Threshold definitions for significant change on the timed 25-foot walk and nine-hole peg test in primary progressive multiple sclerosis

Background and purpose

The timed 25-foot walk (T25FW) and nine-hole peg test (NHPT) exhibit random variability in the short term. A threshold of ≥20% change from baseline has been used to indicate true disability change, but other threshold definitions may be better suited to exclude false and include true change events. The aim of this study was to use patient-level original trial data to investigate the short-term variation in T25FW and NHPT, and to compare its extent with disability change at 12-month follow-up in people with primary progressive multiple sclerosis (PPMS).

Methods

We used original patient-level data from PROMISE, a large PPMS trial. In this trial, three separate T25FW and NHPT measurements were performed 1 week apart during screening. We used these repeated measures to describe the extent of short-term variation. We used binary logistic regression models to investigate the association between screening characteristics and unacceptable short-term variation.

Results

The traditional 20% threshold excluded a reasonable number of false change events, while also yielding a large number of change events at follow-up. Increasing index values on the T25FW and NHPT were associated with higher short-term variation.

Conclusions

The traditional ≥20% change threshold for the T25FW and NHPT represents a reasonable compromise between reducing the number of false change events and achieving the largest number of change events in people with PPMS. Our analyses inform the design of clinical trials in PPMS.     

Fatigue in multiple sclerosis: associations with health‐related quality of life and physical performance

Background and purpose: Fatigue is a common, but still one of the least understood symptoms in multiple sclerosis (MS). We aimed to investigate whether fatigue was associated with demographic‐, clinical‐, health‐related quality of life (HRQoL)‐ and physical performance variables, and whether change in fatigue after treatment was associated with changes in HRQoL and physical performance. Methods: Sixty patients were included for inpatient physiotherapy. Fifty‐six patients completed the study and were available for analysis. Fatigue (Fatigue Severity Scale; FSS), HRQoL (Multiple Sclerosis Impact Scale; MSIS‐29) and physical performance (walking ability and balance) were assessed at screening, baseline, after treatment and at follow‐up after 3 and 6 months. We analysed possible associations between fatigue and other variables at baseline by regression models, and between change in fatigue versus changes in both HRQoL and physical performance variables after physiotherapy by correlation analysis. Results: Fatigue at baseline was associated with HRQoL (explained 21.9% of variance), but not with the physical performance tests. Change in fatigue was correlated with change in HRQoL, but not with changes in physical performance. All measures were improved after treatment (P ≤ 0.001). While improvements in fatigue and HRQoL were lost at follow‐up, improvements in physical performance tests were maintained for at least 6 months (P ≤ 0.05). Conclusions: Fatigue was associated with HRQoL at baseline. Improvement in fatigue seemed to be related to other factors than improvement in physical performance. A broader strategy including both physical and psychological dimensions seems to be needed to improve fatigue over the long‐term.     

The effect of large-dose prednisone therapy on IgG subclasses in multiple sclerosis

The effect of large-dose prednisone therapy (3960 mg over 56 days) on IgG subclasses in the cerebrospinal fluid and sera, as well as on their intrathecal synthesis, was studied in 15 patients with clinically definite multiple sclerosis. The concentration of IgG subclasses was measured using ELISA with monoclonal antibodies against human IgG subclasses, secondary biotinylated antibody and avidin-biotin-peroxidase complex. There was a decrease of IgG1, IgG3 and IgG4 in the CSF of MS patients after the treatment, but the differences did not reach statistical significance. The IgG index was decreased about 34% (p<0.01) after the therapy. This was mainly due to diminished synthesis of IgG1 and IgG3. The significance of IgG subclasses in the pathogenesis of MS is discussed.     

The influence of clinical relapses and steroid therapy on the development of Gd-enhancing lesions: a longitudinal MRI study in relapsing—remitting multiple sclerosis patients

Fifty-three patients with relapsing-remitting multiple sclerosis who had monthly Gd (gadolinium) enhanced MRI (Magnetic Resonance Imaging) and clinical evaluation, were divided into two subgroups: 1) patients with a clinical relapse, treated with IVMP (intravenous methylprednisolone) and at least one enhancing lesion on MRI. 2) patients who did not have a clinical relapse but with at least one enhancing lesion on MRI. In group 1, we evaluated the number and volume of enhancing lesions on the scan before and three scans after IVMP therapy; in group 2, we considered the first scan with enhancing lesions and the subsequent three scans. The mean number and volume of enhancing lesions on the first scan was significantly higher in patients with clinical relapse compared to patients without clinical relapse. In group 1, we found a consistent reduction in the first scan following steroid treatment which returned to initial levels at the following scan. Both volumetric and numerical evaluation are appropiate MRI outcome measures in monitoring therapeutic trials.     

