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Non-CNS Side Effects of Antiepileptic Drugs

  • Authors: Authors: Greg Krauss, MD, and Nathan Crone, MD
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Target Audience and Goal Statement

Non-CNS Side Effects of Antiepileptic Drugs is intended for neurologists, internists, primary care physicians, pediatricians, psychiatrists, pharmacists, dermatologists, advanced nurse clinicians and nurse practitioners.

The goal of this activity is to familiarize clinicians with non-CNS adverse reactions associated with established and newer antiepilepsy drugs (AEDs).

On completion of this continuing medical education offering, participants will be able to:

  1. Recognize adverse reactions associated with various body systems outside the CNS: integumentary, hematopoietic, gastrointestinal, and endocrine/metabolic.
  2. Differentiate among various benign and serious AED-associated rashes.
  3. Discuss issues and controversies surrounding metabolic/endocrine dysfunction associated with AEDs, such as polycystic ovary disease and weight changes.


  • Gregory L. Krauss, MD

    Assoc Professor of Neurology, Johns Hopkins University, Baltimore, MD


    Disclosure: Gregory L. Krauss, MD, has disclosed that he is an investigator for Abbott Labs, Hoechst, Parke Davis, and Novartis. He is a member of the professional advisory board of the Epilepsy Association of Chesapeake.

  • Nathan Crone, MD

    Assistant Professor of Neurology, The Johns Hopkins University School of Medicine, Staff Physician, Department of Neurology, Division of Epilepsy, The Johns Hopkins Hospital, Baltimore, Maryland


    Disclosure: Nathan Crone, MD, has disclosed that he receives funding for clinical grants from the NIH and The Charles A. Dana Foundation. He holds consulting agreements with Ortho-McNeil.

Accreditation Statements

    For Physicians

  • Medical Education Collaborative, a nonprofit education organization, is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

    Medical Education Collaborative designates this educational activity for a maximum of 1 hour in Category 1 credit towards the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity.

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    For Nurses

  • This offering has been approved for 1.2 contact hours by the Arizona Nurses' Association, accredited as an approver of continuing education in nursing by the Western Regional Accrediting Committee of the American Nurse's Association, and hence meets the nursing continuing education requirements of most states. HLC, Inc. is approved as a provider of continuing education by the California Board of Registered Nursing (Provider No.02464), and the Florida Board of Nursing (Provider No. 27I0364), and awards 1.2 contact hours of credit for this activity. Approval for credit is for registered nurses.

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    For Pharmacists

  • Medical Education Collaborative, Inc. has assigned 1 contact hour (0.10 CEUs) of continuing pharmaceutical education credit. ACPE provider number: 815-999-00-013-H01. Certificate is defined as a record of participation.

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For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]

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This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page.

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Non-CNS Side Effects of Antiepileptic Drugs

Authors: Authors: Greg Krauss, MD, and Nathan Crone, MDFaculty and Disclosures


Abstract and Introduction


Central nervous system (CNS)-mediated adverse reactions, such as sedation, dizziness, and cognitive abnormalities, occur frequently in patients treated with antiepileptic drugs (AEDs). Many important adverse reactions involve body systems other than the CNS, however, and these reactions are equally important to recognize. Such reactions include AED-associated benign and serious rashes, hepatotoxicity, hematologic disorders, and changes in metabolic and hormonal homeostasis. This update reviews non-CNS adverse reactions associated with both older and newer AEDs.


Effective pharmacologic treatment of epilepsy requires a consideration not only of the efficacy of various antiepileptic drugs (AEDs) with regard to different seizure types and epileptic syndromes, but also of the potential side effects associated with these drugs. The most common side effects of AEDs involve the central nervous system (CNS), and include dizziness, incoordination, gait disturbance, diplopia, sleep disturbance, and cognitive dysfunction. These side effects commonly occur during the initiation of therapy, are typically proportional to AED levels in serum, and are reversible with reduction or discontinuation of the medication.

In addition to these common, dose-related CNS side effects, AEDs may have clinically relevant side effects that involve other organ systems, including the integumentary, hematopoetic, hepatic and digestive, renal, metabolic, endocrine, and peripheral nervous systems. These side effects are less common than those that affect the CNS and are not as predictably related to AED levels in serum; many seem to be idiosyncratic and are therefore difficult to predict for any given patient. Many are also associated with more than one AED, as in the case of drug-associated rash, but others are fairly specific to individual drugs.

The frequency of side effects of AEDs are classified and listed in the product inserts according to Food and Drug Administration (FDA) guidelines. Adverse reactions are classified as frequent (> 1/100), infrequent (< 1/100), or rare (< 1/1000). Most of the frequent adverse events are dose-related, CNS-mediated side effects. However, some AEDs frequently cause non-neurologic side effects in the treated population (eg, hirsutism and gingival hyperplasia associated with phenytoin, leukopenia and hyponatremia with carbamazepine, and weight gain and hair loss with valproate). Furthermore, some of the most severe and life-threatening adverse events do not affect the CNS (eg, Stevens-Johnson syndrome (SJS), aplastic anemia, and hepatic failure). Although these side effects are rare and always idiosyncratic, early recognition is essential so that the offending agent can be discontinued and life-saving measures initiated.

The purpose of this activity is to familiarize specialists and general practitioners with AED side effects that are not mediated by the CNS. Because comprehensive discussions of this topic may be found in other sources, we will review only briefly the potential side effects of AEDs on other organ systems. Special attention will be given to topics that are sources of controversy among clinical epileptologists.