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

Journal of Neuroinflammation

Sebastian Rauer¹  Rick Dersch¹  Martin Stangel²  Markus Busch³  Mark Stettner⁴  Christoph Kleinschnitz⁴  Catharina C. Gross⁵  Florence Pache⁶  Rea Kalantzis⁶  Klemens Ruprecht⁶  Peter Körtvelyessy⁷  Orhan Aktas⁸  Marius Ringelstein⁹  Michael Khalil^1,10  Harald Hegen^1,11  Achim Berthele^1,12  Ingo Kleiter^1,13  Ilya Ayzenberg^1,14  Makbule Senel^1,15  Jan Lewerenz^1,15  Hayrettin Tumani^1,16  Amanda Eisele^1,17  Katharina Sandner^1,18  Klemens Angstwurm^1,19  Bernhard Neumann^2,20  Friedemann Paul^2,21  Diego Franciotta^2,22  Jan F. Willms^2,23  Axel Regeniter^2,24  Brigitte Wildemann^2,25  Sven Jarius^2,25  Jürgen Haas^2,25  Emanuela Keller^2,26  Ina Reichen^2,27  Ilijas Jelčić^2,27  Thorsten Lenhard^2,28  Marco Capobianco^2,29 

[1] Clinic of Neurology and Neurophysiology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany;Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hanover, Germany;Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany;Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Medicine Essen, University of Duisburg-Essen, Essen, Germany;Department of Neurology with Institute of Translational Neurology, University and University Hospital Münster, Münster, Germany;Department of Neurology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany;Department of Neurology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany;German Center for Neurodegenerative Diseases (DZNE) in Magdeburg, Magdeburg, Germany;Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany;Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany;Department of Neurology, Center for Neurology and Neuropsychiatry, LVR-Klinikum, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany;Department of Neurology, Medical University of Graz, Graz, Austria;Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria;Department of Neurology, School of Medicine, Technical University of Munich, Munich, Germany;Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany;Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany;Department of Neurology, Sechenov First Moscow State Medical University, Moscow, Russia;Department of Neurology, Ulm University, Ulm, Germany;Department of Neurology, Ulm University, Ulm, Germany;Specialty Hospital of Neurology Dietenbronn, Schwendi, Germany;Department of Neurology, University Hospital Zurich, Zurich, Switzerland;Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany;Department of Neurology, University of Regensburg, Regensburg, Germany;Department of Neurology, University of Regensburg, Regensburg, Germany;Department of Neurology, DONAUISAR Klinikum Deggendorf, Deggendorf, Germany;Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité—Universitätsmedizin Berlin, Berlin, Germany;IRCCS Ospedale Policlinico San Martino, Genoa, Italy;Institute of Intensive Care Medicine, University Hospital and University of Zurich, Zurich, Switzerland;Medica Medical Laboratories Dr. F. Kaeppeli AG, Zurich, Switzerland;Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany;Neurocritical Care Unit, Department of Neurosurgery and Institute of Intensive Care, University Hospital and University of Zurich, Zurich, Switzerland;Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich, Zurich, Switzerland;Neuroinfectiology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany;Regional Referral Multiple Sclerosis Centre, Department of Neurology, University Hospital S. Luigi - Orbassano (I), Orbassano, Italy;

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

DOI  :  10.1186/s12974-021-02339-0

来源: Springer

【 摘 要 】

BackgroundComprehensive data on the cerebrospinal fluid (CSF) profile in patients with COVID-19 and neurological involvement from large-scale multicenter studies are missing so far.ObjectiveTo analyze systematically the CSF profile in COVID-19.MethodsRetrospective analysis of 150 lumbar punctures in 127 patients with PCR-proven COVID-19 and neurological symptoms seen at 17 European university centersResultsThe 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.ConclusionsThe 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.

【 授权许可】

CC BY