Tuesday, 20 November 2012

How early can you detect neurodegeneration in MS?

Henry et al. Regional grey matter atrophy in clinically isolated syndromes at presentation. J Neurol Neurosurg Psychiatry. 2008 Nov;79(11):1236-44.

BACKGROUND: The presence and degree of neuronal degeneration already existing in MSers at their initial presentation with a clinically isolated syndrome suggestive of multiple sclerosis (CIS) is unclear, and whole brain or whole normalised grey matter analyses have not demonstrated significant atrophy in CIS cohorts at clinical presentation. 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 study used a modified voxel-based morphometry (VBM) method to correct for lesion effects to analyse regional atrophy and perform voxel-wise correlations between volume and clinical metrics in 41 untreated CISers at presentation compared with 49 healthy controls.

" Voxel-based morphometry (VBM) is a technique that has been developed by MRIers to look at anatomical or structural features of the brain. A voxel is the 3D-analgoue to a pixel, which is a 2D enity."

RESULTS: The results confirmed that there was no significant difference in whole normalised grey matter volume between CIS and controls, whereas VBM showed significant areas of bilateral thalamic, hypothalamic, putamen and caudate atrophy. 

"The thalamus, hypothalamus, putamen and caudate are deep gray matter or cluster of neurones deep within the brain. These structures are often referred to as the deep gray matter."


Voxel-wise correlations with clinical measures showed that cerebellar volumes correlated with clinical cerebellar function, nine-hole peg test scores and the Multiple Sclerosis Functional Composite (MSFC) score, and that the MSFC score was also correlated with putamen volume. Lastly, T1 lesion volumes were found to correlate with thalamic and hippocampal atrophy, suggesting a link between white matter lesions and grey matter degeneration at the earliest stages of multiple sclerosis.

CONCLUSIONS: Atrophy is present in CISers at presentations, particularly in the thalamus, and other deep grey matter structures. Furthermore, the correlations with clinical metrics suggest the importance of this atrophy to clinical status and the correlation with T1 lesion load suggests a possible role of Wallerian degeneration.

"This is one of many studies to show that subtle brain atrophy exists at the very earliest clinical stage of MS, i.e. at presentation with the first attack. Many, including myself, would therefore argue that neurodegeneration is present from the clinical onset of MS. What drives this neurodegeneration is up for debate; is it inflammation that has occurred in the past or is the neurodegeneration driving the inflammation. We are currently trying to sort this out with several treatment trials; each trial is an experiment that adds knowledge. What this study, however  is telling us that we need to take the progressive component of MS very seriously and start looking at ways to prevent or slow down the gray matter loss as early as possible. Apart from MS prevention this is one of the biggest research challenges in MS at present. On a more positive note several emerging DMTs have positive effects on the progressive brain atrophy  that occurs in MSers; therefore I am confident that we will be able to impact on the neurodegenerative processes of MS that appear to occur independently of inflammation."

16 comments:

  1. So what do you think is driving neurodegeneration ? and it does beg the question , why so long ? This paper is from 2008, along I'm sure with many which pre date this saying the same. Does Alemtuzamab offer any protection ?

    Regards as always.

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    1. Sorry just read again, "We are currently trying to sort this out"

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    2. I am posting articles of interest that have relevance to the current debate.

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  2. These areas of early damage are all periventricular, and this is not a coincidense. It is evidence against the viral and the autoimmune hypothesis, since these mechanisms are random processes, unable to create patterns of damage.

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    1. Not true; viruses and autoimmune diseases have a predilection to specific areas of the brain. They are definitely not random; e.g. herpes attacks the temporal lobes. Limbic encephalitis, paraneoplastic brain-stem encephalitis, cerebellitis, Sydenham's chorea are all well-defined autoimmune syndromes that are characteristically well localised!

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    2. Prof G:

      I have often wondered this. Do you know of a reason, or have a theory, as to why MS lesions are periventricular?

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    3. Actually, I meant perivenous.

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    4. I have also wondered as to why over 80% of lesions are perivascular as described by Emma Tallantyre's paper using 7 tesla mri. Having seen this blog over the weekend and what seems to be a 'u' turn on some ideas it would be useful to clarify this one point as I've seen this come up time and again and it never seems to be explained.

      Regards as always

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    5. "Limbic encephalitis, paraneoplastic brain-stem encephalitis, cerebellitis, Sydenham's chorea"

      These conditions are strictly systemic, the areas involved are well defined and functionaly coherent. On the contrary, there is nothing in common in the periventricular areas other than they are periventricular, which means that they are affected for some reason that has nothing to do with the specific functionality of the brain parts they contain. In other words the areas of damage in MS are externally-defined by being all around the ventricles.

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    6. The lesions are perivenous because that is the structure from which lymphocytes leave the blood stream. The veins have a very specialised area where white blood cells slow-down and roll over the surface of the blood vessel that allows them to use their adhesion molecules to leave the blood stream. MS is one of literally 100s of diseases with perivenous infiltrates. Perivenous infiltration is a non-specific finding.

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    7. Andy no U-turn just a realisation that we need to judge DMTs on both attributes separately; i.e. reduction in relapses and MRI activity on the one hand and disability progression / brain atrophy on the other hand. What we need are drugs or combinations of drugs that target both processes. You can't assume that a drug that is very effective at reducing relapses is going to prevent the neurodegenerative processes and vice versa.

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    8. "The lesions are perivenous..."

      Thanks for the answer, Prof G. So throughout the body in general, are the veins the pathway that lymphocytes (or other immune cells) use to migrate from the bloodstream? They can't migrate through arteries, aterioles, etc? (Maybe I need to take physiology 101).

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    9. That is correct; the venules or small veins are the part of body that they use to leave the bloodstream. Perivenular/perivenous cuffs of white cells is non-specific.

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  3. I would not have expected atrophy in CIS at the very beginning of the disease. While this article is not support for CCSVI per se, it is easier for me to reconcile that early atrophy with the CCSVI concept of slow chronic damage beginning prenatally. I wonder if neurodegeneration is present prior to the clinical onset of recognised MS.

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  4. So..are we born w/ MS??? and as we develope & our systems mature the disease quietly starts the damage that presents at later age/time
    OR are we predisposed to autoimmune disorders associated with neurodegeneration which is exacerbated by environmental or viral factors.

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