The impact of inversions across 33,924 families with rare disease from a national genome sequencing project.

Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting >500 million SVs, we focused on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24 bp to 36.4 Mb, 20/47 de novo). Validation utilized a number of orthogonal approaches, including retrospective exome analysis. RNA-seq data supported the respective diagnoses for six participants. Phenotypic blending was apparent in four probands. Diagnostic odysseys were a common theme (>50 years for one individual), and targeted analysis for the specific gene had already been performed for 30% of these individuals but with no findings. We provide formal confirmation of a European founder origin for an intragenic MSH2 inversion. For two individuals with complex SVs involving the MECP2 mutational hotspot, ambiguous SV structures were resolved using long-read sequencing, influencing clinical interpretation. A de novo inversion of HOXD11-13 was uncovered in a family with Kantaputra-type mesomelic dysplasia. Lastly, a complex translocation disrupting APC and involving nine rearranged segments confirmed a clinical diagnosis for three family members and resolved a conundrum for a sibling with a single polyp. Overall, inversions play a small but notable role in rare disease, likely explaining the etiology in around 1/750 families across heterogeneous clinical cohorts.

Cerebral folate deficiency: a treatable cause of late deterioration in epilepsy with developmental delay.

A 25-year-old woman with childhood-onset refractory epilepsy and developmental delay experienced a gradually progressive marked deterioration in mobility and seizure control, with language regression. Investigation identified a homozygous deletion within the contactin-associated protein-like 2 gene (CNTNAP2), underlying her early presentation, but also cerebral folate deficiency that most likely contributed to her later deterioration. Following antiseizure medication adjustment and treatment with folinic acid, she stabilised with improved seizure control and limited improvement in language and motor function; she has remained neurologically stable for more than a decade. That the previously observed neurological decline was halted by folinic acid replacement supports this being due to cerebral folate deficiency. Metabolic conditions are less well recognised in adults and can be under-diagnosed. They are potentially treatable and should be considered even in the presence of another cause, particularly when the presentation is not fully compatible.

New-onset refractory status epilepticus (NORSE).

New-onset refractory status epilepticus and its subcategory febrile infection-related epilepsy syndrome are rare devastating clinical presentations in those without pre-existing relevant history, often in schoolchildren or young adults, without a clear cause on initial investigations. A cause is later identified in up to half of adults, but in many fewer children. Patients often require protracted intensive care and are at significant risk of dying. Functional disability is common and subsequent chronic epilepsy is the norm, but some people do have good outcomes, even after prolonged status epilepticus. Patients need prompt investigations and treatment. Anaesthetic and antiseizure medications are supplemented by other treatment modalities, including the ketogenic diet. Despite limited evidence, it is appropriate to try to modify the presumed underlying pathogenesis with immune modulation early, with a more recent focus on using interleukin inhibitors. Optimising management will require concerted multicentre international efforts.

A 9-month retrospective evaluation of the aetiology and management of patients presenting with encephalitis/meningoencephalitis at a South London hospital.

Encephalitis causes high morbidity and mortality. An incidence of 4.3 cases of encephalitis/100 000 population has been reported in the UK. We performed a retrospective evaluation of the diagnosis and management of adults admitted to hospital with a clinical diagnosis of encephalitis/meningoencephalitis. Clinical, laboratory and radiological data were collated from electronic records. Thirty-six patients, median age 55 years and 24 (67%) male were included. The aetiology was confirmed over nine months in 25 (69%) of whom 16 were infections (six viral, seven bacterial, two parasitic and one viral and parasitic co-infection); 7 autoimmune; 1 metabolic and 1 neoplastic. Of 24 patients with fever, 15 (63%) had an infection. The median time to computed topography, magnetic resonance imaging and electroencephalography (EEG) was 1, 8 and 3 days respectively. Neuroimaging was abnormal in 25 (69%) and 17 (89%) had abnormal EEGs. Only 19 (53%) received aciclovir treatment. Six (17%) made good recoveries, 16 (44%) had moderate disability, 8 (22%) severe disability and 6 (17%) died. Outcomes were worse for those with an infectious cause. In summary, a diagnosis was made in 69.4% of patients admitted with encephalitis/meningoencephalitis. Autoimmune causes are important to consider at an early stage due to a successful response to treatment. Only 53% of patients received aciclovir on admission. Neuroimaging and EEG studies were delayed. The results of this work resulted in further developing the clinical algorithm for managing these patients.

