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Brainstem Abnormalities in SIDS Cases: An Even More Complicated Picture Than Once Thought

Shaw, Gina

doi: 10.1097/01.NT.0000441304.75038.11
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Investigators report significant abnormalities in the brainstem medullary serotonin network of babies whose deaths were attributed to sudden infant death syndrome compared with the normal controls.

Infants who die suddenly and unexpectedly from unexplained causes — whether or not environmental risk factors for sudden infant death syndrome (SIDS), such as bed-sharing or sleeping face-down, were involved — have abnormalities in the brainstem's serotonergic network when compared with babies who died from identifiable causes, according to research published in Nov. 11 online edition of Pediatrics.

Harvard neuropathologist Hannah Kinney, MD, a leading SIDS researcher, and colleagues reviewed data from infants autopsied at the San Diego County Medical Examiner's office from 1997 to 2008 who had brainstem samples available for analysis. They identified 15 infants who died of SIDS in “safe” sleep circumstances that were unlikely to precipitate asphyxia (Group A) and 35 SIDS infants whose deaths could have been asphyxia-related (Group B), and compared those cases with nine control infants who clearly died from other identified causes.

In both the A and B groups, the investigators found significant abnormalities in the brainstem medullary serotonin network compared with the normal controls. “These abnormalities affect multiple nuclei ... involved in protective respiratory and autonomic responses,” they wrote.

“Even the infants dying in unsafe sleep environments had an underlying brainstem abnormality that likely made them vulnerable to sudden death if there was any degree of asphyxia,” Dr. Kinney said in a news release accompanying the study's publication. “The abnormality prevents the brainstem from responding to the asphyxial challenge and waking.”

But the findings challenged previous thinking about how such abnormalities might be involved in unexplained infant deaths. “We did not find that the mean values of the neurochemical parameters in the putatively asphyxia-challenged infants (Group B) as a group are intermediate between those of infants dying suddenly and without obvious asphyxial challenges (Group A) and those of infants dying of known causes (Group F),” the authors wrote. “Thus, this study does not support the idea that the challenged infants (Group B) have borderline values that require an asphyxial trigger to precipitate death, whereas unchallenged infants (Group A) have values that are at a lethal threshold that does not require such a trigger.”

In other words, for a “serotonin hypothesis” to hold true, it would have been expected that the babies who died of truly unexplained SIDS would have the most abnormal serotonergic neurochemistry, and the babies who died of SIDS with some possible environmental trigger would have abnormal serotonergic neurochemistry somewhere between the Group A levels and the control group, who all died of explained causes and would not be expected to have these abnormalities.

Instead, both groups of SIDS deaths had similarly abnormal neurochemistry in this pathway.

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That's contrary to what many in the field expected that the investigators would find. “The feeling was that babies who are apparently healthy, but suddenly succumb to SIDS with no asphyxial component, would have more severe abnormalities of the brainstem serotonergic network than those with clear environmental component involving asphyxia, such as choking on a plastic bag,” said Suresh Kotagal, MD, a pediatric neurologist and sleep disorders specialist at the Mayo Clinic in Rochester, MN. “The serotonergic network is to some extent part of the answer, but this important paper tells us that there are likely other factors, perhaps genetic abnormalities that may render some babies vulnerable to SIDS.”

To some extent, Dr. Kotagal noted, the findings do point to some level of a protective effect against SIDS from the serotonergic network. “The more intact that network was, the greater was the number of extrinsic risk factors necessary for SIDS,” he said.

But one of Dr. Kinney's co-authors on the Pediatrics paper, pathologist David S. Paterson, PhD, argued in a July 2013 analysis in Respiratory Physiology & Neurobiology that the brainstem serotonin network is not likely to be a primary factor in SIDS risk. “Overall, it appears unlikely that any of the 5-HT pathway gene polymorphisms studied to date impart any significant SIDS risk,” he wrote. “Furthermore, any role that they do play in the pathogenesis of SIDS is likely to be part of a complicated interaction of multiple other factors (physiological, environmental and genetic) that is currently unclear...Ultimately, it seems likely that the genetic component to SIDS will include both rare causative mutations as well as a ‘catalogue’ of susceptibility variants that predispose an infant to increased SIDS risk.”

The findings do not shake the conviction of Debra Weese-Mayer, MD, that there is a genetic component to SIDS. “There are so many families who do everything right in terms of what we know to be modifiable risk factors: breastfeeding, no smoking involved, back to sleep, firm bedding, cribs that are so clear of blankets and other things that you'd hardly know a child lived there,” said Dr. Weese-Mayer, professor of pediatrics at Northwestern University Feinberg School of Medicine and chief of the first Center for Autonomic Medicine in Pediatrics at Ann & Robert H. Lurie Children's Hospital. “And yet they still lose a child to SIDS. There may be genes we haven't considered or analyses we haven't done.”

She agrees with Dr. Paterson that the genetic underpinnings of SIDS may be more like a Chinese menu than a straightforward set of risk factors. “If you think of different neurochemical networks in Column A, Column B, and Column C, you may end up with the same tragic outcome if you have one abnormality from the serotonin network, another characteristic from the GABA network, and maybe yet another characteristic from another network that we haven't even looked at yet.”

That's an argument that Dr. Kinney and her colleagues made in their paper as well, pointing to the dominance of prematurity in the Group A category as compared with Group B (40 percent vs. 17 percent) in support of that conclusion.

The same may be true of environmental and other risk factors, Dr. Weese-Mayer suggested. “There may be other modifiable behaviors that interact with genetic risk, and we just don't have our arms around those yet. Just because we don't have gene variants that tie into known risk factors doesn't necessarily dispute the hypothesis that some variants and risk factors alone or in combination heighten vulnerability; it just means that the gene variants described in this publication aren't related to currently identified modifiable risk factors for SIDS and relative asphyxial risk.”

The authors also noted that there are many potential limitations to the study, starting with the small size of the control group (only nine infants), and missing data from some scene reports that may have compromised the ability to accurately count and assess environmental risk factors. “We cannot rule out the possibility that differences exist between infants challenged or not challenged by asphyxia at the time of death; because there is no objective means to quantitate asphyxia in forensic scene investigations, its role in the death is probably not fully appreciated and may be underestimated by subjective observations,” they wrote.

Dr. Weese-Mayer acknowledged that she and her research team are disappointed with the study's findings, but said that this is far from the end the story. “Even negative results can inspire us to search harder, whether it's for environmental factors, compliance, or genetic variants.”

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•. Randall BB, Paterson DS, Kinney HC, et al. Potential asphyxia and brainstem abnormalities in sudden and unexpected death in infants. Pediatrics 2013; E-pub 2013 Nov. 11.
    •. Paterson DS. Serotonin gene variants are unlikely to play a significant role in the pathogenesis of the sudden infant death syndrome. Respir Physiol Neurobiol 2013; 189 (2);301–314.
      •. Neurology Today archive on SIDS:
        © 2013 American Academy of Neurology