The moderating roles of self-efficacy and depression in dual-task walking in multiple sclerosis: A test of self-awareness theory.

OBJECTIVE: Multiple sclerosis (MS) is a debilitating neurological disease associated with a variety of psychological, cognitive, and motoric symptoms. Walking is among the most important functions compromised by MS. Dual-task walking (DTW), an everyday activity in which people walk and engage in a concurrent, discrete task, has been assessed in MS, but little is known about how it relates to other MS symptoms. Self-awareness theory suggests that DTW may be a function of the interactions among psychological, cognitive, and motor processes. METHOD: Cognitive testing, self-report assessments for depression and falls self-efficacy (FSE), and walk evaluations [DTW and single-task walk (STW)] were assessed in seventy-three people with MS in a clinical care setting. Specifically, we assessed whether psychological factors (depression and FSE) that alter subjective evaluations regarding one's abilities would moderate the relationships between physical and cognitive abilities and DTW performance. RESULTS: DTW speed is related to diverse physical and cognitive predictors. In support of self-awareness theory, FSE moderated the relationship between STW and DTW speeds such that lower FSE attenuated the strength of the relationship between them. DTW costs - the change in speed normalized by STW speed - did not relate to cognitive and motor predictors. DTW costs did relate to depressive symptoms, and depressive symptoms moderated the effect of information processing on DTW costs. CONCLUSIONS: Findings indicate that an interplay of physical ability and psychological factors - like depression and FSE - may enhance understanding of walking performance under complex, real-world, DTW contexts.

The association between MRI brain volumes and computerized cognitive scores of people with multiple sclerosis.

BACKGROUND: Computerized cognitive assessment facilitates the incorporation of multi-domain cognitive monitoring into routine clinical care. The predictive validity of computerized cognitive assessment among people with multiple sclerosis (PwMS) has scarcely been investigated. OBJECTIVE: To explore the associations between brain volumes and cognitive scores from a computerized cognitive assessment battery (CAB, NeuroTrax) among PwMS. METHODS: PwMS were evaluated with the CAB and underwent brain MRI within 40 days. Cognitive assessment yielded age- and education-adjusted scores in 9 cognitive domains: memory, executive function, attention, information processing speed, visual spatial, verbal function, motor skills, problem solving, and working memory. The global cognitive score (GCS) is the average of all domain scores. MRI brain and lesion volumes were assessed with icobrain ms, a fully automated tissue and lesion segmentation and quantification software. RESULTS: 91 PwMS were included [Age: 52.1 ± 11.7 years, 64 (70%) female, EDSS: 3.4 ± 2.0, 79 (87%) with a relapsing remitting course]. Significant correlations were found between the GCS and whole brain, white matter, grey matter, thalamic, lateral ventricles, hippocampal and lesion volumes (Correlation coefficients: 0.46, 0.40, 0.25, 0.42, -0.36, 0.21, -0.3, respectively). Regression analysis revealed that lateral ventricles and thalamic volumes were the most consistent predictors of all cognitive domain scores. CONCLUSION: Computerized cognitive scores were significantly associated with quantified MRI. These findings support the predictive validity of multi-domain computerized cognitive assessment for people with multiple sclerosis.

The impact of subjective cognitive fatigue and depression on cognitive function in patients with multiple sclerosis.

