Chapter 6
Degenerative Diseases

Degenerative diseases are noninfectious disorders characterized by progressive disability. Patients often can live for years with their diseases. Although they may not die from degenerative diseases, patients' symptoms usually grow more disabling and they often succumb to complications of their disorders.

ARTHRITIS

The word "arthritis" literally means joint inflammation, and it is applied to more than one hundred related diseases known as rheumatic diseases. When a joint—the point where two bones meet—becomes inflamed, swelling, redness, pain, and loss of motion occur. In the most serious forms of the disease, the loss of motion can be physically disabling.

Normally, inflammation is the body's response to an injury or a disease. It causes pain, redness, swelling, and warmth in the inflamed body part. Once the injury is healed or the disease is cured, the inflammation stops. In arthritis, however, the inflammation does not subside. Instead, it becomes part of the problem, damaging healthy tissues. This generates more inflammation and more damage, and the painful cycle continues. The damage can change the shape of bones and other tissues of the joints, making movement difficult and painful.

Types of Arthritis

More than one hundred types of arthritis have been identified, but four major types affect large numbers of Americans:

• Osteoarthritis—The most common type of arthritis, osteoarthritis generally affects people as they grow older. Sometimes called degenerative arthritis, it causes the breakdown of bones and cartilage (connective tissue attached to bones) and usually causes pain and stiffness in the fingers, knees, feet, hips, and back. The National Institutes of Health (NIH) estimates that osteoarthritis affects about twenty-one million Americans, usually after age forty-five.
• Fibromyalgia—Fibromyalgia affects the muscles and connective tissues and causes widespread pain, fatigue, sleep problems, and stiffness. Fibromyalgia also causes "tender points" that are more sensitive to pain than other areas of the body. According to the National Fibromyalgia Association, ten million Americans, mostly women, have this condition.
• Rheumatoid arthritis—Rheumatoid arthritis is caused by a flaw in the body's immune system that results in inflammation and swelling in joint linings, followed by damage to bone and cartilage in the hands, wrists, feet, knees, ankles, shoulders, or elbows. The Arthritis Foundation, a not-for-profit research and advocacy organization (http://www.arthritis.org/), reports that in the United States more than two million people, mostly women, have this form of arthritis.
• Gout—Gout is an inflammation caused by an accumulation of a natural substance, uric acid, in the joint, usually the big toe, knee, or wrist. The uric acid forms crystals in the affected joint, causing severe pain and swelling. According to the Arthritis Foundation, gout affects more men than women and occurs in about two million Americans.

Other Inflammatory and Autoimmune Disorders

Another less common, but potentially life-threatening, form of rheumatic disease is systemic lupus erythematosus (known as SLE or lupus), an inflammatory autoimmune disease (the immune system mistakenly attacks the body's own tissues) that attacks skin, joints, blood, and kidneys. SLE occurs more frequently among women than men, and three times as many African-American women are diagnosed with SLE than white women. The Arthritis Foundation reports that at least 239,000 Americans have lupus, with women affected from eight to ten times more often than men. Generally diagnosed in people age fifteen to forty-five years, the symptoms of SLE include the following:

• Painful or swollen joints, muscle pain, and fatigue
• Fever, weight loss, hair loss, and skin rashes
• Cold, pale, or blue fingers, also known as Raynaud's phenomenon
• Swollen legs or glands
• Nephritis (inflammation of the kidneys)
• Pleuritis (inflammation of the lungs) that may produce chest pain or increase the risk of developing pneumonia
• Myocarditis, endocarditis, or pericarditis (inflammation of the heart valves and the membrane around the heart, respectively) and vasculitis (inflammation of blood vessels)

As with other inflammatory and autoimmune disorders, each patient experiences the disease differently. SLE symptoms ranging from mild to severe flare up and subside throughout the course of illness. Some patients with SLE also experience headaches, vision disturbances, strokes, or behavior changes as a result of the effects of the disease on the central nervous system.

No cure exists for SLE, and treatment aims to relieve symptoms and reduce the potential for organ damage and complications. Most patients receive corticosteroid hormones, such as prednisone and dexamethasone, which rapidly reduce inflammation. Patients with SLE also are treated with nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Motrin, Advil), naproxen (Naprosyn, Aleve), and indomethacin (Indocin), along with other drugs to combat pain, swelling, and fever. Drugs originally used to treat malaria (antimalarials, such as Plaquenil) also are used to treat the fatigue, joint pain, rashes, and pleuritis resulting from SLE.

Many chronic degenerative diseases, especially autoimmune diseases, are thought to occur when a genetically susceptible individual encounters an environmental trigger. For example, some researchers believe that viruses may be the environmental triggers for diseases such as lupus and scleroderma, an illness in which skin and internal organs thicken and harden.

Prevalence of Arthritis

Arthritis is a very common problem. In 2005 the CDC reported that more than forty-six million Americans had been diagnosed with arthritis, another twenty-three million suffer chronic joint symptoms but have not yet been diagnosed, and more than seven million are disabled by the disease. By 2030 the total number is expected to increase to nearly sixty-five million Americans suffering from some form of arthritis. (See Figure 6.1.)

Arthritis is the leading cause of disability among Americans older than age fifteen. Rheumatic and musculoskeletal disorders are the most frequently reported causes of impairment in the adult population, the leading causes of limitation of mobility, and the second-leading causes of activity restriction. Arthritis and other musculoskeletal diseases are responsible for considerable limitation of activity and disability among American workers. Figure 6.2 shows that arthritis or other musculoskeletal diseases account for the greatest proportion of activity limitation among adults of all ages. The Arthritis Foundation observes that arthritis is a more frequent cause of activity limitation than heart disease, cancer, or diabetes. Lost wages, medical bills, and other costs to the U.S. economy resulting from the effects of arthritis amount to more than $86.2 billion annually ("Support 5% Increase for NIH Arthritis Research Funding," Arthritis Foundation, February 20, 2006, http://www.arthritis.org/advocacy/priorities/priorities_2006research.asp).

