Antiepileptic Drugs Antiepileptic Drugs A Clinician’s Manual Second Edition Ali A. Asadi-Pooya, MD Associate Professor of Epileptology Director, Shiraz Comprehensive Epilepsy Center Department of Neurology Shiraz University of Medical Sciences Shiraz, Iran Jefferson Comprehensive Epilepsy Center Department of Neurology Thomas Jefferson University Philadelphia, PA Michael R. Sperling, MD Baldwin Keyes Professor of Neurology Vice Chair for Clinical Affairs Director, Jefferson Comprehensive Epilepsy Center Department of Neurology Thomas Jefferson University Philadelphia, PA 1 1 Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trademark of Oxford University Press in the UK and certain other countries. Published in the United States of America by Oxford University Press 98 Madison Avenue, New York, NY 006, United States of America. © Oxford University Press 206 First Edition published in 2009 Second Edition published in 206 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by license, or under terms agreed with the appropriate reproduction rights organization. Inquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above. You must not circulate this work in any other form and you must impose this same condition on any acquirer. Library of Congress Cataloging-in-Publication Data Names: Asadi-Pooya, Ali A., 973–, author. | Sperling, Michael R., author. Title: Antiepileptic drugs : a clinician’s manual / Ali A. Asadi-Pooya, Michael R. Sperling. Description: Second edition. | New York, NY : Oxford University Press, 206. | Includes bibliographical references and index. Identifiers: LCCN 205037223 | ISBN 97809024968 (paperback : alk. paper) Subjects: | MESH: Anticonvulsants—therapeutic use—Handbooks. | Epilepsy—drug therapy—Handbooks. Classification: LCC RM322 | NLM QV 39 | DDC 65/.784—dc23 LC record available at http://lccn.loc.gov/205037223 9 8 7 6 5 4 3 2  Printed by Edwards Brothers This material is not intended to be, and should not be considered, a substitute for medical or other professional advice. Treatment for the conditions described in this material is highly dependent on the individual circumstances. And, while this material is designed to offer accurate information with respect to the subject matter covered and to be current as of the time it was written, research and knowledge about medical and health issues is constantly evolving and dose schedules for medications are being revised continually, with new side effects recognized and accounted for regularly. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulation. The publisher and the authors make no representations or warranties to readers, express or implied, as to the accuracy or completeness of this material. Without limiting the foregoing, the publisher and the authors make no representations or warranties as to the accuracy or efficacy of the drug dosages mentioned in the material. The authors and the publisher do not accept, and expressly disclaim, any responsibility for any liability, loss or risk that may be claimed or incurred as a consequence of the use and/or application of any of the contents of this material. Contents . Diagnosis and Evaluation of Patients With Seizures  1 2. Antiepileptic Drug Dosage Forms and Administration Guidelines  15 3. Mechanisms of Action and Pharmacokinetic Properties of Antiepileptic Drugs  79 4. Monitoring Antiepileptic Drugs and Their Toxicity  95 5. Choices of Antiepileptic Drugs Based on Specific Epilepsy Syndromes and Seizure Types  109 6. Clinically Important Drug Interactions With Antiepileptic Drugs  121 7. Aggravation of Seizures by Antiepileptic Drugs  127 8. Polytherapy With Antiepileptic Drugs  131 v 9. Antiepileptic Drugs in Pregnancy  135 0. Antiepileptic Drugs in Lactating Women  141 . Antiepileptic Drugs in the Elderly  145 2. Antiepileptic Drugs in Patients With Renal Disease  153 3. Antiepileptic Drugs in Patients With Liver Disease  165 4. Antiepileptic Drugs and Metabolic Disorders  173 5. Antiepileptic Drugs in Patients With Hyperlipidemia  179 6. Antiepileptic Drugs in Patients With Diabetes Mellitus  183 7. Antiepileptic Drugs in Patients With Cardiovascular Disorders  187 8. Antiepileptic Drugs in Patients With Hematological Disorders  195 9. Antiepileptic Drugs in Patients on Chemotherapy or Immunosuppressive Therapy  203 20. Antiepileptic Drugs in Patients With Brain Tumors  209 2. Antiepileptic Drugs in Patients With Stroke  213 22. Antiepileptic Drugs in Patients With Preexisting Psychiatric Problems or Learning Disabilities  219 23. Antiepileptic Drugs and Cognition  227 S 24. Antiepileptic Drugs in Patients T N E With Migraine Headaches  233 T N O 25. Antiepileptic Drugs in Patients With Neuropathic C Pain Syndromes  237 26. Antiepileptic Drugs and Cutaneous/Allergic Reactions  241 27. Antiepileptic Drugs and Ophthalmologic Problems  255 28. Antiepileptic Drugs and Weight Change  261 29. Antiepileptic Drugs and Bone Health  267 30. Antiepileptic Drugs in Patients With HIV Infection/AIDS  271 Index  279 vi Chapter  Diagnosis and Evaluation of Patients With Seizures Approximately 0% of the general population will experience at least one seizure within their lifetimes in most Western countries, and even higher rates are observed in developing countries. However, not all individuals go on to develop epilepsy, which is characterized by recurring epileptic seizures. An epileptic seizure is the transient occurrence of signs or symptoms due to abnormal excessive, hypersynchronous firing of neurons in the brain. The new practical clinical definition of epilepsy proposed by the International League Against Epilepsy (ILAE) considers epilepsy to be a disease of the brain defined by any of the following conditions: () at least two unprovoked (or reflex) seizures occurring >24 hours apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at 11 least 60%) after two unprovoked seizures, occurring over the next 0 years; and (3) diagnosis of an epilepsy syndrome (Fisher et al., 204). Epilepsy may be due to genetic causes (possessing an inherited trait to have seizures), brain tumors, infections (meningitis or