Multiple Sclerosis

Author: Dr Ari J Green University of California San Francisco 2008-07-28

This page is written for patients with MS, their families, and those who share our commitment to end this devastating and debilitating disease. 
What is MS?

Multiple sclerosis is an autoimmune, demyelinating disease of the central nervous system (CNS).   It most commonly begins during late adolescence, young adulthood, or mid-life, and can occur in people of any age or any race. MS causes attacks of neurological dysfunction (loss of vision, difficulty walking or moving a limb, incoordination, vertigo, loss of sensation) and/or progressive dysfunction in these same areas.  These “attacks” are also known as exacerbations. Exacerbations typically develop over the course of hours or days, and resolve over the course of days to months.   Patients do not always completely recover from an attack and are sometimes left with a disability as a result.   Early on in the course of MS most people have attacks with little or no progressive disability.  However, approximately 10-15% of patients have progressive symptoms from onset.   Furthermore, more than 80% of patients will ultimately develop progressive symptoms after a prolonged period of exacerbations (usually between 10-20 years).

The wide variety of symptoms seen in MS is a result of the extremely diverse function of the central nervous system (CNS).  The CNS works by generating commands and processing/exchanging information.  Messages are sent between cells in the brain on long extensions of the nerve cell (neuron) known as axons.   These axons are insulated by a fatty substance known as myelin.  Myelin is a very effective insulator and helps to allow neighboring axons (which are found in very large bundles of fibers) to transmit their signals without interfering with one another.   A myelinated axon can send an electrical impulse at 50-100x the speed of an unmyelinated axon. 

What is myelin?

Myelin is not a passive insulator but is actively involved in the transmission of electrical signals down the axon.  Myelin works closely with axons to insure the fidelity of the electrical signal being transmitted and to maintain and repair the axon. Although myelin is primarily made up of fat it also has a large number of critical proteins that help it to maintain its function.  Myelin in the central nervous system (brain, spinal cord, and optic nerves) is distinct from myelin in the peripheral nervous system (cranial nerves and nerves to organs and limbs).

Demyelinating diseases are diseases in which myelin is injured or lost due to the disease process.  MS is not the only demyelinating disease nor are the symptoms of the disease strictly caused by demyelination.   Demyelination can be caused by an overactive immune system, as a consequence of certain infections (possibly combined with an overactive immune response) and because the myelin formed in some individuals is not as stable as in most people.   We do not know if all of these factors play a role in the development of MS, but we do know that an overactive immune response is an important part of the disease. 

There are demyelinating diseases of the peripheral nervous system such as Guillain-Barré syndrome, CIDP (chronic inflammatory demyelinating polyneuropathy), and demyelinating Charcot Marie Tooth disease.  These cause different symptoms from MS and can be distinguished from MS by a neurological examination.  Although the targets that lead to the immune destruction of myelin in the peripheral nervous system are better known, we do not know which myelin proteins are stimulating the immune system in MS (nor whether it is always the same myelin proteins in all patients).  There are a few myelin proteins that are strongly suspected as being the targets of the initial immune attack in MS and these include the myelin proteins MBP and MOG (myelin basic protein and myelin oligodendrocyte glycoprotein).  

How are axons important in MS?

Although demyelination is an important cause of neurological dysfunction in MS (especially during acute attacks) not all MS symptoms result from lost myelin.   For many years, physicians and researchers focused their attention exclusively on demyelination because pathology stressed the relative preservation of the underlying axons in demyelinated MS lesions.  However, this relative preservation of axons was mistakenly taken to imply that the axonal injury had no functional consequence.   In truth, axonal injury is closely correlated to the development of disability in MS.   Furthermore, we now know that axonal injury occurs early in MS and that patients with MS lose axons and neurons at an accelerated rate compared with people without the disease.   Understanding 1) how axonal injury occurs, 2) whether it is always the result of demyelination, and 3) how to prevent it from occurring are critical areas of ongoing MS research.  

