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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.

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.

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

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.

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.

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.

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.

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.