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Challenges in Decoding Sudden Unexpected Death in Epilepsy: The Intersection Between Heart and Brain in Epilepsy
Journal of the American Heart Association ( IF 5.4 ) Pub Date : 2021-11-24 , DOI: 10.1161/jaha.121.023571
Babken Asatryan 1
Affiliation  

Patients with epilepsy are at least 2‐ to 3‐fold higher risk for dying prematurely and suddenly than the general population.1, 2, 3 When an unexpected, nontraumatic and nondrowning death occurs suddenly in individuals with epilepsy (excluding status epilepticus), in which postmortem examination does not reveal a toxicologic or anatomic cause of death, the term sudden unexpected death in epilepsy (SUDEP) is used.4 SUDEP is one of the most frequent causes of death among patients with drug‐resistant epilepsy (cumulative lifetime risk estimated 35%)5, 6 and ranks second only to stroke among neurological conditions in the United States in terms of potential years of life lost.2 The annual incidence of SUDEP is estimated to be 1.16 cases for every 1000 patients with epilepsy, in contrast to sudden unexplained death syndrome (SUDS), which is estimated to occur in 0.5 cases for every 1000 individuals per year in the general population.5, 7


The pathophysiology of SUDEP is heterogeneous, likely involving cardiac, autonomic, respiratory, and polygenic contributors.8 Most SUDEP cases occur at night or during sleep when the death is not witnessed, leaving many questions unanswered. The major risk factor for SUDEP is the occurrence of generalized tonic‐clonic and nocturnal seizures. The lack of treatment with antiepileptic drugs or subtherapeutic levels of such drugs, nonadherence to treatment regimens, and frequent changes in regimens are additional risk factors for SUDEP.9 It has been demonstrated that chronic epilepsy may result in hypoxemia and catecholaminergic surges and consequent cardiac and vascular damage, which may contribute to electrical and mechanical dysfunction.10, 11 In some individuals, the lethal trigger might be ictally induced prolonged hypoxemia and hypercapnia resulting in acidosis that predisposes to bradycardia or asystole, whereas in others, it may be a malignant cardiac arrhythmia initiated ictally or via an interictal epileptiform activity.12 Interestingly, although ictal bradycardia/asystole is thought to play a critical role in SUDEP pathophysiology, most SUDS cases attributed to genetically mediated cardiac diseases develop secondary to ventricular tachyarrhythmias, a distinction in the mechanism of cardiac arrest/death between the 2 conditions. Hence, SUDEP may be the consequence of the epileptic seizures itself, in addition to possible direct contribution of pathogenic variants in genes encoding myocardial proteins/channels. In fact, there might be at least 2 distinct clusters of patients with epilepsy at high risk for SUDEP: a younger group with no known comorbidities and infrequent seizures who may host pathogenic variants in primary arrhythmia syndrome genes and an older population with polygenic predisposition, polymedication, and treatment‐refractory severe seizures.13 Currently, there are limited measures to prevent SUDEP. Because a tonic–clonic seizure precedes most SUDEP cases, seizure control with appropriate medication use and counseling on lifestyle is the focus of prevention (reviewed in detail by Devinsky).9


Although the genetic underpinnings of SUDEP are yet to be fully defined, the list of candidate SUDEP genes has been growing rapidly, and discoveries have been facilitated by progress in the field of sudden cardiac death and sudden infant death syndrome and by insights from experimental animal models.13 Data suggest that a pathogenic variant in dominant epilepsy genes is found in up to a quarter of SUDEP cases.14 Most of these variants are established causes of treatment‐resistant epilepsy and associated with frequent generalized tonic‐clonic seizures, for example, SCN1A, SCN8A, and DEPDC5.13 An additional 7% to 10% of cases have a clinically relevant pathogenic variant in cardiac arrhythmia genes, indicating that these cases may be SUDS cases.15, 16 Familial SUDEP cases are, however, rare,17 indicating that genetics might be just one of the contributors to SUDEP pathogenesis. A baseline cardiac evaluation with an ECG may be useful in SUDEP families. Despite the considerable efforts in this area, the complex mechanisms and circumstances surrounding SUDEP remain insufficiently investigated for several reasons, including its relatively low incidence, its unpredictable occurrence often in unwitnessed settings, its low rate of complete autopsy examinations, and the paucity of analytically useful postmortem material for genetic testing.4


