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Objective To compare the frequency and impact on the channel function of KCNH2 variants in SUDEP patients with epilepsy controls comprising patients older than 50 years, a group with low SUDEP risk, and establish loss‐of‐function KCNH2 variants as predictive biomarkers of SUDEP risk. Methods We searched for KCNH2 variants with a minor allele frequency of 20% reduction in maximal amplitude, were observed in 8.9% (8/90) SUDEP patients compared to 3.3% (11/332) epilepsy controls suggesting about threefold enrichment (nominal p = 0.04). KCNH2 variants that did not change channel function occurred at a similar frequency in SUDEP (2.2%; 2/90) and epilepsy control (2.7%; 9/332) cohorts (p > 0.99). Rare KCNH2 variants (

Familial adult myoclonic epilepsy 1 (FAME1), first recognised in Japanese families, was recently shown to be caused by a TTTCA repeat insertion in intron 4 of SAMD12 on chromosome 8. We performed whole genome sequencing on two families with FAME, one of Sri Lankan origin and the other of Indian origin, and identified a TTTCA repeat insertion in SAMD12 in both families. Haplotype analysis revealed that both families shared the same core ancestral haplotype reported in Japanese and Chinese families with FAME1. Mutation dating, based on the length of shared haplotypes, estimated the age of the ancestral haplotype to be ~670 generations, or 17,000 years old. Our data extend the geographic range of this repeat expansion to Southern Asia and potentially implicate an even broader regional distribution given the age of the variant. This finding suggests patients of Asian ancestry with suspected FAME should be screened for the SAMD12 TTTCA expansion.

Background and Purpose— Mobile stroke units (MSUs) are increasingly used worldwide to provide prehospital triage and treatment. The benefits of MSUs in giving earlier thrombolysis have been well established, but the impacts of MSUs on endovascular thrombectomy (EVT) and effect on disability avoidance are largely unknown. We aimed to determine the clinical impact and disability reduction for reperfusion therapies in the first operational year of the Melbourne MSU. Methods— Treatment time metrics for MSU patients receiving reperfusion therapy were compared with control patients presenting to metropolitan Melbourne stroke units via standard ambulance within MSU operating hours. The primary outcome was median time difference in first ambulance dispatch to treatment modeled using quantile regression analysis. Time savings were subsequently converted to disability-adjusted life years avoided using published estimates. Results— In the first 365-day operation of the Melbourne MSU, prehospital thrombolysis was administered to 100 patients (mean age, 73.8 years; 62% men). The median time savings per MSU patient, compared with the control cohort, was 26 minutes ( P P P P =0.001) for EVT hospital arrival to arterial puncture for MSU patients. Estimated median disability-adjusted life years saved through earlier provision of reperfusion therapies were 20.9 for thrombolysis and 24.6 for EVT. Conclusions— The Melbourne MSU substantially reduced time to reperfusion therapies, with the greatest estimated disability avoidance driven by the more powerful impact of earlier EVT. These findings highlight the benefits of prehospital notification and direct triage to EVT centers with facilitated workflow on arrival by the MSU.

OBJECTIVE: Classification of epilepsy into types and subtypes is important for both clinical care and research into underlying disease mechanisms. A quantitative, data-driven approach may augment traditional electroclinical classification and shed new light on existing classification frameworks. METHODS: We used latent class analysis, a statistical method that assigns subjects into groups called latent classes based on phenotypic elements, to classify individuals with common familial epilepsies from the Epi4K Multiplex Families study. Phenotypic elements included seizure types, seizure symptoms, and other elements of the medical history. We compared class assignments to traditional electroclinical classifications and assessed familial aggregation of latent classes. RESULTS: A total of 1120 subjects with epilepsy were assigned to five latent classes. Classes 1 and 2 contained subjects with generalized epilepsy, largely reflecting the distinction between absence epilepsies and younger onset (class 1) versus myoclonic epilepsies and older onset (class 2). Classes 3 and 4 contained subjects with focal epilepsies, and in contrast to classes 1 and 2, these did not adhere as closely to clinically defined focal epilepsy subtypes. Class 5 contained nearly all subjects with febrile seizures plus or unknown epilepsy type, as well as a few subjects with generalized epilepsy and a few with focal epilepsy. Family concordance of latent classes was similar to or greater than concordance of clinically defined epilepsy types. SIGNIFICANCE: Quantitative classification of epilepsy has the potential to augment traditional electroclinical classification by (1) combining some syndromes into a single class, (2) splitting some syndromes into different classes, (3) helping to classify subjects who could not be classified clinically, and (4) defining the boundaries of clinically defined classifications. This approach can guide future research, including molecular genetic studies, by identifying homogeneous sets of individuals that may share underlying disease mechanisms.

Background Whilst often causing posterior circulation strokes, vertebral artery dissections may also, more rarely, cause spinal cord infarction.1 This is the case report of a 39-year-old female with a right-sided high cervical hemi-cord infarction caused by vertebral artery dissection of a hypoplastic right vertebral artery. Presentation A 39-year-old female with a history of migraines, presented with acute onset right neck pain, headache and right-sided paraesthesia of the arm and leg after rapid rotation of the neck to the left. Due to a headache similar to her usual migraine, the patient took Rizatriptan prior to presentation. Neurological examination revealed findings, including right-sided upper and lower limb paraesthesia, weakness and dysmetria, consistent with right hemi-cord infarction. CT angiogram of the neck and brain revealed a small calibre right vertebral artery of unclear aetiology. Subsequent MRA revealed a hypoplastic right vertebral artery with dissection causing a high cervical right hemi-cord infarction. The patient’s right sided paraesthesia and weakness slowly improved over three months with medical therapy and rehabilitation, however some deficits remain, which affect her quality of life. Conclusion This unusual case is a poignant reminder to carefully consider alternative diagnoses that may mimic migraines, especially when neurological signs and symptoms are present. Such differential diagnoses, such as vertebral artery dissection and spinal cord infarction, are of particular importance to consider, even in young patients without any risk factors, given that they can cause significant disability which may impact on quality of life.2 References Hsu J, Cheng M, Liao M, Hsu H, Weng Y, Chang K, et al. The etiologies and prognosis associated with spinal cord infarction. Annals of Clinical and Translational Neurology 2019;6(8):1456–1464. Hsu C, Cheng C, Lee J, Lee M, Huang Y, Wu C, et al. Clinical features and outcomes of spinal cord infarction following vertebral artery dissection: a systematic review of the literature. Neurological Research 2013;35(7):676–683.

