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

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.

Keywords: 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).

Fig. 1

Albumin CSF/serum ratios (A, B) and CSF concentrations (C), CSF white cell counts (D), CSF total protein (E) and CSF L-lactate (F) concentrations and IgG, IgM and IgA CSF/serum ratios (G-I) and CSF concentrations (J-L) in patients with COVID-19 and neurological symptoms. Although some parameters were more markedly or more frequently altered in the ‘B/SC subgroup’ than in patients from the ‘PN/CN/H subgroup’, the differences were not statistically significant. N indicates the number of samples tested. Note that the figure shows all samples with available data; data stratified according to disease duration at the time of LP can be found in Tables 1, 2, 3, 4, 5. Solid lines indicate medians. B/SC brain spinal cord, PN/CN/H peripheral nerve/cranial nerve/headache only; IgG/A/M immunoglobulin G/A/M, QIgG/A/M CSF/serum IgG/A/M ratios, QAlb CSF/serum albumin ratio

Fig. 2

Correlation analyses for QAlb (A) and CSF total protein (B), respectively, and days since onset of the neurological symptoms in the total cohort and in the B/SC subgroup. Although a mildly significant correlation was found for both parameters, it should be noted that both parameters were still pathologically altered > 14 and even > 30 days after onset of the neurological symptoms in a subset of cases (see Results section and Table 1 for details). B/SC brain/spinal cord, N number of samples; QAlb albumin CSF/serum ratio, TP total protein

Fig. 3

Regression analyses of CSF total protein (A), CSF L-lactate (after exclusion of samples with very high QAlb) (B) and CSF IgG concentrations (C-D), respectively, and QAlb, demonstrating a close relationship between these parameters and QAlb. Solid lines indicate medians. Dotted lines represent the upper and lower 95% confidence bands of the regression line. IgG immunoglobulin G, N number of samples, QAlb albumin CSF/serum ratio, TP total protein

Fig. 4

No statistically significant differences in serum IgG (A), IgM (B) and IgA (C) levels between the ‘B/SC subgroup’ and the ‘PN/CN/H subgroup’. B/SC brain spinal cord, N number of samples. PN/CN/H peripheral nerve/cranial nerve/headache only

Fig. 5

Quotient diagram (‘reibergram’) for free kappa light chains in four patients with SARSV-CoV-2 and neurological symptoms. Graph created using FLC-K Statistics v1.02 (Albaum IT Solutions, Möhnesee, Germany)

Fig. 6

Relationship of CSF WCC, SARS-CoV-2-AI, and IL-6 and TNF-alpha CSF ratios and indices. Data from the same individual patient are connected by a line. *Negative SARS-CoV-2-AI in 10 patients; no SARS-CoV-2-AI data in 2. ** Negative SARS-CoV-2-AI in 4 patients; no SARS-CoV-2-AI data in 3. *** Negative SARS-CoV-2-AI in 4 patients; no AI data in 2. IL-6 Interleukin-6, SARS-CoV-2-AI severe acute respiratory syndrome-coronavirus type 2 antibody index, TNF-alpha tumor necrosis factor-alpha, WCC white cell count

Fig. 7

Cytokine and cytokine receptor concentrations in the CSF and serum during hospitalization for COVID-19. IFN interferon, IL interleukin, TNF-alpha tumor necrosis factor-alpha. Dotted lines indicate cut-offs; solid lines indicate medians

Fig. 8

Repeat IL-6 serum measurements over a period of up to 50 (upper panel) or up to 80 (lower panel) days during hospitalization in patients with COVID-19 and neurological complications in 14 patients with available long-term data; each patient is represented by a different colour of symbols and connecting lines. The x-axis indicates days since first IL-6 serum measurement (median 51 days follow-up, range 30-80); if days since the first SARS-CoV-2 PCR-positive swab are considered instead, serum IL-6 was still elevated after at least (last known measurement) 35, 37, 42, 45, 48, 49, 55, 58, 64, 76, 77, 79, 88 and 95 days, respectively, in these patients (median 57 days, range 35-95), partly at high level. The triangles at the top of each panel indicate the time of LP. IL-6 interleukin-6, LP lumbar puncture

Fig. 9

CSF/serum quotient diagrams for IgG, IgM, and IgA (‘reibergrams’). Individual CSF/serum ratios of IgG, IgA, and IgM are plotted against CSF/serum albumin ratios. Values above the upper hyperbolic discrimination line, Q_lim, indicate intrathecal synthesis of the respective immunoglobulin (Ig) class. Individual intrathecal fractions, Ig_IF, can be directly read by interpolation from the percentiles above Qlim (median values are given in Tables 3 and 4). Open circles represent samples from the ‘B/SC subgroup’; filled circles represent samples from the ‘PN/CN/H subgroup’. Graphs were created using CSF Research Tool v3.0 (CoMed GmbH, Soest, Germany). B/SC brain spinal cord, IgG/A/M immunoglobulin G/A/M, PN/CN/H peripheral nerve/cranial nerve/headache only, QIgG/A/M CSF/serum IgG/A/M ratios, QAlb CSF/serum albumin ratio