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Brain : a Journal of Neurology Jul 2022The underlying mechanisms by which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to acute and long-term neurological manifestations remains obscure....
The underlying mechanisms by which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to acute and long-term neurological manifestations remains obscure. We aimed to characterize the neuropathological changes in patients with coronavirus disease 2019 and determine the underlying pathophysiological mechanisms. In this autopsy study of the brain, we characterized the vascular pathology, the neuroinflammatory changes and cellular and humoral immune responses by immunohistochemistry. All patients died during the first wave of the pandemic from March to July 2020. All patients were adults who died after a short duration of the infection, some had died suddenly with minimal respiratory involvement. Infection with SARS-CoV-2 was confirmed on ante-mortem or post-mortem testing. Descriptive analysis of the pathological changes and quantitative analyses of the infiltrates and vascular changes were performed. All patients had multifocal vascular damage as determined by leakage of serum proteins into the brain parenchyma. This was accompanied by widespread endothelial cell activation. Platelet aggregates and microthrombi were found adherent to the endothelial cells along vascular lumina. Immune complexes with activation of the classical complement pathway were found on the endothelial cells and platelets. Perivascular infiltrates consisted of predominantly macrophages and some CD8+ T cells. Only rare CD4+ T cells and CD20+ B cells were present. Astrogliosis was also prominent in the perivascular regions. Microglial nodules were predominant in the hindbrain, which were associated with focal neuronal loss and neuronophagia. Antibody-mediated cytotoxicity directed against the endothelial cells is the most likely initiating event that leads to vascular leakage, platelet aggregation, neuroinflammation and neuronal injury. Therapeutic modalities directed against immune complexes should be considered.
Topics: Adult; Antigen-Antibody Complex; COVID-19; Complement Activation; Endothelial Cells; Humans; Inflammation; Nervous System Diseases; SARS-CoV-2
PubMed: 35788639
DOI: 10.1093/brain/awac151 -
Journal of Neuroinfectious Diseases Jun 2016Zika virus (ZIKV) is a member of the Flaviviridae family that had been associated only with mild disease prior to the 2015 outbreak in Brazil. A dramatic increase in...
Zika virus (ZIKV) is a member of the Flaviviridae family that had been associated only with mild disease prior to the 2015 outbreak in Brazil. A dramatic increase in reported cases of microcephaly and Guillain-Barré syndrome during this time prompted significant research into possible associations with ZIKV and its neurotropic properties. Infection of neural progenitor cells and organoids have been shown to induce apoptosis and dysregulation of growth, and mouse studies have demonstrated viral replication in brain tissue in adults, as well as vertical transmission resulting in embryonic brain abnormalities. Large case series of clinical and radiological findings of congenital ZIKV infection have begun to be published; however, pathology reports have been limited to two case reports and two small case series. Thus far, the findings have largely been restricted to the brain and include diffuse grey and white matter involvement consisting of dystrophic calcifications, gliosis, microglial nodules, neuronophagia, and scattered lymphocytes. Mild chronic villitis was observed in the placental tissue in some cases, and the remaining organs were essentially uninvolved. Larger, systematic studies, including correlation of histological findings with gestational age at the time of maternal infection, will be required to determine the full range of Zika virus-induced abnormalities and to help guide future clinical decision making.
PubMed: 27525286
DOI: 10.4172/2314-7326.1000220 -
COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital.Brain : a Journal of Neurology Oct 2021Many patients with SARS-CoV-2 infection develop neurological signs and symptoms; although, to date, little evidence exists that primary infection of the brain is a...
