Multiple sclerosis

Multiple sclerosis (MS) is a demyelinating disease, a non-contagious chronic autoimmune disorder of the central nervous system which can present with a variety of neurological symptoms occurring in attacks or slowly progressing over time.


The prevalence of multiple sclerosis (MS) is approximately 350,000 cases in the United States and more than 2.5 million worldwide. There are at least 10,000 newly diagnosed cases of MS annually.

In northern Europe, continental North America, and Australasia, about one of every 1000 citizens suffers from multiple sclerosis, whereas in the Arabian peninsula, Asia, and continental South America, the frequency is much lower. In Sub-Saharan Africa, MS is extremely rare. With important exceptions, there is a North-South gradient in the Northern hemisphere and a South-North gradient in the Southern hemisphere, with very low frequencies near the equator (between latitudes 40 degrees North and 40 degrees South. Climate, diet, geomagnetism, toxins, sunlight, genetic factors, and infectious diseases have been discussed as possible reasons for these regional differences. It has been postulated that an environmental factor during childhood might play an important role for the development of MS later in life. This was based on several studies in migrants demonstrating that if migration occurs before the age of 15, the migrant acquires his new region's susceptibility to MS. If migration takes place after 15, the migrant keeps the susceptibility of his home country.

MS occurs mainly in the Caucasian race. It is 20-fold lower in the Inuits of Canada than in other Canadians living in the same region. It is also rare in the Native American tribes of North America, the Australian Aborigine and the Maoris of New Zealand. These few examples point out that the genetic background plays an important role in the development of MS (see below).

As observed in many autoimmune disorders, MS is more common in females than males; the mean sex ratio is about two females for every male. In children, who rarely develop MS, the sex ratio may reach three females for each male, whereas MS occurring in the fifth decade more commonly affects males. Onset of symptoms usually occurs between 20 to 40 years of age, rarely below 15 or above 60, although both is possible.

MS is not strictly a hereditary disease. However, MS is a disease influenced by a variety of factors, one of which is the genetic background of an individual. There is no single gene known to be responsible for MS, though a few genes have been demonstrated to increase the risk of development. Although these genes are of scientific interest and continue to play a part in research, they are not enough to diagnose an individual with MS.

Overall, an average one of every 25 siblings of an individual with MS will also be afflicted. Up to every second identical twin of a MS-affected person will develop MS, but only one of 20 fraternal twins. If one parent is affected by MS, only about 1 of 40 of his children will develop MS later in life. There also seems to be an association with specific HLA antigens (HLA-DR2).

Etiology and Pathogenesis

The ultimate cause of MS is unknown. It is hypothesised that a viral infection or other environmental factor in childhood might prime the immune system for an abnormal reaction later in life. On a molecular level, there might be a structural similarity between an unidentified infectious agent and components of the central nervous system, causing confusion in the immune system later in life (a process called "molecular mimicry"). However, so far there is no known "MS virus". Certainly MS is not an infectious disease and not contagious. The importance of genetic factors has been discussed above.

It is widely accepted that a special subset of white blood cells, called T cells, play a key role in the development of MS. Under normal circumstances, these lymphocytes can distinguish between self and non-self. In a person with MS, however, these cells recognize healthy parts of the central nervous system as foreign, and attack them as they would a virus. In MS, the part of the nervous system primarily attacked is myelin. Myelin is a fatty substance that covers the axons of nerve cells, and which is important for proper nerve conduction. Normally, there is a tight barrier between blood and brain, called the blood-brain barrier (BBB), built up of endothelial cells lining the blood vessel walls.

Lymphocytes (blue) surrounding blood vessel (center) within MS lesionIn MS, the BBB breaks down; autoreactive T cells cross the BBB and trigger an inflammatory process, also mediated by other immune cells, such as cytokines and antibodies. Due to this abnormal behavior of the immune system, MS is considered to be an autoimmune disorder. The inflammatory process finally leads to a destruction of myelin called demyelination. Repair processes, called remyelination, also play an important role. This is one of the reasons why, especially in early phases of the disease, symptoms tend to decrease or disappear temporarily after days to months. Nevertheless, axonal damage and irreversible loss of neurons occur early during the course of the disease. However, due to its plasticity the brain can often compensate for some portion of the damage. MS symptoms develop as a result of multiple lesions in the brain and spinal cord, and can vary greatly between different individuals, depending on where the lesions occur.