MS is an autoimmune disease

Autoimmune diseases are conditions in which a dysregulated immune system improperly attacks our own tissues.   Our immune system is primed for activity against foreign invaders (such as viruses, bacteria, parasites, and pathological funguses) and abnormal uncontrolled growth of a single cell type (e.g., cancer).  However, this work requires a very fine balancing act and in autoimmune diseases our immune system attacks some of the cells in our own body that are otherwise doing their job perfectly well.  Thus, an immune system that becomes improperly regulated and “primed” for activity against our own cells (and their proteins) can lead to an “auto”-immune condition.  Other autoimmune diseases include Lupus, rheumatoid arthritis, psoriasis, asthma, and many types of thyroid disease.

A central feature of all autoimmune diseases is a dysregulated immune system.   MS constitutes a special case because our brain (like only a few other organs in our bodies such as the uterus, testes, and eye) has a special relationship with the immune system (and are said to be “immune-privileged”).   This just means that the immune system does not have full access to these parts of the body and that the activity of the immune system is therefore doubly regulated when it comes to the brain.   Access for many types of immune cells is restricted to the brain and these cell types (neutrophils, macrophages) are not found in these tissues under normal conditions.   This restrictive access is in part maintained by an important structure known as the blood brain barrier (which itself arises from very tight connections between the cells in blood vessels to the CNS which form a restrictive barrier for entry.)

The first clue that MS is an autoimmune disease is the prominent presence of immune cells in the brains of people with MS.  Patients with MS have lesions in the brain where injury is concentrated (manifested mainly by the loss of myelin).  Early on these lesions are filled with immune cells and there is often inflammation surrounding the veins near the site of MS lesions.  After some time immune cells are found mainly at the edge of the lesion, but remain present.  Given the immune-privileged state of the brain mentioned above, we know there are usually no immune cells found in brain tissue of people without MS.  The second clue that MS is an autoimmune disease is that all of the known genetic risks for MS are conferred by genes that are related to the immune system.   These include genes that regulate how our immune system identifies a foreign invader (HLA-DR) and how immune cells interact and “talk” to one another (IL-2R and IL- 7R.) Furthermore, in families where many people have MS we often find other family members with different autoimmune conditions (such as asthma, psoriasis, inflammatory bowel disease, and autoimmune thyroid disease).  The third clue that MS is an autoimmune disease arises from the fact that all the therapies we currently use to treat MS affect or modify the immune system in some way.  Most existing therapies (see below) are meant to modify the way in which the dysregulated immune system behaves in MS.

What Causes MS?

MS is a genetic disease

Susceptibility to MS is partially determined by genes.  This means that patients are born with certain genetic traits that predispose them to developing the disease.   First-degree relatives of patients with MS (children or siblings) are at 20 – 40 times the risk for developing MS as compared with the general population.  In families in which multiple people are affected by MS, this risk may be up to one hundred times the rate for people at large.  However, children of MS patients are still at a very low risk for developing the disease.  Less than 4% of children of MS patients get MS – meaning that 96% never get the disease.

Identical twins are also a greater risk of developing MS than fraternal twins or siblings.  The most reliable studies indicate that if a patient has MS, their identical twin will get MS 30% of the time.  This fact tells us two things:

1.    The risk of MS is partially inherited (because this rate is so much higher than among the general population and non-genetically identical members of the same family).
2.    The risk of MS is partially determined by things we are exposed to during life (because this rate is not 100% or near 100%). 

People of certain ethnicities are also at higher risk of developing MS.  MS is most common among people of northern European heritage, but it occurs in populations around the world.  The highest rates of MS are found in the northern parts of Scotland and Ireland as well as on some of the islands of the North Sea.  There is also good evidence that MS presents slightly different among different populations of the world.   Patients of non-European ancestry appear to be more likely to have a disease which effects the optic nerves and spinal cord and may have a more severe course (especially African Americans). 

Large-scale genetic studies have shown us that MS is not determined by a single gene, but more likely by a number of genes, each of which confers partial susceptibility.   We have found that a few genes – HLA-DR, IL7R and IL2R each contributes a modest amount to the risk of getting MS (i.e., patients without the known genes of risk can also get the disease).   Given the complexity of such studies, very large ongoing genetic investigations are helping us to solve the genetic puzzle posed by MS. 

Why don’t people with these genetic “risk factors” always develop MS?

