Early Predictors of Clinical and MRI Outcomes Using Least Absolute Shrinkage and Selection Operator (LASSO) in Multiple Sclerosis.

OBJECTIVE: The objective of this study was to identify predictors in common between different clinical and magnetic resonance imaging (MRI) outcomes in multiple sclerosis (MS) by comparing predictive models. METHODS: We analyzed 704 patients from our center seen at MS onset, measuring 37 baseline demographic, clinical, treatment, and MRI predictors, and 10-year outcomes. Our primary aim was identifying predictors in common among clinical outcomes: aggressive MS, benign MS, and secondary-progressive (SP)MS. We also investigated MRI outcomes: T2 lesion volume (T2LV) and brain parenchymal fraction (BPF). The performance of the full 37-predictor model was compared with a least absolute shrinkage and selection operator (LASSO)-selected model of predictors in common between each outcome by the area under the receiver operating characteristic curves (AUCs). RESULTS: The full 37-predictor model was highly predictive of clinical outcomes: in-sample AUC was 0.91 for aggressive MS, 0.81 for benign MS, and 0.81 for SPMS. After variable selection, 10 LASSO-selected predictors were in common between each clinical outcome: age, Expanded Disability Status Scale, pyramidal, cerebellar, sensory and bowel/bladder signs, timed 25-foot walk ≥6 seconds, poor attack recovery, no sensory attacks, and time-to-treatment. This reduced model had comparable cross-validation AUC as the full 37-predictor model: 0.84 versus 0.81 for aggressive MS, 0.75 versus 0.73 for benign MS, and 0.76 versus 0.75 for SPMS, respectively. In contrast, 10-year MRI outcomes were more strongly influenced by initial T2LV and BPF than clinical outcomes. INTERPRETATION: Early prognostication of MS is possible using LASSO modeling to identify a limited set of accessible clinical features. These predictive models can be clinically usable in treatment decision making once implemented into web-based calculators. ANN NEUROL 2022;92:87-96.

Serum NfL but not GFAP predicts cognitive decline in active progressive multiple sclerosis patients.

BACKGROUND: Cognitive decline is inadequately captured by the standard neurological examination. Serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are biomarkers of neuronal damage and astrocytic reactivity that may offer an accessible measure of the multiple sclerosis (MS) pathology linked to cognitive decline. OBJECTIVE: To investigate the association of sNfL and sGFAP with cognitive decline in MS patients at high risk for progressive pathology. METHODS: We included 94 MS patients with sustained Expanded Disability Status Score (EDSS) ⩾ 3, available serum samples and cognitive assessment performed by symbol digit modalities test (SDMT) over a median of 3.1 years. The visit for sGFAP/sNfL quantification was at confirmed EDSS ⩾ 3. Linear regression analysis on log-transformed sGFAP/sNfL assessed the association with current and future SDMT. Analyses were adjusted for age, sex, EDSS, treatment group, and recent relapse. RESULTS: sNfL was significantly associated with concurrent SDMT (adjusted change in mean SDMT = -4.5; 95% confidence interval (CI): -8.7, -0.2; p = 0.039) and predicted decline in SDMT (adjusted change in slope: -1.14; 95% CI: -1.83, -0.44; p = 0.001), particularly in active patients. sGFAP was not associated with concurrent or future SDMT. CONCLUSIONS: Higher levels of sNfL were associated with cognitive impairment and predicted cognitive decline in MS patients at high risk for having an underlying progressive pathology.

Accuracy of serum neurofilament light to identify contrast-enhancing lesions in multiple sclerosis.

