https://doi.org/10.1177/1550059420953735 Clinical EEG and Neuroscience 1–5 © EEG and Clinical Neuroscience Society (ECNS) 2020 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/1550059420953735 journals.sagepub.com/home/eeg Case Report Introduction Childhood drug-resistant epilepsy (DRE) imposes a signi- ficant health burden on family and therapeutic challenges to physicians. 1 Children with DRE are referred to comprehensive epilepsy centres for presurgical evaluation wherein they are subjected to an odyssey of investigations such as video electro- encephalographies (EEG), high-resolution magnetic resonance imaging (MRI), functional, metabolic imaging and other modalities, which may often prove noncontributory. 2 DRE in childhood often manifests as epileptic encephalopathy (EE) with its physical, psychomotor, social comorbidities, and may have structural or genetic causes. 3 While most genetic general- ized epilepsy syndromes of adolescence and adulthood such as epilepsy with generalized tonic-clonic seizures (GTCS) only, juvenile myoclonic and juvenile absence epilepsies portend favorable therapeutic response, the same may not hold true for early childhood onset forms. Original descriptions of “severe idiopathic” generalized epilepsy of infancy with GTCS suggested a genetic basis. 4,5 With the availability of viable commercially available epilepsy gene panels and multiplex ligand protein amplification probes, there has been a steady increase in the genetic diagnosis of a number of complex childhood epilepsy syndromes. 3 Genetic testing is, however, 953735EEG XX X 10.1177/1550059420953735Clinical EEG and NeuroscienceJukkarwala et al case-report 2020 1 Geetanjali Medical College & Hospital, Udaipur, Rajasthan, India 2 Sree Chitra Tirunal Institute for Medical Sciences & Technology, Trivandrum, Kerala, India Corresponding Author: Ramshekhar N. Menon, Department of Neurology, R Madhavan Nayar Centre for Comprehensive Epilepsy Care, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Medical College PO, Trivandrum 695011, Kerala, India. Email: rsnmenon@sctimst.ac.in Electroclinical Phenotype-Genotype Homogeneity in Drug-Resistant “Generalized” Tonic-Clonic Seizures of Early Childhood Anis Jukkarwala 1 , Ramshekhar N. Menon 2 , E. R. Sunesh 2 , and Ashalatha Radhakrishnan 2 Abstract Purpose. Children with refractory focal to bilateral tonic-clonic seizures, despite normal high-resolution imaging, are often not subjected to genetic tests due to the costs involved and instead undergo multimodality presurgical evaluation targeted at delineating a focal onset. The objective of this study was to ascertain genotype-phenotype correlations in this group of patients. Method. An online hospital database search was conducted for children who presented in 2019 with drug-resistant epilepsy dominated by nonlateralizing focal-onset/rapid generalized (bilateral) tonic-clonic seizures (GTCS), subjected to presurgical evaluation and subsequent genetic testing due to absence of a clear focus hypothesis. Results. Phenotypic homogeneity was apparent in 3 children who had onset in infancy with drug-resistant GTCS (predominantly unprovoked and occasionally fever provoked) and subsequent delayed development. 3-Tesla magnetic resonance imaging (MRI) scans were negative and video EEG documented a homogeneous pattern of multifocal and/or generalized epileptiform discharges with phenomenology favoring probable focal-onset/generalized-onset bilateral tonic-clonic seizures. All 3 tested positive for SCN1A gene variants (heterozygous missense substitution variants in 2 children, one of which was novel and a novel duplication in one that led to frameshift and premature truncation of the protein), suggestive of SCN1A-mediated epilepsy. This electroclinical profile constituted 3 out of 25 patients with SCN1A-epilepsy phenotypes at our center. Conclusions. These cases suggest that children with early-onset drug-resistant “generalized” epilepsy are likely to have a genetic basis although the presentation may not be typical of Dravet syndrome. Hence, genetic testing for SCN1A variants is recommended in children with drug-resistant MRI negative focal-onset/generalized-onset bilateral tonic-clonic seizures before subjecting them to exhaustive presurgical workup and to guide appropriate treatment and prognostication. Keywords drug-resistant epilepsy, genetics, generalized tonic clonic seizures, SCN1A, EEG Received March 13, 2020; revised June 24, 2020; accepted August 3, 2020.