FitSugar

Eat Yogurt - It's Good For Your Mouth

FitSugar — Tue, 26 Feb 2008 16:00:00 -0800

If you eat yogurt, you'll be happy to know that Japanese research found that it may be keeping your mouth healthy. Eating yogurt and other foods that contain lactic acid such as wheat beer, kefir, and some cottage cheeses are associated with better periodontal health. When adults have periodontal disease, this chronic bacterial infection causes receding gums and tooth loss. Aside from brushing, flossing, and regular cleanings, effective ways to deal with this are limited, so this is great news.

This study found that those who consumed 55 grams or more of yogurt a day, or some other lactic-acid drink, had a significantly lower occurrence of periodontal disease. (That's equal to less than half a 6-ounce container of yogurt). More research needs to be done, because the benefits may have something to do with the lactobacillus bacteria found in yogurt and other lactic-acid foods. Since signs of periodontal disease can show up in your 30s, so it's good to start thinking about ways to prevent it now.

Source

Healthy Gums May Prevent Pancreatic Cancer

FitSugar — Mon, 29 Jan 2007 13:15:00 -0800

All cancer is bad news, but what makes pancreatic cancer so awful is that only 5% of people diagnosed with it will live another 5 years.

There are no recommended screening tests, early warning signs or symptoms to alert a person or their doctor that they have pancreatic cancer.

Some risk factors that could make you more susceptible to pancreatic cancer include cigarette smoking and possibly diabetes and obesity.

Oddly enough, periodontal disease (gum inflammation) and tooth loss may also be associated in some way with an increased risk of pancreatic cancer.

The connection it seems is that over time, the bacterial infection that causes gum disease can also cause loss of the bone that anchors the teeth. The inflammation from the infection may set the stage for other serious diseases, like pancreatic cancer.

There has also been recent interest in a possible link between gum disease and coronary artery disease, based on the theory that gum disease may lead to increased levels of inflammation throughout our bodies.

Fit's Tips: So take care of your teeth and gums people. Get regular dental cleanings twice a year, and whatever you do - don't forget to floss.

Periodontal disease

FitSugar — Wed, 08 Oct 2008 17:35:31 -0700

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Symptoms of Periodontal Disease

Symptoms of periodontal disease include red and swollen gums, persistent bad breath, and gum recession and loose teeth. Smoking, certain types of illnesses (diabetes), older age, and other factors increase the risk for periodontal disease. If you have periodontal disease, your dentist may refer you to a periodontist, a dentist who specializes in treating this condition.

Practice Good Dental Hygiene

Consistent good dental hygiene can help prevent gingivitis and periodontitis. The American Dental Association recommends that everyone:

Brush twice daily with a fluoride toothpaste (be sure to replace toothbrushes every 3 - 4 months).
Clean between the teeth with floss or an interdental cleaner.
Eat a well-balanced diet and limit between meal snacks.
Have regular visits with a dentist for teeth cleaning and oral examinations.

Mouthwashes

In 2007, the American Dental Association stated that antimicrobial mouthwashes may provide additional oral health benefits for preventing and reducing gingivitis and plaque. However, they are not a substitute for daily brushing and flossing.

Research

Intensive treatment of periodontal disease may help reduce inflammation and improve blood flow throughout the body, according to a small study published in 2007 in the New England Journal of Medicine. In the study of patients with severe periodontitis, intensive treatment ultimately resulted in improved endothelial function. Poor endothelial function is associated with increased risk for atherosclerosis and heart disease. Researchers are investigating the connection between periodontal disease and heart disease, and whether treatment of periodontal disease can reduce heart disease risk.

Introduction

Periodontal disease refers to a group of problems that arise in the sulcus, the gap between the gum and the tooth.

The part of the mouth that consists of the gum and supporting structures is called the periodontium. It is made up of the following parts:

Gum (gingiva). When healthy, the gingiva is pale pink, firm, and does not move. It has a smooth or speckled texture. The gingival tissue between teeth is shaped like a wedge.
The space between the gum and tooth, called the sulcus
Root surface (the cementum)
Connective tissue
Bone. The crest of the supporting bone, which can be viewed on x-rays, is normally 2 mm below the point where the crown of the tooth meets the root (the cementoenamel junction).

The structure of the tooth includes dentin, pulp and other tissues, blood vessels, and nerves imbedded in the bony jaw. Above the gum line, the tooth is protected by the hard enamel covering.

Periodontal diseases are generally divided into two groups:

Gingivitis, which causes lesions (wounds) that affect the gums
Periodontitis, which damages the bone and connective tissue that supports the teeth

The process starts with bacteria. Even in healthy mouths, the sulcus is teeming with bacteria, but they tend to be harmless varieties. Periodontal disease develops usually because of two events in the oral cavity: an increase in bacteria quantity and a change in balance of bacterial types from harmless to disease-causing bacteria. These harmful bacteria increase in mass and thickness until they form a film called plaque.

Click the icon to see an image of plaque and damaged gum tissue.

In healthy mouths, plaque itself actually provides some barrier against outside bacterial invasion. When it accumulates to excessive levels, however, plaque sticks to the surfaces of the teeth and adjacent gums and causes cellular injury, with subsequent swelling, redness, and heat.

When plaque is allowed to remain in the periodontal area, it transforms into calculus (commonly known as tartar ). This material has a rock-like consistency and grabs onto the tooth surface. It is much more difficult to remove than plaque, which is a soft mass.

The most important component leading to the disease process, however, is the body's persistent immune response to the bacterial plaque. Specific immune factors are released that cause inflammation and damage that eventually destroys the support structures and bone and can lead to tooth loss.

Gingivitis is an inflammation of the gingiva, or gums. Is nearly always chronic, but an acute form infrequently occurs.

Chronic Gingivitis. Ordinary chronic gingivitis affects over 90% of the population. It is characterized by tender, red, swollen gums that bleed easily and may be responsible for bad breath (halitosis) in some cases. Treatment is very effective if initiated early in the course of gingivitis. Without good management, however, the problem can progress.

Periodontitis is characterized by the following:

Gum inflammation, with redness and bleeding.
Deep pockets (greater than 3 mm in depth) form between the gum and the tooth.
Loose teeth, caused by loss of connective tissue structures and bone.

Gingivitis precedes periodontitis, although it doesn't always lead to this more severe condition. In fact, some experts believe it is an entirely different disease. There are different categories of periodontal disease, including:

Chronic Periodontitis. Chronic periodontitis (also referred to as adult periodontitis) may begin in adolescence as a slowly progressing disease that becomes clinically significant in the mid-30s and continues throughout life. Some experts question whether it is a chronic, unrelenting condition and instead suggest that it waxes and wanes depending on the response of the immune system.

Aggressive Periodontitis. Aggressive periodontitis (also referred to as early onset periodontitis) often occurs in young people. It is subdivided according to whether it begins before or after puberty. Immune deficiencies and a genetic link have been shown to be possible factors for all types of aggressive periodontitis. If the condition is localized and treated, the outlook is positive. People with severe and widespread aggressive periodontitis are at high risk for tooth loss.

Periodontitis that occurs before puberty is very rare. It begins with the eruption of primary teeth in the first year and causes severe inflammation and bone and tooth loss.
Juvenile periodontitis begins at puberty and is defined by severe bone loss around the first molars and incisors. It is more common in girls than in boys. The clinical signs -- such as inflammation, bleeding, and heavy plaque accumulation -- are not present in this relatively rare disease. The treatment is the same as in chronic periodontitis.
Rapidly progressive periodontitis occurs in the early 20s to mid-30s. Severe inflammation and rapid bone and connective tissue loss occur, and tooth loss is possible within a year of onset.

Disease-Related Periodontitis. Periodontitis can also be associated with a number of systemic diseases, including type 1 diabetes, Down syndrome, AIDS, and several rare disorders of white blood cells.

Acute Necrotizing Periodontal Disease. Acute necrotizing periodontal disease is an acute infection in the gums. It is characterized by:

Black, dead tissue (necrosis)
Spontaneous bleeding
Rapid onset of pain
Bad odor
Blunted gum tissue (tissue is normally cone-shaped)

Stress, poor diet, smoking, and viral infections are predisposing factors for this acute necrotizing periodontal disease.

Symptoms

In general, symptoms progress over time and include:

Red and Swollen Gums
Gum Bleeding. Bleeding of the gums, even during brushing, is a sign of inflammation and the major marker of periodontal disease. One exception is juvenile periodontitis, in which symptoms are mild or even absent. It should be noted that the gums of smokers with periodontal disease tend to bleed less than nonsmokers.
Bad Breath. Debris and bacteria can cause a bad taste in the mouth and persistent bad breath.
Gum Recession and Loose Teeth. As the disease advances the gums recede, and supporting structure of bone is lost. Teeth loosen, sometimes causing a change in the way the upper and lower teeth fit together when biting down or a change in the fit of partial dentures.

Abnormally bulging, protruding, or swollen gums are a possible sign of disease.

Click the icon to see an image of recessed gums.

Abscesses. Deepening periodontal pockets between the gums and bone can become blocked by tartar or food particles. Infection-fighting white blood cells become trapped and die. Pus forms, and an abscess develops. Abscesses can destroy both gum and tooth tissue, cause nearby teeth to become loose and painful, and may cause fever and swollen lymph nodes.

Click the icon to see an image of a tooth abscess.

Pain is usually not a symptom, which partly explains why the disease may become advanced before treatment is sought and why some patients avoid treatment even after periodontitis is diagnosed.

Causes

Periodontal disease is marked by bacterial overgrowth. However, a persistent immune response to chronic infections in the mouth is believed to play a major role in gum destruction.

In the healthy mouth, more than 350 species of microorganisms have been found. Periodontal infections are linked to fewer than 5% of these species. Healthy and disease-causing bacteria can generally be grouped into two categories:

The harmless or helpful bacteria are usually known as gram positive aerobic bacteria.
In periodontal disease, the bacterial balance shifts over to gram negative anaerobic bacteria. Inflammatory disease and injury cannot develop without these bacteria.

Following are some of the bacteria most implicated in periodontal disease and bone loss:

Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis. These two bacteria appear to be particularly likely to cause aggressive periodontal disease. Both P. gingivalis and A. actinomycetemcomitans, along with multiple deep pockets in the gum, are associated with resistance to standard treatments for gum disease. P. gingivalis may double the risk for serious gum disease. P. gingivalis produces enzymes, such as one called arginine-specific cysteine proteinase, which may be the specific destructive factors that disrupt the immune system and lead to subsequent periodontal connective tissue destruction.
Bacteroides forsythus is also strongly linked to periodontal disease.
Other bacteria associated with periodontal disease are Treponema denticola, T. socranskii, and P. intermedia. These bacteria, together with P. gingivalis, are frequently present at the same sites, and are associated with deep periodontal pockets.

Some bacteria are related to gingivitis, but not plaque development. They include various streptococcal species.

Evidence now suggests that periodontal disease is an autoimmune disorder, in which immune factors in the body attack the person's own cells and tissue -- in this case, those in the gum. It appears to work as follows:

The bacteria that form plaque and tartar release toxins that stimulate the immune system to overproduce powerful infection-fighting factors called cytokines.
Ordinarily, cytokines are important for healing. In excess, however, they can cause inflammation and severe damage. Cytokines of particular importance in periodontal disease are known as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta, which are very active in the mouth, and are important in causing destructive inflammation.
In addition, white blood cells produced by the immune response to bacteria also release a family of enzymes called matrix metalloproteinases (MMPs), which break down connective tissue.

Studies suggest that this inflammatory response may have damaging effects not only in the gums but also in organs throughout the body, including the heart.

Certain herpes viruses (herpes simplex and varicella-zoster virus, the cause of chickenpox and shingles) are known causes of gingivitis. Other herpes viruses (cytomegalovirus and Epstein-Barr) may also play a role in the onset or progression of some types of periodontal disease, including aggressive and severe chronic periodontal disease. All herpes viruses go through an active phase followed by a latent phase and possibly reactivation.

Some experts theorize that these viruses may cause periodontal disease in different ways, including release of tissue-destructive cytokines, overgrowth of periodontal bacteria, suppressing immune factors, and initiation of other disease processes that lead to cell death.

Risk Factors

More than 75% of American adults have some form of gum disease, but according to a major survey, only 60% have any significant knowledge about the problem. Gum inflammation and ulcers are common, and not all people with these problems develop periodontal disease. Still, about 30% of people are genetically susceptible to periodontal disease. Other factors also put individuals at higher risk.

Lack of Oral Hygiene. Lack of oral hygiene encourages bacterial buildup and plaque formation.

Sugar and Acid. The bacteria that cause periodontal disease thrive in acidic environments. Therefore, eating sugars and other foods that increase the acidity in the mouth increase bacterial counts.

Poorly Contoured Restorations. Poorly contoured restorations (fillings or crowns) that provide traps for debris and plaque can also contribute to its formation.

Anatomical Tooth Abnormalities. Abnormal tooth structure can increase the risk.

Wisdom Teeth. Wisdom teeth, also called third molars, can be a major breeding ground for the bacteria that cause periodontal disease. In fact, for patients in their 20s, periodontal disease is most likely to occur around the wisdom teeth. Research suggests that periodontitis can occur in wisdom teeth that have broken through the gum as well as teeth that are impacted (buried). Periodontal disease can also be present even in patients with wisdom teeth who do not have any symptoms. Experts recommend that adolescents and young adults with wisdom teeth should have a dentist check for signs of periodontal disease

Children and Adolescents. Gingivitis, in varying degrees, is nearly a universal finding in children and adolescents. In rare genetic cases, children and adolescents are subject to destructive forms of the disease. Researchers have also observed some of the organisms seen in periodontal disease in young children without signs of gum problems. Healthy children, however, do not generally harbor two primary periodontal bacteria, P. gingivalis and T. denticola. The disease is also uncommon in teenagers.

Adults. One survey reported that 3.6% of adults between the ages of 18 - 34 had periodontal disease. As people age, the risk for periodontal disease increases. Over half of American adults have gingivitis surrounding 3 - 4 teeth, and 30% have significant periodontal disease surrounding 3 - 4 teeth. In a study of people over 70 years old, 86% had at least moderate periodontitis and over a quarter of them had lost their teeth.

About three-quarters of periodontal office visits are made by women, even though women tend to take better care of their teeth than men. Female hormones affect the gums, and women are particularly susceptible to periodontal problems. Hormone-influenced gingivitis appears in some adolescents, in some pregnant women, and is occasionally a side effect of birth control medication.

Before Menstruation. Gingivitis may flare up in some women a few days before they menstruate, when progesterone levels are high. Gum inflammation may also occur during ovulation. Progesterone dilates blood vessels causing inflammation, and blocks the repair of collagen, the structural protein that supports the gums.

Pregnancy. Hormonal changes during pregnancy can aggravate existing gingivitis, which typically worsens around the second month and reaches a peak in the eighth month. Pregnancy does not cause gum disease, and simple preventive oral hygiene can help maintain healthy gums. Any pregnancy-related gingivitis usually resolves within a few months of delivery. Because periodontal disease can increase the risk for low-weight infants and cause other complications, it is important for pregnant women to see a dentist.

Oral Contraceptives. Some studies report that oral contraceptives containing the synthetic progesterone desogestrel (but not dienogest, another common progesterone) increase the risk for periodontal disease.

Menopause. Estrogen deficiency after menopause reduces bone mineral density, which can lead to bone loss. Bone loss is associated with both periodontal disease and osteoporosis. Bone loss in the alveolar bone (which holds the tooth in place) may be a major predictor of tooth loss in postmenopausal women. Periodontal disease is the main cause of alveolar bone loss. During menopause, some women may also develop a rare condition called menopausal gingivostomatitis, in which the gums are dry, shiny, and bleed easily. Women may also experience abnormal tastes and sensations (such as salty, spicy, acidic, burning) in the mouth.

Periodontal disease often occurs in members of the same family. Genetics, intimacy, hygiene, or a mixture of factors may be responsible. Studies have found that children of parents with periodontitis are 12 times more likely to have the bacteria thought to be responsible for causing plaque and, eventually, periodontal disease.

Genetic Factors. Genetic factors may play the critical role in half the cases of periodontal disease. Up to 30% of the population may have some genetic susceptibility to periodontal disease. For example, some people with severe periodontal disease have genetic factors that affect the immune factor interleukin-1 (IL-1), a cytokine involved in the inflammatory response. Such individuals are up to 20 times more likely to develop advanced periodontitis than those without these genetic factors. Early onset and rapidly progressive periodontal disease also have strong genetic components.

Intimacy. Intimate partners and spouses of people with periodontal disease may also be at risk. Researchers have found that the bacteria P. gingivalis may be contagious after exposure to an infected person over a long period of time. There is no risk from short exposure such as after a fast kiss or when sharing an eating utensil.

Smoking is the single major preventable risk factor for periodontal disease. The habit can cause bone loss and gum recession even in the absence of periodontal disease. A number of studies indicate that smoking and nicotine increase inflammation by reducing oxygen in gum tissue and triggering an over-production of immune factors called cytokines (specifically ones called interleukins). In excess, cytokines are harmful to cells and tissue.

Furthermore, when nicotine combines with oral bacteria, such as P. gingivalis, the effect produces even greater levels of cytokines and eventually leads to periodontal connective tissue breakdown. Studies suggest that smokers are 11 times more likely than nonsmokers to harbor the bacteria that cause periodontal disease and four times more likely to have advanced periodontal disease. In one study more than 40% of smokers lost their teeth by the end of their lives.

The risk of periodontal disease increases with the number of cigarettes smoked per day. Smoking cigars and pipes carries the same risks as smoking cigarettes. Exposure to secondhand smoke is also associated with a 50 - 60% increased risk for developing periodontal disease, according to one study. Fortunately, when smokers quit, their periodontal health gradually recovers to a state comparable to that of nonsmokers.

Diabetes. Much evidence exists on the link between type 1 and 2 diabetes and periodontal disease. Diabetes causes changes in blood vessels, and high levels of specific inflammatory chemicals such as interleukins, that significantly increase the chances of periodontal disease. High levels of triglycerides (which are common in type 2 diabetes) also appear to impair periodontal health. Obesity, common in people with type 2 diabetes, may also predispose a person to gum disease. Controlling both type 1 and 2 diabetes may help reduce periodontal problems. For children with diabetes, good oral hygiene should begin at a young age. A 2006 study suggested that gum problems can start as early as 6 years of age in children with diabetes.

Osteoporosis and Osteonecrosis. Osteoporosis (loss of bone density) has been associated with periodontal disease in postmenopausal women. There have also been a few reports of osteonecrosis (bone decay) of the jaw in patients who take oral bisphosphonate drugs such as alendronate (Fosamax). Symptoms of osteonecrosis of the jaw include loose teeth, exposed jawbone, pain or swelling in the jaw, gum infections, and poor healing of the gums. As a precaution, the American Dental Association (ADA) recommends that patients who are prescribed bisphosphonate drugs get a thorough dental exam before beginning drug therapy, or as soon as possible after beginning therapy. The ADA also recommends that patients who take oral bisphosphonate drugs should discuss with their dentists any potential risks from dental procedures (such as extractions and implants) that involve the jawbone. In any case, be sure to inform your dentist if you are taking a bisphosphonate drug.

Osteoporosis is a condition marked by progressive loss of bone density, thinning of bone tissue, and increased risk of fractures. Osteoporosis may result from disease, dietary or hormonal deficiency, or advanced age. Regular exercise and vitamin and mineral supplements can reduce and may even reverse loss of bone density.

