Inflammatory leptomeningeal cytokines mediate delayed COVID-19 encephalopathy

Remšík, Ján; Ja, Wilcox; Ne, Babady; McMillen, Tracy; Ba, Vachha; Na, Halpern; Dhawan,; Rosenblum, Marc K.; Iacobuzio-Donahue, Christine A.; Ek, Avila; Santomasso, Bianca; Boire, Adrienne

doi:10.1101/2020.09.15.20195511

Cited by 15 publications

(33 citation statements)

References 27 publications

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“…In addition to these reports from France, cumulative CSF results from patients with COVID-19 have been described by other authors, a few examples of which are noted here [ 224 , [281] , [282] , [283] ]. Espindola et al analyzed the CSF of 58 patients in Brazil with COVID-19 diagnosed via nasopharygneal SARS-CoV-2 PCR who had a variety of neurological complaints and found: 10 (17%) patients had a CSF WBC count >5 cells/μL (median 2 cells/μL (interquartile range (IQR) 1–4 cells/μL); 16 (28%) patients had CSF protein >45 mg/dL (median 35 mg/dL (IQR 25.8-48 mg/dL); 2 (3%) patients had detectable SARS-CoV-2 RNA in the CSF (one with persistent headache and one with acute disseminated encephalomyelitis); 3/38 (8%) patients had oligoclonal bands restricted to the CSF consistent with intrathecal IgG synthesis, 4/38 (11%) patients had matched CSF and serum oligoclonal bands while 31/38 (82%) patients had no oligoclonal bands; and median CSF neurofilament light chain was 1,694 pg/mL (IQR 1,091–3,358 pg/mL) and median CSF tau was 318.3 pg/mL (IQR 173-457.4 pg/mL) [ 281 ].…”

Section: Discussionsupporting

confidence: 66%

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Cerebrospinal fluid in COVID-19: A systematic review of the literature

Lewis

Frontera

Placantonakis

et al. 2021

Journal of the Neurological Sciences

150

152

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We sought to review the literature on cerebrospinal fluid (CSF) testing in patients with COVID-19 for evidence of viral neuroinvasion by SARS-CoV-2. Methods: We performed a systematic review of Medline and Embase between December 1, 2019 and November 18, 2020 to identify case reports or series of patients who had COVID-19 diagnosed based on positive SARS-CoV-2 polymerase chain reaction (PCR) or serologic testing and had CSF testing due to a neurologic symptom. Results: We identified 242 relevant documents which included 430 patients with COVID-19 who had acute neurological symptoms prompting CSF testing. Of those, 321 (75%) patients had symptoms that localized to the central nervous system (CNS). Of 304 patients whose CSF was tested for SARS-CoV-2 PCR, there were 17 (6%) whose test was positive, all of whom had symptoms that localized to the central nervous system (CNS). The majority (13/17, 76%) of these patients were admitted to the hospital because of neurological symptoms. Of 58 patients whose CSF was tested for SARS-CoV-2 antibody, 7 (12%) had positive antibodies with evidence of intrathecal synthesis, all of whom had symptoms that localized to the CNS. Of 132 patients who had oligoclonal bands evaluated, 3 (2%) had evidence of intrathecal antibody synthesis. Of 77 patients tested for autoimmune antibodies in the CSF, 4 (5%) had positive findings. Conclusion: Detection of SARS-CoV-2 in CSF via PCR or evaluation for intrathecal antibody synthesis appears to be rare. Most neurological complications associated with SARS-CoV-2 are unlikely to be related to direct viral neuroinvasion.