Many patients with SARS-CoV-2 infection develop neurological signs and symptoms; although, to date, little evidence exists that primary infection of the brain is a significant contributing factor. We present the clinical, neuropathological and molecular findings of 41 consecutive patients with SARS-CoV-2 infections who died and underwent autopsy in our medical centre. The mean age was 74 years (38-97 years), 27 patients (66%) were male and 34 (83%) were of Hispanic/Latinx ethnicity. Twenty-four patients (59%) were admitted to the intensive care unit. Hospital-associated complications were common, including eight patients (20%) with deep vein thrombosis/pulmonary embolism, seven (17%) with acute kidney injury requiring dialysis and 10 (24%) with positive blood cultures during admission. Eight (20%) patients died within 24 h of hospital admission, while 11 (27%) died more than 4 weeks after hospital admission. Neuropathological examination of 20-30 areas from each brain revealed hypoxic/ischaemic changes in all brains, both global and focal; large and small infarcts, many of which appeared haemorrhagic; and microglial activation with microglial nodules accompanied by neuronophagia, most prominently in the brainstem. We observed sparse T lymphocyte accumulation in either perivascular regions or in the brain parenchyma. Many brains contained atherosclerosis of large arteries and arteriolosclerosis, although none showed evidence of vasculitis. Eighteen patients (44%) exhibited pathologies of neurodegenerative diseases, which was not unexpected given the age range of our patients. We examined multiple fresh frozen and fixed tissues from 28 brains for the presence of viral RNA and protein, using quantitative reverse-transcriptase PCR, RNAscope® and immunocytochemistry with primers, probes and antibodies directed against the spike and nucleocapsid regions. The PCR analysis revealed low to very low, but detectable, viral RNA levels in the majority of brains, although they were far lower than those in the nasal epithelia. RNAscope® and immunocytochemistry failed to detect viral RNA or protein in brains. Our findings indicate that the levels of detectable virus in coronavirus disease 2019 brains are very low and do not correlate with the histopathological alterations. These findings suggest that microglial activation, microglial nodules and neuronophagia, observed in the majority of brains, do not result from direct viral infection of brain parenchyma, but more likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ischaemia. Further studies are needed to define whether these pathologies, if present in patients who survive coronavirus disease 2019, might contribute to chronic neurological problems.
Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Bacteremia; Brain; Brain Infarction; COVID-19; Coronavirus Nucleocapsid Proteins; Female; Humans; Hypoxia-Ischemia, Brain; Inflammation; Intensive Care Units; Intracranial Hemorrhages; Male; Microglia; Middle Aged; Neurons; Phagocytosis; Phosphoproteins; Pulmonary Embolism; RNA, Viral; Renal Dialysis; Reverse Transcriptase Polymerase Chain Reaction; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Survival Rate; T-Lymphocytes; Venous Thrombosis
PubMed: 33856027
DOI: 10.1093/brain/awab148 -
BMC Veterinary Research Nov 2018Paralytic form of rabies is frequent in cattle in Latin America, but it is uncommon in goats. There are few clinical reports on furious rabies affecting goats, and the...
BACKGROUND
Paralytic form of rabies is frequent in cattle in Latin America, but it is uncommon in goats. There are few clinical reports on furious rabies affecting goats, and the sporadic cases of rabid goats from surveillance programs worldwide lack clinical data. Furthermore, few studies reported the cerebrospinal fluid findings in rabid livestock.
CASE PRESENTATION
On a farm in Midwestern Brazil, six of 47 Saanen goats died within one week. No vaccination protocols were implemented on the farm and the owner stated bat bites history on the livestock. Although rabies is endemic in Brazil, livestock vaccination is not mandatory. One 1-year-old buck was evaluated and showed non-specific clinical signs evolving within 12-h to nervous signs. Cerebrospinal fluid analysis revealed mononuclear pleocytosis, hyperproteinemia and high glucose levels. At necropsy, no gross lesions were present. Microscopically, discrete to moderate perivascular lymphoplasmacytic cuffing in gray and white matter, neuronal necrosis, neuronophagia, and mononuclear ganglioneuritis was observed in the brainstem and cervical spinal cord. Immunohistochemistry revealed strong anti-rabies virus immunostaining. Fresh central nervous system samples were positive for rabies in direct fluorescent antibody test (dFAT) and mouse intracerebral inoculation test (MIT). Exposed livestock recommendations included immediate vaccination, a strict isolation period of 90 days, and booster vaccinations during the third and eighth weeks.
