key: cord-0808315-m6j08tgz
authors: Mondal, R.; Deb, S.; Shome, G.; Ganguly, U.; Lahiri, D.; Benito Leon, J.
title: Spectrum of spinal cord involvement in COVID-19: A systematic review
date: 2020-09-30
journal: nan
DOI: 10.1101/2020.09.29.20203554
sha: e2aab82825e285e4929c72804917a31ebe002d8c
doc_id: 808315
cord_uid: m6j08tgz

Background and aims- Recent reports reveal incidences of spinal cord involvement in form of para-infectious or post-infectious myelitis raising potential concerns about the possibilities of SARS-CoV-2 behind the pathogenesis of spinal cord demyelination. In this study, we intend to summarise so far available pieces of evidence documenting SARS-CoV-2 mediated spinal demyelination in terms of clinical, laboratory parameters and imaging characteristics. Methodology- This review was carried out based on the existing PRISMA (Preferred Report for Systemic Review and Meta-analyses) consensus statement. Data was collected from four databases: Pubmed/Medline, NIH Litcovid, Embase and Cochrane library and Preprint servers up till 10th September, 2020. Search strategy comprised of a range of keywords from relevant medical subject headings which includes "SARS-COV-2", "COVID-19", "demyelination" etc. Results- A total of 21 cases were included from 21 case reports after screening from various databases and preprint servers. Biochemical analysis reveals that the majority of cases showed elevated CSF protein as well as lymphocytic pleocytosis. Interestingly, a majority of cases were found to be associated with long extensive transverse myelitis (LETM), and remaining cases were found to be associated with isolated patchy involvement or isolated short segment involvement or combined LETM and patchy involvement. Few cases were also found with significant co-involvement of the brain and spine based on the imaging data. Conclusion- It can be interpreted that SARS-CoV-2 may play a potential role in spinal demyelinating disorders in both para-infectious and post-infectious forms.

In recent times, several reports have come up describing spinal cord involvement in the context of COVID-19. Ranging from vascular to demyelinating pathology, various forms of spinal cord involvement have been documented. Additionally, there are reports revealing cord enhancement in association with polyradiculoneuropathy [4] . In sum, spinal cord involvement in COVID-19 has been steadily receiving attention for some time now [7] .

Seemingly the inter-relationship between demyelinating disorders and COVID-19 has two facets. SARS-CoV-2 infection may lead to spinal cord as well as brain demyelination. On the other hand, patients with known primary demyelinating disorders may experience an exacerbation of pre-existing neurological features. In the present systematic review, we set out with the objective of organizing the so far available evidence of spinal cord demyelination in the setting COVID-19 in terms of clinical presentation, laboratory features, and imaging characteristics. The presented summary of COVID-19 associated myelitis has important prognostic as well as therapeutic implications from the perspective of clinical neurology. September 10, 2020. The search strategy consists of a variation of keywords of relevant medical subject headings (MeSH) and keywords, including "SARS-CoV-2", "COVID-19", "coronavirus", "demyelinating disorders", "Multiple sclerosis" and "Encephalomyelitis". Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) were also included in our search strategy to capture related articles. We also hand-searched additional COVID-19 specific articles using the reference list of the selected studies, relevant journal websites, and renowned pre-print servers (medRxiv, bioRxiv, pre-preints.org) from 2019 to the current date for literature inclusion. To decrease publication bias, we invigilated the references of all studies potentially missed in the electrical search. Content experts also searched the grey literature of any relevant articles.

All peer-reviewed, pre-print (not-peer-reviewed) including cohort, case-control studies, and case reports which met the pre-specified inclusion and exclusion criteria were included in this study. 

Studies

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Studies excluded if COVID-19 was not confirmed among patients and written in languages other than English. We also excluded review papers, viewpoints, commentaries, and studies where no information related to neurological manifestations or spinal demyelination was reported.

