Risk Of Sudden Unexplained Death Research Articles

An insertion/deletion polymorphism within 3′UTR of RYR2 modulates sudden unexplained death risk in Chinese populations

Sudden unexplained death (SUD) constitutes a part of the overall sudden death that can not be underestimated. Over the last years, genetic testing on SUD has revealed that inherited channelopathies might play important roles in the pathophysiology of this disease. Ryanodine receptor type-2 (RYR2) is a kind of ion channel extensively distributed in the sarcoplasmic reticulum (SR) of myocardium. Studies on RYR2 have suggested that either dysfunction or abnormal expression of it could lead to arrhythmia, which may cause cardiac arrest. In this study, we conducted a case-control study to evaluate the association of a 4-base pair (4-bp) Indel polymorphism (rs10692285) in the 3′UTR of RYR2 with the risk of SUD and sudden cardiac death induced by coronary heart disease (SCD-AS) in a Chinese population. Logistic regression analysis showed that the insertion allele of rs10692285 had significantly increased the risk of SUD [OR=2.03; 95% confidence interval (CI)=1.08–3.77; P=0.0161; statistical power=0.743]. No relevance was observed between rs10692285 and SCD-AS. Further genotype–phenotype association analysis suggested that the expression level of RYR2 in human myocardium tissues with the insertion allele was higher than that with the deletion allele at both mRNA and protein levels. Dual-Luciferase activity assay system was used to detect the effect of rs10692285 on the transcription activity of RYR2. As expected, the result indicated that the transcription activity of RYR2 with the ins/ins genotype was higher than that with the del/del genotype. Finally, in-silico prediction revealed that different alleles of rs10692285 could alter the local structure of RYR2 mRNA and microRNA (miRNA) binding. In summary, our findings provided evidence that rs10692285 might contribute to SUD susceptibility through affecting the expression of RYR2, which suggest that abnormal ion channel activity is very likely to be the underlying mechanism of SUD, but not for SCD-AS. Thus, rs10692285 may become a potential marker for molecular diagnosis and genetic counseling of SUD.

Treatment of Dravet Syndrome.

Dravet syndrome is among the most challenging electroclinical syndromes. There is a high likelihood of recurrent status epilepticus; seizures are medically refractory; and patients have multiple co-morbidities, including intellectual disability, behaviour and sleep problems, and crouch gait. Additionally, they are at significant risk of sudden unexplained death. This review will focus predominantly on the prophylactic medical management of seizures, addressing both first-line therapies (valproate and clobazam) as well as second-line (stiripentol, topiramate, ketogenic diet) or later options (levetiracetam, bromides, vagus nerve stimulation). Sodium channel agents-including carbamazepine, oxcarbazepine, phenytoin and lamotrigine-should be avoided, as they typically exacerbate seizures. Several agents in development may show promise, specifically fenfluramine and cannabidiol, but they need further evaluation in randomized, controlled trials. In addition to prophylactic treatment, all patients need home-rescue medication and a status epilepticus protocol that can be carried out in their local hospital. Families must be counselled on non-pharmacologic strategies to reduce seizure risk, including avoidance of triggers that commonly induce seizures (including hyperthermia, flashing lights and patterns). In addition to addressing seizures, holistic care for a patient with Dravet syndrome must involve a multidisciplinary team that includes specialists in physical, occupational and speech therapy, neuropsychology, social work and physical medicine.

Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia.

