A new look at cognitive functioning in pediatric MS.

OBJECTIVE: Cognitive involvement in pediatric multiple sclerosis (MS) relative to adult MS is less defined. This study advances our understanding by measuring cognitive performances in pediatric MS, adult MS, and pediatric healthy controls. METHODS: Consecutive relapsing pediatric MS participants from the United States Network of Pediatric MS Centers were compared with pediatric healthy controls and adults with relapsing MS. Participants were compared on two screening batteries: the Brief International Cognitive Assessment for MS and the Cogstate Brief Battery. Results were transformed to age-normative z scores. RESULTS: The pediatric groups (MS vs. Healthy Controls) did not differ on either battery's composite mean score or individual test scores (ps > 0.32), nor in the proportions impaired on either battery, Brief International Cognitive Assessment for MS (26% vs. 24%, p = 0.83); Cogstate Brief Battery (26% vs. 32%, p = 0.41). The pediatric versus adult MS group even after controlling for differences in disease duration performed better on the Brief International Cognition Assessment for MS composite (p = 0.03), Symbol Digit Modalities Test (p = 0.02), Rey Auditory Verbal Learning Test (p = 0.01), and Cogstate choice reaction time (p < 0.001). CONCLUSION: Pediatric MS patients do not differ from healthy pediatric controls on cognitive screens but perform better than adults with MS.

Cognitive processing speed in pediatric-onset multiple sclerosis: Baseline characteristics of impairment and prediction of decline.

BACKGROUND: Cognitive impairment occurs in approximately one-third of pediatric-onset multiple sclerosis (POMS) patients. The Symbol Digit Modalities Test (SDMT), a widely used cognitive screen in adults, has yet to be incorporated early into the standard care of POMS. OBJECTIVE: To screen for cognitive impairment early in the course of POMS and analyze predictive factors. METHODS: Of the 955 POMS or clinically isolated syndrome (CIS) patients prospectively assessed from March 2014 to July 2018, 500 POMS and 116 CIS patients met inclusion criteria (disease onset before the age of 18, one or more SDMTs, and 8 years or older at the time of testing). Those with relapse were analyzed separately from those who were relapse-free. RESULTS: At initial assessment, the mean (interquartile range (IQR)) age at symptom onset was 13.5 years (12.0, 15.9) and the mean (±SD) disease duration was 3.0 ± 2.9 years. Impaired processing speed occurred in 23.4% of POMS and in 16.4% of CIS. On serial testing (n = 383, mean follow-up: 1.8 years), 14.1% had clinically meaningful decline predicted by older age of multiple sclerosis (MS) onset and male gender. Disease relapse or steroid use led to transient worsening on the SDMT. CONCLUSION: Early in the disease, some POMS and CIS patients are at risk for cognitive impairment and subsequent decline.

Remotely supervised transcranial direct current stimulation for the treatment of fatigue in multiple sclerosis: Results from a randomized, sham-controlled trial.

BACKGROUND: Fatigue is a common and debilitating feature of multiple sclerosis (MS) that remains without reliably effective treatment. Transcranial direct current stimulation (tDCS) is a promising option for fatigue reduction. We developed a telerehabilitation protocol that delivers tDCS to participants at home using specially designed equipment and real-time supervision (remotely supervised transcranial direct current stimulation (RS-tDCS)). OBJECTIVE: To evaluate whether tDCS can reduce fatigue in individuals with MS. METHODS: Dorsolateral prefrontal cortex left anodal tDCS was administered using a RS-tDCS protocol, paired with 20 minutes of cognitive training. Here, two studies are considered. Study 1 delivered 10 open-label tDCS treatments (1.5 mA; n = 15) compared to a cognitive training only condition ( n = 20). Study 2 was a randomized trial of active (2.0 mA, n = 15) or sham ( n = 12) delivered for 20 sessions. Fatigue was assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue Short Form. RESULTS AND CONCLUSION: In Study 1, there was modest fatigue reduction in the active group (-2.5 ± 7.4 vs -0.2 ± 5.3, p = 0.30, Cohen's d = -0.35). However, in Study 2 there was statistically significant reduction for the active group (-5.6 ± 8.9 vs 0.9 ± 1.9, p = 0.02, Cohen's d = -0.71). tDCS is a potential treatment for MS-related fatigue.

