How big is the iceberg in your head? #MSBlog #MSReserch
“One of the most popular posts on this blog is my teaser post comparing MS to an iceberg. Why? Most of an iceberg is not visible above water and can only been seen using specialised technology or estimated by what you can see above the water. The following study is a startling reminder of how big the MS iceberg actually is. This study uses a 7 Tesla MRI (there are not many of these around – in fact there are only two in the UK) to look at cortical (gray matter lesions) in MS. Please remember the vast majority of these lesions (>90%) or not seen with conventional MRI. The bad news is that almost all the MSers studied had cortical lesions and these correlated with disability and cognitive impairment. What was quite interesting is that the lesions of the surface of the brain (subpial), but not those on the gray-white matter interface (leukocortical), correlated better with cortical volume. However, the gray-white matter interface, or leukocortical, lesions correlated most strongly with cognitive impairment.”
“Who said MS was not and iceberg? And who said MS was not a preventable dementia?”
“Cortical, and gray matter pathology in general, is to MS what an iceberg was to the Titanic! Fortunately, we have treatments that prevent the icebergs getting too plentiful and big.”
Epub: Harrison et al. Association of Cortical Lesion Burden on 7-T Magnetic Resonance Imaging With Cognition and Disability in Multiple Sclerosis. JAMA Neurol. 2015 Jul 20. doi: 10.1001/jamaneurol.2015.1241.
IMPORTANCE: Cortical lesions (CLs) contribute to physical and cognitive disability in multiple sclerosis (MS). Accurate methods for visualization of CLs are necessary for future clinical studies and therapeutic trials in MS.
OBJECTIVE: To evaluate the clinical relevance of measures of CL burden derived from high-field magnetic resonance imaging (MRI) in MS.
DESIGN, SETTING, AND PARTICIPANTS: An observational clinical imaging study was conducted at an academic MS center. Participants included 36 individuals with MS (30 relapsing-remitting, 6 secondary or primary progressive) and 15 healthy individuals serving as controls. The study was conducted from March 10, 2010, to November 23, 2012, and analysis was performed from June 1, 2011, to September 30, 2014. Seven-Tesla MRI of the brain was performed with 0.5-mm isotropic resolution magnetization-prepared rapid acquisition gradient echo (MPRAGE) and whole-brain, 3-dimensional, 1.0-mm isotropic resolution magnetization-prepared, fluid-attenuated inversion recovery (MPFLAIR). Cortical lesions, seen as hypointensities on MPRAGE, were manually segmented. Lesions were classified as leukocortical, intracortical, or subpial. Images were segmented using the Lesion-TOADS (Topology-Preserving Anatomical Segmentation) algorithm, and brain structure volumes and white matter (WM) lesion volume were reported. Volumes were normalized to intracranial volume.
MAIN OUTCOMES AND MEASURES: Physical disability was measured by the Expanded Disability Status Scale (EDSS). Cognitive disability was measured with the Minimal Assessment of Cognitive Function in MS battery.
RESULTS: Cortical lesions were noted in 35 of 36 participants (97%), with a median of 16 lesions per participant (range, 0-99). Leukocortical lesion volume correlated with WM lesion volume (ρ = 0.50; P = .003) but not with cortical volume; subpial lesion volume inversely correlated with cortical volume (ρ = -0.36; P = .04) but not with WM lesion volume. Total CL count and volume, measured as median (range), were significantly increased in participants with EDSS scores of 5.0 or more vs those with scores less than 5.0 (count: 29 [11-99] vs 13 [0-51]; volume: 2.81 × 10-4 [1.30 × 10-4 to 7.90 × 10-4] vs 1.50 × 10-4 [0 to 1.01 × 10-3]) and in cognitively impaired vs unimpaired individuals (count: 21 [0-99] vs 13 [1-54]; volume: 3.51 × 10-4 [0 to 1.01 × 10-4] vs 1.19 × 10-4 [0 to 7.17 × 10-4]). Cortical lesion volume correlated with EDSS scores more robustly than did WM lesion volume (ρ = 0.59 vs 0.36). Increasing log[CL volume] conferred a 3-fold increase in the odds of cognitive impairment (odds ratio [OR], 3.36; 95% CI, 1.07-10.59; P = .04) after adjustment for age and sex and a 14-fold increase in odds after adjustment for WM lesion volume and atrophy (OR, 14.26; 95% CI, 1.06-192.37; P = .045). Leukocortical lesions had the greatest effect on cognition (OR for log [leukocortical lesion volume], 9.65; 95% CI, 1.70-54.59, P = .01).