Investigating adults with early-onset epilepsy and intellectual or physical disability.

This article focuses on investigating adults with early-onset epilepsy and intellectual or physical disability within adult neurology services. We aim to guide general neurologists in the diagnostic reassessment of people with epilepsy and complex neurological problems of unknown cause. Following an overview, we address imaging, electroencephalography, genetic studies and metabolic testing, and give examples where diagnosis directly influences treatment. Aetiological diagnosis serves to inform prognosis, guide treatment and provide a framework for genetic counselling.

SUDEP, the aftermath: supporting the bereaved.

Sudden unexpected death in epilepsy is a recurring calamity, yet there is little evidence to guide standards of care for supporting the bereaved. Grief in bereavement includes loss, feelings of guilt, anger and blame. There is also the shock and trauma of the sudden event. How can this be alleviated? This paper focuses on guiding the physician to support the bereaved, while recognising the limited evidence and the varying circumstances that may not always facilitate this. We propose a pathway of care and mode of communication with the deceased's family, with whom contact is currently limited. We suggest timely contact by telephone or in person, followed by ongoing support and referral to voluntary organisations and specialist services, as needed. Clarification and discussion may mitigate inappropriate feelings of guilt and blame, and may help the family with their sudden and unexpected loss.

Introduction-Epilepsy Research UK expert workshop 2014: SUDEP: Time for prevention-evidence and clinical translation Proceedings from the Epilepsy Research UK 2014 Expert Workshop.

We offer Epilepsia readers this supplement based on the proceedings of an international workshop on sudden death in epilepsy (SUDEP) held in 2014 at St Anne's College at Oxford and hosted by Epilepsy Research UK (ERUK). This is the second Epilepsia supplement dedicated to SUDEP and its focus is on prevention. As workshop co-chairs, in this introduction we outline why we believe we are on the threshold of a new era of prevention in SUDEP.

After sudden unexpected death in epilepsy: Lessons learned and the road forward.

The devastating effects of sudden unexpected death in epilepsy (SUDEP) can be difficult to navigate, even for experienced clinicians. Mounting evidence supports full disclosure of the risks of epilepsy to those affected and their caregivers, and recommendations from regulatory and professional groups encourage the same. Following a death, families are faced with tragedy, guilt, and sometimes anger. Clinicians are often called upon to provide information and support. The development of a comprehensive approach to SUDEP education requires careful consideration of the people living with epilepsy, facts about SUDEP and known risk factors, as well as experiences of families and care providers. In this article, we share the experiences of those working in SUDEP education and epilepsy care, including the voluntary sector. We explore the experience of bereaved families and clinicians, derive lessons from published research, highlight areas where more research is needed, and report on preliminary data from a nationwide study from France.

Sneddon's syndrome: it is all in the ectoderm.

A 51-year-old man gave a 2-year history of worsening mobility, cognitive decline and headaches. He had a history of thromboembolic stroke, recurrent transient ischaemic attacks and a spontaneous intraventricular haemorrhage. On examination, he had livedo reticularis and perniosis and a systolic murmur. Catheter cerebral angiography showed peripheral small-vessel and medium-vessel vasculopathy resulting in pruning of the distal cortical vessels and tortuous irregular distal collaterals. Skin biopsy showed subtle vasculopathy with ectasia of capillaries and postcapillary venules but no frank vasculitis or arterial thrombosis. Repeated serum antiphospholipid antibody titres were negative. The clinical features, skin biopsy and angiogram findings strongly supported a diagnosis of Sneddon's syndrome. Clinicians should consider Sneddon's syndrome in patients with livedo reticularis and stroke. There are treatment dilemmas in this situation when ischaemic and haemorrhagic cerebral events coexist.

