal neuronal damage is probably similar to the anterior-to-posterior gradient of damage observed in human patients with temporal lobe epilepsy and hippocampal sclerosis (3, 4, 111). Hence, the relative amount of hilar cell damage and the time after injury are two factors that influence the amount of mossy fiber sprouting observed on histologic sections. Another factor that influences the distribution and amount of reactive synaptogenesis is the developmental age
when the denervation injury occurs. Although it is more difficult to induce SE-related neuronal injury in younger animals, once damaged, hippocampal axonal sprouting is greater than similar lesions in mature brains and extends without regard for traditional laminar boundaries. Likewise, in developing human hippocampal studies the amount of mossy fiber sprouting seems out of proportion to the amount of hilar neuronal loss (117, 166). Moreover, an elderly brain does not sprout as much as the juvenile hippocampus when subjected to similar denervation injuries (33, 60–63, 92, 135, 136). Hence, in any study of reactive synaptogenesis, the developmental age when the neuronal injury was incurred needs to be considered when comparing one study with another.
Functional consequences of fascia dentata axon sprouting An important question for researchers is whether reactive synaptogenesis is adaptive, restoring neuronal functions, or maladaptive, leading to a dysfunction or a pathologic substrate capable of generating seizures. To answer this question, investigators have looked for anatomic or electrophysiologic signs that axonal sprouting leads to identifiable abnormalities. This section presents evidence to support the proposition that aberrant supragranular mossy fiber sprouting after SE is associated with alterations in excitatory and inhibitory postsynaptic receptors and with electrophysiologic signs of increased granule cell hyperexcitability. These findings support the hypothesis that aberrant axonal sprouting is most likely maladaptive and contributes to spontaneous limbic seizures (115, 123). P R In SE-induced injury rodent models and in human patients with temporal lobe epilepsy, changes occur in molecular layer excitatory and inhibitory postsynaptic receptors in association with axonal sprouting (see Figure 35.3 and 35.7) (118, 128–131). The antibodies and in situ molecular techniques necessary to study postsynaptic excitatory and inhibitory receptor subunit expression are relatively new, but experiments have uncovered a relationship between increased NMDA, AMPA, and GABA subunit expression, spontaneous limbic seizures, and aberrant molecular layer axonal sprouting (5, 124, 142, 165). For example, Figure 35.7 illustrates immunoreactivity for antibodies against AMPA GluR1, and NMDAR2 from a kindled rat and a spontaneously seizing rat after SE. In the kindled animal, there were no spontaneous chronic limbic seizures, only stimulated ones; there was no significant mossy fiber or GABAergic axon sprouting; and the pattern of GluR1 and NMDAR2 staining was similar to that in control rats (Figures 35.7A, C, and E). In a spontaneously seizing rat after SE, there were hilar neuron loss, mossy fiber, and GABAergic
:
449
F 35.6 (A–D) Photomicrographs of a rat hippocampus 2 months after SE. Compared to the prior 2-week SE animal, sections from this hippocampus show about the same amount of CA3 and hilar neuron losses (left column). However, with the longer
survival, there was significant hippocampal atrophy compared to the control specimen (Figure 35.4), and greater neo-Timm staining of the IML in both sample sites (B and D).
axonal sprouting, and associated with the molecular layer axonal sprouting was increased GluR1-ir and NMDA-ir. For GluR1, in the kindled animal there was immunoreactivity that lightly labeled granule cells and fibers in the molecular layer (Figure 35.7C, arrow and arrowhead), while the epileptic rat showed dark-stained granule cells and molecular layer fibers (Figure 35.7D). Similarly, in the kindled rat, NMDAR2-ir was less in the IML than in the OML (Figure 35.7E, arrow and arrowhead, respectively) but became equally dark in both molecular layers in the spontaneously seizing animal (Figure 35.7F ). In fact, after SE-induced neuronal injury in rats and in humans with hippocampal sclerosis, increased IML NMDAR2-ir positively correlates with greater supragranular mossy fiber sprouting. This finding is further supported by in situ hybridization studies showing that compared with autopsy cases, granule cells from patients with chronic temporal lobe seizures have greater mRNA levels for NMDAR2a and 2b than for NMDAR1, and greater AMPA GluR1 than AMPA GluR2 or AMPA GluR3 (118, 130). These anatomical findings are consistent with electrophysiological studies in animals and humans showing that granule cell hyperexcitability, associated with supragranular mossy fiber sprouting, is blocked by NMDA antagonists (73, 77, 80,
199). Hence, aberrant IML mossy fiber sprouting is anatomically linked with alterations in excitatory postsynaptic NMDA and AMPA receptor subunit composition. Such changes are likely to alter glutamate-mediated granule cell synaptic function and could promote granule cell hyperexcitability in the damaged fascia dentata. In human hippocampal sclerosis cases and rat models of SE, evaluation of the GABAergic system has also shown a relationship between seizures and changes in GABA postsynaptic receptor subunits that may relate to reactive synaptogenesis (18, 19, 121, 171, 177, 182, 195). In pilocarpine-treated rats, once an animal starts to seize spontaneously, intrahippocampal levels of glutamate, glutamine, and GABA increase, consistent with the idea that excitatory and inhibitory synaptic transmission and the transmitters themselves are greater in sprouted epileptic hippocampi (26, 147). Furthermore, in chronically seizing rats with pilocarpine-induced SE, electrophysiologic studies have shown increased current densities and greater zinc blockade of GABA receptor responses and altered sensitivity to benzodiazepine modulation associated with supragranular mossy fiber sprouting (65, 144). Taken together, these results indicate that with neuron loss and axonal sprouting, the regions that receive aberrant axonal sprouting, such as the fascia
450
:
F 35.7 High-power micrographs of the fascia dentata stratum granulosum and molecular layers illustrating glutamate decarboxylase (GAD), AMPA GluR1, and NMDAR2 immunoreactivity in a kindled rat (A, C, and E) compared with a spontaneously seizing rat after limbic SE (B, D, and F). The inner molecular layers (IML) are indicated by the arrow, the outer molecular layers (OML) by the arrowhead, and the hilus is below the layer of granule cells. (A) The kindled rat shows essentially normal GAD-ir. (B) By contrast, there is increased GAD-ir, especially in the
IML (arrow), in the rat with chronic limbic epilepsy after SE. (C and D) Compared to the kindled rat, there is an increase in AMPA GluR1-ir throughout the granule cells and molecular layers in the spontaneously seizing animal. (E and F) In the kindled animal, the IML (arrow) does not stain as dark as the OML (arrowhead). In the spontaneously seizing animal both molecular layers are equally IR, especially in the IML (arrow). In these rats, the increased IML NMDAR2-ir correlated with the amount of aberrant neo-Timm staining (see Figures 35.5 and 35.6). Calibration bar = 50 mm.
:
451
dentata molecular layer, may respond by changing the distribution and amount of postsynaptic excitatory and inhibitory receptors or their subunits. These findings support the concept that aberrant glutamatergic and GABAergic axonal sprouting probably forms functional and abnormal axonal connections on granule cell dendrites and cell bodies. C S S In SE-induced models of neuronal injury in the rats in vivo studies show a relationship between the evolution of spontaneous limbic seizures and the progression of fascia dentata synaptic reorganization (11–13, 27, 91, 113, 122). In rats, after SE-induced injury, spontaneous limbic seizures are first recorded after a silent or latent period, but the initial events are partial or limbic complex partial seizures consisting of a motionless stare with facial automatisms. Over the next several weeks the spontaneous limbic seizures evolve into longer complex partial events with secondary generalizations. This progression from larval to more complex limbic seizures has been suggested to be a form of kindling (13, 27). However, during this same period there is a progressive increase in supragranular mossy fiber and GABAergic axonal sprouting. In addition, animal models after SE-induced neuronal injury show that fascia dentata IML mossy fiber sprouting correlates positively with in vivo interictal hippocampal spike frequencies and the weekly frequency of spontaneous seizures (90, 121). The time course of spontaneous limbic epilepsy in SE models is very similar to that seen in clinical histories of humans with mesial temporal lobe epilepsy and hippocampal sclerosis (113). However, not all authors concur with this assessment. Longo and Mello (96, 97) showed that injection of cycloheximide at the time of SE prevented mossy fiber sprouting, and rats still showed chronic seizures. They suggested that mossy fiber sprouting was not necessary for epileptogenesis. It is unclear from these studies whether cycloheximide completely prevented SE-induced synaptic reorganization in the fascia dentata or other damaged limbic sites, and if the seizures started in the hippocampus or in other limbic and nonlimbic locations. Also, it has been difficult to replicate the cycloheximide experiments in other laboratories (207). There are anatomic and electrophysiologic differences between animal models and human patients with temporal lobe epilepsy that are worth noting. For example, in rats, if multiple limbic sites are studied with intracranial electrodes after SE-induced injury, ictal onsets are often simultaneously recorded bilaterally throughout limbic structures, including the amygdala, entorhinal cortex, and thalamus (11). In contrast, human depth EEG electrode studies of patients with mesial temporal lobe epilepsy and hippocampal sclerosis or temporal tumors, the initial ictal onsets are mostly unilateral within the hippocampus and parahippocampal gyrus (5, 93, 94, 120). Therefore, what is commonly found in humans
452
:
and rats with temporal lobe epilepsy is that spontaneous seizures are associated with hippocampal neuronal loss and fascia dentata excitatory and inhibitory axonal sprouting. However, in chronic animal models, after SE the ictal EEG onsets do not localize as precisely to the area of greatest damage and sprouting as human studies have found. Yet these in vivo human and animal studies still find a strong association between the time course of spontaneous limbic seizures and fascia dentata excitatory and inhibitory axon sprouting. This observation supports the hypothesis that reactive synaptogenesis probably contributes to the generation and maintenance of the epileptogenic process (190). I F D S In vitro electrophysiologic evidence from hippocampal slice studies supports the concept that fascia dentata mossy fiber sprouting is functional and leads to granule cell hyperexcitability (23). At first glance these studies seem confusing and contradictory, but when carefully reviewed they fit into our proposed understanding of the altered, reorganized axon circuits in the fascia dentata after SE-induced neuronal injury (see Figure 35.3) (21, 22, 46, 69, 100, 156). For example, despite differences in animal preparation, in the first 2–3 weeks after SEinduced neuron loss hippocampal slices often show (1) a decrease in the size of excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs), (2) a tendency for neuron populations to discharge synchronously, and (3) loss of paired-pulse depression (99, 103, 107, 176, 208). Similar cellular responses have been found in kindled animals without significant hilar neuron losses and in rats exposed to hypoxic cerebral injury without acute seizures (81, 83, 86, 196). One interpretation, proposed by Sloviter (179, 180), is that these findings represent an acute loss of GABAergic inhibition from selective hilar dendritic interneuron loss and an exclusion of parasomal inhibitory interneurons from the fascia dentata axonal circuitry (i.e., dormant basket cells). Alternatively, other studies have suggested that these acute granule cell electrophysiologic changes may be from increased postsynaptic NMDA receptor sensitivity or increased excitatory cell responsiveness, and not from a loss of inhibition (10, 129). There is, therefore, some controversy regarding the exact pathophysiologic mechanisms responsible for the acute hyperexcitability observed in stimulated or acutely damaged granule cells after SE. Long-term animal hippocampal slice studies show a progressive evolution of increased glutamatergic and GABAergic responses in fascia dentata granule cells that is associated with supragranular aberrant axon sprouting. In chronic animal preparations, (1) granule cell EPSPs become uniformly larger than expected, (2) IPSPs are present but generally smaller than usual, and (3) paired-pulse responses show an increase in inhibition (73, 103, 107, 138, 143, 163,
170, 192, 213). Hence, the early paired-pulse responses suggesting a decrease in fascia dentata inhibition occur before the emergence of intractable epilepsy as determined by in vivo monitoring of seizures in animals. Furthermore, in rats with spontaneous seizures, electrophysiologic studies demonstrate increased granule cell excitation and recovery of inhibitory responses. For example, using hippocampal slices and field potentials in rats 12–21 days following systemic kainite injection, Tauck and Nadler (194) found with hilar antidromic electrical stimulation multiple granule cell population spikes in association with early mossy fiber sprouting, and this response could be potentiated by a conditioning stimulus. They concluded that aberrant mossy fiber sprouting was functional and abnormal, and the results are similar to those of Masukawa et al. (112) in human hippocampal slices from patients undergoing surgery for temporal lobe epilepsy. In addition, single granule cell recordings in rats and humans with mossy fiber sprouting have shown multiple spikes in association with perforant path stimulation (22, 210, 211). Chronic rat studies do not always show granule cell hyperexcitability. For example, Sloviter (180), in the systemic kainate SE model, studied in vivo perforant path pairedpulse responses before and after mossy fiber sprouting. In the first 7 days after kainite, paired perforant path responses showed that the second, normally inhibited population spike resulted in multiple granule cell population spikes. However, after 2 months the responses had returned to normal, suggesting that inhibition had recovered, and there were no signs of granule cell hyperexcitability. Sloviter suggested that in long-term animals after SE, mossy fibers sprouted onto GABAergic basket cells, which increased feedback inhibition. However, these findings would be inconsistent with ultrastructural and electrophysiologic studies showing that aberrant mossy fibers form functional synaptic contacts mostly with granule cell dendrites (215, 217). Therefore, the recovery of inhibitory responses over time is just as likely to be the consequence of GABAergic axon sprouting. Other rat studies support the concept that mossy fiber sprouting is linked with granule cell hyperexcitability, but only after unmasking GABA responses. For example, Cronin et al. (37) studied hippocampal slices 1–4 months after SE, when reactive synaptogenesis would be greater than immediately after injury. With either hilar or perforant path stimulation, they were not able to consistently generate multiple granule cell population spikes similar to Tauck and Nadler’s (194) study. However, with antidromic hilar stimulation and application of a low concentration of bicuculline, a GABA blocker, in control animals, granule cell responses did not change. Yet in long-term animals after SE with mossy fiber sprouting, the same experiment produced multiple shortduration granule cell population spikes. An additional finding from that study was that hilar stimulations at low
intensities showed very prolonged granule cell EPSPs, which provided indirect evidence that there were recurrent excitatory axon circuits onto granule cells. A similar experiment was performed at the same laboratory in which hippocampal slices were prepared only from animals with witnessed spontaneous seizures many months after kainate-induced SE. The spontaneously seizing animals all showed robust mossy fiber sprouting, the slices showed spontaneous and antidromically stimulated seizure-like episodes lasting between 2 and 47 seconds, and microapplication of glutamate resulted in prominent increases in granule cell EPSPs (215). Furthermore, Franck et al. (55) performed nearly the same experiment in human hippocampal slices from patients with temporal lobe epilepsy and found that small amounts of bicuculline generated granule cell spiking only in the cases with mossy fiber sprouting. These experimental findings in hippocampal slices from animals and humans are very consistent with the proposal that aberrant granule cell excitatory circuits have the capacity to generate aberrant epileptiform discharges and seizures, and that the process involves both excitatory mossy fibers and inhibitory GABAergic axons. Although these in vitro slice studies strongly support the concept that collateral mossy fiber sprouting is functional and leads to increased granule cell excitability, little is known about the functional relationship between paraterminal GABAergic sprouting and GABA-mediated granule cell changes. As previously illustrated, fascia dentata GABAergic sprouting has been demonstrated in several animal models of SE and in human patients with temporal lobe epilepsy and hippocampal sclerosis (4, 39, 119, 147). Furthermore, human hippocampal slice studies indicate that in sprouted cases with hilar stimulation, there are functional inhibitory circuits, and in individual granule cells inhibitory responses may be increased (109, 110, 200, 201). Another study in humans found electrophysiologic evidence that the amount of GABA released at the granule cell synapse was probably greater in patients with mossy fiber sprooting than in patients without, results in prolonged postsynaptic IPSCs (35). In addition, Isokawa (73) has shown that GABA-mediated granule cell inhibition decreases in the face of NMDA stimulation, and Westbrook and Mayer (206) have shown that extracellular zinc can antagonize GABA-mediated synaptic responses. Hence, several studies suggest that aberrant IML mossy fiber sprouting may be capable of altering GABAergic efficiency. Furthermore, electrophysiologic data indicate that granule cells respond to orthodromic and antidromic stimulation with signs of increased excitation, and this finding is in agreement with anatomic studies showing signs of excitatory and inhibitory reactive synaptogenesis. How these fascia dentata anatomic and electrophysiologic alterations lead to spontaneous limbic seizures is still an area of intense research, but reactive synaptogenesis
:
453
is likely to contribute to the process of spontaneous limbic epilepsy after status epilepticus.
Summary This chapter has reviewed the basic principles of reactive synaptogenesis as it pertains to SE-induced fascia dentata neuronal injury. Although the discussion focused on the fascia dentata, in the adult brain, reactive axonal sprouting following SE-induced neuronal loss seems the rule rather than the exception. Hence, as investigative tools become more sophisticated and researchers explore other brain regions, it is likely that multiple sites within the CNS will be found to show signs of reactive synaptogenesis as a consequence of neuronal loss from SE. For clinicians, understanding the importance of preventing SE-related neuronal injury is still the first line of defense in treating the late consequences of SE-induced reactive synaptogenesis. This work was supported by NIH grants Nos. R01 NS38992 and PO1 NS02808. Original animal data were obtained through the cooperation of Edward H. Bertram, Luiz Mello, and Joao P. Leite. Special thanks to the members of the UCLA Neurobiology of Epilepsy Laboratory, including James K. Pretorius, Paula A. Kuhlman, Delia Mendoza, and Alana Lozada. Finally, the author thanks the many members of the UCLA Epilepsy Surgery Programs and our other co-investigators inside and outside the United States for their continued collaboration in the study of axonal sprouting in human and animal epileptic hippocampi.
REFERENCES 1. Amaral, D., and M. P. Witer. The hippocampal formation. In G. Paxinos, ed. The Rat Nervous System. 2nd ed. San Diego: Academic Press, 1995:443–494. 2. Anthes, D. L., J. C. LeBoutillier, and T. L. Petit. Structure and plasticity of newly formed adult synapses: A morphometric study in the rat hippocampus. Brain Res. 1993;626:50–62. 3. Babb, T. L., and W. Kupfer. Phagocytic and metabolic reactions to chronically implanted metal brain electrodes. Exp. Neurol. 1984;86:171–182. 4. Babb, T. L., J. P. Lieb, W. J. Brown, J. Pretorius, and P. H. Crandall. Distribution of pyramidal cell density and hyperexcitability in the epileptic human hippocampal formation. Epilepsia 1984;25:721–728. 5. Babb, T. L., G. W. Mathern, J. P. Leite, J. K. Pretorius, K. M. Yeoman, and P. A. Kuhlman. Glutamate AMPA receptors in the fascia dentata of human and kainate rat hippocampal epilepsy. Epilepsy Res. 1996;26:193–205. 6. Babb, T. L., J. K. Pretorius, W. R. Kupfer, and P. H. Crandall. Glutamate decarboxylase-immunoreactive neurons are preserved in human epileptic hippocampus. J. Neurosci. 1989;9:2562–2574. 7. Barber, R., and K. Saito. Light microscopic visualization of GAD and GABA-T in immunocytochemical preparations of the rodent CNS. In E. Robert, T. N. Chase, and D. B. Tower. eds. GABA in Nervous System Functions. New York: Raven Press, 1976:113–132.
454
:
8. Bausch, S. B., and C. Chavkin. Changes in hippocampal circuitry after pilocarpine-induced seizures as revealed by opioid receptor distribution and activation. J. Neurosci. 1997;17: 477–492. 9. Ben-Ari, Y. Limbic seizure and brain damage produced by kainic acid: Mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 1985;14:375–403. 10. Bernard, C., and H. V. Wheal. Plasticity of AMPA and NMDA receptor-mediated epileptiform activity in a chronic model of temporal lobe epilepsy. Epilepsy Res. 1995;21: 95–107. 11. Bertram, E. H. Functional anatomy of spontaneous seizures in a rat model of limbic epilepsy. Epilepsia 1997;38:95–105. 12. Bertram, E. H., and J. F. Cornett. The evolution of a rat model of chronic spontaneous limbic seizures. Brain Res. 1994;661:157–162. 13. Bertram, E. H., and J. Cornett. The ontogeny of seizures in a rat model of limbic epilepsy: Evidence for a kindling process in the development of chronic spontaneous seizures. Brain Res. 1993;625:295–300. 14. Blackstad, T. W. Commissural connections of the hippocampal region of the rat, with special reference to their mode of termination. J. Comp. Neurol. 1956;105:417–537. 15. Blumcke, I., H. Beck, A. A. Lie, and O. D. Wiestler. Molecular neuropathology of human mesial temporal lobe epilepsy. Epilepsy Res. 1999;36:205–223. 16. Blumcke, I., H. Beck, R. Nitsch, C. Eikhoff, B. Scheffler, M. R. Celio, et al. Preservation of calretinin-immunoreactive neurons in the hippocampus of epilepsy patients with Ammon’s horn sclerosis. J. Neuropathol. Exp. Neurol. 1996; 55:329–341. 17. Blumcke, I., W. Zuschratter, J. C. Schewe, B. Suter, A. A. Lie, B. M. Riederer, et al. Cellular pathology of hilar neurons in Ammon’s horn sclerosis. J. Comp. Neurol. 1999;414:437– 453. 18. 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(19):8312–8330. 19. 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. 20. Bruton, C. J. The Neuropathology of Temporal Lobe Epilepsy. New York: Oxford University Press, 1988. 21. Buckmaster, P. S., and F. E. Dudek. Network properties of the dentate gyrus in epileptic rats with hilar neuron loss and granule cell axon reorganization. J. Neurophysiol. 1997;77: 2685–2696. 22. Buckmaster, P. S., and F. E. Dudek. Neuron loss, granule cell axon reorganization, and functional changes in the dentate gyrus of epileptic kainate-treated rats. J. Comp. Neurol. 1997; 385(3):385–404. 23. Buckmaster, P. S., G. F. Zhang, and R. Yamawaki. Axon sprouting in a model of temporal lobe epilepsy creates a predominantly excitatory feedback circuit. J. Neurosci. 2002;22: 6650–6658. 24. Bundman, M. C., and C. M. Gall. Ultrastructural plasticity of the dentate gyrus granule cells following recurrent limbic seizures. II. Alterations in somatic synapses. Hippocampus 1994;4:611–622.
25. Bundman, M. C., R. M. Pico, and C. M. Gall. Ultrastructural plasticity of the dentate gyrus granule cells following recurrent limbic seizures. I. Increase in somatic spines. Hippocampus 1994;4:601–610. 26. Cavalheiro, E. A., M. J. Fernandes, L. Turski, and M. G. Mazzacoratti. Neurochemical changes in the hippocampus of rats with spontaneous recurrent seizures. Epilepsy Res. Suppl. 1992;9:239–247 [discussion 247–248]. 27. 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. 28. Cavazos, J. E., G. Golarai, and T. P. Sutula. Septotemporal variation of the supragranular projection of the mossy fiber pathway in the dentate gyrus of normal and kindled rats. Hippocampus 1992;2:363–372. 29. Chafetz, R. S., W. K. Nahm, and J. L. Noebels. Aberrant expression of neuropeptide Y in hippocampal mossy fibers in the absence of local cell injury following the onset of spikewave synchronization. Mol. Brain Res. 1995;31:111–121. 30. Chronister, R. B., and L. E. White, Jr. Fiberarchitecture of the hippocampal formation: Anatomy, projections, and structural significance. In I. R. L. Isaacson, and K. H. Ribram, eds. The Hippocampus. Vol. I. New York: Plenum Press, 1975:9–45. 31. Cobb, S. R., E. H. Buhl, K. Halasy, O. Paulsen, and P. Somoggi. Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons. Nature 1995;378: 75–78. 32. Coltman, B. W., E. M. Earley, A. Shahar, F. E. Dudek, and C. F. Ide. Factors influencing mossy fiber collateral sprouting in organotypic slice cultures of neonatal mouse hippocampus. J. Comp. Neurol. 1995;362:209–222. 33. Cook, T. M., and K. A. Crutcher. Extensive target cell loss during development results in mossy fibers in the region superior (CA1) of the rat hippocampal formation. Brain Res. 1985;353:19–30. 34. Cotman, C. W., and G. Lynch. Reactive synaptogenesis in the adult nervous system: The effects of partial differentiation on new synapse formation. In S. Barondes, ed. Neuronal Recognition. New York: Raven Press, 1976:69–108. 35. Cotman, C. W., and J. V. Nadler. Reactive synaptogenesis in the hippocampus. In C. W. Cotman, ed. Neuronal Plasticity. New York: Raven Press, 1978:227–271. 36. Cronin, J., and F. E. Dudek. Chronic seizures and collateral sprouting of dentate mossy fibers after kainic acid treatment in rats. Brain Res. 1988;474:181–184. 37. 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. 38. Davenport, C. J., W. J. Brown, and T. L. Babb. GABAergic neurons are spared after intrahippocampal kainate in the rat. Epilepsy Res. 1990;5:28–42. 39. 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. 40. Davis, L., S. L. Vinsant, and O. Steward. Ultrastructural characterization of the synapses of the crossed temporodentate pathway in rats. J. Comp. Neurol. 1988;267:190–202. 41. de Lanerolle, N. C., M. L. Brines, J. H. Kim, A. Williamson, M. F. Philps, and D. D. Spencer. Neurochemical remodelling
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54. 55.
