Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 23, 2023
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In this article, the authors discuss sudden unexplained nocturnal death syndrome. Often fatal, it is a disorder that occurs in young adult Southeast Asian men who are otherwise healthy. This article includes new information on novel mutations associated with the development of critical arrhythmias that could lead to sudden unexplained death syndrome as well as new epidemiological information in Thailand and the correlation of dysfunctional autonomic response in subjects with family history of the condition.
• Sudden unexpected nocturnal death syndrome is the most serious of sleep disorders as it affects otherwise healthy people, mostly young Asian men.
• There is an etiologic relationship between sudden unexpected nocturnal death syndrome and other conditions that can cause sudden cardiac death.
• Prevention is possible, as in the implantation of a defibrillator in near-miss cases.
The Centers for Disease Control in the United States applied the term “sudden unexplained nocturnal death syndrome” to the syndrome first recognized in 1915 in the Philippines, originally called bangungut ("to arise and moan," the word for "nightmare") in the Tagalog language. In Japan, the syndrome was identified and named pokkuri ("sudden death") in 1959. In Thailand, sudden unexplained nocturnal death syndrome is called Lai Tai ("sleep death"); and in the Philippines it is called Bangungut. Sudden unexplained nocturnal death syndrome has been identified in Southeast Asian male refugees, primarily the Hmong people, settling in the United States since 1975 and was the chief cause of death among these male refugees in the early 1980s, which was the peak time of Southeast Asian immigration to the United States (31).
Sudden unexplained nocturnal death syndrome predominantly affects previously healthy, young adult Southeast Asian males, who die suddenly during sleep. Death often occurs 3 to 4 hours after sleep onset, and witnesses have observed choking, gasping, groaning, gurgling, frothing at the mouth, labored breathing without wheezing or stridor, screaming, and other signs of terror. The inability to arouse takes place, which is followed by rapid collapse and death from ventricular fibrillation. Apparent sleep terrors have been reported to occur frequently in subsequent victims of sudden unexplained nocturnal death syndrome. The original diagnostic criteria included sudden death during sleep "of a person at least 2 years of age, born or having had at least one parent born in some Southeast Asian country, for whom a postmortem examination does not reveal the underlying cause of death." Released in 2014, The International Classification of Sleep Disorders, 3rd edition, no longer has diagnostic criteria for sudden unexplained nocturnal death syndrome (01).
Sudden unexplained nocturnal death syndrome results in death. Episodes subsequent to near-miss sudden unexplained death syndrome may result in death unless the ventricular arrhythmia can be controlled.
A prisoner reported that his cellmate, a Japanese man in his thirties, was convulsing and snoring loudly at night. An ambulance transported him to the hospital, and he was found to be in cardiac arrest. CPR was performed but was unsuccessful and he died. Autopsy revealed a thin man with no signs of fatal disease and a negative toxicology screen. Genetic testing revealed a SCN5A gene mutation (14), suggestive of sudden death secondary to a sleep-related cardiac arrhythmia in the context of a congenital cardiac conduction system abnormality.
Sudden unexplained nocturnal death syndrome is most likely caused by congenital cardiac conduction system abnormalities in conjunction with the autonomic discharge accompanying sleep terrors and nightmares. In subjects with family history of sudden unexplained death syndrome there is abnormal central modulation of autonomic outflow under physical stressors (15). Inappropriate respiratory control during sleep has also been postulated (based on eyewitness accounts) to play an etiologic role. Potassium deficiency has also been proposed as a contributing factor. Right bundle-branch block and precordial injury pattern in V1 through V3 is common in sudden unexplained nocturnal death syndrome patients and represents an arrhythmogenic marker that identifies patients who face an inordinate risk of ventricular fibrillation or sudden death. Pyrogenic toxins of Staphylococcus aureus have also been implicated in some cases. Nevertheless, environmental factors and seasonal factors may also be important. Studies have curiously shown lack of atherosclerotic coronary disease among victims of this disorder (31).
Detailed postmortem cardiac examinations show cardiac conduction system anomalies, including mild or moderate fatty, fibrous, or fibrofatty tissue replacement, stenosis of node artery, and punctate hemorrhage in the node area (04). These can be anatomic substrates for sleep-related ventricular fibrillation, acute cardiopulmonary failure, and sudden death, which may be triggered by an overactivation of the sympathetic nervous system during sleep terrors or nightmares. Autopsies done in male sudden unexplained nocturnal death syndrome victims from the northeastern region of Thailand showed mild pulmonary congestion in 88.6% but there were no cardiac or pancreatic abnormalities (21).
