What is MS?

Multiple Sclerosis (MS) is an inflammatory disease of the Central Nervous System (CNS) - the brain and spinal cord. Predominantly, it is a disease of the "white matter" tissue. The white matter is made up of nerve fibers that are responsible for transmitting communication signals to the rest of the body.  In people affected by MS, patches of damage called lesions appear in seemingly random areas of the brain and spinal cord. At the site of a lesion, a nerve insulating material, called myelin, is lost. Depending on which areas of the CNS are affected and how badly they are damaged, the type and severity of symptoms can vary greatly.

 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. The CNS is full of nerve cells called neurons.  There are different types of neurons in different areas of the CNS. Those in the white matter tissue are the ones most likely to be attacked by MS 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 MS is a disease of oligodendrocytes.

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.

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.

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After axons have been demyelinated, several things can happen.

• The inflammation dies back. Neurons which have not been damaged by the relapse can resume their proper function and some recovery (remission) is usual, at least in the early stages of the relapsing-remitting form of the disease.

• Demyelinated axons can exhibit remarkable abilities to function despite losing their myelin. Recent work has shown that they produce greater numbers of sodium channels. These are special chemical gates which are integral in sending nerve transmissions (the action potentials) down the neuron [Moll C et al, 1991]. This increased number of sodium channels contributes to remission in MS.

• The central nervous system is a very plastic organ and new neuronal pathways and connections can be created to get around the damaged neurons. This is analagous to a motorist taking a minor road to avoid a traffic accident on their intended route. Although it is clear that this mechanism contributes to remission, it is far from clear what the exact details are and much work remains to be done in this area.
   
• The myelin maintenance cells in the CNS, the oligodendrocytes, can sponsor remyelination - a process whereby the myelin sheath around the axon is repaired. Despite the fact that evoked potential tests show that remyelinated axons don't function quite as well as those which were never damaged in the first place, to people with MS, this is sometimes not noticeable. Although remyelination usually only occurs at the edges of lesions, it still seems to be a contributory factor in remission.

• Remyelination may not take place or only happen partially, at least for a long time, due to oligodendrocytes not being around to promote it. When this happens the nerve will continue to function in an abnormal way as described above, but the axon remains undamaged. Sometimes after a long period of time, sometimes years, an axon will spontaneously become remyelinated and regain much of the function that had been presumed to be lost for good.

• The lost myelin can be replaced with scar tissue much like when you cut your hand a scar forms to join the separated areas of skin. This scarification is how Multiple Sclerosis got its name: Multiple – many, and Sclerosis - scar forming. Scar tissue can block the formation of new myelin and once axons have become scarified they do not fully regain their former function.

• The underlying axon can become withered and function lost entirely. Needless to say a withered axon will never function at all again. Continuing our electrical wire analogy, this is rather like snipping the cable with wire cutters.

How do you get MS?

There are several theories as to the cause of MS, but the overall process is so poorly understood that no one really knows. Each new discovery seems to beg more questions than it answers.

What we do know is that MS is an autoimmune disease is the "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 defenses 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 there are a lot of very convincing reasons to believe that the immune system plays a role in the destruction of myelin.

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

However, there have been many false dawns in MS 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.

There is overwhelming evidence that there is a genetic component in MS, and family studies show that first degree relatives of people with MS have 20 to 40 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.

What’s with 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 person with MS 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).

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To Sum it Up:

No two people get MS in exactly the same way and the expression of each individual's disease is as unique as their fingerprints. However, the different courses of the disease, both within an individual and within the whole population, principally differ in their timing, location and severity. Underneath similar processes (including demyelination and sometimes other forms of nerve degeneration) are going on.

Although recent research indicates that the biochemical make-up of lesions may vary between different forms of the disease, this is not the reason why people with MS  have such widely differing symptoms - it's because nerve damage to one site usually causes completely different symptoms than damage to another.

In general, people with MS can experience partial or complete loss of any function that is controlled by, or passes through, the brain or spinal cord.

MS can be and often is a very serious disease but almost nobody loses function in all possible areas and some people are affected much worse than others. People with MS can experience any of the following problems either fully or partially - numbness, tingling, pins and needles, muscle weakness, muscle spasms, spasticity, cramps, pain, blindness, blurred or double vision, incontinence, urinary urgency or hesitancy, constipation, slurred speech, loss of sexual function, loss of balance, nausea, disabling fatigue, clinical depression, short term memory problems, other forms of cognitive dysfunction, inability to swallow, inability to control breathing ... you name it.