BACKGROUND: Contrast-enhancing magnetic resonance imaging (MRI) lesions (CELs) indicate acute multiple sclerosis inflammation. Serum biomarkers, neurofilament light (sNfL), and glial fibrillary acidic protein (sGFAP) may increase in the presence of CELs, and indicate a need to perform MRI. OBJECTIVE: We assessed the accuracy of biomarkers to detect CELs. METHODS: Patients with two gadolinium-enhanced MRIs and serum biomarkers tested within 3 months were included (N = 557, 66% female). Optimal cut-points from Bland-Altman analysis for spot biomarker level and Youden's index for delta-change from remission were evaluated. RESULTS: A total of 116 patients (21%) had CELs. A spot sNfL measurement >23.0 pg/mL corresponded to 7.0 times higher odds of CEL presence (95% CI: 3.8, 12.8), with 25.9% sensitivity, 95.2% specificity, operating characteristic curve (AUC) 0.61; while sNfL delta-change >30.8% from remission corresponded to 5.0 times higher odds (95% CI: 3.2, 7.8), 52.6% sensitivity, 81.9% specificity, AUC 0.67. sGFAP had poor CEL detection. In patients > 50 years, neither cut-point remained significant. sNfL delta-change outperformed spot levels at identifying asymptomatic CELs (AUC 0.67 vs 0.59) and in patients without treatment escalation between samples (AUC 0.67 vs 0.57). CONCLUSION: Spot sNfL >23.0 pg/mL or a 30.8% increase from remission provides modest prediction of CELs in patients <50 years; however, low sNfL does not obviate the need for MRI.

Gut Microbiome in Progressive Multiple Sclerosis.

OBJECTIVE: This study was undertaken to investigate the gut microbiome in progressive multiple sclerosis (MS) and how it relates to clinical disease. METHODS: We sequenced the microbiota from healthy controls and relapsing-remitting MS (RRMS) and progressive MS patients and correlated the levels of bacteria with clinical features of disease, including Expanded Disability Status Scale (EDSS), quality of life, and brain magnetic resonance imaging lesions/atrophy. We colonized mice with MS-derived Akkermansia and induced experimental autoimmune encephalomyelitis (EAE). RESULTS: Microbiota ß-diversity differed between MS patients and controls but did not differ between RRMS and progressive MS or differ based on disease-modifying therapies. Disease status had the greatest effect on the microbiome ß-diversity, followed by body mass index, race, and sex. In both progressive MS and RRMS, we found increased Clostridium bolteae, Ruthenibacterium lactatiformans, and Akkermansia and decreased Blautia wexlerae, Dorea formicigenerans, and Erysipelotrichaceae CCMM. Unique to progressive MS, we found elevated Enterobacteriaceae and Clostridium g24 FCEY and decreased Blautia and Agathobaculum. Several Clostridium species were associated with higher EDSS and fatigue scores. Contrary to the view that elevated Akkermansia in MS has a detrimental role, we found that Akkermansia was linked to lower disability, suggesting a beneficial role. Consistent with this, we found that Akkermansia isolated from MS patients ameliorated EAE, which was linked to a reduction in RORγt+ and IL-17-producing γδ T cells. INTERPRETATION: Whereas some microbiota alterations are shared in relapsing and progressive MS, we identified unique bacteria associated with progressive MS and clinical measures of disease. Furthermore, elevated Akkermansia in MS may be a compensatory beneficial response in the MS microbiome. ANN NEUROL 2021;89:1195-1211.

Younger age at multiple sclerosis onset is associated with worse outcomes at age 50.

OBJECTIVE: Older age at multiple sclerosis (MS) onset has been associated with worse 10-year outcomes. However, disease duration often exceeds 10 years and age-related comorbidities may also contribute to disability. We investigated patients with>10 years disease duration to determine how age at MS onset is associated with clinical, MRI and occupational outcomes at age 50. METHODS: We included patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital with disease duration>10 years. Outcomes at age 50 included the Expanded Disability Status Scale (EDSS), development of secondary-progressive multiple sclerosis (SPMS), brain T2-lesion volume (T2LV) and brain parenchymal fraction (BPF), and occupational status. We assessed how onset age was independently associated with each outcome when adjusting for the date of visit closest to age 50, sex, time to first treatment, number of treatments by age 50 and exposure to high-efficacy treatments by age 50. RESULTS: We included 661 patients with median onset at 31.4 years. The outcomes at age 50 were worse the younger first symptoms developed: for every 5 years earlier, the EDSS was 0.22 points worse (95% CI: 0.04 to 0.40; p=0.015), odds of SPMS 1.33 times higher (95% CI: 1.08 to 1.64; p=0.008), T2LV 1.86 mL higher (95% CI: 1.02 to 2.70; p<0.001), BPF 0.97% worse (95% CI: 0.52 to 1.42; p<0.001) and odds of unemployment from MS 1.24 times higher (95% CI: 1.01 to 1.53; p=0.037). CONCLUSIONS: All outcomes at age 50 were worse in patients with younger age at onset. Decisions to provide high-efficacy treatments should consider younger age at onset, equating to a longer expected disease duration, as a poor prognostic factor.

