Disease

What is Multiple sclerosis?

multiple1
Multiple sclerosis (MS), is an inflammatory disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to communicate, resulting in a wide range of signs and symptoms, including physical, mental, and sometimes psychiatric problems. MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or building up over time (progressive forms). Between attacks, symptoms may disappear completely; however, permanent neurological problems often occur, especially as the disease advances.

While the cause is not clear, the underlying mechanism is thought to be either destruction by the immune system or failure of the myelin-producing cells.Proposed causes for this include genetics and environmental factors such as infections. MS is usually diagnosed based on the presenting signs and symptoms and the results of supporting medical tests.
multiple2
There is no known cure for multiple sclerosis. Treatments attempt to improve function after an attack and prevent new attacks.Medications used to treat MS while modestly effective can have adverse effects and be poorly tolerated. Many people pursue alternative treatments, despite a lack of evidence. The long-term outcome is difficult to predict, with good outcomes more often seen in women, those who develop the disease early in life, those with a relapsing course, and those who initially experienced few attacks.Life expectancy is on average 5 to 10 years lower than that of an unaffected population.

Signs and Symptoms

A person with MS can have almost any neurological symptom or sign; with autonomic, visual, motor, and sensory problems being the most common. The specific symptoms are determined by the locations of the lesions within the nervous system, and may include loss of sensitivity or changes in sensation such as tingling, pins and needles or numbness, muscle weakness, very pronounced reflexes, muscle spasms, or difficulty in moving; difficulties with coordination and balance (ataxia);
multiple4
problems with speech or swallowing, visual problems (nystagmus, optic neuritis or double vision), feeling tired, acute or chronic pain, and bladder and bowel difficulties, among others.Difficulties thinking and emotional problems such as depression or unstable mood are also common. Uhthoff’s phenomenon, a worsening of symptoms due to exposure to higher than usual temperatures, and Lhermitte’s sign, an electrical sensation that runs down the back when bending the neck, are particularly characteristic of MS. The main measure of disability and severity is the expanded disability status scale(EDSS).

The condition begins in 85% of cases as a clinically isolated syndrome over a number of days with 45% having motor or sensory problems, 20% having optic neuritis, and 10% having symptoms related to brainstem dysfunction, while the remaining 25% have more than one of the previous difficulties. The course of symptoms occurs in two main patterns initially: either as episodes of sudden worsening that last a few days to months (called relapses, exacerbations, bouts, attacks, or flare-ups) followed by improvement (85% of cases) or as a gradual worsening over time without periods of recovery (10-15% of cases). A combination of these two patterns may also occur or people may start in a relapsing and remitting course that then becomes progressive later on.Relapses are usually not predictable, occurring without warning.Exacerbations rarely occur more frequently than twice per year.Some relapses, however, are preceded by common triggers and they occur more frequently during spring and summer.Similarly, viral infections such as the common cold, influenza, or gastroenteritis increase their risk.Stress may also trigger an attack. Women with MS who become pregnant experience fewer relapses; however, during the first months after delivery the risk increases.Overall, pregnancy does not seem to influence long-term disability.Many events have not been found to affect relapse rates including vaccination, breast feeding,[1] physical trauma,and Uhthoff’s phenomenon.

Causes

The cause of MS is unknown; however, it is believed to occur as a result of some combination of environmental factors such as infectious agents and genetics.Theories try to combine the data into likely explanations, but none has proved definitive. While there are a number of environmental risk factors and although some are partly modifiable, further research is needed to determine whether their elimination can prevent MS.

Geography

MS is more common in people who live farther from the equator, although exceptions exist.These exceptions include ethnic groups that are at low risk far from the equator such as the Samis, Amerindians, Canadian Hutterites, New Zealand Māori, and Canada’s Inuit, as well as groups that have a relatively high risk close to the equator such asSardinians, Palestinians and Parsis.The cause of this geographical pattern is not clear. While the north-south gradient of incidence is decreasing, as of 2010 it is still present.

MS is more common in regions with northern European populations[1] and the geographic variation may simply reflect the global distribution of these high-risk populations.Decreased sunlight exposure resulting in decreased vitamin D production has also been put forward as an explanation.A relationship between season of birth and MS lends support to this idea, with fewer people born in the northern hemisphere in November as compared to May being affected later in life. Environmental factors may play a role during childhood, with several studies finding that people who move to a different region of the world before the age of 15 acquire the new region’s risk to MS. If migration takes place after age 15, however, the person retains the risk of his home country.There is some evidence that the effect of moving may still apply to people older than 15.

Genetics

multiple5
HLA region of Chromosome 6. Changes in this area increase the probability of getting MS.
MS is not considered a hereditary disease; however, a number of genetic variations have been shown to increase the risk. The probability is higher in relatives of an affected person, with a greater risk among those more closely related. In identical twins both are affected about 30% of the time, while around 5% for non-identical twins and 2.5% of siblings are affected with a lower percentage of half-siblings. If both parents are affected the risk in their children is 10 times that of the general population. MS is also more common in some ethnic groups than others.

