Theories: "Auto-Immune" vs. Not

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Post by Shayk » 13 years ago

Hi Bromley, Finn and Raven—

Bromley, first let me apologize for not answering some of the questions you asked several weeks ago. I’ll start there, but not without reinforcing that Finn's got it right, the fact so little is known about MS makes it easier to form my own simplistic opinions.

My idea of neurodegeneration in MS is very simplistic. As someone who is almost a decade beyond meeting entry criteria for the “Golden Age Forum", my idea of neurodegeneration and MS is basically that a) very little is actually known about MS and b) one of the things that is known is that the majority of people with MS tend to experience increasing disability over time (i.e., as they age). That’s neurodegeneration to me, the non-scientist, in a nutshell.

Finn, I agree that the concept of neurodegeneration could help explain the clinical differences between MS-subtypes. I really don’t understand the scientific basis for different clinical MS-subtypes. I have the impression that at least some ideas suggesting MS may be more than one disease are based on Lucchinetti’s work describing the four patterns of demyelination in MS patients. That work reflects lesions at a “point in time”. In the book Multiple Sclerosis in Clinical Practice , 2003, Miller, Lublin and Coyle, make these observations about those research findings:
Of interest, in autopsy cases there was a tendency for all acute lesions to have the same pathological pattern, i.e., intrapatient homogeneity…...The major caveat for this work is that it comes from autopsy cases, which provide only one time point for pathological assessment, and in most cases do not reflect early disease events. Biopsy cases represent, at best, very atypical presentations of MS, and thus may not represent the more usual pathological changes of the illness.
Bromley, in answer to your questions about inflammation and to expand a bit on what Finn’s already said about nerve conduction and reversible RRMS, Peterson and Trapp note in an article Neuropathobiology of MS
“…inflammation, edema, and ongoing demyelination are not expected to make significant contributions to increasing permanent neurologic disability. Chronic demyelination fails to account adequately for the progressive persistent neurologic disability experienced by patients who have SPMS.”
I think treating the inflammation, edema and ongoing demyelination (no doubt all part of the nerve conduction thing) could explain the symptom relief people obtain from anti-inflammatory treatments. In other words, it’s possible that current and in the pipeline strictly anti-inflammatory agents may well diminish the clinical symptoms of MS and some axonal loss, without significantly impacting the long-term progression and increasing disability that's evident in MS.

Bruce Trapp clearly thinks that MS is an “inflammatory demyelinating and neurodegenerative disease.” Select quotes from an abstract
Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease capture some ideas of that perspective.
Axonal degeneration has been identified as the major determinant of irreversible neurological disability in patients with multiple sclerosis (MS). Axonal injury begins at disease onset and correlates with the degree of inflammation within lesions, indicating that inflammatory demyelination influences axon pathology during relapsing-remitting MS (RR-MS). This axonal loss remains clinically silent for many years, and irreversible neurological disability develops when a threshold of axonal loss is reached and compensatory CNS resources are exhausted.
I am personally of the opinion that compensatory CNS resources include the hormones estrogen and progesterone. In women, estrogen and progesterone begin to decline as early as their 30’s. It’s a slow downhill course for those hormones as we age. :roll:

Finn, I do disagree with you about the use of steroids for inflammation. It’s basically my impression that in the long term they don’t appear to impact the disease course. I have serious personal questions about the use of high doses of methylprednisolone. The abstract Methylprednisolone exacerbates axonal loss following optic nerve trauma in rats notes:
Conclusions: We conclude that methylprednisolone exacerbates axonal loss following crush injury in the rat optic nerve. Based on the results of this study, clinical studies of traumatic optic neuropathy in the future should also examine the possibility that corticosteroid treatment may have an adverse effect on visual outcome following optic nerve trauma.
I want to note and emphasize that this study was a) in rats and b) not about ON that may be a part of MS. I arrived at this abstract while pursuing my interest in hormones. I think methylprednisolone is an artificial form of the stress hormone cortisol, which is known to be high in some people with MS and associated with disease progression. In this study the axonal loss in those rats was dose dependent.

I also have serious concerns about methylprednisolone because: Methylprednisolone Increases neuronal Apoptosis during Autoimmune CNS Inflammation by Inhibition of an Endogenous Neuroprotective Pathway
…we provide evidence for negative effects of steroid treatment on neuronal survival during chronic inflammatory autoimmune disease of the CNS, which should result in a reevaluation of the current therapy regimen.
At a minimum Bromely, to answer your question, I think that treatment with steroids should be reevaluated.

Raven, it’s nice to know you’re doing so well on Campath. I wasn’t aware of the axonal connection. I also have a unified theory (unified only around hormones :-)) about MS. I’ll save that for another time.

Take care everyone. We are all trying to get to the same place, namely, putting MS where it rightfully belongs, behind us instead of in front of us.


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Post by finn » 13 years ago

Sorry, time to leave the board.

Last edited by finn 13 years ago, edited 1 time in total.