There are likely factors beyond genes that cause people to develop MS.   Currently these environmental factors are not completely understood.  However, over the last decade we have come to appreciate a number of important environmental (and therefore potentially modifiable) risk factors that may contribute to determining who gets MS.  In this context “environmental factors” means strictly those things which we may come across in our daily environment and which can affect our health.  They can include nutritional components, infections, toxins, and health related habits.  In addition the “environment” may include anything from the “environment” inside a mother’s womb, to the environment created by our climate, to our food supply.  Therefore, we are interested in anything which we may become exposed to which may increase (or decrease) our risk of developing MS.

Vitamin D

For a very long time it has been noted that MS occurs at a greater frequency at locations away from the equator. MS prevalence is strongly tied to geography, especially latitude.   Although some of this so-called “latitudinal gradient” is related to genetic factors (people at the greatest genetic risk likely come from places distant from the equator), recent evidence has illustrated that exposure to sunlight and the related production of Vitamin D probably plays some role in determining risk for MS.  After World War II, it was noted that the rate of MS was highest among those veterans who grew up in states from the northern part of the US (Minnesota, Washington).   Furthermore, researchers noted twenty years ago that people who performed inside desk jobs had higher rates of MS than those who worked outdoors (and presumably had a greater level of sun exposure). 

Vitamin D is not really a “vitamin” at all (an essential nutrient obtained strictly from diet).  It is, in fact, a prohormone (a molecule without hormonal effects on its own but which is converted to molecules with hormonal activity) synthesized in the skin from a cholesterol by-product.   It is then further converted in the liver and then in the kidney.   The first important step in its production takes place in the skin and then only in response to stimulation with ultraviolet light (in the high frequency A and B spectrum of 270-290 nm wavelength).  The production of Vitamin D is therefore heavily dependent on exposure to sunlight.   There are few dietary sources of Vitamin D and these probably cannot supply an adequate amount of Vitamin D.   Traditionally doctors and physiologists had focused on the importance Vitamin D in the production and maintenance of bone because severely Vitamin D-deficient children were noted to develop the bone disease rickets, and adults the bone disease osteomalacia.  However, in recent years attention has turned to all the other important functions of Vitamin D – including a role for Vitamin D in the function of the immune system.  Many types of immune cells respond to Vitamin D (and have sites on their surface intended to respond to stimulation with Vitamin D). Activation of this vitamin D receptor plays a role regulating the activity of certain classes of immune cells.

Recently some important studies have highlighted the role of vitamin D in MS.    One very elegant study showed that people with low vitamin D levels are at nearly a 3x higher risk for developing MS when compared with those with the highest levels.  This difference is particularly pronounced for those patients younger than 20 and implies that vitamin D exposure in childhood and adolescence may be most important.   Another study suggested that among identical twins in which only one twin had MS (discordant twins), the twin who developed MS was much more likely to have a history of sun avoidance behavior.  There is even some evidence for a seasonal variation in relapse rate, with a higher rate seen in winter, especially at more extreme latitudes, meaning that exacerbations may also be tied to vitamin D levels. 

Epstein-Barr Virus and MS

Epstein-Barr virus (EBV) is the virus that causes mono (infectious mononucleosis or glandular fever) as well as rarely causing cancer of the throat and an uncommon type of lymphoma.  EBV is from the family of human herpes viruses and infects between 85-95% of the world’s adult population.  It gains entry for infection through the mucus membranes of the nose and throat, but it lives permanently in white blood cells known as B-Lymphocytes (or B-cells).    Most people are likely infected with EBV in infancy or early childhood.  In fact, those people who develop mono are those who are exposed to the virus at a relatively later age (adolescence or early adulthood). 

Mounting evidence indicates that EBV infection plays an important role in MS and may even be a necessary precondition for the development of disease.   Although a history of EBV infection is very common in the general population, serological studies have found infection rates approaching 100% among MS patients.   Those studies which have failed to find evidence for universal prior infection in the MS population have been limited in terms of the scope of antiviral antibodies screened.  In addition, in large longitudinal studies, markers in the blood of prior EBV infection are very strongly associated with risk of MS (the risk of developing MS among those with highest anti-EBV antibody levels is 20-40x higher than those with the lowest antibody levels).  Furthermore, many children with MS have previously been exposed to EBV and have higher levels of anti-EBV antibodies than children without MS.  There is even some evidence that dysregulated response to EBV may be an additional risk factor for the disease. 

