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PURPOSE: Local anesthetic systemic toxicity (LAST) is a low-frequency, high-risk event that can occur within minutes of a patient receiving a local anesthetic. The goals of this project were to standardize LAST care management across an academic medical center and sustain an improvement in nurses' knowledge of how to recognize signs and symptoms of LAST and how to competently manage a LAST scenario. DESIGN: We used a quantitative design to accomplish the goals of the project. METHODS: Our interdisciplinary team developed a clinical practice guideline based on the LAST Checklist published by the American Society of Regional Anesthesia and Pain Medicine, and used a simulation scaffolded by multimodal education and system changes to ensure sustained knowledge. We measured improvement using a graded knowledge assessment as well as qualitative feedback. FINDINGS: Scores on the assessment increased from 4.76 to 6.34 (out of seven points) following the intervention and remained significantly higher than the baseline 9 months after the educational intervention (9-month score = 6.19, t = 2.99, P = .004). Nurses reported feeling more confident and knowledgeable following the intervention and requested to have regular sessions of the simulation. To sustain improvements, we developed a computer-based learning module. The module and simulation were integrated into nursing orientation and an annual competency. CONCLUSIONS: While standardizing LAST care in accordance with evidence-based guidance is critical to patient safety due to its infrequent occurrence, nurses should consider implementing simulation supplemented with multimodal education and system changes to ensure sustained knowledge.
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PURPOSE: This study explores the impact of the COVID-19 pandemic and lockdown on people with lived experience of sudden bereavement as a consequence of an epilepsy-related death. METHOD: We developed an online survey with fixed choice and open-ended response formats to collect data on grief symptoms and well-being during the pandemic. A total of 275 people bereaved by epilepsy-related deaths between 1980-2020 participated in this study: with 79 participants providing free-text responses for inductive thematic analysis. RESULTS: In total, 84% of participants reported a bereavement following a sudden death of a person aged under 40, with 22% aged 19 and under. The majority (77% of participants) reported they had been thinking more about the person who died compared to before the COVID-19 outbreak and 54% had experienced more distressing flashbacks to the time of death. Additionally, 61% reported more difficulties falling asleep and staying asleep and 88% of participants reported that the outbreak and response measures had negatively impacted upon their mental health. Medication was being taken for a diagnosed mental health condition by 33% of participants at the time of the study. We categorized these negative experiences during COVID in to four main-themes - 'Family', 'Lifestyle', 'Personal Well-being' and 'Health Services and Shielding Populations'. The 'Personal Well-being' theme was inextricably linked to grief symptoms including 'reflection on the death', 're-exposure to feeling', 'grief', 'salience of sudden deaths in the media' and 'inability to commemorate anniversaries and rituals'. These findings were consistent for bereaved people irrespective of the recency of the death. CONCLUSION: This study highlights the impact of the disruption caused by the pandemic on the grief-management of those bereaved by epilepsy-related death. Grief is not static and its management is connected to the psychosocial and formal support structures that were disrupted during the pandemic. The removal of these supports had an adverse effect upon the mental health and well-being of many bereaved. There is an urgent need for a system-wide transformation of epilepsy and mental health services to be inclusive of the needs and experiences of people impacted by sudden deaths in epilepsy and the contribution of the specialist service developed by families and clinicians to meet this gap.
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Aflicción , COVID-19 , Epilepsia , Humanos , Pandemias , Control de Enfermedades Transmisibles , Epilepsia/epidemiología , Muerte Súbita/epidemiologíaRESUMEN
Quinidine has been proposed as a repurposed licensed drug for the treatment of seizures in KCNT1 gain-of-function associated Epilepsy of Infancy with Migrating Focal Seizures (EIMFS). Sparse evidence from case reports suggests limited effectiveness and tolerability. Here we report the adaptation of a n-of-1 trial protocol and results of adjunctive quinidine intervention. We adapted a n-of-1 trial protocol from two unpublished protocols and with expert advice including input from pediatric neurology, cardiology and pharmacy colleagues. We tailored this protocol to a severely disabled patient with EIMFS and a de novo c.1420C>T p.Arg474Lys missense variant. We discussed outcome measures with the family of the patient and initiated adjunctive inpatient quinidine treatment with appropriate safety measures. The trial was terminated as a result of intolerable gastrointestinal adverse effects following the initiation dose. Subsequent reports suggest that quinidine may not be effective for this genotype. Quinidine is poorly tolerated across cardiological and neurological indications. Current pooled evidence suggests limited effectiveness for KCNT1 associated epilepsies at doses ≤40mg/kg/d. It is important to report all clinical evidence in precision medicine trials, whether positive or negative, to counter publication bias. This study highlights universal issues around outcome measurement and the evaluation of evidence in rare disease interventions.
