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Dx Multiple Sclerosis Treatments:

Multiple Sclerosis

The Merck Manual Home Edition
"In multiple sclerosis, patches of myelin and underlying nerve fibers in the eyes, brain, and spinal cord are damaged or destroyed.

*The cause is unknown but may involve an attack by the immune system against the body's own tissues (autoimmune reaction).
*Usually, periods of relatively good health alternate with episodes of worsening symptoms.
*People may have vision problems and abnormal sensations, and movements may be weak and clumsy.
*Usually, doctors base the diagnosis on symptoms and results of a physical examination and magnetic resonance imaging.
*Treatment includes corticosteroids, drugs that help keep the immune system from attacking the body, and drugs to relieve symptoms.
*Often, the disorder slowly worsens, disabling some people, but life span is unaffected unless the disorder is very severe.

The term “multiple sclerosis” refers to the many areas of scarring (sclerosis) that result from destruction of the tissues that wrap around nerves (myelin sheath). This destruction is called demyelination. Sometimes the nerve fibers that send messages (axons) are also damaged. Over time, the brain may shrink in size because axons are destroyed.

In the United States, about 400,000 people, mostly young adults, have multiple sclerosis. Most commonly, it begins between the ages of 20 and 40. It is more common among women. Most people have periods of relatively good health (remissions) alternating with periods of worsening symptoms (flare-ups or relapses). Relapses can be mild or debilitating. Recovery during remission is good but incomplete. Thus, the disorder worsens slowly over time.

The cause is unknown, but a likely explanation is that people are exposed early in life to a virus (possibly a herpes virus or retrovirus) or some unknown substance that somehow triggers the immune system to attack the body's own tissues. The autoimmune reaction results in inflammation, destruction of myelin, and damage to the myelin sheath and the underlying nerve fiber.

Heredity seems to have a role in multiple sclerosis. About 5% of people with the disorder have a brother or sister who is affected, and about 15% have a close relative who is affected. Also, multiple sclerosis is more likely to develop in people with certain genetic markers on the surface of their cells called human leukocyte antigens. These markers help the body to distinguish self from non-self and thus know which substances to attack.

Environment also has a role in multiple sclerosis. Where people spend the first 15 years of life affects their chance of developing multiple sclerosis. It occurs in 1 of 2,000 people who grow up in a temperate climate but in only 1 of 10,000 people who grow up in a tropical climate. Multiple sclerosis almost never occurs in people who grow up near the equator. These differences may be related to vitamin D levels. When the skin is exposed to sunlight, the body forms vitamin D. Thus, people who grow up in temperate climates may have a lower vitamin D level. People with a low level of vitamin D are more likely to develop multiple sclerosis. But how vitamin D may protect against the disorder is unknown. The climate in which later years are spent does not change the chances of developing the disorder.

Cigarette smoking also appears to increase the chances of developing the disorder. The reason is unknown.

Symptoms vary greatly, from person to person and from time to time in one person, depending on which nerve fibers are demyelinated. If nerve fibers that carry sensory information become demyelinated, problems with sensations (sensory symptoms) result. If nerve fibers that carry signals to muscles become demyelinated, problems with movement (motor symptoms) result. Symptoms often come and go, affecting one or several parts of the body. The fluctuating symptoms result from damage to myelin sheaths, followed by repair, followed by more damage. Symptoms may become more severe when people are exposed to high temperatures, such as in very warm weather, a hot bath or shower, or during a fever.

Multiple sclerosis may progress and regress unpredictably. However, there are several patterns of symptoms:
*Relapsing-remitting pattern: Relapses (when symptoms worsen) alternate with remissions (when symptoms are stable). Remissions may last months or years. Relapses can occur spontaneously or can be triggered by an infection such as influenza.
*Primary progressive pattern: The disease progresses gradually with no remissions or obvious relapses, although there may be temporary plateaus during which the disease does not progress.
*Secondary progressive pattern: This pattern begins with relapses alternating with remissions, followed by gradual progression of the disease.
*Progressive relapsing pattern: The disease progresses gradually, but progression is interrupted by sudden relapses. This pattern is rare. Vague symptoms of demyelination in the brain sometimes begin long before the disorder is diagnosed. For example, tingling, numbness, pain, burning, and itching may occur in the arms, legs, trunk, or face. The sense of touch may be reduced. People may lose strength or dexterity in a leg or hand, which may become stiff.

Vision may become dim or blurred. Mainly, people lose the ability to see when looking straight ahead (central vision). Peripheral (side) vision is less affected. In some people, one eye becomes weaker than the other, causing double vision when looking from one side to the other. This disorder is called internuclear ophthalmoplegia. The stronger eye may move involuntarily, rapidly and repetitively moving in one direction, then slowly drifting back (a symptom called nystagmus). Partial blindness may develop in one eye, and pain occurs when the eye is moved. These symptoms result from inflammation of the optic nerve (optic neuritis). Some people with multiple sclerosis have only optic neuritis.

