Cognitive and Behavioral Effects of Epilepsy Treatment

Behavior and cognition in patients with epilepsy may be affected by multiple factors including seizure etiology, type, frequency, duration, and severity; cerebral lesions acquired before seizure onset; age at seizure onset; intraictal and interictal physiological dysfunction due to the seizures; structural 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. However, the cognitive effects of AEDs may be clinically significant. The most common AED cognitive effects include psychomotor slowing, reduced vigilance, and impairments in memory. Phenobarbital (PB) and benzodiazepines (BZDs) possess 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 cognitive effects than CBZ and minimal effects compared with placebo. 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 pharmacokinetic reasons. However, only a few studies have examined the cognitive effects of AEDs in the elderly. Although incomplete, the available data reflect a pattern of relative effects similar to those seen in younger adults. Children also may have increased susceptibility because the relatively modest effects of AEDs could be additive over the course of neurodevelopment. 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 clinically relevant blood levels. However, the magnitude and differential effects of in utero AED exposure on neurodevelopment in humans remain uncertain. AEDs may produce positive or negative behavioral alterations (e.g., mood stabilization, irritability/agitation, depression, psychosis). CBZ, GBP, LTG, and VPA have demonstrated positive psychotropic effects. 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 effects can reduce the patient's quality of life. Thus, the behavioral effects of AEDs should be considered in the choice of AED along with other side effects and efficacy for seizure control.