Opinion
Impaired CO2-Induced Arousal in SIDS and SUDEP

https://doi.org/10.1016/j.tins.2019.02.002Get rights and content

Highlights

SIDS and SUDEP are among the leading causes of death in their respective patient populations (i.e., infants under 1 year of age and patients with refractory epilepsy), but their pathophysiology is poorly understood.

Some common features of SIDS and SUDEP have been identified, including impaired cardiorespiratory function and dysfunctional serotonin signaling.

A possible common pathophysiological mechanism is impaired arousal in response to elevated CO2. Individuals at risk for both conditions experience situations in which serum CO2 concentrations rise (e.g., due to physical airway obstruction, or as a consequence of a seizure). However, the physiological mechanisms of CO2-induced arousal from sleep are not fully understood, and whether a definitive link to SIDS or SUDEP exists remains to be validated.

Better understanding of the mechanisms of CO2-induced arousal, and how these impaired mechanisms possibly contribute to death in SIDS and SUDEP, may help address the pressing need for effective prevention strategies in these conditions.

Premature, sudden death is devastating. Certain patient populations are at greater risk to succumb to sudden death. For instance, infants under 1 year of age are at risk for sudden infant death syndrome (SIDS), and patients with epilepsy are at risk for sudden unexpected death in epilepsy (SUDEP). Deaths are attributed to these syndromic entities in these select populations when other diagnoses have been excluded. There are a number of similarities between these syndromes, and the commonalities suggest that the two syndromes may share certain etiological features. One such feature may be deficiency of arousal to CO2. Under normal conditions, CO2 is a potent arousal stimulus. Circumstances surrounding SIDS and SUDEP deaths often facilitate CO2 elevation, and faulty CO2 arousal mechanisms could, at least in part, contribute to death.

Section snippets

Towards a Pathophysiological Understanding of Sudden, Unexpected Death

Sudden, premature death of individuals takes a heavy toll on their families, circle of acquaintances, and society at large. Often, there is an evident cause for premature death, such as accidental injury, inflicted injury (e.g., suicide or homicide), or critical illness. Unfortunately, too often, there is no immediately identifiable cause for death. In some respects, these cases can be even more devastating for loved ones, as the latter are left with the unsettling questions of why their loved

SIDS

SIDS is defined as the sudden and unexpected death of an infant under the age of 1 year that remains unexplained after thorough review of the clinical history, death scene investigation, and complete autopsy [1]. It is the leading cause of sudden death in infants under 1 year of age. Considerable work has been done in attempts to understand the risk factors for SIDS and its pathophysiological features. Collectively, this work has produced the triple risk model for SIDS. This model fits into the

SUDEP

SUDEP is defined as the ‘sudden, unexpected, witnessed or unwitnessed nontraumatic and non-drowning death in patients with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus, in which postmortem examination does not reveal a toxicological or anatomic cause of death’ [7]. It is the leading cause of death in patients with medically refractory epilepsy [8]. SUDEP is second only to stroke in terms of years of potential life lost to neurological disease,

Similarities between SIDS and SUDEP

There are a number of similarities between SIDS and SUDEP [15] (Table 1). Both are essentially diagnoses of exclusion. In both, the individual is usually healthy (except for epilepsy in SUDEP). In both, autopsy is normal. Similar etiological factors have been proposed for both, including respiratory demise, cardiac demise, and impairment of arousal. In both, the death is commonly unwitnessed, with the individual being found dead in bed/crib and in the prone position. The incidence is comparable

CO2-Induced Arousal from Sleep

Among the proposed etiologies for SIDS and SUDEP, one that is especially intriguing, and that has garnered little attention, is impaired arousal, especially to CO2. CO2 is expelled by the lungs as one breathes. Drive to breathe is dictated in large part by the serum CO2 concentration, which is tightly regulated. In addition to potently driving breathing, CO2 is a powerful arousal stimulus [30]. As can be imagined, acute rises in CO2 levels occur when an individual is unable to expel CO2, such

Serotonin in SIDS, SUDEP, and CO2-Induced Arousal

One candidate for acting as the primary sensor of CO2 in the context of CO2-induced arousal is 5-HT neurons in the DRN (Figure 2). These neurons are robustly chemosensitive in vitro [50] and in vivo [51]. In vitro, most DRN 5-HT neurons tested were chemosensitive and responded with a fourfold increase in firing in response to a pH change from 7.4 to 7.2, well within physiological range [50]. Genetic elimination of 5-HT neurons in the CNS attenuates arousal to inspired CO2 in mice [43]. Direct

Concluding Remarks and Future Perspectives

Discovery of biomarkers to more easily identify individuals at risk for SIDS and SUDEP is underway 8, 54, 62. Once etiological features are clearly defined and at-risk individuals reliably ascertained, prophylactic strategies can be deployed. Converging lines of evidence, as discussed in this article, point at dysregulation of CO2-induced arousal as a shared candidate pathophysiological mechanism in both SIDS and SUDEP. According to this proposed mechanism, prophylactic strategies may include

Acknowledgments

Dr Buchanan is supported by the NIH/NINDS R01NS095842; the Pappajohn Biomedical Institute and Iowa Neuroscience Institute at the University of Iowa; and the Beth Levitt Tross Professorship in Epilepsy Research.

Glossary

Epilepsy
a disease in which the person is subject to spontaneous, unprovoked seizures.
Medically refractory epilepsy
epilepsy in which seizures cannot be controlled after adequate trials of two or more antiseizure medications.
Near-sudden unexpected death in epilepsy (near-SUDEP)
event from which it is perceived that a person would have died following a seizure, but survived at least for one hour because of resuscitative efforts.
Sudden infant death syndrome (SIDS)
sudden and unexpected death of an

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