Hippocampal abnormalities and seizures: a 16-year single center review of sudden unexpected death in childhood, sudden unexpected death in epilepsy and SIDS.

Sudden Unexpected Death in Childhood (SUDC) is the unexplained death of children aged between 1 and 18 years old. Hippocampal abnormalities have previously been described in Sudden Unexpected Death in Epilepsy (SUDEP) and it is possible that SUDC shares similar pathogenic mechanisms with SUDEP. Our aim was to determine the prevalence of hippocampal abnormalities, history of seizures and demographic features in our caseload of SUDC, SUDEP and SIDS cases. A review of post-mortem reports from 2003 to 2018 was carried out to identify cases of SUDC, SUDEP and SIDS. Histological evidence of hippocampal abnormalities, patient demographics (age, gender), sleeping position, and past medical history (history of seizures and illness 72 hours prior to death) were recorded. Statistical analysis was performed to compare the three groups. 48 SUDC, 18 SUDEP and 358 SIDS cases were identified. Hippocampal abnormalities associated with temporal lobe epilepsy were found in 44.4% of SUDC cases. 5/15 SUDC cases with a history of seizures demonstrated hippocampal abnormalities. SUDC cases were also more likely to be found prone compared to SIDS cases. In comparison with SIDS, both SUDC and SUDEP cases were more likely to demonstrate hippocampal abnormalities (SUDC: (OR = 9.4, 95% CI: 3.1-29.1, p < 0.001; SUDEP: OR = 35.4, 95% CI: 8.3-151.5, p < 0.001). We found a potential link between hippocampal abnormalities and epileptic seizures in SUDC. A concerted effort should be directed towards consistent sampling and standardized description of the hippocampus and clinical correlation with a history of seizures/epilepsy in postmortem reports.

Respiratory syncytial virus-associated mortality in a healthy 3-year-old child: a case report.

BACKGROUND: Respiratory syncytial virus (RSV) is the most frequently identified pathogen in children with acute lower respiratory tract infection. Fatal cases have mainly been reported during the first 6 months of life or in the presence of comorbidity. CASE PRESENTATION: A 47-month-old girl was admitted to the pediatric intensive care unit following sudden cardiopulmonary arrest occurring at home. The electrocardiogram showed cardiac asystole, which was refractory to prolonged resuscitation efforts. Postmortem analyses detected RSV by polymerase chain reaction in an abundant, exudative pericardial effusion. Histopathological examination was consistent with viral myoepicarditis, including an inflammatory process affecting cardiac nerves and ganglia. Molecular analysis of sudden unexplained death genes identified a heterozygous mutation in myosin light chain 2, which was also found in two other healthy members of the family. Additional expert interpretation of the cardiac histology confirmed the absence of arrhythmogenic right ventricular dysplasia or hypertrophic cardiomyopathy. CONCLUSIONS: RSV-related sudden death in a normally developing child of this age is exceptional. This case highlights the risk of extrapulmonary manifestations associated with this infection, particularly arrhythmia induced by inflammatory phenomena affecting the cardiac autonomic nervous system. The role of the mutation in this context is uncertain, and it is therefore necessary to continue to assess how this pathogenic variant contributes to unexpected sudden death in childhood.

Sudden unexpected death in early childhood: general observations in a series of 151 cases: Part 1 of the investigations of the San Diego SUDC Research Project.

PURPOSE: The purpose of this study was to determine the major subcategories and clinicopathologic features of sudden unexpected death in young children in a large retrospective cohort, and to confirm the association of sudden unexplained death in children (abbreviated by us for unexplained deaths as SUDC) with hippocampal pathology and/or febrile seizures. METHODS: We undertook analysis of a retrospective cohort of 151 cases, of which 80% (121/151) were subclassified as SUDC, 11% (16/151) as explained, 7% (10/151) as undetermined, and 3% (4/151) as seizure-related. RESULTS: There were no significant differences between SUDC and explained cases in postnatal, gestational, or postconceptional age, frequency of preterm birth, gender, race, or organ weights. In contrast, 96.7% (117/121) of the SUDC group were discovered during a sleep period compared to 53.3% (8/15) of the explained group (p < 0.001), and 48.8% (59/121) of the SUDC cases had a personal and/or family history of febrile seizures compared to 6.7% (1/15) of the explained group (p < 0.001). Of the explained deaths, 56% (9/16) were subclassified as infection, 31% (5/16) cardiac, 6% (1/16) accidental, and 6% (1/16) metabolic. Two of the three cases specifically tested for cardiac channelopathies at autopsy based upon clinical indications had genetic variants in cardiac genes, one of uncertain significance. Bacterial cultures at autopsy typically revealed organisms interpreted as contaminants. Two of the four seizure-related deaths were witnessed, with two of the brains from these cases showing generalized malformations. Hippocampal anomalies, including a specific combination we termed hippocampal maldevelopment associated with sudden death, were found in almost 50% (40/83) of the SUDC and undetermined cases in which hippocampal sections were available. CONCLUSIONS: This study highlights the key role for the hippocampus, febrile seizures, and sleep in SUDC pathophysiology. It also demonstrates the role of known predisposing conditions such as cardiac channelopathies and infections in causing sudden unexpected death in childhood, and the need for improved ancillary testing and protective strategies in these cases, even when the cause of death is established at autopsy.

