Faculty Bibliography

Objective: To test whether the Brief International Cognitive Assessment in Multiple Sclerosis (BICAMS) predicts real-world functioning as measured by timed instrumental activities of daily living (ADLs). Background: The BICAMS is a cognitive screen that is widely-used in clinical practice and research to assess cognitive impairment in persons with multiple sclerosis (MS). It is important for cognitive measures to predict daily functioning. We compared performance on the BICAMS to a test consisting of ten timed instrumental activities of daily living, called the Test of Everyday Cognitive Ability or TECA. Design/Methods: All participants were administered the TECA along with three BICAMS measures: Symbol Digit Modalities Test (SDMT), the Brief Visuospatial Memory Test-Revised (BVMT-R), and either the Rey Auditory Verbal Learning Test (RAVLT) or substituted with the Selective Reminding Test (SRT). The TECA items were scored according to time and errors and averaged for one representative score, with higher scores indicating greater impairment. BICAMS measures were transformed to age-normative z scores for comparison, with scores of <-1.5 considered impaired, and one or more impaired scores indicating overall BICAMS impairment. Results: A total of n=177 MS patients (mean age 45+/- 14 years, 73% female) with a median EDSS=3.0 (range of 0.0 to 8.0) completed the study. Overall, 37% met BICAMS impairment criteria. Each of the individual BICAMS measures significantly predicted performance on the TECA: SDMT, r=-.53, p<.001, BVMT-R r= -0.32, p <0.001, and Verbal Learning r= -.34, p <0.001. Worse TECA scores were associated with poorer performance on the BICAMS. Conclusions: The TECA is a measure of timed instrumental activities of daily living that is valid for use in a diverse MS population. BICAMS significantly predicts performance on the TECA, indicating that it is a useful indicator of real-world functioning

Objective: Speeded Saccadic Eye Movement Predicts Symbol Digit Modalities Test Performance in Multiple Sclerosis Background: Multiple sclerosis is an autoimmune demyelinating disease with estimates of cognitive impairment above 30% in pediatric and 50% in adult patients. The SDMT, a widely-used screening tool that measures speeded information processing, has been used to track cognitive decline in MS. The K-D test is a brief measure of saccadic eye movement speed using a timed number naming test, commonly used for the detection of mild traumatic brain injury. Here, we tested the sensitivity of the K-D test in MS and its association with performance on the SDMT. Design/Methods: Adult and pediatric patients with clinically-definite MS were consecutively recruited through the NYU Langone MS Comprehensive Care Center. All participants completed the SDMT and K-D at a single visit. Results: A total of 30 participants completed the assessments ranging in age from 13 to 72 years (mean 38 +/- 19 years), were 74% female, and with an EDSS range 0.0 to 6.5. Relative to age normative data, the K-D indicated greater impairment than the SDMT (74% vs. 48%, respectively). Controlling for age, both tests were significantly correlated (r=0.44, p =0.02), demonstrating a close contribution of oculomotor function to SDMT performance. Conclusions: The K-D test is sensitive to detecting impairment in MS across the lifespan. Performance on the SDMT is closely associated with oculomotor function in MS

Objective: Report initial results from the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) project. Background: The Learning Health System (LHS) concept involves collecting standardized clinical and imaging data during the course of patient care. The data would then serve two purposes simultaneously: data-driven clinical care decisions and systematic learning. Design/Methods: MS PATHS was designed around the LHS concept, through collaborative meetings in 2015-2016. MS PATHS participants self-administer the Multiple Sclerosis Performance Test (MSPT) at routine clinical visits. MSPT is an iPad-based medical device designed and validated for MS. MSPT includes components of the MSFC-4, NeuroQoL, and a standardized MS history. For imaging data, brain MRIs are acquired on 3T Siemens scanners using identical image acquisition parameters, to allow generation of highly standardized MRI-metrics. Participants may also elect to contribute to a biorepository. Results: As of Oct 19, 2016, seven US centers were participating in MS PATHS in collaboration with Biogen, under guidance of a steering committee of 3 neurologists and 1 neuroradiologist from participating centers and a Biogen representative. From May 17, 2016 through October 19, 2016, 1507 patients with MS were enrolled in MS PATHS, 317 with two or more visits. Data from 1127 MSPT assessments are currently available in the LHS database, 342 with brain MRIs. Opt-in rate for data sharing has exceeded 90%, suggesting the study will yield a representative population from participating centers. Across patients currently enrolled (mean+- SD): age=52+/-12 years, Walking Speed Test = 8.46 +/- 5.54 sec, and Dominant Hand Manual Dexterity Test = 28.3 +/- 7.7 sec. Updated results and lessons learned will be presented. Conclusions: MS PATHS is the first LHS established in MS. Enrollment has been rapid, and patient acceptance high. Standardized, comprehensive clinical and imaging data collection will accelerate collaborative research efforts and support data-driven patient management

