Progressive myoclonic epilepsy type 1 (EPM1) is caused by biallelic alterations in the CSTB gene, most commonly dodecamer repeat expansions. Whilst transcranial magnetic stimulation (TMS)-induced long-interval intracortical inhibition (LICI) was previously reported to be normal in EPM1, short-interval intracortical inhibition (SICI) was reduced. We explored the association between these measures and clinical and genetic features in separate group of patients with EPM1.
TMS combined with electromyography was performed under neuronavigation. LICI induced with inter-stimulus interval (ISI) of 100ms, and SICI with ISIs 2 and 3ms, and their mean (mSICI) were expressed as the ratio of conditioned to unconditioned stimulus. LICI and mSICI were compared between patients and controls. Non-parametric correlation was used to study the association between inhibition and parameters of clinical severity, including Unified Myoclonus Rating Scale (UMRS); among patients with EPM1 due to biallelic expansion repeats also the association with the number of repeats was assessed.
The study protocol was completed in 19 patients (15 with biallelic expansion repeats and 4 compound heterozygotes), and 7 healthy, age and sex-matched control participants. Compared to controls, patients demonstrated significantly less SICI (median mSICI ratio 1.18 vs. 0.38; p<0.001). Neither LICI or SICI were associated with parameters of clinical severity. In those with biallelic repeat expansions, the number of repeats in the more affected allele (greater repeat number, GRN) correlated with LICI (rho=0.872; p<0.001) and SICI (rho=0.689; p=0.006).
Our results strengthen the finding of deranged GABAergic inhibition in EPM1. LICI and SICI may have use as markers of GABAergic impairment in future trials of disease-modifying treatment in this condition. Whether higher number of expansion repeats leads to greater GABAergic impairment warrants further study.