Faculty Bibliography

Introduction: In PARADIGMS, a double-blind phase 3 trial of 215 paediatric MS patients (age 10-< 18 years), fingolimod administered up to 2 years significantly reduced the annualised relapse rate by 81.9%, the annualised rate of new/newly enlarged T2 lesions by 52.6%, and the number of Gadolinium-enhancing T1 lesions by 66.0% compared to interferon (IFN) beta-1a.
Objective(s): To evaluate the effect of fingolimod versus IFN beta-1a on quality of life in this paediatric MS population.
Method(s): Health-related quality of life was assessed using the Pediatric Quality of Life (PedsQL) inventory. Summary statistics of change in patient-or parent-reported PedsQL scores from baseline until study end (up to 2 years) were pre-planned. Inferential testing on between group differences in PedsQL scores was performed as a post-hoc analysis. The change from baseline in Total Scale score, Physical Health Summary score, and Psychosocial Health Summary score was compared by visit for patient-and parent-reported PedsQL using a parametric analysis of covariance (ANCOVA) model adjusted by treatment, region, pubertal status, and the corresponding baseline score.
Result(s): Numerical improvements in PedsQL scores in both patient-and parent-reported Total Scale, Physical Health, and Psychosocial Health Summary scores were observed in fingolimod-treated patients compared with consistent worsening observed in the IFN beta-1a-treated patients. The post-hoc inferential statistical analysis confirmed that treatment with fingolimod resulted in a positive effect on quality of life in both patient-and parent-reported Total score and Physical Health Summary score, as well as in patient-reported Psychosocial Health Summary score compared with IFN beta-1a (all p< 0.05).
Conclusion(s): Consistent with the primary efficacy results, treatment with fingolimod versus IFN beta-1a was associated with a significant improvement in all measures of health-related quality of life as reported by the patients, and in Total score and Physical Health score as reported by their parents

Introduction: Cognitive impairment is common and often disabling in multiple sclerosis (MS), but the risk factors and mechanisms underlying cognitive decline remain poorly understood. Pediatric MS (MS onset < 18 years of age) is unique due to the demyelinating process occurring in the context of development.
Objective(s): To compare cognitive functions in newly diagnosed patients with either adult- or pediatric-onset MS (AOMS vs. POMS).
Aim(s): To test performance in newly diagnosed MS patients using the Symbol Digit Modalities Test (SDMT) and a computer-based measure sensitive to processing speed deficits (Cogstate).
Method(s): As part of an ongoing multi-center longitudinal cognition trial, AOMS and POMS participants were recruited from outpatient visits and matched by years of disease. At the baseline evaluation, all participants were administered the Wide Range Achievement Test-4 (WRAT-4), the SDMT and the Cogstate Brief Battery, which includes three measures of information processing speed tasks:simple (DET) and choice (IDN) reaction time and working memory (ONB). Cogstate scores were converted to z-scores and then averaged for one composite z-score.
Result(s): A total of n=64 participants completed baseline assessments with n= 32 in the AOMS group (mean age 33.36 ?+/- 5.82) and n= 32 in the POMS group (mean age 11.31 ?+/- 3.64). All participants had relapsing remitting disease and the groups were matched for disease duration (4.91 ?+/- 3.05 years for AOMS vs. 6.38 ?+/- 3.54 for POMS). The POMS group had higher estimated premorbid IQ (WRAT-4 reading 112.7 ?+/- 18.5 vs. 105.4 ?+/- 13.4), though the result did not reach significance (p=0.07). Neither group's cognitive performances fell into the impaired range relative to age-normative means. However, the AOMS compared to the POMS group consistently performed significantly worse on the SDMT (mean z-score -0.26 ?+/- 1.15 for AOMS vs. 0.68 ?+/- 1.53 for POMS, p=0.01) and slower on the Cogstate composite (mean z-score of -1.04 ?+/- 1.09 for AOMS vs. 0.35 ?+/- 1.15 for POMS, p=0.04). Estimated premorbid IQ was correlated with SDMT, but not Cogstate performance (r=0.56 p=0.001 and r=0.13 p=0.35, respectively). Age of disease onset was significantly negatively correlated with cognitive processing (SDMT: r= -0.32, p= 0.01 and Cogstate DET: r= -0.33, p=0.02), further indicating that older age of onset is associated with greater cognitive impairment.
Conclusion(s): Adult MS is associated with larger cognitive involvement than pediatric MS

