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Status epilepticus (SE) is a neurological emergency characterized by high rates of short-term and long-term morbidity and mortality. Status epilepticus seems to be a marker of the severity of other underlying conditions rather than a determinant of death on its own. Careful diagnosis and acute treatment of complications and causes of death to SE or its underlying etiology will enable the differentiation of SE patients that would benefit from different levels of treatment intensity. All SE patients should be treated actively with first- and second-line drugs as early as possible. For cases in which seizures continue after second-line treatment, the current guidelines fail to offer possibilities other than the active path with general anesthesia and intensive care unit (ICU) care. However, the intensity of care should be evaluated before starting ICU care or in unclear cases with the time-limited trial at ICU. There are now multiple possibilities for specialty palliative SE care that include sequential and add-on use of second-line drugs and palliative sedation at the ward. If ICU care is prolonged, the patient's status needs to be constantly re-evaluated and communicated to the family. When patients exhibit multiple predictors of mortality and poor functional outcomes, they should be allowed to have a natural death in a peaceful environment without unnecessarily prolonged suffering. This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R.K. Declarations of interest: has received grants from the Academy of Finland, Saastamoinen Foundation, and Vaajasalo Foundation, speaker’s honoraria from Eisai, Omamedical, Orion, Sandoz, Sanofi, and UCB, and honoraria for membership of the advisory boards/consultation from Angelini Pharma, Eisai, Marinus Pharmaceuticals, Orion, and UCB.Z.A. Declarations of interest: has received consulting honoraria from the U.S. Department of State, the UN’s International Organization for Migration, The Association for Medical Education in Europe, ReInnovate Group, Orbital Learning Canada. A-M.K. Declarations of interest: nothing to declare., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Obstructive sleep apnea (OSA) is associated with increased risk for stroke, which is known to further impair respiratory functions. However, it is unknown whether the type and severity of respiratory events are linked to stroke or transient ischemic attack (TIA). Thus, we investigate whether the characteristics of individual respiratory events differ between patients experiencing TIA or acute ischemic stroke and matched patients with clinically suspected sleep-disordered breathing., Methods: Polygraphic data of 77 in-patients with acute ischemic stroke (n = 49) or TIA (n = 28) were compared to age, gender, and BMI-matched patients with suspected sleep-disordered breathing and no cerebrovascular disease. Along with conventional diagnostic parameters (e.g., apnea-hypopnea index), durations and severities of individual apneas, hypopneas and desaturations were compared between the groups separately for ischemic stroke and TIA patients., Results: Stroke and TIA patients had significantly shorter apneas and hypopneas (p < 0.001) compared to matched reference patients. Furthermore, stroke patients had more central apnea events (p = 0.007) and a trend for higher apnea/hypopnea number ratios (p = 0.091). The prevalence of OSA (apnea-hypopnea index ≥ 5) was 90% in acute stroke patients and 79% in transient ischemic attack patients., Conclusion: Stroke patients had different characteristics of respiratory events, i.e., their polygraphic phenotype of OSA differs compared to matched reference patients. The observed differences in polygraphic features might indicate that stroke and TIA patients suffer from OSA phenotype recently associated with increased cardiovascular mortality. Therefore, optimal diagnostics and treatment require routine OSA screening in patients with acute cerebrovascular disease, even without previous suspicion of OSA.

