Thursday, 31 January 2013

Brain atrophy: what to do about it?

#MSBlog: Should we be measuring brain atrophy in routine clinical practice?

"I was asked by a colleague in Porto last week whether or not I let the presence or absence of brain atrophy on MRI affect my clinical decision making about DMTs and treatment? I had to think about the question and haven't stopped thinking about it since. The first problem is that our neuroradiologists don't routinely report brain atrophy, unless it is gross atrophy, i.e. easy to see with the naked eye. Although we know that brain atrophy occurs early in the disease course it is often very subtle and difficult to assess with the naked eye; it has to be assessed using post-acquisition data processing tools. In other words the neuroradiologist has to arrange for the images to be analysed off-line for atrophy and to then compare the results with a previous scans or to a normative data set. At the moment brain atrophy measurements are not a routine in our hospital, although we do collect the correct MRI sequences to measure atrophy."

"The brain atrophy discussion is timely, particularly in view of the recent poll result on this blog in relation to it being used as an outcome to monitor MS."


The generate discussion we came up with the following scenarios:

Scenario 1 - in a recently diagnosed person with MS with active MS has a low or moderate lesion load, would the presence of brain atrophy at baseline push you towards a more aggressive therapy, i.e. a drug that affects brain atrophy, or would you be comfortable with that person choosing interferon-beta or glatiramer acetate?

Scenario 2: A person with established MS who has been on an injectable 1st-line therapy for several years, with no relapses or focal MRI activity, but has evidence of ongoing brain atrophy above what you would expect for their age, would you change them to a DMT that has been shown to have an effect on brain atrophy?

"What these scenarios are testing is the concept of whether or not we should be incorporating brain atrophy measurements into routine MS clinical practice and whether or we should be incorporating brain atrophy into our definition of NEDA (no-evidence of detectable disease-activity). I suspect this may be premature, but I see no reason why we shouldn't start a debate on the issue."

"What does brain atrophy mean for you as someone with MS? Brain atrophy could mean a lot of things. In general it probably implies ongoing loss of axons and neurones. Brain atrophy cannot be a good thing and there is data that associates it with a poor prognosis."

Fisher E, Lee JC, Nakamura K, Rudick RA. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol. 2008 Sep;64(3):255-65. doi: 10.1002/ana.21436.

OBJECTIVE: To determine gray matter (GM) atrophy rates in MSers at all stages of disease, and to identify predictors and clinical correlates of GM atrophy.

METHODS: MSers and healthy control subjects were observed over 4 years with standardized magnetic resonance imaging (MRI) and neurological examinations. Whole-brain, GM, and white matter atrophy rates were calculated. Subjects were categorized by disease status and disability progression to determine the clinical significance of atrophy. MRI predictors of atrophy were determined through multiple regression.

RESULTS: Subjects included 17 healthy control subjects, 7 subjects with clinically isolated syndromes, 36 MSers with relapsing-remitting MS (RRMS), and 27 MSers with secondary progressive MS (SPMS). Expressed as fold increase from control subjects, GM atrophy rate increased with disease stage, from 3.4-fold normal in CISers converting to RRMS to 14-fold normal in SPMS. In contrast, white matter atrophy rates were constant across all MS disease stages at approximately 3-fold normal. GM atrophy correlated with disability. MRI measures of focal and diffuse tissue damage accounted for 62% of the variance in GM atrophy in RRMS, but there were no significant predictors of GM atrophy in SPMS.

INTERPRETATION: Gray matter tissue damage dominates the pathological process as MS progresses, and underlies neurological disabillity. Imaging correlates of gray matter atrophy indicate that mechanisms differ in RRMS and SPMS. These findings demonstrate the clinical relevance of gray matter atrophy in MS, and underscore the need to understand its causes.

"The following is a short survey to assess whether or not brain atrophy is being measured and discussed in routine MS practice. If you feel up to it I would appreciate it if you could answer the poll."