About half of all people older than age sixty-five will experience some form of arthritis in their lifetimes. Although some think of it as only an older person's disease, nearly three of five arthritis sufferers are younger than age sixty-five, and about 30% of people between the ages of forty-five and sixty-four—28.4% of women and 37.3% of men—have arthritis. It also can affect children. According to the Arthritis Foundation, an estimated three hundred thousand children and teenagers suffer from arthritis. Of these, approximately fifty thousand have juvenile rheumatoid arthritis, a potentially crippling disease that eventually destroys the joints ("Arthritis Prevalence: A Nation in Pain," Arthritis Foundation, 2005, http://www.arthritis.org/conditions/Fact_Sheets/Arthritis_Prev_Fact_Sheet.asp).

In all age groups, women have a slightly higher likelihood of developing arthritis, and as they age, women have an increasingly higher prevalence of arthritis than men do, 24.3% versus 17.1%. According to the Arthritis Foundation, if prevalence rates remain about the same, the number of affected persons age sixty-five and older will nearly double to 41.1 million by 2030.

Developments in Arthritis Research

As researchers learn more about inflammation and the body's immune system, they come closer to finding new drugs designed to relieve the pain of arthritis and to block the degenerative process of these diseases. Researchers are investigating ways to improve treatment by using the body's own biologic response modifiers (products that modify immune responses). They expect that these substances can be used to control the destructive processes of autoimmune diseases (in which the immune system attacks one's own cells) without weakening the whole immune system. One thing researchers know for sure is that the sooner arthritis is treated, the better.

Medications used to help relieve the symptoms of joint pain, stiffness, and swelling include NSAIDs, aspirin, analgesics, and corticosteroids. These drugs may be used in combination. Among recent advances are more effective pain-relief drugs with fewer adverse side effects than those already on the market. One of the problems with NSAIDs, the most widely used class of drugs for osteoarthritis, is the potential to irritate the stomach and cause ulcers.

Disease-modifying antirheumatic drugs (DMARDs) help reduce joint inflammation. They are generally effective but take as long as three or four months to produce benefits, so they must be started as early as possible to help prevent joint deformities and disability later in life. Doctors often prescribe an additional medication, such as a corticosteroid or an NSAID, to help control pain and inflammation while the DMARD starts to work.

DMARDs include low doses of methotrexate, leflu-nomide, penicillamine, sulfasalazine, auranofin (also known as oral gold), gold sodium thiomalate (also known as injectable gold), minocycline, azathioprine, hydroxy-chloroquine sulfate (and other antimalarials), cyclospor-ine, and biologic agents. DMARDs are used most often for rheumatoid arthritis, but some DMARDs also can be used for juvenile rheumatoid arthritis, ankylosing spon-dylitis, psoriatic arthritis, and lupus.

Other therapies also are available. For instance, patients with moderate to severe rheumatoid arthritis who have not responded well to DMARDs may try Prosorba therapy. This involves drawing blood, separating plasma from red blood cells, and treating plasma through a Prosorba column (a cylinder the size of a soup can that holds a sand-like substance coated with protein A, a molecule that binds antibodies). Treated plasma then is rejoined with red blood cells and returned to the body. Treatments are given in twelve weekly sessions that last about 2.5 hours each. It may take as long as sixteen weeks for patients to feel the benefits of the therapy.

Investigators are studying how joints respond to different types of stresses. This may help in developing more effective exercises or new self-help devices. Researchers have found that regular exercise, weight control, and other self-care measures considerably reduce the incidence and effects of the disease.

Setbacks in Arthritis Drug Treatment

In 1999 two new drugs, celecoxib, sold as Celebrex, and rofecoxib, sold as Vioxx, were marketed to physicians and directly to consumers as potent painkillers for arthritis sufferers. The drugs, called COX-2 inhibitors, are NSAIDs and were heralded as superior to conventional NSAIDs because they provided the same pain-relieving effects as aspirin and NSAIDs but with less chance of causing ulcers and intestinal bleeding. Almost immediately after their introduction, the drugs joined the ranks of the nation's best-selling prescription pharmaceuticals.

In November 2002 the first reports of increased heart disease among patients taking Vioxx were issued, and in April 2002 the U.S. Food and Drug Administration (FDA) required Merck, the pharmaceutical company that makes Vioxx, to inform the public about the potential for increased risk of heart attack and stroke. The same year, a third COX-2 inhibitor, called Bextra, was introduced by the drug company Pfizer.

When a study released in September 2004 revealed that patients taking Vioxx were twice as likely to suffer from stroke and heart attack as nonusers, Merck withdrew the product, which had annual sales of $2.5 billion, from the market (David J. Graham et al, "Risk of Acute Myocardial Infarction and Sudden Cardiac Death in Patients Treated with COX-2 Selective and Non-Selective NSAIDs," October 2005, http://www.fda.gov/cder/drug/infopage/vioxx/vioxxgraham.pdf). Less than three months later the FDA asked Pfizer to add a "black-box" warning to the Bextra labels alerting doctors and consumers to the increased risk of heart attack and stroke. (A "black-box" warning is the strongest form of warning the FDA can request.) One week later, on December 17, 2004, the National Cancer Institute terminated a colon polyp study due to an increased cardiovascular risk in Celebrex users, and the NIH halted a study of Alzheimer's disease because it suggested that the NSAID naproxen (Naprosyn) also increased risk for heart attack or stroke. At the close of 2004 the FDA formally exhorted limited and cautious use of COX-2 inhibitors and traditional NSAIDs.

In February 2005 the FDA reversed its determination about naproxen, stating that it was not associated with increased cardiovascular risk. The FDA also recommended that COX-2 drugs remain on the market. By April 2005 the FDA asked Pfizer to take Bextra off the market, and manufacturers of over-the-counter and prescription NSAIDs, as well as Celebrex, were asked to change their labels to reflect the increased risk.

Since its withdrawal from the market, nearly ten thousand Vioxx-related lawsuits have been filed against Merck by former Vioxx users or their survivors, alleging harm from the widely marketed drug. Merck lost its first lawsuit—a product liability case—in Texas in the summer of 2005. On August 19, 2005, Merck was found to be negligent in the death of a fifty-nine-year-old marathoner, and his widow was awarded $253 million. The amount will likely be substantially reduced under Texas law that limits awards. Merck, however, won its second case in New Jersey. The jury found that Merck did not fail to warn consumers about the safety of Vioxx, was not guilty of fraud, did not misrepresent the risks of heart attack and stroke when marketing it to physicians, and did not conceal information about the drug (Aaron Smith, "Big Win for Merck in Vioxx 2," CNN/Money.com, November 3, 2005, http://money.cnn.com/2005/11/03/news/fortune500/merck_humeston/index.htm).

