SIDS Traced to Aberrant Brain Chemistry

February 1, 2007
Charles J. Ippolito, MD

Sudden infant death syndrome (SIDS) is the leading cause of postneonatal death in the United States.1 This unfortunate disorder is characterized by the sudden, unexpected death of an of infant between ages 1 and 12 months whose cause of death remains a mystery in the aftermath of a thorough postmortem examination that includes an autopsy, an investigation of the death scene, and a careful review of the infant's medical history. New research, published in the November 2006 issue of The Journal of the American Medical Association,2 that made recent headlines confirmed earlier research by the same investigative team3,4 showing that serotonergic brain stem abnormalities may be the at the root of SIDS.

Sudden infant death syndrome (SIDS) is the leading cause of postneonatal death in the United States.1 This unfortunate disorder is characterized by the sudden, unexpected death of an of infant between ages 1 and 12 months whose cause of death remains a mystery in the aftermath of a thorough postmortem examination that includes an autopsy, an investigation of the death scene, and a careful review of the infant's medical history. New research, published in the November 2006 issue of The Journal of the American Medical Association,2 that made recent headlines confirmed earlier research by the same investigative team3,4 showing that serotonergic brain stem abnormalities may be the at the root of SIDS.

The multicenter research team, led in this most recent study by David S. Paterson, PhD, a neuroscientist at Children's Hospital Boston and Harvard University, studied frozen sections of the medullae of 31 infants who died of SIDS. The specimens were obtained from the San Diego Medical Examiner's office between 1997 and 2005. Ten frozen sections of medullary tissue from infants who died of other causes were used as controls. The investigators concluded that the pathology of the medullary 5-hydroxytryptamine (5-HT) system in SIDS was more extensive than they had previously thought. Included were an abnormally high 5-HT neuron count and abnormalities in 5-HT1A receptor expression and 5-HT transmitter binding. The research team also noted that the abnormalities were indicative of an underlying developmental disorder.

The age of the infants representing the SIDS cases was between 1 and 3 months. The cohort represented a variety of races and ethnicities, and 16 infants were female-although in the general population, SIDS is more common among male infants, with a ratio of 2:1.5 Among other stressors, for example, bed sharing, and risk factors, such as male sex, 15 (48%) of the infants were found in a prone position, 13 (42%) had a history of illness in the week preceding death, and 11 (35%) were born prematurely. In fact, the large majority (87%) of affected infants had at least 1 stressor or risk factor in addition to serotonergic abnormalities. The investigators also found that 5-HT binding density was significantly lower in male infants than in female infants (P = .04), adding to the evidence that infant boys are at greater risk than are infant girls.

Paterson and his team contend that the link between prone sleep positioning in particular, as well as other exogenous risk factors for SIDS, is related to dysregulation of serotonergic-mediated responses to respiratory difficulties and other challenges to homeostatic functions during sleep. Asphyxiation is the trag- ic result.

"This is a very complex area of study and a very important one too," commented Karen M. Weidenheim, MD, professor of pathology, clinical neurology, and clinical neurosurgery, and chief of the division of neuropathology at Albert Einstein College of Medicine in New York. The findings suggest that the brain is trying to compensate for the lack of 5-HT1A receptors by increasing neuron density, she told Applied Neurology.

PATHOLOGY
Most of the infants who die of SIDS are full-term and appear to be well nourished, well developed, and in good health immediately before death. Some investigators, including Paterson and colleagues, have postulated that affected infants have a preexisting pathology that when combined with other factors, place them at risk for SIDS. Gliosis is a common postmortem finding in a large subset of SIDS cases, and this may indicate a brain stem insult associated with chronic hypoxia and recurrent apnea.1 Tissue markers for chronic asphyxia have been recorded in 66% of all SIDS cases.6

Microscopic studies of brain stem abnormalities in infants who have died of SIDS demonstrate hypomyelination, persistent dendritic spines, and focal astrogliosis. Further microscopic examination of the neuropil has revealed brain stem dendritic spines in the magnocellular nucleus of the reticular formation and in the dorsal and solitary nuclei of the vagus nerve.

The number of reactive astrocytes in the medulla oblongata also are significantly increased in SIDS infants compared with normal infants. However, the increase in the number of these astrocytes is not strictly confined to areas responsible for neuroregulatory mechanisms of respiration.