Researchers have identified 13 mutations of SCN5A and related genes, conferring instability on the voltage-gated cardiac sodium channels, in victims, survivors, and family members of this disorder, specifically among the Han Chinese (13). A rare heterozygous variant VCL-M94I was found in a sudden unexplained nocturnal death syndrome victim who suffered sudden nocturnal tachypnea. He lacked pathogenic variants in known arrhythmia-causing genes, linking it to the loss-of-function of cardiac sodium channel in HEK293 cells and iPSC-CMs. This demonstrates a previously unknown functional interaction between VCL and SCN5A genes. D841H, another VCL variant, was detected in 8 of 120 sudden unexplained nocturnal death syndrome cases among the Han Chinese. This was also associated with loss of function of SCN5A under acidotic circumstances. The findings support the idea that nocturnal sleep respiratory disorders with acidosis may play a crucial role in triggering the deadly arrhythmia underlying sudden unexplained nocturnal death syndrome victims (05). Evidence of the influence of low pH was also demonstrated in the SCN5A mutation and R1512W with both extracellular and intracellular mild acidosis at pH 7.0 (32). These account for about 13% of all sudden unexplained nocturnal death syndrome cases (13).
There have been a number of studies showing that variants of another gene, SCN10A, have been associated with arrhythmias. However, a study has shown the presence of SCN10A VUS variant in cases of sudden unexplained death (07). The product of SCN10A is Nav1.8 sodium channel. In the study, Nav1.8 was found to be expressed in vagal fibers and intracardiac ganglia, but not in cardiac myocytes. One of the functions of Nav1.8 is to modulate arrhythmias, which may explain its role in sudden unexplained deaths (07).
Although a mutation of SCN10A accounts for another 3% of sudden unexplained nocturnal death syndrome cases in this population, polymorphisms of the NOS1AP gene have also been associated with sudden unexplained nocturnal death syndrome among the Han Chinese, with some variations being protective and others conferring a higher risk for the condition (11; 28). Also, mutations of desmoplakin or the DSP gene seem to confer a higher risk for sudden unexplained nocturnal death syndrome in this population (29). A heterozygous mutation causing R1193Q polymorphism (amino acid substitution) has also been described (14). Mutations in the KCNQ1, KCNH2, and KCNE2 genes have also been associated with sudden unexplained nocturnal death syndrome, especially among Caucasian men (23). A genetic linkage was found between sudden unexplained nocturnal death syndrome and another syndrome called Brugada syndrome. The common mutation underlying both conditions appears to be a variant of plakophilin 2, or PKP2 (09). SCN5A mutations have also been associated with more severe conduction abnormalities and higher risk for future cardiac events in Brugada Syndrome (26). Brugada syndrome is a related illness characterized by specific ECG changes and nocturnal ventricular fibrillation. It has also been demonstrated that the homeostasis of both magnesium and zinc is altered in sudden unexplained nocturnal death syndrome patients. LRRC10 could be genetically linked to sudden unexplained nocturnal death syndrome and Brugada Syndrome among Chinese men (08). HCN4 variations could induce critical arrhythmias and contribute to the development of sudden unexplained nocturnal death syndrome. Researchers detected one missense variant and four synonymous variants of HCN4 in sudden unexplained nocturnal death syndrome cases in China (25).
Research has linked a novel nonsense mutation on the gene gap junction alpha 1 (GJA1) in sudden unexplained nocturnal death syndrome cases. The detected variant would decrease the expression of Conexin 43 (CX43) GJ channels, thus, very likely causing electrical coupling disorder of cardiac muscle cells and leading to sudden death (24). In a postmortem study performed in Thailand, 28% of sudden unexplained nocturnal death victims had at least one potentially pathogenic variant in TTN that could cause or modify the risk of the disease (22).
A study that included the largest sudden unexplained nocturnal death syndrome cohort to date has found a new possible factor, XIRP, in the pathogenesis of sudden unexplained nocturnal death syndrome (10). The study demonstrated that in sudden unexplained nocturnal death syndrome and Brugada syndrome cases unexplained by genetic testing, variants in 39 known arrhythmia-susceptibility genes were in abundance, with rare variants in XIRP1 and XIRP2. The study has further demonstrated that Xirp2 null hearts exhibit cardiac conduction defects such as A-V block and prolonged QT intervals. In addition, XIRP2 was associated with important cardiac ion channel components, Nav1.5 and Kv1.5. Also, XIRP1 and XIRP2 were found to function as scaffolding proteins that interact with components of actin cytoskeleton, N-cadherin-mediated junction, and ionic channel assembly. Thus, they play a role not only in the structure and function of cardiac myocytes but also in the surface expression of ion channels and action potential propagation. Further studies are needed on the role of XIRP in sudden unexplained nocturnal death syndrome; however, rare variants of XIRP may be the reason behind many unexplained cases of sudden unexplained nocturnal death syndrome and Brugada syndrome (10).
