Short summary

The aim of the study is to

1. Validate the MS-Impairment Scale against biomarkers of pathology and brain MRI lesions in patients with definite secondary progressive multiple sclerosis.
2. In a longitudinal study, to examine the dynamics of disease progression in patients with high risk of SPMS and with possible transition: blood and CSF biomarkers, and prospective longitudinal multimodal MRI.
3. To analyze the dynamics of and interactions between the domains of the WHO-International Classification of Function in relation to disease progression.
1. Validate MSIS against MRI brain lesions, cognitive impairment and biomarkers, compared to EDSS,
2. Analyze the disease impact on patients domains of Activity and Social participation and if there is a correlate between biomarkers, MRI lesions and the cognitive impairment.

Rationale

Multiple sclerosis (MS), the most common neurological disease among young adults, is caused by autoimmune inflammatory demyelination in the central nervous system (CNS). Its prevalence is especially high in Denmark and increased from 62.9 to 154.8 per 100.000 in 50 years.

Early in the course, MS is characterized by clinically active and silent phases (relapsing-remitting, RRMS). A secondary progressive phase evolves in the majority of patients within 10-20 years (SPMS), where a continuous progression is responsible for the advancing disability in young adults, and disease modifying treatments (DMTs) are less effective[4]. There are no established criteria to determine, when RRMS converts to SPMS; the diagnosis of SPMS is made retrospectively. In one report, the median time from the first symptoms of MS (a clinically isolated syndrome) to the development of SPMS was 19 years, while the median time from MS diagnosis to SPMS was 12 years. The mean duration period of uncertainty till definite progression was 2.9 ± 0.8 years in another study.

About 10 percent of MS patients have a primary progressive disease course, by progressive accumulation of disability from disease onset with occasional plateaus, temporary minor improvements, or acute relapses still consistent with the definition. They tend to have a later age of onset, and may have a worse prognosis for ultimate disability in comparison with patients who have RRMS.

The pathology of MS is highly heterogeneous and characterized by inflammation, activated microglia, oligodendrocyte loss, axonal degeneration, failure of remyelination and astrocytosis. Damage to the myelin sheath of axons (demyelination) resulting in neurodegeneration can be caused by both the degenerative and inflammatory processes. Both processes are associated with elevated levels of biomarkers of demyelination and axonal damage in the cerebrospinal fluid (CSF). The biomarker detection is highly specific in the CSF, since it reflects more the CNS pathology than other body fluids such as peripheral blood or urine. In addition, the blood brain barrier is more intact in patients with secondary progressive MS, therefore measuring biomarkers in the blood at this stage of the disease is less sensitive. Newer studies have shown a correlation between serum and CSF levels of neurofilament light chain and some inflammatory biomarkers, but the exact correlation is unrevealed. Low levels of biomarkers in the blood because of all these reasons may hinder correlation analyses and examination of their relation to clinical and paraclinical outcomes.

Health assessment scales are widely used as research outcome measures, and the quality of the psychometric properties of the instruments are of critical importance for the impact of clinical research.  The gold standard instrument for clinical research in multiple sclerosis is the Expanded Disability Status Scale (EDSS) that was published in 1983 with scarcely no psychometric validation.  Afterwards, it has been shown to have very poor psychometric properties.  An important weakness is a very low sensitivity to changes in the middle and upper part of the scale (EDSS 5-9), which makes it unsuitable as clinical outcome measure in studies on secondary progressive MS (SPMS).

The MS-impairment Scale (MSIS) was developed in 1995 as a response to the poor quality of the EDSS, and the initial validation was published in 1997. Further validation of the responsiveness was published in 2005 and its superiority in terms of psychometric characteristics is evident. Later, the MSIS was used as an exploratory outcome in the MECOMBIN study published in 2010, in which the MSIS showed a statistically significant difference between the treatment and the placebo arm, while the EDSS change was statistically non-significant. The MSIS was used as outcome in an MRI study of spinal cord metrics in MS patients and showed a better correlation with the MRI metrics that did the EDSS. The responsiveness of the MSIS is stable over a wider range of impairment including the range of most SPMS patients. Thus, the MSIS might be a better clinical outcome measure for clinical trials on SPMS.  A proper validation of MSIS against brain MRI or a promising biomarker neurofilament light chain in the CSF has still not been performed in secondary progressive MS.

The International Classification of Function (ICF) (WHO) describes the consequences of chronic disease in three domains: 1) Bodily Functions (formerly "impairment"), 2) Activities, and 3) Social Participation (formerly "handicap").

Scales that measure 1) Bodily Functions are mostly administered by health care professionals and based on (semi-) objective clinical observations (e.g. EDSS, MSIS, MSFC), while 2) "Activity" is  a function of the Bodily Functions and generally assessed by means of observer- or self-rated scales that address complex activities of daily living (e.g. FIM, Barthel Index, MSIS-29 and some items of the EDSS). Finally 3) "Social Participation", which comprises family life, occupation and leisure life, is mainly a function of motivation and ability to perform activities. This domain may seem the most relevant for clinical outcomes. Nevertheless, Social Participation is markedly influenced by factors not related to disease, which compromises the signal-to-noise ratio.

Many of the health measurement instruments comprise items from more than one ICF domain, which means that the same trait may be measured more than once. Such redundancies distort the sensitivity of a given scale and should be avoided by limiting the items of the scale to one domain only.

The ICF does not include conceptually defined dimensions for "biological changes" (e.g. MRI lesions; CSF biomarkers), symptoms (purely subjective) or even for "Quality of Life",  although these terms are used in many of the Self-rated Health Measurement Scales. 

Description of the cohort

Secondary progressive multiple sclerosis patients, recruited from the MS out-patient clinic. 

Data and biological material

Clinical data from patient journals regarding disease course, symptoms and treatment.

Biological material (blood, cerebrospinal fluid)

MRI of brain measuring global and regional lesion volumes, white matter and cortical atrophy, white matter tract integrity regarding axonal and myelin damage, multi-voxel MR-spectroscopy and functional connectivity.

Clinical tests: MSIS, EDSS, BICAMS, FSCM, 6-SST, 9-HPG, 25-FTW

Questionnaires: SF-36, MSIS-29

Collaborating researchers and departments

Department of Neurology, Odense University Hospital

• Professor Zsolt Illes
• Phd Mads Henrik Ravnborg

Publications associated with the project

Theodorsdottir A, Larsen P V, Nielsen H V, Illes Z, Ravnborg M H. Multiple sclerosis impairment scale and brain MRI in secondary progressive multiple sclerosis