Direct and Indirect Care of Patients With Multiple Sclerosis: Burden on Providers and Impact of Portal Messages.

BACKGROUND: Multiple sclerosis (MS) indirect patient-care time is often underreported and uncompensated. Data on time spent on indirect and direct care by MS providers is lacking. METHODS: A survey was designed to understand the practice patterns among MS providers in the United States, including time spent on direct and indirect patient care, as well as managing electronic medical record portal messages. The National MS Society and the American Academy of Neurology facilitated the distribution of the survey to MS providers. RESULTS: Most providers spent at least 1 hour on new and at least 30 minutes on follow-up direct patient care. For indirect patient care, 77% of providers spent more than 1 hour and 57% spent more than 2 hours per day. While some providers have support staff to help with portal messages, many do not have protected time or compensation for portal messages. CONCLUSIONS: Multiple sclerosis providers spent a higher-than-average time on direct and indirect patient care tasks, including portal messages, and most lack protected time or compensation for portal messages. These results highlight the potential impact of indirect patient care (notably portal messages) on provider workload and burnout. Better support, protected time and/or compensation for indirect patient care can help ease physician burden and decrease burnout.

Obesity, gut microbiota, and multiple sclerosis: Unraveling the connection.

Obesity is associated with chronic mild-grade systemic inflammation and neuroinflammation. Obesity in early childhood and adolescence is also a significant risk factor for multiple sclerosis (MS) development. However, the underlying mechanisms that explain the link between obesity and MS development are not fully explored. An increasing number of studies call attention to the importance of gut microbiota as a leading environmental risk factor mediating inflammatory central nervous system demyelination, particularly in MS. Obesity and high-calorie diet are also associated with disturbances in gut microbiota. Therefore, gut microbiota alteration is a plausible connection between obesity and the increased risk of MS development. A greater understanding of this connection could provide additional therapeutic opportunities, like dietary interventions, microbiota-derived products, and exogenous antibiotics and probiotics. This review summarizes the current evidence regarding the relationships between MS, obesity, and gut microbiota. We discuss gut microbiota as a potential link between obesity and increased risk for MS. Additional experimental studies and controlled clinical trials targeting gut microbiota are warranted to unravel the possible causal relationship between obesity and increased risk of MS.

Quantitative MRI identifies lesional and non-lesional abnormalities in MOGAD.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a distinct central nervous system (CNS) disorder that shares features with multiple sclerosis (MS) and may be misdiagnosed as MS. MOGAD and MS share a frequently relapsing clinical course and lesions with inflammatory demyelinating pathology. One key feature of MS pathology is tissue damage in normal-appearing white matter (NAWM) outside of discrete lesions, whereas the extent to which similar non-lesional damage occurs in MOGAD is not known and could be assessed using qGRE. The goal of this study was to examine the brains of people with MOGAD using quantitative gradient-recalled echo (qGRE) magnetic resonance imaging and to compare tissue damage with MS patients matched for disability. METHODS: MOGAD and MS patients were recruited to match in terms of age and disability. Similarly aged healthy control (HC) data were drawn from existing studies. qGRE brain imaging of HC (N = 15), MOGAD (N = 17), and MS (N = 15) patients was used to examine the severity and extent of tissue damage within and outside of discrete lesions. The qGRE metric R2t* is sensitive to changes in tissue microstructure and was measured in white matter lesions (WMLs), NAWM, cortical (CGM) and deep gray matter (DGM). Statistical inference was performed with linear models. RESULTS: R2t* was reduced in CGM (p = 0.00047), DGM (p = 0.0055) and NAWM (p = 0.0019) in MOGAD and MS compared to similar regions in age-matched HCs. However, the degree of R2t* reduction in all these regions was less in the MOGAD patients compared with MS. WMLs in MOGAD demonstrated reduced R2t* compared to NAWM but this reduction was modest compared to changes associated with WMLs in MS (p = 0.026). CONCLUSION: These results demonstrate abnormalities in lesional and non-lesional CNS tissues in MOGAD that are not detectable on standard MRI. The abnormalities seen in NAWM, CGM, and DGM were less severe in MOGAD compared to MS. MOGAD-related WMLs showed reduced R2t*, but were less abnormal than WMLs in MS. These data reveal damage to non-lesional tissues in two different demyelinating diseases, suggesting that damage outside of WMLs may be a common feature of demyelinating diseases. The lesser degree of R2t* abnormality in MOGAD tissues compared to MS suggests less underlying tissue damage and may underlie the greater propensity for recovery in MOGAD.

