Multiple sclerosis

Multiple sclerosis

Multiple sclerosis (MS) is 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.

Table of contents

1 Historical overview
2 Geographic, race, sex and age distribution (Epidemiology)
3 Is MS a hereditary disease? (Genetics)
4 Disease mechanisms (Etiology and Pathogenesis)
5 Diagnosis
6 Signs and symptoms
7 Disease course and clinical subtypes
8 Factors triggering a relapse
9 Prognosis
10 Treatment
11 Editorial Note
12 Links to national MS societies

Historical overview

There are no antique reports about a patient who could have suffered from MS. St. Lidwina of Schiedam (1380-1433), a Dutch nun, may be the first reported MS patient. From an age of 16 years she developed pain, weakness of the legs and visual loss in a MS-like fluctuating manner, until she died at an age of 53.

St. Lidwina of Schiedam - the first MS patient?

Augustus Frederick d'Este (1794-1848), an illegitimate grandson of King George III, is another famous MS patient since he kept a diary which gives us a detailed description of his 22 years lasting disease. At an age of 28 it started with sudden transient visual loss after the funeral of a friend. During the course of his disease he developed weakness of legs, clumsiness of hands, numbness, dizziness, bladder disturbances and erectile dysfunction. 1844 he used a wheelchair. Until his death four years later he kept an optimistic view of life.
Robert Hooper (1773-1835), an English pathologist and practising physician, Robert Carswell (1793-1857), an English professor of pathology, and Jean Cruveilhier (1791-1873), a French professor of pathologic anatomy, were the first to describe the disease by medical illustrations as well as by clinical details. Jean-Martin Charcot (1825-1893), a french neurologist, summarised previous reports and made important contributions by his own clinical and pathological observations. He recognised multiple sclerosis (sclerose en plaques) as an entity, i.e. a distinct, separate disease.
After 130 years of intensive research we know much more about the genesis of MS and effective treatment is available. However, MS is still an incurable disease and the final reason for developing MS is still unknown.

Geographic, race, sex and age distribution (Epidemiology)

In northern Europe, continental North America and Australasia about one of 1000 citizens suffers from multiple sclerosis whereas the frequency in the Arabian peninsula, Asia and continental South America is much lower. In Black Africa MS is extremely rare. With important exceptions, in the Northern hemisphere there is a North-South gradient and in the Southern hemisphere there is a South-North gradient with very low frequencies near the equator. Climate, diet, geomagnetism, toxins, sunlight, genetic factors and infective agents 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 an age of 15 years, the migrant acquires the risk to develop MS of his new country. If migration takes place after an age of 15 years, the migrant keeps the risk for MS of his home country.
MS mainly occurs in the Caucasian race. It is 20-fold lower in the Innuits of Canada than in other Canadians living in the same areas. It is also rare in the Indian tribes of North America, the Aborigines of Australia and the Maoris of New Zealand. These few examples point out that the genetic background also 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 2F:1M. In children who rarely can develop MS the sex ratio may reach 3F:1M whereas MS presenting 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.

Is MS a hereditary disease? (Genetics)

MS is no strictly 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 known gene that is mainly responsible for MS. Few genes have been demonstrated to increase the risk of MS. Although those genes are interesting from a scientific point of view, they have no diagnostic relevance since their influence on the risk for developing MS is to low.
Overall, one of 25 siblings of MS-affected individuals will develop MS. 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 about 1 of 40 children will develop MS later in life.

Disease mechanisms (Etiology and Pathogenesis)

The final reason for developing MS is unknown. It is hypothesised that viral infection or another environmental factor in the childhood might prime the immune system for an abnormal reaction later in life. On a molecular level, there might be some 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". For sure, 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 (T lymphocytes) - amongst other functions important in antiviral defence - plays a key role in the development of MS. Under normal circumstances, these T lymphocytes can distinguish between self and non-self (see also immunity). Some of them are thought to recognize myelin components of the central nervous system presented by other immune cells. Myelin is a fatty substance containing a variety of proteins, which covers the nerve fibres (axons) and which is important for proper nerve conduction. In healthy individuals these "autoreactive" T lymphocytes, i.e. recognising structures of the own body, are under control. Normally, there is a tight barrier between blood and brain, called the blood brain barrier (BBB), and there is only low trafficking of T lymphocytes between blood and brain. The BBB is built up by specialised cells covering the inside of the blood vessel walls like wallpaper. These cells are called cerebral endothelial cells.
In MS, the BBB breaks down; autoreactive T lymphocytes cross the BBB and trigger an inflammatory process mediated also by other immune cells and soluble factors, 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 myelin destruction called demyelination. Repair mechanisms 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 after days to months. Nevertheless, axonal damage and irreversible loss of neurons occur early during the disease course. However, due to its plasticity the brain can compensate for a lot of 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.

