Thursday, 24 March 2016

Pathologist view of progression...what do they think...let's sit on the fence.

Larochelle C, Uphaus T, Prat A, Zipp F. Secondary Progression in Multiple Sclerosis: Neuronal Exhaustion or Distinct Pathology? Trends Neurosci. 2016. pii: S0166-2236(16)00025-4

Prevention of progression in neurological diseases, particularly in multiple sclerosis (MS) but also in neurodegenerative diseases, remains a significant challenge. MS patients switch from a relapsing-remitting to a progressive disease course, but it is not understood why and how this conversion occurs and why some patients never experience disease progression. Do aging and accumulation of neuronal damage induce progression, or do cognitive symptoms and accelerated grey matter (GM) atrophy point to distinct processes affecting networks? This review weighs accepted dogma against real data on the secondary progressive phase of the disease, highlighting current challenges in this important field and directions towards development of treatment strategies to slow or prevent progression of disability.

It is clear that the development of progressive MS, on balance is a product of age/ disease duration.

What are the mechanisms of progression suggested?

1. The Same Processes Driving RRMS Eventually Lead to SPMS
As we get older there is a switch from active plaques to slowly expanding inactive and smoldering plaques. Aging and accumulation of damage in the peripheral immune system and the CNS over time can lead to chronic immune activation, increased oxidative stress-related damage, exhaustion of repair mechanisms, and loss of trophic support, all of which could significantly contribute to SPMS onset. Here are some suggestions
  • Alteration of the Peripheral Immune System with Aging
  • Aging is Associated with ‘Low-Grade Immune Activation’ in the CNS and Mitochondrial Dysfunction
  • Aging and Accumulation of Insults Result in Exhaustion of CNS Compensatory Mechanisms
  • Aging of Immune and CNS Cells and Reduced T Cell Infiltration in SPMS Can Result in Loss of Trophic Factors
2. Distinct Neuroinflammatory Processes Drive SPMS
  • High-Grade Chronic Inflammation’ Triggers New Independent Autoimmune Processes Within the CNS
  • Chronic Demyelination and Neuronal Dysfunction Can Exert Reciprocally Deleterious Influences
  • Reduced Social, Physical, and Cognitive Activity Impairs Remyelination and Neurogenesis
  • Microglial Profile in SPMS Can Hamper Neuroglial Repair Mechanisms
  • Intrinsic Neurotransmitter Imbalance in the CNS and loss of inhibitory molecules
Here are the views summarised

Mechanisms Underlying Secondary Progressive Multiple Sclerosis (SPMS) Pathophysiology. 

(A) Proposed schematic representation of events underlying relapsing-remitting multiple sclerosis (RRMS). Because the first trigger of MS relapse and the exact sequence of events leading to lesion formation or to remission are not known, a wheel (black circle and arrows) is used to represent the cycle of peripheral immune activation, central immune activation, and neuroglial damage observed in RRMS. Regulatory mechanisms (in blue) in the peripheral immune system and CNS are intervening to induce remission, and lead to partial or complete clinical recovery. 

(B) Proposed schematic representation of events underlying SPMS. Hypothesis 1 (upper panel): exhaustion of resources through aging and lesion accumulation as the mechanism underlying the clinical shift from RRMS to SPMS. Aging as well as lesion accumulation exacerbate and chronicize the RRMS pathophysiological mechanisms (bold black circle and arrows). Neurosenescence (green), characterized by microglial activation, iron deposition, mitochondrial dysfunction, and decreased network efficiency, is associated with reduced capacity of neuroglial cells to tame inflammation and to repair and regenerate (broken green line). Immunosenescence (orange) is characterized by (in specific immune cell populations) increased cytotoxic capacity, enhanced expression of adhesion molecules, and decreased trophic factor production, and is associated with impaired immunoregulatory capacity (broken orange line). The broken grey line represents the largely unexplored relation between the neuroglial compartment and the BBB alterations found in SPMS. 

Hypothesis 2 (lower panel): distinct CNS-restricted processes triggered by high-grade inflammation and neuroglial injury as the mechanism underlying the clinical shift from RRMS to SPMS. Upon reaching a given inflammatory threshold (shown by red arrow), aggressive immune cells can create an environment that supports the organization and persistence of a chronic inflammatory immune response within the CNS compartment. The CNS inflammatory environment, together with ensuing demyelination and neurotransmitter imbalance, impairs neuronal function while increasing energy demand. This initiates a vicious cycle of chronic demyelination, energy failure, neuronal degeneration, loss of function, disuse, and decreased remyelination and neurogenesis, exposing remaining neuroglial cells to further stress and energy demand, and sustaining independent degenerative and inflammatory processes in the CNS. The broken grey line represents the largely unexplored relation between the neuroglial compartment and the BBB alterations found in SPMS. The broken blue lines underline the impairment of regulatory mechanisms because peripheral regulatory immune cells cannot influence intra-CNS immune processes, and chronic neuroglial injury and neurological disability impair CNS repair mechanisms. 
Abbreviations: BBB, blood–brain barrier; CIS, clinically isolated syndrome; GM, grey matter; WM, white matter.

