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Possible mechanisms of sudden unexpected death in epilepsy (SUDEP). PGES, postictal generalized EEG suppression.
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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 mechanis...
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Background: Neonatal respiratory distress syndrome (RDS) is a common serious disease in neonatal period and is associated with neonatal complications and death.
Citations
... Especially in patients with LQTS mutation, SUDEP was found to be predictable while de novo mutations allow SUDEP to be nonfamilial. Detection of cardiac and respiratory dysfunctions with genetic screening in people with epilepsy may be a big step toward preventing SUDEP (Bagnall et al. 2017). In addition to pulmonary disorder and cardiorespiratory function changes, in which the alveoli are hardened and cannot meet the oxygen demand, genetic susceptibility also contributes to the risk of SUDEP (Shlobin and Sander 2021). ...
Epilepsy is a central nervous system disorder characterized by recurrent seizures. Identification of seizures with excessive electrical activity can disrupt the electricity of tissues including the heart and lungs by also affecting the brain stem, which is the connection to the brain. Dysfunctional chemical transmissions in this autonomic nervous system, especially over the vagus nerve, impair the correct completion of electrical signaling. Since ion channels such as sodium, potassium, and calcium, which are proteins in the cell membrane, manage the membrane and action potential, problems in these ion channels contribute to the mechanism of epilepsy disorder. Mutations in the genes encoding ion channels not only affect the central nervous system, but also disrupt the electrical conduction in autonomic tissues as the heart, leading to sudden death in epilepsy (SUDEP) cases. Defects in genes encoding voltage-gated, ligand-gated, and lipid-gated ion channels unfortunately are resulted in channelopathy and impair the ionic current regarding as gain/loss of function. In this book chapter, the literature of ion channels leading to epilepsy and the emergence of the concept of SUDEP was discussed.
... The postictal phase was characterized by rapid breathing with a median of 30 per minute , and HR showed a median of 90 beats per minute (IQR 76-101). All patients experienced early cardiorespiratory dysfunction after a seizure, with bradycardia occurring within the Fig. 1 Proposed mechanisms underlying SUDEP (Vera et al. 2011;Bagnall et al. 2017). FBTCS focal to bilateral tonic-clonic seizures, GTCS generalized tonic-clonic seizures, HRV heart rate variability, PGES postictal generalized EEG suppression, SUDEP sudden unexpected death in epilepsy. ...
... DEEs of different types have commonly been reported to be associated with GABA A receptor variants, including in GABRA1 (Bai et al., 2019;Johannesen et al., 2016;Kodera et al., 2016;Maillard et al., 2022;Reyes-Nava et al., 2020), GABRA2 , GABRA3 (Niturad et al., 2017), GABRA5 , GABRB2 (Maillard et al., 2022), GABRB3 Bagnall et al., 2017;Johannesen et al., 2022;Liu et al., 2018;Møller et al., 2017;Štěrbová et al., 2018;Zhang et al., 2017), GABRG2 (Komulainen-Ebrahim et al., 2019;Maillard et al., 2022;Scheffer et al., 2023;Shen et al., 2017;Zaganas et al., 2021) and GABRD genes. The variants are rarely inherited and almost always occur de novo. ...
Normal brain function requires a tightly regulated balance between excitatory and inhibitory neurotransmissions. γ-Aminobutyric acid type A (GABAA ) receptors represent the major class of inhibitory ion channels in the mammalian brain. Dysregulation of these receptors and/or their associated pathways is strongly implicated in the pathophysiology of epilepsy. To date, hundreds of different GABAA receptor subunit variants have been associated with epilepsy, making them a prominent cause of genetically linked epilepsy. While identifying these genetic variants is crucial for accurate diagnosis and effective genetic counselling, it does not necessarily lead to improved personalised treatment options. This is because the identification of a variant does not reveal how the function of GABAA receptors is affected. Genetic variants in GABAA receptor subunits can cause complex changes to receptor properties resulting in various degrees of gain-of-function, loss-of-function or a combination of both. Understanding how variants affect the function of GABAA receptors therefore represents an important first step in the ongoing development of precision therapies. Furthermore, it is important to ensure that functional data are produced using methodologies that allow genetic variants to be classified using clinical guidelines such as those developed by the American College of Medical Genetics and Genomics. This article will review the current knowledge in the field and provide recommendations for future functional analysis of genetic GABAA receptor variants.
