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COVID-19 and the risk of CNS demyelinating diseases: A systematic review

Background Viral infections are a proposed possible cause of inflammatory central nervous system (CNS) demyelinating diseases, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). During the past 2 years, CNS demyelinating events associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported, but causality is unclear. Objective To investigate the relationship between CNS demyelinating disease development and exacerbation with antecedent and/or concurrent SARS-CoV-2 infection. Methods A systematic literature review of all publications describing either a new diagnosis or relapse of CNS demyelinating diseases (MS, NMOSD, MOGAD) in association with SARS-CoV-2 infection was performed utilizing PRISMA guidelines. Descriptive statistics were used for data analysis, using a case analysis approach. Results Sixty-seven articles met the inclusion criteria for the study. Most of the reported cases of NMOSD (n = 13, 72.2% of reported cases) and MOGAD (n = 27, 96.5% of reported cases) were of new disease onset, presenting with typical clinical and radiographic features of these conditions, respectively. In contrast, reported MS cases varied amongst newly diagnosed cases (n = 10, 10.5% of reported cases), relapses (n = 63, 66.4%) and pseudo-relapses (n = 22, 23.2%). The median duration between COVID-19 infection and demyelinating event onset was 11.5 days (range 0–90 days) in NMOSD, 6 days (range−7 to +45 days) in MOGAD, and 13.5 days (range−21 to +180 days) in MS. Most cases received high-dose corticosteroids with a good clinical outcome. Conclusion Based upon available literature, the rate of CNS demyelinating events occurring in the setting of preceding or concurrent SARS-CoV-2 infection is relatively low considering the prevalence of SARS-CoV-2 infection. The clinical outcomes of new onset or relapsing MS, NMOSD, or MOGAD associated with antecedent or concurrent infection were mostly favorable. Larger prospective epidemiological studies are needed to better delineate the impact of COVID-19 on CNS demyelinating diseases.


Introduction
Multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are immune-mediated inflammatory demyelinating diseases of the central nervous system (CNS). While the cause of these conditions is unknown, it is proposed that an interaction between genetic predisposition and behavioral, environmental, and personal factors contribute to disease development. Among the environmental factors involved, viral infections are considered a possible triggering factor.
Prior studies have shown a higher rate of multiple sclerosis (MS) exacerbation in temporal association with viral infections, especially upper respiratory tract infections caused by influenza A virus and Epstein Barr virus (EBV) (1). EBV has also been proposed as a causal agent in the onset of MS (2,3). Likewise, preceding infections have been proposed as a possible trigger for the induction of pathogenic mechanisms leading to the development of NMOSD and MOGAD (4)(5)(6)(7)(8)(9)(10).
During the past 2 years, neurological complications associated with SARS-CoV-2 infection, the aetiologic agent of the coronavirus disease 2019 (COVID-19), have been reported. Some of these complications are thought to be caused by direct damage to the nervous system as a result of direct viral invasion (11). However, in most cases, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) CSF RNA test is negative, and an immune-mediated mechanism is postulated (12-15). In this latter category, reports of MS, NMOSD, and MOGAD cases presenting either as new diagnoses or disease relapses in temporal association with COVID-19 have been accumulating.
This systematic review aims to summarize the available data regarding the occurrence of new disease onset and disease exacerbation of MS, NMOSD, and MOGAD associated with SARS-CoV-2 infection.

Materials and methods
This systematic literature review was performed utilizing PRISMA guidelines. Electronic searches for published literature were conducted by a medical librarian using Ovid MEDLINE (1946 to present), Embase.com (1947 to present), and Web of Science (1900 to present). The searches were run in December 2021. A search update was run in May 2022.
The search strategy incorporated controlled vocabulary and free-text synonyms for the concepts of multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), relapse, new diagnosis, and COVID-19. The full database search strategies are documented in Appendix 1. No restrictions on language or any other search filters were applied.
All identified studies were combined and de-duplicated in a single reference manager (EndNote). The citations were then uploaded into Covidence systematic review software.
The full reference list of all selected papers was screened for additional relevant sources. Publications meeting the purpose of the review that were not identified through the initial electronic search were added manually to the final review. The paper selection and data extraction process were carried out independently by two authors (IL and SN), with a third author available in case of disagreements.
To ensure maximal coverage of the currently available data pertinent for the topic of this review, we included all available case reports, case series, and cohort studies that met the pre-defined case selection criteria, presented either as manuscripts in peer-reviewed scientific journals or as posters or oral presentations in a scientific congress.
Descriptive statistics was used to present the data from reported cases, using a case analysis approach. Cases with missing data points were excluded from the analysis of the missing variable.