CoI: multiple

Other posts of interest:


26 Nov 2012
Poll results: outcome measures and brain atrophy. "The headline result is that MSers rate a delay in disease progression the most important outcome measures in relation to DMTs." "The problem with disability progression in ...
17 Nov 2012
"Data from several emerging DMTs now supports the natural history studies and the observation that there is a disconnect between relapses and disease progression and importantly an impact on brain atrophy. We have ...

29 Nov 2011
CONCLUSIONS: Serial magnetic resonance imaging revealed a low 2-year rate of brain atrophy in MS'ers with clinically benign MS, suggesting a less prominent degenerative component in its pathogenesis than in patients ...
23 Nov 2012
BACKGROUND: Brain size, white matter hyperintensity, and the development of brain atrophy are known to be highly heritable. The decrease of brain volume starts from the very onset of MS and is 10-fold compared with ...
21 Nov 2012
More relapses were associated with poorer recovery of neurological function and accelerated brain atrophy. CONCLUSIONS: Neurological impairment is more permanent, brain atrophy is accelerated and focal inflammatory ...
02 Nov 2012
Background: Cognitive dysfunction affects half of MSers. Although brain atrophy generally yields the most robust MRI correlations with cognition, significant variance in cognition between individual MSers remains unexplained ...

20 Nov 2012
Voxel-based analyses allow detection of regional atrophy throughout the brain and, therefore, may be sensitive to regional atrophy in CIS patients, and these changes may correspond with clinical disability. METHODS: This ...
09 Mar 2012
The relationship between inflammatory activity and brain atrophy in natalizumab treated patients.Eur J Radiol. 2012 Mar 3. [Epub ahead of print] OBJECTIVE: To assess the evolution of brain atrophy and its relationship with ...
31 May 2012
BACKGROUND: Brain atrophy (shrinkage) is a well-accepted imaging biomarker of multiple sclerosis (MS) that partially correlates with both physical disability and cognitive impairment. METHODOLOGY/PRINCIPAL ...
08 Jan 2012
In vivo scanning permitted us to evaluate brain structure volumes in individual animals over time and we observed that though brain atrophy progressed differently in each individual animal, all mice with EAE demonstrated ...

20 Mar 2012
Research: Brain Shrinkage. Riccitelli et al. Mapping regional grey and white matter atrophy in relapsing-remitting multiple sclerosis.Mult Scler. 2012 Mar 15. [Epub ahead of print] Objective: We aimed to investigate the regional ...

02 May 2011
The following diagram summarises the MRI data published on the impact of Fingolimod on brain atrophy over 2 years. Please see: Kappos et al. N Engl J Med. 2010 Feb 4;362(5):387-401. COI: Please note my previous COI ...
11 Oct 2012
Objectives: To assess whether high dose simvastatin can slow the rate of whole brain atrophy, and/or disability in secondary progressive multiple sclerosis SPMS. Methods: In a double-blind, placebo-controlled phase II trial, ...
18 Jun 2012
Methods: In 39 multiple sclerosis patients the area of corpus callosum in the sagittal plane, T(2) and T(1) lesion volumes, brain parenchymal fraction and brain atrophy were determined at baseline and 1 year after treatment ...
18 May 2012
Consistent with previous studies, associations were found between neuropsychological scores, and global brain atrophy and T2-lesion volumes (MS lesion volume). Critically, significant associations were found between ...

13 comments:

  1. Very interesting poll!
    Maybe Laquinimod that has excellent safety and efficiancy on brain atrophy and EDSS progression will be a good choice for the MS community?

    AAN has released the abstracts, and one EDSS data at 36 months for Laquinimod confirms the previous data released:

    http://www.abstracts2view.com/aan/view.php?nu=AAN13L_S41.004&terms=

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    1. Yes, Laquinimod is one of the drugs that affects brain atrophy positively. The others are fingolimod and possibly other S1P modulators, ibudilast and simvastatin. The jury is out on several others. The problem we have with brain atrophy is that it has yet to be linked with clinical outcomes within phase 3 trials so the EMA and FDA are not sure if it is clinically meaningful!