56. 57.
58.
59.
of the hippocampus in human temporal lobe epilepsy. Epilepsy Res. Suppl. 1992;9:205–219 [discussion 220]. 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. Deller, T., M. Frotscher, and R. Nitsch. Morphological evidence for the sprouting of inhibitory commissural fibers in response to the lesion of the excitatory entorhinal input to the rat dentate gyrus. J. Neurosci. 1995;15:6868–6878. Deller, T., A. Martinez, R. Nitsch, and M. Frotscher. A novel entorhinal projection to the rat dentate gyrus: Direct innervation of proximal dendrites and cell bodies of granule cells and GABAergic neurons. J. Neurosci. 1996;16:3322–3333. Deller, T., R. Nitsch, and M. Frotscher. Layer-specific sprouting of commissural fibers to the rat fascia dentata after unilateral entorhinal cortex lesion: A Phaseolus vulgaris leucoagglutinin tracing study. Neuroscience 1996;71:651–660. Dudek, F. E., and M. Spitz. Hypothetical mechanisms for the cellular and neurophysiologic basis of secondary epileptogenesis: Proposed role of synaptic reorganization. J. Clin. Neurophysiol. 1997;14:90–101. Du, F., T. Eid, E. W. Lothman, C. Kohler, and R. Schwarcz. Preferential neuronal loss in layer III of the medial entorhinal cortex in rat models of temporal lobe epilepsy. J. Neurosci. 1995;15:6301–6313. Du, F., W. O. Whetsell, Jr., B. Aboo-Khalil, B. Blumenkopf, E. W. Lothman, and R. Schwarcz. Preferential neuronal loss in layer III of the entorhinal cortex in patients with temporal lobe epilepsy. Epilepsy Res. 1993;16:223–333. Edds, M. V., Jr. Collateral regeneration of residual motor axons in partially denervated muscles. J. Exp. Zool. 1950;113:517–552. Esclapez, M., and C. R. Houser. Up-regulation of GAD65 and GAD67 in remaining hippocampal GABA neurons in a model of temporal lobe epilepsy. J. Comp. Neurol. 1999;412: 488–505. Exner, S. Notiz su der Frage von der Faservertheilung mehrer Nerven in Muske. Fluegers Arch Gesamte Physiol. 1885;36: 572–576. Finger, S., and C. R. Almli. Brain damage and neuroplasticity: Mechanisms of recovery or development? Brain Res. 1985;357:177–186. Fowler, K. R., and D. S. Olton. Recovery of function following injections of kainic acid: Behavioral, electrophysiological and neuroanatomical correlates. Brain Res. 1984;321:21– 32. Fowler, M. Brain damage after febrile convulsions. Arch. Dis. Child. 1957;32:67–76. Franck, J. E., et al. Physiologic and morphologic characteristics of granule cell circuitry in human epileptic hippocampus. Epilepsia 1995;36:543–558. Freund, T. F., and G. Buzsaki. Interneurons of the hippocampus. Hippocampus 1996;6:347–470. Frotscher, M., and J. Zimmer. Lesion-induced mossy fibers to the molecular layer of the rat fascia dentata: Identification of postsynaptic granule cells by the Golgi-EM technique. J. Comp. Neurol. 1983;215:299–311. Frotscher, M., B. Heimrich, T. Deller, and R. Nitsch. Understanding the cortex through the hippocampus: Laminaspecific connections of the rat hippocampal neurons. J. Anat. 1995;187(Pt. 3):539–545. Frotscher, M., L. Spress, W. K. Schwerdtfeger, and E. Buhl. The mossy cells of the fascia dentata: A comparative study of
:
455
60.
61. 62.
63.
64.
65.
66.
67.
68. 69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
456
their fine structure and synaptic connections in rodents and primates. J. Comp. Neurol. 1991;312:145–163. Gall, C., and G. Lynch. Fiber architecture of the dentate gyrus following ablation of the entorhinal cortex in rats of different ages: Evidence for two forms of axon sprouting in the immature brain. Neuroscience 1981;6:903–910. Gall, C., and G. Lynch. Rapid axon sprouting in the neonatal rat hippocampus. Brain Res. 1978;153:357–362. Gall, C., R. McWilliams, and G. Lynch. The effect of collateral sprouting on the density of innervation of normal target sites: Implications for theories on the regulation of the size of developing synaptic domains. Brain Res. 1979;175: 37–47. Gall, C., G. Rose, and G. Lynch. Proliferative and migratory activity of glial cells in the partially deafferented hippocampus. J. Comp. Neurol. 1979;183:539–549. Germroth, P., W. K. Scherdtfeger, and E. H. Buhl. GABAergic neurons in the entorhinal cortex project to the hippocampus. Brain Res. 1989;494:187–192. Gibbs, J. W., III, 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. Goodman, D. C., and J. A. Horel. Sprouting of optic tract projections in the brain stem of the rat. J. Comp. Neurol. 1966;127:71–88. Gottlieb, D. I., and W. M. Cowan. Autoradiographic studies of the commissural and ipsilateral association connection of the hippocampus and detentate gyrus of the rat. I. The commissural connections. J. Comp. Neurol. 1973;149:393–422. Haighton, J. An experimental inquiry concerning the reproduction of nerves. Philos. Trans. R. Soc. Lond. 1795;1:190–200. Hellier, J. L., et al. Recurrent spontaneous motor seizures after repeated low-dose systemic treatment with kainate: Assessment of a rat model of temporal lobe epilepsy. Epilepsy Res. 1998;31:73–84. Hjorth-Simonsen, A. Projection of the lateral part of the entorhinal area to the hippocampus and fascia dentata. J. Comp. Neurol. 1972;146:219–232. Hjorth-Simonsen, A., and B. Jeune. Origin and termination of the hippocampal perforant path in the rat studied by silver impregnation. J. Comp. Neurol. 1972;144:215–232. Hoffman, H. Local re-innervation in partially denervated muscle: A histo-physiological study. Austr. J. Exp. Biol. Med. Sci. 1950;28:383–397. Isokawa, M. Decreased time constant in hippocampal dentate granule cells in pilocarpine-treated rats with progressive seizure frequencies. Brain Res. 1996;718:169–175. Isokawa, M. Decrement of GABAA receptor-mediated inhibitory postsynaptic currents in dentate granule cells in epileptic hippocampus. J. Neurophysiol. 1996;75(5):1901–1908. Isokawa, M. Preservation of dendrites with the presence of reorganized mossy fiber collaterals in hippocampal dentate granule cells in patients with temporal lobe epilepsy. Brain Res. 1997;744:339–343. Isokawa, M., and I. Fried. Extracellular slow negative transient in the dentate gyrus of human epileptic hippocampus in vitro. Neuroscience 1996;72:31–37. Isokawa, M., and M. G. Levesque. Increased NMDA responses and dendritic degeneration in human epileptic hippocampal neurons in slices. Neurosci. Lett. 1991;132:212–216. Isokawa, M., M. F. Levesque, T. L. Babb, and J. Engel, Jr. Single mossy fiber axonal systems of human dentate granule
:
79.
80.
81.
82.
83.
84.
85. 86.
87.
88.
89.
90.
91.
92.
93.
94.
95. 96.
cells studied in hippocampal slices from patients with temporal lobe epilepsy. J. Neurosci. 1993;13:1511–1522. Isokawa, M., M. Levesque, T. Matsuki, E. Omoto, et al. Glutamate currents in morphologically identified human dentate granule cells in temporal lobe epilepsy. J. Neurophysiol. 1997;77:3355–3369. Isokawa, M., and L. E. Mello. NMDA receptor-mediated excitability in dendritically deformed dentate granule cells in pilocarpine-treated rats. Neurosci. Lett. 1991;129:69–73. Johansen, F. F. Interneurons in rat hippocampus after cerebral ischemia: Morphometric, functional, and therapeutic investigations. Acta Neurol. Scand. Suppl. 1993;150:1–32. Jones, B. E., and R. Y. Moore. Ascending projections of the locus coeruleus in the rat. II. Autoradiographic study. Brain Res. 1977;127:25–53. 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. Katzir, H., D. Mendoza, and G. W. Mathern. Effect of theophylline and trimethobenzamide when given during kainateinduced status epilepticus: An improved histopathologic rat model of human hippocampal sclerosis. Epilepsia 2000;41(11): 1390–1399. Kennedy, R. The regeneration of nerves. Philos. Trans. R. Soc. Lond. 1897;188:256–305. King, G. L., et al. Abnormal neuronal excitability in hippocampal slices from kindled rats. J. Neurophysiol. 1985;54(5): 1295–1304. Kneisler, T. B., and R. Dingledine. Spontaneous and synaptic input from granule cells and the perforant path to dentate basket cells in the rat hippocampus. Hippocampus 1995;5: 151–164. Koda, L. Y., and F. E. Bloom. A light and electron microscopic study of noradrenergic terminals in the rat dentate gyrus. Brain Res. 1977;120:327–335. Laurberg, S., and J. Zimmer. Lesion-induced sprouting of hippocampal mossy fiber collaterals to the fascia dentata in developing and adult rats. J. Comp. Neurol. 1981;200:433– 459. Leite, J. P., T. L. Babb, J. K. Pretorius, et al. Neuron loss, mossy fiber sprouting, and interictal spikes after intrahippocampal kainate in developing rats. Epilepsy Res. 1996; 26(1):219–231. Leite, J. P., Z. A. Bortolotto, and E. Z. Cavalheiro. Spontaneous recurrent seizures in rats: An experimental model of partial epilepsy. Neurosci. Biobehav. Rev. 1990;14:511–570. Li, D., P. M. Field, and G. Raisman. Failure of axon regeneration in postnatal rat entorhinohippocampal slice coculture is due to maturation of the axon, not that of the pathway or target. Eur. J. Neurosci. 1995;7:1164–1171. Lieb, J. P., G. O. Walsh, T. L. Babb, et al. A comparison of EEG seizure patterns recorded with surface and depth electrodes in patients with temporal lobe epilepsy. Epilepsia 1976;17:137–160. Lieb, J. P., S. C. Woods, A. Siccardi, et al. Quantitative analysis of depth spiking in relation to seizure foci in patients with temporal lobe epilepsy. Electroencephalogr. Clin. Neurophysiol. 1978;44:641–663. Liu, C. N., and W. W. Chambers. Intraspinal sprouting of dorsal root axons. Arch. Neurol. Pychiatry 1958;79:46–61. Longo, B. M., and L. E. Mello. Blockade of pilocarpine- or kainate-induced mossy fiber sprouting by cycloheximide does
97.
98.
99. 100.
101.
102.
103.
104. 105.
106.
107.
108.
109.
110.
111.
112.
113.
not prevent subsequent epileptogenesis in rats. Neurosci. Lett. 1997;226:163–166. Longo, B. M., and L. E. Mello. Supragranular mossy fiber sprouting is not necessary for spontaneous seizures in the intrahippocampal kainate model of epilepsy in the rat. Epilepsy Res. 1998;32:172–182. Lorente de No, R. Studies on the structure of the cerebral cortex. II. Continuation of the study of the ammonic system. J. Psychol. Neurol. 1934;45:113–177. Lothman, E. W., and E. H. Bertram. III. Epileptogenic effects of status epilepticus. Epilepsia 1993;34(Suppl. 1):S59–S70. 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;6:110–118. Lothman, E. W., and R. C. Collins. Kainic acid induced limbic seizures: Metabolic, behavioral, electroencephalographic and neuropathological correlates. Brain Res. 1981;218: 299–318. Lothman, E. W., R. C. Collins, and J. A. Ferrendelli. Kainic acid-induced limbic seizures: Electrophysiologic studies. Neurology 1981;31:806–812. Lothman, E. W., D. A. Rempe, and P. S. Mangan. Changes in excitatory neurotransmission in the CA1 region and dentate gyrus in a chronic model of temporal lobe epilepsy. J. Neurophysiol. 1995;74:841–848. Lugaro, E. Osservazioni sui “gomitoli” nervosi nell rigererazione dei nervi. Riv. Patologia Nerv. Mentale 1906;2:337–348. Lynch, N., and C. W. Cotman. The hippocampus as a model for studying anatomical plasticity in the adult brain. In R. L. Isaacson and K. H. Pribram, eds. The Hippocampus. Vol. I. New York: Plenum Press, 1975:123–155. 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. Mangan, P. S., D. A. Rempe, and E. W. Lothman. Changes in inhibitory neurotransmission in the CA1 region and dentate gyrus in a chronic model of temporal lobe epilepsy. J. Neurophysiol. 1995;74:829–840. Margerison, J. H., and J. A. Corsellis. Epilepsy and the temporal lobes: A clinical, electroencephalographic and neuropathological study of the brain in epilepsy, with particular reference to the temporal lobes. Brain 1996;89: 499–530. Masukawa, L. M., L. J. Burdette, P. McGonigle, et al. Physiological and anatomical correlates of the human dentate gyrus: Consequences or causes of epilepsy. Adv. Neurol. 1999;79:781–794. Masukawa, L. M., M. Higashima, J. H. Kim, and D. D. Spencer. Epileptiform discharges evoked in hippocampal brain slices from epileptic patients. Brain Res. 1989;493: 168–174. Masukawa, L. M., W. M. O’Connor, J. Lynott, et al. Longitudinal variation in cell density and mossy fiber reorganization in the dentate gyrus from temporal lobe epileptic patients. Brain Res. 1995;678:65–75. Masukawa, L. M., K. Uruno, M. Sperling, et al. The functional relationship between antidromically evoked field responses of the dentate gyrus and mossy fiber reorganization in temporal lobe epileptic patients. Brain Res. 1992; 579:119–127. Mathern, G. W. Hippocampal pathophysiology in experimental models. In P. Kotagal, and H. O. Luders, eds. The
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
Epilepsies: Etiologies and Prevention. San Diego, Calif.: Academic Press, 1999:149–166. Mathern, G. W., et al. Onset and patterns of hippocampal sprouting in the rat kainite seizure model: Evidence for progressive cell loss and neo-innervation in region inferior and superior. Dendron 1992;1:69–84. Mathern, C. G., T. L. Babb, and D. L. Armstrong. Hippocampal sclerosis. In J. Engel, Jr., and T. A. Pedley, eds. Epilepsy: A Comprehensive Textbook. New York: Raven Press, 1997:133–155. Mathern, G. W., T. L. Babb, J. P. Leite, K. Pretorius, et al. The pathogenic and progressive features of chronic human hippocampal epilepsy. Epilepsy Res. 1996;26:151–161. Mathern, C. G., T. L. Babb, P. S. Mischel, H. V. Vinters, et al. Childhood generalized and mesial temporal epilepsies demonstrate different amounts and patterns of hippocampal neuron loss and mossy fiber synaptic reorganization. Brain 1996;119(Pt. 3):965–987. Mathern, G. W., J. K. Pretorius, H. I. Kornblum, D. Mendoza, A. Lozada, and J. P. Leite. Human hippocampal AMPA and NMDA mRNA levels in temporal lobe epilepsy patients. Briain 1997;120(Pt. 11):1937–1959. Mathern, G. W., T. L. Babb, J. K. Pretorius, and J. P. Light. Reactive synaptogenesis and neuron densities for neuropeptide Y, somatostatin, and glutamate decarboxylase immunoreactivity in the epileptogenic human fascia dentata. J. Neurosci. 1995;15(5 Pt. 2):3990–4004. Mathern, G. W., T. L. Babb, J. K. Pretorius, M. Melendez, et al. The pathophysiologic relationships between lesion pathology, intracranial ictal EEG onsets, and hippocampal neuron losses in temporal lobe epilepsy. Epilepsy Res. 1995;12: 133–147. Mathern, G. W., E. H. Bertram, III, T. L. Babb, J. K. Pretorius, et al. In contrast to kindled seizures, the frequency of spontaneous epilepsy in the limbic status model correlates with greater aberrant fascia dentate excitatory and inhibitory axon sprouting, and increases staining for N-methyl-aspartate, AMPA and GABA(A) receptors. Neuroscience 1997; 77:1003–1019. Mathern, G. W., F. Cifuentes, J. P. Leite, J. K. Pretorius, and T. L. Babb. Hippocampal EEG excitability and chronic spontaneous seizures are associated with aberrant synaptic reorganization in the rat intrahippocampal kainite model. Electroencephalogr. Clin. Neurophysiol. 1993;87: 326–339. Mathern, G. W., P. A. Kuhlman, D. Mendoza, and J. K. Pretorius. Human fascia dentate anatomy and hippocampal neuron densities differ depending on the epileptic syndrome and age at firs seizure. J. Neuropathol. Exp. Neurol. 1997; 56:199–212. Mathern, G. W., J. P. Leite, T. L. Babb, J. K. Pretorius, et al. Aberrant hippocampal mossy fiber sprouting correlates with greater NMDAR2 receptor staining. Neuroreport 1996;7(5): 1029–1035. Mathern, G. W., J. P. Leite, J. K. Pretorius, B. Quinn, et al. Children with severe epilepsy: Evidence of hippocampal neuron losses and aberrant mossy fiber sprouting during postnatal granule cell migration and differentiation. Dev. Brain. Res. 1994;8:70–80. Mathern, G. W., D. Mendoza, A. Lozada, J. K. Pretorius, et al. Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy. Neurology 1999;52:453–472.
:
457
127. Mathern, G. W., J. K. Pretorius, and T. L. Babb. Quantified patterns of mossy fiber sprouting and neuron densities in hippocampal and lesional seizures. J. Neurosurg. 1995;82: 211–219. 128. Mathern, G. W., J. K. Pretorius, H. I. Kornblum, D. Mendoza, et al. Altered hippocampal kainate-receptor mRNA levels in temporal lobe epilepsy patients. Neurobiol. Dis. 1998;5:151–176. 129. Mathern, G. W., J. K. Pretorius, J. P. Leite, H. I. Kornblum, D. Mendoza, et al. Hippocampal AMPA and NMDA mRNA levels and subunit immunoreactivity in human temporal lobe epilepsy patients and a rodent model of chronic mesial limbic epilepsy. Epilepsy Res. 1998;32:154–171. 130. Mathern, G. W., J. K. Pretorius, D. Mendoza, J. P. Leite, et al. Hippocampal N-methyl--aspartate receptor subunit mRNA levels in temporal lobe epilepsy patients. Ann. Neurol. 1999;46:343–358. 131. Mathern, G. W., J. K. Pretorius, D. Mendoza, A. Lozada, and H. I. Kornblum. Hippocampal AMPA and NMDA mRNA levels correlate with aberrant fascia dentata mossy fiber sprouting in the pilocarpine model of spontaneous limbic epilepsy. J. Neurosci. Res. 1998;54(6):734–753. 132. Mathern, G. W., G. Price, C. Rosales, J. K. Pretorius, et al. Anoxia during kainate status epilepticus shortens behavioral convulsions but generates hippocampal neuron loss and supragranular mossy fiber sprouting. Epilepsy Res. 1998; 30:133–151. 133. Matthews, D. A., C. Cotman, and G. Lynch. An electron microscopic study of lesion-induced synaptogenesis in the dentate gyrus of the adult rat. I. Magnitude and time course of degeneration. Brain Res. 1976;115:1–21. 134. Matthews, D. A., C. Cotman, and G. Lynch. An electron microscopic study of lesion-induced synaptogenesis in the dentate gyrus of the adult rat. II. Reappearance of morphologically normal synaptic contacts. Brain Res. 1976;115: 23–41. 135. McWilliams, J. R., and G. Lynch. Rate of synaptic replacement in denervated rat hippocampus declines precipitously from the juvenile period to adulthood. Science 1983;221: 572–574. 136. McWilliams, J. R., and G. Lynch. Synaptic density and axonal sprouting in rat hippocampus: Stability in adulthood and decline in late adulthood. Brain Res. 1984;294:152– 156. 137. Meiback, R. C., and A. Siegel. Efferent connections of the septal area in the rat: An analysis utilizing retrograde and anterogarade transport methods. Brain Res. 1977;119: 1–20. 138. Meier, C. L., A. Obenaus, and F. E. Dudek. Persistent hyperexcitability in isolated hippocampal CA1 of kainite-lesioned rats. J. Neurophysiol. 1992;68:2120–2127. 139. 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 [discussion 201–202]. 140. Meldrum, B. S. Metabolic factors during prolonged seizures and their relation to nerve cell death. In: A. V. Delgado-Escueta, et al., eds. Status Epilepticus: Mechanisms of Brain Damage and Treatment. Adv. Neurol. 1983;34:261– 275. 141. Mello, L. E., et al. Circuit mechanisms of seizures in the pilocarpine model of chronic epilepsy: Cell loss and mossy fiber sprouting. Epilepsia 1993;34:985–995.
458
:
142. Mikuni, N., et al. NMDAR2 upregulation precedes mossy fiber sprouting in kainite rat hippocampal epilepsy. Neurosci. Lett. 1998;255:25–28. 143. Milgram, N. W., et al. Changes in inhibitory processes in the hippocampus following recurrent seizures induced by systemic administration of kainic acid. Brain Res. 1991;551: 236–246. 144. Mody, I., et al. GABAergic inhibition of granule cells and hilar neuronal synchrony following ischemia-induced hilar neuronal loss. Neuroscience 1995;69:139–150. 145. Moore, R. Y., and A. E. Halaris. Hippocampal innervation by serotonin neurons of the midbrain raphe in the rat. J. Comp. Neurol. 1975;164:171–183. 146. Murray, M., and J. W. Thompson. The occurrence and function of collateral sprouting in the sympathetic nervous system of the cat. J. Physiol. (Lond.) 1957;135:133–162. 147. Nadler, J. V., C. W. Cotman, and G. S. Lynch. Biochemical plasticity of short-axon interneurons: Increased glutamate decarboxylase activity in the denervated area of rat dentate gyrus following entorhinal lesion. Exp. Neurol. 1974;45: 403–413. 148. Nadler, J. V., B. W. Perry, C. Gentry, and C. W. Cotman. Loss and reacquisition of hippocampal synapses after selective destruction of CA3-CA4 afferents with kainic acid. Brain Res. 1980;191(2):387–403. 149. Nadler, J. V., W. F. White, K. W. Vaca, and C. W. Cotman. Calcium-dependent gamma-aminobutyrate release by interneurons of rat hippocampal regions: Lesion-induced plasticity. Brain Res. 1977;131:241–258. 150. Nadler, J. V., W. F. White, K. W. Vaca, D. A. Redburn, et al. Characterization of putative amino acid transmitter release from slices of rat dentate gyrus. J. Neurochem. 1977;29: 279–290. 151. Nafstad, P. H. An electron microscope study on the termination of the perforant path fibers in the hippocampus and the fascia dentate. Z. Zellforsch. Mikrosk. Anat. 1967;76:532– 542. 152. Naquet, R., B. Meldrum, and Y. Ben-Ari. Hippocampal lesions and status epilepticus. Electroencephalogr. Clin. Neurophysiol. Suppl. 1982;35:171–183. 153. Nissinen, J., et al. A new model of chronic temporal lobe epilepsy induced by electrical stimulation of the amygdale in rat. Epilepsy Res. 2000;38:177–205. 154. Okazaki, M. M., D. A. Evenson, and J. V. Nadler. Hippocampal mossy fiber sprouting and synapse formation after status epilepticus in rats: Visualization after retrograde transport of biocytin. J. Comp. Neurol. 1995;352:515–534. 155. Okazaki, M. M., P. Molnar, and J. V. Nadler. Recurrent mossy fiber pathway in rat dentate gyrus: Synaptic currents evoked in presence and absence of seizure-induced growth. J. Neurophysiol. 1999;81:1645–1660. 156. Patrylo, P. R., and F. E. Dudek. Physiological unmasking of new glutamatergic pathways in the dentate gyrus of hippocampal slices from kainite-induced epileptic rats. J. Neurophysiol. 1998;79:418–429. 157. Perez, Y., et al. Axonal sprouting of CA1 pyramidal cells in hyperexcitable hippocampal slices of kainite-treated rats. Eur. J. Neurosci. 1996;8:736–748. 158. Purpura, D. P., and E. M. Housepian. Morphological and physiological properties of chronically isolated immature neocortex. Exp. Neurol. 1961;4:377–401. 159. Raisman, G. Neuronal plasticity in the septal nuclei of the adult rat. Brain Res. 1969;14:25–48.
