Associations among stressors across the lifespan, disability, and relapses in adults with multiple sclerosis.

INTRODUCTION: Stress and adversity during childhood, adolescence, and adulthood could impact the present and future health and well-being of people with multiple sclerosis (PwMS); however, a lifespan approach and nuanced stressor data are scarce in this nascent area of research. Our aim was to examine relationships among comprehensively measured lifetime stressors and two self-reported MS outcomes: (1) disability and (2) relapse burden changes since COVID-19 onset. METHODS: Cross-sectional data were collected from a nationally distributed survey of U.S.-based adults with MS. Hierarchical block regressions were used to sequentially evaluate contributions to both outcomes independently. Likelihood ratio (LR) tests and Akaike information criterion (AIC) were used to evaluate additional predictive variance and model fit. RESULTS: A total of 713 participants informed either outcome. Most respondents (84%) were female, 79% had relapsing remitting multiple sclerosis (MS), and mean (SD) age was 49 (12.7) years. Childhood (R2  = .261, p < .001; AIC = 1063, LR p < .05) and adulthood stressors (R2  = .2725, p < .001, AIC = 1051, LR p < .001) contributed significantly to disability, above and beyond prior nested models. Only adulthood stressors (R2  = .0534, p < .001; AIC = 1572, LR p < .01) significantly contributed above the nested model for relapse burden changes since COVID-19. CONCLUSIONS: Stressors across the lifespan are commonly reported in PwMS and could contribute to disease burden. Incorporating this perspective into the "lived experience with MS" could facilitate personalized health care by addressing key stress-related exposures and inform intervention research to improve well-being.

Personalized B-cell tailored dosing of ocrelizumab in patients with multiple sclerosis during the COVID-19 pandemic.

In this observational study, 159 patients with multiple sclerosis received personalized dosing of ocrelizumab incentivized by the COVID-19 pandemic. Re-dosing was scheduled when CD19 B-cell count was ⩾10 cells/µL (starting 24 weeks after the previous dose, repeated 4-weekly). Median interval until re-dosing or last B-cell count was 34 [30-38] weeks. No clinical relapses were reported and a minority of patients showed Expanded Disability Status Scale (EDSS) progression. Monthly serum neurofilament light levels remained stable during extended intervals. Two (1.9%) of 107 patients with a follow-up magnetic resonance imaging (MRI) scan showed radiological disease activity. Personalized dosing of ocrelizumab could significantly extend intervals with low short-term disease activity incidence, encouraging future research on long-term safety and efficacy.

Safety of Natalizumab infusion in multiple sclerosis patients during active SARS-CoV-2 infection.

COVID-19 pandemic represented a challenge in the management of treatments for Multiple Sclerosis (MS), such as Natalizumab (NTZ). NTZ interferes with the homing of lymphocytes into the central nervous system, reducing immune surveillance against opportunistic infection. Although NTZ efficacy starts to decline 8 weeks after the last infusion, increasing the risk of disease reactivation, evidence is lacking on the safety of reinfusion during active SARS-CoV-2 infection. We report clinical outcomes of 18 pwMS receiving NTZ retreatment during confirmed SARS-CoV-2 infection. No worsening of infection or recovery delay was observed. Our data supports the safety of NTZ redosing in these circumstances.

Association between relapses, stress, and depression in people with multiple sclerosis during the COVID-19 pandemic.

BACKGROUND: Stress is a potential trigger for clinical and radiological activity in Multiple Sclerosis (MS). COVID-19 pandemic has been a relevant source of mental distress in people with MS (pwMS) and deeply impacted on disease management. OBJECTIVE: To investigate the association between stress, anxiety, depression, and risk of relapse during the COVID-19 pandemic. METHODS: From an electronic database used for clinical practice, we extracted data of relapsing-remitting (RR) or relapsing-progressive (RP) MS patients and calculated the annualized relapse rate (ARR) during 2019 and 2020. From 01/12/2020 to 30/12/2020, enrolled patients were invited to fill in a Google Forms survey to investigate depression, anxiety, stress, and Post-Traumatic Stress Disorder (PTSD). RESULTS: We selected 216 patients with RR or RP-MS to calculate ARR: compared to 2019, in 2020 there was a significant increase in ARR (p = 0.0142). Over 216 selected pwMS, 154 completed the survey. Matching the survey responses and incidence of relapses in 2020, there was a significant association between relapses and stress (p = 0.030) and relapses and depression (p = 0.011), but not between relapses and anxiety (p = 0.130) or PTSD (p = 0.279). CONCLUSIONS: Our results support the hypothesis that pandemic-related stress is associated to clinical exacerbations, both as a possible consequence of the COVID-19 impact on MS care.