Clinical Trial-Ready Patient Cohorts for Multiple System Atrophy: Coupling Biospecimen and iPSC Banking to Longitudinal Deep-Phenotyping.

Multiple system atrophy (MSA) is a fatal neurodegenerative disease of unknown etiology characterized by widespread aggregation of the protein alpha-synuclein in neurons and glia. Its orphan status, biological relationship to Parkinson's disease (PD), and rapid progression have sparked interest in drug development. One significant obstacle to therapeutics is disease heterogeneity. Here, we share our process of developing a clinical trial-ready cohort of MSA patients (69 patients in 2 years) within an outpatient clinical setting, and recruiting 20 of these patients into a longitudinal "n-of-few" clinical trial paradigm. First, we deeply phenotype our patients with clinical scales (UMSARS, BARS, MoCA, NMSS, and UPSIT) and tests designed to establish early differential diagnosis (including volumetric MRI, FDG-PET, MIBG scan, polysomnography, genetic testing, autonomic function tests, skin biopsy) or disease activity (PBR06-TSPO). Second, we longitudinally collect biospecimens (blood, CSF, stool) and clinical, biometric, and imaging data to generate antecedent disease-progression scores. Third, in our Mass General Brigham SCiN study (stem cells in neurodegeneration), we generate induced pluripotent stem cell (iPSC) models from our patients, matched to biospecimens, including postmortem brain. We present 38 iPSC lines derived from MSA patients and relevant disease controls (spinocerebellar ataxia and PD, including alpha-synuclein triplication cases), 22 matched to whole-genome sequenced postmortem brain. iPSC models may facilitate matching patients to appropriate therapies, particularly in heterogeneous diseases for which patient-specific biology may elude animal models. We anticipate that deeply phenotyped and genotyped patient cohorts matched to cellular models will increase the likelihood of success in clinical trials for MSA.

Patient-reported outcomes associated with transition to secondary progressive multiple sclerosis.

PURPOSE: To investigate patient-reported outcome (PRO) measures in patients with relapsing-remitting multiple sclerosis (RRMS) who transition to secondary progressive multiple sclerosis (SPMS). METHODS: Subjects enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) who completed PRO measures in the RRMS and SPMS phases were identified (n = 52). The PRO measures were Medical Outcomes Study Short-Form 36 Health Survey (SF-36), the Modified Fatigue Impact Scale (MFIS), and the Center for Epidemiologic Studies Depression Scale (CESD). Two control groups of RRMS CLIMB patients who did not progress to SPMS were identified based on different matching criteria related to age, sex, disease duration and Expanded Disability Status Scale (EDSS). Summary statistics for each PRO were calculated at the last RRMS measurement and first SPMS measurement, and the change over this transition was calculated using a paired t-test. Patients who transitioned were compared to the control groups using linear regression to adjust for age, disease duration and EDSS and a mixed model to further account for the matching with a random effect for matched group. RESULTS: Patients who transitioned from RRMS to SPMS had noticeable deficits in terms of Quality of Life (QOL) and fatigue at the visit prior to the transition. Patients worsened in terms of SF-36 Role Physical (- 3.6 [- 6.6, - 0.7]), Social Functioning (- 3.7 [- 6.4, - 1.0]), and Physical Component Summary (- 2.3 [- 4.5, - 0.1]) during the transition from RRMS to SPMS. When patients who transitioned were compared to the matched subjects, they had worse scores on several outcomes, including Physical Functioning (adjusted mean difference = - 10.8 [- 14.1, - 7.5]), Physical Component Summary (- 5.2 [- 9.3, - 1.0]), fatigue (8.9 [1.7, 16.1]), and depression (3.1 [0.3, 5.9]). CONCLUSIONS: Patients in the period closely preceding transition from RRMS to SPMS have worse physical QOL and fatigue compared to subjects who remain RRMS.

Trajectories of Symbol Digit Modalities Test performance in individuals with multiple sclerosis.