The discovery of mutations in DEPDC5 in familial focal epilepsies has introduced a novel pathomechanism to a field so far dominated by ion channelopathies. DEPDC5 is part of a complex named GAP activity toward RAGs (GATOR) complex 1 (GATOR1), together with the proteins NPRL2 and NPRL3, and acts to inhibit the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) pathway. GATOR1 is in turn inhibited by the GATOR2 complex. The mTORC1 pathway is a major signaling cascade regulating cell growth, proliferation, and migration. We aimed to study the contribution of GATOR complex genes to the etiology of focal epilepsies and to describe the associated phenotypical spectrum. We performed targeted sequencing of the genes encoding the components of the GATOR1 (DEPDC5, NPRL2, and NPRL3) and GATOR2 (MIOS, SEC13, SEH1L, WDR24, and WDR59) complex in 93 European probands with focal epilepsy with or without focal cortical dysplasia. Phospho-S6 immunoreactivity was used as evidence of mTORC1 pathway activation in resected brain tissue of patients carrying pathogenic variants. We identified four pathogenic variants in DEPDC5, two in NPRL2, and one in NPRL3. We showed hyperactivation of the mTORC1 pathway in brain tissue from patients with NPRL2 and NPRL3 mutations. Collectively, inactivating mutations in GATOR1 complex genes explained 11% of cases of focal epilepsy, whereas no pathogenic mutations were found in GATOR2 complex genes. GATOR1-related focal epilepsies differ clinically from focal epilepsies due to mutations in ion channel genes by their association with focal cortical dysplasia and seizures emerging from variable foci, and might confer an increased risk of sudden unexplained death in epilepsy (SUDEP). GATOR1 complex gene mutations leading to mTORC1 pathway upregulation is an important cause of focal epilepsy with cortical malformations and represents a potential target for novel therapeutic approaches.

My Epilepsy Story—Muir Maxwell Trust

My Epilepsy Story—Muir Maxwell Trust

The association between multidose vaccinations and death: comparing case series methods when the first exposure changes the general risk of an event

Many case-control studies have shown a protective effect of vaccinations on the risk of sudden unexplained death (SUD). In this paper we compare the properties of different statistical methods in this situation, when the first vaccination appears to reduce the overall risk of an event (SUD). The first method is the self controlled case series (SCCS) method, which considers only subjects with an event during the observation time. This method yields unbiased estimates in the situation of non-censoring events. We show by simulation studies that the second method considered, the adjusted SCCS method, underestimates the parameter of interest, the effect of the first dose, when the general risk of SUD is lower in control periods after the first vaccination than in the period before vaccination. This type of bias could be eliminated by considering only cases who had received at least one vaccination. Additionally, we compare the adjusted SCCS method with the Cox model as a third method. Cox regression can take into account the time before the first vaccination, and this method yields unbiased estimates at modest effect sizes and short risk periods. We applied the SCCS method and Cox regression to data from the German study on sudden infant death (GeSID) and to a case series study from Italy (the HERA study) examining sudden unexpected deaths and vaccinations during the first 2 years of life. We show that the adjusted SCCS analysis with all cases underestimates the vaccination effect, as expected from the simulation analyses. Using Cox regression, we examined the general risk reduction after vaccination, as was the focus of the above mentioned studies. With a relative incidence of 0.8, our results were less pronounced than in the case-control analysis of the GeSID study (adjusted odds ratio: 0.51). SCCS analyses of both the GeSID and HERA studies yielded very similar estimates for the first and second vaccine doses.

Epilepsy and risk of death and sudden unexpected death in the young: A nationwide study