The timing of EBV infection may be important in initiating a pathological host response. Most people are infected with EBV during infancy or early childhood, however among patients with infectious mononucleosis the rate of MS is 2.5x greater than in matched controls. Newer studies highlight the many ways in which EBV infection is correlated to disease activity in MS. 

What happens to patients with MS?

MS can cause serious neurological disability. Patients can end up with weakness, numbness, imbalance, double vision, visual loss, loss of bowel or bladder control, trouble with thinking, mood disturbances, and difficulty walking, among other problems.  Historically, many patients with MS ended up with walking difficulty and in the popular imagination MS is often associated with canes and wheelchairs.  However, between 10-15% (and maybe up to one quarter) of patients have no major disability at 10 years.   The number of people with this so-called “benign MS” may be growing - partly because we are diagnosing milder cases of the disease and partly because we may be affecting the long-term course of the disease through treatment.   We have traditionally thought that around 50% of patients with MS will have difficulty with their walking 15 years into their disease.   This may no longer be true, but regardless, many patients with MS have their daily lives profoundly impacted by their disease. To make matters worse, it is currently impossible to accurately predict who will become disabled as a result of their MS.  This remains one of the greatest challenges in MS and contributes to the stress and difficulty of living with the disease.

Diagnosing MS

Traditionally diagnosing MS has not been straightforward because we have had no confirmatory tests that cinch the diagnosis.  Furthermore, the variety of symptoms that can be seen, the variable types of disease (relapsing-remitting versus progressive), and the variability in disease severity have all made diagnosis challenging and time-consuming.   Years ago many patients suffered from symptoms for years before reaching a diagnosis (and even this provided little solace because we had no therapies that were proven to affect the disease.)  Clinical criteria were then developed that tried to adhere to two important clinical dictums:

1)    Evidence for dissemination in time and space . This means patients do not just have a single lesion (disseminated in space) and that they have attacks on more than one occasion (dissemination in time.)
2)    No better explanation for the patient’s symptoms. 

Over the years, the specific clinical criteria have undergone a number of important modifications because of changes a) in diagnostic technology, b) in our understanding of the disease, and c) in the treatments available for MS.  This has helped to make diagnosis much more straightforward (but at the risk of increasing the diagnosis of “benign” cases of disease).

MRI (Magnetic Resonance Imaging)

MRI has come to play a very important role in diagnosing and following MS.  In fact, the influence of MRI in diagnosing MS has become so great that sometimes people are offered a diagnosis of MS on imaging alone (in the absence of a clinical history consistent with MS.)   It should be remembered, however, that MRI alone is not a basis for diagnosis and that MS remains a diagnosis dependent on the judgment of a physician and the satisfaction of certain clinical “rules of the road” (see above). 

The most important imaging feature of MS is the presence of “lesions.”  These lesions correspond to the lesions seen by pathologists after a patient dies.  MRI lesions are diverse in appearance and can be round, elongated or patchy.  On traditional MRI these lesions are predominantly (if not exclusively) found in the white matter of the brain/spinal cord.   White matter corresponds to the areas where axons are predominant (in fact it appears white because of the fatty myelin surrounding the axons).  MRI lesions are not all identical in terms of what is going on at a cellular and molecular level.   As an example, some lesions are active with ongoing inflammation and others are chronic scars with minimal or no inflammation.  One weakness to traditional MRI is that it cannot distinguish these active from chronic lesions, although by administering gadolinium (a reactive dye) we can often tell if there is blood-brain-barrier leakage at the site of a lesion.   Leakage through the blood brain barrier suggests an acute lesion, although not all lesions that are active pathologically will leak gadolinium. 

Lesions in certain locations are considered characteristic of multiple sclerosis.  These include lesions in:
(A) Periventricular white matter – this is the white matter surrounding the cerebrospinal fluid -filled ventricles found in the “middle” of the brain.   Lesions that directly come up to the ventricle are most suspicious of MS.
(B) The corpus callosum – the thick band of white matter connecting the two hemispheres of the brain (it is also right next to the ventricle and is not truly distinct form A, above).
(C)  The spinal cord. 
(D) The juxtacortical white matter – this is the white matter space  directly next to the cortex of the brain (gray matter).

