The Expanded Disability Status Scale Score and Demographic Indexes Are Correlated with the Severity of Cognitive Impairment in Multiple Sclerosis Patients

Background and PurposeCognitive impairment (CI) is a common symptom of multiple sclerosis (MS). Although demographic and clinical factors contribute to MS-dependent CI, previous findings have been inconsistent. This study aimed to identify the cognitive domains that are impaired in MS patients, and to determine the impacts of the Expanded Disability Status Scale (EDSS) score and other clinical and demographic factors on them domains.MethodsThis study enrolled 115 MS patients. Cognitive performance was assessed using the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) battery. CI severity was assessed based on the number of impaired tasks in the MACFIMS battery, with impairment in two or more tasks defined as CI cases. Correlation analysis was used to determine whether factors including current age, age at disease onset, EDSS score, disease duration, relapse rate, and education level affect the severity of CI.ResultsThe scores on the Paced Auditory Serial Addition Test and Delis-Kaplan Executive Function System were the most and least affected, respectively. EDSS score (r=0.438, p<0.001), current age (r=0.393, p<0.001), and disease duration (r=0.486, p<0.001) were positively correlated with CI severity, whereas education level (r=−0.527, p<0.001) had a negative correlation with CI severity, and age at disease onset and relapse rate were not correlated with CI severity (r=0.150 and p=0.107, and r=0.052 and p=0.530, respectively). However, all variables (except EDSS score) significantly predicted CI severity in a multiple regression model (p<0.001, r=0.668).ConclusionsInformation processing speed and working memory were the most commonly affected cognitive domains in the present MS patients. CI severity had strong positive correlations with current age, EDSS score, and disease duration, and a negative correlation with education level. The relapse rate and age at disease onset were not correlated with CI severity.     

Injectable Versus Oral First-Line Disease-Modifying Therapies: Results from the Italian MS Register

The current study aims to compare injectable and oral first-line disease-modifying therapies (DMTs) for time to first relapse, time to confirmed disability progression (CDP), and time to discontinuation using a cohort of relapsing remitting multiple sclerosis (RRMS) patients, with data extracted from the Italian MS Register. This multicenter, observational, retrospectively acquired, and propensity-adjusted cohort study utilized RRMS-naïve patients from the Italian MS Register who started either injectable or oral first-line DMTs between January 1, 2010, and December 31, 2017, to evaluate the impact on disability outcomes in patients. Enrolled patients were divided into two groups, namely the injectable group (IG) and the oral group (OG). Of a cohort of 11,416 patients, 4602 were enrolled (3919 in the IG and 683 in the OG). The IG had a higher rate of women (67.3% vs 63.4%, p < 0.05) and a lower mean age (36.1 ± 10.9 vs 38.9 ± 11.8, p < 0.001). The event time to first relapse demonstrated a lower risk in the OG (HR = 0.58; CI 95% 0.48–0.72, p < 0.001). However, no differences were found between the two groups with respect to the risk of CDP (HR = 0.94; CI 95% 0.76–1.29, p = 0.941), while a lower risk of DMT was found in the OG (HR = 0.72; CI 95% 0.58–0.88, p = 0.002) for the event time to discontinuation. Real-world data from the Italian MS Register suggests that first-line oral DMTs are associated with a lower risk of experiencing a new relapse and of therapy discontinuation compared to injectable DMTs.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-020-01001-6.Key Words: Multiple sclerosis, injectable DMTs, oral DMTs, real-world setting, EDSS score     

Interferon-beta and disability progression in relapsing-remitting multiple sclerosis

ObjectiveTo assess the impact of interferon (IFN)-beta treatment on the progression of unremitting disability in IFN-beta treated and untreated relapsing-remitting (RR) patients with multiple sclerosis (MS) using prospective cohort study.MethodsA cohort of 419 RRMS (236 IFN-beta-treated and 183 untreated) patients was followed for up to 7 years. Cox proportional hazards regression models adjusted for the number of relapses in the last year before first visit was used to assess the differences between the two groups for the three end points: secondary progression (SP), and sustained Expanded Disability Status Scale (EDSS) score 4 and 6. Time from disease onset was used as survival time variable.ResultsThe IFN-beta-treated group showed a highly significant reduction (hazard ratio [HR], 0.34, 95% confidence interval [CI] 0.19–0.61, p < 0.001) in the risk of SP when compared with untreated patients. There were significant differences in favor of the IFN-beta-treated group for the end point EDSS score of 4 (HR = 0.45, 95%CI 0.28–0.73, p = 0.001) and EDSS score of 6 (HR = 0.34, 95%CI 0.16–0.75, p = 0.007).ConclusionThis observational study further supports the notion that IFN-beta could have potential beneficial effect on disease progression in RRMS.     

