Sunday, 19 April 2015

Education: Pathways to Progressive MS

This is a repost so a new post or the new readers and a revision for the "old-timers of the blog"

You 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 same delivered 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 occurring.


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 available to treat other diseases such as epilepsy. The guess work is which ones or combination are more likely to succeed.

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? 


Whilst trying to explain how white blood cells enter the brain, using an analogy with a car park , 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?"

In this post 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 inportant 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 (nerve) network.

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 previous post). The nervs impulse (tube trains) transmits its information from the head of the nerve called the soma, 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 wraps myelin 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 power.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.

We don’t think there is necessarily any difference in this whether you have primary progressive or relapsing-remitting MS, although 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.
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?”

Response to Immune Therapy. For many, many years the problem of MS whether it was primary, secondary progressive or relapsing-remitting disease was thought to be a problem of the immune system. Therefore, dealing with the white blood cell problem would sort out MS. Unfortunately this was actually part of the story and bad news for progressive MSers.

The most current drugs that are effective at stopping relapsing MS, aim at stopping white blood cells (green cars) getting into the brain (carpark). Tysabri works by stopping white blood cells crossing the blood vessels of the brains (Stops the cars leaving the road and entering the carpark by building a wall at the carpark entrance). Gilenya stops white cells from entering the blood and Alemtuzumab kills cells (Gren cars) so it clears the blood (roads) of cells so it’s like having a roadblock.



However, doing the same in progressive MS does not work, because the main problem is not the cars in the carpark, but the hole in the car park.


However, once the hole is made, even if you fill in the hole and repair the damage, these treatments may not work (I say may not work rather than will not work as the Jury Tysabri is still out, but in my humble opinion the writing is on the wall, I am afraid to say).

You have sugested that MS drugs don't work, because they don't get into the brain. This a good point but the reason for this failure is that the main problem with progressive MS is not the immune system (green cars), it is that they have caused a problem with the underground network (nervous system). Thus the cars can start a blockage on the Underground line.

This is a current theory, another one is that there could be an inherent problem with the tunnels (that collapse) and the cars in the carpark just influence the collapse. Getting drugs to control white cell function in the brain will be part of the solution. The only way to really decipher how this happens is to target this pathway with drugs that should work and if they do, you have a good idea that you are on the right track...pun not intended.

Therefore, we need a different treatment strategy for progressive MSers. 

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.
We have now built up the picture to understand the probable causes of Progression. 

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 (part III) 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.

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.
Trials aimed at blocking these pathways have begun.. 

Diagnosis Children with MS

Heussinger N, Kontopantelis E, Gburek-Augustat J, Jenke A, Vollrath G, Korinthenberg R, Hofstetter P, Meyer S, Brecht I, Kornek B, Herkenrath P, Schimmel M, Wenner K, Häusler M, Lutz S, Karenfort M, Blaschek A, Smitka M, Karch S, Piepkorn M, Rostasy K, Lücke T, Weber P, Trollmann R, Klepper J, Häußler M, Hofmann R, Weissert R, Merkenschlager A, Buttmann M; GRACE-MS (German-speaking Research Alliance for ChildrEn with MS).Oligoclonal bands predict multiple sclerosis in children with optic neuritis. Ann Neurol. 2015. doi: 10.1002/ana.24409. [Epub ahead of print]

We retrospectively evaluated predictors of conversion to multiple sclerosis (MS) in 357 children with isolated optic neuritis (ON) as a first demyelinating event who had a median follow-up of 4.0 years. Analsysis revealed abnormal cranial magnet resonance imaging (cMRI; HR 5.94; 95% I: 3.39-10.39; p<0.001), presence of cerebrospinal fluid oligoclonal IgG bands (OCB; HR 3.69; 95% CI: 2.32-5.86; p<0.001) and age (HR 1.08 per year of age; 95% CI: 1.02-1.13; p=0.003) as independent predictors of conversion while sex had no influence. Combined cMRI and OCB positivity indicated a 26.84-fold higher HR for developing MS compared to double negativity (95% CI: 12.26-58.74; p<0.001). Accordingly, cerebrospinal fluid analysis may supplement cMRI to determine the risk of MS in children with isolated ON.

This study says if you have MRI and oligoclonal band data it helps working out the risk of a child developing MS.