ClinicSpeak: time to focus on hand function to measure worsening MS

How important is arm function, speech and swallowing to you? #MSBlog #MSResearch #ClinicSpeak

"It is clearly  time to rethink how we do progressive, or worsening, MS trials (I am trying to move away from using the term progressive). The days of relying on the EDSS to measure the impact of worsening/progressive MS are going fast. The study below shows that when using the EDSS-Plus to measure worsening in SPMS it is more sensitive than the EDSS alone. The EDSS-plus is a composite of the EDSS, timed 25-ft walk and the 9-hole peg test. What this study doesn't address is the possibility of different biological processes driving worsening in different neuronal subsystems. The systems with no reserve capacity that are worsening clinically (in old terminology clinically-apparent SPMS) may not be modifiable in the short-term with anti-inflammatory DMTs; these systems may require neuroprotectants. In comparison, the subsystems with reserve, e.g. upper limb and bulbar function, may still be modifiable with anti-inflammatories. Therefore we may need to design our outcomes based on what the proposed DMTs can do and on how advance the disabilities are in the populations being studied. The latter is all part of our length-dependent axonopathy and therapeutic lag hypotheses."


"When you have MS and you lose the function of your legs, your arms and hands become your legs. When you lose the function of your arms your lips, tongue and throat muscles become your arms, hands and legs. At the moment we seem to focus too much attention on leg function and forget the upper body. In the NHS we are meant to stop DMTs when a person becomes wheelchair bound; what we actually saying to them is we don't really care about your upper limb or bulbar function. Clearly this position is wrong and we need to do something about it. Data will emerge later this year that DMTs continue to work on the upper limbs despite lower limb function working. What this observation is telling is that MS is that the pathogenesis of MS may be modifiable regardless of how disabled you are."

Cadavid et al. The EDSS-Plus, an improved endpoint for disability progression in secondary progressive multiple sclerosis. Mult Scler. 2016 Mar 22. pii: 1352458516638941.

BACKGROUND: The Expanded Disability Status Scale (EDSS) has wide scientific and regulatory precedent but limited ability to detect clinically relevant disability progression in secondary progressive multiple sclerosis (SPMS) patients, partly due to a lack of meaningful measurement of short-distance ambulatory and upper-extremity function.

OBJECTIVE: To present a rationale for a composite endpoint adding the timed 25-foot walk (T25FW) and 9-Hole Peg Test (9HPT) to EDSS for SPMS disability progression assessment.

METHODS: Using the International Multiple Sclerosis Secondary Progressive Avonex Clinical Trial (IMPACT) placebo arm (n = 215) data, we analyzed disability progression using a novel progression endpoint, "EDSS-Plus," defined as progression on ⩾1 of 3 components (EDSS, T25FW, and/or 9HPT) confirmed ⩾24 weeks apart and with a ⩾20% minimum threshold change for T25FW and 9HPT.

RESULTS: Over 2 years, subjects classified as T25FW, 9HPT (dominant hand), or 9HPT (non-dominant hand) progressors worsened on average by 103.4%, 69.0%, and 59.2%, respectively, while non-progressors' times remained largely unchanged. Using EDSS-Plus, 59.5% of the patients had 24-week confirmed disability progression versus 24.7% (EDSS), 41.9% (T25FW), and 34.4% (9HPT (either hand)) on each component alone.

CONCLUSION: The 24-week confirmed minimum worsening of ⩾20% for T25FW and 9HPT clearly separates SPMS progressors from non-progressors. We propose that EDSS-Plus may represent an improved endpoint to identify SPMS disability progression.

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