CONCLUSIONS AND RELEVANCE: This study provides in vivo evidence that CLs are associated with cognitive and physical disability in MS and that leukocortical and subpial lesion subtypes have differing clinical relevance. Quantitative assessments of CL burden on high-field MRI may further our understanding of the development of disability and progression in MS and lead to more effective treatments.
Prof G,Given all this cutting edge technology why do we still not know what is happening with this disease ie cause, what is causing the damage etc. What don't we know?
Re; "not knowing the cause.."I disagree; we have a good idea of the factors in the MS causation pathway, what we don't know is how they interact to trigger and drive the disease. Despite this targeting the autoimmune processes, that may be downstream of the pivotal factor, seems to do be doing the job quite well. What we need is for the community accept this and to treat the inflammatory component effectively early.
Please could on of the Barts crew post a diagram of the brain with this article, with nice little arrows showing the areas of the brain which are being referred to…
Re: "Please could on of the Barts crew post a diagram of the brain with this article, with nice little arrows showing the areas of the brain which are being referred to…"Done.
Prof G,Can interferons still treat the inflammatory component effectively early? Or are you referring more to induction treatments like Lemtrada? Also, isn't the jury still out as to whether treating the inflammatory component early even delays or prevents the onset of the neurodegenerative component of the disease becoming the driving force? If SPMS is virtually inevitable, how does aggressive treatment earlier make a difference?
Re: "Also, isn't the jury still out as to whether treating the inflammatory component early even delays or prevents the onset of the neurodegenerative component of the disease becoming the driving force? If SPMS is virtually inevitable, how does aggressive treatment earlier make a difference?"The 4-year brain atrophy data in MSers treated with alemtuzumab looks very impressive; almost normal. Similarly, the brain atrophy data from long term natalizumab and HSCT is also very, very good. You are welcome to wait for the jury to come in regarding SPMS, but the open-label extension study of the Cambridge cohort regarding progression looks remarkably good. Only 5% had fulfilled their definition for developing SPMS, when you would have expected close to 50% to have based on natural history studies. The question is are you prepared to wait 15 years for a definitive answer? Please remember that at present the end-organ damage that occurs in MS in irreversible; what is lost is lost. You may compensate for the damage, but this may come with consequences for the future.
'open-label extension study of the Cambridge cohort regarding progression looks remarkably good. Only 5% had fulfilled their definition for developing SPMS, when you would have expected close to 50% to have based on natural history studies'Could you give a link to where this is documented, please. That is very cheering to hear. Thank you.
http://www.ncbi.nlm.nih.gov/pubmed/24849515
Thanks Prof G. I'm not prepared to wait & 'hope' my disease follows a mild course. But in treating aggressively early, I'll be adopting any associated risks without ever knowing whether those risks outweighed the benefits. The scope of disease severity is huge, are drugs safe enough to warrant treating all ms'ers with an induction treatment early? Maybe when the CD20 MABs make their appearance on the market.. Question is, how long is too long to wait?! I know being in my early 30's & a newly diagnosed Mum of little kids, I'm one of thousands pondering this exact question.
Re: "Could you give a link to where this is documented, please. That is very cheering to hear. Thank you."http://multiple-sclerosis-research.blogspot.com/2014/05/alemtuzumab-long-term-follow-up-for-up.html
It's exciting to see science catching up and validating what MSers experience…when I was diagnosed in 2001 my MSologist said my cognitive issues and pain weren't caused by my disease. Though we have much more to gain in understanding/treatment/cure/prevention we have much to celebrate as well. Thank you for your self sacrificing tireless efforts on our behalf.
"You may compensate for the damage, but this may come with consequences for the future."Presumably, you're talking about the theory that Ampyra improves symptoms in the short-term, but could have negative long-term consequences, correct?
Whilst we do not know the long-term effect of Amprya and there are theorectical possibilities of what this could do. It says do nothing but hope may lead you to a place you do not want to be in the future. Is this a risk you are willing to take…it is your choice.
p.s. What ever happens we don't want you to be singing the chorus with Cherhttps://www.youtube.com/watch?v=BsKbwR7WXN4Because we cannot yet repair the damage done.
Prof. G isn't there anything you can do about this issue?
Prof G,Do I understand correctly that even for someone with "benign on the surface" type of MS, with no new or active lesions and no clinical activity in the last few years, with just 1-2 documented relapses in the past and being on 1st line DMTs like GA or interferons, you'd still recommend to at least seriously consider going for a more aggressive treatment like alemtuzumab, the primary reason being "the silent shredder" leading to gradual brain atrophy not captured by conventional MRI?Thanks a ton for your blog posts, this is very much appreciated.