Systematic literature review and validity evaluation of the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC) in patients with multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that mainly affects young adults. The disease is characterized by the occurrence of relapsing neurological deficits that affect different functional systems of the central nervous system. The majority of patients initially present with a relapsing remitting disease course (RRMS > 80%), however after 10 – 15 years about 60% of these patients show a transition into a secondary progressive disease course (SPMS) that is characterized by a gradual decline of neurological function. In less than 15% of cases, the disease course is progressive from the onset (primary progressive MS, PPMS) [1].

In recent decades, a number of instruments have been developed that describe the clinical severity and the functional deficits in multiple sclerosis. These instruments are increasingly used as an endpoint in clinical trials to assess the effectiveness of therapeutic interventions.

The most popular and widely used instrument is the Expanded Disability Status Scale (EDSS) of Kurtzke [2]. The EDSS is a clinician-administered assessment scale evaluating the functional systems of the central nervous system. The EDSS is used to describe disease progression in patients with MS and to assess the effectiveness of therapeutic interventions in clinical trials. It consists of ordinal rating system ranging from 0 (normal neurological status) to 10 (death due to MS) in 0.5 increments interval (when reaching EDSS 1). The lower scale values of the EDSS measure impairments based on the neurological examination, while the upper range of the scale (> EDSS 6) measures handicaps of patients with MS. The determination of EDSS 4 – 6 is heavily dependent on aspects of walking ability.

Another important instrument is the Multiple Sclerosis Functional Composite (MSFC) [3], which was developed by the MS Society’s Clinical Assessment Task Force [4] as an additional clinical measure of MS disability progression. The primary goal for creating the MSFC was to improve the standard measure of MS disability for clinical trials and to develop a multidimensional metric of overall MS clinical status [4]. The MSFC is a three-part performance scale for evaluating the degree of impairment in MS patients. It includes the assessment of leg function by moving a short walking distance (“Timed 25-Foot Walk”, T25FT), the assessment of arm function using breadboard test (“9-Hole Peg Test”, 9HPT) and an attention/concentration test to assess cognitive functions (“Paced Auditory Serial Addition test”, PASAT). An integrated MSFC score is calculated using z-scores. There is an ongoing debate about which dimensions to include in the MSFC (e.g. the inclusion of a vision testing) as well as how the reference population affect the standardized scoring (z-scores) of the MSFC [5‐13]. In recent years, the MSFC is increasingly used in clinical trials.

A number of other instruments are available to assess MS: the Ambulation Index (AI) [14], the Scripps Neurological Rating Scale (SNRS) [15] and the Illness Severity Scale (ISS) [16], the Guy’s Neurological Disability Scale (GNDS) [17] and the Multiple Sclerosis Impairment Scale (MSIS) [18]. Furthermore, the overall Functional Independence Measure (FIM) [19] and the Cambridge Multiple Sclerosis Basic Score (CAMBS) [20] are clinical assessment instruments that could be used to assess MS [21]. Specific instruments for measuring health-related quality of life in MS patients are the Multiple Sclerosis Quality of Life-54 (MSQOL-54) [22] and the Multiple Sclerosis Quality of Life Inventory (MSQLI) [23]. Only a few of these instruments meet the requirements of methodological standards (e.g. validity, reliability, responsiveness), particularly for use in clinical trials. None of these instruments is recognized to use in clinical trials without any restrictions.

The aim of this study was to identify strengths and weaknesses of EDSS and MSFC. We investigated to what extent the psychometric properties of the two most important instruments – EDSS and MSFC – meet the methodological standards and what value they have in clinical trials. Although different methodological characteristics of the EDSS are the focus of many studies, a summary and synthesis of the study results is missing. In addition, the importance the MSFC is still a matter of debate and a summary of its methodological characteristics is also missing. We addressed this gap by conducting a systematic literature review to specifically answer the following questions:

The study was conducted in two phases. First, an exploratory electronic literature search was undertaken to (a) develop and optimize a systematic search strategy and (b) estimate the extent and quality of available studies. Then, a systematic literature search was conducted using the developed search algorithms. The databases MEDLINE (PubMed), ISI Web of Science, EMBASE, PsycINFO and CINAHL & PSYNDEX were systematically searched. Search terms were: Multiple Sclerosis + Expanded Disability Status Scale OR EDSS (for EDSS) and Multiple Sclerosis + Multiple Sclerosis Functional Composite OR MSFC (for MSFC) (Table 1).