160. Raisman, G., W. M. Cowan, and T. P. Powell. An experimental analysis of the efferent projection of the hippocampus. Brain 1966;89:83–108. 161. Ramón y Cajal, S. Degeneration and Regeneration of the Nervous System. Vol. II (R. M. May, trans.-ed.). London: Oxford University Press, 1928. 162. Ramón y Cajal, S. The Structure of Ammon’s Horn (English trans.). Springfield, Ill.: Charles C. Thomas, 1968. 163. Rempe, D. A., P. S. Manga, and E. W. Lothman. Regional heterogeneity of pathophysiological alterations in CA1 and dentate gyrus in a chronic model of temporal lobe epilepsy. J. Neurophysiol. 1995;74:816–828. 164. Represa, A., E. Tremblay, and Y. Ben-Ari. Kainate binding sites in the hippocampal mossy fibers: Localization and plasticity. Neuroscience 1987;20:739–748. 165. Represa, A., I. Jorquera, G. Le Gall La Salle, et al. Epilepsy induced collateral sprouting of hippocampal mossy fibers: Does it induce the development of ectopic synapses with granule cell dendrites? Hippocampus 1993;3: 257–268. 166. Represa, A., G. Le Gall La Salle, and Y. Ben-Ari. Hippocampal plasticity in childhood epilepsy. Neurosci. Lett. 1989;99:351–355. 167. Rose, J. E., et al. Effects of heavy ionizing monoenergetic particles on the cerebral cortex. II. Histological appearance of nerve fibers after laminar destruction. J. Comp. Neurol. 1960;115:243–296. 168. Routbort, M. J., S. B. Bausch, and J. O. McNamara. Seizures cell death, and mossy fiber sprouting in kainic acid–treated organotypic hippocampal cultures. Neuroscience 1999;94: 755–765. 169. Salin, P., et al. Axonal sprouting in layer V pyramidal neurons of chronically injured cerebral cortex. J. Neurosci. 1995;15: 8234–8245. 170. Schwartzkroin, P. A. Hippocampal slices in experimental and human epilepsy. In A. V. Delgado-Escueta, et al., eds. Basic Mechanisms of Epilepsies: Molecular and Cellular Approaches. Adv. Neurol. 1986;37:991–1010. 171. Schwarzer, C., K. Tsunashima, C. Wanzenbock, et al. GABA(A) receptor subunits in the rat hippocampus. II. Altered distribution in kainic acid–induced temporal lobe epilepsy. Neuroscience 1997;80:1001–1017. 172. Schwarzer, C., J. M. Williamson, E. W. Lothman, et al. Somatostatin, neuropeptide Y, neurokinin B and cholecystokinin immunoreactivity in two chronic models of temporal lobe epilepsy. Neuroscience 1995;69:831–845. 173. Segal, M., and S. Landis. Afferents to the hippocampus of the rat studied with the method of retrograde transport of horseradish peroxides. Brain Res. 1974;78:1–15. 174. Seress, L., and C. E. Ribak. Postnatal development and synaptic connections of hilar mossy cells in the hippocampal dentate gyrus of rhesus monkeys. J. Comp. Neurol. 1995;355: 93–110. 175. Shetty, A. K., and D. A. Turner. Intracerebroventricular kainic acid administration in adult rat alters hippocampal calbindin and non-phosphorylated neurofilament expression. J. Comp. Neurol. 1995;363:581–599. 176. Shirasaka, Y., and C. G. Wasterlain. Chronic epileptogenicity following focal status epilepticus. Brain Res. 1994;655: 33–44. 177. Shumate, M. D., et al. GABA(A) receptor functions in epileptic human dentate granule cells: Comparison to epileptic and control rat. Epilepsy Res. 1998;38:114–128.
178. Sloviter, R. S. Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. Science 1987;235:73–76. 179. 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. 180. Sloviter, R. S. Possible functional consequences of synaptic reorganization in the dentate gyrus of kainite-treated rats. Neurosci. Lett. 1992;137:91–96. 181. Sloviter, R. S., A. L. Sollas, N. M. Barbero, and K. D. Laxer. Calcium-binding protein (calbindin-D28K) and parvalbumin immunocytochemistry in the normal and epileptic human hippocampus. J. Comp. Neurol. 1991;308: 381–396. 182. Sperk, G., et al. GABA(A) receptor subunits in the rat hippocampus. I. Immunocytochemical distribution of 13 subunits. Neuroscience 1997;80:98–100. 183. Steward, O. Topographic organization of the projections from the entorhinal area to the hippocampal formation of the rat. J. Comp. Neurol. 1976;167:285–314. 184. Steward, O., and E. W. Rubel. The fate of denervated neurons: Transneuronal degeneration, dedritic atrophy, and dendritic remodeling. In GA, ed. Neuroregeneration. New York: Raven Press, 1993:37–60. 185. Steward, O., and S. A. Scoville. Cells of origin of entorhinal cortical afferents to the hippocampus and fascia dentate of the rat. J. Comp. Neurol. 1976;169:347–370. 186. Steward, O., W. F. White, and C. Cottman. Potentiation of the excitatory synaptic action of commissural, associational and entorhinal afferents to dentate granule cells. Brain Res. 1977;134:551–560. 187. Storm-Mathisen, J. Glutamate decarboxylase in the rat hippocampal region after lesions of the afferent fiber systems: Evidence that the enzyme is localized in intrinsic neurons. Brain Res. 1972;40:215–235. 188. Sundstrom, L. E., J. Mitchell, and H. V. Wheal. Bilateral reorganization of mossy fibers in the rat hippocampus after a unilateral intracerebroventricular kainic acid injection. Brain Res. 1993;609:321–326. 189. 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. 190. Sutula, T. P., G. Golarai, and J. Cavazos. Assessing the functional significance of mossy fiber sprouting. Epilepsy Res. Suppl. 1992;7:251–259. 191. Swanson, L. W., and B. K. Hartman. The central adrenergic system: An immunofluorescence study of the location of cell bodies and their efferent connections in the rat utilizing dopamine-beta-hydroxylase as a marker. J. Comp. Neurol. 1975;163:467–505. 192. Swanson, T. H., M. R. Sperling, and M. J. O’Connor. Strong paired pulse depression of dentate granule cells in slices from patients with temporal lobe epilepsy. J. Neural Transm. 1998;105:613–625. 193. Tanaka, T., et al. Electroclinical features of kainic acid–induced status epilepticus in freely moving cats: Microinjection into the dorsal hippocampus. Electroencephalogr. Clin. Neurophysiol. 1982;54:288–300. 194. Tauck, D. L., and J. V. Nadler. Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acidtreated rats. J. Neurosci. 1985;5:1016–1022. 195. Tsunashima, K., C. Schwarzer, E. Kirchmair, W. Sieghart, and G. Spert. GABA(A) receptor subunits in the rat hip-
:
459
196.
197. 198.
199.
200.
201.
202.
203.
204.
205. 206.
207.
208.
209.
210.
211.
212.
213.
460
pocampus. III. Altered messenger RNA expression in kainic acid–induced epilepsy. Neuroscience 1997;80:1019–1032. 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. Tuner, D. A., et al. Morphological features of the entorhinalhippocampal connection. Prog. Neurobiol. 1998;55:537–562. Turski, W. A., et al. Limbic seizures produced by pilocarpine in rats: Behavioral, electroencephalographic and neuropathological study. Behav. Brain Res. 1983;9:315–335. Urban, L., et al. 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. 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. 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. Van Harrelveld, A. Re-innervation of denervated muscle fibers by adjacent functioning motor units. Am. J. Physiol. 1945;144:477–493. von Campe, G., D. D. Spencer, and N. C. de Lanerolle. Morphology of dentate granule cells in the human epileptogenic hippocampus. Hippocampus 1997;7:472–488. 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. Wasterlain, C. G., and Y. Shirsaska. Seizures, brain damage and brain development. Brain Dev. 1994;16:279–295. Westbrook, G. L., and M. L. Mayer. Micromolar concentrations of Zn2+ antagonize NMDA and GABA responses of hippocampal neurons. Nature 1987;328:640–643. Williams, P. A., et al. Reassessment of the effects of cycloheximide on mossy fiber sprouting and epileptogenesis in the pilocarpine model of temporal lobe epilepsy. J. Neurophysiol. 2002;88:2075–2087. Williams, S. F., et al. Epileptic focus induced by intrahippocampal cholera toxin in rat: Time course and properties in vivo and in vitro. Epilepsy Res. 1993;16:137–146. Williamson, A., and D. Spencer. Zinc reduces dentate granule cell hyperexcitability in epileptic humans. Neuroreport 1995;6: 1562–1564. Williamson, A., S. S. Spencer, and D. D. Spencer. Depth electrode studies and intracellular dentate granule cell recordings in temporal lobe epilepsy. Ann. Neurol. 1995;38: 778–787. 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. Wilson, C. L., and J. Engel, Jr. Electrical stimulation of the human epileptic limbic cortex. In O. Devinsky, A. Beric, and M. Dogali, eds. Electrical and Magnetic Stimulation of the Brain and Spinal Cord. New York: Raven Press, 1993:103–113. Wilson, C. L., M. Isokawa, T. L. Babb, P. H. Gandall. Functional connections in the human temporal lobe. I. Analysis of limbic system pathways using neuronal responses evoked by electrical stimulation. Exp. Brain Res. 1990;82:279–292.
:
214. Wolff, J. R., and M. Missler. Synaptic remodelling and elimination as integral processes of synaptogenesis. APMIS Suppl. 1993;40:9–23. 215. Wuarin, J. P., and F. E. Dudek. Electrographic seizures and new recurrent excitatory circuits in the dentate gyrus of hippocampal slices, from kainite-treated epileptic rats. J. Neurosci. 1996;16:4438–4448. 216. Zafirov, S., B. Heimrich, and M. Frotcher. Dendritic development of dentate granule cells in the absence of their specific extrinsic afferents. J. Comp. Neurol. 1994;345:472–480. 217. Zhang, N., and C. R. Houser. Ultrastuctural localization of dynorphin in the dentate gyrus in human temporal lobe epilepsy: A study of reorganized mossy fiber synapses. J. Comp. Neurol. 1999;405:472–490. 218. Zhu, Z. Q., et al. Tyrosine hydroxylase-immunoreactive neurons in the temporal lobe in complex partial seizures. Ann. Neurol. 1990;27:564–572. 219. Zimmermann, H. M. The histopathology of convulsive disorder in children. J. Pediatr. 1941;13:859–890.
VII THERAPEUTIC PRINCIPLES
36
Neuroprotective Strategies in Status Epilepticus
. U recently the question of whether it is the seizure discharges themselves that kill neurons or whether the acute neuronal death and subsequent neuronal loss and gliosis following status epilepticus (SE) are the result of secondary systemic factors such as hypoxia, hypotension, or hypoglycemia occurring during SE was unresolved. Almost one hundred years of neuropathologic observations had failed to provide an answer. Experimental studies in animals were the key not only to providing an answer to this question, but also to indicating how long an episode of SE is required, and at least the beginning of an understanding of the mechanisms involved. The key to an understanding of mechanisms in SE was a series of observations by John Olney and colleagues in the 1970s that linked exposure to glutamate, the most abundant excitatory neurotransmitter, to neuronal death (reviewed in ref. 102). This resulted in the excitotoxic hypothesis, which has proved to be an extremely powerful explanation for pathologically induced neuronal death not only in a wide variety of acute neurologic diseases (e.g., SE, cerebral ischemia, traumatic injury to brain and spinal cord), but also at least a contributory explanation for chronic degenerative diseases such as Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Even more recently an approach to the treatment of SE other than the traditional approach of treating systemic complications and trying to stop the seizures with antiepileptic drugs has been proposed. The traditional approach has been and should continue to be the mainstay of treatment, but even it can be improved upon, perhaps thereby lessening the incidence of refractory SE, and an approach based on an understanding of mechanisms could provide an additional arm by which neurons can be salvaged. The discussion in this chapter addresses the following questions: (1) What is the evidence that SE kills neurons? (2) What is the time course by which this occurs? (3) What are the mechanisms by which this occurs? (4) What neuroprotective strategies can be devised, based on this information and related studies of cerebral ischemia? Many more neuroprotective approaches have been tried in experimental cerebral ischemia than in SE. Insofar as the mechanisms of
neuronal death in these conditions overlap, successful neuroprotective strategies in cerebral ischemia are likely to be of use in SE as well.
What is the evidence that SE kills neurons? A S The first evidence that electrographic seizure discharges alone could kill neurons and that SEinduced neuronal death is not simply the result of secondary systemic complications was obtained by Meldrum and colleagues (87, 89), who induced SE with the GABAA receptor antagonist bicuculline in paralyzed, artificially ventilated adolescent baboons (89). The baboons were killed immediately after 3.4–7.5 hours of SE, and cresyl violet and hematoxylin-eosin staining of brain sections revealed “ischemic cell change” in layers 3, 5, and 6 of neocortex, the CA1 pyramidal cell layer and hilus of the hippocampus, and anterior, dorsomedial, and ventrolateral nuclei of the thalamus. Brown (15) subsequently summarized studies showing “ischemic cell change” (neuronal necrosis) in hypoxia-ischemia by light and electron microscopy, and we and others have shown that the same changes occur in SE (37, 46, 49, 50, 66, 104, 125, 131). These changes are described later (see discussion under What Type of Neuronal Death Is Produced?) and are shown in Figures 36.1, 36.3, and 36.4. At the same time, John Olney and colleagues were investigating the neurotoxic effects of exogenous administration of glutamate analogues both in vitro and in vivo (103, 105, 106, 109); the best studied of these analogues, kainic acid, was found to damage neurons in limbic structures by inducing SE (10, 84, 94, 125, 131). Shortly thereafter the muscarinic cholinergic agonist pilocarpine, alone (142) or in combination with lithium chloride pretreatment, which permits a 13-fold lower pilocarpine dose to be used (63), was also found to induce SE that damages neurons in limbic structures; the extent and severity of the neuronal damage were the same whether or not lithium chloride pretreatment was given (24). Once started, SE could not be stopped by administration of the anticholinergic drug scopolamine, suggesting that the seizure discharges had spread beyond the cholinergic system. Finally, sustained, prolonged electrical
:
463
stimulation of the perforant path (PPS) was found to damage postsynaptic hippocampal neurons, providing conclusive evidence that it is excessive presynaptic activity that kills neurons, and not the neurotoxic effects of chemical convulsants (104, 128). H S The evidence that SE kills neurons in humans is in general limited by the lack of information regarding the duration of SE, the presence or absence of complicating systemic factors such as hypotension, hypoxemia, and hypoglycemia, and the duration of survival after SE. In addition, preexisting epilepsy and brain lesions may complicate interpretation of study results. With this in mind, we examine three studies. In 1964, Norman (101) reported on 11 children, ages 1.4–6 years, who had survived 1.5–14 days after SE; 8 had preexisting epilepsy. Acidophilic neurons were found in cerebral cortex, hippocampal CA1, CA3, and hilus, amygdala, thalamus, cerebellum, and striatum. In this study the duration of SE was not specified and the presence or absence of complicating systemic factors was not known. In 1983, Corsellis and Bruton (27) reported 20 cases, 8 in children and 12 in adults. Six of the 8 children who died were less than 3 years old, and had neuronal loss in hippocampus, cerebellum, thalamus, striatum, and neocortex, especially the middle cortical layers. Only 4 of the 12 adults showed variable degrees of neuronal loss. In these cases the duration of SE and the presence or absence of systemic complications were also unspecified. We reported on three men, ages 44, 48, and 56, none with preexisting epilepsy, all of whom had the onset of SE in the hospital, with subsequent ICU monitoring (46). Two of the three had no underlying brain pathology; the third had diffuse carcinomatous meningitis. All three patients were unresponsive, with electrographic SE and focal motor manifestations. The duration of SE was 3 days, 8.8 hours, and 2 days in the three patients, and survival after SE was 15, 11, and 27 days. None of the three had hypotension, hypoxemia, or hypoglycemia until the terminal event. Neuronal loss and gliosis were found in all three cases in hippocampal CA1, 2, and 3 pyramidal cell layers, dentate hilus, corticomedial and basolateral amygdaloid nuclei, layers 2–4 of periamygdaloid (piriform) cortex, layers 5 and 6 of neocortex, and Purkinje cells of the cerebellum. The dorsomedial thalamic nucleus showed neuronal loss and gliosis in two of the cases, and layers 2–6 of entorhinal cortex were involved in one patient. The regional distribution of neuronal loss was remarkably similar to the neuronal necrosis we have found in pilocarpine- and lithium-pilocarpineinduced SE and kainic acid–induced SE in rats (43–45, 47, 49, 50).
464
What is the time course of SE-induced neuronal death? In most of the animal studies of SE, the regional distribution and relative severity of neuronal damage are specified, but the duration of SE and, more important for potential clinical application, the time course over which neuronal death appears are not. In 1985, Nevander and colleagues (98) reported their findings on flurothyl-induced SE in paralyzed, artificially ventilated rats. One week after 30 minutes of SE, large bilateral infarcts were found in three of six rats in the pars reticulata of the substantia nigra (SNPR). After 45 minutes of SE, acidophilic neurons, indicative of neuronal necrosis, were also found in neocortical layers 3–4, and after 60 minutes of SE, the lateral and basal amygdaloid nuclei, ventroposterior thalamic nuclei, and the hippocampal CA1 pyramidal cell layer and hilus also had necrotic neurons. This seizure model is unusual because one of the earliest and most severely damaged regions is the SNPR, and the globus pallidus, which is not damaged in animal models of limbic SE or in humans, had necrotic neurons in three of six rats after 30 minutes of SE. We studied the time course over which necrotic neurons appeared in pilocarpine-induced SE (44). Diazepam and phenytoin were given intraperitoneally (IP) 3 hours after the onset of SE to stop behavioral and electrographic seizure activity (we have since switched to a combination of diazepam and phenobarbital, which stops seizure discharges more quickly and reliably [43, 45, 47, 49, 50]). Immediately after 10 minutes of SE, no neuronal damage was found, but after 20 minutes of SE a few necrotic neurons were found in the ventral hippocampal CA1 and CA3 pyramidal cell layer. After 40 and 60 minutes of, and after 3 hours of SE, between 12 and 15 limbic regions had increasing numbers of necrotic neurons and increasing edema of the neuropil; 24 hours and 72 hours after 3-hours of SE, the number of damaged regions increased to 22 and 21, respectively, and the damage was more pronounced (44) (Figure 36.1 and Table 36.1). Thus, in animal models of SE, widespread neuronal necrosis can occur within 40–60 minutes of the onset of SE. These studies point to the need for rapid diagnosis and treatment, even for strictly electrographic seizures, to minimize SE-induced neuronal death.
What are the mechanisms of SE-induced neuronal death? Because SE-induced neuronal death is closely linked to the excitatory neurotransmitter glutamate, we will begin by reviewing briefly the subtypes of glutamate receptors activated by endogenously released glutamate. There are four known subtypes of glutamate receptors: the three ligandgated receptors enclosing cation channels, named for their principal selective agonists, the ionotropic receptors
F 36.1 Acidophilic neurons, indicative of neuronal necrosis, may be found after only 20 minutes of pilocarpine-induced SE in the rat, and increasing the duration of SE produces progressively more necrotic neurons and neuropil edema. (A) Ventral hippocampal CA1 pyramidal cell layer after 20 minutes of SE. Two necrotic neurons can be seen (arrows). (B–F) Ventral hippocampal CA1 pyramidal cell layer after 40 minutes of SE (B, arrows point
to necrotic neurons), 60 minutes of SE (C), 3 hours of SE (D), 3 hours of SE with a 24-hour survival period (E), and 3 hours of SE with a 72-hour survival period (F). Progressively more necrotic neurons and more neuropil edema are found with increasing seizure duration. Scale bar = 30 mm. These are previously unpublished photomicrographs of hematoxylin-eosin-stained brain regions used in the data analysis by Fujikawa (44).
N-methyl--aspartate (NMDA), a-amino-3-hydroxy-5methyl-4-isoxazole propionic acid (AMPA), and kainic acid, and G protein-coupled receptors, the metabotropic receptors (62) (Figure 36.2). Twenty-eight recombinant glutamate receptor cDNAs, including a number of splice variants, have been cloned since the first AMPA receptor subunit, GluR1, was cloned in 1989 (reviewed in ref. 62). We will focus on NMDA receptors, which gate a Ca2+-selective ion channel, and AMPA receptors containing the GluR2 subunit and kainic acid receptors, which gate a Na+-selective ion channel. Pharmacologic antagonists to NMDA and AMPA receptors and agonists and antagonists to metabotropic receptor subunits are available and have been used to determine the involvement of these glutamate receptor subtypes in a wide variety of pathologic states, thereby confirming the broad applicability of the excitotoxic hypothesis.
terminals. Similar electron microscopic findings following seizures were produced by electrical stimulation of the perforant path for 24 hours (104), by repeated intraventricular (IV) injections of glutamate or aspartate for 1 hour (129), and by pilocarpine, given with or without lithium chloride (24). At the light microscopic level, a similar distribution of neuronal damage was found from seizures induced by kainic acid (10, 23, 49, 84, 94, 112, 125, 131) and by pilocarpine or lithium-pilocarpine (24, 43, 44, 45, 47, 50, 63). These findings led to the application of the excitotoxic hypothesis to SE, namely, that SE induces excessive endogenous release of the excitatory neurotransmitter glutamate, which in turn produces selective postsynaptic neuronal death (102). However, extracellular glutamate concentrations are not increased in hippocampus and piriform cortex during kainate-induced SE (18, 75, 139, 149), nor are they increased in hippocampus and amygdala during pilocarpine-induced SE or lithium-pilocarpine-induced SE (48, 91). The lack of an increase in extracellular glutamate in brain regions damaged in these models of SE is probably due to efficient glutamate uptake by astrocytes and presynaptic terminals, so
T E H SE Ultrastructual studies performed by Olney and colleagues (103, 105, 106, 109) revealed that administration of glutamate and its analogues produced marked swelling of neuronal dendrites and cell bodies, sparing adjacent axons and presynaptic nerve
:
465
T 36.1 The evolution of neuronal damage during seizures and recovery periods of increasing duration
20-min SE (2)
40-min SE (14)
1-hour SE (12)
0–4-hour recovery (15)
Ventral CA1 Ventral CA3
Dorsal CA2 Dorsal hilus Ventral CA1 Ventral CA3 Ventral hilus Dorsal DG Ventral DG Amygdala Piriform cortex Entorhinal cortex FPT cortex Lateral septal nuclei Caudate-putamen SN pars compacta
Dorsal CA2 Dorsal hilus Ventral CA1 Ventral CA3 Ventral hilus Dorsal DG Ventral DG Amygdala Piriform cortex Entorhinal cortex FPT cortex Lateral septal nuclei
Dorsal CA3 Dorsal hilus Ventral CA1 Ventral CA3 Ventral hilus Dorsal DG Ventral DG Amygdala Piriform cortex Entorhinal cortex Thalamus (reuniens n.) FPT cortex Lateral septal nuclei Caudate-putamen SN pars compacta
3-hour SE, 24-hour recovery (22) Dorsal CA1 Dorsal CA2 Dorsal CA3 Dorsal hilus Ventral CA1 Ventral CA2 Ventral CA3 Ventral hilus Dorsal DG Ventral DG Amygdala Piriform cortex Entorhinal cortex Thalamus (5 nuclei) FPT cortex Lateral septal nuclei Caudate-putamen SN pars reticulata
72-hour recovery (21) Dorsal CA1 Dorsal CA2 Dorsal CA3 Dorsal hilus Ventral CA1 Ventral CA2 Ventral CA3 Ventral hilus Dorsal DG Ventral DG Amygdala Piriform cortex Entorhinal cortex Thalamus (5 nuclei) FPT cortex Lateral septal nuclei Caudate-putamen
Note: DG, dentate gyrus granule cell layer; FPT, frontoparietotemporal cortex; SN, substantia nigra. All of the above brain regions showed statistically significant brain damage compared to the control group (no seizures after pilocarpine administration). Numbers in parentheses indicate the number of brain regions affected at each time point. Adapted from Fujikawa (44). Reprinted with permission from Elsevier Science.
F 36.2 Diagrammatic representation of two ionotropic glutamate receptor subtypes (kainate/AMPA receptor and NMDA receptor) and a metabotropic (ACPD) glutamate receptor. The sites for agonists, antagonists, and modulators are shown. GLU, glutamate; KA, kainic acid; AMPA, a-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid; DOM, domoic acid; QA, quisqualic acid; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; APV, 2-amino-5-
466
phosphonopentanoic acid; CPP, 3-(±-2-carboxypiperazin4-yl)propyl-1-phosphonic acid; PCP, phencyclidine; tACPD, 1amino-cyclopentane-trans-1,3-dicarboxylic acid; PLC, phospholipase C. (Modified with permission by Michael Hollmann from the original diagram in Hollmann and Heinemann [62]. © 1994 by Annual Reviews, Inc.)