Continuous daily assessment of multiple sclerosis disability using remote step count monitoring

Disability measures in multiple sclerosis (MS) rely heavily on ambulatory function, and current metrics fail to capture potentially important variability in walking behavior. We sought to determine whether remote step count monitoring using a consumer-friendly accelerometer (Fitbit Flex) can enhance MS disability assessment. 99 adults with relapsing or progressive MS able to walk ≥2-min were prospectively recruited. At 4 weeks, study retention was 97% and median Fitbit use was 97% of days. Substudy validation resulted in high interclass correlations between Fitbit, ActiGraph and manual step count tally during a 2-minute walk test, and between Fitbit and ActiGraph (ICC = 0.76) during 7-day home monitoring. Over 4 weeks of continuous monitoring, daily steps were lower in progressive versus relapsing MS (mean difference 2546 steps, p < 0.01). Lower average daily step count was associated with greater disability on the Expanded Disability Status Scale (EDSS) (p < 0.001). Within each EDSS category, substantial variability in step count was apparent (i.e., EDSS = 6.0 range 1097–7152). Step count demonstrated moderate-strong correlations with other walking measures. Lower average daily step count is associated with greater MS disability and captures important variability in real-world walking activity otherwise masked by standard disability scales, including the EDSS. These results support remote step count monitoring as an exploratory outcome in MS trials.     

Glial fibrillary acidic protein: a potential biomarker for progression in multiple sclerosis

The major intermediate cytoskeletal protein of astrocytes, glial fibrillary acidic protein (GFAP), and that of axons, neurofilament light protein (NFL), may both be released into the cerebrospinal fluid (CSF) during pathological processes in the central nervous system (CNS). We investigated GFAP and NFL levels in CSF as possible biomarkers for progression in multiple sclerosis (MS). Patients with relapsing-remitting MS (RRMS, n = 15) or secondary progressive MS (SPMS, n = 10) and healthy control subjects (n = 28) were examined twice with an interval of 8–10 years apart. Neurological deficits were scored with the Expanded Disability Status Scale (EDSS). GFAP and NFL levels were determined in CSF by enzyme-linked immunosorbent assay (ELISA). GFAP levels and NFL levels correlated with age (r and r _s = 0.50, p = 0.006). Adjusting for age, MS patients had increased GFAP levels compared with controls (p = 0.03) and GFAP levels correlated with neurological disability (EDSS, r = 0.51, p < 0.05) and disease progression [Multiple Sclerosis Severity Score (MSSS), r = 0.47, p < 0.05]. The mean annual increase of GFAP was 6.5 ng/L for controls, 8.1 ng/L for RRMS patients, and 18.9 ng/L for SPMS patients. GFAP level at the first examination had predictive value for neurological disability 8–10 years later (EDSS, r = 0.45, p < 0.05) but not for EDSS increase between the examinations. NFL levels were not significantly increased in MS patients compared with controls and had no relationship to disability or progression and no prognostic value for disability development. GFAP, a marker for astrogliosis, is a potential biomarker for MS progression and may have a role in clinical trials for assessing the impact of therapies on MS progression.     

Short interval intracortical facilitation correlates with the degree of disability in multiple sclerosis

BackgroundThe Expanded Disability Status Scale (EDSS) is the most widely used measure of disability in MS, however because of its limitations surrogate markers of clinical disability progression are of high interest. Transcranial magnetic stimulation (TMS) measures of demyelination and cortical excitability correlate with disability levels in MS.ObjectiveAim of this study was testing whether paired pulse (pp) TMS represents a reliable surrogate marker to measure clinical disability in MS.MethodsppTMS measures of intracortical synaptic transmission such as short interval intracortical inhibition (SICI), long interval intracortical inhibition (LICI), short interval intracortical facilitation (SICF) and intracortical facilitation (ICF) were collected from 74 patients affected by MS. Correlation of EDSS scores with ppTMS measures was analyzed.ResultsEDSS scores correlated with patient’s age, disease duration, Motor Evoked Potentials latency and thresholds and SICF measures but not with age of onset, SICI, ICF and LICI.ConclusionsThese findings support a possible use of SICF and MEP latency as surrogate markers of disability in MS. Further research is warranted to determine the role of SICF in the follow up of disease progression and to validate its use as an endpoint in multiple sclerosis clinical trials.     

