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How does Multiple Sclerosis do its damage?

 

In order to understand what is happening in multiple sclerosis it is necessary to understand a little about the brain and spinal cord - collectively called the central nervous system or CNS for short.

"Ok then, tell me about the CNS"

The CNS is full of nerve cells called neurons. These are the brain cells of popular usage. Here is a simplified diagram of a neuron:

There are different types of neuron in different areas of the CNS. Those in the white matter tissue are are the ones most liable to be attacked in multiple sclerosis. This type of neuron is a long thin cell which has a bulbous head (the soma) containing the cell nucleus and an elongated strand called an axon. The soma has thin, branched tendrils called dendrites growing out of it.

The axon of one neuron joins to the dendrites of other neurons via a special connection called a synapse. Signals or nerve impulses travel down the axon where they are transmitted to other neurons via chemical signals (neurotransmitters) moving across the synapse. The axon itself, is coated with a sheath of insulating fatty protein called myelin which aids the transmission of nerve impulses. A good analogy of the myelin's relation to the axon is the plastic or rubber insulation around electric wires.

Oligodendrocytes are the axon's maintenance cells. Their job is to create and repair the myelin sheath and to feed essential factors to the axon. Each oligodendrocye maintains several axons and each axon is maintained by several oligodendrocyes.

Oligodendrocyes belong to a larger grouping of maintenance cells called glial cells. Their importance has recently become better understood and, as more and more is discovered about MS, the more central oligodendrocytes, or more accurately their death, has become. In some ways, it is fair to say that multiple sclerosis is a disease of oligodendrocytes.

"So what does MS do to the CNS?"

During periods of multiple sclerosis activity, white blood cells (leukocytes) are drawn to regions of the white matter. These initiate and take part in what is known as the inflammatory response. The resulting inflammation is similar to what happens in your skin when you get a pimple.

During the inflammation, the myelin gets stripped from the axons in a process known as demyelination. The effect of this bears many parallels to the rubber insulation on wire perishing - some or all of the electricity in the wire will short out and the efficient conductivity of the wire will be reduced. When the myelin sheath is damaged, the transmission of nerve impulses is slowed, stopped or can jump across into other demyelinated axons.

Additionally, the inflammation can also damage the underlying axonal membrane. This membrane is a sophisticated structure that enables the nerve transmission (the action potential) to travel along the nerve.

It seems that the inflammation also kills the mainenance glial cells, in particular it seems to kill the myelin-producing oligodendrocytes, which are lost in great numbers. Almost no oligodendrocytes persist in the middle of chronic MS lesions.

At least, this has been the prevailing theory for the past few years. Now, however, several pieces of experimental work have produced results which challenge this model. Inflammation and oligodendrocyte loss are both found together in multiple sclerosis but which comes first? Does inflammation cause oligodendrocyte death, does oligodendrocyte death cause inflammation or are they both caused by a third process, perhaps a virus?

Recent research has looked at the brains of people who have died in the very early stages of MS lesion development and found that oligodendrocyte death actually precedes inflammation [Prineas et al, 2004]. It must be emphasised that these are the results of a very small study which have not yet been reproduced. Although few would deny that the inflammation contributes to MS damage, this work has the potential to turn the world of MS research upside-down. It suggests that looking for an autoimmune cause for MS may be misguided. It also challenges the current anti-inflammatory focus of most MS therapies. Are we, by analogy, treating a broken pipe by sticking a bucket under it rather than fixing the leak? That's not to say that these therapies don't produce results, just that tackling inflammation may not be the optimal stategy. For people with MS, this is a space to watch eagery.

As the disease progresses, axons are also destroyed though not necessarily by the inflammatory response. During the secondary progressive phase of the disease, inflammation becomes less and less common but still the axons continue to die. This degeneration of axons is known as Wallerian Degeneration.

One theory is that the axons are dying because there are no oligodendrocytes to feed them the essential factors that they need. Perhaps the most important of these is called, Insulin-like Growth Factor-1 (IGF-1) - so-called because it resembles the sugar-regulating hormone, insulin. Experiments on rats indicate that axons deprived of IGF-1 will eventually die [Gutierrez-Ospina et al, 2002 and Russell et al, 1999].

Another factor, Brain Derived Neutrophic Factor (BDNF), has also been implicated in Wallerian degeneration. The absence of sufficient BDNF has also been linked to a variety of other degenerative diseases of the central nervous system, including Parkinson's disease and motor neuron disease. Interestingly, BDNF is naturally released by the body during vigorous exercise [Gold et al, 2003].

Recent work using newer MRI techniques has shown Wallerian Degeneration in the white matter that looks normal using the older technologies [Ciccarelli et al]. Quite what this discovery means is not yet clear but it may be a further example of the disease process enduring without inflammation.

All these processes, inflamation, demyelination, oligodendrocyte death, membrane damage and axonal death contribute to the symptoms of MS.

"Do nerves get better after demyelination?"

After axons have been demyelinated, several things can happen.

