key: cord-0972155-ar6t2vml
authors: Lewis, Ariane; Jain, Rajan; Frontera, Jennifer; Placantonakis, Dimitris G.; Galetta, Steven; Balcer, Laura; Melmed, Kara R.
title: COVID‐19 associated brain/spinal cord lesions and leptomeningeal enhancement: A meta‐analysis of the relationship to CSF SARS‐CoV‐2
date: 2021-06-08
journal: J Neuroimaging
DOI: 10.1111/jon.12880
sha: d4d95065de5805da571956a5678add373c67b57e
doc_id: 972155
cord_uid: ar6t2vml

BACKGROUND AND PURPOSE: We reviewed the literature to evaluate cerebrospinal fluid (CSF) results from patients with coronavirus disease 2019 (COVID‐19) who had neurological symptoms and had an MRI that showed (1) central nervous system (CNS) hyperintense lesions not attributed to ischemia and/or (2) leptomeningeal enhancement. We sought to determine if these findings were associated with a positive CSF severe acute respiratory syndrome associated coronavirus 2 (SARS‐CoV‐2) polymerase chain reaction (PCR). METHODS: We performed a systematic review of Medline and Embase from December 1, 2019 to November 18, 2020. CSF results were evaluated based on the presence/absence of (1) ≥ 1 CNS hyperintense lesion and (2) leptomeningeal enhancement. RESULTS: In 117 publications, we identified 193 patients with COVID‐19 who had an MRI of the CNS and CSF testing. There were 125 (65%) patients with CNS hyperintense lesions. Patients with CNS hyperintense lesions were significantly more likely to have a positive CSF SARS‐CoV‐2 PCR (10% [9/87] vs. 0% [0/43], p = 0.029). Of 75 patients who had a contrast MRI, there were 20 (27%) patients who had leptomeningeal enhancement. Patients with leptomeningeal enhancement were significantly more likely to have a positive CSF SARS‐CoV‐2 PCR (25% [4/16] vs. 5% [2/42], p = 0.024). CONCLUSION: The presence of CNS hyperintense lesions or leptomeningeal enhancement on neuroimaging from patients with COVID‐19 is associated with increased likelihood of a positive CSF SARS‐CoV‐2 PCR. However, a positive CSF SARS‐CoV‐2 PCR is uncommon in patients with these neuroimaging findings, suggesting they are often related to other etiologies, such as inflammation, hypoxia, or ischemia.

Patients with coronavirus disease 2019 (COVID-19) who have neurological symptoms often have central nervous system (CNS) hyperintense lesions and/or leptomeningeal enhancement on neuroimaging. [1] [2] [3] [4] [5] [6] Postulated mechanisms for these findings include F I G 1 Publication selection for intrathecal SARS-CoV-2 antibody production. 7 We sought to determine whether CNS hyperintense lesions and leptomeningeal enhancement on magnetic resonance imaging (MRI) of the brain or spine in patients with COVID-19 is associated with evidence of SARS-CoV-2 in the CSF.