Before the screening process, a team of two reviewers (GS and SD) participated in calibration and screening exercises. The first reviewer (GS) subsequently screened independently the titles and abstracts of all identified citations, and the second reviewer (SD) verified those citations and screened papers by (GS). Another reviewer (UG) then retrieved and screened independently the full texts of all citations deemed eligible by the reviewer (SD) and analyzed those data. The other two reviewers (RM and DL) independently verified these extracted full texts for eligibility towards analysis and designed the overall study structure. The corresponding author (JBL) had resolved disagreements whenever necessary and took final decisions regarding the study. Throughout the screening and data extraction process, the reviewers used piloted forms. In addition to the relevant clinical data, the reviewers also extracted data on the following characteristics: study characteristics (i.e. study identifier, study design, setting, timeframe); outcomes (qualitative and/or quantitative); clinical factors (definition and measurement methods); study limitations. The Newcastle-Ottawa scale was used to assess the selection procedure, the comparability, and the outcomes of each reviewed study.

Both qualitative and quantitative data were expressed in percentages. Unit discordance among the variables was resolved by converting the variables to a standard unit of measurement. A value of 'p'<0.05 was considered as statistically significant but it could not be calculated due to insufficient data. A meta-analysis was planned to analyze the association of the demographic findings, symptoms, biochemical parameters, outcomes but was later omitted due to lack of sufficient data.

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Around 750 articles were initially identified from the aforementioned databases and 253 articles were identified from different pre-prints servers. Finally, a total of 712 articles were identified from different databases searched after removing the duplicates. Of the selected articles, 600 articles were excluded after screening titles and abstracts, leaving 112 articles for full-text review for possible inclusion in this study. Of these, 60 articles were excluded based on the inclusion and exclusion criteria for the study sample (e.g., excluded demyelination of only brain, pre-existing demyelination related articles), and few other articles were excluded for study types (e.g review papers, correspondence, viewpoints, commentaries). A total of 52 articles were finally selected for this study; 21 articles were included in the analysis, and the remaining 31 articles were synthesized narratively [ Figure 1 ] .

The selected study comprises of 21 case reports with 52% (n=11) male and 48% (n=10) female along with the mean age around (46.66±17.97). They had developed various COVID-19 related symptoms such as fever (n=11, 52%),cough (n=6, 29%), myalgia (n=6, 29%),vomiting (n=2, 10%),nausea (n=1, 5%)and many more. The neurological symptoms reported were weakness (n=14, 66.66%), sensory deficit (n=14, 66.66%) ataxia (n=1, 4.76%), autonomic dysfunction (n=8, 38.09%),cognitive impairment (n=2 , 9.52%).

Various CSF parameters under biochemical analysis such as Glucose (mg/dl) (n=5, 24%), Protein (mg/dl) (n=13, 70%), Adenosine Deaminase (μ/L) (n=1, 5%), Lactate Dehydrogenase (unit/L) (n=1, 5%) were recorded with significant levels of elevation from the normal range.

Moreover certain cell count parameters such as WBC (n=2, 10%), RBC (n=2, 10%) was significantly higher than the normal range. Cases with Lymphocytic pleocytosis (n=5, 24%) were also reported. SARS-COV-2 was detected in (n=5, 24%) cases using RT-PCR (n=4) and IgG positive (n=1). SARS-COV-2 detection came negative in (n=13, 62%) cases whereas SARS-COV-2 testing was not done in two cases and data was unavailable for one case. Autoimmune profiling for . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 30, 2020. . majority of cases came negative except two cases with positive oligoclonal band (OCB) and lupus antigen respectively [ Neuroimaging findings were reported in 20 studies consisting of 20 cases and the remaining 1 case imaging data were not available. Among the imaging modalities, MRI of the spine was done for all the 18 cases whereas brain MRI was found for 16 cases. CT scan of the spine and brain were performed for 1 and 2 cases respectively. Interestingly, we found a majority of cases (n=9, 45%) were associated with isolated LETM whereas a combination of both LETM and patchy was 10% (n=2). Imaging data also reveals that 10% (n=2) cases were associated with isolated patchy involvement and 25% cases (n=5) were associated with isolated short segment involvement. Furthermore, we found co-involvement of both brain and spine for 30% (n=6) cases [ Treatment was mainly carried out with corticosteroids (n=18, 86%) like methyprednisolone (n=14, 67%), dexamethasone (n=2, 10%), oral prednisolone (n=1, 5%) etc.

