SIDS, or crib death, is defined as the sudden death of an infant under 1 year of age which remains unexplained after a thorough investigation of the case, including the 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 occurring during the first year of life, striking one baby in every 700–1,000. Since it is a par- ticularly 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 between SIDS and sleep, and this is combined with data indicating impaired autonomic function in infants who subsequently die of SIDS or suffer apparent life-threatening events (ALTE). The pathology of SIDS is included in the extended domain of neonatal pathology, particularly if within the diagnosis of SIDS one wishes to include so-called “borderline” SIDS not definitely separable from the unifying concept of the syndrome.
SIUD (sudden intrauterine unexplained death) is late fetal death before the complete expulsion or removal of the fetus from the mother. Advances in mater- nal 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 perinatal mortalities, with a prevalence of 5–12 per 1,000 births, and its etiology is largely unexplained.
Knowledge of the ante- and post-mortem aspects of SIDS and SIUD is of interna- tional public concern, since its prevention would save a great number of potentially productive citizens.
In the anatomic/pathological concept, different findings have been reported as possible SIDS substrates: brainstem abnormalities, cardiac conduction system de- velopmental defects, immaturity of the paraganglia, and hyper- or hypoplasia of the carotid bodies. Overall, the abnormalities of the autonomic nervous and cardiac conduction systems do represent a plausible basis for SIDS being reflexogenic in nature (dive, feigned death, cardio-auditory reflexes, Ondine syndrome). Vagal car- diorespiratory 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 re- ferral center for SIDS and late unexplained fetal death for the Lombardy Region (DGR no. 11693 of 20/6/2002). Italian Law no. 31 of 2 February 2006 “Regulations for Diagnostic Post Mortem Investigation in Victims of Sudden Infant Death Syn- drome (SIDS) and unexpected fetal death” designates the Institute of Pathology of the University of Milan as the national referral center being a recognized institution
Summary VI
VI Summary 124
competent in this issue. From an even larger number of cases, a total of 120 SIDS victims, 37 infant controls and 60 late fetal stillbirths, 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 sinoatrial node, SAN) and block 2 (the atrio- ventricular, AV, system). The brainstem was divided into three blocks according to a simplified procedure for brainstem examination, requiring a much lower number of sections and less work for the histotechnicians. For each brainstem nucleus (in particular, the arcuate nucleus (ARCn) and parabrachial/Kölliker-Fuse complex), using serial sections stained with Klüver-Barrera stain, the neuronal cell body areas, neuronal density, transverse section areas and volume were evaluated. The statistical significance of the differences between the means of 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 sectioned. In selected cases, im- munohistochemistry studies were performed on sections of the cardiac conduction system, brainstem, and coronary arteries.
The SIDS victims did not show any abnormality of the ordinary myocardium, while the core of the heart, where cardiac rhythm arises and spreads, showed some abnormalities. More than one cardiac conduction change was present in the same infant, but no peculiar cardiac combined anomaly was observed. Areas of resorptive degeneration were detected in 97% of SIDS infants and in 75% of controls. Macro- phages were sometimes present adjacent to the small foci of degeneration, acting eventually as scavenger cells.
The developmental abnormalities in SIDS include long dendritic spines, markers of neuronal immaturity, and hypoplasia of the brainstem nuclei. In SIDS mono- or bilateral hypoplasia or even agenesis of the ARCn is particularly frequent. It was observed and morphometrically studied in 56.06% of our SIDS infants, and was found to be bilateral in 17.9% and monolateral (always the right side) in 12.16%. We further considered the shape of the cell body, nucleus and nucleolus.
Comparative analysis of serial histological sections obtained from the pons and mesencephalon of SIUD and SIDS victims and those of the two control groups made it possible to define the morphological features of the three principal nuclei of the human PB/KF complex: the lateral parabrachial (lPB) nucleus, the medial parabra- chial (mPB) nucleus, and the Kölliker-Fuse (KF) nucleus.
A combined morphological post-mortem study of the cardiac conduction system and brainstem was performed in 42 SIDS infants and in 12 controls. Mahaim fibers were observed in 16% of control and in 17% of SIDS infants with the ARCn histo- logically well developed, and in 50% (severe bilateral hypoplasia) to 71% (mono- lateral hypoplasia) of SIDS infants with ARCn hypoplasia. The Mahaim fibers were significantly more frequent in SIDS infants with ARCn hypoplasia than in those with a well-developed ARCn (control and other SIDS infants; p<0.005).
Hyperplasia of the aorticopulmonary paraganglia was detected in 25% of SIDS victims. The cell clusters and cell diameters were not significantly different from those of age-matched controls. Two SIDS infants showed intracapsular glomus in
125
the left stellate ganglion and five SIDS infants showed inflammatory foci in the right stellate ganglion.
The observation of frequent anomalies, mostly congenital, of the autonomic ner- vous system structures, both in SIDS and in SIUD indicates a continuity between these two pathologies. Our research supports a new approach to SIDS which in- volves the recognition of its analogical link with SIUD. Indeed, early SIDS may well depend upon postnatal block of respiratory reflexes for fetal survival, involving the KF nucleus, or upon impaired development of central circuitry for respiratory re- flexogenesis. The acronym SIUD-SIDS underlines possible common morphological substrata.
The search will be continued for a better understanding of what is normal and what is abnormal in the infant and fetal cardiac conduction and nervous systems and the herein presented histopathological findings seems to usefully contribute literature information for crib death as well as for unexplained perinatal death.