Introduction: Pediatric onset multiple sclerosis (POMS) is a demyelinating disorder occurring in the context of neurodevelopment with unique clinical challenges due to the potential for disease-related cognitive impairment. A brief cognitive screening battery of computer administered measures of processing speed (Cogstate) and the Brief International Cognitive Assessment in MS (BICAMS) detects cognitive impairment in POMS. However, the neuroanatomic correlates of these deficits are incompletely understood. We have sought to define the neuroimaging correlates of deficits identified with a cognitive screening battery in POMS.
Objective(s): To test the links between white matter integrity and cognitive functioning in pediatric MS patients and matched healthy controls.
Aim(s): Participants cognitive performance as measured by the BICAMS and Cogstate assessments was compared to magnetic resonance imaging (MRI) outcomes.
Method(s): Participants with POMS and age-matched healthy controls (HC) completed cognitive screening with Cogstate and the BICAMS along with 64-direction MRI based diffusion tensor imaging (DTI).
Result(s): The POMS group (n= 15, mean age 17.9+/-3.2 years) compared to the HC group (n= 21, mean age 17.8+/-3.3 years) were significantly slower on a composite Cogstate score (p=0.004), but the groups did not significantly differ using a composite BICAMS score (p = 0.10). The POMS group also presented with increased fractional anisotropy (FA) in the thalamus (p=0.01) and reduced FA in the corpus callosum (p=0.05) and temporal lobe white matter (p=0.03) relative to HCs. Controlling for age and sex within groups, the measured slowed processing speed (Cogstate composite) significantly negatively correlated with regional fractional anisotropy (FA) in the corpus callosum, temporal and occipital lobe white matter, and in the tractography-based uncinate fasciculus in the POMS sample (p=0.002 to 0.025), whereas the reduced verbal learning (RAVLT) was significantly negatively correlated with thalamic FA (p = 0.046). Of these effects, only the relationship between the Cogstate composite and temporal lobe FA was significant in the HCs (p=0.013).
Conclusion(s): Computer administered measures of cognitive processing speed are particularly sensitive to slowing in POMS and are closely linked to MRI diffusion measures

Background/UNASSIGNED:We previously identified air quality as a risk factor of interest for pediatric multiple sclerosis. The purpose of this study is to more closely examine the association between the six criteria air pollutants and pediatric MS as well as identify specific areas of toxic release using data from the Toxic Release Inventory. Methods/UNASSIGNED:= 442) were included as part of an ongoing case-control study. We used the National Emissions Inventory system to estimate particulate exposure by county of residence for each participant. Proximity to Toxic Release Inventory (TRI) sites was also assessed using ArcGIS mapping tools. Risk-Screening Environmental Indicators (RSEI) classified counties at risk to exposure of environmental toxic releases. Results/UNASSIGNED:= 0.002). Average RSEI scores did not differ significantly between cases and controls. Conclusion/UNASSIGNED:, CO, and lead) were statistically associated with higher odds for pediatric MS.

