Cenobamate and Clobazam Combination as Personalized Medicine in Autoimmune-Associated Epilepsy With Anti-Gad65 Antibodies.

BACKGROUND AND OBJECTIVES: Autoimmune-associated epilepsy (AAE) with antiglutamic acid decarboxylase 65 (GAD65) antibodies is considered a T-cell-mediated encephalitis that evolves to drug-resistant epilepsy. We do not have an effective therapeutic strategy for these patients. Because the GAD enzyme is primarily responsible for the conversion of glutamate to GABA, the mechanism of epileptogenesis in this condition predicts decreased levels of GABA content in synaptic vesicles. Cenobamate (CNB) acts as a positive allosteric modulator at synaptic and extra synaptic GABAA receptors, producing increased inhibitory neurotransmission in the brain. This mechanism could be especially beneficial in AAE with anti-GAD65 antibodies because it would be able to correct the imbalance due to the GABAergic stimulation deficit in postsynaptic neurons. METHODS: We recruit a retrospective multicentric consecutive case series of AAE with anti-GAD65 antibodies from 5 epilepsy units in Spain who have received treatment with CNB. RESULTS: A total of 8 patients were recruited. This cohort of highly refractory patients have failed a mean of 9.50 (SD = 3.20) ASM without control of seizures for sustained periods of time. The average number of seizures per month during the previous 3 months before CNB treatment was 19.63 (SD = 17.03). After the introduction of CNB improvement was achieved in all our patients, with a median reduction in the number of seizures of 92.22% (interquartile range [IQR]: 57.25-98.75). The mean follow-up was 156.75 days (SD = 68.23). In patients with concomitant treatment with clobazam (CLB), the median percentage of seizure reduction was higher than those not taking CLB: 94.72% (IQR: 87.25-100) vs 41.50% (p = 0.044) and also higher than the control group of patients with refractory epilepsy not related to anti-GAD65 treated with the same combination: 94.72% (IQR: 87.25-100) vs 45.00% (IQR: 25.00-87.00) (p = 0.019). DISCUSSION: Treatment with the combination CNB + CLB could be a type of personalized medicine in patients with AAE with anti-GAD65. Our preliminary data will need to be endorsed with new prospective and controlled studies.

Real-world safety and effectiveness of cenobamate in patients with focal onset seizures: Outcomes from an Expanded Access Program.

OBJECTIVE: This study investigated early, real-world outcomes with cenobamate (CNB) in a large series of patients with highly drug-resistant epilepsy within a Spanish Expanded Access Program (EAP). METHOD: This was a multicenter, retrospective, observational study in 14 hospitals. Inclusion criteria were age ≥18 years, focal seizures, and EAP authorization. Data were sourced from patient clinical records. Primary effectiveness endpoints included reductions (100%, ≥90%, ≥75%, and ≥50%) or worsening in seizure frequency at 3-, 6-, and 12-month visits and at the last visit. Safety endpoints included rates of adverse events (AEs) and AEs leading to discontinuation. RESULTS: The study included 170 patients. At baseline, median epilepsy duration was 26 years and median number of seizures/month was 11.3. The median number of prior antiseizure medications (ASMs) and concomitant ASMs were 12 and 3, respectively. Mean CNB dosages/day were 176 mg, 200 mg, and 250 mg at 3, 6, and 12 months. Retention rates were 98.2%, 94.5%, and 87% at 3, 6, and 12 months. At last available visit, the rate of seizure freedom was 13.3%; ≥90%, ≥75%, and ≥50% responder rates were 27.9%, 45.5%, and 63%, respectively. There was a significant reduction in the number of seizures per month (mean: 44.6%; median: 66.7%) between baseline and the last visit (P < 0.001). Responses were maintained regardless of the number of prior or concomitant ASMs. The number of concomitant ASMs was reduced in 44.7% of patients. The cumulative percentage of patients with AEs and AEs leading to discontinuation were 68.2% and 3.5% at 3 months, 74.1% and 4.1% at 6 months, and 74.1% and 4.1% at 12 months. The most frequent AEs were somnolence and dizziness. SIGNIFICANCE: In this highly refractory population, CNB showed a high response regardless of prior and concomitant ASMs. AEs were frequent but mostly mild-to-moderate, and few led to discontinuation.

Perampanel in routine clinical use in idiopathic generalized epilepsy: The 12-month GENERAL study.

OBJECTIVE: To analyze the effectiveness and tolerability of perampanel across different seizure types in routine clinical care of patients with idiopathic generalized epilepsy (IGE). METHODS: This multicenter, retrospective, 1-year observational study collected data from patient records at 21 specialist epilepsy units in Spain. All patients who were aged ≥12 years, prescribed perampanel before December 2016, and had a confirmed diagnosis of IGE were included. RESULTS: The population comprised 149 patients with IGE (60 with juvenile myoclonic epilepsy, 51 generalized tonic-clonic seizures [GTCS] only, 21 juvenile absence epilepsy, 10 childhood absence epilepsy, 6 adulthood absence epilepsy, and one Jeavons syndrome). Mean age was 36 years. The retention rate at 12 months was 83% (124/149), and 4 mg was the most common dose. At 12 months, the seizure-free rate was 59% for all seizures (88/149); 63% for GTCS (72/115), 65% for myoclonic seizures (31/48), and 51% for absence seizures (24/47). Seizure frequency was reduced significantly at 12 months relative to baseline for GTCS (78%), myoclonic (65%), and absence seizures (48%). Increase from baseline seizure frequency was seen in 5.2% of patients with GTCS seizures, 6.3% with myoclonic, and 4.3% with absence seizures. Perampanel was effective regardless of epilepsy syndrome, concomitant antiepileptic drugs (AEDs), and prior AEDs, but retention and seizure freedom were significantly higher when used as early add-on (after ≤2 prior AEDs) than late (≥3 prior AEDs). Adverse events were reported in 50% of patients over 12 months, mostly mild or moderate, and irritability (23%), somnolence (15%), and dizziness (14%) were most frequent. SIGNIFICANCE: In routine clinical care of patients with IGE, perampanel improved seizure outcomes for GTCS, myoclonic seizures, and absence seizures, with few discontinuations due to adverse events. This is the first real-world evidence with perampanel across different seizure types in IGE.