Factors triggering a relapse

In general, relapses tend to occur more frequently during spring and summer than during autumn and winter. Infections like the common cold, influenza or unspecific diarrhea increase the risk for a relapse. In contrast, influenza vaccination is safe and does not trigger relapses as demonstrated in several recent studies. It can therefore be recommended for MS patients, especially for those at risk for influenza (e.g. healthcare workers). Tetanus vaccination is considered to be safe as well, although so far it has not been studied in that respect. In general, vaccinations with living, attenuated viruses increase the risk of relapses.

Pregnancy can directly effect the susceptibility for relapse. The last three months of pregnancy offers a natural protection against relapses, whereas during the first few months after pregnancy, especially during the first six weeks, the risk for a relapse is increased 20-40%. According to current knowledge, pregnancy doesn't seem to influence long term disability. MS does not increase the risk of bearing a handicapped child.

Statistically, there is no good evidence for triggering of relapses through trauma or operations. In principle, surgical procedures require no special precautions if not dictated by existing disability. Participation in sports is possible, although extremes, such as marathon running, should probably be avoided. Emotional stress may cause a relapse, although study data has been inconsistent.

Heat can transiently increase symptoms, in something known as Uhthoff's phenomenon. This is why some patients avoid saunas or even hot showers. However, heat is not an established trigger of relapses. Extensive exposure to the sun should be avoided, since ultraviolet radiation is a strong stimulus for the immune system.

Currently there are no clinically established laboratory investigations available to predict prognosis or therapeutic response, although promising approaches have been undertaken that need further confirmation, such as treatments based on the two antibodies anti-MOG and anti-MBP, and TRAIL, a TNF-Related Apoptosis Inducing Ligand.

Disease course and clinical subtypes

In most cases MS starts with an acute flare-up of symptoms within hours to days, called a relapse, exacerbation, bout, episode, or attack. Inflammation of an optic nerve (optic neuritis), causing painfulness of eye movement and visual deterioration frequently is the first symptom. However, not all patients with optic neuritis develop MS. Sensory disturbances such as numbness or tingling sensations are other frequent initial symptoms. In principle, MS can start with any of the symptoms mentioned in the section above.

Especially in early phases of the disease, symptoms frequently decrease or resolve spontaneously within days to months. Therefore, this disease course is called relapsing remitting. New relapses can occur within weeks to many years and can include formerly experienced and/or new symptoms. However, MRI studies have shown that nerve damage can continue in relapsing remitting patients even if symptoms subside. It has long been known that "MS never sleeps". This highlights the importance of preventive treatment if and when it is available.

In many cases, the disease course changes after several years and symptoms start to deteriorate slowly with or without superimposed relapses. This course is called secondary chronic-progressive, or just secondary progressive. However, some patients stay in a relapsing remitting course for the rest of their lives.

About 10% of all MS-affected individuals experience chronic progression without relapses from onset of symptoms. This course is called primary progressive and frequently comes along with weakness of the legs, gait and bladder disturbances. Degenerative processes and not inflammation are thought to play the most important role in this clinical disease course.

Chronic progression from onset of symptoms with superimposed relapses is referred to as relapsing progressive.

Signs and symptoms

MS is suspected in a female, between 15 and 60 years old and usually of Northern European, Northern US or Canadian descent.

Affected individuals may experience a wide variety of symptoms, such as vision loss, double vision, nystagmus, difficulty with speech, various kinds of tremor, clumsiness of the hands, unsteady gait, weakness, spasticity, numbness, and bladder (urgency, hesitancy), bowel, as well as sexual dysfunction. Various cognitive impairments are also common, such as difficulty performing multiple tasks at once, difficulty following detailed instructions, loss of short term memory, depression, and fatigue.

Symptoms and signs may partially disappear after a few days or weeks.

MRI findings

MS plaques appear hyperintense on T2 weighted studies. They usually are oval in shape, and appear in the periventricular region or corpus callosum. Detection of gadolinium enhancement can help differentiate active from chronic lesions and could help in establishing the temporal dissemination of the disease on follow up.

Lumbar puncture

A lumbar puncture, which is a procedure done to collect a sample of cerebrospinal fluid, is useful for providing evidence of chronic inflammation of the central nervous system, often indicated by oligoclonal banding. Nerve conduction studies of optic, sensory and motor nerves can provide further evidence for MS, as the process of demyelination results in reduced nerve conduction velocities. The diagnostic process is completed by several laboratory tests to exclude other diseases that can mimic MS, such as Sarcoidosis, Vasculitis, and Lyme disease).