There is a hypothesis that sudden unexplained nocturnal death syndrome will only occur if three factors present simultaneously during nocturnal sleep: a) carriers of genes that confer higher susceptibility of sudden unexplained nocturnal death syndrome, b) stressors caused by environmental or social factors, and c) disturbance in action potential production and propagation in nocturnal sleep (31).
In northeastern Thailand, the estimated annual rate of death from sudden unexplained nocturnal death syndrome among men 20 to 49 years of age was found to be 25.9 per 100,000 person-years in one study and 38 per 100,000 person-years in another study, indicating that sudden unexplained nocturnal death syndrome is one of the leading causes of death in young men in that region. Sudden unexplained nocturnal death syndrome among Filipino men has a prevalence of 43 per 100,000 per year. The incidence of sudden unexplained nocturnal death syndrome among Thai workers in Singapore is 98 per 100,000 person-years, almost four times greater than the rate for Thai men living in rural Thailand. On the other hand, a study in young, healthy Thai male university students demonstrated that individuals from rural (compared to urban) areas display decreased sympathetic and increased parasympathetic responses to cold and saline loading stressors. The low sympathetic to parasympathetic ratio has been suggested to underlie the cardiac arrhythmias observed on electrocardiograms in sudden unexplained nocturnal death syndrome (02). This could be due to the fact that most Thai workers in Singapore originate from rural Thailand and are exposed to the added stressor of living and working outside their homeland, a factor that could explain why in Thailand urbanites are at lower risk than those from the countryside. Yet once they leave their homeland they may end up with even a higher risk despite the nature of the environment. The phenomenon has been documented in other refugees and immigrants. Laotian and Cambodian refugees in Thailand have the highest documented risk for sudden unexplained nocturnal death syndrome, 574 per 100,000 person-years, in men 25 to 44 years of age. The prevalence of sudden unexplained nocturnal death syndrome among Southeast Asian male refugees settled in the United States is as follows: Hmong Laotians, 92 per 100,000 person-years; other Laotians, 82 per 100,000 person-years; and Kampucheans, 59 per 100,000 person-years. In these last three groups, the fatal event most often occurs within 2 years after arrival in the United States. Sudden unexplained nocturnal death syndrome has also been reported in Asian immigrants residing in metropolitan Toronto, Canada. In southern China, among the Han people, the annual incidence of sudden unexplained nocturnal death syndrome ranges from 1.02 to 2.23 per 100,000 person-years depending on region. Male to female ratio is 14 males to 1 female, and 97.7% of victims were manual laborers with physically demanding jobs and low education level (30; 21). In central China, the male to female ratio was 14 to 1 in the high-risk age group of 30 to 39 years of age, and overall it was 4 to 1 (04). In comparison, in a literature review conducted recently, sudden cardiac death in nighttime hours was more likely to be found among female patients (20). The incidence of deaths peaked in April and January and between 3 AM and 6 AM in the morning; 67% of victims were migrant workers. A series of 44 autopsies performed on sudden unexplained nocturnal death syndrome victims in the northern region of Thailand showed variations in the time of death ranging from midnight to 6:00 AM. Deaths occurred more often during May and there were a few cases of respiratory difficulty, seizures, and urinary incontinence before death. All the autopsies in this study were performed on males between 20 and 49 years of age. Subjects were all nondrug abusers, 62% were nonsmokers, and blood alcohol was elevated only in 20% of cases. Most (93.2%) were blue-collar workers and 72.1% had normal BMI (21).
It has also been observed that most cases of sudden unexplained nocturnal death syndrome occurred in the summer season, which has been replicated in several previous studies and may hint that the season may be a risk factor for sudden unexplained nocturnal death syndrome (21).
Risk factors for sudden unexplained nocturnal death syndrome include congenital cardiac conduction abnormalities, prolonged QT interval, thiamine deficiency, nocturnal hypoxia, major stress (eg, geographic translocation with disruption of familial and social support systems), nightmares, sleep terrors (with or without associated sleep paralysis or hypnagogic hallucinations), obstructive sleep apnea, and male sex (27). Obstructive sleep apnea also has been associated with sudden cardiac death and sudden infant death syndrome. More studies are needed to explain the association between obstructive sleep apnea and sudden death, whereby inflammatory mechanisms such as elevations in IL-6 are hypothesized to link them. It is, thus, recommended to treat obstructive sleep apnea in order to prevent sudden cardiac death, which may be in the differential of sudden unexplained death syndrome (16). Beat-to-beat variability on high-resolution ECG has also been shown to be a risk factor, in addition to widened QRS complexes. A spontaneous change in ST segment is associated with the highest risk for subsequent events in subjects with a Brugada-type ECG. The presence of syncopal episodes, a history of familial sudden death, or late potentials may increase its value. Another ECG finding of some predictive value is fragmented QRS or fQRS, a depolarization abnormality combined with microwave T wave alternans and a marker of repolarization abnormality (06; 18). This anomaly has been studied in sudden cardiac deaths in general, but not specifically in sudden unexplained nocturnal death syndrome, although given the overlap it may prove to be of some value in this condition as well.