BACKGROUND: Although cognitive problems have been identified in people with multiple sclerosis (PwMS), few studies have investigated the long-term change in cognitive functioning. OBJECTIVE: To identify trajectories of change in cognitive functioning for PwMS. METHODS: Participants enrolled in the quality-of-life subgroup from the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) were eligible for our analysis. In 2006, participants in this group began to complete the Symbol Digit Modalities Test (SDMT) annually. Latent trajectory models were used to identify groups of participants with similar longitudinal change in SDMT scores. Linear and quadratic trajectory models were fit, and the models were compared. Latent trajectory models were also fit adjusting for baseline age and disease duration as well as using normalized SDMT scores. The groups identified across the approaches were compared. RESULTS: We found that classes with higher-than-average baseline values improved, classes with average baseline values remained relatively constant, and classes with lower baseline values experienced cognitive worsening. Similar results were observed in the alternative latent trajectory models accounting for other variables. CONCLUSION: Our models show that subjects with higher SDMT scores at baseline showed improvement, while subjects with lower SDMT scores at baseline showed worsening. Baseline age and disease duration were also associated with SDMT performance.

Food allergies are associated with increased disease activity in multiple sclerosis.

OBJECTIVE: The association between allergy and multiple sclerosis (MS) is still unclear. In our study, we assessed the association between a self-reported history of allergic conditions with MS clinical and MRI disease activity. METHODS: A subset of 1349 patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) study completed a self-administered questionnaire on environmental, food and drug allergies. Patients were distributed among four allergy groups: (1) environmental, (2) food, (3) drug, (4) no known allergies (NKA). Clinical (number of attacks, expanded disability status scale (EDSS), MS severity score (MSSS)) and radiological variables (presence of gadolinium-enhancing lesions and lesion count), and their associations with the different allergy groups or those with NKA, were assessed. RESULTS: The food allergy group had a 1.38 times higher rate for cumulative number of attacks compared with the NKA group (P=0.0062); this difference remained significant in the adjusted analysis (relapse rate ratio 1.27, P=0.0305). The food allergy group showed more than twice the likelihood (OR 2.53, P=0.0096) of having gadolinium-enhancing lesions on MRI. The environmental and drug allergy groups did not show significant differences when compared with the NKA group. The EDSS and MSSS were not affected by any type of allergy. CONCLUSIONS: MS patients with food allergy had more relapses and a higher likelihood of gadolinium-enhancing lesions compared with patients with no known allergy. Future prospective studies are needed to confirm our findings and investigate underlying biological mechanisms, which may unveil new therapeutic and preventative strategies for MS.

Assessment of computer adaptive testing version of the Neuro-QOL for people with multiple sclerosis.

BACKGROUND: To date, the computerized adaptive testing (CAT) version of the Neuro-quality of life (QOL) has not been assessed in a large sample of people with multiple sclerosis (MS). OBJECTIVE: The aim of this study was to assess the associations between the CAT version of Neuro-QOL and other clinical and patient-reported outcome measures. METHODS: Subjects (n = 364) enrolled in SysteMS completed the CAT version of the Neuro-QOL and the 36-Item Short Form Survey (SF-36) within 4 weeks of a clinical exam that included the Multiple Sclerosis Functional Composite-4 (MSFC-4). The correlations between the Neuro-QOL domains and the MSFC-4 subscores and the SF-36 scores were calculated. The changes over time in the Neuro-QOL and other measures were also examined. RESULTS: The lower extremity functioning score of the Neuro-QOL showed the highest correlations with MSFC-4 components including Timed 25-Foot Walk, 9-Hole Peg Test, and cognitive score. The expected domains of the Neuro-QOL showed high correlations with the SF-36 subscores, and some Neuro-QOL domains were associated with many SF-36 subscores. There was limited longitudinal change on the Neuro-QOL domains over 12 months, and the change was not associated with change on other measures. CONCLUSION: The CAT version of the Neuro-QOL shows many of the expected associations with clinical and patient-reported outcome measures.

Fatty acid binding protein-4 is associated with disability in multiple sclerosis patients.