Case selection
We included patients of any age with confirmed COVID-19 and case description consistent with a new diagnosis or a relapse of MS, NMOSD, or MOGAD, in accordance with the 2017 revised McDonald criteria for MS (16), the 2015 international consensus diagnostic criteria for NMOSD (17), and the international recommendations on the diagnosis of MOGAD (18), respectively. Patients fulfilling a diagnosis of clinically isolated syndrome (CIS), considered as having a high likelihood of MS, were included as well. A relapse was defined as a clinical episode reflecting a focal or multifocal CNS demyelinating event lasting at least 24 h, in the absence of fever or active infection (16). When such an event was reported during an acute febrile state related to COVID-19, it was regarded as a pseudo-relapse, even when considered a relapse in the original publication.
COVID-19 cases were included if meeting one of the following criteria, as defined by the United States Centers for Disease Control and Prevention and the Infectious Diseases Society of America: (1) clinical symptoms consistent with COVID-19 without laboratory confirmation in the absence of an alternative explanation, (2) nasopharyngeal swab positive for COVID-19 PCR with or without symptoms, or (3) positive COVID-19 serologies with or without symptoms (19,20).
No assumptions were made regarding the duration between COVID-19 and the onset of neurological manifestations. Missing data was noted as not available.

Exclusion criteria
Cases describing clinical manifestations consistent with demyelinating events of the CNS (i.e., optic neuritis, transverse myelitis, acute disseminated encephalomyelitis, etc.) not fulfilling the diagnostic criteria for MS, NMOSD, or MOGAD as described above, were excluded from this review. Papers reporting a suspected diagnosis of COVID-19 that do not fulfill the diagnostic criteria described above, and papers not available for full-text review were also excluded.
Collectively, 13 case reports and one case series describe the occurrence of 18 NMOSD-related clinical events in the context of COVID-19 (21-32, 86, 87). Eight patients were females, four were males, and in six cases the patients' sex was not reported. The mean age was 33.24 ± 18.5 years.
Ten case reports describe the onset of newly diagnosed NMOSD in people without previous neurological disease (22-26, 28-30, 32, 87). Two case reports describe people with previously undiagnosed neurological disease who then presented with a second clinical manifestation in temporal association to COVID-19, leading to an NMOSD diagnosis (27,86). In one case, the aquaporin-4 antibodies (AQP4 Abs) were retrospectively found to be positive in a stored serum sample drawn 11 months before SARS-CoV-2 infection and more than a year before the clinical onset of NMOSD (31). Apostolos-Pereira et al. report a series of 34 NMOSD patients who developed COVID-19. Five of these patients (15%) developed neurological manifestations that were regarded as relapse or pseudo-relapse during or after SARS-CoV2 infection (21). In      . /fneur. . (30,32) and each fulfilled the diagnostic criteria for seronegative NMOSD. In one report, AQ4 serostatus was not reported (28). In the case series by Apostolos-Pereira et al., 15 patients tested positive for the AQP4-IgG Abs, 7 tested negative, and in 7 the antibody testing was not available (all patients fulfilled the NMOSD diagnostic criteria). The AQP4 antibody status of the five patients who had a relapse was not specified (21). Neurological symptoms appeared after a median of 11.5 days (range 0-90 days) from COVID-19 diagnosis. In all cases, COVID-19 symptoms preceded the occurrence of neurological symptoms.

