Cerebrospinal fluid findings in neurological diseases associated with COVID-19 and insights into mechanisms of disease development

Espíndola, Otávio de Melo; Brandão, Carlos Otávio; Gomes, Yago Côrtes Pinheiro; Siqueira, Marilda M.; Soares, Cristiane; Lima, Marco Antônio; Leite, Ana Cláudia Celestino Bezerra; Torezani, Guilherme; Araújo, Abelardo; Silva, Marcus Tulius T.

doi:10.1016/j.ijid.2020.10.044

Cited by 87 publications

(124 citation statements)

References 54 publications

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“…The lack of CSF pleocytosis in COVID-19 subjects, normal protein, and absence of abnormalities in IgG index or Q(Alb), concurs with other studies (16-20). This paucity of CSF inflammatory changes undermines the hypothesis that conventional neuroinflammatory or encephalitic processes play roles in the pathogenesis of the most common neurological complications associated with COVID-19 that were studied here.…”

Section: Discussionsupporting

confidence: 91%

“…Studies focused on the analysis of cerebrospinal fluid (CSF) in COVID-19 infection have outlined a diversity of CSF findings that lack specific profiles associated with the neurological symptoms (16)(17)(18)(19)(20)(21). Interestingly, IgG antibodies against SARS-CoV2 spike protein have been found in the CSF of eight patients with encephalopathy (22), and other case reports have described changes suggestive of an inflammatory process (23,24) and neuronal damage (25,26).…”

Section: Introductionmentioning

confidence: 99%

“…There are several unanswered questions regarding the pathogenesis of these neurological complications including concerns about the neuro-invasiveness or neurovirulence of SARS-CoV2, the role of neuroinflammation and the effects of the “cytokine storm” on the central nervous system (CNS). Studies focused on the analysis of cerebrospinal fluid (CSF) in COVID-19 infection have outlined a diversity of CSF findings that lack specific profiles associated with the neurological symptoms(16-21). Interestingly, IgG antibodies against SARS-CoV2 spike protein have been found in the CSF of eight patients with encephalopathy(22), and other case reports have described changes suggestive of an inflammatory process(23, 24) and neuronal damage(25, 26).…”

Section: Introductionmentioning

confidence: 99%

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Cerebrospinal fluid in COVID-19 neurological complications: no cytokine storm or neuroinflammation

García

Barreras

Lewis

et al. 2021

Preprint

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BACKGROUNDNeurological complications occur in COVID-19. We aimed to examine cerebrospinal fluid (CSF) of COVID-19 subjects with neurological complications and determine presence of neuroinflammatory changes implicated in pathogenesis.METHODSCross-sectional study of CSF neuroinflammatory profiles from 18 COVID-19 subjects with neurological complications categorized by diagnosis (stroke, encephalopathy, headache) and illness severity (critical, severe, moderate, mild). COVID-19 CSF was compared with CSF from healthy, infectious and neuroinflammatory disorders and stroke controls (n=82). Cytokines (IL-6, TNFα, IFNγ, IL-10, IL-12p70, IL-17A), inflammation and coagulation markers (high-sensitivity-C Reactive Protein [hsCRP], ferritin, fibrinogen, D-dimer, Factor VIII) and neurofilament light chain (NF-L), were quantified. SARS-CoV2 RNA and SARS-CoV2 IgG and IgA antibodies in CSF were tested with RT-PCR and ELISA.RESULTSCSF from COVID-19 subjects showed a paucity of neuroinflammatory changes, absence of pleocytosis or specific increases in pro-inflammatory markers or cytokines (IL-6, ferritin, or D-dimer). Anti-SARS-CoV2 antibodies in CSF of COVID-19 subjects (77%) were observed despite no evidence of SARS-CoV2 viral RNA. A similar increase of pro-inflammatory cytokines (IL-6, TNFα, IL-12p70) and IL-10 in CSF of COVID-19 and non-COVID-19 stroke subjects was observed compared to controls. CSF-NF-L was elevated in subjects with stroke and critical COVID-19. CSF-hsCRP was present almost exclusively in COVID-19 cases.CONCLUSIONThe paucity of neuroinflammatory changes in CSF of COVID-19 subjects and lack of SARS-CoV2 RNA do not support the presumed neurovirulence of SARS-CoV2 or neuroinflammation in pathogenesis of neurological complications in COVID-19. Elevated CSF-NF-L indicates neuroaxonal injury in COVID-19 cases. The role of CSF SARS-CoV2 IgG antibodies is still undetermined.FUNDINGThis work was supported by NIH R01-NS110122 and The Bart McLean Fund for Neuroimmunology Research.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cerebrospinal fluid in COVID-19 neurological complications: no cytokine storm or neuroinflammation

García

Barreras

Lewis

et al. 2021

Preprint

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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%

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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“…Human neurons are known to have a low level of ACE2 receptors, which may support the neuroinvasive potential of SARS-CoV-2 [ 6 ]. However, neuroinvasion has not been consistently shown, as numerous studies report undetectable SARS-CoV-2 in cerebrospinal fluid (CSF) [ 7 ]. Several publications using human brain organoid cultures showed SARS-CoV-2 infects neural progenitor cells and neurons with release of infectious virus [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Characterization and Biomarker Analyses of Post-COVID-19 Complications and Neurological Manifestations

Sun

Tang

Peluso

et al. 2021

Cells

156

146

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As the SARS-CoV-2 pandemic continues, reports have demonstrated neurologic sequelae following COVID-19 recovery. Mechanisms to explain long-term neurological sequelae are unknown and need to be identified. Plasma from 24 individuals recovering from COVID-19 at 1 to 3 months after initial infection were collected for cytokine and antibody levels and neuronal-enriched extracellular vesicle (nEV) protein cargo analyses. Plasma cytokine IL-4 was increased in all COVID-19 participants. Volunteers with self-reported neurological problems (nCoV, n = 8) had a positive correlation of IL6 with age or severity of the sequalae, at least one co-morbidity and increased SARS-CoV-2 antibody compared to those COVID-19 individuals without neurological issues (CoV, n = 16). Protein markers of neuronal dysfunction including amyloid beta, neurofilament light, neurogranin, total tau, and p-T181-tau were all significantly increased in the nEVs of all participants recovering from COVID-19 compared to historic controls. This study suggests ongoing peripheral and neuroinflammation after COVID-19 infection that may influence neurological sequelae by altering nEV proteins. Individuals recovering from COVID-19 may have occult neural damage while those with demonstrative neurological symptoms additionally had more severe infection. Longitudinal studies to monitor plasma biomarkers and nEV cargo are warranted to assess persistent neurodegeneration and systemic effects.

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Cerebrospinal fluid findings in neurological diseases associated with COVID-19 and insights into mechanisms of disease development

Cited by 87 publications

References 54 publications

Cerebrospinal fluid in COVID-19 neurological complications: no cytokine storm or neuroinflammation

Cerebrospinal fluid in COVID-19 neurological complications: no cytokine storm or neuroinflammation

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

Characterization and Biomarker Analyses of Post-COVID-19 Complications and Neurological Manifestations

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