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Post by Shayk » 13 years ago


Nice to see we agree. I also think the use of steroids is a personal decision and people do report they’re helpful.
You asked:
Wasn’t estrogen already studied in clinical trials with promising results?
Yes, there was a trial of estriol, a form of estrogen that’s particularly high in the third trimester of pregnancy, when relapses are less frequent. It’s possible I’ve never posted that abstract, so here it is: Treatment of Multiple Sclerosis with the Pregnancy Hormone Estriol
We treated nonpregnant female multiple sclerosis patients with the pregnancy hormone estriol in an attempt to recapitulate the beneficial effect of pregnancy. As compared with pretreatment baseline, relapsing remitting patients treated with oral estriol (8 mg/day) demonstrated significant decreases in delayed type hypersensitivity responses to tetanus, interferon-gamma levels in peripheral blood mononuclear cells, and gadolinium enhancing lesion numbers and volumes on monthly cerebral magnetic resonance images. When estriol treatment was stopped, enhancing lesions increased to pretreatment levels. When estriol treatment was reinstituted, enhancing lesions again were significantly decreased.
This was a very small crossover trial design, 6 women with RRMS and 6 with SPMS. Select quotes from the article:
All of the currently available anti-inflammatory therapies for MS are injections. The purpose of this pilot trial was to test a noninjectable, oral anti-inflammatory hormonal treatment for MS……

The response in the RR patients but not the SP patients reached statistical significance. The efficacy of estriol in RR but not SPMS is consistent with the response to other approved MS therapies with potent anti-inflammatory effects but also could be because of the small sample sizes. Although this is a small trial on a very limited number of RR patients, it is noteworthy that the degree of improvement in enhancing lesions in this study was within the realm of what has been observed previously for the four approved treatments in much larger trials.
It’s my understanding the results warranted a larger multi-center clinical trial that’s in the planning stages. I also want to emphasize that IMO it may well be the neuroprotective properties of hormones rather than their anti-inflammatory properties that turn out to be their most important function in trying to better manage MS.

I also think it’s important for women with an interest in estriol to consider the potential relevance of having balanced hormone levels.

The article by Patricia Coyle Gender issues notes:
Hormones may act synergistically. For example, the effect of estrogen plus progesterone is greater than either one alone. Hormones may show concentration effects, with opposite actions at low and high levels.
There is also very limited research suggesting that it’s the ratios of the hormones rather than absolute amounts per se that may be important in managing the symptoms of MS. Those factors coupled with the fact that so little is known about hormones or about their possible role in MS, is why I elected to try and achieve physiologically balanced hormone levels.

I think the article that was posted earlier this year underscores the potential importance of “balancing” hormones. Sex hormones modulate brain damage in multiple sclerosis: MRI evidence.
In women, a positive correlation was observed between testosterone concentrations and both tissue damage on MRI and clinical disability. In men, there was a positive correlation between oestradiol concentrations and brain damage.
Another article that highlights the potential relevance of hormone ratios is MRI in multiple sclerosis during the menstrual cycle: relationship with sex hormone patterns
The ratio of progesterone/17-beta-estradiol during the luteal phase was significantly associated with both number (r = 0.6, p = 0.03) and volume (r = 0.7, p = 0.009) of enhancing lesions, providing support for a role of these hormones as immunomodulatory factors in MS.
Another example is in this letter, Premenstrual exacerbations of multiple sclerosis
These 3 women with relapsing-remitting multiple sclerosis had a particular disease course, characterised by exacerbations that occurred exclusively during the premenstrual period. This is probably different from the premenstrual transient worsening of existing symptoms that occurs in many women with relapsing-remitting multiple sclerosis. However, we cannot exclude that the underlying mechanism is different and that the patients described here may be at one end of a range. Exacerbations in the premenstrual period are likely to be triggered by dynamic changes in sex hormone concentrations. Before the menstrual bleeding there is a sudden fall in circulating levels of progesterone and oestradiol. Both sex steroids have numerous regulatory effects on the immune system, including an influence on T cell populations, and the production of cytokines.
More research is definitely needed. :) There are lots of questions I’d like to have answered:

Do women with RRMS transition to SPMS due to the declining levels of estrogen and progesterone? (There’s been only one small study indicating approximately 50% of women report worsening of symptoms at menopause.)

Are men with MS more likely to be diagnosed with PPMS simply because they have lower levels of estrogen and progesterone than women?

Are people with MS diagnosed at a later age more likely to be diagnosed PPMS because they’ve already depleted their hormone reservoirs?

And, perhaps my most burning question, because DHEA levels start declining at a relatively young age in both men and women: Is the MS disease process over time attributable, at least in part, to ever increasing levels of cortisol and simultaneously decreasing levels of DHEA? (It’s my understanding DHEA opposes cortisol.)

That last question would be my theory. I don't know about Trapp, but I'm not into buying time with this MS. :)

Take care.


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