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Epilepsia , Quinidina , Niño , Humanos , Quinidina/uso terapéutico , Canales de potasio activados por Sodio , Anticonvulsivantes/uso terapéutico , Proteínas del Tejido Nervioso/genética , Convulsiones/tratamiento farmacológico , Convulsiones/genética , Convulsiones/inducido químicamente , Epilepsia/tratamiento farmacológicoRESUMEN
BACKGROUND: Virtual fracture clinics (VFC) have been widely adopted worldwide as part of the changes in healthcare delivery during the COVID-19 pandemic. They have been shown to be a safe and effective method of delivering trauma care for injuries which do not require immediate intervention or specialist management, whilst maintaining high levels of patient satisfaction. AIMS: Our aim was to evaluate whether VFCs reduce the volume of X-rays performed for common fractures of the wrist and ankle. METHODS: A retrospective cohort review was performed. The pre-VFC group consisted of 168 wrist and 108 ankle referrals from March to September 2019. The VFC group included 75 wrist and 68 ankle referrals, during the period March to September 2020. The total number of X-ray images, carried out within a 3-month period for each fracture was summated, with statistical analysis performed following fracture pattern classification. FINDINGS: A statistically significant decrease in mean X-rays was observed for isolated stable fracture patterns, such as non-displaced distal radius, - 0.976 (p = 0.00025), and Weber A ankle fractures, - 0.907 (p = 0.000013). A reduction was also observed for more complex fracture patterns such as dorsally displaced distal radius, - 0.701 (p = 0.129) and Weber B ankle fractures, - 0.786 (p = 0.235), though not achieving statistical significance. CONCLUSIONS: Virtual fracture clinics can reduce X-ray frequency for common stable wrist and ankle fractures, with resultant benefits for both patients and healthcare systems. These benefits may be sustained in patient care beyond the current COVID-19 pandemic.
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Fracturas de Tobillo , COVID-19 , Fracturas de Tobillo/diagnóstico por imagen , Fracturas de Tobillo/terapia , Humanos , Pandemias , Estudios Retrospectivos , Muñeca , Rayos XRESUMEN
Variants of the SCN1A gene encoding the neuronal voltage-gated sodium channel NaV1.1 cause over 85% of all cases of Dravet syndrome, a severe and often pharmacoresistent epileptic encephalopathy with mostly infantile onset. But with the increased availability of genetic testing for patients with epilepsy, variants in SCN1A have now also been described in a range of other epilepsy phenotypes. The vast majority of these epilepsy-associated variants are de novo, and most are either nonsense variants that truncate the channel or missense variants that are presumed to cause loss of channel function. However, biophysical analysis has revealed a significant subset of missense mutations that result in increased excitability, further complicating approaches to precision pharmacotherapy for patients with SCN1A variants and epilepsy. We describe clinical and biophysical data of a familial SCN1A variant encoding the NaV1.1 L1624Q mutant. This substitution is located on the extracellular linker between S3 and S4 of Domain IV of NaV1.1 and is a rare case of a familial SCN1A variant causing an autosomal dominant frontal lobe epilepsy. We expressed wild-type (WT) and L1642Q channels in CHO cells. Using patch-clamp to characterize channel properties at several temperatures, we show that the L1624Q variant increases persistent current, accelerates fast inactivation onset and decreases current density. While SCN1A-associated epilepsy is typically considered a loss-of-function disease, our results put L1624Q into a growing set of mixed gain and loss-of-function variants in SCN1A responsible for epilepsy.
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BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) accounts for a large percentage of deaths in children with epilepsy. Contributing factors to paediatric SUDEP are incompletely understood. AIMS OF STUDY: The Epilepsy Deaths Register (EDR) is an anonymized register that compiles information on deaths related to epilepsy, across all ages and epilepsy classifications. Using the EDR, we sought to identify key risk factors for SUDEP in children to assist the development of preventive measures. METHODS: All registrations between the ages of 1 and 16 years were reviewed to identify definite or probable SUDEP. These cases were analysed to identify common demographics, comorbidities, monitoring, treatments and circumstances near to the deaths. RESULTS: We identified forty-six cases (27 males) of definite or probable SUDEP. Paediatric SUDEP is more common in a 12- to 16-year age group and in those with neuro-disability. Most paediatric SUDEP occurs during apparent sleep. There were four cases with a vagus nerve stimulator. SUDEP can occur early after the onset of seizures. CONCLUSIONS: This is the largest single cohort of SUDEP reported in children. Reports from caregivers can augment population data. Surveillance in sleep is a priority area of development.
