Saturday, 22 February 2014

Brain atrophy: the ultimate outcome in MS

Brain atrophy the integrator of MS-related end-organ damage. #MSBlog #MSResearch

"I have started thinking about MS as my cardiology and nephrology colleagues think about the heart and kidneys, respectively. They talk about end-organ damage and try and prevent it. When it comes to the heart and kidney it is easy to measure this with functional outcomes. In MS the brain and spinal cord function is much more difficult to measure, because of mutiple pathways and the ability for the damaged nervous system to adapt to damage (plasticity). Therefore a good measure of this is change in volume of the brain; i.e. brain volume loss is a good integrator of end organ damage in MS. This study below confirms other data sets that in MSers who progress they lose much more brain volume than those who don't progress. This is an important point and we therefore should be targeting normalisation of brain volume loss as the ultimate treatment aim in MS after we have switched off inflammation. This is why we want to keep the definition of NEDA (no evident disease activity) open to change. For us to incorporate brain volume loss into NEDA we need to standardise the measure of brain volume loss and get all MS Centres to do the necessary MRI scans to measure it. A question for your neurologist next time you see him/her is to ask if you have progressive brain atrophy. Some centres are already measuring this routinely, but this is a very small number."

Please compare the size of the central black areas between the 18 month scans and the baseline; this is how much brain volume loss can occur in a RRMSer in 18 months. 

Epub: Jacobsen et al. Brain atrophy and disability progression in multiple sclerosis patients: a 10-year follow-up study. J Neurol Neurosurg Psychiatry. 2014 Feb 19.

OBJECTIVES: To identify MRI biomarkers associated with long-term disability progression in patients with multiple sclerosis (MS), and to define the rate of evolution of global, tissue-specific and regional atrophy in patients with MS over long-term.

METHODS: MRI of the brain and clinical neurological assessment was performed in 81 patients at time of first visit and after 5 and 10 years of follow-up. MRI was acquired on 1.5 T scanners. T1-lesion and T2-lesion volumes (LVs) were calculated. Global and tissue-specific atrophy changes were longitudinally assessed, using a direct measurement approach, by calculating percentage volume changes between different time points. Regional tissue volumes for the subcortical deep grey matter (SDGM) structures were also obtained. Disability progression was defined as an increase in Expanded Disability Status Scale of ≥1.0 compared to baseline at 5-year and 10-year follow-up.

RESULTS: Over 5 years, patients with disability progression showed significantly increased loss of whole brain (-3.8% vs -2.0%, p<0.001), cortical (-3.4% vs -1.8%, p=0.009) and putamen volume changes (-10.6% vs -3.8%, p=0.003) compared to patients with no disability progression. No significant change in white matter (WM) volume was observed when comparing progressing and non-progressing patients. Over 10 years, there was a trend for greater decrease in whole brain volume (-5.5% vs -3.7%, p=0.015) in the progressing patients. No significant changes in LV measures were detected between the patients with and without disability progression.

CONCLUSION: This long-term study shows that whole brain, cortical and putamen atrophy occurs throughout the 10-year follow-up of this MS cohort and is more pronounced in the group that showed disability progression at 5, but not at 10 years of follow-up. Overall, GM atrophy showed better association with disease progression than WM atrophy over 5-year and 10-year follow-up.

14 comments:

  1. Your colleagues dealing with hearts and kidneys have the option of transplants and repair (big stem cell trial just started to see whether heart damage can be repaired). Their patients have the chance of getting their lives back. In MS the hit hard and early approach is great for those who will be diagnosedn the near future. However, in the UK the estimate is 100k MSers, and the majority of these won't benefit from that treatment strategy. Repair is the only hope for them if they want to regain lost function. Sadly, I see nothing on the horizon. If only I could have chosen a heart attack or kidney failure over MS.

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    1. Re: "Repair is the only hope for them if they want to regain lost function."

      I agree. The nervous system has built in repair mechanisms that work if you don't overwhelm them. That is why when you switch off MS early before too much damage is done you see improvements. Another thing is age; the younger you are the more likely you are to see recovery.

      Delete
  2. What is the difficulty in measuring atrophy? There is already software available to measure this (SIENA).

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    1. Re: "What is the difficulty in measuring atrophy? There is already software available to measure this (SIENA)."

      SIENA does not come built into scanners. It requires you to load the data file of the MRI onto a workstation and run the analysis programme separately. This requires additional staff who know what they are doing and time. Both these cost money.

      In addition., you need special MRI sequences to run SIENA; i.e. a so called 3D acquisition. Not all Departments run these sequences.

      Delete
  3. If we ask our neurologists to measure brain volume and find it is diminishing at a higher than normal rate, is there anything that can be done (apart from getting depressed!)? In other words, is there any point, except to document our decline?

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    1. Re: "If we ask our neurologists to measure brain volume and find it is diminishing at a higher than normal rate, is there anything that can be done (apart from getting depressed!)? In other words, is there any point, except to document our decline?"

      The more effective DMTs have a greater impact on brain atrophy than the less effective agents. Natalizumab, alemtuzumab and fingolimod are much better at slowing brain atrophy rates than the other drugs.

      Delete
  4. How can the MS community push for standardization of grey matter atrophy and utilization

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    1. Re: "How can the MS community push for standardization of grey matter atrophy and utilization."

      Via academic meetings and discussion. We are trying to do this in the UK and are holding our first UK NEDA meeting with a large component of the meeting dedicated to brain atrophy. There are publications on this topic and an EU MRI consortium called MAGNIMS that does this sort of thing.

      Delete
  5. What evidence is needed to confirm this so it get used in clinical practice?

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    1. Re: "What evidence is needed to confirm this so it get used in clinical practice?"

      The evidence already exists that but it is not all class 3 evidence (randomised placebo-controlled trials) hence the regulators and payers will not accept it. What we need is a large trial showing that when we normalise brain atrophy rates in MSers they do better than MSers who are managed according to standard practice guidelines. This is something we are trying to get off the ground in the UK with our NEDA trial.

      http://multiple-sclerosis-research.blogspot.co.uk/2014/01/clinic-speak-treat-2-target-of-neda-vs.html

      This study will include brain atrophy as one of its secondary outcomes.

      Delete
  6. Can atrophy changes over the years be measured or judged by looking at old MRI films and images?

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    1. Re: "Can atrophy changes over the years be measured or judged by looking at old MRI films and images?"

      Yes, you can look at a simple mertric like the width of the third ventricle.

      Delete
  7. Is it feasible to perform MRI at each visit? Biomarkers such as: GFAP and NFL have been shown to correlate with inflammation and atrophy. Also, less time consuming and labor intensive, RNFL has shown promise in measure of brain atrophy. Can these alternatives be substitutes for MRI or are we not yet at this stage?

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  8. Is it feasible to perform... Yes it would be. It is a matter of cost and organisation

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