Giving intravenous bisphosphonates to patients being treated for bone cancer, or other cancers that have spread to the bone, increases their risk for developing osteonecrosis by 1 - 10%. Patients who take oral bisphosphonate drugs also have a slight risk, but 94% of osteonecrosis of the jaw cases involve patients who received bisphosphonates intravenously. If possible, see a dentist for a complete oral exam before beginning bisphosphonate therapy. In any case, be sure to inform your dentist if you are receiving intravenous bisphosphonates. Your dentist or oral surgeon may need to take special precautions when performing dental surgery

Herpes-Related Gingivitis. Herpes virus is a common cause of gingivitis in children and has become increasingly common in adults. It typically starts out with a purplish color and "boggy" sensation in the gums. Multiple blisters may form across the mucus membranes in the mouth and gums, followed by ulcers. They usually resolve in 7 - 14 days.

HIV-Associated Gingivitis. HIV-associated gingivitis has been reported in 15 - 50% of patients with HIV or AIDS. HIV-positive individuals harbor larger numbers of periodontal bacteria (candida albicans, P. gingivalis, black-pigmented anaerobic rods, and A. actinomycetemcomitans) than people without HIV. Severe pain is characteristic, along with odor, spontaneous bleeding, ulcers, and swollen, bright red gums. The inflammation never recedes, but halitosis and acute episodes can be managed by conventional cleaning treatments. Its severest form, known as necrotizing stomatitis, can be diagnostic for AIDS. In addition to bleeding, the gums in the front of the mouth are a yellowish-gray color, and bone thrusts out.

Autoimmune Diseases. Autoimmune conditions (Crohn's disease, multiple sclerosis, rheumatoid arthritis, lupus erythematosus, CREST syndrome) have been associated with a higher incidence of periodontal disease. Some research suggests that periodontal disease may even play some causal role. For example, one study suggested that P. gingivalis, one of the major bacteria in periodontal disease, was associated with destructive processes in the brain leading to multiple sclerosis. Still, more research is needed to determine a definitive association between these diseases.

Other Diseases. People with tuberculosis, syphilis, Wegener's granulomatosis, amyloidosis, and many genetic disorders are also at higher risk for periodontitis.

Vitamin C helps the body repair and maintain connective tissue, and its antioxidant effects are important in the presence of tissue-destroying oxidants in periodontal disease. Research indicates that vitamin C deficiency contributes to periodontal disease. A study of more than 12,000 adults found that people who consumed less than the recommended daily allowance of vitamin C, 60 mg (about one orange) were 1.5 times more likely to develop severe gingivitis than those who consumed more than 180 mg each day. Vitamin C levels are especially depleted in smokers. Eating citrus fruits high in vitamin C (such as grapefruit) may be helpful for patients with periodontitis.

Click the icon to see an image of the benefits of vitamin C.

Click the icon to see an image of the sources of vitamin C.

Dental disease is most likely to affect the poor. Children and the elderly suffer the worst oral care, and ethnic minorities follow. In the United States, the lack of access to dental insurance is a contributing factor. In a survey of residents of five states (Arizona, California, Hawaii, Oregon, and Wisconsin), the rate of total tooth loss was less than 20%. In three states (Kentucky, Louisiana, and West Virginia) it was greater than 40%.

Gingival overgrowth can be a side effect of nearly 20 different drugs, most commonly phenytoin (Dilantin), cyclosporine (Sandimmune), and a short-acting form of the calcium channel blocker nifedipine (Procardia).

Several other conditions can also cause gum inflammation, and some have been associated with periodontal disease. They include:

Mouth breathing
Psychologic stress. Stress can affect the immune system. Some studies suggest that stress can influence the development of chronic inflammatory diseases, like periodontitis.
Alcohol abuse. One study reported a higher incidence of periodontal disease, tooth decay, and possibly precancerous areas in patients who abuse alcohol.
Canker sores (aphthous ulcers)

Click the icon to see an image of a canker sore.

Self-injury in psychologically disturbed patients
Hereditary gingival fibromatosis. A rare genetic disease associated with both gum overgrowth and hairiness. It is often associated with gingivitis and periodontal disease.
Desquamative gingivitis. With this condition the outer layer of the gum tissue desquamates (peels away), exposing an acutely red surface. It usually occurs as a result of an allergic reaction or of skin diseases such as lichen planus, benign mucous membrane pemphigoid, bullous pemphigoid, and pemphigus vulgaris. (Bacteria may also play a role in this gum disease.) This condition generally resolves when the underlying problem is treated. It is fairly common in middle-aged women.

Complications

The ultimate outcome of uncontrolled periodontal disease is tooth loss. As the destructive factors cause the breakdown of bone and connective tissue, teeth lose their anchor.

A much less severe but nevertheless distressing problem caused by periodontal disease is bad breath, although coatings on the tongue may contribute more to bad breath than periodontal disease.

Studies have reported that people who have heart disease have a 1.5 - 4 times increased risk for periodontal disease. (The risk is highest for patients with extensive gum disease, bleeding from every tooth.) Acute coronary syndrome, high blood pressure (hypertension), and high cholesterol have also been associated with periodontal disease.

Periodontal disease has also been linked to stroke and coronary artery disease (CAD). The more severe the periodontitis, the greater the risk for heart problems. Many experts, however, are still not sure whether periodontal disease is a risk factor for stroke or a marker that reflects various risk factors common to both conditions.

A stroke is caused by a loss of blood circulation to areas of the brain. The blockage usually occurs when a clot or piece of atherosclerotic plaque breaks away from another area of the body and lodges within the blood vessels of the brain.

Recent evidence suggests that the inflammatory response may be the common element. This is an over-reaction of the immune system that causes injury to tissues in the body. A common link between patients with heart conditions and periodontal disease may be elevated levels of C-reactive protein (CRP), a marker for the inflammatory response. Some experts believe that immune factors causing this response are released into the bloodstream during periodontal disease and cause injury in the arteries supplying blood to the heart.

Other evidence suggests that the periodontal disease bacteria themselves -- particularly P. gingivalis, T. denticola, T. forsythia, and streptococci species -- may be the main culprit. In 2005, results from the NIH-sponsored Oral Infections and Vascular Disease Epidemiology Study (INVEST) determined an association between cardiovascular disease and the bacteria that cause periodontal disease. In this study, higher levels of periodontal bacteria were associated with thicker carotid arteries (a predictor of heart attack and stroke), regardless of C-reactive protein levels. While this study's findings are an important advance in understanding the relationship between periodontal and heart disease, it is still not clear if periodontal disease actually causes heart disease. Researchers hope that future results from INVEST will clarify this issue.

Experts are still not sure if treating gum disease can reduce the risks of heart disease and improve health outcomes for patients with periodontal disease and vascular heart problems. Studies have been mixed, but research is ongoing.

Diabetes is not only a risk factor for periodontal disease -- periodontal disease itself can worsen diabetes. Some evidence suggests that the bacteria that causes periodontal disease may enter the bloodstream and activate cytokines (damaging immune system factors), which then destroy cells in the pancreas where insulin is produced. Some studies indicate that treating periodontal disease can reduce the need for insulin and improve blood sugar control in some people with diabetes.

Bacteria that reproduce in the mouth can also be carried into the airways in the throat and lungs, increasing the risks for respiratory diseases and worsening chronic lung conditions, such as emphysema.

Click the icon to see an image of emphysema.

Many studies strongly indicate that bacterial infections that cause moderate-to-severe periodontal disease in pregnant women can increase the risk for premature delivery and low birth weight infants. The more severe the infection, the greater the risk to the baby. Research indicates that bacteria from gum disease and tooth decay may trigger the same factors in the immune system as genital and urinary tract infections. These biologic substances, called prostaglandins and tumor necrosis factor, produce inflammation in the cervix and uterus that can cause premature dilation and contractions. Research also suggests that periodontal disease increases the risk for preeclampsia, a life-threatening disorder that occurs in mid- to late pregnancy and is characterized by high blood pressure.

Experts recommend that women have a periodontal examination before becoming pregnant or as soon as possible thereafter. Because women with diabetes are at higher risk for periodontal disease, it is especially important that they see a dentist early in pregnancy. Experts are still not sure if treating periodontal disease can improve birth outcomes. A 2006 study in the New England Journal of Medicine indicated that the treatment does not affect pre-term birth or birth weight. However, the researchers reported that periodontal treatment is definitely safe for pregnant women.

Prevention

Healthy habits and good oral hygiene are critical in preventing gum disease. Regular and effective tooth brushing and mouth washing, however, are effective only above and slightly below the gum line. Once periodontal disease develops, more intensive treatments are needed.

It is important to reduce both the quantity and, in particular, the frequency of sugar intake. Avoid snacks and drinks with sugar (other than natural sugars found in fruits and vegetables). Eat sugar-containing foods with meals, ideally followed by brushing. Since fruit juices can also cause tooth erosion in children, parents should emphasize milk and water.

Smoking may play a significant role in over half the cases of chronic periodontal disease, according to research published in 2000. For smokers, quitting is one of the most important steps toward regaining periodontal health.

Fluoride treatment in children has helped to account for the decline in periodontal disease in adults. Because fluoride prevents decay, back molars, which keep the teeth in place, are spared, and are thus less vulnerable to bacteria. Even before teeth first erupt, babies' gums should be wiped clean with a bit of gauze bearing a dab of fluoride toothpaste. Supplementation with fluoride tablets or drops may be recommended for children 6 months or older who drink unfluoridated water or who are at risk for dental problems. A prescription from the child's pediatrician or dentist is required.

Some dentists recommend a fluoride gel for adult patients who are still at risk for tooth decay or sensitivity, but extra fluoride is generally not necessary for adults who use fluoride toothpaste.

Periodontitis is a silent disease. People with the disease rarely experience pain and may not be aware of the problem. A periodontal examination by a general dentist once or twice a year should reveal any incipient or progressive problems. A full mouth series of x-rays is advised every 2 - 3 years. This will alert the dentist to early bone loss and other disorders of the oral cavity.

Dentists now often perform Periodontal Screening and Recording (PSR) using a probe to measure gum pockets. Previously performed only by periodontists, this procedure is now encouraged as part of a regular dental examination. The dentist will identify any areas where deep pocketing has occurred, where the health of the gingiva appears compromised, and where there is undue mobility of teeth. It is the general dentist's responsibility to identify periodontal disease and inform the patient. If the condition is severe, the dentist may want to refer the patient to a periodontist.

Correct tooth brushing, mouth cleansing, and flossing should be everyone's defense against periodontal disease. (However, good hygiene is probably not sufficient to prevent periodontal disease in many people. Regular visits to a dentist are extremely important, especially for high-risk individuals.)

Brushing Guidelines. The following are some recommendations for brushing:

Use a dry brush. One study reported that when people brushed their teeth without toothpaste first, using a soft dry brush, their plaque deposits were reduced by 67%, and gum bleeding dropped by 50%.
No brush of any size, shape, or gimmick is effective if it is incorrectly positioned in the mouth. Place the brush where the gum meets the tooth, with bristles resting along each tooth at a 45-degree angle.
Begin by dry brushing the inside the bottom row of teeth, then the inner top teeth, and last the outer surfaces.
Wiggle the brush back and forth so the bristles extend under the gum line.
Scrub the broad, biting surfaces of the back teeth.
Dry brushing should take about a minute and a half.
A paste is then applied, and the teeth should again be brushed in the same way.
The tongue should be scrubbed for a total of about 30 seconds. A tongue scraper used with an anti-bacterial mouthwash (such as Listerine) is more effective than a toothbrush in removing bacteria.
Rinse the toothbrush thoroughly and then tap it on the edge of the sink at least five times to get rid of debris.
Flossing should finish the process. A mouthwash may also be used.

If brushing after each meal is not possible, rinsing the mouth with water after eating can reduce bacteria by 30%.

Toothbrushes. A vast assortment of brushes of varying sizes and shapes are available, and each manufacturer makes its claim for the benefits of a particular brush. Look for the American Dental Association (ADA) seal on both electric and regular brushes.

In spite of the wide variety of nonelectric toothbrushes, both in shape and bristle design, a study of eight brands found no significant differences in effectiveness among them.

Electric toothbrushes, particularly those with a stationary grip and revolving tufts of bristles, can be advantageous for some people with physical disabilities. Electric toothbrushes with heads that move back and forth up to 4,200 times a minute remove significantly more plaque than ordinary brushes. Even more high-tech brushes are now available that use sound waves to remove plaque.

In general, studies have reported no differences between electric and manual toothbrushes in their ability to remove plaque. (One study showed considerable improvement in groups using sonic toothbrushes, particularly in those with moderate periodontal disease.) Experts recommend, however, that if a regular toothbrush works, it isn't necessary to buy an expensive electric one.

For individuals with average dexterity, a four- or five-rowed, soft, nylon-bristled toothbrush is sufficient. The most important factor in buying any toothbrush, electric or manual, is to choose one with a soft head. Soft bristles get into crevices easier and do not irritate the gums, thereby reducing the risk of exposing teeth below the gum line compared to hard brushes.

Experts generally recommend replacing toothbrushes every 1 - 3 months. Not only do they become breeding grounds for bacteria, but the worn bristles are less effective at removing plaque.

Toothpaste. The object of a good toothpaste is to reduce the development of plaque and eliminate periodontal-causing microorganisms without destroying the organisms that are important for a healthy mouth. All brands should show ADA approval. Even a good toothpaste, however, cannot be delivered past 3 mm below the gum line, where periodontitis develops.

Toothpastes are a combination of abrasives, binders, colors, detergents, flavors, fluoride, humectants, preservatives, and artificial sweeteners. Avoid highly abrasive toothpastes, especially for individuals whose gums have receded.

Ingredients contained in toothpastes may include:

Fluoride. Most commercial toothpastes contain fluoride, which both strengthens tooth enamel against decay and enhances remineralization of the enamel. Fluoride also inhibits acid-loving bacteria, especially after eating, when the mouth is more acidic. This antibacterial activity may help control plaque.
Triclosan. Triclosan is an anti-bacterial substance that may help reduce mild gingivitis.
Metal salts. Metal salts, such as stannous and zinc, serve mostly as anti-bacterial substances in toothpastes. Stannous fluoride gel toothpastes do not reduce plaque, however, even though they have some effect against the bacteria that cause it, but slightly reduce gingivitis.
Peroxide and baking soda. Toothpastes with these ingredients claim to have a whitening action, but while they may help remove stains there is little evidence they whiten the actual color of the teeth. In addition, these substances appear to offer no benefits against gum disease.
Antibacterial sugar substitutes (xylitol), and detergents (delmopinol)

Mouthwashes. The American Dental Association recommends (in addition to daily brushing and flossing) antimicrobial mouthwash to help prevent and reduce plaque and gingivitis, and fluoride mouthwashes to help provide additional protection against tooth decay.

Chlorhexidine (Peridex or PerioGard) is an antimicrobial mouthwash available by prescription only. It reduces plaque by 55% and gingivitis by 30 - 45%. Patients should rinse for 1 minute twice daily. They should wait at least 30 minutes (and preferably 2 hours) between brushing and rinsing since chlorhexidine can be inactivated by certain compounds in toothpastes. It has a bitter taste. It also binds to tannins, which are in tea, coffee, and red wine, so it has tendency to stain teeth in people who drink these beverages. Studies are mixed as to its effectiveness for preventing or reducing periodontal disease.
Listerine is another antimicrobial mouthwash. It is composed of essential oils and is available over the counter. It reduces plaque and gingivitis, when used for 30 seconds twice a day. It leaves a burning sensation in the mouth that most people better tolerate after a few days of use. The usual regimen is to rinse twice a day. (Listerine PocketPaks, which are strips that dissolve on the tongue, have no proven effects on plague and gingivitis.)
Mouthwashes containing cetylpyridinium (Scope, Cepacol) have moderate antimicrobial effect on plaque, but only if they are used an hour after brushing. None are as effective as Listerine or chlorhexidine, but they may still have some value for people who cannot tolerate the other mouthwashes.
Mouthwashes containing stannous fluoride and amine fluoride (Meridol) are moderately effective, but are also not as effective as effective as Listerine or chlorhexidine.
Fluoride mouthwashes (Act) are helpful in preventing cavities.
Mouthwashes that contain alcohol are dangerous for children and should be kept away from them.

Flossing. The use of dental floss, either waxed or unwaxed, is critical in cleaning between the teeth where the toothbrush bristles cannot reach. In spite of this, nearly two-thirds of people do not floss.

To floss correctly, the following steps may be helpful:

Break off about 18 inches of floss and wind most of it around the middle finger of one hand and the rest around the other middle finger.
Hold the floss between the thumbs and forefingers and gently guide and rub it back and forth between the teeth.
When it reaches the gum line, the floss should be curved around each tooth and slid gently back and forth against the gum.
Finally, rub gently up and down against the tooth. Repeat with each tooth, including the outside of the back teeth.
If, on repeated flossing attempts, the floss becomes shredded or cannot be removed easily from between the teeth, a rough crown or overhanging filling may be the cause. In such cases, the restoration should be redone. Such areas create spaces for the collection of food debris, plaque, and calculus.

Here are some tips in choosing the right floss or flossing device:

Use a floss that does not shred or break.
Avoid a very thin floss, which can cut the gum if brought down with too much force or not guided along the side of the tooth.
A floss threader is an invaluable aid for the person who has bridgework. Made of plastic, it looks like a needle with a huge eye, or loop. A piece of floss is threaded into the loop, which can then be inserted between the bridge and the gum. The floss that is carried through with it can then be used to clean underneath the false tooth or teeth and along the sides of the abutting teeth.
Another handy device for cleaning under bridges is a Proxabrush, which is an interdental cleaner. This is a tiny narrow brush that can be worked in between the natural teeth and around the attached false tooth or teeth.
Special toothpicks such as Stim-U-Dent may be effective for wide spaces between teeth but should never replace flossing. Standard toothpicks should never be used for regular hygiene.
Electronic products, such as water piks, are also helpful. These devices are expensive but may improve flossing compliance.

Producing Saliva and Drinking Water. Saliva is important for diluting the toxins created by plaque. Drinking at least 7 glasses of water a day helps reduce inflammation in the mouth by producing more saliva. Increasing water intake is particularly important as one ages, when less saliva is produced.

Diagnosis

The dental practitioner typically performs a number of procedures to determine a diagnosis of periodontal disease.

The dentist will first take a medical history to reveal any past or present periodontal problems, any underlying diseases that might be contributing to the problem, and any medications the patient is taking. After noting the general state of oral hygiene, the dentist may ask about the quality of home dental care.

Inspection of the Gum Area. The dentist inspects the color and shape of gingival tissue on the cheek (buccal) side and the tongue (lingual) side of every tooth and compares these qualities to the healthy ideal. Redness, puffiness, and bleeding upon probing indicate inflammation. If the gum formation between teeth is blunt and not pointed, acute necrotizing periodontal disease may be indicated.

Periodontal Screening and Recording (PSR). PSR is a painless procedure used to measure and determine the severity of periodontal disease:

The dentist uses a mirror and a periodontal probe, a fine instrument calibrated in millimeters (mm), which is used to measure pocket depth. (A new automatic probing device may prove to be even more sensitive and accurate than the standard manual probe that most dentists use.)
The probe is held along the length of the tooth with the tip placed in the pocket. The tip of the probe will then touch the point where the connective tissue attaches to the tooth.
The dentist will "walk" the probe to six specified points on each tooth, three on the buccal (cheek) and three on the lingual (tongue) sides. The dentist measures the depth of the probe at each point.
Pocket depths greater than 3 mm indicate disease.

