key: cord-0915818-5gis7i4f
authors: Barzegar, Mahdi; Vaheb, Saeed; Mirmosayyeb, Omid; Afshari-Safavi, Alireze; Nehzat, Nasim; Shaygannejad, Vahid
title: Can Coronavirus Disease 2019 (COVID-19) Trigger Exacerbation of Multiple Sclerosis? A Retrospective Study
date: 2021-04-11
journal: Mult Scler Relat Disord
DOI: 10.1016/j.msard.2021.102947
sha: 362ae6737a2aba814ebb1f97565198925a513100
doc_id: 915818
cord_uid: 5gis7i4f

The effect of coronavirus disease (COVID-19) on the risk of relapse in multiple sclerosis (MS) have been unknown. In this retrospective study of 41 relapsing-remitting MS patients, number of relapses in pre-defined at risk-period (ARP) was compared with the previous two years. During the previous two years, a total of 32 attacks was reported, which 5 (15.6%) were during the at-risk period. After adjusting for age and sex, there was an increased risk of attack during ARP compared to the previous two years (RR: 2.566, 95%CI: 1.075-6.124, P=0.034). Our preliminary study suggested that COVID-19 can trigger exacerbation of MS.

As understanding the clinical features and outcome of coronavirus disease in multiple sclerosis (MS) patients improves, there is a lack of information regarding the effect of this infection on MS disease course. It is known that upper respiratory viral infection (URVI) increase the risk of relapses in MS patients (Buljevac et al., 2002; Edwards et al., 1998) . However, there are currently no data to assess the effects of COVID-19 on the risk of relapse in MS. We aimed to examine the possible association between COVID-19 infection and relapse in patients with MS.

This retrospective observational study was conducted in the outpatient MS clinic of Kashani Hospital affiliated to Isfahan University of Medical Sciences. All relapsing-remitting MS (RRMS) patients with a confirmed COVID-19 diagnosis based on reverse transcriptionpolymerase chain reaction (RT-PCR) who visited our outpatient MS clinic or contacted the center were included. Exclusion criteria were pregnancy and changes in disease-modifying therapy (DMT) within the previous two years.

Information on the number and timing of relapse in the past two years was extracted from the prospectively collected dataset (Mirmosayyeb et al., 2020) . We also collected data on all patients via a telephone interviews. Relapse was defined as worsening of pre-existing symptoms or developing new symptoms, in the absence of fever, lasting at least 24h, after at least 30 days of improvement and stability (Thompson et al., 2018) , and confirmed by presence of gadolinium enhancement on magnetic resonance imaging (MRI). At risk-period (ARP) was defined as a period including two weeks before until five weeks after COVID-19 onset (Sibley et al., 1985) . Any attack in this period was considered related to the COVID-19.

We used Chi square test to compare relapse rate during ARP between patients required hospitalization due to COVID-19 and those didn't need. A generalized estimating equation (GEE) model with a Poisson distribution and a log link function was applied to compare the number of relapses during the at-risk period with the previous two years. The natural logarithm of person-time (week) is used as an offset. All statistical calculations were done using the SPSS 20.0 for Windows (SPSS, Chicago, IL, USA), and the P<0.05 was considered significant.

A total of 41 RRMS patients with confirmed COVID-19 diagnosis were included in this study. The mean age was 35.10±9.20, and 31 (75.6%) were female. The median disease duration and EDSS were 7.0 (5.0-10.7) and 0.0 (0.0-1.5), respectively. Nineteen (46.3%) patients received interferon, 9 (22.0%) were treated with teriflunomide, 8 (19.5%) with rituximab, 3 (7.3%) with fingolimod, and 2 (4.9%) were on dimethyl fumarate. Five patients were hospitalized due to COVID-19, but none required intensive care unit admission.

During the previous two years (4264 patient-weeks), a total of 32 attacks was reported in 22 (53.6%) patients, resulting in an annual average relapse rate of 0.32 (range 0-1). Out of 32 relapses, 5 (15.6%) were during the at-risk period (287 patient-weeks). These relapses occurred in 5 (12.2%) patients, and all started after the COVID-19 onset, with an average of 3.2 weeks (range 1-5). Two other patients reported neurological worsening after COVID-19 onset, but none met clinical relapse definition. One of five patients who experienced a relapse during ARP, required hospitalization due to . No association between hospitalization for COVID-19 and risk of MS attack around the time of COVID-19 was found (P=0.853). After adjusting for age and sex, there was an increased risk of attack during ARP (RR: 2.566, 95%CI: 1.075-6.124, P=0.034) compared to the previous two years (Table   1 ).

In this small retrospective study, COVID-19 infection was shown to increase the risk of relapse in MS patients. Our findings are in line with previous observation that upper respiratory viral infections (Edwards et al., 1998; Kriesel et al., 2004) , of which 10-30% are caused by coronaviruses (Paules et al., 2020) , is associated with risk of MS relapse.

One of the putative mechanism underlying the observed association between COVID-19 and MS attacks could be expression of peripheral pro-inflammatory mediators such as interleukin (IL)-6, IL-7, IL-10, IL-17, granulocyte-colony stimulating factor, interferon (IFN)-γ, tumor necrosis factor (TNF)-α in COVID-19 infection (Vabret et al., 2020) . High amounts of these factors can lead to blood-brain barrier dysfunction and facilitate the migration of monocytes, macrophages, and CD4+ and CD8+ T cells into the central nervous system (Dziedzic et al., 2021) , which consequently can cause neurological worsening and MS exacerbation. Another possible mechanism is a direct invasion of the central nervous system (CNS) by SARS-COV-2 (Song et al., 2021) .

Our study has some limitations including the small number of patients and retrospective nature of the study. We also had few patients with severe COVID-19 and the absence of information on the severity of relapse, and lack of information on presence of gadolinium enhancement on MRI in all patients are other limitations of this study.

In conclusion, this preliminary study suggested that COVID-19 can trigger exacerbation of MS. Further studies are needed to elucidate the possible relationship between COVID-19 and MS. 

Prospective study on the relationship between infections and multiple sclerosis exacerbations

The Impact of SARS-CoV-2 Infection on the Development of Neurodegeneration in Multiple Sclerosis

Clinical relapses and disease activity on magnetic resonance imaging associated with viral upper respiratory tract infections in multiple sclerosis

Multiple sclerosis attacks are associated with picornavirus infections

Clinical characteristics and disability progression of early-and late-onset multiple sclerosis compared to adult-onset multiple sclerosis

Clinical viral infections and multiple sclerosis

Neuroinvasion of SARS-CoV-2 in human and mouse brain