Post-Partum Clinical and Patient-Reported Outcome Changes in Mothers with Multiple Sclerosis: Findings from the NAPPREMS Study.

Background and Objective: Pregnancy in mothers with multiple sclerosis (MS) commonly results in significant changes in disease activity and changes in clinical care, including the discontinuation of disease modifying therapy (DMT). This study aimed at understanding the clinical and patient-reported outcomes (PROs) before, during and 1-year after delivery. Materials and Methods: A total of 30 pregnant mothers with MS were recruited as part of the study. Clinical (relapse activity and disability changes), PRO information and MRI outcomes were collected on four separate visits: one baseline visit-0-30 days post-delivery; and 3 follow-up visits at week 24, week 36 and week 52 from the baseline. PRO was assessed using a validated questionnaire called the Fatigue Scale for Motor and Cognitive Function (FSMC). The MRI scans were analyzed, and the count of new T2 lesions and/or contrast-enhancing lesions was determined. Results: The average time between delivery and the start of DMT was 142.5 days. Relapse activity before the pregnancy was numerically linked with the activity during the pregnancy, where up to 57.1% of the activity during pregnancy occurred in pwMS with previously active disease before conception (statistically trending with p = 0.073). The relapse activity after the pregnancy occurred twice as often in pwMS whose MS was clinically active before conception. All five pwMS who experienced a relapse prior to the pregnancy experienced worsening in their physical PRO domain. Conclusions: Pre-pregnancy activity is crucial in the screening of mothers with MS at risk for post-partum relapses, worsening of clinical disability and/or PRO measures. A post-partum MS period may benefit from the routine PRO utilization and screening for its worsening. The inflammatory activity during pregnancy was not associated with short-term disease progression.

Improvement in time to multiple sclerosis diagnosis: 25-year retrospective analysis from New York State MS Consortium (NYSMSC).

Judicious multiple sclerosis (MS) diagnosis and early start of disease modifying therapy significantly improves long-term disability outcomes in persons with MS (pwMS). Retrospective analysis based on 25-year New York State MS Consortium (NYSMSC) data determined the effect of changes in the respective diagnostic criteria in shortening the time between symptom onset to MS diagnosis. Based on 9378 current and historical MS cases, there was a significant decrease in time to diagnosis in pwMS from 1982-2001 to >2017 periods (average 4.2 vs. 1.1 years, p < 0.001). Additional improvements and better implementation of the MS diagnostic criteria can further decrease the diagnosis lag.

Fatigue at enrollment predicts EDSS worsening in the New York State Multiple Sclerosis Consortium.

BACKGROUND: Fatigue is one of the most common and distressing symptoms among persons with multiple sclerosis (pwMS). OBJECTIVE: The aim of this study is to evaluate fatigue as a predictor for disease worsening among pwMS. METHODS: In this retrospective cohort study of New York State MS Consortium (NYSMSC) registry, MS patients reporting moderate-to-severe fatigue at study enrollment (n = 2714) were frequency matched to less-fatigued subjects (n = 2714) on age, baseline Kurtzke Expanded Disability Status Scale (EDSS), disease duration, and MS phenotype. Change from baseline patient-reported outcomes (PROs), as measured by LIFEware™, categorized participants into two groups: those with stable/improved outcomes and those who worsened. In a subgroup of patients with longitudinal data (n = 1951), sustained EDSS worsening was analyzed using Cox proportional hazards modeling to explore the effect of fatigue. RESULTS: The median survival time from study enrollment to sustained EDSS worsening was 8.7 years (CI: 7.2-10.1). Participants who reported fatigue at baseline were more likely to experience sustained EDSS worsening during follow-up (HR: 1.4, 95% CI: 1.2-1.7). Patients who were fatigued at baseline were also more likely to report worsening psychosocial limitations (all ps ⩽ 0.01). CONCLUSION: In addition to being a common symptom of MS, severe fatigue was a significant predictor for EDSS worsening in the NYSMSC.

Randomised natalizumab discontinuation study: taper protocol may prevent disease reactivation.

