One of the most important obstacles in defining the progressive cognitive and behavioral decline of epilepsy is the need to separate toxicity of antiepileptic drugs (AEDs) from the effects of seizures. Studies that demonstrate stable or improving cognitive function over time may actually reflect benefits gained from seizure control. The AED that provides better seizure control for an individual may be more likely to provide a cognitive or behavioral benefit than another AED that has a statistically better cognitive-behavioral profile in controlled clinical studies.115
The cognitive benefits of treating epilepsy are supported by several studies. Seidenberg et al.27 showed increased Wechsler verbal, performance, and full-scale IQ measurements in patients with improved seizure control but no change in patients with poor seizure control. In another study, neuropsychological testing showed that unmedicated epilepsy patients performed significantly worse than normal controls on fine motor, attention, and cognitive tasks.116
Bourgeois et al.,23 however, found that toxic drug levels and early age of onset were the factors most closely correlated with poor cognitive performance. Seizure control, therefore, should not be achieved at the price of repeated episodes of drug toxicity. Another study showed that treatment with AEDs, especially phenobarbital, caused decreased Wechsler Intelligence Scale for Children–Revised scores.117
Debate concerning the precise cognitive and behavioral effects of different AEDs is far from resolved. In many studies, differences among drugs may reflect differences among the patients taking them rather than differences in the drugs themselves. Although study groups may appear similar, important intrinsic differences may exist between them that can account for different test scores. Dodrill47 noted that when two equally efficacious AEDs are prescribed for two patients with the same seizure type, differences between the patients likely account for different usage of medication. These patient differences may include
In the Holmfrid study, 100 children with epilepsy were seizure-free for 1 year on monotherapy with carbamazepine, phenytoin, or valproic acid.118 The AEDs were withdrawn over a 3-month period, and the children were reevaluated 3 to 4 months later. Significant improvement attributable to drug withdrawal was noted on only the psycho- motor speed test, suggesting a limited role for AEDs on cognitive function. This study showed, however, that phenytoin patients experienced greater cognitive impairment on tests of motor and mental speed than did carbamazepine patients.
Another drug withdrawal study involved children treated with carbamazepine, valproate, or phenytoin as monotherapy.119 Withdrawal of the AED produced improvement in binary choice and visual search tasks, but similar improvements were noted in the normal control group. The performance of the children taking carbamazepine was similar to that of the children in the control group both before and after drug withdrawal. Children taking phenytoin, however, performed poorly both before and after drug discontinuation. A similar impairment, but to a lesser degree, was noted with the valproate group.
Other findings from studies of individual AEDs:
The role of polytherapy is another consideration in assessing cognitive side effects of AEDs. Studies show that reduction of a multidrug regimen to monotherapy has beneficial effects on cognitive functioning and mood.127 However, studies that suggest greater cognitive impairment with polypharmacy usually involve conversion to monotherapy of groups of patients doing poorly on polytherapy.115 Dodrill47 found that seizure frequency is positively correlated with the number and amount of prescribed AEDs, so that polypharmacy is used to treat sicker patients.
Several methodologic problems are present in the study of cognitive side effects of AEDs128:
These problems must be addressed before the role of AEDs in cognitive decline can be definitively stated.
Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.
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