topiramate and Brain-Injuries--Traumatic

Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%-20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease-modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N-acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially "repurposable" medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury-treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose-blood level relationship, brain target engagement, and dose-response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecu

Topics: Acetylcysteine; Animals; Anticonvulsants; Antioxidants; Atorvastatin; Brain Injuries, Traumatic; Ceftriaxone; Dibenzazepines; Drug Repositioning; Epilepsy; Epilepsy, Post-Traumatic; Erythropoietin; Fingolimod Hydrochloride; GABA Agents; Gabapentin; Humans; Immunologic Factors; Inflammation; Interleukin 1 Receptor Antagonist Protein; Isoflurane; Levetiracetam; Losartan; Neuroprotective Agents; Oxidative Stress; Pregabalin; Pyrrolidinones; Sirolimus; Stroke; Topiramate; Translational Research, Biomedical; Vigabatrin

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Topiramate is an effective treatment for alcohol use disorder (AUD) and has also been used in the care of mild traumatic brain injury (mTBI). This pilot study aimed to obtain a preliminary assessment of topiramate's efficacy in reducing alcohol use and post-concussive symptoms, and its potential negative impact on cognitive function in 32 Veterans with co-occurring AUD and mTBI.. This was a prospective 12-week, randomized, double-blind, placebo-controlled pilot study of flexible-dose topiramate or placebo. Primary outcome was reduction of drinking days per week within the topiramate arm. Secondary outcomes included between group comparisons of alcohol use and craving, post-concussive symptoms, and cognitive function.. Drinking days per week significantly decreased within both the topiramate and placebo arm. There were no significant treatment-by-week interactions on alcohol use/craving, or post-concussive symptoms in intent-to-treat analyses. In per-protocol analyses, topiramate significantly reduced number of drinks per week compared with placebo. Topiramate transiently impaired verbal fluency and working memory. Processing speed, cognitive inhibition, and mental flexibility significantly improved between weeks 1 and 12, regardless of treatment arm.. Significant improvement occurred in both the topiramate and placebo groups over 12 weeks of treatment in alcohol use and post-concussive symptoms. Among treatment completers there was greater reduction of alcohol use in the topiramate arm. Topiramate was also associated with negative but transient effects on cognitive function. Results suggest both a possible benefit for topiramate treatment in reducing alcohol use and some potential for negative cognitive effects in Veterans with AUD and mTBI.

Topics: Adult; Alcohol Drinking; Alcoholism; Anticonvulsants; Brain Injuries, Traumatic; Cognition; Craving; Double-Blind Method; Female; Humans; Male; Middle Aged; Pilot Projects; Post-Concussion Syndrome; Prospective Studies; Topiramate; Treatment Outcome; Veterans