Cerebrospinal fluid findings in COVID-19: a multicenter study of 150 lumbar punctures in 127 patients.

Adult Blood-Brain Barrier COVID-19 / cerebrospinal fluid Cerebrospinal Fluid Proteins / cerebrospinal fluid Cytokines / cerebrospinal fluid Europe Female Humans Immunity, Cellular Immunoglobulin G / cerebrospinal fluid Lactic Acid / cerebrospinal fluid Leukocyte Count Male Middle Aged Nervous System Diseases / cerebrospinal fluid Oligoclonal Bands / cerebrospinal fluid Retrospective Studies Spinal Puncture Post-Acute COVID-19 Syndrome

Antibody index Autoantibodies Blood-CSF barrier Central nervous system Cerebrospinal fluid (CSF) Coronavirus disease 2019 (COVID-19) Cytokines Encephalitis Encephalopathy Guillain–Barré syndrome Lumbar puncture Neurological symptoms Oligoclonal bands Polymerase Chain reaction (PCR) SARS-CoV-2 antibodies Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)

Journal

Journal of neuroinflammation

ISSN: 1742-2094

Titre abrégé: J Neuroinflammation

Pays: England

ID NLM: 101222974

Informations de publication

Date de publication:
20 Jan 2022

Historique:

received: 21 06 2021

accepted: 02 12 2021

entrez: 21 1 2022

pubmed: 22 1 2022

medline: 28 1 2022

Statut: epublish

Résumé

Comprehensive data on the cerebrospinal fluid (CSF) profile in patients with COVID-19 and neurological involvement from large-scale multicenter studies are missing so far. To analyze systematically the CSF profile in COVID-19. Retrospective analysis of 150 lumbar punctures in 127 patients with PCR-proven COVID-19 and neurological symptoms seen at 17 European university centers RESULTS: The most frequent pathological finding was blood-CSF barrier (BCB) dysfunction (median QAlb 11.4 [6.72-50.8]), which was present in 58/116 (50%) samples from patients without pre-/coexisting CNS diseases (group I). QAlb remained elevated > 14d (47.6%) and even > 30d (55.6%) after neurological onset. CSF total protein was elevated in 54/118 (45.8%) samples (median 65.35 mg/dl [45.3-240.4]) and strongly correlated with QAlb. The CSF white cell count (WCC) was increased in 14/128 (11%) samples (mostly lympho-monocytic; median 10 cells/µl, > 100 in only 4). An albuminocytological dissociation (ACD) was found in 43/115 (37.4%) samples. CSF L-lactate was increased in 26/109 (24%; median 3.04 mmol/l [2.2-4]). CSF-IgG was elevated in 50/100 (50%), but was of peripheral origin, since QIgG was normal in almost all cases, as were QIgA and QIgM. In 58/103 samples (56%) pattern 4 oligoclonal bands (OCB) compatible with systemic inflammation were present, while CSF-restricted OCB were found in only 2/103 (1.9%). SARS-CoV-2-CSF-PCR was negative in 76/76 samples. Routine CSF findings were normal in 35%. Cytokine levels were frequently elevated in the CSF (often associated with BCB dysfunction) and serum, partly remaining positive at high levels for weeks/months (939 tests). Of note, a positive SARS-CoV-2-IgG-antibody index (AI) was found in 2/19 (10.5%) patients which was associated with unusually high WCC in both of them and a strongly increased interleukin-6 (IL-6) index in one (not tested in the other). Anti-neuronal/anti-glial autoantibodies were mostly absent in the CSF and serum (1509 tests). In samples from patients with pre-/coexisting CNS disorders (group II [N = 19]; including multiple sclerosis, JC-virus-associated immune reconstitution inflammatory syndrome, HSV/VZV encephalitis/meningitis, CNS lymphoma, anti-Yo syndrome, subarachnoid hemorrhage), CSF findings were mostly representative of the respective disease. The CSF profile in COVID-19 with neurological symptoms is mainly characterized by BCB disruption in the absence of intrathecal inflammation, compatible with cerebrospinal endotheliopathy. Persistent BCB dysfunction and elevated cytokine levels may contribute to both acute symptoms and 'long COVID'. Direct infection of the CNS with SARS-CoV-2, if occurring at all, seems to be rare. Broad differential diagnostic considerations are recommended to avoid misinterpretation of treatable coexisting neurological disorders as complications of COVID-19.

Sections du résumé

BACKGROUND BACKGROUND

Comprehensive data on the cerebrospinal fluid (CSF) profile in patients with COVID-19 and neurological involvement from large-scale multicenter studies are missing so far.