BACKGROUND: The association between subjective cognitive fatigue and objective cognitive dysfunction in patients with multiple sclerosis (PwMS) has been studied, with conflicting results. OBJECTIVE: To explore the impact of fatigue on cognitive function, while controlling for the influence of depression, disability, comorbidities, and psychotropic medications. METHODS: PwMS completed a computerized cognitive testing battery with age- and education-adjusted cognitive domain scores. Disability (Expanded Disability Status Scale (EDSS)), cognitive fatigue, and depression were concurrently evaluated. RESULTS: In all, 699 PwMS were included. Both cognitive fatigue and depression were significantly and negatively correlated with the same cognitive domains: information processing speed, executive function, attention, motor function, and memory (-0.15 ⩽ r ⩽ -0.14 for cognitive fatigue; -0.24 ⩽ r ⩽ -0.19 for depression). Multivariate analysis revealed significant but small independent correlations only between depression and neuropsychological test results, while cognitive fatigue had no independent correlation with objective cognitive function except for a trend toward impaired motor function in highly fatigued PwMS. Depression and cognitive fatigue accounted for no more than 6% of the variance in objective cognitive domain scores. CONCLUSION: Cognitive fatigue is not independently related to objective cognitive impairment. Depression may influence cognitive function of PwMS primarily when it is severe. Cognitive impairment in PwMS should not be ascribed to fatigue or mild depression.

Shifting paradigms in multiple sclerosis: from disease-specific, through population-specific toward patient-specific.

PURPOSE OF REVIEW: In recent years we notice paradigm shifts in the understanding of multiple sclerosis (MS), leading to important transition in the patients' management. This review discusses some of the recent findings and developments underlying the conceptual changes being translated from 'treating the disease' to 'treating the patient' with MS (PwMS). RECENT FINDINGS: Applying advanced technologies combined with cross-disciplinary efforts in the fields of neuropathology, neuroimmunology, neurobiology, and neuroimaging, together with clinical neurology provided support for the notion that MS is not a single disease but rather a spectrum. Predictive markers of disease subtypes, disease activity and response to therapy are being developed; some already applied to practice, allowing informed management. In parallel, population-specific issues, some genetic-driven, others caused by environmental (sun-exposure, life-style, etc.), gender-related (hormones) and epigenetic factors, are being elucidated. Additionally, patient empowerment-based approaches, including integration of patient-reported outcome measures (PRO) as well as tools to enhance patients' adherence to medications, are being developed, some already provided as part of emerging mobile-health technologies. SUMMARY: Developments in the MS field, elucidating disease subtypes and interpopulation diversities, together with integration of patient-centered approaches, allow transition toward precision medicine in MS clinical trials and patient care.

[FROM STATISTICAL ASSOCIATIONS TO SCIENTIFIC CAUSALITY].

The pathogenesis of most chronic diseases is complex and probably involves the interaction of multiple genetic and environmental risk factors. One way to learn about disease triggers is from statistically significant associations in epidemiological studies. However, associations do not necessarily prove causation. Associations can commonly result from bias, confounding and reverse causation. Several paradigms for causality inference have been developed. Henle-Koch postulates are mainly applied for infectious diseases. Austin Bradford Hill's criteria may serve as a practical tool to weigh the evidence regarding the probability that a single new risk factor for a given disease is indeed causal. These criteria are irrelevant for estimating the causal relationship between exposure to a risk factor and disease whenever biological causality has been previously established. Thus, it is highly probable that past exposure of an individual to definite carcinogens is related to his cancer, even without proving an association between this exposure and cancer in his group. For multifactorial diseases, Rothman's model of interacting sets of component causes can be applied.

The prevalence of multiple sclerosis in Israel based on validation of a health care organization database.

In Israel there is no registry of multiple sclerosis (MS), thus the prevalence of MS is unknown. Clalit Health Services (CHS) is Israel's largest health care organization. We have developed an algorithm to identify people with MS (PwMS) using CHS database and validated it against a gold-standard diagnosis by expert neurologists. People with a possible diagnosis of MS were identified in CHS database according to ICD-9 code or dispense of MS specific disease modifying treatment (DMT). The electronic medical records (EMRs) of a random sample of 25% of this population, stratified by age and sex were examined to determine positive predictive value (PPV). Another age- and sex- stratified random sample of 15% of pwMS under our care were searched in CHS database to determine database sensitivity (Sn). Finally, a random sample of 40% of people without MS were searched in CHS database to evaluate database specificity (Sp). The best case definition to retrieve pwMS was ICD-9 code 340 as an established diagnosis or at least one dispense of a DMT (PPV = 87%, Sn = 92%, Sp = 90%). Using this definition the prevalence of MS in Israel was 68, 82 and 95 per 100,000 population by the end of 2011, 2016 and 2021, respectively. The prevalence of MS in Israel is rising, in line with the worldwide trend.