The majority of the Vioxx suits have been filed in state court in New Jersey, Merck's home state, or in federal court. The first federal Vioxx trial, Plunkett v. Merck, ended in a hung jury on December 13, 2005, in a federal court in Houston, Texas. An estimated twenty million people took the once-popular painkiller, and Merck faces billions of dollars in potential payouts arising from pending state and federal lawsuits ("Next Vioxx Cases Scheduled for Spring," Associated Press, Forbes.com, January 13, 2006). By May 2006 six Vioxx lawsuits had reached settlements, and Merck had lost three (Linda A. Johnson, "Update 4: Study—Vioxx Risks Started within Months," Associated Press, Forbes.com, May 19, 2006).

OSTEOPOROSIS

Osteoporosis is a skeletal disorder characterized by compromised bone strength, which predisposes affected individuals to increased risk of fracture. The National Osteoporosis Foundation (NOF; http://www.nof.org/) defines osteoporosis as about 25% bone loss compared with a healthy young adult, or on a bone density test, 2.5 standard deviations below normal. Although some bone loss occurs naturally with advancing age, the stooped posture (kyphosis) and loss of height (greater than one to two inches) experienced by many older adults result from vertebral fractures caused by osteoporosis.

Bone density builds during childhood growth and reaches its peak in early adulthood. From then on, bone loss gradually increases, outpacing the body's natural ability to replace bone. The denser bones are during the growth years, the less likely they will be to develop osteoporosis. Proper diet, especially eating foods rich in calcium and vitamin D long before the visible symptoms of osteoporosis appear, is vitally important.

Osteoporosis worsens with age, leaving its sufferers at risk of broken hips or other bones, curvature of the spine, and other disabilities. An estimated eight million women (non-Hispanic white women are disproportionately affected) have a severe form of the disease, which causes many of them to experience spontaneous (without external causes) fractures, generally in the vertebrae of the spine.

The NOF reports that in 2005 about ten million Americans over age fifty had been diagnosed with osteoporosis, and another thirty-four million were considered at risk of developing the condition (http://www.nof.org/osteoporosis/diseasefacts.htm). Like other chronic conditions that disproportionately affect older adults, the prevalence of bone disease and fractures is projected to increase markedly as the population ages. According to a report issued by the U.S. Surgeon General, each year about 1.5 million people suffer an osteoporotic-related fracture, which often leads to a downward spiral in physical and mental health—about 20% of older adults who suffer hip fractures die within one year (Bone Health and Osteoporosis: A Report of the Surgeon General, Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, Office of the Surgeon General, October 14, 2004, http://www.surgeongeneral.gov/library/bonehealth/content.html).

One out of every two women over age fifty will have an osteoporosis-related fracture in her lifetime, with the risk of fracture increasing with age. The aging of the population combined with the historic lack of focus on bone health may together cause the number of hip fractures in the United States to double or even triple by the year 2020.

About one-third of a person's risk of developing osteoporosis is hereditary. In 1994 an Australian research team identified a gene linked to bone density. Two forms of the gene, B and b, exist. People with two b genes, one from each parent, have the highest bone density and are least likely to develop osteoporosis, whereas those with one of each, the Bb genotype, have intermediate bone density. People with two B genes have the lowest bone density and the highest risk of osteoporosis. Women with the BB genotype may be four times as likely to experience hip fractures as those with the bb genotype (Jane E. Brody, "New Study Links Gene to Risk of Bone Disease," New York Times, January 20, 1994, http://query.nytimes.com/gst/fullpage.html?res=9C0DE6DB1430F933A15752C0A962958260&sec=health&pagewanted=print).

The gene discovery was hailed as the most important finding in the osteoporosis field in a decade. Although much research remains to be done, investigators hope the identification of the gene eventually will lead to a simple test to identify children at risk for osteoporosis in later life. The test would allow doctors to prescribe an increased intake of calcium and protein during the growth years for these children, thus preventing or delaying the onset of osteoporosis.

Table 6.1 summarizes the factors that predispose a person to osteoporosis and fractures. Apart from genetics, the risk factors—nutrition, physical activity (especially weight-bearing exercise), and choosing not to smoke—are all modifiable. Because the prevalence of osteoporosis and fractures can be reduced via lifestyle

TABLE 6.1

Causes of bone loss and fractures in osteoporosis

Failure to develop a strong skeleton

Genetics—limited growth or abnormal bone composition

Nutrition—calcium, phosphorous and vitamin D deficiency, poor general nutrition

Lifestyle—lack of weight-bearing exercise, smoking

Loss of bone due to excessive breakdown (resorption)

Decreased sex hormone production

Calcium and vitamin D deficiency, increased parathyroid hormone

Excess production of local resorbing factors

Failure to replace lost bone due to impaired formation

Loss of ability to replenish bone cells with age

Decreased production of systemic growth factors

Loss of local growth factors

Increased tendency to fall

Loss of muscle strength

Slow reflexes and poor vision

Drugs that impair balance

source: "Table 2-2. Causes of Bone Loss and Fractures in Osteoporosis," in "Chapter 2: The Basics of Bone in Health and Disease," Bone Health and Osteoporosis: A Report of the Surgeon General 2004, U.S. Department of Health and Human Services, Public Health Service, Office of the Surgeon General, 2004, http://www.surgeongeneral.gov/library/bonehealth/chapter_2.html (accessed January 16, 2006)

modification, Healthy People 2010, the nation's plan for improving the health of Americans, aims to reduce the number of cases of osteoporosis and hospitalizations for fractures, as well as increase calcium intake by Americans. (See Table 6.2.)

Treatment of Osteoporosis

The primary goal of therapy is to prevent fractures. Nonpharmacologic (without medicine) preventive measures to help prevent osteoporosis include diet modification (an increase in the intake of calcium and vitamin D), exercise programs, and fall-prevention strategies. Current pharmacologic (medication) therapies improve bone mass and reduce fracture risk.