OBJECTIVES: To compare two modes of natalizumab cessation interventions: immediate versus tapered down, as measured by serial MRI and the occurrence of relapses during a 12-month period. BACKGROUND: Weighing progressive multifocal encephalopathy risk associated with ≥24 months of natalizumab therapy against the benefits of disease control, we initiated a natalizumab discontinuation study. METHODS: A phase IV, 12-month, single-blinded randomised (MRI) study. Fifty relapsing patients with multiple sclerosis (MS) who had been on natalizumab therapy ≥24 months and were contemplating natalizumab discontinuation were enrolled. Participants were randomised to either the immediate discontinuation group (IDG) or the tapered group (TG). IDG discontinued natalizumab at once and initiated another disease modifying therapy (DMT) following the last natalizumab infusion, while the TG received two more natalizumab infusions, at 6 and 8 weeks (14 weeks from study entry) before initiating another DMT. Standardised MRI was performed at baseline, 6 and 12 months from the last natalizumab infusion. RESULTS: A higher rate of relapses in the IDG (n=28) compared to the TG (n=8) over 12 months from the last infusion (p=0.007) was observed, most relapses occurred within 3 months of discontinuation (20 vs 7 relapses, p=0.012). The IDG showed a higher number of new T2 lesions within 6-12 months of discontinuation (p=0.025), a higher mean absolute T2-LV change from 0 to 12 months (1.1 vs 0.1 mL, p=0.024) and a higher number of new T1-hypointense lesions over 0-12 months (p=0.005) as well as from baseline to 6 months (p=0.026) compared to the TG. CONCLUSIONS: Natalizumab discontinuation therapy was associated with development of new disease activity. Our tapered protocol showed benefits, as patients in the TG experienced less relapses and lower accumulation of MRI lesions compared to those in the IDG.

Higher weight in adolescence and young adulthood is associated with an earlier age at multiple sclerosis onset.

BACKGROUND: Growing evidence suggests an association between adolescent obesity and increased risk of multiple sclerosis (MS). OBJECTIVE: The objective of this paper is to investigate whether weight or body mass index (BMI) in adolescence and young adulthood was associated with age at MS symptom onset. METHODS: Our cohort is comprised of a sub-group of 184 women enrolled in the New York State MS Consortium registry. Individuals were asked to recall their weight at the time of first menstruation and at age 25. BMI was calculated accordingly for age 25. Regression analyses were carried out to investigate the association between weight or BMI and age at onset. RESULTS: Weight at menarche was significantly related to younger age at symptom onset (ß = -0.073, p = 0.001). These results were also found at age 25 for weight (ß = -0.080, p < 0.001) and BMI (ß = -0.448, p = 0.001). Significantly earlier disease onset (26.9 years ±9.9) was observed in individuals who were overweight at 25 compared to those who were not overweight (32.1 years ±9.2, p = 0.006). CONCLUSIONS: Women who reported higher weight in adolescence and BMI in early adulthood were younger at MS onset. Future research should investigate whether there is a causal link between body weight and MS, as prevention lifestyle and dietary interventions could be implemented.

Characteristics influencing therapy switch behavior after suboptimal response to first-line treatment in patients with multiple sclerosis.

BACKGROUND: Factors driving disease-modifying therapy (DMT) switch behavior are not well understood. OBJECTIVE: The objective of this paper is to identify patient characteristics and clinical events predictive of therapy switching in patients with suboptimal response to DMT. METHODS: This retrospective study analyzed patients with relapsing-remitting multiple sclerosis (MS) and a suboptimal response to initial therapy with either interferon ß or glatiramer acetate. Suboptimal responders were defined as patients with ≥1 MS event (clinical relapse, worsening disability, or MRI worsening) while on DMT. Switchers were defined as those who changed DMT within six to 12 months after the MS event. RESULTS: Of 606 suboptimal responders, 214 (35.3%) switched therapy. Switchers were younger at symptom onset (p = 0.012), MS diagnosis (p = 0.004), DMT initiation (p < 0.001), and first MS event (p = 0.011) compared with nonswitchers. Compared with one relapse alone, MRI worsening alone most strongly predicted switch behavior (odds ratio 6.3; 95% CI, 3.1-12.9; p < 0.001), followed by ≥2 relapses (2.8; 95% CI, 1.1-7.3; p = 0.040), EDSS plus MRI worsening (2.5; 95% CI, 1.1-5.9; p = 0.031) and EDSS worsening alone (2.2; 95% CI, 1.2-4.1; p = 0.009). CONCLUSIONS: Younger patients with disease activity, especially MRI changes, are more likely to have their therapy switched sooner than patients who are older at the time of MS diagnosis and DMT initiation.

Disease-modifying treatment, long-term outcomes and transition to progressive multiple sclerosis: data based on the New York State MS Consortium.