In this issue of the Journal of the American Heart Association (JAHA), Chahal and colleagues18 report on the largest single‐center cohort of SUDEP cases described to date, with whole‐exome sequencing genetic testing performed for cases with DNA available. This is the result of an extraordinary effort of systematic creation and adjudication of cases to build a registry of sudden death. After multisource identification of over 13 000 cases of sudden cardiac death, SUDS, sudden infant death syndrome, and out‐of‐hospital cardiac arrest occurring between 1960 and 2016 in individuals aged 0 to 90 years, the authors identified 368 cases meeting the diagnosis of epilepsy. Subsequently, by cardiac pathologist input, they reevaluated and reclassified these cases as non‐SUDEP, when there was clearly an alternative cause of death such as trauma, drowning, drug overdose, suicide, or homicide, or as SUDEP (with subcategories) according to the unified SUDEP definition and classification.4 Of the 368 cases, 58 were classified as non‐SUDEP and 96 as SUDEP cases; the remaining 214 cases (66%) had only death certificate data and insufficient records for cause of death ascertainment. The age of death in SUDEP decedents spanned from 1 to 84 years. With a mean age of 37 years at death, these individuals were on average 15 years younger than the non‐SUDEP decedents. Only 16% of SUDEP decedents had an antemortem ECG performed, leaving a potential overlap with manifest inherited arrhythmia syndromes not excluded in most cases. Although autopsy was performed in 83/96 (86%) SUDEP cases, only 34 (41%) underwent neuropathological examination. Further, cardiac pathology examination was performed in only 13 (16%), resulting in incomplete records regarding critical pathological findings, such as coronary artery origin and presence/extent of coronary atherosclerosis. Among SUDEP cases, there were 5 individuals with antemortem diagnosis of Dravet syndrome, an infantile‐onset intractable epilepsy caused by heterozygous loss‐of‐function mutations in the SCN1A gene, which encodes brain type‐I voltage‐gated sodium channel NaV1.1. Considering a dominant inheritance model, whole‐exome sequencing and subsequent analysis of variants in 166 sudden death‐susceptibility genes identified 18 ultra‐rare nonsynonymous variants of uncertain significance in 6 out of 11 individuals, in whom genetic material was available for testing, with all 6 cases hosting multiple variants. One of the 6 decedents carried an additional homozygous variant in the CLCN2 gene, which encodes the voltage‐gated chloride channel 2. Four transcript variants encoding different isoforms have been reported for this gene. Pathogenic variants in this gene have been implicated in leukoencephalopathy (autosomal recessive)19 and familial hyperaldosteronism type I (autosomal dominant)20; whether heterozygous pathogenic variants can cause idiopathic generalized epilepsy is currently unclear and remains to be investigated.21, 22


The work of Chahal et al18 highlights many aspects of the current situation of clinical care of people with epilepsy and SUDEP research. First, it underscores the central role of interdisciplinary investigation and care of patients with epilepsy at high risk for SUDEP. To this end, minimal cardiac evaluation in patients with epilepsy should include a detailed history of cardiac events, family history of sudden infant death syndrome, SUDS, or SUDEP, and an ECG, allowing the documentation of manifest primary arrhythmia syndromes, such as long QT syndrome and Brugada syndrome. It should, however, be noted that a single ECG cannot rule out a concealed primary arrhythmia syndrome, as first manifestation of both conditions in the presence of disease‐specific triggers, such as hypokalemia and medication intake in long QT syndrome and fever in Brugada syndrome, is not rare.15 A minimal suspicion of a concomitant cardiac condition should, therefore, warrant cardiologic reevaluation in those with epilepsy. Second, Chahal et al demonstrate the gaps in the current specialist‐pathological examination of SUDEP cases and once again underscore the key role of the ascertainment of cause of death in decedents with epilepsy. Incidental autopsy findings of uncertain significance are common in decedents both with and without epilepsy and may result in erroneous interpretations and misdiagnosis when not evaluated properly by specialist cardiac and neuropathologists.23, 24 Finally, the results of this study show that biological material for genetic testing are often not stored for SUDEP cases, and family history may often not be available at autopsy. Careful review of the family history in SUDEP cases is, however, critical to identify potential familial cardiac and neurological conditions, and any concern should result in a molecular genetics study.13


In summary, SUDEP continues to be an area of active research with the goal of identifying at‐risk individuals and decreasing its incidence. The major lesson from the study by Chahal and colleagues is that SUDEP is underinvestigated even in most advanced centers providing advanced cardiovascular, neurological, and pathological services. Strengthening existing interdisciplinary collaboration is necessary to provide optimal care to patients with epilepsy, in particular, to identify and manage modifiable risk factors for SUDEP and reassure those at substantially low risk. Building international and multidisciplinary consortia that would investigate the causes, mechanisms, and circumstances of SUDEP is of paramount importance to the long‐term care of people with epilepsy and prevention of tragic fatalities.