When the back part of the spinal cord in the neck is affected, bending the neck forward may cause an electrical shock or a tingling sensation that shoots down the back, down both legs, down one arm, or down one side of the body (a response called Lhermitte's sign). Usually, the sensation lasts only a moment and disappears when the neck is straightened. Often, it is felt as long as the neck remains bent.

As the disorder progresses, movements may become shaky, irregular, and ineffective. People may become partially or completely paralyzed. Weak muscles may contract involuntarily (called spasticity), sometimes causing painful cramps. Muscle weakness and spasticity may interfere with walking, eventually making it impossible, even with a walker or another assistive device. Speech may become slow, slurred, and hesitant.

Late in the disorder, dementia and mania (excessive elation) may develop. The nerves that control urination or bowel movements can be affected, leading to frequent and strong urges to urinate, retention of urine, constipation, and, occasionally, urinary and fecal incontinence. If relapses become more frequent, people become increasingly disabled, sometimes permanently.

Because symptoms vary widely, doctors may not recognize the disorder in its early stages. Doctors suspect multiple sclerosis in younger people who suddenly develop blurred vision, double vision, or movement problems and abnormal sensations in various unrelated parts of the body. Fluctuating symptoms and a pattern of relapses and remissions support the diagnosis.

When doctors suspect multiple sclerosis, they thoroughly evaluate the nervous system during a physical examination. They examine the back of the eye (retina) with an ophthalmoscope. The optic disk (the spot where the optic nerve joins the retina) may be inflamed or unusually pale, indicating inflammation of the optic nerve.

Magnetic resonance imaging (MRI) is the best imaging test for detecting multiplesclerosis. It usually detects areas of demyelination in the brain and spinal cord. Before MRI, doctors may inject gadolinium, a paramagnetic contrast agent, into the bloodstream. Gadolinium helps distinguish areas of recent demyelination and active inflammation from areas of long-standing demyelination.

The diagnosis may be clear based on the physical examination and MRI. If not, other tests are done to obtain additional information:
*Spinal tap (lumbar puncture): A sample of cerebrospinal fluid is removed (see see Spinal Tap). The protein content of the fluid may be higher than normal. The concentration of antibodies may be high, and a specific pattern of antibodies is detected in up to 90% of people with multiple sclerosis.
*Evoked responses: For this test, sensory stimuli, such as flashing lights, are used to activate certain areas of the brain, and the brain's electrical responses are recorded (see see Evoked Responses). In people with multiple sclerosis, the brain's response to stimuli may be slow because signal conduction along demyelinated nerve fibers is impaired. This test can also detect slight damage to the optic nerve. Other tests can help doctors distinguish multiple sclerosis from disorders that cause similar symptoms, such as AIDS, vasculitis, arthritis of the neck, Guillain-Barré syndrome, hereditary ataxias, lupus, Lyme disease, rupture of a spinal disk, syphilis, and a cyst in the spinal cord (syringomyelia). For example, blood tests may be done to rule out Lyme disease, syphilis, and lupus, and imaging tests can help rule out arthritis of the neck, rupture of a spinal disk, and syringomyelia.

Three fourths of people with multiple sclerosis never need a wheelchair.

What effects multiple sclerosis has and how quickly it progresses vary greatly and unpredictably. Remissions can last months up to 10 years or more. However, some people, particularly men who develop the disorder during middle age, have frequent attacks and are rapidly incapacitated. Nonetheless, about 75% of people who have multiple sclerosis never need a wheelchair, and for about 40%, normal activities are not disrupted. Unless the disorder is very severe, life span is usually unaffected.

No treatment for multiple sclerosis is uniformly effective. Corticosteroids are most commonly used. They probably work by suppressing the immune system. They are given for short periods to relieve immediate symptoms. For example, prednisone may be taken by mouth, or methyl-prednisolone may be given intravenously. Although corticosteroids may shorten relapses and slow the progression of multiple sclerosis, they do not stop its progression.

Corticosteroids are rarely used for a long time because they can have many side effects, such as increased susceptibility to infection, diabetes, weight gain, fatigue, decreased bone density (osteoporosis), and ulcers. Corticosteroids are started and stopped as needed.

Other drugs that help keep the immune system from attacking myelin sheaths are usually used. They include the following:
*Interferon-beta injections reduce the frequency of relapses and may help prevent or delay disability.
*Glatiramer acetate injections may have similar benefits for people with early mild multiple sclerosis.
*Mitoxantrone, a chemotherapy drug, can reduce the frequency of relapses and slow the progression of the disorder. It is given for only up to 2 years and only when other drugs do not work because it can eventually lead to heart damage.
*Natalizumab is an antibody given intravenously as an infusion once a month. It is more effective than other drugs in reducing the number of relapses and preventing further damage in the brain. However, natalizumab may increase the risk of a rare, fatal infection of the brain and spinal cord (progressive multifocal leukoencephalopathy). Natalizumab is used only by specially trained doctors, and people who take it must be checked periodically for signs of progressive multifocal leukoencephalopathy.
*Immune globulin, given intravenously once a month, occasionally helps when other drugs have been ineffective.