BACKGROUND: The impact of disease-modifying treatments (DMTs) on multiple sclerosis (MS) long-term outcomes is continuously evolving. Retrospective analyses of large and long-term registries could provide information regarding general disease trajectories and risk factors that are commonly not investigated in shorter clinical trial settings. METHODS: Retrospective observational study of people with MS (pwMS) registered in New York State MS Consortium (NYSMSC) since 1996. Disability outcomes of reaching sustained Expanded Disability Status Scale (EDSS) scores of 4.0, 6.0 and transition to secondary-progressive MS (SPMS) were confirmed at follow-up. Four DMT categories were determined (1) continuous DMT use, (2) discontinued DMT, (3) (re)started DMT and (4) never treated with DMT. Patient-reported outcomes (PRO) were acquired using LIFEware system. Kaplan-Meier survival curves and adjusted analysis of covariance (ANCOVA) were used to determine the rate and factors related to disability progression. RESULTS: Total of 1893 pwMS were included with baseline average age of 43.2 years (SD = 10.4), 9.6 years of disease duration (SD = 8.8), median EDSS of 3.0 (IQR 2.0-3.5) and average follow-up time of 6.9 years (SD = 4.9). In addition to being male, older, more disabled and reporting worse PROs at baseline, pwMS who discontinued DMT had more than 5.5 times greater risk of reaching sustained EDSS of 4.0 (OR = 5.56, 95% CI 2.78-11.0, p < 0.001). Similarly, pwMS who discontinued DMT during the NYSMSC follow-up had 3.8- and 4.7-times greater risk to reach sustained EDSS 6.0 (OR = 3.86, 95% CI 2.12-7.02, p < 0.001), and to transition to SPMS (OR = 4.77, 95% CI 2.9-7.87, p < 0.001). Propensity matching analysis confirmed the worse clinical outcomes. CONCLUSIONS: In addition to known predictors of long-term clinical outcomes, pwMS who discontinue DMT have worse long-term disability trajectory when compared to both early and late DMT starters. PRO-based indicators may suggest worse clinical outcomes.

Impact of the COVID-19 Pandemic on the Personal Networks and Neurological Outcomes of People With Multiple Sclerosis: Cross-Sectional and Longitudinal Case-Control Study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has negatively affected the social fabric. OBJECTIVE: We evaluated the associations between personal social networks and neurological function in people with multiple sclerosis (pwMS) and controls in the prepandemic and pandemic periods. METHODS: During the early pandemic (March-December 2020), 8 cohorts of pwMS and controls completed a questionnaire quantifying the structure and composition of their personal social networks, including the health behaviors of network members. Participants from 3 of the 8 cohorts had additionally completed the questionnaire before the pandemic (2017-2019). We assessed neurological function using 3 interrelated patient-reported outcomes: Patient Determined Disease Steps (PDDS), Multiple Sclerosis Rating Scale-Revised (MSRS-R), and Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function. We identified the network features associated with neurological function using paired 2-tailed t tests and covariate-adjusted regressions. RESULTS: In the cross-sectional analysis of the pandemic data from 1130 pwMS and 1250 controls during the pandemic, having a higher percentage of network members with a perceived negative health influence was associated with worse disability in pwMS (MSRS-R: ß=2.181, 95% CI 1.082-3.279; P<.001) and poor physical function in controls (PROMIS Physical Function: ß=-5.707, 95% CI -7.405 to -4.010; P<.001). In the longitudinal analysis of 230 pwMS and 136 controls, the networks of all participants contracted, given an increase in constraint (pwMS-prepandemic: mean 52.24, SD 15.81; pwMS-pandemic: mean 56.77, SD 18.91; P=.006. Controls-prepandemic: mean 48.07, SD 13.36; controls-pandemic: mean 53.99, SD 16.31; P=.001) and a decrease in network size (pwMS-prepandemic: mean 8.02, SD 5.70; pwMS-pandemic: mean 6.63, SD 4.16; P=.003. Controls-prepandemic: mean 8.18, SD 4.05; controls-pandemic: mean 6.44, SD 3.92; P<.001), effective size (pwMS-prepandemic: mean 3.30, SD 1.59; pwMS-pandemic: mean 2.90, SD 1.50; P=.007. Controls-prepandemic: mean 3.85, SD 1.56; controls-pandemic: mean 3.40, SD 1.55; P=.01), and maximum degree (pwMS-prepandemic: mean 4.78, SD 1.86; pwMS-pandemic: mean 4.32, SD 1.92; P=.01. Controls-prepandemic: mean 5.38, SD 1.94; controls-pandemic: mean 4.55, SD 2.06; P<.001). These network changes were not associated with worsening function. The percentage of kin in the networks of pwMS increased (mean 46.06%, SD 29.34% to mean 54.36%, SD 30.16%; P=.003) during the pandemic, a change that was not seen in controls. CONCLUSIONS: Our findings suggest that high perceived negative health influence in the network was associated with worse function in all participants during the pandemic. The networks of all participants became tighter knit, and the percentage of kin in the networks of pwMS increased during the pandemic. Despite these perturbations in social connections, network changes from the prepandemic to the pandemic period were not associated with worsening function in all participants, suggesting possible resilience.