Electrophysiological and clinical correlates of corpus callosum atrophy in patients with multiple sclerosis

Abstract

Multiple sclerosis (MS) is an idiopathic inflammatory demyelinating disorder of the central nervous system (CNS) characterized by demyelination and axonal degeneration. Corpus callosum (CC) is commonly involved during the disease process leading to atrophy (93%). Currently, there are no established markers of disease progression and the interplay of processes leading to brain atrophy in MS remains unknown. The primary aim of this study was to assess the frequency of CC atrophy in MS patients. Furthermore, the relationship between expanded disability status scale (EDSS) and transcranial magnetic stimulation (TMS) evoked motor potentials (MEP) were assessed to capture disease effects by independent parameters. Seventy-nine MS patients and 50 controls were included and their CC volumes were assessed. Out of 79 patients, 31 patients (39·2%) had CC atrophy. The distribution of EDSS scores among the group with CC atrophy [13 (32%) patients with EDSS 0–2; 11 (58%) patients with EDSS 2–4; 19 (24%) patients with EDSS ≥4] was not statistically significant (p>0·05). MEP latency was abnormal in 34 (43%) patients, 67 (85%) patients had abnormal MEP amplitude and CMCT was abnormal in 32 (41%) patients. The relation between EDSS and MEP was statistically significant among the patient population including the subgroup of patients with CC atrophy (p<0.05). Our results lacked to provide an association between disability and CC atrophy, but there was a correlation between CC atrophy and TMS evoked motor potentials. Early evolution of axonal degeneration and brain atrophy should be considered in terms of follow-up measures to provide long-term efficiency impacting disability, progression and brain atrophy.     

Disability and Economic Loss Caused by Headache among Information Technology Workers in Korea

Background and PurposeHeadache disorders are a leading cause of disability globally. However, there is inadequate information available about these disorders and the related economic loss in the workplace in Asian countries. Information technology (IT) jobs are intellectually and cognitively challenging, and hence IT workers are a suitable population for assessing headache disorders and related economic loss.MethodsWe sent invitation emails to all employees of selected IT companies. A comprehensive Web-based questionnaire regarding headache characteristics, disability, quality of life, and economic loss was completed by 522 participants from 8 companies.ResultsThe participants included 450 (86.2%) who had experienced headache more than once during the previous year. The frequencies of migraine, probable migraine (PM), and tension-type headache (TTH) were 18.2%, 21.1%, and 37.0%, respectively. The Migraine Disability Assessment score was higher for participants with migraine [median and interquartile range, 3.0 (0.0–6.0)] than for those with PM [0.0 (0.0–2.0), p<0.001] and TTH [0.0 (0.0–1.0), p<0.001]. The estimated annual economic losses caused by migraine per person associated with absenteeism and presenteeism were USD 197.5±686.1 and USD 837.7±22.04 (mean±standard deviation), respectively. The total annual economic loss per person caused by migraine (USD 1,023.3±1,972.7) was higher than those caused by PM (USD 424.8±1,209.1, p<0.001) and TTH (USD 197.6±636.4, p<0.001).ConclusionsMigraine, PM, and TTH were found to be prevalent among IT workers in Korea. Disability and economic loss were significantly greater in participants with migraine than in those with PM or TTH.     

Efficacy and safety of rituximab in patients with multiple sclerosis: An observational study at a tertiary center in Makkah,Saudi Arabia

Objectives:To assess the efficacy and safety of rituximab for multiple sclerosis (MS) treatment in terms of reduction in clinical relapses, magnetic resonance imaging (MRI) activity, Expanded Disability Status Scale (EDSS) score and adverse events.Methods:This is a retrospective cross-sectional study conducted at King Abdullah Medical City, from January 2017 to August 2021, involving patients with MS given rituximab, with 1-year follow-up. Clinical parameters were noted pre- and post-treatment to determine efficacy; adverse events were noted to analyze safety. A paired samples t-test was used to compare responses pre- and post-treatment. A p-value<0.05 was considered significant.Results:Among 31 patients, 6 (19.4%) had progressive MS, and 25 (80.6%) had relapsing-remitting MS (mean disease duration=8.12±5.65 years). The annual relapse rate reduced from 1.67±0.97 to 0.06±0.25 (p<0.001), the EDSS score from 3.16±2.14 to 2.80±2.28 (p=0.141) and the MRI activity score from 1.84±1.03 to 1.03±0.18 (p<0.001). Only one patient had enhancing lesion activity post-treatment. The commonest side effect was urinary tract infection (25.8%). Only 2 patients discontinued the drug.Conclusion:Rituximab is an efficient drug in reducing the annual relapse rate and MRI activity of patients with MS, with few tolerable side effects not leading to drug discontinuation or any lethal outcome.