These measurements help determine the condition of the connective tissue and amount of gingival overgrowth or recession. PSR appears to be even more reliable than x-rays in diagnosing gum disease.

Testing Tooth Movement. Tooth mobility is determined by pushing each tooth between two instrument handles and observing any movement. Mobility is a strong indicator of bone support loss.

X-rays. X-rays are taken to show any loss of bone structure supporting the teeth. Eighteen x-rays make up the full mouth series necessary for diagnosis.

Treatment

Studies support the effectiveness of active treatment combined with a strict maintenance program for patients with periodontal disease. In one study, for example, people with periodontal disease who were inconsistent in caring for their gums after treatment had 5.6 times the risk for tooth loss as those who were very vigilant.

Some dentists have reported a success rate of 85% when professional treatment and good home maintenance are combined. Treatment helps nonsmokers more than smokers, particularly when pockets are deep and persistent. Some studies suggest that periodontal treatment in people with type 2 diabetes helps improve blood sugar levels. Whether treatment will help reduce other health risks, including heart attack and stroke, is unknown.

Treatment Goals. Once periodontal disease has been identified, the goals of treatment are:

To arrest and control the progress of the disease
To leave the periodontal tissues in an easily maintainable state
If possible, to restore the supporting structures, which include bone, gum tissue, and ligaments

Treatment Phases. To achieve these goals, there are various approaches:

Initial cleaning, scaling, and curettage
Surgery -- if needed for reducing deep pockets that remain underneath the gum after extensive cleaning sessions
Low-dose oral or topical antibiotics
Maintenance

After the active treatment is completed and the mouth is in a relative state of health, the patient should have regular cleanings lasting 45 minutes to 1 hour, approximately every 3 months. These may be done by the dental hygienist, the periodontist, or the general dentist. The patient may alternate between them. Home care, of course, must be continued.

Antibiotics Before Treatment. In cases where the individual has a mitral valve prolapse or history of rheumatic heart disease, pretreatment with an appropriate antibiotic is required before any dental work, including cleaning. This is necessary to prevent the possibility of bacterial endocarditis, which can be life threatening.

Scaling, polishing, and sometimes curettage are used to manage periodontal disease. They are usually accomplished in a series of three to four visits spaced about a week apart. (Patients might ask their dentist about the gas nitrous oxide, which is helpful for many patients and may reduce the visits to a single one.) The dental hygienist or practitioner generally uses both ultrasonic and manual instruments to remove calculus.

Calculus above the gum is easily seen. The dental professional usually detects calculus below the gum by careful probing with an instrument.
The hygienist or dentist may use an ultrasonic instrument for removal of the more accessible calculus. This probe-like device vibrates at a frequency range higher than is audible to the human ear. Some people with low tolerance for the ultrasonic probe may wish to request nitrous oxide.
A spray of water is used with ultrasound to prevent overheating and to flush out the debris that is dislodged.
The dental professional will scrape the plaque from above and below the gum line (called scaling). When the probe contacts the rock-like calculus, deposits fracture off the tooth fairly efficiently.
The hygienist or dentist will then smooth the rough spots on the tooth. Smoothing the surface helps remove bacteria that collect there (root planing) and also helps the gums reattach.
Polishing is the finishing procedure. It uses a rubber cup with an abrasive paste to remove plaque and stains on the crown portion of the tooth. It produces a smooth surface, making it temporarily harder for plaque to adhere.

After the cleaning procedure, the dentist will check the pocket depths around the teeth after the cleaning process has been completed. Further treatment needs are determined by the results of these initial sessions:

If the cleaning processes have reduced inflammation, observation only is needed.
If an abscess is present, surgery may be required.

Finally, the dental hygienist or practitioner should offer thorough instructions on home care to insure the removal of bacteria on a daily basis. This includes proper use of the toothbrush, paste, mouth rinses, floss, floss threaders, and proxabrushes. Home care can effectively eliminate the plaque above the gums and down to 2 mm below the gums.

Gingival curettage removes the soft tissue lining of the periodontal pockets in order to completely eliminate bacteria and diseased tissue. It may be used along with scaling and root planing, but achieves a deeper and more complete cleaning. Evidence indicates, however, that it does not contribute any additional benefits beyond simple scaling and planing.

Surgery allows access for deep cleaning of the root surface, removal of diseased tissue, and repositioning and shaping of the bones, gum, and tissues supporting the teeth. Surgical procedures vary depending on the individual diagnosis and needs of the patient. The basic procedure is known as open flap curettage. It involves:

The periodontal surgeon lifts, or flaps, the gums away from the tooth and surrounding bone.
The diseased root surfaces are cleaned and curetted (scraped) to remove deposits.
Gum tissue is replaced into positions to minimize pocket depth.
The periodontist may also contour the remaining bone and attempt to regenerate lost bone and gingival attachment through bone grafts and guided tissue regeneration or the use of enamel matrix protein derivatives.

There is some debate about whether this procedure is any more effective in preventing disease progression than non-surgical therapies, such as low-dose doxycycline, short-term antibiotics, or antibiotic gels. Some studies have reported that although surgical treatment reduced pocket depth more than non-surgical therapies for at least a year after the procedure, benefits from surgery do not persist beyond 5 years, except in very deep pockets.

Postsurgery Pain and Discomfort. Post-surgery discomfort is usually managed easily with over-the-counter medications such as ibuprofen. If discomfort is severe, stronger analgesics may be prescribed. Some patients experience sensitivity to hot or cold temperatures from exposed roots. These problems can be managed with topical fluoride treatments or, in severe cases, with dental restoration.

Guided Tissue Regeneration. A more advanced technique, called guided tissue regeneration, is used to stimulate bone and gum tissue growth:

First, the root surfaces and diseased bone are meticulously cleaned out. Preventing bacterial contamination is very important. The more residual bacteria, the greater the chance that the treatment will fail.
A specialized piece of fabric is sewn around the tooth to cover the crater in the bone left after the cleaning. It is either absorbable or nonabsorbable. (Some studies report highly beneficial results with new absorbable materials, including those coated with the antibiotic doxycycline.)
The gum is then sewn over the fabric. The fabric prevents the gum tissue from growing down into the bone defect and allows the bone and the attachment to the root to regenerate.
After 4 - 6 weeks, the nonabsorbable fabric must be removed using a minor surgical procedure. The absorbable membrane may be left in. In general, there is little difference in outcome between absorbable and nonabsorbable procedures. The absorbable fabric may not be as effective as standard grafts if gum tissue is thin, although newer materials may prove to produce better results.

Bone Grafting. In some cases of severe bone loss, the surgeon may attempt to encourage regrowth and restoration of bone tissue that has been lost through the disease process. This involves bone grafting:

The surgeon places bone graft material into the defect.
The material may be either bone from the same patient or a substance called decalcified freeze-dried bone allografts (DFDBA) which is obtained from a donor.
This material then stimulates new bone growth in the area.

Enamel Matrix Protein Derivative. Amelogenin is a derivative of a major protein in the structure (the matrix) of enamel that helps stimulate gum tissue growth. A gel containing amelogenin (Emdogain) is applied during surgery and forms a coat over the roots of the teeth. The gel itself dissolves after 2 days, leaving the active substance behind. Studies report that it is safe and may significantly reduce the effects of periodontal disease. One study suggested that the benefits, as indicated by bone attachment, can persist for at least 4 years. (Results were similar to guided tissue regeneration.)

Gum grafting techniques can also be very useful for improving the looks of the gum as well as adding support to the teeth. During this procedure, the periodontist takes gum tissue from the palate or another donor source to cover the exposed root in order to even the gum line and reduce sensitivity. Other procedures are available to improve the look of the gums and teeth. The gum line can be sculpted to improve uneven or excess gums and to cover exposed roots as gums recede.

Periodontists report that they are achieving great success with tooth implants in patients who have lost teeth due to periodontal disease. The average cost for a single implant is high, however, and one implant requires 5 - 7 months for completion.

Medications

Antibiotics are often used in combination with surgery, curettage, or alone to eliminate or prevent disease-causing bacteria after periodontal procedures. They are being investigated in oral forms as well as in topical forms that are applied directly to the gum. Increasingly, dental professionals are finding that local application of antibiotics is more effective than periodontal surgery alone. They may even prove to be an alternative to surgery.

Some experts are concerned, however, that long-term use of antibiotics increases the risk of bacterial resistance to these drugs, which is a growing health problem in general. Of some encouragement was a 2000 review, which indicated that low-dose antibiotics do not increase the risk of bacterial resistance. However, long-term studies are still needed

Antibiotics given orally and at standard doses have some limited applications for periodontal disease. They are typically given for an acute infection. Long-term use of antibiotics is advised for the control of juvenile periodontitis, refractory periodontitis, rapidly progressing periodontitis, and prepubertal periodontitis. Specific antibiotics used in periodontal disease include:

Tetracycline antibiotics -- which include tetracycline hydrochloride, doxycycline, and minocycline -- are the primary drugs used. They not only have anti-bacterial actions but also reduce inflammation and help block collagenase, the protein that destroys connective tissue and bone, even in low doses. In fact, these two actions seem to contribute most to periodontal protection, rather than their antibacterial properties. Short-term use of standard-dose doxycycline (a 10-day treatment) is used for treating acute periodontal infections and for eliminating inflammation. Topical application and long-term use of these antibiotics are showing particular promise.
Some macrolide antibiotics (roxithromycin) may have actions against inflammation and growth involved in periodontal disease.
Some quinolone antibiotics (moxifloxacin, ciprofloxacin) may specifically target A. actinomycetemcomitans, an important bacteria in periodontal disease.
Metronidazole (Flagyl) in combination with tetracycline or amoxicillin (a penicillin) may be used for severe and chronic periodontal disease.

There is growing bacterial resistance to many of these antibiotics, such as roxithromycin and metronidazole, therefore limiting their use in periodontal disease. One study indicated, however, that 3 months after antibiotic administration, the percentage of bacteria that could be eliminated with standard antibiotics returned to normal.

Topical application of antibiotics to the gum surface does not affect the entire body like oral antibiotics do, and they are preferred whenever possible. Studies suggest that, in combination with scaling and planing, any of these approaches are very effective for periodontal health.

Several different topical applications are showing promise, including:

Atridox is a doxycycline gel that conforms to the gum surface and then solidifies. Over the next few days, it releases the antibiotics.
Elyzol is a gel or strip applied to the gum that is composed of metronidazole. It has unique actions that are effective against parasites as well as bacteria. Studies suggest that Atridox, which contains doxycycline, may be more effective than Elyzol. (In one study, however, the doxycycline gel worked faster, but metronidazole achieved a greater bacterial reduction.)
PerioChip is a chip that is placed into the gum pocket after scaling. Over time, it slowly releases chlorhexidine, a powerful bacteria-killing antiseptic. Early studies report benefits in reducing pocket depths, but it is still not known whether these improvements are sustained.
Minocycline microspheres (Arestin) contain antibiotics in tiny capsules, which are applied to the gums after scaling and planing. Studies report that they are more effective in reducing pocket depth and bone loss than standard periodontal maintenance. Patients obtain these benefits regardless of their smoking status, age gender, or extent of the periodontal disease.
Actisite is a thin strip similar to dental floss, which is treated with tetracycline hydrochloride. The treated thread is temporarily inserted between the tooth and gum. (Using multiple strips may be more beneficial than using a single strip.) This was one of the first topical applications of antibiotics. Other topical approaches are being increasingly used.

Subantimicrobial Dose Doxycycline (Periostat). Subantimicrobial dose doxycycline (SDD) is a term used for a treatment that uses very low doses (20 mg) of doxycycline (Periostat). Although doxycycline is a tetracycline antibiotic, the doses used are too low to affect bacteria. However, at these dose levels, the drug blocks matrix metalloproteinases (MMPs) -- enzymes that destroy the connective tissues holding the teeth. Periostat is taken twice a day for months. There is some concern that such long-term use may pose a risk for the development of antibiotic-resistant bacteria or other, still unknown, adverse effects. The doses used in this treatment, however, are too low to have any effect on bacteria, so some experts believe this risk is very low. In fact, several 12-month studies report significant improvements in tooth attachment and pocket depth with no increased incidence of side effects. [Taking a common nonsteroidal anti-inflammatory drug, such as aspirin or ibuprofen (Advil) along with doxycycline, may enhance the effectiveness of this treatment.]

Chemically Modified Tetracyclines. Other tetracyclines are being developed that inhibit MMPs but have no antibiotic properties, which would, theoretically, avoid possible long-term problems with antibiotic resistance.

Other Treatments

Nonsteroidal Anti-inflammatory Drugs (NSAIDs). NSAIDs are drugs that block factors that cause inflammation and pain.

Over-the-counter NSAIDs include aspirin, ibuprofen (Motrin IB, Advil, Nuprin, Rufen), naproxen (Aleve), ketoprofen (Actron, Orudis KT).
Prescription NSAIDs include naproxen (Naprosyn, Anaprox), diclofenac (Voltaren), tolmetin (Tolectin), ketoprofen (Orudis, Oruvail), indomethacin (Indocin).

These drugs are used not only for relieving pain in periodontal disease but also for slowing the disease process. NSAIDs block inflammatory enzymes triggered by cytokines, which are important immune factors in periodontal disease. A number of NSAIDs have been investigated and have been shown to reduce gingivitis and slow progression of periodontal disease.

In one study, long-term use of oral flurbiprofen (Ansaid) resulted in significantly lower bone loss, although disease progression returned when the drug was stopped.

Investigators are also studying rinses, creams, and other topical forms of NSAIDs. For example, a cream containing ketoprofen appears to reduce bone loss. (Ketoprofen is of particular interest because it blocks not only COX-2 but also another pathway involved in the disease process.)

Warning about NSAIDs: Although NSAIDs work well, long-term use can cause stomach problems, such as ulcers and bleeding, and possible heart problems. In April 2005, the FDA asked drug manufacturers of NSAIDs to include a warning label on their product that alerts users of an increased risk for cardiovascular events and gastrointestinal bleeding.

Gels containing growth factors -- including substances called recombinant human (rh), platelet-derived growth factor-BB (PDGF-BB), and (rh) insulin-like growth factor-I (IGF-I) -- are showing promise for restoring bone.

Research is underway to find a vaccine against periodontal disease. To date, animal studies show promise, but an effective vaccine for people is years away.

Researchers are investigating the use of photodynamic therapy (PDT) as an alternative to antibiotic drugs. PDT destroys periodontal bacteria by applying photosensitive drugs to oral regions and exposing the drug-treated area to a light or laser. Research appears promising but is still in its preliminary stages.

Resources

www.nidcr.nih.gov -- National Institute of Dental and Craniofacial Research
www.perio.org -- American Academy of Periodontology
www.ada.org -- American Dental Association
www.aaoms.org -- American Association of Oral and Maxillofacial Surgeons

References

Amaliya , Timmerman MF, Abbas F, Loos BG, Van der Weijden GA, Van Winkelhoff AJ, et al. Java project on periodontal diseases: the relationship between vitamin C and the severity of periodontitis. J Clin Periodontol. 2007 Apr;34(4):299-304.

de Oliveira RR, Schwartz-Filho HO, Novaes AB Jr, Taba M Jr. Antimicrobial photodynamic therapy in the non-surgical treatment of aggressive periodontitis: a preliminary randomized controlled clinical study. J Periodontol. 2007 Jun;78(6):965-73.

Kolahi J, Soolari A. Rinsing with chlorhexidine gluconate solution after brushing and flossing teeth: a systematic review of effectiveness. Quintessence Int. 2006 Sep;37(:605-12.

Persson GR, Yeates J, Persson RE, Hirschi-Imfeld R, Weibel M, Kiyak HA. The impact of a low-frequency chlorhexidine rinsing schedule on the subgingival microbiota (the TEETH clinical trial). J Periodontol. 2007 Sep;78(9):1751-8.

Staudte H, Sigusch BW, Glockmann E. Grapefruit consumption improves vitamin C status in periodontitis patients. Br Dent J. 2005 Aug 27;199(4):213-7, discussion 210.

Review Date:
1/26/2008
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

A.D.A.M., Inc. is accredited by URAC, also known as the American Accreditation HealthCare Commission (www.urac.org). URAC's accreditation program is an independent audit to verify that A.D.A.M. follows rigorous standards of quality and accountability. A.D.A.M. is among the first to achieve this important distinction for online health information and services. Learn more about A.D.A.M.'s editorial policy, editorial process and privacy policy. A.D.A.M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health on the Net Foundation (www.hon.ch).

A.D.A.M. Copyright

The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. A licensed medical professional should be consulted for diagnosis and treatment of any and all medical conditions. Call 911 for all medical emergencies. Links to other sites are provided for information only -- they do not constitute endorsements of those other sites. © 1997-2010 A.D.A.M., Inc. Any duplication or distribution of the information contained herein is strictly prohibited.

adam.com

Alzheimer's disease

FitSugar — Wed, 08 Oct 2008 17:35:13 -0700

In This Report

Highlights
Introduction
Causes
Risk Factors
Prevention
Symptoms
Diagnosis
Medications
Stages
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Alzheimer’s Disease Toll Increasing

More than 5 million Americans now have Alzheimer’s disease, and the number could increase to 16 million by mid-century, according to a 2007 report from the Alzheimer’s Association.

New Drug Indication

In 2006, the FDA expanded the use of donepezil (Aricept) to include treatment of people with severe dementia associated with Alzheimer’s disease. Donepezil was previously approved only for people with mild-to-moderate dementia.

Managing Psychotic and Behavioral Symptoms

Newer antipsychotic drugs are no better than placebo for controlling psychosis, aggression, and agitation in patients with Alzheimer’s disease, indicates an important study in the New England Journal of Medicine. In addition, these drugs can cause severe side effects and have been associated with increased death rate.
Non-drug approaches, such as behavioral techniques and bright light boxes, may be helpful for these patients, suggests an Archives of Internal Medicine study.

Brain Exercises Prevent Mental Decline

Cognitive training exercises that help boost memory, reasoning, and processing speed may help slow mental decline and improve functional abilities in older adults, indicates a Journal of the American Medical Association study.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Do Not Prevent Alzheimer’s

The NSAIDs naproxen (Aleve) and celecoxib (Celebrex) do not protect against Alzheimer’s disease, indicates a data analysis from a large-scale U.S. National Institutes of Health (NIH) clinical trial.

Docosahexaenoic Acid (DHA) for Alzheimer’s Prevention

DHA, an omega-3 fatty acid found in some types of fish, may lower the risk for dementia and Alzheimer’s disease as well as delay its progression. However, researchers are uncertain whether DHA dietary supplements provide the same benefits as food sources (salmon, mackerel, and other types of fatty fish). In 2007, the NIH announced the launch of a national clinical trial to evaluate whether DHA can slow cognitive and functional decline in people with mild-to-moderate Alzheimer’s disease.

Support for Caregivers

Intensive programs that combine counseling, support groups, and problem-solving techniques can dramatically improve caregivers’ quality of life and may help delay patients’ transfers to nursing homes, several recent studies suggest.