At the end of the twentieth century, the traditional treatment for postmenopausal women with osteoporosis, or those at risk for the disease, was hormone replacement therapy (HRT), often combined with daily doses of calcium and regular weight-bearing exercise, such as walking and exercising with weights. This treatment slows the advance of the disease and helps to prevent fractures and disability. Because serious side effects of HRT were publicized in July 2002—including documented increased risks of cardiovascular disease and certain types of cancer—many women discontinued HRT treatment. For some women at heightened risk for osteoporosis who also have fewer risk factors for cardiovascular disease, HRT remains a treatment option.

One of the goals of the treatment of osteoporosis is to maintain bone health by preventing bone loss and by building new bone. Another is to minimize the risk and impact of falls, because they can cause fractures. Figure 6.3 shows the pyramid of prevention and treatment of osteoporosis. At its base is nutrition, with adequate intake of calcium, vitamin D, and other minerals; physical exercise; and preventive measures to reduce the risk of falls. The second layer of the pyramid involves identifying and treating diseases that can cause osteoporosis, such as thyroid disease. The peak of the pyramid involves drug therapy for osteoporosis.

There are two primary types of drugs used to treat osteoporosis. Antiresorptive agents act to reduce bone loss, and anabolic agents are drugs that build bone. Antiresorptive therapies include use of bisphosphonates, estrogen, selective estrogen receptor modulators (SERMs), and calcitonin. Antiresorptive therapies reduce bone loss, stabilize the architecture of the bone, and decrease bone turnover. In 2005 the FDA approved two bisphosphonates—alendronate and risedronate—for prevention or treatment of osteoporosis and one anabolic agent—a synthetic form of parathyroid hormone known as teriparatide that is administered by injection.

EXERCISE IMPROVES BONE HEALTH IN OLDER ADULTS

The first study to examine the impact of exercise independent of other factors, primarily diet, on bone mineral density and the risk of osteoporosis and fractures confirmed that exercise helps to maintain and, in some cases, improve bone mass in persons ages fifty-five to seventy-five. Researchers at Johns Hopkins University School of Medicine in Baltimore, Maryland, followed 104 older men and women and found that six months of aerobic exercise using a bicycle, treadmill, or stepper, combined with weightlifting, resulted in improved overall fitness and fat loss without significant change (loss) in bone mineral density. Further, the study participants who exercised the hardest and had the greatest increases in aerobic fitness, muscle strength, and muscle tissue showed bone mass increases of 1% to 2% (Kerry Stewart et al., "Exercise Effects on Bone Mineral Density: Relationships to Change in Fitness and Fatness," American Journal of Preventive Medicine, vol. 28, no. 5, June 2005).

MULTIPLE SCLEROSIS

Multiple sclerosis (MS) is a chronic, degenerative, and often intermittent disease of the central nervous system. It eventually destroys the myelin protein sheaths that surround and insulate nerve fibers in the brain and spinal cord. Myelin is a fatty substance that aids the flow of electrical impulses from the brain through the spinal cord. These nerve impulses control all conscious and unconscious movements. In MS the myelin sheath disintegrates and is replaced by hard sclerotic plaques (scar tissue) that distort or prevent the flow of electrical impulses along the nerves to various parts of the body.

MS usually appears in young adulthood and is common enough to have earned the title "the great crippler of young adults." Many problems and symptoms are associated with the disease, but the major problem is lost mobility. Symptoms can range from mild problems, such as numbness and muscle weakness, to uncontrollable tremors, slurred speech, loss of bowel and bladder control, memory lapses, and paralysis. Although almost all parts of the nervous system may become involved, the spinal cord is the most vulnerable. Wild mood swings, from euphoria to depression, are another manifestation of the disease. The disease is not fatal in itself, but it weakens its victims and makes them far more susceptible to infection. Life expectancies for those with MS are six years shorter than for people without the disease.

The disease is called "multiple" because it usually affects numerous parts of the nervous system and often is characterized by relapses followed by periods of partial and sometimes complete recovery. It is, therefore, multiple both in how it affects the body and in how often it strikes.

Prevalence

At the beginning of 2006 the National Multiple Sclerosis Society estimated that four hundred thousand people in the United States had been diagnosed with MS, and every week approximately two hundred people are newly diagnosed with the disease (http://www.nationalmssociety.org/Who%20gets%20MS.asp). Symptoms appear most often between ages twenty and thirty-five. A possible clue to the cause of MS is that it is most common in cold, damp climates. In Europe it is found most often in the Scandinavian countries, the Baltic region, northern Germany, and Great Britain. It is rare in the Mediterranean countries, China, and Japan, and among Native Americans. It is also rare among African-Americans. White females are affected twice as often as males. In the United States most cases are found in the northern areas, and it is more common in Canada than in the southern United States. The disease cannot be cured, however, by moving to a warmer climate.

Diagnosing Multiple Sclerosis

The diagnosis of MS generally is made after a thorough history and physical examination and the results of diagnostic tests—such as magnetic resonance imaging (MRI, which provides a detailed view of the brain), spinal tap (to examine spinal fluid for signs of the disease), and evoked potentials (which measure how quickly and accurately a person's nervous system responds to certain stimulation)—have been evaluated. No single test can detect MS; several must be done and compared.

The neurologic examination for MS focuses on detecting hyperactive (as opposed to normal) reflexes and balance and gait disturbances. An eye examination evaluates damage to the optic nerve. Although some cases of MS are readily diagnosed by the physician based on the history and physical examination, most physicians confirm the diagnosis using an imaging study to document evidence of plaques in at least two locations of the central nervous system.

Cause of Multiple Sclerosis

The exact cause of MS is unknown. Many theories about its cause have been proposed—genetics, gender, or exposure to environmental triggers such as viruses, trauma, or heavy metals—but none have been proven. The most widely accepted theory is that damage to myelin results from an abnormal response by the body's immune system. Normally, the immune system defends the body against foreign invaders such as viruses or bacteria; however, in an autoimmune disease the body attacks its own tissue. Some believe that MS is an autoimmune disease in which myelin is attacked.

Like other diseases, genetic factors very likely play a significant role in determining who develops MS. Close relatives of persons with MS—such as children, siblings, or a nonidentical twin—have a higher chance of developing the disease than do persons without relatives with MS, and an identical twin of someone with MS has a one in four chance of developing the disease. If genes were the sole determinant, an identical twin of someone with MS would have a 100% chance of developing the disease. The fact that the risk is only one in four reveals that other factors, such as geography, ethnicity, and viral infection, are probably necessary to trigger development of the disease. Because MS is two to three times more common in women than in men, it also is possible that hormones play a role in determining susceptibility to MS (Multiple Sclerosis Information Sourcebook, Information Resource Center and Library of the National Multiple Sclerosis Society, 2003).

