Frederick Mandell

Decreased muscarinic receptor binding in the arcuate nucleus in Sudden Infant Death Syndrome

Muscarinic cholinergic activity in the human arcuate nucleus at the ventral medullary surface is postulated to be involved in cardiopulmonary control. A significant decrease in [3H]quinuclidinyl benzilate binding to muscarinic receptors in the arcuate nucleus is now shown to occur in sudden infant death syndrome (SIDS) infants, compared to infants dying acutely of known causes. In infants with chronic oxygenation abnormalities, binding is low in other nuclei, as well as in the arcuate nucleus. The binding deficit in the arcuate nucleus of SIDS infants might contribute to a failure of responses to cardiopulmonary challenges during sleep.

Delayed Central Nervous System Myelination in the Sudden Infant Death Syndrome

This study was designed to assess whether development of the central nervous system (CNS) is delayed in victims of the sudden infant death syndrome (SIDS). We selected the parameter of myelination because it is a continuously changing and readily accessible marker of CNS development in the SIDS age-range. We assessed myelination blindly in 61 SIDS and 89 autopsy controls. In 62 sites the degree of myelination was visually graded in myelin-stained histological sections on an ordinal scale of 0-4 using the inferior cerebellar peduncle as an internal standard of degree 3. Cases were stratified by postconceptional age at death and SIDS and controls were compared with respect to myelin degree at each site. Significantly delayed myelination (p < 0.05) occurred in the SIDS group in 25 of the 62 sites examined. Hypomyelination affected fiber systems in which myelination is initiated before or after birth and which myelinate with different tempos and preferentially affect pyramidal and cerebellar (somatomotor) and prefrontal-temporal-limbic (visceromotor) systems. Hypomyelination was not associated with individual clinicopathologic variables in the SIDS group. Somatic growth and brain weight were significantly greater in SIDS than controls. Therefore, we suggest that SIDS is associated with a developmental CNS disorder. Although delayed CNS myelination most likely shares a common antecedent with sudden death and is not its cause, the role of somato- and visceromotor systems in central cardiorespiratory control and arousal warrants further analysis in SIDS.

Decreased Kainate Receptor Binding in the Arcuate Nucleus of the Sudden Infant Death Syndrome

The human arcuate nucleus is postulated to be homologous to ventral medullary surface cells in animals that participate in ventilatory and blood pressure responses to hypercarbia and asphyxia. Recently, we reported a significant decrease in muscarinic cholinergic receptor binding in the arcuate nucleus in victims of the sudden infant death syndrome compared with control patients that died of acute causes. To test the specificity of the deficit to muscarinic cholinergic binding, we examined kainate binding in the arcuate nucleus in the same database. We assessed 3H-kainate binding to kainate receptors with tissue receptor autoradiography in 17 brainstem nuclei. Analysis of covariance was used to examine differences in binding by diagnosis, adjusted for postconceptional age (the covariate). Cases were classified as SIDS, 47; acute control, 15; and chronic group with oxygenation disorder, 17. (Acute controls are infants who died suddenly and unexpectedly and in whom a complete autopsy established a cause of death). The arcuate nucleus was the only region in which there was a significant difference in the age-adjusted mean kainate binding between the SIDS group (37 ± 2 fmol/mg tissue) and both the acute controls (77 ± 4 fmol/mg tissue) (p < 0.0001) and the chronic group (69 ± 4 fmol/mg tissue) (p < 0.0001). There was a positive correlation between the density of muscarinic cholinergic and kainate binding in the SIDS cases only (R = 0.460; p = 0.003). The neurotransmitter deficit in the arcuate nucleus in SIDS victims involves more than one receptor type relevant to carbon dioxide and blood pressure responses at the ventral medullary surface.

Brainstem 3H-Nicotine Receptor Binding in the Sudden Infant Death Syndrome

Maternal cigarette smoking during pregnancy has been shown to be a major risk factor for the sudden infant death syndrome (SIDS). We hypothesized that SIDS is associated with altered 3H-nicotine binding to nicotinic receptors in brainstem nuclei related to cardiorespiratory control and/or arousal. We analyzed 3H-nicotine binding in 14 regions in SIDS and control brainstems using quantitative tissue receptor autoradiography. Three groups were analyzed: SIDS (n = 42), acute controls (n = 15), and a chronic group with oxygenation disorders (n = 8). The arcuate nucleus, postulated to be important in cardiorespiratory control and abnormal in at least some SIDS victims, contained binding below the assay detection limits in all (SIDS and control) cases. We found no significant differences among the 3 groups in mean 3H-nicotine binding in the 14 brainstem sites analyzed. When a subset of the cases were stratified by the history of the presence or absence of maternal cigarette smoking during pregnancy, however, we found that there was no expected increase (upregulation) of nicotinic receptor binding in SIDS cases exposed to cigarette smoke in utero in 3 nuclei related to arousal or cardiorespiratory control. This finding raises the possibility that altered development of nicotinic receptors in brainstem cardiorespiratory and/or arousal circuits put at least some infants, i.e. those exposed to cigarette smoke in utero, at risk for SIDS, and underscores the need for further research into brainstem nicotinic receptors in SIDS in which detailed correlations with smoking history can be made.

