TOPIRAMATE has been recommended as an adjunctive treatment of posttraumatic epilepsy and is also indicated for the treatment of migraine headaches, which commonly occur after concussive injury. Although the use of topiramate may be effective in treating seizures, its association with cognitive side effects may limit its use.

MECHANISM OF ACTION

The mechanism of action of topiramate in treating epilepsy is thought to involve (1) potentiating inhibition via the [gamma]-aminobutyric acid (GABA) neurotransmitter system, (2) blocking voltage-dependent sodium channels, (3) modulating high-voltage-activated calcium channels, and (4) glutamate antagonism by blocking non-NMDA receptors.1 Anti-epileptic drugs (AED) are effective because of their ability to reduce neuronal activation, and thus reduce the likelihood of excessive firing that triggers the seizure. However, the mechanism responsible for its efficacy against seizures may also be responsible for the cognitive problems because of reduced neuronal activation. Yet, not all AEDs are equally impairing to cognition, and it likely involves more than the potentiation of the GABAergic system, since gabapentin is thought to act on the GABA system but has relatively few cognitive effects2; similarly, tiagabine, which acts predominantly by inhibiting reuptake of GABA, has fewer cognitive side effects than topiramate.3 The multiple mechanisms of action of topiramate are thought to play a major role in cognition.4

Functional and anatomical correlates may also provide clues to the mechanisms for topiramate's cognitive effects. One study using functional MRI showed a neuroanatomical relationship between decreased activation of the left prefrontal cortex and cognitive language impairment with topiramate therapy in patients with epilepsy.2 Moreover, healthy volunteers who received topiramate showed changes on evoked potentials consistent with disruption of neuronal mechanisms important for maintenance of information in working memory, which may account for topiramate's adverse impact on performance speed and accuracy.5

COGNITIVE, BEHAVIORAL, AND PSYCHIATRIC SIDE EFFECTS

A number of cognitive, behavioral, and psychiatric side effects of topiramate have been reported in patients with epilepsy. Adverse events were more likely to occur with high doses or rapid titration to maintenance dose.6 Importantly, preexisting cognitive impairments due to the brain injury such as problems with language, attention, memory, and executive functioning may be exacerbated by the adverse effects from topiramate treatment. Although no studies to our knowledge specifically address cognitive effects of topiramate in people with traumatic brain injury (TBI), in one study, patients who were intellectually impaired and had epilepsy showed serious neuropsychological complications including confusion, severe slowing of thinking and acting, and complete helplessness after receiving topiramate.7 In contrast, the use of topiramate in adults with epilepsy, mental retardation, and developmental disabilities was reported to be well-tolerated by many subjects in other studies,8,9 although adverse events did include behavioral problems (15%), decreased alertness (15%), drowsiness (5%), disorientation (5%), and unsteadiness (5%).9

Several studies have documented language impairment due to topiramate use. Word-finding difficulties developed in 7.2% of 431 patients with epilepsy while on topiramate, with greater risk in those with positive family history of epilepsy, simple partial seizures and epileptic involvement of the left temporal lobe.10 Three pediatric cases, 5 to 17 years old, reported significant regression of language abilities after the start of adjunctive topiramate therapy, as shown by decreased expressive output, stuttering, word-finding difficulties, problems with grammar and semantics, telegraphic speech and arrest of speech.1 In a study of the long-term effects of low-dose topiramate on cognition, 44% of the 47 patients with epilepsy demonstrated cognitive impairment, in particular for verbal fluency and working memory.11 Visual motor processing speed was also adversely affected by topiramate.12 Impairments of working memory,12,13 verbal fluency,12,13 and other measures of cognitive and emotional functioning14 were reversible after discontinuation of topiramate. Kockelmann et al13 speculate that topiramate may aggravate preexisting verbal and frontal-lobe associated problems.

Psychiatric symptoms can develop after TBI and care needs to be taken when prescribing medications that may trigger or exacerbate psychiatric conditions. Acute psychiatric and behavioral symptoms have been reported after topiramate therapy in patients with epilepsy, including psychomotor agitation, aggressiveness, auditory and visual hallucinations, paranoid delusions, depersonalization, derealization, and severe anxiety.15 These symptoms abate after stopping topiramate.16 One case report described paranoid delusions, disorganized thought processes, and flattened affect after the use of topiramate for bipolar disorder, which resolved after discontinuation of topiramate.17 In another study, affective disorders developed in 10.7% of 431 patients with epilepsy treated with topiramate, 5.6% began to have aggressive behavior, and 3.9% had other behavioral problems including agitation, anxiety, anger, or hostility.18 Topiramate-induced manic episodes have also been documented in patients treated for epilepsy.19

CONCLUSION

Although topiramate can be successful in treating seizures and migraine headaches after TBI, its effects on cognition, behavior, and emotions are concerning. Physicians should be aware of the potential adverse effects, and use caution when prescribing topiramate in patients with TBI, or avoid using it entirely when possible.

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