Tuesday, 17 February 2015

Answering the unanswered questions: what we don't know about disability in MS

Neurology. 2015 Jan 27;84(4):367-73.

Cervical cord lesion load is associated with disability independently from atrophy in MS.


Abstract

OBJECTIVE:

To investigate whether spinal cord (SC) lesion load, when quantified on axial images with high in-plane resolution, is associated with disability in multiple sclerosis (MS).

METHODS:

Twenty-eight healthy controls and 92 people with MS had cervical SC 3T MRI with axial phase sensitive inversion recovery, T2, and magnetization transfer (MT) sequences. We outlined all visible focal lesions from C2 to C4 to obtain lesion load and also measured upper cervical cord area. We measured MT ratio in normal-appearing cord tissue and in lesions. Disability was recorded using the Expanded Disability Status Scale (EDSS) and MS Functional Composite. We used linear regression models to determine associations with disability.

RESULTS:

SC lesion load was significantly higher in both secondary progressive MS (SPMS) (p = 0.008) and primary progressive MS (PPMS) (p = 0.02) compared to relapsing-remitting MS (RRMS); in each comparison, adjustment was made for age, sex, and brain volume. These differences were not evident when EDSS was added as a covariate. SC area was significantly lower in both SPMS (p < 0.001) and PPMS (p = 0.009) compared to RRMS. In a multiple regression model, cord lesion load (p < 0.001), cord area (p = 0.003), age (p < 0.001), and sex (p = 0.001) were independently associated with EDSS (R(2) = 0.58). Cord lesion load (p = 0.003), cord area (p = 0.034), and brain parenchymal fraction (p = 0.007) were independently associated with the 9-hole peg test (R(2) = 0.42).

CONCLUSIONS:

When quantified on axial MRI with high in-plane resolution, upper cervical cord lesion load is significantly and independently correlated with physical disability and is higher in progressive forms of MS than RRMS.

This work is dedicated to understanding the DIRECT role/contribution of spinal cord pathology to disability in MS. The authors will tell you that this has not been done before (am I hearing this correctly?). In fact, there is a modicum of truth to their assertions; previous studies analyzed sagittal images (see diagram) - this does not fully account for the cross-sectional involvement of the spinal cord by lesions, or when lesion counts were performed on the transverse plane (see diagram) their size was not accounted for. Incomplete science can lead to half-truths or cherry-picking and suppression of the truth intentionally or unintentionally. 

What made me pick up this article was the title, that cord lesion load is more relevant than brain atrophy (i.e. volume loss). In their statistical model they found that only cord lesion load, cord area, age and sex independently associated with EDSS. On balance, I don't think that this alone is enough to dump all the other MRI studies which have been studiously looking at various forms of brain atrophy. I'm afraid the truth probably lies some where in between, and based on this study alone I will not be adding spinal cord evaluation to my routine scanning, year in, year out. 

Also, included in the full article is an interesting table (see below) that is worth discussing today (take a few minutes to look through the figures in the table). Points to note: 1) PPMS is a different entity to that of RRMS and SPMS; 2) There is inflammatory activity in SPMS and PPMS; and 3) by SPMS >1/4 of the spinal cord is lost. These are three major points to consider when designing clinical trials in progressive MS.

Table: Unadjusted mean of MRI parameters analyzed in controls and each subtype of MS



Controls (n=28) RRMS (n=34) SPMS (n=29) PPMS (n=29)
Upper cervical cord lesion load, mm2

8.10 16.68 13.2
Upper cervical cord cross-sectional area, mm2 79.59 76.79 63.64 69.33
% spinal cord area covered by lesions

11.1 28.4 19.3
Whole cord MTR 49.7 47.75 45.59 46.48
Normal-appearing spinal cord MTR 49.7 48.31 46.56 47.51
Spinal cord lesion MTR

43.37 40.54 41.26
Brain parenchymal fraction 0.823 0.811 0.788 0.799
Brain T2 lesion volume, ml

13.00 23.34 16.57

 

9 comments:

  1. Replies
    1. Magnetic transfer ratio, it essential detectswater molecules trappedin a plane ans so is reported to correlate with myelination, so in the lesion the MTR signal is lower. Itis hoped that this can show remyelination...Isit good enough

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  2. Doc,

    Why do you say that 'PPMS is a different entity to that of RRMS and SPMS'?

