Education:Targeting Progressive MS. Prelude

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Whilst trying to explain how white blood cells enter the brain, using an analogy with a carpark, you asked “Whether cars (white blood cells) were central to the problem of progressive MS?”. Others asked “What is the problem in PPMS?”, “Why don’t Current MS drugs work in PPMS?”

No doubt you may already have the answer (However, it is obvious from your comments that some/many of you do not) and for those MSers who don’t like the simplistic approach, I will cut to the chase so that you can then “Switch Off” and not view/comment on the Mini series of the same title that will address the same issue in a more digestable manner.
Relapses are triggered by white blood cells entering the brain and damaging the oligodendrocyte (0) and nerves (N). This coupled with swelling of the nerve, serves to stop the nerve impulses firing properly. This leads to symptoms.


The best treatments of (relapsing) MS aim at preventing white blood cells (WBC) reaching the brain and if this happens it will stop the cascade of damaging events (loss of myelin and nerve damage) from occuring.


Current effective treatments work by stopping the white blood cells entering the brain. In my current opinion these will not work to stop the underlying cause of progressive MS. We know this because of the many failures of trying to treat progressive MS.

Some Doctors however continue to believe that progessive MS is a problem of white blood cells and carry on regardless. Indeed some Progressive MSers will probably respond to these drugs, particularly those with gadolinium enhancing lesions. However, we need a new approach to treat progressive MS, because the main problem appears to not be with the white blood cells (although I think that these need to be dealt with also) but appears to be a problem with the nerves, that has been triggered by the damage caused by white blood cells.

Nerves transmit nerve impulses (see videos in British or American English to Explain) from one nerve to another across a synapse(see video). Transmission of the nerve impulse uses energy to transmit the impulse, which results from movement of ions largely sodium (Na) and potassium. (K) Sodium enters the cell by sodium channels (pores that allow sodium to flow through them) in the nerve. Once the impulse passes the nerve resets itself so that it can transmit the next signal. Within the nerve there is a exchanger (imagine a revolving door). The system pumps calcium (Ca) out of the cell in exchange for sodium. This all helps maintains the health of the cell and te balance of sodium within the cell The myelin sheath made by oligodendrocytes allows the nerve impulse to travel faster. This is because the nerve impulse jumps acrossto the gaps (Nodes of Ranvier) between individual myelin sheaths. (There are lots of videos/tutorials on youtube those by khanacademy.org are informative. (If you watch these- a schwannn celll myelinates peripheral nerves and those in the brain are myelinated by oligodendrocytes but otherwise the message applies to the brain)

In progressive MS (both primary and secondary), loss of myelin is a feature of the disease. Initially this damage may be repaired. But as we get older our repair mechanisms become less effective. Furthermore the disease may kill too many of the repairing-cells and the scarring from the damage may stop repair. This makes the nerves vulnerable to further damage.

Why one person gets relapsing MS verses Progressive MS is not clear at the moment. It may depend on age, sex, where the attack occurs within the nervous system and how well an individual can repair and deal with the consequences of damage. As the compensation mechanisms become exhausted or are not there in the first place (from PP MSers) damage from progressive MS takes over from damage caused during relapsing MS.

Once nerves are demyelinated, to keep the nerve impulses moving the nerve must use alot more energy. Low level inflammation which is present in all MS types such as that produced by microglial cells produces mediators such as nitric oxide that stop cells from making enough energy. This blocks the action of the energy-dependent sodium-potassium pump. This results in excess sodium entering the nerve, via the sodium channels. This excess sodium in the cell can cause the sodium-calcium exchanger to go into reverse and it pushes sodium out of the cell whilst pulling calcium into the cell. This can be bad news as too much calcium in cells triggers them to commit suicide. Therefore simple electrical activity of the nerves can be a problem for demyelinated nerves. As nerve circuits are damaged and lost the brain compensates by using different circuits to perform the task. As nerves are lost it puts more of a strain on the remaining nerves, leading to further nerve loss and the accumulation of progressive disability.

With this scenario progressive disease can occur in the absence of white blood cells and explains why current MS drugs are not useful for progressive MSers. Importantly it gives us clues on how to treat MS. One obvious route is to repair the myelin, but others such as blocking the accumulation of toxic concentrations of ions in the nerve are even more feasible, because these types of drugs are already availble to treat other diseases such as epilepsy. The guess work is which ones or combination are more likely to succeed.

This however is just theory and will become more concrete when treatments based on this theory are shown to be active. Until then we keep an open mind to alterative ideas.

This is currently being investigated in MSers to provide the evidence base that allows change to occur…and more many studies on this aspect are being planned but as you know this takes time.

