Faculty Bibliography

BACKGROUND:Neurologists' perceptions of the presence of cognitive impairment (CI) in people with multiple sclerosis (PwMS) may not always align with findings of objective cognitive assessment. The accuracy of self-reported CI in PwMS can also be highly variable across individuals, and may not align with objective measurement of cognitive disturbances. Research suggests that additional factors impact perceived cognitive ability, such as depression and fatigue. Objective cognitive screening regardless of patient or neurologist perception has been recommended but still is often limited in routine care. Moreover, comprehensive neuropsychological assessment is even less routinely done. OBJECTIVE:To explore how neurologists' perceptions of PwMS' CI compare to the perception of the patient by determining whether PwMS and their clinicians are accurate in detecting the presence and degree of CI as defined by a multi-domain validated computerized test battery in PwMS, as well as investigate what factors influence perception of CI in each group. METHODS:PwMS completed a computerized multi-domain cognitive testing battery, and self-reported measures of disease impact (MSIS-29), fatigue (MFIS), and depression (BDI-II). Disability was assessed by the clinician using the Expanded Disability Status Scale (EDSS). Clinicians and patients also provided an estimation of cognitive deficits along a Likert scale. RESULTS:In this cohort of PwMS (N=202, age range: 20 to 88, gender: 71% female), their level of accuracy in detecting attention deficits (k = -.028, p = .010) was low but statistically significant. In contrast, clinicians' accuracy in detecting global CI (k = -.037, p < .001) and a number of specific domain deficits was moderate. Fatigue (p < .001) and cognitive performance (p = .012) significantly predicted patient perceived cognitive deficits. Clinician perceived cognitive performance was significantly predicted by multiple factors: cognitive scores (p < .001), physical disability (p = .011), age (p = .021), and depression (p = .038). CONCLUSION/CONCLUSIONS:The need to objectively screen for CI in PwMS, regardless of perception, can be aided by a better understanding of the agreement and discrepancies between the patient and clinician regarding perceived cognitive disturbances and the presence of CI defined by a multi-dimensional objective screening battery.

BACKGROUND:Infections in people with multiple sclerosis (PwMS) may have a detrimental effect on disease progression, risk of hospitalization, and healthcare resource utilization (HRU). The infection risk and HRU costs may vary between disease-modifying therapies (DMTs); however, the individual risks and differences associated with DMTs are not well characterized. Some DMTs may increase the risk for infections in PwMS; however, previous studies have reported an intact humoral immune response in dimethyl fumarate (DMF)-treated patients. The objective was to compare infection-related HRU and healthcare costs (HCCs) between PwMS treated with DMF or ocrelizumab (OCR). METHODS:Eligible patients were identified from the Optum US claims database between April 2017 and September 2020 (DMF n = 1429; OCR n = 3170). Patients were followed from index date to first occurrence of: (1) end of study, (2) end of insurance eligibility, (3) discontinuation of index DMT, or (4) switch from index DMT to another DMT. Outcomes were annualized rate of infection encounters (defined as infection encounters [n] during follow-up window / days followed [n] × 365); annualized infection-related HCCs (defined as aggregated costs of infection encounters during follow-up window / days followed [n] × 365); location-specific infections, and overall infection-related events. Propensity score matching (PSM) 1:1 method was used; PS was calculated via logistic regression for probability of DMF treatment conditional on demographics and comorbidities. Mean differences (MD) were reported for infection encounter measures. RESULTS:After PSM, DMF and OCR cohorts (n = 1094 in each cohort) were balanced based on baseline characteristics (standardized MD of adjusted baseline characteristics <0.1). Mean (standard deviation) follow-up was 296 (244) days for DMF patients and 297 (243) for OCR patients. DMF patients experienced lower annualized rates of overall infection encounters vs OCR patients (MD -0.51 [95% confidence interval (CI): -0.92 to -0.11], p = 0.01). When stratified by type of infection encounter, DMF patients experienced significantly lower annualized rates of outpatient (MD [95% CI]: -0.44 [-0.80 to -0.08], p = 0.02) and inpatient/hospitalization infection encounters (-0.08 [-0.14 to -0.02], p<0.01) vs OCR patients. A trend towards a shorter duration of infection-related hospitalization in the DMF vs the OCR group was observed (MD [95% CI]: -2.20 [-4.73 to 0.26] days, p = 0.08). The most common infection types in both DMT groups were urinary tract infections, sepsis, and pneumonia. DMF patients experienced lower annualized infection-related HCCs (MD [95% CI]: -$3642 [-$6380 to -$904], p < 0.01) vs OCR patients, which were driven largely by infection-related hospitalization costs (-$3639 [-$6019 to -$1259], p < 0.01). CONCLUSION/CONCLUSIONS:DMF-treated patients PS-matched with OCR patients experienced lower annualized rates of infection encounters and lower infection-related HCCs.