Gender-related effect of clinical and genetic variables on the cognitive impairment in multiple sclerosis

Abstract. Background: Cognitive impairment may occur at any time during the course of multiple sclerosis (MS), and it is often a major cause of disability in patients with the disease. The APOE-4 allele is the major known genetic risk factor for late onset familial and sporadic Alzheimers Disease (AD), and it seems to be implicated in cognitive decline in normal elderly persons. Objective: To investigate the clinical and genetic variables that can be associated with the cognitive decline in patients with MS. Methods: Five-hundred and three patients with clinically definite MS underwent a battery of neuropsychological tests and, according to the number of failed tests, were divided into cognitively normal and impaired. All patients were genotyped for APOE gene polymorphisms. Results: Fifty-six percent of MS patients showed, to different extents, cognitive impairment. Cognitive decline was predominant in men and was associated with disease duration, Kurtzke Expanded Disability Status Scale (EDSS) score, a low level of education, and, interestingly, the 4 allele of the APOE gene. By contrast, cognitive impairment in women was independent of any investigated variable. Conclusion: The findings demonstrate that clinical and genetic factors play a role in men affected by MS developing cognitive impairment.This work was supported in part by a grant from FISM (Federazione Italiana Sclerosi Multipla).     

The effect of magnesium oral therapy on spasticity in a patient with multiple sclerosis

The effects of magnesium glycerophosphate oral therapy on spasticity was studied in a 35-year-old woman with severe spastic paraplegia resulting from multiple sclerosis (MS). We found a significant improvement in the spasticity after only 1 week from the onset of the treatment on the modified Ashworth scale, an improvement in the range of motion and in the measures of angles at resting position in lower limbs. No side-effects were reported and there was no weakness in the arms during the treatment.     

The multiple sclerosis functional composite: different practice effects in the three test components

BACKGROUND: The multiple sclerosis functional composite (MSFC) is a multidimensional, MS-specific outcome measure for use in clinical trials, comprising three tests: timed 25-foot walk (T25FW), paced auditory serial addition (PASAT), and 9-hole peg (9HP). OBJECTIVE: To assess interrater and intrarater reliability and practice/fatigue effects in the MSFC. METHODS: The MSFC was administered by two neurologists after a formal training session to 32 MS outpatients. Patients were assessed four times by one examiner and twice by the other. The six tests were administered in a single day, with at least 20 min of rest between them. The examiners were blinded to the results of previous assessments. Testing order was random. RESULTS: Interrater reliability was excellent, with intraclass correlation coefficients (ICC) ranging from 0.93 for 9HP (95% confidence interval [CI] 0.84-0.96) to 0.99 for T25FW (95% CI 0.97-0.99). For intrarater reliability, ICC ranged from 0.93 for PASAT (95% CI 0.82-0.97) to 0.98 for T25FW (95% CI 0.93-1.00). We found no practice effect for T25FW after the first administration. However, performance improved with testing over the first three sessions for PASAT and over the first four sessions for 9HP. CONCLUSIONS: The MSFC is characterised by excellent reliability. Practice effects for the three MSFC components differed, being negligible for T25FW and evident for PASAT and 9HP. To improve efficiency, we suggest one prebaseline administration of T25FW, three of PASAT and four of 9HP.     

The effect of hypointense white matter lesions on automated gray matter segmentation in multiple sclerosis

Previous imaging studies assessing the relationship between white matter (WM) damage and matter (GM) atrophy have raised the concern that Multiple Sclerosis (MS) WM lesions may affect measures of GM volume by inducing voxel misclassification during intensity‐based tissue segmentation. Here, we quantified this misclassification error in simulated and real MS brains using a lesion‐filling method. Using this method, we also corrected GM measures in patients before comparing them with controls in order to assess the impact of this lesion‐induced misclassification error in clinical studies. We found that higher WM lesion volumes artificially reduced total GM volumes. In patients, this effect was about 72% of that predicted by simulation. Misclassified voxels were located at the GM/WM border and could be distant from lesions. Volume of individual deep gray matter (DGM) structures generally decreased with higher lesion volumes, consistent with results from total GM. While preserving differences in GM volumes between patients and controls, lesion‐filling correction revealed more lateralised DGM shape changes in patients, which were not evident with the original images. Our results confirm that WM lesions can influence MRI measures of GM volume and shape in MS patients through their effect on intensity‐based GM segmentation. The greater effect of lesions at increasing levels of damage supports the use of lesion‐filling to correct for this problem and improve the interpretability of the results. Volumetric or morphometric imaging studies, where lesion amount and characteristics may vary between groups of patients or change over time, may especially benefit from this correction. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.     

