Functional outcomes of diets in multiple sclerosis (FOOD for MS): Protocol for a parallel arm randomized feeding trial for low glycemic load and calorie restriction.

BACKGROUND: Pilot trials indicate that both a low glycemic load (GL) diet and calorie restriction (CR) can be implemented successfully in people with multiple sclerosis (pMS) and may improve MS symptoms and physical function, but large randomized clinical trials (RCTs) have not yet been conducted. The purpose of this study is to test these interventions alone and in combination to determine their efficacy for improving clinical and patient reported outcomes (PROs) in pMS. METHODS: This 32-week, two-arm, RCT at two centers will randomly assign 100 adults with relapsing-remitting or secondary progressive MS to a low GL diet (n = 50) or a standard GL diet (n = 50). Both diet groups will complete two study phases: a eucaloric phase (16 weeks) and a CR phase (16 weeks). Groceries for the study meal plans will be delivered to participants' homes weekly. The primary outcome is physical function, measured by timed 25-ft walk test. Secondary outcomes are pain, fatigue, mood, and anxiety. DISCUSSION: This will be the most rigorous intervention trial to date of a low GL diet and CR in adults with MS, and among the first to assess the impact of intentional weight loss on MS symptoms. Results will provide valuable insight for recommending dietary change, weight loss, or both to adults with MS. These non-drug interventions pose few risks and have potential to yield significant improvements in MS symptoms. TRIAL REGISTRATION ID: NCT05327322.

Processing speed and memory test performance are associated with different brain region volumes in Veterans and others with progressive multiple sclerosis.

Background: Cognitive dysfunction and brain atrophy are both common in progressive multiple sclerosis (MS) but are seldom examined comprehensively in clinical trials. Antioxidant treatment may affect the neurodegeneration characteristic of progressive MS and slow its symptomatic and radiographic correlates. Objectives: This study aims to evaluate cross-sectional associations between cognitive battery components of the Brief International Cognitive Assessment for Multiple Sclerosis with whole and segmented brain volumes and to determine if associations differ between secondary progressive (SPMS) and primary progressive (PPMS) MS subtypes. Design: The study was based on a baseline analysis from a multi-site randomized controlled trial of the antioxidant lipoic acid in veterans and other people with progressive MS (NCT03161028). Methods: Cognitive batteries were conducted by trained research personnel. MRIs were processed at a central processing site for maximum harmonization. Semi-partial Pearson's adjustments evaluated associations between cognitive tests and MRI volumes. Regression analyses evaluated differences in association patterns between SPMS and PPMS cohorts. Results: Of the 114 participants, 70% had SPMS. Veterans with MS made up 26% (n = 30) of the total sample and 73% had SPMS. Participants had a mean age of 59.2 and sd 8.5 years, and 54% of them were women, had a disease duration of 22.4 (sd 11.3) years, and had a median Expanded Disability Status Scale of 6.0 (with an interquartile range of 4.0-6.0, moderate disability). The Symbol Digit Modalities Test (processing speed) correlated with whole brain volume (R = 0.29, p = 0.01) and total white matter volume (R = 0.33, p < 0.01). Both the California Verbal Learning Test (verbal memory) and Brief Visuospatial Memory Test-Revised (visual memory) correlated with mean cortical thickness (R = 0.27, p = 0.02 and R = 0.35, p < 0.01, respectively). Correlation patterns were similar in subgroup analyses. Conclusion: Brain volumes showed differing patterns of correlation across cognitive tasks in progressive MS. Similar results between SPMS and PPMS cohorts suggest combining progressive MS subtypes in studies involving cognition and brain atrophy in these populations. Longitudinal assessment will determine the therapeutic effects of lipoic acid on cognitive tasks, brain atrophy, and their associations.

Feasibility and acceptability of time-restricted eating in a group of adults with multiple sclerosis.

