Natalizumab extended-interval dosing in a real-life setting.

BACKGROUND: Natalizumab is a high-efficacy therapy for recurrent multiple sclerosis (RMS) with a four-week administration interval. Controlled trials have shown that extending this interval to six weeks led to better safety without increasing the risk of relapse. We aimed to analyze the safety of extending the natalizumab interdose interval from 4 to 6 weeks in a real-life setting. METHODS: This monocentric retrospective self-controlled study included adult patients with RMS treated with natalizumab with a four-week interval between infusions for a minimum of six months, before switching to a six-week interval. The main outcomes were the incidence of MS relapse, new MRI lesions, and MRI activity signs during the two periods, with patients being their own controls. RESULTS: Fifty-seven patients were included in the analysis. The mean (95%CI) annualized relapse rate (AAR) before natalizumab introduction was 1.03 (0.52; 1.55). During the four-week interval dosing period, no patient presented with an MS relapse, and seven (13.5%) patients had new MRI lesions. During the six-week interval dosing period, no relapse was observed and two (3.6%) patients had new MRI lesions. CONCLUSION: We did not observe more relapses or signs of MRI activity when extending the interval between natalizumab infusions from four to six weeks.

SARS-CoV-2 pandemic as a model to assess the relationship between intercurrent viral infections and disease activity in Multiple Sclerosis: A propensity score matched case-control study.

INTRODUCTION: An association between intercurrent viral respiratory infections and exacerbations of Multiple Sclerosis (MS) disease activity has been proposed by several studies. Considering the rapid spread of SARS-CoV2 worldwide and the systematic effort to immediately detect all incident cases with specific diagnostic tests, the pandemic can represent an interesting experimental model to assess the relationship between viral respiratory infections and MS disease activity. AIMS AND METHODS: In this study, we have performed a propensity score matched case-control study with a prospective clinical/MRI follow-up, on a cohort of relapsing-remitting MS (RRMS) patients who tested positive for SARS-CoV2 in the period 2020-2022, with the aim to evaluate if the SARS-CoV2 infection influences the short-term risk of disease activity. Controls (RRMS patients not exposed to SARS-CoV-2, using 2019 as the reference period) were matched 1:1 with cases for age, EDSS, sex and disease-modifying treatment (DMT) (moderate efficacy vs high efficacy). Differences in relapses, MRI disease activity and confirmed disabilty worsening (CDW) between cases in the 6 months following the SARS-CoV-2 infection, and controls in a similar 6 months reference period in 2019 were compared. RESULTS: We identified 150 cases of SARS-CoV2 infection in the period March 2020 - March 2022, out of a total population of approximately 1500 MS patients, matched with 150 MS patients not exposed to SARS-CoV2 (controls). Mean age was 40.9 ± 12.0 years in cases and 42.0 ± 10.9 years in controls, mean EDSS was 2.54±1.36 in cases and 2.60±1.32 in controls. All patients were treated with a DMT, and a considerable proportion with a high efficacy DMT (65.3% in cases and 66% in controls), reflecting a typical real world RRMS population. 52.8% of patients in this cohort had been vaccinated with a mRNA Covid-19 vaccine. We did not observe a significant difference in relapses (4.0% cases, 5.3% controls; p = 0.774), MRI disease activity (9.3% cases, 8.0% controls; p = 0.838), CDW (5.3% cases, 6.7% controls; p = 0.782) in the 6 months after SARS-CoV-2 infection between cases and controls. CONCLUSION: Using a propensity score matching design and including both clinical and MRI data, this study does not suggest an increased risk of MS disease activity following SARS-CoV-2 infection. All MS patients in this cohort were treated with a DMT, and a considerable number with a high efficacy DMT. These results therefore may not be applicable to untreated patients, for which the risk of increased MS disease activity after SARS-CoV-2 infection may not be excluded. A possible hypothesis explaining these results could be that SARS-CoV2 is less prone, compared to other viruses, to induce exacerbations of MS disease activity; another possible interpretation of these data might be that DMT is able to effectively suppress the increase of disease activity triggered by SARS-CoV2 infection.

Multiple sclerosis as a model to investigate SARS-CoV-2 effect on brain atrophy.

