Longitudinal Effects of Bumetanide on Neuro-Cognitive Functioning in Drug-Resistant Epilepsy

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.

Keywords: GABA; TRACULA; bumetanide; cognitive function; drug-resistant epilepsy.

Figure 1

Voxel-based analysis. (A) Fractional anisotropy decrease in TP1 (pretreatment) vs. controls. (B) Fractional anisotropy increases after bumetanide treatment. Significance maps (in red and yellow) overlaid on smooth anisotropy control image. The threshold was set at P < 0.05 (FEW Corrected) and minimum cluster size >5 voxels. Color scale represents t-values. FA, fractional anisotropy; TP, Time Point.

Figure 2

Scatter plot showing a relationship between change related to baseline in FA, MD, and cognitive task. Significant relationships between FA in left ATR, FA, and MD in the right SLFt and % error memory indicating, respectively in (A–C).