Anti-SARS-CoV-2 antibodies in the CSF, blood-brain barrier dysfunction, and neurological outcome: Studies in 8 stuporous and comatose patients.

OBJECTIVE: To investigate the pathophysiologic mechanism of encephalopathy and prolonged comatose or stuporous state in severally ill patients with coronavirus disease 2019 (COVID-19). METHODS: Eight COVID-19 patients with signs of encephalopathy were tested for antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the serum and CSF using a Food and Drug Administration-approved and independently validated ELISA. Blood-brain barrier (BBB) integrity and immunoglobulin G (IgG) intrathecal synthesis were further tested using albumin and IgG indices. The CSF was also tested for autoimmune encephalitis antibodies and 14-3-3, a marker of ongoing neurodegeneration. RESULTS: All patients had anti-SARS-CoV-2 antibodies in their CSF, and 4 of 8 patients had high titers, comparable to high serum values. One patient had anti-SARS-CoV-2 IgG intrathecal synthesis, and 3 others had disruption of the blood-brain barrier. The CSF in 4 patients was positive for 14-3-3-protein suggesting ongoing neurodegeneration. In all patients, the CSF was negative for autoimmune encephalitis antibodies and SARS-CoV-2 by PCR. None of the patients, apart from persistent encephalopathic signs, had any focal neurologic signs or history or specific neurologic disease. CONCLUSIONS: High-titer anti-SARS-CoV-2 antibodies were detected in the CSF of comatose or encephalopathic patients demonstrating intrathecal IgG synthesis or BBB disruption. A disrupted BBB may facilitate the entry of cytokines and inflammatory mediators into the CNS enhancing neuroinflammation and neurodegeneration. The observations highlight the need for prospective CSF studies to determine the pathogenic role of anti-SARS-CoV-2 antibodies and identify early therapeutic interventions.

Isolated intracranial hypertension associated with COVID-19.

BACKGROUND: Headache is a frequent complaint in COVID-19 patients. However, no detailed information on headache characteristics is provided in these reports. Our objective is to describe the characteristics of headache and the cerebrospinal fluid (CSF) profile in COVID-19 patients, highlighting the cases of isolated intracranial hypertension. METHODS: In this cross-sectional study, we selected COVID-19 patients who underwent lumbar puncture due to neurological complaints from April to May 2020. We reviewed clinical, imaging, and laboratory data of patients with refractory headache in the absence of other encephalitic or meningitic features. CSF opening pressures higher than 250 mmH2O were considered elevated, and from 200 to 250 mmH2O equivocal. RESULTS: Fifty-six COVID-19 patients underwent lumbar puncture for different neurological conditions. A new, persistent headache that prompted a CSF analysis was diagnosed in 13 (23.2%). The pain was throbbing, holocranial or bilateral in the majority of patients. All patients had normal CSF analysis and RT-qPCR for SARS-CoV-2 was negative in all samples. Opening pressure >200 mmH2O was present in 11 patients and, in six of these, > 250 mmH2O. 6/13 patients had complete improvement of the pain, five had partial improvement, and two were left with a daily persistent headache. CONCLUSIONS: In a significant proportion of COVID-19 patients, headache was associated to intracranial hypertension in the absence of meningitic or encephalitic features. Coagulopathy associated with COVID-19 could be an explanation, but further studies including post-mortem analysis of areas of production and CSF absorption (choroid plexuses and arachnoid granulations) are necessary to clarify this issue.

Progress in research on the detection of the novel coronavirus in human samples of different groups.

OBJECTIVE: Among the illnesses that may develop from COVID-19, the disease caused by the novel coronavirus (SARS-CoV-2), is pneumonia, a severe acute respiratory infectious disease. SARS-CoV-2 continues to spread worldwide and has caused hundreds of thousands of deaths thus far and has disrupted the world economy. PATIENTS AND METHODS: This review summarized the reported distributions of SARS-CoV-2 in 13 biological samples of the human body, including nose, feces, sperm, tears, breast milk, cerebrospinal fluid, urine, organs, sputum, cell lines, bronchial brush, blood, throat, and bronchoalveolar lavage fluid. Moreover, this review briefly describes the detection of SARS-CoV-2 in human body samples of five other coronaviruses. CONCLUSIONS: This review offers several recommendations for controlling the spread of SARS-CoV-2 control, specifically, sample collection from suspected cases from foreign countries and risk assessment of imported special goods (biological materials).

Acute necrotizing encephalopathy with SARS-CoV-2 RNA confirmed in cerebrospinal fluid.