Risk of Getting COVID-19 in People With Multiple Sclerosis: A Case-Control Study.

BACKGROUND AND OBJECTIVES: Several studies have assessed risk factors associated with the severity of COVID-19 outcomes in people with multiple sclerosis (PwMS). The potential role of disease-modifying therapies (DMTs) and demographic and clinical factors on the risk of acquiring SARS-CoV-2 infection has not been evaluated so far. The objective of this study was to assess risk factors of contracting SARS-CoV-2 infection in PwMS by using data collected in the Italian MS Register (IMSR). METHODS: A case-control (1:2) study was set up. Cases included PwMS with a confirmed diagnosis of COVID-19, and controls included PwMS without a confirmed diagnosis of COVID-19. Both groups were propensity score-matched by the date of COVID-19 diagnosis, the date of last visit, and the region of residence. No healthy controls were included in this study. COVID-19 risk was estimated by multivariable logistic regression models including demographic and clinical covariates. The impact of DMTs was assessed in 3 independent logistic regression models including one of the following covariates: last administered DMT, previous DMT sequences, or the place where the last treatment was administered. RESULTS: A total of 779 PwMS with confirmed COVID-19 (cases) were matched to 1,558 PwMS without COVID-19 (controls). In all 3 models, comorbidities, female sex, and a younger age were significantly associated (p < 0.02) with a higher risk of contracting COVID-19. Patients receiving natalizumab as last DMT (OR [95% CI]: 2.38 [1.66-3.42], p < 0.0001) and those who underwent an escalation treatment strategy (1.57 [1.16-2.13], p = 0.003) were at significantly higher COVID-19 risk. Moreover, PwMS receiving their last DMT requiring hospital access (1.65 [1.34-2.04], p < 0.0001) showed a significant higher risk than those taking self-administered DMTs at home. DISCUSSION: This case-control study embedded in the IMSR showed that PwMS at higher COVID-19 risk are younger, more frequently female individuals, and with comorbidities. Long-lasting escalation approach and last therapies that expose patients to the hospital environment seem to significantly increase the risk of SARS-CoV2 infection in PwMS. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that among patients with MS, younger age, being female individuals, having more comorbidities, receiving natalizumab, undergoing an escalating treatment strategy, or receiving treatment at a hospital were associated with being infected with COVID-19. Among patients with MS who were infected with COVID-19, a severe course was associated with increasing age and having a progressive form of MS, whereas not being on treatment or receiving an interferon beta agent was protective.

Masked face recognition in patients with relapsing-remitting multiple sclerosis during the ongoing COVID-19 pandemic.

BACKGROUND: Face and facial expression recognition abilities have been frequently evaluated in the assessment of social cognition disorders in patients with MS. Investigation of the effect of new difficulties emerging in the field of face recognition with the widespread use of masks during the ongoing COVID-19 pandemic on patients with MS may make new contributions to the literature. MATERIAL AND METHODS: The study included 44 patients with relapsing-remitting MS (RRMSp) and 51 controls who were matched to the case group in terms of age and education level. The Benton face recognition test-short form (BFRT-sf), Beck Depression Inventory, a close-ended 13-item survey on face recognition difficulties due to mask use during the pandemic was administered to all groups. RESULTS: In the RRMSp, the mean disease duration was 8.2 ± 5.6, the mean EDSS score was 1.2 ± 1.0, and the mean MOCA test score was 27.23 ± 2.08. The mean BFRTsf was 19.9 ± 2.4 in the RRMSp and 21.6 ± 1.8 in the healthy controls.Twenty-five percent of RRMSp and 4% of the healthy controls required people to remove their masks to be able to recognize their faces. Improvement in face recognition difficulty over time was reported as 80% in the healthy controls and 34% in the RRMSp. CONCLUSION: RRMSp had worse performance in masked face recognition and required removal of the facial masks more often than healthy controls to recognize the faces. RRMS patients did not show as much improvement in recognizing masked faces over time according to the onset of the pandemic as healthy controls.

Outcomes of COVID-19 among patients treated with subcutaneous interferon beta-1a for multiple sclerosis.