INTRODUCTION: Data on structural brain changes after infection with SARS-CoV-2 is sparse. We postulate multiple sclerosis as a model to study the effects of SARS-CoV-2 on brain atrophy due to the unique availability of longitudinal imaging data in this patient group, enabling assessment of intraindividual brain atrophy rates. METHODS: Global and regional cortical gray matter volumes were derived from structural MRIs using FreeSurfer. A linear model was fitted to the measures of the matching pre-SARS-CoV-2 images with age as an explanatory variable. The residuals were used to determine whether the post-SARS-CoV-2 volumes differed significantly from the baseline. RESULTS: Fourteen RRMS patients with a total of 113 longitudinal magnetic resonance images were retrospectively analyzed. We found no acceleration of brain atrophy after infection with SARS-CoV-2 for global gray matter volume (p = 0.17). However, on the regional level, parahippocampal gyri showed a tendency toward volume reduction (p = 0.0076), suggesting accelerated atrophy during or after infection. CONCLUSIONS: Our results illustrate the opportunity of using longitudinal MRIs from existing MS registries to study brain changes associated with SARS-CoV-2 infections. We would like to address the global MS community with a call for action to use the available cohorts, reproduce the proposed analysis, and pool the results.

CEST MRI and MALDI imaging reveal metabolic alterations in the cervical lymph nodes of EAE mice.

BACKGROUND: Multiple sclerosis (MS) is a neurodegenerative disease, wherein aberrant immune cells target myelin-ensheathed nerves. Conventional magnetic resonance imaging (MRI) can be performed to monitor damage to the central nervous system that results from previous inflammation; however, these imaging biomarkers are not necessarily indicative of active, progressive stages of the disease. The immune cells responsible for MS are first activated and sensitized to myelin in lymph nodes (LNs). Here, we present a new strategy for monitoring active disease activity in MS, chemical exchange saturation transfer (CEST) MRI of LNs. METHODS AND RESULTS: We studied the potential utility of conventional (T2-weighted) and CEST MRI to monitor changes in these LNs during disease progression in an experimental autoimmune encephalomyelitis (EAE) model. We found CEST signal changes corresponded temporally with disease activity. CEST signals at the 3.2 ppm frequency during the active stage of EAE correlated significantly with the cellular (flow cytometry) and metabolic (mass spectrometry imaging) composition of the LNs, as well as immune cell infiltration into brain and spinal cord tissue. Correlating primary metabolites as identified by matrix-assisted laser desorption/ionization (MALDI) imaging included alanine, lactate, leucine, malate, and phenylalanine. CONCLUSIONS: Taken together, we demonstrate the utility of CEST MRI signal changes in superficial cervical LNs as a complementary imaging biomarker for monitoring disease activity in MS. CEST MRI biomarkers corresponded to disease activity, correlated with immune activation (surface markers, antigen-stimulated proliferation), and correlated with LN metabolite levels.

Permanent tissue damage in multiple sclerosis lesions is associated with reduced pre-lesion myelin and axon volume fractions.

BACKGROUND: The use of advanced magnetic resonance imaging (MRI) techniques in MS research has led to new insights in lesion evolution and disease outcomes. It has not yet been determined if, or how, pre-lesional abnormalities in normal-appearing white matter (NAWM) relate to the long-term evolution of new lesions. OBJECTIVE: To investigate the relationship between abnormalities in MRI measures of axonal and myelin volume fractions (AVF and MVF) in NAWM preceding development of black-hole (BH) and non-BH lesions in people with MS. METHODS: We obtained magnetization transfer and diffusion MRI at 6-month intervals in patients with MS to estimate MVF and AVF during lesion evolution. Lesions were classified as either BH or non-BH on the final imaging visit using T₁ maps. RESULTS: Longitudinal data from 97 new T₂ lesions from 9 participants were analyzed; 25 lesions in 8 participants were classified as BH 6-12 months after initial appearance. Pre-lesion MVF, AVF, and MVF/AVF were significantly lower, and T₁ was significantly higher, in the lesions that later became BHs (p < 0.001) compared to those that did not. No significant pre-lesion abnormalities were found in non-BH lesions (p > 0.05). CONCLUSION: The present work demonstrated that pre-lesion abnormalities are associated with worse long-term lesion-level outcome.