Introduction

Alzheimer's disease (AD) is a degenerative disease of the brain from which there is no recovery. The disease slowly attacks nerve cells in all parts of the cortex of the brain and some surrounding structures, thereby impairing a person's abilities to govern emotions, recognize errors and patterns, coordinate movement, and remember. Ultimately, a person with AD loses all memory and mental functioning.

The major areas of the brain have one or more specific functions.

Causes

Researchers are finding specific biologic factors involved with Alzheimer's disease. Various environmental and genetic players appear to contribute to or trigger the process by which these factors destroy nerve cells leading to this disease.

Imaging techniques in patients with Alzheimer's disease have found significant loss of cells and volume in the regions of the brain devoted to memory and higher mental functioning. Important abnormalities have specifically been observed during biopsies:

Twisted nerve cell fibers, known as neurofibrillary tangles
A sticky protein, beta amyloid

Other factors also play a role.

Click the icon to see an animation about Alzheimer's disease.

The Effects of Neurofibrillary Tangles and Beta Amyloid in Alzheimer's Disease. These biologic factors appear to be involved in the development Alzheimer's disease in the following ways:

Neurofibrillary tangles are the damaged remains of microtubules, the support structure that allows the flow of nutrients through the neurons (nerve cells). A key component in these tangled fibers is an abnormal form of the tau protein, which in its healthy version helps in the assembly of the microtubule structure. The defective tau, however, appears to block the actions of the normal version.
Beta Amyloid (also called A beta) is the second significant finding. This insoluble protein accumulates and forms sticky patches called neuritic plaque, which are found surrounded by the debris of dying nerve cells in the brains of Alzheimer's victims.
Amyloid precursor protein (APP) is a large nerve-protecting protein that is the source of beta amyloid. In Alzheimer's certain enzymes, particularly those called gamma-secretases, snip APP into beta amyloid pieces. This process is controlled by factors called presenilin proteins. (Genetic abnormalities that affect either APP or presenilin proteins occur in some inherited cases of early-onset Alzheimer's.)
High levels of beta amyloid are associated with reduced levels of the neurotransmitter acetylcholine. (Neurotransmitters are chemical messengers in the brain.) Acetylcholine is part of the cholinergic system, which is essential for memory and learning and is progressively destroyed in Alzheimer's disease.
Beta amyloid may also disrupt channels that carry sodium, potassium, and calcium. These elements serve the brain as ions, producing electric charges that must fire regularly in order for signals to pass from one nerve cell to another. If the channels that carry ions are damaged, an imbalance can interfere with nerve function and signal transmission.

Click the icon to see an image of amyloidosis.

Other Proteins. Researchers have now identified other important proteins in the areas of the brain affected by Alzheimer's disease.

ERAB (endoplasmic-reticulum associated binding protein) appears to combine with beta amyloid, which in turn attracts new beta amyloid from outside the cells. High amounts of ERAB may also enhance the nerve-destructive power of beta amyloid.
AMY plaques resemble beta amyloid so closely that researchers were able to detect them only with the use of highly sophisticated techniques.
Elevated levels of a protein called prostate apoptosis response-4 (Par-4) may cause nerve cells to self-destruct.

Researchers are also attempting to discover why beta amyloid is so toxic to nerve cells. Some researchers are focusing on two processes in the body that may be involved with Alzheimer's disease: oxidation and the inflammatory process. There is some evidence that such events can begin decades before Alzheimer's disease actually develops. One scenario for their role in Alzheimer's is as follows:

The Role of Oxidation.

As beta amyloid breaks down it releases unstable chemicals called oxygen-free radicals. Once released, oxygen-free radicals bind to other molecules through a process called oxidation.
Oxidation is the result of many common chemical processes in the body, but when oxidants are overproduced, they can cause severe damage in cells and tissue, including even affecting genetic material in cells (its DNA). Oxidation is known to play a role in many serious diseases, including coronary artery disease and cancers, and experts believe it may also contribute to Alzheimer's.

The Inflammatory Response.

One result of oxidation is the marshaling of immune factors to repair the cellular injuries it produces. Overproduction of some of these factors, however, produces the so-called inflammatory response, in which the immune process itself can actually damage the body's own cells themselves.
Principle immune cells in the brain are called macrophage/microglia (M phi). In the healthy brain, they play an important protective role against invading organisms. However, when they are activated by beta amyloid oxidation, they release toxic molecules called cytokines, which are known to cause harm. For example, significantly high levels of interleukin-6, a specific cytokine, have been detected in people with Alzheimer's.
Other inflammatory factors of specific interest in Alzheimer's research are the enzyme cyclooxygenase (COX) and its products called prostaglandins. Excess amounts of these factors may increase levels of glutamate. Glutamate is an amino acid that excites nerves and, when overproduced, is a powerful nerve-cell killer.
The inflammatory process has also been associated with the release of soluble toxins called amyloid beta-derived diffusible ligands, which some investigators believe may prove to key players in the destructive process.

Major research targets in Alzheimer's disease are the factors responsible for beta amyloid build-up and concentration in certain people and not in others. Genetic factors are believed to play a role in many cases. In 2003, the National Institute on Aging (NIA) launched the ambitious AD Genetics Initiative, a 3-year national project to bank genetic material from families who have at least two members with late-onset Alzheimer's.

The ApoE Gene and Late-Onset Alzheimer's. The major target in genetic research on late-onset Alzheimer's disease (called LOAD) has been apolipoprotein E (ApoE), which plays a role in the movement and distribution of cholesterol for repairing nerve cells during development and after injury.

The gene for ApoE comes in three major types:

ApoE4. Studies have reported the greatest deposits of beta amyloid in people with ApoE4, which is now believed to be a major risk factor for late-onset Alzheimer's. Some evidence suggests that the ApoE protein removes beta amyloid but the ApoE4 variant does so less efficiently than other ApoE types. (ApoE4 has also been studied for years as a risk factor for heart disease.)
ApoE3 and ApoE2. Fewer beta amyloid deposits have been observed in people with the ApoE3, and the fewest deposits have been observed in people with ApoE2, which may actually be protective.

People inherit a copy of one type from each parent, but Alzheimer's disease is not inevitable even in people with two copies of the ApoE4 gene. Reports vary widely in estimating the extent of risk:

People without ApoE4 have an estimated risk of between 9 - 20% for developing Alzheimer's by age 85.
In people with one copy of the gene, the risk is between 25 - 60%.
In people with two copies, the risk ranges from 50 - 90%. (Only 2% of the population carries two copies of the ApoE4 gene.)

Some researchers suspect that some specific variation of the ApoE4 gene or combinations with other genes are critical for the disease, since many people who carry the ApoE4 exhibit no signs of Alzheimer's. For example, evidence suggests that genetic factors play a role in a common subtype of late-onset Alzheimer's disease that also includes psychosis. An important 2002 genetic study has identified certain genetic linkages associated with ApoE4 that appear to play a strong role in this subtype.

Other Genetic Factors in Late-Onset Alzheimer's. Most people with late-onset Alzheimer's disease do not carry the ApoE4 gene. Increasingly, researchers believe that many cases of late-onset Alzheimer's result from a combination of genetic factors that participate in the process of producing or degrading beta amyloid. Some under investigation include:

Researchers are targeting chromosomes 9, 10, and 12 as possible locations for genetic factors involved with Alzheimer's disease. (The ApoE4 gene is on chromosome 19.) In 2005, researchers announced that mutations linked to the ubiquilin 1 (UBQLN1) gene, located on chromosome 9, might be associated with increased risk for late-onset Alzheimer's disease.
Researchers have detected mutations in the proteins amyloid precursor protein (APP) and ubiquitin-B (Ubi-B), which may account for some cases of late- and early-onset Alzheimer's. Such mutations are not inherited, however, but appear to be genetic mistakes that occur during transcription, the coding process in which DNA establishes the pattern for the production of its proteins and other molecules.
In 2007, researchers identified mutations in the SORL1 gene as a possible factor in late-onset Alzheimer’s disease. Researchers think that variations in this gene may contribute to amyloid plaque formation in Alzheimer’s disease.

Genetic Factors for Early-Onset Alzheimer's. Scientists are coming closer to identifying defective genes responsible for early-onset Alzheimer's, an uncommon, but extremely aggressive form of the disease.

Mutations in genes known as presenilin-1 (PS1) and presenilin-2 (PS2) account for most cases of early-onset inherited Alzheimer's disease. The defective genes appear to accelerate beta amyloid plaque formation and apoptosis, a natural process by which cells self-destruct.
Genetic mutations in the genes that control amyloid precursor protein (APP) are also being targeted as causes of early-onset Alzheimer's. The genetic disease Down syndrome, for example, overproduces beta-amyloid precursor protein (APP), the source of beta amyloid, and almost always leads to early Alzheimer's. Other APP mutations are being identified.

Researchers are also investigating environmental factors (infections, metals, industrial and other toxins) that may trigger oxidation, inflammation, and the disease process, particularly in people with a genetic susceptibility to Alzheimer's.

Infectious Organisms. Slow, infectious viruses cause a number of other degenerative neurologic diseases, such as kuru and Creutzfeldt-Jakob disease.

Click the icon to see an image of Creutzfeldt-Jakob disease.

Although no specific virus has been linked to Alzheimer's, some researchers theorize that people with a genetic susceptibility to Alzheimer's may be vulnerable to the actions of certain viruses, particularly under circumstances when the immune system may be weakened.

Metals. Some laboratory studies have reported excessive amounts of metal ions such as zinc, copper in the brain of people with Alzheimer's disease. Such ions may possibly change the chemical architecture of normal beta amyloid, making it more harmful. A mildly acidic environment appears to be important in the process that binds these metals to beta amyloid. Experts observe that such conditions (acidic environment and higher levels of zinc and copper) commonly occur as part of the inflammatory response to local injury.

Electromagnetic Fields. Some studies on people exposed to intense electromagnetic fields (EMF) have reported a higher incidence of Alzheimer's. However, the association between EMF and Alzheimer's is very weak.

Risk Factors

Alzheimer's disease is the seventh leading cause of death in American adults. It affects about 5 million Americans and 8 million more people worldwide. According to the U.S. Alzheimer’s Association, 1 in 8 people age 65 and older, and nearly 1 in 2 people over age 85, have Alzheimer’s disease.

Age is the greatest risk factor for Alzheimer's disease. The number of cases of Alzheimer's disease doubles every 5 years in people over 65. By age 85, almost half of all people are afflicted. People with the disease survive, on average, half as long as similarly aged adults without the disease.

With the increasing numbers of aging adults, unless effective methods for prevention and treatment are developed, Alzheimer's disease will reach epidemic proportions, afflicting about 16 million Americans within 50 years. Evidence points to older age, high blood pressure, cholesterol levels, and a family history of the disease as the most important risk factors for Alzheimer's disease.

Several studies have reported that women have a much higher risk for Alzheimer's disease than men. If there is a gender difference, it is likely to be due estrogen, the primary female hormone, which appears to have properties that protect against the memory loss and lower mental functioning associated with normal aging. Such actions include blocking production of beta amyloid, offering antioxidant protection, and regulating blood sugar (glucose) levels in the brain. The drop in estrogen levels after menopause may explain a higher risk for Alzheimer's disease in older women than in men. (Testosterone, the male hormone, converts to estrogen, which may help protect men.) Studies have been mixed, however, on the association between the decline in natural estrogen levels and mental functioning in older women.

People with a family history of the disease are at higher than average risk for Alzheimer's disease. Researchers are identifying important genetic factors, notably the ApoE4 gene, that may be responsible for late- and early-onset cases.

Dietary and other cultural factors that increase the risk for hypertension and unhealthy cholesterol levels may also play a role. For example, a study of Japanese men showed that their risk increased if they emigrated to America. And the disease is much less common in West Africa than in African-Americans, who share the same or higher risk with Caucasians in America.

High blood pressure and unhealthy cholesterol levels -- the same important risk factors for heart disease and stroke -- may also be risk factors for Alzheimer's disease. In fact, they appear to be more important than ApoE4, the genetic factor most commonly associated with Alzheimer's disease.

Blood pressure is the force applied against the walls of the arteries as the heart pumps blood through the body. The pressure is determined by the force and amount of blood pumped and the size and flexibility of the arteries.

High Blood Pressure. Studies have reported an association between Alzheimer's disease and systolic hypertension (the higher and first number in blood pressure measurement). High blood pressure can cause problems with the vascular system, which is responsible for delivering blood to the brain. Recent research suggests that some types of blood pressure medication may lower Alzheimer's risk.

High Cholesterol Levels. Research indicates an association between high cholesterol levels and Alzheimer's disease in some people. One theory is that cholesterol regulates the processing and accumulation of amyloid beta-protein.

Click the icon to see an image of cholesterol.

Stroke. High blood pressure and heart disease can increase the risk for stroke. For people who have Alzheimer’s disease or mild cognitive impairment, stroke can increase the decline of cognitive function and accelerate dementia.

Diabetes. Patients with diabetes often have high blood pressure, lipid imbalances, and circulatory disorders that affect the heart and vascular system, which in turn increases the risk for Alzheimer’s. In patients who do not have other risk factors for Alzheimer’s, diabetes itself may increase risk. Research also suggests that diabetes can increase the risk for mild cognitive impairment, a condition that often precedes Alzheimer’s disease.

High Homocysteine Levels. Homocysteine is an amino acid that has been identified as a modest risk factor in heart disease. It has also been associated with a higher risk for Alzheimer's disease. High levels are general due to deficiencies of the B vitamins B6, B12, and folate. Such vitamins are also related to nerve protection. Researchers theorize that homocysteine impairs the ability of DNA to repair nerve cells. The weakened cells are then more vulnerable to the harmful effects of oxidized beta amyloid.

Nearly all patients who inherit Down syndrome develop changes in the brain that resemble Alzheimer's if they live into their 40s, although onset varies and can occur as late as age 70. Women under the age of 35, but not older mothers, who give birth to children with Down syndrome are also at much higher risk for Alzheimer's.

Lower Education and Economic Groups. A number of studies have reported either a higher risk for Alzheimer's disease in people with less education or a lower risk for Alzheimer's disease in those who remain mentally active. Some experts speculate that learning itself may stimulate more neurons to grow and thus create a larger reserve in the brain so that it takes longer for brain cells to be destroyed. Some evidence suggests that early malnutrition, which is more likely to occur in lower income and educational groups, has been associated with smaller brains and with Alzheimer's disease in old age. Low-birth weight can cause problems in growth factors that could affect both mental and physical health later on in adulthood.

Small Head Size. The size of the skull is fixed by age 7. Brain size approximates the head size until old age, when it begins to shrink. Some evidence has reported an association between small head size (and therefore less brain volume) and Alzheimer's disease, possibly because people who start with larger brains can sustain more injury over time. For example, a 2002 study indicated that it was reduction in overall brain volume, not specific regions, that contributed to mental impairment in older healthy adults. Another study reported that people who had small heads plus the ApoE4 gene had 14 times the risk for Alzheimer's disease than those without this combination. Nevertheless, other studies have found no association between a small head size and Alzheimer's disease.

Some experts suggest that the relationship observed in other research may simply be due to social and economic factors, such as malnutrition or low birth weight, which have been associated with both Alzheimer's disease and small head size. Small head size independent of other factors, they argue, does not pose a higher risk for either Alzheimer's disease or low intelligence

Depression. There is a significant overlap between depression and dementia in the elderly. In fact depression itself is often an early symptom of Alzheimer's disease. In a 2002 study of Catholic nuns, for each of four depressive symptoms, the risk for developing Alzheimer's disease increased by an additional 19%. For example, for a woman with four depressive symptoms the risk increased by 76%. Some evidence suggests that there may even be common genetic factors in people who have both early depression and Alzheimer's disease.

Head Injury. Some studies have found an association between serious head injuries in early adulthood and the development of Alzheimer's. It is not yet known if such injuries directly cause Alzheimer's or simply accelerate the disease in people who are already susceptible to it.

Prevention

Although there is no strong evidence that any lifestyle change can prevent Alzheimer's disease, studies suggest that certain behaviors may help protect against mental decline. In particular, medications and lifestyle choices that protect the heart may be of specific importance. Various preventive drugs are under investigation, including antioxidant and anti-inflammatory therapies.

In 2004, the National Institutes of Health (NIH) halted a large clinical trial that was investigating the use of anti-inflammatory drugs in preventing Alzheimer's disease. While prior data had confirmed that NSAIDs were not effective in treating AD, research continued to explore these drugs' potential preventive benefits.

The Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) was launched in 2001 to investigate whether long-term use of naproxen (Aleve) or celecoxib (Celebrex) could decrease the risk of developing AD. The trial was based on the premise that because inflammation is known to be involved in the process of Alzheimer’s disease, anti-inflammatory drugs may help to prevent it. The NIH suspended this trial due to evidence that the NSAID naproxen was associated with increased incidence of cardiovascular and cerebrovascular events among participants. No adverse effects appeared during this trial for the COX-2 inhibitor celecoxib. However, heart safety concerns about this drug had been raised in other trials, and investigators did not believe that celecoxib's potential benefits outweighed its risks.

Since 2004, the ADAPT investigators have continued to monitor the trial’s participants to see if these treatments had any effect in changing their risk for Alzheimer’s. In an update analysis of ADAPT data published in 2007, the researchers announced that neither naproxen nor celecoxib appear to reduce the risk for Alzheimer’s.

The same lifestyle and medical choices that reduce risk factors for heart disease and diabetes are important for reducing the risk for Alzheimer's disease. And, experts believe that treating high blood pressure and diabetes may help slow the progression of Alzheimer’s disease. The following are some heart-protective medications that may also protect the brain.

Blood Pressure Drugs. Because high blood pressure is associated with increased risk of Alzheimer’s, researchers have been studying whether blood pressure medication can reduce this risk. In a 2006 study of patients who took high blood pressure drugs, researchers found that potassium-sparing diuretics reduced the risk of developing Alzheimer’s by 70%. Beta-blockers and certain calcium channel blockers also helped to a lesser extent. ACE inhibitors appeared to offer no protection.

Statins. Statins are common drugs used to lower cholesterol levels. In past years, a number of studies reported a significantly lower risk for Alzheimer's disease in patients who took statins. However, newer studies have failed to prove that statins can help prevent Alzheimer's disease. In these recent studies, large numbers of elderly people had their dementia evaluated at baseline and then monitored over several years. The results indicated that statin use did not predict onset of AD. In the meantime, the NIH is conducting a clinical trial to investigate whether simvastatin can slow the progression of AD.

Hormone Replacement Therapy. Hormone replacement therapy (HRT) has been studied for years for health effects after menopause, including its effect on mental decline. A number of studies, including a major 2003 analysis, have found no differences in mental performance and no protection from Alzheimer's disease in women taking HRT compared to non-users. The 2003 trial, called the Women's Health Initiative Memory Study (WHIMS), enrolled 4,500 women over 65 years of age. The WHIMS study showed that older postmenopausal women who took combination HRT (estrogen plus progestin) had twice the risk of developing dementia than similarly aged women who received placebo pills. In addition to increasing the risk for dementia (including Alzheimer's disease), combination HRT failed to prevent the development of mild cognitive impairment. Based on these results, the researchers from the National Institute on Aging (NIA) recommended against prescribing combination hormone therapy to older women for maintaining or improving cognitive function. The NIA continued to research whether estrogen-only therapy could prevent or delay the onset of Alzheimer's disease. Results released in 2004 indicated that women ages 65 years and older who took estrogen-only HRT had a slightly increased risk of developing dementia.