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Muerte Súbita e Inesperada en la Epilepsia/epidemiología , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Padres , Sistema de Registros , Factores de RiesgoRESUMEN
OBJECTIVE: We aimed to describe the extent of neurodevelopmental impairments and identify the genetic etiologies in a large cohort of patients with epilepsy with myoclonic atonic seizures (MAE). METHODS: We deeply phenotyped MAE patients for epilepsy features, intellectual disability, autism spectrum disorder, and attention-deficit/hyperactivity disorder using standardized neuropsychological instruments. We performed exome analysis (whole exome sequencing) filtered on epilepsy and neuropsychiatric gene sets to identify genetic etiologies. RESULTS: We analyzed 101 patients with MAE (70% male). The median age of seizure onset was 34 months (range = 6-72 months). The main seizure types were myoclonic atonic or atonic in 100%, generalized tonic-clonic in 72%, myoclonic in 69%, absence in 60%, and tonic seizures in 19% of patients. We observed intellectual disability in 62% of patients, with extremely low adaptive behavioral scores in 69%. In addition, 24% exhibited symptoms of autism and 37% exhibited attention-deficit/hyperactivity symptoms. We discovered pathogenic variants in 12 (14%) of 85 patients, including five previously published patients. These were pathogenic genetic variants in SYNGAP1 (n = 3), KIAA2022 (n = 2), and SLC6A1 (n = 2), as well as KCNA2, SCN2A, STX1B, KCNB1, and MECP2 (n = 1 each). We also identified three new candidate genes, ASH1L, CHD4, and SMARCA2 in one patient each. SIGNIFICANCE: MAE is associated with significant neurodevelopmental impairment. MAE is genetically heterogeneous, and we identified a pathogenic genetic etiology in 14% of this cohort by exome analysis. These findings suggest that MAE is a manifestation of several etiologies rather than a discrete syndromic entity.
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Epilepsias Mioclónicas/patología , Epilepsia Generalizada/patología , Convulsiones/patología , Edad de Inicio , Trastorno por Déficit de Atención con Hiperactividad/complicaciones , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno por Déficit de Atención con Hiperactividad/patología , Trastorno del Espectro Autista/complicaciones , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/patología , Niño , Preescolar , Electroencefalografía , Epilepsias Mioclónicas/complicaciones , Epilepsias Mioclónicas/genética , Epilepsia Generalizada/complicaciones , Epilepsia Generalizada/genética , Femenino , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Masculino , Neuroimagen , Fenotipo , Convulsiones/genética , Secuenciación del ExomaAsunto(s)
Electroencefalografía/métodos , Epilepsia Refleja/fisiopatología , Conducta Alimentaria/fisiología , Convulsiones/fisiopatología , Técnicas Estereotáxicas , Adolescente , Epilepsia Refleja/diagnóstico por imagen , Epilepsia Refleja/psicología , Conducta Alimentaria/psicología , Humanos , Masculino , Convulsiones/diagnóstico por imagen , Convulsiones/psicologíaRESUMEN
Epilepsy-related death in children and young people deserves understanding and intervention along with epilepsy-related deaths in adults. Risk of death from epilepsy varies at different ages, and the specific calculations of risk remains complex and varies between studies. There have been several UK studies examining factors associated with epilepsy-related deaths. A UK national audit with other national initiatives has evidenced improving quality of care and more recently allowed service provision factors associated with reduced epilepsy-related death to be evidenced. A national program of health education, formalized epilepsy networks, commissioned surgical pathways, and patient information resources around risk and participation are examples of quality improvement initiatives. Epilepsy-related death is a key outcome, and there remains many difficulties and opportunities at local, regional, and national level to better understand and improve this outcome for children and young people and the adults that they should become. This paper is for the Special Issue: Prevent 21: SUDEP Summit - Time to Listen.