"Brain age" predicts disability accumulation in multiple sclerosis.

OBJECTIVE: Neurodegenerative conditions often manifest radiologically with the appearance of premature aging. Multiple sclerosis (MS) biomarkers related to lesion burden are well developed, but measures of neurodegeneration are less well-developed. The appearance of premature aging quantified by machine learning applied to structural MRI assesses neurodegenerative pathology. We assess the explanatory and predictive power of "brain age" analysis on disability in MS using a large, real-world dataset. METHODS: Brain age analysis is predicated on the over-estimation of predicted brain age in patients with more advanced pathology. We compared the performance of three brain age algorithms in a large, longitudinal dataset (>13,000 imaging sessions from >6,000 individual MS patients). Effects of MS, MS disease course, disability, lesion burden, and DMT efficacy were assessed using linear mixed effects models. RESULTS: MS was associated with advanced predicted brain age cross-sectionally and accelerated brain aging longitudinally in all techniques. While MS disease course (relapsing vs. progressive) did contribute to advanced brain age, disability was the primary correlate of advanced brain age. We found that advanced brain age at study enrollment predicted more disability accumulation longitudinally. Lastly, a more youthful appearing brain (predicted brain age less than actual age) was associated with decreased disability. INTERPRETATION: Brain age is a technically tractable and clinically relevant biomarker of disease pathology that correlates with and predicts increasing disability in MS. Advanced brain age predicts future disability accumulation.

Perspectives and experiences with COVID-19 vaccines in people with MS.

Background: People with MS may have unique perspectives on COVID-19 vaccines due to their condition and/or medications. Objective: Assess perspectives and experiences with COVID-19 vaccination, and quantify variables impacting COVID-19 vaccine willingness in people with MS. Methods: A survey captured demographics, MS characteristics, and COVID-19 infection and exposures data; opinions on COVID-19 vaccine safety, side effects, and efficacy; and experiences following vaccination. Chi-square tests and a logistic regression model were used to denote between-group differences and variables predicting vaccine willingness, respectively. Results: Most (87.8%) of the 237 participants were willing to receive the vaccine. Fifteen percent held or delayed a DMT dose for vaccination. MS symptoms worsened in a minority (7.6% first/only dose; 14.7% second dose), and most side effects were mild (80.0%; 55.3%). Those not planning to receive the vaccine were primarily concerned with long-term safety (70.4%). Medical comorbidities (adjusted odds ratio [aOR]=5.222; p=0.04) and following infection prevention precautions (aOR=6.330; p=0.008) were associated with vaccine willingness. Conclusion: Most individuals with MS surveyed plan to receive the COVID-19 vaccine. People with MS experience similar side effects to the general population, and few experience transient MS symptom worsening. These results can inform conversations on vaccination between providers and people with MS.

Multiple sclerosis diagnosis: Knowledge gaps and opportunities for educational intervention in neurologists in the United States.

BACKGROUND: Few studies have addressed the results of educational efforts concerning proper use of McDonald criteria (MC) revisions outside multiple sclerosis (MS) subspecialty centers. Neurology residents and MS subspecialist neurologists demonstrated knowledge gaps for core elements of the MC in a recent prior study. OBJECTIVE: To assess comprehension and application of MC core elements by non-MS specialist neurologists in the United States who routinely diagnose MS. METHODS: Through a cross-sectional study design, a previously developed survey instrument was distributed online. RESULTS: A total of 222 neurologists completed the study survey. Syndromes atypical for MS were frequently incorrectly considered "typical" MS presentations. Fourteen percent correctly identified definitions of both "periventricular" and "juxtacortical" lesions and 2% correctly applied these terms to 9/9 images. Twenty-four percent correctly identified all four central nervous system (CNS) regions for satisfaction of magnetic resonance imaging (MRI) dissemination in space. In two presented cases, 61% and 71% correctly identified dissemination in time (DIT) was not fulfilled, and 85% and 86% subsequently accepted nonspecific historical symptoms without objective evidence for DIT fulfillment. CONCLUSION: The high rate of knowledge deficiencies and application errors of core elements of the MC demonstrated by participants in this study raise pressing questions concerning adequacy of dissemination and educational efforts upon publication of revisions to MC.