In a larger systematic review, two board-certified neurologists screened 1182 publications obtained via a search of Medline and Embase from December 1, 2019 and November 18, 2020 using the population search terms "COVID-19" or "SARS-CoV-2" and the intervention search terms "cerebrospinal fluid" or "csf" or "spinal puncture" or "spinal tap" or "lumbar puncture" or "meningitis" or "encephalitis" or "encephalomyelitis" or "seizure" or "encephalopathy" or "myelitis" or "Guillain Barre" or "polyradiculitis" or "Miller Fisher" and identified 242 publications in English that described a unique patient diagnosed with COVID-19 via SARS-CoV-2 PCR or serology who had a neurological symptom and had CSF results reported, but did not have a diagnosis that could impact CSF results, such as subarachnoid hemorrhage or another intracranial infection. 7 These publications were subsequently screened to identify those that described a patient who had symptoms that localized to the CNS, had an MRI of the brain and/or spine, and whose MRI showed (1) CNS hyperintense lesions (on a T2/fluid-attenuated inversion recovery sequence, if specific sequences were specified) that the authors of the case report/case series did not attribute to acute/chronic ischemia and/or (2) leptomeningeal enhancement or (3) no CNS hyperintense lesions (to serve as a comparator group). It was not feasible to review all sequences and images of the MRIs ourselves, so we relied on the authors' reports of the MRI findings, though a board-certified neurologist and/or neuroradiologist reviewed the imaging sequences that were included in the publications. Publications were excluded if they did not describe a patient who had symptoms that localized to the CNS or an MRI of the brain/spine, or whose MRI (1) showed CNS hyperintense lesions attributed to ischemia; (2) showed findings that were reported as a diagnosis rather than described, such as "acute disseminated encephalomyelitis;" or (3) was noted to have CNS hyperintense lesions with no mention of the location of these lesions. This For patients who had >1 lumbar puncture, the findings from all CSF samples were included and the highest CSF white blood cell (WBC) count and CSF protein were reported. The CSF studies were conservatively considered to demonstrate evidence of SARS-CoV-2 if there was (1) a single positive CSF SARS-CoV-2 PCR; or (2) antibody, oligoclonal band, or immunoglobulin findings suggestive of intrathecal antibody synthesis in the absence of an identified autoimmune antibody in the CSF. 7 Severity of COVID-19 infection was determined based on the World Health Organization's criteria. 9 All laboratory test results were converted to a common unit to facilitate comparison.

The CSF results were compared for patients who had ≥ 1 CNS hyperintense lesion to patients with no CNS hyperintense lesions and for patients who had leptomeningeal enhancement to patients who had no leptomeningeal enhancement on an MRI with contrast. Additionally, the CSF results for patients who had CNS hyperintense lesions at each location were compared to those from patients who had an MRI brain who did not have lesions in the location being reviewed (e.g., CSF from patients with cortical hyperintense lesions were compared to CSF from patients who had an MRI brain and did not have cortical hyperintense lesions). Lastly, the CSF results from (1) patients with multifocal CNS hyperintense lesions were compared to those from patients who had an MRI brain and only had unifocal CNS hyperintense lesions and (2) patients with focal leptomeningeal enhancement were compared to those from patients with diffuse leptomeningeal enhancement. Comparisons were made using Chi-square and Fisher tests as appropriate using IBM SPSS Statistics Version 25. A p-value <0.05 was considered statistically significant.

After review of the 117 publications, we identified 193 patients who met inclusion criteria. 1,2,10-124 There were 105/189 (56%) male patients. 1,2,10-12,14,16,17,19,22,26,27,31,33,35,37-40,46,47,50,51,54,57-60,62,64-71, 75,76,79,81,82,84,85,87,89,91,93,95-97,99,101-105,107-109,113-120,124 The median age was 56 (range 2-96) years old. 1, 2, 124 There were 79/167 (47%) patients with severe COVID-19. 1,2,10-12, [14] [15] [16] 18, 22, 26, 33, 36, [40] [41] [42] [43] [44] 49, [51] [52] [53] 55, 58, 61, 63, 70, 71, 77, 80, 81, [87] [88] [89] 95, 96, 99, 108, 116, 117, [121] [122] [123] Of 154 patients with outcome data reported, 22 (14%) died before their case was published. 1, 10, 14, 16, 33, 39, 49, 51, 55, 57, 61, 64, 81, 82, 84, 89, 96, 123 

The primary neurological symptoms that precipitated MRI and CSF acquisition are shown in Figure 3 ; for the majority of patients (144, 75%), this workup was performed due to coma/encephalopathy with or without seizure/abnormal movement/headache. 1, 2, 11, 12, [14] [15] [16] 22, 23, 26, 33, 36, [39] [40] [41] [42] [44] [45] [46] [47] [48] 50, 51, [53] [54] [55] [56] [57] 61, [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [75] [76] [77] [78] [79] [80] [81] [82] [83] [84] 87, 88, [90] [91] [92] [94] [95] [96] [97] [98] [99] [100] [101] [102] [103] [104] [105] 108, 109, [111] [112] [113] [114] [115] [116] [117] [118] [119] [121] [122] [123] Although the number of days between the MRI and lumbar puncture was only specified for the minority of patients (41, 21%), among those where it was, there was a median of 0 (interquartile range