Investigation of glutamine and GABA levels in patients with idiopathic generalized epilepsy using MEGAPRESS.

PURPOSE: Idiopathic generalized epilepsies (IGE) comprise a group of clinical syndromes associated with spike wave discharges, putatively linked to alterations in neurotransmission. The purpose of this study was to investigate whether patients with IGE have altered glutamine and γ-aminobutyric acid (GABA) levels indicative of altered excitatory and inhibitory neurotransmission in frontal regions. MATERIALS AND METHODS: Single-voxel MEGA-edited PRESS magnetic resonance imaging (MRI) spectra were acquired from a 30-mL voxel in the dorsolateral prefrontal cortex in 13 patients with IGE (8 female) and 16 controls (9 female) at 3T. Metabolite concentrations were derived using LCModel. Differences between groups were investigated using an unpaired t-test. RESULTS: Patients with IGE were found to have significantly higher glutamine than controls (P = 0.02). GABA levels were also elevated in patients with IGE (P = 0.03). CONCLUSION: Patients with IGE have increased frontal glutamine and GABA compared with controls. Since glutamine has been suggested to act as a surrogate for metabolically active glutamate, it may represent a marker for excitatory neurotransmission.

Mortality and SUDEP in epilepsy patients treated with vagus nerve stimulation.

OBJECTIVE: The risk of premature death is increased in patients with intractable epilepsy. The effect of vagus nerve stimulation (VNS) on mortality remains unclear. In a previous study by Annegers et al., mortality was raised, comparable to similar intractable cohorts. Our aim was to calculate standardized mortality ratios (SMRs), identify epilepsy-related deaths, and estimate sudden unexpected death in epilepsy (SUDEP) rates in patients treated with VNS for epilepsy. METHODS: All United Kingdom patients undergoing VNS between January 1, 1995 and December 31, 2010 at King's College Hospital, London were flagged through the national Medical Research Information Service. Analysis was performed in relation to all deaths occurring by December 31, 2010. Deceased patients were identified from the national death register, and additional information on cause and circumstances of death sought where appropriate to allow for classification of deaths. RESULTS: The cohort consisted of 466 patients, with 2993.83 person-years of follow-up and a median observation period of 5.9 years. Twenty-nine deaths occurred, 27 with the device active. SMR was 7.1 (95% confidence interval [CI] 4.8-10.3) for the active device; 12 deaths were considered epilepsy related, including 10 definite or probable SUDEP and one fatal near SUDEP. Definite/probable and fatal near SUDEP occurred at a rate of 3.7/1,000 person-years. SMRs decreased from 10.5 (5.6-19.5) in the first 2 years after implantation to 5.9 (3.7-9.5) thereafter, although CIs overlapped. SUDEP rates did not alter over time. SIGNIFICANCE: SMRs and SUDEP rate in this study are comparable to other cohorts with intractable epilepsy, with SUDEP an important cause of death. VNS does not appear to lower the risk of premature death overall. There was a clear trend with lower SMR after 2 years of implantation, although CIs overlapped. SUDEP rates, however, did not change.

SUDEP and epilepsy-related mortality in pregnancy.