Patient-reported outcomes are the strongest predictors of disease disability in intramuscular interferon ß-1a users.

Introduction: Patient-reported outcomes (PROs) are valuable measures for routine clinical care of people with multiple sclerosis (pwMS). Materials: 646 pwMS treated with interferon-ß-1a (IFN-ß-1a) were retrospectively included from the New York State Multiple Sclerosis Consortium. Clinical and PRO data at enrollment and 3 year follow-up were collected. PwMS with stable disease and disability worsening were matched (1:1) based on age, Expanded Disability Status Scale (EDSS) scores and disease duration. Disability worsening was determined based on trial criteria. Results: PwMS with future EDSS worsening had higher baseline and follow-up timed-25-foot walk (6.6 vs 5.5 s; 9.1 vs 5.5 s; p < 0.001) when compared with stable pwMS. Worsening pwMS reported higher baseline difficulties in getting up (odds ratio [OR] = 2.4; p = 0.009), climbing stairs (OR = 1.6; p = 0.024) and standing (OR = 2.2; p < 0.001). Worsening pwMS reported greater lower limb limitations (OR = 2.3; p = 0.004) and fatigue (OR = 1.8; p = 0.002). Conclusion: Higher fatigue and lower limb functional limitations are significant predictors of future disability worsening in pwMS.

A large retrospective study was carried out on people with multiple sclerosis (PwMS) being treated with intramuscular interferon-ß medication from the New York State Multiple Sclerosis Consortium. The aim of the study was to look at whether patient-reported and clinical measures could be used early on to predict whether PwMS have worsening of their disease. The study demonstrated that patient-reported levels of limitations in multiple physical and mental symptoms can predict future worsening in objectively quantified disability in PwMS who take intramuscular interferon-ß medication. Reported limitations in lower extremities and fatigue were the most predictive of future disability worsening.

Patient-reported outcomes based on discontinuation or continuous treatment with natalizumab: New York State Multiple Sclerosis Consortium (NYSMSC) study.

BACKGROUND: Patient-reported outcomes (PRO) are increasingly utilized as part of the routine clinical assessment in people with multiple sclerosis (pwMS). The long-term effect of disease modifying therapies (DMTs) and their discontinuation on PRO measures remains largely unknown. METHODS: Two pwMS groups treated with natalizumab were selected from the New York State MS Consortium (NYSMSC) database. The first group utilized long-term follow-up data of pwMS that either still continue natalizumab treatment or discontinued. Minimal requirement of three visits (before natalizumab initiation, during treatment and after discontinuation/latest follow-up) was implemented. The second group consisted of pwMS that completed PRO questionnaire on the day of the infusion and 7 days later PROs were assessed using the LIFEware System™ that assesses limitations in multiple physical and psychosocial domains. Additional physical disability was assessed using Expanded Disability Status Scale (EDSS) and Timed 25-ft walk test (T25FWT). PRO reports were Rasch-transformed, ranging from 0 to 100, with higher scores indicating a better outcome. Linear mixed-effect models and paired analyses were utilized. RESULTS: Within the prospective cohort, 242 pwMS were followed on average of 6.5 years. Greater number of PRO domains worsened in the 141 pwMS that discontinued natalizumab when compared to 101 pwMS that remained on the drug (10 vs. 2 PRO domains). PwMS that discontinued natalizumab had significant decline in PROs regarding lower extremities, bladder and bower control and psychosocial aspects (feeling lonesome). Contrarily, pwMS that continued natalizumab had significant improvement in bladder and bowel PRO measures. Seven days after the natalizumab infusion, the 67 pwMS from the prospective cohort reported improvement in PRO measures of fatigue (62.8 vs. 66.4, p = 0.019), bladder limitations (80.3 vs. 85.0, p = 0.012), and feelings of lonesomeness (81.2 vs. 88.0, p = 0.009). CONCLUSION: Continuous natalizumab treatment provides long-term stability or improvement in PRO measures. Natalizumab also provides short term improvements recorded after the infusion.

A prospective study to validate the expanded timed get-up-and-go in a population with multiple sclerosis.