OBJECTIVE OBJECTIVE

To analyze systematically the CSF profile in COVID-19.

METHODS METHODS

Retrospective analysis of 150 lumbar punctures in 127 patients with PCR-proven COVID-19 and neurological symptoms seen at 17 European university centers RESULTS: The most frequent pathological finding was blood-CSF barrier (BCB) dysfunction (median QAlb 11.4 [6.72-50.8]), which was present in 58/116 (50%) samples from patients without pre-/coexisting CNS diseases (group I). QAlb remained elevated > 14d (47.6%) and even > 30d (55.6%) after neurological onset. CSF total protein was elevated in 54/118 (45.8%) samples (median 65.35 mg/dl [45.3-240.4]) and strongly correlated with QAlb. The CSF white cell count (WCC) was increased in 14/128 (11%) samples (mostly lympho-monocytic; median 10 cells/µl, > 100 in only 4). An albuminocytological dissociation (ACD) was found in 43/115 (37.4%) samples. CSF L-lactate was increased in 26/109 (24%; median 3.04 mmol/l [2.2-4]). CSF-IgG was elevated in 50/100 (50%), but was of peripheral origin, since QIgG was normal in almost all cases, as were QIgA and QIgM. In 58/103 samples (56%) pattern 4 oligoclonal bands (OCB) compatible with systemic inflammation were present, while CSF-restricted OCB were found in only 2/103 (1.9%). SARS-CoV-2-CSF-PCR was negative in 76/76 samples. Routine CSF findings were normal in 35%. Cytokine levels were frequently elevated in the CSF (often associated with BCB dysfunction) and serum, partly remaining positive at high levels for weeks/months (939 tests). Of note, a positive SARS-CoV-2-IgG-antibody index (AI) was found in 2/19 (10.5%) patients which was associated with unusually high WCC in both of them and a strongly increased interleukin-6 (IL-6) index in one (not tested in the other). Anti-neuronal/anti-glial autoantibodies were mostly absent in the CSF and serum (1509 tests). In samples from patients with pre-/coexisting CNS disorders (group II [N = 19]; including multiple sclerosis, JC-virus-associated immune reconstitution inflammatory syndrome, HSV/VZV encephalitis/meningitis, CNS lymphoma, anti-Yo syndrome, subarachnoid hemorrhage), CSF findings were mostly representative of the respective disease.

CONCLUSIONS CONCLUSIONS

The CSF profile in COVID-19 with neurological symptoms is mainly characterized by BCB disruption in the absence of intrathecal inflammation, compatible with cerebrospinal endotheliopathy. Persistent BCB dysfunction and elevated cytokine levels may contribute to both acute symptoms and 'long COVID'. Direct infection of the CNS with SARS-CoV-2, if occurring at all, seems to be rare. Broad differential diagnostic considerations are recommended to avoid misinterpretation of treatable coexisting neurological disorders as complications of COVID-19.

Identifiants

DOI: 10.1186/s12974-021-02339-0 PMID: 35057809 PMC: PMC8771621

pubmed: 35057809

doi: 10.1186/s12974-021-02339-0

pii: 10.1186/s12974-021-02339-0

pmc: PMC8771621

doi:

Substances chimiques

Cerebrospinal Fluid Proteins 0

Cytokines 0

Immunoglobulin G 0

Oligoclonal Bands 0

Lactic Acid 33X04XA5AT

Types de publication

Journal Article Multicenter Study

Langues

eng

Sous-ensembles de citation

Pagination

Subventions

Organisme : Ministry for Education and Research Baden-Württemberg, Germany

ID : 1499 TG93 U1

Organisme : Swiss National Science Foundation

ID : 4078P0_198345

Pays : Switzerland

Informations de copyright

Références

Leonardi M, Padovani A, McArthur JC. Neurological manifestations associated with COVID-19: a review and a call for action. J Neurol. 2020;267:1573–6.

pubmed: 32436101

Chen X, Laurent S, Onur OA, Kleineberg NN, Fink GR, Schweitzer F, Warnke C. A systematic review of neurological symptoms and complications of COVID-19. J Neurol. 2021;268:392–402.

pubmed: 32691236

Rogers JP, Chesney E, Oliver D, Pollak TA, McGuire P, Fusar-Poli P, Zandi MS, Lewis G, David AS. Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic. Lancet Psychiatry. 2020;7:611–27.

