Saturday, 19 April 2014

Article of interest: the gray matter iceberg

For how much longer can we ignore gray matter pathology? #MSBlog #MSResearch

"I am sure you have heard of the the figure of speech 'looking for a needle in a haystack'? The following post-mortem study shows that only 3-5% of gray matter lesions, on the surface of the brain, are detected using conventional MRI when compared to pathological analysis. In other words 19 out of 20 or more of gray matter lesions are invisible to the MRI scanner. May be we need a better magnet, or a new technique, to find the needle or gray matter lesions?"

"Gray matter is the fraction of the brain where a substantial number of our neurones live and are important for cognition. Therefore it is not surprising that cognitive impairment correlates so poorly with focal MRI lesions numbers, when most of the pathology is being missed. What we need is a better way of detecting and quantifying the gray matter lesion burden in life. One way of doing this is by measuring brain atrophy and regional brain atrophy. There is data emerging that when you look at regional atrophy it correlates much more closely with MS-related cognitive impairment and interestingly MS fatigue."

Example of a tissue sample and the matching area on postmortem MR images. WM lesions (WM), as well as type I lesions (I, mixed GM-WM), can be seen with relative ease on the different MR images. Intracortical lesions (IC) are difficult to detect and define, even in retrospect.A, Photomicrograph (MBP immunohistochemical stain) reveals lesions (arrowheads) in the WM and cortical GM. B, Short-echo T2-weighted SE image. Insert, a higher magnification of the intracortical lesion. C, Long-echo T2-weighted SE image. D, 3D FLAIR image.

"Why all the focus on gray matter, brain atrophy and cognition? I think this is where real burden of MS resides and is what drives early impairment and disability in MSers. Why are 50% of MSers unemployed within 10 years of diagnosis when they are not physically disabled? I suspect this is due to poor cognition and the resulting mental fatigue and depression that occurs downstream of this pathology. If we want to make a difference to MSers' lives we need to intervene early in the disease course to prevent gray matter pathology and its downstream effects. With high-efficacy drugs we now have tools at our disposable to reduce the rate of brain atrophy in MS. Unfortunately, low efficacy drugs have little impact on this aspect of MS pathology. The problem in the field is that at present we don't measure brain atrophy in routine clinical practice and don't use it to make clinical decisions. I recently visited the MS unit in Prague to see how they are using brain atrophy in clinical practice. It was simply amazing to see a system that can be used in real-life to aid clinical decision making. I was particularly amazed to see that some MSers have NEDA, but continue to lose brain volume at a very high rate, implying that our current tools for monitoring MS are missing a substantial burden of the disease. This is why we are exploring a collaboration with Prague to see if we can implement and validate their system in our centre. MSers under our care need to know what is happening to their brain volumes so that the information can be incorporated into decision-making regarding DMTs. May be you disagree?" 


Geurts et al. Cortical lesions in multiple sclerosis: combined postmortem MR imaging and histopathology. AJNR Am J Neuroradiol. 2005 Mar;26(3):572-7.

BACKGROUND AND PURPOSE: Cortical lesions constitute a substantial part of the total lesion load in MS. They have been related to neuropsychological deficits, epilepsy, and depression. However, the proportion of purely cortical lesions visible on MR images is unknown. The aim of this study was to determine the proportion of intracortical and mixed gray matter (GM)-white matter (WM) lesions that can be visualized with postmortem MR imaging.

METHODS: We studied 49 brain samples from nine cases of chronic MS. Tissue sections were matched to dual-echo T2-weighted spin-echo (T2SE) MR images. MS lesions were identified by means of myelin basic protein immunostaining, and lesions were classified as intracortical, mixed GM-WM, deep GM, or WM. Investigators blinded to the histopathologic results scored postmortem T2SE and 3D fluid-attenuated inversion recovery (FLAIR) images. 