Introduction: Performance on the symbol digit modalities test (SDMT) is associated with employment status and activities of daily living. However, most constructs of MS disease progression do not take into account cognitive changes; potentially underestimating disease progression in MS.
Objective(s): Describe the prevalence of cognitive decline in multiple sclerosis (MS) in the absence of motor function decline.
Method(s): Patients with MS and clinically isolated syndrome were enrolled in MS PATHS, a network of 10 healthcare institutions in the US (7) and EU (3). During routine visits, patients used the Multiple Sclerosis Performance Test (MSPT) to complete the Processing Speed Test (PST), Manual Dexterity Test (MDT) and Walking Speed Test (WST), which are electronic adaptations of the SDMT, Nine-hole Peg Test and Timed 25 Foot Walk. Patients also completed the Patient Derived Disease Steps (PDDS). This analysis included all patients enrolled in MS PATHS with two or more completed MSPT assessments. Decline between timepoints was defined as a 4 point change on the PST, 20% change on the MDT or WST, or a 1 point change on the PDDS.
Result(s): 2289 patients had 2 or more complete MSPT assessments. At baseline, the average age was 44.9 yrs (SD: 11.2 yrs) and the average disease duration was 10.7 yrs (SD: 8.1 yrs). The average duration of follow-up was 7.5 mos (SD: 4.5 mos) and the average number of MSPT assessments was 2.5 (SD: 0.93). When comparing a patient's first and last MSPT assessment, 33.7% of patients had a decline on either the PST, MDT, or WST. 15.2% of patients had a decline on the PST only, 13.6% had a decline on the WST or MDT only (i.e. motor tests), and 4.9% of patients had decline on both the PST and a motor test. There were no meaningful differences in the distribution of baseline demographics, socioeconomics, or MS sub-types between patients who did or did not experience any decline and within decline sub-groups. PDDS progression was observed in 16.9% of patients with PST decline only, 22.5% of patients with motor decline only, and 30.4% of patients with both PST and motor decline. Further results will be reported at conference.
Conclusion(s): The prevalence of cognitive decline was as common as motor decline. 75.7% of patients with cognitive decline did not have concurrent motor decline. These results highlight the importance of cognitive monitoring in routine clinical care and the need for effective treatment strategies for cognitive decline in MS

Introduction: Cognitive impairment represents a frequent and troubling symptom of multiple sclerosis (MS) in need of treatment options. Transcranial direct current stimulation (tDCS) uses scalpbased electrodes to pass mild electrical current (< 4mA) through target cortical brain regions and is a safe and well-tolerated treatment. We have developed a protocol to deliver remotely supervised cognitive remediation paired with tDCS to individuals with MS at home.
Objective(s): To test whether at-home cognitive remediation augmented with tDCS will lead to improved training outcomes in MS.
Aim(s): Cognitive processing speed was assessed at baseline and study end by the Cogstate Brief Battery. Age normative z scores were computed for the Cogstate Brief Battery scores, with outcome measured by change in the average z score of information processing assessments.
Method(s): MS participants with cognitive impairment were recruited and randomized to complete 40 sessions of either active or sham tDCS paired with either adaptive or non-adaptive cognitive training (aCT or nCT). Training was completed at home using study-provided equipment and remotely supervised via videoconference using our established probed (RS-tDCS). Training was 20 minutes in duration and was completed five times a week (M-F) for approximately eight weeks. Participants were blinded and received active (2.5mA) or sham stimulation and cognitive training simultaneously during each session.
Result(s): To date, n=19 MS participants have successfully complete the 40 session training program at home: n=6 in active/aCT, n=8 in Sham/aCT, and n=5 in active/nCT. Mean age was 49+/-15 years of age and mean years of education was 16.5+/-2.1. The majority of participants had the RRMS subtype (63%, with 11% PPMS, and 26% SPMS). The participants were matched on cognitive status as measured by the symbol digit modality test (ANOVA p=0.09). tDCS and the cognitive training were uniformly well tolerated with no safety concerns. At the group level, all three groups showed improvement from baseline (0.75, 0.56, 0.59 z-score improvement for each condition respectively), indicating that both tDCS and aCT can be of benefit. Further, as predicted, the active tDCS paired with aCT experienced the greatest benefit (Cohen's d = 0.51).
Conclusion(s): Our telerehabiltiation protocol allows for participants to receive extended cognitive training paired with tDCS at home, resulting in improved outcomes from cognitive remediation