*Plasmapheresis is recommended by some experts for severe relapses not controlled by corticosteroids. However, the benefits of plasmapheresis have not been established. For this treatment, blood is withdrawn, abnormal antibodies are removed from it, and the blood is returned to the person.

Other drugs can be used to relieve or control specific symptoms:
*Muscle spasms: The muscle relaxants baclofen or tizanidine
*Urinary incontinence: Oxybutynin, bethanechol, or tamsulosin
*Pain due to abnormalities in nerves: The anticonvulsant gabapentin or sometimes tricyclic antidepressants (such as amitriptyline), the anticonvulsant carbamazepine, or opioids
*Tremors: The beta-blocker propranolol
*Fatigue: Amantadine (used to treat Parkinson's disease) or, less often, modafinil (used to treat excessive sleepiness)
*Depression: Antidepressants such as sertraline or amitriptyline, counseling, or both

People with multiple sclerosis can often maintain an active lifestyle, although they may tire easily and may not be able to keep up with a demanding schedule. Regular exercise such as riding a stationary bicycle, walking, swimming, or stretching reduces spasticity and helps maintain cardiovascular, muscular, and psychologic health. Physical therapy can help with maintaining balance, the ability to walk, and range of motion and can help reduce spasticity and weakness. People should walk on their own for as long as possible. Doing so improves their quality of life and helps prevent depression. Avoiding high temperatures—for example, by not taking hot baths or showers—can help because heat can worsen symptoms. People who smoke should stop. Taking vitamin D supplements helps prevent osteoporosis or slow its progression and may help slow the progression of multiple sclerosis.

People with urine retention can learn to catheterize themselves and empty the bladder, and those with constipation can take stool softeners or laxatives regularly. People who become weak and unable to move easily may develop pressure sores, so they and their caregivers must take extra care to prevent the sores.

If people are disabled, occupational therapists and social workers can help with rehabilitation."

Medications Used in Treatment:
1. Corticosteroids: prednisone, Medrol®/methylprednisolone, Cortef®/hydrocortisone, see list
2. GABA Agonists: baclofen
3. Interferon Betas: Avonex® Rebif®/interferon Beta-1a, Copaxone®/glatiramer acetate, Extavia® Betaseron®/interferon beta-1b
4. Sphingosine Receptor Modulators: Gilenya®/fingolimod
5. NMDA Receptor Antagonist/ Antiarrhythmic: Nuedexta®/dextromethorphan;quinidine
6. NRF2 Activators: Tecfidera®/dimethyl fumarate
7. Potassium Channel Blocker: Ampyra®/ dalfampridine
8. Pyrimidine Synthesis Inhibitors: Aubagio®/teriflunomide
9. Topoisomerase inhibitors: mitoxantrone
10. Integrin Antagonists: Tysabri®/natalizumab
10. Antimetabolites: Rituxan®/ rituximab
11. CNI Immunosuppressants: Rheumatrex®/ methotrexate

*[Editor] Unfortunately, the successful animal trial with glatirame acetate (Copaxone®) have not been reproduced in humans with Progressive Multiple Sclerosis (PMS) and Relapsing Remitting Multiple Sclerosis (RRMS). This was the largest meta-study to date with 540 RRMS and 1049 PMS patients. The adverse events such as chest tightness,sweating, palpitations, anxiety and local injection-site reactions occurred quite frequently, but no major adverse effects were noted.

*[Editor] The cost-effectiveness results for all three immunomodulatory treatments for MS were unfavorable in the stimulated study population under a wide range of assumptions. For treatment duration less than or equal to five years, expected benefits may not outweight disutility associated with side effects and treatments discomfort.

Suggested Links:
*N.H.S. Choices (with Video)
*Multiple Sclerosis Association of America

*[Editor] Unfortunately, multiple sclerosis is poorly documented and no recommendations can be made to guide prescribing."

*[Editor] Other researchers in
Evaluating sex hormone levels in reproductive age women with multiple sclerosis have found, as we have, that the levels of testosterone, DHEA-sulfate levels were lower than controls all through the month. The higher the FSH and the lower the estradiol, the worse was the disease. Men with MS had lower FSH and testosterone levels and pronounced bone loss. Similarly, the inflammatory markers of IL-6beta, IL-6 and TNF-alpha secreting cells increased with exacerbations. In mice models for SLE with EAE, androstenetriol (an androgen derivative) reduced the immune response including TNF-alpha.

*[Editor] This leads to a 1968 article in which the Europeans published on the treatment of multiple sclerosis with anabolic steroids]. We hypothesize that the 'correct' combination of anabolic steroids (increasing the Free Androgen Index to youthful levels) is the reason we have seen a positive effect on not just hypogonadism and osteoporosis in the male, but the inflammatory markers experienced by both sexes.

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