None.


The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.


For Disclosures, see page 3.


See Article by Chahal et al.




中文翻译:

解码癫痫猝死的挑战:癫痫中心脏和大脑的交叉点

与一般人群相比,癫痫患者过早和突然死亡的风险至少高出 2 至 3 倍。1 , 2 , 3当癫痫患者(不包括癫痫持续状态)突然发生意外、非创伤性和非溺水死亡时,尸检未发现毒理学或解剖学死因,称为癫痫猝死(SUDEP)用来。4 SUDEP是耐药性癫痫患者最常见的死亡原因之一(累积终生风险估计为 35%)5、6美国的神经系统疾病中,就潜在生命损失年数而言,它仅次于中风.2 SUDEP 的年发病率估计为每 1000 名癫痫患者 1.16 例,而在一般人群中,猝死综合征 (SUDS) 的发病率估计为每 1000 人每年 0.5 例。5 , 7


SUDEP 的病理生理学是异质的,可能涉及心脏、自主神经、呼吸和多基因贡献者。8大多数 SUDEP 病例发生在夜间或睡眠期间,没有亲眼目睹死亡,导致许多问题未得到解答。SUDEP 的主要危险因素是发生全身性强直阵挛和夜间癫痫发作。缺乏抗癫痫药物治疗或此类药物的治疗水平低于治疗水平、不依从治疗方案以及治疗方案的频繁变化是 SUDEP 的其他危险因素。9已经证明,慢性癫痫可能导致低氧血症和儿茶酚胺能激增以及随之而来的心脏和血管损伤,这可能导致电和机械功能障碍。10 , 11在某些个体中,致命的触发因素可能是发作期诱发的长期低氧血症和高碳酸血症,导致酸中毒,从而导致心动过缓或心搏停止,而在其他人中,它可能是发作期或发作间期癫痫样活动引发的恶性心律失常。12有趣的是,虽然认为发作期心动过缓/心搏停止在 SUDEP 病理生理学中起关键作用,但大多数归因于遗传介导的心脏病的 SUDS 病例继发于室性快速性心律失常,这是两种情况之间心脏骤停/死亡机制的区别。因此,SUDEP 可能是癫痫发作本身的结果,此外还可能是编码心肌蛋白/通道的基因中致病变异的直接贡献。事实上,可能至少有 2 个不同的癫痫患者群具有 SUDEP 的高风险:一个没有已知合并症和不经常癫痫发作的年轻群体,他们可能携带原发性心律失常综合征基因的致病变异,以及一个具有多基因易感性、多种药物治疗的老年人群和难治性严重癫痫发作。13目前,预防 SUDEP 的措施有限。由于强直-阵挛性癫痫发作先于大多数 SUDEP 病例,因此通过适当的药物使用和生活方式咨询来控制癫痫发作是预防的重点(Devinsky 详细审查)。9


尽管 SUDEP 的遗传基础尚未完全确定,但候选 SUDEP 基因的列表一直在迅速增长,并且由于心源性猝死和婴儿猝死综合征领域的进展以及来自实验动物模型的见解,这些发现已得到促进. 13数据表明,在多达四分之一的 SUDEP 病例中发现了显性癫痫基因的致病变异。14大多数这些变异是难治性癫痫的既定原因,并与频繁的全身强直-阵挛发作相关,例如SCN1ASCN8ADEPDC513另有 7% 至 10% 的病例在心律失常基因中有临床相关的致病性变异,表明这些病例可能是 SUDS 病例。15 , 16然而,家族性 SUDEP 病例很少见,17表明遗传可能只是 SUDEP 发病机制的促成因素之一。使用心电图进行基线心脏评估可能对 SUDEP 家族有用。尽管在这一领域做出了相当大的努力,但围绕 SUDEP 的复杂机制和环境仍然没有得到充分调查,原因有几个,包括其发病率相对较低、其经常在无人见证的环境中发生不可预测、其完整的尸检检查率低以及缺乏分析有用的用于基因检测的尸检材料。4