Treatment of Multiple Sclerosis

No known specific treatment halts the disease process. Once nerve fibers have been destroyed, they cannot recover their function. Current methods of treatment include powerful immune-suppressant drugs that often leave patients vulnerable to secondary infections. The best treatment seems to be to build general resistance and avoid fatigue and exposure to extremes in temperature. Physical therapy and psychotherapy are useful in helping patients and their families cope with the limitations caused by MS.

The National Multiple Sclerosis Society recommends that persons diagnosed with the disease should start drug treatment immediately, before symptoms worsen. The society recommends prompt treatment with medication, because it appears that patients who receive early treatment probably will have fewer disabling symptoms than those who do not. There are five disease-modifying drugs on the market that slow the progression of the disease.

Three drugs to treat MS—Avonex, Betaseron, and Rebif—are beta-interferon products that act by reducing the inflammation of MS lesions and reducing the accumulation of the lesions. All have demonstrated effectiveness in reducing the number and severity of relapses. Two other medications, Copaxone and Novatrone, also are used to treat MS. Copaxone is believed to work by suppressing the immune system's attacks on myelin. Novatrone reduces the activity of white blood cells that attack myelin and is generally prescribed for patients with worsening MS.

PARKINSON'S DISEASE

Parkinsonism refers not to a particular disease but to a condition marked by a characteristic set of symptoms believed to affect about one million people in the United States in 2006, according to the American Parkinson Disease Association (APDA; http://www.apdaparkinson.org/APDA/User1/DetailedInfo.aspx?url=Introduction.htm). Both men and women are affected, and the probability of developing Parkinson's disease increases with advancing age. Parkinson's disease usually strikes persons in their sixth and seventh decades—the average age of when symptoms appear is 62.4 years. Onset before age thirty is rare, but as many as 10% of patients are afflicted by age forty.

Parkinson's disease (PD) is caused by the progressive deterioration of about half a million brain cells in the portion of the brain that controls certain types of muscle movement. These cells secrete dopamine, a neurotransmitter (chemical messenger). Dopamine's function is to allow nerve impulses to move smoothly from one nerve cell to another. These nerve cells, in turn, transmit messages to the muscles of the body to begin movement. When the normal supply of dopamine is reduced, the messages are not correctly sent, and the symptoms of PD appear.

The four early warning signs of PD are tremors, muscle stiffness, unusual slowness, and a stooped posture. Medications can control initial symptoms, but as time goes on they become less effective. As the disease worsens, patients develop tremors, causing them to fall or jerk uncontrollably. (The jerky body movements that patients with PD experience are known as dyskinesias.) At other times rigidity sets in, rendering patients unable to move. About one-third of patients also develop dementia, an impairment of cognition (thought processes).

Treatment of Parkinson's Disease

Management of PD is individualized and includes drug therapy and a program that stresses daily exercise. Exercise often can reduce the rigidity of muscles, prevent weakness, and improve the ability to walk.

The main goal of drug treatment is to restore the chemical balance between dopamine and another neurotransmitter, acetylcholine. The standard treatment for most patients is levodopa (L-dopa), which was first approved for use in 1970. L-dopa is a compound that the body converts into dopamine to replace it in the body and help alleviate symptoms. (Without dopamine, signals from the brain cannot "transmit" properly to the body, and movement is impaired.) Treatment with L-dopa does not, however, slow the progressive course of the disease or even delay the changes in the brain that PD produces, and it may produce some unpleasant side effects because of its change to dopamine before reaching the brain. Simultaneously administering substances that inhibit this change allows a higher concentration of levodopa to reach the brain and also considerably decreases the side effects.

Five classes of drugs are used to treat the symptoms of PD, including anticholinergics, COMT (catechol-O-methyltransferase) inhibitors, MAO-B inhibitors, and amantadine. Anticholinergics work to relieve tremor and rigidity. COMT inhibitors act by prolonging the effectiveness of a dose of levodopa by preventing its breakdown. MAO-B inhibitors slow the breakdown of dopamine in the brain. And amantadine has demonstrated effectiveness in reducing dyskinesias.

Genetic Link to PD

In January 2006 researchers at the Albert Einstein College of Medicine and Beth Israel Medical Center in New York published an article in the New England Journal of Medicine in which they described their discovery of a single genetic mutation on a gene called LRRK2 (leucine-rich repeat kinase 2) that accounts for as many as 30% of all cases of PD in Arabs, North Africans, and Jews. People with the mutation make an abnormal version of a protein called dardarin (a form of the Basque word for tremor) in which a single amino acid—number 2,019—is glycine instead of serine. This finding may help to direct development of a drug to modify the impact of this mutation to prevent or substantially delay onset of the disease (Suzanne Lesage et al, "LRRK2 G2019S as a Cause of Parkinson's Disease in North African Arabs," and Laurie J. Ozelius et al., "LRRK2 G2019S as a Cause of Parkinson's Disease in Ashkenazi Jews," New England Journal of Medicine, vol. 354, no. 4, January 26, 2006).

Experimental Therapies

GENE THERAPY

As of 2006 gene therapy had been tried in only a few PD patients and remained highly experimental. In January 2006 actor Michael J. Fox, who has been diagnosed with PD, gave $4.2 million to a University of Pittsburgh Medical Center affiliate called RheoGene Inc. to develop gene therapy for Parkinson's disease (Byron Spice, "UPMC Affiliate Gets $4.2 Million Grant to Develop Gene Therapy for Parkinson's," Pittsburgh Post-Gazette, January 6, 2005, http://www.post-gazette.com/pg/06006/633543.stm).

The therapy entails inserting a beneficial gene into brain cells using technology developed by RheoGene that allows investigators to turn the gene on or off as needed, an important safety feature if the proteins it produced had some unanticipated, harmful effect. It also permits investigators to custom-tailor the activity of the gene based on the individual needs of each patient.

One of the genes that will be inserted produces glial cell line-derived growth factor (GDNF), a protein that appears to strengthen brain cells more and helps prevent the death of sick cells. In animal studies GDNF has been shown to stop the progression of the disease and perhaps even reverse it. The challenge has been to find a way to deliver the growth factor.

