Efficacy, Tolerability, and Retention of Antiseizure Medications in PRRT2-Associated Infantile Epilepsy

Jan H Döring; Afshin Saffari; Thomas Bast; Knut Brockmann; Laura Ehrhardt; Walid Fazeli; Wibke G Janzarik; Annick Klabunde-Cherwon; Gerhard Kluger; Hiltrud Muhle; Manuela Pendziwiat; Rikke S Møller; Konrad Platzer; Joana Larupa Santos; Julian Schröter; Georg F Hoffmann; Stefan Kölker; Steffen Syrbe

doi:10.1212/NXG.0000000000200020

Efficacy, Tolerability, and Retention of Antiseizure Medications in PRRT2-Associated Infantile Epilepsy

Neurol Genet. 2022 Sep 28;8(5):e200020. doi: 10.1212/NXG.0000000000200020. eCollection 2022 Oct.

Authors

Jan H Döring¹, Afshin Saffari¹, Thomas Bast¹, Knut Brockmann¹, Laura Ehrhardt¹, Walid Fazeli¹, Wibke G Janzarik¹, Annick Klabunde-Cherwon¹, Gerhard Kluger¹, Hiltrud Muhle¹, Manuela Pendziwiat¹, Rikke S Møller¹, Konrad Platzer¹, Joana Larupa Santos¹, Julian Schröter¹, Georg F Hoffmann¹, Stefan Kölker¹, Steffen Syrbe¹

Affiliation

¹ Division of Paediatric Epileptology (J.H.D., A.K.-C., J.S., S.S.), Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg; Division of Paediatric Neurology and Metabolic Medicine (A.S., G.F.H., S.K.), Centre for Paediatric and Adolescent Medicine, University Hospital; Epilepsy Center Kork (T.B.), Kehl-Kork; Medical Faculty (T.B.), University of Freiburg, Freiburg im Breisgau; Interdisciplinary Pediatric Center for Children With Developmental Disabilities and Severe Chronic Disorders (K.B.), Children's Hospital, University Medical Center, Göttingen; Department of Pediatrics (L.E.), University Medicine Mainz; Pediatric Neurology (W.F.), Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne; Institute for Molecular and Behavioral Neuroscience (W.F.), Faculty of Medicine and University Hospital Cologne, University of Cologne; Department of Neuropediatrics and Muscle Disorders (W.G.J.), Faculty of Medicine, University of Freiburg; Clinic for Neuropediatrics and Neurorehabilitation (G.K.), Epilepsy Center for Children and Adolescents, Schoen Clinic Vogtareuth, Germany; Research Institute for Rehabilitation (G.K.), Transition and Palliation, PMU Salzburg, Austria; Department of Neuropediatrics (H.M., M.P.), University Medical Center Schleswig-Holstein, Christian-Albrechts University; Institute of Clinical Molecular Biology (M.P.), Christian-Albrechts-University of Kiel, Germany; The Danish Epilepsy Centre (R.S.M.), Dianalund; Institute for Regional Health Research (R.S.M.), University of Southern Denmark, Odense, Denmark; Institute of Human Genetics (K.P.), University of Leipzig Medical Center, Germany; Wilhelm Johannsen Centre for Functional Genome Research (J.L.S.), Department of Cellular and Molecular Medicine, University of Copenhagen; and Department of Biomedical Sciences (J.L.S.), University of Copenhagen, Denmark.

Abstract

Background and objectives: Pathogenic variants in PRRT2, encoding for the proline-rich transmembrane protein 2, were identified as the main cause of self-limiting sporadic and familial infantile epilepsy. Reported data on treatment response to antiseizure medications (ASMs) in defined monogenic epilepsies are limited. The aim of this study was to evaluate the treatment response of ASMs in children with monogenic PRRT2-associated infantile epilepsy.

Methods: A multicenter, retrospective, cross-sectional cohort study was conducted according to the Strengthening the Reporting of Observational Studies in Epidemiology criteria. Inclusion criteria were occurrence of infantile seizures and genetic diagnosis of likely pathogenic/pathogenic PRRT2 variants.

Results: Treatment response data from 52 individuals with PRRT2-associated infantile epilepsy with a total of 79 treatments (defined as each use of an ASM in an individual) were analyzed. Ninety-six percent (50/52) of all individuals received ASMs. Levetiracetam (LEV), oxcarbazepine (OXC), valproate (VPA), and phenobarbital (PB) were most frequently administered. Sodium channel blockers were used in 22 individuals and resulted in seizure freedom in all but 1 child, who showed a reduction of more than 50% in seizure frequency. By contrast, treatment with LEV was associated with worsening of seizure activity in 2/25 (8%) treatments and no effect in 10/25 (40%) of treatments. LEV was rated significantly less effective also compared with VPA and PB. The retention rate for LEV was significantly lower compared with all aforementioned ASMs. No severe adverse events were reported, and no discontinuation of treatment was reported because of side effects.

Discussion: In conclusion, a favorable effect of most ASMs, especially sodium channel blockers such as carbamezepine and OXC, was observed, whereas the efficacy and the retention rate of LEV was lower in PRRT2-associated childhood epilepsy. Tolerability in these young children was good for all ASMs reported in the cohort.

Classification of evidence: This study provides Class IV evidence that in individuals with PRRT2-associated infantile epilepsy, sodium channel blockers are associated with reduced seizure frequency but levetiracetam is not.