pubmed: 7234781 pmcid: 7234781

Fuchs V, Kutza M, Wischnewski S, Deigendesch N, Lutz L, Kulsvehagen L, Ricken G, Kappos L, Tzankov A, Hametner S, et al. Presence of SARS-CoV-2 transcripts in the choroid plexus of ms and non-ms patients with COVID-19. Neurol Neuroimmunol Neuroinflamm 2021;8:e957.

pubmed: 33504636 pmcid: 7862096

Meinhardt J, Radke J, Dittmayer C, Franz J, Thomas C, Mothes R, Laue M, Schneider J, Brunink S, Greuel S, et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci. 2021;24:168–75.

pubmed: 33257876

Song E, Zhang C, Israelow B, Lu-Culligan A, Prado AV, Skriabine S, Lu P, Weizman OE, Liu F, Dai Y, et al. Neuroinvasion of SARS-CoV-2 in human and mouse brain. J Exp Med. 2021.

Alexopoulos H, Magira E, Bitzogli K, Kafasi N, Vlachoyiannopoulos P, Tzioufas A, Kotanidou A, Dalakas MC. Anti-SARS-CoV-2 antibodies in the CSF, blood-brain barrier dysfunction, and neurological outcome: Studies in 8 stuporous and comatose patients. Neurol Neuroimmunol Neuroinflamm 2020;7:e893.

pubmed: 32978291 pmcid: 7577546

Bodro M, Compta Y, Llanso L, Esteller D, Doncel-Moriano A, Mesa A, Rodriguez A, Sarto J, Martinez-Hernandez E, Vlagea A, et al. Increased CSF levels of IL-1beta, IL-6, and ACE in SARS-CoV-2-associated encephalitis. Neurol Neuroimmunol Neuroinflamm 2020;7:e821.

pubmed: 32611761 pmcid: 7357418

Tandon M, Kataria S, Patel J, Mehta TR, Daimee M, Patel V, Prasad A, Chowdhary AA, Jaiswal S, Sriwastava S. A Comprehensive Systematic Review of CSF analysis that defines Neurological Manifestations of COVID-19. Int J Infect Dis. 2021;104:390–7.

pubmed: 33434662 pmcid: 7837002

Tuma RL, Guedes BF, Carra R, Iepsen B, Rodrigues J, Camelo-Filho AE, Kubota G, Ferrari M, Studart-Neto A, Oku MH, et al. Clinical, cerebrospinal fluid, and neuroimaging findings in COVID-19 encephalopathy: a case series. Neurol Sci. 2021;42:479–89.

pubmed: 33409828

Lewis A, Frontera J, Placantonakis DG, Lighter J, Galetta S, Balcer L, Melmed KR. Cerebrospinal fluid in COVID-19: a systematic review of the literature. J Neurol Sci. 2021;421:117316.

pubmed: 33561753 pmcid: 7833669

Lersy F, Benotmane I, Helms J, Collange O, Schenck M, Brisset JC, Chammas A, Willaume T, Lefebvre N, Solis M, et al. Cerebrospinal fluid features in patients with coronavirus disease 2019 and neurological manifestations: correlation with brain magnetic resonance imaging findings in 58 patients. J Infect Dis. 2021;223:600–9.

pubmed: 33249438

Jarius S, Pellkofer H, Siebert N, Korporal-Kuhnke M, Hummert MW, Ringelstein M, Rommer PS, Ayzenberg I, Ruprecht K, Klotz L, et al. Cerebrospinal fluid findings in patients with myelin oligodendrocyte glycoprotein (MOG) antibodies. Part 1: Results from 163 lumbar punctures in 100 adult patients. J Neuroinflammation. 2020;17:261.

pubmed: 32883348 pmcid: 7470615

Jarius S, Lechner C, Wendel EM, Baumann M, Breu M, Schimmel M, Karenfort M, Marina AD, Merkenschlager A, Thiels C, et al. Cerebrospinal fluid findings in patients with myelin oligodendrocyte glycoprotein (MOG) antibodies. Part 2: Results from 108 lumbar punctures in 80 pediatric patients. J Neuroinflammation. 2020;17:262.

pubmed: 32883358 pmcid: 7470445

Jarius S, Paul F, Franciotta D, Ruprecht K, Ringelstein M, Bergamaschi R, Rommer P, Kleiter I, Stich O, Reuss R, et al. Cerebrospinal fluid findings in aquaporin-4 antibody positive neuromyelitis optica: results from 211 lumbar punctures. J Neurol Sci. 2011;306:82–90.

