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EDITED BY
R. EUGENE RAMSAY International Center for Epilepsy, Department of Neurology, University of Miami
School of Medicine, Miami, Florida, USA; Department of Neurology Miami VA Medical Center, Miami, Florida, USA
JAMES C. CLOYD Department of Experimental and Clinical Pharmacology
College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA
KEVIN M. KELLY Department of Neurology, Allegheny General Hospital
Pittsburgh, Pennsylvania, USA
ILO E. LEPPIK Epilepsy Research and Education Program, University of Minnesota
Minneapolis, Minnesota, USA
EMILIO PERUCCA Clinical Pharmacology Unit, Department of Internal Medicine and Therapeutics
University of Pavia, Pavia, Italy; Institute of Neurology IRCCS C. Mondino Foundation, Pavia, Italy
AMSTERDAM • BOSTON • HEIDELBERG • LONDON
NEW YORK • OXFORD • PARIS • SAN DIEGO
SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO
r,l ,SrV 1 t̂ IV Academic Press is an imprint of Elsevier
CONTENTS
C O N T R I B U T O R S XV
ACKNOWLEDGMENT xvii
Epilepsy in the Elderly: Scope of the Problem
I LO E. LEPPIK
I. Introduction 2 II. Known Knowns 2
III. Known Unknowns 11 IV. Unknown Unknowns 11 V. Unknown Knowns 12
VI. Conclusion 12 References 12
Animal Models in Gerontology Research
N A N C Y L. N A D O N
I. Animal Models in Aging Research: Consideraüons for Experimental Design 15
II. The Age Factor 16 III. Genetic Background 18 IV. Choice of Strain 19 V. Environmental Influences 22
VI. Genomic Manipnlations 24 VII. Resources 25
References 26
Animal Models of Geriatrie Epilepsy
LAUREN J. M U R P H R E E , L Y N N M. R U N D H A U G E N , AND KEVIN M. KELLY
I. Introduction 30 II. Mouse Models 30
III. Gerbil Model 32 IV. Rat Models 33 V. Conclusions , 37
References 37
vii
Vlll CONTENTS
Life and Death of Neurons in the Aging Cerebral Cortex
J O H N H. M O R R I S O N AND PATRICK R. H O F
I. Introduction 42
II. Cortical Circuitry and Alzheimers Disease 42 III. AAMI: Functional Decline Without Neuron Loss 46 IV. Interactions Between Neural and Endocrine Senescence 50
V. Conclusions 53 References 53
An In Vitro Model of Stroke-Induced Epilepsy: Elucidation of the Roles of Glutamate and Calcium in the Induction and Maintenance of
Stroke-Induced Epileptogenesis
ROBERT J. D E L O R E N Z O , DAVID A. SUN, R O B E R T E. BLAIR, AND
S O M P O N G SOMBATI
I. Introduction 60 II. Role of Glutamate in the Pathophysiology of Stroke 61
III. Developing an In Vitro Model of Glutamate Injury That Causes a Mixed Population of Injured and Dead Neurons in Preparations of Hippocampal Neurons in Culture 63
IV. Development of SREDs in Neurons Surviving Injury 64
V. Neuronal Networks Display Synchronizcd SREDs and Respond to Anticonvulsant Treatment 67
VI. Use of the In Vitro Model of Stroke-Induced AE to Evaluatc the Calcium Hypothesis of Epileptogenesis 68
VII. Role of Ca + and NMDA Receptor Activation in Epileptogenesis 69 VIII. Antagonism of Non-NMDA Receptor Subtypes of Glutamate Receptors
Does Not Inhibit Glutamate Injury-Induced AE 72 IX. Stroke-Induced AE Is Associated With Prolonged Eievations in Neuronal
[Ca2+]j Levels and Alterations in Ca2H Homeostatic Mechanisms 73 X. Glutamate Injury-Induced Epileptogenesis Causes Long-Lasting
Eievations in Basal Neuronal [Ca + ] i Levels 73 XI. Epileptic Neurons Demonstrate Impaired Recovery of Resting [Ca2+] ;
After Brief Glutamate-Induced Ca + Loading 75 XII. The Importance of In Vitro Models of Stroke-Induced AE 75
XIII. Calcium Plays a Role in the Induction of Stroke-Induced Epileptogenesis 78
XrV. Long-Lasting Changes in [Ca ]; Levels and Ca2+ Homeostatic Mechanisms Play a Role in Maintaining AE 80 References 81
CONTENTS ix
Mechanisms of Action of Antiepileptic Drugs
H. STEVE W H I T E , M I S T Y D. S M I T H , AND KAREN S. W I L C O X
I. Introduction 86 II. Modulation of Voltage-Gated Ion Channels 86
III. Enhanced Inhibition 88 IV. Excitation Reduction 88 V. First-Generation AEDs 89
VI. Second-Generation AEDs 93 VII. Summary and Implications for the Management of the Older Patient
With Epilepsy 102 References 102
Epidemiology and Outcomes of Status Epilepticus in the Elderly
A L A N R. T O W N E
I. Introduction 112 II. Definitions 112
