title: Neuronal cell death in the arcuate nucleus of the medulla oblongata in stillbirth.
abstract: The hypothesis that unexplained stillbirth arises in a similar manner as the sudden infant death syndrome (SIDS) is based in part on shared neuropathologic features between the two entities, including hypoxic-ischemic lesions such as white matter and brainstem gliosis, as well as aplasia or hypoplasia of the arcuate nucleus on the ventral surface of the medulla. The arcuate nucleus is the putative homologue of the respiratory chemosensory region at the ventral medullary surface in animals that is involved in central chemosensitivity. To determine arcuate nucleus pathology in stillbirth, and its co-occurrence with evidence of hypoxia-ischemia, we reviewed brain specimens from the archives of our hospitals from 22 consecutive stillbirths from 22 to 41 gestational weeks. Explained causes of death (n=17) included nuchal cord, acute chorioamnionitis, placental abruption, and fetal glomerulosclerosis; 5 cases were unexplained. In 12 brains, we observed nuclear karyorrhexis and/or pyknosis with cytoplasmic hypereosinophilia in neurons in the arcuate nucleus in both explained (n=8) and unexplained (n=4) cases (54.5% of total cases). Three additional cases had arcuate aplasia (n=1) or hypoplasia (n=2) (13.6% of total cases); one of the latter cases also had neuronal necrosis in the hypoplastic arcuate. The degree of gliosis in the region of the arcuate nucleus was variable across all cases, without statistically significant differences between groups with and without arcuate nucleus necrosis. Other lesions in association with (n=14) and without (n=8) arcuate nucleus abnormalities were diffuse cerebral white matter gliosis, periventricular leukomalacia (PVL), and neuronal necrosis in the hippocampus, basal ganglia, thalamus, basis pontis, and brainstem tegmentum. In 16/20 (80.0%) cases (with or without histologic necrosis of the arcuate), immunostaining with caspase-3 demonstrated positive neurons. Our findings suggest that neuronal pathology in the arcuate nucleus may be both developmental (13.6%) and acquired (54.5%). The association of neuronal necrosis and apoptosis in the arcuate nucleus with systemic entities involving fetal ischemia, and with other brain lesions consistent with ischemia, e.g., cerebral white matter gliosis, suggests that ischemia plays a role in the arcuate nucleus damage as well. Thus, the underpopulation of arcuate neurons detected postnatally in some SIDS infants may be secondary to an acquired insult in mid- or late gestation, and in other cases, a primary developmental lesion in early gestation, or both. The role of arcuate nucleus pathology in the pathogenesis of fetal demise remains to be determined.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. rfolkerth@partners.org
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Folkerth
authors.forename: Sallie
authors.initials: S
authors.lastname: Zanoni
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Andiman
authors.forename: Saraid S
authors.initials: SS
authors.lastname: Billiards
mesh_terms: D001111:Arcuate Nucleus of Hypothalamus / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D005260:Female; D005333:Fetus; D005865:Gestational Age; D006801:Humans; D008297:Male; D009474:Neurons / Q000473:pathology*; D012189:Retrospective Studies; D050497:Stillbirth
chemical_list: D053148:Caspase 3