Overall, 3680 results were identified (4272 of the initially generated 8132 hits were excluded as duplicates); the abstracts were reviewed by two independent scientists and structured according to the following criteria:

When the theme did not meet the research question, the abstract was excluded. A total of 684 publications were classified as relevant and ordered as full-text publications in electronic copy or selected in lending (psychometric publications n = 295; papers on clinical studies n = 364; reviews, summaries etc. n = 25).

In a further selection process the full-text psychometric papers (n = 295) were reviewed and subdivided into:

The categories 2 and 3 were excluded. Ultimately, 120 papers were identified as relevant methodological publications. Figure 1 gives an overview of the selection process.

We identified 120 publications with methodological content for EDSS and/or MSFC. Table 2 gives an overview of scores distribution and period of publication.

Numerous relevant studies of EDSS were published before 2000 [24‐32]. The majority of the MSFC studies as well as the head-to-head comparisons were published between the years 2000 and 2009.

This study examined the extent to which the psychometric properties of the most important instruments to assess disease progression in MS – EDSS and MSFC – meet the methodological standards and what value they have as outcome measures in clinical trials.

In a systematic literature review of 120 relevant full-text publications, we found that while the EDSS is the most widely used instrument in clinical trials assessing the effectiveness of therapeutic interventions, the MSFC is becoming increasingly important.

Single methodological characteristics of the two instruments have been investigated in numerous studies. The EDSS has some documented weaknesses in reliability and sensitivity to change. Although the MSFC was developed rigorously, its weaknesses include interpreting the z-scores (which are used to calculate the summary score from the three components), the learning effects of the PASAT, low acceptance by patients and lack of a visual dimension. However, the MSFC has better sensitivity and reliability compared to EDSS. The methodological quality criterion of validity is sufficiently met by both instruments.

Despite the criticisms, in particular the EDSS could be classified as an important endpoint. In neither publication, the EDSS (or MSFC) are discussed as a surrogate parameter (in contrast to MRI measurements). Cohen et al. [73] emphasized in their review of clinical outcome parameters, the general acceptance of the EDSS as an endpoint by different authorities. In contrast, the MSFC is usually used as a secondary endpoint.

The importance of the instruments is also reflected in our evaluation of clinical trials: in 50 of 66 identified relevant phase-III and phase-IV studies, disease progression as measured by EDSS was used as primary (27 studies) or secondary outcome (23 studies). The MSFC was used in eight studies as a secondary endpoint and only one study as a primary endpoint.

In summary, both instruments are acceptable outcome criteria to assess the effectiveness of clinical interventions and to monitor disease progression. When using the EDSS, its limited inter-and intra-rater reliability should be considered. All possibilities to increase reliability should be used, including training of investigators, assessment by the same doctor/neurologist during the study, specified times of detection, standardized protocols for neurological examination and a precise definition of all requirements. When using the MSFC, the learning effects of the PASAT and 9HPT should be considered and controlled (e.g. using control groups).

Concerning the natural history of MS, Weinshenker and colleagues [1] observed an average change of 0.5 points on the EDSS scale in a year. A clear recommendation on interpreting changes in EDSS and MSFC values does not yet exist. EDSS changes by 1.0 points from a baseline EDSS less than or equal to 5.5 and 0.5 points over a baseline 5.5 are commonly recognized as a clinically increase in disability. However, it is now understood that it is more accurate to define disability change as a sustained change for 12 weeks or, even more reliably, for 24 weeks.

For the MSFC, changes by 20% in the individual components are considered to be clinically relevant. However, it is difficult for a clinician to understand what a 20% change in MSFC subscores is while a significant EDSS change is more intuitively understood.

Overall, the literature reveals that the EDSS is the most widely used and best-known instrument to assess disease progression in MS. The advantages and disadvantages of EDSS and MSFC have been investigated frequently. The great advantage of the EDSS is its international acceptance (including the EMA) as a primary endpoint in clinical trials. Because it is so commonly used, studies that use the EDSS can easily compare results to other findings. Following the current literature, we can conclude that the importance of the EDSS will be unabated in future. Major changes of the EDSS are not recommended, as not to jeopardize its advantage.

In addition, the use of other measurements as clinical trial endpoints (e.g. the MSFC) is recommended to provide information on dimensions no covered in the EDSS, such as upper limb function or cognitive skills.

The assessment instruments we examined, EDSS and MSFC, both are frequently and internationally used in clinical studies – despite their well know methodological limitations. They are suitable to detect patient-relevant endpoints in MS with reasonable validity in spite of some methodological concerns.

Written informed consent was obtained from the patients for the publication of the reviewed studies and accompanying images.