Objectives This study aimed to determine the history features, signs and symptoms identified during a code stroke that correlate with the diagnosis of ischemic stroke or transient ischemic attack (TIA). We investigated the rate of stroke mimics and aimed to develop a clinical prediction model. Methods Consecutive code stroke presentations to a primary stroke centre were recruited. Patient characteristics, medical history, signs or symptoms on activation of code stroke were collected from the medical record. Diagnosis of ischemic stroke was determined by radiographic evidence of infarction. Univariate analysis and multivariable logistic regression analysis were used to determine the features that predict ischemic stroke/TIA versus mimic. Results Among 493 code strokes, 64.5% were mimics. The most commonly diagnosed mimics were migraine, peripheral vertigo and seizure. Upper limb sensory change (OR 3.27 [95% CI, 1.75-6.11]), hemiplegia (OR 2.70 [95% CI, 1.65-4.43]), dysphasia (OR 2.62 [95% CI, 1.56-4.40]) and history of atrial fibrillation (OR 2.01 [95% CI, 1.14-3.54]) or hypertension (OR 1.77 [95% CI, 1.10-2.83]) are highly predictive of stroke/TIA. Headache (OR 0.40 [95% CI, 0.23-0.69]) is predictive of a mimic. Dizziness and vertigo were more common in stroke mimics. C-statistic for the study models ranged from 0.70 to 0.76. Conclusion Objective signs such as unilateral motor weakness and dysphasia are highly predictive of ischemic stroke/TIA whereas symptoms of headache and dizziness are suggestive of stroke mimic. Stroke mimic rate is influenced by local prevalence and threshold for code stroke activation. Incorporating positive and negative predictive features may improve future stroke prediction tools.

Background and Purpose: Although a target of 80% medication adherence is commonly cited, it is unclear whether greater adherence improves survival after stroke or transient ischemic attack (TIA). We investigated associations between medication adherence during the first year postdischarge, and mortality up to 3 years, to provide evidence-based targets for medication adherence. Methods: Retrospective cohort study of 1-year survivors of first-ever stroke or TIA, aged ≥18 years, from the Australian Stroke Clinical Registry (July 2010–June 2014) linked with nationwide prescription refill and mortality data (until August 2017). Adherence to antihypertensive agents, statins, and nonaspirin antithrombotic medications was based on the proportion of days covered from discharge until 1 year. Cox regression with restricted cubic splines was used to investigate nonlinear relationships between medication adherence and all-cause mortality (to 3 years postdischarge). Models were adjusted for age, sex, socioeconomic position, stroke factors, primary care factors, and concomitant medication use. Results: Among 8363 one-year survivors of first-ever stroke or TIA (44% aged ≥75 years, 44% female, 18% TIA), 75% were supplied antihypertensive agents. In patients without intracerebral hemorrhage (N=7446), 84% were supplied statins, and 65% were supplied nonaspirin antithrombotic medications. Median adherence was ≈90% for each medication group. Between 1% and 100% adherence, greater adherence to statins or antihypertensive agents, but not nonaspirin antithrombotic agents, was associated with improved survival. When restricted to linear regions above 60% adherence, each 10% increase in adherence was associated with a reduction in all-cause mortality of 13% for antihypertensive agents (hazard ratio, 0.87 [95% CI, 0.81–0.95]), 13% for statins (hazard ratio, 0.87 [95% CI, 0.80–0.95]), and 15% for nonaspirin antithrombotic agents (hazard ratio, 0.85 [95% CI, 0.79–0.93]). Conclusions: Greater levels of medication adherence after stroke or TIA are associated with improved survival, even among patients with near-perfect adherence. Interventions to improve medication adherence are needed to maximize survival poststroke.

ObjectiveTo compare the frequency and impact on channel function of KCNH2 variants in SUDEP patients with epilepsy controls comprising patients older than 50 years, a group with low SUDEP risk, and establish loss-of-function KCNH2 variants as predictive biomarkers of SUDEP risk.MethodsWe searched for KCNH2 variants with a minor allele frequency of < 5%. Functional analysis in Xenopus laevis oocytes was performed for all KCNH2 variants identified.ResultsKCNH2 variants were found in 11.1% (10/90) of SUDEP individuals compared to 6.0% (20/332) of epilepsy controls (p = 0.11). Loss-of-function KCNH2 variants, defined as causing > 20% reduction in maximal amplitude, were observed in 8.9% (8/90) SUDEP patients compared to 3.3% (11/332) epilepsy controls suggesting about three-fold enrichment (nominal p = 0.04). KCNH2 variants that did not change channel function occurred at a similar frequency in SUDEP (2.2%; 2/90) and epilepsy control (2.7%; 9/332) cohorts (p > 0.99). Rare KCNH2 variants (< 1% allele frequency) associated with greater loss of function and an ∼11-fold enrichment in the SUDEP cohort (nominal p = 0.03). In silico tools were unable to predict the impact of a variant on function highlighting the need for electrophysiological analysis.ConclusionsThese data show that loss-of-function KCNH2 variants are enriched in SUDEP patients and suggest that cardiac mechanisms contribute to SUDEP risk. We propose that genetic screening in combination with functional analysis can identify loss-of-function KCNH2 variants that could act as biomarkers of an individual’s SUDEP risk.