But MS is usually a slowly progressing disease, and few people, if any, experience all the possible symptoms. Three quarters of people with MS don't need to use a wheelchair, though many people will require a cane after a number of years of disease activity. Other people will have only very mild and occasional symptoms. Still others have been found to have had MS as a result of an autopsy even though they never presented with any clinical symptoms during their lives. A minority of people with MS die as an indirect result of the disease in its later stages. The majority of people with MS will fall somewhere between these extremes. Adjustments have to be made, but most people with MS can live fulfilled and active lives.

There are four main varieties of Multiple Sclerosis:

1. Relapsing/Remitting (RRMS):

This is characterized by relapses (also known as exacerbations) - new symptoms can appear and old ones resurface or worsen. The relapses are followed by periods of remission, during which time the person fully or partially recovers from the deficits acquired during the relapse. Relapses can last for days, weeks or months and recovery can be slow and gradual or almost instantaneous. The vast majority of people presenting with Multiple Sclerosis are first diagnosed with relapsing/remitting. This is typically when they are in their twenties or thirties, though diagnoses much earlier or later are known. Around twice as many women as men present with this variety.

2. Secondary Progressive (SPMS):

After a varying amount of time, many people who have had RRMS will pass into a secondary progressive phase of the disease. This is characterized by a gradual worsening of the disease between relapses. In the early phases of Secondary Progressive, the person may still experience a few relapses but after a while these merge into a general progression. People with secondary progressive may experience good and bad days or weeks, but, apart from some remission following relapsing episodes, no real recovery. After 10 years, 50% of people with relapsing/remitting MS will have developed secondary progressive [Weinshenker et al, 1989, Runmarker and Andersen, 1993, Minderhoud et al, 1988]. By 25 to 30 years, that figure will have risen to 90% [Ref].

3. Progressive Relapsing Multiple Sclerosis (PRMS):

This form of MS follows a progressive course from onset, punctuated by relapses. There is significant recovery immediately following a relapse but between relapses there is a gradual worsening of symptoms.

4. Primary Progressive (PPMS):

This type of MS is characterized by a gradual progression of the disease from its onset with no remissions at all. There may be periods of a leveling off of disease activity and, as with secondary progressive, there may be good and bad days or weeks. PPMS differs from Relapsing/Remitting and Secondary Progressive in that onset is typically in the late thirties or early forties, men are as likely women to develop it and initial disease activity is in the spinal cord and not in the brain. Primary Progressive MS often migrates into the brain, but is less likely to damage brain areas than relapsing/remitting or secondary progressive - for example, people with Primary Progressive are less likely to develop cognitive problems.

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Diagnosing MS:

Diagnosing multiple sclerosis is anything but easy. Usually, the first thing anyone does when they notice strange neurological symptoms is to go to see their family doctor. "It's nothing to worry about" - "It's a pinched nerve" - "It's the side effect of a virus" - "It's all in your head" - "It's a temporary side effect of a migraine" - "It's Conversion Disorder". These and many other labels are used to dismiss what are very real symptoms.

Provided that they aren't dismissive of the patient, I don't blame the Primary Care Physicians - MS is a very varied disease with a score of different manifestations. It is common medical practice to assume the most likely outcome rather than the more malign possibilities. Additionally, MS has a score of differential diagnoses (conditions that present with one of more of the same symptoms as MS). PCPs aren't neurologists and they can't be expected to perform neurological examinations with the same level of expertise as neurologists can, nor are they as skilled at interpreting them. This is understandable - a General Practitioner will usually have between zero and six patients with MS on their books and, even then, rely heavily on the patient's neurologist for diagnosis and treatment.

We know that something is wrong - often we fear a plethora of malignant outcomes, including MS, which we generally do not understand at this point in time. We certainly don't need to be told that we are making it all up

Sooner or later we wind up with a referral to a neurologist. Now come a battery of tests designed to eliminate the various differential diagnoses, some of which are more urgent or more serious than MS, others are more benign or self-limiting.

The first thing a neurologist will do is go through the patient's medical history and that of their family. It may well be that the patient has had previous symptoms consistent with multiple sclerosis or have relatives with the disease. This makes MS more likely. They will then ask the patient to describe their current symptoms. The patient's description of his/her symptoms is an important indicator.

