Perampanel as Precision Therapy in Rare Genetic Epilepsies

Objective: Perampanel, an antiseizure drug with AMPA-receptor antagonist properties, may have a targeted effect in genetic epilepsies with overwhelming glutamate receptor activation. Special interest holds epilepsies with loss of GABA inhibition (e.g. SCN1A), overactive excitatory neurons (e.g. SCN2A, SCN8A ), and variants in glutamate receptors (e.g. GRIN2A). We aimed to collect data from a large rare genetic epilepsy cohort treated with perampanel, to detect possible subgroups with high efficacy. Methods: A multicenter project based on the framework of NETRE (Network for Therapy in Rare Epilepsies), a web of pediatric neurologists treating rare epilepsies. Retrospective data from patients with genetic epilepsies treated with perampanel was collected. Outcome measures were responder rate (50% seizure reduction), and percentage of seizure reduction after 3 months of treatment. Subgroups of etiologies with high efficacy were identified. Results: 137 patients, with 79 different etiologies, aged 2 months-61 years (mean 15.48±9.9) were enrolled. The mean dosage was 6.45±2.47 mg, and treatment period was 2.0±1.78 years (1.5 months-8 years). 62 patients (44.9%) were treated for >2 years. 98 patients (71%) were responders, and 93 (67.4%) chose to continue therapy. The mean reduction in seizure frequency was 56.61±34.36%. 60 patients (43.5%) sustained over 75% reduction in seizure frequency, including 38 (27.5%) with > 90% reduction in seizure frequency. The following genes showed high treatment efficacy: SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, POLG1, POLG2, NEU1. 11/17 (64.7%) of patients with SCN1A, 35.3% of which had over 90% seizure reduction. Other etiologies remarkable for over 90% reduction in seizures were GNAO1 and PIGA. 14 patients had a CSWS EEG pattern and in 6 subjects perampanel reduced epileptiform activity. Significance: Perampanel demonstrated high safety and efficacy in patients with rare genetic epilepsies, especially in SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, CDKL5, NEU1 and POLG, suggesting a targeted effect related to glutamate transmission

Opposite changes of regulatory T cell blood content may differentially contribute to atherosclerosis or lymphoproliferative disorders

Background. Chronic autoimmune inflammation in arterial wall may lead to atherosclerosis progression. Objective. The aim of this study was to investigate the association between Treg, Th17 and B1a cell blood frequencies as well as IgM autoantibodies to oxLDL and the abundance of carotid atherosclerosis. Material and methods. 18 patients with increased IMT (intima-media thickness) and 65 patients with different severity of carotid atherosclerotic plaques were included. Treg, Th17 and B1a cell blood frequencies were assessed via direct immunofluorescence staining and flow cytometry, oxLDL as well as IgM autoantibodies to oxLDL were measured with commercial kits. Results. We observed higher values of Treg in patients without carotid atherosclerosis. Patients with intact carotid arteries as compared to patients with mild atherosclerotic plaques had decreased Th1 levels. OxLDL IgM levels were higher in patients with intact carotid arteries. Patients who received statin treatment had higher levels of Treg. Immunophenotyping of B cells revealed two cases of monoclonal B-cell lymphocytosis and 1 case of B-CLL (B-cell chronic lymphocytic leukemia) in elderly patients with intact carotid arteries. Conclusion. We hypothesize that certain parameters of cell immunity may hamper atherosclerosis while protecting from lymphoproliferative disorders