Introduction: Intermittent fasting (IF) has become a popular dietary pattern for adults with multiple sclerosis (MS), and initial studies in animal models and human trials indicate promising results for improving symptoms and slowing disease progression. Most studies published to date have focused on alternate day fasting or fasting mimicking diets including a 5:2 pattern, in which participants greatly restrict calorie intake on two non-consecutive days and eat regularly on other days; however, time restricted eating (TRE) may be equally effective for improving symptoms and may lead to better long term adherence due to its focus only on the time of day in which calories are consumed with no restriction on number of calories or types of food consumed. Methods: The purpose of this pilot study was to determine the feasibility and acceptability of a TRE intervention in adults with relapsing remitting MS (RRMS). Participants (n = 12) were instructed to eat all food within an 8-h window every day and fast the remaining 16 h for 8 weeks. Results: The eating pattern was determined to be feasible based on retention rates (n = 11; 92%) and acceptable based on participant feedback. Discussion: Exploratory results of changes in cognition, pain, and fatigue, indicate that further study of TRE in this population is warranted. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04389970; NCT04389970.

Randomized feasibility trial to assess tolerance and clinical effects of lithium in progressive multiple sclerosis.

BACKGROUND: Disability accumulation in progressive multiple sclerosis (MS) results from inflammatory and neurodegenerative mechanisms. In animal models of MS, lithium acts to reduce inflammatory demyelination, and in models of neurodegenerative diseases, lithium also slows neuronal death. Prospective studies of lithium in MS patients have not been previously undertaken. OBJECTIVE: To determine the tolerance and feasibility of using low-dose (150-300 mg/daily) lithium as a pharmaceutical intervention in a cohort of subjects with progressive MS, and to gauge preliminary effects of lithium on change in brain volume over time. METHODS: Patients with primary or secondary progressive MS were recruited into a 2-year, single-blind crossover trial in which subjects were randomly assigned to take lithium in year 1 or 2. The primary outcomes of interest were tolerance of lithium and percentage brain volume change (PBVC) on vs. off lithium. Secondary outcomes included relapse rates, disability changes, and self-report scales assessing fatigue, mood, and quality of life (QOL). RESULTS: Of 24 screened patients, 23 were randomized to take lithium during year 1 (n = 11) or 2 (n = 12). Two subjects discontinued the trial due to lithium side effects. Other reasons for discontinuation included personal reasons (n = 2), worsening MS (n = 1), and development of multiple myeloma (n = 1). For the 17 who completed the trial, change in PBVC on lithium (+0.107) did not significantly differ from the observation period (-0.355, p = 0.346). Disability measured by Expanded Disability Status Scale and MS Functional Composite did not differ by lithium treatment status. On patient reported measures of mental well-being, subjects reported fewer depressive symptoms on the Beck Depression Inventory (12.3 vs. 15.8, p = 0.016) and more favorably on the mental domains of the MSQOL inventory (56.7 vs. 52.4, p = 0.028). CONCLUSIONS: Low-dose lithium is well tolerated in persons with MS. Taking lithium did not result in differences in PBVC, relapses, or disability, but conclusions were limited by study design and sample size. Despite concern for lithium-associated neurological side effects, subjects taking lithium did not report worsened fatigue or physical well-being. On measures of mood and mental health QOL, subjects scored more favorably while taking lithium. CLINICALTRIALSGOV IDENTIFIER: NCT01259388.

The Future of Progressive Multiple Sclerosis Therapies.

INTRODUCTION: Multiple sclerosis (MS) affects more than a million people in the US. A considerable portion of these patients either begin with primary progressive disease or eventually transition to secondary progressive MS. A progressive disease course is the most critical factor affecting disability accumulation. The relatively recent development of treatments for relapsing multiple sclerosis has had a profound impact on the disease course for many with MS. Unfortunately, therapies for progressive MS have not had the same degree of advancement in general. New insights into the pathophysiology of progressive MS may lead to new treatments. OBSERVATIONS: In this review, we identify some of the significant challenges encountered in the development of therapies for progressive MS, assess the evidence for use of currently approved therapies for patients with progressive MS, identify some of the current therapies in development from progressive MS, and consider the role for discontinuing therapy in certain patients. CONCLUSIONS: Developing effective disease modifying therapies that slow or stop the gradual accumulation of neurologic disability in progressive MS represents a critical unmet need. As the understanding of the inflammatory and neurodegenerative aspects of MS are better elucidated there may be opportunity for advancement in the treatment of progressive MS.