A definite diagnosis of MS requires evidence for dissemination of lesions within the central nervous system both in space and in time. This means that not only must there exist evidence of at least two distinct lesions, verifiable by clinical symptoms or by Magnetic Resonance Imaging (MRI), there must also be evidence of an occurrence of new symptoms or lesions within a time interval of at least 30 days.

Diagnosis of multiple sclerosis is made using the 2005 revised McDonald diagnostic criteria [1]:

Generally speaking, three parameters are used to assess the diagnosis.

  1. An attack refers to an episode of neurological disturbance that has lasted for at least 24 hours. This is usually a subjective report by the patient and should be backed by objective findings.

  2. A clinical lesion refers to a neurological lesion detected by history and physical examination.

  3. A paraclinical lesion refers to a lesion that is detected by MRI, evoked response testing or urodynamic studies.

In addition to the assessment of the three parameters discussed above, the criteria require that evidence for dissemination of lesions in both space (spatial dissemination) and time (temporal dissemination).

2005 revised McDonald Diagnostic Criteria for Multiple Sclerosis

For relapsing-remitting disease

  • Two attacks (temporal dissemination) + two clinical lesions (spatial dissemination)

  • Two attacks (temporal dissemination) + one clinical lesion + one paraclinical lesion (spatial dissemination).

For monosymptomatic / clinically isolated disease

  • One attack + one clinical lesion + evidence of spatial dissemination by MRI, CSF + evidence of temporal dissemination by MRI or evidence of second clinical attack.

For primary progressive disease

One year of disease progression + two of the following

  • Positive brain MRI

  • Positive spinal cord MRI

  • Positive CSF


There is no known definitive cure for multiple sclerosis. However, several drugs have proven to be effective in its treatment. Intensive research is underway to study a variety of promising new drugs. Treatment is aimed at maintaining a maximum quality of life. Physiotherapy plays an important role.

There are three primary forms of medication used to treat the symptoms:

During an exacerbation, corticosteroids (such as prednisone or methylprednisolone) used at high dosages (500 mg - 2 g per day intravenously for a course of 3 to 5 days) can accelerate regression of symptoms. Subsequent tapering with pills may be reasonable in certain cases. There is clear evidence that sole treatment with oral steroids at dosages of 100 mg per day or less and subsequent tapering is inferior to intravenous high dose treatment. In principle, steroid treatment during pregnancy is possible. There is no good evidence that corticosteroids influence longterm outcome.

Long-term treatment can influence the course of the disease:

Interferon-beta1a or beta1b (Avonex; Betaseron [in Europe Betaferon]; Rebif) has been shown to reduce the relapse rate by about 30%, decrease the number of new MRI lesions and slow progression of disability. Interferon-beta is a cytokine that under natural conditions is produced by the body during viral infections; as a drug it is extracted either from special mammalian cells or special bacteria. All preparations must be injected into either muscle or skin every second day to once per week, depending on the preparation. Attempts to develop pills containing Interferon-beta have not been successful so far. Some of the interferons have been proven to be effective not only in relapsing remitting MS, but also in secondary progressive MS, as long as superimposed relapses occur. Main side effects include flu-like symptoms which tend to decrease during ongoing therapy and which can be alleviated, for example, by paracetamol or ibuprofen. Another frequent side effect is inflammatory skin reactions at the injection site if Intereferon-beta is injected into the skin. Regular blood monitoring is required.

Glatiramer acetate (Copaxone) has also been shown to reduce the relapse rate by about 30%, decrease the number of new MRI lesions and slow progression of disability. Concerning its therapeutic effect it is approximately comparable to Interferon-beta. Glatiramer acetate consists of synthetic peptides made of four different amino acids, which are basic modules of all proteins in the human body. Once per day must be injected into the skin. Attempts to develop pills containing glatiramer acetate have also been unsuccessful. Copaxone is effective in the treatment of relapsing remitting MS. So far, beneficial effects in secondary progressive MS have not been convincingly demonstrated. Main side effects include inflammatory skin reactions at the injection site, and a rare but transient and perturbing "post-injection" reaction manifested by flushing, chest tightness, heart palpitations, breathlessness, and anxiety. A post-injection reaction does not require discontinuation of therapy. In general, Copaxone is considered to cause fewer side effects than Interferon-beta. However, most MS patients injecting Interferon-beta also tolerate their therapy well. Regular blood monitoring is required.