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Section: Discussionsupporting

confidence: 66%

“…Remsik et al analyzed the CSF of 13 patients with cancer, COVID-19 and neurological symptoms [ 283 ]. None of the patients had a positive CSF SARS-CoV-2 PCR.…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid in COVID-19: A systematic review of the literature

Lewis

Frontera

Placantonakis

et al. 2021

Journal of the Neurological Sciences

150

152

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“…TNFRSF1B showed consistent expression changes in AD or AD-related pathologies, as well as in COVID-19 patient CSF samples. We also found that CXCL10 protein level was increased in CSF of COVID-19 patients [84] (Fig. 3b).…”

Section: Neuroinflammation-mediated Association Between Neuro-covid-1supporting

confidence: 54%

Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment

Zhou

Hou

et al. 2021

Preprint

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Background: Dementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive interventions. Methods: In this study, we conducted a network-based, multimodal genomics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9 based genetic assay results, and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimer disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2. Results: We found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors (BSG and FURIN) and antiviral defense genes (LY6E, IFITM2, IFITM3, and IFNAR1) was significantly elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Notably, individuals with the AD risk allele APOE E4/E4 displayed reduced levels of antiviral defense genes compared to APOE E3/E3 individuals. Conclusion: Our results suggest significant mechanistic overlap between AD and COVID-19, strongly centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions.

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“…Similarly, neurotoxicity grade in ICANS correlates with CSF cytokine levels but not with CAR T‐cells in CSF 17 . In both conditions, CSF investigations revealed normal or mildly elevated cell counts with variable protein levels and elevated cytokine levels with molecular consistency across conditions 10,13,16,17,37,38,66 . Therefore, a cytokine‐mediated neuroinflammatory process has been suggested as the underlying pathogenic mechanism 5,10,12,14 …”

Section: Comparison Of Covid‐19‐related Encephalopathy and Icansmentioning

confidence: 99%

“…Additionally, CSF analysis, neuroimaging, and neuropathological findings, as well as the clinical response to various immunotherapies, are not consistent with an infectious disease targeting the brain but rather with an immune‐mediated pathogenesis 4,9–11 . Therefore, a cytokine‐mediated neuroinflammatory process, associated with cytokine storm, has been suggested as the underlying pathogenic mechanism 5,10,12–14 …”

Section: Introductionmentioning

confidence: 99%

Brain dysfunction in COVID‐19 and CAR‐T therapy: cytokine storm‐associated encephalopathy

Pensato

Muccioli

Cani

et al. 2021

Ann Clin Transl Neurol

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Objective Many neurological manifestations are associated with COVID‐19, including a distinct form of encephalopathy related to cytokine storm, the acute systemic inflammatory syndrome present in a subgroup of COVID‐19 patients. Cytokine storm is also associated with immune effector cell‐associated neurotoxicity syndrome (ICANS), a complication of chimeric antigen receptor T‐cell (CAR‐T) therapy, a highly effective treatment for refractory hematological malignancies. We investigated whether COVID‐19‐related encephalopathy, ICANS, and other encephalopathies associated with cytokine storm, share clinical and investigative findings. Methods Narrative literature review. Results Comparisons between COVID‐19‐related encephalopathy and ICANS revealed several overlapping features. Clinically, these included dysexecutive syndrome, language disturbances, akinetic mutism and delirium. EEG showed a prevalence of frontal abnormalities. Brain MRI was often unrevealing. CSF elevated cytokine levels have been reported. A direct correlation between cytokine storm intensity and severity of neurological manifestations has been shown for both conditions. Clinical recovery occurred spontaneously or following immunotherapies in most of the patients. Similar clinical and investigative features were also reported in other encephalopathies associated with cytokine storm, such as hemophagocytic lymphohistiocytosis, sepsis, and febrile infection‐associated encephalopathies. Interpretation COVID‐19‐related encephalopathy and ICANS are characterized by a predominant electro‐clinical frontal lobe dysfunction and share several features with other encephalopathies associated with cytokine storm, which may represent the common denominator of a clinical spectrum of neurological disorders. Therefore, we propose a unifying definition of cytokine storm‐associated encephalopathy (CySE), and its diagnostic criteria.

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Inflammatory leptomeningeal cytokines mediate delayed COVID-19 encephalopathy

Cited by 15 publications

References 27 publications

Cerebrospinal fluid in COVID-19: A systematic review of the literature

Cerebrospinal fluid in COVID-19: A systematic review of the literature

Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment

Brain dysfunction in COVID‐19 and CAR‐T therapy: cytokine storm‐associated encephalopathy

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