[IQR] −2 to 0) days between the MRI and lumbar puncture. 15, 16, 18, 23, 33, 40, 45, 47, 51, 53, 55, 60, 61, 67, 73, [76] [77] [78] 81, 87, [91] [92] [93] 98, [100] [101] [102] 109, 116, 118, 119, 121 There were 17 (9%) patients with CSF cell count, protein, SARS-CoV-2 PCR or antibody results from >1 lumbar puncture and 34 (18%) patients with results from >1 MRI. 1, [15] [16] [17] [18] 21, [23] [24] [25] 27, 28, 30, 33, 34, 38, 40, 45, [52] [53] [54] 58, 63, [67] [68] [69] [70] [72] [73] [74] [75] 80, 81, 84, 91, 92, 95, 98, 108, 115, 118, 119, 121, 124 Additional details on MRI and CSF acquisition are in Table 1 The presence of CNS hyperintense lesions did not significantly correlate with CSF protein >60 mg/dl or "increased," but patients with hyperintense lesions in the limbic system, basal ganglia/thalamus, or brainstem/cerebellum/spinal cord were significantly more likely to have CSF protein >60 mg/dl or "increased" than patients who did not have hyperintense lesions in these locations (64% (Figures 7 and 8 ) and 8 (40%) had focal enhancement. 2, 28, 29, 37, 55, 56, 61, 62, 82, 84, 92, 93, 96 Patients with leptomeningeal enhancement were significantly less likely to have CNS hyperintense lesions than patients without leptomeningeal enhancement (55% [11/20] vs. 80% [44/55] 

Although numerous case series have demonstrated CNS hyperintense lesions and/or leptomeningeal enhancement may be seen on neuroimaging in patients with COVID-19 who have neurological symptoms, questions remain about the etiology for these findings. [1] [2] [3] [4] [5] [6] In this meta-analysis of 193 patients with COVID-19 described in the literature who had an MRI brain and/or spine and CSF testing, we found a significant relationship between these neuroimaging findings and a positive CSF SARS-CoV-2 PCR. 1,2,10-124 These data may improve our understanding of the pathophysiology of these neuroimaging findings and guide decision-making about CSF testing in patients with COVID-19 who have neurological symptoms. Awareness of the MRI findings that can be seen in patients with evidence of SARS-CoV-2 in the CSF will also be important once the pandemic is over when COVID-19 is no longer part of the differential diagnosis for every patient, as there is a characteristic MRI phenotype associated with many viral encephalitides. 125 For example, herpes simplex virus-1 has a proclivity for the frontal and temporal lobes; Japanese encephalitis commonly involves the thalami and sometimes affects the basal ganglia, pons, midbrain, or cerebellum; varicella encephalitis causes cerebellar, thalamic, cortical or basal ganglia hyperintense lesions; and

Parechovirus encephalitis affects the cerebral white matter and corpus callosum. Our results suggest that cortical hyperintense lesions and cranial nerve/cauda equina hyperintense lesions, in particular, are significantly associated with evidence of SARS-CoV-2 in the CSF, and that there is a trend toward increased likelihood of a positive CSF SARS-CoV-2 PCR in patients with diffuse leptomeningeal enhancement as compared with patients with focal leptomeningeal enhancement. However, in contrast with a recent study that showed leptomeningeal enhancement is common in patients with multiple sclerosis who have cortical or thalamic lesions, we found that patients with leptomeningeal enhancement were significantly less likely to have CNS hyperintense lesions. 126 of transudation of antibodies, or the cells that secrete them, via a damaged blood-brain barrier or a traumatic tap, rather than intrathecal antibody synthesis. 14, 107, 108, 115, 148, 149 Our statistical analysis was also impacted by the low number of patients with a positive CSF SARS-CoV-2 PCR, evidence of possible intrathecal SARS-CoV-2 antibody synthesis, and CSF autoimmune antibodies. Further, certain imaging findings (such as cranial nerve/cauda equina hyperintense lesions) were quite rare, which is notable given that it is believed that viruses may enter the CNS via cranial or peripheral nerves. 150 

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The authors received no external funding for this work and report no financial conflicts-of-interest.

Ariane Lewis https://orcid.org/0000-0002-0756-7320Kara R. Melmed https://orcid.org/0000-0003-4084-8586