Background Chronic lymphocytic infiltration with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a neuro-inflammatory syndrome first described in 2010. It has a relationship with lymphoproliferative disorders that has not been fully elucidated. This case represents an unusual progression of CLIPPERS to Epstein-Barr Virus (EBV)-related lymphomatoid granulomatosis (LYG). The exact connection between CLIPPERS and LYG remains poorly understood. Case presentation We present a case of a 75-year-old man who was diagnosed with CLIPPERS with initial response to immunosuppression but later progressed to EBV-related LYG. EBV polymerase chain reaction (PCR) was detected in his cerebrospinal fluid (CSF), and repeat imaging revealed findings that were uncharacteristic for CLIPPERS; thereby prompting a brain biopsy which led to a diagnosis of EBV-related LYG. This case highlights the following learning points: 1) CLIPPERS cases are often part of a spectrum of lymphomatous disease, 2) CLIPPERS can be associated with EBV-related lymphoproliferative disorders such as LYG, and 3) EBV detection in CSF should prompt earlier consideration for brain biopsy in patients. Conclusions Our case highlights the difficulty in distinguishing CLIPPERS from other steroid-responsive conditions such as neoplastic and granulomatous diseases. Given the association of CLIPPERS with EBV-related LYG as demonstrated in this case, we recommend testing for EBV in CSF for all patients with suspected CLIPPERS. An early referral for brain biopsy and treatment with rituximab should be considered for patients with suspected CLIPPERS who test positive for EBV in their CSF.

Background and Purpose: Severity-based assessment tools may assist in prehospital triage of patients to comprehensive stroke centers (CSCs) for endovascular thrombectomy (EVT), but criticisms regarding diagnostic inaccuracy have not been adequately addressed. This study aimed to quantify the benefits and disadvantages of severity-based triage in a large real-world paramedic validation of the Ambulance Clinical Triage for Acute Stroke Treatment (ACT-FAST) algorithm. Methods: Ambulance Victoria paramedics assessed the prehospital ACT-FAST algorithm in patients with suspected stroke from November 2017 to July 2019 following an 8-minute training video. All patients were transported to the nearest stroke center as per current guidelines. ACT-FAST diagnostic accuracy was compared with hospital imaging for the presence of large vessel occlusion (LVO) and need for CSC-level care (LVO, intracranial hemorrhage, and tumor). Patient-level time saving to EVT was modeled using a validated Google Maps algorithm. Disadvantages of CSC bypass examined potential thrombolysis delays in non-LVO infarcts, proportion of patients with false-negative EVT, and CSC overburdening. Results: Of 517 prehospital assessments, 168/517 (32.5%) were ACT-FAST positive and 132/517 (25.5%) had LVO. ACT-FAST sensitivity and specificity for LVO was 75.8% and 81.8%, respectively. Positive predictive value was 58.8% for LVO and 80.0% when intracranial hemorrhage and tumor (CSC-level care) were included. Within the metropolitan region, 29/55 (52.7%) of ACT-FAST-positive patients requiring EVT underwent a secondary interhospital transfer. Prehospital bypass with avoidance of secondary transfers was modeled to save 52 minutes (95% CI, 40.0–61.5) to EVT commencement. ACT-FAST was false-positive in 8 patients receiving thrombolysis (8.1% of 99 non-LVO infarcts) and false-negative in 4 patients with EVT requiring secondary transfer (5.4% of 74 EVT cases). CSC bypass was estimated to over-triage 1.1 patients-per-CSC-per-week in our region. Conclusions: The overall benefits of an ACT-FAST algorithm bypass strategy in expediting EVT and avoiding secondary transfers are estimated to substantially outweigh the disadvantages of potentially delayed thrombolysis and over-triage, with only a small proportion of EVT patients missed.

Objective: The cause of mesial temporal lobe epilepsy (MTLE) is often unknown. We ascertained to what extent newly-diagnosed non-lesional MTLE actually represents familial MTLE (FMTLE). Methods: We identified all consecutive patients presenting to the Austin Heath First Seizure Clinic with MTLE and a normal MRI or MRI-evidence of hippocampal sclerosis over a 10-year period. Patients' first-degree relatives and pairwise age- and sex-matched controls underwent a comprehensive epilepsy interview. Each interview transcript was reviewed independently by two epileptologists, blinded to relative or control status. Reviewers classified each subject as follows: epilepsy, specifying if MTLE; manifestations suspicious of epilepsy; or unaffected. Physiological deja vu was noted. Results: Forty-four patients were included. At the Clinic, MTLE had been recognized to be familial in 2 patients only. Among 242 subjects interviewed, MTLE was diagnosed in 9/121 relatives vs 0/121 controls (p=0.008). All affected relatives had seizures with intense deja vu and accompanying features; 6 relatives had not been previously diagnosed. Deja vu experiences which were suspicious, but not diagnostic, of MTLE occurred in 6 additional relatives vs none of the controls (p=0.04). Physiological deja vu was common, and did not differ significantly between relatives and controls. After completing the relatives' interviews, FMTLE was diagnosed in 8 of 44 patients (18.2%). Interpretation: FMTLE accounts for almost one-fifth of newly diagnosed non-lesional MTLE, and it is largely unrecognized without direct questioning of relatives. Relatives of patients with MTLE may experience deja vu phenomena which clinically lie in the ‘borderland' between epileptic seizures and physiological deja vu. This article is protected by copyright. All rights reserved.

Background and Purpose— Interhospital transfer is a critical component in the treatment of acute anterior circulation large vessel occlusive stroke transferred for mechanical thrombectomy. Real-world data for benchmarking and theoretical modeling are limited. We sought to characterize transfer workflow from primary stroke center (PSC) to comprehensive stroke center after the publication of positive thrombectomy trials. Methods— Consecutive patients transferred from 3 high-volume PSCs to a single comprehensive stroke center between January 2015 and August 2016 were included in a retrospective study. Factors associated with key time metrics were analyzed with emphasis on PSC intrahospital workflow. Results— Sixty-seven patients were identified. Median age was 74 years (interquartile range [IQR], 63.5–78) and National Institutes of Health Stroke Scale 17 (IQR, 12–21). Median transfer time measured by PSC-door-to-comprehensive stroke center-door was 128 minutes (IQR, 107–164), of which 82.8% was spent at PSCs (door-in-door-out [DIDO]; 106 minutes; IQR, 86–143). The lengthiest component of DIDO was computed-tomography-to-retrieval-request (median 59.5 minutes; IQR, 44–83). The 37.3% had DIDO exceeding 120 minutes. DIDO times differed significantly between PSCs ( P =0.01). In multivariate analyses, rerecruiting the initial ambulance crew for transfer ( P P =0.04) were associated with shorter DIDO times. Conclusions— In a metropolitan hub-and-spoke network, PSC-door-to-comprehensive stroke center-door and DIDO times are long even in high-volume PSCs. Improving PSC workflow represents a major opportunity to expedite mechanical thrombectomy and improve patient outcomes.

Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7. The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved., Familial cortical myoclonic tremor (FAME) has so far been mapped to regions on chromosome 2, 3, 5 and 8 and pentameric repeat expansions in SAMD12 were identified as cause of FAME1. Here, Corbett et al. identify ATTTT/ATTTC repeat expansions in intron 1 of STARD7 in individuals with FAME2.”

Objective The leading cause of epilepsy-related premature mortality is sudden unexpected death in epilepsy (SUDEP). The cause of SUDEP remains unknown. To search for genetic risk factors in SUDEP cases, we performed an exome-based analysis of rare variants. Methods Demographic and clinical information of 61 SUDEP cases were collected. Exome sequencing and rare variant collapsing analysis with 2,936 control exomes were performed to test for genes enriched with damaging variants. Additionally, cardiac arrhythmia, respiratory control, and epilepsy genes were screened for variants with frequency of

People with epilepsy are at heightened risk of sudden death compared to the general population and the leading cause of epilepsy-related premature mortality is sudden unexpected death in epilepsy (SUDEP). Postmortem investigation of people with SUDEP, including histological and toxicological analysis, does not reveal a cause of death and the mechanisms of SUDEP remain largely unresolved. Emerging studies in humans and animal models suggest there may be an underlying genetic basis to SUDEP in some cases. Inherited cardiac arrhythmia syndromes, such as the long QT syndrome, cause unexplained sudden cardiac death, and pathogenic variants previously found in people with long QT syndrome are also found in SUDEP. Furthermore, the long QT gene, KCNH2, is among the genes with the highest number of variants in SUDEP compared to people without epilepsy. Some genetic epilepsies have an increased risk of SUDEP. For example, there is a high mortality rate in Dravet syndrome, with approximately half of deaths due to SUDEP, and pathogenic variants in the familial focal epilepsy gene, DEPDC5, are more common in SUDEP than in people without epilepsy. Observational reports of SUDEP, or near SUDEP, in epilepsy monitoring units have highlighted the importance of impaired respiratory control, suggesting that genetic variants involved in central respiratory drive represent strong candidates for determinants of SUDEP risk. Animal models have also implicated epilepsy genes, impaired cardiac electrophysiology and respiratory arrest in the pathogenesis of SUDEP. In particular, animal models have suggested KCN1A and SCN8A as SUDEP genes, and a mouse model of Dravet syndrome recapitulates features of the disease, including SUDEP. This review will highlight a mounting body of evidence for the involvement of genetic risk factors in SUDEP, with a particular focus on the role of cardiac arrhythmia genes in SUDEP.

We recently identified DEPDC5 as the gene for familial focal epilepsy with variable foci and found mutations in >10% of small families with nonlesional focal epilepsy. Here we show that DEPDC5 mutations are associated with both lesional and nonlesional epilepsies, even within the same family. DEPDC5-associated malformations include bottom-of-the-sulcus dysplasia (3 members from 2 families), and focal band heterotopia (1 individual). DEPDC5 negatively regulates the mammalian target of rapamycin (mTOR) pathway, which plays a key role in cell growth. The clinicoradiological phenotypes associated with DEPDC5 mutations share features with the archetypal mTORopathy, tuberous sclerosis, raising the possibility of therapies targeted to this pathway.

Gene identification in epilepsy has mainly been limited to large families segregating genes of major effect and de novo mutations in epileptic encephalopathies. Many families that present with common non-acquired focal epilepsies and genetic generalized epilepsies remain unexplained. We assembled a cohort of 'genetically enriched' common epilepsies by collecting and phenotyping families containing multiple individuals with unprovoked seizures. We aimed to determine if specific clinical epilepsy features aggregate within families, and whether this segregation of phenotypes may constitute distinct 'familial syndromes' that could inform genomic analyses. Families with three or more individuals with unprovoked seizures were studied across multiple international centres. Affected individuals were phenotyped and classified according to specific electroclinical syndromes. Families were categorized based on syndromic groupings of affected family members, examined for pedigree structure and phenotypic patterns and, where possible, assigned specific familial epilepsy syndromes. A total of 303 families were assembled and analysed, comprising 1120 affected phenotyped individuals. Of the 303 families, 117 exclusively segregated generalized epilepsy, 62 focal epilepsy, and 22 were classified as genetic epilepsy with febrile seizures plus. Over one-third (102 families) were observed to have mixed epilepsy phenotypes: 78 had both generalized and focal epilepsy features within the same individual (n = 39), or within first or second degree relatives (n = 39). Among the genetic generalized epilepsy families, absence epilepsies were found to cluster within families independently of juvenile myoclonic epilepsy, and significantly more females were affected than males. Of the 62 familial focal epilepsy families, two previously undescribed familial focal syndrome patterns were evident: 15 families had posterior quadrant epilepsies, including seven with occipito-temporal localization and seven with temporo-parietal foci, and four families displayed familial focal epilepsy of childhood with multiple affected siblings that was suggestive of recessive inheritance. The findings suggest (i) specific patterns of syndromic familial aggregation occur, including newly recognized forms of familial focal epilepsy; (ii) although syndrome-specificity usually occurs in multiplex families, the one-third of families with features of both focal and generalized epilepsy is suggestive of shared genetic determinants; and (iii) patterns of features observed across families including pedigree structure, sex, and age of onset may hold clues for future gene identification. Such detailed phenotypic information will be invaluable in the conditioning and interpretation of forthcoming sequencing data to understand the genetic architecture and inter-relationships of the common epilepsy syndromes.

