Table 3.

Clinical assessments used to evaluate MS

Assessment	Description	Considerations
EDSS [56, 66, 67]	Assessment of disability in 7 functional systems (pyramidal, cerebellar, brainstem, sensory, bowel/bladder, visual, cerebral) and ambulation	• Widely used in MS clinical trials • Limited sensitivity in the lower ranges and with subtle changes • Fatigue and cognitive function are not adequately measured • Variable intra- and inter-rater reliability
EDSS-Plus [68]	Composite assessment of 3 physical disability parameters to facilitate evaluation of disability progression: 1. EDSS 2. T25-FW 3. 9-HPT	• More sensitive than the EDSS in identifying disability progression • Suitable measure for SPMS and PPMS, but the EDSS alone is better for RRMS • May be difficult to distinguish between RRMS and early SPMS in real-world clinical practice
NEDA-3 [11, 69]	Composite assessment of 3 parameters, weighted toward neuroinflammation: 1. No disability progression based on EDSS score* 2. No Gd+ lesions and no new/enlarging T2 hyperintense lesions on MRI 3. No clinical relapses	• Focus on inflammatory components of disease • Complements use of HETs but may expose patients to safety risks • Predictive of long-term disability if targeted early • Limited sensitivity with subtle changes • Does not capture full scope of clinical information
NEDA-4 [24]	Composite assessment of 4 parameters, includes neuroinflammation and neurodegeneration: 1. No disability progression based on EDSS score* 2. No Gd+ lesions and no new/enlarging T2 hyperintense lesions on MRI 3. No clinical relapses 4. Brain volume loss < 0.4% on MRI	• Addition of brain volume loss as a surrogate for disability and cognitive function • Currently not routinely measured in MS MRI sequences
MSFC	Quantitative measure of physical and cognitive function: 1. Leg function and ambulation (T25-FW) 2. Hand/arm function (9-HPT) 3. Cognitive function (PASAT)	• Considered more sensitive with the same patient over time • Practicable for everyday clinical use • Correlates with quality of life metric • The PASAT is difficult to administer
SDMT [70]	Assessment of cognitive function	• Better predictive validity and easier to administer than the PASAT
MSDM [56]	Alternative criteria for assessment of NEDA to support early treatment adjustment: 1. Disability progression (modified MSFC: T25-FW, 9-HPT, addition of LCSLC, SDMT instead of PASAT) 2. Number, severity, and type of relapses 3. MRI findings (Gd+ lesions, new/enlarged T2 lesions) 4. Neuropsychology: fatigue (FSMC), depression (HADS), anxiety (HADS), quality of life (MSIS-29)	• Practicable for everyday clinical use • Can detect clinical changes even in early stages of disease • Good sensitivity • Neuropsychology domain considered increasingly important
MEDA
MEDA (MAGNIMS score) [71]	Based on the MAGNIMS “low” risk score for future disability, defined as: 1. No relapses 2. ≤ 2 contrast-enhancing lesions	• Good accuracy in predicting severe long-term disability • May be more realistic for some patients to achieve in clinical practice • Low positive predictive value • Not verified in patients treated with oral DMTs or HETs
Rio score [72] [73]	Scoring system (range 0–3) to identify patients with poor short-term responses to therapy in the first year on treatment: 1. MRI findings (1 point if > 2 active T2 lesions) 2. Number of relapses (1 point if ≥ 1 relapse) 3. Disability progression (1 point if EDSS score increased by ≥ 1 point for ≥ 6 months)	• Can identify patients at risk of having a poor response to treatment • Disability progression in first year of treatment may be a poor predictor of subsequent clinical activity
Modified Rio score [69, 73]	Simplified version of the Rio score (range 0–3) that omits disability progression: 1. MRI findings (1 point if > 5 new T2 lesions) 2. Number of relapses (1 point if 1 relapse; 2 points if ≥ 2 relapses)	• Uses long-term data to improve upon the Rio score • Predictive value in different ethnic cohorts and for other DMTs • Difficulty classifying patients with an intermediate score
PROs [74–78]	Incorporates patients’ experience of non-clinical or invisible symptoms into assessment of disease status: • Quality of life (SF-36, MSQOL-54, MSQLI, MSIS-29) • Multidomain: physical, cognitive, quality of life (Neuro-QoL)	• Can be completed before the appointment at home or while waiting in the office

9-HPT 9-Hole Peg Test, DMT disease-modifying therapy, EDSS Expanded Disability Status Scale, FSMC Fatigue Scale for Motor and Cognitive Functions, Gd+ gadolinium-enhancing, HADS Hospital Anxiety and Depression Scale, HET high-efficacy therapy, LCSLC low-contrast Sloan letter chart, MAGNIMS magnetic resonance imaging in MS, MEDA minimal evidence of disease activity, MRI magnetic resonance imaging, MS multiple sclerosis, MSDM multiple sclerosis decision model, MSFC Multiple Sclerosis Functional Composite, MSIS-29 Multiple Sclerosis Impact Scale, MSQLI Multiple Sclerosis Quality of Life Inventory, MSQOL-54 Multiple Sclerosis Quality of Life-54, NEDA no evidence of disease activity, NEDA-3 3-parameter no evidence of disease activity, NEDA-4 4-parameter no evidence of disease activity, PASAT Paced Auditory Serial Addition Test, PPMS primary progressive multiple sclerosis, PRO patient-reported outcome, RRMS relapsing–remitting multiple sclerosis, SDMT Symbol Digit Modalities Test, SF-36 36-Item Short Form Survey, SPMS secondary progressive multiple sclerosis, T25-FW Timed 25-Foot Walk

*Differences exist in definitions of EDSS-based worsening disability between studies [11]: one proposed definition of worsening disability is an increase in EDSS score of 1.5 points from baseline score of 0, an increase of 1.0 points from baseline score of ≥ 1.0, or an increase of 1.5 points from baseline score of ≥ 5.0, confirmed after 3 or 6 months [24]