Objective: To design and implement a strategy to enable high quality, standardized MRI acquisitions across a network of participating healthcare institutions (MS PATHS). Background: Although imaging guidelines for MS patients have been recommended and MRI protocols are specified for clinical trials, there remains a high degree of variability in acquisition parameters that limit the reliability of quantitative measurements. As part of MS PATHS, we are collaborating with a network of MS centers to standardize the acquisition of MRI images for quantitative analysis. Our goal is to test the feasibility and clinical utility of collecting research-quality MRI data during routine clinical care. Design/Methods: A standardized MRI protocol was designed by healthcare institution neuroradiologists and imaging scientists at Biogen and Siemens to be feasible for routine use for multicenter imaging of any MS patient referred for MRI, and optimized for automated quantitative analysis of brain volume and MS lesions. Incorporation of these agreed-upon sequences into the routine MS-MRI protocol was part of the MS PATHS start-up process. Results: The MS PATHS brain imaging protocol includes two 1mm isotropic product sequences optimized for Siemens 3T scanners: a pre-contrast 3D MPRAGE and 3D SPACE FLAIR with a total scan time of 11.42 minutes. Currently, the highly standardized sequences have been implemented as standard of care in 8 institutions. Within the first 2 weeks since activation, 383 retrospective MRI studies from 342 unique patients were received from the first institution and 98.5% of these scans passed automated QA/QC, demonstrating the initial feasibility of this approach. Conclusions: To our knowledge this is the first implementation of a rigorously standardized MRI protocol across MS centers to generate research quality imaging metrics in clinical practice. Integration into a learning health system will improve clinical care and research

Objective: To test whether changes in fine motor speed predict change in cognitive functioning in pediatric onset MS (POMS). Background: Multiple sclerosis is an autoimmune demyelinating disease that has a pediatric (<18 years) onset in 3-5% of all cases. Cognitive impairment is a frequent and disabling symptom for approximately 30% of POMS patients. As in adults, the earliest cognitive involvement can be measured by the Symbol Digit Modalities Test or SDMT, a measure of speeded information processing. Fine motor slowing occurs frequently in both adult and pediatric patients, but its relation to cognitive functioning remains unclear. The Lafayette grooved pegboard serves as a measure of fine motor functioning and has previously been shown to be sensitive in MS samples. Design/Methods: POMS patients were consecutively recruited through the Lourie Center for Pediatric MS and the NYU Langone MS Comprehensive Care Center. All participants completed the SDMT and the Lafayette grooved pegboard (dominant and non-dominant hand conditions) at two separate visits (using an alternate form for the SDMT). Both SDMT and pegboard performances were transformed to age-normative z scores for comparison. Results: A total of n=26 POMS participants completed both assessments. The mean age was 16.5+/-3.08 years and 58% were female. The mean time between study visits was 193+/-148 days. Both measures improved at repeat administration, with mean SDMT and pegboard z scores improving from 0.11+/-1.39 to 0.34+/-1.41 and -1.56+/-1.68 to -1.21+/-2.55, respectively. Change in pegboard performance significantly predicted change in the SDMT (r=0.58, p=0.002)

Objective: To investigate patient reported outcomes predictive of conversion to SPMS in an aging sample of MS patients. Background: The secondary progressive (SP) phase of multiple sclerosis (MS) is characterized by a progressive accumulation of neurological disability, preceded by a relapsing remitting (RR) disease course. Older age at disease onset, high frequency of relapses and male sex have frequently been found to be predictive of a higher risk of disease conversion. Design/Methods: Subjects are part of the New York State Multiple Sclerosis Consortium (NYSMSC). Patients with an RRMS disease type at study enrollment, age 50 or over, with a disease duration of at least 15 years were selected for this study (n=155). Chi-squared tests and logistic regression modelling were used to investigate the predictive value of patient reported outcomes at study enrollment and conversion to SPMS at year 5. Results: Five years after study enrollment (median disease duration=22 years), 47 (30.3%) RRMS subjects progressed to SPMS. Those who converted were older at study enrollment (54.8 vs 52.1, p=.01), and had a higher Kurtzke Expanded Disability Status Scale (EDSS) at both baseline (3.5 vs 2.6, p<.001), and at year 5 (5.6 vs 3.0, p<.001). Patients who progressed at year 5 were more likely to report lower limb problems at baseline (53.2% vs 21.5%, OR: 3.0, p<.001), and were more likely to report some degree of fatigue (91.5% vs 68.2%, OR: 4.2, p=.004), compared to those who did not progress, even after adjusting for age, disease duration and EDSS. Fatigue and lower limb problems were strongly correlated (p-value=0.001). Conclusions: Fatigue and lower limb problems at baseline were predictive of a higher chance of conversion after 5 years of follow-up. Targeting patients with these symptoms may result in more successfully predicting patients at higher risk of disease conversion and subsequently tailoring therapeutic strategies

