Emerging role of targeted therapy in drug-resistant epilepsy in patients with glioma

Seizures are among the most frequent and disabling manifestations of gliomas, and in some patients remain drug-resistant despite optimal antiseizure medication and standard antitumour treatments. This review examines the clinical evidence that targeted therapies may improve seizure control in patients with glioma.

The strongest signal comes from mutant isocitrate dehydrogenase (IDH1/2) inhibition. In the phase 3 INDIGO trial, exploratory and posthoc analyses showed an on-treatment seizure rate of 18.2 per person-year with vorasidenib vs. 51.2 with placebo [rate ratio 0.36, 95% confidence interval (CI) 0.14-0.89]. Emerging real-world series and individual case reports support these findings, and preclinical work indicates an antiseizure effect at least partly independent of tumour control. BRAF/MEK inhibition and mTOR inhibition have an established antitumour role in circumscribed astrocytic and glioneuronal tumours, and everolimus reduces both tumour volume and pharmacoresistant seizures in tuberous sclerosis complex. Beyond genotype, the shared circuitry of tumourigenesis and epileptogenesis, such as neuron-glioma synapses, has generated a second wave of candidate targets, none yet clinically validated.

Targeted agents are emerging as disease-modifying options that may also reduce seizure burden, but seizure freedom must be tested in future trials as a prespecified endpoint rather than inferred from exploratory analyses.