Disability Rating Scales In Multiple Sclerosis

There are a few reports about handicap and SocioEconomic status in patients with Multiple Sclerosis (MS) based on Epidemiological studies.

The objective of our work is to evaluate handicap in patients with Multiple Sclerosis in the sanitary area of Calatayud, northern Spain.

As well as the SocioEconomic situation - in comparison with patients from other parts off the world.

In this study we included 34 patients with Clinically Definite MS found in a long-term and prospective population-based survey.

For assessing the handicap degree and SocioEconomic status we used the Environmental Status Scale (ESS) recommended by the International Federation of MS.

We compared the results with those found in 1116 patients from 7 different international series. The global mean score in ESS was 9.9 (sd 9.3, range 0-31).

The mean score for the item:
1. Actual Work Status: 3.3 (sd 2.3, range 0-5)
2. Financial/Economic Status: 1 (sd 1.7, range 0-5)
3. Personal Residence/Home: 0.8 (sd 1, range 0-4)
4. Personal Assistance: 1.2 (sd 1.7, range 0-5)
5. Transportation: 1.5 (sd 1.7, range 0-5)
6. Community Health Services: 0.7 (sd 1.3, range 0-5)
7. Social Activity: 1.3 (sd 1.5, range 0-4)

In the comparative assessment we found that our patients were better in all items, but in the item "Actual Work Status" where our patients yielded higher scores than those obtained in other series.

SocioEconomic status measured with ESS correlates well with the degree of Impairment measured with EDSS and it is more favorable than previously recognized, except for "Actual Work Status" item.

The high rate of labor incapacity in our series could be due to the considerable restrictions handicapped people have to cope with in order to find employment in rural areas.

Objective
To determine whether the MS Functional Composite (MSFC) can predict future disease progression in patients with Relapsing/Remitting MS (RR-MS).

Background
The MSFC was recommended by the Clinical Outcomes Assessment Task Force of the National MS Society as a new clinical outcome measure for clinical trials.

The MSFC, which contains a test of Walking Speed, Arm Dexterity, and Cognitive function, is expressed as a single score on a continuous scale.

It was thought to offer improved reliability and responsiveness compared with traditional clinical MS outcome measures. The predictive value of MSFC scores in RR-MS has not been determined.

Methods
The authors conducted a follow-up study of patients with RR-MS who participated in a phase III study of IFN-ß-1a (Avonex) to determine the predictive value of MSFC scores.

MSFC scores were constructed from data obtained during the Phase III Trial. Patients were evaluated by Neurologic and MRI examinations after an average interval of 8.1 years from the start of the clinical trial.

The relationships between MSFC scores during the clinical trial and follow-up status were determined.

Results
MSFC scores from the Phase III Clinical Trial strongly predicted clinical and MRI status at the follow-up visit.

Baseline MSFC scores, and change in MSFC score over 2 years correlated with both Disability Status and the severity of Whole Brain Atrophy at follow-up.

There were also significant correlations between MSFC scores during the clinical trial and patient-reported quality of life at follow-up.

The correlation with Whole Brain Atrophy at follow-up was stronger for baseline MSFC than for baseline EDSS.

Conclusion
MSFC scores in patients with RR-MS predict the level of disability and extent of Brain Atrophy 6 to 8 years later.

MSFC scores may prove useful to assign prognosis, monitor patients during early stages of MS, and to assess treatment effects.

Objectives
Recent Phase III Clinical Trials of ImmunoModulatory therapies in Relapsing/Remitting Multiple Sclerosis have shown significant benefits of active treatment on relapse related end points, but effects on disability outcomes have been inconsistent.

These apparent discrepancies could be due to differences in the clinical end points employed, the behavior of placebo cohorts, or both.

Methods
Disability data from the placebo cohorts of two large Phase III Studies, the United States Glatiramer Acetate Trial (Copolymer-1 Multiple Sclerosis Study Group) and the multinational Interferon-ß-1a trial (PRISMS Study Group) were combined and masked (n=313).

Two groups of disability outcome measures were assessed.

• Firstly, measures of disability change (2 year EDSS difference and area under the EDSS/time curve, AUC) were calculated.

• Secondly, conventional disease progression end points ("confirmed progression" and "worsening to EDSS 6.0") were evaluated by using Kaplan-Meier analysis and compared with a categorical classification based on EDSS trends.