Polysomnography parameters in a large cohort of people with multiple sclerosis.

BACKGROUND: Disordered and disturbed sleep is quite common among people with multiple sclerosis (PwMS). It is associated with fatigue one of most disabling symptoms in MS. This study aims at comparing polysomnographic (PSG) sleep parameters in a large single cohort of PwMS from a single center to that of the published norms. Hence establishing PSG parameters in PwMS. METHODS: This is a retrospective review of 299 consecutive adult PwMS who were seen and evaluated with an overnight PSG at a Comprehensive MS Care Center between 11/19/2001 to 9/17/2014. Data extracted from the PSG included Total Sleep Time (TST), sleep efficiency (SE), sleep onset latency (SOL), Relative REM latency, total apnea-hypopnea indices (AHI), spontaneous arousal indices (AI), total periodic leg movements indices (PLMI) and, sleep architecture metrics including percentage spent in stages N1/N2, N3, and REM. RESULTS: PwMS, compared to normative data, had, on average, 85.9 min shorter TST (p < 0.001), 27.3 min longer SOL (p < 0.0001), 62.1 min longer REM latency (p < 0.0001), 10.7 % lower SE (p < 0.0001), 16.4 % more N1/N2 (p < 0.0001) and 11.4 % less N3 (p < 0.0001). REM latency The prevalence of Obstructive Sleep Apnea (OSA) was high at 60.7 % and the mean AHI was higher by 11.1 events per hour (p < 0.0001). CONCLUSIONS: This study establishes PSG parameters in the largest PwMS cohort reported to date. It is important to be vigilant of sleep complaints in PwMS. Future prospective large single cohort studies with standardized methods are needed to further understand sleep disturbances in PwMS as well as their causes and implications.

Multiple Sclerosis, Fatigue, Expanded Disability Status Scale: A Cross-Sectional Exploration of Sleep Efficiency and Quantitative Sleep Parameters.

BACKGROUND: Poor sleep quality and sleep disorders are more prevalent in individuals with multiple sclerosis (MS) than in the general population. Poor sleep has been correlated with worse MS outcomes. Sleep efficiency (SE) is one of the most sensitive markers of sleep quality. There is very little written about SE and other polysomnography (PSG) parameters and MS measures. METHODS: This is a retrospective review of 280 consecutive individuals with MS evaluated by PSGs and other standardized MS measures over 13 years at a comprehensive MS center. In addition, the cohort was assessed with 2 fatigue scales, the Epworth Sleepiness Scale, and the Expanded Disability Status Scale. A comparison of means test (independent t test) and a correlation coefficient (r) were used. RESULTS: The PSG measures of SE and Total Sleep Time were significantly different between a group of individuals with MS with a disease duration of more than 5 years vs a group of individuals with MS with a disease duration less than or equal to 5 years. Prevalence of obstructive sleep apnea was 63%, higher than reported in the literature while the prevalence of moderate to severe obstructive sleep apnea was 33.4%, which was lower than reported. CONCLUSIONS: Longer disease duration and worse disability correlate with sleep quality as measured by SE.

Peering further into the mind's eye: combining visual evoked potential and optical coherence tomography measures enhances insight into the variance in cognitive functioning in multiple sclerosis.