在本期美国心脏协会杂志 (JAHA)中,Chahal 及其同事18报告了迄今为止描述的最大的 SUDEP 病例单中心队列,对有可用 DNA 的病例进行了全外显子组测序基因检测。这是系统创建和裁决案件以建立猝死登记册的非凡努力的结果。在对 1960 年至 2016 年间发生在 0 至 90 岁个体中的 13000 多例心源性猝死、SUDS、婴儿猝死综合征和院外心脏骤停病例进行多源识别后,作者确定了 368 例符合诊断为癫痫。随后,根据心脏病理学家的意见,他们重新评估并将这些病例重新分类为非 SUDEP,当有明显的替代死亡原因时,如创伤、溺水、药物过量、自杀或他杀,或根据统一的 SUDEP 定义和分类作为SUDEP (带有子类别)。4在 368 例病例中,58 例被归类为非 SUDEP,96 例被归类为 SUDEP;其余 214 例 (66%) 仅有死亡证明数据且记录不足,无法确定死因。SUDEP 死者的死亡年龄从 1 岁到 84 岁不等。这些人的平均死亡年龄为 37 岁,比非 SUDEP 死者平均年轻 15 岁。只有 16% 的 SUDEP 死者进行了生前心电图检查,这与大多数情况下未排除的明显遗传性心律失常综合征存在潜在重叠。尽管 83/96 (86%) SUDEP 病例进行了尸检,但只有 34 (41%) 例接受了神经病理学检查。此外,仅 13 例(16%)进行了心脏病理学检查,导致有关关键病理学发现的记录不完整,例如冠状动脉起源和冠状动脉粥样硬化的存在/程度。在 SUDEP 病例中,有 5 人在死前被诊断为 Dravet 综合征,这是一种由 SUDEP 杂合子功能丧失突变引起的婴儿期顽固性癫痫。SCN1A基因,编码脑 I 型电压门控钠通道 Na V 1.1。考虑到显性遗传模型,全外显子组测序和随后对 166 个猝死易感基因变异的分析在 11 个个体中的 6 个个体中确定了 18 个极其罕见的非同义变异,这些个体的遗传物质可用于测试,所有6 个包含多个变体的案例。6 名死者中的一名在CLCN2基因中携带了一个额外的纯合变体,该基因编码电压门控氯离子通道 2。据报道,该基因有四种编码不同亚型的转录变体。该基因的致病性变异与白质脑病(常染色体隐性遗传)有关19和家族性醛固酮增多症 I 型(常染色体显性遗传)20;杂合致病变异是否会导致特发性全身性癫痫目前尚不清楚,仍有待研究。21 , 22


Chahal 等人的工作18突出了癫痫患者临床护理现状和 SUDEP 研究的许多方面。首先,它强调了对 SUDEP 高危癫痫患者进行跨学科调查和护理的核心作用。为此,癫痫患者的最低心脏评估应包括详细的心脏事件史、婴儿猝死综合征家族史、SUDS 或 SUDEP,以及心电图,以便记录明显的原发性心律失常综合征,例如长 QT综合征和 Brugada 综合征。然而,应该注意的是,单一的心电图不能排除隐匿性原发性心律失常综合征,这是两种疾病在存在疾病特异性触发因素时的首发表现,例如长 QT 综合征的低钾血症和药物摄入以及 Brugada 综合征的发热,并不罕见。15因此,对伴有心脏病的最小怀疑应该保证对癫痫患者进行心脏重新评估。其次,Chahal 等人证明了当前 SUDEP 病例的专科病理学检查存在的差距,并再次强调了确定癫痫死者死因的关键作用。具有不确定意义的偶然尸检结果在患有或未患有癫痫症的死者中很常见,如果心脏和神经病理学专家没有正确评估,可能会导致错误的解释和误诊。23 , 24最后,这项研究的结果表明,用于基因检测的生物材料通常不会储存在 SUDEP 病例中,而且在尸检时可能通常无法获得家族史。然而,仔细审查 SUDEP 病例的家族史对于识别潜在的家族性心脏和神经系统疾病至关重要,任何问题都应进行分子遗传学研究。13


总之,SUDEP 仍然是一个活跃的研究领域,其目标是识别高危个体并降低其发病率。Chahal 及其同事研究的主要教训是,即使在提供先进的心血管、神经和病理学服务的最先进的中心,SUDEP 的研究也不足。有必要加强现有的跨学科合作,以便为癫痫患者提供最佳护理,特别是识别和管理 SUDEP 的可改变风险因素,并让那些处于相当低风险的人放心。建立国际和多学科联盟来调查 SUDEP 的原因、机制和情况,对于癫痫患者的长期护理和预防悲剧性死亡至关重要。


没有任何。


本文所表达的观点不一定是编辑或美国心脏协会的观点。


有关披露,请参阅第 3 页。


参见 Chahal 等人的文章。


更新日期:2021-12-07
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