Central vein sign and other radiographic features distinguishing myelin oligodendrocyte glycoprotein antibody disease from multiple sclerosis and aquaporin-4 antibody-positive neuromyelitis optica.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) can radiographically mimic multiple sclerosis (MS) and aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD). Central vein sign (CVS) prevalence has not yet been well-established in MOGAD. OBJECTIVE: Characterize the magnetic resonance imaging (MRI) appearance and CVS prevalence of MOGAD patients in comparison to matched cohorts of MS and AQP4+ NMOSD. METHODS: Clinical MRIs from 26 MOGAD patients were compared to matched cohorts of MS and AQP4+ NMOSD. Brain MRIs were assessed for involvement within predefined regions of interest. CVS was assessed by overlaying fluid-attenuated inversion recovery (FLAIR) and susceptibility-weighted sequences. Topographic analyses were performed on spinal cord and orbital MRIs when available. RESULTS: MOGAD patients had fewer brain lesions and average CVS+ rate of 12.1%, compared to 44.4% in MS patients (p = 0.0008). MOGAD spinal cord and optic nerve involvement was lengthier than MS (5.8 vs 1.0 vertebral segments, p = 0.020; 3.0 vs 0.5 cm, p < 0.0001). MOGAD patients tended to have bilateral/anterior optic nerve pathology with perineural contrast enhancement, contrasting with posterior optic nerve involvement in NMOSD. CONCLUSION: CVS+ rate and longer segments of involvement in the spinal cord and optic nerve can differentiate MOGAD from MS, but do not discriminate as well between MOGAD and AQP4+ NMOSD.

Reduced antibody activity against SARS-CoV-2 B.1.617.2 delta virus in serum of mRNA-vaccinated individuals receiving tumor necrosis factor-α inhibitors.

BACKGROUND: Although vaccines effectively prevent coronavirus disease 2019 (COVID-19) in healthy individuals, they appear to be less immunogenic in individuals with chronic inflammatory disease (CID) or receiving chronic immunosuppression therapy. METHODS: Here we assessed a cohort of 77 individuals with CID treated as monotherapy with chronic immunosuppressive drugs for antibody responses in serum against historical and variant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses after immunization with the BNT162b2 mRNA vaccine. FINDINGS: Longitudinal analysis showed the greatest reductions in neutralizing antibodies and Fc effector function capacity in individuals treated with tumor necrosis factor alpha (TNF-α) inhibitors (TNFi), and this pattern appeared to be worse against the B.1.617.2 delta virus. Within 5 months of vaccination, serum neutralizing titers of all TNFi-treated individuals tested fell below the presumed threshold correlate for antibody-mediated protection. However, TNFi-treated individuals receiving a third mRNA vaccine dose boosted their serum neutralizing antibody titers by more than 16-fold. CONCLUSIONS: Vaccine boosting or administration of long-acting prophylaxis (e.g., monoclonal antibodies) will likely be required to prevent SARS-CoV-2 infection in this susceptible population. FUNDING: This study was supported by grants and contracts from the NIH (R01 AI157155, R01AI151178, and HHSN75N93019C00074; NIAID Centers of Excellence for Influenza Research and Response (CEIRR) contracts HHSN272201400008C and 75N93021C00014; and Collaborative Influenza Vaccine Innovation Centers [CIVIC] contract 75N93019C00051).

Effect of Immunosuppression on the Immunogenicity of mRNA Vaccines to SARS-CoV-2 : A Prospective Cohort Study.