Although data are limited, research in 2004 estimated a 10-fold increase in mortality in pregnancy in the United Kingdom in women with epilepsy (WWE) compared to women without epilepsy. We highlight epilepsy mortality in pregnancy based on the 2011 report of the United Kingdom Confidential Enquiries into Maternal Deaths, relating its findings to previous reports and epilepsy-rates in pregnancy. Among 2,291,493 maternities (2006-2008), we estimated 0.6% or 13,978 were in WWE. Fourteen deaths were epilepsy-related, of which 11 (79%) were sudden and unexpected (SUDEP). Nine occurred during pregnancy and five were postpartum. Nine (64%) were in women taking lamotrigine, seven as monotherapy. We estimated that 1:1,000 women died from epilepsy (mostly SUDEP) during or shortly after pregnancy. Epilepsy-related mortality is a significant risk in pregnancy. Antiepileptic drug-related factors may be relevant. The high proportion of women taking lamotrigine may reflect United Kingdom prescribing practice. Recent observations from the European and International Registry of Antiepileptic Drugs and Pregnancy (EURAP), whereby women on lamotrigine, the levels of which significantly decrease in pregnancy, had more difficulties with epilepsy control, argue against this being the sole explanation. Given the potential risks, every attempt should be made to prevent seizures, particularly convulsive, during pregnancy and postpartum. This, we believe, includes being proactive in maintaining lamotrigine levels during pregnancy.

Transition: driving and exercise.

There are many social aspects to consider at the time of transition of adolescents with epilepsy. The role of both pediatric and adult health care providers includes education and guidance within the larger framework of family, society, and country. This section focuses on driving and exercise considerations for those undergoing transition.

Impaired cognitive function in idiopathic generalized epilepsy and unaffected family members: an epilepsy endophenotype.

OBJECTIVE: Idiopathic generalized epilepsy (IGE) has a strong genetic component, and patients with IGE show deficits in a range of frontal lobe functions. Previous studies provide hints that unaffected siblings of people with IGE may share some of these cognitive deficits, suggesting that these deficits may be genetically determined endophenotypes. Establishment of a neurocognitive endophenotype of IGE would contribute to genetic studies and increase our understanding of the pathophysiology of IGE. To identify potential neurocognitive endophenotypes of IGE, this study aimed to measure neuropsychological performance in patients with IGE, their unaffected relatives, and healthy controls. METHODS: Thirty-six patients with IGE, 38 first-degree relatives, and 40 healthy controls were examined using a battery of neuropsychological tests sensitive to frontal lobe dysfunction (executive function, nonverbal reasoning, verbal generativity, response inhibition, attention, and working memory). Subject groups were compared using robust Bonferroni-corrected statistics. RESULTS: Patients with IGE showed deficits in nonverbal reasoning, verbal generativity, attention, and working memory. Relatives exhibited a parallel profile of cognitive abilities, with significant deficits in these tasks. Patients tended to show greater impairment than relatives in these tasks. SIGNIFICANCE: This study shows that measures of nonverbal reasoning, verbal generativity, sustained attention, and working memory are endophenotypes of IGE and offer the potential for aiding molecular genetic studies and elucidating the pathophysiology of IGE. Patients tended to demonstrate greater impairment in these tasks, possibly because of a greater genetic contribution and/or disease-related factors. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Prevention of sudden unexpected death in epilepsy: a realistic goal?

Sudden unexpected death in epilepsy (SUDEP) represents one of the most severe consequences of drug-resistant epilepsy, for which no evidence-based prevention is available. Development of effective prevention will depend on the following: (1) better understanding of the pathophysiology of SUDEP to define the most appropriate targets of intervention, and (2) identification of risk factors for SUDEP that would allow for the design of feasible clinical trials to test targeted interventions in high-risk populations. The most important known risk factor is the occurrence and frequency of generalized tonic-clonic seizure (GTCS), a seizure type that triggers the majority of witnessed SUDEP. Therefore, one likely way to prevent SUDEP is to minimize the risk of GTCS with optimal medical management and patient education. However, whether one might prevent SUDEP in patients with refractory epilepsy by using more frequent review of antiepileptic treatment and earlier referral for presurgical evaluation, remains to be seen. Another hypothetical strategy to prevent SUDEP is to reduce the risk of GTCS-induced postictal respiratory distress. This might be achieved by using lattice pillow, providing nocturnal supervision, reinforcing interictal serotoninergic tone, and lowering opiate- or adenosine-induced postictal brainstem depression. Promising interventions can be tested first on surrogate markers, such as postictal hypoxia in epilepsy monitoring units (EMUs), before SUDEP trials can be implemented. EMU safety should also be improved to avoid SUDEP occurrence in that setting. Finally, the development of ambulatory SUDEP prevention devices should be encouraged but raises a number of unsolved issues.