F 36.3 The competitive NMDA receptor antagonist CGP 40116 and the noncompetitive antagonist ketamine provide widespread protection against SE-induced neuronal necrosis, despite ongoing electrographic seizures. All photomicrographs are of the ventral hippocampal CA1 pyramidal cell layer. (A and C) Rats with 3-hour SE and a 24-hour survival period, treated with normal saline 15 minutes after SE onset. Almost all of the neurons in A and many in C are necrotic (arrows point to some), and the neuropil is mildly edematous; a few neurons with normal-appearing
nuclei can be seen (arrowheads point to two in A and C). (B and D) Rats with 3-hour SE and a 24-hour survival period, treated with CGP 40116, 12 mg/kg IP (B) or ketamine, 100 mg/kg IP (D) 15 minutes after SE onset. Neurons and neuropil are normal in appearance. Scale bar = 30 mm. Hematoxylin-eosin stain. A and B are previously unpublished photomicrographs of brain regions used in the data analysis by Fujikawa et al. (45), and C and D are previously unpublished photomicrographs of brain regions used in the data analysis by Fujikawa (43).
that although glutamate release probably increases during SE, the net result is a relatively constant concentration. Moreover, microdialysis probes sample average extracellular concentrations, not synaptic concentrations, which could be much higher.
onist ketamine, also given 15 minutes after SE onset, protected 22 of 24 brain regions (43). NMDA receptor blockade is neuroprotective despite persistence of electrographic seizure activity, indicating that the protection provided is not simply a nonspecific antiepileptic effect (23, 39, 43, 45). However, enthusiasm for the use of NMDA receptor antagonists clinically has been dampened by a series of reports from Olney and colleagues which suggest that noncompetitive antagonists in particular damage posterior cingulate and retrosplenial neurons in layers 3 and 4 in rodents (42, 107, 108). MK-801 in doses as low as 0.4 mg/kg SC and ketamine in doses of 40 mg/kg SC produced cytoplasmic vacuoles which on electron microscopic examination appeared to be dilated mitochondria and endoplasmic reticulum (107). This reaction peaked at 12 hours after administration and was gone at 24 hours. Interestingly, it could be prevented with muscarinic cholinergic antagonists or barbiturates (phenobarbital was not tested), and, although not as
NMDA R A P A SEI N D There is indirect evidence that an increased number of postsynaptic NMDA receptors are activated by SE, because noncompetitive NMDA receptor antagonists protect against neuronal death from kainateinduced SE (23, 39) and both competitive and noncompetitive NMDA receptor antagonists protect against neuronal death in the lithium-pilocarpine model of SE (43, 45) (Figure 36.3). For example, the competitive NMDA receptor antagonist CGP 40116, at 12 mg/kg IP, even when given 15 minutes after SE onset, protected 19 of 24 damaged brain regions (45), and the noncompetitive NMDA receptor antag-
:
467
effective, diazepam at 1–7 mg/kg IP provided up to 50% protection (108). If higher doses of MK-801 are used (5 or 10 mg/kg SC), acidophilic (necrotic) neurons begin to appear in retrosplenial cortex 1 day after administration, becoming more numerous at 2–14 days (42). These findings raise concerns about using NMDA receptor antagonists in humans, especially in high doses. However, the protective effect of anticholinergic agents, barbiturates, and benzodiazepines to a certain extent offsets these concerns, especially when one considers the neuroprotective efficacy of NMDA receptor antagonists in SE. An alternative approach is the use of antagonists at the strychnine-insensitive glycine coagonist site and polyamine modulatory site of the NMDA receptor. Although these agents are neuroprotective in focal cerebral ischemia in rodents (52, 55, 150) and do not produce the early vacuolization of retrosplenial neurons (33, 57), studies have not been undertaken to determine if the later appearance of neuronal necrosis is also avoided. Furthermore, in the period of synaptogenesis in rats, from the late fetal period through the first postnatal week, which corresponds to the third trimester in humans (64), NMDA receptor antagonists and benzodiazepines and barbiturates, modulators of GABAA receptors, cause massive neuronal apoptosis in neocortex and thalamus (64, 65). It must be determined if this is also true in humans, because of the potentially devastating effects to the fetal brains of pregnant women with SE. Based on these studies in rats, human neonates with SE may not be at risk, but this also remains to be determined. AMPA R A SE Unlike the consistent neuroprotective effect of the potent and selective AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f )quinoxaline (NBQX) in transient global ischemia (32, 97, 126), there is conflicting evidence regarding the neuroprotective effect of AMPA/kainate receptor blockade on SE-induced neuronal death. For example, systemic administration of NBQX (8 mg/kg, 15 mg/kg, and 30 mg/kg ¥ 3), when given before, together with, or after kainate injection, did not protect the hippocampus from SE-induced neuronal death (13). On the other hand, the AMPA receptor antagonist NBQX given 1–1.5 mg/kg/hr for 90 minutes protected somatostatin- and neuropeptide Y-positive hilar neurons from neuronal death induced by 24-hour PPS (111). The dorsal and ventral hippocampal hilus are two regions in which neurons are not protected by CGP 40116 in the lithium-pilocarpine model of SE (45), which is consistent with the finding of AMPA receptor-mediated neuronal death from PPS. In addition, 30 mg/kg of NBQX given IP 30, 60, and 90 minutes after 12 mg/kg of kainate injection IP reduced the severity of SE and hippocampal CA1 and CA3 neuronal death (90). In this study, the neuroprotective effect of NBQX may have been the result of reduced endogenous
468
glutamate-induced, AMPA receptor-mediated neuronal depolarization, thus accounting for the reduced severity of SE, rather than a direct antagonistic effect of NBQX on kainate-induced activation of AMPA/kainate receptors. The excitotoxic hypothesis identifies the initial event, namely, excessive NMDA receptor activation of, and calcium influx into, postsynaptic neurons, due to excessive presynaptic glutamate release. This first step activates various biochemical pathways that contribute to SE-induced neuronal death. Since many of these mechanisms are “programmed” and are associated with apoptotic cell death, they are discussed in the next section.
What type of neuronal death is produced? Two major forms of cell death have been described morphologically, necrosis and apoptosis (151). On the light microscopic level, acidophilic cytoplasm and nuclear pyknosis identified with hematoxylin-eosin or acid fuchsin-cresyl violet staining techniques have been correlated with electron microscopic evidence of cellular necrosis in the brain (4, 47, 49, 50, 66) and in peripheral tissue (151). The light microscopic and ultrastructural features of neuronal necrosis have been described in cerebral hypoxia-ischemia (15, 26, 77, 148) and SE (37, 47, 49, 50, 66). Hematoxylin-eosin staining reveals shrunken, necrotic neurons with acidophilic cytoplasm and dark-stained, pyknotic nuclei (see Figures 36.1 and 36.3), the electron microscopic equivalent of which are shrunken, electron-dense neurons with cytoplasmic vacuoles of varying sizes, derived from swollen mitochondria and endoplasmic reticulum, and condensed, pyknotic nuclei with small, dispersed chromatin clumps (Figure 36.4). Cytoplasmic vacuolization can be seen after only 15 minutes of hypoxia-ischemia in the rat (16); the full spectrum of changes can be found within 2 hours after an episode of hypoxiaischemia in the rat (16) and persists for at least 72 hours after 3-hours SE (49, 50) (Figure 36.4). However, recent reports suggest that prolonged seizures induced by kainate can also trigger apoptosis (11, 38, 41, 53, 54, 70, 78, 79, 93, 112, 118, 119, 140, 143), which until the past decade was thought to be restricted primarily to normal developmental processes and cell turnover (153). However, careful ultrastructural examination shows that both lithiumpilocarpine-induced SE and kainate-induced SE in adult rats produce neuronal necrosis with no apoptosis 24 hours and 72 hours after 3-hours SE, together with internucleosomal DNA cleavage (DNA “laddering”) at both time points and in situ DNA nick-end labeling (positive TUNEL staining) at 24 and 72 hours (47, 49, 50) (Figure 36.4). These signs of DNA fragmentation (51, 152) were until recently considered specific for apoptosis, which, together with the activation of programmed cell death mechanisms by kainate-induced SE, are the principal reasons why so many
F 36.4 Ultrastructural examination of brain regions with acidophilic neurons 24 hours and 72 hours after 3-hour lithiumpilocarpine-induced SE reveals that they correspond to necrotic neurons, and that internucleosomal DNA cleavage (DNA laddering) occurs in these brain regions. (A, B, D, and E) Electron microscopic photomicrographs of ventral CA1 neurons from control and SE rats with 24-hour (A and B, respectively) and 72-hour survival periods (D and E, respectively). A and D show normal neurons with normal nuclei and cytoplasm with normal mitochondria and endoplasmic reticulum. B and E show necrotic neurons with dark, shrunken cell bodies, pyknotic nuclei with small, dispersed chromatin clumps, and cytoplasmic vacuolar degeneration. Many of the vacuoles are swollen mitochondria with disrupted cristae. Scale bar = 3 mm. A, B, D, and E are previously unpublished photomicrographs of brain regions used in the data analysis by Fujikawa
et al. (50). (C and F) Results of agarose gel electrophoresis of DNA extracted from brain regions examined by electron microscopy in control rats and those with SE and a 24-hour (C) or a 72-hour recovery period (F). In both C and F, the first lane (L) is a 100 basepair DNA standard ladder, lanes 1 and 2 are negative and positive apoptotic tissue controls, and subsequent lanes are control and SE dorsal hippocampus (3 and 4), ventral hippocampus (5 and 6), neocortex (7 and 8), amygdala and piriform cortex (9 and 10), and entorhinal cortex (11 and 12). Internucleosomal DNA cleavage at approximately 200 base-pair intervals (DNA laddering) is present in the positive tissue control and in all five brain regions from SE rats, demonstrating that DNA laddering can occur in necrotic as well as apoptotic cells. (C and F modified with permission from Fujikawa et al. [50]. © 1999 by Blackwell Science Ltd.)
investigators have concluded incorrectly that the kainate model of SE produces morphologically apoptotic (11, 38, 41, 53, 54, 70, 78, 79, 93, 112, 118, 119, 140, 143) rather than necrotic neurons (49, 125, 131). Programmed cell death mechanisms associated with cellular apoptosis have been shown to be activated by kainateinduced SE, so it appears that they can be triggered in morphologically necrotic neurons as well. For example, kainate-induced SE is associated with mRNA and protein expression of the p53 tumor-suppressor gene, which inhibits cell proliferation (118, 119), and the protein synthesis inhibitor cycloheximide prevents p53 mRNA expression and neuronal death (119, 122). Although p53-null mice were reportedly protected against kainate SE-induced neuronal
death (93), this was probably the result of using a strain of mice resistant to kainate SE-induced neuronal death, rather than the genetic deletion of p53 (121). Nevertheless, p53 immunoreactivity has been colocalized with CD95/Fas/ APO-1 and Bax immunoreactivity in the same hippocampal neurons (although in nuclei and not in cytoplasm or mitochondria, as would be expected), suggesting that the Fas receptor-activated extrinsic caspase-dependent cell death pathway and cell-death-promoting Bcl-2 family member Bax might be activated following lithium-pilocarpineinduced SE (138). An interaction between p53 and the extrinsic caspase-dependent pathway following 40-minute seizures evoked by intra-amygdalar injection of kainic acid might be mediated by death-associated protein (DAP) kinase,
:
469
which is present within p53 immunoprecipitates (3) and which also binds to tumor necrosis factor receptor 1 (TNFR1) and Fas-associated death domain (FADD) protein, resulting in caspase-8 cleavage and activation (59). Kainic acid–induced SE also produces expression of the mRNA of the cysteine protease caspase-3 in rat hippocampus (9, 53) and triggers caspase-3-like activity (53, 60) and caspase-3 immunoreactivity (60), including a cleaved, active fragment (38, 40, 70), in hippocampal neurons. In addition, following kainate-induced SE there is increased bax mRNA expression (2, 54) and translocation of Bax immunoreactivity (although from cytoplasm to nuclei instead of from cytoplasm to mitochondria, as would be expected) in a subset of dying neurons (83), Western blot evidence of translocation of cytochrome c from mitochondria to cytosol (60), and cyclin D1 mRNA expression (140) and protein expression (79) in hippocampal neurons. All of these processes are involved in programmed cell death. Furthermore, intracerebroventricular administration of the caspase-3 inhibitor N-benzoyloxycarbonyl-Asp(OMe)Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone (Z-DEVDFMK) protects hippocampal neurons from SE-induced neuronal death (60, 70, 95). However, Puig and Ferrer (114) failed to find translocation of cytochrome c from mitochondria to cytosol or Bax translocation from cytosol to mitochondria following KASE. In addition, Kondratyev and Gale (70) did not find caspase3 activation in hippocampus despite Z-DEVD-FMK neuroprotection, and the specificity of caspase inhibitors has been questioned (69, 116). Moreover, other reports (2, 47, 96, 114) indicate that caspase-3 is either minimally or not activated and that broad-spectrum caspase inhibition is not neuroprotective (47) in seizure-induced neuronal death. Since caspase-3 is the central downstream effector caspase upon which both the intrinsic (mitochondrial) caspase-9 and extrinsic (death receptor–activated) caspase-8 pathways converge, the importance of these programmed mechanisms in seizure-induced neuronal death is open to question. Kainic acid–induced SE has been associated with activation of the calcium-activated cysteine protease calpain I (also called m calpain) in hippocampus (127) and with increased immunoreactivity of a lysosomal aspartic protease, cathepsin D, in degenerating neurons in hippocampus, piriform cortex, amygdala, and neocortex (61). Calpain I and cathepsin B have been linked in the calpain-cathepsin hypothesis of ischemia-induced necrotic neuronal death (see later discussion under Neuroprotective Strategies in SE), and they may play an important role in caspase-independent, SEinduced neuronal necrosis. A recent report of mutant mice overexpressing or lacking the sole specific calpain inhibitor, calpastatin, suggests mechanisms by which excitotoxic calpain activation leads to neuronal death (136). Intrahippocampal kainate injection
470
activated calpain, which cleaved Bid, a cell-death-promoting member of the Bcl-2 family of proteins, into its active, trunkated fragment (tBID). tBID was shown to translocate to mitochondria, with subsequent translocation from mitochondria to nuclei of apoptosis-inducing factor (AIF), which produces large-scale (50-kilobase) DNA cleavage (133), and endonuclease G (EndoG), which produces DNA laddering (76, 110) and nuclear condensation and pyknosis, all occurring without caspase-3 activation. However, in the calpastatin study (136), the occurrence of seizures was not monitored, there was no description of how far from the injection site hippocampal CA1 pyramidal cell counting was done or how it was done, the statistical analysis was not appropriate, and only calpastatin-deficient mice showed convincing colocalization of nuclear propidium iodide, AIF, and EndoG; the wild-type photomicrographs appeared similar to those of calpastatin-overexpressing mice (136). This is a potentially important study, but the reported results must be confirmed in a standard model of SE. In addition to EndoG, it has been suggested that caspaseactivated DNase (CAD, also known as DNA fragmentation factor 40, or DFF40) may be responsible for the DNA laddering that occurs in excitotoxic neuronal injury (20, 72, 141). In control cells, CAD exists as a heterodimer with its inhibitor, inhibitor of CAD (ICAD, also known as DNA fragmentation factor 45, or DFF45) (36, 80, 81, 117). Caspase3 cleaves ICAD from CAD, thereby activating CAD, which can cleave DNA into 180 base-pair internucleosomal fragments (DNA laddering) (36, 80, 81, 117). Forty-eight hours after 2 hours of kainic acid–induced SE, ICAD is cleaved from CAD in the rat hippocampus and rhinal cortex; however, DNA laddering is first seen 24 hours after SE and persists for the next 48 hours (72). This suggests that another DNase might be responsible for the early DNA laddering. A recent study also failed to find cleavage of ICAD 24 hours after intrahippocampal kainate injection (136). In addition, there is evidence that caspase-3 is not activated in damaged neurons following SE, which implies either that another enzyme can cleave ICAD from CAD or that another DNase is responsible for the DNA laddering. Finally, since inhibition of protein synthesis protects against kainate SE–induced neuronal necrosis (118, 122), the neuronal death produced may depend on the synthesis of new protein. Whether the protein synthesis dependence is a programmed type of cell death or whether blocking protein synthesis interferes with other aspects of neuronal function, such as vesicular glutamate release, remains to be determined. These studies point to the activation of programmed cell death mechanisms in kainate-induced SE. NMDA receptor antagonists may protect against SE-induced neuronal death in part by preventing the initiation of programmed cell death mechanisms.
Neuroprotective strategies in SE Based on animal studies of SE-induced neuronal death, the window of opportunity for optimal neuroprotection is 1 hour or less, even in paralyzed, artificially ventilated rats (98). Although the time course of SE-induced neuronal death in the rat should not be extrapolated directly to humans, the rat data point to the need for rapid recognition and prompt, effective treatment of SE under continuous electroencephalographic (EEG) monitoring. This point has been emphasized in a recent study of nonconvulsive seizures and SE in a neurologic intensive care unit (ICU) in which continuous EEG monitoring was available (157). Of 23 patients with nonconvulsive SE, 13 died (a 57% mortality); variables significantly associated with mortality were seizure duration and delay to diagnosis. Current antiepileptic drug (AED) regimens for treating SE are presented elsewhere and will not be discussed here. Instead, we will focus on pharmacologic agents that elucidate mechanisms by blocking excitotoxic neuronal death, because they suggest specific neuroprotective strategies that could be used as adjuncts to the AED treatment of SE. These agents act at different points in the excitotoxic
cascade, from inhibition of glutamate release to inhibition of downstream postsynaptic biochemical reactions triggered by glutamate-induced ionotropic and metabotropic receptor activation and the resultant calcium influx through receptoroperated cation channels and calcium release from intracellular stores (see Figure 36.2 and Table 36.2). Agents acting at different points in the excitotoxic cascade could be combined into a cocktail that in principle could provide more complete protection than a single agent acting at a single point in the cascade. However, if glutamate receptors are blocked, coupled perhaps with inhibition of glutamate release, inhibiting or enhancing biochemical reactions triggered by activated glutamate receptors may not be necessary, whereas if glutamate receptors are not blocked, it may be necessary to inhibit or enhance multiple downstream biochemical reactions to obtain comparable neuroprotection. If adjunctive neuroprotective drugs are used to prevent SE-induced neuronal death, two questions must first be answered. First, when should adjunctive therapy be started? If neuroprotective drugs are given only in cases of refractory SE, neuronal damage may already have occurred, so maximal benefit will not be achieved. On the other hand,
T 36.2 Neuroprotective strategies in status epilepticus Postsynaptic glutamate receptor blockade: • NMDA-receptor blockade • AMPA-receptor blockade • Blockade of the glycine coagonist site of the glutamate receptor • Blockade of the polyamine modulatory site of the glutamate receptor • Use of metabotropic glutamate receptor subunit 2 and 3 (mGluR2 and 3) agonists and/or 1 and 5 (mGluR1 and 5) antagonists Postsynaptic blockade of calcium influx through -type calcium channels Use of cell-permeant calcium chelators Reduction of free radical generation (e.g., peroxynitrite) with neuronal nitric oxide synthase inhibitors or free radical scavengers Inhibition of calcium-sensitive proteases (calpains) and lysosomal cathepsins Blockade of presynaptic calcium-dependent, vesicular glutamate release: • Sodium channel blockade • Blockade of N- and P-type calcium channels Reduction of calcium-independent, sodium-dependent glutamate release Blockade of pre- and postsynaptic neuronal depolarization with a sodium channel blocker (e.g., phenytoin) Administration of growth factors (e.g., acidic and basic fibroblast growth factors, nerve growth factor, transforming growth factor-b1, etc.) Administration of platelet-activating factor antagonists Poly(ADP-ribose) polymerase-1 (PARP-1) inhibition Pharmacologic inhibition of cell-death-promoting proteins (e.g., caspases) or upregulation of cell-deathinhibiting proteins (e.g., Bcl-2, Bcl-x-long, and p35) Brief antecedent seizures as neuroprotectants
:
471
can giving such agents at the beginning of treatment be justified, if AED treatment alone is effective in the majority of cases? Second, during the stage in which these agents are being evaluated, what criteria should be used to determine the efficacy of adjunctive therapy? Measuring hippocampal volumes by magnetic resonance imaging (MRI) in matched groups with and without adjunctive therapy is one possibility. Ideally, patients without hypoxemia, hypotension, hypoglycemia, or hyperpyrexia and without underlying brain lesions or a history of epilepsy would be studied in order to avoid inclusion of patients with previous hippocampal damage. Detailed neuropsychological testing in the matched groups is another possibility. The design would be less than ideal, since it is unlikely that most patients would have undergone MRI or neuropsychological testing prior to SE. With these considerations in mind, the discussion turns to potential neuroprotective approaches. These potential approaches are summarized in Table 36.2. P G R B In its current formulation, the excitotoxic hypothesis states that excessive glutamate release, either from presynaptic vesicular stores or from depolarization-induced reversal of astrocytic and presynaptic glutamate uptake, activates postsynaptic glutamate receptors and opens their cation channels, allowing excessive calcium influx and calcium release from intracellular stores, which in turn activates cytoplasmic proteases, phospholipases, and nitric oxide synthase (NOS), generating reactive oxygen species, damaging mitochondria, cytoplasmic membranes, cytoskeletal proteins, and essential enzymes, and activating one or more endonucleases, creating internucleosomal double-stranded DNA fragments; the intracellular processes triggered lead to neuronal death and, possibly, to the continued postmortem digestion of intracellular components prior to phagocytosis. As discussed previously, both competitive and noncompetitive NMDA receptor antagonists are neuroprotective in animal models of SE; however, their neurotoxicity in rodents has raised concern about their use in humans. The animal studies in which the AMPA receptor antagonist NBQX was used gave mixed results; more studies are needed. Strychnine-insensitive glycine site antagonists and polyamine modulatory site antagonists are neuroprotective in cerebral ischemia and have the advantage that they do not show the NMDA-associated early cytoplasmic vacuolization in retrosplenial neurons; however, no studies have been done to determine whether or not the delayed neuronal necrosis seen with NMDA receptor antagonists occurs. If not, these agents would be attractive adjunctive neuroprotectants in SE. There are eight metabotropic receptor subunits (mGluR1–8); mGluR1 and mGluR5 antagonists, which reduce calcium release from intracellular stores, and mGluR2 and mGluR3 agonists, which reduce cyclic AMP
472
activity, have been shown to be neuroprotective in vitro (100). Studies of these agents in animal models of SE would be welcome. P B C I T -T C C -Type calcium channel antagonists such as nimodipine prevent postsynaptic calcium influx through voltage-sensitive calcium channels. A metaanalysis has shown that in both clinical trials and animal studies in which it was given after arterial occlusion, nimodipine failed to provide protection in cerebral ischemia (31). Similarly, nimodipine failed to protect against neuronal damage from KASE (12). Combined, these data suggest that -type calcium channel antagonists would not be effective adjunctive neuroprotectants. U C-P C C An alternative strategy to blocking excessive calcium entry into neurons is to increase their capacity to buffer excessive calcium loads. The neuroprotective efficacy of this approach was first demonstrated in the rat hippocampal slice with the cellpermeant calcium chelator 1,2-bis-[2-amino-phenoxy] ethane-N,N,N ¢,N ¢-tetraacetic acid (BAPTA) (120). The feasibility of IV administration of BAPTA-AM (the acetoxymethyl ester of BAPTA) was demonstrated in focal cerebral ischemia in the rat, in which administration prior to ischemia reduced infarct volume by 50% 24 hours after combined common carotid and middle cerebral artery occlusion (144). However, BAPTA-AM was infused over a period of 40–50 minutes 4 hours prior to ischemia, so whether similar results can be obtained after the onset of ischemia or SE awaits further investigation. R P F R G A review of the literature on the neuroprotective effect of reduction of free radical generation with (1) NOS inhibitors, which reduce the generation of NO and its neurotoxic reaction product, peroxynitrite (ONOO-), or (2) free radical scavengers in cerebral ischemia is beyond the scope of this chapter. The reader is referred to general reviews of the role of NO in neurotoxicity (29) and of free radical scavengers in neurodegenerative diseases (123). Kainic acid–induced SE generates reactive oxygen species (17, 145), and the free radical scavenger ascorbic acid injected systemically before or at the same time as kainic acid protects the hippocampal CA1 and CA3a regions (85). Further research is needed to determine if free radical scavengers given after SE onset are neuroprotective, and if protection extends to other vulnerable brain regions. I C-S P (C) L C The calcium-sensitive protease calpain breaks down cytoskeletal proteins such as spectrin,