The effect of inflammation and its reduction on brain plasticity in multiple sclerosis: MRI evidence

Brain plasticity is the basis for systems‐level functional reorganization that promotes recovery in multiple sclerosis (MS). As inflammation interferes with plasticity, its pharmacological modulation may restore plasticity by promoting desired patterns of functional reorganization. Here, we tested the hypothesis that brain plasticity probed by a visuomotor adaptation task is impaired with MS inflammation and that pharmacological reduction of inflammation facilitates its restoration. MS patients were assessed twice before (sessions 1 and 2) and once after (session 3) the beginning of Interferon beta (IFN beta), using behavioural and structural MRI measures. During each session, 2 functional MRI runs of a visuomotor task, separated by 25‐minutes of task practice, were performed. Within‐session between‐run change in task‐related functional signal was our imaging marker of plasticity. During session 1, patients were compared with healthy controls. Comparison of patients' sessions 2 and 3 tested the effect of reduced inflammation on our imaging marker of plasticity. The proportion of patients with gadolinium‐enhancing lesions reduced significantly during IFN beta. In session 1, patients demonstrated a greater between‐run difference in functional MRI activity of secondary visual areas and cerebellum than controls. This abnormally large practice‐induced signal change in visual areas, and in functionally connected posterior parietal and motor cortices, was reduced in patients in session 3 compared with 2. Our results suggest that MS inflammation alters short‐term plasticity underlying motor practice. Reduction of inflammation with IFN beta is associated with a restoration of this plasticity, suggesting that modulation of inflammation may enhance recovery‐oriented strategies that rely on patients' brain plasticity. Hum Brain Mapp 37:2431–2445, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.     

The effect of cyclophosphamide on T lymphocytes and T lymphocyte subsets in patients with chronic progressive multiple sclerosis

ABSTRACT— The lymphocytes in peripheral blood and cerebrospinal fluid of patients with chronic progressive multiple sclerosis (MS) were characterized with monoclonal antibodies to surface antigens of T cells, helper/inducer T cells and suppressor/cytotoxic T cells. The influence of cyclophosphamide treatment on these immune parameters was investigated.
Compared to healthy persons, the mononuclear cell fraction of the peripheral blood of patients with chronic progressive MS consisted of normal %s of T cells and helper/inducer T cells, but decreased %s of suppressor/cytotoxic T lymphocytes. Intensive as well as chronic treatment of MS patients with cyclophosphamide resulted in a decline in the %s of T cells and helper/inducer T cells, whereas the %s of suppressor/cytotoxic T cells returned to normal. In cerebrospinal fluid, cyclophosphamide also induced a relative decrease in the % of helper/inducer T cells and an increase in the % of suppressor/cytotoxic T cells compared to untreated MS patients. Intensive as well as chronic therapy with cyclophosphamide both led to a significant decrease in the absolute number of T cells and T cell subsets in the blood of the patients.     

The Global Adherence Project (GAP): a multicenter observational study on adherence to disease‐modifying therapies in patients with relapsing‐remitting multiple sclerosis