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: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.

BACKGROUND:Fatigue is a common problem experienced by people with multiple sclerosis (PwMS) and can impact physical, cognitive, and psychosocial aspects of daily living and quality of life. The tracking of meaningful longitudinal change in subjective fatigue that occurs as a result of MS activity may be enhanced by incorporating objective neurophysiological measures into longitudinal assessment. To examine this possibility, we examined the longitudinal relationship between visual evoked potential (VEP) measures and a variety of fatigue measures over an approximately two-year period in PwMS. METHODS:VEP measures were obtained using a checkerboard pattern-reversal paradigm. Fatigue was assessed with the Modified Fatigue Impact Scale (MFIS Global, Physical, Cognitive, and Psychosocial subscales) and the Fatigue Severity Scale (FSS) questionnaires. Multiple linear regression analyses were conducted in which the change in each fatigue scale score from baseline to follow-up (T1-to-T2) served as the outcome variables for separate models. Predictor variables included the peak latency of the P100 component of the VEP (maximum peak among the two eyes) and the inter-ocular latency (IOL) at T1, the T1-to-T2 change score for maximum VEP latency and IOL, and the fatigue score at T1 that corresponded to each outcome measure. RESULTS:Prolonged baseline VEP latency was a significant predictor of the T1-to-T2 increase in MFIS Global score, and increased VEP latency from baseline to follow-up was significantly associated with MFIS Cognitive score over the same time period. Furthermore, VEP latency measures in these two models were better predictors of changes in fatigue than baseline fatigue scores were, based on the magnitude of the standardized beta coefficients. Subsequent post-hoc analyses revealed that the relationship between change in VEP latency and change in MFIS Cognitive score was evident primarily for PwMS that had elevated MFIS Cognitive score at baseline. CONCLUSION/CONCLUSIONS:The present study provides novel evidence that prolonged VEP latency is predictive of worsening of global and cognitive fatigue in PwMS. VEP latency measures may therefore provide clinical utility for monitoring changes in fatigue in PwMS, when used in conjunction with other clinical tools.

Visual evoked potentials (VEP) index visual pathway functioning, and are often used for clinical assessment and as outcome measures in people with multiple sclerosis (PwMS). VEPs may also reflect broader neural disturbances that extend beyond the visual system, but this possibility requires further investigation. In the present study, we examined the hypothesis that delayed latency of the P100 component of the VEP would be associated with broader structural changes in the brain in PwMS. We obtained VEP latency for a standard pattern-reversal checkerboard stimulus paradigm, in addition to Magnetic Resonance Imaging (MRI) measures of whole brain volume (WBV), gray matter volume (GMV), white matter volume (WMV), and T2-weighted fluid attenuated inversion recovery (FLAIR) white matter lesion volume (FLV). Correlation analyses indicated that prolonged VEP latency was significantly associated with lower WBV, GMV, and WMV, and greater FLV. VEP latency remained significantly associated with WBV, GMV, and WMV even after controlling for the variance associated with inter-ocular latency, age, time between VEP and MRI assessments, and other MRI variables. VEP latency delays were most pronounced in PwMS that exhibited low volume in both white and gray matter simultaneously. Furthermore, PwMS that had delayed VEP latency based on a clinically relevant cutoff (VEP latency ≥ 113 ms) in both eyes had lower WBV, GMV, and WMV and greater FLV in comparison to PwMS that had normal VEP latency in one or both eyes. The findings suggest that PwMS that have delayed latency in both eyes may be particularly at risk for exhibiting greater brain atrophy and lesion volume. These analyses also indicate that VEP latency may index combined gray matter and white matter disturbances, and therefore broader network connectivity and efficiency. VEP latency may therefore provide a surrogate marker of broader structural disturbances in the brain in MS.

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.