Background: Stroke causes death, disability and increases the use of healthcare resources worldwide. The outcome of intravenous thrombolysis and mechanical endovascular thrombectomy highly depends on the delay from symptom onset to initiation of definitive treatment. The purpose of this study was to compare the various patient transportation strategies to minimize pre-hospital delays., Methods: Emergency medical services (EMS) mission locations and ambulance response times in Finland with urgent stroke-suspected dispatch codes were collected from Emergency Response Centre (ERC) records between 1 January 2016 and 31 December 2016. Four transport scenarios were simulated for each mission, comparing ground and helicopter transportation to hospital with different treatment capabilities., Results: In 2016, a total of 20,513 urgent stroke-suspected missions occurred in Finland. Of these, we were able to locate and calculate a route to scenario-based hospitals in 98.7% (20,240) of the missions. For ground transport, the estimated median pre-hospital time to a thrombolysis-capable and thrombectomy-capable hospital were 54.5 min (95% confidence interval (CI), 31.7-111.4) and 94.4 min (95% CI, 33.3-195.8), respectively. Should patients be transported on the ground to thrombectomy-capable hospitals only, the pre-hospital time would increase in 11,003 (54.4%) of missions, most of which were in rural areas. With the fastest possible transportation method, the estimated mean transport time to a thrombectomy-capable hospital was 80.84 min (median, 80.80 min; 95% CI, 33.3-143.1). Helicopter transportation was the fastest method in 68.8% (13,921) of missions, and the time saved was greater than 30 min in 27.1% (5475) of missions. In rural areas, helicopter transportation was the fastest option in nearly all missions if dispatched simultaneously with ground ambulance., Conclusion: Helicopter transportation may significantly decrease pre-hospital delays for stroke patients, especially in rural areas, but the selection of an optimal transportation method or chain of methods should be determined case-by-case.

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., Competing Interests: Declaration of Competing Interest JS has received grants from the Finnish Epilepsy Research Foundation and the Maire Taponen Foundation and institutional funding from the Finnish State Research Funding via the Neuro Center, Kuopio University Hospital. AMK has received a grant from the Finnish Cultural Foundation, a speaker’s honoraria from Orion, Boehringer Ingelheim, MSD, BMS and a travel grant from Sanofi. HH has received a speaker’s honoraria from Orion and Boehringer Ingelheim and an honoraria for the membership of the advisory board from MSD. RK has received grants from the Academy of Finland and the Saastamoinen Foundation, a speaker’s honoraria from Eisai, UCB, and Orion and an honoraria for the membership of the advisory boards from Eisai, GW Pharmaceuticals, Marinus Pharmaceuticals, Sage Therapeutics, Takeda and UCB., (Copyright © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: The objective of this study was to determine the incidence in Eastern Finland of the different stages of status epilepticus (SE): 1) at the early stage of SE (a prolonged seizure lasting over 5 min);, 2) refractory SE (RSE), and 3) super-refractory SE (SRSE)., Methods: Firstly, we conducted a retrospective study on the incidence and outcome of intensive care unit (ICU)-treated RSE and SRSE in the adult population (≥16 years) in Kuopio University Hospital (KUH)'s special care responsibility area (840,000 inhabitants). Secondly, we conducted a prospective study using the International League Against Epilepsy (ILAE)'s new definition for SE (prolonged seizures lasting over 5 min), in adult (≥16 years) patients in the KUH municipality district (North Savo, 248,000 inhabitants)., Results: The retrospective study on ICU-treated RSE and SRSE from 2010 to 2012 identified 75 patients with RSE, of whom 21% were treated as SRSE, resulting in an annual age-adjusted incidence of ICU-treated RSE of 3.0/100,000 (95% confidence interval [CI]: 2.4-3.8) and 0.6/100,000 (95% CI: 0.4-1.0) for SRSE. In the prospective study of early stage SE (seizures lasting over 5 min), we identified 151 consecutive episodes during the 9-month study period in 2015, corresponding to an annual age-adjusted incidence of 81.1/100,000 (95% CI: 75.8-87.0). In this study, 11 seizure episodes became refractory, resulting in an age-adjusted incidence of RSE of 6.0/100,000 (95% CI: 3.4-10.4), of which seven were treated in the ICU [3.8/100,000 (95% CI: 1.8-7.8)], four were treated palliatively [2.2/100,000 (95% CI: 0.82-5.7)], and two evolved to SRSE [1.1/100,000 (95% CI: 0.3-4.3)]., Conclusions: The new ILAE 2015 definition of SE resulted in a four-fold increase in incidence of SE compared to the earlier 30-min definition reported earlier in Europe. In the epidemiology of RSE, the incidence of ICU-treated RSE, palliatively treated RSE, and SRSE needs to be separated. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