Post-COVID-MOGAD
Post-COVID-19 MOGAD cases are summarized in Table 2. A total of 28 cases of MOGAD occurring in temporal relation to COVID-19 have been described (33-47, 56, 86, 87). Seventeen were males, and 11 were females. The mean age was 28.1 ± 20.3 years (range 1-69 years; 10 patients <18 years old). The median time between COVID-19 and neurological symptoms was 6 days (range−7-+45 days). In one case, the neurological symptoms preceded the diagnosis of COVID-19 by 1 week (33). In four cases, neurological symptoms developed concomitantly with COVID-19 (37,39,42,86), and in the remaining 23, COVID-19 diagnosis preceded the onset of neurological symptoms. In 27 (96.5%), a new diagnosis of MOGAD was made in people without prior neurological disease. In one case, a relapse occurred in a patient with known MOGAD (43). The MOG-IgG antibodies were positive in all cases. In one case, NMDAR antibodies and MOG-IgG antibodies were detected concomitantly (86). In another case, human herpes virus 6 (HHV6) PCR was also positive (46). Eighteen patients were treated with CS alone (intravenous methylprednisolone followed by oral prednisone taper, n = 15; IVMP alone, n = 2; details of steroid regimen were not described, n = 1) (42). One patient was treated with intravenous immunoglobulins (IVIG) alone (33). One patient received IVMP+ IVIG (45), three received IVMP + PLEX (40, 43,46), and three received IVMP+ PLEX+ IVIG (48, 55, 56). One patient was not treated (87). The treatment regimen was not described for one patient (38). Clinical improvement was reported for 26 patients (93%). Considering all the reported cases, a total of 73 demyelinating events consistent with CIS/MS (10 new diagnoses and 63 relapses) and 22 events defined as pseudo-relapse were reported in 1,305 people (5.6 and 1.7%, respectively). Of these 73 events, 11 were in females, 10 in males, and sex was not reported in the remaining 64 cases. The mean age was 38.45 ± 15.93 years. Most relapses or first demyelinating events consistent with MS/CIS occurred after the onset of COVID-19. However, in two cases neurological symptoms preceded the diagnosis of COVID-19 by 6 and 21 days, respectively (57, 76). The median time from COVID-19 diagnosis to demyelinating event onset was 13.5 days (range−21-180 days).

Post COVID-MS
Nine hundred eighty-six people with a known MS and COVID-19 diagnosis were reported. Of these, 624 (63.3%) were treated with various disease-modifying treatments (DMTs), 14 (1.5%) were not treated, and for 165 (16.7%), the information on DMTs was not reported. Twenty-one MS patients treated with DMTs (3.4%) had a relapse in temporal association with COVID-19. Five MS patients treated with DMTs (0.8%) had a pseudo relapse, and 144 (23.1%) did not have neurological worsening. The remaining 455 MS patients treated with DMTs (73%) were reported in larger cohorts in which some people were not treated. The information regarding relapses in these cohorts was not stratified between treated and untreated patients (61, 75).

