Sunday, 20 December 2015

Bringing science to spasticity may show effects

Wininger M, Craelius W, Settle J, Robinson S, Isaac B, Maloni H, Moradi M, Newby NA, Wallin M.Biomechanical analysis of spasticity treatment in patients with multiple sclerosis.Ther Adv Neurol Disord. 2015 Sep;8(5):203-11. doi: 10.1177/1756285615601390.

OBJECTIVES:New metrics for clinical spasticity are needed to assess motor performance, since scales such as the Ashworth and Tardieu are unreliable. Here, we assessed outcomes of baclofen treatment in patients with multiple sclerosis (MS) using biomechanical analysis of voluntary movements.
METHODS:Patients with MS and symptomatic limb spasticity were recruited for a pre-post baclofen titration study, along with age-matched healthy controls. Oral baclofen was titrated to optimize spasticity symptoms in all MS cases over 4 weeks. Clinical assessments included the Modified Ashworth Scale (MAS), Tardieu Scale (TS); elbow kinematics were measured via the Transient Acceleration Measurement Interface (TAMI); performance was measured as the score at 4 weeks minus the baseline score in all measures. Movement proficiency within TAMI was quantified through a scale-free smoothness measure, according to the regional excursion deviation (RED) from a constant-velocity approximant.
RESULTS: Twelve patients with MS [age: 47.8 ± 9.8 years; women: 4; disease duration: 20 ± 10 years; disease-modifying therapy use: 7; Expanded Disability Status Scale (EDSS): 6.8 ± 1.4] and eight age-matched healthy controls were evaluated concurrently (mean age: 49.5 ± 13.1 years; women = 3). In MS cases, no significant improvement in arm spasticity was observed with main effects: MAS: -41.6 ± 72.6 (p = 0.09); EDSS: -1.6 ± 10.4% (p = 0.49); and TS: -8.3 ± 2.1% (p = 0.32), -24.9 ± 63.6% (p = 0.42), and -30.7 ± 79.9% (p = 0.06), at slow, moderate, and fast speeds, respectively. However, voluntary motion smoothness, as measured by TAMI: RED, decreased significantly: 0.62 ± 0.08 versus 0.54 ± 0.09, p < 0.001, indicating significant increase in movement smoothness post treatment.
CONCLUSION:A simple biomechanical analysis of voluntary movements revealed a significant reduction of spasticity after 30 days of baclofen therapy in patients with MS that was not detected by clinical assessments.

Just had a review about one of our papers on spasticity were we actually measured limb stiffness in mice and they said it wasn't the classical way to do this...I ask what way is classical this in rodents..in humans it has been the Ashworth scale, which is a physio or neuro looking at a muscle and saying that looks stiff and giving it a number. Not very quantitative.



In the trials with sativex there was no effect of the drug on the Ashworth scale in the original trials so they use a numerical rating scale where the person with MS saying I feel not stiff to stiff, so not very quantitative.

Some places use the TARDIEU scale.
This scale quantifies muscle spasticity by assessing the response of the muscle to stretch applied at specified velocities. Grading is always performed at the same time of day, in a constant position of the body for a given limb. For each muscle group, reaction to stretch is rated at a specified stretch velocity with 2 parameters x and y. Velocity to stretch (V) Quality of muscle reaction (X) V1 As slow as possible 
0 No resistance throughout passive movement V2 Speed of the limb segment falling 
1 Slight resistance throughout, V3 As fast as possible (> natural drop) with no clear catch at a precise angle V1 is used to measure the passive range of 
2 Clear catch at a precise angle, Motion. (PROM). Only V2 and V3 are used followed by release to rate spasticity 
3 Fatigable clonus (<10secs) occurring at a precise angle 
4 Unfatigable clonus (>10secs) occurring at a precise angle 
5. Joint Immobile Angle of muscle reaction (Y) Measure relative to the position of minimal stretch of the muscle (corresponding at angle) Spasticity Angle R1 Angle of catch seen at Velocity V2 or V3 R2 Full range of motion achieved when muscle is at rest and tested at V1 velocity Boyd, Graham 1999 ƒ A large difference between R1 & R2 values in the outer to middle range of normal m. length indicates a large dynamic component ƒ A small difference in the R1 & R2 measurement in the middle to inner range indicates predominantly fixed contracture 

Not very qunatitative either.

But the expert referee said also that (a) spasticity is nothing to do with flexor (bending) muscles (WRONG) (b) It is just a problem of Motor Nerves (WRONG) (c) H reflex (exaggerated electrophysiological response of the stretch reflex between the sensory signals from the muscle synapsing in the  spinal cord and exiting into motor signals to the muscle, due to loss of inhibitory activity within the spinal cord due the damage that causes spasticity) is nothing to do with spasticity (WRONG).

So after I said b*******s.....the reviewer is talking nonsense, we get a re-revew

Or it maybe the pictures that I sent the editors that only a moron (yes I do get annoyed by idiot reviewers) would say that spasticity has nothng to do with flexor (bending) muscle goups

Maybe too late to save the paper but indicates the knowledge of some of our so called peers..I wish if people don't have anything and constructive to say....say nothing!

Anyway rant over. This paper says we need better outcomes than the Tardieu or the Ashworth (which the FDA seems to be fixated on as an outcome in spasticity trials) Scales are needed. In the beasties we made equipment to do this and get quantitative data.

Baclofen causes many side effects and also it causes the down-regulation of the GABA receptor signalling that baclofen causes, so you have to slowly increase the dose to limit this receptor desensitization (turning off of the effect at a give dose) and the zombification/rag doll effect (floppyiness). 

In this study however baclofen failed to have an effect using the subjective Ashworth and Tardieu scales. This is not unusual as many any spastic agents have failed to affect these outcomes in trials. However a quantitative outcome worked. 

So should we stick with ineffectual scales and throw drugs away or get into the modern era and use quantitative outcomes and maybe not throw drugs away?. 

I bet you will be scratching you head when I say this, we are nearly in 2016 and still practise science stone-age. It would be funny if it were not so sad and frustrating!

Unfortunately the regulators controlling whether drugs are approved are "old farts" that stick with the EDSS and the likes of the Ashworth scales. They are part of the problem of why you are not getting drugs to treat progessive MS...robotic regulators that do their work by numbers.

It took GW pharma about 4 trials and an extra 5-6 years to bin the Ashworth Scale in Europe, costing millions, and it is still stuck with this with the FDA, so Sativex may never get approved in the USA as they may companies do studies that are very hard to show extra benefit on the Ashworth.

This rigid reviewing is a problem and could mean the end of our paper and also the end lof the ine for our anti-spasticty drug too...which is assessing Ashworth and Tardieu (Sorry nothing to do with me) as well as a NRS. However who knows if our trial design may allow an effect to be seen (also nothing to do with me). Time will tell. Maybe we can adopt these modern outcomes for our phase III programme assuming we get there fingers crossed.

If you meet the current criteria and want to give our new anti-spastic treatment a go please read this (Click). The trial is recruiting in the London Area and Soon to Increase into the Shires in the New Year.

Apologises I can't tell you more about the drug, until it is published....maybe you understand why I  have to rant every now and again.

CoI: We are developing an alternative to baclofen



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