November 2019 Case

Kate Raastad, MD (Resident)

The decedent is a 33-year-old male with past medical history significant for recent headaches, for which he was taking an unspecified herbal medicine, but otherwise healthy. He was a tobacco smoker, but reportedly did not use alcohol or drugs. He was found unresponsive in his apartment in the early morning hours. His post-mortem examination did not reveal any abnormal findings. The heart was normal in weight and showed no ischemic changes, hypertrophy or valvular disease. There were no pulmonary emboli identified, no gastrointestinal bleeding, and no neurologic findings. Standard microscopy sections taken from the heart, lungs, liver and kidney showed moderate autolysis but normal histology. Urine and blood toxicology results were negative for alcohol and drugs of abuse.

Sudden unexplained nocturnal death syndrome

An estimated 300,000-400,00 individuals die from sudden death each year in the United States. Most of these cases is elderly with cardiac abnormalities identifiable on autopsy. An estimated 1,000-5,000 young people (under the age of 35) die suddenly, and up to 50% of these cases remain unexplained, with no identifiable gross anatomic lesion on autopsy.

Amongst sudden death cases, particularly sudden cardiac death is the leading cause of mortality worldwide. These typically occur in young men, with highest incidence in the 30-35 age group. They most commonly result from either coronary artery disease, or inherited cardiomyopathies. In cases of unexplained sudden cardiac death, the victim's hearts are normal, both grossly and histologically. These tend to occur in younger males, strike at night, and are often attributed to cardiac arrhythmias, such as inheritable cardiac channelopathies.

Sudden unexplained nocturnal death syndrome (SUNDS) was first described in the Philippines in 1917. It was noticed to happen in males in the 20-40 age range of Southeast Asian descent, particularly during the winder months. Deaths occurred at night, during sleep or rest, with victims being in apparent good health prior to demise. On autopsy, there were no pathologic findings. Interestingly, majority of victims had a history of night terrors, sleep paralysis, and were frequently observed convulsing, gagging, frothing at the mouth, gasping for air and tongue-biting prior to death.

Throughout the years, multiple theories have been proposed to try and explain SUNDS. For one, hypokalemia can lead to arrhythmias, muscle weakness, and even paralysis. High upper airway resistance and hypoventilation during REM sleep can lead to hypoxemia and acidosis, decreasing sodium currents and predisposing to arrythmias. And lastly, night terrors increase sympathetic discharge, causing increased cardiac vulnerability to arrythmias in patients with cardiac conduction defects.

Perhaps the best explanation is the relation of SUNDS to Brugada syndrome, a cardiac channelopathy related to the mutation of sodium channel gene SCN5A. It is inherited in autosomal dominant fashion, and affects an estimated 5 in 10,000 people worldwide, more frequently in Japanese and Southeast Asian populations, and particularly in men. Clinical criteria for diagnosis include documented episode of ventricular tachycardia or fibrillation on EKG, family history of sudden cardiac death under the age of 45 years old, inducibility of ventricular tachycardia with programmed electrical stimulation, and episodes of syncope and nocturnal agonal respirations. A variety of risk factors can unmask or augment those with the syndrome, including fever, certain drugs, hypokalemia, hypothermia, and cardioversion.

Although multiple genes can be mutated in the Brugada syndrome, SCN5A is the most common, with almost 300 different mutations linked to the syndrome. SCN5A encodes the alpha subunit of the sodium channel, and mutations in the gene result in loss of function due to either decreased expression of sodium channel proteins, expression of non-functional channels, or altered gating properties. Loss of function of sodium channel current decreases the upstroke velocity of the action potential at phase 0, slowing atrial and ventricular electrical conduction and leading to arrhythmogenesis if not corrected.

Both SUNDS and Brugada syndrome share similar characteristics. Both predispose to sudden cardiac death secondary to ventricular tachycardia, harbor no structural cardiac abnormalities, tend to occur in males in the 20-40 age group, occur at night or during periods of rest, and have the same EKG pattern. However, SCN5A mutations have only been documented in 8% of SUNDS cases, with mutation in the DSP gene (provides instruction for making desmoplakin, major component of cardiac and skin desmosomes) having the highest yield of variation in SUNDS but has not been associated with Brugada syndrome. Unlike Brugada syndrome, SUNDS is rarely familial, and victims have a larger heart size and increased mitral valve circumference when compared to those of Brugada syndrome. Thus, it is safe to conclude that although the two conditions share some genetic basis, they are not identical but closely related entities.

In conclusion, SUNDS appears to be a multifactorial entity with involvement of channelopathies and cardiomyopathy-associated genetic variants. The so-called "triple risk hypothesis" requires a vulnerable young person carrying susceptible variants, stressors caused by environmental or social factors, and disturbance in action potential production and propagation in nocturnal sleep to cause death. Although more studies are needed to provide a definite molecular diagnosis, final mechanism of death can confidently be attributed to some sort of arrythmia.