Sudden Unexpected Death in Childhood in Greater Manchester (United Kingdom): A Five-Year Review (2015-2020).

The sudden, unexpected death of a child (SUDC) is a devastating experience. It is vital that supportive and investigative services are effective and promote the best outcomes for families. Analysis of 5 years of data from 309 SUDC cases in Greater Manchester, United Kingdom (UK) shows how a number of key service outcomes can be measured and achieved through a raft of actions which are commensurate with and exceed the service level recommended by the UK Government. Annual reports covering the work of the Greater Manchester SUDC team are compiled from audit forms completed by the attending SUDC pediatrician for each case. Data from these reports from April 1, 2015 to March 31, 2020 were analyzed. Most cases happened out of normal working hours, predominantly on Sundays. This supports the need for a 24-hour, 7 days per week SUDC service to enable early investigation and timely support for families. The review demonstrated that the Greater Manchester model is able to deliver this in a rapid response with early attendance in emergency departments and early home visits; effective joint agency working with police, children's social services, and other agencies; and provision of support to families. The proposed instigation of a key worker role in the SUDC team is a welcome development. This is central to ameliorating the experience for parents by providing bereavement support separate from the investigative role of the SUDC team. Research is needed into the role of the key worker, potentially as a dedicated bereavement nurse, and understanding of families' experiences to ensure that support is optimal.

Neuropathology of Pediatric SARS-CoV-2 Infection in the Forensic Setting: Novel Application of Ex Vivo Imaging in Analysis of Brain Microvasculature.

Two years into the COVID-19 pandemic, there are few published accounts of postmortem SARS-CoV-2 pathology in children. We report 8 such cases (4 infants aged 7-36 weeks, 4 children aged 5-15 years). Four underwent ex vivo magnetic resonance neuroimaging, to assist in identification of subtle lesions related to vascular compromise. All infants were found unresponsive (3 in unsafe sleeping conditions); all but 1 had recent rhinitis and/or influenza-like illness (ILI) in the family; 1 had history of sickle cell disease. Ex vivo neuroimaging in 1 case revealed white matter (WM) signal hyperintensity and diffuse exaggeration of perivascular spaces, corresponding microscopically to WM mineralization. Neurohistology in the remaining 3 infants variably encompassed WM gliosis and mineralization; brainstem gliosis; perivascular vacuolization; perivascular lymphocytes and brainstem microglia. One had ectopic hippocampal neurons (with pathogenic variant in DEPDC5). Among the children, 3 had underlying conditions (e.g., obesity, metabolic disease, autism) and all presented with ILI. Three had laboratory testing suggesting multisystem inflammatory syndrome (MIS-C). Two were hospitalized for critical care including mechanical ventilation and extracorporeal membrane oxygenation (ECMO); one (co-infected with adenovirus) developed right carotid stroke ipsilateral to the ECMO cannula and the other required surgery for an ingested foreign body. Autopsy findings included: acute lung injury in 3 (1 with microthrombi); and one each with diabetic ketoacidosis and cardiac hypertrophy; coronary and cerebral arteritis and aortitis, resembling Kawasaki disease; and neuronal storage and enlarged fatty liver. All 4 children had subtle meningoencephalitis, focally involving the brainstem. On ex vivo neuroimaging, 1 had focal pontine susceptibility with corresponding perivascular inflammation/expanded perivascular spaces on histopathology. Results suggest SARS-CoV-2 in infants may present as sudden unexpected infant death, while in older children, signs and symptoms point to severe disease. Underlying conditions may predispose to fatal outcomes. As in adults, the neuropathologic changes may be subtle, with vascular changes such as perivascular vacuolization and gliosis alongside sparse perivascular lymphocytes. Detection of subtle vascular pathology is enhanced by ex vivo neuroimaging. Additional analysis of the peripheral/autonomic nervous system and investigation of co-infection in children with COVID-19 is necessary to understand risk for cardiovascular collapse/sudden death.

Sudden unexpected death in GEFS+ families with sodium channel pathogenic variants.

We aimed to describe families with genetic epilepsy with febrile seizures plus (GEFS+) in which individuals suffered sudden unexpected death. The Epilepsy Pharmacogenomics Research Database was reviewed for GEFS + families in which at least one individual had suffered sudden death, and two families were identified. In Family A, five males had febrile seizures and one girl had febrile seizures plus. The latter died at 22 months of age and was classified as definite SUDEP. Molecular genetic testing identified a pathogenic SCN1B variant. In Family B, two brothers had recurrent focal status epilepticus with fever, and were classified as having atypical multifocal Dravet syndrome. The elder brother died suddenly at seven years of age, but was not classified SUDEP because the event occurred following status epilepticus. SCN1A sequencing in the surviving brother identified a likely pathogenic variant. These two cases of sudden death in GEFS + families with likely pathogenic variants in sodium channel genes demonstrate that sudden death may occur in GEFS+, even with mild phenotypes. The presence of sodium channel variants may have further increased the sudden death risk, particularly in the case of SCN1B, a gene which has also been associated with cardiac conditions including Brugada syndrome and long QT.