Results
The average increase in Disability for the entire cohort as assessed by mean 2 year EDSS change (<0.5 EDSS point) or mean AUC (+0.57 EDSS-years) was small.

For the "confirmed progression" end points, increasing the stringency of the definition lowered their incidence (from 32% with 1.0 point at 3 months, to 9% with 2.0 points at 6 months).

But, did not improve the positive predictive accuracy for "sustained progression" maintained to the end of the study.

The error rate for this outcome was about 50%. Worsening to EDSS 6.0 was a more reliable end point, but had even lower sensitivity (incidence <10%).

EDSS trend analysis showed markedly heterogeneous disease courses, which were then categorized into "stable" (26%), "Relapsing/Remitting" (59%), and "Progressive" (15%) courses.

Patients with the last course had deteriorated considerably by the end of 2 years (mean worsening of 2.0 EDSS points).

Conclusion
In Relapsing/Remitting Multiple Sclerosis treatment trials, the conventional measure of mean EDSS change has low sensitivity.

Whereas the widely applied confirmed Progression end points have high error rates regardless of their definition stringency.

Alternative methods with better data utilization include AUC summary measures and categorical disease trend analysis.

The Heterogeneity of Disability outcomes in short trials, combined with unreliable clinical end points, diminishes the credibility of therapeutic claims aimed at reducing irreversible Neurological Deficits.

The behavior of patients treated with placebo should be carefully analyzed before conclusions are drawn on the efficacy of putative treatments.

Many clinical rating scales have been proposed to assess the impact of Multiple Sclerosis on patients, but only few have been evaluated formally for reliability, validity and responsiveness.

We assessed the Psychometric properties of five commonly used scales in Multiple Sclerosis:

• The Expanded Disability Status Scale (EDSS)
• The Scripps Neurological Rating Scale (SNRS)
• The Functional Independence Measure (FIM)
• The Ambulation Index (AI)
• The Cambridge Multiple Sclerosis Basic Score (CAMBS)

The score frequency distributions of all five scales were either bimodal (EDSS and AI) or severely skewed (SNRS, FIM and CAMBS). The reliability of each scale depended on the definition of 'agreement'.

Inter-and intra-rater reliabilities were high when 'agreement' was considered to exist despite a difference of up to 1.0 EDSS point (two 0.5 steps), 13 SNRS points, 9 FIM points, 1 AI point and 1 point on the various CAMBS domains.

The FIM, AI, and the relapse and progression domains of the CAMBS were sensitive to clinical change, but the EDSS and the SNRS were unresponsive.

The validity of these scales as impairment (SNRS and EDSS) and disability (EDSS, FIM, AI and the disability domain of the CAMBS) measures was established.

All scales correlated closely with other measures of handicap and quality of life.

None of these scales satisfied the psychometric requirements of outcome measures completely, but each had some desirable properties.

The SNRS and the EDSS were reliable and valid measures of impairment and disability, but they were unresponsive.

The FIM was a reliable, valid and responsive measure of disability, but it is cumbersome to administer and has a limited content validity.

The AI was a reliable and valid ambulation-related disability scale, but it was weakly responsive.

The CAMBS was a reliable (all four domains) and responsive (relapse and progression domains) outcome measure, but had a limited validity (handicap domain).

These psychometric properties should be considered when designing further clinical trials in Multiple Sclerosis.

Purpose
To determine how sensitive and specific the Magnetic Resonance (MR) Imaging finding of SubCallosal Striations is for Multiple Sclerosis (MS).

Materials & Methods
In 18 patients with clinically suspected MS and 32 age-matched patients without MS, Sagittal 2-mm Fast Fluid-Attenuated Inversion-Recovery (FLAIR) imaging was added to the routine MR studies of the Brain.

The images were reviewed for the presence of SubCallosal striations, that is, linear, 1-mm-thick foci of HyperIntensity perpendicular to the Ependyma, like a stack of coins.

The images were masked to exclude the Hemispheric White Matter and were interpreted without knowledge of patient age or medical history.

Results
Seventeen patients with clinical MS had SubCallosal Striations (beneath the Corpus Callosum); one did not. Of the 32 patients without MS, five had SubCallosal striations and 27 did not.