There are other challenges for gene therapy in the treatment of this disease. Scant research has been performed in humans to date, and it is possible that the success reported in animal studies will not be replicated in human trials. There also are financial considerations—treatment with levodopa is much less costly than gene therapy, and although the drug is not optimally effective and patients develop increased tolerance to the drugs over time, newer drugs such as dopamine agonists may produce a better alternative.

THE FUTURE OF STEM CELL RESEARCH

The election of President George W. Bush in 2000 prompted concern among human embryonic stem cell researchers. President Bush had expressed his opposition to this field of stem cell research throughout his campaign and through the early days of his presidency, and researchers expected him to reinstate the ban during his presidency. Researchers and patients hoping to benefit from treatment based on this promising area of scientific study were partially relieved when, on August 9, 2001, President Bush announced that federal funds could be used to conduct stem cell research on existing stem cell lines. His decision bans the creation or use of new embryos for federally funded experimental purposes. This means that federal funds will not be completely withheld from researchers in this field, but it places significant limits on the scope of research that will be eligible for federal support.

The excitement and optimism about human embryonic stem cells centers on these cells' capacity to renew themselves and develop into specialized cell types. Unlike other cells that have predetermined roles and functions, such as heart or brain cells, stem cells can develop into nearly all the specialized cells of the body—with the potential to replace cells for the nervous system, heart, pancreas, kidneys, skin, bone, or blood.

Research is under way that uses stem cells to treat neurologic disorders by replacing diseased or malfunctioning cells in the brain and spinal cord. The results of this research could have life-changing consequences for people suffering from PD, MS, Alzheimer's disease (AD), and spinal cord injuries. Other research focuses on developing organs and tissues for transplantation, because there is an urgent need for donor organs. Still other investigators are looking at ways to induce stem cells to become insulin-producing cells of the pancreas to treat diabetes.

FETAL PIG BRAIN IMPLANTS

In late 1995 a team from the Harvard Medical School reported that transplants of fetal pig brain cells into the brains of rats relieved PD-like symptoms. Limited trials on human beings also have been successful, but in 2006 the APDA reports that two recent placebo-controlled studies found that consistent benefit was only observed in PD patients age sixty or younger and that some patients experienced serious side effects such as dyskinesias, even when they were not taking levodopa. Still, if future planned human trials can overcome these obstacles, the procedure could revolutionize the treatment of PD without raising the ethical and moral issues involved in stem cell research and fetal tissue transplants.

ELECTRODE IMPLANTS

Another procedure being tested is the use of electrical implants. Electrodes are surgically implanted in the brain and connected to a battery-operated device, also implanted in the body. The device allows patients to "turn off" the tremors that prevent them from performing the activities of daily living such as pouring a glass of milk and feeding themselves. One drawback is that the device's batteries must be surgically replaced every three to five years.

ALZHEIMER'S DISEASE

Alzheimer's disease (AD) is a progressive, degenerative disease that affects the brain and results in severely impaired memory, thinking, and behavior. It is the fourth-leading cause of death in adults, and the incidence of the disease rises with age. AD affects an estimated four million American adults and is the most common form of dementia, or loss of intellectual function. The U.S. Department of Health and Human Services (HHS) estimates that 4.5 million Americans suffered from AD in 2004, and in 2003 it was the eighth-leading cause of death in the United States. (See Table 5.4 in Chapter 5.) AD also contributes to many more deaths that are attributed to other causes, such as heart and respiratory failure.

The German physician Alois Alzheimer first described the disease in 1907 after he had cared for a patient with an unusual mental illness. Dr. Alzheimer observed anatomic changes in his patient's brain and described them as abnormal clumps and tangled bundles of fibers. Nearly a century later these abnormal findings, now described as amyloid plaques and neurofibrillary tangles, along with abnormal clusters of proteins in the brain, are recognized as the characteristic markers of AD.

The disease knows no social or economic boundaries and affects men and women almost equally. While 90% of AD victims are over age sixty-five, AD can strike as early as the thirties, forties, and fifties. Most patients are cared for at home as long as possible, a situation that can be emotionally and physically devastating for the affected individuals and their families.

The financial consequences of caring for patients with AD also are devastating. The Alzheimer's Association (AA) and the National Institute of Aging estimate that the costs of diagnosis, treatment, nursing home care, informal care, and lost wages are about $100 billion each year. Their families provide about 75% of the total care for people with AD. Half of all nursing home residents have AD or a related disorder. In 2004 the cost of one year's stay in a nursing home was estimated to be $42,000 per year, but the cost can exceed $70,000 per year in some areas (http://www.alz.org/AboutAD/Statistics.asp).

The AA asserts that if a cure or prevention is not found, by 2050 the number of Americans with AD is estimated to range from 11.3 million to 16 million, with a middle estimate of 13.2 million. On the other hand, discovery of a treatment that could delay the onset of AD by five years could reduce the number of individuals with the disease by nearly 50% after fifty years.

SUSPECTED CAUSES

AD is not a normal consequence of growing older, and researchers continue to seek its cause. It is a disease of the brain that is influenced by genetic and nongenetic factors.

Researchers have found some promising genetic clues to the disease and have observed the different patterns of inheritance, ages of onset (when symptoms begin), genes, chromosomes, and proteins linked to the development of AD. Mutations in four genes, situated on chromosomes 1, 14, 19, and 21, are thought to be involved in the disease.

The first genetic breakthrough was reported in the February 1991 issue of the British journal Nature. Investigators reported that they had discovered that a mutation in a single gene could cause this progressive neurological illness. Scientists found the defect in the gene that directs cells to produce a substance called amyloid protein. Researchers at the Massachusetts Institute of Technology found that low levels of the brain chemical acetylcholine contribute to the formation of hard deposits of amyloid protein that accumulate in the brain tissue of AD patients. In normal people the protein fragments are broken down and excreted by the body. Amyloid protein is found in cells throughout the body, and researchers do not know how it becomes a deadly substance in the brain cells of some people and not others.

In 1995 three more genes linked to AD were identified. One gene appears to be related to the most devastating form of early-onset AD, which can strike people in their thirties. When defective, the gene may prevent brain cells from correctly processing a substance called beta amyloid precursor protein. The second gene is linked to another early-onset form of AD that strikes before age sixty-five. This gene also appears to be involved in producing beta amyloid. Researchers believe that the discovery of these two genes will allow them to narrow their search for the proteins responsible for early-onset AD and give them clues to the causes of AD in older people.