"So what causes Multiple Sclerosis?"

This is the 64 thousand dollar question of MS. There are several theories as to the cause of MS but the overall process is so poorly understood that none has yet delivered the coup-de-grace. Each new discovery seems to beg more questions than it answers. The research process advances so fast that each new iteration of this section is out of date even as I post it onto my web server.

The cause of MS is a complex subject and, later on, I will devote several sections to what I believe are valid theories. For the time being, I will simply list some of the contenders.

Autoimmunity

That MS is an autoimmune disease is the leading theory in the scientifico-medical world. "Auto" is derived from the Greek for self and autoimmunity means immune to self. When applied to MS, it means that the body's natural defences are actually attacking its own myelin. One particular theory, called molecular or epitopic mimicy, attempts to explain how the immune system might do this. Another possible explanation is that the myelin is lost in collateral damage as the immune system attacks something else.

Either way, the immune system is an incredibly complicated "organ" with many strands to its bow and is very poorly understood. Much of what is known derives from recent work done in the last 10 years or so. A friend of mine who is an immunologist working in the field said, "We are all very proud of ourselves because we have mapped out a metaphorical area the size of my back garden but that has only made us realise that the whole metaphorical immune system is the size of London".

There are a lot of very convincing reasons to believe that the immune system plays a role in the destruction of myelin.

Pathogen mediated

This is the other leading scientific theory of the mechanism for how multiple sclerosis operates. "Pathogen" is a generic word for the nasty little bacteria, virii, fungi and other microbes that cause so many other diseases. Some tantalising work has found statistically significant links to a number of virii and bacteria including Epstein-Barr virus, Human Herpes Virus 6, Clamydia Pneumonia and other pathogens.

However, there have been many false dawns in multiple sclerosis research and we must wait and see whether these (or any other pathogens) are primary instigators of the disease process or whether they are merely opportunist invaders of an already damaged CNS.

Genetic components

There is overwhelming evidence that there is a genetic component in MS and family studies show that first degree relatives of PwMS have twenty to forty times the probability of developing the disease than the observed incidence for the locality in which they grow up. However the link is rather weak compared to other inherited diseases and it is very likely that several genes are operating in tandem.

It is probable that there are more than just genes at work. Several studies have shown that, when one identical twin has MS, the other twin has only a 30% chance of developing the disease. This means that even if you inherit a susceptibility to contract MS, there is less than a third chance that you will contract the actual disease.

Despite extensive work in mapping the human genome, researchers have so far been unable to pinpoint any specific genes. However, target sections of the MS genome have been strongly implicated and we can look forward to breakthroughs in this area very soon.

In many ways, genetics, virology, bacteriology and immunology are intimately bound up with each other and it may be that a combination of all these disciplines will provide the eventual answer.

Damage to the Blood-Brain-Barrier

The Blood-Brain-Barrier (BBB) is a protective barrier formed by the cells lining the blood vessels (the endothelial cells). It allows for the exchange of oxygen, essential nutrients, carbon dioxide and other waste materials between the blood and the CNS while preventing the majority of pathogens from crossing into the brain. Researchers have shown that, under the right circumstances, everybody's immune systems will attack myelin so why doesn't everyone have MS?

Immune system cells are entering the CNS of people with MS but they are not going into the brains of others. How and why do they get there? Does this imply that the BBB has somehow become damaged or is this a normal response to something going wrong elsewhere in the body? If the damaged BBB theory is true, how does it get damaged? Is it possible that a pathogen is damaging or has damaged the BBB? Some point at trauma as a potential candidate - that the PwMS has had a fall or other mechanical injury that has damaged the BBB prior to contracting the disease.

Preventing these immune system cells from entering the central nervous system is the aim of an experimental therapy for MS, called Natalizumab (brand name Antegren).

Biochemical events in utero

It has been proposed that interactions with the foetal genome in the womb during very early life or at a later stage still prior to birth affect the development of the immune system. Recent evidence shows that some of the mother's genome can pass through into the foetus and become part of the individual. This work is very preliminary but tantalising nevertheless.

Diet and vitamin deficiencies

A number of people believe that MS is a side effect of an inappropriate diet. Various diets including the Swank diet, the Paleolithic diet, Bachmann B12 supplements, the Cari Loder treatment and the Atkins diet amongst others have been proposed as potential treatments for MS and some people claim considerable success. Most of these success stories are anecdotal and some well conducted affirmative studies are needed in this area.

Allergic reaction and other alternatives

There is no shortage of candidates for a cause of MS. Some say it is an allergic reaction and advocate histamines as a treatment - this is the idea behind Procarin. The problem is that MS is, by its very nature, unpredictable and large studies are needed to determine the veracity of many of these claims. Such studies are expensive and funding is an acutely limited resource. Some people suggest that MS is not a single disease or that, if it is a single disease, that it has multiple causes. Some of the alternative theories are very bizarre ranging from exposure to cattle and geomagnetic fields to the angle at which we sleep.

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