SubCallosal striations were highly associated (P < .001) with clinical MS.

Conclusion
SubCallosal Striations are thought to represent PeriVenular DeMyelination, that is, the same process that later produces the "ovoid" lesions visible on routine MR images.

SubCallosal Striations are not seen on routine Axial MR images and can be seen only on 2-mm sagittal FLAIR images.

Objective
To compare MS Normal-Appearing White Matter (NAWM) where new Gadolinium-enhancing (Gd⁺) lesions do and do not arise.

Methods
A total of 22 Relapsing/Remitting MS patients and 11 healthy control subjects completed as many as 12 monthly Brain MRI sessions.

Quantitative measures of Gadolinium Enhancement (GDR), water Proton Density (PDN), water proton T₂ relaxation time constants (T₂), Magnetization Transfer Ratio (MTR), and T₁-weighted signal intensity (T₁N) were followed serially in healthy control and MS NAWM.

Results
A total of 129 new Gd⁺ lesions were identified in 11 patients. PDN, T₂, MTR, and T₁N were diffusely abnormal in MS NAWM.

NAWM regions in which new Gd⁺ lesions arose have increased GDR, PDN, and T₂, and reduced MTR and T₁N compared with ContraLateral homologous NAWM regions in which no new Gd⁺ lesions arose.

Differences between these NAWM regions preceded lesion appearance for at least several months. After lesions became visible, GDR returned to baseline within 2 months, and PDN and MTR had larger residual abnormalities than T₂ or T₁N.

Conclusions
Quantitative MRI measures are diffusely abnormal in MS NAWM. These measures are, on average, more abnormal in NAWM regions in which new Gd⁺ lesions arise.

After the appearance of Gd⁺ lesions, measures of PDN and MTR may provide more appealing markers of relatively irreversible tissue damage than measures of T₂ and T₁N.

In this review, we analyzed clinical outcome measures used in Multiple Sclerosis (MS) clinical trials in which the primary goal is to slow or arrest progression of disease.

In addition, we examined rating scales that quantify symptomatic complications of MS (for example, Spasticity) and the current role of Magnetic Resonance Imaging in MS treatment trials.

Each proposed scale has advantages and deficiencies, and none meets all the criteria for an ideal outcome measure.

The validity of trial design may be improved by using combinations of selected components of current scales as well as new instruments targeted to specific variables (such as motor strength).

Symptom-specific rating scales are most appropriately used in trials of symptomatic therapeutic strategies for MS.

Until serial Magnetic Resonance Imaging changes are definitely known to predict long-term Impairment and Disability in patients with MS, clinical outcome measures will remain the primary means of assessing therapeutic efficacy in Phase III Clinical Trials.

Objectives
The EDMUS system is a clinical database specifically tailored to the description of Multiple Sclerosis (MS).

The EVALUED (Evaluation of the EDMUS system) study is an European project with two objectives:

1) to assess the inter-examiner reliability of the whole EDMUS system;

2) to validate the EDMUS-Grading Scale (EGS),which is a simplified version of the Kurtzke Disability Status Scale (DSS).

Methods
The protocol included 12 Neurologists working in pairs within six European centres (Bari, Basel, Florence, London, Lyon, Wurzburg). They assessed independently 30 MS patients in their centre, filling in the EDMUS forms.

The reliability of the system was assessed on selected key items in the history of the MS onset, the clinical course and the disease course classification.

The clinical examination of the patients permitted an assessment of the Kurtzke Expanded Disability Status Scale (EDSS) and the EGS. Level of agreement was measured in terms of kappa and weighted kappa indexes whenever appropriate.

Results
The study included 180 patients with Definite or Probable MS of whom 37% were males. Age was 35.8+/-9.6 years (mean +/- SD), disease duration 7.8+/-5.7 years, and mean EDSS score 4.1+/-2.2.

The disease course was Relapsing/Remitting in 67%, Secondary/Progressive in 22%, and Progressive from disease onset in 11%. For key items of the history, the inter-examiner reliability level ranged from moderate to excellent.

Concerning the disability scales, perfect agreement was reached in 59 % for EDSS and 78% for EGS. The close correlation and linear association (r=0.94, p < 0.0001) between both scales demonstrated EGS's construct validity.