BACKGROUND: Spectral Optical Coherence Tomography (OCT) and Visual Evoked Potentials (VEPs) have both emerged as potentially useful biomarkers of cognitive decline in people with multiple sclerosis (PwMS). Their combined use may provide additional predictive value for identifying disease impact, progression, and remyelination capacity above-and-beyond what is captured using either approach alone. OBJECTIVE: We examined the relationship between OCT/VEP measures and cognitive functioning in 205 PwMS. OCT measures included Retinal Nerve Fiber Layer Volume (RNFLV), Papillo-Macular Bundle Volume (PBMV), and Macular Volume (MV). VEP measures included latency of the P100, and inter-ocular latency. Cognitive performance was evaluated across seven separate domains of performance, and for overall cognition, using the NeuroTrax computerized testing battery. RESULTS: Both OCT and VEP measures were significantly correlated with cognitive performance across several domains. Linear regression models that controlled for the influence of visual acuity revealed (1) that reduced MV was significantly predictive of poorer visual-spatial functioning, and (2) that delayed VEP latency was significantly predictive of performance in global cognitive functioning and visual-spatial functioning, after controlling for multiple comparisons. Among PwMS with normal visual acuity, PwMS with a combination of both relatively low MV and delayed VEP latency tended to have poorer performance in the domains of global, executive, and visual-spatial functioning compared to PwMS with both high MV and normal VEP latency. CONCLUSION: Approaches that combine the use of OCT and VEP measures can enhance insight into underlying factors that contribute to variance in cognitive functioning in PwMS.

De-escalation of Disease-Modifying Therapy for People with Multiple Sclerosis Due to Safety Considerations: Characterizing 1-Year Outcomes in 25 People Who Switched from Ocrelizumab to Diroximel Fumarate.

INTRODUCTION: Switching disease-modifying therapy (DMT) may be considered for relapsing-remitting multiple sclerosis (RRMS) if a patient's current therapy is no longer optimal. This was particularly important during the recent COVID-19 pandemic because of considerations around immune deficiency and impaired vaccine response associated with B cell-depleting DMTs. This real-world, single-center study aimed to evaluate change or decline in functional ability and overall disease stability in people with RRMS who were switched from B cell-depleting ocrelizumab (OCRE) to diroximel fumarate (DRF) because of safety concern related to the COVID-19 pandemic. METHODS: Adults with RRMS were included if they had been clinically stable for ≥ 1 year on OCRE. Data collected at baseline and 1 year post switch included relapse rate, magnetic resonance imaging (MRI), blood work for assessment of peripheral immune parameters, the Cognitive Assessment Battery (CAB), optical coherence tomography (OCT), and patient-reported outcomes (PROs). RESULTS: Participants (N = 25) had a mean (SD) age of 52 (9) years, and a mean (SD) duration of 26 (8) months' treatment with OCRE before the switch to DRF. Median washout duration since the last OCRE infusion was 7 months (range 4-18 months). No participants relapsed on DRF during follow-up, and all remained persistent on DRF after 1 year. There were no significant changes in peripheral immune parameters, other than an increase in the percentage of CD19+ cells 1 year after switching (p < 0.05). Similarly, there were no significant changes in CAB, OCT, and PROs. CONCLUSION: These preliminary findings suggest that transition to DRF from OCRE may be an effective treatment option for people with RRMS who are clinically stable but may need to switch for reasons unrelated to effectiveness. Longer follow-up times on larger samples are needed to confirm these observations.

Exploring the relationship between manual dexterity and cognition in people with multiple sclerosis: 9-hole peg and multiple cognitive functions.

AIM AND RATIONALE: Problems with manual dexterity and cognition impact the everyday performance of people with multiple sclerosis (PwMS). Accumulated findings point to the relationship between deficits in manual dexterity and auditory domains of cognition with a lack of evidence on visuospatial and verbal aspects of cognitive functioning. Therefore, this study explores the relationship between manual dexterity and cognition in a cohort of PwMS. METHOD: This cross-sectional study collected data from 63 PwMS aged 22 to 55 through a convenient sampling method. Participants were diagnosed with relapsing-remitting multiple sclerosis (RRMS). Cognition was measured using a multi-domain computerized cognitive testing, NeuroTrax, and manual dexterity was measured using a 9-hole peg assessment. Spearman correlation was used to identify the correlation among cognition subtests as well as with manual dexterity. Linear regression analysis was also conducted to identify whether manual dexterity predicts cognitive functioning. RESULTS: A significant negative correlation was found between 9-hole peg scores and global cognitive scores (GCS), r = -0.34, p = 006. The manual dexterity scores were also shown to predict GCS, R2= 0.165, p = 0.001. CONCLUSION: Manual dexterity was found to not only predict cognitive dysfunction but was also associated with multiple cognitive domains. Understanding the relationship between manual dexterity and cognition and the inferred progression of deficits can assist clinicians to provide interventions at earlier stages of disease progression to potentially increase daily functioning and quality of life (QoL).