Testosterone. Some testosterone converts to estrogen, which may be why older men appear to have a lower risk for Alzheimer's disease than older women. Animal studies have suggested that testosterone may help reduce levels of beta amyloid. There is also some evidence that low testosterone levels may be a particular risk factor in men with the ApoE4 gene. Some experts believe that giving testosterone to elderly men, and combinations of testosterone and estrogen to older women, may prove to be protective. Side effects of testosterone in women include increased body hair, acne, fluid retention, anxiety, and depression. Long term benefits or serious adverse effects are unknown.

DHEA. Dehydroepiandrosterone (DHEA) is a male-like hormone in the body that declines with age. Some evidence suggests that it may help reduce mental decline in older women, but not in older men. Studies are under way. The hormone may, however, reduce HDL (the so-called good cholesterol) when taken in higher doses. While its effect on cancer-cell growth is unknown, some evidence indicates that high levels may increase cancer risk. In any case, DHEA is not regulated, and brands vary widely in their content.

Because Alzheimer's disease rates vary among different populations, investigators are researching how diet can help in prevention. Caloric intake itself may play a role in brain health. In one study on animals, restricting calories below normal (but above starvation levels) helped prevent age-related nerve degeneration. However, in patients with existing Alzheimer's, weight loss is a strong indicator of mental decline.

Fats and Oils. Some studies suggest an association between fat and Alzheimer's disease:

In China and Nigeria, where fat intake is low, the risk of developing Alzheimer's is 1% at age of 65 compared to 5% in the U.S.
A study in the Netherlands reported an association between dementia and diets high in total fat, saturated fat, and cholesterol.
A number of studies suggest that a high-fat high-calorie diet in people who carry the ApoE4 gene may confer a particularly high risk. For example, in one study, adults who carried the ApoE4 gene and whose diet consisted of 40% fat calories had 29 times the risk for Alzheimer's compared to non-ApoE4 carriers on the same high-fat diet.

The recommended dietary goal is to limit total fat intake to 25 - 35% of total daily calories. But not all fats are alike. Unhealthy fats include saturated fats (contained in animal products such as meat) and trans-fatty acids (contained in fast foods and commercially baked products). The American Heart Association recommends limiting saturated fat intake to less than 7% of total daily calories and trans-fatty acid intake to less than 1% of total daily calories.

It is best to replace saturated fats and trans-fatty acids with unsaturated fats from plant and fish oils. Omega-3 fatty acids are excellent sources of unsaturated fats. Plant sources of omega-3 fatty acids include canola oil, soybeans, flaxseed, and certain types of nuts such as walnuts. For fish sources, salmon, mackerel, sardines, lake trout, herring, and albacore tuna are especially high in marine omega-3 fatty acids. For heart health, and possibly brain health, experts recommend eating these types of fish at least twice a week.

Two types of omega-3 fatty acids are found in fish oils: Docosahexaenoic acid (DHA) and eicosapentaneoic acid (EPA). Researchers are particularly interested in the role that DHA may play in Alzheimer’s disease prevention. DHA has been linked to many brain cell functions, and appears to have particular importance for aging brains. Studies indicate that people who have higher blood levels of DHA have a much lower risk of developing dementia and Alzheimer’s disease.

Although evidence suggests that consuming DHA-rich foods later in life helps to increase DHA levels in the brain, it is unclear whether dietary supplements can provide similar benefits. A 2007 study indicated that omega-3 fatty acid supplements may help slow cognitive decline in some patients with very mild Alzheimer’s disease, but that the supplements have little effect for advanced stages of the disease. In 2007, the U.S. National Institutes of Health launched a large-scale clinical trial to evaluate whether DHA supplements can slow the progression of cognitive and functional decline in people with mild-to-moderate Alzheimer’s disease.

Mediterranean diet is an eating plan that has specific heart-health benefits. It is rich in fiber and nutrients, including omega-3 fatty acids and antioxidant vitamins. The diet emphasizes fish, fruits, vegetables, and monounsaturated (“good”) fats, particularly olive and canola oils. A 2006 study suggested that the Mediterranean diet may also be good for the brain. In the study, patients who strictly followed the diet had a 40% lower risk of developing Alzheimer’s disease than patients who ate a conventional American diet. Other studies also indicate the Mediterranean diet is associated with a lower risk for Alzheimer’s.

Omega-3 fatty acids, found plentifully in oily fish and flaxseed and canola oils, are beneficial to people afflicted with IBD (inflammatory bowel disease).

Fruits and Vegetables. According to several studies, eating plenty of darkly colored fruits and vegetables may slow brain aging. Blueberries, which are very rich in antioxidants, are of particular interest. A 2006 study of over 3,000 elderly adults found that consumption of vegetables (especially green leafy vegetables) helped reduce the rate of cognitive decline, but fruit intake had no effect.

Alcohol. Some studies have suggested that moderate intake of alcohol (one or two drinks a day) may protect the aging brain, possibly by releasing acetylcholine, the chemical in the brain that is deficient in Alzheimer's disease. Not all studies have been positive. In any case, heavy alcohol consumption offers no protection and is dangerous.

Folate and Vitamin B12. Some studies suggest that deficiencies of vitamins B6, B12, and folate (folic acid) may be a risk factor for Alzheimer' diseases. Deficiencies in these vitamins can increase homocysteine levels, which some research associates with a higher risk for Alzheimer's disease. Foods containing folate include avocados, bananas, oranges, asparagus, green leafy vegetables, and dried beans. In the United States and some other countries, grain and cereal products are fortified with folate. B12 is found only in animal, dairy, and fish products. B6 is found in a variety of foods, including fortified cereals, beans, meat, fish, and some fruits and vegetables.

Click the icon to see an image of vitamin B12 sources.

Click the icon to see an image of folate sources.

Research is still inconclusive and conflicting about whether increased consumption of folate, through food or dietary supplements, can help prevent Alzheimer’s disease or slow its progression. A small 2006 study of healthy older adults, published in the New England Journal of Medicine, found that supplements containing folate, vitamin B12, and vitamin B6 did not help improve cognitive performance. A 2007 Lancet study indicated that folic acid supplements may help slow cognitive decline. People in the Lancet study took 800 mcg of folic acid daily, which is twice the recommended daily allowance of 400 mcg. However, this study was conducted in the Netherlands, where people tend to get less folate in their daily diets than in the United States.

Another 2007 study found that elderly people who consumed folate from both diet and supplement sources had a reduced risk for Alzheimer’s disease. Neither diet alone nor supplements alone affected Alzheimer’s risk; only the combination of the two produced an effect. The study also indicated that vitamins B6 and B12 do not affect Alzheimer’s risk.

Antioxidant Supplements. Much research on Alzheimer's disease has indicated that oxidation (release of damaging unstable particles) may play an important role in the disease process. Some reports, including a large 2002 population study, have suggested that vitamin E intake, from food or supplements, may protect against mental decline. Other studies suggest that vitamin E protects only those who carried the ApoE4 gene. Most of the evidence finding any benefits from other antioxidants comes from using a combination of antioxidant vitamins, such as vitamins C and E, but not from using them separately. However, there is no strong evidence of protection to date from using antioxidant supplements.

Physical Exercise. Studies indicate that exercise may help prevent the development of Alzheimer’s disease and other forms of dementia. A 2006 study found that older adults (65 years and older) who exercised three times a week reduced their risk for Alzheimer’s by about 40%. Exercise in the study included walking, hiking, aerobics, calisthenics, swimming, water aerobics, weight training, and stretching.

Mental Exercise. Cognitive training that includes exercises to stimulate memory, reasoning, and mental processing speed may help improve both mental ability and daily functioning. In an important 2006 study in the Journal of the American Mental Association, older community-dwelling adults who received cognitive training showed reductions in cognitive decline. In addition, they were better able to handle daily living tasks -- such as performing housework, managing money, and preparing meals -- than people who did not receive the training. The benefits of cognitive training lasted for up to 5 years afterwards. Other studies indicate that participating in intellectually engaging activity -- such as doing crossword puzzles or learning a new language -- may help reduce the risk of Alzheimer’s disease.

Social Interaction. Social interaction is also important for maintaining emotional health as well as keeping the mind active and energized. A 2007 study indicated that adults who are lonely have twice the risk of developing Alzheimer’s dementia as those who are not socially isolated.

Symptoms

The early symptoms of Alzheimer's disease (AD) may be overlooked because they resemble signs of natural aging. Older adults who begin to notice a persistent mild memory loss of recent events may have a condition called mild cognitive impairment (MCI). MCI is now believed to be a significant sign of early-stage Alzheimer's in older people. Studies now suggest that older individuals who experience such mild memory abnormalities can later develop Alzheimer's disease.

Early symptoms of Alzheimer's disease may include:

Forgetfulness (particularly of recent events or information)
Loss of concentration (having trouble planning or completing familiar tasks, difficulty with abstract thinking such as simple arithmetic problems)
Language problems (forgetting the names of objects, mixing up words, difficulty completing sentences)
Confusion about time and place (difficulty recognizing familiar neighborhoods or remembering how you arrived at a location, confusion about months or seasons )
Impaired judgment (dressing inappropriately or making poor financial decisions)
Impaired movement and coordination (slowing of movements, halting gait, reduced sense of balance)
Mood and behavior changes (rapid mood swings, emotional outbursts, personality changes, increased fear or suspicion)
Apathy and depression (loss of interest in activities, increased sleeping, sitting in front of the television for long periods of time)

Diagnosis

A definitive test to diagnose Alzheimer's disease, even in patients showing signs of dementia, has not yet been developed. A number of expert groups have developed criteria to help diagnose Alzheimer's disease and rule out other disorders. A diagnosis often involves answering questions about the patient:

Do psychological tests indicate dementia?
Does the patient have deficits in two or more areas of mental functioning (such as language, motor skills, and perceptions)?
Has memory and mental functions gotten progressively worse?
Is consciousness disturbed? (It is not in Alzheimer's disease.)
Is the patient over age 40?
Are other medical or physical conditions present that could account for the same symptoms?
Are daily activity impaired or has the behavior changed?
Is there a family history of Alzheimer's disease?
Are there other symptoms, such as depression, insomnia, incontinence, delusions, hallucinations, dramatic verbal, emotional or physical outbursts, sexual disorders, and weight loss?

Other steps involved in making a decision include laboratory tests (EEG and possibly tests to rule out other diseases) and psychological testing to determine the presence of dementia.

Although some memory impairment occurs in many people as they age, only some of these people develop Alzheimer's disease. Many similar symptoms can occur in healthy older individuals from other conditions associated with aging:

Fatigue
Grief or depression
Illness
Vision or hearing loss
The use of alcohol or certain medications
Simply the burden of too many details to remember at once

The first step in diagnosing Alzheimer's disease is to rule out other conditions that might cause memory loss or dementia. There are a number of causes for dementia in the elderly besides Alzheimer's disease:

Vascular dementia (abnormalities in the vessels that carry blood to the brain)
Lewy bodies variant (LBV), also called dementia with Lewy bodies
Parkinson's disease
Frontotemporal dementia

Experts believe that 60% of cases of dementia are due to Alzheimer's, 15% to vascular injuries, and the rest are a mixture of the two or caused by other factors.

Vascular Dementia. Vascular dementia is primarily caused by either multi-infarct dementia (multiple small strokes) or Binswanger's disease (which affects tiny arteries in the midbrain). One major analysis suggested that patients with vascular dementia have better long-term verbal memory than patients with Alzheimer's disease, but poorer executive function (less ability to integrate and organize).

Lewy Bodies Variant. Lewy bodies are abnormalities found in the brains of patients with both Parkinson's disease and Alzheimer's. They can also be present in the absence of either disease; in such cases, the condition is called Lewy bodies variant (LBV). In all cases, the presence of Lewy bodies is highly associated with dementia. LBV was defined in 1997, and some experts believe it may be responsible for about 20% of people who have been diagnosed with Alzheimer's. They can be difficult to distinguish. Compared to Alzheimer's disease patients, those with LBV may be more likely to have hallucinations and delusions early on, to walk with a stoop (similar to Parkinson's disease), to have more fluctuating attention problems, and to perform better than Alzheimer's disease patients on verbal recall but less well with organizing objects.

Parkinson's Disease. Dementia is about six times more common in the elderly Parkinson patient than in the average older adult. It is most likely to occur in older patients who have had major depression. Unlike in Alzheimer's, language is not usually affected in Parkinson's related dementia. Visual hallucinations occur in about a third of people on long-term medications.

Parkinson's disease is a slowly progressive disorder that affects movement, muscle control, and balance. Part of the disease process develops as cells are destroyed in certain parts of the brain stem, particularly the crescent-shaped cell mass known as the substantia nigra. Nerve cells in the substantia nigra send out fibers to tissue located in both sides of the brain. There the cells release essential neurotransmitters that help control movement and coordination.

Frontotemporal Dementia (FTD). Once considered rare, FTD is now considered to be the second most common cause of early-onset dementia. People who develop this condition tend to be in their mid-fifties although it can develop later on. It results in greater behavioral impairment (apathy, reduced empathy, poor self-care, unrestrained behavior) than with Alzheimer's disease. It may also be marked by speech problems and early incontinence. Brain imaging scans can help diagnose this problem.

Other Conditions that Cause Similar Symptoms. Some elderly people have a condition called mild cognitive impairment, which involves more severe memory loss than normal but no other symptoms of Alzheimer's. A number of conditions, including many medications, can produce symptoms similar to Alzheimer's:

Severe depression
Drug abuse
Thyroid disease
Severe vitamin B12 deficiency
Blood clots
Hydrocephalus (excessive accumulation of spinal fluid in the brain)
Syphilis
Huntington's disease
Creutzfeldt-Jakob disease
Brain tumors

It is important that the doctor recognize any treatable conditions that might be causing symptoms or worsening existing dementia caused by Alzheimer's or vascular abnormalities.

A number of psychological tests are used or being developed to assess difficulties in attention, perception, and memory and problem-solving, social, and language skills. Experts are researching specific tests that may help identify early on people with mild memory impairment who are at high risk for Alzheimer's disease.

Two commonly used tests that are very useful in identifying individuals who may be at risk for Alzheimer's are the Mini-Mental State Exam (MMSE) and the Mattis Dementia Rating Scale. Still, these tests have limitations.
A clock drawing test is also a good test for Alzheimer's disease. The patient is given a piece of paper with a circle on it and is first asked to write the numbers in the face of a clock and then to show "10 minutes after 11." The score is based on spacing between the numbers and the positions of the hands.

Electroencephalography (EEG) traces brain-wave activity; in some patients with Alzheimer's disease this test reveals "slow waves." EEG data helps distinguish a potential patient with Alzheimer's disease from a patient with severe depression, whose brain waves are normal.

Imaging tests include magnetic resonance imaging (MRI), positron-emission tomography (PET), and single photon emission computed tomography (SPECT). These tests are sometimes used to rule out other disorders, such as multi-infarct dementia, stroke, blood clots, and tumors. Research is being conducted to determine if these tests can help to confirm a diagnosis of Alzheimer's disease and improve understanding of disease progression. Researchers hope that imaging tests may also be able to provide diagnoses of Alzheimer’s disease while it is still in its early stages.

In 2006, scientists developed a new imaging molecule called FDDNP that they hope will enable earlier detection of Alzheimer’s disease. Research also continues on Pittsburgh compound B, a tracer molecule used in PET brain scans to highlight beta-amyloid protein deposits. Results from all this research may help to define potential drug targets and aid in the development of new Alzheimer's drugs.

Click the icon to see an image of an MRI of the brain.

In 2005, the National Institute of Aging, in collaboration with industry partners, launched the $60 million Alzheimer's Disease Neuroimaging Initiative (ADNI). This landmark 5-year clinical trial, which will be conducted at 50 sites throughout the United States and Canada, will investigate whether neuroimaging techniques, such as MRI and PET scans, can be combined with biomarkers and neuropsychological tests to measure the progression of AD and mild cognitive impairment. In 2004, the U.S. Medicare system expanded insurance coverage of PET scans for eligible beneficiaries who meet specific diagnostic criteria for both Alzheimer's disease and fronto-temporal dementia. Medicare also covers the costs for patients enrolled in its agency-approved imaging clinical trials.

Blood Tests. Blood tests are currently used to check for anemia and other disorders that can produce dementia symptoms. Investigators are researching serum biomarkers, such as the iron transport protein p97, that might help detect the presence of Alzheimer's disease.

Cerebrospinal Fluid Test. Scientists are developing new nanotechnology screening methods that may eventually be used to identify Alzheimer's disease while it is still in its earliest stages and before plaque deposits accumulate. In 2005, a research team announced it had used a bio-barcode assay to detect tiny amounts of a protein called amyloid-beta-derived diffusable ligand (ADDL) in cerebrospinal fluid. ADDLs may be involved in cognitive decline and are a potential biomarker for early stage Alzheimer's disease. Tests for other proteins are also being developed.

Odor Test. Investigators are also using the impairment of smell in Alzheimer's disease to develop tests that require patients to distinguish between odors.

Once a diagnosis has been made, some experts observe that certain factors at the time of diagnosis indicate a higher risk for a more rapid decline:

Older age
Being male
The presence of high blood pressure
Signs of loss of motor control and coordination
Tremor
Social withdrawal
Loss of appetite and severe weight loss
Accompanying sensory problems, such as hearing loss and a decline in reading ability
General physical debility

Medications

Most drugs used to treat Alzheimer's, and those under investigation, are aimed at slowing progression. There are no cures to date. In addition, the improvements from some of these drugs may be so modest that even the patients and their families are not aware of them. Even in these cases, however, the drugs may delay the need for admission to nursing homes.

There are currently two drug classes that have been approved by the U.S. Food and Drug Administration (FDA) to treat the cognitive symptoms of Alzheimer's disease:

Cholinesterase inhibitors (generally used to treat mild-to-moderate Alzheimer's; donepezil is also approved for treatment of severe dementia )
N-methyl-D-aspartate (NMDA) receptor antagonists (used to treat moderate-to-severe Alzheimer's)

Cholinesterase inhibitors are designed to protect the cholinergic system, which is essential for memory and learning and is progressively destroyed in Alzheimer's. These drugs work by preventing the breakdown of the brain chemical acetylcholine and are recommended for the treatment of mild-to-moderate Alzheimer's. The first cholinesterase inhibitor, tacrine, was approved in 1993 but is rarely prescribed today due to safety concerns. The three most commonly prescribed cholinesterase inhibitors are donepezil (approved in 1996), rivastigmine (approved in 2000), and galantamine (approved in 2001).

Cholinesterase inhibitors may increase the risk for gastrointestinal bleeding or ulcers, and patients should be cautious about using these medicines with NSAIDs (which can also cause gastric irritation). Common side effects of cholinesterase inhibitors, especially when taken at higher doses, may include nausea, vomiting, diarrhea, and upset stomach.