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Recolección de Datos/métodos , Epilepsia/mortalidad , Pediatría/métodos , Vigilancia de la Población , Niño , Preescolar , Epilepsia/complicaciones , Epilepsia/prevención & control , Femenino , Humanos , Masculino , Vigilancia de la Población/métodos , Factores de Riesgo , Muerte Súbita e Inesperada en la Epilepsia/prevención & control , Reino Unido/epidemiologíaRESUMEN
Febrile infection-related epilepsy syndrome (FIRES) is a severe epilepsy disorder that affects previously healthy children. It carries high likelihood of unfavourable outcome and putative aetiology relates to an auto-inflammatory process. Standard antiepileptic drug therapies including intravenous anaesthetic agents are largely ineffective in controlling status epilepticus in FIRES. Deep brain stimulation of the centromedian thalamic nuclei (CMN-DBS) has been previously used in refractory status epilepticus in only a few cases. The use of Anakinra (a recombinant version of the human interleukin-1 receptor antagonist) has been reported in one case with FIRES with good outcome. Here we describe two male paediatric patients with FIRES unresponsive to multiple anti-epileptic drugs, first-line immune modulation, ketogenic diet and cannabidiol. They both received Anakinra and underwent CMN-DBS. The primary aim for CMN-DBS therapy was to reduce generalized seizures. CMN-DBS abolished generalized seizures in both cases and Anakinra had a positive effect in one. This patient had a favourable outcome whereas the other did not. These are the first reported cases of FIRES where CMN-DBS has been used.
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Encefalopatía Aguda Febril/terapia , Terapia Combinada/métodos , Estimulación Encefálica Profunda/métodos , Epilepsia Refractaria/terapia , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Encefalopatía Aguda Febril/complicaciones , Anticonvulsivantes/uso terapéutico , Niño , Epilepsia Refractaria/etiología , Humanos , Masculino , Estado Epiléptico/etiología , Estado Epiléptico/terapia , Núcleos Talámicos/fisiología , Resultado del TratamientoRESUMEN
OBJECTIVE: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. METHODS: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. RESULTS: We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. CONCLUSION: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies.
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Síndromes Epilépticos/genética , Sintaxina 1/genética , Adolescente , Anticonvulsivantes/uso terapéutico , Niño , Preescolar , Discapacidades del Desarrollo , Epilepsia Refractaria/genética , Electroencefalografía , Epilepsias Parciales/genética , Epilepsias Parciales/fisiopatología , Síndromes Epilépticos/tratamiento farmacológico , Síndromes Epilépticos/fisiopatología , Síndromes Epilépticos/psicología , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Recién Nacido , Discapacidades para el Aprendizaje , Mutación con Pérdida de Función , Masculino , Mutación Missense , Fenotipo , Convulsiones Febriles , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
We evaluated a new epilepsy genetic diagnostic and counseling service covering a UK population of 3.5 million. We calculated diagnostic yield, estimated clinical impact, and surveyed referring clinicians and families. We costed alternative investigational pathways for neonatal onset epilepsy. Patients with epilepsy of unknown aetiology onset < 2 years; treatment resistant epilepsy; or familial epilepsy were referred for counseling and testing. We developed NGS panels, performing clinical interpretation with a multidisciplinary team. We held an educational workshop for paediatricians and nurses. We sent questionnaires to referring paediatricians and families. We analysed investigation costs for 16 neonatal epilepsy patients. Of 96 patients, a genetic diagnosis was made in 34% of patients with seizure onset < 2 years, and 4% > 2 years, with turnaround time of 21 days. Pathogenic variants were seen in SCN8A, SCN2A, SCN1A, KCNQ2, HNRNPU, GRIN2A, SYNGAP1, STXBP1, STX1B, CDKL5, CHRNA4, PCDH19 and PIGT. Clinician prediction was poor. Clinicians and families rated the service highly. In neonates, the cost of investigations could be reduced from £9362 to £2838 by performing gene panel earlier and the median diagnostic delay of 3.43 years reduced to 21 days. Panel testing for epilepsy has a high yield among children with onset < 2 years, and an appreciable clinical and financial impact. Parallel gene testing supersedes single gene testing in most early onset cases that do not show a clear genotype-phenotype correlation. Clinical interpretation of laboratory results, and in-depth discussion of implications for patients and their families, necessitate multidisciplinary input and skilled genetic counseling.
