Subtle Autonomic and Respiratory Dysfunction in Sudden Infant Death Syndrome Associated With Serotonergic Brainstem Abnormalities: A Case Report

Abstract

Sudden infant death syndrome (SIDS) is characterized by a sleep-related death in a seemingly healthy infant. Previously, we reported abnormalities in the serotonergic (5-HT) system of the medulla in SIDS cases in 2 independent datasets, including in the Northern Plains American Indians. The medullary 5-HT system is composed of 5-HT neurons in the raphé, extra-raphé, and arcuate nucleus at the ventral surface. This system is thought to modulate respiratory and autonomic function, and thus abnormalities within it could potentially lead to imbalances in sympathetic and parasympathetic tone. We report the case of a full-term American Indian boy who died of SIDS at 2 postnatal weeks, and who had subtle respiratory and autonomic dysfunction measured prospectively on the second postnatal day. Cardiorespiratory assessment of heart rate variability suggested that the ratio of parasympathetic to sympathetic tone was higher than normal in active sleep and lower than normal in quiet sleep in this case. At autopsy, arcuate nucleus hypoplasia and 5-HT receptor-binding abnormalities in the arcuate nucleus and other components of the medullary 5-HT system were found. This case suggests that medullary 5-HT system abnormalities may be able to be identified by such physiological tests before death. Replication of these findings in a large population may lead to the development of predictive cardiorespiratory assessment tools for future screening to identify infants with medullary 5-HT abnormalities and SIDS risk.

Sudden Infant Death Syndrome: Rare Mutation in the Serotonin System FEV Gene

“…Evidence is growing indicating dysfunction of the serotonergic system in the pathway leading to autonomic dysregulation and vulnerability to SIDS (2)(3)(4)(5)(6)(7)(8)26,27). The focus of this study, the ETS domain transcription factor FEV, has been …”

Neuropathology provides new insight in the pathogenesis of the sudden infant death syndrome

“…A major discovery in SIDS research in the last two decades is that the Wnal lethal event may be preceded by chronic episodes of bradycardia and/or apnea days and even weeks prior to the time of death, as detected by physiological tracings in infants who were monitored prior to death and by various physiological assessments in prospective studies of infants who subsequently died of SIDS [24,25,31,66,71]. The lethal event itself involves, at least in some cases, a failure in autoresuscitation, i.e., gasping [60,67].…”

“…The association of SIDS with these risk factors underscores the validity of the brainstem hypothesis because they are exogenous stressors that trigger asphyxia, hypoxia, hypercapnia, thermal imbalance, and/or cardiovascular instability which in turn require intact brainstem defense systems to protect against lethal consequences. These defense systems involve central chemosensitivity to carbon dioxide and oxygen, autoresuscitation, and arousal with head lifting and turning to escape asphyxiating microenvironments via gaining fresh air and/or crying [25,31,60,67,71,77].…”

“…The rationale for the SIDS brainstem hypothesis is based upon three main lines of evidence: (1) established human and animal data that the brainstem plays a critical role in respiratory and autonomic regulation, sleep, and arousal [63], i.e., in the primary physiological processes considered abnormal in SIDS infants, (2) analogy to human entities of sleep-related sudden death in children or adults in which isolated or primary pathology is found by neuroimaging and/or at autopsy in the brainstem [55], and (3) reports of subclinical defects in cardiorespiratory control and/or arousal that are consistent with brainstem dysfunction in infants who are studied prospectively and subsequently die of SIDS [24,25,31,60,66,67,71,77]. These defects include impaired autoresuscitation (gasping), abnormal respiratory patterning, episodic obstructive apnea during sleep, autonomic dysfunction (episodic tachycardia/bradycardia, abnormal heart rate variability), and arousal deWcits, as well as potential impaired mechanisms that maintain homeostasis during Xuctuations in heart rate and blood pressure as the infant transitions among REM, NREM, and waking states during the night or nap-time [24,25,31,60,66,67,71,77]. In the decade following the review by Hunt and Brouillette, major risk factors for SIDS were discovered, including prone sleep position, face-down position, covered face in the supine position, soft bedding, bed sharing, over-bundling, elevated room temperature, and minor infection around the time of death [43,71,77].…”

Potential Asphyxia and Brainstem Abnormalities in Sudden and Unexpected Death in Infants

“…3,11,12 The association of unsafe sleep environmentswith SIDS raises the possibility that normal infants die of asphyxia and that eliminating these dangerous sleeping conditionswill in turn eradicate all SIDS deaths. Yet there is mounting evidence that at least some infants who die of SIDS are not "normal" before death but rather have underlying vulnerabilities, 5,[13][14][15][16][17][18][19][20][21][22][23][24][25][26] including genetic susceptibilities, 27 that put them at risk.…”