Purpose: Refractory status epilepticus (RSE) is a neurological emergency with significant morbidity and mortality. We aimed to analyze the long-term outcome of intensive care unit (ICU)-treated RSE and super-refractory status epilepticus (SRSE) patients in a population based cohort., Methods: A retrospective study of ICU- and anesthesia-treated RSE patients in Kuopio University Hospital's (KUH) special responsibility area hospitals in the central and eastern part of Finland from Jan. 1, 2010 to Dec. 31, 2012 was conducted. KUH's catchment area consists of five hospitals-one university hospital and four central hospitals-and covers a population of 840 000. We included all consecutive adult (16 years or older) RSE patients admitted in the participating ICUs during the 3-year period and excluded patients with postanoxic etiologies. We used a modified Rankin Scale (mRS) as a long-term (1-year) outcome measure: good (mRS 0-3, recovered to baseline function) or poor (mRS 4-6, major functional deficit or death)., Key Findings: We identified 75 patients with ICU- and anesthesia-treated RSE, corresponding to an annual incidence of 3.0 (95% confidence interval (CI) 2.4-3.8). 21% of the patients were classified as SRSE, with the annual incidence being 0.6/100 000 (95% CI 0.4-1.0). For RSE, the ICU mortality was 0%, hospital mortality was 7% (95% CI 1.2%-12.8%) (n=5), and one-year mortality was 23% (CI 95% 13.4%-32.5%) (n=17). 48% (n=36) of RSE patients recovered to baseline, and 29% (n=22) showed neurological deficit at 1year. Poor outcome (mRS 4-6) was recorded for 52% (n=39) of the patients. Older age was associated with poorer outcome at 1year (p=0.03). For SRSE, hospital mortality was 6% (n=1) and 1-year mortality was 19% (n=3) (95%CI 0%-38.2%)., Significance: During 1-year follow-up, nearly 50% of the ICU-treated RSE patients recovered to baseline function, whereas 30% showed new functional defects and 20% died. SRSE does not have a necessarily poorer outcome. The outcome is worse in older patients and in patients with progressive or fatal etiologies. SE should be treated with generalized anesthesia only in refractory cases after failure of adequately used first- and second-line antiepileptic drugs., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The aim was to determine predictors of hospital and 1-year mortality in patients with intensive care unit (ICU)-treated refractory status epilepticus (RSE) in a population-based study., Methods: This was a retrospective study of the Finnish Intensive Care Consortium (FICC) database of adult patients (16 years of age or older) with ICU-treated RSE in Finland during a 3-year period (2010-2012). The database consists of admissions to all 20 Finnish hospitals treating RSE in the ICU. All five university hospitals and 11 out of 15 central hospitals participated in the present study. The total adult referral population in the study hospitals was 3.92 million, representing 91% of the adult population of Finland. Patients whose condition had a post-anoxic aetiological basis were excluded., Results: We identified 395 patients with ICU-treated RSE, corresponding to an annual incidence of 3.4/100,000 (95% confidence interval (CI) 3.04-3.71). Hospital mortality was 7.4% (95% CI 0-16.9%), and 1-year mortality was 25.4% (95% CI 21.2-29.8%). Mortality at hospital discharge was associated with severity of organ dysfunction. Mortality at 1 year was associated with older age (adjusted odds ratio (aOR) 1.033, 95% CI 1.104-1.051, p = 0.001), sequential organ failure assessment (SOFA) score (aOR 1.156, CI 1.051-1.271, p = 0.003), super-refractory status epilepticus (SRSE) (aOR 2.215, 95% CI 1.20-3.84, p = 0.010) and dependence in activities of daily living (ADL) (aOR 2.553, 95% CI 1.537-4.243, p < 0.0001)., Conclusions: Despite low hospital mortality, 25% of ICU-treated RSE patients die within a year. Super-refractoriness, dependence in ADL functions, severity of organ dysfunction at ICU admission and older age predict long-term mortality., Trial Registration: Retrospective registry study; no interventions on human participants.