Here, we report a case of COVID-19-related acute necrotizing encephalopathy where SARS-CoV-2 RNA was found in CSF 19 days after symptom onset after testing negative twice. Although monocytes and protein levels in CSF were only marginally increased, and our patient never experienced a hyperinflammatory state, her neurologic function deteriorated into coma. MRI of the brain showed pathologic signal symmetrically in central thalami, subinsular regions, medial temporal lobes, and brain stem. Extremely high concentrations of the neuronal injury markers neurofilament light and tau, as well as an astrocytic activation marker, glial fibrillary acidic protein, were measured in CSF. Neuronal rescue proteins and other pathways were elevated in the in-depth proteomics analysis. The patient received IV immunoglobulins and plasma exchange. Her neurologic status improved, and she was extubated 4 weeks after symptom onset. This case report highlights the neurotropism of SARS-CoV-2 in selected patients and emphasizes the importance of repeated lumbar punctures and CSF analyses in patients with suspected COVID-19 and neurologic symptoms.

Acute myelitis and SARS-CoV-2 infection. A new etiology of myelitis?

The etiological agent of coronavirus disease-19 (COVID-19), SARS-coronavirus-2 (SARS-CoV-2), emerged in Wuhan, China, and quickly spread worldwide leading the World Health Organization (WHO) to recognize it not only as a pandemic but also as an important thread to public health. Beyond respiratory symptoms, new neurological manifestations are being identified such as headache, ageusia, anosmia, encephalitis or acute cerebrovascular disease. Here we report the case of an acute transverse myelitis (TM) in a patient with SARS-CoV-2 infection detected by the nasopharyngeal swab technique but not in cerebrospinal fluid (CSF) analysis. Anti-herpes simplex virus (HSV) 1 and varicella-zoster IgM antibodies were not detected in serum samples and spinal and brain magnetic resonance imaging (MRI) showed no abnormal findings. This case remarks that COVID-19 nervous system damage could be caused by immune-mediated mechanisms.

Coronavirus disease 2019 associated with aggressive neurological and mental abnormalities confirmed based on cerebrospinal fluid antibodies: A case report.

INTRODUCTION: Coronavirus disease (COVID-19) is spreading worldwide. The reported possible neurological symptoms are varied and range from subtle neurologic deficits to unconsciousness. Knowledge regarding the detection, diagnosis, treatment, and follow-up of COVID-19-associated neurological damage is still limited. We report a case of serious neurological damage and mental abnormalities in a patient who was finally confirmed to have COVID-19 based on IgM and IgG antibodies in the cerebrospinal fluid (CSF). PATIENT CONCERNS: A 68-year-old man had slight flu-like symptoms and transient loss of consciousness in early February. Exaggerated unconsciousness and deteriorating mental abnormalities occurred over the next month without severe respiratory symptoms. Craniocerebral computed tomography showed normal results, but antibodies against severe acute respiratory syndrome coronavirus 2 were 100 times higher in the CSF than in the serum; tests for viral ribonucleic acid showed negative results with both a nasopharyngeal swab and CSF sample. DIAGNOSIS: COVID-19 pneumonia was diagnosed based on symptoms and positive results for IgM and IgG in the CSF. INTERVENTIONS: Antiviral, fluid, and nutritional support were administered for 30 days before admission without obvious improvement. A further 18 days of routine antiviral therapy, immunoglobulin therapy (10 g per day for 5 days), and antipsychotic drug treatment were administered. OUTCOMES: The patient's neurological and mental abnormalities were greatly ameliorated. He was discharged with mild irritability, slight shaking of the hands, and walking fatigue. These symptoms have persisted up to our last follow-up (May 4, 2020). CONCLUSION: We believe this is the first case involving neural system injury in a patient who confirmed COVID-19 based on CSF antibody test results. Negative ribonucleic acid test results, strong positivity for antibodies, and high protein levels in the CSF suggest the possibility of autoimmune encephalitis secondary to COVID-19. This case highlights additional novel symptoms of COVID-19, and these data are important for the assessment and follow-up of COVID-19 patients.

Headache and pleocytosis in CSF associated with COVID-19: case report.

In December 2019, a new coronavirus infection was identified in China. Although the clinical presentation of COVID-19 is predominantly respiratory, more than 35%% of patients have neurological symptoms. We report an elderly female with asthenia, dry cough, anosmia, ageusia, fever, nausea, and a severe and persistent headache. She had confirmed COVID-19 using the nasal swab RT-PCR technique. Her cranial tomography was normal. The CSF analysis demonstrated a cell count of 21 cells/mm3 (80% lymphocytes and 20% monocytes), 34 mg/dl protein, and 79 mg/dl glucose. She improved after 4 days. Our report draws attention to the meningeal involvement of SARS-Cov-2.

First report of manic-like symptoms in a COVID-19 patient with no previous history of a psychiatric disorder.

