Sudden Death in Toddlers Associated with Developmental Abnormalities of the Hippocampus: A Report of Five Cases

Abstract

Sudden unexplained death in childhood (SUDC) is the sudden death of a child older than 1 year of age that remains unexplained after review of the clinical history, circumstances of death, and autopsy with appropriate ancillary testing. We report here 5 cases of SUDC in toddlers that we believe define a new entity associated with hippocampal anomalies at autopsy. All of the toddlers died unexpectedly during the night, apparently during sleep. Within 48 hours before death, 2 toddlers had fever, 3 had a minor upper respiratory tract infection, and 3 experienced minor head trauma. There was a history of febrile seizures in 2 (40%) and a family history of febrile seizures in 2 (40%). Hippocampal findings included external asymmetry and 2 or more microdysgenetic features. The incidence of certain microdysgenetic features was substantially increased in the temporal lobes of these 5 cases compared with the temporal lobes of 39 (control) toddlers with the causes of death established at autopsy (P < 0.01). We propose that these 5 cases define a potential subset of SUDC whose sudden death is caused by an unwitnessed seizure arising during sleep in the anomalous hippocampus and producing cardiopulmonary arrest. Precipitating factors may be fever, infection, and/or minor head trauma. Suggested risk factors are a history of febrile seizures and/or a family history of febrile seizures. Future studies are needed to confirm these initial findings and to define the putative links between sudden death, hippocampal anomalies, and febrile seizures in toddlers.

Complex Brain Malformations Associated with Chromosome 6q27 Gain that Includes THBS2, Which Encodes Thrombospondin 2, an Astrocyte-Derived Protein of the Extracellular Matrix

“…Nevertheless, it is possible that the observed brain anomalies affected the medullary serotonin network and could have placed this patient at increased risk for sudden death. Temporal lobe anomalies including hippocampal abnormalities have also been described in sudden unexpected death in infancy, and we observed small poorly rotated hippocampi [14], which may have played a role in the infant's demise. Thrombospondin 2 is synthesized by astrocytes and is a nonfibrillar extracellular matrix protein; since it does not seem to have a structural role in the matrix it is referred to as a matricellular protein [1], Thrombospondin 2 is important in the assembly of the extracellular matrix, in mediating cell-cell and cell-matrix interactions, and in regulating the activity of matrix metalloproteinases (reviewed in Calabro and colleagues [15]).…”

The Structural Connectome of the Human Central Homeostatic Network

“…Medullary-forebrain connectivity through the human LFB also provides a potential neuroanatomic basis for CHN disorders such as SUDEP (Engel et al, 2013;Richardson, 2012;Sowers et al, 2013), which is associated with temporal lobe epilepsy (Mueller et al, 2014;Schuele et al, 2011), as well as SIDS and SUDC, which are associated with hippocampal anomalies in infants and young children, respectively (Kinney et al, 2007(Kinney et al, , 2009(Kinney et al, , 2015. A paradoxical feature of the CHN is its marked susceptibility to generate and propagate seizures (Harper, 1986;Oliveira et al, 2011)-paradoxical in that a network so vital to survival is so prone to seizures that are inherently dangerous and potentially lethal.…”

“…Furthermore, the concept of a CHN is based upon the recognition that the network regulates not only autonomic functions (i.e., cardiac muscle, smooth muscle, and sweat glands) but also respiratory functions, which are mediated by skeletal muscle. The CHN connectome identified in this study represents an initial step toward elucidating the neuroanatomy of human homeostasis and defining altered connectivity in future studies of patients with disorders of homeostasis, such as sudden infant death syndrome (SIDS) (Kinney et al, 2015), sudden unexplained death in childhood (SUDC) (Kinney et al, 2007(Kinney et al, , 2009, and sudden unexplained death in epilepsy (SUDEP) (Massey et al, 2014).…”

Characterization of the of the Pathological and Biochemical Markers That Correlate to the Clinical Features of Autism. Subproject 2. Contribution of Significant Delay of Neuronal Development and Metabolic Shift of Neurons to Clinical Phenotype of Autism

“…Similar hippocampal developmental abnormalities observed in sudden unexpected and unexplained death in childhood (SUDC) cases (Kinney et al, 2007) are considered an epileptogenic focus that might be triggered by infection, fever, or head trauma and result in seizures and unwitnessed death Frysinger and Harper, 1990;Yang et al, 2001). SUDC in two subjects and SUDEP in five cases with dup (15) and autism and several-fold higher prevalence of hippocampal and cortical dysplasia than in idiopathic autism appears to be the clinicopathological criterion for stratification between and within these cohorts.…”

“…SUDC in two subjects and SUDEP in five cases with dup (15) and autism and several-fold higher prevalence of hippocampal and cortical dysplasia than in idiopathic autism appears to be the clinicopathological criterion for stratification between and within these cohorts. These developmental alterations are not pathognomonic of an 'epileptic brain' (Kinney et al, 2007), but the combination of microcephaly, the 2.5-fold higher prevalence of several types of developmental abnormalities, the 2.3-fold higher prevalence of epilepsy, and the six-times higher prevalence of epilepsy-related death in the dup(15) cohort suggests that unique genetic and molecular modifications and developmental structural defects distinguish these two cohorts of autistic subjects.…”