The pathologists take on progressive MS

Ann Neurol. 2015 Aug 3. doi: 10.1002/ana.24497. [Epub ahead of print]

Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque.


Frischer JM, Weigand SD, Guo Y, Kale N, Parisi JE, Pirko I, Mandrekar J, Bramow S, Metz I, Brück W, Lassmann H, Lucchinetti CF.



An extensive analysis of white matter plaques in a large sample of multiple sclerosis (MS) autopsies provides insights into the dynamic nature of MS pathology.


One hundred twenty MS cases (1,220 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. A total of 2,476 MS white matter plaques were identified. Plaque type distribution was analyzed in relation to clinical data.


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 relapsing-remitting MS (RRMS) were active. Among secondary progressive MS (SPMS) cases with attacks, all plaque types could be distinguished including active plaques, in contrast to SPMS without attacks, in which 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.


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.

 Distribution of white matter plaques by disease duration

Lassmann H and Lucchinetti CF lab over a decade have defined MS at the tissue level. They’ve vacillated about the different patterns of MS lesions (e.g. demyelinating, predominantly oligodendrogial pathology etc), and visualized grey matter plaques, thereby spiking our interest in cortical pathology. However, this time around they’ve kept it simple, or as simple as you can keep MS pathology.

Firstly, active plaques are only found in early MS, whereas, inactive plaques dominate chronic longstanding MS. Interpretation: MS autoimmunity is burnt out in chronic progressive MS. Ergo, anti-inflammatory strategies will not succeed in progressive MS.

Secondly, smoldering (slowly expanding) plaques are frequently found in progressive MS, especially in PPMS. Interpretation: smoldering plaques contribute to disease progression (eureka!). Taking this a step further, the substrates for smoldering plaques are a) microglial activation, b) axonal damage and neurodegeneration.

Thirdly, male patients have more smoldering plaques than female patients, especially at 45 years and older. Interpretation: this maybe why the female gender is associated with a more favorable disease course and PPMS has a less female predominance.

An interesting set of findings to ponder over in, say, the next decade??

About the author

Neuro Doc Gnanapavan


  • how does this fit with active chronic-active, chronic inactive, shadow plaque is the smoldering plaque a chronic inactive plaque and all that has been achieved is supplying a new name

    • So what they've done is divided active plaques into early and late (the latter based on macrophage infiltration), those which were smoldering contain an inactive center surrounded activated microglia, the inactive plaques with only a few macropahges or active microglia, and remylinated plaques as shadow plaques. And yup it sounds like a new classification but I think they just simplified it see if there were trends when looking at the bigger picture. You and I will not be the last to sat that the whole thing is quite confusing – but this one makes some sense!

    • Well for b) It has been the lamotrigine trial in SPMS – some positive data in lowering neurofilaments, and the phenytoin trial in optic neuritis – again positive data in conserving RNFL thickness. Others have been the failed fingolimod, riluzole trials. There's the ibudilast, idebenone trials which are ongoing. a) the microglial stuff as far as I'm aware are still in the investigative stages.

  • No new clues about why progression can show acceleration or plateaus in this? As a female with slowly smouldering PPMS, should I fear the menopause, I wonder… But maybe there's a new drug come that time, for me and for others…

    • Smoldering plaques seem to be bad news, but we already knew this; ergo the reason for scanning to see if there's enhancement. PPMS is different, very few lesions but there is loss of spinal cord voume over time – I wonder what's going on here?? Generally, the immune system ages with you – MD/MD2 can correct me on this, so probably a good thing?

  • So – in simple terms – is this why some of my symptoms are still getting a bit worse, even though I have never had what can be identified as a clear acute relapse, and have had almost completely stable MRIs? (there's plenty of lesions but no enhancing lesions when Gad was used for the first time about six months ago) Does this indicate that I've probably been progressive from the start or ???

    • Provisor of having a lot of lesions is probably that its RRMS onset. Often when MRI's are reported lesions are counted but unless clearly obvious no one comments on the expanding lesions (can you imagine the workload if you had to do this with every MRI scan? Having said this there are now imaging software which circle lesions and this is being pioloted here and in other centres) and also very difficult when you have a number of lesions coalesced into larger lesions. Gad is hit and miss, and delayed scanning, for instance has a greater pick up. DWI positivity is probably reflective of something more recent. In short, maybe we're over-reliant on MRI?

    • Hi neurodoc,

      that's why it's so important to develop lesion-counting software – I've read somewhere that the Australians are doing something in that direction.

      Can you define 'expanding' lesions? Old lesions that refuse to heal and then get bigger by submerging with new ones maybe?

    • When brain lesions heal without recovery, they scar over and shrink in size. They should not be expanding, some may even have a rim of enhancement. Things may, however, coalesce simple because at the time of scanning the boundries of the lesions in question was not apparent but become more clearly defined on follow up scans. I agree more automation of these techniques of analysing images will be able to tell us more in the future, of course with someone actually setting the parameters beforehand and checking it afterwards.

    • Hi NeuroDoc,
      so this is a normal MRI evaluation of a new brain lesion, when it appears it got fluffy borders and when it recovers it got sharp borders? If someone got all of his lesions on a first scan described as having "fluffy" borders and on subsequent in ~1 year the borders sharpen, does it mean there was no lesions before first shot was made (or lesions simply gone with no traces left?)?

    • Anon at 2.00pm again
      Thanks for the explanation NDG.
      So, if it is likely that it all started as RRMS, how common is it for RRMS to NEVER produce an acute and identifiable relapse? Even with the benefit of hindsight I cannot identify ever having had a "relapse" that fits the normal definition of one. Maybe if I had, then I might have been diagnosed years earlier and possibly gained some benefits from some treatment. Or was I just unlucky and it gave these hidden relapses the opportunity to do lots of damage? (several big lesions in spine, plus the brain ones)

    • Not all lesions can be described as having a fluffy border and some can be sharply demarcated from the beginning – I don't think anyone has looked into what the significance of these lesions are. What we do know is that T1 black holes (noted on a T1 weighted scan) are there because the axons have been lost in these areas.

      In your final sentence are you referring to disappearing lesions? This has been noted and probably represent successful repair of these lesions.

  • NDG- it would be great if you could spend more time explaining your posts- I find them interesting but with lots of comments that sound like you are speaking to yourself so they are hard to follow.
    best regards

  • Are T1 Black Holes considered inactive lesions? I had two of these show up on my intial MRI along with 8 T2 lesions. Do black holes carry any prognostic value or do they represent progressive MS in anyway? I am a 30 year old male just diagnosed with MS.



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