Valproate-induced reversible cognitive decline presenting as dementia and associated clinical features: A literature review.

BACKGROUND/AIM: Valproate (VPA) is an effective broad-spectrum anti-seizure medication. Both VPA induced encephalopathy and reversible cognitive decline (VIRCD) have been reported as rare side effects. While the former is well-described in terms of risk factors, mechanism and management, the latter is less recognised and can be easily mistaken for neurodegenerative dementia. In this paper, we present a literature review of VIRCD, describe its clinical features and compare our findings to those in VPA-induced encephalopathy. METHODS: We used PubMed search for valproate induced (dementia OR cognitive impairment OR cognitive decline OR cognitive dysfunction). Patients included were those with normal or well-defined cognitive baseline who presented with dementia after valproate therapy, in whom cognitive decline reversed after VPA dose reduction or discontinuation. Clinical features were compared to published descriptions of VPA-induced encephalopathy. RESULTS: A total of 33 cases in 11 publications were included. Mean age was 51.2 years. Most were being treated for epilepsy on VPA with good seizure control and no encephalopathic features. VPA levels were within the usual quoted range. Mean latency after VPA initiation and symptoms was 6.87 years. Most had parkinsonian features. The most commonly reported cognitive deficits were in short-term memory and processing speed. All recovered fully on VPA discontinuation. CONCLUSION: VIRCD mimics neurodegenerative dementia but is reversible on VPA discontinuation. The absence of encephalopathic features and good seizure control in addition to the prolonged latency make it easy to miss. VIRCD should be considered in relevant patient groups, especially in the presence of extrapyramidal signs.

Cenobamate in refractory epilepsy: Overview of treatment options and practical considerations.

Management of drug resistant epilepsy (DRE) represents a challenge to the treating clinician. This manuscript addresses DRE and provides an overview of treatment options, medical, surgical, and dietary. It addresses treatment strategies in polytherapy, then focuses on the role cenobamate (CNB) may play in reducing the burden of DRE while providing practical advice for its introduction. CNB is a recently approved, third generation, anti-seizure medication (ASM), a tetrazole-derived carbamate, thought to have a dual mechanism of action, through its effect on sodium channels as well as on GABAA receptors at a non-benzodiazepine site. CNB, having a long half-life, is an effective add-on ASM in refractory focal epilepsy with a higher response rate and a higher seizure-freedom rate than is usually seen in regulatory clinical trials. Experience post-licensing, though still limited, supports the findings of clinical trials and is encouraging. Its spectrum of action in relation to generalized epilepsies and seizures remains to be established, and there are no data on its efficacy in monotherapy. At the time of writing, CNB has been prescribed for some 50 000 individuals with DRE and focal epilepsy. A larger number is needed to fully establish its safety profile. It should at all times be introduced slowly to minimize the risk of serious allergic drug reactions. It has clinically meaningful interactions which must be anticipated and managed to maximize tolerability and likelihood of successful treatment. Despite the above, it may well prove to be of major benefit in the treatment of many patients with drug resistant epilepsy.

