Multiple Sclerosis

What is multiple sclerosis?

Multiple sclerosis (MS) is a disease in which the nerves of the central nervous system (brain and spinal cord) degenerate. Myelin, which provides a covering or insulation for nerves, improves the conduction of impulses along the nerves and also is important for maintaining the health of the nerves. In multiple sclerosis, inflammation causes the myelin to disappear. Consequently, the electrical impulses that travel along the nerves decelerate, that is, become slower. In addition, the nerves themselves are damaged. As more and more nerves are affected, a person experiences a progressive interference with functions that are controlled by the nervous system such as vision, speech, walking, writing, and memory.
About 350,000 people in the U.S. have multiple sclerosis. Usually, a person is diagnosed with multiple sclerosis between 20 and 50 years of age, but multiple sclerosis has been diagnosed in children and in the elderly. Multiple sclerosis is twice as likely to occur in Caucasians as in any other group. Women are twice as likely as men to be affected by multiple sclerosis earlier in life.

What causes multiple sclerosis?

The cause of multiple sclerosis is still unknown. In the last 20 years, researchers have focused on disorders of the immune system and genetics for explanations. The immune system is the body's defender and is highly organized and regulated. If triggered by an aggressor or foreign object, the immune system mounts a defensive action which identifies and attacks the invader and then withdraws. This process depends upon rapid communication among the immune cells and the production of cells that can destroy the intruder. In multiple sclerosis, researchers suspect that a foreign agent such as a virus alters the immune system so that the immune system perceives myelin as an intruder and attacks it. The attack by the immune system on the tissues that it is supposed to protect is called autoimmunity, and multiple sclerosis is believed to be a disease of autoimmunity. While some of the myelin may be repaired after the assault, some of the nerves are stripped of their myelin covering (become demyelinated). Scarring also occurs, and material is deposited into the scars and forms plaques

Is multiple sclerosis inherited?

Although its role is unclear, genetics may play a role in multiple sclerosis. European gypsies, Eskimos and African Bantu essentially do not develop multiple sclerosis, while Native Indians of North and South America, Japanese and other Asian groups have a low incidence. The general population has less than a one-percent chance of developing multiple sclerosis. The chance increases in families where a first-degree relative has the disease. Thus, a brother, sister, parent, or child of a person with multiple sclerosis stands a one-percent to three percent chance of developing multiple sclerosis. Similarly, an identical twin runs a nearly 30% chance of acquiring multiple sclerosis whereas a non-identical twin has only a 4% chance if the other twin has the disease. These statistics suggest that genetic factors play a major role in multiple sclerosis. However, other data suggest that environmental factors also play an important role.

What are the types of multiple sclerosis?

There are different clinical manifestations of multiple sclerosis. During an attack, a person experiences a sudden deterioration in normal physical abilities that may range from mild to severe. This attack, sometimes referred to as an exacerbation of multiple sclerosis, typically lasts more than 24 hours and generally more than a few weeks (rarely more than four weeks).
About 65%-80% of individuals begin with relapsing-remitting (RR) MS, the most common type. In this type, they experience a series of attacks followed by complete or partial disappearance of the symptoms (remission) until another attack occurs (relapse). It may be weeks to decades between relapses.
In primary-progressive (PP) MS, there is a continuous, gradual decline in a person's physical abilities from the outset rather than relapses. About 10%-20% of individuals begin with PP-MS.
Those beginning with RR-MS can then enter a phase where relapses are rare but more disability accumulates, and are said to have secondary-progressive (SP) MS. About 50% of RR-MS individuals will develop SP-MS within 10 years. Over several decades, most RR-MS persons will experience progression to SP-MS. Progressive-Relapsing (PR) MS is a type of multiple sclerosis characterized by a steady decline in abilities accompanied by sporadic attacks. There are cases of multiple sclerosis that are mild and can be recognized only retrospectively after many years and also rare cases of extremely rapid progression of multiple sclerosis symptoms (sometimes fatal) known as malignant or fulminant (Marburg variant) multiple sclerosis.

What are the symptoms of multiple sclerosis?

Symptoms of multiple sclerosis may be single or multiple and may range from mild to severe in intensity and short to long in duration. Complete or partial remission from symptoms occurs early in about 70% of individuals with multiple sclerosis.