Multiple sclerosis (MS) is a condition of the central nervous system carrying a chronic course and having autoimmune etiology. The disease has a prevalence of 40.4 per 100,000 people in Saudi Arabia. ¹ MS can have a relapsing-remitting course which begins with an acute attack and is then followed by full or partial recovery (also known as relapsing-remitting MS [RRMS]). Alternative clinical presentation of MS is characterized by progressive neurological worsening without any acute attack (also known as primary progressive MS). Secondary Progressive MS is another advanced stage in the course of disease where disability worsens gradually without a new relapse. ^2,3 The disease process was earlier thought to be mediated by T cells, but research has brought forth the suggestion that B cells, too, do play a role in the pathological process. ⁴ It is now well understood that antigen presentation by B cells is a necessary step in the pathogenesis of the immune-mediated process against the glycoprotein myelin found in central nervous system. ⁵ Therapies targeting T cells (for example, interferon-beta and natalizumab) have been traditionally used for MS, but not all patients improve despite treatment compliance. Moreover, interferon causes a myriad of highly stressful side effects, and natalizumab, in addition to causing minor adverse effects, has a risk of causing a serious condition like progressive multifocal leukoencephalopathy (PML). ⁶ New therapies that target B cells are increasingly being investigated. Rituximab (RTX) is one such drug that targets CD 20 expressing B cells and also reduces T cells. The drug has shown promising results in the treatment process. ^7,8 The safety of RTX usage is established by Class IV evidence. ⁹ Phase 2 trials have shown that RTX reduces magnetic resonance imaging (MRI) inflammatory lesions by up to 88% in the patients of MS. ^10,11 Off-label RTX usage in MS is further supported by several trials. ^11,12,13 One such study showed MRI activity reduce from 88% to 8.3% in only a year and annual relapse rate reduce from 0.75 to 0.36 with the use of RTX. ¹³ The common side effects of RTX usage in patients with MS include infections (36%), with urinary tract infection being the most common, and infusion reactions (8%). This CD 20 targeting drug also increases the risk for fungal infections. ^14,15 Studies comparing the efficacy of RTX to conventional therapies have concluded that RTX has better performance in MS, especially in newly diagnosed cases of RRMS. ¹⁶ Our aim was to study the reduction in MRI inflammatory lesions, disability changes and relapses in patients with MS presenting at King Abdullah Medical City as a result of RTX therapy.     

Corpus callosum index correlates with brain volumetry and disability in multiple sclerosis patients

Objectives:To analyze the correlation between corpus callosum index (CCI), brain volumetry, and disability in multiple sclerosis (MS) patients. The brain volumetry consists of the corpus callosum, cortical gray matter, subcortical gray matter, and white matter volumes.Methods:This was a retrospective cross-sectional study from October 2018 to February 2019 of 30 patients with MS aged 20 to 61 years old. Brain volumetry was performed using FreeSurfer© software. The CCI were measured manually using conventional best mid-sagittal T1W brain MRI. The anterior, posterior, and medium segments were measured and divided to its greatest anteroposterior diameter. Higher CCI values indicated greater corpus callosum volumes. Clinical evaluation was comprised of MS subtype, age of onset, relapse frequency and Expanded Disability Status Scale (EDSS).Results:Thirty MS patients with median of age 22 years were included. Relapsing-remitting (RRMS) subtype were 73.3%. Very significant correlations were shown between the CCI and corpus callosum volume (CCV) (r=0.79; p<0.0001) and cerebral white matter volume (r=0.81; p<0.0001). Significant correlations were shown between the CCI and cortical gray matter volume (r=0.64; p<0.0001) and subcortical gray matter volume (r=0.69; p<0.0001). The CCI was positively correlated with age of onset and inversely with EDSS. The CCV and CCI were smaller in secondary progressive MS (SPMS).Conclusion:The CCI is easy and fast to obtain in conventional MRI and significantly correlated with brain volumetry, age of onset and disability in MS patients.