Feasibility of improving dietary quality using a telehealth lifestyle intervention for adults with multiple sclerosis.

BACKGROUND: Evidence from observational studies increasingly highlights the association between unhealthy diet and poor health outcomes in adults with multiple sclerosis (MS), but very few intervention trials for dietary change have been completed. Improving diet quality via a low glycemic load (GL) diet has demonstrated improvements in cardiometabolic risks, cognitive risks, and psychosocial variables in diseases other than MS. The purpose of this study was to test the feasibility of delivering a low GL dietary intervention implemented via telehealth in a sample of adults with relapsing remitting MS (RRMS). The secondary purpose was to explore the potential impact of the diet on MS outcomes and cardiometabolic risks. METHODS: Participants followed a low GL diet consisting of 100g of carbohydrate and GL of ≤45 points/1000 kcal daily for 12 weeks. Each participant received weekly calls from a telecoach, education and behavioral supports via weekly emails, and recorded all food intake on a mobile app. Feasibility was measured as time to recruit, retention and study completion, and intervention adherence. An a priori cut point of 80% completion was used to determine feasibility. Exploratory outcomes included the Multiple Sclerosis Functional Composite (MSFC) and patient-reported outcomes of anxiety, pain, mood, and fatigue. Cardiometabolic risks included body composition, fasting glucose, hemoglobin A1c, and blood pressure. RESULTS: Twenty adults with RRMS (85% female, 50% African American) enrolled in the study and n=18 (90%) completed the intervention and follow-up measures. Participants completed 90% of scheduled calls and recorded at least one meal on 82% of intervention days (mean (SD) = 68 (25.5) days). Participants exceeded recommended daily GL reductions (recommended daily GL: 96.66 (12.97) points, reported follow-up daily GL: 90.32 (39.36) points). Timed 25-foot walk test and symbol digit modalities test both changed in the desired direction. Sleep, mood, anxiety, emotional health, and pain all moved in the expected directions, and anxiety (r=.24), pain (r=-.43), and emotional health (r=-.36) were moderately correlated with reductions in GL. Participants lost a mean of 2.93 (6.31, p=.003) kg, and had reductions in both fat and lean mass (fat mass: 1.94 (2.5) kg; lean mass: .72 (1.29) kg). CONCLUSION: A low GL dietary intervention is feasible for adults with RRMS and may lead to improvements in MS outcomes and cardiometabolic risk. Additional research is needed with more tightly controlled feeding trials and larger sample sizes to further understand the impact of this dietary pattern on RRMS.

Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation.

Triggering receptor expressed on myeloid cells 2 (TREM-2) is a membrane-bound receptor expressed by microglia and macrophages. Engagement of TREM-2 on these cells has been reported to reduce inflammatory responses and, in microglial cells, to promote phagocytosis. TREM-2 function is critical within the CNS, as its genetic deficiency in humans causes neurodegeneration with myelin and axonal loss. Blockade of TREM-2 worsened the mouse model for multiple sclerosis. In the present study, a soluble form of TREM-2 protein has been identified by immunoprecipitation and by ELISA. Soluble TREM-2 protein (sTREM-2) was detected in human CSF, and was compared among subjects with relapsing-remitting multiple sclerosis (RR-MS; n = 52), primary progressive multiple sclerosis (PP-MS; n = 21), other inflammatory neurologic diseases (OIND; n = 19), and non-inflammatory neurologic diseases (NIND; n = 41). Compared to NIND subjects, CSF sTREM-2 levels were significantly higher in RR-MS (P = 0.004 by ANOVA) and PP-MS (P < 0.001) subjects, as well as in OIND (P < 0.001) subjects. In contrast, levels of sTREM-2 in blood did not differ among the groups. Furthermore, TREM-2 was detected on a subset of CSF monocytes by flow cytometry, and was also highly expressed on myelin-laden macrophages in eight active demyelinating lesions from four autopsied multiple sclerosis subjects. The elevated levels of sTREM-2 in CSF of multiple sclerosis patients may inhibit the anti-inflammatory function of the membrane-bound receptor suggesting sTREM-2 to be a possible target for future therapies.