Too technical? See Part I and the rest of the series.

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MouseDoctor

9 comments

  • Re: "…and more many studies on this aspect are being planned but as you know this takes time."

    Yes, I wish I had time but, alas, I do not as MS progression waits for no man.

    By reading your piece I am alarmed at how much about what's happening in MS progression you do know, yet shocked that there is, currently, zero treatments and we're years and years away from getting anything approved.

    I have a sneaking suspicion that the main plan in MS research is to focus on preventing future cases of MS (good luck with that one!), while correcting lost function is in no way a priority right now.

    Decade after decade neurologists have witnessed young people suffer and perish as a result of this disease. The concept in improving the lives of has become a de facto futile acceptance.

    We want timelines. We want to know when there can be something tangible for progressive MS’ers. I'm sick of hearing about pipedreams. Pipedreams won’t fix my foggy thinking. Pipedreams won't fix my walking. Pipedreams won't improve my hand function so that I can tuck my kids in at night.

    Do me a favour and tell me some good news or at least be honest about how hopeless a cause progressive MS is.

  • re – 'However, we need a new approach to treat progressive MS, because the main problem appears to not be with the white blood cells (although I think that these need to be dealt with also) but appears to be a problem with the nerves, that has been triggered by the damage caused by white blood cells.'

    I'm really interested in this part of the disease. You must have some ideas concerning what may be going on with these nerves. Any chance you can elucidate? Is the myelin simply self-destructing? If so what is causing this to happen?

  • I am "shocked that there is, currently, zero treatments and we're years and years away from getting anything approved. I have a sneaking suspicion that the main plan in MS research is to focus on preventing future cases of MS".

    I don't agree with you! Preventing MS is a plan, but it is a future plan. This will need your help to get it off the ground. In contrast treating progressive MS is a real, immediate aim for many MS researchers and also the MS Charities.

    We (in team G) have already been working towards this for many years. We (MS researchers) will have a rocky road whilst we work out how best to show a useful effect. This took some time in relapsing MS, but now there are drugs and we know how to test them.

    As for progressive MS, the initial trials have already begun. Some will fail because the drugs are no good or the trial design is not correct to show an effect. We learn for these and try again. The current cannabis trial is over 3 years (and if positive would deliver a drug within about 1.5-2 years) but we have a new one about to start that aims to give an answer within about 12 months.

    There are many things planned in the pipeline, but to be real I cannot put a time line on this as it is outside my control.

  • I do not think myelin is self-destructing something is causing this.
    This myelin destruction is either via a response of the white blood cells or perhaps
    due to infection.

  • Re – "This myelin destruction is either via a response of the white blood cells or perhaps
    due to infection."

    So that would mean that white blood cells are in fact still penetrating the BBB in progressive forms of MS, yes?

    If it's an infection then does that mean an infection of the brain, or is it an infection of the blood, or is an infection in the nerves.

    I have a feeling what I'm asking is muddled and confusing, but I'm struggling to simplify and hope you get the gist.

    I really wish you luck in finding effective treatments for progressive MS. I don't think I've ever willed the success of something more than this. I suppose my ultimate hope is that myelin regeneration becomes an actuality and those limbs, somehow and in some way, return back to life.

    If the latter ever happens then I, and millions of others too, will campaign for you to get the Nobel Prize in Medicine. In fact, whoever gets there first will get my endorsement. That's a promise!

  • Dunno about giving Team G the Nobel Prize in Medicine seeing the drugs they're trialling already exist, they're just throwing mud against the wall to see what, if anything, sticks for MS treatment.

    But seriously, I too hope you're super successful in this new aim to treat progressive MS.

  • Re: "Dunno about giving Team G the Nobel Prize in Medicine seeing the drugs they're trialling already exist, they're just throwing mud against the wall to see what, if anything, sticks for MS treatment."

    Please see the following article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1150960/

    Progressive MS is an orphan disease; I bet there are several compounds sitting on the shelf that work. We need to find them. By going this route you cut the development time in half or may be more.

  • There are white blood cells in brains of progressive MSers but at a different level to that found in relapsing MSers.

    In the context that I was talking about infection I was thinking it is of oligodendrocytes, the cells that make the myelin in the brain. The reason being is that if you look in MS brains things occur in oligodendrocytes before white blood cells appear. Dr Love will tell you more about this when she does a series on pathology.

  • Re: "…if you look in MS brains things occur in oligodendrocytes before white blood cells appear."

    Whoa, this is a big deal and deserves greater exposition. When can we expect a report from Dr. Love on this?

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