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Sudden unexplained nocturnal death syndrome

By Hrayr P Attarian MD (Dr. Attarian, Director of the Northwestern University Sleep Fellowship at Northwestern University, has no relevant
financial relationships to disclose.)
Originally released September 9, 1993; last updated June 12, 2016; expires June 12, 2019

Introduction

This article includes discussion of sudden unexplained nocturnal death syndrome, bangungut, laitai, nonlaitai, Pokkuri,
sudden unexplained death syndrome, SUDS, and SUNDS. The foregoing terms may include synonyms, similar
disorders, variations in usage, and abbreviations.

Overview

In this article, the author discusses 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 information on mutations
leading to sudden unexplained nocturnal death syndrome among the Han Chinese. It also includes findings from
autopsies and demographic variables in sudden unexplained nocturnal death syndrome victims from central China.

Key points
• 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.

Historical note and terminology

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 laitai ("sleep death"); in Laos it is called
non-laitai ("sleep death"), and in Hawaii it is called “dream disease.” 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 (Nakajima et al 2011).

Clinical manifestations

Presentation and course

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 SUNDS (American Academy of Sleep
Medicine 2014).

Prognosis and complications

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.

Clinical vignette
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 (Matsusue et al 2012), suggestive of sudden death secondary to a
sleep-related cardiac arrhythmia in the context of a congenital cardiac conduction system abnormality.

Biological basis

Etiology and pathogenesis

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. Respiratory
dyscontrol 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 (Nakajima et al 2011).

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
(Chen et al 2016). 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.

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 (Liu et al 2014). These account for about 13% of all sudden unexplained nocturnal death syndrome cases (Liu
et al 2014). 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 (Huang et al 2014; Zhang et al 2016). Also, mutations of desmoplakin or the DSP gene
seem to confer a higher risk for sudden unexplained nocturnal death syndrome in this population (Zhao et al 2016). A
heterozygous mutation causing R1193Q polymorphism (amino acid substitution) has also been described (Matsusue et
al 2012). Mutations and variants of this channel gene have also been implicated in the pathogenesis of some atrial
fibrillation cases (Darbar et al 2008), as well as long-QT syndrome type 3 (LQT3), Brugada syndrome, conduction
disease, sinus node dysfunction, and atrial standstill (Remme et al 2008). Mutation of another sodium channel gene,
SCN1B, has also been implicated as conferring genetic susceptibility for cardiac conduction defects in patients with
similar conditions (Watanabe et al 2008). Mutations in the KCNQ1, KCNH2 and KCNE2 genes have also been associated
with sudden unexplained nocturnal death syndrome, especially among Caucasian men (Tester et al 2012). 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 (Huang
et al 2016). 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.

Epidemiology"

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 1 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 4 times greater than the rate for Thai men living in rural
Thailand. 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 3 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 (Zheng et al 2015). 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 (Chen et al 2016). 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.

Prevention

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 (Young et al 2013). 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 (Das and El Masry 2010). 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.

Differential diagnosis

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, autonomic dysfunction and hypoglycemia in diabetes mellitus (Gill et al 2009), occult cardiopulmonary disease,
multiple system atrophy (MSA) (Shimohata et al 2008), 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. Rarely certain medications have caused sudden death or
near death in sleep by ventricular tachycardia and Brugada-like syndrome; these have included indapamide,
propafenone, amiodarone, lithium, amitriptyline, and other psychotropic medications (Chutani et al 2008; Mok et al
2008; Nägele et al 2008; Pirotte et al 2008; Sicouri and Antzelevitch 2008). Hyponatremia has been implicated in some
of these cases, leading further credence to the involvement of sodium in the pathogenesis of these related conditions
(Mok et al 2008).

Diagnostic workup

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 (Macedo et al 2011), 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 (Young et al 2013).

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.
Management

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.

Special considerations

Anesthesia

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 ST prolongation is observed intraoperatively (Carey and
Hocking 2011).

References cited

American Academy of Sleep Medicine. International Classification of Sleep Disorders: Diagnostic and Coding Manual
(AASM ICSD-3). 3rd edition. Westchester, IL: American Academy of Sleep Medicine, 2014.

Carey SM, Hocking G. Brugada syndrome--a review of the implications for the anaesthetist. Anaesth Intensive Care
2011;39(4):571-7. PMID 21823372

Chen Z, Mu J, Chen X, Dong H. Sudden unexplained nocturnal death syndrome in Central China (Hubei): a 16-year
retrospective study of autopsy cases. Medicine (Baltimore) 2016;95(9):e2882.** PMID 26945374

Chutani S, Imran N, Grubb B, Kanjwal Y. Propafenone-induced Brugada-like ECG changes mistaken as acute myocardial
infarction. Emerg Med J 2008;25(2):117-8. PMID 18212157

Darbar D, Kannankeril PJ, Donahue BS, et al. Cardiac sodium channel (SCN5A) variants associated with atrial
fibrillation. Circulation 2008;117(15):1927-35. PMID 18378609

Das MK, El Masry H. Fragmented QRS and other depolarization abnormalities as a predictor of mortality and sudden
cardiac death. Curr Opin Cardiol 2010;25(1):59-64. PMID 19881337

Gill GV, Woodward A, Casson IF, Weston PJ. Cardiac arrhythmia and nocturnal hypoglycaemia in type 1 diabetes--the
'dead in bed' syndrome revisited. Diabetologia 2009;52(1):42-5. PMID 18972096