pubmed: 21550068

Jarius S, Konig FB, Metz I, Ruprecht K, Paul F, Bruck W, Wildemann B. Pattern II and pattern III MS are entities distinct from pattern I MS: evidence from cerebrospinal fluid analysis. J Neuroinflammation. 2017;14:171.

pubmed: 28851393 pmcid: 5576197

Jarius S, Wurthwein C, Behrens JR, Wanner J, Haas J, Paul F, Wildemann B. Balo’s concentric sclerosis is immunologically distinct from multiple sclerosis: results from retrospective analysis of almost 150 lumbar punctures. J Neuroinflammation. 2018;15:22.

pubmed: 29347989 pmcid: 5774135

Jarius S, Haas J, Paul F, Wildemann B. Myelinoclastic diffuse sclerosis (Schilder’s disease) is immunologically distinct from multiple sclerosis: results from retrospective analysis of 92 lumbar punctures. J Neuroinflammation. 2019;16:51.

pubmed: 30819213 pmcid: 6396538

Tumani H, Petereit H-F: Leitlinie Lumbalpunktion und Liquordiagnostik, S1-Leitlinie, 2019, in: Deutsche Gesellschaft für Liquordiagnostik und Klinische Neurochemie (Hrsg.), Leitlinien für Diagnostik und Therapie in der Neurologie. Online: www.dgn.org/leitlinien . abgerufen am 07 May 2020.

Petereit HF, Sindern E, Wick M. [CSF diagnostics. Guidelines and catalogue of methods of the German Society for Cerebrospinal Fluid Diagnostics and Clinical Neurochemistry]. Heidelberg: Springer; 2007.

Tumani H, Petereit HF, Gerritzen A, Gross CC, Huss A, Isenmann S, Jesse S, Khalil M, Lewczuk P, Lewerenz J, et al. S1 guidelines “lumbar puncture and cerebrospinal fluid analysis” (abridged and translated version). Neurol Res Pract. 2020;2:8.

pubmed: 33324914 pmcid: 7650145

Andersson M, Alvarez-Cermeno J, Bernardi G, Cogato I, Fredman P, Frederiksen J, Fredrikson S, Gallo P, Grimaldi LM, Gronning M, et al. Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report. J Neurol Neurosurg Psychiatry. 1994;57:897–902.

pubmed: 8057110 pmcid: 1073070

Reiber H. Cerebrospinal fluid–physiology, analysis and interpretation of protein patterns for diagnosis of neurological diseases. Mult Scler. 1998;4:99–107.

pubmed: 9762655

Reiber H, Ungefehr S, Jacobi C. The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis. Mult Scler. 1998;4:111–7.

pubmed: 9762657

Reiber H. Flow rate of cerebrospinal fluid (CSF)–a concept common to normal blood-CSF barrier function and to dysfunction in neurological diseases. J Neurol Sci. 1994;122:189–203.

pubmed: 8021703

Kuzior H, Fiebich BL, Yousif NM, Saliba SW, Ziegler C, Nickel K, Maier SJ, Suss P, Runge K, Matysik M, et al. Increased IL-8 concentrations in the cerebrospinal fluid of patients with unipolar depression. Compr Psychiatry. 2020;102:152196.

pubmed: 32927367

Cao Y, Tao X, Xu M. Value of cerebrospinal fluid IL-8 and IFN-γ level in early diagnosis of tuberculous meningitis and evaluation of prognosis. Acta Medica Mediterranea. 2020;36:2875.

Kaminska J, Lyson T, Chrzanowski R, Sawicki K, Milewska AJ, Tylicka M, Zinczuk J, Matowicka-Karna J, Dymicka-Piekarska V, Mariak Z, Koper-Lenkiewicz OM. Ratio of IL-8 in CSF versus Serum Is Elevated in Patients. J Clin Med. 2020;9:1761.

pmcid: 7356854

Fassbender K, Hodapp B, Rossol S, Bertsch T, Schmeck J, Schutt S, Fritzinger M, Horn P, Vajkoczy P, Kreisel S, et al. Inflammatory cytokines in subarachnoid haemorrhage: association with abnormal blood flow velocities in basal cerebral arteries. J Neurol Neurosurg Psychiatry. 2001;70:534–7.

pubmed: 11254783 pmcid: 1737308

Postal M, Ruocco HH, Brandao CO, Costallat LTL, Silva L, Cendes F, Appenzeller S. Interferon-gamma Is Associated with Cerebral Atrophy in Systemic Lupus Erythematosus. NeuroImmunoModulation. 2017;24:100–5.

pubmed: 28848179

Zaremba J, Losy J. Early TNF-alpha levels correlate with ischaemic stroke severity. Acta Neurol Scand. 2001;104:288–95.