BACKGROUND: Patients with chronic inflammatory disease (CID) treated with immunosuppressive medications have increased risk for severe COVID-19. Although mRNA-based SARS-CoV-2 vaccination provides protection in immunocompetent persons, immunogenicity in immunosuppressed patients with CID is unclear. OBJECTIVE: To determine the immunogenicity of mRNA-based SARS-CoV-2 vaccines in patients with CID. DESIGN: Prospective observational cohort study. SETTING: Two U.S. CID referral centers. PARTICIPANTS: Volunteer sample of adults with confirmed CID eligible for early COVID-19 vaccination, including hospital employees of any age and patients older than 65 years. Immunocompetent participants were recruited separately from hospital employees. All participants received 2 doses of mRNA vaccine against SARS-CoV-2 between 10 December 2020 and 20 March 2021. Participants were assessed within 2 weeks before vaccination and 20 days after final vaccination. MEASUREMENTS: Anti-SARS-CoV-2 spike (S) IgG+ binding in all participants, and neutralizing antibody titers and circulating S-specific plasmablasts in a subset to assess humoral response after vaccination. RESULTS: Most of the 133 participants with CID (88.7%) and all 53 immunocompetent participants developed antibodies in response to mRNA-based SARS-CoV-2 vaccination, although some with CID developed numerically lower titers of anti-S IgG. Anti-S IgG antibody titers after vaccination were lower in participants with CID receiving glucocorticoids (n = 17) than in those not receiving them; the geometric mean of anti-S IgG antibodies was 357 (95% CI, 96 to 1324) for participants receiving prednisone versus 2190 (CI, 1598 to 3002) for those not receiving it. Anti-S IgG antibody titers were also lower in those receiving B-cell depletion therapy (BCDT) (n = 10). Measures of immunogenicity differed numerically between those who were and those who were not receiving antimetabolites (n = 48), tumor necrosis factor inhibitors (n = 39), and Janus kinase inhibitors (n = 11); however, 95% CIs were wide and overlapped. Neutralization titers seemed generally consistent with anti-S IgG results. Results were not adjusted for differences in baseline clinical factors, including other immunosuppressant therapies. LIMITATIONS: Small sample that lacked demographic diversity, and residual confounding. CONCLUSION: Compared with nonusers, patients with CID treated with glucocorticoids and BCDT seem to have lower SARS-CoV-2 vaccine-induced antibody responses. These preliminary findings require confirmation in a larger study. PRIMARY FUNDING SOURCE: The Leona M. and Harry B. Helmsley Charitable Trust, Marcus Program in Precision Medicine Innovation, National Center for Advancing Translational Sciences, and National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Glucocorticoids and B Cell Depleting Agents Substantially Impair Immunogenicity of mRNA Vaccines to SARS-CoV-2.

BACKGROUND: Individuals with chronic inflammatory diseases (CID) are frequently treated with immunosuppressive medications that can increase their risk of severe COVID-19. While novel mRNA-based SARS-CoV-2 vaccination platforms provide robust protection in immunocompetent individuals, the immunogenicity in CID patients on immunosuppression is not well established. Therefore, determining the effectiveness of SARS-CoV-2 vaccines in the setting of immunosuppression is essential to risk-stratify CID patients with impaired protection and provide clinical guidance regarding medication management. METHODS: We conducted a prospective assessment of mRNA-based vaccine immunogenicity in 133 adults with CIDs and 53 immunocompetent controls. Blood from participants over 18 years of age was collected before initial immunization and 1-2 weeks after the second immunization. Serum anti-SARS-CoV-2 spike (S) IgG + binding, neutralizing antibody titers, and circulating S-specific plasmablasts were quantified to assess the magnitude and quality of the humoral response following vaccination. RESULTS: Compared to immunocompetent controls, a three-fold reduction in anti-S IgG titers (P=0.009) and SARS-CoV-2 neutralization (p<0.0001) were observed in CID patients. B cell depletion and glucocorticoids exerted the strongest effect with a 36- and 10-fold reduction in humoral responses, respectively (p<0.0001). Janus kinase inhibitors and antimetabolites, including methotrexate, also blunted antibody titers in multivariate regression analysis (P<0.0001, P=0.0023, respectively). Other targeted therapies, such as TNF inhibitors, IL-12/23 inhibitors, and integrin inhibitors, had only modest impacts on antibody formation and neutralization. CONCLUSIONS: CID patients treated with immunosuppressive therapies exhibit impaired SARS-CoV-2 vaccine-induced immunity, with glucocorticoids and B cell depletion therapy more severely impeding optimal responses.

Challenges in multiple sclerosis diagnosis: Misunderstanding and misapplication of the McDonald criteria.