Background: Timed 25-foot walk (T25FW) test serves as gold standard in care of persons with multiple sclerosis (PwMS) and as walking measure of regulatory trials. Objective: To validate and determine the clinical utility of Expanded Timed Get-Up and Go (ETGUG) as a disability measure in MS. Methods: ETGUG intra-rater and inter-rater reproducibility was determined in 65 PwMS that were examined twice in two centres over 1-week. Values below the 5th and above the 95th percentile were considered minimally detectable change. A longitudinal cohort (32.4 months) of 145 PwMS from New York State MS Consortium (NYSMSC) was used for clinical validation as a predictor of disability worsening measured by Expanded Disability Status Scale (EDSS). Results: ETGUG and T25FW had noteworthy intra-rater and inter-rater reproducibility (Cronbach coefficient>0.949). One-week ETGUG difference ranged from 15.07% to -14.84% (5th and 95th percentile). Over the NYSMSC follow-up, PwMS had significant slowing in walking as measured by ETGUG (20.8 to 25.9s, p = 0.009) but not by T25FW. 15% ETGUG worsening had similar ability to predict EDSS worsening when compared to 20% T25FW worsening (AUC 0.596 vs. 0.552). Conclusion: Over 32-month follow-up, PwMS experience slowing in ETGUG walking time but not in T25FW. Although the scoring may be more challenging, ETGUG could be more sensitive to change and provide more comprehensive measure of lower extremity performance and ambulation in PwMS.

Discontinuation of disease modifying therapies is associated with disability progression regardless of prior stable disease and age.

BACKGROUND: Multiple sclerosis (MS) patients with stable disease course might view continued treatment as unnecessary. However, guidelines regarding treatment discontinuation are currently lacking. OBJECTIVE: To assess the clinical course after treatment discontinuation in MS patients with long disease duration. METHODS: Patients who discontinued disease-modifying treatments (DMTs) and not resume treatment (n = 216) were extracted from New York State MS Consortium (NYSMSC) and followed across three time points (average 4.6 years). Stable course was defined as no change in Expanded Disability Status Scale (EDSS) scores (<1.0 increase if EDSS<6.0 or <0.5-point increase if EDSS≥6.0) from baseline (time 1) to DMT discontinuation (time 2). Both stable and worsening MS patients were later assessed again after the DMT discontinuation (time 3). Additional analyses were performed based on disease subtype, type of medication, age cut-off of 55 and EDSS of 6.0. RESULTS: From the cohort of 216 MS patients who discontinued DMT, 161 (72.5%) were classified as stable before DMT discontinuation. After DMT discontinuation, 53 previously stable MS patients (32.9%) experienced disability worsening/progression (DWP). 29.2 and 40% of previously stable RRMS and SPMS respectively had DWP after DMT discontinuation. Over two years after DMT discontinuation, the rate of DWP was similar between patients younger or older than 55 years (31.1% vs 25.9%, respectively). MS patients with EDSS≥6.0 had greater DWP when compared to less disabled patients while remaining on therapy as well as after discontinuation (40.7% vs 15.4%, p < 0.001 and 39.6% vs 15.2%, p < 0.001, respectively). CONCLUSION: MS patients with stable disease course experience DWP after treatment discontinuation, with no clear relation to age and disease subtype. Patients with EDSS≥6.0 are at higher risk for DWP.

Impact of the COVID-19 Pandemic on Personal Networks and Neurological Outcomes of People with Multiple Sclerosis: A Case-Control Cross-sectional and Longitudinal Analysis.

Background: The COVID-19 pandemic has negatively impacted the social fabric of people with multiple sclerosis (pwMS). Objective: To evaluate the associations between personal social network environment and neurological function in pwMS and controls during the COVID-19 pandemic and compare with the pre-pandemic baseline. Methods: We first analyzed data collected from 8 cohorts of pwMS and control participants during the COVID-19 pandemic (March-December 2020). We then leveraged data collected between 2017-2019 in 3 of the 8 cohorts for longitudinal comparison. Participants completed a questionnaire that quantified the structure and composition of their personal social network, including the health behaviors of network members. We assessed neurological disability using three interrelated patient-reported outcomes: Patient Determined Disease Steps (PDDS), Multiple Sclerosis Rating Scale â€" Revised (MSRS-R), and Patient Reported Outcomes Measurement Information System (PROMIS)-Physical Function. We identified the network features associated with neurologic disability using paired t-tests and covariate-adjusted regressions. Results: In the cross-sectional analysis of the pandemic data from 1130 pwMS and 1250 control participants, higher percent of network members with a perceived negative health influence was associated with greater neurological symptom burden in pwMS (MSRS-R: Beta[95% CI]=2.181[1.082, 3.279], p<.001) and worse physical function in controls (PROMIS-Physical Function: Beta[95% CI]=-5.707[-7.405, -4.010], p<.001). In the longitudinal analysis of 230 pwMS and 136 control participants, the networks of both pwMS and controls experienced an increase in constraint (pwMS p=.006, control p=.001) as well as a decrease in network size (pwMS p=.003, control p<.001), effective size (pwMS p=.007, control p=.013), maximum degree (pwMS p=.01, control p<.001), and percent contacted weekly or less (pwMS p<.001, control p<.001), suggesting overall network contraction during the COVID-19 pandemic. There was also an increase in percentage of kin (p=.003) in the networks of pwMS but not controls during the COVID-19 pandemic when compared to the pre-pandemic baseline. These changes in personal social network due to the pandemic were not associated with worsening neurological disability during the pandemic. Conclusions: Our findings suggest that perceived negative health influences in personal social networks are associated with worse disability in all participants during the COVID-19 pandemic. Despite the perturbation in social environment and connections during the pandemic, the stability in neurological function among pwMS suggests potential resilience.