Discussion
This systematic review summarizes the currently available data on the occurrence of demyelinating CNS events in the context of COVID-19. As noted, the vast majority of NMOSD and MOGAD cases represent newly diagnosed cases presenting with the typical clinical, radiological, and laboratory findings associated with these two disorders. In contrast, the MS cases described vary between newly diagnosed cases, relapses, and pseudo-relapses. The patients' age of diagnosis in the three disease groups was relatively similar to the age of diagnosis reported in the literature for non-COVID-19 related cases. The clinical presentations and treatment approach were also similar to non-COVID-19 related cases (for further details, please see Tables 1-3).
Several mechanisms involved in the pathogenesis of demyelinating events in the context of SARS-CoV-2 infection have been proposed. These may be related to either direct viral neurotropism or induction of aberrant immune response. The neurotrophic features of the Coronavirus family have been previously reported for the Middle East respiratory syndrome coronavirus (MERS-COV) and SARS-COV-1, and similar evidence has been occasionally reported for SARS-CoV-2 (88-91). However, the fact that the SARS-CoV-2 PCR test in the CSF was negative in many of the reported cases (25,35,37,39,40,42,44,66,68,(77)(78)(79)81) would argue against this mechanism of direct pathogenicity. Conversely, some evidence favors the theory of para-infectious or post-infectious immune-mediated etiology. In fact, SARS-CoV-2 infection leads to hyperactivation of pro-inflammatory T cells resulting in increased levels of inflammatory cytokines and chemokines (92) and decreased regulatory T cells to impair immune response (93). The resulting pro-inflammatory hyperimmune state may activate specific immune-mediated mechanisms resulting in CNS inflammation and damage. The favorable response to immunotherapy in the majority of the reported cases appears to support this theory.
The distinction between relapse and pseudo-relapse may not always be straightforward. According to the 2017 McDonald criteria, a relapse should be defined in the absence of fever or acute infection; hence, new or worsening neurological symptoms developed during a febrile illness or in the presence of acute infection in a patient with a known diagnosis of MS should not be defined as true relapse, but rather regarded as a pseudorelapse. However, there may be situations where the diagnosis of true relapse should still be considered even in the context of acute infection. For example, a true relapse should be considered if the onset of new symptoms is associated with clinical signs that can be attributed to a specific anatomical localization that has not been previously described or correlated with the presence of a new symptomatic MRI lesion. Following this rationale, a few of the described clinical worsening in MS cases were felt to be better classified as pseudo-relapses (67, 69).
Prior studies propose that MS relapses in temporal association with viral infections occur between 1 and 2 weeks before infection to 3-5 weeks after (94)(95)(96)(97)(98) the relapse rate ratio during different time intervals and found that the highest rate ratio was observed from weeks 1 to 4, while the exacerbation rate ratio for weeks 3-5 was lower and not statistically significant compared to the non-at risk period (97, 98). Considering these data, MS relapses occurring more than 4-5 weeks from an infection are probably not related to the prior infectious insult. Therefore, MS cases that occurred >6 weeks from COVID-19 (64, 66, 68, 79, 83), although included in this review in order to provide a comprehensive review of available data, are thought to be more likely coincidental and not related to the preceding infectious insult. Likewise, the relation between SARS-CoV-2 infection and the NMOSD and MOGAD cases developing >6 weeks after the infection (31, 32, 49, 54) remains uncertain. The case of MOGAD occurring in temporal association to both HHV6 and COVID-19 infection (46) may also confound the association between COVID-19 and MOGAD.
The use of disease-modifying therapies (DMTs) may be associated with an increased risk of viral and bacterial infections. Early in the course of the COVID-19 pandemic, this notion led to significant concerns regarding COVID-19 outcomes for people with neuroimmunological diseases. While some reports described a less favorable COVID-19 course in people treated with B-cell depleting agents, the use of other DMTs does not seem to be associated with such an increased risk (99)(100)(101). Another aspect of interest is whether the efficacy of DMTs is maintained during the pandemic. However, the currently available data is not sufficient to answer this question. While relapses were reported in only 3.4% of MS patients treated with DMTs, information about DMTs use and relapses was available for a relatively small proportion of patients (169/624, 27.1%). The fact that the majority of NMOSD and MOGAD cases reported are of newly diagnoses rather than relapses of previously diagnosed disease, may suggest that the efficacy of immunotherapy during the pandemic is maintained. In the series reported by Apostolos-Pereira et al., 97% of NMOSD patients (33/34) continued their prescribed immunotherapy during the pandemic. The relatively low incidence of neurological exacerbation reported by the authors (5/34, 15%) may further support this theory (21). Still, prospective studies comparing the rate of relapse between COVID-19 patients treated with DMTs and untreated patients are required to answer this question.
The current literature pertaining to the occurrence of demyelinating events in temporal association with COVID-19 is primarily composed of case reports, case series, and relatively small cohort studies. Therefore, while the rate of such events appears low based upon this review, especially considering the high prevalence of SARS-CoV-2 infection, the available data does not permit the determination of whether the rate of CNS demyelinating events (either new onset or true relapse) differs among people with confirmed COVID-19 compared to those who do not contract the infection. Additional questions that remain unanswered at this point are whether there are differences in the severity of demyelinating attacks and the response to acute treatments between demyelinating events occurring in association with COVID-19 and those not associated with the infection.
In conclusion, the rate of CNS demyelinating events occurring in the context of SARS-CoV-2 infection is relatively low given the global prevalence of infection. The clinical outcomes of new-onset or relapsing MS, NMOSD, or MOGAD associated with antecedent or concurrent SARS-CoV-2 infection is mostly favorable. Larger prospective epidemiological studies are needed to better characterize the impact of COVID-19 on CNS demyelinating diseases.

Data availability statement
The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.