BACKGROUND: Increased adiposity is a risk factor for multiple sclerosis (MS) and is associated with increased disability scores. Adipokines may mediate the effects of adiposity on MS disease course. OBJECTIVE: The objective of this study is to examine the association between the adipokines (leptin and fatty acid binding protein-4, FABP4) and clinical course in individuals with MS. METHODS: Subjects (18-65 years) with relapsing-remitting MS or clinically isolated syndrome and <10 year disease duration were selected from a longitudinal clinical study. Cross-sectional and longitudinal models assessed the relationship between two adipokines (leptin and FABP4) and disease severity in women and men, adjusting for age, disease duration and disease type, Vitamin D level, testosterone level, and as well by body mass index (BMI). RESULTS: Mean age of subjects ( N = 163, 56% women) was 39.3 years. Higher FABP4 levels were associated with higher Expanded Disability Status Scale (EDSS) scores in women in both univariate and multivariate analyses (odds ratio: 1.30; p = 0.005). In men, higher FABP4 level was significantly associated with change in EDSS over time (estimate: 0.0062; p = 0.035). We found no association of FABP4 levels with time to next relapse or a measure of processing speed. CONCLUSION: FABP4 levels may be associated with increased disability in both men and women with MS independent of effects of BMI and other hormones. Future studies should expand these analyses and further explore downstream mechanisms of adiposity-related effects in MS.

The neutrophil-to-lymphocyte and monocyte-to-lymphocyte ratios are independently associated with neurological disability and brain atrophy in multiple sclerosis.

BACKGROUND: Serum hematological indices such as the neutrophil-lymphocyte ratio (NLR) or monocyte-lymphocyte ratio (MLR) have been used as biomarkers of pathogenic inflammation and prognostication in multiple areas of medicine; recent evidence shows correlation with psychological parameters as well. OBJECTIVES/AIMS: To characterize clinical, neuroimaging, and psycho-neuro-immunological associations with NLR and MLR in persons with multiple sclerosis (MS). METHODS: We identified a large cohort of clinically well-defined patients from our longitudinal database that included MS-related outcomes, disease-modifying therapy, patient-reported outcome (PRO) measures, and quantified cerebral MRI at 1.5 T. We queried hospital records for complete blood counts within 2 months of each clinic visit and excluded those obtained during clinical relapses. Four hundred eighty-three patients, with a mean of 3 longitudinal observations each, were identified who met these criteria. Initial analyses assessed the association between NLR and MLR as the outcomes, and psychological and demographic predictors in univariable and multivariable models controlling for age, gender and treatment. The second set of analyses assessed the association between clinical and MRI outcomes including whole brain atrophy and T2-hyperintense lesion volume, with NLR and MLR as predictors in univariable and multivariable models. All analyses used a mixed effects linear or logistic regression model with repeated measures. RESULTS: Unadjusted analyses demonstrated significant associations between higher (log-transformed) NLR (but not MLR) and PRO measures including increasing depression (p = 0.01), fatigue (p < 0.01), and decreased physical quality of life (p < 0.01). Higher NLR and MLR strongly predicted increased MS-related disability as assessed by the Expanded Disability Status Scale, independent of all demographic, clinical, treatment-related, and psychosocial variables (p < 0.001). Lastly, higher NLR and MLR significantly discriminated progressive from relapsing status (p ≤ 0.01 for both), and higher MLR correlated with increased whole-brain atrophy (p < 0.05) but not T2 hyperintense lesion volume (p > 0.05) even after controlling for all clinical and demographic covariates. Sensitivity analyses using a subset of untreated patients (N = 146) corroborated these results. CONCLUSIONS: Elevated NLR and MLR may represent hematopoetic bias toward increased production and pro-inflammatory priming of the myeloid innate immune system (numerator) in conjunction with dysregulated adaptive immune processes (denominator), and consequently reflect a complementary and independent marker for severity of MS-related neurological disability and MRI outcomes.

Oral contraceptives and MS disease activity in a contemporary real-world cohort.

BACKGROUND: There is uncertainty regarding the effect of oral hormonal contraceptives (OC) on multiple sclerosis (MS) course. OBJECTIVE: To evaluate the hypothesis that OC use is associated with decreased risk of relapses in an observational study of women of childbearing age with new-onset MS starting a first-line injectable disease-modifying therapy (DMT). METHODS: From our CLIMB longitudinal observational study, we identified 162 women with MS or CIS with known OC use who initiated injectable DMT within two years of symptom onset, and categorized OC use at DMT onset as past, ever or never. Our primary analysis was comparison of annualized relapse rate from baseline DMT start across the three OC use categories using a negative binomial regression model. RESULTS: In this cohort of 162 women, 81 were treated with interferon therapy and 81 with glatiramer acetate. Mean ages for current-, past-, and never-OC users were 31.4 ( n = 46), 40.3 ( n = 66), and 37.9 ( n = 50) years, respectively ( p < 0.05); mean disease duration (1.0 years) and median baseline EDSS (1.0) did not differ between groups. Prior OC users had significantly lower relapse rates than never-users ( p = 0.031); the lower annualized relapse rate in current-users relative to never-users was not significant ( p = 0.91). Annualized relapse rate was not significantly different across the OC groups ( p = 0.057, three-group comparison). RESULTS: These observations provide reassurance for women newly diagnosed that OC use, past or current, does not appear to be associated with greater risk of relapses.

