With the exception of clobazam, which is not approved for use in the United States, there are virtually no formal neuropsychological investigations of the recently introduced AEDs in children. Children on clobazam have similar neuropsychological profiles to those on carbamazepine or phenytoin after one year of treatment, with the exception of one test measuring psychomotor processing speed (WISC-R Coding). Practice effects were also present for many neuropsychological measures, and without an appropriate control group, the magnitude of cognitive side effects cannot be determined because negative cognitive effects associated with AED treatment may be offset by performance improvement from repeated test exposure.
Felbamate (Felbatol) was the first of the new generation AEDs to be introduced to the U.S. market, but the development of idiosyncratic aplastic anemia and hepatotoxicity has markedly limited its use. Gabapentin (Neurontin) soon followed, and, in studies of young adults, it has repeatedly been associated with good neuropsychological profiles with little or no cognitive impairment (Leach et al., 1997; Martin et al., 1999; Meador et al., 1999). Gabapentin appears to decrease peak alpha frequency of the EEG, however, even in the absence of a cognitive effect (Salinsky et al., 2002). The clinical significance of this EEG effect is not known, although it demonstrates a gabapentin effect directly on the central nervous system, which raises the possibility that long-term treatment in children may be associated with some degree of cumulative cognitive side effects. The amount of EEG slowing with gabapentin is less than that seen with carbamazepine and, as already discussed, EEG slowing in children with epilepsy being treated with carbamazepine may be related to later IQ subtest performance.
Lamotrigine (Lamictal) is also associated with little or no objective cognitive impairment (Martin et al., 1999; Meador et al., 2005, 2001). Because of its positive psychotropic effects, lamotrigine has been used in treating bipolar disorder. However, it is important to recognize that mood as a moderator variable is a subjective report of cognitive functioning. In multiple reports, there is a discrepancy between self-reports of cognitive functioning and objective neuropsychological performance. There is little direct correlation between objective and subjective findings, although a robust relationship between subjective ratings of cognitive performance and mood is consistently reported (Salinsky et al., 2002). Thus, patient self-reports of improved cognition must be interpreted cautiously, even when mood is statistically controlled (Khan et al., 2004). Improved alertness may be seen with lamotrigine, even in patients with severe epilepsy syndromes, including tuberous sclerosis (Franz et al., 2001). Parents rated children as improved, with a longer attention span and improved alertness, in slightly more than half of one group sample of children with epilepsy who began lamotrigine therapy (Uvebrant and Bauziene, 1994). However, open-label studies using ratings are subject to the criticism of being confounded by expectations on the part of the nonblinded rater.
Levetiracetam (Keppra), which has been associated with some reports of irritability and aggression, appears to have a favorable cognitive side-effect profile. In an open-label study in autism, levetiracetam had beneficial effects on attention, hyperactivity and mood instability (Rugino and Samsock, 2002). It has been associated with nonsignificant increases in reaction time, but the size of reaction time slowing for levetiracetam was smaller than for oxcarbazepine (Trileptal) and carbamazepine. Unlike these other two AEDs, levetiracetam was not associated with a change in any EEG or visual evoked potential parameter (Mecarelli et al., 2004).
Oxcarbazepine is structurally similar to carbamazepine, but appears to have a better cognitive profile. It has been associated with both neuropsychological impairment and EEG slowing in healthy volunteers (Salinsky et al., 2004), although the magnitude of effect appears to be smaller than with carbamazepine (Mecarelli et al., 2004). Again, the long-term significance of slight EEG slowing, if any, has not been established.
There is little information about tiagabine (Gabitril) and vigabatrin. Very little formal cognitive data about tiagabine exist, although any cognitive effects appear modest (Dodrill et al., 1998). In one small add-on study, tiagabine was associated with a decline in verbal memory as well as less energy (Fritz et al., 2005). Vigabatrin has not been approved for use in the United States due to risk of visual field constriction, although its cognitive profile is reportedly good (Provinciali et al., 1996).
The greatest concern of cognitive side effects in the new generation of AEDs is seen with topiramate (Topamax) (Martin et al., 1999; Meador et al., 2005; Salinsky et al., 2005; Thompson et al., 2000) and, to a smaller degree, zonisamide (Zonegran) (Akaho, 1996; Berent et al., 1987). Little formal study of the cognitive side effects of zonisamide has been done, but there have been both clinical trials and clinical reports indicating concern for topiramate.
Topiramate has an approvable letter from the U.S. Food and Drug Administration for pediatric use, although there is evidence from many sources that at certain doses there is a risk of neuropsychological impairment (Dooley et al., 1999; Kockelmann et al., 2003; Meador et al., 2003; Salinsky et al., 2005). The possibility that some patients may be at heightened risk for cognitive impairment with topiramate remains a possibility (Meador et al., 2003). Although worse than those of most newer AEDs, the cognitive side effects of topiramate are generally comparable to those associated with valproate sodium (Meador et al., 2003). These adult studies have been conducted using doses and escalation schedules that are higher and faster than those used in current practice. Whether these deficits are present at lower doses is not presently known, and there has been a recent trend for lower dose use.