Objectives: Hospital data used to assess regional variability in disease management and outcomes, including mortality, lack information on disease severity. We describe variance between hospitals in 30-day risk-adjusted mortality rates (RAMRs) for stroke, comparing models that include or exclude stroke severity as a covariate. Design: Cohort design linking Australian Stroke Clinical Registry data with national death registrations. Multivariable models using recommended statistical methods for calculating 30-day RAMRs for hospitals, adjusted for demographic factors, ability to walk on admission, stroke type, and stroke recurrence. Setting: Australian hospitals providing at least 200 episodes of acute stroke care, 2009–2014. Main outcome measures: Hospital RAMRs estimated by different models. Changes in hospital rank order and funnel plots were used to explore variation in hospital-specific 30-day RAMRs; that is, RAMRs more than three standard deviations from the mean. Results: In the 28 hospitals reporting at least 200 episodes of care, there were 16 218 episodes (15 951 patients; median age, 77 years; women, 46%; ischaemic strokes, 79%). RAMRs from models not including stroke severity as a variable ranged between 8% and 20%; RAMRs from models with the best fit, which included ability to walk and stroke recurrence as variables, ranged between 9% and 21%. The rank order of hospitals changed according to the covariates included in the models, particularly for those hospitals with the highest RAMRs. Funnel plots identified significant deviation from the mean overall RAMR for two hospitals, including one with borderline excess mortality. Conclusions: Hospital stroke mortality rates and hospital performance ranking may vary widely according to the covariates included in the statistical analysis.

International audience; Familial adult myoclonus epilepsy (FAME) is a rare autosomal dominant disorder characterized by adult onset, involuntary muscle jerks, cortical myoclonus and occasional seizures. FAME is genetically heterogeneous with more than 70 families reported worldwide and five potential disease loci. The efforts to identify potential causal variants have been unsuccessful in all but three families. To date, linkage analysis has been the main approach to find and narrow FAME critical regions. We propose an alternative method, pedigree free identity-by-descent (IBD) mapping, that infers regions of the genome between individuals that have been inherited from a common ancestor. IBD mapping provides an alternative to linkage analysis in the presence of allelic and locus heterogeneity by detecting clusters of individuals who share a common allele. Succeeding IBD mapping, gene prioritization based on gene co-expression analysis can be used to identify the most promising candidate genes. We performed an IBD analysis using high-density single nucleotide polymorphism (SNP) array data followed by gene prioritization on a FAME cohort of ten European families and one Australian/New Zealander family; eight of which had known disease loci. By identifying IBD regions common to multiple families, we were able to narrow the FAME2 locus to a 9.78 megabase interval within 2p11.2-q11.2. We provide additional evidence of a founder effect in four Italian families and allelic heterogeneity with at least four distinct founders responsible for FAME at the FAME2 locus. In addition, we suggest candidate disease genes using gene prioritization based on gene co-expression analysis.

We measured the mortality rate and the rate of Sudden Unexpected Death in Epilepsy (SUDEP) in Dravet Syndrome (DS). We studied a cohort of 100 consecutively recruited, unrelated patients with DS; 87 had SCN1A mutations. Living cases had a median follow-up of 17 years. Seventeen patients died, at a median age of seven years (inter-quartile range 3-11 years) with causes of death: 10 SUDEP, four status epilepticus, two drowning and one asphyxia. The SUDEP classification included three Definite, one Definite Plus and six Probable. The Dravet-specific mortality rate/1000-person-years was 15.84 (98% CI 9.01-27.85). The Dravet-specific SUDEP rate was 9.32/1000-person-years (98% CI 4.46-19.45). The Dravet-specific SUDEP rate is the only documented syndrome-specific SUDEP rate. SUDEP in DS occurs mainly in childhood. It is also the highest SUDEP rate, considerably higher than the recent 5.1 SUDEP rate/1000-person-years for adults with refractory epilepsy.

Glucose transporter 1 (GLUT1) deficiency caused by mutations of SLC2A1 is an increasingly recognized cause of genetic generalized epilepsy. We previously reported that >10% (4 of 34) of a cohort with early onset absence epilepsy (EOAE) had GLUT1 deficiency. This study uses a new cohort of 55 patients with EOAE to confirm that finding. Patients with typical absence seizures beginning before 4 years of age were screened for solute carrier family 2 (facilitated glucose transporter), member 1 (SLC2A1) mutations or deletions. All had generalized spike-waves on electroencephalography (EEG). Those with tonic and/or atonic seizures were excluded. Mutations were found in 7 (13%) of 55 cases, including five missense mutations, an in-frame deletion leading to loss of a single amino acid, and a deletion spanning two exons. Over both studies, 11 (12%) of 89 probands with EOAE have GLUT1 deficiency. Given the major treatment and genetic counseling implications, this study confirms that SLC2A1 mutational analysis should be strongly considered in EOAE.

Temporal lobe epilepsy is the commonest partial epilepsy of adulthood. Although generally perceived as an acquired disorder, several forms of familial temporal lobe epilepsy, with mesial or lateral seizure semiology, have been described. Descriptions of familial mesial temporal lobe epilepsy have varied widely from a benign epilepsy syndrome with prominent déjà vu and without antecedent febrile seizures or magnetic resonance imaging abnormalities, to heterogeneous, but generally more refractory epilepsies, often with a history of febrile seizures and with frequent hippocampal atrophy and high T₂ signal on magnetic resonance imaging. Compelling evidence of a genetic aetiology (rather than chance aggregation) in familial mesial temporal lobe epilepsy has come from twin studies. Dominant inheritance has been reported in two large families, though the usual mode of inheritance is not known. Here, we describe clinical and neurophysiological features of 20 new mesial temporal lobe epilepsy families including 51 affected individuals. The epilepsies in these families were generally benign, and febrile seizure history was infrequent (9.8%). No evidence of hippocampal sclerosis or dysplasia was present on brain imaging. A single individual underwent anterior temporal lobectomy, with subsequent seizure freedom and histopathological evidence of hippocampal sclerosis was not found. Inheritance patterns in probands' relatives were analysed in these families, together with 19 other temporal lobe epilepsy families previously reported by us. Observed frequencies of epilepsies in relatives were lower than predicted by dominant Mendelian models, while only a minority (8/39) of families could be compatible with recessive inheritance. These findings strongly suggest that complex inheritance, similar to that widely accepted in the idiopathic generalized epilepsies, is the usual mode of inheritance in familial mesial temporal lobe epilepsy. This disorder, which appears to be relatively common, and not typically associated with hippocampal sclerosis, is an appropriate target for contemporary approaches to complex disorders such as genome-wide association studies for common genetic variants or deep sequencing for rare variants.

