Physiologic Effects of Topiramate on Cognition

Background:

Cognitive side-effects of antiepileptic drugs (AEDs) are important components of treatment tolerability, although the physiologic mechanisms associated with their cognitive effects are poorly understood. Quantitative EEG and other neurophysiologic measures are sensitive indicators of central AED effects and in the older AEDs, with slowing consistent with a diffuse encephalopathy, tend to covary with neuropsychological performance. EEG changes are generally more sensitive than neuropsychological testing to AEDs, and have been demonstrated for oxcarbazepine, phenytoin, carbamazepine, lamotrigine, and levetiracetam.

Recent evidence demonstrates that the cognitive effects of these agents cannot be explained simply by diffuse reduction of neuronal excitability. Older AEDs are associated with a mild-to-moderate generalized cognitive effect such as decreased psychomotor speed, which is also accompanied by encephalopathic EEG patterns including increased spectral EEG power in the lower frequency bands. Several of the newer AEDs have not demonstrated this pattern. Some of these have reduced cognitive effects; however, one of the new AEDs, topiramate (TPM), which also does not possess this EEG encephalopathic pattern, actually produces greater cognitive deficits than many older AEDs.

Although newer AEDs tend to have a more favorable cognitive profile, TPM, which is indicated for partial or primary generalized epilepsy as well as migraine prophylaxis, is being increasingly prescribed for a wide range of neuropsychiatric disorders including bipolar disorder, weight loss and even eating disorders despite carrying a high risk of neuropsychological impairment with a prominent effect on verbal fluency. Although TPM's effect on verbal fluency may reflect a more widespread disruption of frontal lobe function, TPM's effect on verbal fluency has also been interpreted by some as reflecting a more general effect on language. TPM has multiple mechanisms of actions including modification of Na+ or Ca2+ dependent action potentials, enhancement of gamma-aminobutyric acid (GABA)-mediated receptors, and inhibition of kainate-mediated conductance at glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA)/kainate type. In addition, TPM is a carbonic anhydrase (CA) II inhibitor, and although the functions of CA in the central nervous system (CNS) is not well-established, at least some CA isoenzymes (CA II) have heavy human brain concentrations in oligodendrocytes and myelin. Because TPM is unique in that its neuropsychological effects are not accompanied by quantitative spectral EEG components, a generalized reduction in neuronal excitation is insufficient to account for TPM's neuropsychological profile. Therefore, investigators are investigating whether the physiologic mechanisms underlying TPM's negative cognitive effect is reflected by altered patterns of neuronal EEG connectivity following a single dosing.

TPM's inhibitory effect on carbonic anhydrase suggests that its mechanism of cognitive impairment may be related to white matter dysfunction altering neuronal connectivity. If true, then TPM's effects should be greater on generative fluency than semantic-decision due to disruption of intentional system connectivity of the frontal lobe and anterior cingulate with other brain regions. Semantic-conceptual processing with semantic-decision should be unaffected. However, TPM has multiple mechanisms which may contribute to its cognitive effects. If a generalized "frontal lobe" effect is present, then similar TPM effects should be present for working memory activations. EEG provides the opportunity to explore differential changes in functional connectivity associated with AEDs as a function of task.