Instead, I'll ask a couple of questions:[list][*]If inflammation is the primary cause of the damage, why there is more permanet disability when there is less noticeable inflammation (RRMS vs. SPMS/PPMS)?
[*]Current disease modifying therapies (DMT) have been used for almost 15 years. A lot of post marketing studies have been made, but why there is no reliable unbiased data about the ability of DMTs to prevent the permanent damage?
[*]If axonal degeneration is the primary disease process, why our system decides to attack against myelin and oligodendrocytes?
In this review, data is summarized supporting the hypothesis that axonal loss is a major pathologic process responsible for irreversible neurologic disability in patients with multiple sclerosis. Pathologic studies implicate inflammatory demyelination as a principal cause of axonal transection and subsequent axonal degeneration. Axonal degeneration caused by chronic demyelination in the absence of active inflammation may also contribute to progressive disability in the later stages of the disease. Studies using magnetic resonance spectroscopy suggest that axonal loss begins at the onset of the disease, and studies using magnetic resonance imaging have documented brain atrophy in the earliest stages of multiple sclerosis. Brain atrophy increases during the relapsing-remitting disease stage without concurrent disability progression. This suggests that compensatory mechanisms maintain neurologic function, despite progressive brain tissue loss during the early stages of the disease. Beyond a threshold, however, further axonal loss leads to continuously progressive neurologic disability. We hypothesize that the rate and extent of axonal loss during relapsing-remitting multiple sclerosis determines when a patient enters the secondary progressive stage of the disease. This view of disease pathogenesis has several important implications. First, surrogate markers of axonal loss are needed to monitor the disease process for patient care and for clinical trials. We propose brain parenchymal fraction, a precise measure of whole-brain atrophy, as an attractive candidate for this purpose. Second, disease-modifying therapy should be used early in multiple sclerosis patients, before extensive axonal loss has occurred. Third, neuroprotective drugs should be tested in combination with anti-inflammatory drugs in multiple sclerosis patients. Finally, studies of the time course of axonal loss, and its mechanisms are critical for effective therapeutic intervention.
If inflammation is the primary cause of the damage, why there is more permanet disability when there is less noticeable inflammation (RRMS vs. SPMS/PPMS)?
Current disease modifying therapies (DMT) have been used for almost 15 years. A lot of post marketing studies have been made, but why there is no reliable unbiased data about the ability of DMTs to prevent the permanent damage?
OBJECTIVE: To determine the time course of brain atrophy during treatment with once-weekly IM interferon beta-1a (IFNbeta-1a). METHODS: The MRI cohort (n = 386) of the European IFNbeta-1a dose comparison study in relapsing multiple sclerosis (MS) was analyzed. In addition to baseline and three annual scans, a frequent subgroup (n = 138) had two scans before treatment initiation and scans at months 4, 5, 6, 10, and 11. Brain parenchymal fraction (BPF), a normalized measure of whole-brain atrophy, and volume of Gd-enhancing lesions (T1Gd) and T2 hyperintense lesions (T2LL) were evaluated. RESULTS: BPF decrease was -0.686% (first year), -0.377% (second year), and -0.378% (third year). Analysis of the frequent subgroup showed that 68% of the first-year BPF decrease occurred during the first 4 months of treatment. This change was paralleled by a drop in T1Gd and T2LL. In the frequent subgroup, an annualized atrophy rate was determined by a regression slope for the pretreatment period and from month 4 of treatment onward. Annualized pretreatment rate (-1.06%) was significantly higher than the under-treatment rate (-0.33%). CONCLUSIONS: In the first year of treatment with anti-inflammatory agents, atrophy measurements are possibly confounded by resolution of inflammatory edema or more remote effects of previous damage to the CNS. The atrophy rate reduction observed after treatment month 4 may reflect a beneficial but partial effect of interferon beta-1a and was sustained over the 3-year study period.
If axonal degeneration is the primary disease process, why our system decides to attack against myelin and oligodendrocytes?
raven wrote:. It is of course only theory but one that I feel best explains the processes seen in MS. I do not believe that suppressing inflammation results in a faster transition from RRMS to SPMS.
Btw, Harry, thanks for your kind comments, but I do know my limitations. I'm really convincing only in Finnish
The critical issue for the treatment of multiple sclerosis is whether this death of nerve cells can be prevented. At present, all we have available to us are drugs that act on the immune system to suppress inflammation and demyelination. Now, we believe that nerve cells die off in multiple sclerosis because they have lost the beneficial effects of their myelin wrapping. In which case, if we can suppress inflammation early enough, and prevent too much demyelination, we should be able to stop nerve cell death. This is a hypothesis only. Some neurologists think multiple sclerosis is primarily a disease where nerve cells are destined to die, and that the inflammation we see in the brain is secondary; in which case no anti-inflammatory treatment will prevent the progressive phase of multiple sclerosis.
'Drugs causing even the most intense suppression of inflammation do not stop disability progressing in MS. This is probably because other, non-inflammatory mechanisms cause progressive axon loss. We believe that perhaps the main cause of axon loss is persistent loss of oligodendrocytes and myelin: these appear to protect and support axons, as well as providing insulation. Their absence results in slow but steady axon death. For this reason, replacing myelin and oligodendrocytes might have beneficial effects not only in the short term, but also for the long term prevention of axon degeneration'.
'I have tried to find out how demyelination changes the properties of nerve fibres, causing them to generate the symptoms of MS. Research from several laboratories has revealed that demyelination initially blocks conduction, causing symptoms such as visual problems, weakness and numbness, depending on which groups of nerve fibres are affected. However, nerve fibres can adapt to the demyelination and then conduction can be restored, leading to recovery from the symptoms.
Recovery does not always occur sufficiently, and then some residual symptoms can persist. Sometimes demyelinated nerve fibres can become hyperexcitable, and then they can generate tingling sensations, which are sometimes initiated by body movements. The demyelinated nerve fibres are sometimes repaired by remyelination, and when this happens normal function can be restored.
Together with my colleagues in the research community, I have tried to uncover why and how these changes in function occur. Most recently we have tried to understand why nerve fibres degenerate in MS. Once degeneration has occurred, function is likely to be permanently damaged because nerve fibres do not regrow in the brain and spinal cord. It is therefore very important to try to find ways to protect the nerve fibres from degeneration'.
'Now, that’s all I’m saying about suppressing or modulating or interfering with inflammation with the immune system. I really want to come back to the key point that was made by Richard and that I made earlier on, that if we’re going to make a real difference to this condition we have got to have a much broader approach to it. And we’ve got to think about protecting the axon and we’ve got to think about encouraging repair. I think effecting or influencing the immune system has a limited impact and may only have a limited impact, even if you start early'.
I'll join you and Finn for that drink if they ever solve the mystery (HarryZ can join us too as long as he doesn't mention Tysabri).
All of these quotes come from the last 12 months. I think there's a recognition that this disease is much more complicated than was originally thought.
The evidence of course is very mixed and confusing. It now appears that grey matter as well as white matter (myelin) is involved in ms.
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