Abstract

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.

Highlights

  • 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

  • The Cerebrospinal fluid (CSF) profile in COVID-19 with neurological symptoms is mainly characterized by blood-CSF barrier (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’

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Summary

Introduction

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. COVID-19, first described in December 2019, is an infectious disease caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Comprehensive data from large-scale multicenter studies that take into account a wide spectrum of parameters, including CSF white cell counts (WCC) and cytology, quantitative and qualitative evidence of intrathecal IgG, IgM and IgA synthesis (including Reiber diagrams [‘reibergrams’]), markers of blood-CSF barrier (BCB) dysfunction, total protein, l-lactate, glucose, and SARS-CoV-2 CSF polymerase chain reaction (PCR), antibody indices (AI), autoantibody findings, and cytokine levels, are widely missing so far. On behalf of the German Society for CSF Diagnostics and Clinical Neurochemistry (DGLN) we conducted a systematic analysis of CSF findings from 150 lumbar punctures in 127 patients with PCR-proven COVID-19 and neurological symptoms. Patients were stratified according to the type and severity of the neurological symptoms, acuity, co-/preexisting neurological conditions, and treatment status

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