OBJECTIVE: To assess comprehension and application of the McDonald criteria. BACKGROUND: Studies suggest that knowledge gaps for specific core elements of the McDonald criteria may contribute to multiple sclerosis (MS) misdiagnosis. METHODS: Neurology residents (NR) and multiple sclerosis specialists (MSS) in North America completed a web-based survey. RESULTS: A total of 160 participants were included: 72 NR and 88 MSS. Syndromes incorrectly identified as typical of MS included: complete transverse myelopathy (35% NR and 15% MSS), intractable vomiting/nausea/hiccoughs (20% NR and 5% MSS), and bilateral optic neuritis/unilateral optic neuritis with poor visual recovery (17% NR and 10% MSS). Periventricular magnetic resonance imaging (MRI) lesions were correctly identified by 39% NR and 52% MSS, and juxtacortical lesions were correctly identified by 28% NR and 53% MSS. The correct definition of "periventricular" was chosen by 38% NR and 61% MSS, and that of "juxtacortical" was chosen by 19% NR and 54% MSS. Regions incorrectly identified for MRI dissemination in space fulfillment included the optic nerve (31% NR and 26% MSS) and the subcortical white matter (11% NR and 18% MSS). The majority of participants assessed previous non-specific neurological symptoms without objective evidence of a central nervous system (CNS) lesion as sufficient for clinical dissemination in time. CONCLUSION: The McDonald criteria are often misunderstood and misapplied. Concerted educational efforts may prevent MS misdiagnosis.

Rapid transfer of knowledge for multiple sclerosis clinical care during COVID-19: ECHO MS.

BACKGROUND: Healthcare providers caring for people with multiple sclerosis (MS) have had significant concerns about the intersection of MS and COVID-19. As a result, there has been an urgency to understand and share information about how to best provide MS clinical care during COVID-19. The Project ECHO model is well-suited for this challenge, as it provides a uniquely efficient and effective approach to sharing information in real-time using real cases. We report on the translation of the Project ECHO model for the rapid sharing of knowledge among MS clinical providers during COVID-19. METHODS: The ECHO MS COVID-19 Response Clinic was a videoconference-based education and case consultation program offered to providers in the U.S. who care for individuals with MS. The Response Clinic was offered as four sessions, each delivered by three regional hubs. Data were collected on participation and the self-reported impact of the program. RESULTS: A total of 132 unique providers participated in the Response Clinic, which consisted of 11 didactic modules and 43 case consultations. Participant providers overwhelmingly indicated that the program improved their knowledge, attitude, and skills for providing healthcare for people with MS during the COVID-19 pandemic. DISCUSSION: The Project ECHO model was successfully adapted to serve the needs of the MS community during COVID-19, suggesting the program could be continued or could be expanded to other disease areas for a similar purpose. More research is needed to objectively measure the impact of the program on patient outcomes.

Clinical and laboratory features distinguishing MOG antibody disease from multiple sclerosis and AQP4 antibody-positive neuromyelitis optica.

BACKGROUND: Antibodies to myelin oligodendrocyte glycoprotein (MOG) are associated with a CNS inflammatory disorder distinct from multiple sclerosis (MS) and aquaporin-4 antibody-positive neuromyelitis optica (NMO). Knowledge of the clinical spectrum of MOG antibody disease (MOGAD) remains incomplete, particularly in comparison to two related inflammatory demyelinating diseases, MS and NMO. OBJECTIVE: Compare demographics, clinical characteristics, estimated disability, laboratory results, and treatment responses of a U.S. MOGAD cohort with age- and sex-matched MS and NMO patients. DESIGN, SETTING, AND PARTICIPANTS: This observational, case-control, single-center study identified each group via ICD-10 diagnosis code searches through the electronic medical records of adult patients seen at the John L. Trotter MS Center between January 1, 2019 and January 1, 2020. MOGAD and NMO patients were confirmed to have at least one positive antibody test; those in the MS group had a confirmed diagnosis by a physician with MS subspecialty training. Data were collected after IRB approval. RESULTS: Twenty-six patients were included in each group. MOGAD patients were predominantly Caucasian (88.5%) with mean onset age of 43.9 years. MOGAD patients had no comorbid other autoimmune diseases and comparatively lower rates of family members with autoimmune disease (20.0%) than either MS (40.0%) or NMO (34.6%) matched cohorts. 91% of MOGAD attacks were monofocal, and over 70% presented with optic neuritis. Severity of MOGAD attacks was similar to that of seropositive NMO, but the robust degree of recovery was more similar to MS. Four MOGAD patients converted to negative antibody status, with no attacks occurring after conversion. Serum ANA and ENA were less frequently elevated in MOGAD (21.7%, 5.0%) than in seropositive NMO patients (66.7%, 42.9%). Elevated IgG synthesis rate and positive CSF-restricted oligoclonal bands were not seen in our MOGAD cohort, and only one MOGAD patient had an elevated IgG index. Despite anti-CD20 therapy, 28.6% of MOGAD patients continued to suffer relapses. CONCLUSIONS: MOGAD was characterized by a predominantly monofocal presentation (typically optic neuritis) and severe attacks with better recovery than seen with seropositive NMO attacks. Lack of CSF-restricted oligoclonal bands distinguished MOGAD from MS.