Intravenous immunoglobulin was given to (n=5, 24%) cases. Sessions of therapeutic plasma exchange were given to (n=8, 38%) patients. Antivirals drugs such as acyclovir, lopinavir/ritonavir, ganciclovir, favipiravir were administered to (n=7, 33.33%) patients with the most common drug of choice being Acyclovir in (n=5, 24%) cases. Hydroxychloroquine was given to three patients (14.28%). Two cases were reported where anti-epileptic drug was given. A majority of the patients recovered/discharged (n=15, 71%) with mortality of two cases (n=2, 10%) and four patients (n=4, 19%) were still under treatment during the period of study.

During the course of this ongoing pandemic, several immunological features of SARS-CoV-2, affecting different organ systems have been observed by clinicians and researchers across the globe.

In the context of neurological manifestations of COVID-19, immunological mechanisms are known to play important roles in giving rise to diverse clinical presentations affecting both CNS as well as . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 30, 2020. . PNS [29] . Quite antithetical to how SARS-CoV-2 affects PNS (mostly in the form of GBS) [29] , data regarding spinal cord involvement are scarce. Acute or post-infectious myelitis is not uncommon with several viruses ascribable to its cause, such as Epstein-Barr virus, cytomegalovirus, measles virus, or rhinovirus. In addition, infection-related spinal cord demyelination is known to be associated with brain involvement as well, giving rise to the clinical picture of ADEM.

Spinal cord involvement in COVID-19 might be an under-recognized neurological complication of this novel infectious disease. In the present systematic review, we have found spinal cord involvement in 21 patients with COVID-19 along with their laboratory features and imaging abnormalities. We found 38.1% (n=8) of patients with para-infectious acute myelitis and 14.3% Besides, neuroimaging data revealed that half of the patients presented with longitudinally extensive transverse myelitis (LETM) followed by patchy (11.1%) and short (27.7%) segment involvement. LETM is usually observed in neuromyelitis optica spectrum disorder (NMOSD), infectious myelitis, lupus-related demyelination, and, occasionally, in MS. In India, tuberculosis is a known cause of LETM [30] . Of interest, half of the reported cases of myelitis in COVID-19 present with long-segment spinal cord involvement. From a clinician's perspective, this observation basically extends the differential diagnosis of LETM to include COVID-19 related spinal cord demyelination. Due to the small number of available cases, we could not establish a definite pattern of brain involvement. Noteworthy, one-third of our patients revealed co-existent demyelination in varied areas across the brain (including the brainstem) in addition to the spinal cord. Laboratory parameters revealed elevated CSF protein and lymphocytic pleocytosis among reported cases of acute myelitis. These observations are also important from the perspective of a clinical neurologist.

Concerning the prognosis, most of the patients came up with a complete disease resolution and the mortality rate was low (<10%). Noteworthy, microbes including Mycobacterial pneumoniae, . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 30, 2020. . https://doi.org/10.1101/2020.09.29.20203554 doi: medRxiv preprint Epstein Barr Virus (EBV), cytomegalovirus (CMV), rhinovirus, and measles are implicated in post infectious acute myelitis [31] [32] [33] . Reports have already suggested severe cytokine storm with significant elevation of IL-6, IL-7, IL-8, IL-9, TNF-alpha, IFN-gamma cytokines, and depletion of CD8 + T c cells and NK cells; i.e. lymphocytopenia [34].This event raises a possible hypothesis that the infectious organisms are targeted by the immune system which may also invade the CNS tissue including the spine due to structural similarities of microbial components and neuronal receptors.