Not all patients with MS have lesions in these location and not all patients with lesions in these locations have MS.  In general it takes experience and a trained eye to distinguish MS lesions from lesions related to other diseases of the central nervous system.   In fact lesions seen in the white matter areas between the periventricular and juxtacortical white matter are often referred to as “non-specific”  (also known as “subcortical white matter”) because of the wide number of diseases that can cause lesions there.

Lumbar puncture (LP)

CSF (cerebrospinal fluid) is a colorless, watery fluid that bathes the brain and spinal cord.  A lumbar puncture or spinal tap is a collection of CSF taken from below the level of the spinal cord in the lower back.  A small volume of fluid is taken with a thin needle after a patient is given some local anesthetic. We look for both the presence and absence of some important laboratory findings in the CSF in MS.   While a full discussion of what is tested in CSF is beyond the scope of this page, two important laboratories can be an important part of making a diagnosis.   These tests are known as oligoclonal bands and IgG index.  They reflect excess and possibly restricted synthesis of antibodies in the central nervous system.   While the exact significance of oligoclonal bands and elevated IgG index is unknown, more than 85% of patients with MS have abnormal CSF.  This abnormality is particularly common in patients with the primary progressive form of the disease. 

Evoked potentials

Evoked potentials are tests in which we look at the brain’s electrical response to a particular stimulus (such as a particular visual pattern, a click in the ear, or electrical stimulation of a peripheral nerve).   Neurologists sometimes use evoked potentials as a method for demonstrating evidence of demyelination in a second white matter pathway when a diagnosis of MS is in question after an initial attack.  In addition, newer evoked potential studies, known as multifocal visual evoked potentials, show some promise as a method for predicting whether a patient will go on to develop MS after an initial demyelinating episode.   Furthermore, they may help follow disease and even help predict who will become disabled with time.  


How is a diagnosis of MS confirmed?

As mentioned above, a diagnosis of MS can never be truly “confirmed” by a laboratory test because no such laboratory test currently exists.  However, given a characteristic clinical history and appropriate brain imaging, a trained neurologist can comfortably arrive at a diagnosis of MS.   Still, there are a number of diseases that affect the central nervous system that can be mistaken for MS.  Obviously, those diseases which cause multiple lesions in the central nervous system, and which follow a relapsing course are the ones most commonly confused with MS.  Given the “no better explanation standard” mentioned above, this often requires ruling out appropriate MS mimics.   In many cases, physicians will order a number of labs to rule out these conditions.  The specific tests ordered are dependent on a patient’s clinical history and imaging findings.   The list of possible diseases that can mimic MS is extensive and depends on the patient’s presenting symptoms.  Because the symptoms of MS can be so varied, any attempt to be exhaustive will doubtlessly be incomplete. I have included some of the most common or otherwise important mimics below in a discussion of “rule out” laboratories.


Other autoimmune diseases

”Rule-out” tests for other autoimmune diseases that can effect the brain include lupus and Sjögren’s syndrome. Routine tests include ANA, SSA, and SSB.     These tests are sometimes followed by additional tests if they are abnormal (Anti-DS DNA, Anti Sm-ab). Sometimes, other inflammatory diseases, such as sarcoidosis, must be ruled out.   Testing for sarcoid is complex and will depend on an individual’s symptoms but may include a serum ACE level, spinal tap (with a cell count, glucose level, and ACE level), careful eye exam by an ophthalmologist or neuro-ophthalmologist, Chest CT with contrast, and FDG-PET scan (fluorodeoxyglucose–positron emission tomography) or Gallium scan.

A disease known as neuromyelitis optica (NMO) is a severe demyelinating disease of the central nervous system that affects the optic nerves and spinal cord (generally sparing the brain, at least clinically).  There is currently controversy about whether NMO is a subtype of MS or a separate disease.   The full spectrum seen in NMO is still undefined and determining the appropriate way to think about the relationship between MS and NMO (as well as the cross-over disease known as optico-spinal MS) is still a matter of controversy.   There is a laboratory test known as the NMO antibody that can be evaluated when NMO is under consideration.

There are less common autoimmune diseases that are sometimes considered in patients with particular clinical symptoms.  

