Abstracts

Rationale: Familial focal epilepsy with variable foci (FFEVF) and focal cortical dysplasia are increasingly recognized as associated with mutations in the mTOR pathway. Despite its safety and efficacy, surgery is often considered late or denied in cases of drug-resistant focal epilepsy, not uncommonly after failure to demonstrate a causative lesion. Recent experience from our epilepsy program suggests that genetics may be an additional criterion to pursue surgical candidacy.

Methods: We describe three subjects (proband, sister, cousin) with drug resistant FFEVF. All were evaluated using a standard pre-surgical evaluation including genetic investigation (via commercially available epilepsy panel in the proband, known familial mutation testing in the others), MRI, FDG-PET, SPECT with SISCOM and video-EEG monitoring. All underwent research-based MEG and EEG-fMRI. Careful review by the epileptologist and the neuroradiologist was performed when initial interpretation of MRI data failed to reveal a lesion. Research-based MRI voxel-based post-processing (VBPP) was performed for one subject whose MRI did not reveal an anomaly. All underwent surgical excision of the lesion using standard surgical techniques supplemented by intra-operative MRI-based neuronavigation. Specimen were submitted to neuropathology for clinical diagnosis, and for research-based genetic analyses.

Results: The proband had a clearly visible FCD on MRI with corresponding PET hypometabolism. Surgery was not initially considered due to a suspicion of bilateral independent seizures. Next-generation sequencing revealed pathogenic mutations in NPRL3 and MT-TK, with a low degree of mosaicism for MT-TK and no end-organ dysfunction. The proband’s sibling and cousin had long standing focal epilepsy but no diagnosed lesion. Genetic investigations confirmed the mutation in NRPL3 but not MT-TK in both. Review of available MRIs revealed a transmantle dysplasia in the sibling, with congruent hypometabolism on previous PET. VBPP revealed a small transmantle dysplasia, supported by MEG results, that was overlooked on visual inspection of the MRI. All had ictal and interictal EEG anomalies and semiology compatible with their respective lesions. Pathology found FCD IIa in all cases. Genetics results on the excised tissue is underway. The proband and sister were four and five months seizure-free at the time of submission (from daily seizures prior), with the cousin operated two weeks prior to submission but seizure-free at the moment.

Conclusions: In the context of MRI-negative drug resistant epilepsy, especially when faced with FFEVF, genetic investigations should be considered. Whenever a mTOR pathway mutation is found, the likelihood of a previously undiagnosed FCD and therefore favorable surgical outcome should lead the clinician to reevaluate available investigations and obtain necessary data to assess surgical candidacy.

Funding: Please list any funding that was received in support of this abstract.: Canadian Institute of Health Research; Fond de Recherche du Quebec; Canada Foundation for Innovation; Foundation of the Department of Neurosurgery, McGill University; Epilepsy Canada.