Cognitive side-effects of chronic antiepileptic drug treatment: a review of 25 years of research.

Over 90 investigations have been conducted over the past 25 years to determine what effect AEDs have on cognition. No satisfactory answer to this problem can be given, however, chiefly because there is a paucity of studies that pass fairly basic standards of methodology, design and analysis that apply to the evaluation of any clinical research. This severely limits the precision of statements regarding cognitive AED effects. More particularly, there is little reason to recommend any of the first-line AEDs as the AED of choice from the standpoint of cognitive side-effects. On the basis of the present review we are not in a position to provide a straightforward answer to the most pertinent question, i.e., whether AEDs in therapeutic doses have any cognitive effects at all, good or bad. If we reduce the available database to monotherapy studies in epilepsy that use control group data for comparison, employ an appropriate form of repeated measures analysis, and provide sufficient information, very few studies remain that are directly relevant to this issue. This in itself precludes definitive conclusions. As can be seen from Table 9, absolute effects of CBZ and VPA have been examined in epilepsy patients three times each (in four studies), PB has been examined two times, PHT only once. In addition to the paucity of relevant data, there are miscellaneous validity concerns in all of these studies, one recurring theme being that of inconclusive 'no effect' findings with small samples. Without firm knowledge about absolute effects, relative effects, and particularly their absence, are difficult to interpret. Employing the above criteria (except that concerning controls), ten epilepsy studies that address this issue remain (Table 10). It is instructive to look at the number of times particular AEDs have been compared against each other (Table 11). CBZ has been compared to PHT five times, other comparisons occur only once or twice. Again, this is hardly a basis for definitive statements, particularly because validity concerns occur here as well. Recurring concerns here are scattered significant findings that tend to disappear if adjustment of the significance level for multiple comparisons is done, and inconclusive 'no difference' findings with small samples. Even if there were no conclusion validity concerns in individual studies, comparison between studies would be complicated by considerable variation in the subjects studied. Five of the studies summarized in Tables 8 and 9 use children as subject, nine use adults; results obtained in one group may not be generalizable to the other. Also, subjects may be newly diagnosed cases, or patients already on chronic treatment. The latter choice of subjects may be a factor working against detecting cognitive side-effects, as the damage (if any) may already have been done before the beginning of the trial. In addition, a wide variety of assessment tools have been used to search for cognitive effects of AEDs, ranging from measurements of reaction time and motor speed to intelligence tests. Some of these may be more sensitive to drug induced changes in cognition than others. Still, the tentative overall picture emerging from the creme de la creme of research on cognitive AED effects is that differences in cognitive profiles may not be very large. An important point here, of course, is the magnitude of the difference one considers worth detecting. Very few studies have attempted to answer this question. In the majority of studies we examined, a large treatment effect was anticipated implicitly, judging from the generally limited sample sizes. The choice of a study design based on a large treatment effect size may not always be appropriate, though. Of course, one could argue that it is only large effects that may be of practical or clinical significance anyways [30] and that effects of lesser magnitude are of no consequence. However, there are many examples where even a small benefit of one treatme