Huang L, Tang S, Peng L, Chen Y, Cheng J. Molecular autopsy of desmosomal protein plakophilin-2 in sudden
unexplained nocturnal death syndrome. J Forensic Sci 2016;61(3):687-91. PMID 27122407

Huang L, Yu Y, Chen Y, et al. Association of common variants in NOS1AP gene with sudden unexplained nocturnal
death syndrome in the southern Chinese Han population. Int J Legal Med 2014;128(6):933-8. PMID 24504561

Liu C, Tester DJ, Hou Y, et al. Is sudden unexplained nocturnal death syndrome in Southern China a cardiac sodium
channel dysfunction disorder. Forensic Sci Int 2014;236:38-45. PMID 24529773

Macedo PG, Brugada J, Leinveber P, et al. Sleep-disordered breathing in patients with the Brugada syndrome. Am J
Cardiol 2011;107(5):709-13. PMID 21247540

Matsusue A, Kashiwagi M, Hara K, Waters B, Sugimura T, Kubo SI. An autopsy case of sudden unexpected nocturnal
death syndrome with R1193Q polymorphism in the SCN5A gene. Leg Med (Tokyo) 2012;14(6):317-9. PMID 22682427

Mok NS, Tong CK, Yuen HC. Concomitant-acquired Long QT and Brugada syndromes associated with indapamide-
induced hypokalemia and hyponatremia. Pacing Clin Electrophysiol 2008;31(6):772-5. PMID 18507554
Nägele H, Behrens S, Castel A. Ventricular tachycardia and aggravation of Brugada ECG pattern in a patient with
coronary artery disease and combined amiodarone and beta blocker therapy. Clin Res Cardiol 2008;97(1):56-60. PMID
18075767

Nakajima K, Takeichi S, Nakajima Y, Fujita M. Pokkuri Death Syndrome; sudden cardiac death cases without coronary
atherosclerosis in South Asian young males. Forensic Sci Int 2011;207(1-3):6-13. PMID 21084168

Pirotte MJ, Mueller JG, Poprawski T. A case report of Brugada-type electrocardiographic changes in a patient taking
lithium. Am J Emerg Med 2008;26(1):113.e1-3. PMID 18082804

Remme CA, Wilde AA, Bezzina CR. Cardiac sodium channel overlap syndromes: different faces of SCN5A mutations.
Trends Cardiovasc Med 2008;18(3):78-87. PMID 18436145

Shimohata T, Ozawa T, Nakayama H, Tomita M, Shinoda H, Nishizawa M. Frequency of nocturnal sudden death in
patients with multiple system atrophy. J Neurol 2008;255(10):1483-5. PMID 18670800

Sicouri S, Antzelevitch C. Sudden cardiac death secondary to antidepressant and antipsychotic drugs. Expert Opin
Drug Saf 2008;7(2):181-94. PMID 18324881

Tester DJ, Medeiros-Domingo A, Will ML, Haglund CM, Ackerman MJ. Cardiac channel molecular autopsy: insights from
173 consecutive cases of autopsy-negative sudden unexplained death referred for postmortem genetic testing. Mayo
Clin Proc 2012;87(6):524-39. PMID 22677073

Watanabe H, Koopmann TT, Le Scouarnec S, et al. Sodium channel beta1 subunit mutations associated with Brugada
syndrome and cardiac conduction disease in humans. J Clin Invest 2008;118(6):2260-8. PMID 18464934

Young E, Xiong S, Finn L, Young T. Unique sleep disorders profile of a population-based sample of 747 Hmong
immigrants in Wisconsin. Soc Sci Med 2013;79:57-65. PMID 22832325

Zhang L, Zhou F, Huang L, et al. Association of common and rare variants of SCN10A gene with sudden unexplained
nocturnal death syndrome in Chinese Han population. Int J Legal Med 2016. [Epub ahead of print] PMID 27272739

Zhao Q, Chen Y, Peng L, et al. Identification of rare variants of DSP gene in sudden unexplained nocturnal death
syndrome in the southern Chinese Han population. Int J Legal Med 2016;130(2):317-22. PMID 26585738

Zheng J, Huang E, Tang S, et al. A case-control study of sudden unexplained nocturnal death syndrome in the southern
Chinese Han population. Am J Forensic Med Pathol 2015;36(1):39-43.** PMID 25621881

**References especially recommended by the author or editor for general reading.

Former authors

Carlos H Schenck MD (original author)

ICD and OMIM codes

ICD codes

ICD-9:
Sleep disturbances: 780.5
Death occurring in less than 24 hours from onset of symptoms not otherwise explained: 798.2

ICD-10:
Sleep disorder, unspecified: G47.9
Death occurring less than 24 hours from onset of symptoms, not otherwise explained: R96.1

OMIM numbers

Sudden unexplained nocturnal death syndrome: #601144


Profile

Age range of presentation

02-05 years
06-12 years
13-18 years
19-44 years
45-64 years

Sex preponderance

male>female, >2:1
male>female, >1:1

Family history

family history may be obtained

Heredity

none

Population groups selectively affected

Southeast Asians

Occupation groups selectively affected

none selectively affected

Differential diagnosis list

idiopathic ventricular fibrillation


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
autonomic dysfunction in diabetes mellitus
occult cardiopulmonary disease
Brugada syndrome
long QT syndrome
multiple system atrophy

Associated disorders

Congenital cardiac conduction abnormalities


Nightmares
Nocturnal hypoxia
Sleep terror
Thiamine deficiency

Other topics to consider

Nightmares
Sleep disorders
Sleep terror
Parasomnias

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