These include:

1)    Behçet’s disease  - oral and genital ulcers, eye pain and floaters, headache – Lab test HLA-B51/B52
2)    CNS vasculitis - headaches, fevers, and acute episodes of neurological worsening – Erythrocyte sedimentation rate (“sed rate”), C-reactive protein (“CRP”)
3)    Susac syndrome  - acute episodes of visual loss, hearing loss, and cognitive decline – Important tests are eye exam and audiology

Infections

A few treatable infections are sometimes considered when a patient is being evaluated for MS. The two most common infections screened for are:
1) Lyme disease
2) Syphilis

Much less commonly considered infections that may form part of the evaluation of possible MS include Whipple’s disease, HIV infection (especially in combination with the opportunistic infection PML [progressive multifocal leukoencephalopathy]), and HTLV (Human T-lymphotropic virus).   Each of these infections is associated with particular symptoms and is only considered in special cases. 

Metabolic deficiencies

On rare occasion, B12 deficiency can mimic MS, especially the progressive form of disease.  In appropriate patients this is best evaluated with a serum B12 level and a methylmalonic acid (MMA) level.   Patients with low-normal B12 can still be functionally deficient and MMA helps the physician to determine if an otherwise normal B12 level is functionally significant.  

Treating MS

There are now 6 drugs approved by the FDA for treating multiple sclerosis (5 for treating relapsing remitting disease and 1 for treating secondary progressive disease).  Each existing treatment has its champions and detractors.   The essential truth is that each therapy has its strengths and limitations as well as different assortment of risks associated with its use. A one-sized fits all approach is rarely useful in MS.   Doctors must consider a patient’s needs, their lifestyle, their clinical history, and their symptoms when considering a therapy. 

Interferons

The first drugs approved to treat MS were the interferons.   These drugs were initially considered because of their antiviral properties but were found to beneficially modify the immune system in patients suffering from MS.   All the current available therapies are forms of a compound known as interferon beta and all are injectable therapies.   They all have relatively similar side effects although some may be better tolerated than others.  

The three interferons are:

1) Interferon-beta 1a subcutaneous injection (Rebif)
This drug is injected under the skin three times a week and is one of the two high-dose/high-frequency interferons.   Although it is approved for use at two dosage levels, it is most commonly used at its higher dose of 44 mcg/injection.

2) Interferon beta 1b subcutaneous injection (Betaseron/Betaferon)
This drug is injected under the skin every other day and it is the other high-dose/high-frequency interferon.  Betaseron has most of the same benefits and drawbacks as Rebif although it may have a higher rate of neutralizing antibodies so may be less likely to cause certain side effects. 

3) Interferon beta 1 a intramuscular injection (Avonex)
This drug is injected directly into the muscle once a week.

All the interferons reduce the average number of attacks a patient has per year, reduce the number of new lesions they develop on MRI, and reduces their chance of developing short-term progression in disability (new disability developing over a few years – not long term progression to a wheelchair).   There is recent evidence that the high dose drugs (Rebif and Betaseron) are more effective over the short term (2 years) than Avonex.   However, Avonex has the advantage of requiring less frequent injections and being less likely to induce an immune response from the patient against the treatment (so called neutralizing antibodies). 

All the interferons have similar side effects.  These include:
Depression/worsening of depression
Hair loss
Injection site reactions
Flu-like symptoms
Liver enzyme elevations
Pancytopenia/leucopenia
Hyperthyroidism/Early Graves’ disease

The injection site reactions and flu like symptoms typically improve with time.  They can also be managed with co-administration of medicines like Tylenol (acetaminophen) and Benadryl (diphenhydramine).   Liver enzyme changes, declines in the white blood cell count, and abnormal thyroid function are all uncommon and are typically screened for once a patient is on therapy. 

Glatiramer acetate (Copaxone)

Copaxone is a drug specifically developed for the treatment of MS.   It is generally well tolerated and is known to reduce the rate of new exacerbations. It is given as a subcutaneous injection on a daily basis.    Many MS specialists had thought Copaxone was less effective than the high dose interferons in preventing relapses and treating disease.  However, recent trials comparing Copaxone with high-dose/high-frequency interferons including both Rebif and Betaseron have suggested that it is equally effective.   These trials also revealed that Copaxone was less well tolerated than we had previously thought. 