Cognitive impairment in pediatric-onset multiple sclerosis is detected by the Brief International Cognitive Assessment for Multiple Sclerosis and computerized cognitive testing.

BACKGROUND: Cognitive impairment is a common and troubling feature of pediatric-onset multiple sclerosis (POMS). Brief cognitive assessment in the outpatient setting can identify and longitudinally monitor cognitive involvement so that early intervention is possible. OBJECTIVES: The goal of this study was to measure the sensitivity of two cognitive assessment approaches that are brief, repeatable, and suitable for clinical practice and for multicenter investigation. METHODS: Participants with POMS ( n = 69) were consecutively evaluated as part of outpatient neurologic visits and compared to healthy control participants (HC, n = 66) using the Brief International Cognitive Assessment for MS (BICAMS) approach and timed information processing measures from Cogstate, a computer-based assessment. RESULTS: There was strong agreement in the detection rate of impairment between both assessments, with 26% for the BICAMS and 27% for Cogstate. Two of the Cogstate tasks were the most sensitive individual measures. CONCLUSION: Both the BICAMS and Cogstate timed processing measures offer practical, sensitive, and standardized approaches for cognitive screening assessment in POMS.

Neuropsychology of Multiple Sclerosis: Looking Back and Moving Forward.

The neuropsychological aspects of multiple sclerosis (MS) have evolved over the past three decades. What was once thought to be a rare occurrence, cognitive dysfunction is now viewed as one of the most disabling symptoms of the disease, with devastating effects on patients' quality of life. This selective review will highlight major innovations and scientific discoveries in the areas of neuropathology, neuroimaging, diagnosis, and treatment that pertain to our understanding of the neuropsychological aspects of MS. Specifically, we focus on the recent discovery that MS produces pathogical lesions of gray matter (GM) that have consequences for cognitive functions. Methods for imaging these GM lesions in MS are discussed along with multimodal imaging studies that integrate structural and functional imaging methods to provide a better understanding of the relationship between cognitive test performance and functional reserve. Innovations in the screening and comprehensive assessment of cognitive disorders are presented along with recent research that examines cognitive dysfunction in pediatric MS. Results of innovative outcome studies in cognitive rehabilitation are discussed. Finally, we highlight trends for potential future innovations over the next decade. (JINS, 2017, 23, 832-842).

Genetic predictors of relapse rate in pediatric MS.

BACKGROUND: Genetic ancestry, sex, and individual alleles have been associated with multiple sclerosis (MS) susceptibility. OBJECTIVE: To determine whether established risk factors for disease onset are associated with relapse rate in pediatric MS. METHODS: Whole-genome genotyping was performed for 181 MS or high-risk clinically isolated syndrome patients from two pediatric MS centers. Relapses and disease-modifying therapies were recorded as part of continued follow-up. Participants were characterized for 25-hydroxyvitamin D serum status. Ancestral estimates (STRUCTURE v2.3.1), human leukocyte antigen (HLA)-DRB1*15 carrier status (direct sequencing), sex, and a genetic risk score (GRS) of 110 non-HLA susceptibility single-nucleotide polymorphisms (SNPs) were evaluated for association with relapse rate with Cox and negative binomial regression models. RESULTS: Over 622 patient-years, 408 relapses were captured. Girls had greater relapse rate than boys (incident rate ratio (IRR) = 1.40, 95% confidence interval (CI) = 1.04-1.87, p = 0.026). Participants were genetically diverse; ~40% (N = 75) had <50% European ancestry. HLA-DRB1*15 status modified the association of vitamin D status (pixn = 0.022) with relapse rate (per 10 ng/mL, in DRB1*15+ hazard ratio (HR) = 0.72, 95% CI = 0.58-0.88, p = 0.002; in DRB1*15- HR = 0.96, 95% CI = 0.83-1.12, p = 0.64). Neither European ancestry nor GRS was associated with relapse rate. CONCLUSION: We demonstrate that HLA-DRB1*15 modifies the association of vitamin D status with relapse rate. Our findings emphasize the need to pursue disease-modifying effects of MS genes in the context of environmental factors.

