Cognitive and Behavioral Effects of Epilepsy Treatment David W. Loring and Kimford J. Meador Department of Neurology, Medical College of Georgia, Augusta, Georgia, U.S.A. Summary: Behavior and cognition in patients with epilepsy may be affected by multiple factors including seizure etiology, type, frequency, duration, and severity; cerebral lesions ac- quired before seizure onset; age at seizure onset; intraictal and interictal physiological dysfunction due to the seizures; struc- tural cerebral damage due to repetitive or prolonged seizures; hereditary factors; psychosocial factors; sequelae of epilepsy surgery; and untoward effects of antiepileptic drugs (AEDs). Although the behavioral and cognitive effects of AEDs are less than the total of other factors in epilepsy, AEDs are of special concern because they are the major therapeutic modality for seizures. The risk of AED cognitive side effects is increased with polypharmacy and at higher dosages and higher AED blood levels. In general, the cognitive effects of AEDs are modest when used in monotherapy with AED blood levels within the standard therapeutic ranges. Further, the cognitive effects of AEDs are offset in part by reduced seizures. How- ever, the cognitive effects of AEDs may be clinically signifi- cant. The most common AED cognitive effects include psychomotor slowing, reduced vigilance, and impairments in memory. Phenobarbital (PB) and benzodiazepines (BZDs) pos- sess the most marked adverse cognitive effects. Regarding the other major older AEDs, carbamazepine (CBZ), phenytoin (PHT), and valproate (VPA) have cognitive effects that are similar to each other. In contrast, some of the newer AEDs appear to produce fewer adverse cognitive effects. Gabapentin (GBP) and lamotrigine (LTG) have demonstrated fewer cogni- tive effects than CBZ and minimal effects compared with pla- cebo. Tiagabine (TGB) and vigabatrin (VGB) also have shown few cognitive effects compared with placebo. Of the new AEDs, topiramate (TPM) appears to have the greatest cognitive side effects, but slow titration during drug initiation reduces these effects. Additional studies are needed to delineate fully the relative effects of all the new AEDs to each other and to the older AEDs. The elderly have increased susceptibility to the cognitive effects of AEDs for both pharmacodynamic and phar- macokinetic reasons. However, only a few studies have exam- ined the cognitive effects of AEDs in the elderly. Although incomplete, the available data reflect a pattern of relative ef- fects similar to those seen in younger adults. Children also may have increased susceptibility because the relatively modest ef- fects of AEDs could be additive over the course of neurode- velopment. Again in children, the cognitive effects of CBZ, PHT, and VPA are comparable, whereas the effects of PB are worse. Unfortunately, there are no studies on the cognitive effects of the new AEDs in children. The effects of AEDs on cognition may have even greater consequences for the children of mothers with epilepsy, who are exposed to AEDs in utero. Animal studies have demonstrated that in utero AED exposure can impair behavioral neurodevelopment at dosages below those required to produce somatic malformations and at clini- cally relevant blood levels. However, the magnitude and dif- ferential effects of in utero AED exposure on neuro- development in humans remain uncertain. AEDs may produce positive or negative behavioral alterations (e.g., mood stabili- zation, irritability/agitation, depression, psychosis). CBZ, GBP, LTG, and VPA have demonstrated positive psychotropic ef- fects. Patients with epilepsy are at increased risk for behavioral disorders, and these AEDs may be particularly useful in such patients. The most severe negative behavioral effects of AEDs occur in a small percentage of patients. However, more subtle adverse behavioral effects are much more common. A patient’s perception of his or her quality of life is correlated more with neurotoxicity symptoms and mood than with seizure frequency in the absence of seizure freedom. Even subtle behavioral ef- fects can reduce the patient’s quality of life. Thus, the behav- ioral effects of AEDs should be considered in the choice of AED along with other side effects and efficacy for seizure control. Key Words: Epilepsy—Epilepsy treatment— Cognitive effects—Anticonvulsants—Antiepileptic drugs. The first goal in epilepsy management is seizure con- trol. The initial drug selection is frequently based on factors other than risk of cognitive impairment, and some patients can be well controlled with a single medication without significant physical or behavioral side effects. Side effects of treatment, however, may adversely affect a patient’s quality of life. Thus, an optimal balance of risks and benefits should be sought for each individual patient. There are a substantial number of patients, un- fortunately, whose seizures cannot be adequately man- aged with a single medication. In these cases, the side effects of treatment must be carefully weighed, either when choosing among options that provide incomplete seizure relief or more aggressive treatments with in- creased risks (e.g., polytherapy or surgery). There are, of course, cognitive risks involved with failure to control Address correspondence and reprint requests to Dr. D.W. Loring at Department of Neurology, Medical College of Georgia, Augusta, GA 30912-3275, U.S.A. E-mail: dwloring@neuro.mcg.edu Epilepsia, 42(Suppl. 8):24–32, 2001 Blackwell Science, Inc. © International League Against Epilepsy 24