CONCLUSION
IHC revealed the widespread distribution of rabies virus antigen in the goat's CNS, contrasting the discrete pathological changes. In this goat, definitive diagnosis of paralytic rabies was obtained through the association of epidemiological, clinical, laboratorial, pathological findings (histology and IHC) and gold standard confirmatory tests (dFAT and MIT).
Topics: Animals; Brazil; Goat Diseases; Goats; Male; Paralysis; Rabies
PubMed: 30419906
DOI: 10.1186/s12917-018-1681-z -
Frontiers in Veterinary Science 2022Inflammation in meninges and/or brain is regularly noticed in red foxes and other wild carnivores during rabies control programs. Despite negative rabies virus (RABV)...
Inflammation in meninges and/or brain is regularly noticed in red foxes and other wild carnivores during rabies control programs. Despite negative rabies virus (RABV) results, the etiologies of these cases remain unknown. Thus, the aim of this study was to provide an overview of the occurrence of pathogens that may cause diseases in the brains of wild carnivores and pose a risk to humans and other animals. In addition to RABV and canine distemper virus (CDV), a variety of pathogens, including members of , as well as bacteria and parasites can also cause brain lesions. In 2016 and 2017, brain samples of 1,124 wild carnivores were examined by direct fluorescent antibody test for RABV as well as (reverse-transcriptase) quantitative polymerase chain reaction (PCR) for the presence of CDV as part of a monitoring program in Saxony-Anhalt, Germany. Here, we applied similar methods to specifically detect suid herpesvirus 1 (SuHV-1), West Nile virus (WNV), Borna disease virus 1 (BoDV-1), canid alphaherpesvirus 1 (CaHV-1), canine parvovirus type 2 (CPV-2), fox circovirus (FoxCV), and (). Further, bacteriogical examination for the existence of () and immunohistochemistry of selected cases to detect () antigen were performed. Of all pathogens studied, CDV was found most frequently (31.05%), followed by FoxCV (6.80%), CPV-2 (6.41%), (4/15; 26.67%), nematode larvae (1.51%), (0.3%), and various other bacterial pathogens (1.42%). In 68 of these cases (6.05%), multiple pathogen combinations were present simultaneously. However, RABV, WNV, BoDV-1, SuHV-1, CaHV-1, and were not detected. The majority of the histopathological changes in 440 animals were inflammation (320/440; 72.73%), predominantly non-suppurative in character (280/320; 87.50%), and in many cases in combination with gliosis, satellitosis, neuronophagia, neuronal necrosis, and/or vacuolization/demyelination, or in single cases with malacia. Thus, it could be shown that wild carnivores in Saxony-Anhalt are carriers mainly for CDV and sometimes also for other, partly zoonotic pathogens. Therefore, the existing monitoring program should be expanded to assess the spill-over risk from wild carnivores to humans and other animals and to demonstrate the role of wild carnivores in the epidemiology of these zoonotic pathogens.
PubMed: 35464387
DOI: 10.3389/fvets.2022.826355 -
Acta Neuropathologica Communications Aug 2020We document the neuropathologic findings of a 73-year old man who died from acute cerebellar hemorrhage in the context of relatively mild SARS-CoV2 infection. The...