microtubule-associated protein (MAP2), and neurofilament proteins. In rats, calpain inhibitors reduce CA1 neuronal damage in transient global ischemia (74, 115) and infarct volume in focal cerebral ischemia (6). The study by Bartus et al. (6) is particularly important from a clinical standpoint, because the calpain inhibitor was given through rats’ internal carotid arteries 1.25 hours after their middle cerebral arteries were occluded, whereas other studies have utilized intracerebroventricular (ICV) or intracisternal infusions beginning prior to the onset of ischemia. Although the latter approach is useful from a research standpoint because it demonstrates mechanisms, it is obviously of limited clinical utility. Calpain inhibitors have not been tested in animal models of SE. In addition to cleavage of cytoskeletal proteins, in global cerebral ischemia in primates, calpain I damages lysosomal membranes, causing release of lysosomal cathepsins and DNase II (141, 156), and inhibition of cathepsin B provides neuroprotection (155). These findings have given rise to the calpain-cathepsin hypothesis of cerebral ischemia-induced necrotic neuronal death, a caspase-independent, programmed pathway that may also be important in SEinduced neuronal death. B P C-D, V G R Depolarization of voltage-sensitive sodium channels in presynaptic terminals contributes to vesicular glutamate release by permitting voltage-sensitive calcium influx, which in turn leads to calcium-activated vesicular glutamate release. Blockade of these channels reduces glutamate release in focal and global cerebral ischemia and is neuroprotective (56, 73, 88). The voltagesensitive sodium channel blocker phenytoin has been available as an AED for SE for years; its water-soluble precursor fosphenytoin is now available. Presynaptic vesicular glutamate release is also dependent on depolarization-induced calcium influx. Blockade of N-type presynaptic calcium channels is neuroprotective in both focal and global cerebral ischemia (19, 137, 147, 154), and P-type presynaptic calcium channel blockade protects against combined oxygen-glucose deprivation in the rat hippocampal slice preparation (130). The voltage-sensitive sodium channel blocker phenytoin (and its precursor fosphenytoin) is already a first-line AED in SE; whether or not presynaptic calcium channel blockers will also be effective in SE awaits future studies. R C-I, S-D G R In addition to calcium-dependent, presynaptic vesicular glutamate release, calcium-independent, sodium-dependent glutamate uptake may be reversed by excessive neuronal depolarization, which reduces the physiologic sodium gradient across cell membranes and pro-
motes glutamate release from astrocytes and presynaptic terminals (99). By reducing excessive neuronal depolarization and sodium influx into neurons and reestablishing a more physiologic sodium gradient across cell membranes, glutamate uptake can be reestablished. In principle, this can be accomplished by voltage-sensitive sodium channel blockers such as phenytoin (fosphenytoin), which is already available as an AED. B P- P N D S C B The use of voltage-sensitive sodium channel blockers for reducing presynaptic terminal depolarization and glutamate release has already been discussed. These agents can also reduce postsynaptic neuronal depolarization by blocking postsynaptic voltage-sensitive sodium channels and sodium influx, thereby reducing cell swelling. They also reduce voltagesensitive, postsynaptic NMDA receptor activation, so that the voltage-dependent magnesium block of its receptoroperated cation channel is maintained. Again, with phenytoin (fosphenytoin), this approach is already available. A G F Although growth factors such as nerve growth factor, basic fibroblast growth factor, brain-derived neurotrophic factor, and transforming growth factor b-1 have been shown to be neuroprotective in vitro, in in vivo models of cerebral ischemia, growth factors have had to be administered through catheters placed into rodents’ lateral ventricles for neuroprotective effects to be demonstrated (8, 58, 113), making their use in SE problematic. Two studies with kainate-induced SE have also shown the neuroprotective effect of ICV administration of basic fibroblast growth factor (82) and glial-derived neurotrophic factor (86). More important, a study of acidic fibroblast growth factor given IV 10 minutes after subcutaneous kainic acid injection showed neuroprotection in rat hippocampus (28). More studies are needed to determine if systemic administration of growth factors will provide significant neuroprotection in cerebral ischemia and widespread neuroprotection in SE. A P-A F A Increased NMDA receptor activation caused by excessive glutamate release during SE results in activation of phospholipase A2, which in turn results in the formation of free arachidonic acid, eicosanoids, and plateletactivating factor (PAF ) (reviewed in ref. 5). Arachidonic acid potentiates NMDA receptor ion currents (92), and it also inhibits glutamate uptake by glia (5). PAF mediates the induction of early response genes and their transcriptional cascades, but it may also increase excitotoxicity by enhancing glutamate release (21, 67). The PAF antagonist BN 50739, administered IV during postischemic reoxygenation,
:
473
reduces brain free fatty acid accumulation, an early event in cerebral ischemia (22, 132). Such antagonists may prove to be effective neuroprotectants in cerebral ischemia and SE. It should be noted, however, that the noncompetitive NMDA receptor antagonist MK-801 blocks phospholipase A2-mediated arachidonic acid release (146), showing that preventing upstream NMDA receptor activation may eliminate the need to inactivate a downstream excitotoxic mechanism. I P(ADP-R) P-1 Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear DNA repair enzyme that, when activated, hydrolyzes nicotinamide adenine dinucleotide (NAD) to nicotinamide, transferring ADP ribose units to nuclear proteins such as histones and PARP-1 itself (30), utilizing ATP in the process. However, excessive PARP-1 activation can produce significant reductions in cellular NAD and ATP, resulting in energy failure, which contributes to neuronal death from a variety of insults, the common mechanism being excitotoxicity from NMDA receptor activation (159). Inhibition of PARP-1 has been shown to be neuroprotective in cerebral ischemia (134, 135), and genetic deletion of PARP substantially reduces infarct volume in mice after reversible middle cerebral artery occlusion (35), but there are no studies in SE. PARP-1 activation is also necessary for translocation of apoptosis-inducing factor (AIF ) from the mitochondrial membrane to the nucleus (158), where it produces largescale (approximately 50-kilobase) DNA cleavage (133). A recent study in mutant mice, cited previously, has shown that SE-induced calpain activation results in release of AIF (and EndoG) from mitochondria, with their translocation to nuclei and nuclear condensation and pyknosis (136). Further study of this downstream caspase-independent programmed pathway may result in even more potential avenues of neuroprotection. M C-D-P CD-I P In vitro studies of the nematode Caenorhabditis elegans and of mammalian cells have revealed that many different types of external signals can trigger apoptotic neuronal death, which proceeds by a predetermined program, at least one essential component of which is the Ced3/ICE (interleukin-1b converting enzyme) family of cysteine proteases (reviewed in refs. 14, 25, 34, and 124). In 1996, this family of cysteine proteases was renamed caspases, for cysteine proteases that cleave proteins at aspartate residues, to unify the nomenclature of the 10 cysteine proteases identified at the time (1). The question of whether caspase-3 activation occurs in seizure-induced neuronal death is controversial. Seizures evoked by intra-amygdalar injection of kainic acid have been reported to induce caspase-3-like protease activity and cleav-
474
age of caspase-3 into its active p17 fragment (60), and ICV delivery of Z-DEVD-FMK protects hippocampal neurons from seizure-induced neuronal death (60, 70, 95). However, other recent reports indicate that significant caspase-3 activation does not occur in seizure-induced neuronal death (2, 47, 96, 114, 136) and that the currently used caspase inhibitors are not specific for caspases (69, 116). Currently, the question is moot, because these peptides have relatively poor cell membrane permeability and are not effective if given systemically. The alternative approach, upregulation of cell-deathinhibiting proteins (e.g., baculovirus proteins Bcl-2, Bcl-XL, and p35), is at present only a hypothetical in vivo neuroprotective strategy. Neither approach is likely to be useful clinically in early-appearing SE-induced neuronal necrosis. However, if there were a significant number of neurons undergoing delayed neuronal death, pharmacologic inhibition of cell-death-promoting proteins or upregulation of cell-death-inhibiting proteins could be of use clinically. B A S N Previously hippocampal-kindled rats have more severe kainic acid–induced behavioral and electrographic seizures than nonkindled rats, yet paradoxically, they have less neuronal damage in hippocampus and no damage in piriform cortex and substantia nigra pars reticulata (68). Similarly, noninjurious, daily electroconvulsive shocks (ECS) prior to kainic acid–induced SE protect against SE-induced neuronal death and DNA fragmentation in hippocampus and rhinal cortex (71). Although the mechanistic basis for these observations is not immediately apparent, and although a clinical application is not likely in the near future, further research in this area could provide more directly applicable nonpharmacologic neuroprotective approaches in the future. A S F A N SE Based on the experimental information outlined in this chapter, can a rational, practical neuroprotective strategy be devised for SE? Currently, many neurologists give lorazepam IV, following by a loading dose of phenytoin IV, to patients in SE. Instead of phenytoin, its precursor, fosphenytoin, is now available and preferred because of its water solubility and its ability to be infused more rapidly. To this combination the noncompetitive NMDA receptor antagonist ketamine, currently used as a dissociative anesthetic, could be added because of its demonstrated neuroprotective effect in kainate-induced SE and lithium-pilocarpine-induced SE in rats (23, 43). The use of lorazepam, to increase GABAergic inhibition; phenytoin, to decrease pre- and postsynaptic neuronal depolarizations, thereby decreasing glutamate release, postsynaptic sodium influx through voltage-sensitive sodium
channels, and voltage-sensitive NMDA receptor activation; and ketamine, to block postsynaptic NMDA receptor activation represents a rational combination of drugs that are already available. However, many questions must be answered before ketamine is used clinically. Does it damage cingulate/retrosplenial neurons in primates as well as in rodents? If damage is found with ketamine alone, is it eliminated by combining lorazepam and ketamine? What dosage regimen of ketamine should be used in humans? What criteria for determining the efficacy of ketamine should be used, and what criteria should be used to select patients for inclusion in a clinical trial? As an alternative to ketamine, a strychnine-insensitive, glycine site antagonist that does not produce the early cytoplasmic vacuolization seen with NMDA receptor antagonists could be used. However, studies to determine the efficacy of such agents in SE must first be performed, and if they are found to be neuroprotective, studies to rule out high-dose delayed neuronal necrosis should also be done. Finally, we should be cautious about using NMDA receptor antagonists, benzodiazepines, and barbiturates in pregnant women in their third trimester, given the recent reports that these agents produce extensive neuronal apoptosis in rodents during the period of rapid synaptogenesis (64, 65). As more neuroprotective agents are shown to be effective in SE and become available for clinical use, rational combinations of agents could be used to enhance blockade of glutamate release, pre- and postsynaptic neuronal depolarization and postsynaptic intracellular processes that contribute to SE-induced neuronal death. For example, the addition of an AMPA receptor antagonist to lorazepam, phenytoin (fosphenytoin), and ketamine to decrease sodium influx and cell swelling and further reduce postsynaptic depolarization would be a logical next step. As our understanding of the intracellular events that participate in neuronal death expands, new, as yet undiscovered approaches will undoubtedly appear.
Conclusions Although the excitotoxic hypothesis has generated many potential neuroprotective strategies, most have not yet been tested in SE. NMDA receptor antagonists are neuroprotective in SE, but their potential neurotoxicity has lessened enthusiasm for their use. Animal studies indicate that 40–60 minutes of SE, even in paralyzed, artificially ventilated animals, produces widespread neuronal death in the same limbic structures that are damaged in human SE. Based on these considerations, the most important neuroprotective strategy at the present time is rapid recognition of SE and prompt and permanent elimination of electrographic seizure discharges under continuous EEG monitoring; behavioral
observation alone is not adequate in less than fully awake and fully responsive subjects. The possibility of adding an NMDA receptor antagonist such as ketamine or a strychnine-insensitive glycine site antagonist to the currently widely used combination of lorazepam and phenytoin awaits further animal studies to determine the safety of the former and the efficacy in SE of the latter. As more neuroprotective agents are shown to be effective in SE, rational combinations that increase neuroprotective efficacy may eventually be used clinically. This work was supported by the Medical Research Service, Office of Research and Development, Department of Veterans Affairs, Washington, D.C. The excellent collaborative assistance of Baiyuan Cai, Jianjun Zhang, Aiguo Wu, and Xingrao Ke, as well as that of John Kim, Allan Daniels, Thomas Sohn, Steve Shinmei, Rosen Trinidad, and the expert technical assistance of Suni Allen and Alejandro Alcaraz are gratefully acknowledged.
REFERENCES 1. Alnemri, E. S., D. J. Livingston, D. W. Nicholson, et al. Human ICE/CED-3 protease nomenclature. Cell 1996;87:171. 2. Ananth, C., S. Tharmeem Dheen, P. Gopalakrishnakone, and C. Kaur. Domoic acid–induced neuronal damage in the rat hippocampus: Changes in apoptosis related genes (bcl-2, bax, caspase-3) and microglial response. J. Neurosci. Res. 2000;66:177–190. 3. Araki, T., S. Shinoda, C. K. Schindler, et al. Expression, interaction and proteolysis of death-associated protein kinase and p53 within vulnerable and resistant hippocampal subfields following seizures. Hippocampus 2004;14:326–336. 4. Auer, R. N., H. Kalimo, Y. Olsson, and B. K. Siesjö. The temporal evolution of hypoglycemic brain damage. I. Light- and electron microscopic findings in the rat cerebral cortex. Acta Neuropathol. (Berl.) 1985;67:13–24. 5. Barbour, B., M. Szatkowski, N. Ingledew, and D. Attwell. Arachidonic acid induces a prolonged inhibition of glutamate uptake into glial cells. Nature 1989;342:918–920. 6. Bartus, R. T., N. J. Hayward, P. J. Elliott, et al. Calpain inhibitor AK295 protects neurons from focal brain ischemia. Stroke 1994;25:2265–2270. 7. Bazan, N. G., E. B. Rodriguez de Turco, and G. Allan. Mediators of injury in neurotrauma: Intracellular signal transduction and gene expression. J. Neurotrauma 1995;12: 791–814. 8. Beck, T., D. Lindholm, E. Castrén, and A. Wree. Brainderived neurotrophic factor protects against ischemic cell damage in rat hippocampus. J. Cereb. Blood Flow Metab. 1994;14:689–692. 9. Becker, A. J., F. Gillardon, I. Blümke, D. Langendörfer, H. Beck, and O. D. Wiestler. Differential regulation of apoptosis-related genes in resistant and vulnerable subfields of the rat epileptic hippocampus. Mol. Brain Res. 1999;67: 172–176. 10. Ben-Ari, Y., 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.
:
475
11. Bengzon, J., Z. Kokaia, E. Elmér, A. Nanobashvili, M. Kokaia, and O. Lindvall. Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures. Proc. Natl. Acad. Sci. U.S.A. 1997;94:10432–10437. 12. Berg, M., T. Bruhn, A. Frandsen, A. Schousboe, and N. H. Diemer. Kainic-acid-induced seizures and brain damage in the rat: Role of calcium homeostasis. J. Neurosci. Res. 1995;40: 641–646. 13. Berg, M., T. Bruhn, F. F. Johansen, and N. H. Diemer. Kainic acid–induced seizures and brain damage in the rat: Different effects of NMDA- and AMPA-receptor antagonists. Pharmacol. Toxicol. 1996;73:262–268. 14. Bredesen, D. E. Neural apoptosis. Ann. Neurol. 1995;38: 839–851. 15. Brown, A. W. Structural abnormalities in neurones. J. Clin. Pathol. 1977;30(Suppl. 11):155–169. 16. Brown, A. W., and J. B. Brierley. The earliest alterations in rat neurones and astrocytes after anoxia-ischaemia. Acta Neuropathol. (Berl.) 1973;23:9–22. 17. Bruce, A. J., and M. Baudry. Oxygen free radicals in rat limbic structures after kainate-induced seizures. Free Radical Biol. Med. 1995;18:993–1002. 18. Bruhn, T., M. Cobo, M. Berg, and N. H. Diemer. Limbic seizure-induced changes in extracellular amino acid levels in the hippocampal formation: A microdialysis study of freely moving rats. Acta Neurol. Scand. 1992;86:455–461. 19. Buchan, A. M., S. Z. Gertier, D. Xue, et al. A selective Ntype Ca2+-channel blocker prevents CA1 injury 24 h following severe forebrain ischemia and reduces infarction following focal ischemia. J. Cereb. Blood Flow Metab. 1994;14:903–910. 20. Cao, G., W. Pei, J. Lan, et al. Caspase-activated DNase/DNA fragmentation factor 40 mediates apoptotic DNA fragmentation in transient cerebral ischemia and in neuronal cultures. J. Neurosci. 2001;21:4678–4690. 21. Chen, T., H. Kato, H. Ban, et al. Protective effects of a novel calcium antagonist with platelet-activating factorantagonistic action, F-0401, against ischemic brain damage. Arch. Int. Pharmacodyn. 1994;327:266–278. 22. Clark, G. D., L. T. Happel, C. F. Zorumski, and N. G. Bazan. Enhancement of hippocampal excitatory synaptic transmission by platelet-activating factor. Neuron 1992;9:1211– 1216. 23. 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. 24. 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. 25. Cohen, G. M. Caspases: The executioners of apoptosis. Biochem. J. 1997;326:1–16. 26. Colbourne, F., G. R. Sutherland, and R. N. Auer. Electron microscopic evidence against apoptosis as the mechanism of neuronal death in global ischemia. J. Neurosci. 1999;19: 4200–4210. 27. Corsellis, J. A. N., and C. J. Bruton. Neuropathology of status epilepticus in humans. 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;34:129–139. 28. Cuevas, P., C. Revilla, O. Herreras, C. Largo, and G. Gimenez-Gallego. Neuroprotective effect of acidic fibroblast
476
29. 30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
growth factor on seizure-associated brain damage. Neurol. Res. 1994;16:365–369. Dawson, V. L., and T. M. Dawson. Nitric oxide neurotoxicity. J. Chem. Neuroanat. 1996;10:179–190. de Murcia, G., V. Schreiber, M. Molinete, et al. Structure and function of poly(ADP-ribose) polymerase. Mol. Cell Biochem. 1994;138:15–24. Di Mascio, R., R. Marchioli, and G. Tognoni. From pharmacological promises to controlled clinical trials and back: The case of nimodipine in cerebrovascular disorders. Clin. Trials Metaanal. 1994;29:57–79. Diemer, N. H., M. B. Jorgensen, F. F. Johansen, M. Sheardown, and T. Honoré. Protection against ischemic hippocampal CA1 damage in the rat with a new non-NMDA antagonist, NBQX. Acta Neurol. Scand. 1992;86:45–49. Duval, D., N. Roome, C. Gauffeny, J. P. Nowicki, and B. Scatton. SL 82.0715, an NMDA antagonist acting at the polyamine site, does not induce neurotoxic effects on rat cortical neurons. Neurosci. Lett. 1992;137:193–197. Earnshaw, W. C., L. M. Martins, and S. H. Kaufmann. Mammalian caspases: Structure, activation, substrates, and functions during apoptosis. Annu. Rev. Biochem. 1999;68: 383–424. Eliasson, M. J., K. Sampei, A. S. Mandir, et al. Poly(ADPribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat. Med. 1997;3:1089–1095. Enari, M., H. Sakahira, H. Yokoyama, K. Okawa, A. Iwamatsu, and S. Nagata. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 1998;391:43–50. Evans, M. C., 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. Faherty, C. J., S. Xanthoudakis, and R. J. Smeyne. Caspase3-dependent neuronal death in the hippocampus following kainic acid treatment. Mol. Brain Res. 1999;70:159– 163. Fariello, R. G., G. T. Golden, G. G. Smith, and P. F. Reyes. Potentiation of kainic acid epileptogenicity and sparing from neuronal damage by an NMDA receptor antagonist. Epilepsy Res. 1989;3:206–213. Ferrer, I., E. López, R. Blanco, R. Rivera, J. Krupinski, and E. Martí. Differential c-Fos and caspase expression following kainic acid excitotoxicity. Acta. Neuropathol. 2000;99: 245–256. Filipkowski, R. K., M. Hetman, B. Kaminska, and L. Kaczmarek. DNA fragmentation in rat brain after administration of kainate. Neuroreport 1994;5:1538–1540. Fix, A. S., J. W. Horn, K. A. Wightman, et al. Neuronal vacuolization and necrosis induced by the noncompetitive N-methyl--aspartate (NMDA) antagonist MK(+)801 (dizocilpine maleate): A light and electron microscopic evaluation of the rat retrosplenial cortex. Exp. Neurol. 1993;123: 204–215. Fujikawa, D. G. The neuroprotective effect of ketamine administered after status epilepticus onset. Epilepsia 1995;36: 186–195. Fujikawa, D. G. The temporal evolution of neuronal damage from pilocarpine-induced status epilepticus. Brain Res. 1996;725:11–22. Fujikawa, D. G., A. H. Daniels, and J. S. Kim. The competitive NMDA-receptor antagonist CGP 40116 protects
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
against status epilepticus-induced neuronal damage. Epilepsy Res. 1994;17:207–219. Fujikawa, D. G., H. H. Itabashi, A. Wu, and S. S. Shinmei. Status-epilepticus-induced neuronal loss in humans in the absence of systemic complications or epilepsy. Epilepsia 2000;41:981–991. Fujikawa, D. G., X. Ke, R. B. Trinidad, S. S. Shinmei, and A. Wu. Caspase-3 is not activated in seizure-induced neuronal necrosis with internucleosomal DNA cleavage. J. Neurochem. 2002;83:229–240. Fujikawa, D. G., J. S. Kim, A. H. Daniels, and A. F. Alcaraz. Lithium-pilocarpine-induced status epilepticus produces changes in extracellular amino acid concentrations in the rat amygdala. Abstr. Soc. Neurosci. 1993;19:1697. Fujikawa D. G., S. S. Shinmei, and B. Cai. Kainicacid-induced seizures produce necrotic, not apopotic, neurons with internucleosomal DNA cleavage: Implications for programmed cell death mechanisms. Neuroscience 2000;98: 41–53. Fujikawa, D. G., S. S. Shinmei, and B. Cai. Lithiumpilocarpine-induced status epilepticus produces necrotic neurons with internucleosomal DNA fragmentation in adult rats. Eur. J. Neurosci. 1999;11:1605–1614. Gavrielli, Y., Y. Sherman, and S. A. Ben-Sasson. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J. Cell Biol. 1992;119: 493–501. Gill, R., R. J. Hargreaves, and J. A. Kemp. The neuroprotective effect of the glycine site antagonist 3R-(+)-cis-4methyl-HA966 (L-687, 414) in a rat model of focal ischaemia. J. Cereb. Blood Flow Metab. 1995;15:197–204. Gillardon, F., B. Böttinger, B. Schmitz, M. Zimmerman, and K.-A. Hossmann. Activation of CPP-32 protease in hippocampal neurons following ischemia and epilepsy. Mol. Brain Res. 1997;50:16–22. Gillardon, F., H. Wickert, and M. Zimmerman. Upregulation of bax and down-regulation of bcl-2 is associated with kainate-induced apoptosis in mouse brain. Neurosci. Lett. 1995;192:85–88. Gotti, B., J. Benavides, E. MacKenzie, and B. Scatton. The pharmacotherapy of focal cortical ischaemia in the mouse. Brain Res. 1990;522:290–307. Graham, S. H., J. Chen, F. R. Sharp, and R. P. Simon. Limiting ischemic injury by inhibition of excitatory amino acid release. J. Cereb. Blood Flow Metab. 1993;13:88– 97. Hargreaves, R. J., M. Rigby, D. Smith, and R. G. Hill. Lack of effect of L-687,414 [(+)-cis-4-methyl-HA-966), an NMDA receptor antagonist acting at the glycine site, on cerebral glucose metabolism and cortical neuronal morphology. Br. J. Pharmacol. 1993;110:36–42. Henrich-Noack, P., J. H. Prehn, and J. Krieglstein. TGF-b1 protects hippocampal neurons against degeneration caused by transient global ischemia: Dose-response relationship and potential neuroprotective mechanisms. Stroke 1996;27: 1609–1614. Henshall, D. C., T. Araki, C. K. Schindler, S. Shinoda, J. Q. Lan, and R. P. Simon. Expression of death-associated protein kinase and recruitment to the tumor necrosis factor signaling pathway following brief seizures. J. Neurochem. 2003: 1260–1270. Henshall, D. C., J. Chen, and R. P. Simon. Involvement of caspase-3-like protease in the mechanism of cell death
61.