pubmed: 11696023

Glimaker M, Kragsbjerg P, Forsgren M, Olcen P. Tumor necrosis factor-alpha (TNF alpha) in cerebrospinal fluid from patients with meningitis of different etiologies: high levels of TNF alpha indicate bacterial meningitis. J Infect Dis. 1993;167:882–9.

pubmed: 8450254

Mogi M, Harada M, Riederer P, Narabayashi H, Fujita K, Nagatsu T. Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci Lett. 1994;165:208–10.

pubmed: 8015728

Starhof C, Winge K, Heegaard NHH, Skogstrand K, Friis S, Hejl A. Cerebrospinal fluid pro-inflammatory cytokines differentiate parkinsonian syndromes. J Neuroinflammation. 2018;15:305.

pubmed: 30390673 pmcid: 6215346

Wildemann B, Oschmann P, Reiber H. Laboratory diagnosis in neurology. Stuttgart: Thieme; 2011.

Wurster U, Stachan R, Windhagen A, Petereit HF, Leweke FM. Reference values for standard cerebrospinal fluid examinations in multiple sclerosis. Results from 99 healthy volunteers. Mult Scler. 2006;12:P248.

Schwenkenbecher P, Janssen T, Wurster U, Konen FF, Neyazi A, Ahlbrecht J, Puppe W, Bonig L, Suhs KW, Stangel M, et al. The influence of blood contamination on cerebrospinal fluid diagnostics. Front Neurol. 2019;10:584.

pubmed: 31249547 pmcid: 6582628

Abela I, Pasin C, Schwarzmüller M, Epp S, Sickmann M, Schanz M, Rusert P, Weber J, Schmutz S, Audigé A, et al. Multifactorial SARS-CoV-2 seroprofiling dissects interdependencies with human coronaviruses and predicts neutralization activity. Nat Commun 2021;12:6703.

pubmed: 34795285 pmcid: 8602384

Jarius S, Eichhorn P, Franciotta D, Petereit HF, Akman-Demir G, Wick M, Wildemann B. The MRZ reaction as a highly specific marker of multiple sclerosis: re-evaluation and structured review of the literature. J Neurol. 2017;264:453–66.

pubmed: 28005176

Dalmau J, Graus F. Antibody-mediated encephalitis. N Engl J Med. 2018;378:840–51.

pubmed: 29490181

Hermetter C, Fazekas F, Hochmeister S. Systematic review: syndromes, early diagnosis, and treatment in autoimmune encephalitis. Front Neurol. 2018;9:706.

pubmed: 30233481 pmcid: 6135049

Jarius S, Probst C, Borowski K, Franciotta D, Wildemann B, Stoecker W, Wandinger KP. Standardized method for the detection of antibodies to aquaporin-4 based on a highly sensitive immunofluorescence assay employing recombinant target antigen. J Neurol Sci. 2010;291:52–6.

pubmed: 20117794

Jarius S, Wildemann B. Aquaporin-4 antibodies (NMO-IgG) as a serological marker of neuromyelitis optica: a critical review of the literature. Brain Pathol. 2013;23:661–83.

pubmed: 24118483 pmcid: 8028894

Reiber H, Zeman D, Kusnierova P, Mundwiler E, Bernasconi L. Diagnostic relevance of free light chains in cerebrospinal fluid—The hyperbolic reference range for reliable data interpretation in quotient diagrams. Clin Chim Acta. 2019;497:153–62.

pubmed: 31351929

Schwenkenbecher P, Konen FF, Wurster U, Witte T, Gingele S, Suhs KW, Stangel M, Skripuletz T. Reiber’s diagram for kappa free light chains: the new standard for assessing intrathecal synthesis? Diagnostics (Basel). 2019;9:194.

Kestner M, Rosler AE, Baumgärtner M, Lindner A, Orth M. CSF interleukin 6—a useful biomarker of meningitis in adults?/Liquor Interleukin 6—a ein sinnvoller Biomarker für die Meningitis beim Erwachsenen. J Lab Med. 2011;35:107–13.