Neuropsychological correlates of multiple sclerosis across the lifespan.

Multiple sclerosis can adversely affect cognitive functioning whether the disease has an adult or pediatric onset. The research thus far suggests that pediatric MS shares many features with adult MS but is also unique in several respects. One particular characteristic of pediatric MS is that, while physical disability develops more slowly as compared with adult patients, the impact of cognitive deficits in children may be more substantial as they are in a period of life during which they acquire many skills that are needed to transition into independently functioning adults. Our review takes a lifespan approach to MS, comparing and contrasting the neuropsychology (i.e., cognitive, psychological, and psychosocial factors) of these two populations. Understanding how MS manifests across the lifespan has important implications for tailoring assessment and treatment for individuals with MS as they transition from childhood to adulthood, and later life.

Relapsing White Matter Disease and Subclinical Optic Neuropathy: From the National Multiple Sclerosis Society Case Conference Proceedings

A 16-year-old adolescent boy presented with recurrent episodes of weakness and numbness. Brain MRI demonstrated subcortical, juxtacortical, and periventricular white matter T2 hyperintensities with gadolinium enhancement. CSF was positive for oligoclonal bands that were not present in serum. Despite treatment with steroids, IV immunoglobulins, plasmapheresis, and rituximab, he continued to have episodes of weakness and numbness and new areas of T2 hyperintensity on imaging. Neuro-ophthalmologic examination revealed a subclinical optic neuropathy with predominant involvement of the papillomacular bundle. Genetic evaluation and brain biopsy led to an unexpected diagnosis.

Metabolomic approach to human brain spectroscopy identifies associations between clinical features and the frontal lobe metabolome in multiple sclerosis.

Proton magnetic resonance spectroscopy ((1)H-MRS) is capable of noninvasively detecting metabolic changes that occur in the brain tissue in vivo. Its clinical utility has been limited so far, however, by analytic methods that focus on independently evaluated metabolites and require prior knowledge about which metabolites to examine. Here, we applied advanced computational methodologies from the field of metabolomics, specifically partial least squares discriminant analysis and orthogonal partial least squares, to in vivo (1)H-MRS from frontal lobe white matter of 27 patients with relapsing-remitting multiple sclerosis (RRMS) and 14 healthy controls. We chose RRMS, a chronic demyelinating disorder of the central nervous system, because its complex pathology and variable disease course make the need for reliable biomarkers of disease progression more pressing. We show that in vivo MRS data, when analyzed by multivariate statistical methods, can provide reliable, distinct profiles of MRS-detectable metabolites in different patient populations. Specifically, we find that brain tissue in RRMS patients deviates significantly in its metabolic profile from that of healthy controls, even though it appears normal by standard MRI techniques. We also identify, using statistical means, the metabolic signatures of certain clinical features common in RRMS, such as disability score, cognitive impairments, and response to stress. This approach to human in vivo MRS data should promote understanding of the specific metabolic changes accompanying disease pathogenesis, and could provide biomarkers of disease progression that would be useful in clinical trials.

International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions.

BACKGROUND: There has been tremendous growth in research in pediatric multiple sclerosis (MS) and immune mediated central nervous system demyelinating disorders since operational definitions for these conditions were first proposed in 2007. Further, the International Pediatric Multiple Sclerosis Study Group (IPMSSG), which proposed the criteria, has expanded substantially in membership and in its international scope. OBJECTIVE: The purpose of this review is to revise the 2007 definitions in order to incorporate advances in delineating the clinical and neuroradiologic features of these disorders. METHODS: Through a consensus process, in which input was sought from the 150 members of the Study Group, criteria were drafted, revised and finalized. Final approval was sought through a web survey. RESULTS: Revised criteria are proposed for pediatric acute disseminated encephalomyelitis, pediatric clinically isolated syndrome, pediatric neuromyelitis optica and pediatric MS. These criteria were approved by 93% or more of the 56 Study Group members who responded to the final survey. CONCLUSIONS: These definitions are proposed for clinical and research purposes. Their utility will depend on the outcomes of their application in prospective research.