Multiple sclerosis (MS) is one of the most common neurological diseases of the central nervous system and has various clinical manifestations, affecting the sensory, motor, cerebellar, brainstem, and autonomic systems.1–4 The MS progression will lead to disability that can affect the quality of life. In 2013, the prevalence of MS was 33 per 100,000 globally, an increase from approximately 30 per 100,000 in 2008.5 Regarding the cognitive impairment, it has been found in a study by Rao et al6 a 45% frequency of cognitive impairment in MS patients. Furthermore, it has been found in several studies that the decline in visual and verbal episodic memory as well as decelerated cognitive processing speed are the most frequent cognitive domains impaired in multiple sclerosis.7 Between these 2 domains, it has been shown that memory impairment were slightly more common than those with memory impairment and processing speed impairment in 128 patients with relapsing-remitting MS (RRMS).8 In our previous study, we found impairments in the Symbol Digit Modality test (up to 50%), California Verbal Learning test-II (27.5%), and Brief Visuospatial Memory test-revised (32.5%) in MS patients.9Brain volume in MS patients were found to be significantly smaller compared to healthy subjects and associated with the progression of disability.10 Brain atrophy in MS can occur by 3 mechanisms: volume loss within the lesion itself, retrograde degeneration, and Wallerian degeneration in the remote area of the fiber pathway.4,11,12 Brain atrophy can be seen in earliest stages of MS (clinically isolated syndrome).13 Gray matter atrophy begins early in the course of the disease and is correlated with the progression of disability, especially motor and cognitive disability.14–16 Measuring brain atrophy has been proposed as one of several treatment monitoring parameters for MS.17The corpus callosum is one of the main white matter pathways and affected by the progress of chronic diseases, including MS.1,3,4 Corpus callosum damage is correlated with cognitive impairment and motor disability in MS patients. Corpus callosum atrophy could be a clinically relevant marker of cognitive impairment.18–20Brain volumetry using magnetic resonance imaging (MRI) is a useful, noninvasive tool in assessing subcortical morphometric changes as well as evaluating the regional neurological impact of psychopathology, such as dementia, psychiatric disorders, and normal aging.21 Some software packages have been developed for measuring brain tissue volume using MRI with semi-automatic segmentation, such as FreeSurfer© (The General Hospital Corporation, Boston MA, USA), FIRST (FMRIB’s Integrated Registration and Segmentation Tool), FSL (FMRIB’s Software Library), and SPM (Statistical Parametric Mapping).22With this background, the objective of this study was to determine the correlation between the corpus callosum index (CCI) measurements and the corpus callosum, cortical gray matter, subcortical gray, and cerebral white matter volumes determined through brain MRI volumetry and clinical characteristics in MS patients.     

Persistently Gadolinium-Enhancing Lesion Is a Predictor of Poor Prognosis in NMOSD Attack: a Clinical Trial

Gadolinium (Gd)-contrast MRI for reliable detection of blood–brain barrier (BBB) breakdown is widely used in neuromyelitis optica spectrum disorder (NMOSD) attack. Nonetheless, little is known about the predictive role of gadolinium-enhancing lesion in prognosis of NMOSD attack. The aim of this work is to investigate the predictive value of persistently Gd-enhanced lesions to medium-term outcome after attack. Data for this analysis came from an ongoing prospective cohort study (CLUE). NMOSD patients with acute attack were enrolled from January 2019 to March 2020. All patients underwent Gd-contrast MRI at baseline and 1 month, and disability was assessed by Expanded Disability Status Scale (EDSS). Primary outcome was EDSS improvement from baseline to month 6. Multiple logistic regression identified predictors for poor recovery of NMOSD attack. Forty-one participants were analyzed, of which 21 patients had persistently Gd-enhancing lesions. Patients in no enhancement (NE) group showed a significant shift in 6-month EDSS distributions compared with those in persistent enhancement (PE) group (p = 0.005). Poor recovery rate of the PE group was higher than that of the NE group at 6 months (p = 0.033). In patients with aquaporin-4-positive, first-attack, transverse myelitis or in a high-dose steroid treatment subgroup, the improvement of EDSS scores in the PE group was still less compared with that in the NE group (p < 0.05). The presence of persistently Gd-enhancing lesion appears to be associated with poor recovery after attack (OR = 5.473, p = 0.014). Our study found that persistently gadolinium-enhancing lesion is a poor prognosis predictor after NMOSD attack. Trial registration ID: {"type":"clinical-trial","attrs":{"text":"NCT04106830","term_id":"NCT04106830"}}NCT04106830Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-020-00973-9.Key Words: NMOSD, acute attack, MRI, prognosis, clinical trial     

The impact of disability, fatigue and sleep quality on the quality of life in multiple sclerosis

Background:

Only few papers have investigated the impact of multiple sclerosis (MS), especially MS-related fatigue and the impact of the quality of sleep on the quality of life (QoL) in MS patients.

Objective:

The objective of this study was to measure the quality of life in MS patients and the impact of disability, fatigue and sleep quality, using statistical modeling.

Materials and Methods:

A cross-sectional study was conducted and data was collected from 141 MS patients, who were referred to the Mottahari Clinic, Shiraz, Iran, in 2005. Data on health-related quality of life (MSQoL-54), fatigue severity scale (FSS), and Pittsburgh sleep quality Index (PSQI) were obtained in the case of all the patients. Epidemiology data concerning MS type, MS functional system score, expanded disability status scale (EDSS) etc. were also provided by a qualified neurologist. Spearman α coefficient, Mann-Whitney U test, and linear regression model were used to analyze the data.