BACKGROUND: In accordance with expert guidance, patients have typically continued to receive treatment with subcutaneous interferon beta-1a (sc IFN ß-1a) for relapsing multiple sclerosis (MS) during the COVID-19 pandemic. METHODS: We provide a summary of outcomes among sc IFN ß-1a-treated patients with adverse events related to confirmed or suspected COVID-19, as reported to the Merck Global Patient Safety Database (as of 2 February 2021). Serious COVID-19-related adverse events (as classified by the reporting clinician) included those leading to hospitalization, admission to intensive care, or death. Outcomes were classified per usual pharmacovigilance practice. RESULTS: The evaluable cohort comprised 603 patients of median age 43 (range, 13-84) years and 75.1% were female. COVID-19 was experienced at a median of 33.0 (range, 0-321.8) months after start of treatment with sc IFN ß-1a. A total of 136 (22.6%) patients experienced serious COVID-19 events, including 59 hospitalizations (4 patients admitted to intensive care) and 5 deaths (fatality rate, 0.8%). Regarding non-fatal outcomes, 47.8% of patients (289/603) with COVID-19 adverse events were recovered or recovering at time of analysis; similar findings were apparent for the serious and hospitalized cohorts. CONCLUSION: Findings of this analysis from the Merck Global Patient Safety Database suggest that, compared with available statistics for the general population and those with MS, patients receiving sc IFN ß-1a for treatment of relapsing MS have relatively low rates of serious disease and/or severe outcomes with COVID-19.

Wearing-off symptoms during standard and extended natalizumab dosing intervals: Experiences from the COVID-19 pandemic.

Natalizumab effectively prevents disease activity in relapsing-remitting multiple sclerosis, but many treated patients report subjective wearing-off symptoms at the end of the 4-week interval between infusions. Extended interval dosing (EID) is a promising strategy to mitigate the risk of natalizumab-associated progressive multifocal leukoencephalopathy, but it is unknown whether EID affects wearing-off symptoms. In this observational study, we evaluated if prevalence or intensity of wearing-off symptoms changed when natalizumab dosing intervals were extended from 4 to 6 weeks in 30 treated patients during the outbreak of COVID-19 in Norway. New or increased wearing-off symptoms during EID were reported by 50%. Symptom increase was more frequent among patients with pre-existing wearing-off symptoms during standard dosing compared to patients without such pre-existing symptoms [p = 0.0005]. Our observations support the need to study the effect of EID on wearing-off symptoms in randomized controlled trials.

SARS-CoV-2 Infection in Multiple Sclerosis: Results of the Spanish Neurology Society Registry.

OBJECTIVE: To understand COVID-19 characteristics in people with multiple sclerosis (MS) and identify high-risk individuals due to their immunocompromised state resulting from the use of disease-modifying treatments. METHODS: Retrospective and multicenter registry in patients with MS with suspected or confirmed COVID-19 diagnosis and available disease course (mild = ambulatory; severe = hospitalization; and critical = intensive care unit/death). Cases were analyzed for associations between MS characteristics and COVID-19 course and for identifying risk factors for a fatal outcome. RESULTS: Of the 326 patients analyzed, 120 were cases confirmed by real-time PCR, 34 by a serologic test, and 205 were suspected. Sixty-nine patients (21.3%) developed severe infection, 10 (3%) critical, and 7 (2.1%) died. Ambulatory patients were higher in relapsing MS forms, treated with injectables and oral first-line agents, whereas more severe cases were observed in patients on pulsed immunosuppressors and critical cases among patients with no therapy. Severe and critical infections were more likely to affect older males with comorbidities, with progressive MS forms, a longer disease course, and higher disability. Fifteen of 33 patients treated with rituximab were hospitalized. Four deceased patients have progressive MS, 5 were not receiving MS therapy, and 2 were treated (natalizumab and rituximab). Multivariate analysis showed age (OR 1.09, 95% CI, 1.04-1.17) as the only independent risk factor for a fatal outcome. CONCLUSIONS: This study has not demonstrated the presumed critical role of MS therapy in the course of COVID-19 but evidenced that people with MS with advanced age and disease, in progressive course, and those who are more disabled have a higher probability of severe and even fatal disease.

COVID-19 in Argentine teriflunomide-treated multiple sclerosis patients: First national case series.

We report COVID-19 presentation, course and outcomes in teriflunomide-treated MS patients in Argentina. METHODS: descriptive, retrospective, multicentre, study that included MS patients receiving teriflunomide who developed COVID-19, with clinical follow-up at reference MS centres, also listed in a nationwide registry. RESULTS: Eighteen MS patients on teriflunomide treatment, from eight MS centres developed COVID-19. The mean age was 41,2 years and 72% of them were female; 94% had diagnosis of relapsing-remitting MS and 6% presented a radiologically isolated syndrome. Median EDSS was 2 (range 0-5.5). The average time on teriflunomide therapy was 3 years. COVID-19 diagnosis was confirmed with nasal swab in 61%. None required hospitalization and they completely recovered from the acute-phase within 7-14 days. All the patients continued their teriflunomide therapy during COVID-19 course. No MS relapses occurred during or after COVID-19 course. CONCLUSION: Our report adds to the evidence that COVID-19 is mild in patients receiving teriflunomide therapy and that continuing with teriflunomide therapy during Sars-CoV-2 infection is safe and advisable for MS patients.