It's not always an infection: Pyoderma gangrenosum of the urogenital tract in two patients with multiple sclerosis treated with rituximab.

B-cell depleting therapies such as rituximab and ocrelizumab are widely used for the treatment of Multiple Sclerosis but have increased risks of adverse reactions compared to earlier MS therapies. One rarely reported reaction is pyoderma gangrenosum (PG), an inflammatory, ulcerative, skin disease of unclear etiology. Here we describe a male and female patient, each with Relapsing-Remitting Multiple Sclerosis, and both of whom developed PG while on rituximab. Both PG diagnoses were supported by persistent fever, biopsy reports of sterile neutrophilia, and leukocytosis in the absence of an identifiable infectious agent. The diagnoses were further confirmed by dramatic clinical improvement following initiation of high dose steroids and intravenous immunoglobulins, and discontinuation of rituximab.

Agreement Between Published Reference Resources for Neurofilament Light Chain Levels in People With Multiple Sclerosis.

OBJECTIVES: To examine the agreement between published reference resources for neurofilament light chain (NfL) applied to a large population of people with multiple sclerosis (MS). METHODS: Six published reference resources were used to classify NfL in participants in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network as elevated or normal and to derive age-specific NfL Z-scores. NfL values were classified as elevated if they exceeded the >95th percentile (i.e., Z-score >1.645) of the age-specific reference range. Furthermore, age-specific NfL Z-scores could be derived for 4 of 6 reference resources. RESULTS: NfL measurements were assessed from 12,855 visits of 6,687 people with MS (median 2 samples per individual [range 1-7]). The mean ± SD age was 47.1 ± 11.7 years, 72.1% of participants were female, disease duration was 15.0 ± 10.6 years, body mass index was 28.6 ± 6.9 kg/m2, and serum NfL was 12.87 ± 12.86 pg/mL. Depending on the selection of the reference resource, the proportion of NfL measurements classified as elevated varied from 3.7% to 30.9%. The kappa coefficient across the 6 reference resources used was 0.576 (95% CI 0.571-0.580) indicating moderate agreement. Spearman correlations between Z-scores derived from the various reference resources exceeded 0.90; however, concordance coefficients were lower, ranging from 0.72 to 0.89. DISCUSSION: Interpretation of blood NfL values may vary markedly depending on the selection of the reference resource. Borderline elevated values should be interpreted with caution, and future studies should focus on standardizing NfL measurement and reporting across laboratories/platforms, better characterizing the effects of confounding/influencing factors, and defining the performance of NfL (including as part of multimodal predictive algorithms) for prediction of disease-specific outcomes.

Associations of sNfL with clinico-radiological measures in a large MS population.

OBJECTIVE: Evaluation of serum neurofilament light chain (sNfL), measured using high-throughput assays on widely accessible platforms in large, real-world MS populations, is a critical step for sNfL to be utilized in clinical practice. METHODS: Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) is a network of healthcare institutions in the United States and Europe collecting standardized clinical/imaging data and biospecimens during routine clinic visits. sNfL was measured in 6974 MS and 201 healthy control (HC) participants, using a high-throughput, scalable immunoassay. RESULTS: Elevated sNfL levels for age (sNfL-E) were found in 1238 MS participants (17.8%). Factors associated with sNfL-E included male sex, younger age, progressive disease subtype, diabetes mellitus, impaired renal function, and active smoking. Higher body mass index (BMI) was associated with lower odds of elevated sNfL. Active treatment with disease-modifying therapy was associated with lower odds of sNfL-E. MS participants with sNfL-E exhibited worse neurological function (patient-reported disability, walking speed, manual dexterity, and cognitive processing speed), lower brain parenchymal fraction, and higher T2 lesion volume. Longitudinal analyses revealed accelerated short-term rates of whole brain atrophy in sNfL-E participants and higher odds of new T2 lesion development, although both MS participants with or without sNfL-E exhibited faster rates of whole brain atrophy compared to HC. Findings were consistent in analyses examining age-normative sNfL Z-scores as a continuous variable. INTERPRETATION: Elevated sNfL is associated with clinical disability, inflammatory disease activity, and whole brain atrophy in MS, but interpretation needs to account for comorbidities including impaired renal function, diabetes, and smoking.

