Brain autopsies of critically ill COVID-19 patients demonstrate heterogeneous profile of acute vascular injury, inflammation and age-linked chronic brain diseases.

BACKGROUND: This study examined neuropathological findings of patients who died following hospitalization in an intensive care unit with SARS-CoV-2. METHODS: Data originate from 20 decedents who underwent brain autopsy followed by ex-vivo imaging and dissection. Systematic neuropathologic examinations were performed to assess histopathologic changes including cerebrovascular disease and tissue injury, neurodegenerative diseases, and inflammatory response. Cerebrospinal fluid (CSF) and fixed tissues were evaluated for the presence of viral RNA and protein. RESULTS: The mean age-at-death was 66.2 years (range: 26-97 years) and 14 were male. The patient's medical history included cardiovascular risk factors or diseases (n = 11, 55%) and dementia (n = 5, 25%). Brain examination revealed a range of acute and chronic pathologies. Acute vascular pathologic changes were common in 16 (80%) subjects and included infarctions (n = 11, 55%) followed by acute hypoxic/ischemic injury (n = 9, 45%) and hemorrhages (n = 7, 35%). These acute pathologic changes were identified in both younger and older groups and those with and without vascular risk factors or diseases. Moderate-to-severe microglial activation were noted in 16 (80%) brains, while moderate-to-severe T lymphocyte accumulation was present in 5 (25%) brains. Encephalitis-like changes included lymphocytic cuffing (n = 6, 30%) and neuronophagia or microglial nodule (most prominent in the brainstem, n = 6, 30%) were also observed. A single brain showed vasculitis-like changes and one other exhibited foci of necrosis with ball-ring hemorrhages reminiscent of acute hemorrhagic leukoencephalopathy changes. Chronic pathologies were identified in only older decedents: 7 brains exhibited neurodegenerative diseases and 8 brains showed vascular disease pathologies. CSF and brain samples did not show evidence of viral RNA or protein. CONCLUSIONS: Acute tissue injuries and microglial activation were the most common abnormalities in COVID-19 brains. Focal evidence of encephalitis-like changes was noted despite the lack of detectable virus. The majority of older subjects showed age-related brain pathologies even in the absence of known neurologic disease. Findings of this study suggest that acute brain injury superimposed on common pre-existing brain disease may put older subjects at higher risk of post-COVID neurologic sequelae.

Autoimmune encephalitis after BBIBP-CorV (Sinopharm) COVID-19 vaccination: a case report.

BACKGROUND: Vaccination is an important public health strategy; however, many neurological adverse effects are associated with COVID-19 vaccination, being encephalitis a rare manifestation. CASE PRESENTATION: We present the case of a 33-year-old woman who received the first dose of the BBIBP-CorV vaccine against COVID-19 on April 4 and the second dose on April 28, 2021. Three days after receiving the second dose, she experienced a subacute episode of headache, fever, insomnia, and transient episodes of environment disconnection. We obtained negative results for infectious, systemic, and oncological causes. Brain magnetic resonance imaging showed lesions in the bilateral caudate nucleus and nonspecific demyelinating lesions at the supratentorial and infratentorial compartments. The results of the neuronal autoantibodies panel were negative. She had an adequate response to immunoglobulin and methylprednisolone; however, she experienced an early clinical relapse and received a new cycle of immunosuppressive treatment followed by a satisfactory clinical evolution. CONCLUSIONS: We report the first case of severe encephalitis associated with BBIBP-CorV (Sinopharm) vaccination in Latin America. The patient had atypical imaging patterns, with early clinical relapse and a favorable response to corticosteroid therapy.

Modeling SARS-CoV-2: Comparative Pathology in Rhesus Macaque and Golden Syrian Hamster Models.

Coronavirus disease 2019 (COVID-19) in humans has a wide range of presentations, ranging from asymptomatic or mild symptoms to severe illness. Suitable animal models mimicking varying degrees of clinical disease manifestations could expedite development of therapeutics and vaccines for COVID-19. Here we demonstrate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection resulted in subclinical disease in rhesus macaques with mild pneumonia and clinical disease in Syrian hamsters with severe pneumonia. SARS-CoV-2 infection was confirmed by formalin-fixed, paraffin-embedded (FFPE) polymerase chain reaction (PCR), immunohistochemistry, or in situ hybridization. Replicating virus in the lungs was identified using in situ hybridization or virus plaque forming assays. Viral encephalitis, reported in some COVID-19 patients, was identified in one macaque and was confirmed with immunohistochemistry. There was no evidence of encephalitis in hamsters. Severity and distribution of lung inflammation were substantially more in hamsters compared with macaques and exhibited vascular changes and virus-induced cytopathic changes as seen in COVID-19 patients. Neither the hamster nor macaque models demonstrated evidence for multisystemic inflammatory syndrome (MIS). Data presented here demonstrate that macaques may be appropriate for mechanistic studies of mild asymptomatic COVID-19 pneumonia and COVID-19-associated encephalitis, whereas Syrian hamsters may be more suited to study severe COVID-19 pneumonia.

COVID-19-associated immune-mediated encephalitis mimicking acute-onset Creutzfeldt-Jakob disease.