Specific genes that have been linked with MS include differences in the human leukocyte antigen (HLA) system—a group of genes onchromosome 6 that serves as the major histocompatibility complex (MHC).

Infectious agents

Many microbes have been proposed as triggers of MS, but none have been confirmed. Moving at an early age from one location in the world to another alters a person’s subsequent risk of MS.An explanation for this could be that some kind of infection, produced by a widespread microbe rather than a rare one, is related to the disease. Proposed mechanisms include the hygiene hypothesis and the prevalence hypothesis. The hygiene hypothesis proposes that exposure to certain infectious agents early in life is protective, the disease being a response to a late encounter with such agents.The prevalence hypothesis proposes that the disease is due to an infectious agent more common in regions where MS is common and where in most individuals it causes an ongoing infection without symptoms. Only in a few cases and after many years does it cause demyelination. The hygiene hypothesis has received more support than the prevalence hypothesis.

Pathophysiology

The three main characteristics of MS are the formation of lesions in the central nervous system (also called plaques), inflammation, and the destruction of myelin sheaths of neurons. These features interact in a complex and not yet fully understood manner to produce the breakdown of nerve tissue and in turn the signs and symptoms of the disease.Additionally, MS is believed to be an immune-mediated disorder that develops from an interaction of the individual’s genetics and as yet unidentified environmental causes.Damage is believed to be caused, at least in part, by attack on the nervous system by a person’s own immune system.

Diagnosis

Multiple sclerosis is typically diagnosed based on the presenting signs and symptoms, in combination with supporting medical imaging and laboratory testing. It can be difficult to confirm, especially early on, since the signs and symptoms may be similar to those of other medical problems.The McDonald criteria, which focus on clinical, laboratory, and radiologic evidence of lesions at different times and in different areas, is the most commonly used method of diagnosis .While the above criteria allow for a non-invasive diagnosis, some state that the only definitive proof is an autopsy or biopsy where lesions typical of MS are detected.
multiple3
MRI Showing Plaques Clinical data alone may be sufficient for a diagnosis of MS if an individual has had separate episodes of neurologic symptoms characteristic of the disease. In those who seek medical attention after only one attack, other testing is needed for the diagnosis. The most commonly used diagnostic tools are neuroimaging, analysis of cerebrospinal fluid and evoked potentials. Magnetic resonance imaging of the brain and spine may show areas of demyelination (lesions or plaques). Gadolinium can be administered intravenously as a contrast agent to highlight active plaques and, by elimination, demonstrate the existence of historical lesions not associated with symptoms at the moment of the evaluation. Testing of cerebrospinal fluid obtained from a lumbar puncture can provide evidence of chronic inflammation in the central nervous system. The cerebrospinal fluid is tested for oligoclonal bands of IgG on electrophoresis, which are inflammation markers found in 75–85% of people with MS. The nervous system in MS may respond less actively to stimulation of the optic nerve and sensory nerves due to demyelination of such pathways. These brain responses can be examined using visual- and sensory-evoked potentials.

Types

multiple6

Progression of MS subtypes

Several subtypes, or patterns of progression, have been described. Subtypes use the past course of the disease in an attempt to predict the future course. They are important not only for prognosis but also for treatment decisions. In 1996, the United States National Multiple Sclerosis Society described four clinical courses:

  • Relapsing-remitting
  • Secondary progressive
  • Relapsing progressive
  • Primary progressive

The relapsing-remitting subtype is characterized by unpredictable relapses followed by periods of months to years of relative quiet (remission) with no new signs of disease activity. Deficits that occur during attacks may either resolve or leave problems, the latter in about 40% of attacks and being more common the longer a person has had the disease.This describes the initial course of 80% of individuals with MS.[1] When deficits always resolve between attacks, this is sometimes referred to as benign MS, although people will still build up some degree of disability in the long term.[1] On the other hand, the term malignant multiple sclerosis is used to describe people with MS having reached significant level of disability in a short period of time. The relapsing-remitting subtype usually begins with a clinically isolated syndrome (CIS). In CIS, a person has an attack suggestive of demyelination, but does not fulfill the criteria for multiple sclerosis. 30 to 70% of persons experiencing CIS later develop MS.

Secondary progressive MS occurs in around 65% of those with initial relapsing-remitting MS, who eventually have progressive neurologic decline between acute attacks without any definite periods of remission.Occasional relapses and minor remissions may appear.The most common length of time between disease onset and conversion from relapsing-remitting to secondary progressive MS is 19 years.