Multiple white matter tract abnormalities underlie cognitive impairment in RRMS.

Diffusion tensor imaging (DTI) is a sensitive tool for detecting microstructural tissue damage in vivo. In this study, we investigated DTI abnormalities in individuals with relapsing remitting multiple sclerosis (RRMS) and examined the relations between imaging-based measures of white matter injury and cognitive impairment. DTI-derived metrics using tract-based spatial statistics (TBSS) were compared between 37 individuals with RRMS and 20 healthy controls. Cognitive impairment was assessed with three standard tests: the Symbol Digit Modalities Test (SDMT), which measures cognitive processing speed and visual working memory, the Rey Auditory Verbal Learning Test (RAVLT), which examines verbal memory, and the Paced Auditory Serial Addition Test (PASAT), which assesses sustained attention and working memory. Correlations between DTI-metrics and cognition were explored in regions demonstrating significant differences between the RRMS patients and the control group. Lower fractional anisotropy (FA) was found in RRMS participants compared to controls across the tract skeleton (0.40 ± 0.03 vs. 0.43 ± 0.01, p<0.01). In areas of reduced FA, mean diffusivity was increased and was dominated by increased radial diffusivity with no significant change in axial diffusivity, an indication of the role of damage to CNS myelin in MS pathology. In the RRMS group, voxelwise correlations were found between FA reduction and cognitive impairment in cognitively-relevant tracts, predominantly in the posterior thalamic radiation, the sagittal stratum, and the corpus callosum; the strongest correlations were with SDMT measures, with contributions to these associations from both lesion and normal-appearing white matter. Moreover, results using threshold-free cluster enhancement (TFCE) showed more widespread white matter involvement compared to cluster-based thresholding. These findings indicate the important role for DTI in delineating mechanisms underlying MS-associated cognitive impairment and suggest that DTI could play a critical role in monitoring the clinical and cognitive effects of the disease.

Unemployment in multiple sclerosis: the contribution of personality and disease.

BACKGROUND: Multiple sclerosis (MS) is the leading cause of neurological disability among young and middle-aged adults. One of the most devastating consequences of MS in this relatively young population group is unemployment. Although certain demographic and disease factors have been associated with employment, few studies have examined the contribution of person-specific factors, such as personality. OBJECTIVE: The goal of this study was to determine the extent to which personality, demographics, and clinical measures contribute to unemployment in MS. METHOD: A total of 101 individuals with MS who were enrolled in a clinical trial on cognition underwent a brief neuropsychological battery and completed questionnaires related to vocation, mood, fatigue, and personality. Neurological impairment was measured with the Expanded Disability Status Scale (EDSS). RESULTS: Employment status was related with disease duration, MS subtype, level of neurological impairment, fatigue, performance on measures assessing information processing speed (Symbol Digit Modalities Test (SDMT)), learning and memory (Selective Reminding Test), and the personality characteristic of persistence. Based on a forward logistic regression analysis, EDSS, SDMT, and persistence were the strongest predictors of employment status. CONCLUSIONS: These findings underscore the importance of personality on outcomes in MS and point to the need for more clinical attention and research in this area.

A novel disease specific scale to characterize the symptoms and impacts of fatigue in US adults with relapsing multiple sclerosis: A real-world study.