Donepezil. Donepezil (Aricept) is the only Alzheimer’s drug approved for all stages of dementia, from mild to severe. It is taken once a day and has only modest benefits, but it does help slow loss of function and reduce caregiver burden. It works equally in patients with or without the ApoE4 gene. Several trials, including an important 2005 New England Journal of Medicine (NEJM) study, have found that donepezil may have short-term benefits for patients with mild cognitive impairment by delaying progression to AD. In the NEJM study, donepezil slowed progression during the first year of therapy, but demonstrated no benefits by the conclusion of the 3-year trial. Studies also suggest that donepezil may help improve behavior and memory in patients with moderate-to-severe Alzheimer’s when it is given in combination with memantine (Namenda).
Rivastigmine. Rivastigmine (Exelon) targets two enzymes: Acetylcholinesterase and butyrylcholinesterase. It is taken as a pill twice a day. (The FDA approved a skin patch version of the drug in 2007.) Rivastigmine may be particularly helpful for patients with rapidly progressing disease. It has slowed or slightly improved disease status even in patients with advanced disease. Rivastigmine may cause significantly more side effects than donepezil, including nausea, vomiting, and headache.
Galantamine (Razadyne). Galantamine not only protects the cholinergic system but also acts on nicotine receptors, which are also depleted during Alzheimer's. Studies report that it improves daily living, behavior, and mental functioning, including in patients with mild to advanced-moderate Alzheimer's disease and those with a mix of Alzheimer's disease and vascular dementia. Some studies have suggested that the effects of galantamine may persist for a year or longer and even strengthen over time. In 2005, the name of galantamine was changed from Reminyl to Razadyne.
Tacrine. Tacrine (Cognex) was the first cholinergic protective drug. It needs to be taken four times a day, has only modest benefits, and has no benefits for patients who carry the ApoE4 gene. In high doses, it can also injure the liver. In general, newer cholinergic protective drugs that do not pose as great a risk for the liver are now used for Alzheimer's.

About half of patients with mild-to-moderate disease show slight improvement with these drugs. Comparative studies have reported little differences in effectiveness among them. All drugs have gastrointestinal side effects, including nausea. Of note, some of the drugs often used in elderly Alzheimer's disease patients are known as anticholinergics and may offset the effects of the Alzheimer's disease pro-cholinergic drugs. Such drugs include antihistamines, antipsychotic drugs, and some anti-incontinence drugs.

In any case, the benefits of these drugs are far from dramatic. In fact, many experts have reservations about developing any additional drugs that affect the cholinergic system since, at best, they only slow progression and do not appear to affect the basic destructive disease process. When patients go off the drugs, the deterioration continues. In 2005, the United Kingdom’s National Institute for Clinical Excellence (NICE) recommended against the use of donepezil, rivastigmine, galantamine, and memantine for Alzheimer’s disease treatment. The agency contended that the costs of these drugs outweigh their modest benefits.

Memantine (Namenda) is approved for treatment of moderate-to-severe Alzheimer’s disease. (Most cholinesterase inhibitors are used to treat mild-to-moderate stages of the disease.) By blocking NDMA receptors, memantine protects against the overstimulation of glutamate, an amino acid that excites nerves and, in excess, is a powerful nerve-cell killer.

Memantine is prescribed either alone or in combination with donepezil. Studies indicate that memantine may help improve cognitive function and delay the progression of Alzheimer’s disease for up to 1 year. Side effects are generally mild but may include dizziness, drowsiness, or fainting.

In one study of effects on moderate-to-severe Alzheimer's, patients who received memantine showed a small but statistically significant benefit in cognitive function and performance of daily abilities compared with those patients who were given placebo. In a 2004 study, memantine was added to the drug regimen of patients with moderate-to-severe Alzheimer's who had taken donepezil for at least 6 months. In comparison to patients who took only donepezil, patients who received the combination donepezil-memantine therapy showed a greater improvement in measures of cognitive function, activities of daily living, and behavior parameters. A 2006 study indicated that memantine combined with donepezil may help reduce behavior problems -- such as agitation, aggression, and irritability -- and improve disturbances in appetite and eating.

Although cholinesterase inhibitors and memantine are the best available medications for Alzheimer's, their benefits are, unfortunately, quite modest. More effective methods of prevention and treatment are urgently needed.

There has been considerable controversy over whether NSAIDs may help in the treatment of Alzheimer's disease. As inflammation is involved in the destruction of brain cells, it has been suggested that anti-inflammatory drugs might be able to halt this process and thus slow the progression of the disease. In a rigorous 2003 study, patients with mild-to-moderate Alzheimer's were randomized to receive either naproxen (Aleve) or rofecoxib (Vioxx) or placebo. After 12 months of treatment, patients in the anti-inflammatory groups did not show any difference in cognitive improvement compared to those patients who received placebo.

Results from another large study, published in 2004, also failed to demonstrate improvement in cognitive function for patients with mild-to-moderate Alzheimer's who were treated with rofecoxib. Since the completion of these studies, rofecoxib was withdrawn from the market, and the NIH suspended a clinical study assessing naproxen’s preventive benefits (see Nonsteroidal Anti-Inflammatory Drugs as Prevention). As mentioned earlier, patients should be cautious about taking NSAIDs in combination with cholinesterase inhibitors as they may increase the risk of gastrointestinal bleeding.

Nicotine enhances the actions of the cholinergic system (which is depleted in Alzheimer's disease) and is known to improve concentration and memory in the short term. Some studies have suggested that nicotine may protect nerve cells and help prevent the formation of beta amyloid. One study indicated that nicotine might help protect against Alzheimer's disease in carriers, but not noncarriers, of the ApoE4 gene. Another reported improvement in verbal recall and word retrieval in healthy relatives of Alzheimer's disease patients who wore a low-dose nicotine patch. Research to date, however, has found no strong evidence of improvement in Alzheimer's disease patients with nicotine replacement methods. No one should smoke to prevent or treat Alzheimer's disease.

Manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like a drug, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been several reported cases of serious and even lethal side effects from herbal products. Always check with your doctor before using any herbal remedy or dietary supplement.

Ginkgo Biloba. Ginkgo biloba is a common herb that has antioxidant properties and appears to increase blood flow to the brain. A 2002 study of healthy people who took over-the-counter ginkgo for 6 weeks reported no improvements in memory or mental function. Studies are reporting that a ginkgo biloba extract, called Egb 761, may slightly improve the memory of patients with mild to moderate Alzheimer's disease. The herb poses a small increased risk for bleeding, which may be hazardous in combination with other blood-thinning medications, such as warfarin or high-doses of vitamin E.

Turmeric. Studies suggest that circumin, a compound found in the spice turmeric, has properties that may protect against the Alzheimer's disease process.

Melatonin. Melatonin, a natural hormone involved in sleep regulation, is of interest to researchers. It is an antioxidant, may break down beta amyloid, and is able to pass through the blood-brain barrier. Deficiencies have been observed in patients with Alzheimer's disease. A number of studies (but not all) report that melatonin may improve sleep habits in these patients. Some studies reported slower progression of mental impairment.

A number of drugs are being investigated for treatment and prevention of Alzheimer's disease. Intense areas of research are focusing on drugs that prevent beta amyloid build-up, its toxic effects on nerve cells, or other mechanisms of the disease process. Promising research in late-stage clinical trials include.

Tramiprosate (Alzhemed) is an experimental drug designed to prevent beta-amyloid accumulation in the brain.
Flurizan (MPC-7869) may help reduce amyloid plaque development. It is currently being studied in Phase III trials for adults with mild Alzheimer’s disease.
Rosiglitazone XR (Avandia) is an extended-release formulation of a drug used to treat type 2 diabetes. Its anti-inflammatory properties are being studied as a treatment for patients with mild-to-moderate Alzheimer’s who do not carry the APOE-e4 gene. Phase III results have been promising, but this drug has been linked to increased risk for heart attack deaths in patients with diabetes. In 2007, a panel of experts from the Food and Drug Administration (FDA) agreed the drug increases the risk of heart attacks -- but concluded it should remain on the market. The panel did, however, recommend the FDA require rosiglitazone's maker to add warnings to the drug's label. Patients or caregivers of patients who take rosiglitazone, especially those who have heart disease or who are at high risk for heart attack, should discuss their treatment options with their doctors.
Dimebon is an antihistamine, which researchers think may help prevent brain cell death. The drug is currently in Phase II trials.
Antioxidants such as vitamin E and selenium are being investigated for their preventive effects. Antioxidant treatment trials include curcumin (the yellow pigment found in turmeric spice) and a combination trial with fish oil and alpha-lipoic acid.

Depression. Major depression with dementia that occurs in elderly people may be an early sign of Alzheimer's. In such cases, it precedes Alzheimer's by 2 years or less. (It is, in fact, sometimes difficult to differentiate major depression from early-stage Alzheimer's disease.) Antidepressants known as selective serotonin reuptake inhibitors (SSRIs), including fluoxetine (Prozac) and sertraline (Zoloft), may be effective in relieving depression, irritability, and restlessness associated with Alzheimer's in some patients.

Apathy. Depression is often confused with apathy. An apathetic patient lacks emotions, motivation, interest, and enthusiasm while a depressed patient is generally very sad, tearful, and hopeless. According to one study, apathy is more common than depression in patients with Alzheimer's disease. It responds to stimulants, such as methylphenidate (Ritalin), rather than antidepressants.

Psychosis. Antipsychotic drugs are used to treat verbally or physically aggressive behavior and hallucinations. Because older antipsychotic drugs, such as haloperidol (Haldol), have severe side effects, most doctors now prescribe newer atypical antipsychotics, such as risperidone (Risperdal) or olanzapine (Zyprexa).

However, these newer antipsychotic drugs still can cause serious side effects, including confusion, sleepiness, and Parkinsonian-like symptoms. In addition, studies indicate that their safety risks may outweigh any possible benefits. A 2005 study showed that these drugs produce a slightly increased rate of death in patients with Alzheimer’s disease or dementia. In addition, several studies from 2006 and 2007 published in the New England Journal of Medicine suggested that atypical antipsychotics work no better than placebo in controlling psychosis, aggression, and agitation in patients with Alzheimer’s.

Most experts now recommend that doctors delay prescribing antipsychotic medication unless absolutely necessary. They recommend first trying behavioral treatments and controlling changes in the patient’s environment and routine. Anti-seizure drugs, such as carbamazepine (Tegretol) or valproate (Depakote), can also sometimes treat agitation and other psychotic symptoms. Non-drug treatments, such as bright light boxes, are also showing promise for managing psychotic and behavioral symptoms.

Disturbed Sleep. Patients with Alzheimer's disease commonly experience disturbances in their sleep/wake cycles. Moderately short-acting sleeping drugs, such as temazepam (Restoril), zolpidem (Ambien), or zaleplon (Sonata), or sedating antidepressants, such as trazodone (Desyrel, Molipaxin), may be useful in managing insomnia. Some research suggests that exposure to brighter-than-normal artificial light during the day for patients with normal vision may help reset wake/sleep cycles and prevent nighttime wandering and sleeplessness. Trials on melatonin, a natural hormone that helps trigger sleep at night, are in progress.

Stages

The lifespan of patients with Alzheimer's is generally reduced, although a patient may live anywhere from 3 - 20 years after diagnosis. The final phase of the disease may last from a few months to several years, during which time the patient becomes increasingly immobile and dysfunctional. Caregivers should understand the phases of this illness in order to help determine their own capacities for dealing with this painfully sad disease.

Telling the Patient. Often doctors will not tell patients that they have Alzheimer's. If a patient expresses a need to know the truth, it should be disclosed. Both the caregiver and the patient can then begin to address issues that can be controlled, such as access to support groups and drug research.

Mood and Emotional Behavior. Patients display abrupt mood swings, and many become aggressive and angry. Some of this erratic behavior is caused by chemical changes in the brain. But it may also be due to the experience of losing knowledge and understanding of one's surroundings, causing fear and frustration that patients can no longer express verbally.

The following recommendations for caregivers may help soothe patients and avoid agitation:

Keep environmental distractions and noise at a minimum if possible. (Even normal noises, such as people talking outside a room, may seem threatening and trigger agitation or aggression.)
Speak clearly. Most experts recommend speaking slowly to a patient with Alzheimer's disease, but some caregivers report that patients respond better to clear, quickly spoken, short sentences that they can more easily remember.
Use a combination of facial expressions, voice tones, and words for communicating emotions. (One study suggested that patients may have difficulty in recognizing the meaning of facial expressions, particularly those signaling sadness, surprise, and disgust.)
Limit choices (such as clothing selection).
Offer diversions, such as a snack or car ride, if the patient starts shouting or exhibiting other disruptive behavior.
Simply touching and talking may also help.
Maintain as natural an attitude as possible. Patients with Alzheimer's disease can be highly sensitive to the caregiver's underlying emotions and react negatively to patronization or signals of anger and frustration.
Showing movies or videos of family members and events from the patient's past may be comforting.

Although much attention is given to the negative emotions of patients with Alzheimer's disease, some patients become extremely gentle, retaining an ability to laugh at themselves or appreciate simple visual jokes even after their verbal abilities have disappeared. Some patients may seem to be in a drug-like or "mystical" state, focusing on the present experience as their past and future slip away. Encouraging and even enjoying such states may bring some comfort to a caregiver.

There is no single Alzheimer's personality, just as there is no single human personality. All patients must be treated as the individuals they continue to be, even after their social self has vanished.

Appearance and Cleanliness. For the caregiver, grooming the patient may be an alienating experience. For one thing, many patients resist bathing or taking a shower. Some spouses find that showering with their afflicted mate can solve the problem for a while. Often patients with Alzheimer's disease lose their sense of color and design and will put on odd or mismatched clothing. It is important to maintain a sense of humor and perspective and to learn which battles are worth fighting and which ones are best abandoned.

Driving. As soon as Alzheimer's is diagnosed, the patient should be prevented from driving. One study found that more than half of elderly people involved in fatal accidents had some degree of neurologic damage.

Wandering. A potentially dangerous trait is the patient's tendency to wander. At the point the patient develops this tendency, many caregivers feel it is time to seek out nursing homes or other protective institutions for their loved ones. For those who remain at home, the following precautions are recommended:

Locks should be installed outside the door, which the caregiver can open, but the patient cannot.
Alarms may be installed at exits.
A daily exercise program should be implemented, which may help tire the patient. One study showed that walking 30 minutes, three times a day, also improved communication.
The caregiver should contact organizations, such as Alzheimer's Association or Medic Alert, for identification supplies and procedures that help locate patients who wander away from home and become lost.
Some experts are discussing the benefits versus the ethics of electronic tagging, which would emit a radio signal or alarm that allows the patient to be tracked using a detector.

Speech Problems. Some evidence suggests that speech therapy combined with Alzheimer's disease medications may be helpful for maintaining verbal skills patients with mild symptoms.

Sexuality. In many cases, the patient becomes uninhibited sexually. At the same time, the patient's physical deterioration and receding capacity to recognize the spouse as a known and loved individual can make sexual activity unattractive for the caregiving spouse. Other patients may lose interest in sex. If sexual issues are a problem, they should be discussed openly with the doctor. Ways should be found to maintain non-sexual physical affection that can bring comfort to both the patient and the spouse.

Patients with Alzheimer's disease need 24-hour a day attention. Even if the caregiver has the resources to keep the patient at home during later stages of the disease, outside help is still essential. If available, home visits by a health profession can have a favorable impact on survival and delay the need for a nursing home. Medicare now covers many Alzheimer's services, and patients should be able to stay at home longer than previously.

Incontinence. A patient's incontinence is generally devastating to the caregiver and a primary reason why many caregivers decide to seek nursing home placement when the patient reaches this stage. When the patient first shows signs of incontinence, the doctor should make sure that it is not caused by an infection. Urinary incontinence may be controlled for some time by trying to monitor times of liquid intake, feeding, and urinating. Once a schedule has been established, the caregiver may be able to anticipate incontinent episodes and get the patient to the toilet before they occur.

Immobility and Pain. As the disease progresses, patients become immobile, literally forgetting how to move. Eventually, they become almost entirely wheelchair-bound or bedridden. Bedsores can be a major problem. Sheets must be kept clean, dry, and free of food. The patient's skin should be washed frequently, gently blotted thoroughly dry, and moisturizers applied. The patient should be moved every 2 hours and the feet kept raised with pillows or pads. Exercises should be administered to the legs and arms to keep them flexible.

Dehydration. Dehydration can become a problem. It is essential to encourage fluid intake equal to 8 glasses of water daily. Coffee and tea are diuretics and will deplete fluid.

Eating Problems. Weight loss and the gradual inability to swallow are two major related problems in late-stage Alzheimer's and are associated with an increased risk of death. Weight gain, however, is linked to a lower risk of dying. The patient can be fed through a feeding syringe, or the caregiver can encourage chewing action by pushing gently on the bottom of the patient's chin and on the lips. The caregiver should offer the patient foods of different consistency and flavor. Because choking is a danger, the caregiver should learn to administer the Heimlich maneuver, which may be taught by the local Red Cross. In very late stages, some caregivers choose feeding tubes for the patient. They should be aware that feeding tubes have no measurable impact on survival.

About 80% of patients with Alzheimer's disease are cared for by family members, who often lack adequate support, finances, or training for this difficult job. Few diseases disrupt patients and their families so completely or for so long a period of time as Alzheimer's. The patient's family endures two separate losses and grieves twice:

First, they must grieve for the ongoing disappearance of the personality they recognize. Dealing with the patient throughout the course of the disease is like Alice's fall down the rabbit hole into Wonderland. No sooner has the caregiver grappled with one set of problems, when the patient's further deterioration creates new and more intractable ones.
Finally, the caregiver must grieve the actual death of the person.

Often, caregivers themselves begin to show signs of mental disorder or ill health. Depression, empathy, exhaustion, guilt, and anger can play havoc with even a healthy individual faced with the care of a loved one suffering from Alzheimer's.

Fortunately, research shows that intensive support services can greatly improve caretakers’ quality of life and make it easier for them to continue caring for patients in their homes. In a 2006 study, caregivers who received individual and family counseling, telephone counseling, support groups, and stress management and problem-solving techniques reported reduced rates of depression and improved self-confidence compared with those who received only written educational materials. Another 2006 study indicated that improving caregivers’ access to counseling and support services can help delay nursing home placement of patients. National and local Alzheimer's associations can provide important support and other services.

A point comes when the most devoted caregiver will probably need to institutionalize the patient. That point is determined not only by the caregiver's emotional endurance, but also by their physical strength and stamina, as a patient typically takes on the random, undisciplined behavior of a very young child. Financial considerations in finding a nursing home are often paramount, but the kind of care is equally important. Although fully half of all nursing home patients suffer from Alzheimer's, not all nursing homes have programs specifically designed for them. Some institutions may claim that they do, but often they simply group patients together without offering any special programs. If a caregiver manages to find a facility that offers good services, it may be located far from home, making visits difficult. The caregiver must then decide whether superior care at a distant institution is worth seeing the patient less frequently. When the patient's illness becomes terminal, a hospice program may be another option.

1. Although I cannot control the disease process, I need to remember I can control many aspects of how it affects my relative.

2. I need to take care of myself so that I can continue doing the things that are most important.

3. I need to simplify my lifestyle so that my time and energy are available for things that are really important at this time.

4. I need to cultivate the gift of allowing others to help me, because caring for my relative is too big a job to be done by one person.

5. I need to take one day at a time rather than worry about what may or may not happen in the future.

6. I need to structure my day because a consistent schedule makes life easier for me and my relative.

7. I need to have a sense of humor because laughter helps to put things in a more positive perspective.

8. I need to remember that my relative is not being difficult on purpose; rather their behavior and emotions are distorted by the illness.