COVID-19 Vaccination in Multiple Sclerosis and Inflammatory Diseases: Effects from Disease-Modifying Therapy, Long-Term Seroprevalence and Breakthrough Infections.

Background: To determine the effect of disease-modifying therapies (DMT) on humoral postvaccine seroconversion, long-term humoral response, and breakthrough COVID-19 infections in persons with multiple sclerosis (PwMS) and other neuroinflammatory disorders. Methods: A total of 757 PwMS and other neuroinflammatory disorders were recruited in two MS centers and vaccinated with one of the FDA-approved vaccines (BNT162b2, mRNA-1273, Ad26.COV2.S). The primary outcomes are the rate of humoral postvaccine seroconversion and anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) immunoglobulin G (IgG) differences between patients on different DMTs. Secondary measures include breakthrough infections and humoral response after six months. Other outcomes include differences in vaccine response between SARS-CoV-2 vaccines and the effects of age and comorbidities on the vaccine response. Results: A total of 465 (68.4%) PwMS and 55 (74.3%) patients with neuroinflammatory diseases were seropositive at 4−12 weeks after vaccination. A significant difference in seroconversion based on the DMT used at the time of vaccination (p < 0.001) was observed, with the lowest rates seen in patients treated with anti-CD20 antibodies (23.2%) and sphingosine-1-phosphate modulators (S1P) (30.8%). In seropositive patients, there was a significant decrease in anti-SARS IgG from mean 20.0 to 4.7 at six months (p = 0.004). Thirty-nine patients had breakthrough infection, but only two seronegative patients required hospitalization. mRNA vaccines resulted in significantly greater seroconversion compared to Ad26.COV2.S (p < 0.001). Older age and presence of cardiovascular comorbidities were associated with lower anti-SARS IgG (p = 0.021 and p = 0.003, respectively) Conclusions: PwMS and neuroinflammatory disorders treated with anti-CD20 and S1P medications have lower humoral response after anti-SARS-CoV-2 vaccination, even after booster dose. Waning of the humoral response puts vaccinated PwMS at a greater risk of COVID-19 breakthrough.

Vaccination Against SARS-CoV-2 in Neuroinflammatory Disease: Early Safety/Tolerability Data.

BACKGROUND: Patients with autoimmune disease and on immunotherapy were largely excluded from seminal anti-SARS-CoV-2 vaccine trials. This has led to significant vaccine hesitancy in patients with neuroinflammatory diseases (NID); including, but not limited to: multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), neurosarcoidosis and myelin oligodendrocyte antibody-mediated disease (MOG-AD). Data is urgently needed to help guide clinical care in the NID population. METHODS: This was a cross-sectional observational study evaluating adults with a neurologist-confirmed diagnosis of a neuroinflammatory disease (NID) and a neurologically asymptomatic control population. Participants were recruited from multiple academic centers participating in the MS Resilience to COVID-19 Collaborative study. We analyzed participant responses from a vaccine-specific questionnaire collected between February and May 2021. RESULTS: 1164 participants with NID and 595 controls completed the vaccine survey. Hesitancy rates were similar between NID and control groups (n = 134, 32.7% NID vs. n = 56, 30.6% control; p = 0.82). The most common reasons for hesitancy in NID participants were lack of testing in the autoimmune population and fear of demyelinating/neurologic events. Unvaccinated patients who had discussed vaccination with their doctor were less likely to be hesitant (n=184, 73.6% vs. n=83, 59.7%; p = 0.007). 634 NID patients and 332 controls had received at least one dose of a vaccine against SARS-CoV-2 at the time of survey completion. After adjusting for age, BMI, and comorbidities, there was no difference in self-reported side effects (SE) between groups with the first dose (n = 256, 42.2% NID vs. 141, 45.3% control; p = 0.20) or second dose (n = 246, 67.0% NID vs. n = 114, 64.8% control, p = 0.85) of the mRNA vaccines nor with the viral-vector vaccines (n = 6, 46% NID vs. n = 8, 66% control; p = 0.39). All reported SEs fell into the expected SE profile. There was no difference in report of new/recurrent neurologic symptoms (n = 110, 16.2% vaccinated vs. 71, 18.2% unvaccinated; p = 0.44) nor radiologic disease activity (n = 40, 5.9% vaccinated vs. n = 30, 7.6% unvaccinated) between vaccinated and unvaccinated NID participants. CONCLUSIONS: We found no difference in patient-reported vaccine side effects and no evidence of NID worsening after vaccination. Large-scale real-world evidence is needed for further validation.