Background: Most disease‐modifying therapies (DMTs) for multiple sclerosis (MS) are self‐injectable medications that must be taken on an ongoing basis to reduce disease activity. Thus, adherence to therapy becomes an important challenge that must be addressed to maximize benefits of therapy. This study evaluated rates of adherence to prescribed treatment and explored factors affecting adherence amongst patients with relapsing‐remitting MS. Methods: This was an observational, multicenter, multinational, phase 4 study. Patients and physicians received paper questionnaires regarding adherence to DMTs approved at the time of the study, including intramuscular interferon beta‐1a (IFNβ‐1a), subcutaneous IFNβ‐1a, IFNβ‐1b, and glatiramer acetate. Quality of life and cognition data also were collected. Multivariate analysis was conducted to identify factors associated with adherence to long‐term DMTs. Results: Two thousand six hundred and forty‐eight patients were studied, revealing an average treatment duration of 31 months. Seventy‐five percent of patients (n = 1923) were adherent to therapy. The most common reasons for non‐adherence were forgetting to administer the injection (50.2%) and other injection‐related reasons (32.0%). Adherent patients reported better quality of life (P < 0.05) and fewer neuropsychological issues (P < 0.001) than non‐adherent patients. Adherent patients had significantly shorter duration of disease (P < 0.001) and shorter duration of therapy (P = 0.005) than non‐adherent patients. Women were more likely than men to adhere to treatment. Conclusion: Identifying factors that affect adherence to prescribed treatments is the first step in improving adherence of patients with MS to therapy, thereby helping maximize the benefits of long‐term DMTs.     

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.     

A prospective, open-label treatment trial to compare the effect of IFN β-1a (Avonex), IFNβ-1b (Betaseron), and glatiramer acetate (Copaxone) on the relapse rate in relapsing-remitting multiple sclerosis

A prospective, non‐randomized, open‐label treatment trial was performed in patients with relapsing‐remitting multiple sclerosis (RRMS), with follow up for 12 months. Our primary objective was to prospectively compare the effect of IFNβ‐1a (Avonex), IFNβ‐1b (Betaseron), and glatiramer acetate (GA, Copaxone) on the relapse rate in patients with RRMS. Between August 1996 and September 1999, 156 consecutive patients with clinically definite RRMS with a Kurtzke scale (EDSS) score of 4 or less were followed for 12 months, from the time of initiating therapy or electing to remain untreated. Prior 2‐year relapse history and available chart information was carefully reviewed at the time of enrolment. Thirty‐three of 156 elected no treatment (mean age 32.5 years; mean EDSS 2.64) at enrolment; 40 elected IFNβ‐1a (mean age 32.4 years; mean EDSS 2.69), 41 IFNβ‐1b (mean age 32.1 years; mean EDSS 2.56), and 42 chose GA (mean age 31.5 years; mean EDSS 2.57). Annual relapse rate based upon the 2 years prior to enrolment was 1.08 in the untreated group, 1.20 in the AV group, 1.21 in the BE group, and 1.10 in the GA group. There were no statistically significant differences among the four groups at enrolment. After 12 months of treatment, patients in the untreated groups had a relapse rate of 0.97, whereas patients in the IFNβ‐1a, IFNβ‐1b, and GA groups had relapse rate of 0.85, 0.61, and 0.62, respectively. Compared to the untreated group, reduction in the relapse rate was statistically significant only in the GA (P=0.003) and IFNβ‐1b (P=0.002) groups, in contrast to the IFNβ‐1a treated patients, who did not show a significant reduction (P=0.309). Compared to the untreated patients, mean EDSS was significantly reduced only in the GA (P=0.001) and IFNβ‐1b (P=0.01), in contrast to IFNβ‐1a treated patients (P=0.51). In this prospective, controlled, open‐label, non‐randomized 12‐month study, treatment with only GA and IFNβ‐1b significantly reduced the relapse rate compared to untreated patients, supporting early treatment in RRMS. Our results are similar to the observations made after 12 months of therapy in phase III studies of IFNβ‐1a, IFNβ‐1b, and GA. Despite some limitations of the study design, the results provide helpful clinical information regarding the relative efficacy of each therapy in mildly affected treatment‐naïve RRMS patients.     

In vivo effect of interferon-beta 1a on interleukin-12 and TGF-beta(1) cytokines in patients with relapsing-remitting multiple sclerosis

We have studied in vivo effect of interferon-beta 1a (IFN-beta 1a) (6 MIU once weekly i.m.) on interleukin-12 (IL-12) and transforming growth factor-beta(1) (TGF-beta(1)) serum levels during 6 months of therapy in group of 20 patients with relapsing-remitting multiple sclerosis (MS). IL-12 and TGF-beta(1) concentrations were measured by enzyme linked immunoabsorbent assay (ELISA). There was a significant increase of IL-12 levels in MS patients in comparison with control group, suggesting a role of this cytokine in immunity of MS. We have also found a significant increase of TGF-beta(1) levels after 6 months of therapy with IFN-beta 1a, however, there was no in vivo effect of the therapy on IL-12 levels. The results suggest that IFN-beta 1a may exert its action through up- regulation and increase secretion of TGF-beta(1).