Personalizing ocrelizumab treatment in Multiple Sclerosis: What can we learn from Sars-Cov2 pandemic?

During SARS-CoV-2 pandemic, we adopted a personalized delayed protocol for ocrelizumab infusions in Relapsing Remitting Multiple Sclerosis (RRMS) patients according to the national recommendations. Out of the 83 RRMS patients whose infusion was scheduled between March and December 2020, 56 patients experienced a delay in treatment based on MS severity and SARS-CoV2 infection risk profile. In most cases, the immunophenotype was performed monthly to guide re-infusions. Specifically, B CD19 + cells repopulation rate was monitored. Mean infusion delay was 103,1 [SD 40,6] days, and none of the patients presented relapses or active disease at MRI at the end of the observation period. Treatment naïve status and the interval between immunophenotyping and the last ocrelizumab infusion were predictors of earlier B CD19 + cells repopulation. Two patients contracted SARS-CoV2 with complete recovery. Definitive data about Sars-Cov2 vaccine efficacy in patients treated with ocrelizumab are still lacking. Our findings suggest that a personalized treatment with a delayed infusion schedule does not compromise ocrelizumab short-term efficacy and may help to lengthen the therapeutic window for an effective response to SARS-CoV2 vaccine.

COVID-19 and the Risk of Relapse in Multiple Sclerosis Patients: A Fight with No Bystander Effect?

BACKGROUND: COVID-19 is speculated to increase the likelihood of relapsing-remitting multiple sclerosis (RRMS) exacerbation. OBJECTIVE: To investigate the association between contraction of COVID-19 and incidence of acute MS attacks in RRMS patients six months post-infection. METHODS: This retrospective cohort study compares the risk of relapse in RRMS patients with (n=56) and without COVID-19 (n=69). Incidence of relapse was recorded for six-month following contraction of COVID-19. Incidence of RRMS exacerbation in patients with COVID-19 was compared to patients without COVID-19 (the independent control group) and the same patients six months prior to the COVID-19 pandemic. RESULTS: A lower incidence rate of RRMS exacerbation was observed in patients that contracted COVID-19 than in patients who did not contract COVID-19 (incidence rate ratio: 0.275; p=0.026). Self-controlled analysis showed no significant difference in relapse rates before the COVID-19 pandemic and after contracting COVID-19 (p=0.222). The relapse risk was not different between patients who had been hospitalized due to COVID-19 severity and those who had not (p=0.710). CONCLUSION: COVID-19 contraction may not increase the risk of acute MS attacks shortly following contraction. We hypothesize that COVID-19-associated lymphopenia may partly preclude the autoreactive memory cells from expansion and initiating relapses through a so-called bystander effect of COVID-19 infection.

Surveillance Study of Acute Neurological Manifestations among 439 Egyptian Patients with COVID-19 in Assiut and Aswan University Hospitals.

BACKGROUND: COVID-19 can be accompanied by acute neurological complications of both central and peripheral nervous systems (CNS and PNS). In this study, we estimate the frequency of such complications among hospital inpatients with COVID-19 in Assiut and Aswan university hospitals. MATERIALS AND METHODS: We screened all patients with suspected COVID-19 admitted from 1 June to 10 August 2020 to the university hospitals of Assiut and Aswan in Upper Egypt. Clinical and laboratory tests, CT/MRI of the chest and brain, and neurophysiology study were performed for each patient if indicated. RESULTS: 439 patients had confirmed/probable COVID-19; neurological manifestations occurred in 222. Of these, 117 had acute neurological disease and the remainder had nonspecific neuropsychiatric symptoms such as headache, vertigo, and depression. The CNS was affected in 75 patients: 55 had stroke and the others had convulsions (5), encephalitis (6), hypoxic encephalopathy (4), cord myelopathy (2), relapse of multiple sclerosis (2), and meningoencephalitis (1). The PNS was affected in 42 patients: the majority had anosmia and ageusia (31) and the others had Guillain-Barré syndrome (4), peripheral neuropathy (3), myasthenia gravis (MG, 2), or myositis (2). Fever, respiratory symptoms, and headache were the most common general symptoms. Hypertension, diabetes mellitus, and ischemic heart disease were the most common comorbidities in patients with CNS affection. CONCLUSION: In COVID-19, both the CNS and PNS are affected. Stroke was the most common complication for CNS, and anosmia and/or ageusia were common for PNS diseases. However, there were 6 cases of encephalitis, 2 cases of spinal cord myelopathy, 2 cases of MG, and 2 cases of myositis.