The third gene, known as apolipoprotein E (apoE), was reported as associated with AD in 1993, but its role in the body was not known at that time. Researchers have since found that the gene plays several roles. Within the body, it regulates lipid metabolism within the organs and helps to redistribute cholesterol. In the brain, apoE participates in repairing nerve tissue that has been injured. There are three forms (alleles) of the gene: apoE-2, apoE-3, and apoE-4. Until recently, people with two copies of apoE-4, one from each parent, were thought to have a greatly increased risk of developing AD before age seventy. From one-half to one-third of all AD patients have at least one apoE-4 gene, while only 15% of the general population has an apoE-4 gene. In 1998 researchers discovered that the apoE-4 gene seems to affect when a person may develop AD, not whether the person will develop the disease.

Another recently discovered gene, A2M-2, appears to affect whether a person will develop AD. Nearly one-third (30%) of Americans may carry A2M-2, a genetic variant that more than triples their risk of developing late-onset AD compared with siblings with the normal version of the A2M gene. The discovery of A2M-2 opens up the possibility of developing a drug that mimics the A2M gene's normal function. This has the potential to protect susceptible persons against brain damage or perhaps even reverse it.

Symptoms of Alzheimer's Disease

AD begins slowly. The symptoms include difficulty with memory and a loss of cognitive function (intellectual abilities). The patient with AD also may experience confusion; language problems, such as trouble finding words; impaired judgment; disorientation in place and time; and changes in mood, behavior, and personality. How quickly these changes occur varies from person to person, but eventually the disease leaves its victims unable to care for themselves. In their terminal stages, patients with AD require care twenty-four hours a day. They no longer recognize family members or themselves, and they need help with such daily activities as eating, dressing, bathing, and using the toilet. Eventually, they may become incontinent, blind, and unable to communicate. Finally, their bodies may "forget" how to breathe or make the heart beat. Many patients die from pneumonia.

Testing for Alzheimer's Disease

A complete physical, psychiatric, and neurologic evaluation usually can produce a diagnosis of AD that is about 90% accurate. For many years the only sure way to diagnose the disease was to examine brain tissue under a microscope, which was not possible while the AD victim was still alive. An autopsy of someone who has died of AD reveals a characteristic pattern that is the hallmark of the disease—tangles of fibers (neurofibrillary tangles) and clusters of degenerated nerve endings (neuritic plaques) in areas of the brain that are crucial for memory and intellect. Also, the cortex of the brain is shrunken.

In 1996 a San Francisco biotechnology firm developed a diagnostic test for AD. The test, which involves analysis of blood and spinal fluid, produced conclusive results in 60% of older patients with dementia.

In 2000 researchers at Brigham and Women's Hospital in Boston found that the use of MRI techniques could measure the volume of brain tissue in areas of the brain used for memory, organizational ability, and planning. In addition, the use of these measurements could accurately identify persons with AD and predict which people would develop AD. That same year scientists at New York University Medical Center, the Mayo Clinic, and the National Hospital for Neurology and Neurosurgery in London reported using MRI to identify parts of the brain affected by AD before symptoms appear and measure brain atrophy to monitor the progression of AD.

In 2005 researchers Chad Mirkin and William Klein at Northwestern University announced development of yet another diagnostic test that detects small amounts of protein in spinal fluid. The test is called a bio-barcode assay and is as much as a million times more sensitive than other tests. First used to identify a marker for prostate cancer, the test is used to detect a protein in the brain called amyloid-beta-derived diffusible ligand (ADDL). ADDLs are small soluble proteins. To detect them the researchers used nanoscale particles that had antibodies specific to ADDL. The researchers' findings were reported in the February 9, 2005, issue of the Proceedings of the National Academy of Science.

Investigators continue to look at other biological markers, such as blood tests, for AD and at neuropsycho-logical tests, which measure memory, orientation, judgment, and problem solving, to see if they can accurately predict whether healthy, unaffected older adults will develop AD or whether those with mild cognitive impairment will go on to develop AD.

Physicians and neuroscientists have long been eager for a simple and accurate test that can distinguish people with AD from those with cognitive problems or dementias arising from other causes. An accurate test would allow the detection of AD early enough for the use of experimental medications to slow the progression of the disease and would identify people at risk of developing AD. However, the availability of tests raises ethical and practical questions: do patients really want to know their risk of developing AD? Will health insurers use test results to deny insurance coverage?

Treatments for Alzheimer's Disease

As of 2006 there was still no cure or prevention for AD, and treatment has focused on managing symptoms. Medication can reduce some of the symptoms, such as agitation, anxiety, unpredictable behavior, and depression. Physical exercise and good nutrition are important, as is a calm and highly structured environment. The object is to help the patient with AD maintain as much comfort, normalcy, and dignity as possible.

By 2006 there were five FDA-approved prescription drugs for the treatment of AD. The first drugs to be approved were cholinesterase inhibitors, which are drugs designed to prevent the breakdown of acetylcholine. Cholinesterase inhibitors keep levels of the chemical messenger high, even while the cells that produce the messenger continue to become damaged or die. About half of the people who take cholinesterase inhibitors see modest improvement in cognitive symptoms. Until 1997 tacrine (marketed as Cognex) was the nation's only AD medication, but tacrine rarely is prescribed today because of associated side effects, including possible liver damage. However, there are three other cholinesterase inhibitors currently used that produce some delay in the deterioration of memory and other cognitive skills—donepezil (Aricept), approved in 1996; rivastigmine (Exelon), approved in 2000; and galantamine (Reminyl), approved in 2001.

Memantine (Namenda) was approved by the FDA in October 2003 for treatment of moderate to severe AD. It is classified as an uncompetitive low-to-moderate affinity N-methyl-D-aspartate (NMDA) receptor antagonist, and it is the first Alzheimer drug of this type approved in the United States. According to the AA, it seems to work by regulating the activity of glutamate, one of the brain's specialized messenger chemicals involved in information processing, storage, and retrieval.