RESULTS: Immunohistochemistry confirmed 70 WM, eight deep GM, 27 mixed GM-WM, and 63 purely cortical lesions. T2SE images depicted only 3% of the intracortical lesions, and 3D FLAIR imaging showed 5%. Mixed GM-WM lesions were most frequently detectable on T2SE and 3D FLAIR images (22% and 41%, respectively). T2SE imaging showed 13% of deep GM lesions versus 38% on 3D FLAIR. T2SE images depicted 63% of the WM lesions, whereas 3D FLAIR images depicted 71%. Even after side-by-side review of the MR imaging and histopathologic results, many of the intracortical lesions could not be identified retrospectively.

CONCLUSION: In contrast to WM lesions and mixed GM-WM lesions, intracortical lesions remain largely undetected with current MR imaging resolution.

25 comments:

  1. I was particularly amazed to see that some MSers have NEDA, but continue to lose brain volume at a very high rate, implying that our current tools for monitoring MS are missing a substantial burden of the disease."

    Prof G,

    Some of your conclusions just don't stack up. If patients have NEDA but are still experiencing brain atrophy is means that (i) the measurement of NEDA is wrong (as there is disease activity) and (ii) the highly effective treatments which are used to achieve NEDA aren't addressing brain atrophy.

    I really enjoyed this blog, but the constant stream of bad news has given me the push I need to stop visiting. The bottom line is that MS is a really bad disease and MS research is an industry that will keep expanding for the foreseeable future. I've found out today that we have progressive disease from the start and that brain atrophy continues despite achieving NEDA. Combo trials might be the answer, but these will take years to set up / report etc and then the battle of licensing / funding. It would have been nice to have come away with some positive news from this blog, but your comparison of MS with dementia is quite right - once you have it there's no chance. I'm envious that you got to 50 and can do whatever you want. Thank your lucky stars that you didn't get a neurological disease, because the doctors in the field don't really have a clue what's happening in these disease and really can't do much for you in terms of stopping the inevitable decline. So farewell Team G and my hope now rests with Prof Franklin.

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    1. Re: "If patients have NEDA but are still experiencing brain atrophy is means that (i) the measurement of NEDA is wrong ..."

      Yes, I agree, which is why a lot of us are trying to get a brain atrophy measurement included in the definition of NEDA. I also think in the future we need a PROM (patient-related outcome measure) in NEDA as well and CSF metrics (neurofilament levels). The concept of NEDA is to suppress all disease activity, that we can measure, i.e. see clinically and on MRI, and that which we cannot see, but can measure (brain atrophy and CSF levels).

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    2. Re: ".... positive news from this blog..."

      I have been saying for several months now that both alemtuzumab and natalizumab reduce brain atrophy rates in year two into the normal range (0.1-04% per year). Whether these drugs truly normalise brain atrophy rates is hard to tell as no normal control subjects were followed up in the same way. The results are the same with bone marrow transplant once you discard year 1 atrophy rates due to pseudoatrophy as a result of suppressing inflammation. Fingolimod also reduces brain atrophy rates to the upper limit of normal.

      It is clear to me that the highly efficacious route is the only route to go to get on top of this disease.

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  2. Prof G,

    In your pst you say that:

    MSers under our care need to know what is happening to their brain volumes so that the information can be incorporated into decision-making regarding DMTs. May be you disagree?

    I'd like to know, but only if something can be done about it. I'm on Tysabri and doing well, but if I was still losing brain tissue what can be done about it. I don't believe there's any treatment, so what's the point of me knowing?

    Do treatments such as Alemtuzumab or the B cell depleting treatments in trial have an impact on grey cell lesions?

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    1. Re: "Do treatments such as Alemtuzumab or the B cell depleting treatments in trial have an impact on grey cell lesions?"

      The data for natalizumab and alemtuzumab on brain atrophy rates in year 2 is very encouraging. I am not aware of any data anti-CD20 therapies. Please note that alemtuzumab is also a B cell depleting agent; I have hypothesised before that this may be how it is working.

