We will explore how Progressive MS develops and indicate how it may be treated, compared with Relapsing MS.
This starts with roads (blood vessels) along which cars (white blood cells) travel, with the aim of destroying something.
(For people not familiar with British Roads the M above refers to motorway numbers like the I5 in American. These are roads around London. It is not important to know this to follow the story)
These cars travel along roads and once they get in the brain represented by a car park
they cause havoc. These cars (white blood cells) leave the road (blood) and can enter the capark (brain) via an open barrier (blood brain barrier)
. Once inside they can damage the myelin-forming cells.
But before we can start to think about the carpark, we need to understand the underground
To talk about progressive MS, we first need to get you thinking about- how things in the body are being affected so that we can build a final picture and then talk about solutions.
The Nerve Network is made up of clusters of nerves that connect the brain with every bit of the body. Just imagine that this is an underground network
with many tube lines each with a destination to a different part of the body.
The information is sent from the tissues such as the bladder, muscles etc. to the brain via the spinal cord and then the brain transmits information back to the tissues telling them what to do.. So sensors in the skin may detect when a finger goes near a flame. The sensors send information to the the brain "Ouch thats hot" the brain sends the command "move" back to the muscles in the hand and arm. Therefore you don't burn yourself.
The information is sent by electrical energy along the nerves. This can be viewed as Tube Trains (nerve impulses
) travelling along tube lines (axons
of the nerve), surrounded by a tunnel (myelin of the nerve).
Whilst many of you MSers know this already, in case you are not familiar (see video links in previouspost
). The nervs impulse (tube trains) transmits its information from the head of the nerve
, down the axon (nerve body-tubes lines) of the nerve to the nerve terminals
or nerve feet. The nerve impulse must then must jump from the feet to the head of the next nerve to keep the impulse going. This space between the nerves is called a synapse
(interchange between differnt lines). This occurs as nerves do not stretch from one tissue to another. It is a relay race using many different nerves (underground network).
The impulse travels down the axon like a wave by moving chemicals with an electrical charge (passengers), called ions
, out of the nerve whilst letting others into the nerve. Therefore in this scenario passengers (see little people on the platform below) need to get on and off at the stations for the trains to travel and for the underground network to function. To speed this process of moving this impulse down the nerve oligodendrocyte
round the axon (tube tunnel). This is a bit like the plastic insulation round an electrical wire. When the wire gets stripped of this insulation as occurs in MS, short circuits occur and the wire can sometimes burn out. There are gaps between individual myelin wraps called Nodes of Ranvier
(Tube Stations) and allow the nerve impulse to jump from one node to the next and allow the nerve impulse to travel quickly. This process is known as saltatory conduction
. When the myelin is removed the nerve impulse travels very slowly.
Now you have got idea of the nerve network (The underground), we can ask what can ask what happens when a tube train breaks-down?Imagine that in health that the nerve impulse (tube train) only has to travel between point A (Bond Street) and Point B (Tottenham Court Road) on the central line for things to work.
Now because of MS, the central tube line is blocked between Oxford Circus and Tottenham Court Road. Therefore to get from Bond Street, you need to take the Jubilee Line southbound, then change onto the Northern Line to return Tottenham Court Road. This is like the internet (the information superhighway) and the brain, which finds other routes to do the same thing when one information pathway gets blocked. The signal gets to its destination but takes a little longer and uses a bit more of the Tube Networks
However, to speed up the new route we could add an interchange (synapse) with the circle & district lines. This is called plasticity and occurs when blockade of pathways in the nervous system occurs.
We know this occurs because we can see this occurring using a technique called functional magnetic resonance imaging (fMRI
). This works because when areas of the brain work, they use energy that consumes oxygen. Using an oxygen dye that can be seen by the brain scanner, we can see which area of the brain is activated when we are responding to something…..women’s brains and maps, men’s brains and shoes….…Nothing…… but the other way round….. a firework display (You get the drift, despite a sex stereotype for which I apologise). So for any particular task we can see which bit of the brain controls it. After damage to nerve pathway we can see different bits of the brain light up showing us that plasticity has occurred.
