{'fraction_non_alphanumeric': 0.03302171290711701, 'fraction_numerical': 0.017943305186972257, 'mean_word_length': 4.975225225225225, 'pattern_counts': {'":': 0, '<': 1, '<?xml version=': 0, '>': 2, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 4, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
COVID-19 y sus implicaciones en el curso clínico-radiológico de la esclerosis múltiple: un estudio de casos y controles


 Antecedentes: la esclerosis múltiple (EM) es una enfermedad inmunomediada que se ha relacionado con varios factores de riesgo, como diversas infecciones virales. Realizamos este estudio para establecer una relación entre la infección por COVID-19 y la gravedad de la EM.
 Métodos: En un estudio de casos y controles, reclutamos pacientes con esclerosis múltiple remitente-recurrente (EMRR). Los pacientes se dividieron en dos grupos según la PCR positiva para COVID-19 al final de la fase de inscripción. Cada paciente fue seguido prospectivamente durante 12 meses. Los antecedentes demográficos, clínicos y médicos anteriores se recogieron durante la práctica clínica habitual. Las evaluaciones se realizaron cada seis meses; La resonancia magnética se realizó en el momento de la inscripción y 12 meses después.
 Resultados: Trescientos sesenta y dos pacientes participaron en este estudio. Los pacientes con EM con infección por COVID-19 tuvieron aumentos significativamente más altos en el número de lesiones de resonancia magnética (p: 0.019, OR (IC): 6.37 (1.54-26.34)) y puntajes EDSS (p: 0.017), pero no se encontraron diferencias en total recaídas anuales o tasas de recaída. Las infecciones por COVID-19 se correlacionaron positivamente con la progresión de EDSS (p: 0,02) y la cantidad de nuevas lesiones en la resonancia magnética (p: 0,004) y predijeron la probabilidad de la cantidad de nuevas lesiones en la resonancia magnética con una probabilidad de 5,92 (p: 0,018).
 Conclusión: COVID-19 puede conducir a puntajes de discapacidad más altos en la población de RRMS y está asociado con el desarrollo de nuevas lesiones realzadas con Gd en imágenes de resonancia magnética. Sin embargo, no se observó diferencia entre los grupos en cuanto al número de recaídas durante el seguimiento.
 
 
 Background: Multiple sclerosis (MS) is an immune-mediated disease that has been related to several risk factors such as various viral infections. We carried out this study in order to establish a relationship between COVID-19 infection and MS severity.
 
 Methods: In a case-control study, we recruited patients with relapsing-remitting multiple sclerosis (RRMS). Patients were divided into two groups based on positive COVID-19 PCR at the end of the enrollment phase. Each patient was prospectively followed for 12 months. Demographical, clinical, and past medical history were collected during routine clinical practice. Assessments were performed every six months; MRI was performed at enrollment and 12 months later.
 
 Results: Three hundred and sixty-two patients participated in this study. MS patients with COVID-19 infection had significantly higher increases in the number of MRI lesions (p: 0.019, OR(CI): 6.37(1.54-26.34)) and EDSS scores (p: 0.017), but no difference was found in total annual relapses or relapse rates. COVID-19 infections were positively correlated with EDSS progression (p: 0.02) and the number of new MRI lesions (p: 0.004) and predicted the likelihood of the number of new MRI lesions by an odds of 5.92 (P: 0.018).
 
 Conclusion: COVID-19 may lead to higher disability scores in the RRMS population and is associated with developing new Gd-enhancing lesions in MRI imaging. However, no difference was observed between the groups regarding the number of relapses during follow-up.