A subset of SIDS infants have hypoplasia of the arcuate nucleus, the area of respiratory control in the ventral medulla, which is integrated with other brain stem sections responsible for autonomic chemosensory and arousal functions. Biochemically, large amounts of substance P, an important neurotransmitter found in many primary neurons of the CNS, has been found in the pontes of SIDS infants.6

These multifactorial neurologic and neurochemical abnormalities point to a delayed neuronal maturation of medullary catecholaminergic neurons in addition to augmented activity in afferent neurons. As noted by Paterson and colleagues and others, a pathophysiology appears to exist in the neural and cardiorespiratory control of the wake-sleep mechanisms in SIDS infants.

Paterson and his colleagues postulated that the decrease in the density of 5-HT1A receptors might be developmental. This begs a clinical question: If there were a way to increase the number of these receptors or supply exogenous 5-HT to infants at risk for SIDS, would the intervention take place in utero or shortly after the birth of the infant?

"Much more work needs to be done in this area before any clinical interventions can be postulated," Weidenheim commented. "Any attempts to give infants exogenous 5-HT would be ill-advised. When you think about altering the neurotransmitter levels in an infant with a developing brain, you have to be extremely circumspect. Not enough is known about the neuroscience involved to make any kind of preventive or treatment recommendations. Until we have a good handle on what's going on in the higher structures of the brain, we would not want to add an exogenous neurotransmitter to the developing brain of an infant, where it might have adverse effects. But down the road, prevention and treatment of SIDS may be possible."

SIDS BIOMARKER?
The study findings suggest that circulating 5-HT levels might be a potential biomarker for SIDS risk. "Testing for the 5-HT molecule, a serotonin transporter, or a test for the density of the medullary 5-HT1A receptors might help uncover those infants at risk for SIDS," said Weidenheim. "Many of these tests already exist but remain in the realm of complex research protocols. In addition, you need a certain amount of infant blood beyond the regular heel stick to perform these tests. Furthermore, the tests are not routine; they require expensive equipment and expert technical assistance is essential."

Weidenheim noted that an investigation using a very large study cohort would be needed to determine whether it was possible to detect changes in 5-HT molecules in the peripheral blood of infants at risk for SIDS. "An easy test or some subtle neurologic maneuver, provocative quirk of infant behavior, distinctive breathing pattern, or other easily applied intervention or detected physical abnormality just does not exist at this time. Much more work needs to be done in this area before the practicing neurologist might get involved," she said.

"The definitive diagnosis of SIDS is basically a postmortem process. In practical terms, putting your finger on the cause of SIDS is really a process of elimination," Weidenheim continued. "At autopsy, you must show that other processes, such as undiagnosed tumors, undiagnosed metabolic diseases, trauma, and child abuse, were not already present at the time of death. Autopsy complicates the study of SIDS even further because it is the only way to confirm this cause of death."

Many parents are reluctant to consent to an autopsy because prolonging postmortem technicalities exacerbates the trauma of losing the infant. However, research cannot go forward without studying the brains of SIDS infants, Weidenheim stressed. "It is critically important that when a family suffers the terrible tragedy of SIDS, that all attempts be made to get autopsy permissions. Each brain examination is another step closer to the prevention of another SIDS catastrophe and to a potential treatment for another infant," she said.

In discussing the parameters of the Paterson study further, Weidenheim remarked that "this area of research will eventually include a much more intensive dissection of the medullary serotonergic pathways. An obvious extension of related work might investigate the serotonergic pathways beyond the brain stem into the remainder of the brain, including the cerebrum and the neocortex."

PREVENTION TACTICS
"There is a logical explanation for SIDS," remarked Weidenheim. "The Paterson study has emphasized the aberrant brain chemistry. Right now, the best preventive measure we have is to encourage parents to have their infants sleep on their backs." Indeed, in 1992, the American Academy of Pediatrics Task Force on Infant Positioning recommended that infants be placed in the supine position during sleep to prevent SIDS.7 As a result, deaths classified as SIDS decreased by more than 50% between 1992 and 2001.8

"The Paterson study confirmed that if infants slept on their sides or in the prone position, they were at higher risk of succumbing to SIDS. Babies sleeping on their bellies often cover their mouths inadvertently and obstruct their airways. With their faces pointing downwards, these infants may respond adequately to increases in circulating CO2 and go into hypercapnia. In infants predisposed to SIDS, the serotonergic system in the brain stem does not respond adequately to the elevation in the levels of circulating CO2, and the respiratory and arousal reflexes are more likely to malfunction when the infant is in the prone position.

"The Paterson study has vast implications for the future of SIDS, but not anything immediate. It demonstrates the importance of basic neuroscience," concluded Weidenheim. "The study also shows that no one is at fault when a baby dies of SIDS. Further research into pathophysiology will eventually bring prevention and cure."

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