Dead-in-bed syndrome

The syndrome of sudden unexpected death or "dead in bed" syndrome is considered to account for around 5% of deaths in type 1 diabetes, a rate equivalent to 2-6 cases per 10,000 patient-years. The condition may be 10 times more common in type 1 diabetes than in the rest of the population, and males are more commonly affected. Typically, the patient is found lying in an undisturbed bed, with no obvious antecedents or abnormal post-mortem findings. The proximate cause of death is likely to be a cardiac dysrhythmia, possibly triggered by hypoglycaemia against a background of autonomic dysfunction.

Background

The syndrome first came to attention against the background of concerns about the possible risks of human insulin. This was at one time considered to be a cause of loss of hypoglycaemia awareness, and a pathologist in the UK linked this to a number of cases which occurred at around the time when many were converted from animal source to biosynthetic insulin - see Porcine insulin. The syndrome occurs in insulin-treated patients, but is no longer considered to be linked to any specific formulation.

Tattersall and Gill published the first report on the condition in 1991. This described 22 apparently healthy people with type 1 diabetes aged 12-43 years who died in their sleep with no evidence of a struggle, and suggested nocturnal hypoglycaemia as the cause[1].

Further experience

Subsequent reports identified around 100 further similar deaths. Thus, although rare, the syndrome accounts for an important minority - some 5-10%[2] - of all deaths in type 1 diabetes.

One challenge has been to estimate the frequency of this phenomenon in the non-diabetic population. The syndrome has some similarity to the sudden-infant death syndrome (SIDS), but no common factors have been identified. Sudden unexpected death at night is also reported in epilepsy, with a male preponderance, but most often with evidence of a terminal seizure[3].

A recent analysis based upon two type 1 diabetes registries found that 19/255 adjudicated deaths (8%) were attributed to the syndrome, an estimated 10-fold higher rate than in the background population. Deaths were more common in males (13/19), and in those with higher HbA1c and insulin doses but lower BMI. The mean age at onset was 9 years, and mean duration of diabetes was 22.4 years[4].

Possible causes

The sporadic and unexpected nature of these tragic deaths has made understanding difficult. Many are poorly reported, and autopsy evidence is often missing. Hence, some deaths may have been due to other conditions such as cardiomyopathy or diabetic precoma. Notwithstanding, there are a number of characteristic features.

Hypoglycaemia

Insulin treatment is a constant factor, which points suspicion towards hypoglycaemia. Furthermore, unrecognised nocturnal hypoglycaemia is common in type 1 diabetes. This was indeed documented in one patient, a 23-year old man treated with a subcutaneous insulin pump who was attached to a continuous glucose monitoring system (CGMS) at the time of death, at which time his blood glucose was recorded as below 1.7 mmol/l (30 mg/dl). No abnormal findings were reported at autopsy[5].

This leaves the actual mechanism of death unexplained, since sudden death is not a recognised complication of hypoglycaemia. Convulsions appear to be ruled out by the presentation, which would be more consistent with a cardiac dysrhythmia. This might be mediated by hypoglycaemia-induced hypokalaemia if superimposed upon the diurnal rhythm of circulating potassium, which reaches its nadir in the early hours of the morning. Cardiac autonomic dysfunction is however more generally considered responsible.

Autonomic neuropathy

The relationship between diabetic autonomic neuropathy and mortality in diabetes is unquestioned[6], but this may well be secondary to its strong association with other life-threatening complications of diabetes. In all events, its role in causing death by dysrhythmia remains speculative.

One potential mechanism by which autonomic neuropathy might interact with hypoglycaemia is prolongation of the corrected QT interval (QTc). Thus, ECG recordings of patients during nocturnal hypoglycaemia showed prolongation of QTc together with rhythm disturbances, suggesting a possible trigger for fatal dysrhythmias[7]. The importance of cardiac autonomic neuropathy in this interaction was however cast into some doubt by a study which found that QT lengthening was less marked during hypoglycaemia in those with cardiac autonomic neuropathy than in those without[8]. A further reason for questioning the association is that the syndrome, unlike autonomic neuropathy, is only weakly correlated with duration of diabetes.

Autopsy and other findings

An Australian study of 22 people who died in this way was essentially negative. In particular, no cellular abnormality was demonstrated in cardiac tissue. Genetic analysis provided no clear leads, although the sample was too small for firm conclusions[9]. The lack of autopsy abnormalities appears characteristic of this condition.

Summary

The dead-in-bed syndrome, although mercifully rare, remains a cause for considerable concern, not least because its causes are so poorly understood. On current evidence, unrecognised nocturnal hypoglycaemia may well be a key causal factor, but the mechanism by which it induces rhythm disturbance and the role of autonomic dysfunction remain conjectural. Avoidance of nocturnal hypoglycaemia appears prudent.

References

  1. ^ Tattersall RB, Gill GV. Unexplained deaths of type 1 diabetic patients. Diabet Med 1991;8:49-58

  2. ^ Koltin D, Daneman D. Dead-in-bed syndrome - a diabetes nightmare. Pediatr Diabetes 2008;9:504-7

  3. ^ Opeskin K, Berkovic SF. Risk factors for sudden unexpected death in epilepsy: a controlled prospective study based on coroners cases. Seizure 2003;12:456-64

  4. ^ Secrest AM et al. Characterising sudden death and dead-in-bed syndrome in Type 1 diabetes: Analysis from 2 childhood-onset Type 1 diabetes registries. Diabet Med 2011;28:293-300

  5. ^ Tanenberg RJ et al. Confirmation of hypoglycaemia in the "dead-in-bed" syndrome, as captured by a retrospective continuous glucose monitoring system. Endocr Pract 2010;16:244-8

  6. ^ Vinik AI et al. Autonomic imbalance: prophet of doom or scope for hope? Diabet Med 2011;28:643-51

  7. ^ Gill GV et al. Cardiac arrhythmia and nocturnal hypoglycaemia in type 1 diabetes - the "dead in bed" syndrome revisited. Diabetologia 2009;52:42-25

  8. ^ Lee SP et al. Influence of autonomic neuropathy on QTc lengthening during hypoglycaemia in type 1 diabetes. Diabetes 2004;53:1535-42

  9. ^ Tu E et al. Post-mortem pathologic and genetic studies in "dead in bed" syndrome cases in type 1 diabetes mellitus. Hum Path 2010;41:392-400

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