As of 2006 NIH affiliates, pharmaceutical companies, and the AA were involved in clinical trials of about twenty new drugs to treat AD. All of the drugs being tested are intended to improve the symptoms of AD and slow its progression, but none are expected to "cure" AD. The investigational drugs aim to address three aspects of AD—improve cognitive function in people with early AD; slow or postpone the progression of the disease; and control behavioral problems such as wandering, aggression, and agitation of patients with AD.

Other research under way in 2006 involved the use of NSAIDs. Such as ibuprofen or naproxen, to reduce the risk of developing AD, because AD involves inflammatory processes in the brain. Another National Institute on Aging-funded study was trying to find out whether antioxidants, such as vitamin E, can prevent persons with mild memory impairment from progressing to AD.

Research to see if estrogen reduces the risk of AD or slows the disease has been done, and one study showed that estrogen does not slow the progression of the already-diagnosed disease. Also, a study on combination hormone therapy (estrogen and progestin) showed that women older than age sixty-five participating in the study had twice the rate of dementia, including AD, compared with women who did not take the medication. Substances already used to reduce cardiovascular risk factors, such as statin drugs and folic acid, also are being studied to determine whether they also reduce AD risk.

In 2005 the National Institute of Aging and AA launched the AD Genetics Study, recruiting subjects from families in which two siblings developed AD after age sixty. The study aims to compare the genes of the afflicted siblings with those from another family member who does not have AD in an effort to find the genes that contribute to AD (http://ncrad.iu.edu/).

Caring for the AD Patient

AD can affect every member of the patient's family. While medication may suppress some symptoms and occasionally slow the progression of the disease, eventually most AD patients require constant care and supervision. Until recently nursing homes and residential care facilities were not equipped to provide this kind of care and, if they accepted AD patients at all, admitted only those in the very earliest stages of the disease. Since 2000 a growing number of nursing homes have welcomed AD patients despite the fact that they are more difficult and costly to care for than older adults without AD. Although this change was primarily financially motivated, as nursing home occupancy rates dropped in response to the growth of alternative housing for older adults, it does offer families with ample financial resources—the average annual stay costs $75,000 and varies somewhat depending on geography and intensity of services—an alternative to caring for the AD patient at home ("The MetLife Market Survey of Nursing Home and Home Care Costs," MetLife, September 2005, http://www.metlife.com/WPSAssets/41453139101127828650V1F2005%20NH%20and%20HC%20Market%20Survey.pdf).

SECOND VICTIMS

The suffering of a patient with AD is only part of the devastating emotional, physical, and financial trauma of AD. People who care for loved ones with AD are considered "second victims" of the disease. Caregivers often neglect their own needs, including their health and social lives, and the needs of other family members. As a result, they may develop more stress-related illnesses and are at greater risk for depression.

Many professionals recommend support groups for caregivers of patients with AD, made up of family members, friends, and health care professionals. These groups encourage members to share information and ideas, give and receive mutual support, and exchange coping skills with each other. A study of 206 spouses of patients with AD found that caregivers benefited greatly from support groups and counseling. Those who received this kind of support were able to care for the patients at home for almost one year longer than caregivers who lacked support (Mary S. Mittelman et al, "A Family Intervention to Delay Nursing Home Placement of Patients with Alzheimer Disease: A Randomized Controlled Trial," Journal of the American Medical Association, vol. 276, no. 21, December 4, 1996).

CAREGIVING CAN COMPROMISE HEALTH AND WELL-BEING

For many people, caring for a person with AD can, over time, become an enormous burden. Caregivers may neglect their own health and other needs because no one else is available to care for their AD-affected spouse or parent.

Deputy Secretary of Health and Human Services Claude Allen and panelists Michael O'Grady, John Hoff, Josefina Carbonell, Donald Showers, Katryna Gould, and Bill Kays at a December 2003 town hall meeting, "Ensuring the Health and Wellness of Our Nation's Family Caregivers" (http://aspe.hhs.gov/daltcp/CaregiverEvent/overview.htm), reported that about one third of caregivers describe their own health as "fair to poor." The stress associated with family caregiving has been found to compromise immune function, increasing the risks of infectious diseases, such as colds and flu. It also is linked to increased risk for depressive symptoms, as well as chronic diseases, such as heart disease, diabetes, and cancer.

Key research findings about the relationship between caregiving and compromised health include:

• Spouses who suffer from chronic conditions, serve as caregivers, and report stress related to their caregiving efforts have a mortality rate that is nearly two-thirds (63%) higher than their noncaregiving peers. Caregivers experienced more depression and anxiety and a reduced level of health. They also were less likely to get adequate rest, to have time to rest when they were sick, or to have time to exercise (Richard Schulz and Scott R. Beach, "Caregiving as a Risk Factor for Mortality," Journal of the American Medical Association, vol. 282, no. 23, December 15, 1999).
• The stress of caring for older adults with dementia has been shown to compromise caregivers' immune systems for as long as three years after their caregiving ends (Janice Kiecolt-Glaser and Ronald Glaser, "Chronic Stress and Age-related Increases in the Proinflammatory Cytokine IL-6," Proceedings of the National Academy of Sciences, June 30, 2003).
• Caregivers remain at risk for depression and anxiety after the older adults with dementia they have cared for are placed in long-term health care facilities. Depressive symptoms and anxiety in caregivers were as severe after caregivers institutionalized their relatives compared with when they served as in-home caregivers (Richard Schulz et al, "Long-term Care Placement of Dementia Patients and Caregivers Health and Well-being," Journal of the American Medical Association, vol. 292, no. 8, August 25, 2004).
• Caregivers who provide care thirty-six or more hours weekly are more likely than noncaregivers to experience symptoms of depression or anxiety. For spouses serving as caregivers the rate is six times higher; for those caring for a parent the rate is twice as high (Carolyn Cannuscio et al, "Reverberation of Family Illness: A Longitudinal Assessment of Informal Caregiver and Mental Health Status in the Nurses' Health Study" American Journal of Public Health, vol. 92, no. 8, August 2002).

Research also has demonstrated that at-risk care-givers are less likely than their peers who do not provide care for older relatives to engage in health-promoting behaviors that are important for chronic disease prevention and health promotion. The town hall panelists observed that in view of caregivers' risks of developing health problems, there is an urgent need to exhort family caregivers to engage in activities such as regular exercise and preventive medical care that will benefit their own health, well-being, and longevity.