BACKGROUND: Fatigue is among the most frequent and disabling symptoms in patients with relapsing multiple sclerosis (RMS). OBJECTIVE: To measure MS fatigue and its impact on daily life in a real-world US population using an MS-specific patient-reported outcome (PRO) instrument, the Fatigue Symptoms and Impacts Questionnaire-RMS (FSIQ-RMS). METHODS: This ongoing prospective study recruited RMS patients from an online patient community (Carenity) across US. Baseline assessment data are reported. Participants completed questionnaires, including the 20-item FSIQ-RMS questionnaire, with the first seven symptom-related items collected daily for seven days, and the other 13 items on the seventh day assessing impacts of fatigue. The FSIQ-RMS scores range from 0 to 100 (higher score=greater severity). The impact of fatigue on several aspects of patients' lives was rated from 0 (no impact) to 10 (very high impact). Data on disease history, disease status, sleep, social and emotional functioning were also captured. Baseline assessment data of 300 RMS patients are reported while follow-up assessments up to 18 months are planned. RESULTS: 300 RMS participants completed the 7-day assessment (mean age 43.0 years, 88% women). Fatigue was rated as severe, with a mean score of 57.3 for the FSIQ-RMS symptom domain; 3 impact sub-domain scores were 42.3, 43.4 and 50.1 (physical, cognitive/emotional, and coping). Participants who were not in relapse (78%) reported less severe fatigue than those in relapse (22%): mean±SD symptom score of 54.6 ± 17.8 vs. 67.0 ± 19.7, p< 0.001. Fatigue had a higher intensity among those with depression than without (49% vs. 51%, with mean ± SD symptom score of 62.8 ± 16.9 vs. 52.1 ± 19.3, p< 0.001), and among those with sleep disorder than without (27% vs. 73%, 61.2 ± 19.2 vs. 55.9 ± 18.6; p< 0.05). The most common factor associated with increased fatigue was heat exposure (82%). Most participants (52%) reported experiencing fatigue before their MS diagnosis. CONCLUSION: Fatigue influences daily functioning for most patients with RMS. The FSIQ-RMS is a novel and MS-specific PRO measure that can advance the understanding and management of fatigue.

No difference in radiologic outcomes for natalizumab patients treated with extended interval dosing compared with standard interval dosing: Real-world evidence from MS PATHS.

BACKGROUND: Extended interval dosing (EID; average dosing interval approximately every 6 weeks) of natalizumab is associated with significantly lower risk of progressive multifocal leukoencephalopathy than standard interval dosing (SID; every 4 weeks) in patients with relapsing-remitting multiple sclerosis (MS). Real-world studies, though limited, suggest that natalizumab effectiveness is generally maintained in patients who switch to EID after initiation of stable treatment with SID. MS PATHS (Multiple Sclerosis Partners Advancing Technology and Health Solutions) is a collaborative, multicenter learning health system that generates real-world clinical and MRI data using highly standardized acquisition protocols. We compared MRI outcomes in MS PATHS patients treated with natalizumab EID versus SID. We also compared MRI outcomes in patients treated with natalizumab (EID and/or SID) versus injectable MS platform therapy. METHODS: Natalizumab infusion data from the TOUCH Prescribing Program database and MS PATHS MRI assessment data from seven US sites as of July 23, 2020, were used to identify patients with relapsing-remitting MS who had received natalizumab EID or SID in the interval between two MRI scans (an MRI segment). Patients who received injectable platform MS therapy between two MRI scans were also identified. MRI data were used to determine the incidence rate and odds of developing new or enlarging T2 lesions, annualized percentage change in T2 lesion volume (T2LV), and annualized percentage change in brain parenchymal fraction (BPF). MRI outcomes were compared for 1) natalizumab EID treatment versus natalizumab SID treatment, 2) natalizumab treatment (EID + SID) versus platform therapy, and 3) natalizumab EID versus platform therapy. Propensity score-based weighting or matching were used to balance covariates at the start of MRI segments for all comparisons. RESULTS: The MRI outcomes observed with natalizumab EID treatment did not differ significantly from those observed with natalizumab SID treatment. The odds ratio for any new or enlarging T2 lesion was 1.07 (95% confidence interval [CI]: 0.93, 1.24; p = 0.355), and the rate ratio (95% CI) for new or enlarging T2 lesions was 1.62 (0.93, 2.82; p = 0.090). Differences (95% CI) between EID and SID patients in mean annualized percentage change in T2LV and BPF were 1.56% (-3.77%, 6.90%; p = 0.566) and -0.11% (-0.25%, -0.10%; p = 0.096), respectively. Conversely, when MRI outcomes in natalizumab and platform therapy patients were compared, there were significant differences favoring natalizumab in all assessments: the odds of any new or enlarging T2 lesion (odds ratio: 0.69 [95% CI: 0.64, 0.75]; p<0.001), the incidence rate of new or enlarging T2 lesions (rate ratio: 0.47 [95% CI: 0.37, 0.61]; p<0.001), annualized percentage change (decrease) in T2LV (difference: -3.68% [95% CI: -7.06%, -0.30%]; p = 0.033), and annualized percentage change (increase) in BPF (difference: 0.22% [95% CI: 0.16%, 0.29%]; p<0.001). Results of the subgroup comparison of natalizumab EID patients with platform therapy patients were similar to those of the overall-natalizumab-group-versus-platform-therapy comparison. CONCLUSIONS: The results indicate that natalizumab EID and SID provide comparable real-world effectiveness on quantitative MRI metrics. These data further demonstrate that natalizumab EID can provide superior real-world effectiveness to injectable platform therapy on quantitative MRI metrics.

Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis.

OBJECTIVE: We sought to determine if vitamin D status, a risk factor for multiple sclerosis, is associated with the rate of subsequent clinical relapses in pediatric-onset multiple sclerosis. METHODS: This is a retrospective study of patients with pediatric-onset multiple sclerosis or clinically isolated syndrome who were consecutively recruited into a prospective cohort at their clinical visit at the pediatric multiple sclerosis center of University of California, San Francisco or State University of New York at Stony Brook. Of 171 eligible patients, 134 (78%) with multiple sclerosis/clinically isolated syndrome were included in the cohort; a further 24 were excluded from this analysis due to lack of available serum (n = 7) or lack of follow-up (n = 17). Serum 25-hydroxyvitamin D(3) levels were measured and were adjusted to reflect a deseasonalized value. The adjusted serum 25-hydroxyvitamin D(3) level was the primary predictor in a multivariate negative binomial regression model in which the main outcome measure was the number of subsequent relapses. RESULTS: Among the 110 subjects, the mean unadjusted 25-hydroxyvitamin D(3) level was 22 +/- 9 ng/ml. After adjustment for age, gender, race, ethnicity, disease duration, disease-modifying therapy, and length of follow-up, every 10 ng/ml increase in the adjusted 25-hydroxyvitamin D(3) level was associated with a 34% decrease in the rate of subsequent relapses (incidence rate ratio, 0.66; 95% confidence interval, 0.46-0.95; p = 0.024). INTERPRETATION: Lower serum 25-hydroxyvitamin D(3) levels are associated with a substantially increased subsequent relapse rate in pediatric-onset multiple sclerosis or clinically isolated syndrome, providing rationale for a randomized controlled trial of vitamin D supplementation.

A phase 3 trial of extended release oral dalfampridine in multiple sclerosis.

OBJECTIVE: A previous phase 3 study showed significant improvement in walking ability in multiple sclerosis (MS) patients treated with oral, extended-release dalfampridine (4-aminopyridine) 10mg twice daily. The current study was designed to confirm efficacy and further define safety and pharmacodynamics. METHODS: This was a 39-center, double-blind trial in patients with definite MS of any course type. Participants were randomized to 9 weeks of treatment with dalfampridine (10mg twice daily; n = 120) or placebo (n = 119). Response was defined as consistent improvement on the Timed 25-Foot Walk, with percentage of timed walk responders (TWRs) in each treatment group as the primary outcome. The last on-treatment visit provided data from 8 to 12 hours postdose, to examine maintenance of effect. RESULTS: One patient from each group was excluded from the modified Intention to Treat population. The proportion of TWRs was higher in the dalfampridine group (51/119 or 42.9%) compared to the placebo group (11/118 or 9.3%, p < 0.0001). The average improvement in walking speed among dalfampridine-treated TWRs during the 8-week efficacy evaluation period was 24.7% from baseline (95% confidence interval, 21.0-28.4%); the mean improvement at the last on-treatment visit was 25.7%, showing maintenance of effect over the interdosing period. There were no new safety findings. INTERPRETATION: This interventional study provides class 1 evidence that dalfampridine extended-release tablets produce clinically meaningful improvement in walking ability in a subset of people with MS, with the effect maintained between doses.