Post-mortem review and genetic analysis of sudden unexpected death in epilepsy (SUDEP) cases.
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ABSTRACT:
SUBMITTER: Tu E
PROVIDER: S-EPMC8094243 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AimsSudden unexpected death in epilepsy (SUDEP) is one of the leading causes of death in people with epilepsy. For classification of definite SUDEP, a post mortem (PM), including anatomical and toxicological examination, is mandatory to exclude other causes of death. We audited PM practice as well as the value of brain examination in SUDEP.MethodsWe reviewed 145 PM reports in SUDEP cases from four UK neuropathology centres. Data were extracted for clinical epilepsy details, circumstances of death and neuropathological findings.ResultsMacroscopic brain abnormalities were identified in 52% of cases. Mild brain swelling was present in 28%, and microscopic pathologies relevant to cause or effect of seizures were seen in 89%. Examination based on whole fixed brains (76.6% of all PMs), and systematic regional sampling was associated with higher detection rates of underlying pathology (P < 0.01). Information was more frequently recorded regarding circumstances of death and body position/location than clinical epilepsy history and investigations.ConclusionOur findings support the contribution of examination of the whole fixed brain in SUDEP, with high rates of detection of relevant pathology. Availability of full clinical epilepsy-related information at the time of PM could potentially further improve detection through targeted tissue sampling. Apart from confirmation of SUDEP, complete neuropathological examination contributes to evaluation of risk factors as well as helping to direct future research into underlying causes.
| S-EPMC4864133 | biostudies-literature
Project description:ObjectiveTo characterize peri-ictal apnea and postictal asystole in generalized convulsive seizures (GCS) of intractable epilepsy.MethodsThis was a prospective, multicenter epilepsy monitoring study of autonomic and breathing biomarkers of sudden unexpected death in epilepsy (SUDEP) in patients ≥18 years old with intractable epilepsy and monitored GCS. Video-EEG, thoracoabdominal excursions, nasal airflow, capillary oxygen saturation, and ECG were analyzed.ResultsWe studied 148 GCS in 87 patients. Nineteen patients had generalized epilepsy; 65 had focal epilepsy; 1 had both; and the epileptogenic zone was unknown in 2. Ictal central apnea (ICA) preceded GCS in 49 of 121 (40.4%) seizures in 23 patients, all with focal epilepsy. Postconvulsive central apnea (PCCA) occurred in 31 of 140 (22.1%) seizures in 22 patients, with generalized, focal, or unknown epileptogenic zones. In 2 patients, PCCA occurred concurrently with asystole (near-SUDEP), with an incidence rate of 10.2 per 1,000 patient-years. One patient with PCCA died of probable SUDEP during follow-up, suggesting a SUDEP incidence rate 5.1 per 1,000 patient-years. No cases of laryngospasm were detected. Rhythmic muscle artifact synchronous with breathing was present in 75 of 147 seizures and related to stertorous breathing (odds ratio 3.856, 95% confidence interval 1.395-10.663, p = 0.009).ConclusionsPCCA occurred in both focal and generalized epilepsies, suggesting a different pathophysiology from ICA, which occurred only in focal epilepsy. PCCA was seen in 2 near-SUDEP cases and 1 probable SUDEP case, suggesting that this phenomenon may serve as a clinical biomarker of SUDEP. Larger studies are needed to validate this observation. Rhythmic postictal muscle artifact is suggestive of post-GCS breathing effort rather than a specific biomarker of laryngospasm.
| S-EPMC6340388 | biostudies-literature
Project description:BackgroundSudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology.ObjectivesThis study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives.MethodsWe evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls.ResultsA clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13%). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 [6%] and 11 [4%], respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p = 5 × 10-5). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26% to 39%.ConclusionsMolecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. Our data highlighted the predominant role of catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes. Furthermore, we showed the enhanced utility of combined clinical and genetic evaluation.
