Independent distribution between tauopathy secondary to subacute sclerotic panencephalitis and measles virus: An immunohistochemical analysis in autopsy cases including cases treated with aggressive antiviral therapies

Abstract

Subacute sclerotic panencephalitis (SSPE) is a refractory neurological disorder after exposure to measles virus. Recently, SSPE cases have been treated with antiviral therapies, but data on the efficacy are inconclusive. Abnormal tau accumulation has been reported in the brain tissue of SSPE cases, but there are few reports in which this is amply discussed. Five autopsied cases diagnosed as definite SSPE were included in this study. The subject age or disease duration ranged from 7.6 to 40.9 years old or from 0.5 to 20.8 years, respectively. Cases 3 and 4 had been treated with antiviral therapies. All evaluated cases showed marked brain atrophy with cerebral ventricle dilatation; additionally, marked demyelination with fibrillary gliosis were observed in the cerebral white matter. The brainstem, cerebellum, and spinal cord were relatively preserved. Immunoreactivity (IR) against measles virus was seen in the brainstem tegmentum, neocortex, and/or limbic cortex of the untreated cases but was rarely seen in the two treated cases. Activated microglia were broadly observed from the cerebrum to the spinal cord and had no meaningful difference among cases. Neurofibrillary tangles characterized by a combination of 3- and 4-repeat tau were observed mainly in the oculomotor nuclei, locus coeruleus, and limbic cortex. IR against phosphorylated tau was seen mainly in the cingulate gyrus, oculomotor nuclei, and pontine tegmentum, and tended to be observed frequently in cases with long disease durations but also tended to decrease along with neuronal loss, as in Case 5, which had the longest disease duration. Since the distribution of phosphorylated tau was independent from that of measles virus, the tauopathy following SSPE was inferred to be the result of diffuse brain inflammation triggered by measles rather than a direct result of measles virus. Moreover, antiviral therapies seemed to suppress measles virus but not the progression of tauopathy.

Keywords: autopsy; measles virus; neurofibrillary tangle; subacute sclerotic panencephalitis; tau.

FIGURE 1

Common neuropathological findings in subacute sclerotic panencephalitis. (A–D) These images were taken from Case 2 and are representative of the five included cases. The cerebrums of these patients showed marked atrophy with cerebral ventricle dilatation, but the brainstems and cerebellums were relatively preserved. The myelin in the white matter (including the cerebrospinal tract) of these cases was poorly stained by Klüver–Barrera (KB) staining. (E) Gliotic scarring, which was visualized by Holzer staining, was observed mainly in the demyelinated white matter. (F) In active lesions, perivascular lymphocyte infiltrations and aggregations of hypertrophic astrocytes were noted. (G–J) The perivascular lymphocytes were composed chiefly of CD20+ or CD4+ lymphocytes. Abundant activated microglia were extensively observed in the active lesions. (K‐N) Neurons with intranuclear inclusions, which were labeled using an antibody against measles virus, were frequently observed in the brainstem tegmentum. (A–D) KB staining; (E) Holzer staining; (F,K) hematoxylin and eosin staining; (G–J,M,N,L): immunohistochemistry for CD4 (G), CD8 (H), CD20 (I), Iba1 (J), and p‐measles (M, N, L). Bar: 1 cm for (A–E,M,N), 200 μm for (F), 50 μm for (G–J), and 20 μm for (K,L)

FIGURE 2

Representative pathology regarding tauopathy following subacute sclerotic panencephalitis. (A–K) These images were taken from Case 4. (A–C,E,F) Flame‐shaped and globose‐type neurofibrillary tangles (NFTs) were broadly distributed particularly in the superficial layers of the cerebral cortex, oculomotor nuclei, and locus coeruleus. (D,G–K) These NFTs were labeled by silver impregnation methods, such as Gallyas–Braak (J) and Bodian (K) staining, and immunostained with antibodies against AT8 (D,G), RD3 (H), and anti‐4R (I). Bar: 1 cm for (A), 500 μm for (B), 20 μm for (C,F), 50 μm for (D,G–K), and 2 mm for (E)

FIGURE 3

Electron microscopy and western blot in a case of tauopathy following subacute sclerotic panencephalitis. (A,B) By electron microscopy, the neurofibrillary tangles (NFTs) in the cingulate cortex of Case 4 were observed to be composed of paired helical filaments with a half‐period of approximately 50 nm and straight tubules. (C) Western blots of the right cingulate cortex of Case 4 using AT8 and T46 antibodies showed triplet bands of 60, 64, and 68 kDa, the same molecular weights as the bands found in sample from Alzheimer's disease case. Bar: 2 μm for (A) and 50 nm for (B)

FIGURE 4

Heatmap visualization of the distributions of phosphorylated tau and measles virus in cases of subacute sclerotic panencephalitis. IR against measles virus was seen mainly in the tegmentum of the midbrain and pons, neocortex, and/or limbic cortex, and was rarely seen in the treated cases (Cases 2 and 3). IR against phosphorylated tau was seen mainly in the cingulate gyrus, the oculomotor nuclei, and/or the pontine tegmentum, and tended to be observed frequently in cases with long disease durations. Moreover, IR against Iba1 was broadly observed from the cerebrum to the spinal cord, and there was no meaningful difference in Iba1 expression among these cases. NA: not available