Protocol for a systematically-developed, phase I/II, single-blind randomized controlled trial of treadmill walking exercise training effects on cognition and brain function in persons with multiple sclerosis.

Slowed cognitive processing speed (CPS) is a common and debilitating consequence of multiple sclerosis (MS) that is notoriously difficult to treat. As such, we undertook a systematic line of research that indicated that supervised, progressive treadmill walking exercise (TMWX) training might improve CPS and brain functioning among fully-ambulatory persons with MS. The current study will be the first adequately-powered, single-blind randomized controlled trial (RCT) that examines the efficacy of 12-weeks of TMWX training compared with an active control condition on CPS, thalamocortical brain connectivity (based on resting-state fMRI), and exploratory functional outcomes in 88 fully-ambulatory persons with MS who present with slowed CPS. The intervention condition involves supervised, progressive TMWX training 3 times/week over 12-weeks; this initially involves 15-min of light-to-moderate intensity TMWX that progresses up to 40-min of vigorous intensity TMWX. The active control condition involves supervised, minimal intensity, stretching-and-resistance exercise that will be delivered on the same frequency as the intervention condition. The primary study outcomes involve Symbol Digit Modalities Test performance (i.e., CPS) and fMRI-based measures of thalamocortical resting-state functional connectivity. Exploratory study outcomes involve measures of community participation, activities of daily living, quality of life, and functional mobility. All study outcomes will be administered before and after the 12-week study period by treatment-blinded assessors. If successful, the current study will provide the first Class I evidence for the effects of TMWX training as an approach for improving CPS and its neural correlate, and possibly mitigating the impact of slowed CPS on functional outcomes in MS.

Rationale and design of a single-blind, randomised controlled trial of exercise training for managing learning and memory impairment in persons with multiple sclerosis.

INTRODUCTION: This randomised controlled trial (RCT) examines treadmill walking exercise training effects on learning and memory performance, hippocampal volume, and hippocampal resting-state functional connectivity in persons with multiple sclerosis (MS) who have objective impairments in learning new information. METHODS AND ANALYSIS: Forty fully ambulatory persons with MS who demonstrate objective learning and memory impairments will be randomly assigned into either the intervention or active control study conditions. The intervention condition involves supervised, progressive treadmill walking exercise training three times per week for a 3-month period. The active control condition involves supervised, progressive low-intensity resistive exercise that will be delivered at the same frequency as the intervention condition. The primary outcome will involve composite performance on neuropsychological learning and memory tests, and the secondary outcomes involve MRI measures of hippocampal volume and resting-state functional connectivity administered before and after the 3-month study period. Outcomes will be administered by treatment-blinded assessors using alternate test forms to minimise practice effects, and MRI data processing will be performed by blinded data analysts. ETHICS AND DISSEMINATION: This study has been approved by a university institutional review board. The primary results will be disseminated via peer-reviewed publications and the final data will be made available to third parties in applicable data repositories. If successful, the results from this study will eventually inform subsequent RCTs for developing physical rehabilitation interventions (ie, treadmill walking exercise training) for improving learning and memory and its relationship with hippocampal outcomes in larger samples of cognitively impaired persons with MS. The results from this early-phase RCT will further lay preliminary groundwork for ultimately providing clinicians and patients with guidelines for better using chronic treadmill walking exercise for improving cognition and brain health. This approach is paramount as learning and memory impairment is common, burdensome and poorly managed in MS. TRIAL REGISTRATION NUMBER: NCT03319771; Pre-results.

Effect of Template Reporting of Brain MRIs for Multiple Sclerosis on Report Thoroughness and Neurologist-Rated Quality: Results of a Prospective Quality Improvement Project.