The influence of vitamin D supplementation on melatonin status in patients with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) incidence is higher in geographic regions with less sunlight exposure. Both vitamin D and melatonin are essential mediators of the effect of sunlight in health, and as such are candidates to play a key role in MS. We hypothesized that vitamin D and melatonin may have related influences in patients with MS. METHODS: In a randomized, double blind study of 40 IFN-ß treated MS patients, 21 patients were assigned to 800 IU of vitamin D3 per day (low dose), while 19 patients received 4,370 IU vitamin D3 per day (high dose) for one year. Serum 25-hydroxy-vitamin-D (25-OH-D) and nighttime urine melatonin metabolite, 6-sulphatoxy-melatonin (6-SMT), were measured at baseline, 3 months and 1 year from enrolment. RESULTS: After 3 months supplementation, 25-OH-D levels increased and nighttime melatonin secretion decreased significantly in the high dose group, but not in the low dose group. After 1 year, a decrease in 25-OH-D levels, accompanied by an increase of urine nighttime 6-SMT were observed in the high dose group. Percent change in serum 25-OH-D was significantly and negatively correlated with percent change in urine 6-SMT after 3 months and between 3 months to 1 year. 25-OH-D levels by the end of the study were significantly and negatively correlated to BMI. CONCLUSIONS: Melatonin secretion is negatively correlated with alterations in serum 25-OH-D in IFN-ß treated patients with MS. The finding suggests that melatonin should be considered as a potential mediator of vitamin D neuro-immunomodulatory effects in patients with MS.

Vitamin D supplementation for patients with multiple sclerosis treated with interferon-beta: a randomized controlled trial assessing the effect on flu-like symptoms and immunomodulatory properties.

BACKGROUND: Flu-like symptoms (FLS) are common side effects of interferon beta (IFN-ß) treatment in patients with Multiple Sclerosis (PwMS) and are associated with post-injection cytokine surge. We hypothesized that vitamin D3 supplementation would ameliorate FLS by decreasing related serum cytokines' levels. METHODS: In a randomized, double blind study of 45 IFNß-treated PwMS, 21 patients were assigned to 800 IU of vitamin D3 per day (low dose), while 24 patients received 4,370 IU per day (high dose) for one year. FLS were assessed monthly by telephonic interviews. Serum levels of 25-hydroxy-D (25-OH-D), calcium, PTH, IL-17, IL-10 and IFN-γ were measured periodically. EDSS, relapses, adverse events and quality of life (QoL) were documented. RESULTS: 25-OH-D levels increased to a significantly higher levels and PTH levels decreased in the high dose group. There was no significant change in FLS. IL-17 levels were significantly increased in the low dose group, while patients receiving high dose vitamin D had a heterogeneous IL-17 response. No significant differences in relapse rate, EDSS, QoL, serum IL-10 and IFNγ were found. Hypercalcemia or other potential major adverse events were not observed. CONCLUSION: Vitamin D supplementation to IFN-ß treated PwMS, at the doses used, seems safe and associated with dose-dependent changes in IL-17 serum levels, while not affecting IFN-ß related FLS. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01005095.

Safety of lumbar puncture for people who are treated with ADP receptor antagonists.

