Abstracts

Rationale:
There is increasing interest in the usage of precision medicine in the treatment of the epilepsies. In this regard, genomics has been of central importance to facilitate this approach
Method:
The first case is a 33 year old male patient with refractory epilepsy since the age of three. Despite the use of 18 different anti-seizure medicines over the course of his life, focal seizures did not respond. Psychiatric and cognitive symptoms were also very prominent in this case, to the extent that this man lived in a supervised living arrangement. Brain magnetic resonance imaging did not show any potentially epileptogenic lesions, and EEG showed bilateral independent epileptiform discharges, thus resective surgery was not an option. Whole exome sequencing revealed a pathogenic variant in DEPDC5. The second case is of a 48 year-old man with epilepsy since age four and similarly proved refractory to medication, with failure of six anti-seizure medicines and nocturnal seizures that occurred between once and three times per night without remission at any point. Again brain imaging did not show any lesions, and EEG was complex and demonstrated involvement of both parietal and frontal lobes without any clear focal onset for seizures, surgery was not considered as a treatment therefore. Whole exome sequencing again revealed a pathogenic variant in DEPDC5.
Results:
Both cases were started on 10mg of everolimus once a day. Everolimus is an mTOR inhibitor typically used for the treatment of tuberous sclerosis but never previously reported to be used in epilepsy arising from variants in the DEPDC5 gene. The rationale for use as a precision medicine in these cases was that the systems biology of DEPDC5 has demonstrated involvement of the mTOR pathway. Following six months of treatment case one had an improvement in cognition, and a reduction in seizure frequency estimated to be one third by family members. The second case, who had exclusively nocturnal seizures had an 85% reduction in seizure frequency as confirmed by his partner. Neither case experienced any adverse side effects with everolimus.
Conclusion:
We describe the first usage of everolimus as a precision medicine in the treatment of non-lesional refractory focal epilepsy due to pathogenic variants in the DEPDC5 gene. Both cases had previously failed more than six anti-seizure medicines and following initiation of everolimus experienced a significant improvement in seizure control due to an adoption of a precision medicine approach.
Funding:
:This work was supported by research grants from Epilepsy Ireland, the Health Research Board (MRCG-HRB-2018-05) and Science Foundation Ireland (SFI) (16/RC/3948 and 13/CDA/2223) and co-funded under the European Regional Development Fund and by FutureNeuro industry partners