Potential for Therapeutic Alteration of the Underlying Biology of Epilepsy

Approximately 30-35% of people with epilepsy experience seizures despite taking antiseizure medications. Recurrent seizures that are independent of status epilepticus can be associated with neuronal injury and structural changes to the brain, as well as diminished cognitive function, mood, and quality of life. A treatment that alters the underlying biology of epilepsy, thereby reducing the seizure burden and its attendant consequences, would be of great value in preventing these detrimental effects. In this review, we summarize preclinical and clinical research on pharmacological treatments that may favorably alter the underlying biology of epilepsy (i.e., disease modification or antiepileptogenesis). A reduction in seizures over time (e.g., increase in responder rates) or prevention of epilepsy in susceptible individuals has been observed with therapies that target neurotransmission (cenobamate, cannabidiol, vigabatrin, and diazepam nasal spray) and inflammation (everolimus), though evidence is limited and in preliminary stages. Pharmacological treatments that target neuroinflammation and oxidative stress have the potential to modify seizure phenotype and 1 or more comorbidities in preclinical studies (e.g., stress/anxiety and depression). Gene therapies and stem-cell-derived treatments also hold promise in reducing seizure burden in preclinical models, with several therapeutic candidates having advanced to phase 1/2 and 3 clinical trials. Effective disease-modifying strategies in epilepsy might include seizure control with novel antiseizure medications in combination with therapeutic targeting of key pathophysiological mechanisms. Standard criteria and a definition of disease modification should be established. Importantly, given the heterogeneity of the epilepsies, syndrome- or seizure-specific methods and trial design would likely be required.