Clinical and basic research on Sudden Infant Death Syndrome (SIDS) has focused on sleep-disordered cardiorespiratory control during a critical period of brainstem maturation. Recently, some SIDS cases have been reported to have abnormalities of the arcuate nucleus of the medulla. The human arcuate nucleus is thought to be homologous to the medullary raphe in rats and cats, a widely projecting serotonergic system that is functionally linked to both respiration and sleep. Neurons of the medullary raphe are now known to be highly sensitive to respiratory acidosis in vitro and are candidates for central chemoreceptors. The relevance of changes in the arcuate nucleus to the mechanisms of death in SIDS remains controversial. However, based on this new data, a specific hypothesis is proposed here. In combination with Immaturity of respiratory control mechanisms, dysfunction of arcuate neurons may lead to a fatal exaggeration of a normal physiologic inhibition of central chemoreception during sleep. The major elements of this working hypothesis are testable in animal experiments and clinical studies.
WillingerMJamesLSCatzC.Defining the sudden infant death syndrome (SIDS): Deliberations of an expert panel convened by the National Institute of Child Health and Human Development. Pediatr Pathol Lab Med1991; 11:677–684.
2.
WegmanME.Annual summary of vital statistics—1988. Pediatrics1989; 84:943–956.
3.
BrooksJG.Apnea of infancy and sudden infant death syndrome. Am J Dis Child1982; 136:1012–1023.
4.
ShannonDCKellyDH.SIDS and near-SIDS (first of two parts). N Engl J Med1982; 306:959–965.
5.
HoffmanHJDamusKHillmanLKrongradE.Risk factors for SIDS. Results of the National Institute of Child Health and Human Development SIDS Cooperative Epidemiological Study. Ann N Y Acad Sci1988; 533:13–30.
6.
HuntCE.Sudden Infant Death Syndrome. In: Respiratory control disorders in infants and children. BeckermanRCBrouilletteRTHuntCE, editors. Baltimore: Williams & Wilkins1992;190–211.
7.
SteinschneiderA.Prolonged apnea and the sudden infant death syndrome: Clinical and laboratory observations. Pediatrics1972; 50:646–654.
8.
MellinsRBHaddadGG.Cardiorespiratory control in sudden infant death syndrome. Prog Clin Biol Res1983; 136:51–57.
9.
SchlaefkeME.Central chemosensitivity: A respiratory drive. Rev Physiol Biochem Pharmacol1981; 90:171–244.
10.
MenyRGCarrollJLCarboneMTKellyDH.Cardiorespiratory recordings from infants dying suddenly and unexpectedly at home. Pediatrics1994; 93:44–49.
11.
BazzyARHaddadGGChangSLMellinsRB.Respiratory pauses during sleep in near-miss sudden infant death syndrome. Am Rev Respir Dis1983; 128:973–976.
12.
GuilleminaultCAriagnoRSouquetMDementWC.Abnormal polygraphic findings in near-miss sudden infant death. Lancet1976; 1:1326–1327.
13.
KellyDHShannonDC.Periodic breathing in infants with near-miss sudden infant death syndrome. Pediatrics1979; 63:355–360.
14.
KahnAGroswasserJRebuffatESleep and cardiorespiratory characteristics of infant victims of sudden death: A prospective case-control study. Sleep1992; 15:287–292.
15.
ShannonDCKellyDHO'ConncllK.Abnormal regulation of ventilation in infants at risk for sudden-infant-death syndrome. N Engl J Med1977; 297:747–750.
16.
HuntCEMcCullochKBrouillctteRT.Diminished hypoxic ventilatory responses in near-miss sudden infant death syndrome. J Appl Physiol1981; 50:1313–1317.
17.
ColemanJMMammelMCReardonCBorosSJ.Hypercarbic ventilatory responses of infants at risk for SIDS. Pediatr Pulmonol1987; 3:226–230.
18.
AriagnoRNagelLGuillcminaultC.Waking and ventilatory responses during sleep in infants near-miss for sudden infant death syndrome. Sleep1980; 3:351–359.
19.
HaddadGGLeistnerHLLaiTLMellinsRB.Ventilation and ventilatory partem during sleep in aborted sudden infant death syndrome. Pediatr Res1981; 15:879–883.
20.
WilliamsAVawterGReidL.Increased muscularity of the pylmonary circulation in victims of sudden infant death syndrome. Pediatrics1979; 63:18–23.
21.
NaeyeRL.Brain-stem and adrenal abnormalities in the sudden-infant-death syndrome. Am J Clin Pathol1976; 66:526–530.
22.
KinneyHCFilianoJJHarperRM.The neuropathology of the sudden infant death syndrome. A review. J Neuropathol Exp Neurol1992; 51:115–126.