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BACKGROUND: Rolandic epilepsy (RE) is the most common genetic childhood epilepsy, consisting of focal, nocturnal seizures and frequent neurodevelopmental impairments in speech, language, literacy and attention. A complex genetic aetiology is presumed in most, with monogenic mutations in GRIN2A accounting for >5% of cases. OBJECTIVE: To identify rare, causal CNV in patients with RE. METHODS: We used high-density SNP arrays to analyse the presence of rare CNVs in 186 patients with RE from the UK, the USA, Sardinia, Argentina and Kerala, India. RESULTS: We identified 84 patients with one or more rare CNVs, and, within this group, 14 (7.5%) with recurrent risk factor CNVs and 15 (8.0%) with likely pathogenic CNVs. Nine patients carried recurrent hotspot CNVs including at 16p13.11 and 1p36, with the most striking finding that four individuals (three from Sardinia) carried a duplication, and one a deletion, at Xp22.31. Five patients with RE carried a rare CNV that disrupted genes associated with other epilepsies (KCTD7, ARHGEF15, CACNA2D1, GRIN2A and ARHGEF4), and 17 cases carried CNVs that disrupted genes associated with other neurological conditions or that are involved in neuronal signalling/development. Network analysis of disrupted genes with high brain expression identified significant enrichment in pathways of the cholinergic synapse, guanine-exchange factor activation and the mammalian target of rapamycin. CONCLUSION: Our results provide a CNV profile of an ethnically diverse cohort of patients with RE, uncovering new areas of research focus, and emphasise the importance of studying non-western European populations in oligogenic disorders to uncover a full picture of risk variation.
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Neuronas Colinérgicas , Variaciones en el Número de Copia de ADN , Epilepsia Rolándica/genética , Predisposición Genética a la Enfermedad , Argentina , Femenino , Pruebas Genéticas , Humanos , India , Italia , Masculino , Sinapsis , Estados UnidosRESUMEN
OBJECTIVES: To evaluate the efficacy of intracranial stimulation to treat refractory epilepsy in children. METHODS: This is a retrospective analysis of a pilot study on all 8 children who had intracranial electrical stimulation for the investigation and treatment of refractory epilepsy at King's College Hospital between 2014 and 2015. Five children (one with temporal lobe epilepsy and four with frontal lobe epilepsy) had subacute cortical stimulation (SCS) for a period of 20-161 h during intracranial video-telemetry. Efficacy of stimulation was evaluated by counting interictal discharges and seizures. Two children had thalamic deep brain stimulation (DBS) of the centromedian nucleus (one with idiopathic generalized epilepsy, one with presumed symptomatic generalized epilepsy), and one child on the anterior nucleus (right fronto-temporal epilepsy). The incidence of interictal discharges was evaluated visually and quantified automatically. RESULTS: Among the three children with DBS, two had >60% improvement in seizure frequency and severity and one had no improvement. Among the five children with SCS, four showed improvement in seizure frequency (>50%) and one chid did not show improvement. Procedures were well tolerated by children. CONCLUSION: Cortical and thalamic stimulation appear to be effective and well tolerated in children with refractory epilepsy. SCS can be used to identify the focus and predict the effects of resective surgery or chronic cortical stimulation. Further larger studies are necessary.
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Estimulación Encefálica Profunda/métodos , Epilepsia del Lóbulo Frontal/rehabilitación , Epilepsia del Lóbulo Temporal/rehabilitación , Adolescente , Corteza Cerebral/fisiopatología , Niño , Epilepsia del Lóbulo Frontal/fisiopatología , Epilepsia del Lóbulo Temporal/fisiopatología , Femenino , Humanos , Masculino , Proyectos Piloto , Estudios Retrospectivos , Tálamo/fisiopatología , Resultado del TratamientoRESUMEN
OBJECTIVE: The high prevalence and impact of neurodevelopmental comorbidities in childhood epilepsy are now well known, as are the increased risks and familial aggregation of reading disability (RD) and speech sound disorder (SSD) in rolandic epilepsy (RE). The risk factors for RD in the general population include male sex, SSD, and ADHD, but it is not known if these are the same in RE or whether there is a contributory role of seizure and treatment-related variables. METHODS: An observational study of 108 probands with RE (age range: 3.6-22 years) and their 159 siblings (age range: 1-29 years; 83 with EEG data) were singly ascertained in the US or UK through a proband affected by RE. We used a nested case-control design, multiple logistic regression, and generalized estimating equations to test the hypothesis of an association between RD and seizure variables or antiepileptic drug treatment in RE; we also assessed an association between EEG focal sharp waves and RD in siblings. RESULTS: Reading disability was reported in 42% of probands and 22% of siblings. Among probands, RD was strongly associated with a history of SSD (OR: 9.64, 95% CI: 2.45-37.21), ADHD symptoms (OR: 10.31, 95% CI: 2.15-49.44), and male sex (OR: 3.62, 95% CI: 1.11-11.75) but not with seizure or treatment variables. Among siblings, RD was independently associated only with SSD (OR: 4.30, 95% CI: 1.42-13.0) and not with the presence of interictal EEG focal sharp waves. SIGNIFICANCE: The principal risk factors for RD in RE are SSD, ADHD, and male sex, the same risk factors as for RD without epilepsy. Seizure or treatment variables do not appear to be important risk factors for RD in probands with RE, and there was no evidence to support interictal EEG focal sharp waves as a risk factor for RD in siblings. Future studies should focus on the precise neuropsychological characterization of RD in families with RE and on the effectiveness of standard oral-language and reading interventions.