Espindola OM, Siqueira M, Soares CN, Lima M, Leite A, Araujo AQC, Brandao CO, Silva MTT. Patients with COVID-19 and neurological manifestations show undetectable SARS-CoV-2 RNA levels in the cerebrospinal fluid. Int J Infect Dis. 2020;96:567–9.

pubmed: 32505878 pmcid: 7271861

Destras G, Bal A, Escuret V, Morfin F, Lina B, Josset L, Group CO-DHS. Systematic SARS-CoV-2 screening in cerebrospinal fluid during the COVID-19 pandemic. Lancet Microbe. 2020;1:e149.

pubmed: 32835345 pmcid: 7289579

Weil AA, Glaser CA, Amad Z, Forghani B. Patients with suspected herpes simplex encephalitis: rethinking an initial negative polymerase chain reaction result. Clin Infect Dis. 2002;34:1154–7.

pubmed: 11915008

Tunkel AR, Glaser CA, Bloch KC, Sejvar JJ, Marra CM, Roos KL, Hartman BJ, Kaplan SL, Scheld WM, Whitley RJ, Infectious Diseases Society of A. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2008;47:303–27.

pubmed: 18582201

Steiner I, Schmutzhard E, Sellner J, Chaudhuri A, Kennedy PG, European Federation of Neurological S, European Neurologic S. EFNS-ENS guidelines for the use of PCR technology for the diagnosis of infections of the nervous system. Eur J Neurol. 2012;19:1278–91.

pubmed: 22882231

Huang YH, Jiang D, Huang JT. SARS-CoV-2 detected in cerebrospinal fluid by PCR in a case of COVID-19 encephalitis. Brain Behav Immun. 2020;87:149.

pubmed: 32387508 pmcid: 7202824

Jarius S, Stich O, Rasiah C, Voltz R, Rauer S. Qualitative evidence of Ri specific IgG-synthesis in the cerebrospinal fluid from patients with paraneoplastic neurological syndromes. J Neurol Sci. 2008;268:65–8.

pubmed: 18096187

Jarius S, Stich O, Speck J, Rasiah C, Wildemann B, Meinck HM, Rauer S. Qualitative and quantitative evidence of anti-glutamic acid decarboxylase-specific intrathecal antibody synthesis in patients. J Neuroimmunol 2010;229:219–24.

pubmed: 20813415

Stich O, Graus F, Rasiah C, Rauer S. Qualitative evidence of anti-Yo-specific intrathecal antibody synthesis in patients with paraneoplastic cerebellar degeneration. J Neuroimmunol. 2003;141:165–9.

pubmed: 12965268

Felgenhauer K, Reiber H. The diagnostic significance of antibody specificity indices in multiple sclerosis and herpes virus induced diseases of the nervous system. Clin Investig. 1992;70:28–37.

pubmed: 1318123

Frederiksen JL, Sindic CJ. Intrathecal synthesis of virus-specific oligoclonal IgG, and of free kappa and free lambda oligoclonal bands in acute monosymptomatic optic neuritis. Comparison with brain MRI. Mult Scler. 1998;4:22–6.

pubmed: 9532588

Jarius S, Eichhorn P, Wildemann B, Wick M. Usefulness of antibody index assessment in cerebrospinal fluid from patients negative for total-IgG oligoclonal bands. Fluids Barriers CNS. 2012;9:14.

pubmed: 22849518 pmcid: 3487855

Stich O, Kluge J, Speck J, Rauer S. Oligoclonal restriction of antiviral immunoreaction in oligoclonal band-negative MS patients. Acta Neurol Scand. 2015;131:381–8.

pubmed: 25402869

Sindic CJ, Monteyne P, Laterre EC. The intrathecal synthesis of virus-specific oligoclonal IgG in multiple sclerosis. J Neuroimmunol. 1994;54:75–80.

pubmed: 7523446

Brecht I, Weissbrich B, Braun J, Toyka KV, Weishaupt A, Buttmann M. Intrathecal, polyspecific antiviral immune response in oligoclonal band negative multiple sclerosis. PLoS ONE. 2012;7:e40431.

pubmed: 22792316 pmcid: 3392215

Stich O, Kluge J, Speck J, Rauer S. Detection of virus-specific (measles, rubella, zoster) oligoclonal IgG-bands in CSF from multiple sclerosis patients without oligoclonal bands of total IgG. Mult Scler. 2009;15:S86.

