Cerebrospinal fluid findings in COVID-19: a multicenter study of 150 lumbar punctures in 127 patients
Authors: Jarius Sven , Pache Florence , Körtvelyessy Peter , Jelčić Ilijas , Stettner Mark , Franciotta Diego , Keller Emanuela , Neumann Bernhard , Ringelstein Marius , Senel Makbule , Regeniter Axel , Kalantzis Rea , Willms Jan F. , Berthele Achim , Busch Markus , Capobianco Marco , Eisele Amanda , Reichen Ina , Dersch Rick , Rauer Sebastian , Sandner Katharina , Ayzenberg Ilya , Gross Catharina C. , Hegen Harald , Khalil Michael , Kleiter Ingo , Lenhard Thorsten , Haas Jürgen , Aktas Orhan , Angstwurm Klemens , Kleinschnitz Christoph , Lewerenz Jan , Tumani Hayrettin , Paul Friedemann , Stangel Martin , Ruprecht Klemens , Wildemann Brigitte ,   in cooperation with the German Society for Cerebrospinal Fluid Diagnostics and Clinical Neurochemistry
Published: January 2022

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.