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Dislexia/epidemiología , Dislexia/fisiopatología , Epilepsia Rolándica/epidemiología , Epilepsia Rolándica/fisiopatología , Lectura , Hermanos , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Preescolar , Dislexia/diagnóstico , Electroencefalografía/métodos , Epilepsia Rolándica/diagnóstico , Familia , Femenino , Humanos , Lactante , Masculino , Estudios Prospectivos , Factores de Riesgo , Adulto JovenRESUMEN
Sudden unexpected death in epilepsy (SUDEP) represents the most severe degree of the spectrum of epilepsy severity and is the commonest cause of epilepsy-related premature mortality. The precise pathophysiology and the genetic architecture of SUDEP remain elusive. Aiming to elucidate the genetic basis of SUDEP, we analysed rare, protein-changing variants from whole-exome sequences of 18 people who died of SUDEP, 87 living people with epilepsy and 1479 non-epilepsy disease controls. Association analysis revealed a significantly increased genome-wide polygenic burden per individual in the SUDEP cohort when compared to epilepsy (P = 5.7 × 10(- 3)) and non-epilepsy disease controls (P = 1.2 × 10(- 3)). The polygenic burden was driven both by the number of variants per individual, and over-representation of variants likely to be deleterious in the SUDEP cohort. As determined by this study, more than a thousand genes contribute to the observed polygenic burden within the framework of this study. Subsequent gene-based association analysis revealed five possible candidate genes significantly associated with SUDEP or epilepsy, but no one single gene emerges as common to the SUDEP cases. Our findings provide further evidence for a genetic susceptibility to SUDEP, and suggest an extensive polygenic contribution to SUDEP causation. Thus, an overall increased burden of deleterious variants in a highly polygenic background might be important in rendering a given individual more susceptible to SUDEP. Our findings suggest that exome sequencing in people with epilepsy might eventually contribute to generating SUDEP risk estimates, promoting stratified medicine in epilepsy, with the eventual aim of reducing an individual patient's risk of SUDEP.
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Epilepsia/genética , Variación Genética , Estudio de Asociación del Genoma Completo/métodos , Herencia Multifactorial/genética , Adulto , Causas de Muerte , Muerte Súbita , Epilepsia/mortalidad , Epilepsia/patología , Exoma/genética , Femenino , Estudios de Asociación Genética/métodos , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Factores de Riesgo , Análisis de Secuencia de ADN/métodos , Índice de Severidad de la EnfermedadAsunto(s)
Odontólogos/economía , Administración de la Práctica Odontológica/economía , Sociedades Odontológicas , Odontólogos/legislación & jurisprudencia , Educación Continua en Odontología , Administración Financiera/economía , Humanos , Seguro de Responsabilidad Civil/economía , Relaciones Interprofesionales , Irlanda , Administración de la Práctica Odontológica/legislación & jurisprudencia , Impuestos/economíaRESUMEN
N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is a well-recognized clinico-immunological syndrome that presents with a movement disorder, cognitive decline, psychiatric symptoms, and epileptic seizures. A pure monosymptomatic presentation is rare; however, some patients present predominantly with a movement disorder in the absence of encephalopathy. Here, we describe three paediatric patients with an NMDAR antibody-mediated movement disorder: a 5-year-old female with acute onset hemichorea, a 10-year-old female with generalized chorea, and a 12-year-old male with abdominal myoclonus. These patients did not develop the characteristic encephalopathy syndrome seen in NMDAR encephalitis, but all three had other associated subtle cognitive deficits. The patients demonstrated good responses to immunotherapy.