Paroxysmal losses of consciousness and other episodic neurological symptoms have many causes. Distinguishing epileptic from non-epileptic disorders is fundamental to diagnosis, but even this basic dichotomy is often challenging and is certainly not new. In 1907, the British neurologist William Richard Gowers published his book The Border-land of Epilepsy in which he discussed paroxysmal conditions "in the border-land of epilepsy-near it, but not of it" and their clinical differentiation from epilepsy itself. Now, a century later, we revisit the epilepsy borderland, focusing on syncope, migraine, vertigo, parasomnias, and some rarer paroxysmal disorders. For each condition, we review the clinical distinction from epileptic seizures. We then integrate current understanding of the molecular pathophysiology of these disorders into this clinical framework. This analysis shows that, although the clinical manifestations of paroxysmal disorders are highly heterogeneous, striking similarities in molecular pathophysiology are seen among many epileptic and non-epileptic paroxysmal phenomena.

Genome-wide association studies are utilized for gene discovery in common diseases. Genotypes of large groups of unrelated patients are compared to controls. This has become feasible due to the recent technical advances in genomics and convincing positive results are now regularly being published. This review is an accessible introduction to the genetic and technical knowledge needed to interpret such studies. Genome-wide association studies are being applied to many neurologic diseases. Here we use idiopathic generalized epilepsy as an example to highlight the phenotyping, sample size, and statistical issues that must be addressed in such studies. These studies are likely to transform our understanding of complex neurologic diseases in the next few years.

For some time, paediatric neurologists have recognised glucose transporter type 1 (GluT1) deficiency syndrome as a cause of intractable infantile seizures, microcephaly, developmental delay and hypoglycorrhachia in the presence of a normal plasma glucose. It is caused by mutations in the SLC2A1 gene, coding for GluT1, leading to a reduction in the available glucose transporter sites; it responds to the ketogenic diet. Recently, a wider spectrum of seizure syndromes have been associated with functional impairment of glucose transport caused by SLC2A1 mutations. These syndromes include 12% of early-onset absence epilepsy and 1% of genetic generalised epilepsies, where they represent a risk allele contributing to polygenic inheritance. We describe a young man with early-onset absence seizures and paroxysmal exercise-induced dyskinesia. While this syndrome is uncommon, it is recognisable and its diagnosis allows consideration of treatment with the ketogenic diet. We discuss the role of genetic testing in early-onset absence seizures and genetic generalised epilepsy.

Neuroferritinopathy is a progressive potentially treatable adult-onset movement disorder caused by mutations in the ferritin light chain gene (FTL1). Features overlap with common extrapyramidal disorders: idiopathic torsion dystonia, idiopathic Parkinson's disease and Huntington's disease, but the phenotype and natural history have not been defined. We studied a genetically homogeneous group of 41 subjects with the 460InsA mutation in FTL1, documenting the presentation, clinical course, biochemistry and neuroimaging. The mean age of onset was 39.4 years (SD = 13.3, range 13-63), beginning with chorea in 50%, focal lower limb dystonia in 42.5% and parkinsonism in 7.5%. The majority reported a family history of a movement disorder often misdiagnosed as Huntington's disease. The disease progressed relentlessly, becoming generalized over a 5-10 year period, eventually leading to aphonia, dysphagia and severe motor disability with subcortical/frontal cognitive dysfunction as a late feature. A characteristic action-specific facial dystonia was common (65%), and in 63% there was asymmetry throughout the disease course. Serum ferritin levels were low in the majority of males and post-menopausal females, but within normal limits for pre-menopausal females. MR brain imaging was abnormal on all affected individuals and one presymptomatic carrier. In conclusion, isolated parkinsonism is unusual in neuroferritinopathy, and unlike Huntington's disease, cognitive changes are absent or subtle in the early stages. Depressed serum ferritin is common and provides a useful screening test in routine practice, and gradient echo brain MRI will identify all symptomatic cases.

Neuroferritinopathy is a recently recognized, dominantly inherited movement disorder caused by a mutation of the ferritin light chain gene. We present video case reports of 4 individuals with neuroferritinopathy chosen to illustrate how this disorder can present and subsequently progress clinically. The clinical phenotype of this disorder is highly variable with symptoms beginning in the third to sixth decades. Chorea, dystonia, or an akinetic-rigid syndrome can predominate in different individuals. Neuroferritinopathy is not restricted to the UK and it has been described in apparently sporadic cases. The diagnosis should therefore be considered in patients with a wide variety of different movement disorders. Characteristic neuroimaging assists in identifying affected individuals.

Neuroferritinopathy is a recently recognised genetic disease resulting in a dominantly inherited movement disorder. The condition was mapped by linkage analysis to chromosome 19q13.3 and found to be due to a single adenine insertion in the ferritin light chain ( FTL) gene at position 460 - 461 which is predicted to alter the C terminus of the FTL polypeptide. Clinical features of neuroferritinopathy are highly variable, with chorea, dystonia, and Parkinsonian features predominating in different affected individuals. The most consistent feature is a dystonic dysarthria. Symptoms and abnormal physical signs appear to be restricted to the nervous system and onset is typically in the fourth to sixth decades. Low serum ferritin also characterises this condition. Brain MR imaging of affected patients demonstrates iron deposition in the basal ganglia, progressing over years to cystic degeneration, and brain histochemistry shows abnormal aggregates of ferritin and iron. Now that the molecular basis of the condition is known, therapeutic interventions to reduce or reverse brain iron deposition are being evaluated. This rare disease provides evidence of a central role for iron metabolism in neurodegenerative disorders. © 2002 Elsevier Science (USA)

Objective: To determine the contribution of sequence variations in PHOX2B to sudden unexpected death in epilepsy (SUDEP). Methods: Patients who died of SUDEP were identified in 2 major Australian cohorts, the Epilepsy Genetics research program in Melbourne and postmortem cases at the Department of Forensic Medicine in Sydney. Coding exons of the PHOX2B gene were sequenced and a fluorescent sizing assay was used to measure the PHOX2B polyalanine repeat sequence. Results: Sequencing of 68 cases of SUDEP identified a 15-nucleotide deletion in the PHOX2B polyalanine repeat region in one case, a 16-year-old adolescent with focal dyscognitive seizures from age 5 years. This deletion was verified using a fluorescent sizing assay. Two synonymous variants were identified in 4 cases, but no PHOX2B polyalanine repeat expansion alleles or point mutations were found. Conclusions: The absence of PHOX2B polyalanine repeat expansion alleles or point mutations in 68 Australian cases of SUDEP, with one deletion of uncertain significance, shows that PHOX2B mutations are not a common risk factor for SUDEP.