Clinical onset of CNS demyelinating disease after COVID-19 vaccination: denovo disease?

BACKGROUND: Clinical onset of multiple sclerosis (MSpostvacc) and myelin-oligodendrocyte-glycoprotein-antibody-associated disease (MOGADpostvacc) has been reported in association with SARS-CoV-2-vaccination. There is uncertainty as to whether this is causality (denovo disease) or temporal coincidence (manifestation of a preexisting, subclinical neuroinflammation). OBJECTIVES: Comparing the clinical characteristics of MSpostvacc-patients versus patients with MS (PwMS) whose clinical onset occurred independently of vaccination (MSreference). METHODS: Consecutive patients with clinical onset ≤30 days after SARS-CoV-2-vaccination were included. Clinical data, cerebrospinal fluid (CSF) parameters and magnetic resonance imaging (MRI) as well as optical coherence tomography (OCT) data were compared to an age- and sex-matched MSreference-cohort. RESULTS: We identified 5 MSpostvacc and 1 MOGADpostvacc patients who developed their clinical onset ≤ 30 days after SARS-CoV-2-vaccination. Clinical characteristics, CSF, MRI and OCT parameters from MSpostvacc patients were comparable to the MSreference cohort and showed evidence of preexisting subclinical CNS disease. The single case with MOGADpostvacc clearly differed from PwMS in higher CSF cell counts, remission of MRI lesions during follow-up, and absence of oligoclonal bands. CONCLUSIONS: Our case series indicates that MSpostvacc patients showed a rather typical initial manifestation in temporal association with SARS-CoV-2-vaccination and harbored preexisting subclinical neuroinflammation. This argues against the denovo development of MS in this cohort.

Lung involvement correlates with disability in MS patients with COVID-19 pneumonia.

INTRODUCTION: The visual-well aerated lung (V-WAL) is a score for the visual quantification of the well aerated lung on CT scan in COVID-19 patients and its value at admission seems to predict future COVID-19 severity. The aim of the present study was to analyze the association between V-WAL and risk factors for severe COVID-19 evolution in people with multiple sclerosis. MATERIALS AND METHODS: This is an observational retrospective study, including people with multiple sclerosis and concomitant COVID-19, who were investigated with a lung CT scan at Hospital admission. The association of V-WAL with age, sex, EDSS, comorbidities, recent steroid use, and treatment (anti-CD20 vs other) was assessed by a multivariate linear regression model. RESULTS: In this observational retrospective study, the only factor that was significantly associated to a lower V-WAL at multivariable analysis was an increasing level of the EDSS (R2 = 0.41, p = 0.001), with an average decrease of 8% of V-WAL for each additional EDSS point. DISCUSSION AND CONCLUSION: This analysis shows that a high EDSS level is the main factor associated to the severity of lung involvement in a group of people with multiple sclerosis who were hospitalized for Covid-19.

MRI and laboratory monitoring of disease-modifying therapy efficacy and risks.

PURPOSE OF REVIEW: Increasingly, therapeutic strategy in multiple sclerosis (MS) is informed by imaging and laboratory biomarkers, in addition to traditional clinical factors. Here, we review aspects of monitoring the efficacy and risks of disease-modifying therapy (DMT) with both conventional and emerging MRI and laboratory measures. RECENT FINDINGS: The adoption of consensus-driven, stable MRI acquisition protocols and artificial intelligence-based, quantitative image analysis is heralding an era of precision monitoring of DMT efficacy. New MRI measures of compartmentalized inflammation, neuro-degeneration and repair complement traditional metrics but require validation before use in individual patients. Laboratory markers of brain cellular injury, such as neurofilament light, are robust outcomes in DMT efficacy trials; their use in clinical practice is being refined. DMT-specific laboratory monitoring for safety is critical and may include lymphocytes, immunoglobulins, autoimmunity surveillance, John Cunningham virus serology and COVID-19 vaccination seroresponse. SUMMARY: A biomarker-enhanced monitoring strategy has immediate clinical application, with growing evidence of long-term reductions in disability accrual when both clinically symptomatic and asymptomatic inflammatory activity is fully suppressed; and amelioration of the risks associated with therapy. Emerging MRI and blood-based measures will also become important tools for monitoring agents that target the innate immune system and promote neuro-repair.