Patients with epilepsy are at increased risk of premature death from all causes and likely also from sudden unexplained death (SUD). Many patients with epilepsy have significant comorbidity, and it is unclear how much of the increased risk can be explained by epilepsy itself. We aimed to chart the incidence of sudden unexpected death in epilepsy (SUDEP) and estimate the risk of death from all causes and SUD conferred by epilepsy independently. We conducted a historical cohort study using data from Danish registries and a complete manual review of all death certificates. The population studied consisted of all Danish residents in the age group 1-35 years, in the period 2000-2006 (inclusive), and the main outcome measures were risk of death and SUD. We identified 33,022 subjects with epilepsy (median follow-up 3.7 years) and 3,001,952 subjects without (median follow-up 7.0 years). Among 685 deaths in the population with epilepsy, we identified 50 cases of definite and probable SUDEP corresponding to an incidence rate of 41.1 (95% confidence interval [CI] 31.6-54.9) per 100,000 person-years. Incidence rates increased with age from 17.6 (95% CI 9.5-32.8) in the age group 1-18 years to 73.8 (95% CI 52.5-103.8) for the age group 24-35 years. Having epilepsy increased the crude risk of death with a hazard ratio (HR) of 11.9 (95% CI 11.0-12.9). When adjusting for sex and comorbidities often encountered in patients with epilepsy (neurologic disease including cerebral palsy, psychiatric disease including mental retardation, and congenital disorders), as well as the Charlson comorbidity score, the HR fell to 5.4 (95% CI 4.9-6.0). The crude HR for SUD was 27.5 (95% CI 18.1-41.8) and fell to 16.3 (95% CI 9.8-26.9) when adjusted for the same covariates as above. Epilepsy in and of itself carries a significant risk of premature death and SUD. These findings highlight the potential gains of risk factor modification for the prevention of premature death and SUDEP in patients with epilepsy.

Inheritance of Febrile Seizures in Sudden Unexplained Death in Toddlers

Sudden unexplained death in toddlers has been associated with febrile seizures, family history of febrile seizures, and hippocampal anomalies. We investigated the mode of inheritance for febrile seizures in these families. A three-generation pedigree was obtained from families enrolled in the San Diego Sudden Unexplained Death in Childhood Research Project, involving toddlers with sudden unexplained death, febrile seizures, and family history of febrile seizures. In our six cases, death was unwitnessed and related to sleep. The interval from last witnessed febrile seizure to death ranged from 3 weeks to 6 months. Hippocampal abnormalities were identified in one of three cases with available autopsy sections. Autosomal dominant inheritance of febrile seizures was observed in three families. A fourth demonstrated autosomal dominant inheritance with incomplete penetrance or variable expressivity. In two families, the maternal and paternal sides manifested febrile seizures. In this series, the major pattern of inheritance in toddlers with sudden unexplained death and febrile seizures was autosomal dominant. Future studies should develop markers (including genetic) to identify which patients with febrile seizures are at risk for sudden unexplained death in childhood, and to provide guidance for families and physicians.

Characterizing sudden death and dead‐in‐bed syndrome in Type 1 diabetes: analysis from two childhood‐onset Type 1 diabetes registries

Type 1 diabetes mellitus increases the risk for sudden unexplained death, generating concern that diabetes processes and/or treatments underlie these deaths. Young (< 50 years) and otherwise healthy patients who are found dead in bed have been classified as experiencing 'dead-in-bed' syndrome. We thus identified all unwitnessed deaths in two related registries (the Children's Hospital of Pittsburgh and Allegheny County) yielding 1319 persons with childhood-onset (age < 18 years) Type 1 diabetes diagnosed between 1965 and 1979. Cause of death was determined by a Mortality Classification Committee (MCC) of at least two physician epidemiologists, based on the death certificate and additional records surrounding the death. Of the 329 participants who had died, the Mortality Classification Committee has so far reviewed and assigned a final cause of death to 255 (78%). Nineteen (8%) of these were sudden unexplained deaths (13 male) and seven met dead-in-bed criteria. The Mortality Classification Committee adjudicated cause of death in the seven dead-in-bed persons as: diabetic coma (n =4), unknown (n=2) and cardiomyopathy (n=1, found on autopsy). The three dead-in-bed individuals who participated in a clinical study had higher HbA(1c) , lower BMI and higher daily insulin dose compared with both those dying from other causes and those surviving. Sudden unexplained death in Type 1 diabetes seems to be increased 10-fold and associated with male sex, while dead-in-bed individuals have a high HbA(1c) and insulin dose and low BMI. Although sample size is too small for definitive conclusions, these results suggest specific sex and metabolic factors predispose to sudden unexplained death and dead-in-bed death.