The neurologist will then go through a thorough neurological examination, testing reflexes with hammers, sticking you with pins, tickling the bottom of your feet, examining you with opthalmoscopes and testing your senses with tuning forks. You are made to stand still with your eyes closed, walk heel-to-toe and your muscle strength is tested. The neurologist will be looking for specific deficits and testing for certain signs.

There are many different neurological tests and the ones your neurologist chooses to perform will depend, in part, on the symptoms that you present with. Here are some of the more common ones.

Romberg's sign: This is a test for ataxia (incoordination or clumsiness of movement that is not the result of muscular weakness) and involves standing with your feet together with your eyes closed. Ataxics have great problems standing still under these conditions.

Gait and coordination: The neurologist evaluates ataxia in various parts of the body by observing the patient walking normally, walking heel-to-toe and finger-to-nose tests. The neurologist will also be looking for intention tremor (shaking when performing small motor movements) as well as ataxia in this last test.

Heel/Shin test: This is a test for ataxia and cerebellar dysfunction. You have to bring the ball of your heel onto the knee of your other leg and then move it down the shin.

L'Hermittes sign: This is a test for lesions on the spinal cord in the neck. The neurologist will ask you to lower your head towards your chest. A positive L'Hermittes will generate buzzing, tingling or electrical shock sensations in one or more parts of the body.

Optic Neuritis: This is a condition of the eye caused by inflammation and demyelination of the Optic Nerve and is perhaps the most commonly presenting symptom in MS. The tests involve the ubiquitous reading of letters from a board and a test for colour vision using an "Ishihara" colour chart. An examination with an opthalmoscope will reveal pallor of the optic nerve in old optic neurites.

Hearing Loss: This is done by lightly clicking the fingers next to each ear and asking the patient which ear the click was done next to.

Muscle Strength: This involves resisting the neurologist with various muscle groups. Differences in strength between left and right sides are easier to evaluate than symmetrical loss unless the weakness is severe.

Reflexes: This is done with both ends of the hammer. The reflexes can be normal, brisk, i.e. too easily evoked, or non-existent.

Babinski's sign: A test for signs of disease process in the motor neurons of the pyramidal tract. The test involves drawing a semi-sharp object along the bottom of the foot. The normal response in adults and children is for the toes to reflex downwards (flexor response). In babies and people with neurological problems of the corticospinal tract, the big toe moves upwards (extensor response).

Chaddock's Sign: Similar to Babinsky's but testing for lesions in the corticospinal tract. The neurologist touches the skin at the outside of the ankle. A positive response in upwards fanning of the big toe just like in Babinski's test.

Hoffman's sign: This is also similar to Babinski's but involves the hands rather than the feet. Again it tests for problems in the corticospinal tract. The test involves tapping the nail on the third or forth finger. A positive response is seen in flexion of terminal phalanx of thumb.

Doll's Eye Sign: The neurologist is looking for dissociation between movement of the eyes and of the head. A positive response is when the eyes moves up and head moves down.

Sensory:  This is done with tuning forks and pins and tests the level of sensory perception in certain parts of your body.


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It is very rare to get a definite diagnosis at this stage. Certain signs and symptoms are more indicative of MS than others, but, assuming that you do have the disease, the most definitive dx you will get will be "probable MS". You are much more likely to get a dx of "possible MS".

The neurologist will probably book you in for several tests including MRI scans, spinal taps and evoked potential tests.

It is important to note that whatever the results of these tests or the neurological exam, it is not possible to diagnose definite MS from a single episode. There are a number of demyelinating conditions of unknown aetiology which are self-limiting and strike only once. In order to diagnose MS, there must be at least two episodes separated by at least one month and the location of the lesions must be in a least two distinct sites in the central nervous system. This means that the person with MS will, by definition, have to wait at least the period of time that separate the first two relapses that cause clinical symptoms. This could be as little as one month but is more likely to be several months or even years.

Neurologists used to use a checklist called the Schumacher criteria to confirm a diagnosis of MS. Though these criteria are now largely outdated, an MS diagnosis remains a clinical one and they still form the basis for later revisions. They are also worth looking at because they are the simplest statement of what MS is, clinically. The Schumacher criteria are:

• Neurological examination reveals objective abnormalities of CNS function.
• History indicates involvement of two or more parts of CNS.
• CNS disease predominately reflects white matter involvement.
• Involvement of CNS follows one of two patterns:
  • Two or more episodes, each lasting at least 24 hours and at least one month apart.
  • Slow or stepwise progression of signs and symptoms over at least 6 months.
• Patient aged 10 to 50 years old at onset.
• Signs and symptoms cannot be better explained by other disease process.