23.
FolgeringHKuyperFKilleJF.Primary alveolar hypoventilation (Ondine's curse syndrome) in an infant without external arcuate nucleus. Case report. Bull Eur Physiopathol Respir1979; 15:659–665.
24.
FilianoJJKinneyHC.Arcuate nucleus hypoplasia in the sudden infant death syndrome. J Neuropathol Exp Neurol1992; 51:394–403.
25.
DevNBLoeschckeHH.A cholinergic mechanism involved in the respiratory chemosensitivity of the medulla oblongata in the cat. Pflugers Arch1979; 379:29–36.
26.
KinneyHCFilianoJJSleeperLAMandellFValdes-DapenaMWhiteWF.Decreased muscarinic receptor binding in the arcuate nucleus in sudden infant death syndrome. Science1995; 269:1446–1450.
27.
GilsonTPBalkoMGBlisardKSTaylorKL.Morphologic variations of the external arcuate nucleus in infants dying of SIDS: A preliminary report. J Forensic Sci1994; 39:1076–1083.
28.
FilianoJJChoiJCKinneyHC.Candidate cell populations for respiratory chemosensitive fields in the human infant medulla. J Comp Neurol1990; 293:448–465.
29.
FukudaYLoeschckeHH.Effect of H+ on spontaneous neuronal activity in the surface layer of the rat medulla oblongata in vitro. Pflugers Arch1977; 371:125–134.
30.
JacobsBLAzmitiaEC.Structure and function of the brain serotonin system. Physiol Rev1992; 72:165–229.
31.
DeanCMarsonLKampineJP.Distribution and co-localization of 5-hydroxy-tryptamine, thyrotropin-releasing hormone and substance-p in the cat medulla. Neuroscience1993; 57:811–822.
32.
MossIRInmanJG.Neurochemicals and respiratory control during development. J Appl Physiol1989; 67:1–13.
33.
LalleyPM.Serotoninergic and non-serotoninergic responses of phrenic motoneurones to raphe stimulation in the cat. J Physiol (Lond)1986; 380:373–385.
34.
RichersonGB.Response to CO2 of neurons in the rostral ventral medulla in vitro. J Neurophysiol1995; 73:933–944.
35.
RigattoHFitzgeraldSCWillisMAYuC.In search of the central respiratory neurons: II. Electrophysiologic studies of medullary fetal cells inherently sensitive to CO2 and low pH. J Neurosci Res1992; 33:590–597.
36.
EldridgeFLGill-KumarPMillhomDE.Input-output relationships of central neural circuits involved in respiration in cats. J Physiol (Lond)1981; 311:81–95.
37.
DeanJBBaylissDAEricksonJTLawingWLMillhomDE.Depolarization and stimulation of neurons in nucleus tractus solitarii by carbon dioxide does not require chemical synaptic input. Neuroscience1990; 36:207–216.
38.
DillonGHWaldropTG.In vitro responses of caudal hypothalamic neurons to hypoxia and hypercapnia. Neuroscience1992; 51:941–950.
39.
VeaseySCFornalCAMetzlerCWJacobsBL.Response of serotonergic caudal raphe neurons in relation to specific motor activities in freely moving cats. J Neurosci1995; 15:5346–5359.
40.
LamicolNWalloisFBerquinPGrosFRoseD.C-fos-like immunoreactivity in the cat's neuraxis following moderate hypoxia or hypercapnia. J Physiol (Paris)1994; 88:81–88.
41.
BernardDGLiANattieEE.Evidence for central chemoreception in the midline raphe. J Appl Physiol1996; 80:108–115.
42.
WangWRichersonGB.Rat ventromedial medullary neurons sensitive to acidosis are bulbospinal. Soc Neurosci Abstr1996;22
43.
DekinMSRichersonGBGettingPA.Thyrotropin-releasing hormone induces rhythmic bursting in neurons of the nucleus tractus solitarius. Science1985; 229:67–69.
44.
HaddadGGMazzaNMDefendiniRCongenital failure of automatic control of ventilation, gastrointestinal motility and heart rate. Medicine (Baltimore)1978; 57:517–526.
45.
VerloesAElmerCLacombeDOndine-Hirschsprung syndrome (Haddad syndrome). Further delineation in two cases and review of the literature. Eur J Pediatr1993; 152:75–77.
46.
KrygerMHRothTDementWC.Principles and practice of sleep medicine. 2nd ed. Philadelphia: Saunders1994.
47.
HaddadGGWalshEMLeistnerHLGrodinWKMellinsRB.Abnormal maturation of sleep states in infants with aborted sudden infant death syndrome. Pediatr Res1981; 15:1055–1057.