Unifying the definitions of sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy (SUDEP) is a category of death in people with epilepsy occurring in the absence of a known structural cause of death and is most likely heterogeneous with regard to mechanisms and circumstances. SUDEP is particularly difficult to investigate in research studies for several reasons, including its relatively low incidence, its unpredictable occurrence often in unwitnessed settings, and its low rate of complete autopsy examinations. Over the past two decades, two complementary definitions have been used in most SUDEP studies, but often with variations. We propose here a unified SUDEP definition and classification to resolve current ambiguities and to retrieve cases that would not have been further studied if the previous definitions were used. The proposed Unified SUDEP Definition and Classification contains, in addition to concepts inherent in the previous definitions, nine main recommendations. (1) The word "unexpected," and not the word "unexplained," should be uniformly used in the term SUDEP. (2) The SUDEP category should be applied when appropriate, whether or not a terminal seizure is known to have occurred. (3) The "Possible SUDEP" category should be used only for cases with competing causes of death, with cases left unclassified when data are insufficient to reasonably permit their classification. (4) Cases that would otherwise fulfill the definition of SUDEP should be designated as "SUDEP Plus" when evidence indicates that a preexisting condition, known before or after autopsy, could have contributed to the death, which otherwise is classified as SUDEP (e.g., coronary insufficiency with no evidence of myocardial infarction or long-QT syndrome with no documented primary ventricular arrhythmia leading to death). (5) To be considered SUDEP, the death should have occurred within 1 h from the onset of a known terminal event. (6) For status epilepticus as an exclusion criterion for SUDEP, the duration of seizure activity should be 30 min or more. (7) A specific category of SUDEP due to asphyxia should not be designated, the distinction being largely impractical on circumstantial or autopsy evidence, with more than one mechanism likely to be contributory in many cases. (8) Death occurring in water but without circumstantial or autopsy evidence of submersion should be classified as "Possible SUDEP." If any evidence of submersion is present, the death should not be classified as SUDEP. (9) A category of "Near-SUDEP" should be agreed to include cases in which cardiorespiratory arrest was reversed by resuscitation efforts with subsequent survival for more than 1 h. Scenarios that demonstrate the basis for each SUDEP category are described. If disagreement exists about which category fits a particular case, we suggest the use of consensus decision by a panel of informed reviewers to adjudicate the classification of the case.

Mortality after temporal lobe epilepsy surgery.

PURPOSE: To report mortality, after a longer interval, in a cohort of patients with drug-resistant epilepsy treated by temporal lobe surgery between 1975 and 1995. A previous audit of these patients ending December 1, 1997 observed a standardized mortality ratio (SMR) of 4.5. METHODS: We analyzed mortality in a cohort of 306 patients with temporal lobe epilepsy (TLE) who underwent temporal lobe resections between December 1, 1975 and December 1, 1995. Deaths occurring after December 1,1997 and until December 1, 2009 were evaluated. Medical records, death certificates, postmortem examination reports, coroner officer's reports, and coroner's inquest reports were sought, and causes of death were ascertained. Sudden unexpected death in epilepsy (SUDEP) cases were identified. KEY FINDINGS: In 3,569 person-years of follow-up 19 deaths occurred, [SMR 2.00, 95% confidence interval (CI) 1.27-3.13], 14 men (SMR 2.01, 95% CI 1.19-3.39) and 5 women (SMR 1.68, 95% CI 0.70-4.03). On analysis of subgroups, SMRs were significantly elevated in patients with mesial temporal sclerosis (MTS) (SMR 2.50, 95% CI 1.38-4.51), men with MTS (SMR 3.12, 95% CI 1.56-6.25), men with nonspecific lesions (SMR 2.68, 95% CI 1.00-7.09), and right-sided resections in MTS (SMR 3.33, 95% CI 1.39-8.00). During follow-up, six SUDEP cases were observed with a rate of 1/595 person-years. SIGNIFICANCE: In this cohort, the risk for premature death in patients undergoing TLE surgery decreased over time but remained above the standard population. Men had a slightly higher risk than women, as did right-sided resections in MTS, confirming this observation in the original cohort. Although lower, the risk of SUDEP remained. Without up-to-date information on seizure outcome, we were unable to directly relate this to mortality.