62. 63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
following focally evoked limbic seizures. J. Neurochem. 2000;74:1215–1223. Hetman, M., R. K. Filipkowski, W. Domagala, and L. Kaczmarek. Elevated cathepsin D expression in kainateevoked rat brain neurodegeneration. Exp. Neurol. 1995;136: 53–63. Hollmann, M., and S. Heinemann. Cloned glutamate receptors. Annu. Rev. Neurosci. 1994;17:31–108. 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. Ikonomidou, C., P. Bittigau, M. J. Ishimaru, et al. Ethanolinduced apoptotic neurodegeneration and fetal alcohol syndrome. Science 2000;287:1056–1060. Ikonomidou, C., F. Bosch, M. Miksa, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999;283:70–74. 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. (Berl.) 1988;75:362–369. Kato, K., G. D. Clark, N. G. Bazan, and C. F. Zorumski. Platelet-activating factor as a potential retrograde messenger in CA1 hippocampal long-term potentiation. Nature 1994; 367:175–179. Kelly, M. E., and D. C. McIntyre. Hippocampal kindling protects several structures from neuronal damage resulting from kainic acid–induced status epilepticus. Brain Res. 1994;634: 245–256. Knoblach, S. M., D. A. Alroy, M. Nikolaeva, I. Cernak, B. A. Stoica, and A. I. Faden. Caspase inhibitor z-DEVD-fmk attenuates calpain and necrotic cell death in vitro and after traumatic brain injury. J. Cereb. Blood Flow Metab. 2004;24: 1119–1132. Kondratyev, A., and K. Gale. Intracerebral injection of caspase-3 inhibitor prevents neuronal apoptosis after kainic acid-evoked status epilepticus. Mol. Brain Res. 2000;75: 216–224. Kondratyev, A., N. Sahibzada, and K. Gale. Electroconvulsive shock exposure prevents neuronal apoptosis after kainic acid–evoked status epileptcus. Mol. Brain Res. 2001; 91:1–13. Kondratyev, A., D. Selby, and K. Gale. Status epilepticus leads to the degradation of the endogenous inhibitor of caspase-activated DNase in rats. Neurosci. Lett. 2002;319: 145–148. Leach, M. J., J. H. Swan, D. Eisenthal, M. Dopson, and M. Nobbs. BW619C89, a glutamate release inhibitor, protects against focal cerebral ischemic damage. Stroke 1993;24: 1063–1067. Lee, K. S., S. Frank, P. Vanderklish, A. Arai, and G. Lynch. Inhibition of proteolysis protects hippocampal neurons from ischemia. Proc. Natl. Acad. Sci. U.S.A. 1991;88:7233–7237. Lehmann, A., H. Hagberg, I. Jacobson, and A. Hamberger. Effects of status epilepticus on extracellular amino acids in the hippocampus. Brain Res. 1985;359:147–151. Li, L. Y., X. Luo, and X. Wang. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 2001;412:95–99. Liu, C. L., K. Siesjö, and B. R. Hu. Pathogenesis of hippocampal neuronal death after hypoxia-ischemia changes during brain development. Neuroscience 2004;127:113– 123.
:
477
78. Liu, H., Y. Cao, A. I. Basbaum, A. M. Mazarati, R. Sankar, and C. G. Wasterlain. Resistance to excitotoxin-induced seizures and neuronal death in mice lacking the preprotachykinin A gene. Proc. Natl. Acad. Sci. U.S.A. 1999;96: 12096–12101. 79. Liu, W., X. Bi, G. Tocco, M. Baudry, and S. S. Schreiber. Increased expression of cyclin D1 in the adult rat brain following kainic acid treatment. Neuroreport 1996;7:2785– 2789. 80. Liu, X., P. Li, P. Widlak, et al. The 40-kDa subunit of DNA fragmentation factor induces DNA fragmentation and chromatin condensation during apoptosis. Proc. Natl. Acad. Sci. U.S.A. 1998;95:8461–8466. 81. Liu, X., H. Zou, C. Slaughter, and X. Wang. DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell 1997;89: 175–184. 82. Liu, Z., P. A. D’Amore, M. Mikati, A. Gatt, and G. A. Holmes. Neuroprotective effect of chronic infusion of basic fibroblast growth factor on seizure-associated hippocampal damage. Brain Res. 1993;626:335–338. 83. López, E., E. Pozas, R. Rivera, and I. Ferrer. Bcl-2, Bax and Bcl-x expression following kainic acid administration at convulsant doses in the rat. Neuroscience 1999;91: 1461–1470. 84. Lothman, E. W., and R. C. Collins. Kainic acid induced limbic seizures: Metabolic, behavioral, electroencephalographic and neuropathological correlates. Brain Res. 1981; 218:299–318. 85. MacGregor, D. G., M. J. Higgins, P. A. Jones, et al. Ascorbate attenuates the systemic kainic-induced neurotoxicity in the rat hippocampus. Brain Res. 1996;727:133–144. 86. Martin, D., G. Miller, M. Rosendahl, and D. A. Russell. Potent inhibitory effects of glial derived neurotrophic factor against kainic acid mediated seizures in the rat. Brain Res. 1995;683:172–178. 87. 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. 88. Meldrum, B. S., J. H. Swan, M. J. Leach, et al. Reduction of glutamate release and protection against ischemic brain damage by BW 1003C87. Brain Res. 1992;593:1–6. 89. 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. 90. Mikati, M. A., S. Werner, A. Gatt, et al. Consequences of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor blockade during status epilepticus in the developing brain. Dev. Brain Res. 1999;113:139–142. 91. 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. 92. Miller, B., M. Sarantis, S. F. Traynelis, and D. Attwell. Potentiation of NMDA receptor currents by arachidonic acid. Nature 1992;355:722–725. 93. Morrison, R. S., H. J. Wenzel, Y. Kinoshita, C. A. Robbins, L. A. Donehower, and P. A. Schwartzkroin. Loss of the p53 tumor suppressor gene protects neurons from kainateinduced cell death. J. Neurosci. 1996;16:1337–1345. 94. Nadler, J. V., and G. J. Cuthbertson. Kainic acid neurotoxicity toward hippocampal formation: Dependence on specific excitatory pathways. Brain Res. 1980;195:47–56.
478
95. Narkilahti, S., J. Nissinen, and A. Pitkänen. Administration of caspase 3 inhibitor during and after status epilepticus in rat: Effect on neuronal damage and epileptogenesis. Neuropharmacology 2003;44:1068–1088. 96. Narkilahti, S., T. J. Pirttilä, K. Lukasiuk, J. Tuuanen, and A. Pitkänen. Expression and activation of caspase 3 following status epilepticus in the rat. Eur. J. Neurosci. 2003;18: 1486–1496. 97. Nellgård, B., and T. Wieloch. Postischemic blockade of AMPA but not NMDA receptors mitigates neuronal damage in the rat brain following transient severe cerebral ischemia. J. Cereb. Blood Flow Metab. 1992;12:2–11. 98. Nevander, G., M. Ingvar, R. Auer, and B. Siesjö. Status epilepticus in well-oxygenated rats causes neuronal necrosis. Ann. Neurol. 1985;18:281–290. 99. Nicholls, D., and D. Attwell. The release and uptake of excitatory amino acids. Trends Pharmacol. Sci. 1990;11:462–468. 100. Nicoletti, F., V. Bruno, A. Copani, G. Casabona, and T. Knöpfel. Metabotropic glutamate receptors: A new target for the therapy of neurodegenerative disorders? Trends Neurosci. 1996;19:267–271. 101. Norman, R. M. The neuropathology of status epilepticus. Med. Sci. Law 1964;4:46–51. 102. Olney, J. W. Excitatory transmitters and epilepsy-related brain damage. Int. Rev. Neurobiol. 1985;27:337–362. 103. Olney, J. W. Glutamate-induced neuronal necrosis in the infant mouse hypothalamus. J. Neuropathol. Exp. Neurol. 1971; 30:75–90. 104. 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. 105. Olney, J. W., T. Fuller, and T. de Gubareff. Acute dendrotoxic changes in the hippocampus of kainate-treated rats. Brain Res. 1979;176:91–100. 106. Olney, J. W., O. L. Ho, and V. Rhee. Cytotoxic effects of acidic and sulphur containing amino acids on the infant mouse central nervous system. Exp. Brain Res. 1971;14:61–76. 107. Olney, J. W., J. Labruyere, and M. T. Price. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 1989;244:1360–1362. 108. Olney, J. W., J. Labruyere, G. Wang, D. F. Wozniak, M. T. Price, and M. A. Sesma. NMDA antagonist neurotoxicity: mechanism and prevention. Science 1991;254:1515–1518. 109. Olney, J. W., V. Rhee, and O. L. Ho. Kainic acid: A powerful neurotoxic analogue of glutamate. Brain Res. 1974;77: 507–512. 110. Parrish, J., L. Li, K. Klotz, D. Ledwich, X. Wang, and D. Xue. Mitochondrial endonuclease G is important for apoptosis in C. elegans. Nature 2001;412:90–94. 111. Penix, L. P., and C. G. Wasterlain. Selective protection of neuropeptide containing dentate hilar interneurons by nonNMDA receptor blockade in an animal model of status epilepticus. Brain Res. 1994;644:19–24. 112. Pollard, H., C. Charriaut-Marlangue, S. Cantagrel, et al. Kainate-induced apoptotic cell death in hippocampal neurons. Neuroscience 1994;63:7–18. 113. Prehn, J. H., C. Backhauss, and J. Krieglstein. Transforming growth factor-b1 prevents glutamate neurotoxicity in rat neocortical cultures and protects mouse neocortex from ischemic injury in vivo. J. Cereb. Blood Flow Metab. 1993;13: 521–525.
114. Puig, B., and I. Ferrer. Caspase-3-associated apoptotic cell death in excitotoxic necrosis of the entorhinal cortex following intraperitoneal injection of kainic acid in the rat. Neurosci. Lett. 2002;321:182–186. 115. Rami, A., and J. Krieglstein. Protective effects of calpain inhibitors against neuronal damage caused by cytotoxic hypoxia in vitro and ischemia in vivo. Brain Res. 1993;609: 67–70. 116. Rozman-Pungercar, J., N. Kopitar-Jerala, M. Bogyo, et al. Inhibition of papain-like cysteine proteases and legumain by caspase-specific inhibitors: When reaction mechanism is more important than specificity. Cell Death Differ. 2003;10: 881–888. 117. Sakahira, H., M. Enari, and S. Nagata. Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis. Nature 1998;391:96–99. 118. Sakhi, S., A. Bruce, N. Sun, G. Tocco, M. Baudry, and S. S. Schreiber. p53 induction is associated with neuronal damage in the central nervous system. Proc. Natl. Acad. Sci. U.S.A. 1994;91:7525–7529. 119. Sakhi, S., N. Sun, L. L. Wing, P. Mehta, and S. S. Schreiber. Nuclear accumulation of p53 protein following kainic acid–induced seizures. Neuroreport 1996;7:493–496. 120. Scharfman, H. E., and P. A. Schwartzkroin. Protection of dentate hilar cells from prolonged stimulation by intracellular calcium chelation. Science 1989;246:257–260. 121. Schauwecker, P. E., and O. Steward. Genetic determinants of susceptibility to excitotoxic cell death: Implications for gene targeting approaches. Proc. Natl. Acad. Sci. U.S.A. 1997;94: 4103–4108. 122. Schreiber, S. S., G. Tocco, I. Najm, R. F. Thompson, and M. Baudry. Cycloheximide prevents kainate-induced neuronal death and c-fos expression in adult rat brain. J. Mol. Neurosci. 1993;4:149–159. 123. Schulz, J. B., and M. F. Beal. Neuroprotective effects of free radical scavengers and energy depletion in animal models of neurodegenerative disease. Ann. N. Y. Acad. Sci. 1995;765: 100–110. 124. Schwartz, L. M., and C. E. Milligan. Cold thoughts of death: The role of ICE proteases in neuronal cell death. Trends Neurosci. 1996;19:555–562. 125. Schwob, J. E., T. E. 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. 126. Sheardown, M. J., O. Nielsen, A. J. Hansen, P. Jacobsen, and T. Honoré. 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(f ) quinoxaline: A neuroprotectant for cerebral ischemia. Science 1990;247:571–574. 127. 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. 128. 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. 129. 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. 130. Small, D. L., R. Monette, G. Mealing, A. M. Buchan, and P. Morley. Neuroprotective effects of w-Aga-IVA against in vitro
131.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
ischaemia in the rat hippocampal slice. Neuroreport 1995;6: 1617–1620. 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. Sun, D., D. Kintner, J. H. Fitzpatrick, et al. The effect of a free radical scavenger and platelet-activating factor antagonist on FFA accumulation in post-ischemic canine brain. Neurochem. Res. 1994;19:525–528. Susin, S. A., H. K. Lorenzo, N. Zamzami, et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 1999;397:441–446. Takahashi, K., J. H. Greenberg, P. Jackson, K. Macklin, and J. Zhang. Neuroprotective effects of inhibiting poly(ADPribose) synthetase on focal cerebral ischemia in rats. J. Cereb. Blood Flow Metab. 1997;17:1137–1142. Takahashi, K., A. A. Pieper, S. E. Croul, J. Zhang, S. H. Snyder, and J. H. Greenberg. Post-treatment with an inhibitor of poly(ADP-ribose) polymerase attenuates cerebral damage in focal ischemia. Brain Res. 1999;829:46–54. Takano, J., M. Tomioka, S. Tsubuki, et al. Calpain mediates excitotoxic DNA fragmentation via mitochondrial pathways in adult brains: Evidence from calpastatin-mutant mice. J. Biol. Chem. 2005;280:16715–16784. Takizawa, S., K. Matsushima, H. Fujita, K. Nanri, S. Ogawa, and Y. Shinohara. A selective N-type calcium channel antagonist reduces extracellular glutamate release and infarct volume in focal cerebral ischemia. J. Cereb. Blood Flow Metab. 1995;15:611–618. Tan, Z., R. Sankar, W. Tu, et al. Immunohistochemical study of p53-associated proteins in rat brain following lithium-pilocarpine status epilepticus. Brain Res. 2002;929: 129–138. Tanaka, K., S. H. Graham, and R. P. Simon. The role of excitatory neurotransmitters in seizure-induced neuronal injury in rats. Brain Res. 1996;737:59–63. Timsit, S., S. Rivera, P. Ouaghi, et al. Increased cyclin D1 in vulnerable brain regions in the hippocampus after ischaemia and epilepsy: A modulator of in vivo programmed cell death? Eur. J. Neurosci. 1999;11;263–278. Tsukada, T., M. Watanabe, and T. Yamashima. Implications of CAD and DNase II in ischemic neuronal necrosis specific for the primate hippocampus. J. Neurochem. 2001;79: 1196–1206. Turski, W. A., E. A. Cavalheiro, M. Schwarz, S. J. Czuczwar, Z. Kleinrok, and L. Turski. Limbic seizures produced by pilocarpine in rats: Behavioural, electroencephalographic and neuropathological study. Behav. Brain Res. 1983;9:315–335. Tuunanen, J., K. Lukasiuk, T. Halonen, and A. Pitkänen. Status epilepticus-induced neuronal damage in the rat amygdaloid complex: Distribution, time-course and mechanisms. Neuroscience 1999;94:473–495. Tymianski, M., I. Spigelman, L. Zhang, et al. Mechanism of action and persistence of neuroprotection by cell-permeant Ca2+ chelators. J. Cereb. Blood Flow Metab. 1994;14:911– 923. Ueda, Y., H. Yokoyama, R. Niwa, R. Konaka, H. OhyaNishiguchi, and H. Kamada. Generation of lipid radicals in the hippocampal extracellular space during kainic acid–induced seizures in rats. Epilepsy Res. 1997;26:329–333. Umemura, A., H. Mabe, H. Nagal, and F. Sugino. Action of phospholipases A2 and C on free fatty acid release during
:
479
147.
148.
149.
150.
151.
152.
153. 154.
155.
156.
157.
158.
159.
480
complete ischemia in rat neocortex. J. Neurosurg. 1992;76: 648–651. Valentino, K., R. Newcomb, T. Gadbois, et al. A selective N-type calcium-channel antagonist protects against neuronal loss after global cerebral ischemia. Proc. Natl. Acad. Sci. U.S.A. 1993;90:7894–7897. van Lookeren Campagne, M., and R. Gill. Ultrastructural morphological changes are not characteristic of apoptotic cell death following focal cerebral ischemia in the rat. Neurosci. Lett. 1996;213:111–114. 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. Warner, D. S., H. Martin, P. Ludwig, A. McAllister, J. F. Keana, and E. Weber. In vivo models of cerebral ischemia: Effects of parenterally administered NMDA receptor glycine site antagonists. J. Cereb. Blood Flow Metab. 1995;15: 188–196. Wyllie, A. H. Cell death: A new classification separating apoptosis from necrosis. In I. D. Bowen, and R. A. Lockshin, eds. Cell Death in Biology and Pathology. London: Chapman and Hall, 1981:9–34. Wyllie, A. H. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 1980;284:555–556. Wyllie, A. H., J. F. R. Kerr, and A. R. Currie. Cell death: The significance of apoptosis. Int. Rev. Cytol. 1980;68:251–306. Yamada, K., T. Teraoka, S. Morita, T. Hasegawa, and T. Nabeshima. w-conotoxin GVIA protects against ischemiainduced neuronal death in the Mongolian gerbil but not against quinolinic acid–induced neurotoxicity in the rat. Neuropharmacology 1994;33:251–254. Yamashima, T., Y. Kohda, K. Tsuchiya, et al. Inhibition of ischaemic hippocampal neuronal death in primates with cathepsin B inhibitor CA-074: A novel strategy for neuroprotection based on “calpain-cathepsin hypothesis.” Eur. J. Neurosci. 1998;10:1723–1733. Yamashima, T., T. Saido, M. Takita, A. Mityazawa, J. Yamano, A. Miyakawa, et al. Transient brain ischemia provokes Ca2+ PIP2 and calpain responses prior to delayed neuronal death in monkeys. Eur. J. Neurosci. 1996;8:1932– 1944. 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. Yu, S.-W., H. Wang, M. F. Poitras, et al. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 2002;297:259–263. Zhang, J., V. L. Dawson, T. M. Dawson, and S. H. Snyder. Nitric oxide activation of poly(ADP-ribose) synthetase in neurotoxicity. Science 1994;265:722–723.
37
Generalized Convulsive Status Epilepticus: Principles of Treatment
.
Introduction Generalized convulsive status epilepticus (GCSE) is a medical emergency (2, 18, 20). Rapid and effective treatment decreases brain injury and death (1, 2, 18, 20, 31, 32, 34). Delays in treatment increase morbidity and mortality and contribute to drug resistance (1, 2, 31, 32, 34). Exciting developments herald a new era in treatment: a new definition of SE, rectal diazepam for home, clinic, and institutional use, prehospital benzodiazepine infusion by paramedics, fosphenytoin as an alternative to phenytoin, and the growing use of alternative agents such as midazolam and propofol for refractory SE. This chapter reviews these new developments and relates the basic principles of treatment to the actual provision of care.
Treatment considerations and the environment of care Ideally, SE should be treated in a monitored environment in an emergency department (ED), intensive care unit (ICU), or monitored inpatient setting, or if in the field by trained paramedics (17). Because of the risk of hypotension, respiratory depression, and metabolic acidosis, pulse oximetry, electrocardiographic (ECG) monitoring, serial blood pressure monitoring, supplemental oxygen, intravenous (IV) access, and ready access to intubation equipment and cardiac resuscitation are essential. If physicians or caretakers find themselves without adequate support, the facility’s emergency medical system (EMS), frequently designated as “code blue,” should be activated. Before any anticonvulsants are infused, the basic elements of care for any critically ill patient must be implemented. Immediate attention should be given to the airway, breathing, and vital signs. Oxygen should be provided by nasal cannula or mask, and a reliable high-flow IV line with normal saline should be established. The patient should be in a monitored bed, with blood pressure monitoring performed every 5–10 minutes and continuous ECG recording. Pulse oximetry is recommended to monitor for desaturation and hypoxemia. Glucose levels should be checked to rule
out hypoglycemia. If the glucose level is low (<60 mg/dL), 50 mL of D50 (50% dextrose) should be infused, with 100 mg of thiamine IV or IM (17, 47, 50, 66). Treatment should not be delayed. The history, a focused physical examination, and laboratory studies should be completed rapidly. IV therapy must be started within 5–10 minutes of the onset of SE. Quick onset of action is the premier criterion for a drug, but not the only one. Safety, ease of use, and duration of effect are important considerations. The effect of a single dose should last long enough to allow a smooth transition to maintenance therapy. Chronic maintenance therapy can be instituted later, within 24 hours, and need not duplicate acute treatment. For example, phenytoin or phenobarbital may be infused as an IV bolus, but there is no evidence that maintenance therapy with either drug must be used. New practice guidelines are encouraging the use of safer agents, such as oxcarbazepine, gabapentin, topiramate, or zonisamide. These agents can be initiated once the patient’s condition has stabilized (22).
Prehospital care R D Since the Food and Drug Administration approved rectal diazepam for use in 1997, this application has revolutionized the treatment of acute repetitive seizures (8, 9, 37). For the first time, families and caregivers in residential facilities can safely intervene to terminate acute clusters of seizures and reduce ED visits. The full impact of this relatively new treatment has yet to be determined, but evidence is growing that ED visits, hospitalizations, and hospital costs may be substantially reduced with its use (9, 10, 13). Rectal diazepam is rapidly absorbed, with a bioavailability of 90%. Levels peak within 3–30 minutes, and effective antiepileptic drug (AED) levels of >200 ng/mL are achieved within 15 minutes. Although IV diazepam peaks more rapidly, levels drop to less than 200 ng/mL within 2 hours. In contrast, rectal diazepam levels stay above 200 ng/mL for
:
481
at least 8 hours (12). Clinically, this translates into sustained efficacy. Two pivotal, double-blind studies have confirmed the safety and efficacy of rectal diazepam in adults and in children (9, 10). The time to the next seizure was significantly prolonged in diazepam-treated patients compared with placebo-treated controls. Seizure frequency 15 minutes after administration was significantly reduced in the rectal diazepam-treated group: 71% remained seizure-free for 12 hours, compared with only 28% of the placebo-treated patients (9, 10). When used to treat SE in a long-term care facility, rectal diazepam successfully terminated seizures in 83% within 10 minutes (13). On retrospective review, nursing personnel were more successful in delivering rectal diazepam than in delivering IV lorazepam (13). The results of the two double-blind studies support a more widespread use of rectal diazepam (9, 10). Home treatment with rectal diazepam should lead to a reduction in the risk for brain injury and respiratory failure from subsequent SE and should reduce the frequency and cost of hospitalizations. Patients who are at risk for clusters of seizures or who have a history of SE in the past should be offered rectal diazepam by physicians early (47). Table 37.1 summarizes the doses of rectal diazepam for use in children and adults. EMS/P-I T Because a delay in initiating treatment increases the morbidity and mortality from SE, there has been a move toward prehospital intervention (1, 2, 50). If treatment cannot be initiated at home, evidence now supports the administration of IV lorazepam or diazepam by EMS personnel prior to the patient’s arrival in the ED (1). In a randomized, double-blind comparison, lorazepam and diazepam were each superior to placebo for out-of-hospital treatment of SE (1). Of 205 patients who were studied prospectively, 66 received lorazepam, 2 mg, 68 received diazepam, 5 mg, and 71 received placebo (1). Lorazepam successfully terminated SE upon arrival in the ED in 59% of those so treated, diazepam was successful in
T 37.1 Rectal diazepam doses for use in children and adults Age 2–5 Years (0.5 mg/kg)
Age 6–11 Years (0.3 mg/kg)
Age ≥12 Years (0.2 mg/kg)
Weight (kg)
Dose (mg)
Weight (kg)
Dose (mg)
Weight (kg)
Dose (mg)
6–11 12–22 23–33 34–44
5 10 15 20
10–18 19–37 38–55 56–74
5 10 15 20
14–27 28–50 51–75 76–111
5 10 15 20
482
43%, and placebo terminated SE in 21% on arrival in the ED. Lorazepam was statistically superior to diazepam or placebo. Respiratory depression and hypotension occurred less often in those pretreated with lorazepam or diazepam: 10% of patients who received lorazepam or diazepam, compared with 20% for placebo (1). This study strongly supports the prehospital use of lorazepam or diazepam, which is now included in treatment protocols (48).