BACKGROUND: In December 2019, the novel coronavirus (SARS-CoV-2) infection was first reported in Wuhan city, central China, which has spread rapidly. The common clinical features of patients with SARS-CoV-2 infection included fever, fatigue, and damage to the respiratory or digestive system. However, it is still unclear whether SARS-CoV-2 infection could cause damage to the central nervous system (CNS) inducing psychiatric symptoms. CASE REPORT: Herein, we present the first case of SARS-CoV-2 infection with manic-like symptoms and describe the diagnosis, clinical course, and treatment of the case, focusing on the identifications of SARS-CoV-2 in the specimen of cerebrospinal fluid (CSF). The patient developed manic-like symptoms when his vital signs recovered on illness day 17. After manic-like attack, the detection of SARS-CoV-2 specific IgG antibody in CSF was positive, while the reverse transcriptase-polymerase chain reaction (RT-PCR) on CSF for the SARS-CoV-2 was negative. The patient received Olanzapine for treatment and his mood problems concurrently improved as indicated by scores of Young Manic Rating Scale (YMRS). LIMITATION: This is a single case report only, and the RT-PCR test for SARS-CoV-2 in CSF was not performed simultaneously when SARS-CoV-2 was positive in samples of sputum and stool. CONCLUSION: This first case of COVID-19 patient with manic-like symptoms highlights the importance of evaluation of mental health status and may contribute to our understanding of potential risk of CNS impairments by SARS-CoV-2 infection.

First case of SARS-COV-2 sequencing in cerebrospinal fluid of a patient with suspected demyelinating disease.

The association between coronaviruses and central nervous system (CNS) demyelinating lesions has been previously shown. However, no case has been described of an association between the novel coronavirus (SARS-COV-2) and CNS demyelinating disease so far. SARS-COV-2 was previously detected in cerebrospinal fluid (CSF) sample of a patient with encephalitis. However, the virus identity was not confirmed by deep sequencing of SARS-COV-2 detected in the CSF. Here, we report a case of a patient with mild respiratory symptoms and neurological manifestations compatible with clinically isolated syndrome. The viral genome of SARS-COV-2 was detected and sequenced in CSF with 99.74-100% similarity between the patient virus and worldwide sequences. This report suggests a possible association of SARS-COV-2 infection with neurological symptoms of demyelinating disease, even in the absence of relevant upper respiratory tract infection signs.

Neurotropism of SARS-CoV-2: COVID-19 presenting with an acute manic episode.

A 41-year-old man with no significant medical history presented with acute behavioural disruption on the background of a 1-day history of severe headache and a 10-day history of dry cough and fever. He was sexually disinhibited with pressured speech and grandiose ideas. His behaviour worsened, necessitating heavy sedation and transfer to intensive care for mechanical ventilation despite no respiratory indication. Investigations confirmed that he was positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neuroimaging and a lumbar puncture were normal. Initial screening for SARS-CoV-2 in the cerebrospinal fluid was negative although no validated assay was available. The patient's mental state remained abnormal following stepdown from intensive care. Psychiatric assessment found features consistent with acute mania, and he was detained under the Mental Health Act. This case indicates the need to consider COVID-19 in a wider series of clinical presentations and to develop a validated assay for SARS-CoV-2 in the cerebrospinal fluid.

Patients with COVID-19 and neurological manifestations show undetectable SARS-CoV-2 RNA levels in the cerebrospinal fluid.

We report that patients with COVID-19 displaying distinct neurological disorders have undetectable or extremely low levels of SARS-CoV-2 RNA in the cerebrospinal fluid, indicating that viral clearance precede the neurological involvement. This finding points to the need for the development of more sensitive molecular tests and the investigation of other neurotropic pathogens to exclude concurrent neuroinfection.

Encephalopathy and Encephalitis Associated with Cerebrospinal Fluid Cytokine Alterations and Coronavirus Disease, Atlanta, Georgia, USA, 2020.

There are few detailed investigations of neurologic complications in severe acute respiratory syndrome coronavirus 2 infection. We describe 3 patients with laboratory-confirmed coronavirus disease who had encephalopathy and encephalitis develop. Neuroimaging showed nonenhancing unilateral, bilateral, and midline changes not readily attributable to vascular causes. All 3 patients had increased cerebrospinal fluid (CSF) levels of anti-S1 IgM. One patient who died also had increased levels of anti-envelope protein IgM. CSF analysis also showed markedly increased levels of interleukin (IL)-6, IL-8, and IL-10, but severe acute respiratory syndrome coronavirus 2 was not identified in any CSF sample. These changes provide evidence of CSF periinfectious/postinfectious inflammatory changes during coronavirus disease with neurologic complications.