Tritiated-naloxone binding to brainstem opioid receptors in the sudden infant death syndrome

The sudden infant death syndrome (SIDS) is defined as the sudden death of an infant under 1 year of age that remains unexplained after a thorough case investigation, including a complete autopsy. We hypothesized that SIDS is associated with altered 3H - naloxone binding to opioid receptors in brainstem nuclei related to respiratory and autonomic control. We analyzed 3H - naloxone binding in 21 regions in SIDS and control brainstems using quantitative tissue receptor autoradiography. Three groups were analyzed: SIDS (n = 45); acute controls (n = 14); and a chronic group with oxygenation disorders (n = 15). Opioid binding was heavily concentrated in the caudal nucleus of the solitary tract, nucleus parabrachialis medialis, spinal trigeminal nucleus, inferior olive, and interpeduncular nucleus in all cases analyzed (n = 74). The arcuate nucleus on the ventral medullary surface contained negligible binding in all cases (n = 74), and therefore binding was not measurable at this site. We found no significant differences among the three groups in the age-adjusted mean 3H - naloxone binding in 21 brainstem sites analyzed. The only differences we have found to date between SIDS and acute controls are decreases in 3H - quinuclidinyl benzilate binding to muscarinic cholinergic receptors and in 3H - kainate binding to kainate receptors in the arcuate nucleus in alternate sections of this same data set. The present study suggests that there is not a defect in opioid receptor binding in cardiorespiratory nuclei in SIDS brainstems.

AN HEPATIC METABOLIC PROFILE IN SUDDEN INFANT DEATH (SIDS)

Levels of 18 enzymes and metabolites were measured in liver obtained at autopsy from 41 infants, 28 of whom were found unexpectedly dead at home. Four infants had meningitis, 11 had pathologic findings not clearly sufficient to explain death (SUD), and 13 were considered totally unexplained pathologically (SIDS). The possible contributions of postmortem interval, age and diet to the results are reviewed. No characteristic metabolic profile was recognized amongst SUD and SIDS groups. It is speculated that the amount of glycogen found in liver may provide insight into premortal events and reflect the rapidity of the death mechanism. Five individuals (20%) were suspected of having major metabolic abnormality including glycogenosis (1), urea cycle defect (1), and possibly abnormal levels of carnitine palmityl transferase (3).

Pediatrics: Sudden Infant Death Syndrome: The Disease and Its Survivors

Sudden infant death syndrome (SIDS) is a peculiar entity in that the self-condemning reactions of the surviving family go far beyond the death itself. The parents should be helped to understand that SIDS is a disease, even though the mechanism of death is not known, and that it is neither preventable nor predictable. Surviving siblings should not be excluded from the mourning process and should be reassured about their good health and blamelessness in causing the death. If parents defer having another child until the grief process is complete, the psychologic environment for subsequent children will be healthier.

DERMATOGLYPHICS IN SUDDEN INFANT DEATH SYNDROME

An analysis of digital and palmar dermatoglyphic patterns was conducted in 173 victims of the sudden infant death syndrome (SIDS). The results expose four dermatoglyphic regions with pattern frequencies differing from those in a control population. These are an excess of Sydney creases, hypothenar patterns, open fields (with fewer vestiges) in interdigital region IV, and arches on all digits (females only). These findings indicate a genetic or early intrauterine environmental influence in SIDS infants. An increased incidence of dysmorphism and anomalies including recognition of specific syndromes support this contention. One could speculate that these dermatoglyphic deviations reflect specific genotypes and/or phenotypes particularly vulnerable to postnatal challenges. Differences in multiple dermatoglyphic categories support the concept of heterogeneity of the SIDS population and multicausality of SIDS.

Violence on television and imitative behavior: impact on parenting practices

In the past 30 years, four federal government commissions have reported on the relationship between television violence and aggressive behavior. The latest report concluded categorically that there is a causal relationship between television violence and aggressive behavior. Two infants were seen at an emergency room as a direct consequence of their socially isolated single mothers seeing a particular made-for-television movie. In one case, the infant died as a possible result of a parent imitating an act of child abuse; in the other case, early medical intervention precluded possible tragedy. These cases illustrate another way in which children may be victimized by violence on television; namely, by parents imitating inappropriate parental behavior. The origins of imitative behavior are discussed with specific reference to the impact on vulnerable parents. The concept of media-influenced parenting behavior is presented and implications for physicians are discussed.

CEREBROSPINAL FLUID MET-ENKEPHALIN IN SUDDEN INFANT DEATH SYNDROME

Impaired neuroregulatory responses are suspected to be crucial in Sudden Infant Death Syndrome (SIDS). It has been proposed that elevated endogenous opiates, generally respiratory depressants, might contribute to a vulnerability to SIDS.We examined met-enkephalin levels in lumbar CSF obtained at autopsy in 35 infants with SIDS and 15 age matched controls dying of other causes. Samples were frozen at -80 C and analyzed by RIA for met-enkephalin like immunoreactivity (MKI). SIDS infants had a greater mean CSF MKI (0.54 pmol/ml) than controls (0.41 pmol/ml) (p=.01). Time from death to autopsy and age, when examined as possible confounding variables, did not contribute to the MKI difference between groups. No subpopulation in the SIDS group were evident relative to MKI.The effects of death on CSF met-enkephalin levels and the relationship of CSF met-enkephalin to more central levels and effects are unknown. Nevertheless, this study has shown a small, yet statistically significant excess of CSF MKI in SIDS relative to controls. The clinical significance of this finding requires further research.