Initiating treatment D C The administration of inadequate doses of medication, typically diazepam, lorazepam, or phenytoin, is a common error (8). Subtherapeutic levels, a result of inadequate dosing, are associated with treatment failure. In a hospital-based study conducted in Olmstead County, Minnesota, between 1965 and 1984, 76% of patients received inadequate dosages for initial treatment. Interestingly, despite increasing recognition of SE as a medical emergency, the rate of inadequate dosing did not improve over 20 years (8). Inadequate dosing is driven by physician fears of respiratory depression and hypotension. However, the risk of clinically significant hypotension and respiratory depression is not excessive. Only 12% of patients treated in the Veterans Affairs Status Epilepticus Cooperative Study with full loading doses of either phenobarbital, phenytoin, lorazepam, or a combination of diazepam-phenytoin experienced hypoventilation. Many did not require intubation; simply reducing the rate of infusion resulted in the resumption of normal ventilatory effort before intubation was accomplished. Contrary to common perceptions, the incidence of respiratory depression was no higher with benzodiazepines or phenobarbital than with phenytoin alone (56). Similarly, hypotension was also relatively uncommon. Respiratory depression and hypotension do occur, but the dangers of inadequate treatment of the seizures outweigh the risks of complications from drug infusion in most cases. Confusion about the definition of SE also contributes to delays in drug administration (31, 65, 66). Early guidelines recommended waiting for 30 minutes before initiating treatment, or withholding an initial dose of a benzodiazepine if convulsions were not present at the moment, and proceeding with phenytoin or phenobarbital loading (66). This practice should be abandoned. There is now a consensus that SE should be treated aggressively at 5–10 minutes of continuous seizure activity, a significant departure from the standard of practice just a few years ago (32, 57, 66). I T H: C C T Until the pivotal VA cooperative study, few wellcontrolled clinical trials of treatments for SE had been conducted. Urgency, blinding, and informed consent issues
create barriers. The investigators in the VA SE study addressed the consent issue by arguing that any of the four treatment arms were considered the standard of care; obtaining consent before the administration of one of the study drugs was not considered reasonable or prudent, given that SE is a medical emergency (56). In 1983, Leppik et al. reported the first randomized, double-blind trial of IV lorazepam compared with diazepam as initial treatment in 78 subjects (29). Subjects were randomly assigned to receive 4 mg of lorazepam or 10 mg of diazepam. Lorazepam was successful in terminating SE in 89% of subjects, versus 76% for diazepam. This difference was not significant. The time to stop SE was the same for the two drugs. The study nevertheless established that lorazepam was at least equivalent to diazepam, and lorazepam rapidly became a treatment of choice nationwide. Shortly thereafter, in 1985, Treiman et al. reported a prospective study of 87 subjects in SE who were randomly assigned to lorazepam, 0.1 mg/kg, or phenytoin, 18 mg/kg (56). As second-line therapy, subjects in whom the initial drug failed were crossed over to the other. As an initial therapy, lorazepam was superior to phenytoin in terminating all electrical or clinical seizures (80% vs. 56%). Treiman et al. also found that phenytoin failures were correlated with insufficient loads and low peak levels: seizures were more successfully controlled at phenytoin levels above 20 mg/mL than at levels less than 20 mg/mL (56). The paucity of randomized controlled trials and variations in physician preferences led to regional differences in what was considered the drug of first choice for SE. At some centers, diazepam plus phenytoin was the therapy of choice, whereas at others, phenobarbital, phenytoin, or lorazepam was used alone or in combination. At many pediatric centers, phenobarbital has been a drug of first choice. In a prospective trial of 36 patients, Shaner et al. compared phenobarbital and a combination of diazepam and phenytoin. In this small sample, the time to stop SE was shorter for phenobarbital, and the safety (rates of respiratory depression and hypotension) was similar. The small sample size prevented the study from achieving significance, yet the study confirmed what many pediatric neurologists had long believed: for them, phenobarbital was the drug of choice (46). T VA C S In 1998, the VA Cooperative Study Group reported the results of the largest and bestcontrolled multicenter trial to date, a randomized, double-blind comparison of four commonly used treatments for SE (57). This study enrolled 384 subjects with overt convulsive SE. The primary outcome variable was successful termination of clinical or electrographic status within 20 minutes of the start of the infusion and with no recurrence after 60 minutes. Lorazepam was superior to phenytoin in successfully terminating SE, confirming the original
lorazepam versus phenytoin study (56). However, lorazepam, phenobarbital, and diazepam-phenytoin were equally successful, indicating that all except phenytoin alone are acceptable initial therapies. All drug treatments were associated with similar risks of hypotension and respiratory depression (57). I T: U C S Because of the scarcity of controlled and blinded trials, it is necessary to take into account several open-label or uncontrolled treatments. For the most part, these series are supportive of conclusions reached in the few controlled trials. Table 37.2 summarizes key drugs for both initial treatment and for refractory SE. Phenobarbital was introduced for the treatment of epilepsy in 1912 but did not come into general use for SE until the 1940s. Although it has since been widely used, few quantitative data on its efficacy have been available until recently (57). Intravenous phenytoin has been used since the 1950s. Wallis et al. in 1968 described a series of 33 patients with acute seizures who were treated with IV phenytoin (60). This seminal report seems to be the origin of the 1,000 mg loading dose and 50 mg/min infusion rate recommendation often used in practice. However, recent evidence from the VA cooperative study supports the use of higher doses, currently 20 mg/kg of phenytoin or fosphenytoin (57). Rates of 50 mg/min for phenytoin have been challenged, and lower rates of infusion based on body weight are recommended (0.3 mg/kg/min) (17, 62). Diazepam has been used and approved for the initial treatment of SE for more than 30 years (40, 42). It is highly lipid soluble and rapidly peaks to effective AED levels within minutes of infusion (12). Concerns about its use as a single agent were expressed early, because of the frequent recurrence of seizures after 10–20 minutes and because only 50% of patients remained seizure-free for 2 hours after a single injection (42). For this reason, coadministration with phenytoin has often been recommended, a fact evidenced by the VA cooperative study (57). Lorazepam has been available in the United States since 1977. In an open-label study, lorazepam controlled SE in 22 of 25 patients, an unusually high rate of success for any case series (59). The initial dose of 4 mg was followed by another 4 mg if seizures persisted longer than 15 minutes. Sixteen of 25 patients remained seizure-free without additional drugs for at least 48 hours, an early indication that lorazepam exerted a more lasting effect than diazepam (59). In a retrospective study of 77 children and young adults, the first dose of lorazepam was successful in 79% (15). Repeated doses were progressively less likely to succeed, which the investigators aptly named tachyphylaxis, a fact now widely recognized and confirmed in an animal model (15, 61).
:
483
T 37.2 Commonly used drugs for status epilepticus Lorazepam Adult dose
0.1 mg/kg
Phenytoin 18–20 mg/kg
Phenobarbital
Midazolam
Propofol
Pentobarbital
15 mg/kg (10–20 mg/kg)
0.2 mg/kg by slow IV push, followed by 1–2 mg/kg/min for 12–24 hr Monitor with continuous EEG and blood pressure monitoring in ICU setting See above
1–2 mg/kg by slow IV push, followed by 1–5 mg/kg/hr for 12–24 hr Monitor with continuous EEG and blood pressure monitoring in ICU setting See above
10–15 mg/kg over 1 hr, followed by 0.5–1 mg/kg/hr for 12–24 hr
Frequent and severe, when doses are >5 mg/kg/hr or for long durations Frequent
Frequent and severe
26% (VA cooperative study data)
<50 mg/min (reduce for elderly, those with liver disease, or the critically ill, to 0.3 mg/kg/min) 27% (VA cooperative study data)
34% (VA cooperative study data)
Infrequent
<20% (VA cooperative study data)
<20% (VA cooperative study data)
<20% (VA cooperative study data)
Frequent
Maximum infusion rate
2 mg/min
Hypotension
Respiratory depression
50–100 mg/min
In a prospective study, children arriving in an ED with SE on odd days were assigned to treatment with diazepam, 0.3–0.4 mg/kg; those arriving on even days were assigned to lorazepam, 0.05–0.1 mg/kg. Convulsions were stopped in 70% of the 27 lorazepam-treated patients and in 65% of the diazepam-treated patients. Recurrence rates tended to be lower with lorazepam (4).
Adverse effects of drugs H Respiratory failure or arrest is a principal concern but fortunately is relatively uncommon with standard dosages of benzodiazepines or phenobarbital. Hypoventilation, defined as requiring a change in therapy but not necessarily intubation, ranged from 10.3% for lorazepam to 13.2% for phenobarbital and 16.8% for diazepam-phenytoin, but it was also 9.9% for phenytoin alone. These rates were not significantly different (57). Nevertheless, respiratory rate, effort, and pulse oximetry should be monitored at least every 5 minutes during IV therapy. Respiratory depression manifests with a slowing of the rate and a lightening of the depth of chest excur-
484
Monitor with continuous EEG and blood pressure monitoring in ICU setting See above
Frequent
sions rather than with sudden apnea. At this point the infusion should be stopped and preparations should be made to intubate. Manual ventilation can be employed until preparations to intubate are complete. Sometimes the respiratory drive will recover quickly and the intubation can be stayed, with the infusion then resumed more slowly. H Hypotension occurs frequently in subjects in SE. Hypotension occurred in 26%–34% of patients with overt SE in the VA cooperative study (57). No differences in the rate of clinically significant hypotension were noted between any of the four treatments (the number of patients with blood pressure <100 or 90 mm Hg systolic and the number of patients needing pressor agents were not described). In contrast, patients who received IV phenytoin or fosphenytoin in EDs for various reasons—new-onset seizure, prophylaxis, withdrawal, SE—have lower rates of hypotension, 5%–6.5% (5, 14). The difference is likely due to how hypotension is defined, the doses used, and the medical condition of the subjects. Hypotension is more common with higher doses and in patients with abnormal neurologic findings on examination (5). When loading doses
of phenytoin and fosphenytoin were compared in ED patients, the rates of clinically significant hypotension were low (0%–0.5%) (14). Hypotension frequently occurred in a prehospital study of subjects with SE who had received only placebo, which indicates that SE itself may cause hypotension, independent of drugs (1). Often, stopping the infusion, placing the patient in a head-down position, and administering a bolus of normal saline are effective measures for managing hypotension. In the VA study, pressor agents were usually unecessary for patients with overt convulsive SE but were routinely used for patients with subtle SE (unpublished data, D. M. Treiman et al., 1989). C A Phenytoin and fosphenytoin are sodium channel blockers and class 1b anti-arrhythmics, and can cause changes in the PR and QRS intervals and ventricular arrythmias (3, 5, 40). Serious ventricular arrhythmias are rare; they occurred in one child of 22 loaded with phenytoin at 18–20 mg/kg and in none of 164 patients loaded with relatively low doses (average, 537–787 mg total) (3, 5). The incidence of rhythm disturbance in the VA cooperative study was 6.9% for phenytoin alone, not significantly different from the rate with the three other treatments (57). P T N Intravenous phenytoin, because of its high pH, is caustic to veins and tissue. Pain at the infusion site is common, and local phlebitis occurred in 8 of 12 subjects in one series (27). Burning during infusion occurred in 9% of ED patients receiving phenytoin but in only 0.5% in those who received fosphenytoin (14). Tissue necrosis from extravasation can occur. The “purple glove” syndrome is a rare but serious consequence, reported in three of 179 patients in one series (7, 37). Equivalent doses of fosphenytoin are clearly associated with a lower risk of phlebitis because of the drug’s neutral pH (6, 14, 27).
Treatment sequences and protocols Treatment protocols vary among individuals and institutions. Several protocols have been published, and the data indicate that lorazepam, phenobarbital, and diazepam-phenytoin combinations are acceptable initial treatements. The sequence of benzodiazepine, phenytoin, and phenobarbital was recommended by the Epilepsy Foundation Working Group (66). However, in the VA study, regardless of the order of drugs used, the second and third drug treatments had a combined success rate of only 9.3%. In this study, the next step was usually general anesthesia (typically IV pentobarbital, midazolam, or propofol), which terminated SE in an additional 23.2% of patients (57). This finding has prompted recommendations to move more aggressively toward treatments previously reserved for refractory cases, skipping the phenobarbital and possibly the phenytoin step (48). There
are certainly circumstances under which a rigid sequence needs to be altered and therapy tailored to an individual patient (33). Some patients are allergic to hydantoins or barbiturates. Phenytoin or fosphenytoin are more likely to cause hypotension in the elderly and in patients with heart or liver disease. Nevertheless, the greatest problem of treatment is not that protocols are too closely followed, but that too often no protocol is followed at all. Therefore, we advocate the use of a highly structured and well-publicized protocol for a particular hospital, with recognition that it may need violating for the occasional good reason. F- T I I T F Status is terminated with initial treatment in most patients. Success rates range from 80%–89% in early studies with lorazepam as initial therapy to 65% in the VA cooperative study (29, 56, 57). The lower rates in the VA cooperative study are due to a more rigorous definition of success: the termination of all clinical and electrical seizure activity within 20 minutes after the infusion (57). Thus, in 20%–35% of patients, initial therapy will fail. Failure of the seizures to respond to initial treatment was associated with poorer outcome, indicating that treatment-refractory SE may need to be defined as SE that does not respond to initial therapy rather than SE that does not respond to two or three drugs, as commonly viewed (57). There is insufficient evidence defining the best second drug if initial therapy fails. Data from the original lorazepam-phenytoin comparison in 1985 indicated that more than 90% of subjects in whom lorazepam fails will respond to phenytoin as the second agent (56). In light of these findings, fosphenytoin or phenytoin is an attractive second choice if further treatment is necessary. They are less likely to produce prolonged sedation than phenobarbital. Elderly patients and those with cardiac disease or hepatic failure are less likely to tolerate loading with phenytoin or fosphenytoin. If the patient is allergic to phenytoin, IV valproate may be used. Although there are no controlled studies of valproate in SE, three case series suggest efficacy (24, 49, 63). Phenobarbital should, in most cases, be skipped as a second or third drug, for the following reasons: as a second drug after a benzodiazepine, the risk of respiratory suppression may be greater, and, like all third drugs, it is unlikely to work. It is more appropriate as a first drug in a situation in which benzodiazepine use is contraindicated or not available. T T D: G A The third drug should be a general anesthetic, given the low rate of success with standard third-line drugs (57). Of course, intubation must precede anesthetic drug dosing. If intubation cannot for any reason be accomplished forthwith, valproate may be administered or an additional 5 mg/kg of fosphenytoin or phenytoin can be given.
:
485
T 37.3 Recommended algorithm for the treatment of generalized convulsive status Treatment Protocol for Generalized Convulsive Status Epilepticus in Adults Time (min) 0 5
Establish a diagnosis of SE (2 or more convulsions without recovery of consciousness, or continuous clinical or electrical seizures lasting longer than 5 min). 1. Initiate monitoring with EEG, pulse oximetry, O2 by nasal cannula/face mask. 2. Intravenous catheter with normal saline. Call code blue if appropriate. 3. Check blood glucose by finger stick. If hypoglycemia, give thiamine, 100 mg IV or IM, and dextrose, 50 mL of 50% dextrose solution.
10
Lorazepam, 0.5–0.1 mg/kg IV push, no faster than 2 mg/min.
25
If status continues: Fosphenytoin, 18–20 mg/kg at 50–150 phenytoin equivalents mg/min. or Phenytoin, 18–20 mg/kg at 0.3 mg/kg/min (e.g., 25 mg/min for an 80-kg adult). Carefully monitor blood pressure every 5–10 min for at least 1 hr after infusion.
60
1. Intubate and ventilate. 2. Monitor temperature and keep £37°. 3. If neuromuscular blockade needed, consider vecuronium, 0.1 mg/kg, and infuse one of the following as the third agent: • Midazolam, 0.2 mg/kg by slow IV push, followed by 1–2 mg/kg/min for 12–24 hr. Monitor with continuous EEG and blood pressure monitoring in ICU setting. • Propofol, 1 mg/kg over 5 min, then 1–5 mg/kg/hr; attempt to taper after 12–24 hr. Watch for hypotension and the propofol infusion syndrome. Monitor with continuous EEG and blood pressure monitoring in ICU setting. • Phenobarbital, 15–20 mg/kg at <100 mg/min. • Pentobarbital, 5–15 mg/kg over 1 hr, then 0.5–5 mg/kg/hr; monitor blood pressure by central line, pressors on standby. Prepare for significant hypotension. Monitor with continuous EEG and blood pressure monitoring in ICU setting.
S P Table 37.3 is a suggested protocol for overt GCSE, based on the results of clinical trials and other published experience. This protocol employs lorazepam, 0.1 mg/kg, as the initial agent, followed if necessary by fosphenytoin, then followed if necessary by one of several agents used in anesthetic dosages. This simple three-level procedure can be implemented within 60 minutes if necessary. Although data on the efficacy of this specific sequence are not available, adding efficacy figures from initial lorazepam, a second drug, and a general anesthetic agent from the VA SE study would suggest a total efficacy of above 90%. Similar protocols have been recommended by multiple authors (17, 31, 48, 50). Some authors suggest an initial dose of only 4 mg of lorazepam, followed by an additional dose if seizures do not stop (42, 46). Smith suggests variations from this general scheme in certain scenarios (50). For example, he advocates proceeding directly to anesthetic agents such as midazolam, propofol, or pentobarbital if SE has endured more than 60 minutes and
486
an initial benzodiazepine dose has failed. This approach is consistent with the fact that intractability occurs early and outcomes are poorer in subjects in whom initial therapy fails. In an effort to reduce delays entailed in infusing phenytoin or phenobarbital as a second drug, Tasker outlined a benzodiazepine-only protocol, beginning with prehospital rectal diazepam, then IV lorazepam, then midazolam as a 0.15 mg/kg IV bolus, followed by midazolam given as a continuous infusion (52). One might worry that a protocol relying exclusively on these drugs could encounter earlier problems with tachyphylaxis, but that is unknown (15). Tasker does suggest that phenobarbital would be a superior choice to lorazepam in patients already on chronic benzodiazepines (52). Repeated doses of benzodiazepines should be avoided because of accumulation of these lipid-soluble drugs in body fat stores, with cumulative effects on alertness or respiration, as well as the likely development of tachyphylaxis.
Continuing care V C After successful control of seizures, attention turns to diagnosis and maintenance therapy. However, a central question that must be answered is, are the seizures really controlled? Generalized tonic-clonic SE may be converted into subtle “nonconvulsive” status or complex partial status by partially effective treatment, or may proceed into that state after a prolonged duration (56, 57). The cessation of convulsions can engender a false sense of relief in the treatment team. Electroencephalography (EEG) is the only definitive way to know whether seizures have been completely controlled, and the study should be done right away if the patient does not awaken within a reasonable length of time after visible seizures cease (54, 57). This time may vary with the duration and number of convulsions and the medications used, but if verbal responsiveness is not present within 1 hour after the last convulsion, continued seizures should be suspected. In this case and in all cases in which altered consciousness persists after initial treatment, continuous EEG monitoring should be performed. T M T Maintenance AED therapy should be established in effective dosages before the effect of the initial treatment wanes. Because lorazepam and phenytoin/fosphenytoin provide control for at least 12–24 hours, the initiation of maintenance therapy can wait until the patient is stable. Only 12.1% of patients experienced a recurrence of seizures within 12 hours after treatment with any of the four regimens used in the VA SE study, including lorazepam alone (57). Therefore, there is time to consider the best drug for continued use; this will often be something other than phenytoin. Patients treated with continuous midazolam or propofol infusions also need to have adequate levels of a maintenance drug established before the infusion is stopped.
Prevention of recurrence Patients with epilepsy who sustain an episode of SE are at risk for SE in the future. They and their families should be instructed in how to recognize SE and how to use rectal diazepam. Patients should be educated about compliance. Physicians should avoid rapid tapering of medications, which could precipitate SE in at-risk individuals.
Refractory SE Refractory status has traditionally been defined as failure to control all clinical and electrographic seizures after two or three drugs, usually after one hour (11, 33). Overt GCSE is successfully treated in 65%–80% of patients with initial
treatment, indicating that 20%–35% of subjects are at risk for refractory status (33, 45, 51, 57). In one retrospective study, 30% of patients with overt GCSE did not have convulsions controlled by two or more agents and met the above criteria for refractory status (33). Refractory SE is associated with a high mortality, prolonged hospitalization, and poorer functional status on discharge in survivors (33). In a recent literature review, 48 (25%) of 193 patients described with refractory SE, and in whom two or more agents failed, died (11). The mortality was highest in the elderly, those with long durations of status (24 hours vs. 12 hours), and those with acute symptomatic causes of SE (11). The treatment of choice after initial therapy has failed varies from center to center. A recent survey of European epileptologists and critical care physicians confirmed interphysician variability, which likely reflects a lack of randomized clinical trials and evidencebased medicine in the treatment of refractory SE. Some 58% reported using barbiturates as the anesthetic of choice after initial treatment had failed, 29% preferred propofol, and 13% preferred midazolam (25). The following discussion reviews the commonly used treatments for refractory SE. Table 37.2 summarizes the initial dose and infusion rates for agents used for refractory SE. P/T R SE Pentobarbital is a reliable and definitive treatment for refractory SE. It has a rapid onset and usually terminates SE within seconds to minutes (11, 17, 30, 43). The half-life of pentobarbital is shorter with short-duration infusions but increases with prolonged use, varying between 15 and 50 hours (17, 40). In 1987, Rashkin et al. found pentobarbital extremely effective but noted frequent severe side effects, including severe hypotension requiring pressors. They emphasized the need to initiate pentobarbital within 2 hours of refractory SE (43). In a small, nonrandomized comparison of thiopental and midazolam in children, there was no difference in efficacy (30). Respiratory complications were less frequent in the midazolam-treated group (30). Pentobarbital is usually administered as a bolus of 5– 15 mg/kg infused slowly over 1 hour to avoid hypotension, followed by 0.5–1 mg/kg/hr (17). Severe hypotension, respiratory depression, hypothermia, and prolonged mechanical ventilation due to difficulty weaning are common complications (11, 17, 43). In a recent meta-analysis of refractory SE treated with pentobarbital, midazolam, or propofol, pentobarbital was less likely to fail (8% vs. 23%) than the other agents. However, hypotension (systolic blood pressure <100 mm Hg) was significantly more likely with pentobarbital (77% vs. 34%) than with the other agents (11).
:
487
M R SE Midazolam is an ultrashort-acting benzodiazepine, with a half-life in healthy individuals of 1.8–6.4 hours and a mean half-life of 3 hours. Midazolam is hydroxylated in the liver primarily to a 1hydroxy-midazolam, via cytochrome CYP-3A. The kidneys then excrete the hydroxylated metabolite as a glucuronide. Diltiazem, verapamil, erythromycin, cimetidine, keto- and itraconazole, and potentially other enzyme inhibitors cause increases in plasma levels of midazolam due to inhibition of CYP-3A. When the dosage of midazolam is increased from 0.15 mg/kg to 0.45–0.6 mg/kg, the clearance is reduced, indicating nonlinear kinetics and a longer half-life at higher doses. Continuous infusions of midazolam also result in accumulation. Renal and hepatic failure result in substantial accumulation of the drug, reduced clearance, and a longer half-life. The use of midazolam in renal failure usually results in an increase in half-life of the parent drug to 13 hours when continuously infused at 5–15 mg/hr. In patients with hepatic failure or cirrhosis, the elimination half-life of midazolam is also increased twofold (40). The efficacy of midazolam for refractory SE has been described in several open, noncontrolled studies (11, 21, 28, 38, 41, 58). Kumar and Bleck reported its efficacy in seven patients (28). In their retrospective study, Kumar and Bleck found that midazolam terminated refractory SE in less than 2 minutes (100 seconds) in all seven patients, which was confirmed in four by EEG criteria. All patients had been in refractory SE. The mean loading dose was 0.22 mg/kg (range, 0.02–0.42 mg/kg), and the maximum infusion rate was 0.17 mg/kg/hr (range, 0.08–0.39 mg/kg/hr). The duration of the infusion ranged from 10 to 70 hours (average, 31 hours) (28). The advantages of midazolam are its high lipid solubility, its rapid onset, and the low risk of hypotension (only one patient out of seven in Kumar and Bleck’s report had hypotension, which was mild and easily managed with dopamine). The dose can easily be titrated to effect. Because of the low rate of hypotension, midazolam is an excellent alternative to pentobarbital. In a meta-analysis of treatment results in children, Gilbert et al. compared studies that used diazepam, phenytoin, lorazepam, paraldehyde, and phenobarbital for refractory SE (23). The mortality associated with midazolam was significantly lower than that associated with all other treatments. No deaths occurred in children treated with midazolam (n = 29), compared with a mortality of 17%–40% associated with other treatments for refractory SE (23). In 2002, Ulvi et al. reported results in 19 subjects in refractory SE in whom diazepam had failed and who were then treated with phenytoin and phenobarbital (58). An initial bolus of midazolam, 0.2 mg/kg, was followed by a continuous infusion of 0.001 mg/kg/min for 12–25 hours.