Kreye J, Reincke SM, Pruss H. Do cross-reactive antibodies cause neuropathology in COVID-19? Nat Rev Immunol. 2020;20:645–6.

pubmed: 33024283

Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, Mehra MR, Schuepbach RA, Ruschitzka F, Moch H. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395:1417–8.

pubmed: 32325026 pmcid: 7172722

Perico L, Benigni A, Casiraghi F, Ng LFP, Renia L, Remuzzi G. Immunity, endothelial injury and complement-induced coagulopathy in COVID-19. Nat Rev Nephrol. 2021;17:46–64.

pubmed: 33077917

Jin Y, Ji W, Yang H, Chen S, Zhang W, Duan G. Endothelial activation and dysfunction in COVID-19: from basic mechanisms to potential therapeutic approaches. Signal Transduct Target Ther. 2020;5:293.

pubmed: 33361764 pmcid: 7758411

Huang X, Hussain B, Chang J. Peripheral inflammation and blood-brain barrier disruption: effects and mechanisms. CNS Neurosci Ther. 2021;27:36–47.

pubmed: 33381913

Shi H, Zuo Y, Gandhi AA, Sule G, Yalavarthi S, Gockman K, Madison JA, Wang J, Zuo M, Shi Y, et al. Endothelial cell-activating antibodies in COVID-19. MedRxiv. 2021;109:67.

Yang YH, Huang YH, Chuang YH, Peng CM, Wang LC, Lin YT, Chiang BL. Autoantibodies against human epithelial cells and endothelial cells after severe acute respiratory syndrome (SARS)-associated coronavirus infection. J Med Virol. 2005;77:1–7.

pubmed: 16032747 pmcid: 7166512

Buja LM, Wolf DA, Zhao B, Akkanti B, McDonald M, Lelenwa L, Reilly N, Ottaviani G, Elghetany MT, Trujillo DO, et al. The emerging spectrum of cardiopulmonary pathology of the coronavirus disease 2019 (COVID-19): Report of 3 autopsies from Houston, Texas, and review of autopsy findings from other United States cities. Cardiovasc Pathol. 2020;48:107233.

pubmed: 32434133 pmcid: 7204762

Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, Vanstapel A, Werlein C, Stark H, Tzankov A, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2020;383:120–8.

pubmed: 32437596 pmcid: 7412750

Lacout C, Rogez J, Orvain C, Nicot C, Rony L, Julien H, Urbanski G. A new diagnosis of systemic capillary leak syndrome in a patient with COVID-19. Rheumatology (Oxford). 2021;60:e19–20.

Case R, Ramaniuk A, Martin P, Simpson PJ, Harden C, Ataya A. Systemic capillary leak syndrome secondary to coronavirus disease 2019. Chest. 2020;158:e267–8.

pubmed: 32622823

Sussmuth SD, Sperfeld AD, Ludolph AC, Tumani H. Hypercapnia is a possible determinant of the function of the blood-cerebrospinal fluid barrier in amyotrophic lateral sclerosis. Neurochem Res. 2010;35:1071–4.

pubmed: 20333464

Pellegrini L, Albecka A, Mallery DL, Kellner MJ, Paul D, Carter AP, James LC, Lancaster MA. SARS-CoV-2 infects the brain choroid plexus and disrupts the blood-CSF barrier in human brain organoids. Cell Stem Cell. 2020;27:951-961.e955.

pubmed: 33113348 pmcid: 7553118

McMahon CL, Staples H, Gazi M, Carrion R, Hsieh J. SARS-CoV-2 targets glial cells in human cortical organoids. Stem Cell Reports. 2021;16:1156–64.

pubmed: 33979600 pmcid: 8111796

Jacob F, Pather SR, Huang WK, Zhang F, Wong SZH, Zhou H, Cubitt B, Fan W, Chen CZ, Xu M, et al. Human pluripotent stem cell-derived neural cells and brain organoids reveal SARS-CoV-2 neurotropism predominates in choroid plexus epithelium. Cell Stem Cell. 2020;27:937-950.e939.

pubmed: 33010822 pmcid: 7505550

Fishman RA, Sligar K, Hake RB. Effects of leukocytes on brain metabolism in granulocytic brain edema. Ann Neurol. 1977;2:89–94.

Jordan GW, Statland B, Halsted C. CSF lactate in diseases of the CNS. Arch Intern Med. 1983;143:85–7.

pubmed: 6849611

Kolmel HW, von Maravic M. Correlation of lactic acid level, cell count and cytology in cerebrospinal fluid of patients with bacterial and non-bacterial meningitis. Acta Neurol Scand. 1988;78:6–9.

pubmed: 3176884

Andersen NE, Gyring J, Hansen AJ, Laursen H, Siesjo BK. Brain acidosis in experimental pneumococcal meningitis. J Cereb Blood Flow Metab. 1989;9:381–7.

pubmed: 2497112

Simchowitz L, Textor JA. Lactic acid secretion by human neutrophils. Evidence for an H+ + lactate- cotransport system. J Gen Physiol. 1992;100:341–67.