We document the neuropathologic findings of a 73-year old man who died from acute cerebellar hemorrhage in the context of relatively mild SARS-CoV2 infection. The patient developed sudden onset of headache, nausea, and vomiting, immediately followed by loss of consciousness on the day of admission. Emergency medical services found him severely hypoxemic at home, and the patient suffered a cardiac arrest during transport to the emergency department. The emergency team achieved return of spontaneous circulation after over 17 min of resuscitation. A chest radiograph revealed hazy bilateral opacities; and real-time-PCR for SARS-CoV-2 on the nasopharyngeal swab was positive. Computed tomography of the head showed a large right cerebellar hemorrhage, with tonsillar herniation and intraventricular hemorrhage. One day after presentation, he was transitioned to comfort care and died shortly after palliative extubation. Autopsy performed 3 h after death showed cerebellar hemorrhage and acute infarcts in the dorsal pons and medulla. Remarkably, there were microglial nodules and neuronophagia bilaterally in the inferior olives and multifocally in the cerebellar dentate nuclei. This constellation of findings has not been reported thus far in the context of SARS-CoV-2 infection.
Topics: Aged; Betacoronavirus; Brain Stem Infarctions; COVID-19; Cerebellar Diseases; Cerebellar Nuclei; Coronavirus Infections; Headache; Heart Arrest; Humans; Hypoxia; Intracranial Hemorrhages; Male; Medulla Oblongata; Microglia; Neurons; Olivary Nucleus; Pandemics; Phagocytosis; Pneumonia, Viral; Pontine Tegmentum; SARS-CoV-2; Tomography, X-Ray Computed
PubMed: 32847628
DOI: 10.1186/s40478-020-01024-2 -
Journal of Veterinary Diagnostic... Jan 2020Porcine rabies is exceedingly rare worldwide. We describe herein the neuropathology and the diagnostic features of an outbreak of rabies in a litter of piglets attacked... (Review)
Review
Porcine rabies is exceedingly rare worldwide. We describe herein the neuropathology and the diagnostic features of an outbreak of rabies in a litter of piglets attacked by a skunk in Georgia, United States. Rabies viral infection was confirmed in 2 of 3 piglets submitted for testing. Inflammatory and degenerative changes were more prominent in the brainstem and consisted of lymphoplasmacytic meningoencephalitis with glial nodules, neuronal necrosis, and neuronophagia. No viral inclusions (Negri bodies) were observed in multiple sections of brain. A fluorescent antibody test on fresh samples of brainstem and cerebellum was confirmatory for the eastern United States raccoon rabies virus variant. Immunoreactivity for rabies virus was detected across all brain sections in both cases but was more prominent in the thalamic and brainstem nuclei, as well as in the medial lemniscus. Rabies is an important differential diagnosis in pigs with neurologic disease.
Topics: Animals; Brain; Georgia; Rabies; Rabies virus; Swine; Swine Diseases; United States
PubMed: 31916501
DOI: 10.1177/1040638719898687 -
Journal of Neurology, Neurosurgery, and... Jul 1974A 65 year old man developed progressive signs of pontine and medullary dysfunction with striking bilateral paralysis of lateral gaze, dysarthria, dysphagia, and ataxia....
A 65 year old man developed progressive signs of pontine and medullary dysfunction with striking bilateral paralysis of lateral gaze, dysarthria, dysphagia, and ataxia. A respiratory death occurred seven months from the onset. Pathological examination revealed focal brain-stem changes of perivascular lymphocytic cuffing, microglial infiltration, glial nodules, and neuronophagia. No underlying malignancy or general disease impairing immunity mechanisms was discovered.
Topics: Aged; Ataxia; Brain Injuries; Brain Stem; Encephalitis; Gliosis; Humans; Male; Ophthalmoplegia; Phagocytosis; Respiratory Insufficiency; Speech Disorders
PubMed: 4854509
DOI: 10.1136/jnnp.37.7.811 -
BMC Veterinary Research Aug 2017Tick-borne encephalitis (TBE) is the most important viral tick borne zoonosis in Europe. In Germany, about 250 human cases are registered annually, with the highest...
