Faculty Bibliography

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

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: 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: 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:There is limited information about the potential associations of multiple sclerosis (MS) and commonly used household chemicals. Methods/UNASSIGNED:We performed a case-control study of exposures to common household chemicals during childhood in children with MS and healthy pediatric controls. Exposures to household products were collected from a comprehensive questionnaire (http://www.usnpmsc.org/Documents/EnvironmentalAssessment.pdf) completed by parents at the time of enrollment in the study. Cases included children diagnosed with MS or clinically isolated syndrome with at least two silent T2 bright lesions on MRI, recruited within 4 years of disease onset from 16 pediatric MS clinics in the USA. Multivariate analyses using logistic regression were adjusted for possible confounders including age, sex, race, ethnicity, mother's highest level of education, and urban versus rural living. Results/UNASSIGNED: ≤ 0.001) anytime during childhood were associated with an increased risk for pediatric-onset MS in adjusted and multiple comparisons analyses. Conclusions/UNASSIGNED:Our findings suggest that exposure to specific household chemicals during early childhood is associated with the risk of developing pediatric-onset MS. Future studies are needed to elucidate a causal relationship and the exact agents involved.

Children with pediatric-onset multiple sclerosis and pediatric controls were enrolled across 16 pediatric multiple sclerosis centers in the United States and completed questionnaires that addressed time of first unaided walking and acquisition of 2-word phrases. A total of 467 (308 female) cases and 428 (209 female) controls were enrolled. Pediatric multiple sclerosis (n = 467) were not delayed in walking or using 2-word phrases compared to healthy controls (n = 428) (2.2% vs 5.7%, respectively). Children with disease onset before age 11 versus onset at 11 years or after were more likely to need an individualized education plan ( P = .002), reading assistance ( P = .0003), and math assistance ( P = .001). Children with multiple sclerosis onset prior to age 18 are not delayed in meeting the 2 major early developmental milestones but do have a significantly increased use of special services or learning assistance at school. Further research will need to address whether other measures of development (eg, rate of language acquisition or fine motor skills) differ between pediatric multiple sclerosis and controls.