Disease-Modifying Therapy Adherence and Associated Factors in a National Sample of Medicare Patients With Multiple Sclerosis.

OBJECTIVES: Disease-modifying therapies (DMTs) reduce relapse rates and disability progression for relapsing multiple sclerosis (MS). Although 25% to 30% of all US patients with MS are Medicare beneficiaries, limited information exists on this population. This is the first study using national Medicare data to (1) describe characteristics of patients with MS using DMTs, (2) estimate adherence to DMTs over a 1-year and 3-year follow-up, and (3) examine factors associated with DMT adherence. METHODS: This retrospective claims analysis used 2011-2014 100% Medicare files. Monthly adherence to MS DMTs was defined as the proportion of days covered ≥0.80 with any DMT in each month for 1-year (n = 36 593) and 3-year (n = 17 599) follow-up samples of MS DMT users. Generalized estimating equation logistic regressions were used to estimate factors associated with adherence to DMTs. RESULTS: Over 90% of patients were eligible for Medicare owing to disability, and about three-quarters qualified for low-income subsidies. A downward trend in DMT adherence was observed over time in both samples. Monthly adherence dropped significantly between December of the prior year to January of the following year (from 76% to 65% in the 1-year follow-up sample and similar drops seen across all years in the 3-year follow-up sample). Multivariable regressions indicated characteristics such as being low-income, having a disability, and having high patient out-of-pocket DMT costs associated with poor adherence to DMTs. CONCLUSION: Our study provides important insights into the characteristics and DMT adherence of Medicare patients with MS and highlights the need for interventions and policies mitigating barriers to adherence in this population.

Clinical instrument to retrospectively capture levels of EDSS.

BACKGROUND: The Expanded Disability Status Scale (EDSS), a common outcome measure in Multiple Sclerosis (MS), is obtained prospectively through a direct standardized evaluation. The objective of this study is to develop and validate an algorithm to derive EDSS scores from previous neurological clinical documentation. METHODS: The algorithm utilizes data from the history, review of systems, and physical exam. EDSS scores formally obtained from research patients were compared to captured EDSS (c-EDSS) scores. To test inter-rater reliability, a second investigator captured scores from a subset of patients. Agreement between formal and c-EDSS scores was assessed using a weighted kappa. Clinical concordance was defined as a difference of one-step in EDSS (0.5) and functional system (1.0) scores. RESULTS: Clinical documentation from 92 patients (EDSS range 0.0-8.5) was assessed. Substantial agreement between the c-EDSS and formal EDSS (kappa 0.80; 95% CI 0.74-0.86) was observed. The mean difference between scores was 0.16. The clinical concordance was 78%. Near-perfect agreement was found between the two raters (kappa 0.89; 95% CI 0.84-0.95). The mean inter-rater difference in c-EDSS was 0.23. CONCLUSIONS: This algorithm reliably captures EDSS scores retrospectively with substantial correlation with formal EDSS and high inter-rater agreement. This algorithm may have practical implications in clinic, MS research and clinical trials.

Uncovering the association between fatigue and fatigability in multiple sclerosis using cognitive control.