BACKGROUND
Tick-borne encephalitis (TBE) is the most important viral tick borne zoonosis in Europe. In Germany, about 250 human cases are registered annually, with the highest incidence reported in the last years coming from the federal states Bavaria and Baden-Wuerttemberg. In veterinary medicine, only sporadic cases in wild and domestic animals have been reported; however, a high number of wild and domestic animals have tested positive for the tick-borne encephalitis virus (TBEV) antibody.
CASE PRESENTATION
In May 2015, a five-month-old lamb from a farm with 15 Merino Land sheep and offspring in Nersingen/Bavaria, a TBEV risk area, showed impaired general health with pyrexia and acute neurological signs. The sheep suffered from ataxia, torticollis, tremor, nystagmus, salivation and finally somnolence with inappetence and recumbency. After euthanasia, pathological, histopathological, immunohistochemical, bacteriological, parasitological and virological analyses were performed. Additionally, blood samples from the remaining, healthy sheep in the herd were taken for detection of TBEV antibody titres. At necropsy and accompanying parasitology, the sheep showed a moderate to severe infection with Trichostrongylids, Moniezia and Eimeria species. Histopathology revealed mild to moderate necrotising, lymphohistiocytic and granulocytic meningoencephalitis with gliosis and neuronophagia. Immunohistochemistry for TBEV was negative. RNA of a TBEV strain, closely related to the Kumlinge A52 strain, was detected in the brain by quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) and subsequent PCR product sequencing. A phylogenetic analysis revealed a close relationship to the TBEV of central Europe. TBEV was cultured from brain tissue. Serologically, one of blood samples from the other sheep in the herd was positive for TBEV in an enzyme-linked immunosorbent assay (ELISA) and in a serum neutralisation test (SNT), and one was borderline in an ELISA.
CONCLUSION
To the authors' knowledge this is the first report of a natural TBEV infection in a sheep in Europe with clinical manifestation, which describes the clinical presentation and the histopathology of TBEV infection.
Topics: Animals; Antibodies, Viral; Brain; Encephalitis Viruses, Tick-Borne; Encephalitis, Tick-Borne; Sheep; Sheep Diseases
PubMed: 28830430
DOI: 10.1186/s12917-017-1192-3 -
Journal of Comparative Pathology 2014A central nervous system (CNS) disorder characterized by non-suppurative encephalomyelitis with neurological signs was induced experimentally in gnotobiotic pigs by...
A central nervous system (CNS) disorder characterized by non-suppurative encephalomyelitis with neurological signs was induced experimentally in gnotobiotic pigs by intravenous and oral or intranasal inoculation of the porcine teschovirus (PTV) Toyama 2002 strain isolated from breeding pigs in Japan. Lesions consisting of perivascular cuffing of mononuclear cells, focal gliosis, neuronal necrosis and neuronophagia were observed in the brainstem, cerebellum and spinal cord. Non-suppurative ganglionitis in the spinal ganglion and neuritis in the spinal root were also observed. Regardless of the route of inoculation, all pigs infected experimentally with PTV showed a similar distribution of CNS lesions. Histological lesions in the CNS caused by oral or intranasal inoculation of the virus were mild compared with those induced by intravenous infection. Immunohistochemically, the distribution of PTV antigens corresponded closely with the distribution of brain lesions. PTV particles were detected via electron microscopy in the cytoplasm of nerve cells and the endothelial cells of blood vessels in the spinal cord of inoculated pigs. Polymerase chain reaction analysis demonstrated the presence of PTV RNA in the CNS, tonsils and large intestines of 21 of the 22 pigs inoculated. Direct CNS invasion via the blood vessels appears to be a major route of infection for PTV. The gnotobiotic pig provides a useful model for further study of PTV pathogenesis.
Topics: Animals; Brain Stem; Cerebellum; Encephalomyelitis, Enzootic Porcine; Germ-Free Life; Spinal Cord; Swine; Teschovirus
PubMed: 24650890
DOI: 10.1016/j.jcpa.2013.08.004