Neuropathology of sudden infant death (syndrome): literature review and evidence of a probable apoptotic degenerative cause

Abstract

Background: The agonizing enigma of sudden infant death syndrome (SIDS) endures. Contemporary research concentrates on the central nervous system (CNS) as the prime cause. Review and discussion: What follows is a review of the neuropathology of SIDS. A persuasive, but as yet unproved, hypothesis is that the lethal pathophysiologic derangement or mechanism in SIDS involves dysfunction of sleep-related cardiorespiratory homeostatic controls or failure to arouse or both. Neuropathological investigation of SIDS continues to be closely linked to the study of specific anatomic structures and regions of the CNS. The structures in these regions underpin and regulate normal cardiorespiratory function. It follows that dysfunction of one or more of these loci probably precipitates SIDS. Under this large umbrella review we include histological, immunohistochemical, and biochemical markers in the cerebrospinal fluid (CSF), ce-rebrum, cerebellum, brain stem, pituitary gland, and pineal gland. With variable effect, these regions are deemed to mediate the functionality of cardiorespiratory activity and the diurnal rhythms of sleep/arousal. The following factors, which (a) are associated with altered electrochemical or neural transmission and biochemical changes in the CNS and (b) predispose to systemic derangements that most probably precipitate SIDS, are subjects of ongoing investigation: evidence of delayed development; ischemic insult; degenerative changes; and synaptic alterations. Conclusion: On the basis of current data, we add to these theoretical constructs by postulating that apoptotic neurodegeneration constitutes the anatomic substrate accounting for the pathophysiologic mechanism and proximate cause of SIDS.

Hyperoxia, reactive oxygen species, and hyperventilation: oxygen sensitivity of brain stem neurons

“…In these contexts, it may be significant that normobaric hyperoxia increases the incidence of sleep-related apneic episodes in rats (13), introduces periodic breathing and destabilizes breathing further during periodic breathing in lambs (71), and destabilizes breathing in infants presenting with recurrent apnea and cyanosis (5). Likewise, other forms of chronic oxidative stress, caused by metabolic defects, may render the developing brain stem network vulnerable to impaired functioning under certain conditions (32,54,62). For example, high levels of iron (53,70) and low levels of melatonin (39) result in chronic oxidative stress and occur in children that die from sudden infant death syndrome.…”

“…Given the significant effects that elevated O 2 levels have on ventilation, further studies of the role of hyperoxia on brain stem neurons are clearly of interest. Identifying the effects of the O 2 continuum on basic cellular properties, which includes anoxia/hypoxia through normoxia and hyperoxia, we will gain insight into the O 2 sensitivity of the brain stem and the role that redox signaling plays in respiratory control (1,22,37,38,44) as well as the possible role for oxidative stress in diseases of respiratory control (22,32,39,53,54,62,67,70).…”

Sudden infant death syndrome: Postulated role of impaired vasoactive neuropeptide-related inflammatory modulation

“…Moreover studies examining hypoxia in SIDS support a role for these VNs. PACAP deficient mice have been shown to have reduced respiratory chemoresponse and are more susceptible to apnea and apoptotic neurodegeneration [72][73][74].…”

Canadian Association of Neuroscience Review: Respiratory Control and Behavior in Humans: Lessons from Imaging and Experiments of Nature

“…Such delay in arousal and responsiveness prevents these infants from benefitting from the powerful effect of wakefulness on breathing. 19,33 A repetition of such episodes may produce recurrent hypoxemia which, in turn, may result in apoptosis in various brainstem and supramedullary regions 34 that may further increase the vulnerability of these infants and set the stage for their demise.…”