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.

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.

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.

Long-term outcome of vagus nerve stimulation for drug-resistant epilepsy using continuous assessment, with a note on mortality.

PURPOSE: To examine the outcome of vagus nerve stimulation (VNS) for drug-resistant epilepsy using data from a National Health Service VNS clinic. METHODS: Clinical records of patients implanted with VNS for epilepsy between1995 and 2010 were examined. Patients were selected for study who had at least one year of therapeutic stimulation (minimum 1 mA stimulator current) and follow-up by our service with analysable electronic records, providing continuous assessment of seizure control during available follow-up. Seizure status at each attendance was assessed and graded 1-4 (1=seizure free or <5 seizures/year; 2 =≥50%reduction in seizure frequency; 3=<50% reduction; 4=no improvement compared to baseline). Responders were those whose grades improved consistently (Grades 1,2 and 3). RESULTS: Of 464 patients, 171 fulfilled the inclusion criteria and were divided into three groups: a) Responders (n = 81); b) non-responders (n = 80) and c) others (n = 10), the latter showing a late step-wise change (six improved; four deteriorated). After initial ramping up of current, groups were very stable over subsequent periods varying from one to 12 years (median 3.8 years). Sixteen patients died, 10 of non-epilepsy causes with 6 epilepsy-related deaths. There was a significant relation between epilepsy-related deaths and response (p < 0.00001). Patients with longer time as non-responders had more likelihood of suffering an epilepsy death than responders, though numbers were small. CONCLUSION: This study shows that meaningful data can be obtained retrospectively from routine clinic records. In this cohort about half of patients treated with VNS responded and the response generally remaining stable over time.

Two-center experience of cannabidiol use in adults with Dravet syndrome.

We describe real-world experience with cannabidiol (CBD) in adults with Dravet Syndrome (DS) via GW Pharma early access programme at two UK neurology centres. Adults with genetically-confirmed DS had CBD added to existing therapy, titrated up to 20 mg/kg, as tolerated. The primary outcome measure was percentage reduction in convulsive seizures. Secondary outcome measures included changes in myoclonic seizures, and in cognition and quality of life as assessed by the Caregiver Global Impression of Change (CGIC), and incidence of adverse events (AEs). 18 adults (7 female; median age 27.5 years; range 20-51) were included. Median follow-up was 176 days. In one, another antiseizure drug, clobazam, was introduced during the programme. 3/17 (17.6%) had >30% reduction in convulsive seizures (range: 87.5-100%). AEs occurred in all, the most common being transaminitis (52.9%). Behavioural AEs led to discontinuation in 3/18 (16.7%), including a seizure-free responder. In 7/18, CBD was stopped due to lack of effect. 8/18 continue on treatment. Improvements in CGIC were reported in 41.2% and 47.1% by physicians and families, respectively. 17.6% achieved sufficient reduction in convulsive seizure frequency to qualify for NHS funding. AEs led to withdrawal in only 16.7%. Close monitoring and dose adjustments of other antiseizure drugs were necessary.

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.

Perampanel for the treatment of epilepsy; Longitudinal actuarial analysis and dose responses based on monthly outcomes.

PURPOSE: To explore the retention rates and the efficacy and tolerability of perampanel (PER) by using monthly real life data for a period of 12 months. METHODS: Longitudinal outcomes of (PER) usage were assessed using actuarial statistics in an observational nonrandomised multicentre study of 181 people with epilepsy (PWE) refractory to first and second line drugs. Graded seizure outcomes, toxicity and the dose of PER were recorded for each month. RESULTS: PWE were followed for a mean of 15.1 months. The total cumulative probability for retention on PER at 12 months was 61.7% and for ≥50% improvement was 38.2%. Most improvements in seizure control occurred soon after initiation of PER, 17% by one month, 32% by six months and 38% by twelve months, and mostly at low doses 53% on 2 mg and 90% up to 6 mg. Improvements, when they occurred, were sustained. The most common side effects were neuropsychiatric, occurring in 28%. The emergence of side effects did not appear to be dose related. Although people with intellectual disability (ID) were more likely to remain on PER they did not show improved seizure control and also reported more side effects. Patients treated with VNS and PER had a worse outcome. CONCLUSION: Overall around a third of people showed a useful, response to PER therapy. The response to PER is noted usually early in the treatment and for the majority of the patients for doses up to 8 mg.

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.

An audit of external trigeminal nerve stimulation (eTNS) in epilepsy.