Results:

The mean ±SD age of 141 MS patients was 32.6±9.6 year. Thirty five (24.8%) of them were male and the others were female. Eighty two (58.1%) of the patients had EDSS score of ≤ 2, 36 (25.5%) between 2.5 and 4.5, and 23 (16.3%) ≥ 5. As per PSQI scores, two (1.4%) of the patients had good sleep, 16 (11.3%) had moderate sleep and 123 (87.2%) had poor sleep. There was a significant high positive correlation between the quality of mental and physical health composite scores (r = 0.791, P<0.001). There was a significant negative correlation between the quality of physical score and age (r = -0.88, P<0.001), fatigue score (r = -0.640, P<0.001), EDSS score (r = -0.476, P<0.001) and PSQI (sleep quality r = -0.514, P<0.000). Linear regression analysis showed that PSQI score, EDSS, and fatigue score were predictors in the model between the quality of physical score and covariates (P<0.001). Linear regression model showed that fatigue score and PSQI were predictors in the model between the quality of mental score and covariates (P<0.001).

Discussion and Conclusion:

In conclusion, it may be said that MS patients had poor and moderate quality of mental and physical health. The quality of life was impaired as seen by PSQI, EDSS, and FSS. It is our suggestion that these patients require the attention of health care professionals, to be observed for the need of possible psychological support.     

Functional correlates of motor control impairments in multiple sclerosis: A 7 Tesla task functional MRI study

Upper and lower limb impairments are common in people with multiple sclerosis (pwMS), yet difficult to clinically identify in early stages of disease progression. Tasks involving complex motor control can potentially reveal more subtle deficits in early stages, and can be performed during functional MRI (fMRI) acquisition, to investigate underlying neural mechanisms, providing markers for early motor progression. We investigated brain activation during visually guided force matching of hand or foot in 28 minimally disabled pwMS (Expanded Disability Status Scale (EDSS) < 4 and pyramidal and cerebellar Kurtzke Functional Systems Scores ≤ 2) and 17 healthy controls (HC) using ultra‐high field 7‐Tesla fMRI, allowing us to visualise sensorimotor network activity in high detail. Task activations and performance (tracking lag and error) were compared between groups, and correlations were performed. PwMS showed delayed (+124 s, p = .002) and more erroneous (+0.15 N, p = .001) lower limb tracking, together with lower cerebellar, occipital and superior parietal cortical activation compared to HC. Lower activity within these regions correlated with worse EDSS (p = .034), lower force error (p = .006) and higher lesion load (p < .05). Despite no differences in upper limb task performance, pwMS displayed lower inferior occipital cortical activation. These results demonstrate that ultra‐high field fMRI during complex hand and foot tracking can identify subtle impairments in lower limb movements and upper and lower limb brain activity, and differentiates upper and lower limb impairments in minimally disabled pwMS.     

A longitudinal study of cerebral glucose metabolism, MRI, and disability in patients with MS.

OBJECTIVE: To study the time-related changes in cerebral metabolic rate of glucose (CMRglc) in MS patients and to correlate these with changes in MRI lesion load and disability. BACKGROUND: Measurements of MRI lesion load and neurologic disability are used widely to monitor disease progression in longitudinal studies of MS patients, but little is known about the associated changes in cerebral neural function. METHODS: The authors studied 10 patients with clinically definite MS who underwent serial measurements of CMRglc, MRI T2-weighted total lesion area (TLA), and clinical evaluation of disability (Expanded Disability Status Scale [EDSS]) over a period of approximately 2 years (three examinations). CMRglc was calculated using PET and 18-fluorodeoxyglucose (FDG). RESULTS: The global cortical CMRglc decreased with time (p<0.001) and the most pronounced reductions of CMRglc were detected in frontal and parietal cortical areas. There was a statistically significant increase of disability (p<0.01) and TLA (p<0.05) measurements during the study, but changes in CMRglc were not correlated to changes in TLA and EDSS. CONCLUSIONS: Global cortical cerebral metabolism in MS is decreased significantly during a 2-year observation period, suggesting a deterioration of cortical activity with disease progression. The time-related changes of cortical CMRglc are statistically stronger than changes in TLA measurements and neurologic disability, and might be a useful secondary measure of treatment efficacy.     

