Righteous Doc :>)uprightdoc wrote:These statements won't fly with neurologists or radiologists and they are so full of errors and controversy that I don't know where to start. Among other things, although there is a great degree of variability, MS has characteristic signs and symptoms clearly recognized by neurologists and radiologists. More importantly, the signs and symptoms commonly seen in MS aren't necessarily associated with the location of the lesions.
You are right. Something I likely wrote at 3am in response to a message from Nigel without any thought is probably "so full of errors and controversy" that it isn't worth responding to! This was just one message out of many in a long conversation and not something I put together to be carefully scrutinized.
Not to defend my views, but to put all this in context, let me explain my hypothesis which I see as neither gospel nor science just something that makes sense to me.
Prof Hayes at U Wis has recently published a study which shows that she can cure EAE in 100% of her mice and keep it in remission in 100% of her mice with a single, high dose of calcitriol followed by daily, moderate doses of vitamin D3.
Her explanation for why this works if I am correctly understanding it, is that in EAE and likely MS, something has blocked the ability of cells to convert 25(OH)D3 to calcitriol, the bioactive form of vitamin D which if available would cause programmed cell death in CD4+ T-cells, particularly Th1 cells which are effectively immortal without calcitriol.
It goes beyond just CD4+ T-cells because without the ability to make calcitriol, there may well be other pro-inflammatory actors and anti-inflammatory actors which are not functioning properly in the CNS.
CD4+ Th1 cells have an affinity for myelin so may be the main cause of dymyelination in MS. Prof Hayes has focused on these as a key factor in EAE and MS based on years of research and this is what she measures to determine the effectiveness of the treatment.
A single, quite high dose of calcitriol effectively halts the disease by making calcitriol directly available to CD4+ Th1 cells which die off very quickly. This has the effect of essentially restarting the immune system. Pro-inflammatory cytokines are down regulated and anti-inflammatory cytokines upregulated. She doesn't explicitly say that calcitriol restarts the immune system. That is my characterization of it based on the fact that after administration of calcitriol, the cells are then able to convert D3 to calcitriol and pro-inflammatory cytokines disappear and anti-inflammatory ones increase.
My overview is a gross over simplification of something Prof Hayes has been studying for 25 years and running tests on in EAE mice for at least the past 10 years, but I think it is essentially correct in terms of what happens.
This raises the question of whether a single high dose of calcitriol + ongoing administration of vitD3 will have the same effect in pwMS.
Unlike mice, people are quite varied genetically. EAE is mimic of MS and likely differs with it in many critical ways, one of the most important being what sets off the disease in mice compared with what actually happens in humans.
That begs the question of what is MS and what is the initial trigger?
Grossly oversimplifying this and perhaps totally wrong because I do not fully understand it, I proposed that MS is a disease characterized by a break down in the blood brain barrier in which demyelination occurs, at least in part because CD4+ T-cells have an affinity for myelin which they tag for destruction by the CNS immune system. They don't belong on the CNS side of the BBB and they get there because it has been breached.
I think it is not unfair to say that a breach in the BBB and demyelination are two common characteristics of MS and possibly the only two that are true with everyone having MS. And I am the first to say I could be totally wrong here. There is certainly hypoxia. Some people may have a pathogenic infection. Almost all likely have venous malformation. But to have MS, I propose that you have to have a breach in the BBB and that myelin has to be damaged.
What I like about this simple view is that it allows for almost all the theories of what causes MS if it is viewed as starting initially with the breach of the BBB.
That could be caused by a viral, bacterial, fungal or protozoan pathogen. Or it could be caused by turbulent blood flow stemming from CCSVI. It could also be caused by injury or problems that cause turbulence in blood flow which is damaging to the endothelium.
I am fully aware that there is no agreement on what causes MS and that many theories have been offered. The only one that makes no sense to me and as far as I can see is unproven in spite of having been around for decades is that immune system for no reason goes haywire and begins attacking myelin.
I like the simplicity of this view of MS and the fact that it accounts for the variety of clinical symptoms of the disease. What happens individual by individual will likely depend on where the BBB is being injured. What is causing that injury and what further damage it can do if things that shouldn't cross the BBB into the CNS, do.
Bringing this back to whether calcitriol + D3 will work in humans as well as it has in mice is the question of whether the same process is at work, ie, are the cells in the CNS, particularly those involved in the inflammatory response which appears to be relatively immortal in MS, unable to convert D3 to calcitriol?
And what causes that?
A number of recent studies in Alzheimer's, IBD, cholangiocarcinoma, and other diseases have suggested that what happens is a proliferation of pro-inflammatory cytokines, particularly TNF-alpha and IL-6, blocks the operation of the CYP27B1 gene or in some way disrupt the process it initiates. This blocks the conversion of 25(OH)D3 to calcitriol which cells do when they are unable to obtain calcitriol from the blood.
Prof Hayes' approach of providing a single high dose of calcitriol bypasses this problem by making calcitriol directly available to the cells needing it.
If this works in psMS, we will have a way to manage the disease which supports, rather than suppresses the immune system, and does this with a single dose of an inexpensive, FDA-approved pharmaceutical (albeit off label because it isn't approved in MS or at these doses) and $35 worth of D3 every year.
Regardless of whether my interpretation and theories about the science that underlies this are correct, I think it is something that should be tested in humans ASAP.
It does not fix things like an EBV or CPn infection. It won't correct spinal misalignment if that is what is causing damage to the BBB, nor will it fix CCSVI venous malformations and blood flow. Nor will it work as a silver bullet that allows people to eat crappy food, not exercise and so on. It is a piece of the puzzle, not the whole solution.
It may be that this is just a short term fix and it will be necessary to take a high dose of calcitriol periodically to maintain the effect since unlike EAE, the original cause of the problem in MS has not gone away without treatment. But how bad would that be compared with what we are doing today.
Hack away at this. I have a very thick skin and am happy to learn something by being shown the error of my ways. :>)