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    2. 'not sure if clinically meaningful'?!! Can't it be more obvious if parts of your brain die that it means irreversible damage. High time in including brain atrophy as a marker of MS - the problem is cost as ever and willingness of neuros/radiologists to sit and look through pictures. Maybe technology has an answer to this. This is all very important G, keep discussing it with your colleagues.

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    3. You are speaking to the converted. We need to convince the neurology community and the regulators. It is a bit of a "no-brainer" that brain atrophy is not a good thing; if you can prevent atrophy or slow it down why not?

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  2. Looked on the MSRC website (now MS-UK) and it's quoting BBC news 31/1/13 that in the New England Journal of Medicine there is a claim that brain scans of people who've been treated with alemtuzumab have increased in size compared to those treated with beta interferons, and that it 'may allow damaged brain tissue to repair itself'. Is this old news, or has something else been reported on the effects of alemtuzumab?

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    Replies
    1. Had a look on the new england site and saw nothing yet, but could be a press release before the paper is actually goes online... However my only concern is that on the MSRC website it has a comment that Lee Dunster..head of research at MS Society. Either Lee has returned to MS Society or this post is a few years old as Lee left ages ago and one wonders if it then refers to the phase II trial where there was also indication that EDSS improved and was published in N Engl J. Prof G not heard this. If it appears we will post

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  3. Dear Mr GAvin,

    Could you please elaborate a little more about this poll, where responders answered "what clinical outcome measure is most important to you", as illustrated by you by this cake / pie chart above:

    1.
    I guess the patients were the responders in this poll ...?
    2.
    Who performed this poll ?
    3.
    How many responders did this poll include?

    Happy to receive your answers

    Sincerely

    Peter Bush

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    Replies
    1. Dear Peter as you may notice Prof G performs polls all the time, he has been learning how to programe websites and has been learning Java so the polls are part of his learning skills. If there was a question about the disease then it will be seen in the pole. Look through the website to see when prof G asked the question then you will see what is in the pole. These are anonymous so we do not have demographics. Number it be depends on how long poll was going they are usually not huge n numbers. It would be great if more people voted.

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    2. Please check-out the following two posts:

      http://multiple-sclerosis-research.blogspot.co.uk/2012/11/relapses-vs-mri-activty-vs-progression.html

      http://multiple-sclerosis-research.blogspot.co.uk/2012/11/poll-results-outcome-measures-and-brain.html

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  4. What about spinal atrophy? Not many posts on the spine in general. Yet, there are some very interesting findings regarding spinal cord atrophy that none of the current theories are able to explain. You know what i'm talking about, don't you?

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  5. Do you talk about much else:-). Maybe if you could condense the works of your favourite author into a few paragraphs, it will enlighten the readers who do not want to read 100 pages or more.

    Spinal cord atrophy is equally important to brain atrophy.There are less posts on the spine because it is much harder to image than the brain because of breathing and the movement associated with breathing which affect image quality. The over all structure is small. Is there anything different about the processes in brain and spinal cord, I suspect not, but I know you have a different world view.

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  6. I am a 41 yr old female, who has not been diagnosed with MS, however each emergency room visit yrs ago, when i had a bout of severe symptoms (wheel chair and walker situation) came back no MS. I am now finally seeing neurologist, neuro optho, and having evoked potential tests done, due to progressive deterioration of neuro symotoms once again. My new MRI agaib came back clean for MS, however with my research and speaking directky to the attending radiologist, I have discovered my brain has larger loss now than two yrs ago, and the anomalies seen, because they werent high emitting, were dismissed. I also have many bkack holes in various parts of my brain now, and 3 in my spinal cord, all which were dismissed upon rad interpretation of my MRI. My new symptoms include double, blurred vision and the color red being "muted" or less bright in my left eye, as well as my eyes having decreased tracking ability when looking to the sides (left eye off center). I agree, that brain atrophy has a large significance in the matter of diagnosing MS, among hypointense lesions, and should b brought to the for-front in treatment and diagnisis. Thank you for listening.
    Teena

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