Clinical Research Associate UCL Queen Square Institute of Neurology London, United Kingdom
Rationale: SCN1A encodes the alpha subunit of type 1 voltage-gated sodium channel (NaV1.1). NaV1.1 channels are highly expressed in GABAergic interneurons, with loss-of-function variants leading to impaired action potential generation; this is the assumed parsimonious disease mechanism in Dravet Syndrome (DS) (Curr Opin Physiol 2018;2:42–50), though further complexity is likely. In contrast, milder epilepsy phenotypes such as genetic epilepsy with febrile seizures plus (GEFS+) are associated with SCN1A variants with predicted less severe effect on channel function (Neurology 2011;76:594–600). By using transcranial magnetic stimulation combined with electromyography (TMS-EMG), it was shown that individuals with SCN1A-related DS lack short-interval intracortical inhibition (SICI), a measure of gamma-aminobutyric acid (GABA) type A receptor -mediated inhibition (Neurology 2017;88:1659–65). We hypothesised that loss of SICI in SCN1A-related epilepsies is specific to more severe phenotypes, such as DS. Methods: SICI was measured from the first dorsal interosseus muscle using a conditioning stimulus intensity 70% of the resting motor threshold; interstimulus intervals (ISIs) were 2ms and 3ms. SICI was expressed as the mean ratio of conditioned/unconditioned motor evoked potential amplitudes. Average SICI (across both ISIs) was compared between ten healthy controls (HC), 40 people with non-monogenic epilepsies (EC), 15 SCN1A variant-carrying individuals with DS and 3 SCN1A variant-carrying individuals with GEFS+ using a one-way ANOVA with “group” as factor of analysis. Tukey's honestly significant difference test was used for post-hoc analysis. P-values < 0.05 were considered significant. Results: The effect of “group” on average SICI was significant (F(3,64)=12.11, p< 0.001). Average SICI in the DS group (ratio 1.15) was significantly higher than HC (ratio 0.610, p< 0.001) and EC (ratio 0.592, p< 0.001) groups. SICI in the GEFS+ group (ratio 0.593) did not differ significantly from either the HC or EC groups; the difference to the DS group was significant (p=0.034). Conclusions: We confirmed that SICI is impaired in DS. In keeping with our hypothesis, we found SICI was preserved in SCN1A-variant-carrying GEFS+. Our findings suggest that SICI might be a biomarker for loss of NaV1.1 function in SCN1A-related epilepsies, with potential use in advancing personalised medicine. Funding: Please list any funding that was received in support of this abstract.: EC grant 279062, EpiPGX; UK Department of Health’s NIHR Biomedical Research Centres funding scheme (to NIHR University College London Hospitals Biomedical Research Centre); Epilepsy Society; Wellcome Trust Strategic Award (WT104033AIA); grant funding from UCB to Epilepsy Society.