9. I need to focus on and enjoy what my relative can still do rather than constantly lament over what is gone.

10. I need to increasingly depend upon other relationships for love and support.

11. I need to frequently remind myself that I am doing the best that I can at this very moment.

12. I need to draw upon the Higher Power, which I believe is available to me.

Source: The American Journal of Alzheimer's Care and Related Disorders & Research, Nov/Dec 1989

Resources

www.alzheimers.org -- Alzheimer's Disease Education and Referral Center
www.alz.org -- Alzheimer's Association
www.alzforum.org -- Alzheimer's Research Forum
www.alzfdn.org -- Alzheimer's Foundation of America
www.alz.co.uk -- Alzheimer's Disease International
www.nia.nih.gov -- National Institute on Aging
www.ninds.nih.gov -- National Institute of Neurological Disorders and Stroke
www.aan.com -- American Academy of Neurology
www.medicalert.org -- Medic Alert
www.ahaf.org -- American Health Assistance Foundation
www.clinicaltrials.gov -- Find clinical trials
www.medicare.gov/NHCompare/Home.asp -- Find a nursing home

References

ADAPT Research Group, Lyketsos CG, Breitner JC, Green RC, Martin BK, Meinert C, et al. Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology. 2007 May 22;68(21):1800-8. Epub 2007 Apr 25.

Akomolafe A, Beiser A, Meigs JB, Au R, Green RC, Farrer LA, et al. Diabetes mellitus and risk of developing Alzheimer disease: results from the Framingham Study. Arch Neurol. 2006 Nov;63(11):1551-5.

Ayalon L, Gum AM, Feliciano L, Arean PA. Effectiveness of nonpharmacological interventions for the management of neuropsychiatric symptoms in patients with dementia: a systematic review. Arch Intern Med. 2006 Nov 13;166(20):2182-8.

Belle SH, Burgio L, Burns R, Coon D, Czaja SJ, Gallagher-Thompson D, et al. Enhancing the quality of life of dementia caregivers from different ethnic or racial groups: a randomized, controlled trial. Ann Intern Med. 2006 Nov 21;145(10):727-38.

Cummings JL, Schneider E, Tariot PN, Graham SM; Memantine MEM-MD-02 Study Group. Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology. 2006 Jul 11;67(1):57-63.

Durga J, van Boxtel MP, Schouten EG, Kok FJ, Jolles J, Katan MB, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet. 2007 Jan 20;369(9557):208-16.

Freund-Levi Y, Eriksdotter-Jonhagen M, Cederholm T, Basun H, Faxen-Irving G, et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006 Oct;63(10):1402-8.

Gamaldo A, Moghekar A, Kilada S, Resnick SM, Zonderman AB, O'Brien R. Effect of a clinical stroke on the risk of dementia in a prospective cohort. Neurology. 2006 Oct 24;67(:1363-9.

Luchsinger JA, Reitz C, Patel B, Tang MX, Manly JJ, Mayeux R. Relation of diabetes to mild cognitive impairment. Arch Neurol. 2007 Apr;64(4):570-5.

Luchsinger JA, Tang MX, Miller J, Green R, Mayeux R. Relation of higher folate intake to lower risk of Alzheimer disease in the elderly. Arch Neurol. 2007 Jan;64(1):86-92.

McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann JI, Williams SM. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med. 2006 Jun 29;354(26):2764-72.

Mittelman MS, Haley WE, Clay OJ, Roth DL. Improving caregiver well-being delays nursing home placement of patients with Alzheimer disease. Neurology. 2006 Nov 14;67(9):1592-9.

Morris MC, Evans DA, Tangney CC, Bienias JL, Wilson RS. Associations of vegetable and fruit consumption with age-related cognitive change. Neurology. 2006 Oct 24;67(:1370-6.

Regan C, Katona C, Walker Z, Hooper J, Donovan J, Livingston G. Relationship of vascular risk to the progression of Alzheimer disease. Neurology. 2006 Oct 24;67(:1357-62.

Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007 Feb;39(2):168-77. Epub 2007 Jan 14.

Scarmeas N, Stern Y, Mayeux R, Luchsinger JA. Mediterranean diet, Alzheimer disease, and vascular mediation. Arch Neurol. 2006 Dec;63(12):1709-17. Epub 2006 Oct 9.

Schaefer EJ, Bongard V, Beiser AS, Lamon-Fava S, Robins SJ, Au R, et al. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch Neurol. 2006 Nov;63(11):1545-50.

Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007 Jun 13; [Epub ahead of print]

Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. N Engl J Med. 2006 Oct 12;355(15):1525-38.

Small GW, Kepe V, Ercoli LM, Siddarth P, Bookheimer SY, Miller KJ, et al. PET of brain amyloid and tau in mild cognitive impairment. N Engl J Med. 2006 Dec 21;355(25):2652-63.

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Review Date:
7/31/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Coronary artery disease

FitSugar — Wed, 08 Oct 2008 17:35:07 -0700

In This Report

Highlights
Introduction
Prognosis
Risk Factors
Diagnosis
Managing Heart Disease
Anti-Clotting Medications...
Other Medications
Surgery
Coronary Artery Bypass Graf...
Angioplasty and Stents
Other Treatments
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Angioplasty Versus Drugs

Angioplasty works no better than drug therapy (high blood pressure, cholesterol, anti-platelet, and other medication) in preventing heart attack and stroke in patients with stable coronary artery disease (CAD), according to an important New England Journal of Medicine study. Experts still recommend angioplasty for patients with unstable or severe CAD.

Stents

Stents coated with drugs may have a slightly higher risk of causing blood clots than bare metal stents, according to FDA meetings held in late 2006. Researchers still need to conduct more research before reaching final conclusions.
Drug-coated stents work well when they are used for patients with specific types of heart conditions, indicate several studies published in the New England Journal of Medicine. However, problems may develop when these stents are used for “off-label” purposes. Experts are also concerned that both bare metal and drug-coated stents may be used too frequently.
Patients who receive a drug-coated stent must take both aspirin and an anti-platelet thienopyridine drug (usually clopidogrel) for at least 1 year after the stent is inserted, advises an important statement from the American Heart Association. Patients who cannot take a thienopyridine drug should receive a bare metal stent instead of a drug-coated stent.

Anti-Bleeding Drugs for Coronary Artery Bypass Graft (CAGB)

Aprotinin (Trasylol), a drug used to control bleeding during CABG, is more dangerous than other types of anti-bleeding drugs, according to a 2007 study in the Journal of the American Medical Association. Many experts now recommend against its use.

Diagnosis

Blood tests for biomarkers do not provide much more predictive information than standard disease risk factors, suggest several recent studies. In a 2006 study published in the New England Journal of Medicine, researchers found that risk factors such as high blood pressure, high cholesterol, and diabetes are still the best methods for predicting the likelihood of heart disease and heart-related death.

Introduction

The heart is the human body's hardest working organ. Throughout life it continuously pumps blood enriched with oxygen and vital nutrients through a network of arteries to all parts of the body's tissues.

The external structures of the heart include the ventricles, atria, arteries, and veins. Arteries carry blood away from the heart while veins carry blood into the heart. The vessels colored blue indicate the transport of blood with relatively low content of oxygen and high content of carbon dioxide. The vessels colored red indicate the transport of blood with relatively high content of oxygen and low content of carbon dioxide.

In order to perform the difficult task of pumping blood to the rest of the body, the heart muscle itself needs a plentiful supply of oxygen-rich blood, which is provided through a network of coronary arteries. These arteries carry oxygen-rich blood to the heart's muscular walls (the myocardium).

Click the icon to see an image of the anterior heart arteries.

If blood flow to the myocardium is interrupted, an injury known as an infarct occurs. This is also known as myocardial infarction or, more commonly, a heart attack.

Click the icon to see an animation about coronary artery disease.

Coronary artery disease is the end result of a complex process called atherosclerosis (commonly called "hardening of the arteries"). This causes blockage of arteries (ischemia ) and prevents oxygen-rich blood from reaching the heart. There are many steps in the process leading to atherosclerosis, some not fully understood.

Click the icon to see an image of atherosclerosis.

Increasingly, however, researchers are studying the interactions between cholesterol and processes known as oxidation and the inflammatory response.

Cholesterol and Lipoproteins. The story begins with cholesterol and sphere-shaped bodies called lipoproteins that transport cholesterol.

Cholesterol is a white, crystalline substance that is found in all animal cells and in animal-based foods. It is critical for many functions, but under certain conditions cholesterol can have harmful effects.
The lipoproteins that transport cholesterol are referred to by their size. The most commonly known are low-density lipoproteins (LDL) and high density lipoproteins (HDL). LDL is often referred to as the "bad" cholesterol and HDL as the "good" cholesterol.

Click the icon to see an image of cholesterol inside an artery.

Oxidation. The damaging process called oxidation is an important trigger in the atherosclerosis story.

Oxidation is a chemical process in the body caused by the release of unstable particles known as oxygen-free radicals. It is one of the normal processes in the body, but under certain conditions (such as exposure to cigarette smoke or other environment stresses) these free radicals are overproduced.
In excess amounts, they can be very dangerous, causing damaging inflammation and even affecting genetic material in cells.
In heart disease, free radicals are released in artery linings and oxidize low-density lipoproteins (LDL). The oxidized LDL is the basis for cholesterol build-up on the artery walls and damage leading to heart disease.

Inflammatory Response. For the arteries to harden there must be a persistent reaction in the body that causes ongoing harm. Researchers now believe that this reaction is an immune process known as the inflammatory response. The following is one theory about how the inflammatory response contributes to heart disease:

The injuries to the arteries during oxidation signal the immune system to release white blood cells (particularly those called neutrophils and macrophages) at the site. These factors initiate the inflammatory response.
Macrophages literally "eat" foreign debris, in this case oxidized LDL cholesterol.
The process converts LDL cholesterol into foamy material that attaches to the smooth muscle cells of the arteries. The cholesterol becomes mushy and accumulates on artery walls.
Over time the cholesterol dries and forms a hard plaque, which causes further injury to the walls of the arteries.
In response to this additional harm, the immune system releases other factors called cytokines. These are powerful inflammatory molecules that attract more white blood cells and perpetuate the whole cycle, causing persistent injury to the arteries.

Click the icon to see an image of atherosclerosis.

Evidence is growing that the inflammatory response may be present not only in local plaques in single arteries but also throughout the arteries leading to the heart.

Blockage in the Arteries. Eventually these calcified (hardened) arteries become narrower (a condition known as stenosis).

As this narrowing and hardening process continues, blood flow slows and prevents sufficient oxygen-rich blood from reaching the heart.
Such oxygen deprivation in vital cells is called ischemia. When it affects the coronary arteries, it causes injury to the tissues of the heart.
Injured inner vessel walls also fail to produce enough nitric oxide, a substance critical for maintaining blood vessel elasticity. (Nitric oxide has complex effects and may increase inflammation in the arteries.)
These narrow and inelastic arteries not only slow down blood flow but also become vulnerable to injury and tears.

Click the icon to see an image of coronary artery blockage

The End Result: Heart Attack. Heart attack can occur as a result of one or two effects of atherosclerosis.

(1) If the artery becomes completely blocked and ischemia becomes so extensive that oxygen-bearing tissues around the heart die.

(2) If the plaque itself develops fissures or tears. Blood platelets adhere to the site to seal off the plaque, and a blood clot (thrombus) forms. A heart attack can then occur if the formed blood clot completely blocks the passage of oxygen-rich blood to the heart.

Click the icon to see an image of the developmental process of atherosclerosis.

Angina is the primary symptom of coronary artery disease and, in severe cases, of a heart attack. It is typically experienced as chest pain and occurs when the heart muscle does not get as much blood (hence as much oxygen) as it needs for a given level of work (ischemia). Angina is usually referred to as one of two states:

Click the icon to see an image about angina.

Stable Angina (which is predictable)
Unstable Angina (which is less predictable and a sign of a more serious situation)

Angina itself is not a disease. Much evidence indicates that onset of angina less than 48 hours before a heart attack may be protective, possibly by conditioning the heart to resist the damage resulting from the attack. Angina may be experienced in different ways and can be mild, moderate, or severe.

Click the icon to see an image of angina.

Specific factors are typically considered in determining whether symptoms indicate angina:

Quality of the pain. Angina pain is typically described by patients as squeezing, heavy, suffocating, or griplike. It is rarely described as stabbing or burning. Changing one's position or breathing in and out does not affect the pain. The intensity of the pain does not always relate to the severity of the medical problem. Some people may feel a crushing pain from mild ischemia, while others might experience only mild discomfort from severe ischemia. In some cases, the patient experiences shortness of breath, fatigue, or palpitations instead of pain. In others, the ischemia is entirely asymptomatic ("silent ischemia").
Duration. A typical angina attack lasts minutes. If it is more fleeting or lasts for hours, it is probably not angina.
Location. Pain is usually in the chest under the breast bone. It often radiates to the neck, jaw, or left shoulder and arm. Less commonly, patients report symptoms that radiate to the right arm or back.
Triggers of Angina. Angina is usually triggered by physical exertion, emotional stress, or exposure to cold.
Factors that Relieve Angina. Angina is usually relieved by rest or by taking nitroglycerine under the tongue.

Stable Angina. Stable angina is predictable chest pain. Although less serious than unstable angina, it can be extremely painful. It is usually relieved by rest and responds well to medical treatment (typically nitroglycerin). Any event that increases oxygen demand can cause an angina attack. Some typical triggers include:

Exercise
Cold weather
Emotional tension
Large meals

Angina attacks can occur at any time during the day, but most occur between 6 a.m. and noon.

Unstable Angina and Acute Coronary Syndrome. Unstable angina is a much more serious situation and is often an intermediate stage between stable angina and a heart attack, in which an artery leading to the heart (a coronary artery) becomes completely blocked. A patient is usually diagnosed with unstable angina under one or more of the following conditions:

Pain awakens a patient or occurs during rest.
A patient who has never experienced angina has severe or moderate pain during mild exertion (walking two level blocks or climbing one flight of stairs).
Stable angina has progressed in severity and frequency within a 2-month period, and medications are less effective in relieving its pain.

Unstable angina is now usually discussed as part of a condition called acute coronary syndrome (ACS). ACS also includes people with a condition called NSTEMI (non ST-segment elevation myocardial infarction) -- also referred to as non-Q wave heart attack. With NSTEMI, the blood tests suggest a developing heart attack. These conditions are less severe than heart attacks but may develop into full-blown attacks without aggressive treatment. [See In-Depth Report #12: Heart attack and acute coronary syndrome.]

Prinzmetal's Angina. A third type of angina, called variant or Prinzmetal's angina, is caused by a spasm of a coronary artery. It almost always occurs when the patient is at rest. About two-thirds of people with it have severe atherosclerosis in at least one major blood vessel. Irregular heartbeats are common, but the pain is generally relieved immediately with standard treatment.

Click the icon to see an image of a coronary artery spasm.

Silent Ischemia. Some people with severe coronary artery disease do not experience angina pain. This condition is known as silent ischemia, which some experts attribute to abnormal processing of heart pain by the brain. This is a dangerous condition because patients have no warning signs of heart disease. Some studies suggest that people with silent ischemia experience higher complication and mortality rates than those with angina pain. (Angina pain may actually protect the heart by conditioning it before a heart attack.)

Syndrome X. Syndrome X is a condition that occurs when patients have atypical angina chest pain. Their electrocardiograms are abnormal during a stress test, but they have no signs of blocked arteries. It is more likely to occur in women. Although it unclear what causes this condition, imaging tests suggest that Syndrome X may also be caused by ischemia, as is angina.

Prognosis

According to a 2007 report, nearly 16 million Americans have coronary artery disease. In the U.S., coronary artery disease is the leading killer of both men and women. In 2004, nearly 500,000 people died because of CAD. On the positive side, heart attack mortality rates have been declining. Half of men and 63% of women who die of heart disease do not have angina or other warning symptoms prior to their fatal attacks. Although at this time no tests can reliably predict whether a heart attack will occur, experts estimate that up to 30% of fatal attacks and many follow-up surgeries could be avoided with healthy lifestyle changes and by sticking to medical treatments. Two-thirds of patients who have suffered a first heart attack, however, do not take the necessary steps to prevent another.

The following syndromes suggest different degrees of severity among patients with heart disease.

Stable Angina. This condition can usually be managed with lifestyle measures and medications, such as low-dose aspirin. The more severe the angina, however, the greater the chance for progressing to a more serious condition.

Acute Coronary Syndromes (ACS). ACS includes severe and sudden heart conditions that require aggressive treatment but have not developed into a full-blown heart attack. ACS refers to either unstable angina or NSTEMI (non ST-segment elevation myocardial infarction). NSTEMI is also known as non Q-wave myocardial infarction.

Angina is a specific type of pain in the chest caused by inadequate blood flow through the blood vessels (coronary vessels) of the heart muscle (myocardium).

Unstable angina is potentially serious and chest pain is persistent, but blood tests do not show markers for heart attack.
With NSTEMI, the blood tests suggest a developing heart attack, but, most likely, injury in the arteries is less serious than with a full-blown heart attack.

Most discussions of the treatment of unstable angina now refer to acute coronary syndrome. Doctors use the presence of a number of factors to help predict which ACS patients are most at risk for developing a heart attack.

First, patients are categorized by whether they have a history of heart disease or risk factors for heart disease (such as diabetes, high blood pressure, peripheral artery disease) or other complicating conditions (such as lung disease, heart failure). The doctor also evaluates the severity of the angina. Other factors that pose a high risk for ACS include:

Age 65 years or older
Evidence of severe heart tissue injury
Having a lighter weight
Having a history of severe chronic angina
Having abnormal lung sounds called rales (a bubbling or crackling sound) on examination
ST-segment deviation
Having either very slow or very fast heat beats
Having very low blood pressure

Heart Attack. A full-blown heart attack occurs with severe damage to the heart, which blocks oxygen.

ANYONE WHO BELIEVES THEY ARE HAVING A HEART ATTACK SHOULD IMMEDIATELY CALL THE EMERGENCY MEDICAL SYSTEM (911 IN THE UNITED STATES).

People with known heart disease and any unusual chest pain or other symptoms of heart attack that do not clear up with medications should go to the hospital. The degree of pain and the specific symptoms before a heart attack vary greatly among individuals. Symptoms can be abrupt, gradual, or intermittent.

Chest Pain. People with heart disease or risk factors should be concerned about any chest pain, usually precipitated by exercise or stress, that interrupts normal activities and does not clear up after resting or taking angina medications. Chest symptoms might be experienced as follows:

Pain is typically felt as a crushing weight against the chest, accompanied by profuse sweating. The pain may radiate to the left shoulder and arm, the neck or jaw, and even infrequently to the right arm. The arm may be tingling or numb.
Some people may have only a tingling sensation or a sense of fullness, squeezing, or pressure in the chest.
In some patients with a history of heart disease, chest pain is mild. Such patients may have experienced unexplained fatigue, depression, and ill health within a month of a heart attack. Although chest pain is the classic symptom, it occurs in only about half of patients with a heart attack.

Other Common Symptoms.

Nausea, vomiting, and cold sweats
A feeling of indigestion or heartburn
Fainting
A great fear of impending death, a phenomena known as angor animi

Atypical Symptoms. Some studies suggest that nearly half of patients with heart attack do not have chest pain as the primary symptom. Common atypical symptoms of a heart attack include:

Shortness of breath
Cardiac arrest
Dizziness, weakness, and fainting
Abdominal pain

Patients most likely to have atypical symptoms are women and the very elderly (although they can certainly have classic heart attack symptoms as well).