COVID-19 severity is associated with worsened neurological outcomes in multiple sclerosis and related disorders.

BACKGROUND: Neurologic outcomes in patients with multiple sclerosis (MS) and related disorders (MSRD) following COVID-19 is not well understood. The objective of this study was to investigate neurologic outcomes in patients with MSRD post-COVID-19. METHODS: This was a retrospective medical records review study of adult patients with MSRD and COVID-19 infection at the Brigham MS Center. Neurologic worsening post-COVID-19 was defined as having a relapse, pseudorelapse, new brain MRI activity, worsening of preexisting MSRD symptoms, or development of other long-term neurologic symptoms. RESULTS: 111 patients, 85 (76.6%) females, with a mean [SD] age of 49.3 [12.2] years and median [range] EDSS of 2.5 [0, 8.5] were identified. 41 patients (36.9%) had neurologic worsening post-COVID-19. Of those, 19 (46.3%) had pseudorelapses, 2 (4.8%) had relapses, and 24 (58.5%) patients reported worsening of preexisting MSRD symptoms, or other new long-term neurologic symptoms. Neurologic worsening was associated with hospitalized (moderate or severe) COVID-19 (p = 0.001), treatment for COVID-19 (p = 0.006), and incomplete COVID-19 recovery (p = 0.0267) but not with age, sex, MS type, race, disease duration, EDSS, vitamin D use, or disease modifying therapy use. CONCLUSIONS: COVID-19 severity and lack of complete systemic recovery were associated with new or worsening neurologic symptoms in 36.9% of MSRD patients.

SARS-CoV-2 triggered relapse of multiple sclerosis.

OBJECTIVES: There are indications that SARS-CoV-2 can trigger new onset or relapses of neuro-immunological disease. We report a patient with relapsing remitting multiple sclerosis (RRMS) under disease-modifying therapy (DMT) who experienced a relapse of RRMS after mild COVID-19. CASE REPORT: The patient is a 27-year-old female with RRMS who developed a third exacerbation of RRMS under DMT two weeks after mild COVID-19. Compared to previous imaging findings, new studies revealed an increase in the lesion load and an enhancing lesion over two segments in the thoracic spine. The patient profited from steroids and replacement of her previous DMT. She tolerated the first SARS-CoV-2 vaccination without side effects 6 months after the SARS-CoV-2 infection. CONCLUSIONS: SARS-CoV-2 infections can be followed by exacerbation of MS and failure of DMT. More arguments in favour than against a causal relation can be raised. Neurologist should remain vigilant for new or relapsing neuro-immunological disease following SARS-CoV-2 infections.

Characteristics of COVID-19 in patients with multiple sclerosis.

BACKGROUND: Regarding the high prevalence of multiple sclerosis (MS) and COVID-19 in Iran, a multicenter study of COVID-19 in Iranian MS patients with is carried out to address the concerns of this population. METHODS: Data on MS patients with COVID-19 from nine provinces of Iran were entered in a web-based registry system, between July 2020 and March 2021. Among the COVID-19 symptoms, dyspnea, altered mental status, or those resulting in hospital admission were considered severe. RESULTS: A total of 397 eligible patients were identified. In addition, 310 (78%) were female. The mean age was 36.5 ± 9.5. 294 (74%) patients had relapsing- remitting form. Also, four patients (1%) expired due to COVID-19 infection. The mean duration of admission in hospitalized patients was 9 (± 5.3) days. MRI was performed on 111 (28%) patients after developing COVID-19. MRI changes were observed in 27 (24%) of these cases. MS drug was changed in 26 (6%) patients. Steroid use in the past three months (OR: 2.43, 95% CI: 1.003-5.88) (p value: 0.049) and antiCD20s (OR: 4.03, 95% CI: 2.41-6.68) (p value < 0.001) showed significant association with severe COVID-19 symptoms. CONCLUSION: The death rate of COVID-19 among MS patients (1%) is lower than the overall death rate of the pandemic in Iran (3%). Those who received steroid in the past three months may be at increased risk of more severe forms of COVID-19. There are still doubts about the effect of anti CD20s on COVID-19 severity.