PURPOSE: External trigeminal nerve stimulation (eTNS) is a non-invasive neurostimulation treatment for drug refractory epilepsy. There is limited published data on the efficacy of eTNS and none relating to quality of life, mood or effect on sleep quality. METHODS: We audited its use in 42 patients with drug refractory epilepsy at a tertiary centre, between 02/04/2013 and 14/08/2015. Data was collected on seizure frequency, quality of life, mood and sleep quality before and after initiating treatment. RESULTS: 45% of patients continued to use eTNS at the end of the audit period. We observed a significant improvement in both quality of life and mood in those without intellectual disabilities. A decrease in seizures (-11.0%, min -60, max +65) was observed though this did not reach statistical significance with the relatively small numbers available for analysis. CONCLUSION: Further controlled studies are required to confirm the efficacy of eTNS. However, as it is non-invasive, flexible and safe eTNS can be considered as an option in patients with drug refractory epilepsy.

Sudden unexpected death in epilepsy (SUDEP): what every neurologist should know.

This review aims to empower general neurologists to provide better informed person-centred advice on sudden unexpected death in epilepsy (SUDEP) to people with epilepsy in order to help keep them safe. Past and present evidence is consolidated in order to inform readers about SUDEP, and up-to-date insights into the epidemiology, diagnostic classification, pathophysiology, risk factors, influence of co-morbidity, and importance of sensitive person-centred communication are outlined. This review provides "fingertip" information to the practicing neurologist with regards to identifying and communicating risks for SUDEP and suggests practical measures for managing these risks in partnership with the patient.

Cortical excitability correlates with seizure control and epilepsy duration in chronic epilepsy.

OBJECTIVE: Cortical excitability differs between treatment responders and nonresponders in new-onset epilepsy. Moreover, during the first 3 years of epilepsy, cortical excitability becomes more abnormal in nonresponders but normalizes in responders. Here, we study chronic active epilepsy, to examine whether cortical excitability continues to evolve over time, in association with epilepsy duration and treatment response. METHODS: We studied 28 normal subjects, 28 patients with moderately controlled epilepsy (≤4 seizures per year) and 40 patients with poorly controlled epilepsy (≥20 or more seizures per year). Resting motor threshold (RMT), active motor threshold (AMT), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF) and cortical silent period (CSP) were measured, using transcranial magnetic stimulation (TMS). Disease and treatment covariates were collected (age at onset of epilepsy, epilepsy duration, number of drugs prescribed, total drug load, sodium channel drug load). RESULTS: RMT and AMT were higher in patients than in normal subjects; RMT and AMT were higher in poorly controlled than moderately controlled patients. ICF at 12 msec and 15 msec were lower in poorly controlled patients than in normal subjects. Long-interval intracortical inhibition (LICI) at 50 msec was higher in poorly controlled compared to moderately controlled patients. These differences were not explained by antiepileptic drug (AED) treatment or duration of epilepsy. RMT and AMT increased with duration in the poorly controlled group, but did not increase with duration in the moderately controlled group. INTERPRETATION: Cortical excitability differs markedly between moderately controlled and poorly controlled patients with chronic epilepsy, not explained by disease or treatment variables. Moreover, the evolution of cortical excitability over time differs, becoming more abnormal in the poorly controlled group.

Analysis of rare copy number variation in absence epilepsies.

OBJECTIVE: To identify shared genes and pathways between common absence epilepsy (AE) subtypes (childhood absence epilepsy [CAE], juvenile absence epilepsy [JAE], and unclassified absence epilepsy [UAE]) that may indicate common mechanisms for absence seizure generation and potentially a diagnostic continuum. METHODS: We used high-density single-nucleotide polymorphism arrays to analyze genome-wide rare copy number variation (CNV) in a cohort of 144 children with AEs (95 CAE, 26 UAE, and 23 JAE). RESULTS: We identified CNVs that are known risk factors for AE in 4 patients, including 3x 15q11.2 deletion. We also expanded the phenotype at 4 regions more commonly identified in other neurodevelopmental disorders: 1p36.33 duplication, 1q21.1 deletion, 22q11.2 duplication, and Xp22.31 deletion and duplication. Fifteen patients (10.5%) were found to carry rare CNVs that disrupt genes associated with neuronal development and function (8 CAE, 2 JAE, and 5 UAE). Four categories of protein are each disrupted by several CNVs: (1) synaptic vesicle membrane or vesicle endocytosis, (2) synaptic cell adhesion, (3) synapse organization and motility via actin, and (4) gap junctions. CNVs within these categories are shared across the AE subtypes. CONCLUSIONS: Our results have reinforced the complex and heterogeneous nature of the AEs and their potential for shared genetic mechanisms and have highlighted several pathways that may be important in epileptogenesis of absence seizures.

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.