Abstracts

Rationale: Inherited channelopathies have become increasingly recognized as an important cause of epilepsy. Over the past decade, hundreds of mutations of the SCN1A gene have been associated with a wide range of epilepsy phenotypes, including generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy in infancy (SMEI or Dravet Syndrome). The leading hypothesis for the patholophysiologic mechanism underlying the epilepsy in patients with sodium channel mutations is that an alteration of sodium currents, particularly in interneurons, leads to decreased inhibition and an epileptic state. Targeted pharmacological management, however, is often unsuccessful and not all patients placed on sodium channel blocking agents develop worsening seizures. The question arises whether other pathophysiologic mechanisms may be involved. In this cases series, we describe the clinical features and surgical pathology of 4 patients with treatment resistant epilepsy who underwent focal cortical resection and were later found to carry SCN1A mutations.Methods: We performed a retrospective review of the medical records of four SCN1A-mutation positive patients with treatment-resistant childhood onset epilepsy. Data regarding clinical course, neuro-imaging, electroencephalographic reports, and SCN1A mutation type were extracted. Surgical pathology specimens were reviewed and immunohistochemistry performed for the presence of the SNC1A receptor in this tissue.Results: All patients carried diagnoses of intractable epilepsy with mixed seizure types. Seizure onset in all patients occurred within the first year of life. All patients had tried and failed at least five antiepileptic medications. Two patients carried SCN1A mutations previously associated with severe phenotype (one deletion, and one missense mutation). One patient possessed a frame shift (insertion) leading to premature stop. One patient carried a novel mutation of unknown significance in a highly conserved region of the gene. All patients had MRI and/or MEG findings that colocalized with seizure semiology and cranial and/or intracranial electrographic findings. Age at surgery ranged from 18 months to 20 years. All four patients underwent focal cortical resection; one underwent simultaneous corpus callosotomy. All patients showed some clinical improvement immediately following surgery but subsequently continued seizing. Surgical histopathology showed an increased number of neurons in the white matter in three subjects. One patient each showed indistinct cortical layers and multifocal intracortical neuron clusters. In patients with excess neurons in the white matter, these neurons were SCN1A positive on immunostaining.Conclusions: In this case series of four SCN1A-mutation positive children with treatment-resistant epilepsy who underwent focal resective surgery, three patients neuropathological specimens demonstrated cortical microdysgenesis. This raises the possibility that the increased epileptogenicity in SCN1A mutation positive patients maybe due in part to disruption of normal brain development.