Correlating serum micrornas and clinical parameters in amyotrophic lateral sclerosis.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a debilitating neurologic disorder with poor survival rates and no clear biomarkers for disease diagnosis and prognosis. METHODS: We compared serum microRNA (miRNA) expression from patients with ALS with healthy controls and patients with multiple sclerosis and Alzheimer disease. We also correlated miRNA expression in cross-sectional and longitudinal cohorts of ALS patients with clinical parameters. RESULTS: We identified 7 miRNAs (miR-192-5p, miR-192-3p, miR-1, miR-133a-3p, miR-133b, miR-144-5p, miR-19a-3p) that were upregulated and 6 miRNAs (miR-320c, miR-320a, let-7d-3p, miR-425-5p, miR-320b, miR-139-5p) that were downregulated in patients with ALS compared with healthy controls, patients with Alzheimer disease, and patients with multiple sclerosis. Changes in 4 miRNAs (miR-136-3p, miR-30b-5p, miR-331-3p, miR-496) correlated positively and change in 1 miRNA (miR-2110) correlated negatively with changes in clinical parameters in longitudinal analysis. DISCUSSION: Our findings identified serum miRNAs that can serve as biomarkers for ALS diagnosis and progression. Muscle Nerve 58: 261-269, 2018.

Exploration of changes in disability after menopause in a longitudinal multiple sclerosis cohort.

BACKGROUND: Onset of multiple sclerosis (MS) is typically in early adulthood. The impact, if any, of menopause on the MS course is unknown. Our objective was to determine whether menopause is associated with changes in MS severity in a longitudinal clinical cohort. METHODS: Responses from an ongoing reproductive questionnaire deployed in all active female CLIMB observational study participants with a diagnosis of clinically isolated syndrome (CIS) or MS were analyzed when the response rate was 60%. Reproductive data were linked with clinical severity measures that were prospectively collected every six months, including our primary measure, the Expanded Disability Status Scale (EDSS). RESULTS: Over one-half of the respondents (368 of 724 women) were postmenopausal. Median age at natural menopause was 51.5 years. In our primary analysis of 124 women who were followed longitudinally (mean duration 10.4 years) through their menopausal transition (natural or surgical), menopause represented an inflection point in their EDSS changes (difference of 0.076 units; 95% CI 0.010-0.14; p = 0.024). These findings were not explained by vitamin D levels, nor changes in treatment or smoking status over this period. There was no effect of hormone replacement therapy (HRT) exposure, but HRT use was low. CONCLUSIONS: We observed a possible worsening of MS disability after menopause. Larger cohorts are required to assess any HRT effects.

Fatigue predicts disease worsening in relapsing-remitting multiple sclerosis patients.

BACKGROUND: It is unclear whether fatigue is a consequence or a predictive trait of disease worsening. OBJECTIVE: To investigate the predictive value of fatigue toward conversion to confirmed moderate-severe disability in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: We retrospectively selected from the Comprehensive Longitudinal Investigations in MS at the Brigham and Women's Hospital (CLIMB) study cohort RRMS patients who converted to confirmed (⩾2 years) Expanded Disability Status Scale (EDSS) score ⩾3 within a follow-up period ⩾3 years. We contrasted the Modified Fatigue Impact Scale (MFIS) score of 33 converters, obtained at least 1 year before conversion to EDSS ⩾3, with that of 33 non-converter RRMS patients matched for baseline characteristics. RESULTS: Total MFIS score was higher in converter versus non-converter MS patients (median 37 vs 13; p < 0.0001). EDSS and Center for Epidemiological Studies Depression scale (CES-D) scores were also higher in the converters (median EDSS 1.5 vs 0, p < 0.0001; median CES-D 30 vs 24, p < 0.0001) and were both associated with MFIS score (EDSS: rho = 0.42, p = 0.0005; CES-D: rho = 0.72, p < 0.0001). After adjusting for EDSS and CES-D in multivariate analysis, MFIS remained a significant predictor of subsequent conversion to confirmed EDSS ⩾3. CONCLUSION: Fatigue is a promising indicator of risk for conversion to confirmed moderate-severe disability in RRMS patients.