| S-EPMC5405216 | biostudies-literature
Project description:People with epilepsy are at heightened risk of sudden death compared to the general population. The leading cause of epilepsy-related premature mortality is sudden unexpected death in epilepsy (SUDEP). Postmortem investigation of people with SUDEP, including histological and toxicological analysis, does not reveal a cause of death, and the mechanisms of SUDEP remain largely unresolved. In this review we present the possible mechanisms underlying SUDEP, including respiratory dysfunction, cardiac arrhythmia and postictal generalized electroencephlogram suppression. Emerging studies in humans and animal models suggest there may be an underlying genetic basis to SUDEP in some cases. We will highlight a mounting body of evidence for the involvement of genetic risk factors in SUDEP, with a particular focus on the role of cardiac arrhythmia genes in SUDEP.
| S-EPMC5517398 | biostudies-other
Project description:The circumstances surrounding SUDEP suggest autonomic or respiratory collapse, implying central failure of regulation or recovery. Characterisation of the communication among brain areas mediating such processes may shed light on mechanisms and noninvasively indicate risk. We used rs-fMRI to examine network properties among brain structures in people with epilepsy who suffered SUDEP (n?=?8) over an 8-year follow-up period, compared with matched high- and low-risk subjects (n?=?16/group) who did not suffer SUDEP during that period, and a group of healthy controls (n?=?16). Network analysis was employed to explore connectivity within a 'regulatory-subnetwork' of brain regions involved in autonomic and respiratory regulation, and over the whole-brain. Modularity, the extent of network organization into separate modules, was significantly reduced in the regulatory-subnetwork, and the whole-brain, in SUDEP and high-risk. Increased participation, a local measure of inter-modular belonging, was evident in SUDEP and high-risk groups, particularly among thalamic structures. The medial prefrontal thalamus was increased in SUDEP compared with all other control groups, including high-risk. Patterns of hub topology were similar in SUDEP and high-risk, but were more extensive in low-risk patients, who displayed greater hub prevalence and a radical reorganization of hubs in the subnetwork. SUDEP is associated with reduced functional organization among cortical and sub-cortical brain regions mediating autonomic and respiratory regulation. Living high-risk subjects demonstrated similar patterns, suggesting such network measures may provide prospective risk-indicating value, though a crucial difference between SUDEP and high-risk was altered connectivity of the medial thalamus in SUDEP, which was also elevated compared with all sub-groups. Disturbed thalamic connectivity may reflect a potential non-invasive marker of elevated SUDEP risk.
| S-EPMC6849487 | biostudies-literature
Project description:The sudden infant death syndrome (SIDS) is one of the leading causes of postneonatal infant death. It has been shown that there exists a complex relationship between SIDS and inherited cardiac disease. Next-generation sequencing and surveillance of cardiac channelopathy and cardiomyopathy genes represent an important tool for investigating the cause of death in SIDS cases. In the present study, targeted sequencing of 80 genes associated with genetic heart diseases in a cohort of 31 SIDS cases was performed. To determine the spectrum and prevalence of genetic heart disease associated mutations as a potential monogenic basis for SIDS, a stringent variant classification was applied and the percentage of rare (minor allele frequency ≤ 0.2%) and ultra-rare variants (minor allele frequency ≤ 0.005%) in these genes was assessed. With a minor allele frequency of ≤ 0.005%, about 20% of the SIDS cases exhibited a variant of uncertain significance (VUS), but in only 6% of these cases, gene variants proved to be "potentially informative." The present study shows the importance of careful variant interpretation. Applying stringent criteria misinterpretations are avoided, as the results of genetic analyses may have an important impact of the family members involved.
| S-EPMC7782403 | biostudies-literature
Project description:AimsSudden unexpected death in epilepsy (SUDEP) likely arises as a result of autonomic dysfunction around the time of a seizure. In vivo MRI studies report volume reduction in the medulla and other brainstem autonomic regions. Our aim, in a pathology series, is to correlate regional quantitative features on 9.4T MRI with pathology measures in medullary regions.MethodsForty-seven medullae from 18 SUDEP, 18 nonepilepsy controls and 11 epilepsy controls were studied. In 16 cases, representing all three groups, ex vivo 9.4T MRI of the brainstem was carried out. Five regions of interest (ROI) were delineated, including the reticular formation zone (RtZ), and actual and relative volumes (RV), as well as T1, T2, T2* and magnetization transfer ratio (MTR) measurements were evaluated on MRI. On serial sections, actual and RV estimates using Cavalieri stereological method and immunolabelling indices for myelin basic protein, synaptophysin and Microtubule associated protein 2 (MAP2) were carried out in similar ROI.ResultsLower relative RtZ volumes in the rostral medulla but higher actual volumes in the caudal medulla were observed in SUDEP (P < 0.05). No differences between groups for T1, T2, T2* and MTR values in any region was seen but a positive correlation between T1 values and MAP2 labelling index in RtZ (P < 0.05). Significantly lower MAP2 LI were noted in the rostral medulla RtZ in epilepsy cases (P < 0.05).ConclusionsRostro-caudal alterations of medullary volume in SUDEP localize with regions containing respiratory regulatory nuclei. They may represent seizure-related alterations, relevant to the pathophysiology of SUDEP.
