Faculty Bibliography

INTRODUCTION:Diroximel fumarate (DRF) is an oral fumarate for relapsing multiple sclerosis (MS) with the same active metabolite as dimethyl fumarate (DMF). DRF has a safety/efficacy profile similar to DMF but with improved gastrointestinal (GI) tolerability and low (< 1%) treatment discontinuation due to GI adverse events (AEs). Efficacy and safety outcomes in patients who switched to DRF from other disease-modifying therapies (DMTs) have not been evaluated. METHODS:EVOLVE-MS-1 is an ongoing, 2-year, open-label, phase 3 study of DRF in adults with relapsing-remitting MS. Patients either entered as newly enrolled to DRF trials, or from the 5-week, randomized, head-to-head, phase 3 EVOLVE-MS-2 study of DRF and DMF. This analysis evaluated safety and GI tolerability in patients continuing on DRF (DRF-rollover) or switching from DMF (DMF-rollover) following EVOLVE-MS-2. Safety and efficacy were evaluated in a subset of newly enrolled patients who had received prior glatiramer acetate (GA; GA/DRF) or interferons (IFN; IFN/DRF) as their most recent DMT, prior to switching to DRF in EVOLVE-MS-1. RESULTS:As of September 1, 2020, 1057 patients were enrolled in EVOLVE-MS-1, including 166, 182, 239, and 225 patients in the GA/DRF, IFN/DRF, DRF-rollover, and DMF-rollover groups, respectively. Treatment discontinuation due to GI AEs was < 1% in all groups. GA/DRF and IFN/DRF patients experienced improvements from baseline in clinical and radiological efficacy outcomes, including significantly reduced annualized relapse rates. Rollover patients had low rates of new or recurrent GI AEs (DRF-rollover, 26.8%/4.2%; DMF-rollover, 27.1%/4.9%). CONCLUSION:After 2 years of DRF exposure, patients with prior GA, IFN, or fumarate treatment had safety outcomes consistent with previous fumarate studies. Efficacy in patients with prior GA or IFN treatment was consistent with previous fumarate studies. The data suggest that transition to DRF from GA, IFN, or DMF is a reasonable treatment strategy, with low rates of discontinuation due to GI AEs. TRIAL REGISTRATION:ClinicalTrials.gov (NCT02634307). INFOGRAPHIC.

BACKGROUND:The Symbol Digit Modalities Test (SDMT) is a common screen of cognitive function for people with Multiple Sclerosis (pwMS) but growing acknowledgement that people with cognitive impairment are a heterogeneous population suggests that a single screen may provide limited information. OBJECTIVE:To assess the adequacy of the SDMT in capturing impairment across specific cognitive domains as measured by a multi-domain cognitive assessment battery (CAB, NeuroTrax). METHODS:113 pwMS were assessed with SDMT and the CAB. Cognitive impairment in each CAB domain was defined as ≥1.5 SD below the normalized mean. Logistic regression models were fit for each CAB domain with domain-specific cognitive impairment as the outcome and SDMT as the predictor, and a classifier created by selecting cutpoints using the Youden Index. Model performance was assessed by predicting domain-specific cognitive impairment in an independent data set consisting of 81 pwMS. RESULTS:SDMT was a significant predictor of cognitive impairment in all outcomes considered (Odds Ratio: 0.885-0.950), but prediction metrics such as area under the receiver operating curve (AUC) were modest (0.623-0.778), and the alignment between observed/predicted impairment was less than optimal. CONCLUSION/CONCLUSIONS:The SDMT is not sufficient to differentiate between impaired and non-impaired pwMS across several cognitive domains.

