Martin Stangel1, Klemens Ruprecht2, Brigitte Wildemann3, Sven Jarius4, Florence Pache2, Peter Körtvelyessy2,5, Ilijas Jelčić6, Mark Stettner7, Diego Franciotta8, Emanuela Keller9, Bernhard Neumann10,11, Marius Ringelstein12,13, Makbule Senel14, Axel Regeniter15, Rea Kalantzis2, Jan F Willms16, Achim Berthele17, Markus Busch18, Marco Capobianco19, Amanda Eisele20, Ina Reichen6, Rick Dersch21, Sebastian Rauer21, Katharina Sandner22, Ilya Ayzenberg23,24, Catharina C Gross25, Harald Hegen26, Michael Khalil27, Ingo Kleiter23, Thorsten Lenhard28, Jürgen Haas3, Orhan Aktas12, Klemens Angstwurm10, Christoph Kleinschnitz7, Jan Lewerenz14, Hayrettin Tumani14,29, Friedemann Paul30. 1. Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hanover, Germany. 2. Department of Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. 3. Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany. 4. Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany. sven.jarius@med.uni-heidelberg.de. 5. German Center for Neurodegenerative Diseases (DZNE) in Magdeburg, Magdeburg, Germany. 6. Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich, Zurich, Switzerland. 7. Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Medicine Essen, University of Duisburg-Essen, Essen, Germany. 8. IRCCS Ospedale Policlinico San Martino, Genoa, Italy. 9. Neurocritical Care Unit, Department of Neurosurgery and Institute of Intensive Care, University Hospital and University of Zurich, Zurich, Switzerland. 10. Department of Neurology, University of Regensburg, Regensburg, Germany. 11. Department of Neurology, DONAUISAR Klinikum Deggendorf, Deggendorf, Germany. 12. Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany. 13. Department of Neurology, Center for Neurology and Neuropsychiatry, LVR-Klinikum, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany. 14. Department of Neurology, Ulm University, Ulm, Germany. 15. Medica Medical Laboratories Dr. F. Kaeppeli AG, Zurich, Switzerland. 16. Institute of Intensive Care Medicine, University Hospital and University of Zurich, Zurich, Switzerland. 17. Department of Neurology, School of Medicine, Technical University of Munich, Munich, Germany. 18. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. 19. Regional Referral Multiple Sclerosis Centre, Department of Neurology, University Hospital S. Luigi - Orbassano (I), Orbassano, Italy. 20. Department of Neurology, University Hospital Zurich, Zurich, Switzerland. 21. Clinic of Neurology and Neurophysiology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 22. Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. 23. Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany. 24. Department of Neurology, Sechenov First Moscow State Medical University, Moscow, Russia. 25. Department of Neurology with Institute of Translational Neurology, University and University Hospital Münster, Münster, Germany. 26. Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria. 27. Department of Neurology, Medical University of Graz, Graz, Austria. 28. Neuroinfectiology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany. 29. Specialty Hospital of Neurology Dietenbronn, Schwendi, Germany. 30. Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Berlin, Germany.
Abstract
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: To analyze systematically the CSF profile in COVID-19. 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: 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.
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: To analyze systematically the CSF profile in COVID-19. 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: 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.
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