Objectives: Super-refractory status epilepticus (SRSE) is defined as status epilepticus (SE) that continues or recurs 24h or more after the onset of anesthetic therapy. We defined the incidence and outcome of SRSE in adults in Finland., Methods: We analyzed retrospectively the Finnish Intensive Care Consortium database in order to identify adult patients with SRSE treated in ICUs in Finland during a three-year period (2010-2012). The database consists of admissions to all 20 Finnish hospitals treating refractory SE (RSE) with general anesthesia in the intensive care unit (ICU). We included consecutive adult (16 years or older) patients with RSE and identified those who had SRSE. Patients with postanoxic etiologies were excluded., Results: All five university hospitals and 10/15 of the central hospitals participated. The adult referral population of the study hospitals is 3.9 million, representing 91% of the total adult population of Finland. We identified 395 patients with ICU-treated RSE, 87 (22%) of whom were classified as having SRSE. This corresponds to an annual incidence of SRSE of 0.7/100,000 (95% confidence interval [CI]: 0.6-0.9). The one-year mortality rates were 36% (95% CI: 26-46%) for patients with SRSE and 22% (95% CI: 17-27%) for patients with RSE. Mortality was highest (63%) in patients with SRSE aged over 75 years., Conclusions: Approximately 20% of patients with RSE treated in Finnish ICUs progressed to having SRSE. The incidence of SRSE, 0.7/100,000, is about 5-10% of the incidence of SE. The mortality of patients with SRSE, 36%, was comparable to earlier studies and twofold higher than the mortality of patients with RSE. This article is part of a Special Issue entitled "Status Epilepticus"., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Acute EEG is vastly underutilized in acute neurological settings. The most common reason for this is simply the fact that acute EEG is not available when needed or getting EEG is delayed as it requires trained technicians and equipment to be properly recorded. We have recently described a handy disposable forehead EEG electrode set that is suitable for acute emergency EEG recordings. The specific objective in this study was to assess the forehead electrode's utility when the clinical demand was to exclude SE., Patients and Methods: One hundred consecutive acute neurological patients (53 women, 47 men, age: 18-90 years) with unexplained altered mental state were studied with acute emergency EEG to rule out SE. Electroencephalographic recordings were obtained simultaneously with forehead EEG electrode and routine 10-20 system full-head scalp electrodes to clarify the clinical usefulness of forehead EEG electrode in this setting. Electroencephalographic recordings were interpreted blindly by three experienced clinical neurophysiologists first only based on forehead EEG and then by full-head EEG., Results: Ninety-six out of the 100 patients did not show EEG evidence of SE. There was 100% agreement with forehead and routine EEG. Four out of the 100 patients showed EEG evidence of SE in routine EEG, with 50% agreement between different electrode types. The forehead EEG missed two cases because the EEG findings supporting SE were restricted to the posterior parts of the brain., Major Conclusions: With a forehead EEG set, the sensitivity of detecting NCSE was 50%. There were no false positive cases yielding a specificity of 100%. Patients with AMS can benefit from forehead EEG recording in prehospital, hospital, and ICU settings. Since EEG recording can be started within a few minutes with the forehead EEG set, it will significantly reduce the delay in treatment of SE. This article is part of a Special Issue entitled "Status Epilepticus"., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Left atrial appendage (LAA) volume has been shown to be increased in patients with acute cryptogenic stroke. Atrial fibrillation (AF) is a well-recognized risk factor but it is not the only one associated with LAA enlargement. The aim of the study was to clarify the multifactorial etiology of LAA enlargement in cardiogenic stroke/TIA patients without AF., Methods: Altogether 149 patients with suspected cardioembolic stroke/TIA (47 females; mean age 61 years) underwent cardiac CT. Diagnosed AF on admittance was an exclusion criteria but 24-hour Holter ambulatory ECG revealed paroxysmal AF (PAF) in 20 patients. Body surface area adjusted LAA volume was evaluated. Eighteen different variables were registered including general characteristics, definite and potential causal risk factors for ischemic stroke/TIA, clinical echoparameters and CT based cardiac volumetric and adipose tissue measurements. A stepwise linear regression analysis was performed to achieve a model adjusted for the number of predictors of LAA volume increase., Results: In linear regression analysis, the best model accounted for 30% of the variability in LAA volume, including PAF (19%) and enlarged left atrial volume (6%), enlarged left ventricle end-systolic diameter (3%) and decreased pericardial adipose tissue (2%). No multi-colinearity between variables was observed. In addition to PAF, no other definitive or potential causal risk factors could account for the LAA volume in these patients., Conclusions: LAA volume increase seems to be poorly associated with currently known stroke/TIA risk factors, except for AF. Targeting more comprehensive ECG monitoring for stroke patients with increased LAA volume should be considered.

