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 eventually 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 patient 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 patient 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 myelin disappears and nerves are stripped of this 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 ever contracting 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 patient 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 patients begin with Relapsing–Remitting (RR) MS, the most common type. In this type, patients 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 patient's physical abilities from the outset rather than relapses. About 10%–20% of patients begin with PP–MS.

Patients beginning with RR–MS can then enter a phase where relapses are rare but more disability accumulates, and are said to have the Secondary–Progressive (SP) type of multiple sclerosis. About 50% of RR–MS patients will develop SP–MS within 10 years. 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 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 multiple sclerosis patients.

• Visual disturbances may be the first symptoms of multiple sclerosis, but they usually subside. A patient may notice blurred vision, red–green distortion (color desaturation), or sudden monocular blindness (blindness in one eye).
  
  
• Muscle 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 patients 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, patients may experience sexual dysfunction or reduced bowel and bladder control. Heat appears to intensify multiple sclerosis symptoms for about 60% of patients. Pregnancy seems to reduce the number of attacks.

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) and in anatomical space (for example, within the central nervous system) 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 reducing the number of attacks, improving recovery from attacks, and attempting to slow further progression of the disease (treatment with disease–modifying drugs). 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 disease–modifying drugs once the diagnosis of 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. Finally, utilizing support groups or counseling may be helpful for patients and their families whose lives may directly be affected 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 and their use may cause numerous side effects, corticosteroids now tend to be used to manage only sudden, severe multiple sclerosis attacks.

Interferon

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 viral infections. 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 to manage RR–MS in 1993. In 1996, interferon beta–1a (Avonex®) gained FDA approval for RR–MS.

Overall, patients treated with interferons experience fewer relapses or a longer interval between relapses. Clinical trials have also shown effects on slowing the accumulation of 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 interferon beta–1b. With the concomitant use of analgesics and local skin measures, the tolerability to interferons has increased.

Clinical trials of interferon beta drugs in patients with the first attack of multiple sclerosis showed that in this early patient population, these drugs delay the onset of the second attack. Avonex® is administered intramuscularly once a week, Betaseron® is administered subcutaneously every other day, and Rebif® is administered subcutaneously three times per week.

Available interferon betas include:

IFN beta–1b (Betaseron®) that is 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.

IFN beta–1a (Rebif®) that 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.

IFN beta–1a (Avonex®) that 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 chronic progressive multiple sclerosis has not been established.

Other medications

Glatiramer acetate

Glatiramer acetate (Copaxone) is another disease–modifying drug 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 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 tissue beneath the skin at the site of injection. Glatiramer acetate is used for reducing the frequency of relapses in patients with relapsing–remitting multiple sclerosis.

Natalizumab

Natalizumab (Tysabri®) is a drug approved by the FDA to treat multiple sclerosis. Natalizumab is a monoclonal antibody against VLA–4, a molecule required for immune cells to adhere to other cells, penetrate the blood brain barrier and enter 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 get this treatment.

Natalizumab is used as monotherapy 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. 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 alternate multiple sclerosis therapies.

Mitoxantrone

Mitoxantrone (Novantrone®) is also approved by the FDA for the treatment of multiple sclerosis. Mitoxantrone is a chemotherapy drug that carries the risk of serious cardiac side effects or cancer. Because of these serious side effects, physicians tend to reserve its use for more advanced or worsening cases of multiple sclerosis.

Mitoxantrone is used for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing–remitting multiple sclerosis (for example, patients whose neurologic status is significantly abnormal between relapses). Mitoxantrone is not used in the treatment of patients with primary progressive multiple sclerosis.

How are the 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 therapy, and comments about complications and/or management.

Table. Multiple sclerosis complications with examples of drug and non–drug management (this list is not exhaustive; some of the drugs listed below are used to treat multiple sclerosis symptoms even though they have not been FDA–approved for this particular purpose)

Complication	Drugs	Non–drug management and comments
Muscle spasticity	baclofen (Lioresal) tizanidine (Zanaflex) diazepam (Valium) clonazepam (Klonopin) dantrolene (Dantrium)	Physical therapy may also provide benefit. Most drugs are given by mouth. Some drugs are given via spinal pumps.
Weakness	None	Physical therapy and exercise mostly are used. 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 urine retention. Oxybutynin (Ditropan, Ditropan LX, Oxytrol) or tolterodine (Detrol, Detrol LA)is used for bladder spasms.
Constipation		Increase fluids and fiber.
Sexual dysfunction	sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), papaverine (Pavabid, Vasal) 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 extreme.

What are the future directions for managing multiple sclerosis?

There is a great deal of ongoing research in multiple sclerosis, and there continues to be a focus on the immune system in investigational therapies. In addition, scientists are trying to develop techniques that allow brain cells to generate new myelin or that prevent neuronal death. Other promising approaches include the use of precursor (neuronal stem or progenitor) cells that could be implanted into the brain or spinal cord to repopulate areas of missing cells. Future therapy may involve methods designed to improve impulses traveling over the damaged nerves. Scientists also are exploring the effects of diet on multiple sclerosis.

Multiple Sclerosis At A Glance

• Multiple sclerosis (MS) is a disease which progressively injures the nerves of the brain and spinal cord.
  
  
• Injury to the nerves in multiple sclerosis may be reflected by alterations of virtually any sensory or motor (muscular) function in the body.
  
  
• The cause of multiple sclerosis is unknown, but it has become widely accepted that genetic, immunological, and environmental factors play a role.
  
  
• Current FDA–approved multiple sclerosis treatments include the beta–interferons (Betaseron®, Rebif® and Avonex®), glatiramer acetate (Copaxone®), mitoxantrone (Novantrone®) and natalizumab (Tysabri®). The selection of therapy should be made after the multiple sclerosis patient has been properly informed of drug efficacy, administration routes, risks of adverse events, and methods to enhance tolerability and compliance.