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  3. I do disagree with you, Prof G. Measuring brain atrophy via MRI is hugely problematic: one scan may demonstrates shrinkage and then the next scan of the same brain display brain growth. There is too much fallibility when doing MRIs and the inconsistencies are alarming. There is no proof that new DMTs cease the onset of progression. Data available shows that the rate of those that do not develop SPMS has not changed, bearing in mind that a percentage of sufferers will never develop insidious progression anyway.

    On a long enough timeline all MSers will get progressive disease. There are countless MSers that were treated with Lemtrada that have now succumb to SPMS. That is the reality of the situation, sir.

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    1. Re: "I do disagree with you, Prof G. Measuring brain atrophy via MRI is hugely problematic: one scan may demonstrates shrinkage and then the next scan of the same brain display brain growth."

      Yes, it is problematic if you do multiple scans over the short-term. However, when you use the metric of many years; i.e. 2, 3, 5, 7 etc. the measurements are very meaningful. In Prague the have atrophy measurements in some of their subjects over 12 years. Some of the newer techniques for measuring brain atrophy are decreasing the variability, which is why some centres are now measuring brain atrophy.

      Like all measurements it is variable and this can be reduced by standardisation and technological improvements.

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    2. Re: "On a long enough timeline all MSers will get progressive disease. There are countless MSers that were treated with Lemtrada that have now succumb to SPMS. That is the reality of the situation.;.."

      Please show me your data. There are some MSers who have been treated with alemtuzumab who get progressive disease. It tends to be those treated late in their course of their disease. The majority of those who have been treated with alemtuzumab early in their course of their disease have flat-lined or improved. Of those under my care none are secondary progressive. Professor Coles is due to publish his long-term (12 year) follow-up you will be surprised how few are SP; according to natural history studies more than 50% of these should be secondary progressive by now.

      If you don't believe in the early-aggressive approach that is fine by me. The experiment is running now and if the majority of these MSers go 20 years without developing SPMS would you accept the result? The problem is by the time you wait for that result you may have missed the window opportunity at a personal level. This is why I am prepared to give those MSers with active MS the option of choosing early aggressive treatments provided they are aware of the risk and potential for undefined risks in the future.

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    3. > The majority of those who have been treated with alemtuzumab early in their course of their disease have flat-lined or improved. Of those under my care none are secondary progressive.

      Great news! Thanks, Prof G.

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    4. Re: "Great news!"

      Please note this comment refers to those MSers treated early. I have seen two MSers treated late who continued to progress before stabilising; they are part of my therapeutic lag hypothesis.

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    5. Prof G, are you honestly saying that no-ne under your care treated with alemtuzumab has developed SPMS? That's weird when I can recall you once stating on this blog that you had two patients who had undergone alemtuzumab treatment that did develop SPMS. Do you now retract that statement?

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    6. Prof G, the danger you face is that of extolling alemtuzumab as a cure for all RRMSers. It may not cure MS, merely delay progression. Your rhetoric is almost reckless. You cannot cure something that you don't know why it happens.

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    7. Prof G, can you please define what you mean by early treatment? What is the window of opportunity? This is very important to know.

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    8. Re: " ... I can recall you once stating on this blog that you had two patients who had undergone alemtuzumab treatment that did develop SPMS."

      That is correct; both these patients were treated late. The same thing happens with natalizumab. If you use the drug late you stop relapses and MRI activity, but not necessarily progression. However, I have seen a number of these patients who progress early stabilise after several years, which is why I have put forward the therapeutic lag hypothesis.

      http://multiple-sclerosis-research.blogspot.co.uk/2014/01/therapeutic-lag-is-it-time-for-new.html

      In the interim I have asked Biogen-Idec to look at their data to see if they can extract any information to support this hypothesis. We are also auditing our natalizumab-treated patient data to see if we can get any data to support this hypothesis. Another data source may be MSBase; I will email Helmut and asked him to interrogate the database as well.

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    9. Re: "Prof G, can you please define what you mean by early treatment? What is the window of opportunity? This is very important to know."