PURPOSE: To assess the impact of structured reporting templates on the objective and subjective quality of radiology reports for brain MRIs in patients with multiple sclerosis (MS). METHODS: A HIPAA-compliant prospective quality improvement initiative was undertaken to develop and implement a 12-item structured reporting template for brain MRI examinations in patients with known or suspected MS based on published guidelines. Reports created 1 year before implementing the template served as the baseline. A random sample of 10 template and 10 non-template reports was sent to five neurologists outside the study institution with MS expertise, who reviewed the reports for comprehensiveness and quality. The number of MS-relevant elements in template and non-template reports were compared with unpaired t tests. Proportions were compared with χ2 and Fisher exact tests. RESULTS: There were 63 reports in the pre-template period and 93 reports in the post-template period. Use of the template increased over time in the post-template period (P = .04). All 12 MS-relevant findings were addressed more often and with less variability in template reports: (11.1 ± 0.7 findings versus 5.8 ± 2.2 findings in non-template reports, P < .001). Neurologists were more likely to give the template reports the highest positive rating (56% [107/190] versus 28% [56/199], P < .001) and less likely to give the template reports a lower rating (7% [13/190] versus 15% [29/199], P = .01) compared with the non-template reports. CONCLUSION: Template reporting of brain MRI examinations increases the rate at which MS-relevant findings are included in the report. Standardized reports are preferred by neurologists with MS expertise.

Symptomatic Management of Multiple Sclerosis-Associated Tremor Among Participants in the NARCOMS Registry.

BACKGROUND: Tremor affects 25% to 58% of patients with multiple sclerosis (MS) and is associated with poor prognosis and increased disability. MS-related tremor is difficult to treat, and data regarding patient-reported characterization and response to treatment are limited. We describe the symptomatic treatment of tremor in 508 enrollees in the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry who self-reported tremor. METHODS: From 777 surveys sent to NARCOMS participants who indicated mild or greater tremor using the Tremor and Coordination Scale, we compiled data regarding disability, tremor severity, symptomatic medication use, and reported response to medications. RESULTS: Symptomatic medications reported to reduce tremor were used by 238 respondents (46.9%). Symptomatic medication use was associated with increased rates of unemployment and disability, and many other characteristics were similar between groups. Symptomatic drug use was more likely in participants reporting moderate (53.9%) or severe (51.3%) tremor than in those with mild (36.6%) or totally disabling (35.0%) tremor. This disparity held true across multiple tremor severity scores. The most commonly used drug classes were anticonvulsants (50.8%) and benzodiazepines (46.2%), with gabapentin and clonazepam used most often in their respective classes. CONCLUSIONS: Tremor in MS remains poorly treated; less than half of the participants reported benefit from symptomatic medications. Patients with moderate-to-severe tremor are more likely to report tremor benefit than are those with mild or disabling tremor. γ-Aminobutyric acid-active medications were most commonly reported as beneficial.

Prevalence and characteristics of tremor in the NARCOMS multiple sclerosis registry: a cross-sectional survey.

OBJECTIVES: (1)To describe the prevalence and severity of tremor in patients with multiple sclerosis (MS) registered within a large North American MS registry; (2) to provide detailed descriptions on the characteristics and severity of tremor in a subset of registrants and (3) to compare several measures of tremor severity for strength of agreement. SETTING: The North American Research Committee on MS (NARCOMS) registry. PARTICIPANTS: Registrants of NARCOMS reporting mild or greater tremor severity. OUTCOME MEASURES: We determined the cross-sectional prevalence of tremor in the NARCOMS registry over three semiannual updates between fall 2010 and fall 2011. A subset of registrants (n=552) completed a supplemental survey providing detailed descriptions of their tremor. Outcomes included descriptive characteristics of their tremors and correlations between outcome measures to determine the strength of agreement in assessing tremor severity. RESULTS: The estimated prevalence of tremor in NARCOMS ranged from 45% to 46.8%, with severe tremor affecting 5.5-5.9% of respondents. In the subset completing the supplemental survey, mild tremor severity was associated with younger age of MS diagnosis and tremor onset than those with moderate or severe tremor. However, tremor severity did not differ by duration of disease or tremor. Respondents provided descriptions of tremor symptoms on the Clinical Ataxia Rating Scale, which had a moderate to good (ρ=0.595) correlation with the Tremor Related Activities of Daily Living (TRADL) scale. Objectively scored Archimedes' spirals had a weaker (ρ=0.358) correlation with the TRADL. Rates of unemployment, disability and symptomatic medication use increased with tremor severity, but were high even among those with mild tremor. CONCLUSIONS: Tremor is common among NARCOMS registrants and severely disabling for some. Both ADL-based and symptom-descriptive measures of tremor severity can be used to stratify patients.

Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab.

BACKGROUND: Tremor is among the most physically disabling symptoms associated with MS. The effect of MS disease modifying therapies (DMTs) on the severity of MS tremor is unclear. OBJECTIVE: To compare the change over time in scores reflecting tremor severity between subjects treated with natalizumab and other disease modifying drugs. METHODS: Questionnaires were sent to North American Research Committee on MS registrants reporting mild or greater tremor on semiannual updates. Respondents on natalizumab and other MS therapies completed a survey which included tremor-specific scales to indicate tremor severity both currently and when the current therapy was initiated. Differences between natalizumab and non-natalizumab groups were compared using ANOVA. RESULTS: Surveys were returned by 567 registrants, including 202 taking natalizumab. Subjects on natalizumab were more likely to report tremor improvement (29.6%) than those never (15.2%) or previously (14.8%, p=0.0002) on natalizumab. Over a mean recall period of 6.2+4.6 years, the Tremor Related Activities of Daily Living score worsened by 1.8 points among natalizumab-treated subjects, 3.3 points among those previously on natalizumab, and 5.3 points among those who never took natalizumab (p=0.009). CONCLUSION: Respondents taking natalizumab were more likely to experience tremor improvement than those taking other MS disease modifying therapies.

A retrospective review of lithium usage in veterans with multiple sclerosis.

OBJECTIVE: Lithium (Li) reduces disease activity in animal models of multiple sclerosis (MS), but has not been previously studied in human MS. While developing a clinical trial to test the effects of Li in MS, we performed a retrospective chart review to determine the safety and tolerability of Li among US veterans with MS. METHODS: We identified all veterans with MS prescribed Li from 1998 to 2009 using the Department of Veterans Affairs Pharmacy Benefits Management. Charts were reviewed for Li-related adverse events and effects on the MS disease course. RESULTS: Among 21,847 veterans with MS, 101 met inclusion criteria and took Li ≥6 months. Eighteen percent of subjects experienced a Li-associated adverse event. Later age of MS onset was associated with increased risk of Li-related adverse events (p=0.004). Associations between Li use and MS disease activity were mixed: Li was not associated with increased risk of enhancing MRI lesions (p=0.655), but annualized relapse rates were higher on Li (0.34 vs. 0.20, p=0.044). In contrast, change in Expanded Disability Status Scale scores was greater in the off-Li period than the on-Li period (0.8 vs. 0.3, p=0.003). CONCLUSION: Adverse events occur in a minority of Li-treated MS patients. A consistent effect of Li on MS disease activity was not apparent. These findings indicate a clinical trial will be needed to ascertain Li's effects on the MS disease course.

Multiple sclerosis therapies in pediatric patients with refractory multiple sclerosis.

BACKGROUND: Currently available disease-modifying therapies (DMTs) are known to be only partially effective in adults with multiple sclerosis (MS). Little is known about pediatric patients with MS who experience refractory disease while receiving first-line DMTs. OBJECTIVE: To assess the occurrence and management of refractory disease in a group of pediatric patients with MS treated with first-line DMTs approved for adult patients within a network of pediatric MS centers in the United States. DESIGN, SETTING, AND PATIENTS: A multicenter, retrospective, longitudinal, open-label study design involving record review of 258 patients with pediatric-onset MS (68.6% female; mean [SD] age at disease onset, 13.2 [3.5] years; range of age at onset, 2.0-17.9 years) who were seen at 6 pediatric MS centers in the United States. INTERVENTION: We evaluated medication changes owing to refractory disease in cases of pediatric-onset MS. MAIN OUTCOME MEASURE: Disease stability as represented by lack of medication change for breakthrough disease. RESULTS: Records of 258 children with a confirmed diagnosis of MS and exposure to DMTs were reviewed. Interferon beta (prescribed to 200 of 258 children [77.5%]) and glatiramer acetate (prescribed to 53 of 258 children [20.5%]) were the 2 most frequently used first-line DMTs. Overall, 144 children (55.8%) continued receiving 1 therapy, while 65 (25.2%), 29 (11.2%), and 20 (7.8%) received 2, 3, or 4 or more sequential therapies, respectively, during a mean (SD) observation period of 3.9 (2.8) years. Second-line DMT use was restricted to interferon beta and glatiramer acetate in 203 children (78.7%), whereas other treatments such as broad-spectrum chemotherapies (cyclophosphamide, mitoxantrone hydrochloride), natalizumab, corticosteroids (monthly), and daclizumab were used at some point during the observation period for disease management in 55 children (21.3%). Hispanic children were more likely to experience breakthrough disease while receiving first-line DMTs than non-Hispanic children. CONCLUSION: Although switching between first-line DMTs may be effective in pediatric patients with disease that is refractory to initial treatment, a subset of patients may require second-line therapeutic interventions.