The primary progressive subtype occurs in approximately 10–20% of individuals, with no remission after the initial symptoms. It is characterized by progression of disability from onset, with no, or only occasional and minor, remissions and improvements.The usual age of onset for the primary progressive subtype is later than of the relapsing-remitting subtype. It is similar to the age that secondary progressive usually begins in relapsing-remitting MS, around 40 years of age.
Progressive relapsing MS describes those individuals who, from onset, have a steady neurologic decline but also have clear superimposed attacks. This is the least common of all subtypes.

Unusual types of MS have been described; these include Devic’s disease, Balo concentric sclerosis, Schilder’s diffuse sclerosis, and Marburg multiple sclerosis. There is debate on whether they are MS variants or different diseases. Multiple sclerosis behaves differently in children, taking more time to reach the progressive stage. Nevertheless, they still reach it at a lower average age than adults usually do.

Management

Although there is no known cure for multiple sclerosis, several therapies have proven helpful. The primary aims of therapy are returning function after an attack, preventing new attacks, and preventing disability. As with any medical treatment, medications used in the management of MS have several adverse effects. Alternative treatments are pursued by some people, despite the shortage of supporting evidence.

Acute attacks

During symptomatic attacks, administration of high doses of intravenous corticosteroids, such as methylprednisolone, is the usual therapy.Although, in general, effective in the short term for relieving symptoms, corticosteroid treatments do not appear to have a significant impact on long-term recovery. The consequences of severe attacks that do not respond to corticosteroids might be treatable by plasmapheresis

Disease-modifying treatments

Relapsing remitting multiple sclerosis

Eight disease-modifying treatments have been approved by regulatory agencies for relapsing-remitting multiple sclerosis (RRMS) including: interferon beta-1a, interferon beta-1b,glatiramer acetate, mitoxantrone, natalizumab, fingolimod,teriflunomide and dimethyl fumarate. In RRMS they are modestly effective at decreasing the number of attacks. The interferons and glatiramer acetate are first-line treatments and are roughly equivalent, reducing relapses by approximately 30%.Early-initiated long-term therapy is safe and improves outcomes. Natalizumab reduces the relapse rate more than first-line agents; however, due to issues of adverse effects is a second-line agent reserved for those who do not respond to other treatments or with severe disease. Mitoxantrone, whose use is limited by severe adverse effects, is a third-line option for those who do not respond to other medications. Treatment of clinically isolated syndrome (CIS) with interferons decreases the chance of progressing to clinical MS. Efficacy of interferons and glatiramer acetate in children has been estimated to be roughly equivalent to that of adults.

Progressive multiple sclerosis

No treatment has been shown to change the course of primary progressive MS and as of 2011 only one medication, mitoxantrone, has been approved for secondary progressive MS. In this population tentative evidence supports mitoxantrone moderately slowing the progression of the disease and decreasing rates of relapses over two years.

Adverse effects

The disease-modifying treatments have several adverse effects. One of the most common is irritation at the injection site for glatiramer acetate and the interferons (up to 90% with subcutaneous injections and 33% with intramuscular injections).Over time, a visible dent at the injection site, due to the local destruction of fat tissue, known as lipoatrophy, may develop.[63] Interferons may produce flu-like symptoms.some people taking glatiramer experience a post-injection reaction with flushing, chest tightness, heart palpitations, breathlessness, and anxiety, which usually lasts less than thirty minutes.More dangerous but much less common are liver damage from interferons, systolic dysfunction (12%), infertility, and acute myeloid leukemia (0.8%) from mitoxantrone, and progressive multifocal leukoencephalopathy occurring with natalizumab (occurring in 1 in 600 people treated).

Fingolimod may give rise to hypertension and slowed heart rate, macular edema, elevated liver enzymes or a reduction in lymphocyte levels.Tentative evidence supports the short term safety of teriflunomide, with common side effects including: headaches, fatigue, nausea, hair loss, and limb pain.There have also been reports of liver failure and PML with its use and it is dangerous for fetal development.] Most common side effects of dimethyl fumarate are flushing and gastrointestinal problems. While dimethyl fumarate may lead to a reduction in the white blood cell count there were no reported cases of opportunistic infections during trials.

Associated symptoms

Both medications and neurorehabilitation have been shown to improve some symptoms, though neither changes the course of the disease. Some symptoms have a good response to medication, such as an unstable bladder and spasticity, while others are little changed.[1] For neurologic problems, a multidisciplinary approach is important for improving quality of life; however, it is difficult to specify a ‘core team’ as many different health services may be needed at different points in time. Multidisciplinary rehabilitation programs increase activity and participation of people with MS but do not influence impairment level.There is limited evidence for the overall efficacy of individual therapeutic disciplines, although there is good evidence that specific approaches, such as exercise, and psychology therapies, in particular cognitive behavioral approaches are effective.

Useful links

FAQ