Abstracts

Rationale: Previous work has shown that epilepsy has a complex inheritance. Transcranial magnetic stimulation (TMS) is a non-invasive technique used to measure cortical excitability in vivo. Numerous studies have shown abnormal cortical excitability in people with a variety of epilepsy syndromes (Neurology, 2001, 57(10) 1793-1799). It is postulated that abnormal cortical excitability causing seizure predisposition may be the result of intrinsic neuronal membrane instability (Annu Rev Physiol, 2001, 63:815-40), or instability in local cortical networks (Epilepsia, 2003, 44, (12) 72-83). One observed TMS phenomenon is intrinsic variability in the motor evoked potential (MEP) waveform (Clinical Neurophys, 2003, 114, 2362-2369). Anecdotally, the authors have noted the MEP in people with epilepsy to be polyphasic (multiple peaks and troughs within an MEP) and hypothesise that this may reflect this cortical instability. Endophenotypes are heritable traits observable with special investigation and may be present in asymptomatic family members. Endophenotypes can help increase our understanding of the pathophysiology of complex genetic diseases such as epilepsy. TMS parameters have been shown to be heritable (J Neurosci 2009; 28(6): 464-73). Methods: We studied twenty three IGE patients (5 JME, 1 JAE, 4 CAE, 3 unclassified, 9 with GTCS only, 1 with absence with eyelid myoclonus), 32 of their first-degree relatives and 31 age- and gender-matched healthy controls. TMS was performed using two Magstim 200 stimulators connected via a MagStim BiStim with EMG activity measured from first dorsal interosseus muscle. Single pulse TMS was used to obtain resting (RMT) and active motor threshold (AMT). A widely-used protocol from paired-pulse data was used in these subjects; here, we extracted only the unconditioned MEPs for further analysis. We used a semi-automated method to count the phases of the MEPs. Group differences were investigated using Mann-Whitney U. Results: Participants with epilepsy had significantly increased number of phases in the MEP (a larger number of peaks and troughs) in comparison to controls (left hemisphere (LH) U=245, P=0.022; right hemisphere (RH) U=175, p=0.006). First-degree relatives also had significantly increased polyphasic activity in comparison to controls (LH) U=378.5, P=0.093, (RH) U=333.5, P=0.018. There were no significant differences between patients and relatives. Conclusions: Increased polyphasia of the MEP in patients and their first degree relatives may reflect increased membrane instability of the cortical neurons activated by TMS. This may also reflect increased instability in cortical networks, giving rise to multiple descending corticospinal volleys, possibly as a result of brief abnormal oscillations induced by TMS. It could be argued that differences between patients and controls are due to anti-epileptic medication; however, the polyphasic activity in first-degree relatives may demonstrate an innate inherited alteration in cortical excitability i.e. an endophenotype of epilepsy.