Every thing is caused by autoimmunity, this is the average EAEologists world view that every thing to do with MS is caused by autoimmunity, crack autoimmnity you crack the lot...only problem is....therapy in MS does not support this...hey if you look hard enough EAE does not support this view either. 

Maybe we have been flogging a dead horse too long and this is why treatments for progressive MS are lacking.

But what do the reviewers do...yep do what I would do and sit on the fence! Abit of this here and a bit of that there

"When weighing up the above-mentioned data for and against a specific pathology in SPMS, there is a degree of balance, and it is conceivable that both (i) the sum of aging and cumulative inflammatory injury exhausts resources and drives the system towards failure, and (ii) distinct intrinsic mechanisms in the CNS, emergent or present from onset, are triggered at some point and lead to chronic sustained neuroglial injury. In fact, aging and lesion accumulation could contribute to a threshold of inflammation and neuroglial dysfunction being reached upon which distinct intra-CNS mechanisms are triggered and in turn contribute to accumulation of damage. 

It remains to be determined if both (i) and (ii) are necessary to eventually lead to the typical disability progression seen in later stages of the disease".

So the only way to get a handle on this is get MS sorted early and then see what happens, quell autoimmunity and see if progression occurs. I think I know what happens in EAE, what will happen in MS, we need to use highly effective agents ASAP as we know that progressive nerve damage starts from the earliest time point.


  1. As indicated from the previous post on Tysabri, using "highly effective" therapies will reduce the relapse rate but has no effect on progression or brain atrophy.

    Throwing the kitchen sink at the problem is one way of making it seem like you are halting disease but since Science doesn't understand the cause of progression this is a shot in the dark.

    1. RE: "As indicated from the previous post on Tysabri, using "highly effective" therapies will reduce the relapse rate but has no effect on progression or brain atrophy."

      Natalizumab had a great impact on brain atrophy; you just need to look in the correct window. It increase atrophy rates in year 1 (pseudoatrophy), but slows it in year 2 and brings it towards the normal range in year 3 & 4. It is not as good as the alemtuzumab data, but I don't trust the alemtuzumab data as there is reversal of pseudoatrophy that has not been taken into account.

    2. Therefore Dr. G you do not agree with the failure of the ASCEND trial for Tysabri in SPMS (i.e. no slowing of brain atrophy after 96 weeks). ? You think the trial was too short I presume.

    3. He only chooses to believe in data that supports his position.

  2. Throwing a kitchen sink at a horse that has already left the kitchen means a broken sink and a horse that is running wild.
    As to not knowing what causes progression if you read I think we do.

    1. Researchers may have insight into what is causing progression, but the narrative promoted by this blog is not backed up by data. Giving people false hope of using what has been labeled "highly effective" therapies to halt progression is a good marketing ploy when you are obviously connected to pharma, but there is little basis to these claims.

    2. As the Dude, so rightly said, "That's just like your opinion, man".It takes a while for the clinical results to catch up with what has been found experimentally (for a number of reasons).
      To say there is no data is wrong.

  3. "Maybe we have been flogging a dead horse too long"

    You don't say!

    "So the only way to get a handle on this is get MS sorted early and then see what happens, quell autoimmunity and see if progression occurs."

    For the love of...

    And those of us who never showed highly inflammatory disease, i.e. PPMS, get to wait in the wings and watch, while progression goes on, and on, and the real root of MS - together with any potential of a real solution - gets to stay deeply buried in the dark? Aging? My PPMS started in my early twenties.

    1. I got PPMS at 27. I'm 37 now and about EDSS 6.5. It's an evil and cruel disease. In the ten years of having MS not one treatment has materialised for my pathoclincal brand of disease. I now realise I'll just get worse and worse and then die. But I guess that's just the way it is.

  4. Unfortunately the main stream MS community is focused on ways to suppress your immune system in novel ways to produce the least side effects. But suppressing your immune system in itself is not a healthy thing to do to start with.

    The other option is to look at viral causes such as EBV, but this has been investigated to death but still is brought up again when a new generation has no clue about its history as a cause for MS. It looks novel when so much time has passed where the idea was investigated and dropped, but revived again.