Sarcoidosis is a multisystem granulomatous disorder of unknown aetiology and establishing the correct diagnosis can be challenging. Although dysfunction of the anterior visual pathways is uncommon, it is the most common neuro-ophthalmological manifestation of this condition and given the potential for irreversible, severe visual loss, prompt diagnosis and treatment are essential. We describe a patient with optic perineuritis as a rare initial presentation of sarcoidosis and discuss the underlying pathophysiology and management.

The majority of epilepsies are focal in origin, with seizures emanating from one brain region. Although focal epilepsies often arise from structural brain lesions, many affected individuals have normal brain imaging. The etiology is unknown in the majority of individuals, although genetic factors are increasingly recognized. Autosomal dominant familial focal epilepsy with variable foci (FFEVF) is notable because family members have seizures originating from different cortical regions. Using exome sequencing, we detected DEPDC5 mutations in two affected families. We subsequently identified mutations in five of six additional published large families with FFEVF. Study of families with focal epilepsy that were too small for conventional clinical diagnosis with FFEVF identified DEPDC5 mutations in approximately 12% of families (10/82). This high frequency establishes DEPDC5 mutations as a common cause of familial focal epilepsies. Shared homology with G protein signaling molecules and localization in human neurons suggest a role of DEPDC5 in neuronal signal transduction. Refereed/Peer-reviewed

The diagnosis of phenomena that mimic epilepsy is anongoingchallengefortheclinicalneurologist.SirWilliamGowers published his classic book The Border-land ofEpilepsyin1907,basinghisanalysisanddifferentialdiag-noses solely on clinical information. He focused on faints,vagal and vasovagal attacks (which he differentiated fromfaints), migraine, vertigo, and some sleep symptoms,particularly narcolepsy. Over the last 100 years, majorinvestigative advances—including electroencephalogra-phy(EEG),imaging,and,morerecently,moleculargenet-ics—have revolutionized the clinical and basic sciencesrelevant to Gowers’ borderland. We have revisited theepilepsy borderland, from the clinical and molecularviewpoints, focusing on syncope, migraine, parasomnias,and some rarer disorders including the paroxysmal dyski-nesias and organic causes of nonepileptic convulsions(Crompton & Berkovic, 2009). Many of the basic clinicaltenets of Gowers’ analysis from a century ago remain,although the importance of vertigo as an epileptic mimichas diminished and the clinical approach to syncope hasbeen considerably modified. Interestingly, nonepilepticseizures (pseudo seizures) were not regarded as a signifi-cantclinicalissuebyGowers.A major advance in scientific thinking, made possibleby molecular genetics, is that the epilepsies are, at least inpart, afamily ofchannelopathies. Ion channeldysfunctionis the major known mechanism of the inherited idiopathicepilepsies, and roles in the acquired epilepsies (‘‘acquiredchannelopathies’’) are also likely. It is of interest to notethat when analyzing the mechanisms of disorders withinthe epilepsy borderland, ion channels also featurestrongly.The clinical distinction of epileptic seizures fromsyncope, particularly convulsive syncope, is a commonclinical problem which, just like in Gowers’ era, remainslargely based on the clinical history. In certain cardiacdisorders causing syncope, such as arrhythmias includingthe long QT syndrome and Brugada syndrome, the majormechanisms are of inherited cardiac ion channel dysfunc-tion. Remarkably, epileptic seizures and cardiac channel-opathies causing syncope rarely coexist. This is becauseion channel subunits present in the heart are generally notexpressedinthebrainandviceversa.However,themolec-ular and cellular mechanisms of electrical instability aresimilar, thus illustrating the parsimony of nature in termsofmechanismsofparoxysmaldisordersaffectingdifferentorgans.Migraine and epilepsy are usually easily distinguished,but a complex clinical overlap of migraine and epilepsydoes occur, as shown by epidemiologic studies, by analy-sis of certain families segregating both disorders, and byspecific but uncommon migraine–epilepsy syndromes.The molecular mechanisms of migraine are slowly beingunravelled, particularly in the autosomal dominantfamilial forms. Again, the genetic culprits are largely ionchannel subunits. Indeed, dysfunction of certain ion chan-nels can cause both migraine and epilepsy, although themolecular mechanisms, cortical-spreading depression inmigraine aura, and paroxysmal high frequency dischargesin epileptic seizures, are quite different. This paradox hasyettobefullyexplainedatamolecularlevel.Theparasomniasprovideanextremelychallengingareaof clinical differential diagnosis from nocturnal epilepticseizures. Moreover, there appears to be a genetic relation-ship between what are regarded as nocturnal seizures andparasomnias.Thediscoveryofacetylcholinereceptorsub-unit mutations in some families with autosomal dominantnocturnal frontal lobe epilepsy has provided a windowinto this issue, although the mechanism of seizure genesishas not been elucidated. Mouse models with humanmutations may show spontaneous epileptic seizures, butapparently nonepileptic phenomena can occur as well,furthercomplicatingthisfascinatingborderland.Paroxysmal dyskinesias are uncommon disorders,often familial, where the underlying molecular defects

usc Refereed/Peer-reviewed Objective: To assess the presence of DEPDC5 mutations in a cohort of patients with epileptic spasms. Methods: We performed DEPDC5 resequencing in 130 patients with spasms, segregation analysis of variants of interest, and detailed clinical assessment of patients with possibly and likely pathogenic variants. Results: We identified 3 patients with variants in DEPDC5 in the cohort of 130 patients with spasms. We also describe 3 additional patients with DEPDC5 alterations and epileptic spasms: 2 from a previously described family and a third ascertained by clinical testing. Overall, we describe 6 patients from 5 families with spasms and DEPDC5 variants; 2 arose de novo and 3 were familial. Two individuals had focal cortical dysplasia. Clinical outcome was highly variable. Conclusions: While recent molecular findings in epileptic spasms emphasize the contribution of de novo mutations, we highlight the relevance of inherited mutations in the setting of a family history of focal epilepsies. We also illustrate the utility of clinical diagnostic testing and detailed phenotypic evaluation in characterizing the constellation of phenotypes associated with DEPDC5 alterations. We expand this phenotypic spectrum to include epileptic spasms, aligning DEPDC5 epilepsies more with the recognized features of other mTORopathies.