BACKGROUND: Adverse childhood experiences (ACEs) exert a psychological and physiological toll that increases risk of chronic conditions, poorer social functioning, and cognitive impairment in adulthood. OBJECTIVE: To investigate the relationship between childhood adversity and clinical disease features in multiple sclerosis (MS). METHODS: Sixty-seven participants with MS completed the ACE assessment and neuropsychological assessments as part of a larger clinical trial of cognitive remediation. RESULTS: Adverse childhood experience scores, a measure of exposure to adverse events in childhood, significantly predicted age of MS onset (r = -0.30, p = 0.04). ACEs were also linked to reading recognition (a proxy for premorbid IQ) (r = -0.25, p = 0.04). ACE scores were not related to age, current disability, or current level of cognitive impairment measured by the Symbol Digit Modalities Test (SDMT). CONCLUSION: Childhood adversity may increase the likelihood of earlier age of onset and poorer estimated premorbid IQ in MS.

Cognitive impairment affects more than half of all individuals living with multiple sclerosis (MS). We hypothesized that training at home with an adaptive online cognitive training program would have greater cognitive benefit than ordinary computer games in cognitively-impaired adults with MS. This was a double-blind, randomized, active-placebo-controlled trial. Participants with MS were recruited through Stony Brook Medicine and randomly assigned to either the adaptive cognitive remediation (ACR) program or active control of ordinary computer games for 60 hours over 12 weeks. Training was remotely-supervised and delivered through a study-provided laptop computer. A computer generated, blocked stratification table prepared by statistician provided the randomization schedule and condition was assigned by a study technician. The primary outcome, administered by study psychometrician, was measured by change in a neuropsychological composite measure from baseline to study end. An intent-to-treat analysis was employed and missing primary outcome values were imputed via Markov Chain Monte Carlo method. Participants in the ACR (n = 74) vs. active control (n = 61) training program had significantly greater improvement in the primary outcome of cognitive functioning (mean change in composite z score+/-SD: 0.25+/-0.45 vs. 0.09+/-0.37, p = 0.03, estimated difference = 0.16 with 95% CI: 0.02-0.30), despite greater training time in the active control condition (mean+/-SD:56.9 +/- 34.6 vs. 37.7 +/-23 .8 hours played, p = 0.006). This study provides Class I evidence that adaptive, computer-based cognitive remediation accessed from home can improve cognitive functioning in MS. This telerehabilitation approach allowed for rapid recruitment and high compliance, and can be readily applied to other neurological conditions associated with cognitive dysfunction. TRIAL REGISTRATION: Clinicaltrials.gov NCT02141386.

The International Pediatric Multiple Sclerosis Study Group held its inaugural educational program, "The World of Pediatric MS: A Global Update," in September 2014 to discuss advances and challenges in the diagnosis and management of pediatric multiple sclerosis (MS) and other neuroinflammatory CNS disorders. Highlights included a discussion on the revised diagnostic criteria, which enable the differentiation of MS, acute disseminated encephalomyelitis, neuromyelitis optica, and other neuroinflammatory disorders. While these criteria currently identify clinical and MRI features for a particular diagnosis, advances in biomarkers may prove to be useful in the future. An update was also provided on environmental factors associated with pediatric MS risk and possibly outcomes, notably vitamin D deficiency. However, optimal vitamin D intake and its role in altering MS course in children have yet to be established. Regarding MS outcomes, our understanding of the cognitive consequences of early-onset MS has grown. However, further work is needed to define the course of cognitive function and its long-term outcome in diverse patient samples and to develop strategies for effective cognitive rehabilitation specifically tailored to children and adolescents. Finally, treatment strategies were discussed, including a need to consider additional drug treatment options and paradigms (escalation vs induction), although treatment should be tailored to the individual child. Of critical importance, clinical trials of newer MS agents in children are required. Although our understanding of childhood MS has improved, further research is needed to have a positive impact for children and their families.