ResearchSpeak: how bad is your end-organ damage?

Brain volume loss predicts poor MS outcome. Can you do anything about it? #MSBlog #ResearchSpeak #MSResearch

"We have been talking about NEDA (no evident disease activity) on this blog for sometime. We changed the name from DAF (disease-activity free) to NEDA for philosophical reasons; DAF implies we know everything we need to know about MS disease activity and NEDA does not. NEDA allows the definition to evolve as new knowledge and technologies come online. That is why we talk about NEDA-1, NEDA-2, NEDA-3, NEDA-4, etc."

NEDA-1 = relapse free

NEDA-2 = + disability progression free
NEDA-3 = + focal MRI activity free (no new T2- and Gd-enhancing lesions)
NEDA-4 = + normalisation of brain atrophy rates or brain volume loss (e.g. less than 0.4% per year)
NEDA-5 = + normalisation of CSF neurofilament levels
NEDA-6 = + stabilisation of a PROM (a patient-related outcome)*
NEDA-7 = + stabilisation of cognitive function*
NEDA-8 = + clearance of CSF OCBs (oligoclonal IgG bands)*

*Hypothetical, these have not been discussed widely in the MS community. We need a PROM in the NEDA definition to engage pwMS with the concept of monitroing their own disease. 

"The study below shows how important the NEDA construct is when we start to think about what our aims of treatment are in MS. Don't we want to suppress MS disease activity as much as possible and protect the end organ (brain and spinal cord) from damage? The analysis of the fingolimod trial data shows that pwMS with the greatest brain volume loss in the first 2-years of the study do much worse in terms of disability progression and further brain volume loss over the next 2 years. The message is clear to me; if you want to optimise the treatment effect in MS you need to treat to a target that reduce end-organ damage (brain volume loss). The problem we have at the moment is that it is difficult to use brain volume loss to manage individuals with MS in our clinics. The measure is too variable at present, which is why we are moving towards lumbar punctures and measuring spinal fluid neurofilament levels (NEDA-5). However, we are not giving up on the brain volume technology yet, it is evolving very rapidly and hopefully we will have a method that works on the individual patient level very soon. We used to have the same discussion about the routine measurement of T2 and Gd-enhancing lesions in clinical practice and now most MSologists are measuring these routinely; although many are not."


Jeffery et al. The relationship between the rate of brain volume loss during first 24 months and disability progression over 24 and 48 months in relapsing MS. Journal of Neurology February 2016, Volume 263, Issue 2, pp 299-305. 

Background: Clinical evidence in patients with relapsing-remitting multiple sclerosis suggests an association between MRI outcome measures and disability progression (DP). 


Objectives: Post hoc analysis to investigate the association and potential predictive value of brain volume loss (BVL) with long-term DP in FREEDOMS. 

Methods: Patients were categorized into quartiles by SIENA-calculated percent brain volume change from baseline to month (M) 24. Patient characteristics at baseline were determined for each quartile, as were the proportions of patients at M24 and M48 reaching Expanded Disability Status Scale (EDSS) scores of ≥4.0 or ≥6.0 or DP confirmed at 3 months (CDP3) or 6 months (CDP6), and change in EDSS and Multiple Sclerosis Functional Composite. 

Results: MS disease activity and severity as well as brain volume at baseline were predictive of subsequent BVL over 24 months. The quartiles of patients with greater BVL at 24 months were at highest risk (odds ratio, p value) for reaching EDSS ≥4 (2.8, p = 0.001) or ≥6 (5.73, p = 0.0005) and experienced more DP at M24 (CDP3 2.13,p = 0.002; CDP6 2.17, p = 0.003) and M48 (CDP3 1.98, p = 0.006; CDP6 1.87, p = 0.018) compared to the quartile of patients with the least amount of BVL. 

Conclusio CoI ns: These findings confirm the clinical relevance of early brain volume changes for long-term DP.

CoI: multiple

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