A mutation in the sodium channel SCN1A was identified in a small Italian family with dominantly inherited generalized epilepsy with febrile seizures plus (GEFSϩ). The mutation, D1866Y, alters an evolutionarily conserved aspartate residue in the C-terminal cytoplasmic domain of the sodium channel ␣ subunit. The mutation decreased modulation of the ␣ subunit by ␤1, which normally causes a negative shift in the voltage dependence of inactivation in oocytes. There was less of a shift with the mutant channel, resulting in a 10 mV difference between the wild-type and mutant channels in the presence of ␤1. This shift increased the magnitude of the window current, which resulted in more persistent current during a voltage ramp. Computational analysis suggests that neurons expressing the mutant channels will fire an action potential with a shorter onset delay in response to a threshold current injection, and that they will fire multiple action potentials with a shorter interspike interval at a higher input stimulus. These results suggest a causal relationship between a positive shift in the voltage dependence of sodium channel inactivation and spontaneous seizure activity. Direct interaction between the cytoplasmic C-terminal domain of the wild-type ␣ subunit with the ␤1 or ␤3 subunit was first demonstrated by yeast two-hybrid analysis. The SCN1A peptide K1846-R1886 is sufficient for ␤ subunit interaction. Coimmunoprecipitation from transfected mammalian cells confirmed the interaction between the C-terminal domains of the ␣ and ␤1 subunits. The D1866Y mutation weakens this interaction, demonstrating a novel molecular mechanism leading to seizure susceptibility.

ObjectiveTo evaluate whether vagus nerve stimulation (VNS) as adjunct to best medical practice (VNS + BMP) is superior to BMP alone in improving long-term health-related quality of life (HRQoL).MethodsPuLsE (Open Prospective Randomized Long-term Effectiveness) was a prospective, randomized, parallel-group, open-label, and long-term effectiveness study (conducted at 28 sites in Europe and Canada). Adults with pharmacoresistant focal seizures (n = 112) received VNS + BMP or BMP (1:1 ratio). Medications and VNS parameters could be adjusted as clinically indicated for optimal seizure control while minimizing adverse effects. Primary endpoint was mean change from baseline HRQoL (using Quality of Life in Epilepsy Inventory-89 total score; QOLIE-89). Secondary endpoints included changes in seizure frequency, responder rate (≥50% decrease in seizure frequency), Centre for Epidemiologic Studies Depression scale (CES-D), Neurological Disorders Depression Inventory-Epilepsy scale (NDDI-E), Clinical Global Impression-Improvement scale (CGI-I), Adverse Event Profile (AEP), and antiepileptic drug (AED) load. The study was prematurely terminated due to recruitment difficulties prior to completing the planned enrollment of n = 362. Results for n = 96 who had baseline and at least one follow-up QOLIE-89 assessment (from months 3-12) were included in this analysis. Mixed model repeated measures (MMRM) analysis of variance was performed on change from baseline for the primary and secondary endpoints.ResultsSignificant between-group differences in favor of VNS + BMP were observed regarding improvement in HRQoL, seizure frequency, and CGI-I score (respective p-values < 0.05, 0.03, and 0.01). More patients in the VNS + BMP group (43%) reported adverse events (AEs) versus BMP group (21%) (p = 0.01), a difference reflecting primarily mostly transient AEs related to VNS implantation or stimulation. No significant difference between treatment groups was observed for changes in CES-D, NDDI-E, AEP, and AED load.SignificanceVNS therapy as a treatment adjunct to BMP in patients with pharmacoresistant focal seizures was associated with a significant improvement in HRQoL compared with BMP alone.

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A historical cohort study was undertaken to determine the risk of epilepsy in a population of 371 newborns with an acute neurological disorder related to fetal and/or neonatal hypoxia compared with a control population of 362 normal newborns. The results showed that the risk of epilepsy was 5.1 times higher in the group of subjects affected at birth by a hypoxia-related acute neurological syndrome than in the control group. (Although the incidence of epilepsy is higher in the first year of life, epileptic seizures connected to perinatal hypoxia may occur in early childhood or later on.) Also, there were frequently persistent neuropsychiatric disorders in children with perinatal hypoxia (5.4%). There was no difference in the two groups regarding the incidence of febrile convulsions. The data show that perinatal hypoxia plays a role in the etiology of epilepsy, although at birth the hypoxia might result in only a modest and oftentimes completely reversible neurological syndrome.

Background Epilepsy and hypertension are common chronic conditions, both showing high prevalence in older age groups. This review outlines current experimental and clinical evidence on both direct and indirect role of hypertension in epileptogenesis and discusses the principles of drug treatment in patients with hypertension and epilepsy. Methods We selected English-written articles on epilepsy, hypertension, stroke, and cerebrovascular disease until December, 2018. Results Renin-angiotensin system might play a central role in the direct interaction between hypertension and epilepsy, but other mechanisms may be contemplated. Large-artery stroke, small vessel disease and posterior reversible leukoencephalopathy syndrome are hypertension-related brain lesions able to determine epilepsy by indirect mechanisms. The role of hypertension as an independent risk factor for post-stroke epilepsy has not been demonstrated. The role of hypertension-related small vessel disease in adult-onset epilepsy has been demonstrated. Posterior reversible encephalopathy syndrome is an acute condition, often