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SIDS: It’s not the parents’ fault
Sudden Infant Death Syndrome (SIDS)
Sunday, March 28, 2010

••• The dusky hours before dawn may appear to be the most serene of times. For infants, whose arousal mechanisms and reflexes are not yet fully mature, they can be a time of peril. Sudden infant death syndrome (SIDS) strikes more babies in the early morning than at any other time.

One explanation for these mysterious and tragic deaths is that they are caused by a defect in the brain that renders the baby incapable of responding appropriately to the rising levels of carbon dioxide that result when babies breathe stale air trapped under blankets. And yet this hunch has been difficult to prove.

“By conventional histology, the brains of SIDS victims look normal,” says Hannah Kinney, Harvard Medical School associate professor of neuropathology at Children’s Hospital.

Sounding the Alarm
Kinney and her colleagues have recently uncovered a subtle but potentially fatal flaw in the brains of some SIDS babies. The defect lies in a scatter of neurons, known as the arcuate nucleus, located on the underbelly of the brain stem.

Normally, cells in the arcuate nucleus are studded with receptors for a neurotransmitter that responds to carbon dioxide in the blood. When levels of carbon dioxide rise, the receptors signal the respiratory system to increase the rate of breathing. They may also be part of a delicate alarm system in the brain that is designed to wake the sleeping baby.

It appears that the arcuate nucleus of some SIDS babies is deficient in its binding of the neurotransmitter. As a result, the carbon-dioxide warning system of SIDS babies is less sensitive to rising levels of carbon dioxide in the blood and does not sound the alarm to other systems in the body.
The arcuate nucleus, normally located on the underside of the brain stem (dark splotches in L and center images), is absent in the brains of some SIDS babies (R image).

Not all SIDS babies have this defect, Kinney says. In fact, the decreased carbon-dioxide sensitivity is probably one of several causes of SIDS. However, the discovery does help to dispel some of the apparent capriciousness surrounding SIDS. “It is not a normal baby that dies of SIDS,” Kinney says.

Knowledge of SIDS was in its infancy when Kinney first began her research. Despite an ancient and grim history-occurrences of “crib death” are well-documented throughout history and even in the Bible-it was only in 1969 that SIDS was identified as a syndrome.

When Kinney began a residency in pediatrics at Children’s Hospital in the mid-1970s, SIDS was still an ill- defined syndrome, with no discernible cause. Although some parents reported that their babies had some symptoms-such as coughs, gastrointestinal trouble and listlessness-in the 48 hours before death, most said their babies had been completely well. Some babies were found face down in their blankets, suggesting asphyxiation, and yet others were found on their backs.

“What I remember most about that is the tremendous sadness and suddenness of the death and the tremendous despair that the parents had,” says Kinney.

Nor did autopsies help alleviate the parents’ confusion. Typically, there were no signs of disease-pneumonia, meningitis or hemorrhages-in the brains or bodies of the babies.

The first clue to a possible brain defect came in 1977 when a pediatric pathologist reported subtle gliosis-or scarring-in the brain stems of SIDS patients. Gliosis, which is an overgrowth of glial cells, occurs when neurons die, leaving room for new growth. Yet it was not clear from the study what was causing the neurons to die in the first place. “It just told us something had gone on in these brains,” says Kinney.

Locating the Flaw
Suspecting an “invisible” flaw in the brains of SIDS patients, Kinney spent the next few years learning new high- tech methods for studying the chemistry of the brain at HMS. Richard Sidman, Bullard professor of neuropathology, had developed computer-based methods for imaging the brain in three dimensions that allowed subtle quantitative differences in the brain to be assessed. Frost White, who was also in the HMS neuropathology department at the time, had developed methods for labeling chemical receptors in three dimensions. Kinney spent time working in both men’s labs.

It was old-fashioned brainstorming with Jim Filiano, a postdoc in her lab, that led to the site of the hidden brain flaw. “Jim and I used to have long conversations about this. Where can the defect in SIDS be? What respiratory controlling mechanism could it be?” says Kinney.

By 1987, the arcuate nucleus had been identified, but its function was unknown. It was Filiano who first demonstrated that the arcuate nucleus in humans might be involved in the control of breathing.