Different strains of coronaviruses such as HCoV-OC43 and MERS-CoV have been found to initiate several immunopathogenic responses which further cause the progression of demyelinating events in the central nervous system (CNS) [35] . The presence of HCoV RNA was found in the CNS of patients with demyelinating disorders, which suggests a possible association between coronaviruses and demyelination [36] . In a previous study, nucleic acids of HCoV-229E have been detected in the CNS tissue in four out of eleven multiple sclerosis (MS) patients, which suggest neurotropism of this species of coronavirus [37] . Moreover, coronavirus-like particles under electron microscopy were found from autopsies of two MS patients [38] . Using in situ hybridization technique with cloned coronavirus cDNA probes, Murray et.al detected coronavirus RNA in the demyelinating plaques in twelve out of twenty-two MS patients. Significant amounts of coronavirus antigen and RNA were observed in active demyelinating plaques from two patients with rapidly progressive MS [39] . A 3-year-old girl who was admitted with lower respiratory tract infection and acute flaccid paralysis showed co-infection with HCoV-229E and HCoV-OC43, which was detected by real-time PCR analysis of nasal swab samples [40] . Further, a 15-year old boy, who presented with acute disseminated encephalomyelitis (ADEM), tested positive for HCoV-OC43 in cerebrospinal fluid (CSF) using RT-PCR [41] . In a series of 4 patients affected with neurological complications due to MERS-CoV, one of them met a few criteria for diagnosis of the ADEM [42] . Furthermore, RNA recombination demonstrated that the S gene of the coronavirus mouse hepatitis virus (MHV) is related to certain molecular aspects of demyelination, which indicates the potential role of viral envelope S glycoproteins in autoimmune-induced demyelination [43] .According to Kim et al, an . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. There are some implicit limitations in the present endeavor. Given the notable asymmetry between the total number of affected cases and reported cases of infection-related myelitis, it can be assumed that cases are presently under-reported which may be due to several reasons. Therefore, the present systematic review is based on a small number of cases even after an extensive search of available literature, both peer-reviewed, and pre-print. Also, several of the available reports do not describe the timeline of events in an organized manner making interpretation difficult. Laboratory features have also not been mentioned in detail in a few of the cases. In addition, there is considerable heterogeneity in the available data that may be considered a hindrance in advanced analysis. Despite these shortcomings, the present organized review will act as a preliminary guide 

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(which was not certified by peer review) Table-2) . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease

Update on neurological manifestations of COVID-19

COVID-19 Pandemic: A Neurological Perspective

Neurological associations of COVID-19

Seizures associated with coronavirus infections

Neurological manifestations of COVID-19: a systematic review

Spinal cord injury and COVID-19: some thoughts after the first wave

Acute Flaccid Myelitis in COVID-19. BJR Case 11

First case of SARS-COV-2 sequencing in cerebrospinal fluid of a patient with suspected demyelinating disease

Transverse Myelitis in a Child With COVID-19

Acute transverse myelitis in a HIVpositive patient with COVID-19

Acute necrotizing myelitis and acute motor axonal neuropathy in a COVID-19 patient

Acute Demyelinating Encephalomyelitis (ADEM) in COVID-19 infection: A Case Series medRxiv 2020.07.15

Myelin Oligodendrocyte Glycoprotein Antibody-Associated Optic Neuritis and Myelitis in COVID-19

A case of possible atypical demyelinating event of the central nervous system following COVID-19

Neurological and Neuropsychiatric Impacts of COVID-19 Pandemic

Longitudinal extensive transverse myelitis due to tuberculosis: a report of four cases

Acute Transverse Myelitis: Demyelinating, Inflammatory, and Infectious Myelopathies

Acute Flaccid Myelitis Temporally Associated with Rhinovirus Infection: Just a Coincidence?

Acute Myelitis as Presentation of a Reemerging Disease: Measles

Neuroinvasion by human respiratory coronaviruses

Human coronavirus gene expression in the brains of multiple sclerosis patients

Two coronaviruses isolated from central nervous system tissue of two multiple sclerosis patients

Detection of coronavirus RNA and antigen in multiple sclerosis brain

A rare cause of acute flaccid paralysis: Human coronaviruses

Detection of coronavirus in the central nervous system of a child with acute disseminated encephalomyelitis

Severe neurologic syndrome associated with Middle