#ResearchSpeak & #ThinkHand: MS outcomes - are we closer to the holy grail

Are we closer to doing defining a new battery of outcome measures for progressive MS? #ThinkHand #ResearchSpeak #MSBlog

Those of you who follow this blog will realise that we are gradually developing an online suite of apps to help you self-monitor your disease. Why? To empower you to ask the right questions about your prognosis and treatments.

It is clear that when DMTs for progressive MS are licensed you will need to show that your disability is worsening. There is no way that the payers will allow all-comers access to DMTs for progressive MS. Access to treatments will be based on the inclusion criteria for the clinical trials. Most trials have required 'objective evidence' of worsening disability. 

We are also aware that most neurologists, at least in the UK, don't have time in routine clinical practice to do an EDSS, or a battery of other tests, to monitor worsening disability. The solution is to get you to monitor your own disease. We have therefore developed an online web-EDSS that we think is pretty good. We have also produced an affordable, environmentally-friendly 9-HPT and will be adding walking-distance and the self-measured 25-FTW to the battery. We are also developing visual function tests and potentially other outcome measures in the future. What we are lacking is an engaging, responsive cognitive test. The current online cognitive tests are very boring and simply not engaging enough to bring people back to repeat them over time. If you have any suggestions for creating a good online cognitive screening and monitoring tool that can be used to assess MS-related cognitive impairment please let us know.

We have chosen our self-monitoring tests carefully to map onto what is acceptable by the field. The MS Outcome Assessments Consortium (MSOAC) is an initiative that has come together to put together a battery of tests that will be acceptable to the regulators as an outcome for progressive trials. MSOAC now report on their work in a series of very well written papers in the MSJ. It is clear that the four assessments they have evaluated will now become the new 'gold-standard' for progressive trials. One thing that is not clear is how this battery will be used for assessing disease improvement. The 20% threshold for disability-worsening may be too high a bar for disability improvement.

Don't you think it is incredible that the field is now asking the community to design trials to assess improvement in disability and not just worsening disability? This just shows you how far the field has come and where it is going in the not too distant future.

The MS Outcome Assessments Consortium (MSOAC) includes representatives from advocacy organisations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with MS. Among the MSOAC goals are acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful to persons with MS. A critical step for these neuroperformance metrics is elucidation of clinically relevant benchmarks, well-defined degrees of disability, and gradients of change that are deemed clinically meaningful

Feys et al. The Nine-Hole Peg Test as a manual dexterity performance measure for multiple sclerosis. Mult Scler. 2017 :1352458517690824. doi: 10.1177/1352458517690824.

Impaired manual dexterity is a frequently reported disability in people with multiple sclerosis (MS) and is increasingly prevalent with worsening disease. While various tests and patient-reported outcome measures are available, the Nine-Hole Peg Test (NHPT) is considered as a gold standard measure of manual dexterity and most frequently used in MS research and clinical practice. We find that the NHPT is reliable within and between test sessions, discriminates between healthy subjects and MS patients with different levels of upper limb impairment, and shows high convergent validity with other manual dexterity as well as more comprehensive upper limb measures. Ecological validity is established by its relation to perceived upper limb use in daily life and perceived difficulty in performing activities of daily living. The NHPT is responsive to deterioration in longitudinal studies, and research suggests that a 20% change in test score is commonly used to define clinically meaningful worsening, a definition that needs further validation in all stages of the disease.

Benedict et al. Validity of the Symbol Digit Modalities Test as a cognition performance outcome measure for multiple sclerosis. Mult Scler. 2017:1352458517690821. doi: 10.1177/1352458517690821. [Epub ahead of print]

Cognitive and motor performance measures are commonly employed in multiple sclerosis (MS) research, particularly when the purpose is to determine the efficacy of treatment. The increasing focus of new therapies on slowing progression or reversing neurological disability makes the utilization of sensitive, reproducible, and valid measures essential. Processing speed is a basic elemental cognitive function that likely influences downstream processes such as memory. The Symbol Digit Modalities Test (SDMT), recognized as being particularly sensitive to slowed processing of information that is commonly seen in MS. The research in MS clearly supports the reliability and validity of this test and recently has supported a responder definition of SDMT change approximating 4 points or 10% in magnitude.

Balcer et al. Validity of low-contrast letter acuity as a visual performance outcome measure for multiple sclerosis. Mult Scler. 2017:1352458517690822. doi: 10.1177/1352458517690822. [Epub ahead of print]

Low-contrast letter acuity (LCLA) has emerged as the leading outcome measure to assess visual disability in multiple sclerosis (MS) research. As visual dysfunction is one of the most common manifestations of MS, sensitive visual outcome measures are important in examining the effect of treatment. Low-contrast acuity captures visual loss not seen in high-contrast visual acuity (HCVA) measurements. MS and disease-free controls have similar median HCVA, while MS patients have significantly lower LCLA. Deficits in LCLA and vision-specific quality of life are found many years after an episode of acute optic neuritis, even when HCVA has recovered. Studies reveal correlations between LCLA and the Expanded Disability Status Score (EDSS), Multiple Sclerosis Functional Composite (MSFC), retinal nerve fiber layer (RNFL) and ganglion cell layer plus inner plexiform layer (GCL + IPL) thickness on optical coherence tomography (OCT), brain magnetic resonance imaging (MRI), visual evoked potential (VEP), electroretinogram (ERG), pupillary function, and King-Devick testing. This review also concludes that a 7-point change in LCLA is clinically meaningful. The overall goal of this review is to describe and characterize the LCLA metric for research and clinical use among persons with MS.

Motl et al. Validity of the timed 25-foot walk as an ambulatory performance outcome measure for multiple sclerosis. Mult Scler. 2017 :1352458517690823. doi: 10.1177/1352458517690823. [Epub ahead of print}

The T25FW has strong reliability over both brief and long periods of time in MS across a large range of disability levels. The outcome of walking speed from the T25FW has obvious real-world relevance and has correlated strongly with other measures of walking and lower extremity function. The T25FW is responsive for capturing intervention effects in pharmacological and rehabilitation trials and has an established value for capturing clinically meaningful change in ambulation. Directions for future research involve validating clinically meaningful improvements on the T25FW as well as determining whether 20% change is clinically meaningful across the disability spectrum. Researchers might further consider synchronizing accelerometers and motion sensors with the T25FW for capturing walking speed in everyday life and the patient's real environment.

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