BACKGROUND:Treatment of patients younger than 18 years of age with multiple sclerosis has not been adequately examined in randomized trials. We compared fingolimod with interferon beta-1a in this population. METHODS:In this phase 3 trial, we randomly assigned patients 10 to 17 years of age with relapsing multiple sclerosis in a 1:1 ratio to receive oral fingolimod at a dose of 0.5 mg per day (0.25 mg per day for patients with a body weight of ≤40 kg) or intramuscular interferon beta-1a at a dose of 30 μg per week for up to 2 years. The primary end point was the annualized relapse rate. RESULTS:-weighted magnetic resonance imaging (MRI) was 4.39 with fingolimod and 9.27 with interferon beta-1a (absolute difference, 4.88 lesions; relative difference, 53%; P<0.001). Adverse events, excluding relapses of multiple sclerosis, occurred in 88.8% of patients who received fingolimod and 95.3% of those who received interferon beta-1a. Serious adverse events occurred in 18 patients (16.8%) in the fingolimod group and included seizures (in 4 patients), infection (in 4 patients), and leukopenia (in 2 patients). Serious adverse events occurred in 7 patients (6.5%) in the interferon beta-1a group and included infection (in 2 patients) and supraventricular tachycardia (in 1 patient). CONCLUSIONS:Among pediatric patients with relapsing multiple sclerosis, fingolimod was associated with a lower rate of relapse and less accumulation of lesions on MRI over a 2-year period than interferon beta-1a but was associated with a higher rate of serious adverse events. Longer studies are required to determine the durability and safety of fingolimod in pediatric multiple sclerosis. (Funded by Novartis Pharma; PARADIG MS ClinicalTrials.gov number, NCT01892722 .).

OBJECTIVE:Cognitive impairment is a common symptom of multiple sclerosis (MS) that can lead to declines in daily functioning. Timed instrumental activities of daily living (TIADLs) have been useful to bridge between cognitive testing and real-world functioning in disorders such as Alzheimer's disease and other dementias. However, these have not been standardized for general use, and the tasks that are typically employed have not been sensitive to the detection of milder forms of cognitive deficits. We developed a test of ten TIADLs tasks to measure a broader range of functioning, entitled the "Test of Everyday Cognitive Ability" or TECA, and tested its utility in a diverse sample of participants with MS. METHOD/METHODS:TECA performance was characterized in n = 177 participants with MS and compared to healthy controls (n = 49). A subset from each group received repeated administration. In addition, all participants completed a standard battery of neuropsychological measures. RESULTS:TECA performances were significantly different between MS and control participants. Further, MS participants with cognitive impairment performed significantly slower relative to those MS participants without impairment. CONCLUSIONS:The TECA is a TIADLs assessment appropriate for use in those with MS as it includes a broad range of task difficulties, requires minimum motor involvement, and is sensitive to MS-related cognitive impairment. The TECA is a brief and repeatable test of TIADLs and its ease of administration makes it suitable for both clinical practice and research settings.

Background and aims: Approximately 3-5% of Multiple Sclerosis (MS) cases manifest in childhood and adolescence, characteristically with highly active inflammatory disease course. Paediatric-onset MS (POMS) has an impact on brain integrity and may increase Brain Volume Loss (BVL) above age-expected rates. This study assessed the effect of oral Fingolimod up to 0.5mg daily versus intramuscular interferon (IFN) beta-1a 30mug once weekly on MRI outcomes in POMS patients. Methods: In this double-blind, double-dummy, activecontrolled, multicentre study, patients with POMS (aged 10-<18 years) received either Fingolimod (dose adjusted for body weight; N=107) or IFN beta-1a (N=107) for up to 2 years. MRI was performed at baseline and every 6 months until the End Of The Study (EOS) core phase. Key MRI outcomes were the number of new/newly enlarging T2 (n/ neT2) lesions and Gd-enhancing T1 (Gd+T1) lesions, Annual Rate Of Brain Volume Change (ARBVC), annualised rate of number of new T1 hypointense lesions, change in total T2 Hyperintense Lesion Volume (T2LV) and the number of Combined Unique Active Lesions (CUAL). Results: At the EOS, compared with IFN beta-1a, fingolimod significantly reduced the annualised rate of n/ neT2 lesions (52.6%; p<0.001), number of Gd+T1 lesions per scan (66.0%; p<0.001), ARBVC (-0.48% vs. -0.80%, p=0.014), annualised rate of number of new T1 hypointense lesions (62.8%; p<0.001), T2LV (percent change from baseline: 18.4% vs. 32.4%, p<0.001) and CUAL per scan (60.7%; p<0.001). Conclusion: Fingolimod significantly reduced MRI activity and slowed BVL for up to 2 years vs. IFN beta-1a in paediatric-onset MS