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Anti–SARS-CoV-2 antibodies in the CSF, blood-brain barrier dysfunction, and neurological outcome: Studies in 8 stuporous and comatose patients
Open accessAbstract
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.
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“Several studies implied that blood–brain barrier disruption is associated with encephalopathy, favoring the neuro-inflammation theory [150, 151].”
From Cognitive decline following acute viral infections: literature review and projections for post-COVID-19 (2022) · cites this paper as [150]
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“CSF analysis of patients with neurological symptoms showed SARS-CoV-2 immunoreactivity, resulting from serum antibody leakage to the CSF, rather than to intrathecal antibody production [150, 160].”
From Cognitive decline following acute viral infections: literature review and projections for post-COVID-19 (2022) · cites this paper as [150]
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A first case of meningitis/encephalitis associated with SARS-Coronavirus-2
Moriguchi, T., Harii, N., Goto, J., Harada, D., Sugawara, H., Takamino, J., Ueno, M., Sakata, H., Kondo, K., Myose, N., et al. (2020) · International Journal of Infectious Diseases · doi:10.1016/j.ijid.2020.03.062 · Cited by 2,024
Multiorgan and Renal Tropism of SARS-CoV-2
Puelles, V. G., Lütgehetmann, M., Lindenmeyer, M. T., Sperhake, J. P., Wong, M. N., Allweiss, L., Chilla, S., Heinemann, A., Wanner, N., Liu, S., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmc2011400 · Cited by 1,775 · cited 2×
“The CSF was also tested for (1) SARS-CoV-2 genetic determination with PCR; (2) autoimmune encephalitis autoantibodies, including antiNMDAr, AMPAr, GABAbr, CASPR2, DPPX, and LGI1, using a cell-based assay (Euroimmun); and (3) for 14-3-3 protein, a marker of neurodegeneration, using Western Blot and an anti-14-3-3 polyc…”
MethodStringhini, S., Wisniak, A., Piumatti, G., Azman, A. S., Lauer, S. A., Baysson, H., De Ridder, D., Petrovic, D., Schrempft, S., Marcus, K., et al. (2020) · The Lancet · doi:10.1016/s0140-6736(20)31304-0 · Cited by 990
Zubair, A. S., McAlpine, L. S., Gardin, T., Farhadian, S., Kuruvilla, D. E., & Spudich, S. (2020) · JAMA Neurology · doi:10.1001/jamaneurol.2020.2065 · Cited by 923
COVID ‐19: A Global Threat to the Nervous System
Koralnik, I. J., & Tyler, K. L. (2020) · Annals of Neurology · doi:10.1002/ana.25807 · Cited by 480
Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19
Kanberg, N., Ashton, N. J., Andersson, L., Yilmaz, A., Lindh, M., Nilsson, S., Price, R. W., Blennow, K., Zetterberg, H., & Gisslén, M. (2020) · Neurology · doi:10.1212/wnl.0000000000010111 · Cited by 373
Guillain-Barré syndrome: The first documented COVID-19–triggered autoimmune neurologic disease
Dalakas, M. C. (2020) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000000781 · Cited by 257
Self-citationStatus of SARS-CoV-2 in cerebrospinal fluid of patients with COVID-19 and stroke
Saiegh, F. A., Ghosh, R., Leibold, A. T., Avery, M. B., Schmidt, R. F., Theofanis, T. N., Mouchtouris, N., Philipp, L. R., Peiper, S. C., Wang, Z., et al. (2020) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2020-323522 · Cited by 254
Benussi, A., Pilotto, A., Premi, E., Libri, I., Giunta, M., Agosti, C., Alberici, A., Baldelli, E., Benini, M., Bonacina, S., et al. (2020) · Neurology · doi:10.1212/wnl.0000000000009848 · Cited by 238
Macrophages: a Trojan horse in COVID-19?
Park, M. D. (2020) · Nature reviews. Immunology · doi:10.1038/s41577-020-0317-2 · Cited by 165
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Metadata
- Authors
- Alexopoulos, H., Magira, E., Bitzogli, K., Kafasi, N., Vlachoyiannopoulos, P., Tzioufas, A., Kotanidou, A., & Dalakas, M. C.
- Affiliations
- National and Kapodistrian University of Athens (GR)
- From the Neuroimmunology Unit (H.A., K.B., M.C.D.), Department of Pathophysiology (P.V., A.T.), and 1st Department of Intensive Care Medicine (E.M., A.K.), Evangelismos Hospital, Faculty of Medicine, National and Kapodistrian University of Athens; and Department of Immunology and Histocompatibility (N.K.), Laikon University Hospital, Athens, Greece.
- Corresponding author
- Dalakas, Marinos C.
- ORCID
- Venue
- Neurology Neuroimmunology & Neuroinflammation
- Published
- 2020-11
- Volume
- 7
- Issue
- 6
- ISSN
- 2332-7812 (ISSN-L)
- PMC
- PMC7577546
- OpenAlex
- W3089322801
- Cited by
- 131
- References
- 12
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 14 · 2023: 20 · 2022: 31 · 2021: 51 · 2020: 6
- FWCI
- 11.69
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Neurology Neuroimmunology & Neuroinflammation (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Long-Term Effects of COVID-19
- Health Sciences › Medicine › Infectious Diseases › Infectious Encephalopathies and Encephalitis
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Keywords
- COVID-19 pandemic, SARS-CoV-2, SARS-CoV-2 antibodies, cerebrospinal fluid, blood-brain barrier dysfunction, intrathecal IgG synthesis, encephalopathy, prolonged coma, 14-3-3 proteins, neurodegeneration, neuroinflammation, albumin index
- MeSH terms
- Betacoronavirus, COVID-19, SARS-CoV-2, Aged, Aged, 80 and over, Autoantibodies, Blood-Brain Barrier, Coma, Female, Humans, Male, Middle Aged, Nervous System Diseases, Pneumonia, Viral, Biomarkers, Treatment Outcome, Coronavirus Infections, Stupor, Pandemics
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