Monday, 14 July 2014

Predicting progression

Bosma L, Sonder J, Kragt J, Polman C, Uitdehaag B. Detecting clinically-relevant changes in progressive multiple sclerosis.
Mult Scler. 2014 Jul. pii: 1352458514540969. [Epub ahead of print]

OBJECTIVE: To investigate which changes in different clinical outcome measures contribute most to increased disease impact, as reported by the patient, in progressive multiple sclerosis (MS).
METHODS: From a cohort of prospectively-followed MS patients, we selected progressive patients with two visits, 4-6 years apart. We assessed long-term changes on the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT) and Guy's Neurological Disability Scale (GNDS). We defined the presence or absence of clinically meaningful change by using the Multiple Sclerosis Impact Scale (MSIS-29) as an anchor measure. We also studied change on recently identified sub-scales of GNDS.
RESULTS: Change on GNDS (especially the spinal-plus subscale) contributed most to increased disease impact. Also change on the T25FW contributed largely. Specific profiles of change in T25FW and MSIS seemed to exist (generally, a lower increase in disease impact in patients with longer disease duration and higher baseline impact/disability). In some patients a dissociation existed between increased impact, according to the MSIS-29, and objective physical worsening of the T25FW.
CONCLUSION: These results support using GNDS (particularly the spinal-plus domain) and T25FW in outcome measurement in progressive MS. We suggest there is a relation between baseline clinical characteristics and an increased impact at follow-up. This may have implications for patient selection in trials for progressive MS.


The Guy's Neurological Disability Scale (GNDS) was devised as a simple and user-friendly clinical disability scale capable of embracing the whole range of disabilities which could be encountered in the course of multiple sclerosis. It has 12 separate categories which include cognition, mood, vision, speech, swallowing, upper limb function, lower limb function, bladder function, bowel function, sexual function, fatigue, and 'others' In this study progression could be captured by walking ability and spinal outcomes, which are likely to have motor deficits and so it not surprising that they correlate with EDSS disability with is a scale based on movement. This study also suggests that there may be characteristics that can predict progressors and this may be of value in trials such that people most likely to progress are studied. This will mean getting outcomes quicker. 

In the CUPID trial of THC the group did not progress as predicted...maybe the placebo effect of being in a progressive trial and whilst the whole  group did not shown any difference in progression and the trial is considered a failure.

However in MSers with an EDSS less than 5.5 there was a significant neuroprotective effect. So if the trial had been loaded with this subset of MSers it may have been a positive trial and you would have the first drug or progressive MS. 

This is why trial design is so important as Neuros seldom get a second bite at the cherry and will they spend another 7 years to do a trial in a group of MSers that can be show a benefit from treatment within a "short" trial design.

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