BACKGROUND: Current guidelines state that clopidogrel and other adenosine-diphosphate receptor antagonists (ADPra) should be stopped for at least 7 days before lumbar puncture (LP). This practice may delay the diagnosis of treatable neurological emergencies and may increase the risk of cardiovascular morbidity due to withholding antiplatelets. We aimed to summarize all cases under our care, in which LP was performed without discontinued ADPra. METHODS: A retrospective case series study of all patients who underwent LP without interruption of ADPRa or with treatment interruption that was shorter than 7 days. Medical records were searched for documented complications. Traumatic tap was defined as cerebrospinal fluid red cell count ≥ 1000 cell/µL. Incidence of traumatic tap among people who underwent LP under ADPRa was compared to traumatic tap incidence in two control groups: LP under aspirin and LP without any anti-platelet. RESULTS: 159 patients underwent LP under ADPRa [Age: 68.4 ± 12.1, Female: 63 (40%), 81 (51%) were treated with both aspirin and ADPRa]. 116 procedures were carried out without any interruption of ADPRa. In the other 43, the median delay between treatment interruption and the procedure was 2 days (range: 1-6 days). Incidence of traumatic tap was 8/159 (5%), 9/159 (5.7%) and 4/160 (2.5%) among those who underwent LP under ADPRa, under aspirin and without any anti-platelet, respectively. [X2(2) = 2.13, P = 0.35)]. No patient developed spinal hematoma or any neurological deficit. CONCLUSIONS: Lumbar puncture without discontinuation of ADP receptor antagonists seems safe. Similar case series may ultimately lead to guidelines change.

Risk of breakthrough COVID-19 after vaccination among people with multiple sclerosis on disease-modifying therapies.

BACKGROUND: Disease-modifying therapies (DMTs) for people with multiple sclerosis (pwMS) may decrease vaccine effectiveness. We aimed to explore the association between various DMTs and the risk for breakthrough COVID-19. METHODS: Population-based data from Clalit Health Services, Israel's largest healthcare organization, were used. PwMS treated with DMTs without prior COVID-19 were followed from the commencement of the mass vaccination campaign in December 2020. The end of follow-up was at the time of COVID-19 infection, the receipt of a third vaccine dose or until the end of August 2021. Time-dependent multivariate Cox proportional hazard models were used to estimate hazard ratios for COVID-19 according to vaccination, DMT, age, gender, disability and comorbidities. RESULTS: 2511 PwMS treated with DMTs were included (Age: 46.2 ± 14.6, 70% Female, EDSS: 3.0 ± 2.1). Of whom, 2123 (84.5%) received 2 vaccine doses. On multivariate models that included all pwMS, vaccination was protective (HR = 0.41, P < 0.001). On multivariate models that included only fully vaccinated pwMS cladribine, ocrelizumab, S1P receptor modulators and natalizumab were associated with breakthrough COVID-19 (HR = 6.1, 4.7, 3.7 and 3.3; P = 0.004, 0.008, 0.02 and 0.05, respectively). On multivariate models that included unvaccinated and fully vaccinated pwMS on each DMT separately, a protective trend was noted for vaccination on all DMTs (0.09 < HR < 0.65), except for cladribine (HR = 1.1). This protective trend was not statistically significant on ocrelizumab, S1P receptor modulators and natalizumab. COVID-19 among pwMS was generally mild. Only 2 vaccinated pwMS had a severe infection with eventual recovery. CONCLUSIONS: Vaccination effectively protects pwMS from COVID-19. An increased risk of breakthrough infection was noted on high-efficacy DMTs, however COVID-19 after vaccination was usually mild.

Cognitive impairment in people with multiple sclerosis: Perception vs. performance - factors that drive perception of impairment differ for patients and clinicians.

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: 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.

Multiple sclerosis and quality of life: The role of cognitive impairment on quality of life in people with multiple sclerosis.