BACKGROUND: Fatigue and cognitive dysfunction are two common symptoms experienced by patients with multiple sclerosis (MS). The relationship between subjective and objective fatigue (fatigability) in MS is poorly understood. Cognitive control tasks might be more conducive to fatigability and more likely to show associations between subjective and objective cognitive fatigue in MS. OBJECTIVE: To study the association between objective fatigability, as induced by a cognitive control task called the Blocked Cyclic Naming Task (BCNT), subjective fatigue and baseline cognitive functioning in patients with MS. METHODS: Twenty-one patients with MS completed baseline questions about their disease, the Montreal Cognitive Assessment (MoCA) battery and self-reported questionnaires on trait fatigue, sleep and depression. Disability was captured using the expanded disability status scale (EDSS). Participants then performed the BCNT and were asked about their level of state momentary fatigue before and after the BCNT. The BCNT consists of several blocks of either related or unrelated pictures that participants name as quickly as possible. The pictures cycled 4 times in each block and the difference in the response times (RTs) between related and unrelated blocks was captured. Data were analyzed using repeated measures analysis of variance and Pearson correlations. RESULTS: MS participants' performance declined for the related, but not unrelated blocks. The difference in RTs between related and unrelated conditions increased with repetition across cycles (p < 0.001). Participants also showed objective fatigability with less repetition priming (p = 0.02) in the 4th quarter and with greater differences between related and unrelated conditions in the later part of the task. Objective fatigability was strongly associated with participants' assessment of their level of momentary state fatigue (r = 0.612, p = 0.007). CONCLUSION: Using the appropriate tools, this study showed an association between subjective and objective cognitive fatigue in people with MS. The BCNT and cognitive control are useful tools in assessing patients with MS and should be explored in future, larger studies in this population.

Effectiveness of alternative dose fingolimod for multiple sclerosis.

BACKGROUND: Fingolimod is a daily oral medication used to treat relapsing multiple sclerosis (MS). Clinicians often adopt less frequent dosing for patients with profound drug-induced lymphopenia or other adverse events. Data on the effectiveness of alternate dose fingolimod are limited. METHODS: We conducted a multicenter, retrospective, observational study at 14 sites and identified 170 patients with MS taking alternate doses of fingolimod for ≥1 month. Clinical and radiologic outcomes were collected and compared during daily and alternate fingolimod dosing. RESULTS: Profound lymphopenia (77%), liver function abnormalities (9%), and infections (7%) were the most common reasons for patients to switch to alternate fingolimod dosing. The median follow-up was 12 months on daily dose and 14 months on alternate dose. Most patients (64%) took fingolimod every other day during alternate dosing. Disease activity was similar on alternate dose compared to daily dose: annualized relapse rate was 0.1 on daily dose vs 0.2 on alternate dose (p = 0.25); proportion of patients with contrast-enhancing MRI lesions was 7.6% on daily vs 9.4% on alternate (p = 0.55); proportion of patients with cumulative MS activity (clinical and radiologic disease) was 13.5% on daily vs 18.2% on alternate (p = 0.337). Patients who developed contrast-enhancing lesions while on daily dose were at higher risk for breakthrough disease while on alternate dose fingolimod (odds ratio 11.4, p < 0.001). CONCLUSIONS: These data support the clinical strategy of alternate dosing of fingolimod in patients with good disease control but profound lymphopenia or other adverse events while on daily dose. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with MS on daily dose fingolimod with adverse events, alternate dose fingolimod is associated with disease activity similar to daily dose fingolimod.

Impact of Cost-Sharing Increases on Continuity of Specialty Drug Use: A Quasi-Experimental Study.

OBJECTIVE: To examine the impact of cost-sharing increases on continuity of specialty drug use in Medicare beneficiaries with multiple sclerosis (MS) or rheumatoid arthritis (RA). DATA SOURCES/STUDY SETTING: Five percent Medicare claims data (2007-2010). STUDY DESIGN: Quasi-experimental study examining changes in specialty drug use among a group of Medicare Part D beneficiaries without low-income subsidies (non-LIS) as they transitioned from a 5 percent cost-sharing preperiod to a ≥25 percent cost-sharing postperiod, as compared to changes among a disease-matched contemporaneous control group of patients eligible for full low-income subsidies (LIS), who faced minor cost sharing (≤$6.30 copayment) in both the pre- and postperiods. DATA COLLECTION/EXTRACTION METHODS: Key variables were extracted from Medicare data. PRINCIPAL FINDINGS: Relative to the LIS group, the non-LIS group had a greater increase in incidence of 30-day continuous gaps in any Part D treatment from the lower cost-sharing period to the higher cost-sharing period (MS, absolute increase = 10.1 percent, OR = 1.61, 95% CI 1.19-2.17; RA, absolute increase = 21.9 percent, OR = 2.75, 95% CI 2.15-3.51). The increase in Part D treatment gaps was not offset by increased Part B specialty drug use. CONCLUSIONS: Cost-sharing increases due to specialty tier-level cost sharing were associated with interruptions in MS and RA specialty drug treatments.