• Visual disturbances may be the first symptoms of multiple sclerosis, but they usually subside. A person may notice a patch of blurred vision, red-to-orange or red-to-gray distortions (color desaturation), or monocular visual loss (loss of vision in one eye). Visual symptoms due to optic nerve inflammation (optic neuritis) in multiple sclerosis usually are accompanied or preceded by eye pain.
• Limb weakness with or without difficulties with coordination and balance may occur early.
• Muscle spasms, fatigue, numbness, and prickling pain are common symptoms.
• There may be a loss of sensation, speech impediment (typically a problem articulating words), tremors, or dizziness.

Fifty-percent of people experience mental changes such as:

• decreased concentration,
• attention deficits,
• some degree of memory loss,
• inability to perform sequential tasks, or
• impairment in judgment.

Other symptoms may include:

• depression,
• manic depression,
• paranoia, or
• an uncontrollable urge to laugh and weep.

As the disease worsens, individuals may experience sexual dysfunction or reduced bowel and bladder control. Heat appears to intensify multiple sclerosis symptoms for about 60% of those with the disease. Pregnancy seems to reduce the number of attacks, especially during the third trimester

How is multiple sclerosis diagnosed?

Due to the broad range and subtleties of symptoms, multiple sclerosis may not be diagnosed for months to years after the onset of symptoms. Physicians, particularly neurologists, take detailed histories and perform complete physical and neurological examinations.

• MRI (magnetic resonance imaging) scans with intravenous gadolinium helps to identify, describe, and in some instances date lesions in the brain (plaques).
• An electro-physiological test, evoked potentials, examines the impulses traveling through the nerves to determine if the impulses are moving normally or too slowly.
• Finally, examining the cerebro-spinal fluid that surrounds the brain and spinal cord may identify abnormal chemicals (antibodies) or cells that suggest the presence of multiple sclerosis.

Collectively, these three tests help the physician in confirming the diagnosis of multiple sclerosis. For a definite diagnosis of multiple sclerosis, dissemination in time (at least two separate symptomatic events or changes on MRI over time) and in anatomical space (at least two separate locations within the central nervous system, which can be demonstrated by MRI or neurological exam) must be demonstrated.

How is multiple sclerosis treated?

There are many issues for the patient and physician to consider in treating multiple sclerosis. Goals may include:

• improving the speed of recovery from attacks (treatment with steroid drugs);
• reducing the number of attacks or the number of MRI lesions; or
• attempting to slow progression of the disease (treatment with disease modifying drugs or DMDs).

An additional goal is relief from complications due to the loss of function of affected organs (treatment with drugs aimed at specific symptoms).
Most neurologists will consider treatment with DMDs once the diagnosis of relapsing remitting multiple sclerosis is established. Many will begin treatment at the time of the first multiple sclerosis attack, since clinical trials have suggested that patients in whom treatment is delayed may not benefit as much as patients who are treated early.
It is important for patients to talk to their doctor before deciding to go on therapy since DMDs differ in their uses (for example, one DMD may be used for slowing progressing disability but not for treatment of the first attack of MS; another DMD may be used for reducing relapses but not for slowing progressing disability). Finally, utilizing support groups or counseling may be helpful for patients and their families whose lives may be affected directly by multiple sclerosis.
Once goals have been set, initial therapy may include medications to manage attacks, symptoms, or both. An understanding of the potential side effects of drugs is critical for the patient because sometimes side effects alone deter patients from drug therapy. Patients may choose to avoid drugs altogether or choose an alternative drug that may offer relief with fewer side effects. A continuous dialogue between the patient and physician about the medications is important in determining the needs for treatment.
Drugs known to affect the immune system have become the primary focus for managing multiple sclerosis. Initially, corticosteroids, such as prednisone (Deltasone, Liquid Pred, Deltasone, Orasone, Prednicen-M) or methylprednisolone (Medrol, Depo-Medrol), were widely used. However, since their effect on the immune system is non-specific (general) and they may use may cause numerous side effects, corticosteroids now tend to be used to manage only severe multiple sclerosis attacks (that is, attacks leading to physical disability or causing pain).

Interferons for relapsing multiple sclerosis

Since 1993, medications that alter the immune system, particularly interferons, have been used to manage multiple sclerosis. Interferons are protein messengers that cells of the immune system manufacture and use to communicate with one another. There are different types of interferons, such as alpha, beta, and gamma. All interferons have the ability to regulate the immune system and play an important role in protecting against intruders including viruses. Each interferon functions differently, but the functions overlap. The beta interferons have been found useful in managing multiple sclerosis.