Cognitive and patient-reported outcomes in adults with pediatric-onset multiple sclerosis.

BACKGROUND: Little is known about long-term cognitive and patient-reported outcomes of pediatric-onset multiple sclerosis (POMS). OBJECTIVE: The objective of this paper is to compare cognitive and patient-reported outcomes in adults with POMS vs. adult-onset MS (AOMS). METHODS: We compared standardized patient-reported measures MSQOL54, MFIS, CES-D and SDMT in adult patients with MS onset prior to and after age 18, using data gathered in the Comprehensive Longitudinal Investigations in MS at Brigham and Women's Hospital (CLIMB) study. RESULTS: Fifty-one POMS and 550 AOMS patients were compared. SDMT scores were significantly lower in POMS after adjusting for age (-7.57 (-11.72, -3.43; p < 0.001), but not after adjusting for disease duration. Estimated group difference demonstrated lower normative z scores in POMS vs. AOMS in unadjusted analysis (-0.74 (95% CI: -1.18, -0.30; p = 0.0009) and after adjusting for disease duration (-0.60; 95%CI: -1.05, -0.15; p = 0.0097). Findings were unchanged in a subset of POMS diagnosed prior to age 18. In unadjusted and adjusted analyses, no significant differences were observed in health-related quality-of-life, fatigue, depression or social support between POMS and AOMS. CONCLUSIONS: Younger age of onset was associated with more impairment in information-processing speed in adults with POMS compared to AOMS, and remained significant when controlling for disease duration in age-normed analysis. The two groups were similar in terms of patient-reported outcomes, suggesting similar qualitative experiences of MS.

Stigma in Multiple Sclerosis: A Narrative Review of Current Concepts, Measures, and Findings.

Stigma is an undesired differentness associated with a particular characteristic or condition that distinguishes a person as being outside the norm and cueing stereotypes. Stigma is common in people with multiple sclerosis (MS) and is associated with several disease variables including disease duration, age, age of onset, and disease course. Stigma is also associated with psychological and psychosocial variables such as depression, anxiety, and quality of life. This article reviews our current understanding of stigma in people with MS with a focus on the various stigma types including anticipated, experienced, and internalized stigma, and the lack of consistent definitions across studies. It also describes the 7 instruments that are most commonly used to measure stigma in people with MS, and the limitations of each measure. We conclude that a better understanding of stigma that includes standard definitions of stigma types could lead to more direct intervention strategies aimed at reducing particular stigma concepts and resulting in improved health-related quality of life in people with MS.

No sex-specific difference in disease trajectory in multiple sclerosis patients before and after age 50.

BACKGROUND: The disease course in multiple sclerosis (MS) is influenced by many factors, including age, sex, and sex hormones. Little is known about sex-specific changes in disease course around age 50, which may represent a key biological transition period for reproductive aging. METHODS: Male and female subjects with no prior chemotherapy exposure were selected from a prospective MS cohort to form groups representing the years before (38-46 years, N=351) and after (54-62 years, N=200)age 50. Primary analysis assessed for interaction between effects of sex and age on clinical (Expanded Disability Status Scale, EDSS; relapse rate) and radiologic (T2 lesion volume, T2LV; brain parenchymal fraction, BPF) outcomes. Secondarily, we explored patient-reported outcomes (PROs). RESULTS: As expected, there were age- and sex- related changes with male and older cohorts showing worse disease severity (EDSS), brain atrophy (BPF), and more progressive course.There was no interaction between age and sex on cross-sectional adjusted clinical (EDSS, relapse rate) or radiologic (BPF, T2LV) measures, or on 2-year trajectories of decline.There was a significant interaction between age and sex for a physical functioning PRO (SF-36): the older female cohort reported lower physical functioning than men (p=0.002). There were no differences in depression (Center for Epidemiological Study - Depression, CES-D) or fatigue (Modified Fatigue Impact Scale, MFIS) scores. CONCLUSIONS: There was no interaction between age and sex suggestive of an effect of reproductive aging on clinical or radiologic progression. Prospective analyses across the menopausal transition are needed.