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.

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.

Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions., (Copyright (c) 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

The recent completion of the International HapMap Project has rapidly advanced our understanding of linkage disequilibrium (LD) in the human genome. Today, tagging SNPs (tSNPs) can be quickly and easily selected and consequently HapMap data are regularly applied to both small- and large-scale genetic mapping studies. However, to correctly interpret the application of HapMap-derived tSNPs in a genetic mapping study, an understanding of how well HapMap data represents LD in the study population is critical. The Irish population had not previously been characterised in this way. Here, we do so using a set of 4424 SNPs selected from 279 candidate genes for epilepsy genotyped across 1118 healthy individuals from the Irish, British, Finnish and Australian populations. By considering the Irish population alongside surrounding European populations, our results confirm that the HapMap European-derived population accurately estimates patterning of LD in European descent populations. The Irish population appears notably well matched to the European HapMap population, and is markedly similar to the neighbouring British population. Although we were unable to detect significant substructure within the Irish population (a favourable result for genetic mapping), methods for controlling stratification should always be incorporated. This analysis therefore confirms that the genetic architecture of the Irish population is well suited to the study of complex traits and that tSNPs selected using the HapMap data can be confidently applied to the Irish population.

Background: The Epilepsy Genetics (EPIGEN) Consortium was established to undertake genetic mapping analyses with augmented statistical power to detect variants that influence the development and treatment of common forms of epilepsy., Methods: We examined common variations across 279 prime candidate genes in 2717 case and 1118 control samples collected at four independent research centres (in the UK, Ireland, Finland, and Australia). Single nucleotide polymorphism (SNP) and combined set-association analyses were used to examine the contribution of genetic variation in the candidate genes to various forms of epilepsy., Findings: We did not identify clear, indisputable common genetic risk factors that contribute to selected epilepsy subphenotypes across multiple populations. Nor did we identify risk factors for the general all-epilepsy phenotype. However, set-association analysis on the most significant p values, assessed under permutation, suggested the contribution of numerous SNPs to disease predisposition in an apparent population-specific manner. Variations in the genes KCNAB1, GABRR2, KCNMB4, SYN2, and ALDH5A1 were most notable., Interpretation: The underlying genetic component to sporadic epilepsy is clearly complex. Results suggest that many SNPs contribute to disease predisposition in an apparently population-specific manner. However, subtle differences in phenotyping across cohorts, combined with a poor understanding of how the underlying genetic component to epilepsy aligns with current phenotypic classifications, might also account for apparent population-specific genetic risk factors. Variations across five genes warrant further study in independent cohorts to clarify the tentative association.