... DEEs of different types have commonly been reported to be associated with GABA A receptor variants, including in GABRA1 (Bai et al., 2019;Johannesen et al., 2016;Kodera et al., 2016;Maillard et al., 2022;Reyes-Nava et al., 2020), GABRA2 , GABRA3 (Niturad et al., 2017), GABRA5 , GABRB2 (Maillard et al., 2022), GABRB3 Bagnall et al., 2017;Johannesen et al., 2022;Liu et al., 2018;Møller et al., 2017;Štěrbová et al., 2018;Zhang et al., 2017), GABRG2 (Komulainen-Ebrahim et al., 2019;Maillard et al., 2022;Scheffer et al., 2023;Shen et al., 2017;Zaganas et al., 2021) and GABRD genes. The variants are rarely inherited and almost always occur de novo. ...
Objective:
Variants in GABRA1 have been associated with a broad epilepsy spectrum, ranging from genetic generalized epilepsies to developmental and epileptic encephalopathies. However, our understanding of what determines the phenotype severity and best treatment options remains inadequate. We therefore aimed to analyse the electro-clinical features and the functional effects of GABRA1-variants to establish genotype-phenotype correlations.
Methods:
Genetic and electro-clinical data of 27 individuals (22 unrelated and 2 families) harbouring 20 different GABRA1 variants were collected and accompanied with functional analysis of 19 variants.
Results:
Individuals in this cohort could be assigned into different clinical subgroups based on the functional effect of their variant and its structural position within the GABRA1 subunit. A homogenous phenotype with mild cognitive impairment and infantile-onset epilepsy (focal seizures, fever sensitivity and EEG posterior epileptiform discharges) was described for variants in the extra-cellular domain and the small transmembrane loops. These variants displayed loss-of-function (LoF) effects and the patients generally had a favourable outcome. A more severe phenotype was associated with variants in the pore-forming transmembrane helices. These variants displayed either gain-of-function (GoF) or LoF effects. GoF-variants were associated with severe early-onset neurodevelopmental disorders, including early infantile developmental and epileptic encephalopathy.
Interpretation:
Our data expand the genetic and phenotypic spectrum of GABRA1-epilepsies and permit to delineate specific sub-phenotypes for LoF and GoF variants, though the heterogeneity of phenotypes and variants. Generally, variants in the transmembrane helices cause more severe phenotypes, in particular GoF variants. These findings establish the basis for a better understanding of the patho-mechanism and precision medicine approach in GABRA1-related disorders. Further studies in larger populations are needed to provide a conclusive genotype-phenotype correlation. This article is protected by copyright. All rights reserved.
... Kcna1-null mice were used as the model of chronic epilepsy and SUDEP. [3][4][5][6][7] In the hippocampus and the PreBötzinger Complex, a critical brainstem region for breathing rhythmogenesis, partial pressure of oxygen [pO 2 ], and electrical activity were monitored, as was heart rate and respiration. After the series of seizures was induced via kainate, the team zoomed in on the sequence of events that followed the terminal seizure to identify what changed first. ...
... Kcna1-null mice have spontaneous seizures that are refractory to anti-seizure drugs, cognitive impairment and cardiac arrhythmias, and 100% mortality rate, modeling multiple aspects of clinical SUDEP. [3][4][5][6][7] Importantly, at the time of sudden death, both models have a generalized tonic-clonic seizure, respiratory dysfunction, and terminal apnea, mimicking the clinically recorded terminal events before SUDEP, and increasing relevance and generalizability. ...
Sudden Unexpected Death in Epilepsy Is Prevented by Blocking Postictal Hypoxia
George AG, Farrell JS, Colangeli R, Wall AK, Gom RC, Kesler MT, Rodriguez de la Hoz C, Villa BR, Perera T, Rho JM, Kurrasch D, Teskey GC. Neuropharmacology. 2023;231:109513. doi:10.1016/j.neuropharm.2023.109513. PMID: 36948357
Epilepsy is at times a fatal disease. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality in people with intractable epilepsy and is defined by exclusion; non-accidental, non-toxicologic, and non-anatomic causes of death. While SUDEP often follows a bilateral tonic-clonic seizure, the mechanisms that ultimately lead to terminal apnea and then asystole remain elusive and there is a lack of preventative treatments. Based on the observation that discrete seizures lead to local and postictal vasoconstriction, resulting in hypoperfusion, hypoxia and behavioural disturbances in the forebrain we reasoned those similar mechanisms may play a role in SUDEP when seizures invade the brainstem. Here we tested this neurovascular-based hypothesis of SUDEP in awake non-anesthetized mice by pharmacologically preventing seizure-induced vasoconstriction, with cyclooxygenase-2 or L-type calcium channel antagonists. In both acute and chronic mouse models of seizure-induced premature mortality, ibuprofen and nicardipine extended life while systemic drug levels remained high enough to be effective. We also examined the potential role of spreading depolarization in the acute model of seizure-induced premature mortality. These data provide a proof-of-principle for the neurovascular hypothesis of SUDEP rather than spreading depolarization and the use of currently available drugs to prevent it.