Azathioprine is an agent available as a pill approved for the treatment of relapsing remitting MS in some countries. However, its effectiveness has not been proven as stringently as for the interferons and glatiramer acetate, and an effect in secondary progressive MS has not been demonstrated. In general, it is well tolerated. After longtime therapy the risk of cancer increases slightly (after 10 years of therapy about fourfold). Regular blood monitoring is required.

There is some evidence that immunoglobulins (antibodies) are effective in the treatment of relapsing remitting MS, a large clinical trial (PRIVIG) is presently continuing. Immunoglobulins have not been proven to be effective in secondary progressive MS.
The currently most effective drug in the preventive treatment of MS is Mitoxantrone. It has been proven to be effective in relapsing remitting and in secondary progressive MS. In most cases it is administered every three months intravenously. Therapy with Mitoxantrone is generally well tolerated, however, since with ongoing therapy the risk for damage of the heart muscle increases, at an average Mitoxantrone can only be administered for 3 to 4 years. This is why Mitoxantrone is only used in cases of rapid disease progression. Mitoxantrone treatment requires monitoring of the heart function during therapy. Regular blood monitoring is required. With these precautions Mitoxantrone treatment is safe.

A family of cholesterol-lowering drugs, the statins, have shown anti-inflammatory effects in animal models of MS. However, so far there has not been provided sufficient evidence that statins are beneficial in the treatment of human MS patients with normal cholesterol levels.

Recently, scientists found women who took vitamin D supplements were 40% less likely to develop multiple sclerosis than women who did not take supplements. However, this study does not allow to conclude that vitamin D has a beneficial influence on ongoing MS. Furthermore it could not distinguish between a beneficial effect of vitamin D and multivitamin drugs including vitamin E and various B vitamins which may also exert a protective effect.

Primary progressive MS is very difficult to treat. High dose corticosteroids every three months can show some effect. In principle, there is no efficient preventive treatment for primary progressive MS available. Symptomatic therapy as described in the next paragraph and physiotherapy play an important role.

A variety of medications are used to treat symptoms without influencing the inflammatory nature of the disease (symptomatic treatment):

  • Baclofen and tizanidine can be useful against spasticity. There is no convincing evidence that cannabinoids (marijuana) can improve spasticity.

  • The anticonvulsant drugs Gabapentin and Carbamazepine and the antidepressant amitriptyline can improve pain and tingling sensations in certain cases.

  • SSRIs be used for depression, as well as for fatigue. Fatigue can also be influenced by amantadine and modafinil.

  • There is also treatment for bladder disturbances available which is effective in many cases. Examples are oxybutynin and trospium chloride.

  • Treatment with sildenafil (Viagra?) or similar substances can improve male erectile dysfunction in many cases.

  • Additional treatment options include plasmapheresis ("washing the blood", showing similarities to dialysis) for severe, non-steroidresponsive relapses.


Because of improved treatment for complications such as lung and bladder infections, the life expectancy of those diagnosed with MS is only slightly reduced. The earlier in life disease onset occurs, the slower disability progresses. This is due to more frequent chronic progressive courses with faster accumulation of disability when onset occurs at a higher age. Disability after 5 years correlates well with disability after 15 years: 2/3 of MS patients with low disability after 5 years will not markedly deteriorate during the next ten years. Further MS cases in the family do not influence disease progression. 1 of 3 patients will still be able to work after 15-20 years. Visual loss as the initial symptom is a marker for a rather good prognosis; gait disturbance, weakness or numbness for a rather poor prognosis. Rapid regression of initial symptoms, age at onset below 35, only a single symptom at onset, rapid development of initial symptoms and short duration of the last relapse indicate a good prognosis. When the initial disease course is relapsing remitting, the statistical duration until a wheelchair is needed, is 20 years. This means that many MS patients will never need a wheelchair. If the disease course is primary progressive then a wheelchair at an average will be needed after 6 to 7 years. It has to be noted that most of this longterm data was acquired before the advent of modern immunomodulatory drugs about 10 years ago, which have been shown to delay disease progression over a period of several years.

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