Introduction
Multiple sclerosis (MS) is an immune-mediated condition that results in demyelination and axonal injury (progressive neurodegeneration) in the central nervous system (CNS) 1, 2 . The relapsing-remitting form of multiple sclerosis (RRMS), the most common type of the disease, is characterized by periodic bouts of acute exacerbations followed by periods of relative clinical stability 3 . The neurological impairment in MS is usually assessed using an expanded disability status scale (EDSS), which evaluates the different neurological domains that might be comprised by the disease 4 . Magnetic resonance imaging (MRI) is the preferred imaging technique for MS diagnosis and follow-up. The number of lesions and presence of brain atrophy could be seen with MRI 5 . Several risk factors have been suggested for MS susceptibility and increased attack rates, including female sex, genetic, and environmental factors. Several lines of evidence suggest that the immune system plays an integral and perhaps defining role in the development of MS 6 ; alternative theories of MS pathogenesis state that a chronic viral infection may contribute to its pathogenesis 7 . A foreign antigen, such as a virus or bacteria, seems to provide an antigenic trigger for MS autoimmunity through molecular mimicry 8 . However, the cause of MS remains unknown 9 .
COVID-19 could involve many organs and present with numerous manifestations from asymptomatic to death 10 . Neurological symptoms are a less likely presentation of COVID-19, including headache, dizziness, myalgia, anosmia, dysgeusia, seizure, Guillain-Barré syndrome, encephalitis, and acutely demyelinating encephalomyelitis, optic neuritis, and MS [11][12][13][14][15] . Some reports suggest an association between MS and other infections like the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 12 . Simultaneous involvement of two mechanisms has been proposed for this concurrence; first, an enhanced inflammatory response, which results in J o u r n a l P r e -p r o o f blood-brain barrier dysfunction and subsequent immune cell migration into the central nervous system (CNS), and the second is a direct neuroinvasion [16][17][18] .
COVID-19 has been examined to determine whether it affects the natural course of RRMS since the previous studies were inconclusive. The study aimed to determine how the attack rate, disability status, clinical presentation, and neuroimaging findings changed during the COVID-19 pandemic in a cohort of Iranian men and women.

Study design
This is a case-control study conducted at the tertiary MS Center of Sina Hospital in Tehran based on the MS-COVID-19 registry system of Iran 19  A study center staff member instructed the patients to call when they felt sick or experienced neurological impairment and visit the outpatient clinic every six months (specific dates were set for each patient). After a suspected infection or exacerbation, an additional outpatient clinic visit was scheduled within three days. In the case of suspected infection (worsening of cold symptoms, including nasal congestion, nasal discharge, fever, cough, myalgia, and headache), Nasal swab specimens were collected in duplicate to detect SARS-COV-2 (COVID-19) by reverse transcriptase-polymerase chain reaction (RT-PCR); In the course of the study, patients positive for COVID-19 were excluded, and their information was not included in the final analysis 19 . Patients kept a weekly diary to ensure that infections and neurological complaints were being reported to the clinician throughout the entire study period. Each patient was prospectively followed for 12 months.
The case group included 71 MS patients with a positive COVID-19 PCR at the end of the enrollment phase, and the control group included the other 496 patients. A total of 19 patients from the case group and 186 patients from the control group were withdrawn during the study due to positive COVID-19 PCR's, unwillingness to participate, or inaccurate reporting of suspected infections or exacerbations.

Baseline assessment
Demographic characteristics (age, BMI, smoking, and marital status), clinical disability (assessed by the Expanded Disability Status Scale (EDSS)), and past medical history (underlying diseases and family history of MS) were collected as part of routine clinical practice with assessments scheduled every six months. All patients underwent an MRI scan at enrollment phase. A second J o u r n a l P r e -p r o o f scan was performed at the third outpatient visit (12 months after the investigation began) to nonexcluded patients. All patients had their EDSS re-evaluated in the course of a twelve-month follow-up, but those who had exacerbations or hospitalizations around the end of the study were re-evaluated following a month of improvement or stabilization.