... The importance of genetic analysis in SUDEP and the potential preventative measure for high-risk living relatives is highlighted by knowledge of these underlying genetics. 28 Metabolic disorders: SUDI is a term used to refer to all sudden unexpected deaths that occur between the ages of birth and up to 12 months, including occurrences of SIDS. 29 ...
Introduction: The term "molecular autopsy" refers to a technique in
forensic medicine that focuses on the use of genetic diagnostic in postmortem
samples in the absence of a definitive diagnosis, therefore
classifying the death as sudden unexplained death (SUD). In addition to
traditional autopsy, these post-mortem molecular investigations have
the ability to identify genetic changes that may have contributed to the
disease that resulted in the SUD. Challenges: There are
multiple reasons for implementation of this procedure, comprising of
economic causes or the legal restrictions involved with the sample
collection, The storage time and the number of genes analysed,
as well as the ethical implications of inheritable results attained after a
molecular necropsy. Medicolegal issues: Post-mortem examinations
within the country are performed as per the minimal prescribed
standards, there is void in uniformity of the procedures followed in
multiple countries thereby creating hindrance to appropriate rendition
in clinical practice. A negative autopsy in the cases of sudden death
creates a room of suspicion or dissatisfaction in the minds of the
relatives of the deceased about the death of the deceased. In such case
molecular autopsy can be considered as critical approach to uncover the
pathogenic inheritable condition. Conclusion: Ascertaining of
the cause of death of the deceased permits to satisfy the family members
of deceased to exclude suspicion. It also aids the treating doctors to
detect promptly the occurrence in the condition in the relatives of the
deceased and performing the preventive measures of causing genetic
abnormalities
... Emerging genetic research suggests a correlation between mutations in ion channel genes and familial LQTS and SUDEP (33) and variants of KCNQ1, KCNH2, and SCN5A genes (34)(35)(36)(37). Patients with sodium channel mutations are predisposed to progress from mild cerebral edema to severe cerebral edema which may represent an additional contributing factor in the events leading to the sudden death of patients with epilepsy (38,39). The complexity of the histopathological mechanisms of SUDEP is simply schematized in Figure 1. ...
Introduction
The diagnosis of unexpected death by excluding non-natural causes, particularly in subjects with epilepsy, is a topic of interest and it is difficult to identify in the forensic field. Health professionals sometimes are faced with cases of sudden death, generally in young adults with a long history of epilepsy that require, for judicial purposes, an explanation in terms of cause and means to determine the death. SUDEP is an entity diagnosed by the exclusion of other causes that may have led to death, and then for forensic purposes, it requires particular attention and knowledge, and there is difficulty in identifying it. Our contribution aims to illustrate the scientific community pathological findings, medical history, and circumstantial evidence of four cases of sudden death in epileptic subjects.
Method
We illustrated four cases of judicial autopsies from the Institute of Forensic Medicine of Palermo, Italy; the purpose was to exclude the criminal intervention in determining the death as non-natural. The study of victims’ medical history, the toxicological investigations, and the autopsy findings analyzed both from macroscopic and microscopic aspects have made it possible to highlight some findings that can be traced back to SUDEP despite the small sample of subjects studied.
Results
These presented findings of four SUDEP cases could help forensic pathologists in recognizing this entity, by highlighting its characteristics, and allowing for a pathological classification, also in relation to the use of drugs for epilepsy treatment and circumstances of death.
Discussion
To obtain a definite diagnosis of SUDEP, a complex investigation process is required in a multidisciplinary approach. Considering the literature review with criticism, it could allow health professionals to select the characteristics of epileptic patients at risk of sudden death. Processing human behaviors, molecular and histopathological findings of the autopsies, but also the physiological, and pathological human body system functions thanks to Artificial Intelligence, could be the key to explaining SUDEP mechanisms and the future results to prevent it.
... Recent studies have identified other genes associated with an increased risk of SUDEP, which encode for proteins expressed in the heart and brain tissue or both. [181][182][183][184] From a systematic review by Chahal et al. 176 it emerges that SUDEP occurs in individuals with epilepsy carrying mutations associated with different cardiac disorders, including arrhythmias (LQTS, short QT syndrome, BS, and others) and cardiomyopathies (hypertrophic cardiomyopathy, dilated cardiomyopathy) and genes associated with primary brain SUDEP. ...
