Abstract
Antiepileptic drugs (AEDs) have repeatedly shown inconsistent and almost contradictory effects on the neurocognitive system, from substantial impairments in processing speed to the noticeable improvement in working memory and executive functioning. Previous studies have provided a novel insight into the cognitive improvement by bumetanide as a potential antiepileptic drug. Through the current investigation, we evaluated the longitudinal effects of bumetanide, an NKCC1 co-transporter antagonist, on the brain microstructural organization as a probable underlying component for cognitive performance. Microstructure assessment was completed using SPM for the whole brain assay and Freesurfer/TRACULA for the automatic probabilistic tractography analysis. Primary cognitive operations including selective attention and processing speed, working memory capacity and spatial memory were evaluated in 12 patients with a confirmed diagnosis of refractory epilepsy. Participants treated with bumetanide (2 mg/ day) in two divided doses as an adjuvant therapy to their regular AEDs for 6 months, which followed by the re-assessment of their cognitive functions and microstructural organizations. Seizure frequency reduced in eight patients which accompanied by white matter reconstruction; fractional anisotropy (FA) increased in the cingulum-cingulate gyrus (CCG), anterior thalamic radiation (ATR), and temporal part of the superior longitudinal fasciculus (SLFt) in correlation with the clinical response. The voxel-based analysis in responder patients revealed increased FA in the left hippocampus, right cerebellum, and right medial temporal lobe, while mean diffusivity (MD) values reduced in the right occipital lobe and cerebellum. Microstructural changes in SLFt and ATR accompanied by a reduction in the error rate in the spatial memory test. These primary results have provided preliminary evidence for the effect of bumetanide on cognitive functioning through microstructural changes in patients with drug-resistant epilepsy.
Highlights
Impairment in diverse cognitive domains is a frequently occurring component in epileptic syndromes either due to the natural course of the disease or the antiepileptic drug (AED) related adverse effects
The overexpression of NKCC1, a chloride concentration regulating transporter, and resulting abnormal alterations in gammaaminobutyric acid (GABA) functional polarity have been reported in several neuropsychological disorders such as epilepsy, tuberous sclerosis complex (TSC), Down syndrome, Huntington disease and autism spectrum disorders [10,11,12]
The principle superiority of TRACULA is its ability to analyze longitudinal tract alterations in a probabilistic way [25, 26]; through the current study, we aimed to investigate the association between longitudinal effects of bumetanide on the whole brain structure using voxel-based analysis, white matter changes using TRACULA, and their relations to the cognitive performance indices
Summary
Impairment in diverse cognitive domains is a frequently occurring component in epileptic syndromes either due to the natural course of the disease or the antiepileptic drug (AED) related adverse effects. The specific drug-induced dysfunctions which are irreversible in some circumstances could deleteriously affect medication tolerability, behavioral performance, and psychosocial functioning within a long-term scope [4,5,6]. Even with these cognitive sequels, a number of antiepileptic drugs have been able to improve executive functions in some ways [7]. The overexpression of NKCC1, a chloride concentration regulating transporter, and resulting abnormal alterations in GABA functional polarity have been reported in several neuropsychological disorders such as epilepsy, tuberous sclerosis complex (TSC), Down syndrome, Huntington disease and autism spectrum disorders [10,11,12]. The earlier studies provided considerable insights into cognitive recovery by bumetanide, no research has been found that surveyed the neuro-cognitive impacts of bumetanide add-on therapy on patients with pharmaco-resistant epilepsy
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