Dimethyl fumarate induces changes in B- and T-lymphocyte function independent of the effects on absolute lymphocyte count.

BACKGROUND: Dimethyl fumarate (DMF) is used to treat relapsing multiple sclerosis and causes lymphopenia in a subpopulation of treated individuals. Much remains to be learned about how the drug affects B- and T-lymphocytes. OBJECTIVES: To characterize changes in B- and T-cell phenotype and function induced by DMF and to investigate whether low absolute lymphocyte count (ALC) is associated with unique functional changes. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from DMF-treated patients, untreated patients, and healthy controls. A subset of DMF-treated patients was lymphopenic (ALC < 800). Multiparametric flow cytometry was used to evaluate cellular phenotypes. Functional response to non-specific and viral peptide stimulation was assessed. RESULTS: DMF reduced circulating memory B-cells regardless of ALC. Follicular T-helper cells (CD4+ CXCR5+) and mucosal invariant T-cells (CD8+ CD161+) were also reduced. DMF reduced T-cell production of pro-inflammatory cytokines in response to polyclonal (PMA/ionomycin) and viral peptide stimulation, regardless of ALC. No differences in activation-induced cell death or circulating progenitors were observed between lymphopenic and non-lymphopenic DMF-treated patients. CONCLUSION: These data implicate DMF-induced changes in lymphocytes as an important component of the drug's efficacy and expand our understanding of the functional significance of DMF-induced lymphopenia.

Binocular low-contrast letter acuity and the symbol digit modalities test improve the ability of the Multiple Sclerosis Functional Composite to predict disease in pediatric multiple sclerosis.

BACKGROUND: Outcome measures to capture disability, such as the Multiple Sclerosis Functional Composite (MSFC), were developed to enhance outcome measurements for clinical trials in adults with multiple sclerosis (MS). The MSFC initially included three components: a timed 25-foot walk [T25FW], 9-hole peg test [9HPT], and the Paced Auditory Serial Addition Task [PASAT]. Modifications to the original MSFC, such as adding binocular low-contrast letter acuity (LCLA) or substituting the symbol digit modalities test (SDMT) for the PASAT, improved the capacity to capture neurologic impairment in adults. Similar outcome scales for pediatric MS have not yet been established. OBJECTIVE: To determine whether the three-component MSFC or a modified MSFC with LCLA and the SDMT better identifies neurological deficits in pediatric MS. METHODS: We evaluated 5 measures (T25FW, 9HPT, Children's PASAT [ChiPASAT], SDMT, and binocular LCLA [Sloan charts, 1.25% contrast]) in children with MS (disease onset <18 years) and healthy controls. To be able to compare measures whose scores have different scales, Z-scores were also created for each test based on the numbers of standard deviations from a control group mean, and these individual scale scores were combined to create composite scores. Logistic regression models, accounting for age, were used to determine whether the standard 3-component MSFC or modified versions (including 4 or 5 metrics) best distinguished children with MS from controls. RESULTS: Twenty pediatric-onset MS subjects, aged 6-21 years, and thirteen healthy controls, aged 6-19 years, were enrolled. MS subjects demonstrated worse scores on the 9HPT (p=0.004) and SDMT (p=0.001), but not the 25FTW (adjusted for height, p=0.63) or the ChiPASAT (p=0.10): all comparisons adjusted for age. Decreased (worse) binocular LCLA scores were associated with MS (vs. control status, p=0.03, logistic regression; p=0.08, accounting for age). The MSFC composite score for the traditional 3 components did not differ between the groups (p=0.28). Replacing the ChiPASAT with the SDMT (OR 0.72, p=0.05) better distinguished MS from controls. A modified MSFC-4 with the SDMT replacing the ChiPASAT and including binocular 1.25% LCLA had the greatest capacity to distinguish pediatric MS from controls (OR 0.89, p=0.04, logistic regression). Including all 5 metrics as a composite MSFC-5 did not improve the model (p=0.18). CONCLUSIONS: A modified MSFC (25FTW, 9HPT, SMDT, and binocular 1.25% LCLA) is more sensitive than the traditional MSFC or its components to capture the subtle impairments that characterize pediatric MS and should be validated in order to be considered for future pediatric MS trials.