Abstract
BackgroundIn epilepsy, cognitive difficulties are common, partly a consequence of anti-seizure medications (ASM), and cognitive side-effects are often considered to be more disabling than seizures and significantly affect quality of life. Functional MRI during verbal fluency tasks demonstrated impaired frontal activation patterns and failed default mode network deactivation in people taking ASM with unfavourable cognitive profiles. The cognitive effect of ASMs given at different dosages in monotherapy, or in different combinations, remains to be determined.MethodsHere, we compared the effects of different drug loads on verbal fluency functional MRI (fMRI) in people (i) taking dual therapy of ASMs either considered to be associated with moderate (levetiracetam, lamotrigine, lacosamide, carbamazepine/oxcarbazepine, eslicarbazepine, valproic acid; n = 119, 56 females) or severe (topiramate, zonisamide) side-effects; n = 119, 56 females), (ii) taking moderate ASMs in either mono-, dual- or triple-therapy (60 subjects in each group), or (iii) taking different dosages of ASMs with moderate side-effect profiles (n = 180). “Drug load” was defined as a composite value of numbers and dosages of medications, normalised to account for the highest and lowest dose of each specific prescribed medication.ResultsIn people taking “moderate” ASMs (n = 119), we observed higher verbal-fluency related to left inferior frontal gyrus and right inferior parietal fMRI activations than in people taking “severe” ASMs (n = 119). Irrespective of the specific ASM, people on monotherapy (n = 60), showed greater frontal activations than people taking two (n = 60), or three ASMs (n = 60). People on two ASMs showed less default mode (precuneus) deactivation than those on monotherapy. In people treated with “moderate” ASMs (n = 180), increased drug load correlated with reduced activation of language-related regions and the right piriform cortex.ConclusionOur study delineates the effects of polytherapy and high doses of ASMs when given in monotherapy on the functional anatomy of language. Irrespective of the cognitive profile of individual ASMs, each additional ASM results in additional alterations of cognitive activation patterns. Selection of ASMs with moderate cognitive side effects, and low doses of ASMs when given in polytherapy, could reduce the cognitive effect.
Highlights
The ultimate goal of treatments with anti-seizure medications (ASM) for epilepsy is to prevent seizures without causing side effects
Comparing ASMs with moderate and severe cognitive side effects (SE), we focused on the dual therapy group (119 vs. 119), due to small number on mono- or triple-therapy with severe cognitive SEs
Our findings emphasise the concept that each additional drug matters concerning the cognitive effect of polytherapy (Witt et al, 2015), even if a given drug has moderate cognitive side effects
Summary
The ultimate goal of treatments with anti-seizure medications (ASM) for epilepsy is to prevent seizures without causing side effects. Higher drug load is usually a reflection of a more severe epilepsy, but polytherapy, or too high a dose of ASMs in monotherapies, can do more harm in terms of side effects (SE) than good in terms of seizure control (Perucca and Kwan, 2005). The cognitive effect of ASMs increased when drugs are combined, as shown on neuropsychological testing (Rösche et al, 2011; Phabphal and Kanjanasatien, 2011; Witt and Helmstaedter, 2013; Witt et al, 2015), but these studies usually include ASMs with known severe or moderate cognitive SEs. Cognitive difficulties may be more disabling than seizures, significantly affecting quality of life (Baxendale and Thompson, 2016). Cognitive difficulties are common, partly a consequence of anti-seizure medications (ASM), and cognitive side-effects are often considered to be more disabling than seizures and significantly affect quality of life. The cognitive effect of ASMs given at different dosages in monotherapy, or in different combinations, remains to be determined
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