Diagnosis

A definite diagnosis of MS requires evidence for dissemination of lesions within the central nervous system both in space and in time. This means, on the one hand there has to be evidence for at least two distinct lesions, which can be demonstrated by clinical symptoms or Magnetic Resonance Imaging (MRI); on the other hand definite diagnosis requires occurrence of new symptoms or MRI lesions within a time interval of at least 30 days. Lumbar puncture, which especially in young adults is usually not much more painful than normal blood withdrawal, is useful to provide evidence for chronic inflammation of the central nervous system by demonstrating oligoclonal banding (OCB). Nerve conduction studies of optic, sensory and motor nerves (VEP, SEP, MEP) can provide further evidence for MS since the process of demyelination results in reduced nerve conduction velocities which can be frequently detected in MS patients. The diagnostic process is completed by several laboratory investigations to exclude other diseases that can mimic MS (e.g. Sarcoidosis, Vasculitis, Lyme disease [syn. Borreliosis]).

Signs and symptoms

Affected individuals may experience a wide variety of symptoms, such as loss of vision, double vision, nystagmus, difficulty with speech, different kinds of tremor, clumsiness of hands, unsteadiness of gait, weakness, spasticity, numbness, bladder or bowel as well as sexual dysfuction. 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.

Disease course and clinical subtypes

In most cases MS starts with an acute flare-up of symptoms within hours to days, called relapse, exacerbation, bout, episode or attack. Inflammation of an optic nerve (optic neuritis), causing painfulness of eye movement and subsequent visual deterioration frequently is the first symptom. However, not all patients with optic neuritis develop MS. Sensory disturbances like numbness or tingling sensations are other frequent initial symptoms. In principle, MS can start with each of the symptoms mentioned in the section "Signs and symptoms".
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 showed that nerve damage can continue in relapsing remitting patients even if symptoms subside. It has been known for a long time that "MS never sleeps". That highlights the importance of preventive treatment if 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 life.
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.

Factors triggering a relapse

In general, relapses tend to occur more frequently during spring and summer than during autumn and winter.
Infections like common cold, influenza or unspecific diarrhoea 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. those working in a pharmacy). Tetanus vaccination is considered to be safe as well although so far not studied in that detail. In general, vaccinations with living, attenuated viruses increase the risk of relapses.
Especially during the last three months of pregnancy there is a natural protection against relapses although relapses can also occur during pregnancy. During the first months after pregnancy, especially during the first six weeks, the risk for a relapse is increased (20-40% of all female MS patients after a birth). According to current knowledge pregnancy seems not to influence long term disability.
Statistically, there is no good evidence for triggering of relapses through trauma or operations. In principle, operations require no special cautions if not dictated through existing disability.
Sport is possible although extremes like a marathon should rather be avoided.
Emotional stress may cause a relapse although study data are inconsistent.
Heat can transiently increase symptoms which is called Uhthoff's phenomenon. This is why some patients avoid sauna or even hot showers. However, heat is no established trigger of relapses.
Extensive sun bathes should be avoided since sun radiation is a strong stimulus for the immune system; the same is true for fastening cures.

Prognosis

Due to improved treatment of complications like lung or bladder infections life expectancy is only slightly reduced. The earlier in life disease onset occurs, the slower disability progression goes on. 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 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 these longterm data were acquired before the advent of the modern immunomodulatory drugs about 10 years ago which have been shown to delay disease progression over a period of several years.
Currently there is no clinically established laboratory investigation available to predict prognosis or therapeutic response although promising approaches have been untertaken that need further confirmation (most recently anti-MOG, anti-MBP, TRAIL).

Treatment

There is no known definite cure for multiple sclerosis. However, several drugs have proven to be effective in the treatment of MS. Intensive research is undertaken to study a variety of promising new drugs. Treatment is aimed maintaining the maximum quality of life.

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. There is no good evidence that corticosteroids influence longterm outcome.

Long-term treatment can influence the course of the disease:
- Interferon-beta1a or 1b (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 have to 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 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 it has to be injected into the skin. Attempts to develop pills containing glatiramer acetate have also not been successful so far. Copaxone is effective in the treatment of relapsing remitting MS. So far beneficial effects in secondary progressive MS could not convincingly be demonstrated. Main side effects include inflammatory skin reactions at the injection site and rarely a harmless and transient but perturbing "post-injection" reaction manifesting by flushing, chest tightness, heart palpitation, 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 are effective in the treament of relapsing remitting MS. 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.
- 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, many originally developed for other purposes, are used to treat symptoms without influencing the inflammatory nature of the disease (symptomatic treatment). For example, the anti-seizure drugs gabapentine (Neurontin) and carbamazepine can improve pain and tingling sensations in certain cases. Anti-spasmatics such as baclofen are useful against spasticity. There is no convincing evidence that cannabinoids (marijuana) can improve spasticity. SSRIs are used for depression as well as for fatigue. Fatigue can also be influenced by amantadine as well as with a variety of stimulants, such as histamine and caffeine. There is also treatment for bladder disturbances available which is effective in many cases. Treatment with Viagra or similar substances can improve male erectile dysfuntion in many cases.

Editorial Note

No guarantee for anything stated in this article. But I guarantee independence from industry. Check whether I approved the current version (Buttmann). I wrote this article as a private person. If you would like to improve this article linguistically or textually (which I would appreciate very much) please discuss with me before you make changes to ensure optimal quality and reliability (please understand that I can not answer personal questions):
Dr. Mathias Buttmann
m.buttmann@mail.uni-wuerzburg.de