Sudden Infant Death Syndrome (SIDS) or "crib death" is an abrupt and inexplicable death of an apparently healthy infant. Most of the cases involve infants from ages 1-12 months, and the event occurs during the night. Various theories have been postulated from research results but without consistency of the etiology. Since the death is sudden, prior diagnostic criteria or patterns are not available for correlation, although some near-miss infants have been followed. A number of possibilities have been documented in current literature, to include beta-endorphin changes, abnormal temperature regulation, pineal abnormalities, carotid body irregularities, lead poisoning, elevated fetal hemoglobin, brainstem immaturity, and cerebral hypoperfusion. The following is an overview of these pathologies in their relation to Sudden Infant Death Syndrome.

As with most physiological processes, several intermediate steps can lead to a certain event, thus making the mechanism more controlled. However, as more steps that are required, there arises a greater number of possible problems. SIDS is no exception. Most literature supports the view that victims of SIDS suffer a failure of the automatic control of respiration, producing periodic apnea and eventually death.

Neural control of respiration involves three anatomical structures (Armstrong et al., 1982~. The first is the motor system, which contains the neurons which initiate and maintain respiration. These include the dorsal motor nucleus of the vague, the nucleus tractus solitarius, the nucleus ambiguous, the nucleus retro-ambiguous, the reticulo-spinal tracts in the anterior and lateral columns and the anterior horn cells of the cervical and thoracic cord. Also included are motor neurons which control muscles of the larynx via the vagus nerve, and those of the tongue from the hypoglossal nerve. Corresponding upper motor neuron innervation for the aforementioned motor component are also involved. The second and third parts encompass the mechanoreceptor system, which responds to stretch and irritants to regulate the rate and volume of respiration, and the chemoreceptor system.

In the motor part of the anatomical structure, Quattrochi et. al., 1985, studied the effects of brainstem immaturity; specifically, spine density in specific brainstem regions. Significant differences in spine density were seen between the n. ambiguous, n. solitaries, and reticular/non-reticular formation areas within the SIDS brainstem. This suggests that this asynchronous structural development could exert significant effects on integrative neuronal activity and result in a functional imbalance between brainstem regions concerned with the automatic control of respiration. Evidence further suggests that inherent stress placed upon an immature sleep-respiratory system during post-natal development, due to upper respiratory infections, periods of apnea, or intrinsic maturation of sleep states, could precipitate a sudden respiratory crisis during sleep in a vulnerable infant unable to modulate a successful adaptation to such stresses.

Another focus of research is the changes of the carotid bodies of SID victims. Cole et. al., 1979, from the University of Connecticut, using light and electron microscopy, observed the changes of carotid bodies between infants of SIDS and control infants. In six infants with SIDS that were studied, the chemoreceptor cells of the carotid bodies were small compared with those of the control infants. In addition, there was an apparent decrease or absence of dense cytoplasmic granulation in the chemoreceptor cells of infants with SIDS. Since the cytoplasmic granules are thought to represent chemoreceptor mediator substances, the absence or diminution of granules may imply a defect in the chemoreceptor function.

Another postulate may be the result of research which found increased levels of beta-endorphin in the cerebrospinal fluid (Myer et. al., 1987). Respiratory depression has been observed in animals after administration of it into the CSF. This respiratory depression may be the result of interaction of opioid peptides with mu-opioid receptors located in respiration areas of the brain such as the solitary nucleus, the ambiguous nucleus, and the anterior hypothalamus. Included in this study were respiratory improvements after the administration of nalaxone, an opioid antagonist, thus indicating a possible prophylactic treatment for infants at risk.

Other researchers (Takashima et. al., 1978) centered on cerebral hypoperfusion. In comparing SIDS infants with those that had died from congenital heart disease, brainstem gliosis was evident in both cases. In SIDS, the gliosis was notably increased in areas crucial to respiratory control, including the solitary nucleus, dorsal motor nucleus of the vagus, nucleus ambiguous, retro-ambigualis, and the reticular formation. Their reasoning for the gliosis centers on the brainstem micro-vasculature. Midline gliosis occurred in areas with sparse, small vessels, while subependymal gliosis was found in an area that contained a network of vessels (dilated capillaries). All other areas of gliosis were at the arterial end or in border zones, consistent with findings of subcortical leukomalacia in vascular watershed areas of the subcortical white matter of SIDS victims. These findings may indicate that gliosis is caused by hypoperfusion, rather than hypoxemia, might occur during the bradycardia that accompanies apnea.