We report a subtype of immune-mediated encephalitis associated with COVID-19, which closely mimics acute-onset sporadic Creutzfeldt-Jakob disease. A 64-year-old man presented with confusion, aphasia, myoclonus, and a silent interstitial pneumonia. He tested positive for SARS-CoV-2. Cognition and myoclonus rapidly deteriorated, EEG evolved to generalized periodic discharges and brain MRI showed multiple cortical DWI hyperintensities. CSF analysis was normal, except for a positive 14-3-3 protein. RT-QuIC analysis was negative. High levels of pro-inflammatory cytokines were present in the CSF and serum. Treatment with steroids and intravenous immunoglobulins produced EEG and clinical improvement, with a good neurological outcome at a 6-month follow-up.

Activation of Endogenous Retrovirus, Brain Infections and Environmental Insults in Neurodegeneration and Alzheimer's Disease.

Chronic neurodegenerative diseases are complex, and their pathogenesis is uncertain. Alzheimer's disease (AD) is a neurodegenerative brain alteration that is responsible for most dementia cases in the elderly. AD etiology is still uncertain; however, chronic neuroinflammation is a constant component of brain pathology. Infections have been associated with several neurological diseases and viruses of the Herpes family appear to be a probable cause of AD neurodegenerative alterations. Several different factors may contribute to the AD clinical progression. Exogeneous viruses or other microbes and environmental pollutants may directly induce neurodegeneration by activating brain inflammation. In this paper, we suggest that exogeneous brain insults may also activate retrotransposons and silent human endogenous retroviruses (HERVs). The initial inflammation of small brain areas induced by virus infections or other brain insults may activate HERV dis-regulation that contributes to neurodegenerative mechanisms. Chronic HERV activation in turn may cause progressive neurodegeneration that thereafter merges in cognitive impairment and dementia in genetically susceptible people. Specific treatment for exogenous end endogenous pathogens and decreasing pollutant exposure may show beneficial effect in early intervention protocol to prevent the progression of cognitive deterioration in the elderly.

Neurological manifestations of COVID-19: available evidences and a new paradigm.

The recent pandemic outbreak of coronavirus is pathogenic and a highly transmittable viral infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2). In this time of ongoing pandemic, many emerging reports suggested that the SARS-CoV-2 has inimical effects on neurological functions, and even causes serious neurological damage. The neurological symptoms associated with COVID-19 include headache, dizziness, depression, anosmia, encephalitis, stroke, epileptic seizures, and Guillain-Barre syndrome along with many others. The involvement of the CNS may be related with poor prognosis and disease worsening. Here, we review the evidence of nervous system involvement and currently known neurological manifestations in COVID-19 infections caused by SARS-CoV-2. We prioritize the 332 human targets of SARS-CoV-2 according to their association with brain-related disease and identified 73 candidate genes. We prioritize these 73 genes according to their spatio-temporal expression in the different regions of brain and also through evolutionary intolerance analysis. The prioritized genes could be considered potential indicators of COVID-19-associated neurological symptoms and thus act as a possible therapeutic target for the prevention and treatment of CNS manifestations associated with COVID-19 patients.

SARS-CoV-2 and the Nervous System: From Clinical Features to Molecular Mechanisms.

Increasing evidence suggests that Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2) can also invade the central nervous system (CNS). However, findings available on its neurological manifestations and their pathogenic mechanisms have not yet been systematically addressed. A literature search on neurological complications reported in patients with COVID-19 until June 2020 produced a total of 23 studies. Overall, these papers report that patients may exhibit a wide range of neurological manifestations, including encephalopathy, encephalitis, seizures, cerebrovascular events, acute polyneuropathy, headache, hypogeusia, and hyposmia, as well as some non-specific symptoms. Whether these features can be an indirect and unspecific consequence of the pulmonary disease or a generalized inflammatory state on the CNS remains to be determined; also, they may rather reflect direct SARS-CoV-2-related neuronal damage. Hematogenous versus transsynaptic propagation, the role of the angiotensin II converting enzyme receptor-2, the spread across the blood-brain barrier, the impact of the hyperimmune response (the so-called "cytokine storm"), and the possibility of virus persistence within some CNS resident cells are still debated. The different levels and severity of neurotropism and neurovirulence in patients with COVID-19 might be explained by a combination of viral and host factors and by their interaction.

COVID-19-Associated Encephalitis Mimicking Glial Tumor.

BACKGROUND: Reports on neurologic manifestations of coronavirus disease 2019 (COVID-19) have attracted broad attention. We present an unusual case of COVID-19-associated encephalitis mimicking a glial tumor. CASE DESCRIPTION: A 35-year-old woman presented with headache and seizures. T2 fluid-attenuated inverse recovery imaging showed hyperintensities in the left temporal lobe. Magnetic resonance spectroscopy showed an elevated choline peak. Imaging findings were suggestive of high-grade glioma. Antiepileptic medication failed to achieve seizure control. A left anterior temporal lobectomy was performed. The patient had no postoperative deficits, and her symptoms completely improved. Histologic examination revealed encephalitis. Postoperatively, our patient tested positive for COVID-19. CONCLUSIONS: Our case raises awareness of neurologic manifestations of the disease and their potential to mimic glial tumors. For prompt diagnosis and prevention of transmission, clinicians should consider COVID-19 in patients with similar presentation.