Anti–SARS-CoV-2 antibodies in the CSF, blood-brain barrier dysfunction, and neurological outcome

Abstract

ObjectiveTo investigate the pathophysiologic mechanism of encephalopathy and prolonged comatose or stuporous state in severally ill patients with coronavirus disease 2019 (COVID-19).MethodsEight COVID-19 patients with signs of encephalopathy were tested for antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the serum and CSF using a Food and Drug Administration-approved and independently validated ELISA. Blood-brain barrier (BBB) integrity and immunoglobulin G (IgG) intrathecal synthesis were further tested using albumin and IgG indices. The CSF was also tested for autoimmune encephalitis antibodies and 14-3-3, a marker of ongoing neurodegeneration.ResultsAll patients had anti–SARS-CoV-2 antibodies in their CSF, and 4 of 8 patients had high titers, comparable to high serum values. One patient had anti–SARS-CoV-2 IgG intrathecal synthesis, and 3 others had disruption of the blood-brain barrier. The CSF in 4 patients was positive for 14-3-3-protein suggesting ongoing neurodegeneration. In all patients, the CSF was negative for autoimmune encephalitis antibodies and SARS-CoV-2 by PCR. None of the patients, apart from persistent encephalopathic signs, had any focal neurologic signs or history or specific neurologic disease.ConclusionsHigh-titer anti-SARS-CoV-2 antibodies were detected in the CSF of comatose or encephalopathic patients demonstrating intrathecal IgG synthesis or BBB disruption. A disrupted BBB may facilitate the entry of cytokines and inflammatory mediators into the CNS enhancing neuroinflammation and neurodegeneration. The observations highlight the need for prospective CSF studies to determine the pathogenic role of anti–SARS-CoV-2 antibodies and identify early therapeutic interventions.

Neurological Manifestations of COVID-19 Feature T Cell Exhaustion and Dedifferentiated Monocytes in Cerebrospinal Fluid

“…Most likely, our study was not sufficiently powered to achieve significance in this direct subgroup comparison. In accordance with an underpowered study size, the increase of BCBD in severe Neuro-COVID reported previously ( Alexopoulos et al., 2020 ) also did not reach significance in our severe versus mild comparison ( Figure S2 H).

Figure 4 Broad Clonal T Cell Expansion in Severe Neuro-COVID (A) Principal component analysis (PCA) of T cell subcluster abundances in Neuro-COVID patients categorized by neurological severity (mild, n = 5; severe, n = 3).

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Inflammatory Leptomeningeal Cytokines Mediate COVID-19 Neurologic Symptoms in Cancer Patients

“…There was no evidence of SARS-CoV-2 viral RNA detection, nucleocapsid protein, or spike protein in the CSF of our cancer population, which is reassuring given the baseline immunocompromised state and high degree of medical comorbidities afflicting our patients. Only one patient had detectable SARS-CoV-2 antibodies in the CSF, contrary to what has been observed among other patient cohorts with neurologic manifestations of COVID-19 ( Alexopoulos et al., 2020 ; Song et al., 2020 ). This can be in part explained by different extent of the disease encompassing the CNS and the use of assays with different sensitivities and specificities.…”

Cerebrospinal fluid in COVID-19: A systematic review of the literature

“…After review of the 242 documents, we identified 430 patients with COVID-19 diagnosed based on PCR or serologic testing who had acute neurological symptoms prompting CSF testing [ [5] , [6] , [7] , [8] , [9] , [10] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , [66] , [67] , [68] , [69] , [70] , [71] , [72] , [73] , …”

“…7 patients had IgG index <0.77 (authors indicated threshold to identify intrathecal synthesis was >0.77) [ 25 ]…”

“…1 patient had positive SARS-CoV-2 antibodies and IgG index 1.85 indicating some intrathecal synthesis (authors indicated threshold to identify intrathecal synthesis was IgG index >1; as noted above) [ 25 ]…”