Tuesday, 29 March 2016

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.


  1. I agree completely. The term "progressive" is probably not going into the night easily. Several neuro's here do not like the term remitting either as they have encountered many patients / caregivers who akin the term to remission in cancer.

    The current tests towards disability progression are just not adequate. I did the 25 foot walk as well as the peg test no problem. But for example with my dominant hand when I try eat soup lets say which requires steady hand from bowl to mouth slight tremors sometimes happen.

    Since there are differing disability scales for varied facets of disability things become more complex for both clinician, patient and family.

    I realize near impossible to make a gold standard. But really, walking 25 feet and the peg test? In comparison to what MS may bring, this is at best a minimal assessment. Especially if at some point in time insurers make more granular rating required.

    My vision on one side is about half the other. Its occurred over time so it did not result in the form of trainwreck it may have had it been instant and lasting.

    Point being everyones level of disability is as unique as the plaques. Surely a more granular means can be created. My neuro is talking about wanting me try Ampyra

  2. For gawds sake - just adding the 25 foot walk and the 9 hole peg test to the already useless EDSS is so pathetic it doesn't qualify to even be considered as tinkering around the edges!

    The whole EDSS need a major overhaul - better still - scrap it and start again. It does not reflect the impacts of MS in any realistic way. I know, I know, it is the measure used in clinical trials etc and results have to be translatable but that is not an insurmountable obstacle.

    1. Biomarkers in plasma are needed ASAP. It's 2016! We don't need archaic tests that had their place in the 20th Century.

    2. http://archneur.jamanetwork.com/article.aspx?articleid=2506517
      GFAP is detectable in the blood for traumatic brain injury. It has been shown to be elevated in RRMS and more so in SPMS. Why isn't this biomarker being utilized?

    3. Gfap is marker of astrocytes. you find it but what are you going to do about it. At present nothing so as a biomarker it lacks functional utility

    4. Gfap is marker of astrocytes. you find it but what are you going to do about it. At present nothing so as a biomarker it lacks functional utility

    5. If it is detectable, steroids and onto a more effective therapy. Why wait?

  3. "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."

    For balance I'd like to say that I will have left this mortal coil when my lips, tongue and throat muscles become my arms. A doctor's job is to limit suffering and not prolong it. A doctor's job is to retain a patient's dignity. When a patient gets to such a dreadful position the doctor must put their hands up and say I have failed. Can someone remind neuros that it is 2016. Where's the neuroprotectors and repair agents?

  4. No DMTs once you're in a wheelchair, say the NHS? I've been in a wheelchair since 6 months in to my MS. Luckily I live in Canada because who knows what life I would have had for the last 7 years without them.

  5. I think there is some confusion here about disease activity and disability. Measuring disease activity in an easier, less stressful or intrusive way would be wonderful. Sure, there is research going on. Some researchers here I have spoken with have said it may well be a double edged sword. That is to say a truly accurate mechanism may show the treatments are not as effective as percentiles show in the endpoints in trials.

    Measuring actual disability is important in many respects. Insurers at some point and to an extent do now measure access to care, assistive devices and more based on disability levels.

    People with MS who wish to engage in forms of therapies and those assisting them with those therapies need know what to target. Be able to create a protocol that is granular towards the patient.

    Lots and lots of talk in the medical community about personalized care and medicine. Cant do this with chronic illnesses unless one has a roadmap towards best long term outcomes and quality of life.

    A peg test and walking 25 feet simple does not suffice especially with MS since not only can it be physically debilitating but mentally debilitating as well. This makes proper assessments extremely complex and really requires multiple disciplines. In fact, for some, nearly all disciplines of physicians.

    Tis' why I said, creating a gold standard, probably possible but would be so expensive to do, track, on and on it's not feasible. However on the other side of the coin, something considerably more granular CAN be done w/o costing becoming a significant factor.


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