| S-EPMC7749076 | biostudies-literature
Project description:Sudden unexpected death in epilepsy (SUDEP) is the leading seizure-related cause of death in epilepsy patients. There are no validated biomarkers of SUDEP risk. Here, we explored peri-ictal differences in topological brain network properties from scalp EEG recordings of SUDEP victims. Functional connectivity networks were constructed and examined as directed graphs derived from undirected delta and high frequency oscillation (HFO) EEG coherence networks in eight SUDEP and 14 non-SUDEP epileptic patients. These networks were proxies for information flow at different spatiotemporal scales, where low frequency oscillations coordinate large-scale activity driving local HFOs. The clustering coefficient and global efficiency of the network were higher in the SUDEP group pre-ictally, ictally and post-ictally (p < 0.0001 to p < 0.001), with features characteristic of small-world networks. These results suggest that cross-frequency functional connectivity network topology may be a non-invasive biomarker of SUDEP risk.
| S-EPMC10013055 | biostudies-literature
Project description:Sudden unexpected death in epilepsy (SUDEP) is the most common epilepsy-related cause of death, yet the cause is unknown. Our previous studies suggest a role for arrhythmia-related ion channel genes in the pathogenesis of SUDEP. Hyperpolarization-activated cyclic nucleotide-gated cation (HCN1-4) channels are ion channels involved in generating spontaneous rhythmic activity in cardiac pacemaker and neuronal cells. This study sought to determine the role of pathogenic DNA variants in the HCN1-4 genes in a large SUDEP cohort collected from 1993 to 2009. Post-mortem DNA samples were amplified and analyzed for each HCN exon. Genetic analysis in 48 SUDEP cases (age range 12-82 years) identified six novel and three previously reported nonsynonymous (amino acid changing) variants in HCN1 (n = 1), HCN2 (n = 2), HCN3 (n = 2) and HCN4 (n = 4). The Phe738Cys and Pro802Ser variants in HCN2, and Gly973Arg in HCN4 were absent in control alleles and affecting highly conserved residues in the carboxyl-cytoplasmic tail region. Our results support a pathogenic link between the heart and brain in SUDEP, mediated by the HCN neuro-cardiac ion channel genes.
| S-EPMC8094053 | biostudies-literature
Project description:BackgroundSudden unexplained death may be the first manifestation of an unknown inherited cardiac disease. Current genetic technologies may enable the unraveling of an etiology and the identification of relatives at risk. The aim of our study was to define the etiology of natural deaths, younger than 50 years of age, and to investigate whether genetic defects associated with cardiac diseases could provide a potential etiology for the unexplained cases.Methods and findingsOur cohort included a total of 789 consecutive cases (77.19% males) <50 years old (average 38.6±12.2 years old) who died suddenly from non-violent causes. A comprehensive autopsy was performed according to current forensic guidelines. During autopsy a cause of death was identified in most cases (81.1%), mainly due to cardiac alterations (56.87%). In unexplained cases, genetic analysis of the main genes associated with sudden cardiac death was performed using Next Generation Sequencing technology. Genetic analysis was performed in suspected inherited diseases (cardiomyopathy) and in unexplained death, with identification of potentially pathogenic variants in nearly 50% and 40% of samples, respectively.ConclusionsCardiac disease is the most important cause of sudden death, especially after the age of 40. Close to 10% of cases may remain unexplained after a complete autopsy investigation. Molecular autopsy may provide an explanation for a significant part of these unexplained cases. Identification of genetic variations enables genetic counseling and undertaking of preventive measures in relatives at risk.
| S-EPMC5145162 | biostudies-literature