From Schumacher et al, 1965

The Poser criteria have updated the Schumacher criteria in recognition of the diagnostic benefits of laboratory data. They have not changed the fact that MS is still essentially a clinical diagnosis and are themselves about to be replaced by new criteria that acknowledge the importance of Magnetic Resonance Imaging (MRI). The Poser criteria are:

• Clinically definite MS
  • 2 attacks and clinical evidence of 2 separate lesions
  • 2 attacks, clinical evidence of one and paraclinical evidence of another separate lesion

• Laboratory supported Definite MS
  • 2 attacks, either clinical or paraclinical evidence of 1 lesion, and cerebrospinal fluid (CSF) immunological abnormalities
  • 1 attack, clinical evidence of 2 separate lesions & CSF abnormalities
  • 1 attack, clinical evidence of 1 and paraclinical evidence of another separate lesion, and CSF abnormalities

• Clinically probable MS
  • 2 attacks and clinical evidence of 1 lesion
  • 1 attack and clinical evidence of 2 separate lesions
  • 1 attack, clinical evidence of 1 lesion, and paraclinical evidence of another separate lesion

• Laboratory supported probable MS
  • 2 attacks and CSF abnormalities

From Poser, 1983

Still more recently, 4th May 2001, an international panel in collaboration with the NMSS of America has recommended revising the diagnostic criteria for multiple sclerosis.

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The new proposed diagnostic criteria are:
 

Along with the neurological exam, this is by far and away the most useful and definitive of diagnostic tools. MRI is a branch of Nuclear Magnetic Resonance (NMR) a procedure that involves detecting how molecules spin in powerful magnetic fields. MRI was first used in medicine in 1977 and, though expensive, it is unparalleled at detecting changes and abnormalities inside soft bodily tissue. Water molecules, which are present in all soft tissue, carry a small electromagnetic polarity and, as a result, act like minuscule magnets. MRI scanners exert enormously powerful magnetic fields around the patient who lies in a tube in the middle of the scanner. This causes all the water molecules to wobble and this is detected and imaged on a computer, from which it can be printed onto a negative.

MRI is completely harmless provided that you do not have any magnetic metals around your person during the scan. For more details on MRI and safety procedures, follow this link: Magnetic Resonance Imaging.

MRI scans give detailed high resolution images of cross sections of the brain and to a lesser extent, the spinal cord. Multiple Sclerosis lesions show up as paler areas on those images. From an MRI, the neurologist can not only identify that there have been probable demyelination events but can also see where those lesions are and use them to explain both present and potential signs and symptoms.

Surprisingly perhaps, and despite its accuracy, an MRI scan alone cannot be used to make a definite diagnosis of MS. Clinical symptoms are usually necessary and, because there are a number of other demyelinating conditions, these must be ruled out. As already mentioned, the clinician will also want evidence that there has been at least two identified demyelinating episodes separated by at least one month in at least two different locations in the CNS.

Nor do MRI scans always pick up MS lesions. There is evidence that some older lesions remyelinate sufficiently to be undetectable with MRI scans. Having said this, the vast majority of people with a definite dx of MS will show evidence of disease activity on MRI scans.

A spinal tap (also known as a lumbar puncture) is a procedure whereby a sample of cerebrospinal fluid (CSF) is taken from close to the spinal cord. At the same time a blood sample is taken usually from the arm and a quantity of  blood serum is isolated. Both of these samples are then processed using a technique called electrophoresis. A positive spinal tap will produce oligoclonal bands in the CSF but not in the blood serum. These bands indicate a type of immune system activity. Although uncomfortable, the spinal tap itself is often not too painful, whereas in the period following the tap, the patient may experience dizziness, nausea, vomiting and severe headaches, occasionally for as much as a week. There are a few rare but serious side-effects of spinal taps. 95% of people with a definite diagnosis of MS exhibit oligoclonal bands on a spinal tap.

Before MRI, electrophoresis of spinal fluid played a major role in supporting diagnoses and underpinned the Poser criteria. Now, however, these criteria have become overshadowed by MRI and, if an MRI is positive, the new diagnostic criteria (2001) allow for a definitive diagnosis without laboratory support. The old "Laboratory supported Definite MS" has been dispensed with.