Worsening physical functioning in patients with neuroinflammatory disease during the COVID-19 pandemic.

OBJECTIVE: To quantify changes in psychological wellbeing and physical function as reported by people with neurological inflammatory disease (PwNID) during the COVID-19 pandemic. METHODS: 1134 PwNID and 868 control participants were recruited through five major academic medical centers in the Northeast/Mid-Atlantic U.S. beginning in April 2020. Participants completed serial surveys throughout the COVID-19 pandemic that aimed to quantify mood symptoms and physical function, analyzed cross-sectionally with a smaller cohort analyzed longitudinally. RESULTS: Throughout the pandemic, depression scores were not significantly different between PwNID and controls, although a higher proportion of PwNID reported clinically significant depression at study entry. Depression scores did not worsen over time for either group. Loneliness was the strongest predictor of worse depression, along with older age, male gender in both PwNID and controls, as well as lack of disease modifying therapy use, and disease duration in PwNID only. In contrast, physical disability worsened significantly over time for both PwNID and controls. Age, DMT status and comorbid health conditions emerged as significant predictors of physical function. CONCLUSIONS: Depressive symptoms remained consistent for both PwNID and controls throughout the COVID-19 pandemic, but physical function worsened significantly over time for both groups. This is particularly impactful for PwNID, who have higher baseline levels of physical disability, and underscores the importance of reinstituting services and interventions that facilitate exercise and reconditioning for this population.

Impact of resilience, social support, and personality traits in patients with neuroinflammatory diseases during the COVID-19 pandemic.

BACKGROUND AND OBJECTIVE: The COVID-19 pandemic negatively impacted the well-being of persons with neuroinflammatory diseases (pwNID). Identifying factors that influence the response to challenging conditions could guide supportive care. METHODS: 2185 pwNID and 1079 healthy controls (HCs) from five US centers completed an online survey regarding the effects of the COVID-19 pandemic on physical and psychological well-being. Survey instruments included resilience (Connor-Davidson Resilience Scale, CD-RISC), loneliness (UCLA Loneliness Scale), social support (modified social support survey, MSSS-5), personality traits (NEO-Five Factor Inventory, NEO-FFI), and disability (Patient-Determined Disability Steps (PDDS). Step-wise regression models and mediation analyses assessed whether the level of self-reported resilience, size of the social support, and specific personality traits (study predictors) were associated with self-reported disability and/or loneliness (study outcomes). RESULTS: The response rate varied significantly between the questionnaires. While, all pwNID completed the demographic questionnaire, 78.8% completed the loneliness questionnaire and 49.7% completed the NEO-FFI. Based on 787 responses, greater neuroticism (standardized ß = 0.312, p < 0.001), less social support (standardized ß = -0.242, p < 0.001), lower extraversion (standardized ß = -0.083, p=0.017), lower agreeableness (standardized ß = -0.119, p < 0.001), and lower resilience (standardized ß = -0.125, p = 0.002) were associated with the feeling of loneliness. Social support and resilience modestly but significantly mediated the association between personality traits and loneliness. Older age (standardized ß = 0.165, p < 0.001) and lower conscientiousness (standardized ß = -0.094, p = 0.007) were associated with worse disability (higher PDDS scores). There were no differences in outcomes between pwNID and HCs. CONCLUSION: Greater social support potentially attenuates the association between neuroticism and the feeling of loneliness in pwNID during the COVID-19 pandemic. Assessment of personality traits may identify pwNID that are in greater need of social support and guide targeted interventions.

Hyperdense middle cerebral artery sign and response to combination of mechanical Thrombectomy plus intravenous thrombolysis in acute stroke patients.