Assessing disability and relapses in multiple sclerosis on tele-neurology.

BACKGROUND: As a consequence of the coronavirus disease 2019 (COVID-19) pandemic, a large amount of consultations will be delivered through tele-medicine, especially for diseases causing chronic disability and requiring immunomodulatory treatments, such as multiple sclerosis (MS). METHODS: We have hereby reviewed available tools for tele-neurology examination in MS, including components of neurological examination that can be assessed through video, patient-reported outcome measures (PROMs), and digital technology. RESULTS: Overall, we have suggested a battery for assessing MS disability and relapses on tele-medicine, which brings together conventional examination, PROMs (e.g., Patient Determined Disease Steps, MS Impact Scale), and cognitive tests (Symbol Digit Modalities Test) that can be delivered remotely and in multiple languages. DISCUSSION: The use of common tools for neurological examination could improve tele-neurology practice for both general neurologists and MS specialists, and quality of care for people with MS.

Extending rituximab dosing intervals in patients with MS during the COVID-19 pandemic and beyond?

OBJECTIVE: To evaluate disease activity in patients with relapsing-remitting MS (RRMS) receiving rituximab with an extended dosing interval. METHODS: In the context of COVID-19 pandemic, this was an interim analysis of an ongoing prospective observational study of patients who were stable on rituximab for at least 6 months and who had a planned extended dosing interval of 24 months. Only data for patients with active RRMS before rituximab were analyzed. RESULTS: Among 177 patients receiving rituximab, 33 had RRMS and MRI activity before rituximab and at least 8 months of follow-up after the last infusion. The mean (SD) age was 40 (14) years, 25 were females, the mean disease duration was 10 (6.8) years, the mean annual relapse rate (ARR) before rituximab was 1.7 (1.3), and the median Expanded Disability Status Scale (EDSS) score before rituximab was 4.5 (1-7). Before extended dosing, when rituximab was infused every 6 months, the mean (SD) ARR decreased to 0.04 (0.1) (p < 0.0001) and the EDSS score to 4 (0-7) (p = 0.04). At the time of this analysis, the median follow-up since the last infusion was 11 (8-31) months. No patient showed relapse or disability progression. In total, 30 patients had at least 1 MRI performed since the last infusion (median time between the last MRI and the last infusion 10 [8-31] months). No MRI showed activity. The CD19+ cell proportion was >1% for 10 of 25 patients at the last count (median time 8 [6-25] months). CONCLUSIONS: An extended dosing interval for rituximab for patients with stable MS during the COVID-19 pandemic may be associated with a low risk of disease activity.

B-cell depleting therapies may affect susceptibility to acute respiratory illness among patients with multiple sclerosis during the early COVID-19 epidemic in Iran.

OBJECTIVE: To determine whether the course of COVID-19 is more severe in patients with MS and if MS disease-modifying treatments (DMTs) affect the risk of contracting the disease. METHODS: In a cross-sectional survey, data were collected by sending a questionnaire to 2000 patients with a demyelinating disease through an online portal system. Collected data included the current MS DMT and patient-reported disability level, history of recent sick contact, recent fever, respiratory symptoms, diagnosis with COVID-19, and the disposition after the diagnosis. We defined a COVID-19-suspect group as patients having fever and cough or fever and shortness of breath, or a presumptive diagnosis based on suggestive chest computed tomography. We calculated the proportion of COVID-19-suspect patients and compared their demographics, clinical characteristics, and DMT categories with the rest of survey-responders, using univariable and multivariable models. RESULTS: Out of 712 patients, 34 (4.8%) fulfilled our criteria for being in the COVID-19-suspect group. Only two patients required hospitalization. No patient required intensive care. In a multivariable model, disease duration (p-value=0.017), DMT category (p-value=0.030), and history of sick contact (p-values<0.001) were associated with the risk of being in the COVID-19-suspect group. Being on B-cell depleting antibodies (as compared to non-cell depleting, non-cell trafficking inhibitor DMTs) was associated with a 2.6-fold increase in the risk of being in the COVID-19-suspect group. (RR: 3.55, 95%CI: 1.45, 8.68, p-value=0.005). CONCLUSIONS: The course of infection in patients with MS suspected of having COVID-19 was mild to moderate, and all patients had a full recovery. B-cell depleting antibodies may increase the susceptibility to contracting COVID-19.