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So what will MS do to me?

Predicting MS is like forecasting the weather.  Weathermen can only give the vaguest of indications of how things may turn out and, even then, only for the next few days. MS is similar - you can say that a number of factors are correlated with a poorer disease outcome but not with a great degree of certainty. Long-term benign disease courses can suddenly become progressive just as malignant courses can suddenly reach plateau. With MS, nothing is certain.

Because of the perverse nature of this disease, you cannot say with any degree of certainty that, even if you match with some of the negative factors, that MS is going to be malignant for you. For example, there are plenty of men who have a benign disease course and yet, statistically, male sex is one of the factors correlated with relatively a fast progression. Remember also that 75% of people with MS will never need to use a wheelchair and that the majority of us will not die from MS, either directly or indirectly.

Factors indicative of a benign disease course:

• Initial symptoms purely sensory or optic neuritis.
• A long interval between the first two relapses.
• Disease onset before 25 years of age.
• Few lesions showing on MRI scan onset
• Low number of affected neurological systems 5 years after onset
• Low neurological deficit score 5 years after onset
• High degree of remission from the last relapse
• The absence of Myelin Basic Protein (MBP) in the cerebrospinal fluid (CSF) during remissions.
• Onset symptoms from only one region.
• Female sex.

Factors indicative of a malignant disease course:

• A greater number of neurological areas affected at onset.
• Many lesions showing on MRI scan at onset
• Pyramidal, cerebellar and sphincter involvement at onset.
• Co-ordination symptoms at onset.
• Progressive disease course at onset.
• Oligoclonal banding in spinal tap present in the early phases of the disease.
• Disease onset after 40 years of age.
• Less than one year interval between the first two relapses.
• Motor symptoms at onset.
• Brainstem involvement at onset.
• Male sex.

The presence of sensory symptoms in addition to motor and/or co-ordination symptoms at onset indicate a better prognosis than co-ordination and/or motor symptoms alone.

Most people's disease course lies somewhere in between benign and malignant and a person's disease may have features that belong to both sets of indicators.

In general, it seems that one of the better indicators of an individual's future disease course is their past disease course. If your disease progression has been slow so far, then it will be more likely to continue to be slow than if it has been aggressive in the past.

There really is no typical course for this disease. Everyone's disease is different and unique to them. However, despite the unpredictable nature of MS, one can identify different phases of the relapsing-remitting (RRMS) and secondary progressive (SPMS) forms of the disease.

See this diagram (after June Halper, 2001):

... and this diagram (after several authors including Compston and Coles, 2002):

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Here, we can see that during the early phases of the disease there are inflammatory lesions but these don't produce any symptoms. Neither the neurologist nor the person with MS is aware anything is wrong unless an MRI scan is done. This phase is known as asymptomatic MS. Some people's disease never progresses beyond this phase and it is only recognized that they ever had MS from autopsy. Some researchers estimate that as many as 40% of all people with MS have asymptomatic multiple sclerosis.

As the disease progresses to the relapsing-remitting phase, some of the inflammatory attacks start to produce symptoms - these are the relapses - although most inflammatory lesions still fall below a clinical threshold. These silent lesions outnumber symptomatic lesions in a ratio of 25:1. Again, for some people, MS never progresses beyond this phase.

As time goes by, remission from relapses becomes incomplete and the person with MS is left with some residual deficits. This phase is known as worsening relapsing-remitting MS.

Typically, worsening RRMS is followed by secondary-progressive MS. During this phase, there are still inflammatory relapses, but in between there is a gradual worsening of symptoms. The onset of SPMS is when disability really begins to take hold.

During the whole course of the disease, inflammatory attacks become less and less frequent. Despite this, people with SPMS continue to deteriorate and eventually move into a secondary progressive phase where there are no more relapses.

The average (mean) age of onset is thirty years old for relapsing/remitting and thirty-seven years old for primary progressive. The mean relapse rate ranges from approximately 0.5 to 0.8 relapses per year and decreases with time. Most people will recover from relapses within 4 weeks.

What are the Symptoms?

The central nervous system (CNS) controls much of the body's functioning and much of this activity passes through the white matter at some point. It is not surprising, therefore, that a disease which damages white matter can produce a very wide range of symptoms. Indeed, there are few diseases with more potential symptoms than multiple sclerosis.

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