Imaging Drug Resistance in Juvenile Myoclonic Epilepsy with MRI-derived Cortical Markers

Juvenile myoclonic epilepsy (JME) is the most common idiopathic generalized epilepsy (IGE) syndrome and can present a significant clinical challenge due to lack of seizure control and concomitant neuropsychological impairment. Its underlying mechanisms remain poorly understood. MRI studies have described structural changes in individuals with IGE syndromes but have so far not identified a distinct structural profile associated with drug resistant IGE. In this cross-sectional case-control neuroimaging analysis we included 79 participants with JME recruited at two European epilepsy centres, 43 of whom were drug resistant, as defined by recurrent seizures in the last 12 months despite adequate trials of at least two antiseizure medications (ASM), a drug sensitive group (n=37), and 78 healthy controls. Participants underwent T1-weighted MRI and a comprehensive neuropsychological test battery including measures within two different domains: verbal memory and executive function. We performed vertex-wise measurements of cortical thickness and neurodevelopmental cortical measures, i.e. white matter surface area and local gyrification index (LGI), through a surface-based framework with subsequent correction of scanner-related effects. Group comparisons (family-wise error (FWE) corrected at p <0.05, family-wise error corrected) showed an increase of surface area in prefrontal, cingulate and temporal regions with left-sided predominance accompanied by increased LGI in the left temporal lobe in drug-resistant compared to drug-responsive individuals with JME. Performance on executive function in participants with drug resistant JME was reduced compared to drug sensitive JME (pBonferroni <0.01) and controls (pBonferroni <0.001). Impaired executive function correlated with increased surface area in medial prefrontal and temporal cortical regions (r < -0.75, p <0.01) after adjusting for disease duration and total ASM load. In conclusion, we identified a cognitive-developmental profile in drug resistant JME characterized by left-weighted changes in surface area and cortical folding complexity, the extent of which correlates with the degree of executive dysfunction. Our results shed further light onto the pathophysiological mechanisms of JME and suggest a neurodevelopmental/network basis for both drug refractoriness and cognitive impairment.