Neuropathology provides new insight in the pathogenesis of the sudden infant death syndrome.

The sudden infant death syndrome (SIDS) is deWned as the sudden, sleep-related death of an infant less than 12 months of age that remains unexplained after a complete autopsy, death scene investigation, and review of the clinical history [35]. Typically, a seemingly healthy infant is unexpectedly found dead after a sleep period. Despite a dramatic reduction in the overall rate with national campaigns advocating the supine (back) sleep position [43], SIDS remains the leading cause of postneonatal infant mortality and the third leading cause of infant mortality in general in the United States today [43]. The brain has long been thought to play a critical role in the cause and pathogenesis of SIDS. The recent publication of three excellent articles on brain pathology in SIDS in Acta Neuropathologica indicates that brain research into this major pediatric disorder continues to be important in guiding all SIDS research. Basically, brain research in SIDS follows three directions: (1) analysis to determine a primary (neural) cause of death, (2) analysis to uncover secondary changes that points to the primary cause, either within the brain or in other organ systems, and (3) analysis to determine the age of onset of the chain of events—prenatally and/or postnatally—that results in sudden death in the vulnerable postnatal period. The search for a primary cause is driven by the hypothesis that SIDS is due to intrinsic abnormalities in brain regions critical for the control of arousal and/ or state-dependent respiratory and/or autonomic function that lead to sleep-related death which is precipitated by a homeostatic stressor within a susceptible age-range. Secondary changes in the brain are postulated to result mainly from hypoxia–ischemia complicating repetitive apnea and/or bradycardia prior to the lethal cardiorespiratory event, as well as during the lethal event itself. Finally, the brain disorder is postulated to be developmental in origin due to the parallel onset and occurrence of SIDS with the major critical period in human brain development, i.e., gestation through the Wrst year of life. Yet, despite the compelling rationale for a key role of the brain in SIDS, the brain looks normal under the light microscope, or at the very most, demonstrates seemingly trivial or nonspeciWc changes. Thus, the challenge for us as neuropathologists in the analysis of SIDS brains—as in the analysis of autistic and schizophrenic brains—is to uncover neurochemical, cellular, and/or molecular abnormalities with the right quantitative tools. The three recent SIDS studies in Acta Neuropathologica cover the spectrum of neuropathological directions in SIDS research with quantitative methodologies: (1) the search for the primary abnormality in the brainstem with the application of an antibody to the serotonin 1A (5-HT1A) receptor by Machaalani et al. [37], (2) the determination of secondary hypoxic–ischemic changes in the cerebral cortex and hippocampus with MAP2 immunostaining by Oehmichen et al. [49], and (3) the report of critical evidence for a developmental origin of brain pathology, i.e., increased leptomeningeal neurons in the brainstem by Rickert et al. [62]. In the following commentary, I highlight the new insights that these studies bring to our understanding of the brain’s role in SIDS in the context of previous neuropathologic and other SIDS studies. H. C. Kinney (&) Department of Pathology, Enders Building 1112, Children’s Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA e-mail: Hannah.kinney@childrens.harvard.edu