Antecedent Neonatal Hypoglycaemic Brain Injury, commonest cause of Early-Childhood Epilepsy in Indian Children

Abstract

Paediatric epilepsies have diverse etiologies from structural brain lesions to monogenic disorders. Prospective studies from low-middle income countries which had used modern diagnostic methods like 3-T MRI and genetic testing for underlying causes in early-childhood epilepsies, are lacking. Similarly, data on long-term epilepsy outcomes is also not available. In this prospective study, consecutive patients with onset of epilepsy till five years of age were enrolled. Following detailed clinical phenotyping and after ruling out a structural-acquired cause on 3T-MRI, sequential genetic testing with Exome sequencing (ES) as a trio and if required Chromosomal Microarray (CMA)/Multiplex ligand PCR assay (MLPA) were performed. After this evaluation, patients were classified into International League Against Epilepsy (ILAE) defined etiological groups. Phenotypic differences between acquired and congenital causes were also evaluated. Epilepsy outcome at 24 months follow-up was ascertained. Two hundred and thirty-one children were recruited over 12 months. The underlying etiology could be confirmed in 176 (76%) patients. The structural group (54%) was the commonest, followed by genetic (19.5%), metabolic (2%), Unknown (19%) and incompletely investigated (5%: Normal MRI, genetic evaluation not consented). Neonatal Hypoglycaemic Brain Injury (NHBI) was the most common single cause (50; 22%). The broad aetiological groups included acquired causes in 47% and congenital causes in 53%. In the acquired cohort, the predominant initial seizure type was a focal seizure (P = 0.01) or an Infantile Spasm (P < 0.001), while generalized seizures were more frequent in the congenital group (P < 0.001). Patients with an acquired cause were more likely to have IUGR, developmental delay, cortical visual impairment, and hypertonia (all P < 0.001). MRI helped confirm the underlying cause in 126 (54.5%) of the patients. A molecular diagnosis was achieved in 61 (54%) of 113 tested. ES as a trio was diagnostic in 50%, while CMA was 3%. Mutation positivity was more likely with seizure onset in infancy, developmental delay or presence of hypotonia (all P < 0.001), or Developmental and Epileptic Encephalopathy (P = 0.01). A total of 57 of 207 (28%) patients at 24 months follow-up had drug-resistant epilepsy (DRE). On multivariate regression, only the younger age of seizure onset (P = .027) and developmental delay (P = .025) were associated with DRE. In this comprehensive prospective study of Indian children with early childhood epilepsy, using cutting-edge technology, we could confirm an underlying etiology in a majority of our patients. NHBI, a preventable condition was the commonest underlying cause. It is pertinent, that in India, guidelines on correct postnatal feeding practices are formulated urgently.