Impact of COVID-19 pandemic on frequency of clinical visits, performance of MRI studies, and therapeutic choices in a multiple sclerosis referral centre.

INTRODUCTION: To evaluate the impact of the COVID-19 pandemic on (1) number of clinical visits, (2) magnetic resonance (MR) scans, and (3) treatment prescriptions in a multiple sclerosis (MS) referral centre. METHODS: Retrospective study covering January 2018 to May 2021. RESULTS: The monthly mean (standard deviation [SD]) of visits performed in 2020 (814[137.6]) was similar to 2018 (741[99.7]; p = 0.153), and 2019 (797[116.3]; p = 0.747). During the COVID-19 period (2020 year), 36.3% of the activity was performed through telemedicine. The number of MR scans performed dropped by 76.6% during the "first wave" (March 14 to June 21, 2020) compared to the mean monthly activity in 2020 (183.5[68.9]), with a recovery during the subsequent two months. The monthly mean of treatment prescriptions approved in 2020 (24.1[7.0]) was lower than in 2019 (30[7.0]; p = 0.049), but similar to 2018 (23.8[8.0]; p = 0.727). Natalizumab prescriptions increased in the "first wave" and onwards, whereas anti-CD20 prescriptions decreased during the COVID-19 period. CONCLUSION: Maintenance of the number of clinical visits was likely due to telemedicine adoption. Although the number of MR dramatically dropped during the "first wave", an early recovery was observed. Treatment prescriptions suffered a slight quantitative decrease during 2020, whereas substantial qualitative changes were found in specific treatments.

Interferons and Multiple Sclerosis: Lessons from 25 Years of Clinical and Real-World Experience with Intramuscular Interferon Beta-1a (Avonex).

Recombinant interferon (IFN) ß-1b was approved by the US Food and Drug Administration as the first disease-modifying therapy (DMT) for multiple sclerosis (MS) in 1993. Since that time, clinical trials and real-world observational studies have demonstrated the effectiveness of IFN therapies. The pivotal intramuscular IFN ß-1a phase III trial published in 1996 was the first to demonstrate that a DMT could reduce accumulation of sustained disability in MS. Patient adherence to treatment is higher with intramuscular IFN ß-1a, given once weekly, than with subcutaneous formulations requiring multiple injections per week. Moreover, subcutaneous IFN ß-1a is associated with an increased incidence of injection-site reactions and neutralizing antibodies compared with intramuscular administration. In recent years, revisions to MS diagnostic criteria have improved clinicians' ability to identify patients with MS and have promoted the use of magnetic resonance imaging (MRI) for diagnosis and disease monitoring. MRI studies show that treatment with IFN ß-1a, relative to placebo, reduces T2 and gadolinium-enhancing lesions and gray matter atrophy. Since the approval of intramuscular IFN ß-1a, a number of high-efficacy therapies have been approved for MS, though the benefit of these high-efficacy therapies should be balanced against the increased risk of serious adverse events associated with their long-term use. For some subpopulations of patients, including pregnant women, the safety profile of IFN ß formulations may provide a particular benefit. In addition, the antiviral properties of IFNs may indicate potential therapeutic opportunities for IFN ß in reducing the risk of viral infections such as COVID-19.

COVID-19 in a temporal relation to the onset of multiple sclerosis.

Neurological complications of COVID-19 have been described. We present the case of a 27-year-old woman who developed COVID-19 in April 2020. She continued to present anosmia and ageusia eight months later. Six months after contracting COVID-19, she developed dysesthesia, hypoesthesia and hyperreflexia. Her magnetic resonance imaging showed demyelinating lesions, of which two were enhanced by gadolinium. She was positive for oligoclonal bands in her spinal fluid. This patient developed multiple sclerosis with a temporal relationship to COVID-19. We believe that SARS-CoV-2 led to her autoimmune disease through a virus-induced neuroimmunopathological condition.