Candidate gene analysis of selectin cluster in patients with multiple sclerosis.

Three single nucleotide polymorphisms (SNPs) with a potential impact on the function of selectins (rs6133, rs4987310 and rs5368 substitutions localized in the coding regions of P-sel, L-sel and E-sel, respectively) were analyzed in an Italian population of 165 patients with multiple sclerosis (MS) as compared with 149 controls and in a replication American population of Caucasian descent consisting of 122 patients and 50 controls. No significant differences in either allelic or genotypic frequency in all the SNPs tested were found in the Italian population. A tendency to an increased frequency of the rs6133 T allele was observed in the American population, but applying the Bonferroni correction the significance threshold was not reached. Haploview analysis demonstrated that rs4987310 and rs5368 markers are in strong LD (D' = 0.97) in both populations. Combining the two SNPs, we found no difference in haplotype distribution in patients compared with controls, either in Italian or in American population. Despite the fact that selectins play a role in the pathogenesis of MS and their encoding genes are located in regions associated with the disease, the selectin gene cluster studied likely does not influence the susceptibility to MS in Caucasians.

Higher IgG index found in African Americans versus Caucasians with multiple sclerosis.

BACKGROUND: African Americans (AAs) experience greater disability from multiple sclerosis (MS) compared with Caucasian Americans (CAs). Interethnic immunologic differences in MS and their relationship to disease-related disability have not been described. OBJECTIVE: To compare measures of CSF humoral immunity between AAs and CAs with MS. METHODS: Using a case-control design, all AA MS patients with CSF immune studies at the Washington University MS center were compared with randomly selected CAs with MS. Two CA controls were selected for every AA case. Immunoglobulin G (IgG) index and synthesis rates, oligoclonal band positivity, white blood cell count, and CSF protein were compared between groups. Survival analysis was conducted to compare times to ambulatory assistance. RESULTS: Sixty-six AA cases and 132 CA controls were identified. Measures of CSF humoral activity were all higher in the AA group. The mean IgG index of AAs was 1.35 (SD 0.62), and that of CAs was 1.05 (SD 0.55), for a mean difference of 0.30 (p = 0.001). The median IgG synthesis rate was also higher among AAs (13.55 vs 8.20 mg/day), for a median difference of 5.35 mg/day (p = 0.010). Survival analysis confirmed previous reports of earlier ambulatory assistance requirement among AAs. Despite differences in both humoral immune response and times to ambulatory assistance, Cox proportional hazards modeling did not show IgG index as predictive of earlier ambulatory assistance. CONCLUSIONS: The CSF humoral immune response is more active among African Americans (AAs) than among Caucasian Americans (CAs) with multiple sclerosis. AAs also progress to ambulatory assistance earlier than CAs, but high immunoglobulin G index does not predict earlier progression to the disability endpoint.

Elevated CSF free kappa light chains correlate with disability prognosis in multiple sclerosis.

Elevated CSF free kappa light chains (FKLCs) may predict disability in multiple sclerosis (MS). We reviewed records of 57 patients with MS with 15-year median follow-up for correlations of disability and CSF FKLCs. Levels > or = 1.53 microg/mL predicted progression to need for ambulatory assistance during follow-up (specificity 87.5%, positive predictive value 88.9%) or within 10 years (specificity 78.6%, positive predictive value 66.7%).