Neuropsychiatric manifestations in multiple sclerosis: correlation of fatigue and depression with disease progression

Abstract

Fatigue is one of the most common disabling symptoms in multiple sclerosis (MS) with significant impact on daily life. The aim of this study is to explore the association among MS fatigue, clinical disability and depression. Fifty-seven patients were assessed by fatigue severity scale (FSS), expanded disability status scale (EDSS) and Beck depression inventory (BDI). Mean FSS score was 4·1 ± 1·6. Based on FSS scores, patients were divided into three groups: Patients with FSS score >5 (n = 10, 32%) were evaluated to present with fatigue symptoms, patients with borderline fatigue (n = 29, 50%) had an FSS score between 4 and 5 and patients with no fatigue (n = 18, 18%) had an FSS<4. When the patients were compared according to the presence of fatigue symptoms, patients with fatigue had significantly higher EDSS scores (p = 0·03). BDI evaluation revealed that 33 (57%) patients had a score 11. MS patients with fatigue showed significantly higher BDI scores when compared to patients without fatigue (p = 0·0002). A significant relationship among fatigue, disease disability and depression was observed in our study, implying the complex interplay of fatigue and depression with disability.     

Utilidad de la ecografía de nervio óptico como predictor de progresión en esclerosis múltiple

IntroductionProgressive neuronal and axonal loss are considered the main causes of disability in patients with multiple sclerosis (MS). The disease frequently involves the visual system; the accessibility of the system for several functional and structural tests has made it a model for the in vivo study of MS pathogenesis. Orbital ultrasound is a non-invasive technique that enables various structures of the orbit, including the optic nerve, to be evaluated in real time.Material and methodsWe conducted an observational, ambispective study of MS patients. Disease progression data were collected. Orbital ultrasound was performed on all patients, with power set according to the ‘as low as reasonably achievable’ (ALARA) principle. Optical coherence tomography (OCT) data were also collected for those patients who underwent the procedure. Statistical analysis was conducted using SPSS version 22.0.ResultsDisease progression was significantly correlated with ultrasound findings (P = .041 for the right eye and P = .037 for the left eye) and with Expanded Disability Status Scale (EDSS) score at the end of the follow-up period (P = .07 for the right eye and P = .043 for the left eye). No statistically significant differences were found with relation to relapses or other clinical variables.DiscussionUltrasound measurement of optic nerve diameter constitutes a useful, predictive factor for the evaluation of patients with MS. Smaller diameters are associated with poor clinical progression and greater disability (measured by EDSS).     

The functional limitations profile may be a valid,reliable and sensitive measure of disability in multiple sclerosis

This pilot study was designed to evaluate the usefulness of the Functional Limitations Profile (FLP), a validated interval measure of self-report of disability, in studies of multiple sclerosis (MS). It is compared with the standard measure of disability in MS, the Kurtzke Expanded Disability Status Scale (EDSS), and the Illness Severity Score (ISS), which is an interval score derived from the EDSS. Inherent problems of all measures are discussed. On two occasions separated by 6 months, 50 MS patients were assessed prospectively by a neurologist and a psychologist, using the above measures. Validity was reflected in correlation and in agreement between measures. The FLP Physical dimension correlated significantly with the EDSS for both visits (at visit 1:r = 0.77; at visit 2:r = 0.77). Agreement between the interval measures, FLP and ISS, was satisfactory (mean difference +0.18, SD 6.8). The reliability of FLP was assessed by comparing FLP Physical dimension scores in the 30 patients who had not changed clinically between visits (EDSS change < 1.0, ISS change < 3.8). For this unchanged group the mean difference was +0.56 (SD 6.2); the 95% confidence interval (CI) was –2.87 to +1.75. For sensitivity of the FLP the 20 MS patients who had clinically changed between visits were assessed (EDSS =/> 1.0, ISS =/> 3.8). For this changed group the mean difference was –8.0 (SD 9.21); 95% CI was –12.3 to –3.69. The FLP Physical dimension in this pilot study seems to be a valid, reliable and sensitive measure of MS disability. If confirmed by larger studies it would be useful in prospective clinical studies of treatments for MS.Judith Hutchinson died on the 4 March 1995     

Interferon β1a (Avonex®) treatment in multiple sclerosis: similarity of effect on progression of disability in patients with mild and moderate disability