BACKGROUND AND PURPOSE: Combining intra-arterial mechanical thrombectomy (IAMT) and intravenous thrombolysis (IVT) has shown to have an excellent recanalization rate and better clinical outcome in acute ischemic stroke (AIS) patients. Hyperdense middle cerebral artery sign (HMCAS) on pretreatment non-contrast head CT scan of AIS patients is one of the early ischemic radiological findings in middle cerebral artery territory AIS. We aimed to evaluate whether the presence of HMCAS predicts the outcome of AIS patients receiving combination therapy with IAMT and IVT. METHODS: We retrospectively reviewed medical records and cerebrovascular images of the patients treated with IAMT and IVT for AIS in our center. Patients with occlusion in the terminal internal carotid artery or middle cerebral artery on pretreatment CT angiogram of the head were included. Clinical outcome was compared between subjects with HMCAS and those without. Modified Rankin Score (mRS) and symptomatic intracranial hemorrhage (sICH) were used as measures of efficacy and safety, respectively. RESULTS: Of 93 patients, 46 (49%) had HMCAS on their initial head CT scan. Both groups had comparable baseline characteristics and stroke severity. After adjusting for age, NIHSS score, time from symptom onset to starting IVT, and history of diabetes mellitus in multivariate logistic regression analysis, there was no difference in terms of a poor outcome (mRS >2) (OR = 0.5 [CI 0.2-1.4], p = 0.188) or rate of sICH (OR = 3.3 [CI 0.6-19.0], p = 0.190) between the two groups. CONCLUSIONS: HMCAS is not a predictor of poor outcome in AIS patients receiving combination therapy with IAMT and IVT and does not affect treatment safety.

Laboratory factors associated with symptomatic hemorrhagic conversion of acute stroke after systemic thrombolysis.

BACKGROUND: Laboratory factors associated with hemorrhagic conversion (HC) after Intravenous thrombolysis with rtPA (IVT) for Acute Ischemic Stroke (AIS) remain nebulous despite advances in our knowledge of AIS. This study aimed to investigate the laboratory factors predisposing to HC in AIS patients receiving IVT. METHODS: We retrospectively reviewed the medical records of patients who received IV tPA for AIS at our comprehensive stroke center over a 9.6-year period. Besides age, gender, NIHSS, history of diabetes mellitus (DM), history of atrial fibrillation (Afib), we gathered their laboratory data including International Normalized Ratio (INR), lipid panel, serum albumin, serum creatinine, hemoglobin A1c (HbA1c), and admission blood glucose. Post-thrombolysis brain imagings were reviewed to evaluate for symptomatic ICH (sICH). The mean values of above mentioned laboratory data were compared between the group with sICH and patients with no sICH. Univariate and multivariate logistic regression were performed to evaluate the association of the laboratory findings with presence of sICH. sICH was defined as ICH causing an increase in NIHSS ≥4. RESULTS: Of the 794 subjects in this study 51 (6.4%) had sICH. In the univariate analysis, patients who developed sICH had significantly higher NIHSS on admission (14.2 ± 5.4 vs 11.2 ± 6.5, p < .001), LDL-cholesterol (113.3 mg/dl ±36.9 vs. 101.8 mg/dl ± 38.2, p = .032), HbA1c (6.9% ± 2.3 vs. 6.1 ± 1.3, p = .003) and lower levels of Albumin (3.5 g/dl ±0.4 vs. 3.9 g/dl ± 0.5, p < .001). Furthermore, a higher prevalence of history of DM (45% vs. 21.6%, p = .020) and Afib (25.4% vs. 10.4%, p = .028) was found in subjects who developed sICH. There were no significant group differences regarding age, sex, total cholesterol, blood glucose on admission, serum creatinine or INR levels (p > .05). After adjusting for multiple covariates, lower Albumin level and and higher HbA1c were significantly associated with an increased risk for sICH development (p < .05). Chances of sICH increased by 33% for every 1 g/dl below a normal albumin level of 4.0 g/dl (p < .05). CONCLUSION: Lower endogenous albumin level and higher HbA1c have shown to predispose to a higher risk of sICH after IVT for AIS and might be good predictors of sICH post IVT.

Epidemiology and treatment of multiple sclerosis in elderly populations.

The prevalence of multiple sclerosis (MS) and the age of affected patients are increasing owing to increased longevity of the general population and the availability of effective disease-modifying therapies. However, ageing presents unique challenges in patients with MS largely as a result of their increased frequency of age-related and MS-related comorbidities as well as transition of the disease course from an inflammatory to a neurodegenerative phenotype. Immunosenescence (the weakening of the immune system associated with natural ageing) might be at least partly responsible for this transition, which further complicates disease management. Currently approved therapies for MS are effective in preventing relapse but are not as effective in preventing the accumulation of disability associated with ageing and disease progression. Thus, ageing patients with MS represent a uniquely challenging population that is currently underserved by existing therapeutic regimens. This Review focuses on the epidemiology of MS in ageing patients. Unique considerations relevant to this population are discussed, including the immunology and pathobiology of the complex relationship between ageing and MS, the safety and efficacy of disease-modifying therapies, when discontinuation of treatment might be appropriate and the important role of approaches to support wellness and cognition.