Maggs & Palace wrote:Trapp et al., who also used autopsy tissue from MS patients, examined tissue for axonal transection, identified by the presence of terminal axonal ovoids. Not only did they demonstrate that axonal transection appeared early during lesion evolution, but occasionally, terminal axonal ovoids were surrounded by myelin which appeared normal. More recently, brain biopsy specimens from living MS patients have been studied histologically. One study found that axonal damage did not appear to be related to demyelinating activity and thus concluded that axonal injury is an independent process.
Maggs & Palace wrote:Recent studies suggest that this axonal damage is actually detectable at onset: patients with clinically isolated syndromes (CIS) who go on to develop MS already have grey matter and spinal cord atrophy at the time of presentation, and show a significant increase in ventricular volume even over the first year. This atrophy is not significantly correlated with gadolinium-enhancing MRI lesions, suggesting that the majority of atrophy is attributable to alternative mechanisms. Additionally, patients with CIS show decreased whole brain NAA at presentation. So it seems that axonal injury does occur from onset in MS, and so is a candidate for the primary pathological process. Can axonal loss cause inflammation?
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Suppression of neuronal activity in vitro allows induction, by IFNg, of MHC expression on the neurons themselves as well as neighbouring glial cells. Transection of axons induces an immune response with MHC expression, T-cell infiltration and proinflammatory cytokines in regions distant from the lesion. Thus primary damage to neurons or axons can lead to inflammation. Indeed almost all neurodegenerative diseases (i.e., diseases involving neuronal loss) are associated with inflammation, the degree depending on the underlying aetiology of the disease.
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Not only can axonal damage lead to inflammation, but studies suggest that this inflammation may actually be protective. Data from an experimental model of a partial lesion of optic nerves of rats have shown that T cells show neuroprotective effects, with significantly less secondary degeneration when anti-MBP T cells are injected.
Maggs & Palace wrote:Studies have noted that there is not a simple relationship between inflammatory activity measures (such as the number of relapses in RRMS or MRI activity) and either time to progression of disability or the severity ofirreversible disability. In fact disability may be accruing earlier than clinically detected: studies show similar rates of disability progression from Expanded Disability Status Scale (EDSS) 4.0 and 2.0 in the relapsing/remitting phase when compared to progressive phases. The longer time from onset to disability in RRMS compared to the primary progressive (PP) form may in fact reflect a protective effect of the early inflammatory phase of the disease: among patients with secondaryprogressive (SP)MS the rate of progression appears slower among patients who have superimposed relapses than among those who do not.
The suggestion that inflammation may be secondary could explain the PP phenotype: it has been suggested that the presence of an early relapsing/remitting phase depends on the individual’s innate immune response being more reactive than that in patients with PPMS. Less inflammatory activity is seen in PPMS compared to the relapsing/remitting/secondary progressive cohort in MRI studies. The relatives of patients with PPMS have lower markers of inflammation (higher IL-10 and lower TNF) than those of relapsing/remitting patients. Thus if PPMS is the same disease pattern as SPMS only without the initial inflammatory phase, this would explain the observation that SPMS and PPMS become clinically apparent at the same age, and progress at the same rate.
Maggs & Palace wrote:The disease modifying therapies recombinant betainterferons and glatiramer acetate are now widely used in the treatment of RRMS, but questions remain concerning their efficacy in preventing long term disability. The reduction in relapses of around 30% is undoubted as it was seen in all trials, both those studying RRMS and those with SPMS. However, the effect on disability is less clear, as a small effect was seen in only half the trials. In fact, even when an effect on permanent disability was reported, this assumed relapses last less than three or six months. As subsequent analysis showed, many patients took longer to recover. It has been suggested that the treatments only reduced reversible disability.
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MRI measures of inflammation and lesion load are often dramatically reduced in treated patients. In contrast, the effect on cerebral atrophy is unconvincing: in the European Study Group interferon beta-1b trial33and in the glatiramer study34 a treatment effect was not seen. Only post-hoc analysis of one study showed an effect of interferon beta-1a on brain atrophy progression during the second year of the trial.
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Campath 1H (a humanized monoclonal antibody which targets the CD52) is a powerful immunosuppressive agent leading to prolonged lymphocyte depletion. Studies have shown that a single pulse of Campath 1H suppressed disease activity, as measured by MRI, for six months. However, whereas radiological markers of cerebral inflammation and relapses are profoundly suppressed, brain and spinal cord atrophy, and progressive disability, continue.
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Thus, evidence from clinical trials suggests that immunosuppressants, while being effective in suppressing inflammatory activity, may not reduce progressive axonal damage. It is possible, but as yet purely hypothetical, that a reduction in inflammation could lead to a similar effect on progression after a lag period. Indeed this hope fuels the present practice by many neurologists of treating early to prevent longer-term disability. Nevertheless, as already discussed, the very early appearance of atrophy is against such a lag, and the 12-year cohort data also dispute this hypothesis.
Maggs & Palace wrote:The conventional hypothesis that inflammation is the primary event leading to axonal loss in MS is not supported by the evidence presented here. Axonal loss occurs early, and, disappointingly, recent clinical trials have revealed that immunotherapies do not have the hoped for effect on axonal damage and disability. Axonal damage can lead to inflammation, and inflammation may actually play a protective role (Figure 1B). Clearly some types of inflammation may lead to damage, seen as the residual deficit from a relapse, but this is unlikely to be a major contributor to overall disability. It is possible that the cryptic aetiological agent may both cause axonal damage and demyelination, as well as inducing an inflammatory response, which plays a minor role only. Of course, much of the data is group data and the pathological basis of MS is likely to be heterogeneous between patients. Nevertheless, what is clear is that we should consider designing a different therapeutic profile for MS drugs, aimed at targeting primarily the process of axonal loss i.e., ‘neuroprotection’, rather than inflammation.
Not necessarily – it means that we have to treat MS early and not after too much damage has happened. It takes a long time for damage axons and neurons to die, probably months to years. This study just confirms our clinical observation that treating progressive MS aggressively, simply stops the relapses and not the progression. Good thing that you have had your Campath early.
RESULTS: Over 2 years of treatment in AFFIRM, natalizumab delayed the onset of sustained disability progression by 42% compared with placebo...In addition, natalizumab reduced disability progression as measured by change from baseline in MSFC...the percentage of patients who reached an EDSS of 4.0 (5% vs. 13%...) or an EDSS of 6.0 (2% vs. 6%...), and mean (standard deviation) change in EDSS (0.04 0.86 vs. 0.41 1.09...)
natalizumab delayed the onset of sustained disability progression by 42% compared with placebo
but reduce the relative risk of disability progression by 42%.
Hi Ian,bromley wrote: So in my case, a powerful immuno-suppressant has been good news. Dr Coles told me last year that none of the RR patients given Campath have moved into the progressive phase. Only time will tell if this holds good for the long term.
Frank wrote:As far as I understand, it says, that for example in placebo group 100 people had progression, while in verum group only 58 people got worse.
Is that right?
Hi Finn,finn wrote: Now, perhaps you could tell me the way you see the primary disease process of MS and its similarities with other "autoimmune" diseases?
. I admit that there are no similarities to the other "autoimmune" diseases in what you and others consider the "primary MS disease process" (increased permeability of the blood brain barrier, inflammation, myelin loss, lesions, axon loss and brain atrophy) nor should we expect there to be.Now, perhaps you could tell me the way you see the primary disease process of MS and its similarities with other "autoimmune" diseases?
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