Conclusion
The EDMUS system allows a consistent clinical description of MS using a common language. This standardized follow-up of MS patients is valuable especially in studies requiring a critical mass of informative patients.

We compared the Relative Measurement Precision (RMP) of the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC).

For discriminating between groups of patients known to differ in their extent of Multiple Sclerosis (MS). A total of 133 patients were rated with the EDSS and MSFC and had Magnetic Resonance Imaging (MRI) scans.

Patients were grouped on the basis of MRI appearances (T1- and T₂-weighted lesion loads, Parenchymal and Ventricular Fractions - T₁ LL, T₂ LL, PF, VF, respectively) and RMP was determined using the method of Group Differences.

For each MRI parameter, the total sample was arranged in ascending order of magnitude and divided into two, three, four and five similar sized groups.

For each division (two, three, four or five groups), EDSS and MSFC scores for the groups were compared using parametric (paired samples t-tests, one-way ANOVA) and nonparametric (Wilcoxon's rank-sum test, Kruskal-Wallis analysis of variance) statistical methods and RMP was estimated.

The EDSS and MSFC were correlated substantially (r = -0.64). Relative to the MSFC, the EDSS had inferior measurement precision regardless of the number of groups into which the total sample was divided, or the statistical method.

However, the RMP of the EDSS compared with the MSFC varied from 2% to 86%. Results suggest the MSFC is better than the EDSS for detecting differences between groups of patients, defined by these MRI markers of MS.

However, the finding that both scales correlated weakly with MRI markers, indicated that they are limited as predictors of MS pathology as defined by MRI.

An explanation for this well-established clinical-MRI paradox is that rating scales and MRI measure fundamentally different manifestations of MS.

We compared the Relative Measurement Precision (RMP) of the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC).

For discriminating between groups of patients known to differ in their extent of Multiple Sclerosis (MS).

A total of 133 patients were rated with the EDSS and MSFC and had Magnetic Resonance Imaging (MRI) scans.

Patients were grouped on the basis of MRI appearances (T₁- and T₂-weighted Lesion Loads, Parenchymal and Ventricular Fractions - T₁LL, T₂LL, PF, VF, respectively) and RMP was determined using the method of group differences.

For each MRI parameter, the total sample was arranged in ascending order of magnitude and divided into two, three, four and five similar sized groups.

For each division (two, three, four or five groups), EDSS and MSFC scores for the groups were compared using Parametric (paired samples t-tests, one-way ANOVA).

And NonParametric (Wilcoxon's Rank-Sum Test, Kruskal-Wallis analysis of variance) statistical methods and RMP was estimated.

The EDSS and MSFC were correlated substantially (r = -0.64).

Relative to the MSFC, the EDSS had inferior measurement precision regardless of the number of groups into which the total sample was divided, or the statistical method.

However, the RMP of the EDSS compared with the MSFC varied from 2% to 86%.

Results suggest the MSFC is better than the EDSS for detecting differences between groups of patients, defined by these MRI markers of MS.

However, the finding that both scales correlated weakly with MRI markers, indicated that they are limited as predictors of MS pathology as defined by MRI.

An explanation for this well-established clinical-MRI paradox is that rating scales and MRI measure fundamentally different manifestations of MS.

Background
There is no consensus method for determining progression of disability in patients with Multiple Sclerosis (MS) when each patient has had only a single assessment in the course of the disease.

Methods
Using data from two large longitudinal databases, the authors tested whether cross-sectional disability assessments are representative of disease severity as a whole.

An algorithm, the Multiple Sclerosis Severity Score (MSSS), which relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations, was devised and then applied to a collection of 9,892 patients from 11 countries to create the Global MSSS.

In order to compare different methods of detecting such effects the authors simulated the effects of a genetic factor on disability.

Results
Cross-sectional EDSS measurements made after the first year were representative of overall disease severity. The MSSS was more powerful than the other methods the authors tested for detecting different rates of disease progression.

Conclusion
The Multiple Sclerosis Severity Score (MSSS) is a powerful method for comparing disease progression using single assessment data.

The Global MSSS can be used as a reference table for future disability comparisons.

While useful for comparing groups of patients, disease fluctuation precludes its use as a predictor of future disability in an individual.