Looking at another aspect of tissue perfusion, a group from the University of Wisconsin (Giulian et. al., 1987) tested the hypothesis that SIDS is associated with a delay in the maturation of hematopoiesis. Hemoglobin F (fetal hemoglobin) is generally replaced by adult hemoglobin, hemoglobin A, during the first six months after birth. Their studies indicated that SIDS victims had a significantly reduced replacement than that in the controls, although cause of the delay in replacement was uncertain. If this delay does occur, prolonged elevation in the levels of fetal hemoglobin in infants with SIDS could denote a compromised delivery of oxygen to sensitive tissue sites. Diagnostically, one may be able to use this parameter in assessing infants at risk.

SIDS incidents occur mostly in the night during sleep, and more specifically, during non-REM sleep. Correlation’s have been made (Takashima et al., 1978) that respiration while awake is largely determined by behavioral demands, while during sleep, respiration is dominated by metabolic control, which is particularly vulnerable during non-REM sleep. Suggestions have been made that the intense reticular activity in REM sleep is akin to the behavioral input during the awake state.

In correlating this information, Koceard-Varo (1991) studied the physiological role of the pineal gland and the affect of changes on infants. The hypothesis was that the master switch of life and death is invested in the pineal gland which, by its neurohormonal influence and its neuronal connections in the brain, gives hypothalamic noradrenaline levels to which the function of the autonomic nervous system and breathing are integrated. He states that CO² blood content triggers adrenomedullary release by increased C0² content , which in turn triggers neuronal connections via the superior cervical ganglia, which end on the pineal gland. This then releases the pineal thyrotropin releasing hormone (TRH), setting in motion the sympathetic system by activating the hypothalamic-hypophysial-adrenomedullary system. This induces adrenomedullary adrenaline release, which activates beta-receptors on pinealocytes cell membranes, which reflectorily regulates hypothalamic noradrenaline content to stay within autonomic balance. During sleep, hypothalamic noradrenaline content is controlled by lifesaving reflexes directly related to C0² levels in the blood. If pineal receptors fail to raise hypothalamic noradrenaline content when too cold, or when overheating lowers it to a level which is beyond correction, all systems serving postnatal life functions become reflectorily disconnected and death follows, without leaving any obvious sign of malfunction.

The hypothalamus also plays a part in this path, but the exact nature of its role is postulated differently. Dunne et al., 1991, followed three infants which had recurrent unexplained life-threatening episodes of apnea followed later by episodes of hypothermia (this suggested that a link between severe apneic attacks and temperature disturbances is a defect in hypothalamic functions). They noted temperature regulation problems in general, such as abnormalities in fatty acid metabolism, and defects in heat production, which are metabolically mediated and accentuated by a cold environment. Most SIDS occur in winter, and depleted brown adipose tissue was documented. Realizing the SIDS may not be from one particular defect, Drasch et al., 1988, suggests that certain cases may be due to high levels of lead which may produce negative influences on pre--and post-natal maturation of the brain. Additionally, they felt that lead in umbilical cord blood is bound to the erythrocytes (mainly to HbF).

As one can realize, the etiology of SIDS is uncertain. Many research results are contradicted by others, giving no clear pathway which leads to this quiet death of infants. Generally, researchers believe that SIDS may not have one cause but rather affect different physiological processes or steps in those pathways. The uncertainty of the cause makes the diagnosis of infants at risk very difficult. Frustratingly, researchers continue to seek diagnostic tests which may help to identify this group.

BIBLIOGRAPHY:

Armstrong, D., Sachis, P., Bryan, C., and Becker, L. Pathological features of Persistent Infantile Sleep Apnea with reference to the pathology of Sudden Infant Death Syndrome. Ann. Neurol., 12:169-174, 1982.

Cole, S., et al. Ultrastructural abnormalities of the carotid body in Sudden Infant Death Syndrome. Pediatrics, 63:13-17, 1979.

Drasch, G., Kretschmer, E., and Lochner, C. Lead and sudden infant death. Europe. J. Pediat., 147:79-84, 1988.

Dunne, K., and Matthews, T. Hypothermia and Sudden Infant Death Syndrome. Archives of Disease in Childhood, 63:438-440, 1988.

Giulian, G., Gilbert, E., and Moss, R. Elevated fetal hemoglobin levels in Sudden Infant Death Syndrome. N. Engl. J. Med. 316:1122-1126, 1978.

Koceard-Varo, G. The physiological role of the pineal gland as the masterswitch of life, turning on at birth breathing and geared to it the function of the autonomic nervous system. The cause of SIDS examined in this context. Medical Hypothesis, 34:122-126, 1991.

Myer, E., Morris, D., et. al. Increased cerebrospinal fluid beta-endorphin immunoreactivity in infants with apnea and in siblings of victims of Sudden Infant Death Syndrome. J. Pedia., 111:660-666, 1987.

Quattrochi, J., McBride, P., and Yates, A. Brainstem immaturity in Sudden Infant Death Syndrome: A quantitative rapid Golgi study of dendritic spines in 95 infants. Brain Research, 325:39-48, 1985.