• Interferon beta-1b (Betaseron®) was the first interferon approved in the U. S. to manage RR-MS in 1993.
• In 1996, intramuscular interferon beta-1a (Avonex®) gained FDA approval for RR-MS.
• Subcutaneous Interferon beta-1a (Rebif®) was approved in the U. S. in 2002.
• The FDA also approved the marketing of Interferon beta-1b under the brand name Extavia® in 2009.

Overall, patients treated with interferons experience fewer relapses or a longer interval between relapses. Avonex® and Rebif® are used to slow progressing disability. The most common side effect is a flu-like syndrome that includes fever, tiredness, weakness, chills, and muscle aches. This syndrome tends to occur less frequently as therapy continues. Other common side effects are injection site reactions, changes in blood cell counts, and abnormalities of liver tests. Regular liver tests and blood counts are recommended for patients receiving beta-interferons. Periodic thyroid function testing also is recommended because of the effects of beta-interferons on the thyroid gland. With the concomitant use of analgesics and evolving nursing experience with managing local skin reactions, the tolerability to interferons seems to have improved over the years.
Clinical trials of beta-interferon in patients with the first attack of multiple sclerosis showed that in this early patient population, the second attack was delayed. Interferons approved by the FDA for treatment at the first attack of multiple sclerosis include Avonex®, which is administered intramuscularly once a week, and Betaseron® or Extavia®, which are administered subcutaneously every other day.
Available beta-interferons include:
Interferon beta-1b (Betaseron® and Extavia®) are used for the treatment of relapsing forms of multiple sclerosis, to reduce the frequency of clinical relapses. Patients with multiple sclerosis in whom efficacy has been demonstrated include patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis.
Interferon beta-1a (Rebif®) is used for the treatment of patients with relapsing forms of multiple sclerosis to decrease the frequency of clinical relapses and delay the accumulation of physical disability. Efficacy of Rebif® in chronic progressive multiple sclerosis has not been established.
Interferon beta-1a (Avonex®) is used for the treatment of patients with relapsing forms of multiple sclerosis to slow the accumulation of physical disability and decrease the frequency of clinical relapses. Patients with multiple sclerosis in whom efficacy has been demonstrated include patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis. Safety and efficacy in patients with progressive multiple sclerosis has not been established.

Other medications approved for relapsing multiple sclerosis

Glatiramer acetate (Copaxone)
Glatiramer acetate (Copaxone) is another DMD that is approved for reducing the frequency of relapses in RR-MS. Glatiramer acetate is a synthetic (man-made) amino acid mixture that may resemble a protein component of myelin. It is thought that the immune system reaction against myelin in multiple sclerosis may be blocked or diminished by glatiramer acetate. A reaction occurring immediately after the injection of glatiramer acetate is common, affecting one out of 10 patients. The reaction may involve flushing, chest pain or tightness, palpitations, anxiety, shortness of breath, tightness in the throat, or hives. The reaction usually resolves within 30 minutes and requires no treatment. Some patients may be at risk of developing lipoatrophy, inflammation and destruction of fat tissue beneath the skin at the site of injection.
Natalizumab (Tysabri®)
Natalizumab (Tysabri®) is a drug approved by the FDA to treat relapsing multiple sclerosis. Natalizumab is a monoclonal antibody against VLA-4, a molecule required for immune cells to adhere to other cells, and penetrate into the brain. It is administered via monthly intravenous infusions. It carries a warning for a potentially fatal disease, progressive multifocal leukoencephalopathy (PML), a viral infection of the brain that usually leads to death or severe disability. For this reason only patients who have signed up for treatment under a controlled drug distribution program can receive treatment with natalizumab.
Natalizumab is used alone for the treatment of patients with relapsing forms of multiple sclerosis to delay the progression of physical disability and reduce the frequency of clinical relapses. The safety and efficacy of natalizumab beyond two years are unknown. The risk of PML may increase with prolonged exposure to natalizumab. Because natalizumab increases the risk of PML, it is generally recommended only for patients who have had an inadequate response to, or are unable to tolerate an alternate multiple sclerosis therapy.
Mitoxantrone (Novantrone®)
Mitoxantrone (Novantrone®) is approved by the FDA for the treatment of multiple sclerosis (SP-MS, PR-MS, and worsening RR-MS). Mitoxantrone is a chemotherapy drug that carries the risk of serious cardiac side effects or cancer (leukemia). Because of these serious side effects, physicians tend to reserve its use for more advanced or worsening cases of multiple sclerosis, and there is a limit to the total amount of mitoxantrone that can be administered. Cardiac monitoring prior to each dose and yearly following the last dose of mitoxantrone also is necessary.
Mitoxantrone is used for reducing neurologic disability and/or the frequency of clinical relapses in patients with SP-MS, PR-MS, or worsening RR-MS (for example, patients whose neurologic status is significantly abnormal between relapses). Mitoxantrone is not used in the treatment of patients with PP-MS.
Fingolimod (Gilenya®)
Fingolimod (Gilenya®) is a daily oral medication to treat MS that was approved by the US FDA in September 2010 as the first oral medication to treat MS. Although the exact mechanism of action of fingolimod is unclear, it appears to work by reducing the number of lymphocytes (a type of white blood cell that is important for immunity and the inflammation process) in the blood. Fingolimod is taken daily in capsule form. It is not a cure for MS, but it has been shown to decrease the number of MS flares and slow down the development of physical disability caused by MS. Like many injectable therapies for MS, the long-term safety of fingolimod is unknown. The most common side effects of fingolimod are headache, flu, diarrhea, back pain, elevations of liver enzymes in the blood, and cough. Other side effects are also possible including eye problems, so those taking this drug should have regular ophthalmologic evaluations.