Sudden unexpected death in epilepsy (SUDEP) is a sudden, unexpected, witnessed or unwitnessed, non‐traumatic and non‐drowning death, occurring in benign circumstances, in an individual with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus in which postmortem examination does not reveal other causes of death. Lower diagnostic levels are assigned when cases met most or all of these criteria, but data suggested more than one possible cause of death. The incidence of SUDEP ranged from 0.09 to 2.4 per 1000 person‐years. Differences can be attributed to the age of the study populations (with peaks in the 20–40‐year age group) and the severity of the disease. Young age, disease severity (in particular, a history of generalized TCS), having symptomatic epilepsy, and the response to antiseizure medications (ASMs) are possible independent predictors of SUDEP. The pathophysiological mechanisms are not fully known due to the limited data available and because SUDEP is not always witnessed and has been electrophysiologically monitored only in a few cases with simultaneous assessment of respiratory, cardiac, and brain activity. The pathophysiological basis of SUDEP may vary according to different circumstances that make that particular seizure, in that specific moment and in that patient, a fatal event. The main hypothesized mechanisms, which could contribute to a cascade of events, are cardiac dysfunction (included potential effects of ASMs, genetically determined channelopathies, acquired heart diseases), respiratory dysfunction (included postictal arousal deficit for the respiratory mechanism, acquired respiratory diseases), neuromodulator dysfunction, postictal EEG depression and genetic factors.
... In the debate regarding the nature of SUDEP, there is also increasing evidence for the counter-argument that SUDEP represents a subset of SCD and is predominantly driven by the same mechanisms [41, 42••, 43]. A range of pathogenic genetic variants has been identified to date with concurrent effects on both the heart and brain, creating a substrate for "cardiocerebral channelopathies" [44] (Table 2). ...
Purpose of Review
This review examines the significance of seizures in young athletes and the complex inter-relationship between seizures, epilepsy, and sudden cardiac death.
Recent Findings
A history of seizures may reflect a diagnosis of epilepsy, which should be medically optimized for athletic participation. Epilepsy is associated with sudden unexplained cardiac death (sudden unexplained death in epilepsy, SUDEP), with multiple genetic links identified to define some patients as experiencing a “cardiocerebral channelopathy.” It is also important to consider that a history of seizures may reflect a misdiagnosis of cardiac syncope, requiring careful cardiac evaluation and risk stratification.
Summary
A history of seizures in a young athlete is important to characterize fully and investigate as required. The association of seizures with young sudden cardiac death is still under investigation.
... Epilepsy: SUDEP is one of the main causes of the increase in mortality of epileptic patients and can account for up to 18% of deaths in this population [35,36]. It is defined by Nashef et al. as "a sudden, unexpected, witnessed or unwitnessed, non-traumatic, and non-drowning death in patients with epilepsy with or without evidence for a seizure, and excluding documented status epilepticus, in which postmortem examination does not reveal a structural or toxicologic cause of death" [37]. ...
... It is defined by Nashef et al. as "a sudden, unexpected, witnessed or unwitnessed, non-traumatic, and non-drowning death in patients with epilepsy with or without evidence for a seizure, and excluding documented status epilepticus, in which postmortem examination does not reveal a structural or toxicologic cause of death" [37]. Factors associated with increased risk for SUDEP include generalized tonic-clonic seizures, history of nocturnal seizures, longstanding history of epilepsy, diagnosis at a young age, male sex, intellectual disability, and age between the 20s and 40s [35]. ...
... The exact mechanism of SUDEP is unknown; however, many theories have been proposed to explain the underlying mechanism of SUDEP, mostly pertaining to dysfunction in the respiratory, cardiac, and nervous systems [35,36]. ...
Sudden unexpected death (SUD) is one of the challenging situations encountered in forensic medicine. As a rule, a comprehensive forensic assessment is performed to identify the cause of death in such cases; however, the absence of findings suggestive of a cause, i.e., a negative autopsy, warrants further investigation such as a molecular autopsy. In this review, we aim to highlight the genetic causes of SUD, tools used in a molecular autopsy, and the role of screening in surviving relatives. As per several guidelines, the most preferred samples for DNA extraction are whole blood and fresh frozen tissues. Furthermore, Sanger sequencing and next-generation sequencing are the technologies that are used for genetic analysis; the latter overcomes the former's drawbacks in terms of cost-effectiveness, time consumption, and the ability to sequence the whole exome. SUD have diverse etiologies; we can generally classify them into cardiac and non-cardiac causes. Regarding cardiac causes, many conditions having an underlying genetic basis are included, such as channelopathies and cardiomyopathies. Regarding non-cardiac causes of SUD, the main etiologies are epilepsy and metabolic disorders. Nevertheless, it has been proposed that there is a genetic overlap between channelopathies, especially long QT syndromes and epilepsy. Additionally, fatty acid oxidation disorders are major metabolic conditions that are caused by certain genetic mutations that can lead to SUD in infancy. Since many SUD causes have an underlying genetic mutation, it is important to understand the genetic variations not only to recognize the cause of death but also to undertake further preventive measures for surviving relatives. In conclusion, a molecular autopsy has a major role in the forensic examination of cases of SUD.