Objective To compare clinical responses to once-weekly intramuscular interferon-β-1 a [IFNβ-1 a, Avonex^®, Biogen] in multiple sclerosis (MS) patients with baseline Expanded Disability Status Scale (EDSS) ≤ 3.5 or > 3.5. Methods Patients with relapsing-remitting MS (RRMS), 124 with baseline EDSS ≥ 3.5 and 64 RRMS patients with EDSS > 3.5, were consecutively recruited to receive IFNβ-1 a 30 μg as a once weekly injection for 18 months. The primary endpoint of the study was the number of patients in each group with sustained worsening in disability, defined as 1-point deterioration in EDSS that persisted for at least 6 months during the 18 month follow-up period. Subordinate endpoints included relapse rates and the number of treatment dropouts. Results Among patients with baseline EDSS ≤ 3.5, 16.9 % experienced a deterioration in EDSS of at least 1 point ; 22.5 % experienced a deterioration of at least 0.5 %. Corresponding rates in patients with baseline EDSS > 3.5 were 23.4 % and 29 % respectively (no significant differences between patients stratified according to baseline EDSS status). The proportion of patients discontinuing therapy was significantly higher in patients with baseline EDSS > 3.5 than in those with baseline EDSS ≤ 3.5 (16/64 versus 12/124 ; p = 0.005). At the conclusion of follow-up, IFNβ-1 a therapy was associated with a 31.7 % reduction in relapse rate in patients with baseline EDSS ≤ 3.5 and a 37 % reduction in those with baseline EDSS > 3.5 (difference not significant). Conclusions During 18 months of treatment and follow-up, no difference was observed in clinical responses to IFNβ-1 a between RRMS patients with mild and moderate disability but discontinuation of therapy was more frequent in the more disabled group.     

Predictors of Ocrelizumab Effectiveness in Patients with Multiple Sclerosis

Data regarding effectiveness and safety of ocrelizumab in the post-marking setting are lacking. The aim of our study was to provide effectiveness and safety data of ocrelizumab treatment in patients with relapsing–remitting (RR-) and progressive multiple sclerosis (PMS) and to evaluate clinical and immunological predictors of early treatment response. In this single-center prospective observational study, we investigated effectiveness outcomes (time-to-confirmed disability worsening, time-to-first relapse, time-to-first evidence of MRI activity and time-to-first evidence of disease activity), clinical and immunological predictors of early treatment response, and incidence of adverse events (AEs). One hundred and fifty-three subjects were included (93 RRMS; 84 females). Median follow-up was 1.9 (1.3–2.7). At 2-year follow-up (FU), disability worsening-free survival were 90.5%, 64.7%, and 68.8% for RRMS, primary-progressive MS (PPMS), and secondary-progressive MS (SPMS) patients, respectively. At 2-year FU, 67.1%, 72.7%, and 81.3% of patients with RRMS, PPMS, and SPMS were free of MRI activity, with NEDA-3 percentages of 62.1%, 54.6%, and 55.1%, respectively. Lower baseline EDSS was independently associated with a reduced risk of disability worsening (HR(95%CI) = 1.45(1.05–2.00), p = 0.024) and previous treatment exposure was independently associated with increased probability of radiological activity (HR = 2.53(1.05–6.10), p = 0.039). At 6-month FU, CD8 + cell decrease was less pronounced in patients with inflammatory activity (p = 0.022). Six patients (3.9%) discontinued ocrelizumab due to severe AEs. Our findings suggest that ocrelizumab is an effective treatment in real-world patients with RRMS and PMS, with a manageable safety profile. Better outcomes were observed in treatment-naïve patients and in patients with a low baseline disability level. Depletion of CD8 + cells could underlie early therapeutic effects of ocrelizumab.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01104-8.     

Survival, and time to an advanced disease state or progression, of untreated patients with moderately severe multiple sclerosis in a multicenter observational database: relevance for design of a clinical trial for high dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation

Despite prolonged survival, patients with multiple sclerosis (MS) experience considerable morbidity, which adversely impacts quality of life. To assess the risk-benefit of a clinical trial of high dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation for MS, we sought to determine the natural history of the disease in a comparison group of untreated patients. We identified 285 individuals with 2132 combined observation years (median: 5.6 years; 5th to 95th percentile: 1-21 years), with Expanded Disability Status Scale (EDSS) scores of 3.0-5.5 at baseline observation. Disease-related mortality was zero at five years, 5.4% at 10 years, and 22% at 15 years (40 patients contributing to the data point; 95% confidence interval: 4-32%). Risk for progression to advanced disability, defined as an EDSS score of 8, was very low for the subgroup with a baseline EDSS score of 3-3.5; however, for those with a baseline EDSS score of 4-5.5, 3% had advanced disability after two years, 5% after three years, 6% after four years, 12% after five years, and 40% after 10 years. The estimated probability of disease progression, defined as an increase in EDSS score by > or = 1.0 sustained for at least 180 days, was 5% after one year, 14% after two years, 22% after three years, 38% after five years, 57% after 10 years, and >80% after 20 years of observation. The relevance of these features to the design of the clinical trial is discussed.