      A lot of commentators say within 2 years of disease onset. I think it is wider than this. The window really means treating this disease before too much damage has occurred and primed the brain and spinal cord to continue to degenerate. In the alemtuzumab trials inclusion criteria were within 5 and 10 years of disease onset for the two trials. I hope this answers your question.

      I also believe that progressive MS is modifiable; we just have to be a little more realistic in what we can do in this phase of the disease.

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    10. Re "It may not cure MS, merely delay progression" :
      If it delays progression long enough for a full, near-normal life - that's good enough for me.
      Very few people are lucky enough not to be hit by something or other as they grow old

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  4. Does the problem with the routine monitoring of the atrophy partially lies in a technical plane?
    I think there is no commercially available tools for that? And FSL/SIENA is so user-unfriendly (as usual for the academic-born software) that I hardly imagine a medic using it.

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    1. Re: "Does the problem with the routine monitoring of the atrophy partially lies in a technical plane?"

      Well put. It is technical and will the tools will improve in time. Some of the newer techniques being developed in Montreal, NIH, Buffalo, etc. look very promising.

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  5. Prof G,

    Are you saying that drugs, even the highly effective treatments such as Alemtuzumab, have no impact on grey matter lesions?

    How does the Charcot project link to this research i.e. Will the anti-viral impact grey matter lesions?

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    1. Re: "Are you saying that drugs, even the highly effective treatments such as Alemtuzumab, have no impact on grey matter lesions?"

      No not at all. I am saying that the lower efficacy drugs that have little or no impact on brain atrophy are less likely to have an impact on gray matter pathology. Alemtuzumab is one of the drugs that has a remarkable impact on brain atrophy rates (year 2 data).

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    2. Re: "How does the Charcot project link to this research i.e. Will the anti-viral impact grey matter lesions?"

      Not sure; one of the hypotheses underpinning MS is that it is due to a virus and if you can identify and treat that virus you will stop the disease.

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  6. Redefining MS as a dementia. I launched this campaign when the EMA were assessing alemtuzumab. I wanted to supplement the message that MS is a bad disease and if you don't treat it early and aggressively to prevent damage you may miss the boat. In other words MS is a preventable dementia. I have subsequently had feedback from the community, yes you the readers of this blog that using the term dementia is stigmatizing hence I have softened my message.

    I deliberately don't pull my punches. You need to know how bad MS can potentially be to make decisions early in course of the disease when you are relatively well that have major implications. In the past neurologists have deliberately been paternalistic and withheld information on prognosis as they didn't have treatments that were very good. Now that we have treatments that are transformational things have changed.

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  7. DAF bs. NEDA

    We used to refer to NEDA (no evident disease activity) as DAF (disease-activity free). We lobbied against that latter as we knew that we could really be sure of you being disease-activty free with the current definition. NEDA at least allows us to change the definition with time as technologies improve and our understanding of the disease changes. This is why we can incorporate new metrics into our definition of NEDA without a problem; it is not that easy with DAF.

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  8. I'm confused about something. You recommend highly effective treatments to your patients with active disease. But if our current markers for disease hide so much, why not recommend highly effective treatments to even those who seem to be responding to the old CRABs?

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    1. Re: "But if our current markers for disease hide so much, why not recommend highly effective treatments to even those who seem to be responding to the old CRABs?"


      NICE and NHS England won't let us. This is why we are proposing the NEDA trial. Interestingly, the Australian neurologists who I discussed this NEDA trial to thought it was unethical. We are doing the PROXIMUS study in those who are on CRAB by relapse free, but feel they are progressing. The idea is to add-on a neuroprotective drug.

      I agree with you whole heartedly that a large proportion of MSers who are doing well on the CRABS are not doing that well, which is why we need to shift the paradigm to monitoring and rapid escalation. The sad fact of the matter is that in the UK only 1 in 4 neurologists use MRI to monitor their patients disease.

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