Trends in Neurosciences
OpinionImpaired CO2-Induced Arousal in SIDS and SUDEP
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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