Perampanel as add-on in high-grade glioma–related epilepsy: Seizure control and QoL in a prospective, multicenter, real-world 6-month follow-up study

Objective: High-grade astrocytomas, including glioblastomas, are aggressive brain tumors with poor prognosis and a 5-year survival below 7%. Seizures affect up to 75% of glioma patients, especially in low-grade tumors but also in high-grade cases. Elevated extracellular glutamate in peritumoral tissue—due to tumor release, impaired uptake, and metabolic changes like D-2-hydroxyglutarate in IDH1-mutated tumors—contributes to neuronal hyperexcitability and tumor progression via AMPA and NMDA receptors' activation. Perampanel (PER), a selective noncompetitive AMPA receptor antagonist, targets this pathway, potentially reducing seizures and tumor growth. Clinical data on the use of perampanel in brain tumor-related epilepsy, particularly in patients with high-grade gliomas, are still limited. Methods: This prospective multicenter observational study included 14 patients with brain tumor-related epilepsy (BTRE) from four Italian neuro-oncology centers. Patients received PER and were followed for 6 months. Seizure frequency, adverse events, quality of life (QoL), and survival were evaluated as real-world effectiveness outcomes. Results: Seizure frequency decreased from 12.5 to 3 seizures/month at 6 months (p = 0.0023). Responder rate (≥50% seizure reduction) was 78.6%, with 57.1% seizure-free. Adverse events were mild; two patients discontinued PER treatment. QoL analyses showed improvement in communication and appetite even if not statistically significant. Survival analyses revealed no significant associations with clinical variables. Sensitivity analyses supported the consistency of results. Significance: This real-world study suggests that PER may be effective and well tolerated in BTRE. While findings are exploratory, they provide useful clinical insight and highlight the need for larger studies to confirm efficacy, QoL effects, and the influence of molecular factors. Plain Language Summary: Patients with aggressive brain tumors often develop seizures that are difficult to control. In this study, perampanel reduced the number of seizures and did not worsen quality of life, being generally well tolerated. Patient survival was mainly determined by the tumor itself. Larger studies are needed to confirm the drug's effectiveness in reducing seizures, improving quality of life, evaluating survival, and monitoring side effects.