How are the physical manifestations of multiple sclerosis treated?

There are numerous medications that are used to manage complications associated with multiple sclerosis. The following table lists common complications, examples of drug and non-drug therapies, and comments about complications and/or management. Among these, only dalfampridine (Ampyra®) has been approved by the FDA as a symptomatic (non-DMD) treatment for multiple sclerosis.
Table. Multiple sclerosis complications with examples of drug and non-drug management (this list is not exhaustive; most of the drugs listed below are used to treat multiple sclerosis symptoms even though they have not been FDA-approved for these particular purposes).

Complication	Drugs	Non-drug management and comments
Difficulty walking (slowness)	dalfamipridine (Ampyra)	dalfamipridine (Ampyra) was FDA- approved in 2010 to improve walking in patients with MS. Physical therapy, orthotic equipment, and walking aids also my be of benefit.
Muscle spasticity	baclofen (Lioresal) tizanidine (Zanaflex) diazepam (Valium) clonazepam (Klonopin) dantrolene (Dantrium)	Physical therapy also may provide benefit. Most drugs are given by mouth. Some drugs are given via spinal pumps.
Weakness	None	Physical therapy and exercise are used primarily. Foot braces, canes or walkers are of benefit.
Eye problems (acute optic neuritis)	methylprednisolone (Solu-Medrol)	Solu-Medrol is given during the acute attack intravenously, sometimes followed by a corticosteroid by mouth.
Fatigue, emotional outbursts	Anti-depressants amantadine (Symmetrel) for fatigue; modafinil (Provigil) for fatigue	Decrease or avoid physical activity and heat exposure. Amitriptyline is used for sudden laughing/weeping.
Pain	aspirin Ibuprofen acetaminophen anti-convulsants anti-depressants	Aspirin, NSAIDs, acetaminophen, or physical therapy are used for muscle and back pain. Anti-convulsants, like carbamazepine (Tegretol) or gabapentin (Neurontin) are used for face or limb pain. Anti-depressants or electrical stimulation are used for prickling pain, intense tingling, and burning. Referral to pain specialist is recommended with severe pain.
Bladder dysfunction	Antibiotics Vitamin C oxybutynin (Ditropan)	Antibiotics are used to manage infections. Vitamin C and cranberry juice are used to prevent infections. Catheters are used to relieve retention of urine. Oxybutynin (Ditropan, Ditropan LX, Oxytrol) or tolterodine (Detrol, Detrol LA) is used for bladder dysfunction.
Constipation		Increase fluids and fiber.
Sexual dysfunction	sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), papaverine,  Vaginal gels	For males, erectile dysfunction drugs,  papaverine, penile implant, or electrostimulation are used. For females, vaginal gels or a vibrating device are used.
Tremors		Often resistant to treatment. Sometimes drugs or surgery are used if tremors are severe.

source:medicinenet.com