    This is akin to the theory of venous restriction investigated over a century ago but was revived with the CCSVI fanatism.

    It's unfortunate that this is where we are, but I think researchers are unraveling what is causes MS but they are not part of the established MS industrial complex.!po=3.99361

    1. You have to work with what's available. Personally, I'm hoping we can get neuroprotectants for MS on stream asap but we need pharma on board, whether we like it or not.

    2. Which neuroprotectants you have in mind?

    3. "The other option is to look at viral causes such as EBV, but this has been investigated to death"

      Is that true? If so, why was I and my family persuaded by that video to donate so generously to Charcot? Personally, I find the EBV evidence persuasive and compelling.

      As much as I would appreciate a neuroprotective, it must have an excellent safety profile.

    4. As much as I would appreciate a neuroprotective, it must have an excellent safety profile.

      Working on it

    5. "Which ones do I have in mind"

      Sorry I know better than to make suggestions of things you can get your hands on...that is besides cladribine:-)

  5. Hi doctors, I'm newly diagnosed with RRMS and I'm hoping to start alemtuzumab soon. I'm (naively?) hopeful that it will stop the relapses and give me at least a few more years of 'near-normality'. But the secondary progressive phase of the disease sounds quite hopeless and it scares me.

    You've previously blogged that early treatment with highly-effective DMTs like natalizumab/alemtuzumab could potentially slow the onset of secondary progression. For a non-clinician like myself, it's hard to make sense of the two hypotheses in the study you talk about above. Do either of these two hypotheses support your theory about early treatment delaying SPMS, or do they go against it? As someone hoping that early treatment with lemtrada will delay SPMS, should I be rooting for hypothesis #1 or #2?

    My second question doesn't really relate to the study above. You've previously talked about alemtuzumab/natalizumab apparently slowing the rate of brain atrophy (aka BVL) and that this is good news. But I'm a little confused about whether slowing brain atrophy makes a meaningful difference to my outcomes. Do you think that brain atrophy itself accelerates disability progression/SPMS onset - or is brain atrophy probably just a secondary side-effect of MS and not an actual driver of disability?

    Sorry, I realise these are complex questions and you may not have a lot of time to go into depth answering them, but I'm trying to wrap my head around my disease and I'd appreciate any clarification you can offer.

    I also just wanted to say a heartfelt thank you for maintaining this blog. Some of your commenters are quite critical of your theories, but personally I find them fascinating and they give me a little hope that we're inching closer to understanding and treating the progressive disease. I really appreciate you taking the time to communicate with us like this.

    1. Do either of these two hypotheses support your theory about early treatment delaying SPMS, or do they go against it?

      Both support it in my mind

      "should I be rooting for hypothesis #1 or #2?"

      I don't know I think the real world will be abit of both and based on response to therapy one may think hypothesis #2 may be a better bet because we should have done better for PPMS/SPMS if hypothesis one was the central issue. However ProfG throws in a few curve balls that may question this and this is the length dependent hypothesis in that the legs go quicker than the arms and that targeting progression too late may not save the legs but may save the arms.

      Based on the beasties if you stop disease early enough although there is progression in some nerve tracts, clinically the disease is stopped. If you wait too long that is not the case. Is this going to happen in MS lets hope so.

      Atrophy is brain shrinkage and brains shrink because they loose nerves and this can't be a good thing. However, brain loss happens to us all, but in MS it happens abit quicker and in Altzheimers it occurs quicker than in MS. So we don't want it but we can compensate for it for quick some time. However, the problem is brain atrophy as measured by MRI is that it is a balance of nerve loss, glial scarring filling the space lost by nerve loss and swelling that makes the brain look bigger than it really is and the unwelcome fact is that MRI is missing massive amounts of nerve loss, which is lulling us into a false sense of security.

      Now back to the beasties when does clinical progression become visible. When there is a certain amount of nerve loss and once it reaches a tipping point I think every % is precious such as the beasties loose 10-15% of there nerves after one attack and this is hardly noticable then about 5% more for each attack but at 40% the attacks burn out and progression kicks in but I then 0.1% nerve loss at that stage makes a clinical difference.

      "Does atrophy accellerate progression"
      If we look at the second idea that the neural enviroment is created by immune attack and this kicks of a damaging environment. So we know that the demyelination is a problem in MS, probably caused by immune attack. demyelination creates and enegergetic strain on nerve function to keep signals going but as each nerve drops out it passes on that strain to the remaining nerves.

      So back to the beasties, those with more damage progress more rapidly

  6. I think you should focus your research in why some patients never experience disease progression. RR maybe is a warning of MS disease.


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