BACKGROUND:The Expanded Disability Status Scale (EDSS) is widely utilized in clinical trials and routine care to evaluate disease burden and progression among people with multiple sclerosis (pwMS). However, instrumental gait measures may be more suitable than EDSS to track walking disability in pwMS. In this cross-sectional study, we aimed to quantify the variability of spatiotemporal gait measures within homologous EDSS categories. METHODS:A total of 205 pwMS (age=46.5[SD=10.5] years, 72.2% female, EDSS range=1.0-6.5) were studied in this retrospective analysis. Participants underwent walking assessments through the GAITRite system and the following spatiotemporal gait measures were recorded: gait speed, mean normalized velocity (MNV), base of support, stride length, step length, percentage of gait cycle spent in double support and single support, and functional ambulation profile. The EDSS was evaluated by a certified neurologist. RESULTS:≤0.17). Overall, the percent variability of gait measures increased across EDSS categories, with coefficients of variation ranging from 6.9% to 37.2% in the minimal disability group (EDSS≤2.5), 8.1% to 33.4% and 22.3% to 53.8% in the moderate (2.5<EDSS≤4.5) and severe (EDSS>4.5) disability groups, respectively. CONCLUSION/CONCLUSIONS:Spatiotemporal gait measures have great variability within homologous EDSS categories. The high percent variability of gait speed and MNV (up to more than 50%) suggests that walking ability varies substantially within and across disability levels. Therefore, in addition to the EDSS, more comprehensive (multidimensional), objective patient-centric metrics would be needed to accurately evaluate disability in pwMS.

BACKGROUND:Fatigue in people with multiple sclerosis (PwMS) can impact physical, cognitive, and psychosocial domains of daily life. The experience of fatigue in PwMS is thought to originate from the central nervous system, particularly for the domain of cognitive fatigue. Here, we tested the hypothesis that fatigue scores in PwMS would be significantly associated with an index of neural activity - the latency of the P100 of the visual evoked potential (VEP) - in line with the notion of a centralized origin of fatigue. We predicted that prolonged VEP latency would be associated with greater fatigue, and that this relationship would be the most pronounced within the domain of cognitive fatigue. METHODS:PwMS (n=249) completed the Modified Fatigue Impact Scale (Global, Physical, Cognitive, and Psychosocial scales of the MFIS) and Fatigue Severity Scale. VEP latency was obtained using an alternating checkerboard paradigm. We also examined the influence of depression (Beck Depression Inventory, second edition, BDI-II) and cognitive functioning (NeuroTrax testing battery) on the VEP/fatigue relationship. RESULTS:Surprisingly, we observed that earlier (not later) VEP latency was significantly associated with higher MFIS Cognitive score. The negative relationship between VEP latency and cognitive fatigue was evident in PwMS that had poor cognitive performance as measured by a latent variable that reflected attention, executive function, information processing speed, and motor skills; but a significant relationship was not observed in PwMS that exhibited good performance on this measure. CONCLUSIONS:These findings can be interpreted within a metacognitive framework - greater fatigue may be perceived when neural performance and the level of mental effort expended does not translate to efficient cognitive performance. Cognitive fatigue may be particularly salient in PwMS when neural resources are unable to compensate for cognitive difficulties. The mismatch between the expectation of what ought to occur and what does occur during cognitive performance may be a key feature of the experience of cognitive fatigue for some PwMS.

Prior studies have reported an association between visual evoked potentials (VEPs) and cognitive performance in people with multiple sclerosis (PwMS), but the specific mechanisms that account for this relationship remain unclear. We examined the relationship between VEP latency and cognitive performance in a large sample of PwMS, hypothesizing that VEP latency indexes not only visual system functioning but also general neural efficiency. Standardized performance index scores were obtained for the domains of memory, executive function, visual-spatial processing, verbal function, attention, information processing speed, and motor skills, as well as global cognitive performance (NeuroTrax battery). VEP P100 component latency was obtained using a standard checkerboard pattern-reversal paradigm. Prolonged VEP latency was significantly associated with poorer performance in multiple cognitive domains, and with the number of cognitive domains in which performance was ≥ 1 SD below the normative mean. Relationships between VEP latency and cognitive performance were significant for information processing speed, executive function, attention, motor skills, and global cognitive performance after controlling for disease duration, visual acuity, and inter-ocular latency differences. This study provides evidence that VEP latency delays index general neural inefficiency that is associated with cognitive disturbances in PwMS.