Lung‐function tests in neonates and infants with chronic lung disease: Tidal breathing and respiratory control

This paper is the fourth in a series of reviews that will summarize available data and critically discuss the potential role of lung-function testing in infants with acute neonatal respiratory disorders and chronic lung disease of infancy. The current paper addresses information derived from tidal breathing measurements within the framework outlined in the introductory paper of this series, with particular reference to how these measurements inform on control of breathing. Infants with acute and chronic respiratory illness demonstrate differences in tidal breathing and its control that are of clinical consequence and can be measured objectively. The increased incidence of significant apnea in preterm infants and infants with chronic lung disease, together with the reportedly increased risk of sudden unexplained death within the latter group, suggests that control of breathing is affected by both maturation and disease. Clinical observations are supported by formal comparison of tidal breathing parameters and control of breathing indices in the research setting.

Thioridazine and sudden unexplained death in psychiatric in-patients.

Sudden death has been linked to antipsychotic therapy, but the relative risk associated with specific drugs is unknown. To assess the risk of sudden unexplained death associated with antipsychotic drug therapy and its relation to drug dose and individual agents. A case-control study of psychiatric in-patients dying suddenly in five hospitals in the north-east of England and surviving controls matched for age, gender and mental disorder. Logistic regression analysis was used to identify significant risk factors, and odds ratios were calculated. Sixty-nine case-control clusters were identified. Probable sudden unexplained death was significantly associated with hypertension, ischaemic heart disease and current treatment with thioridazine (adjusted odds ratio=5.3, 95% CI 1.7-16.2, P=0.004). There was no significant association with other individual antipsychotic drugs. Thioridazine alone was associated with sudden unexplained death, the likely mechanism being drug-induced arrhythmia.

Mortality in antiepileptic drug development programs.

Pooled data from New Drug Applications (NDAs) submitted to the U.S. Food and Drug Administration (FDA) provide an opportunity to study the incidence of and risk factors for rare events. To examine the incidence and causes of mortality in patients with epilepsy participating in clinical trials of antiepileptic drugs (AEDs); and to examine the incidence of and risk factors for sudden unexplained death in such patients. Exposure data and death narratives were obtained from the NDAs of five recently reviewed AEDs. Deaths were classified as sudden unexplained, accidental, or other cause using the 1993 Burroughs-Wellcome expert panel criteria, and mortality rates were calculated for each category. Add-on trials were analyzed separately from monotherapy initiation trials. Among 9,144 patients in the add-on trial database, the all-cause and sudden unexplained mortality rates were 9.1 and 3.8 deaths per 1,000 person-years (124 and 52 deaths in 13,617.1 person-years of drug exposure). Sixty-five percent of all deaths were related to the underlying epilepsy. Of the examined risk factors, only age was associated with the incidence of sudden unexplained death. Among 1,293 patients in the monotherapy initiation trials, the all-cause and sudden unexplained mortality rates were 7.1 and 0 deaths per 1,000 person-years (7 and 0 deaths in 982.5 person-years of drug exposure). A large proportion of the deaths in the add-on cohort was attributable to epilepsy-related causes. Mortality due to sudden death in the add-on cohort falls into the high end of the reported range for patients with epilepsy. The difference in mortality due to sudden death between the add-on and monotherapy initiation cohorts suggests that disease severity is the primary determining factor for risk of sudden unexplained death.