A bit of the visual cortex (back bit of the brain) lights up when visual stimulation is given.
As you have seen some of this before in the Carpark
. We don’t think there is necessarily any difference in this whether you have primary progressive or relapsing-remitting MS, althoiugh in progressive MS the the following aspect is less pronounced.
In health you have white blood cells (green cars) circulating round the blood (road), looking for an infection to kill. These are normally kept out of brain (carpark) by the blood brain barrier (ticket barrier). In multiple sclerosis, the disease triggers the barrier to open allowing white blood cells to enter the brain.
As you suggest, once inside the brain, it's demolition/destruction derby. In MS the white blood cells attack your nerve cells (the myelin-forming cells to be precise) as if they were an infection, and cause damage. This is the start of MS being noticed.
You're half way there. More Next Time, When we look at how we respond to the attack
As part of the normal process of inflammation
the body clears up the debris/damage caused during the fight to kill the infection by the white blood cells. This happens in MS after the demolition derby that causes the MS attack. People with relapsing-remitting MS are good at dealing with the damage (tow trucks) caused by the attack and have modern tow trucks to clear the debris and repair the damage.
However, as you get older your tow trucks become more vintage. These work less efficiently than modern tow trucks and the damage in the car park may not be dealt with as quickly as it once was. People that are prone to get progressive MS are probably more likely to have vintage tow trucks that do not deal with the attack as well as one would like.
As the weight of all the car debris accumulates in the carpark, it causes the foundation to collapse and a hole develops in the carpark, this is the beginning of progressive MS. It can start after relapsing MS, as secondary progressive MS, but may develop shortly after the onset with primary progressive MS.
Why doesn’t progressive MS respond to the MS drugs that hit Relapsing MS?”
We have now built up the picture to understand the probable causes of Progression. I say probable as this is still theory, I'm afraid to say.
At each tube station (Node of Ranvier), people (ions) will enter and leave the train (nerve impulse). In health this is a balance between people leaving the train (red characters) and people entering the train (black characters) and the trains do not stay in stations too long. Therefore, trains do not get over crowded.
However once a trainline gets blocked because the cars fall on a train and break the tunnel (demyelination
), the nerve impulse is slowed or stopped.
Synaptic plasticity will begin, so you use different tube lines to get where you are going, but as the train stay in stations longer, more people enter the train. Overcrowding starts
Too many people enter the train and someone faints. The train overheats and breaks down. This blocks another piece of the tube networks. Progressive MS has begun. This no longer concerns the cars (white blood cells) on the road above.
Therefore Progression needs a different treatment
We have now built up the picture to understand the probable causes of progression we can see how it progresses and what we need for treatment.
Nerves are stopping working as trains are breaking down, as they overheat
As more of the lines are block the more stain is put on the other lines to cope with the passenger load as they try use other lines to travel and so more and more trains break down. The tube network is slowly blocked.
The solution is not to stop cars entering roads, but to stop people entering underground stations therefore the treatment for relapsing-remitting and progressive MS must be dramatically different. Likewise we want to repair the broken tunnels (remyelinate), which will allow the trains to operate again.
I think you can see that there can be different processes that drive progression and relapses and they may need different treatments. The first line treatments appear to have little dramatic activity to stop the progressive process but the question is whether the immune processes trigger the neurodegenerative process or whether they are independent?
As to the second line treatments there is likewise no proof they inhibit the progressive process(es). Some companies think they will, for some I have doubts and predict they will not work. It is not appropriate to say which ones I think will not work because some are still in trial or recruiting and until it is shown they do not work, they could work.
In animal models of autoimmunity one (relapsing disease) triggers the other (progressive disease). In MS we cannot be sure until we see the long-term data of potent (I mean potent) DMT given at disease onset, such as CIS. At present Neuros in UK have their hands tied when it comes to this.