Still, it was not clear what role the arcuate nucleus might play in SIDS. To find out, Kinney and her collaborators began analyzing a database of serially sectioned brain stems collected from autopsies of 41 SIDS babies and 27 controls. “We looked through it blinded, without knowledge of who the SIDS babies were,” Kinney says. They found two cases where the arcuate nucleus was absent. When they decoded the cases, they found that both had died of SIDS.

Yet other babies in the sample had died of SIDS, and they appeared to have an arcuate nucleus. Suspecting that the two cases might be the most severe from an anatomical point of view, and that the other babies might have had more subtle biochemical defects in this region of their brains, the researchers began investigating the neurochemical structure of the arcuate nucleus of SIDS babies.

They found that cells in the arcuate nucleus of some SIDS babies, though not all, were less able to bind acetylcholine than babies suffering from other acute diseases. Acetylcholine normally attaches to a particular receptor on the arcuate cells known as the muscarinic receptor.
A Lack of Receptivity
This finding suggests that the culprit, in at least some SIDS cases, is the muscarinic receptor. Babies with a full complement of muscarinic receptors are able to respond to distress signals.

“A normal infant meets a challenge during the night like hypercardia-increased carbon dioxide-or low oxygen-asphyxiation,” Kinney says. “This could happen from upper airway occlusion or from the face being down in the bedding.” Once stimulated, the muscarinic receptors, which are part of a more complex relay system, signal the respiratory system to increase the rate of breath. “The infant would turn its head to take in more air and presumably wake up.”

However, babies with fewer-or defective-muscarinic receptors would not respond to rising carbon dioxide levels in the blood and would fail to arouse.

Why there should be a scarcity of muscarinic receptors is not clear. Kinney speculates that the defect may lie in the failure of the nucleus to develop normally. “This is basically a clue. It doesn’t tell us why SIDS occurs,” she says.

Even normal infants do not respond to arousal signals very well in the early morning. This is especially true during the first six months of life when the baby is still making the transition from being a fetus. “There are many changes going on in the respiratory, autonomic and sleep- wake systems,” Kinney says. In fact, 90 percent of SIDS cases occur during the first six months of life; 75 percent occur between two and four months.

In addition to this critical developmental danger zone, there are two other factors contributing to SIDS, Kinney believes. One is that the baby has an underlying vulnerability, such as a defective arcuate nucleus. Second, there must be a stressor. Such stressors might include the prone sleeping position, infection, swaddling and fever, all of which can contribute to an overabundance of carbon dioxide in the blood.

An obvious way to reduce the number of SIDS deaths would be to eliminate the stressors. Campaigns to encourage parents to put babies to sleep on their backs have worked in countries like New Zealand, England and Australia. Such campaigns have decreased the incidence of SIDS by 50 percent. China, where babies have always been trained to sleep on their backs, has one of the lowest rates of SIDS in the world.

Women who safeguard their health while pregnant may also be protecting their babies from SIDS. Kinney believes that the defects in the brain that make a baby more vulnerable to SIDS could develop as a result of suboptimal intrauterine environments. “This may be due to smoking, drugs-such as cocaine-and also to lack of access to medical care and good nutrition,” Kinney says, adding that “these are things that come along with poverty.”

The United States, where access to cigarettes and drugs is relatively easy, has one of the highest rates of SIDS in the world. SIDS is currently the leading cause of death among American infants, killing 6,000 babies each year. The rate is especially high among the poor. The rate of SIDS among Native Americans is six times the national average.

Ultimately, there may be a way to predict clinically who is at risk for SIDS, although Kinney thinks that such tests will be a long time in coming. Developing a clinical test for a receptor system in the arcuate nucleus “would be extremely difficult,” she says. An alternative approach would be to look for some other factor that correlates with decreased binding to the muscarinic receptors in the arcuate nucleus.

Kinney and her colleagues are currently investigating whether the muscarinic defect is part of a more general neuronal defect. “The more we know about the causes of SIDS, the more ideas of how to test for it and prevent it may come to us.”
• Source(s): Harvard Medical School
• Sudden Infant Death Syndrome – Also called: Crib death, SIDS
• American Sudden Infant Death Syndrome Institute
Related: SIDS Research Breakthrough