488
Midazolam was exceptionally well tolerated and did not cause hypotension, bradycardia, or respiratory depression. Once the infusion was stopped, patients woke up within 2–8.5 hours. The exceptional safety of midazolam makes it an excellent substitute for pentobarbital, and one of the authors has frequently used midazolam safely as a replacement for high-dose barbiturates. P R SE Propofol (2,6diisopropylphenol) is a general anesthetic that modulates the GABAA receptor and can induce burst suppression (40). It is packaged as a 1% or 2% lipid emulsion and is primarily metabolized in the liver. Single boluses or infusions of up to 24 hours have a short elimination half-life of 30–60 minutes, with rapid awakening within 10–15 minutes following cessation of the drug. Prolonged infusions over several days result in slower clearance and accumulation of the drug. The terminal half-life of propofol after prolonged infusions (10 days) is 1–3 days. Prolonged elimination of propofol after long-term infusion reflects the distribution of propofol into the tissue compartments. After prolonged infusion, release of propofol from tissue is delayed, resulting in accumulation and delayed awakening. Clearance is reduced and plasma levels are higher in elderly patients (40). Propofol can cause bradycardia and severe hypotension due to peripheral vasodilation, and it reduces systolic blood pressure by up to 30%. It can cause seizures in the recovery phase in patients with known seizures. Propofol may cause acute respiratory depression within 30 seconds of induction. The doses used for SE have been 1–2 mg/kg as a bolus, then 2–10 mg/kg/hr (45, 51). Rosetti et al. recently reported a retrospective study on the use of high-dose propofol in 27 patients with 31 episodes of refractory SE (45). The dose was relatively high, and patients were treated for an average of 3 days (median dose, 4.8 mg/kg/hr, treated for 1–9 days). Refractory SE treated with propofol after clonazepam and phenytoin had failed successfully terminated SE in 67% of episodes, but seven deaths occurred. The authors did not attribute the deaths to propofol, but hypotension, requiring pressors, occurred in 48% of subjects, similar to rates in barbiturate-treated patients. The authors were able to taper the drug rapidly and progressively over a 24-hour period. Electroclinical recurrence during the period of taper occurred in five of the 27 subjects (45). Overall, the safety profile of propofol was similar to that noted in other series of barbiturate coma. Prasad et al. compared the outcomes of patients treated with propofol (n = 14) versus midazolam (n = 6) for refractory SE and found a higher rate of hypotension with propofol (two subjects, 14% versus 0%) (41). However, the authors admit the sample size was too small to make statistical comparisons, and they make a strong case for the need for a ran-
domized study. In regard to the dose and duration of treatment, the infusion rate was 5–10.5 mg/kg/hr for 40–48 hours, similar in dosage to the 2–13 mg/kg/hr in the report by Rosetti et al. (41, 45). Over the past few years, propofol has received increased scrutiny because of safety concerns related to the “propofol infusion syndrome” of heart failure, acidosis, and rhabdomyolysis. Cremer et al. reported seven deaths associated with this syndrome in head-injured patients receiving high doses of propofol for prolonged periods (16). The dosage of propofol in the seven subjects was significantly higher than in a cohort of 60 subjects without the syndrome, 6.5 mg/ kg/hr versus 4.8 mg/kg/hr. The duration of propofol infusion at the onset of the syndrome ranged from 35 hours to 95 hours, longer than reported by Rosetti et al. (16). Evidently, higher doses and prolonged infusions of propofol place patients at risk for hypotension, vasodilation, heart failure, metabolic acidosis, rhabdomyolysis, sepsis, and death. Pressors such as dopamine may actually worsen the propofol infusion syndrome. The newer 2% formulation may also increase this risk, as was the case in the majority of patients in Cremer’s cohort (five of seven patients). Problematically, the report of Cremer et al. included patients who were comedicated with pentobarbital, which increases the risk of hypotension. Therefore, the seven deaths may also have been related to comedication with propofol and barbiturate together, which should be avoided whenever possible. Rosetti et al. found that 50% of patients comedicated with propofol and thiopental died (45). Recently, Niermeijer et al. warned about the potential for mortality due to propofol in refractory SE (36). Shorter lengths of infusion at lower doses (<5 mg/kg/hr), avoiding comedication with thiopental or pentobarbital, may reduce the risk of serious propofolrelated complications. V A A Valproate is an alternative agent approved for IV treatment for complex partial or partial seizures (40). It has not been approved for the treatment of SE, and its role has not been adequately studied. Rapid loading with IV valproate, 25 mg/kg, at a rate of 3–6 mg/kg/min produces effective blood levels of 100–150 mg/mL with minimal hypotension or respiratory depression (63). IV valproate (Depacon) has been used as an alternative treatment of SE in children and the elderly, and retrospective evidence indicates it is very well tolerated, even in the presence of cardiovascular instability and hypotension (49, 63, 67). In 13 predominantly elderly subjects in SE, IV valproate was well tolerated and caused no hypotension (49). A loading dose of 15–33 mg/kg was used. In children with either SE or acute repetitive seizures, IV valproate infused at a dose of 25 mg/kg was well tolerated and terminated SE in all 18 subjects within 20 minutes (67). As for other alternative treatments, a controlled trial of valproate has
not been performed. IV valproate has an excellent safety profile, but its efficacy and its role in therapy are yet to be defined.
Summary Generalized convulsive status epilepticus is a common and potentially lethal medical emergency. There is now a consensus that SE should be aggressively treated at 5–10 minutes of continuous seizure activity. Fortunately, families and caregivers can intervene early with rectal diazepam, and paramedics can initiate effective treatment, terminating SE with benzodiazepines prior to the patient’s arrival in the ED. Newer agents offer real alternatives for treating refractory SE. These new developments should lead to reduced morbidity and mortality from SE in the immediate future. REFERENCES 1. Alldredge, B. K., A. M. Gelb, S. M. Isaacs, 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. Appleton, R. E., and A. Gill. Adverse events associated with intravenous phenytoin in children: A prospective study. Seizure 2003;12:369–372. 4. 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. 5. Binder, L., J. Trujillo, D. Parker, and A. Cuettter. Association of intravenous phenytoin toxicity with demographic, clinical, and dosing parameters. Am. J. Emerg. Med. 1996;14:398–401. 6. Boucher, B. A., C. A. Feler, J. C. Dean, et al. The safety, tolerability, and pharmacokinetics of fosphenytoin after intramuscular and intravenous administration in neurosurgery patients. Pharmacotherapy 1996;16:638–645. 7. Burneo, J. G., J. V. Anandan, and G. L. Barkley. A prospective study of the incidence of the purple glove syndrome. Epilepsia 2001;42:1156–1159. 8. Cascino, G. D., D. Hesdorffer, G. Logroscino, and W. A. Hauser. Treatment of nonfebrile status epilepticus in Rochester, Minn., from 1965 through 1984. Mayo Clin. Proc. 2001;76:39–41. 9. Cereghino, J. J., J. C. Cloyd, R. I. Kuzniecky, and the North American Diastat Study Group. Rectal diazepam gel for treatment of acute repetitive seizures in adults. Arch. Neurol. 2002;59:1915–1920. 10. 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. 11. Claasen, J., L. J. Hirsch, R. G. Emerson, et al. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: A systematic review. Epilepsia 2002;43:146– 153.
:
489
12. 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. 13. Collins, M., H. Marin, P. Rutecki, and D. Heller. A protocol for status epilepticus in a long-term care facility using rectal diazepam (Diastat). J. Am. Med. Dir. Assoc. 2001;2:66–70. 14. Coplin, W. M., D. H. Rhoney, J. A. Rebuck, et al. Randomized evaluation of adverse events and length of status with routine emergency department use of phenytoin or fosphenytoin. Neurol. Res. 2002;24:842–848. 15. Crawford, T. O., W. G. Mitchell, and S. R. Snodgrass. Lorazepam in childhood status epilepticus and serial seizures: Effectiveness and tachyphylaxis. Neurology 1987;37:190–195. 16. Cremer, O. L., K. G. Moons, E. A. Bouman, J. E. Kruijswijk, A. M. de Smet, and C. J. Kalkman. Long-term propofol infusion and cardiac failure in adult head-injured patients. Lancet 2001;357:117–118. 17. 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. 18. DeGiorgio, C. M., and D. M. Treiman. Status epilepticus. In J. Noseworthy et al., eds. Neurologic Therapeutics: Principles and Practice. London: Martin Dunitz, 2003. 19. Delgado-Escueta, A. V., and F. Enrile-Bacsal. Combination therapy for status epilepticus: Intravenous diazepam and phenytoin. Adv. Neurol. 1983;34:477–485. 20. Fountain, N. B. Status epilepticus: Risk factors and complications. Epilepsia 2000;41(Suppl. 2):S23–S30. 21. Fountain, N. B., and R. E. Adams. Midazolam treatment of acute and refractory status epilepticus. Clin. Neuropharmacol. 1999;22:261–267. 22. French, J. A., A. M. Kanner, J. Bautista, B. Abou-Khalil, T. Browne, C. L. Harden, et al. Efficacy and tolerability of the new antiepileptic drugs. I. Treatment of new onset epilepsy: Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2004;62:1252–1260. 23. Gilbert, D. L., P. S. Gartside, and T. A. Glauser. Efficacy and mortality of refractory generalized convulsive status epilepticus in children: A meta-analysis. J. Child Neurol. 1999; 14:602–609. 24. Giroud, M., and R. Dumas. Treatment of status epilepticus by sodium valproate. Neurophysiol. Clin. 1988;18:21–32. 25. Holtkamp, M., F. Masuhr, L. Harms, K. M. Einhaupl, et al. The management of refractory generalized convulsive and complex partial status epilepticus in three European countries: Survey among epileptologists and critical care neurologists. J. Neurol. Neurosurg. Psychiatry 2003;74:1095–1099. 26. Hirsch, L. J., and J. Claassen. The current state of treatment of status epilepticus. Curr. Neurol. Neurosci. Rep. 2002;2:345–356. 27. Jamerson, B. D., G. E. Dukes, K. L. Brouwer, K. H. Donn, J. A. Messenheimer, and J. R. Powell. Venous irritation related to intravenous administration of phenytoin versus fosphenytoin. Pharmacotherapy 1994;14:47–52. 28. Kumar, A., and T. P. Bleck. Intravenous midazolam for the treatment of refractory status epilepticus. Crit. Care Med. 1992;20:483–488. 29. 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.
490
30. Lohr, A., Jr., and L. C. Werneck. Comparative nonrandomized study with midazolam versus thiopental in children with refractory status epilepticus. Arq. Neuropsiquiatr. 2000;58: 282–287. 31. Lowenstein, D. Treatment options for status epilepticus. Curr. Opin. Pharmacol. 2003;3:6–11. 32. Lowenstein, D., T. Bleck, and R. L. Macdonald. It’s time to revise the definition of status epilepticus. Epilepsia 1999;40: 752–758. 33. Mayer, S. A., J. Claassen, J. Lokin, et al. Refractory status epilepticus: Frequency, risk factors, and impact on outcome. Arch. Neurol. 2002;59:205–210. 34. 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. 35. Mitchell, W. G. Status epilepticus and acute repetitive seizures in children, adolescents, and young adults: Etiology, outcome, and treatment. Epilepsia 1996;37(Suppl. 1):S74– S80. 36. Niermeijer, J. M., C. S. Uiterwaal, and C. A. Van Donselaar. Propofol in status epilepticus: Little evidence, many dangers? J. Neurol. 2003;250:1237–1240. 37. O’Brian, T. J., G. D. Cascino, E. L. So, and D. R. Hanna. Incidence and clinical consequence of the purple glove syndrome in patients receiving intravenous phenytoin. Neurology 1998;51:1034–1039. 38. Parent, J. M., and D. H. Lowenstein. Treatment of refractory generalized convulsive status with continuous infusions of midazolam. Neurology 1994;44:1837–1840. 39. Pellock, J. M. Safety of Diastat, a rectal gel formulation of diazepam for acute seizure treatment. Drug Safety 2004;27: 383–392. 40. Physicians Desk Reference. Montvale, N.J. Medical Economics, 2004. 41. 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. 42. Prensky, A. L., M. C. Raff, M. J. Moore, and R. S. Schwab. Intravenous diazepam in the treatment of prolonged seizure activity. N. Engl. J. Med. 1967:276:779–784. 43. Rashkin, M. C., C. Youngs, and P. Penovich. Pentobarbital treatment of refractory status epilepticus. Neurology 1987;37: 500–503. 44. Rosenow, F., A. Arzimanoglou, and M. Baulac. Recent developments in treatment of status epilepticus: A review. Epileptic Disord. 2002;4(Suppl. 2):S41–S51. 45. Rossetti, A. O., M. D. Reichhart, M. D. Schaller, P. A. Despland, and J. Bogousslavsky. Propofol treatment of refractory status epilepticus: A study of 31 episodes. Epilepsia 2004; 45:757–763. 46. 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. 47. Shorvon, S. The management of status epilepticus. J. Neurol. Neurosurg. Psychiatry 2001;70(Suppl. 2):II22–II27. 48. Shorvon, S. Status Epilepticus: Its Clinical Features and Treatment in Children and Adults. Cambridge, U.K.: Cambridge University Press, 1994. 49. Sinha, S., and D. K. Naritoku. Intravenous valproate is well tolerated in unstable patients with status epilepticus. Neurology 2000;55:722–724.
50. Smith, B. J. Treatment of status epilepticus. Neurol. Clin. 2001; 19:347–369. 51. 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. 52. Tasker, R. C. Emergency treatment of acute seizures and status epilepticus. Arch. Dis. Child. 1998;79:78–83. 53. 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. 54. Treiman, D. M. Generalized convulsive status epilepticus in the adult. Epilepsia 1993;34(Suppl. 1):S2–S11. 55. Treiman, D. M. The role of benzodiazepines in the management of status epilepticus. Neurology 1990;40(Suppl. 2):32–42. 56. Treiman, D. M., C. M. DeGiorgio, E. Ben-Menachem, D. Gehret, L. Nelson, S. M. Salisbury, et al. Lorazepam vs. phenytoin in treatment of generalized convulsive status: Report of an ongoing study. Neurology 1985;35(Suppl. 1):284. 57. 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. 58. Ulvi, H., T. Yoldas, B. Mungen, and R. Yigiter. Continuous infusion of midazolam in the treatment of refractory generalized convulsive status epilepticus. Neurol. Sci. 2002;23:177–182. 59. Walker, J. E., R. W. Homan, M. R. Vasko, I. L. Crawford, R. D. Bell, and W. G. Tasker. Lorazepam in status epilepticus. Ann. Neurol. 1979;6:207–213. 60. Wallis, W., H. Kutt, and F. McDowell. Intravenous diphenylhydantoin in treatment of acute repetitive seizures. Neurology 1968;18:513–525. 61. Walton, N. Y., and D. M. Treiman. Lorazepam treatment of experimental status epilepticus in the rat: Relevance to clinical practice. Neurology 1990;40;990–994. 62. Weise, K. L., and T. P. Bleck. Status epilepticus in adults and children. Crit. Care Clin. 1997;13:629–646. 63. Wheless, J. W., and V. Venkataraman. Safety of high IV loading doses of valproate. Epilepsia 1998;39(Suppl. 6):50. 64. Wilder, B. J., R. E. Ramsay, L. J. Willmore, G. F. Feussner, R. J. Perchalski, and J. B. Shumate, Jr. Efficacy of intravenous phenytoin in the treatment of status epilepticus: Kinetics of central nervous system penetration. Ann. Neurol. 1977;1: 511–518. 65. Willmore, L. J. Epilepsy emergencies: The first seizure and status epilepticus. Neurology 1998;51(Suppl. 4):S34–S38. 66. 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. 67. Yu, K. T., S. Mills, N. Thompson, and C. Cunanan. Safety and efficacy of intravenous valproate in pediatric status and acute repetitive seizures. Epilepsia 2003;44:724–726.
:
491
38
Therapeutic Attitudes and Therapeutic Algorithms
.
Introduction Despite recent advances in pharmacology and the completion of a major controlled therapeutic trial (40), status epilepticus (SE) remains a major medical emergency and a persistent, serious public health problem in the United States. Population-based studies indicate that it is still associated with a 27% mortality in adults, and with very serious morbidity in survivors (8). In terms of the amount of clinical research devoted to it and the education of the medical public, SE is very much an orphan disease and probably should be defined as such. Those who frequently see and treat SE rarely study it. Most SE is treated in emergency departments (EDs) and in intensive care units (ICUs), but essentially all the research work on the topic is published in the neurology literature. By the same token, most of those who study SE in the experimental laboratory (and this is a small number of laboratories) rarely treat it. The extent to which this lack of education of the medical public might account for the poor outcome of treating SE is unknown. At the Santa Monica meeting, we surveyed the audience as a first step in the study of that problem. The survey addressed therapeutic attitudes and therapeutic protocols, and it targeted a medical public that is clearly not representative of the medical profession as a whole. However, the meeting participants were likely to know more about SE than the average emergency physician or neurologist, so that any lack of education that might be detected would be likely to underestimate the extent of the problem and its impact on the poor outcome of SE. The results of that survey are discussed in this chapter. We have also added to that discussion some therapeutic algorithms that are currently in use at our center (the West Los Angeles Veterans Affairs Medical Center) in order to highlight some of the issues raised by the survey regarding the current treatment of SE. Recent estimates of the outcome of SE suggest that it is still responsible for approximately 30,000 deaths yearly in the United States (8, 13, 36; see also Chapters 2 and 3), and comparisons with the figures available at the time of the first Santa Monica Symposium on Status Epilepticus in 1980 (7) suggest that this number may represent an improvement of only about 20,000 deaths per year over the outcome estimated at that time. The Veterans Affairs
Status Epilepticus Cooperative Study has provided type I evidence of the profound loss of efficacy of pharmacologic treatment once the first two drugs fail. Our therapeutic strategies try to address one of the possible causes of this failure, by using short-acting medications for a limited period of time, so that, if the first drug or drugs fail, the lingering cardiovascular depression due to those agents does not prevent delivery of a full dose of the next agent.
A survey of therapeutic attitudes A O D SE T P Because the most commonly accepted definition of SE up to the time of the meeting was seizures lasting at least 30 minutes (3, 34, 45), it is remarkable that only 2% of the respondents indicated that waited that long before treating as SE. When seizures are continuous, 45% of respondents said they treated after 5 minutes of seizure activity, and an additional 43% said they treated after 10 minutes. Ten percent treated after 20 minutes, and only 2% waited until 30 minutes of continuous seizure activity to treat (Table 38.1). The mean period of waiting was 8 minutes, although it should be kept in mind that this figure is an average of estimates and not a true measurement. These therapeutic attitudes would support a proposal to shorten the duration of seizures needed in order to make the therapeutic decision to treat as a case of SE, with large amounts of intravenous (IV) drugs, but they do not necessarily imply that all the patients so treated are in full SE (see Chapter 2 for review). When seizures are intermittent, the majority of respondents (52%) defined SE as two seizures without recovery of consciousness between them. An additional 29% defined SE as two seizures without full recovery of consciousness. This result also suggests that, in their everyday practice, most physicians with an interest in SE used an operational definition of SE that was briefer and less severe than the official definition. Because this survey was taken at the end of the Santa Monica meeting, we cannot rule out the possibility that the answers were influenced by the evidence shown at the meeting, suggesting that brain damage can be seen in animals with brief periods of stimulation, and that many ED
:
493
T 38.1 Timing of treatment of generalized convulsive status epilepticus: A survey of current practices Initial Treatment Intermittent Seizures
Continuous Seizures
Secondary Treatment
5 min (52%) 10 min (29%) 20 min (10%) 30 min (8%) 60 min (2%)
30 min (24%) 60 min (47%) 90 min (13%) 120 min (8%) 3 hours (5%) 6 hours (3%)
2 seizures without recovery of consciousness (45%) 2 seizures without recovery of consciousness (43%) >2 seizures in 1 hour (10%) 2 seizures in 1 hour (2%) 2 seizures in 24 hours (0)
T 38.2 Initial treatment of generalized convulsive status epilepticus: A survey of current practices
Single drug 2 drugs sequentially 2 drugs simultaneously Hydantoin = phenytoin Hydantoin = fosphenytoin Lorazepam Æ phenytoin Lorazepam Æ fosphenytoin Diazepam Æ phenytoin Lorazepam + fosphenytoin Lorazepam Lorazepam + phosphenytoin Diazepam Æ fosphenytoin Phenytoin Clonazepam Æ phenytoin Phenytoin Æ midazolam Diazepam Phenobarbital Fosphenytoin Diazepam + phenytoin Lorazepam Æ phenobarbital Phenobarbital Æ phenytoin
Total (%)
Academic (%)
Clinical Practice (%)
15 63 21 63 37 27 16 11 11 8 8 6 3 3 2 1 1 1 1 1 1
9 80 11 72 28 31 26 20 11 6
9 64 27 53 47 38 14 5 38 5 5
3
3
Note: Some responses did not indicate type of practice.
physicians treat very quickly with IV drugs. The answers could also have been influenced by our proposal, presented earlier at the meeting, to shorten the operational definition of SE to 5 minutes of continuous seizures, and by the evening workshop on the definition of SE. There seemed to be no difference among full-time academics, physicians in university practice, and those in private practice in the answer to these questions. The mean time to treatment was 8.5 minutes for full-time academics, 9 minutes for people in university practice, and 7 minutes for people in private practice. A majority in the first two groups defined
494
SE as two seizures without recovery of consciousness, while a majority of the private practice physicians defined SE as two seizures without full recovery of consciousness. I T G C SE One drug or two? Only 10 (15%) of 63 respondents started treatment with a single drug. Only 21% did not give two drugs routinely. However, only 21% always gave the initial drugs simultaneously; 63% gave them sequentially, implying that they
probably did not give the second drug if the first agent terminated seizures (Table 38.2).
patient from seizure recurrence (Table 38.3). The initial diazepam peak should help break self-sustaining seizures, while cardiovascular depression inadvertently induced by diazepam is of much shorter duration than that due to lorazepam, for the same reasons. From a pharmacokinetic viewpoint, neither lorazepam nor diazepam is an ideal drug for the treatment of SE, because both have a very long elimination half-life. As a result, if these drugs are ineffective in stopping seizures, the sedation and cardiovascular depression that they cause would complicate patient management for many hours and limit the amounts of alternate anticonvulsants that could be given without depressing blood pressure. For that reason, we advocate the use of midazolam as the first-line benzodiazepine. Midazolam has a half-life of 1–11/2 hours, so that if it fails it does not linger and potentiate cardiovascular depression for days, as do the other benzodiazepines (10, 28, 32). Its cardiovascular toxicity is also remarkably low, and it has been used successfully as the primary treatment of SE (17, 18, 25), as well as for refractory SE (31). Midazolam’s toxic effects can be quickly reversed by flumazenil. Its higher cost compared to diazepam is likely to be counterbalanced by shorter ICU stays due to more rapid recovery of consciousness after IV loading for SE.
Phenytoin or fosphenytoin? The most commonly chosen drug was phenytoin (52% of all respondents and 63% of those who used two drugs). Only 30% selected the more expensive fosphenytoin. Among those who used a hydantoin, fosphenytoin was selected more often by physicians in clinical practice (47%) than by fulltime academics (28%). The low penetration of fosphenytoin use among academic physicians, who traditionally give cost a low priority in treating life-threatening conditions, is surprising, since that drug is associated with fewer local complications (the “purple glove” syndrome [29]), and may cause fewer cardiac arrhythmias due to propylene glycol. It can be infused at three times the rate of phenytoin, making up for its 15-minute half-life, and it displaces phenytoin from its albumin-binding sites, resulting in higher free phenytoin levels in patients treated with that drug, although total levels are similar (4, 16). This combination of lowered local toxicity and more favorable pharmacokinetics did not convince the majority of meeting participants. Which benzodiazepine is best? It appeared from the discussions held at the workshops that most neurologists favored lorazepam, while a majority of ED physicians favored diazepam as the benzodiazepine of choice. However, that question was not included in the survey. The choice of benzodiazepine may have reflected the composition of the audience: 71% used lorazepam, as opposed to 16% who used diazepam, perhaps neurologists made up the majority of the audience. Although controlled trials show both drugs to be equally efficacious (21), the extreme liposolubility of diazepam, which provides very high but unsustained initial brain concentrations, could be seen as an asset because the faster delivery rate of fosphenytoin should mean therapeutic phenytoin levels by the time diazepam brain levels start decreasing, protecting the
Protocols vary widely. It is remarkable that there were no fewer than 16 different therapeutic protocols for the initial treatment of GCSE. There is clearly a need for comparative studies of SE therapy, and for comparative animal data. Lorazepam followed by phenytoin was the most popular combination; 27% gave lorazepam and phenytoin sequentially and 11% gave these drugs simultaneously, while 16% used lorazepam followed by fosphenytoin. There was no significant difference among academic physicians, university practice physicians, and private practice physicians in this respect. Treatment with phenytoin alone was selected by 5% of respondents (3 of 63). This treatment was shown to be
T 38.3 Choice of therapeutic agents for refractory generalized convulsive status epilepticus: A survey of current practices
Agent Phenobarbital Pentobarbital Midazolam Propofol General anesthesia with volatile agent Thiopental Paraldehyde Chlormethiazole
Total Responses (%)
Academics (%)
Physicians in Practice (%)
54 23 7 7 3 3 1 1
45 26 16 3 3 6 — —
58 29 — 8 — — — 4
:
495