    Also, the issue for MSers when these stats / observations are presented is 'what can we do about it'? For RRMS I suppose the option is possibly to go for a highly effective treatment. For SPMS and PPMS it seems like it is a case of 'watch your spinal cord be eaten away!'. Is there anything in the pipeline to limit the damage or (I know this is science fiction) repair some of the damage?

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    1. Going back to the table, PPMS has an intermediate upper cervical lesion load (indicator of inflammatory activity) between RRMS and SPMS, not surprisingly it also has an intermediate lesion load in the brain (brain T2 lesion volume), it also has an intermediate MTR (an indicator of remyelination/recovery). The probability that PPMS is an intermediate pathology to RRMS and SPMS is improbable, RRMS through to SPMS are on a continuous spectrum. The underlying driver is more likely to be an entity which is inflammatory but not rampant like it's in RRMS but does not have the potential to repair as effectively as in RRMS. There are also multiple other research out there suggesting that PPMS behaves differently and may be a different entity.

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  3. NDG I don't understand your posts. Will you be at the research day to explain?

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    1. Please feel free to ask any questions you may have, especially on the details of the post. I provide a lot more of the scientific garble, because I feel this provides a more holistic picture of the work. And MouseDoctor has beaten you to it about the MS research day!

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  4. NDG – this is an interesting post even if quite a bit of it goes over my head or seems contradictory within the article itself (I can make very little sense of the comparative table). However, it does make sense to me that spinal cord lesions would have a greater impact on disability levels as there is not the neuroplasticity available which the brain can use to potentially overcome or improve some of the impacts of brain lesions.

    What I do struggle with is why in the UK it is not routine to include the spinal cord in MRI scans (yes – I know the NHS is broke, but so are many other health systems in the world, and the article is only referring to cervical cord lesions). If there are cord lesions present anywhere in the spine then surely both doctor and patient would want to know about them, especially with the first scan that a patient has. While I can to some extent understand not including the spine in subsequent scans unless new symptoms emerge which could warrant including the spine it still seems to me that the “picture” is incomplete if the spine is not included. My own experience has been that since my first scan my MRIs have been stable apart from the most recent one showing that a thoracic lesion is more pronounced (with no enhancement from Gad, and I have several significant cervical lesions as well). If I were in the UK neither my neurologist nor I would even know that these lesions existed!

    In December last year there was a posting on lesion loads and CISers where high lesion load was given as being >10 lesions on T2 images.
    http://multiple-sclerosis-research.blogspot.com/2014/12/clinicspeak-what-is-definition-of-high.html
    I did post a question asking “The above from Prof G refers a lot to CISers as that is what the study was based on. However, is the data on lesion numbers still relevant for other MSers with PPMS if the date of their diagnosis is taken as being the “equivalent” of the CIS baselines noted above?” but no answer was posted – can you answer? (I am quite a bit >10 brain lesions, but given that the article was about baseline lesion load for CISers, is it even relevant to me?)

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    1. "If I were in the UK neither my neurologist nor I would even know that these lesions existed!"
      Sadly too true, I had a full spinal and brain MR on first diagnosis some 13 years ago then only brain until a few weeks ago. In that time I've developed lesions at all segments in cervical spine. It accounts for a lot of the symptoms I've experienced in the last 13 years but still a complete shock to see/learn of this. I suspect I'm not the only one but unless spinal MRIs are done more regularly, then you wouldn't know -definitely.

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    2. As often the case clinical practice is driven by research findings (I think correctly so - or medical practice cannot be considered evidence based), and to date there has been little success in standardising spinal cord imaging to meet the strict requirements of research. This has meant a stagnation in spinal cord imaging based work and therefore very little consensus on it in the clinical setting. Having said this, I think most MS physicians realise that some of our patients have predominantly spinal cord disease as opposed to brain lesions and preferentially request whole spine imaging to back our treatment decisions.

      In answer to your final question about GG's blog, the CIS category is broad and includes all forms of MS, the clinical subdivisions often being made retrospectively. However, in most research studies the reference is to CIS leading to RRMS which in fact doesn't include PPMS. Infact, there is a hole with regard to this type of work in PPMSers. There is a hint that T2 lesions and Gd-enhancing lesions are predictive of brain volume in PPMS, but little is known about their relevance in early PPMS. It seems as far as PPMS is concerned white matter atrophy is more closely related to disability than anything else: http://www.sciencedirect.com/science/article/pii/S1053811904001016.

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