Definitions
An exacerbation of multiple sclerosis was defined as developing a new neurological symptom or worsening an existing symptom or symptoms attributable to multiple sclerosis lasting >24 h after a period of ≥30 days of improvement or stability 22 . Neurological deterioration temporarily associated with the occurrence of fever was not considered as exacerbation. The state of COVID-19 vaccination was not assessed as a variable in this study because only eighteen patients got the first dose of COVID-19 in the last three months of follow-up.

Statistical analysis
Continuous variables were presented as mean ± standard deviation (SD), and categorical variables were described in frequency and percentage. Preliminary analyses showed no outliers, J o u r n a l P r e -p r o o f as assessed by a boxplot. The variables were tested for normality using the Shapiro-Wilk's test; Continuous and parametric data with a normal distribution (Shapiro-Wilk's test (p > 0.05)) were compared between two independent groups with an independent t-test. In contrast, categorical data were analyzed with the chi-squared test followed by Fischer's exact test. Variables without normal distribution (Shapiro-Wilk's test (p < 0.05)) and the nonparametric data were compared between two independent groups with the Mann-Whitney U test; the Man-Whitney U test assumption of equal distribution were tested by using Levene's test for equality of variances   Table-2

EDSS increase
We used a multiple regression model to predict how the EDSS increase would be affected by the SARS-COV-2 infection. The regression model was adjusted for age, sex, baseline EDSS, BMI, disease duration, underlying diseases, and MS family history. The SARS-COV-2 infection was statistically significant in predicting patient's EDSS increase (p: 0.026). The regression coefficients are reported in Table-

New MRI lesions and Relapses
New  (Table-4).  29 . TLRs' role in COVID-19 induced cytokine storm and subsequent demyelinating neuropathy has been noted in some studies 30,31 . It has also been demonstrated that the activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome and the J o u r n a l P r e -p r o o f following rise in IL-1β and IL-18 is a major risk factor for MS progression 32 . Interestingly, COVID-19 infection can induce a rapid expression of NLRP3, leading to inflammatory cytokines' release. Thus, this mechanism might serve as a possible explanation for the observed CNS involvements 33 . Increased blood-brain barrier (BBB) permeability is an important step in developing Gd-enhancing lesions [34][35][36] . It has been demonstrated that infections can upregulate the production of inflammatory cytokines such as IL-1β, IL-6, and TNF-α, which leads to disruption of BBB and stimulation of microglial cells, which in turn facilitates the migration of activated T cells into the central nervous system (CNS) 37,38 .
Similar to the observations in our study, the association between infectious diseases and the development of MRI enhancements have also been mentioned in several articles 24,39 . In contrast, a prospective cohort study has documented that, while viral infections lead to an increased rate of MS relapse, these relapses are not accompanied by the formation of new Gdenhancing lesions 25 . Some studies suggest parasitical infections and microbial agents such as Helicobacter pylori might decrease MS exacerbations and associated disability, preventing new enhancing lesions in MRI [40][41][42][43] .
The higher risk of disability and morbidity after COVID-19 infection in MS patients, as demonstrated by an increase in EDSS score in this study, highlights the importance of disease prevention strategies in this population. However, the controversy and the scarcity of studies regarding this subject require additional studies to be carried out to ascertain the reproducibility of our results.
This study was prospective and prone to distortions such as selection bias due to loss of followup or patients' informed refusal. Since the method of infection diagnosis was based on clinical symptoms, patients with asymptomatic infections were possibly underdiagnosed. Another shortcoming in this study was not accounting for infections other than COVID-19 as confounding factors. Furthermore, the severity of infections was not assessed in our study. This study's larger sample size would have allowed us to conclude with narrower confidence intervals.

Conclusion
Our results can be considered preliminary evidence for the association of COVID-19 and higher overall EDSS scores and new MRI enhancements in RRMS patients. These findings highlight the increased risks of the recent pandemic for the MS patient population and underscore the importance of appropriate protective measures to prevent further deterioration of the patients' disease and quality of life. Nevertheless, additional studies are required for a more robust conclusion.