BACKGROUND: Multiple Sclerosis (MS), a chronic disease of the central nervous system (CNS), affects functional ability and quality of life (QoL). Depression, fatigue, and disability status are among the many factors that have been shown to impact QoL in people with MS, but the extent to which MS-related cognitive impairment is related to QoL is understudied in the literature. OBJECTIVE: The purpose of this study was to determine relevant predictors of QoL from a wide list of symptoms including physical disability, and a multi-dimensional computerized cognitive assessment battery (CAB), depression, fatigue, and demographic variables (including employment status). In addition, the unique predictive power of cognitive impairment on QoL was explored in relation to other common factors of disease impact. METHODS: 171 people with MS (PwMS) were evaluated with a computerized assessment battery (CAB), EDSS examination, and validated Patient Reported Outcome (PRO) measures (Multiple Sclerosis Impact Scale, MSIS-29; Beck Depression Inventory - Second Edition BDI-2; and the Modified Fatigue Impact Scale, MFIS). RESULTS: 171 PwMS were included [Age: 46.02 years ± 9.85, 124 (72.5%) female]. Depression and fatigue scores were highly correlated with MSIS-29. EDSS, unemployment, memory, executive functioning, and motor skills were moderately correlated with MSIS-29. Predictors of QoL were EDSS, depression, fatigue, executive functioning, and attention. Attention and executive functioning were predictive of QoL even after controlling for demographic variables, fatigue, depression, and physical disability status. CONCLUSION: Findings indicate the need for comprehensive and quantified evaluation of all factors associated with disease burden, which will ultimately serve to improve the QoL in PwMS through more targeted and patient-centered care.

Cognitive impairment, fatigue and depression in multiple sclerosis: Is there a difference between benign and non-benign MS?

INTRODUCTION: Multiple Sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). The severity of disability in people with MS (PwMS) is generally measured with the Expanded Disability Status Scale (EDSS). A variant of MS known as 'benign MS' (BMS) has been defined as an EDSS score of 3 or lower, combined with a disease duration of 10 years or longer; however, there is disagreement in the field about whether BMS really exists. Given that the EDSS does not capture cognitive issues, communication dysfunction, fatigue, depression, or anxiety properly, its ability to accurately represent disability in all PwMS, including BMS, remains questionable. METHODS: In this study, 141 persons with BMS (PwBMS) were included, consisting of 115 females (82%) and 26 males (18%) with a mean age of 50.8 (±8.68). A computerized test battery (NeuroTrax®) was used to assess cognition, covering seven cognitive domains (memory, executive function, visual-spatial processing, verbal function, attention, information processing, and motor skills). Fatigue was measured using the Fatigue Severity Scale (FSS). The Beck Depression Inventory (BDI) was used to assess symptoms of depression. Cognitive impairment was defined for this study as when someone has a score lower than 85 in at least two subdomains of the cognitive test battery. Rates of impairment were compared to 158 persons with non-benign MS (PwNBMS; with a disease duration of 10 years and longer and an EDSS score higher than 3) and 487 PwMS with a disease duration of fewer than 10 years. RESULTS: Cognitive impairment was found in 38% of PwBMS and in 66% of PwNBMS (p<0.001). In PwBMS, the lowest rate of impairment was found in the verbal function domain (18%) and the highest rate of impairment in the domain of information processing (32%). Fatigue and depression were found in 78% and 55% of all PwBMS, with no difference in these rates between PwBMS and PwNBMS (p = 0.787 and p = 0.316 resp.) CONCLUSION: Cognitive impairment, fatigue and depression are common among people with an EDSS-based definition of benign MS. These aspects should be incorporated into a new and better definition of truly benign MS.

Variability of objective gait measures across the expanded disability status scale in people living with multiple sclerosis: A cross-sectional retrospective analysis.

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: All gait measures exhibited fair to very strong correlations with scores on the EDSS (-0.81≤ρs≤0.25) and poor to fair correlations with disease duration (-0.32≤ρs≤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 (2.54.5) disability groups, respectively. CONCLUSION: 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.

Prolonged visual evoked potential latency predicts longitudinal worsening of fatigue in people with multiple sclerosis.

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: 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.