encephalitis), brain trauma, stroke, develop- mental anomalies (eg, cortical dysplasia), malformations (tuberous sclerosis, neurofibromatosis), vascular malformations (arteriovenous malformations), and other causes. To properly diagnose “epilepsy” a physician must do more than simply establish that recurrent seizures have occurred or are highly likely to occur after the first one. It is important that an attempt be made to diagnose a specific epilepsy syndrome. This syndrome forms the basis for the health provider to decide on therapy. The syndrome reflects the constellation of historical features, symptoms, signs, and laboratory test results that define a distinct condition. Hence, the syndromic diagnosis involves more than just the seizure type; frontal lobe seizures, for instance, do not constitute a syndrome. In contrast, benign Rolandic epilepsy of childhood does con- stitute a distinct syndrome, with its characteristic etiology, natural history, seizure type, developmental history, neurological examination, and elec- troencephalogram (EEG) abnormality (Box .). An idiopathic (genetic) epi- lepsy syndrome is the direct result of a known or inferred genetic defect(s). Seizures are the core symptom of the disorder. It appears at a specific age (age dependent) with no underlying structural brain lesions or related neu- rological abnormalities. Examples of idiopathic (genetic) syndromes include benign Rolandic epilepsy of childhood, childhood absence epilepsy, and juvenile myoclonic epilepsy. A symptomatic (structural-metabolic) epilepsy syndrome is the result of an identifiable structural or metabolic lesion of the ts Box . Important Epilepsy Syndromes Based on the n e International League Against Epilepsy (ILAE) Classification ti a P General Syndrome Description of Classification on Idiopathic Childhood and Childhood absence epilepsy (pyknolepsy) ti (genetic) juvenile absence occurs in children of school age (peak a u generalized epilepsies manifestation age 6 to 7 years), with a al epilepsies strong genetic predisposition in otherwise v E normal children. It is characterized by d very frequent (several to many per day) n a absences. The EEG reveals bilateral sis usually 3 Hz, synchronous spike waves o or polyspikes and waves, on a normal n g background activity. During adolescence, Dia generalized tonic-clonic seizures often develop.  R  Juvenile absence epilepsy develops E T insidiously in physically and mentally p A healthy adolescents. Age at onset is usually H C between 0 and 7 years (peak between 0 and 2 years). Because the frequency of the absences is low and the symptoms are relatively trivial, the disorder may go unnoticed until generalized tonic-clonic 2 seizures appear. Juvenile Juvenile myoclonic epilepsy typically myoclonic appears in the second decade of life. epilepsy The age of onset often ranges from 8 to 24 years, with peak onset between 4 and 6 years. It is characterized by myoclonic seizures, associated at times with generalized tonic-clonic seizures or absence seizures. Epilepsy with prior to the onset of myoclonic-astatic myoclonic- seizures, most affected children show astatic seizures normal development. The seizures usually (Doose begin between 2 and 5 years of age. The syndrome) first seizure is most often a generalized tonic-clonic seizure and rarely a myoclonic, astatic, myoclonic-astatic, or absence seizure. Drop attacks may result from pure astatic, myoclonic-astatic, or atypical absence seizures. Epileptic West syndrome West syndrome is an age-dependent encephalopathies epilepsy syndrome that comprises a triad (in which the of epileptic spasms in clusters, mental epileptiform retardation, and diffuse and profound abnormalities paroxysmal EEG abnormalities in infancy. may contribute to progressive dysfunction) (continued) Box . (Continued) ts n e General Syndrome Description ti a Classification P Severe Severe myoclonic epilepsy begins during the of myoclonic first year of life. Development is normal prior n o epilepsy in to the onset of seizures. Affected infants ti infancy (Dravet develop either generalized or unilateral clonic ua syndrome) seizures without prodromal signs. Myoclonic al v jerks, absence seizures, and partial seizures E usually appear later. The occurrence of d n status epilepticus is frequent. psychomotor a retardation and other neurological deficits s occur in affected children. osi n Lennox-Gastaut The Lennox-Gastaut syndrome is, with g a syndrome rare exception, a condition of children. Di It is characterized by the clinical triad  of multiple types of seizures, including R  E especially atypical absences and tonic T p and atonic seizures, diffuse slow A H spikes-and-waves and/or generalized C paroxysmal fast activity on an abnormal background activity in EEG, and mental retardation (mental retardation is not a mandatory element). Landau-Kleffner Age of onset for Landau-Kleffner 3 syndrome syndrome ranges from 3 to 8 years, and boys are more frequently affected than girls. Acquired aphasia (verbal auditory agnosia) is the more prominent feature, because seizures are present in only 70% to 80% of the patients. progressive myoclonic epilepsies Include: ceroid lipofuscinosis, sialidosis, Lafora disease, Unverricht-Lundborg disease, neuroaxonal dystrophy, MERRF, and dentatorubropallidoluysian atrophy. Idiopathic BECTS (Rolandic Benign epilepsy of childhood with (genetic) focal epilepsy) centrotemporal spikes (BECTS) has five epilepsies criteria for the diagnosis: () onset between the ages of 2 and 3 years; (2) absence of neurological or intellectual deficit before the onset; (3) partial seizures with motor signs, frequently associated with somatosensory symptoms or precipitated by sleep; (4) a spike focus located in the centrotemporal (rolandic) area with normal background activity on the interictal EEG; and (5) spontaneous remission during adolescence. Benign occipital panayiotopoulos syndrome is best epilepsies described as early-onset benign childhood seizure susceptibility syndrome with mainly autonomic seizures (e.g., ictus emeticus) and autonomic status epilepticus. (continued)