Growing identification of genetic aetiologies for neonatal‐onset epilepsies: lessons from the Neonatal Seizure Registry

Abstract

Neonatal seizures affect 1-5 per 1000 live births. While most neonates have seizures secondary to an acute insult, some have a neonatal epilepsy syndrome, typically caused by a genetic mutation and/or a brain malformation (1–3). The evaluation and management of these patients are evolving, complicated by the rarity of these disorders. Shellhaas et al. (2017) have made a significant contribution to the field by assembling one of the largest prospective cohorts of neonates with seizures, 79 of whomhad epilepsy. The cohort was rigorously collected using consecutive enrolment and following ACNS guidelines for EEG-confirmation of seizures to standardise diagnosis (4). Practice variations across centres can make assessment of seizure burden challenging. The authors successfully quantified seizure burden with a novel categorical scale, though the clinical significance of these categories is not explained in the study. Despite the impressive collaboration, certain neonatal epilepsy syndromes (i.e. vitamin-responsive epilepsies) were not captured, highlighting the need for larger studies of longer duration. The study provides an interesting comparison between children with acute symptomatic seizures and those with neonatal epilepsy. The groups were similar in most ways, though neonates with acute symptomatic seizures had a longer duration of EEG monitoring and more subclinical seizures than those with epilepsy. These differences may have been driven by clinical guidelines that dictate all neonates with HIE undergo 72–96 hours of EEG monitoring. As different standards of monitoring were applied, there may have been underestimation of subclinical seizures in the epilepsy group due to this information bias. The study provides a careful description of the hospital courses of neonates with epilepsy, including their seizure characteristics, work-up and treatment. Most interestingly, 59% of children with neonatal epilepsy who underwent testing had an identifiable genetic cause, including 83% of those with an epileptic encephalopathy. The detailed genetic testing results in Table e-1 further highlight the diagnostic yield of such testing, with variants of uncertain significance in only 5/35 tested. However, even in this cohort taken from level IV NICUs, only 73% underwent genetic testing. The authors conclude that genetic testing is warranted to guide management and prognosis. In considering this conclusion, clinicians must weigh the limitations of this study, which include issues inherent to the observational study design. The clinical rationale behind genetic testing is not detailed in the paper, and it therefore cannot be determined whether the untested and tested groups were comparable. Finally, this study does not address whether genetic information influences clinical decision making; for many genetic mutations, there is still little clinical consensus on management. Despite these caveats, this work illustrates that genetic testing identifies the aetiology of neonatal epilepsy in a substantial subset of the population. Diagnostic yield will increase as epilepsy gene panels and whole exome sequencing techniques evolve. Understanding the genetic basis for neonatal epilepsy may change the course of these illnesses, as there is growing evidence that specific genetic conditions benefit from specific medications (i.e. carbamazepine for KCNQ2 mutations) (5,6). Improved early seizure control may in turn lead to improved cognitive outcomes (3,7).