Clinical and histopathological outcomes in patients with SCN1A mutations undergoing surgery for epilepsy

Abstract

obJect Mutations in the sodium channel alpha 1 subunit gene (SCN1A) have been associated with a wide range of epilepsy phenotypes including Dravet syndrome. There currently exist few histopathological and surgical outcome reports in patients with this disease. In this case series, the authors describe the clinical features, surgical pathology, and outcomes in 6 patients with SCN1A mutations and refractory epilepsy who underwent focal cortical resection prior to uncovering the genetic basis of their epilepsy. methods Medical records of SCN1A mutation-positive children with treatment-resistant epilepsy who had undergone resective epilepsy surgery were reviewed retrospectively. Surgical pathology specimens were reviewed. results All 6 patients identified carried diagnoses of intractable epilepsy with mixed seizure types. Age at surgery ranged from 18 months to 20 years. Seizures were refractory to surgery in every case. Surgical histopathology showed evidence of subtle cortical dysplasia in 4 of 6 patients, with more neurons in the molecular layer of the cortex and white matter. conclusions Cortical resection is unlikely to be beneficial in these children due to the genetic defect and the unexpected neuropathological finding of mild diffuse malformations of cortical development. Together, these findings suggest a diffuse pathophysiological mechanism of the patients' epilepsy which will not respond to focal resective surgery. However, other authors have hypothesized that SCN1A mutations may actually protect from hippocampal sclerosis.2 Few pathological cases of Dravet syndrome have been published to date. 3,5,13,15,18 Most were case reports of autopsy specimens, and many had not undergone SCN1A testing. In this study, we review the clinical features and surgical pathology in 6 patients with treatment-resistant epilepsy who underwent surgery for intractable focal seizures and were later found to have presumed pathogenic mutations in SCN1A. We also review their outcomes and seek to draw conclusions regarding surgical evaluation and management. methodsThe medical records of 6 children with SCN1A mutations who underwent epilepsy surgery for medically refractory epilepsy were reviewed retrospectively. Patients were identified at the Children's Hospital of Philadelphia by surveying the epilepsy group to identify patients who had undergone epilepsy surgery and were later found to have SCN1A mutations. An additional patient was identified at the Cincinnati Children's Hospital. Data extracted included age at seizure onset, initial seizure types, clinical course, and neuroimaging and electroencephalography (EEG) reports. Surgical outcomes were classified using the International League Against Epilepsy (ILAE) surgical outcome scale as of their last follow-up visit. 24SCN1A mutation testing was done at commercially available laboratories (Athena and Transgenomics). A mutation was considered pathogenic if it was previously described as such, was a truncation mutation, or was a novel mutation with predicted pathogenicity (based o...

Epilepsy surgery for patients with genetic refractory epilepsy: a systematic review

“…These epileptogenic mutations were found in the voltage-gated sodium channels SCN1A and SCN1B (Helbig et al, 2008), the gene CNTNAP2 which is involved in AMPA-receptor trafficking and excitatory neuronal network activity (Anderson et al, 2012;Varea et al, 2015), and STXBP1, which is involved in the release of neurotransmitters (Weckhuysen et al, 2013). Epilepsy surgery did not lead to complete seizure freedom in any of the eight patients with SCN1A mutations who underwent epilepsy surgery, even though six of them had focal seizure semiology which co-localized with MRI-visible lesions (Barba et al, 2014;Skjei et al, 2015). Outcome data concerning specific seizure types that were primarily targeted by the surgical procedure (e.g.…”

Epilepsy surgery in patients with autism

“…Our results are also consistent with recent reports of poor outcomes of surgery in patients with SCN1A mutations. 4,42 On the other hand, the patient in Case 10, with a family history of epilepsy associated with developmental delay (who could not be positively diagnosed using the genetic testing available at the time) became seizure free and made excellent developmental progress after a resection. Although many of the patients in our series were able to reduce the number of medications following surgery, only 3 of the 22 patients who underwent resection with a > 2-year follow-up were able to discontinue all AEDs (Cases 10, 32, and 33).…”

A stereo EEG study in a patient with sleep-related hypermotor epilepsy due to DEPDC5 mutation

“…Even considering other genetic forms of FE, data on the role of genetics as a predictor of surgical outcome are controversial. While some case reports showed a good outcome in pediatric NPRL3-related epilepsy [14], others demonstrated that a surgical approach gave no benefits, such as in SCN1A-related epilepsy [15]. Other conditions, such as tuberous sclerosis, have their own management.…”