Sudden Infant Death Syndrome (SIDS) : cardiac and neuropathological involvement

The Sudden Infant Death Syndrome (SIDS) or crib death is defined as the sudden death of an infant under one year of age which remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and a review of the clinical history. SIDS is the most frequent death-causing syndrome during the first year, striking 1 baby every 700-1000. Since it is a particularly tragic event for a healthy vigorous infant to die suddenly and unexpectedly, it is not surprising that the subject is of great medical and public interest. There is an association of SIDS with sleep, combined with data indicating impaired autonomic function in infants who subsequently die of SIDS, or who suffer apparent life-threatening events (ALTE), in the basis of the central cardio-pulmonary function. The pathology of SIDS includes an extended domain of neonatal pathology, particularly if within the diagnosis of SIDS one wishes to enclose the so-called "borderline" SIDS not definitely separable from the unifying concept of syndrome. SIUD (Sudden Intrauterine Unexplained Death) is the late fetal death before the complete expulsion or retraction of the fetus from the mother. Advances in maternal and fetal care have produced a significant reduction in perinatal mortality, but have not changed the prevalence of SIUD. SIUD represents about one half of the perinatal mortality, with a prevalence of 5-12 per thousand births and its etiology is largely unexplained. The knowledge of the ante and post mortem aspects of SIDS and SIUD is of international public concern, since its prevention would save a great number of potentially productive citizens. On the anatomo-pathological plan, different findings have been reported as possible SIDS substrata: brainstem abnormalities, cardiac conduction system developmental defects, immaturity of the paraganglia, hyper - or hypoplasia of the carotid bodies. Overall, the abnormalities of the autonomous nervous and cardiac conduction systems do represent a plausible substrate for a reflexogenic SIDS of vagal inhibitory nature (dive, feigned death, cardio-auditory reflexes, Ondine syndrome). Vagal cardiorespiratory reflexes, if pathological, could lead to SIDS. From 1987 to 2003, at the Institute of Pathology, University of Milan, many cases of sudden infant and fetal death have been analyzed, since the Institute is the Reference Center for the Lombardy Region for SIDS and late unexplained fetal death (DGR n° 11693 of 20/6/2002). The bill n. 396 "Autopsy regulation on SIDS and unexpected fetal death victims", proposed to the Italian Parliament and recently approved by the Senate of the Italian Republic, designs the Institute of Pathology of the University of Milan as the national reference center "being a recognized institution competent in this issue". Among an even larger amount of cases, a total of 120 SIDS victims, 37 infant controls and 60 late fetal stillborn, after the exclusion of violent causes, were selected for this work. For each analyzed case, the cardiac conduction system was removed in two blocks for paraffin embedding: block 1 (the Sino-atrial node -SAN) and the block 2 (the atrio-ventricular -AV system). The brainstem was divided into three blocks, according to the simplified procedure for the simplified brainstem examination, requiring a much lower number of sections and less work for the histotechnicians. For each brainstem nucleus (in particular, arcuate nucleus and parabrachial/Kölliker-Fuse complex), using serial sections stained with Klüver-Barrera: the neuronal cell body areas, neuronal density, transverse section areas and volume were evaluated. The statistical significance of direct comparison of the means between the two fetus groups (SIUD and stillbirth controls) and two infant groups (SIDS and infant controls) was determined by one-way analysis of variance. The carotid bifurcations, cardiac plexus ganglia and paraganglia were embedded separately and serially cut. In selected cases, immunohistochemistry studies were performed on sections of cardiac conduction system, brainstem, and coronary arteries. The SIDS cases did not show any abnormality of the ordinary myocardium, while the core of the heart, where cardiac rhythm arises and spreads, shows some abnormalities. More than one cardiac conduction change were present in the same infant, but no peculiar cardiac combined anomaly was observed. Areas of resorptive degeneration were detected in 97% of SIDS cases and in 75% of controls. Macrophages were sometimes present adjacent to the small foci of degeneration, acting eventually as scavenger cells. The developmental abnormalities of SIDS include long dendritic spines, marker of neuronal immaturity and hypoplasia of the brainstem nuclei. In SIDS the mono- or bilateral hypoplasia or even agenesis of the arcuate nucleus is particularly frequent. It has been observed and morphometrically studied in 57% of our cases - bilateral in 29/66 cases (44%) and monolateral - always the right side - in 8/66 (12%). We further considered the shape of the cell body, nucleus and nucleolus. Comparative analysis of the serial histological sections obtained from the pons and mesencephalon of SIUD and SIDS cases with those of the two control groups, made it possible to define the morphologic features of the three principal nuclei of the human PB/KF complex: Lateral parabrachial nucleus (lPB), Medial parabrachial nucleus (mPB) and Kölliker-Fuse nucleus (KF). A combined morphologic post mortem study of the cardiac conduction system and brainstem was performed in 42 cases of SIDS and in 12 controls. The Mahaim fibers were observed in 16% of control and in 17% of SIDS cases with arcuate nucleus (ARCn) histologically well developed, and from 50% (severe bilateral hypoplasia) to 71% (monolateral hypoplasia) in SIDS cases with ARCn hypoplasia. The Mahaim fibers were statistically more frequent in SIDS with ARCn hypoplasia than in the cases with well developed ARCn (control and other SIDS cases) (p<0.005). Hyperplasia of the aorticopulmonary paraganglia (APP) was detected in 25% of SIDS cases. The cell clusters and cell diameters were not significantly different from age-matched controls. Two SIDS cases showed intracapsular glomus in the left stellate ganglion and 5 cases presented inflammatory foci in the right stellate ganglion. The observation of frequent anomalies, mostly congenital, of the autonomic nervous system structures, both in SIDS and in SIUD indicates a continuity between these two pathologies. Our research upheld a new approach to SIDS by analogical link with SIUD. Indeed, early SIDS may well depend upon postnatal block of respiratory reflexes for fetus survival, warranted by Kölliker-Fuse nucleus, or upon impaired development of central circuitry for respiratory reflexogenesis. The acronym SIUD-SIDS underlines a possible common morphological substrate. The search shall be continued for a better definition of what is normal or abnormal in the infant and fetal cardiac conduction and autonomic nervous systems.