1 , 2 While modulating hyperactive mTOR pathway with everolimus may lead to a meaningful improvement in epilepsy, its effect on cognition and behavior remains less well defined. Although preclinical data suggested improvement, a 6-month long administration of everolimus to children with TSC in a randomized, placebo-controlled trial showed a possible trend but not a statistically significant improvement in neurocognitive functioning or in behavior, and similar results were noted in EXIST-3 substudy in Japan. 5 , 7 Considering the logistical challenges of these trials (patient heterogeneity, confounding effects of medications, comorbid conditions, and others), results of these clinical studies hardly mean absolute lack of efficacy but rather highlight the biological complexity that underlies neurocognitive dysfunction in TSC.
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