ffo A/ewv6toJbffff of

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

X CONTENTS

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

Xll CONTENTS

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