A previously well 68-year-old woman presented with sudden onset, painless diplopia and paraesthesia of the tongue and fingers bilaterally. Neurological examination revealed exotropia of the right eye, convergence failure and bilateral internuclear ophthalmoplegias (INOs). Thrombolysis was considered but was withheld as CT angiography showed a …

Activation of the innate immune system due to single gene mutations is a hallmark of the autoinflammatory syndromes. Typically, these disorders are not associated with autoimmune phenomena. Here we describe a Caucasian male with a complex phenotype comprising features of both an autoinflammatory state and autoimmunity. He had a life-long history of recurrent encephalopathic episodes during which fever, anorexia and drowsiness would develop over a period of a few hours and last for up to seven days. His phenotype was additionally characterised by a mixed connective tissue disorder with an inflammatory arthritis, restrictive lung disease and variably elevated autoantibodies. Furthermore, he experienced autoimmune thrombocytopenia, gastro-intestinal bleeding and epilepsy on a background of mild to moderate intellectual compromise. Radiological examination demonstrated periarticular, subcutaneous soft tissue and intracranial calcification, together with cerebellar vermis hypoplasia. EEG showed features of a generalised epilepsy. All other investigations were essentially non-contributory. He died at 19 years of age of acute respiratory failure secondary to restrictive lung disease and pneumonia. We hypothesise that this phenotype represents a previously undescribed autoinflammatory syndrome, with secondary autoimmune sequelae.

The shaking-B gene of Drosophila encodes two functions: one specifically neural and the other required for viability. Flies carrying neural mutations show a range of defects, the best characterized of which is a disruption of some synapses in the giant fibre system, while mutations in the essential function cause animals to die as first instar larvae. We have characterised an essential transcript from this locus and show that mutant lesions underlying two lethal shaking-B alleles map to its coding sequence. We also propose a new model for the topologies of Shaking-B proteins and their relatives. Essential shaking-B transcripts are found in embryonic mesodermal derivatives, while during metamorphosis both essential and neural transcripts are dynamically expressed in the pupal nervous system. Although the expression patterns of these transcripts overlap in many cells, only the neural form is expressed in the giant fibre cell bodies and the lamina and medulla of the optic lobes. This observation correlates with the phenotypes of mutations which disrupt the coding region of this neural transcript. On the basis of the expression patterns of shaking-B transcripts and the phenotypes conferred by mutations of shaking-B and homologous genes, we suggest that Shaking-B proteins and their homologues may be involved in the organisation of cellular membranes.

Background Familial adult myoclonic epilepsy (FAME) is an autosomal dominant syndrome characterized by a core triad of cortical tremor, multifocal myoclonus, and generalized tonic-clonic seizures. Objectives To expand the phenotypic spectrum of FAME, to highlight diagnostic pointers to this underrecognized disorder, and to refine the FAME2 genetic locus. Design Observational family study. Setting The study was coordinated in a tertiary academic hospital, with data acquired in diverse primary, secondary, and tertiary care settings. Participants Consenting members of a single large family. Results A 6-generation FAME kindred of European descent was ascertained in New Zealand and Australia. Affected family members (N = 55) had fine hand tremor, with onset typically in adolescence (median age, 15 years; age range, 4-60 years). Proximal myoclonus was present in 44 of 55 (80%), arising later than hand tremor (median age, 17 years; age range, 5-60 years). Generalized tonic-clonic seizures occurred in 8 of 55 (15%), with a median age at onset of 43.5 years (age range, 18-76 years). Neurophysiological testing confirmed features of cortical reflex myoclonus. Genetic mapping narrows the FAME2 (OMIM 607876) locus on chromosome 2 to a 13.3-megabase interval, harboring 99 known protein-coding genes. Conclusions The most common FAME phenotype in this large family is mild postural hand tremor resembling essential tremor, combined with subtle proximal myoclonus. Generalized tonic-clonic seizures are uncommon and occur around sleep onset following severe generalized myoclonus.

An important but not widely recognised complication of lumboperitoneal shunting is the development of a Chiari 1 deformity and syringomyelia. We present a case of a patient who developed symptomatic cerebellar tonsillar descent and syrinx formation following treatment of pseudotumour cerebri with lumboperitoneal shunting. A 31 year old woman was diagnosed with pseudotumour cerebri following development of headaches, loss of vision, and papilloedema, in association with a cerebrospinal fluid (CSF) opening pressure of 36 cm H2O. Cranial imaging showed an attenuated ventricular system and no other abnormality. In particular, the posterior fossa was …

We recently described a dominantly inherited movement disorder in a large family from Cumbria in the north west of England resulting from an adenine insertion at position 460–461 in the ferritin light polypeptide gene (FTL).1 The disease presented between the ages of 38 and 58 years with chorea in some subjects, focal dystonia in other subjects, and an akinetic rigid parkinsonian syndrome in others. Brain imaging showed basal ganglia cavitation that was confirmed at necropsy. Neuronal loss was accompanied by the formation of neuroaxonal spheroids, with intraneural and extraneural iron deposition. Serum ferritin levels were low in the presence of normal serum iron, transferrin and haemoglobin levels. The results of these investigations provided a direct link between a primary disorder of iron storage metabolism and a late onset neurodegenerative movement disorder.1 Cumbria has a stable, largely white population of Anglo-Saxon and Norman origins. All of the affected subjects described in the original report lived within a 30 mile radius and were traced, using parish records, back to a probable common founder born around 1790.1 A further 10 familial cases with the same mutation were found by screening over 100 patients from northern England with undiagnosed extrapyramidal disease and a small number of other cases referred to us from other parts of the country. The nature of the mutation and our report here of a common haplotype around the gene suggested to us that neuroferritinopathy would be a rare disorder in the UK, likely to have been inherited from a single founder. However, a careful review of published reports identified a number of potentially similar families outside the United Kingdom, including one family from the north of France.