III. The Epidemiology of SE in the Older Patient 113 IV. Etiologies of SE in the Elderly 115 V. Mortality of SE in the Elderly 116
VI. Electroencephalogram 118 VII. Treatment 119
VIII. Conclusions 123 References 124
Diagnosing Epilepsy in the Elderly
R. E U G E N E RAMSAY, FLAVIA M. MACIAS, AND A. JAMES R O W A N
I. Introduction 130 II. Etiology 131
III. Clinical Manifestations 132 IV. Differential Diagnosis 133 V. Cardiovascular and Cerebrovascular Diseases 135
VI. Confusional Migraine 135 VII. Drug Use 136
VIII. Infection 136 IX. Metabolie Disturbances 138 X. Sleep Disorders 141
XL Syncope 141 XII. Psychiatric Disorders 142
XIII. Transient Global Amnesia 146 XIV. Dementia 147 XV. Primary Generalized Seizures (Idiopathic) 147
XVI. Summary 148 References 148
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Pharmacoepidemiology in Community-Dwelling Elderly Taking
Antiepileptic Drugs
D A N R. BERLOWITZ AND MARY J O V. P U G H
I. Introduction 154 II. Methods 154
III. Results 156 IV. Discussion 159
References 162
Use of Antiepileptic Medications in Nursing Homes
J U D I T H GARRARD, SUSAN L. H A R M S , LYNN E. EBERLY, AND ILO E. L E P P I K
I. Introduction 166 II. Methods 168
III. Results 173 IV. Discussion 178
References 180
Age-Related Changes in Pharmacokinetics: Predictability and
Assessment Methods
E M I L I O PERUCCA
I. Introduction 184 II. The Effect of Aging on Pharmacokinetics 185
III. Predicting Aging-Associated Pharmacokinetic Changes 189 IV. Assessing Aging-Associated Pharmacokinetic Changes 192 V. Conclusions 195
References 196
Factors Affecting Antiepileptic Drug Pharmacokinetics in
Community-Dwelling Elderly
JAMES C. CLOYD, SUSAN M A R I N O , AND ANGELA K. BIRNBAUM
I. Introduction 202 11. Preliminary Studies of PHT and CBZ Pharmacokinetics in
Community-Dwelling Elderly 205 III. Discussion and Conclusion 209
References 209
CONTENTS xi
Pharmacokinetics of Antiepileptic Drugs in Elderly Nursing
Home Residents
ANGELA K. BIRNBAUM
I. Introduction 212 II. Older AEDs 212
III. Newer AEDs 218 References 218
The Impact of Epilepsy on Older Veterans
MARY J O V. P U G H , D A N R. BERLOWITZ, AND L E W I S KAZIS
I. Introduction 222 IL Methods 223
III. Results 225 IV. Discussion 230
References 232
Risk and Predictability of Drug Interactions in the Elderly
R E N E H. LEVY AND C A R O L COLLINS
I. Introduction 236 IL Antiepileptic Drugs Used in the Elderly 237
III. Methods for Pharmacokinetic Evaluation 238 IV. Antidepressants and Drugs Used to Treat Dementia 238 V. Cardiovascular Agents 242
VI. Conclusions 245 References 246
Outcomes in Elderly Patients With Newiy Diagnosed and
Treated Epilepsy
M A R T I N J. B R O D I E AND L I N D A J. S T E P H E N
I. Introduction 254 IL The Glasgow Registry 255
III. Analysis of the 1982-2001 Cohort 256 IV Supplemental Analysis 258 V. Difficulties in Diagnosing Epilepsy in the Elderly 258
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VI. Studies Comparing Newer and Older AEDs 259 VII. Initiating AED Treatment 261
VIII. Conclusions 262 References 262
Recruitment and Retention in Clinical Trials of the Elderly
FLA V IA M. MACIAS, R. EUGENE RAMSAY, A N D A. JAMES ROWAN
I. Introduction 266 II. Recruitment Outcomes of Veterans Affairs Cooperative Study 428 266
III. Factors Influencing Recruitment 2V0 IV. Cost of Recruitment 271 V. Retention Results From VA Cooperative Study 428 271
References 272
Treatment of Convulsive Status Epilepticus
D A V I D M. T R E I M A N
I. Introduction 274 II. Presentation, Progression, and Diagnosis 275
III. Consequences and Prognosis 276 IV. Treatment 277 V. Conclusions 283
References 283
Treatment of Nonconvulsive Status Epilepticus
M A T T H E W C. WALKER
I. Introduction 288 II. Diagnosis 288
III. Neuronal Damage Models 291 IV. Complex Partial Status Epilepticus 292 V. NCSE in Coma 294
VI. Typical Absence Status Epilepticus 295 VII. Conclusions 295
References 296
CONTENTS Xlll
Antiepileptic Drug Formulation and Treatment in the Elderly: Biopharmaceutical Considerations
BARRY E. G I D A L
I. Introduction 300 II. Biopharmaceutical Considerations 300
III. Gl Function and Age 303 IV. Conclusions 308
References 309
I N D E X 313
C O N T E N T S O F R E C E N T V O L U M E S 321