Monday, 10 August 2015

The progressive Lesion identified

Frischer JM, Weigand SD, Guo Y, Kale N, Parisi JE, Pirko I, Mandrekar J, Bramow S, Metz I, Brück W, Lassmann H, Lucchinetti CF. Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosisplaque. Ann Neurol. 2015. doi: 10.1002/ana.24497. [Epub ahead of print]

BACKGROUND:An extensive analysis of white matter plaques in a large sample of MS autopsies provides insights into the dynamic nature of MS pathology.
METHODS:120 MS cases (1220 tissue blocks) were included. Plaque types were classified according to demyelinating activity based on stringent criteria. Early-active, late-active, smoldering, inactive, and shadow plaques were distinguished. 2476 MS white matter plaques were identified. Plaque type distribution was analyzed in relation to clinical data.
FINDINGS:Active plaques were most often found in early disease, whereas at later stages, smoldering, inactive and shadow plaques predominated. The presence of early-active plaques rapidly declined with disease duration. Plaque type distribution differed significantly by clinical course. The majority of plaques in acute-monophasic and RRMS were active. Among SPMS cases with attacks, all plaque types could be distinguished including active plaques, in contrast to SPMS without attacks in whom inactive plaques predominated. Smoldering plaques were frequently and almost exclusively found in progressive MS. At 47-years of age, an equilibrium was observed between active and inactive plaques, whereas smoldering plaques began to peak. Men displayed a higher proportion of smoldering plaques.
INTERPRETATION: Disease duration, clinical course, age and gender contribute to the dynamic nature of white matter MS pathology. Active MS plaques predominate in acute and early RRMS and are the likely substrate of clinical attacks. Progressive MS transitions to an accumulation of smoldering plaques characterized by microglial activation and slow expansion of pre-existing plaques. Whether current MS therapeutics impact this pathological driver of disease progression remains uncertain.

It has been asked "will the real MS stand up" and based on the clinical profile, MS comes in two main flavours relapsing and progressive. 

After a hundred and fifty years the pathologists are saying yes their are two pathologies - the smouldering and the active lesion, because we have known about the slow-burn causing progression for a long time.

The smouldering lesion has an active edge with lots of microglia and few macrophages and limited amounts of myein engulfment
The active lesions are associated with relapsing MS and the smouldering is associated with progressive MS with (SP+) or without (SP-) super imposed relapses

The older you are the more the smouldering progressive lesion occurs but they occur early after diagnosis

Based on the clinical profile of secondary progression it is not an all or nothing change but a slow transition, which fits with the imaging or the clinical profile and some people with progressive MS will benefit from immunosuppressive therapy.

Yet it makes perfect sense for their to be two lesion types

In EAE the relapse is caused by resolving peri-vascular lesions around blood vessels. The progressive lesion has glial activity in and around the edge of damage in MS. In this study they say the progressive lesion is the same. Therefore MS and EAE are the same.

The peri-vascular cuff is an acute peri-vascular lesion. In ths study the early active lesion is a lesion full of macrophages gobling up myelin.

In EAE the active lesion responses to lymphocyte treatment the smouldering lesion does not and an anti-glial treatment is needed.

In this study in early lesions they are active and end inactive lesions.

This sounds fantastic but is it too good to be true? 

Do other pathologists agree?...(.Please, make up your minds quickly and repeat this). This current group gave us four MS lesion types but the rest of the pathology world did not agree. Will it be the same here?

However this may help the lymphocytes are everything-world (This is a large part of science including the MS science mafia-otherwise why would we see this endless trail of failed progressive MS trials. They influence pharma direction!) to see that a different world view is needed.


  1. Maybe I'm just dumb, but this reads to me as though MS which is progressive (i.e. no identifiable relapses) from the start is a different disease to the RR "flavour". (would you like chicken salt or ordinary salt with your chips/MS, or perhaps you'd prefer vinegar?)

    So it comes back again to the question of what causes MS - and I still think that there is more than one cause, and that MS is an outcome of "something". To me this makes sense of why some people respond to some drugs and not to others, given the different modes of action of the various drug options.

    1. If the cause was known maybe we wouldn't need the drugs in the future. Why do some people die of cancer and some don't? Loads of us have never been asked how we're doing if we're not on treatments?

    2. This is one view but I do not think there are two diseases but just a spectrum and that influences dictate when progression occurs

  2. Very interesting. I understand as you get older there will be more inactive lesions but how do you know what a smouldering lesion is? Would an MS neurologist know what I mean if I were to ask about 'smouldering" lesions? Also what are shadow lesions, sounds almost Jungian.

  3. "However this may help the lymphocytes are everything-world (This is a large part of science including the MS science mafia-otherwise why would we see this endless trail of failed progressive MS trials. They influence pharma direction!) to see that a different world view is needed."

    Excellent - very interesting indeed. (From a shadowy, smouldering PPMS-person).

  4. Mouse,

    Does this mean anything in terms of treatments? Are we making any headway regarding smouldering plaques?

    1. Yes it focuses the mind in a direction. I think it is no big shakes for me as i have been thinking along these lines for ages, but it will wake some peole up.

  5. Microglia have been studied for some time will they be targeted for progressive disease in the near future?


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