Side effects with Copaxone are uncommon, but include injection site reactions and shaking chills immediately following injection.  No routine laboratory tests need to be done as a result. 

Natalizumab (Tysabri)

Tysabri is a monoclonal antibody designed for use in MS.   It prevents white blood cells, specifically lymphocytes, from crossing the blood brain barrier and getting into the central nervous system.   Recent trials have shown it be very effective at treating MS; especially at preventing new attacks, developing new gadolinium enhancing lesions, and at reducing short-term progression of disability.   There was a suggestion from the trials that Tysabri may be up to twice as effective as our previously existing therapies for treating MS.  However, there are two caveats.   First, we have learned that new trials suggest that all our therapies are more effective than we had previously thought (perhaps because early treatment is more effective than starting once patients are disabled).   Second, the use of Tysabri was associated with the occurrence of a potentially fatal brain infection known as PML (often seen in HIV), which has tempered its use.   We are still learning how common this brain infection is likely to be and whether Tysabri will be able to used in much larger numbers of patients. 

In general natalizumab is very well tolerated.   As noted, however, there is a dangerous side effect of PML. We don’t know how long patients need to be on Tysabri before this risk develops.   We also can’t predict who is at risk of getting PML.  As a result, natalizumab is only indicated for those patients who don’t respond to treatment with interferons and/or Copaxone.   A few recent reports also suggest that Tysabri use may be related to a risk of developing melanoma and to liver dysfunction (especially soon after the initiation of use).  The significance of these risks is also currently unknown.

Emerging treatments in the fight against MS

The last 5 years has seen the early phase testing of many exciting new drugs that may help us in the battle against MS.   Many of these drugs are currently being tested for approval.   The most promising include Rituximab, FTY 720, and Daclizumab (among others).   The recently published trial looking at Rituximab has extended our understanding of MS and offers promise as a therapy.  We will likely have 3-5 new approved therapies by the early part of the next decade.  

Symptomatic treatment in MS

Given that we still lack a cure for MS, an important part of caring for MS patients is helping them to manage their symptoms.   The symptom burden is varied, and it is difficult to provide a complete list of all possible treatments. The many potential treatments are best administered with the advice of an MS specialist, general neurologist, urologist, psychiatrist, or rehab specialist (physiatrist). 

One of the most important “symptomatic” treatments worthy of mention is the use of steroids for acute MS exacerbations.   Overall, we consider these treatments symptomatic because we have no good evidence that their use affects the long term course of the disease.   In fact most evidence indicates that steroids only help to shorten the course of an exacerbation and do not prevent the development of long-term disability.  However, given that many exacerbations can significantly impact a patient’s ability to work, go to school, or care for family, steroids are often used to help ameliorate an acute attack (most often 3-5 days of IV steroids).  If there is any long-term benefit from steroids it probably only comes from their very early use – and this leads most MS specialists to conclude that if they are to be used for exacerbations, steroids should be given sooner rather than later. 

How do we follow MS patients?

As mentioned above, we currently lack the ability to accurately predict which patients are likely to become disabled from their MS.  The most important part of following an MS patient is the annual or semiannual neurological examination from their provider.  Clinical progression on exam may be a sign that the disease is active and that management plans may need to be re-evaluated.  Additional imaging tests are best planned at the discretion of a trained provider.  We have good reason to believe that there is a relationship between early activity of disease and long-term disability.   In addition, we know that there is a modest correlation between the volume of lesions a patient has at diagnosis and their risk of long-term disability.  We also know that people with active disease – as measured by new gadolinium-enhanced lesions seen on MRI – are at greater risk for developing new disability.   As a result, many MS specialists follow their patients with annual MRIs in addition to their clinical exams.  Some tests with emerging potential include optical coherence tomography (OCT), which can quantitatively assess the volume of axons in the retina (at the back of the eye).  This test may serve as a measure of the number of intact axons in the central nervous system in general.  As the technology advances this test is showing promise for use in the MS clinic but it still needs further study to prove its usefulness. 

Web links

NMSS -  http://www.nationalmssociety.org/index.aspx
CWOW -  http://www.erasems.org/
UCSF MS Center Website http://www.ucsf.edu/msc/index.html
Northern California NMSS http://can.nationalmssociety.org/site/PageServer?pagename=CAN_homepage