Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A.

Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10(-9), odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.

Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study.

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio<1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies.

Status epilepticus: Practice variation and adherence to treatment guideline in a large community hospital.

PURPOSE: To evaluate the treatment of status epilepticus (SE) and adherence to treatment guideline in a large Finnish community hospital. MATERIALS AND METHODS: A consecutive series of 137 patients treated in the emergency department of Kuopio University Hospital. Enrollment took place between March 23 and December 31, 2015. Pediatric patients and postanoxic seizures were excluded. The Finnish Status Epilepticus Current Care Guideline was used as the evaluation benchmark. RESULTS: Seventeen patients recovered spontaneously. First-line treatment was given to 108 patients with 35.2% efficacy. Second-line treatment was given to 81 patients with 87.7% efficacy. Six patients with refractory SE received successful third-line treatment and four were excluded from intensive care because of futility. The starting dose of a first-line drug was lower than the lowest therapeutic dose in 37.0% of the patients. The escalation from first- to second-line treatment took longer than 60 min in 55.1% of the 70 patients who received both treatments. The first loading dose of a second-line drug was markedly low (<80% of the recommended dose) in 26.2% of the 81 patients treated with second-line drugs. CONCLUSIONS: Prompt and effective pharmacotherapy is the cornerstone of good SE treatment. Subtherapeutic doses of first-line benzodiazepines should be avoided. Benzodiazepine-resistant SE must be recognized early to facilitate rapid treatment escalation. The quality of second-line treatment suffers from excessive delays and inadequate weight-based dosing of antiseizure medications.

Outcome of status epilepticus and the predictive value of the EMSE and STESS scores: A prospective study.

PURPOSE: To assess the short-term outcome of status epilepticus (SE) and test the Epidemiology-based Mortality score in Status Epilepticus (EMSE) and the Status Epilepticus Severity Score (STESS) performance in outcome prediction. METHODS: Consecutive adults with SE in the Kuopio University Hospital emergency department were recruited between March 23 and December 31, 2015. The one-month outcome was assessed by a combined phone interview and medical record review using the Glasgow Outcome Scale-Extended. The prognostic performance of the EMSE-EAC (EMSE using the combination of etiology, age and comorbidity) and STESS were statistically evaluated. RESULTS: We recorded 151 SE episodes in 137 patients, of whom 47 had a first-time epileptic event (seizure or SE). Of the SE episodes, 9.0% resulted in death, 31.6% in functional decline. For mortality prediction, the AUCs of the EMSE-EAC and STESS were 0.790 (95% CI: 0.633-0.947) and 0.736 (95% CI: 0.559-0.914), respectively. The optimal cutoff points were ≥ 34 for the EMSE-EAC and ≥ 4 for STESS. Negative predictive values for mortality using the EMSE-EAC-34 and STESS-4 were 97.5% and 96.7%, respectively. For functional decline prediction, the EMSE-EAC yielded statistically insignificant results, the STESS performance was poor (AUC = 0.621, 95% CI: 0.519-0.724). CONCLUSIONS: Over 40% of SE patients suffer adverse outcomes. The EMSE-EAC and STESS are useful in short-term mortality prediction, with a high negative predictive value. The optimized cutoff points for the EMSE-EAC and STESS were ≥ 34 and ≥ 4 for cohort, respectively.

Treatment delay in status epilepticus - more effective prehospital symptom recognition warranted.

BACKGROUND: The outcome of status epilepticus (SE) can be improved by facilitating early recognition and treatment with antiepileptic drugs. The purpose of this study was to analyze the treatment delay of SE in a prospectively recruited patient cohort. Improvements to the treatment process are suggested. METHODS: Consecutive adult patients with SE were recruited in the emergency department of Kuopio University Hospital (KUH) between March 23 and December 31, 2015. SE was defined as a prolonged (> 5 min) epileptic seizure or recurrent tonic-clonic seizures (≥ 3 seizures within any 24 h). Diagnostic and treatment delays and the features of SE were subject to statistical analysis. RESULTS: We recorded 151 cases of SE during the study period. First-line treatment was initiated outside of hospital in 79 cases (52.3%), with a significantly shorter median delay compared to intrahospital initiation (28 min vs. 2 h 5 min, p < 0.001). Forty-six episodes of SE (30.5%) were not recognized during the prehospital phase. The median delay in recognition of tonic-clonic SE (23 min) was significantly shorter than in focal aware (2 h 0 min, p = 0.045) or focal impaired awareness SE (2 h 25 min, p < 0.001). Second-line treatment was used in 91 cases (60.3%), with a median delay of 2 h 42 min. Anesthesia was used in seven cases (4.6%) with refractory SE, with a median delay of 6 h 40 min. CONCLUSIONS: SE is often not recognized during the prehospital phase of treatment, which delays the initiation of first-line treatment. Intrahospital delay could be reduced by streamlining patient transition between the three lines of treatment.