As sudden infant death syndrome is in the differential of sudden unexplained nocturnal death syndrome, it may be worthwhile to discuss some risk factors associated with SIDS and how to prevent them. Recent exposure to pollution is a risk factor that has been studied. It has been shown that recent exposure to carbon monoxide and nitrogen dioxide, even for a short term, was found to significantly increase the risk of SIDS in the postneonatal period; therefore, reducing the exposure of infants to pollutants may provide a new way to reduce the risk of SIDS (03). Physicians also call for a safe sleep environment to reduce the risk of SIDS. There has been an association between bed-sharing between the parents and the infant and sudden infant death syndrome, and the risk is increased when the parents smoke or consume alcohol or anxiolytic medications. Hence, bed-sharing is not advisable. In addition, there is strong evidence (Grade A) that supine sleeping may reduce the risk of SIDS. Other recommendations include avoiding overheating and head coverage, having a firm sleeping surface for the infant, keeping loose bedding and other soft objects away from the sleeping area, sharing the room with the infant but not the same bed, breastfeeding on demand, and vaccinating the infant according to the national recommendations (12).
The differential diagnosis includes: idiopathic ventricular fibrillation that occurs at night and without prodromal symptoms, death caused by REM sleep-related sinus arrest, REM sleep-related myocardial infarction, obstructive sleep apnea, sudden unexplained death in epilepsy that usually occurs in sleep, pulmonary hypertension in central sleep apnea, and Brugada syndrome, an inherited cardiac conduction defect that is genetically linked to both sudden unexplained nocturnal death syndrome and sudden infant death syndrome. Seven forms of congenital long QT syndrome have been identified related to mutations in the ion channel. Long QT syndrome is a genetic disease characterized by prolonged ventricular repolarization, syncope, ventricular arrhythmias, and sudden death, often precipitated by emotion or exercise.
Diagnostic workup applies only to rare cases of "near-miss" sudden unexplained nocturnal death syndrome. Comprehensive cardiologic evaluation is indicated along with a sleep-wake, medical, and psychiatric assessment. Polysomnography may be helpful as men at risk for sudden unexplained nocturnal death syndrome and the related Brugada syndrome tend to have a higher prevalence of sleep-related breathing disorders, but appropriate precautions must be taken in the event that ventricular fibrillation occurs during the study. The need for screening polysomnography is even more important among the Hmong population in the United States, as one survey showed a significantly increased prevalence of sleep apnea without necessarily an increase in the report of habitual snoring (27).
In unexplained nocturnal death syndrome survivors and first-degree relatives, ECG with special right ventricular leads shows evidence of RSR' and ST elevation in leads V1 to V3, a pattern present in the genetically related Brugada syndrome.
Research is developing different tools that could diagnose and prevent sudden unexplained nocturnal death syndrome in the future. On the one hand, according to a postmortem study using whole-exome sequencing, screening for TTN mutations could improve the molecular diagnosis of this condition (22). On the other hand, a prospective multicenter registry proved that the clinical screening of the relatives of young subjects who died of sudden cardiac death due to general causes provided a diagnosis in 25% of the cases (19).
Sudden unexplained nocturnal death syndrome results in death. For rare cases of near-miss sudden unexplained nocturnal death syndrome, antiarrhythmic medications and implantable defibrillators may be required in an attempt to prevent death from occurring during subsequent episodes. A study found implantable defibrillators to be superior to beta blockers in preventing sudden unexplained nocturnal death syndrome, and they have been shown to be well tolerated for over a year.
In near-miss cases or in the related Brugada syndrome, anesthesia seems to be safe, but extra caution needs to be exercised when using propofol infusions. It is preferred that the dose be low and the duration short. Alternatively, sevoflurane may be preferred. Regional anesthesia is preferred, but buprivacaine and ropivacaine are contraindicated with lignocaine being the drug of choice. Electrolyte abnormalities should also be diligently corrected preoperatively to prevent any arrhythmias. Isoprenaline infusion may be used if arrhythmic storms are observed intraoperatively (17).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Hrayr P Attarian MD
Dr. Attarian, Director of the Northwestern University Sleep Disorders Program, received honorariums from Clearview and Harmony Bioscience for consulting work and grant support from Harmony Bioscience.See Profile
Ali Karaki MD
Dr. Karaki of Lebanese American University Medical Center has no relevant financial relationships to disclose.See Profile
Antonio Culebras MD FAAN FAHA FAASM
Dr. Culebras of SUNY Upstate Medical University at Syracuse received an honorarium from Jazz Pharmaceuticals for a speaking engagement.See Profile
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