Cause of Death Analysis in a 9½-Year-Old with COVID-19 and Dravet Syndrome

Abstract

Background: Cause of death analysis is fundamental to forensic pathology. We present the case of a 9½-year-old girl with a genetically confirmed diagnosis of Dravet syndrome who died in her sleep with no evidence of motor seizure. She also had a lifelong history of recurrent pneumonias and, along with her family, had tested positive for COVID-19 10 days before death. Methods: Long-term clinical history of Dravet Syndrome and respiratory infections were obtained from patient's medical charts and radiology reports. A Rapid-Antigen Test was used to confirm SARS-CoV2 infection days prior to death. At autopsy, brain, heart and lung tissues were obtained. Paraffin-embedded tissues were double-stained with H&E, and immunohistochemically stained using various antibodies. Results: Autopsy revealed evidence of previous seizure activity in the brain and cellular interstitial thickening in the lung. The brain showed edema and fibrillary gliosis without neuronal loss in neocortex and hippocampus. The lung showed inflammatory interstitial thickening with histiocytes, megakaryocytes, B-lymphocytes, and T-lymphocytes, including helper/suppressor cells and cytotoxic T-lymphocytes. Diffuse alveolar damage was observed as alveolar flooding with proteinaceous fluid. Conclusions: The cause of death may be attributed to Sudden Unexpected Death in Epilepsy (SUDEP) in Dravet syndrome, sudden death in viral pneumonia, or some combination of the two. When two independent risk factors for sudden unexpected death are identified due to co-pathology, it may not be possible to determine a single cause of death beyond a reasonable doubt.

Keywords: COVID-19; Dravet syndrome; SUDEP; cellular interstitial pneumonia; co-pathology; epilepsy; seizure; sudden unexpected death in epileptic patients; virus.

Figure 1

Neuropathological abnormalities in 9½-year-old patient with Dravet syndrome. (A). Gross examination reveals the brain to be small, in keeping with global developmental delay, with no atrophy of the cerebellum. (B). Macroscopic view of the coronal section shows edema, which is evidenced by compressed lateral ventricles (black arrowhead) as well as swollen and flattened gyri.

Figure 2

Histological changes in gray and white matter of the cortex in a 9½-year-old patient with Dravet syndrome. (A,B). Neuropil vacuolization of gray matter edema is seen, especially around blood vessels (arrowheads). (C,D). Lower magnification shows gray matter (GM) and white matter (WM) of the neocortex (C), and higher magnification shows fiber-splitting around blood vessel, indicative of white matter edema (D). (E,F). CD68-positive microglia are seen infiltrating the perivascular space (red arrows). (G,H). GFAP-positive fibrillated astrocytes are seen under the pia mater (arrowheads) as well as layers I and II of the frontal cortex (H). Scale bars—(A,B,E) magnification 10×. Bars = 200 µm, (C) magnification 4×. Bar = 500 µm and (D,F–H) magnification 20×. Bars = 100 µm.

Figure 3

Histological changes in the hippocampus of a 9½-year-old patient with Dravet syndrome. (A–D). H&E-stained sections show no neuronal loss in the dentate gyrus (arrow), CA1 (B), CA3 (C), and CA4 regions (D–H). GFAP immunohistochemistry shows hippocampal astrogliosis, with minimal gray matter gliosis in CA1 (F) compared to CA3 (G) and CA4 regions (H). Scale bar—(A,E) magnification 4×. Bars = 1 mm, (B–D) and (F–H) magnification 20×. Bars = 100 µm.

Figure 4

Histological changes in the lungs of a 9½-year-old patient with Dravet syndrome positive for COVID-19. (A). Martius Scarlet Blue (MSB)-stained section shows a section of the lung at 1× magnification, highlighting a sharp demarcation (arrows) between aerated (at left) and flooded airspaces (at right) (B). H&E-stained section shows alveolar edema with features of proteinosis and hyaline membranes (arrowheads). (C). Magnification of MSB image shows infiltration of macrophages into the bronchiole and alveolar ducts (arrows). (D). Vimentin immunohistochemistry shows activated macrophages, especially in the alveoli. (E). CD68-positive macrophages are seen in clumps and individually scattered. Some are binucleated (E,F). CD61-positive megakaryocytes are seen individually as well as clustered in groups. (G,H). B-lymphocytes are seen on H&E (G) and CD20 (H) forming perivascular aggregates and individually scattered throughout the interstitium. (I,J). CD8 cytotoxic T-lymphocytes (I) and CD4-positive T-helper/suppressor cells (J) are scattered throughout the lung and form perivascular aggregates (arrowheads) (K,L). CD3 T-cells follow a similar perivascular and peribronchiolar distribution. Scale bars—(C,G,H,K) magnification 10×. Bars = 300 µm and (B,D–F,I,J,L) magnification 20×. Bars = 100 µm.