Title: Effects of COVID-19 on Multiple Sclerosis Relapse: A Comprehensive Review

1 IJMS Title: Effects of COVID-19 on Multiple Sclerosis Relapse: A Comprehensive Review 1 2 3 Author names: 4 1. Matthew Topolski 5 2. Varun Soti 6 7 Degrees and Affiliations: 8 1. Second-year Medical Student. Lake Erie College of Osteopathic Medicine, Elmira, New York 14901, 9 USA 10 2. Ph.D. Lake Erie College of Osteopathic Medicine, Elmira, New York 14901, USA 11 12 ORCID (Open Researcher and Contributor Identifier): 13 1. https://orcid.org/0000-0003-3438-7947 14 2. https://orcid.org/0000-0002-1914-0295 15 16 About the author: 17 Matthew Topolski is a second-year medical student at Lake Erie College of Osteopathic Medicine, Elmira, NY. 18 Dr. Varun Soti is a medical educator. He is Medical Faculty and Pharmacology Professor at Lake Erie College 19 of Osteopathic Medicine, Elmira, NY. 20 21 Corresponding author email: vsoti@lecom.edu 22 Acknowledgment: Learning Resource Center at Lake Erie College of Osteopathic Medicine, Elmira, NY. 23 Financing: Not applicable 24 Conflict of interest statement by authors: The authors declare that they have no competing interests. 25 Compliance with ethical standards: Not applicable 26 27 Authors Contribution Statement: 28


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We conducted a literature search through the PubMed and EBSCO databases from March 2020 3 through July 2021 for studies measuring relapses in PwMS who had been infected by COVID-19. Inclusion 4 criteria included: 1) studies being written in English; 2) any case report, retrospective cohort study, and 5 prospective cohort study that included PwMS who were infected with SARS-CoV-2; 3) studies that measured 6 neurologic symptom exacerbation or relapse. We used the following search terms: "Coronavirus Multiple 7 Sclerosis," "Coronavirus MS Relapse," "Coronavirus MS Exacerbation," "COVID-19 Multiple Sclerosis," 8 "COVID-19 MS Relapse," "COVID-19 MS Exacerbation," "SARS-CoV-2 Multiple Sclerosis," "SARS-CoV-2 MS 9 Relapse," "SARS-CoV-2 MS Exacerbation." Our search resulted in 399 articles in total. Of those, one study was not written in English, 390 were 11 not case reports, retrospective cohort studies, or prospective cohort studies that included PwMS who were 12 infected with SARS-CoV-2, and one study did not measure neurologic symptom exacerbation or relapse. Of 13 the seven studies meeting the inclusion criteria, two were retrospective studies, one was a prospective cohort 14 study, one was an observational study, and three were case reports. The level of evidence for the included 15 studies was determined based on the previous literature. 10 The methodology used in the review is illustrated 16 in Figure 1, which is based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. 11 IJMS PATHOPHYSIOLOGY.

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MS is an autoimmune disease characterized by plaque-like sclerosis found throughout the CNS, its 3 most common disease course is RRMS that is identified by symptom exacerbations; during exacerbations, 4 acute demyelinating attacks occur between more prolonged periods of quiescence. 8 Throughout these 5 demyelinating episodes, myelin basic protein (MBP), a critical component of the myelin sheath, is adversely 6 impacted. 12 These inflammatory lesions are more significantly found in the white matter but have also been 7 seen in the gray matter; lesions are widely observed in the periventricular region, juxtacortical areas,   1 2 SARS-CoV-2 that causes COVID-19, has a well-described cell entry mechanism. 33 Antigen 3 presentation by antigen-presenting cells (APCs) is crucial to antiviral cell-mediated immunity. A recent study 4 suggests a defect in the MHC class II gene expression for the presentation of SARS-CoV-2 by APCs. 34

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The polymorphic nature of the MHC region of the human genome plays an essential role in individual 6 susceptibility to diseases such as MS. 35 The innate and adaptive immune system response to coronaviruses 7 is integral to the infection's clinical presentation; the innate immune response is triggered by pattern

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In an observational study of MS patients with COVID-19 (72 MS patients), 21.1% reported neurologic 3 symptoms suggestive of relapse. 54 A retrospective cohort study by Etemadifar et al. found 7.14% of the 56 4 PwMS experienced a relapse from the period of two weeks before and six months after recovering from 5 COVID-19. 55 6 Another retrospective study assessing 41 PwMS found an increased relapse rate of 0.017 attacks per 7 "at-risk" week compared to 0.007 attacks per week during a not "at-risk" period of the two years prior. The "at-8 risk" period was defined as the two weeks before and five weeks after COVID-19 infection. 56

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In another case report, a 29-year-old female with a history of asthma presented with COVID-19 26 symptoms, including anosmia, dysgeusia, asthenia, and proximal myalgias in her limbs that disappeared 27 within a week after developing COVID-19. She presented two weeks later with a ten-day history of right visual    (Table 2). First, the definition of relapse or exacerbation varies between studies. A couple of research 4 studies used a formal definition of relapse involving the new onset of symptoms lasting more than 24 hours, 5 but one study defined relapse as any neurologic symptom that suggested a recurrence. Second, the period 6 utilized to measure COVID-19-related exacerbations was not consistent. One research group used a period of 7 two weeks before COVID-19 infection to six months after the illness. While another group only utilized the