Sickle Cell Trait and Military Service

In the community great efforts have been made to educate those with sickle cell trait that their condition is not a handicap and that they are fit to lead a normal life. It would be seen as a retrograde step for the Armed Forces to imply that they are in some way unfit for normal duties. The evidence presented demonstrates that with the exception of a small excess risk of sudden unexplained death during training there is no objection to recruiting those with sickle cell trait into the Royal Navy. At present those with sickle cell disorders are barred from service in the Royal Marine Commandos and from diving, submarine and aircrew service. On the basis of the evidence presented in this review a case can be made for allowing those with sickle cell trait to enter as aircrew in helicopters but not as pilots. In view of the requirements for military divers to operate in cold water under stressful conditions the exclusion of those with sickle cell trait is entirely justified. The overriding requirement must be the safety of both the affected individual and of others and the current regulations reflect this. Screening of all recruits and officer entrants in appropriate racial groups is not performed at present but would allow counselling and advice to be given to those affected by sickle cell trait at an early stage of their careers and the reasons for their exclusion from certain branches fully explained either by establishment Medical Officers or by the haematologist.(ABSTRACT TRUNCATED AT 250 WORDS)

Sickle-cell trait as a risk factor for sudden death in physical training.

Case reports of sudden death during exertion have not established an association between the sickle-cell trait (hemoglobin AS) and exercise-related death. To test this association, all deaths occurring among 2 million enlisted recruits during basic training in the U.S. Armed Forces in 1977 to 1981 were classified from autopsy and clinical records as non-sudden deaths or as sudden deaths explained or unexplained by preexisting disease. On the basis of known numbers of entering recruits (according to race, age, and sex) and published prevalence rates for hemoglobin AS (8 percent for black and 0.08 percent for nonblack recruits), death rates (per 100,000) were 32.2 for sudden unexplained deaths, 2.7 for sudden explained deaths, and 0 for non-sudden deaths among black recruits with hemoglobin AS, as compared with 1.2, 1.2, and 0.7 among black recruits without hemoglobin S and 0.7, 0.5, and 1.1 among nonblack recruits without hemoglobin S. Among black recruits the relative risk of sudden unexplained death (hemoglobin AS vs. non-hemoglobin S) was 27.6 (95 percent confidence interval, 9 to 100; P less than 0.001), whereas among all recruits this risk was 39.8 (95 percent confidence interval, 17 to 90; P less than 0.001). The relative risk of sudden unexplained death among all recruits increased with age (P less than 0.04), from 13 (ages 17 to 18) to 95 (ages 26 to 30). We conclude that recruits in basic training with the sickle-cell trait have a substantially increased, age-dependent risk of exercise-related sudden death unexplained by any known preexisting cause.

LACK OF OBJECTIVITY IN DISTINGUISHING INFANTS IN NEED OF HOME MONITORING OR PREDICTING SUBSEQUENT APNEA

Seventy patients referred following an apparent "apneic episode" were evaluated by detailed history (H), physical examination (PE) and objective studies (OS) which were indicated by the H&PE. These included CBC, serum chemistry & electrolytes, chest X-ray, ABG, pneumogram (P), ECG, EEG, esophagram and esophageal pH monitoring. Home monitoring (HM) was prescribed in 43 infants who were considered by an attending physician to be at high risk for sudden unexplained death. All infants were monitored for apnea (> 20 sec) & bradycardia for a minimum of 2 months. Twenty-seven infants were not monitored (Group I). A diagnosis other than apnea was made in 13, mostly gastroesophageal reflux (GER) and/or seizures. Twenty-three infants on HM had no subsequent events requiring intervention (Group II); twenty infants on HM had subsequent A requiring intervention (Group III). All patients were followed at least past their first birthday with no deaths. In all patients the severity of the presenting episode failed to predict recurrent A. Of 20 infants requiring mouth-to-mouth (MTM) or cardiopulmonary resuscitation by H, 13 were monitored. Only 2/13 had subsequent A (1 requiring gentle shake, the other MTM). P obtained in 60 infants was abnormal in 7 (Group I-0/21;Group II-3/19;Group III-4/20), but not predictive of future A. GER was found in 16/49, 9 of whom were monitored. Eight of these infants had another A. The results of all other studies were non-contributory. We conclude that the decision for HM was largely subjective and that neither H or OS were predictive of outcome.