pubmed: 1402785

Walz W, Mukerji S. Lactate production and release in cultured astrocytes. Neurosci Lett. 1988;86:296–300.

pubmed: 3380321

Walz W, Mukerji S. Lactate release from cultured astrocytes and neurons: a comparison. Glia. 1988;1:366–70.

pubmed: 2976396

Posner JB, Plum F. Independence of blood and cerebrospinal fluid lactate. Arch Neurol. 1967;16:492–6.

pubmed: 6022530

Plum F, Posner JB. Blood and cerebrospinal fluid lactate during hyperventilation. Am J Physiol. 1967;212:864–70.

pubmed: 6024452

Hebant B, Miret N, Bouwyn JP, Delafosse E, Lefaucheur R. Absence of pleocytosis in cerebrospinal fluid does not exclude herpes simplex virus encephalitis in elderly adults. J Am Geriatr Soc. 2015;63:1278–9.

pubmed: 26096420

Sili U, Kaya A, Mert A, Group HSVES. Herpes simplex virus encephalitis: clinical manifestations, diagnosis and outcome in 106 adult patients. J Clin Virol. 2014;60:112–8.

pubmed: 24768322

Jarius S, Paul F, Aktas O, Asgari N, Dale RC, de Seze J, Franciotta D, Fujihara K, Jacob A, Kim HJ, et al. MOG encephalomyelitis: international recommendations on diagnosis and antibody testing. J Neuroinflammation. 2018;15:134.

pubmed: 29724224 pmcid: 5932838

Jarius S, Ruprecht K, Wildemann B, Kuempfel T, Ringelstein M, Geis C, Kleiter I, Kleinschnitz C, Berthele A, Brettschneider J, et al. Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: a multicentre study of 175 patients. J Neuroinflammation. 2012;9:14.

pubmed: 22260418 pmcid: 3283476

Levy M, Wildemann B, Jarius S, Orellano B, Sasidharan S, Weber MS, Stuve O. Immunopathogenesis of neuromyelitis optica. Adv Immunol. 2014;121:213–42.

pubmed: 24388217

Blinder T, Lewerenz J. Cerebrospinal fluid findings in patients with autoimmune encephalitis-a systematic analysis. Front Neurol. 2019;10:804.

pubmed: 31404257 pmcid: 6670288

Jarius S, Hoffmann L, Clover L, Vincent A, Voltz R. CSF findings in patients with voltage gated potassium channel antibody associated limbic encephalitis. J Neurol Sci. 2008;268:74–7.

pubmed: 18068189

Guilmot A, Maldonado Slootjes S, Sellimi A, Bronchain M, Hanseeuw B, Belkhir L, Yombi JC, De Greef J, Pothen L, Yildiz H, et al. Immune-mediated neurological syndromes in SARS-CoV-2-infected patients. J Neurol. 2021;268:751–7.

pubmed: 32734353

Franke C, Ferse C, Kreye J, Reincke SM, Sanchez-Sendin E, Rocco A, Steinbrenner M, Angermair S, Treskatsch S, Zickler D, et al. High frequency of cerebrospinal fluid autoantibodies in COVID-19 patients with neurological symptoms. Brain Behav Immun. 2021;93:415–9.

pubmed: 33359380

Xu R, Zhou Y, Cai L, Wang L, Han J, Yang X, Chen J, Chen J, Ma C, Shen L. Co-reactivation of the human herpesvirus alpha subfamily (herpes simplex virus-1 and varicella zoster virus) in a critically ill patient with COVID-19. Br J Dermatol. 2020;183:1145–7.

pubmed: 32790074

Tartari F, Spadotto A, Zengarini C, Zanoni R, Guglielmo A, Adorno A, Valzania C, Pileri A. Herpes zoster in COVID-19-positive patients. Int J Dermatol. 2020;59:1028–9.

pubmed: 32530063

Saati A, Al-Husayni F, Malibari AA, Bogari AA, Alharbi M. Herpes zoster co-infection in an immunocompetent patient with COVID-19. Cureus. 2020;12:e8998.

pubmed: 32670724 pmcid: 7358933

Nofal A, Fawzy MM, El Sharaf Deen SM, El-Hawary EE. Herpes zoster ophthalmicus in COVID-19 patients. Int J Dermatol. 2020;59:1545–6.

pubmed: 33040343 pmcid: 7675560

Patel P, Undavia A, Choudry R, Zhang Y, Prabhu AM. COVID-19 associated with concomitant varicella zoster viral encephalitis. Neurol Clin Pract. 2021;11:e219–21.

pubmed: 33842100