In one study, 52% of elderly people with acute coronary syndrome had atypical symptoms that included shortness of breath, nausea, profuse sweating, pain in the arms, and fainting. Such symptoms were more likely to occur in people with personal or family history of heart disease.
Before a heart attack, women are more likely than men to be nauseous and experience pain high in the abdomen or chest. Their first symptom may be extreme fatigue after physical activity rather than chest pain. Chest pain in women is also more likely to be caused by non-heart problems than in men.

Symptoms That Are Less Likely to Indicate a Heart Attack. The following symptoms are less likely to be due to a heart attack:

Sharp pain brought on by lung movements or coughing
Pain that is mainly or only in the middle or lower abdomen
Pain that can be pinpointed with the top of one finger
Pain that can be reproduced by moving or pressing on the chest wall or arms
Pain that is constant and lasts for hours (although no one should wait hours if they suspect they are having a heart attack)
Pain that is very brief and lasts for a few seconds
Pain that spreads to the legs

However, the presence of these symptoms does not always rule out a serious heart event.

Chest pain is a very common symptom in the emergency room, but heart problems account for only 10 - 33% of all episodes.

The most common causes of chest pain are muscular and bone problems. Problems affecting the ribs and chest muscles include injured muscles, fractures, arthritis, spasms, and infections.

Other causes of chest pain include:

Anxiety attacks
Gastrointestinal disorders (gallstone attacks, peptic ulcer disease, hiatal hernia, heartburn)
Asthma
Spasm in the coronary artery
Abnormalities of the heart muscle
Rupture of the aorta
Collapsed lung
Acute inflammation of the heart
Blood clot in the lung
High thyroid levels (hyperthyroidism)
Anemia
Vasculitis (a group of disorders that cause inflammation of the blood vessels)
Exposure to high altitudes (rare)

Individuals who experience symptoms of a heart attack should take the following actions:

For angina patients, take one nitroglycerin dose either as an under-the-tongue tablet or in spray form at the onset of symptoms. Take another dose every 5 minutes up to three doses or when the pain is relieved, whichever comes first.
Call 911 or the local emergency number. This should be the first action taken if angina patients continue to experience chest pain after taking the full three doses of nitroglycerin. However, only 20% of heart attacks occur in patients with long-standing angina. Therefore, anyone who has heart disease or risk factors for it and experiences heart attack symptoms should contact emergency services.
The patient should chew an aspirin (250 - 500 mg) and be sure that emergency health providers are informed of this so an additional dose is not given.
Patients with chest pain should go immediately to the nearest emergency room, preferably traveling by ambulance. They should not drive themselves.

Click the icon to see an image about heart attack symptoms.

Click the icon to see another image about heart attack symptoms.

Risk Factors

Over 13 million Americans have had angina, a heart attack, or both. Each year, about 1.2 million people will experience a serious heart event. About 25% of all Americans have one or more risk factors for heart disease. Most risk factors for heart disease are related to lifestyle and environmental factors.

Over the past decades, heart disease rates declined in both men and women as they quit smoking and improved dietary habits. This rate, however, has stabilized in recent years, most likely because of the dramatic increase in obesity in the U.S. and other industrialized nations. There have also been minimal changes in other risk factors, including smoking, sedentary behavior, and blood pressure control. Some risk factors cannot be changed, including age, gender, and genetics. Nevertheless, their effects can still be modified with healthy lifestyle changes.

Heart disease may be prevented with a healthy diet and regular exercise, and by quitting smoking if you smoke. Follow your health care provider's recommendations for the treatment and prevention of heart disease.

The American Heart Association guidelines for preventing heart disease recommend:

Improve Cholesterol. People with at least two risk factors and a 10-year risk for heart disease or stroke of more than 20% should aim for LDL levels of less than 100 mg/dl. Statins are now used in more cases.

Keep Blood Pressure Low. People in normal health should have a blood pressure reading of 120/80 mm Hg or less. According to the latest guidelines, blood pressure readings of 120/80 are considered normal, readings of 140/90 or higher indicate hypertension, and readings in between the two are called pre-hypertension. Patients with diabetes or chronic kidney disease should maintain blood pressure readings of 130/80 mm Hg or less, while others should be no higher than 140/90 mm Hg.

Exercise. Everyone in normal health should engage in at least moderate physical activity for a minimum of 30 minutes on most, if not all, days of the week.

Healthy Diet. Everyone should aim for a diet that contains a healthy balance of fruits, vegetables, grains, fish, nuts, legumes, poultry, lean meat, and low-fat dairy items. Avoid saturated fats and trans-fatty acids.

Quit Smoking. Also avoid exposure to secondhand smoke.

Maintain Weight. People should aim for a BMI index of 18.5 - 24.9.

Taking Aspirin. People whose risk for heart disease within 10 years is 10% or more should take a low-dose aspirin every day, unless they have medical reasons to avoid aspirin.

Control Diabetes. People with diabetes should aim for fast blood glucose levels of less than 110 mg/dl and hemoglobin A1C or less than 7%.

Control Atrial Fibrillation. People with atrial fibrillation should use anticoagulants to reduce the risk for blood clots.

Age. About 85% of people who die from heart disease are over the age of 65.

Gender. Coronary artery disease and heart attacks are much more common in middle-aged men. Women have, on average, 10 - 15 more years of heart disease-free life than do men, but as women age, they catch up to men. Women, in fact, are more likely to have angina than men. Younger women with heart disease often do not have the same symptoms as their male counterparts and may be less likely to be diagnosed correctly. They are also more likely than men to die after a heart attack.

In 2007, the American Heart Association issued updated guidelines focusing on prevention of heart disease in women. The new guidelines recommend:

Healthy diet (fresh fruits and vegetables, low-fat dairy products, salt and saturated fat restrictions, alcohol moderation)
Eating oily fish (such as salmon) at least twice a week. Women with existing heart disease should consider taking fish oil supplements of 850 – 1,000 mg eicosapentaenoic acid (EPA) and docosahexaenoic acid (DPA).
Increased physical activity (60 – 90 minutes, preferably 7 days a week)
Quitting smoking
Low-dose aspirin therapy for all women age 65 years and older who can safely take aspirin. High-risk women may require 75 – 325 mg / day; lower-risk women may benefit from 81 mg a day or 100 mg every other day.

Genetic Factors. Genetics are involved in increasing the likelihood of developing important risk factors such as diabetes and high blood pressure. For example, one genetic variant called apolipoprotein E4 (ApoE4) affects cholesterol levels, particularly those associated with heart disease.

Ethnicity. African-American women face the highest risk for death from heart disease, and their rate of heart attacks is increasing. (Mortality rates in men do not differ much by race.) Native American men have a lower risk for heart disease than Caucasian men, and Hispanics have the lowest risk for heart disease of all major American population groups.

African-Americans face a number of biologic and social dangers to their hearts.

They have a higher prevalence of diabetes and hypertension than do Caucasians.
They tend to have poorer diets, higher stress levels, and less access to health care.
All African-Americans risk discrimination in obtaining optimal treatments, but women may be at particular risk for unequal treatment. In one study in which female actors portrayed heart patients, African-American women were 60% less likely to receive aggressive (and expensive) diagnostic tests than African-American men or any Caucasians, even though they presented with similar symptoms.
While African-Americans comprise 13% of the U.S. population, African-Americans have comprised only 2 - 9% of subjects in most major research trials, so knowledge about their specific risks is limited.
Some African-Americans with coronary artery disease appear to have a genetic trait that increases the danger of triglycerides, which may be particularly hazardous for women.

Click the icon to see an image about ethnicity and heart disease risks.

Cholesterol. In spite of its bad press, cholesterol is an essential nutrient necessary for many cellular functions. However, when certain cholesterol levels rise in the blood, they can have dangerous consequences, depending on the type of cholesterol. Low-density lipoprotein (LDL) cholesterol is the "bad" cholesterol responsible for many heart problems. Triglycerides are another type of lipid (fat molecule) that can be bad for the heart. High-density lipoprotein (HDL) cholesterol is the "good" cholesterol that helps protect against heart disease. Doctors test for a "total cholesterol" profile that includes measurements for LDL, HDL, and triglycerides. The ratio of these lipids can affect heart disease risk.

For example, according to one study, men with total cholesterol levels over 240 mg/dl have a risk that is two to four times higher than men whose cholesterol is below 200. A number of studies have demonstrated that reducing LDL and total cholesterol levels and boosting high-density lipoprotein (HDL) levels can improve survival and prevent heart attacks in people with and without heart disease.

It is very difficult to measure LDL levels by themselves, but LDL levels can be reliably calculated by the Friedewald formula: LDL=TC-HDL-TG/5. (LDL=low-density lipoprotein; TC= total cholesterol; HDL=high-density lipoprotein; TG=triglycerides.)

Click the icon to see an image about serum cholesterol.

Cholesterol Goals. In 2004, the National Cholesterol Education Program updated its clinical practice guidelines. The new recommendations set lower treatment goals for LDL levels based on a patient's risk factors for heart disease.

These risk factors include:

Having a first-degree female relative diagnosed with heart disease before age 65 or a first-degree male relative diagnosed before age 55
Being male and over age 45 or female and over age 55
Cigarette smoking
Diabetes
High blood pressure
Metabolic syndrome (risk factors associated with obesity such as low HDL levels and high triglycerides

Having two or more of these risk factors indicates a greater than 20% chance of having a heart attack within 10 years.


Risk Level	Goal (d/L)	Optimal Goal(d/L)
Very High Risk	70	70
High Risk	100	70
Moderate Risk	130	100
Low Risk	160	130

LDL cholesterol, together with other risk factors for heart disease, is the best determinant for whether cholesterol therapy is needed and whether it is working properly. In particular, the new guidelines emphasize lower LDL levels and earlier treatment for people with coronary artery disease, or other forms of atherosclerosis, and diabetes.


Total Cholesterol Goals	LDL Goals	HDL Goals	Triglyceride Goals
Less than 200 mg/dL is desirable. Between 200 and 239 is borderline. Over 240 is high.	70 mg/dL or less is the new goal for very high-risk patients (recent heart attack; current active or unstable cardiovascular or cerebrovascular disease; or two multiple risk factors as defined above.) Below 100 mg/dl is optimal for everyone. It should be the goal for high-risk people including those with existing heart disease, diabetes, or two or more risk factors for heart disease; 70 mg/dL is an optimal goal for these individuals. 130 mg/dl or below for people with two or more risk factors; 100 mg/dL is the optimal goal. 160 mg/dl or less for people at less risk (one or zero risk factors); 130 mg/dL is the optimal goal. Anything over 160 is high with levels over 190 being very high. LDL levels over 190 require medication even with no other cardiac risk factors present.	Levels above 40 mg/dL are desirable; levels above 60 mg/DL are optimal.	Below 150 mg/dL is normal. 150-199 is borderline high. 200-499 is high. Over 500 is very high.
*Risk factors for heart disease include a family history of early heart problems before age 55 for men, before age 65 for women, smoking, high blood pressure, diabetes, being older (over 45 for men and 55 for women), and having HDL levels below 35 mg/dl. People with two or more of these risk factors may have a 10-year risk of heart attack that exceeds 20%, and may therefore need to aim for LDL levels of 100 mg/dL or below.

Other Lipids. Elevated levels of other fatty molecules (lipids) are also now thought to be important indicators of heart disease risk. Studies are finding an elevated risk for angina and first heart attacks in people with elevated levels of lipoprotein(a), or lp(a). This lipoprotein falls somewhere in density between HDL and LDL and may have some properties that increase the risk for blood clots. Some experts suggest, however, that high levels of lp(a) may merely be markers of late-stage atherosclerosis, not a cause.

[See In-Depth Report #23: Cholesterol; and In-Depth Report #43: Heart-healthy diet.]

High blood pressure, or hypertension, has long been a proven cause of coronary artery disease. Blood pressure is categorized as normal, prehypertensive, and hypertensive (which is further divided as Stage 1 or 2 according to severity). High blood pressure is generally considered to be a blood pressure reading greater than or equal to 140 mm Hg (systolic) or greater than or equal to 90 mm Hg (diastolic). Blood pressure readings in the prehypertension category (120 - 139 systolic or 80 - 89 diastolic) indicate an increased risk for developing hypertension. [See Table Blood Pressure Ranges.]

A normal blood pressure reading is 120/80 mm Hg or lower. Most people with high blood pressure should aim for a goal of below 140/90 mm Hg. Patients with certain health problems should aim lower (blood pressure in patients with kidney disease, heart failure, or diabetes should be equal to or lower than 130/80 mm Hg.)

Click the icon to see an image about hypertension.


Blood Pressure Category	Ranges for Most Adults (systolic/diastolic)
Normal Blood Pressure (systolic/diastolic)	Systolic below 120 mm Hg Diastolic below 80 mm Hg
Prehypertension (Formerly Classified as Normal to High-Normal Blood Pressure)	Systolic 120 to 139 mm Hg Diastolic 80 to 89 mm Hg (NOTE: 139/89 or below should be the minimum goal for everyone. People with diabetes or chronic kidney disease should strive for 130/80 or less.)
Mild Hypertension (Stage 1)	Systolic 140 to 159 mm Hg Diastolic 90 to 99 mm Hg
Moderate-to-Severe Hypertension (Stage 2)	Systolic over 160 mm Hg and/or Diastolic over 100 mm Hg
Note: If one of the measurements is in a higher category than the other, the higher measurement is usually used to determine the stage. For example, if systolic pressure is 165 (Stage 2) and diastolic is 92 (Stage 1), the patient would still be diagnosed with Stage 2 hypertension. A high systolic pressure should be a major focus of concern in most adults.

American obesity is at epidemic levels in all age groups. The effect of obesity on cholesterol levels is complex. Although obesity does not appear to be strongly associated with overall cholesterol levels, among obese individuals triglyceride levels are usually high while HDL (beneficial cholesterol) levels tend to be low, both risk factors for heart disease. Obesity has other effects (hypertension, increase in inflammation) that pose major risks to the heart.

Click the icon to see an image of childhood obesity.

Obesity is particularly hazardous when it is one of the components of the metabolic syndrome. This syndrome is diagnosed when three of the following are present: abdominal obesity, low HDL cholesterol, high triglyceride levels, high blood pressure, and insulin resistance. Metabolic syndrome is a pre-diabetic condition that is significantly associated with heart disease and higher mortality rates from all causes. A 2002 study estimated that 24% of the population now has this condition. Obesity is highly linked with type 2 diabetes, and diabetes itself poses a significant risk for high cholesterol levels and heart disease.

Some obese patients with coronary artery disease may consider having bariatric surgery (stomach bypass) to lose excess weight. The weight lost after surgery can help improve blood pressure, cholesterol, blood sugar and other factors associated with CAD. A 2005 study reported that bariatric surgery is safe for patients with CAD who cannot lose weight with diet and exercise, which should always be tried first.

[See In-Depth Report #53: Weight control and diet.]

People who are sedentary are almost twice as likely to suffer heart attacks as are people who exercise regularly. Exercise has a number of effects that benefit the heart and circulation, including:

Improving cholesterol and lipid levels
Reducing inflammation in the arteries
Assisting weight loss programs
Helping to keep blood vessels flexible and open

Studies continue to show that physical activity and avoiding high-fat foods are the two most successful means of reaching and maintaining heart healthy levels of fitness and weight.

Experts have been attempting to define how much exercise is needed to produce heart benefits. In 2002, a well-conducted study on overweight adults confirmed previous research that reported beneficial changes in cholesterol and lipid levels even when people performed low amounts of moderate or high intensity exercise (walking or jogging 12 miles a week). However, more intense exercise is required to significantly change cholesterol levels, notably by increasing HDL (the so-called good cholesterol). Overweight people who have trouble losing pounds can still achieve considerable heart benefits by exercising. Resistance (weight) training has also been associated with heart protection. Exercises that train and strengthen the chest muscles may prove to be very important for patients with angina.

Click the icon to see an image about exercise.

Click the icon to see an image about hypertension and lifestyle changes.

Some studies suggest that for the greatest heart protection, it is not the duration of a single exercise session that counts but the total daily amount of energy expended. Therefore, the best way to exercise may be in multiple short bouts of intense exercise, which can be particularly helpful for older people.

Sudden strenuous exercise (such as snow shoveling and mowing lawns) puts many people at risk for angina and heart attack. Activities that involve raising the arms above the head may also be risky. Patients with angina should never exercise shortly after eating. People with risk factors for heart disease should seek medical clearance and a detailed exercise prescription. And all people, including healthy individuals, should listen carefully to their bodies for signs of distress as they exercise. [See In-Depth Report #29: Exercise.]

Heart disease and stroke are the leading causes of death in people with diabetes. People with diabetes are at risk for the following heart-risk conditions, and the more of these conditions they have, the worse the outlook.

High blood pressure (hypertension). Up to 75% of cardiovascular problems in people with diabetes may be due to hypertension.
Very unhealthy cholesterol and lipid balances (high triglyceride levels and lower HDL).
Blood clotting problems.
Impaired nerve function (neuropathy), which can also damage the heart. Some experts estimate that the mortality rates from neuropathy-related heart conditions range from 15 - 53%.

People with both diabetes and heart disease may have a higher risk for silent ischemia, a condition in which people have blocked arteries but do not experience the angina, the chest pain that signals heart disease. [See In-Depth Report #9: Diabetes - type 1; or In-Depth Report #60: Diabetes - type 2.]

Peripheral artery disease (PAD) occurs when atherosclerosis affects the extremities, particularly the feet and legs. The major risk factors for heart disease and stroke are also the most important risk factors for PAD. (The combination of such conditions with PAD also produces more severe forms of heart or circulatory disease.) Although signs of heart disease are detected in only 20 - 40% of patients with PAD after an initial diagnosis, studies suggest that when intense heart-diagnostics tests are performed, such as angiography or thallium stress tests, co-existing heart disease is detected in up to 90% of all PAD patients. [See In-Depth Report #102: Peripheral artery disease.]

Smokers in their 30s and 40s have a heart-attack rate that is five times higher than their nonsmoking peers. Cigarette smoking may be directly responsible for at least 20% of all deaths from heart disease, or about 120,000 deaths annually. Smoking cigars may increase the risk of early death from heart disease, although evidence is much stronger for cigarette smoking. Although heavy cigarette smokers are at greatest risk, a 2002 study suggested that people who smoke as few as three cigarettes a day are at higher risk for blood vessel abnormalities that endanger the heart. Regular exposure to passive smoke also increases the risk of heart disease in nonsmokers. [See In-Depth Report #41: Smoking.]

Eating habits can be protective or dangerous to the heart. Avoiding saturated fats and trans-fatty acids is particularly important for controlling cholesterol.

Diet plays an important role in the health of the heart. In 2006, the American Heart Association (AHA) issued revised diet and lifestyle recommendations. The current guidelines recommend:

Balance calorie intake and physical activity to achieve or maintain a healthy body weight. (Controlling weight, quitting smoking, and exercising regularly are essential companions of any diet program. Try to get at least 30 minutes, and preferably 60 – 90 minutes, of daily exercise.)
Consume a diet rich in a variety of vegetables and fruits. Vegetables and fruits that are deeply colored (spinach, carrots, peaches, berries) are especially recommended as they have the highest micronutrient content.
Choose whole-grain, high-fiber foods. These include fruits, vegetables, and legumes (beans). Good whole grain choices include whole wheat, oats/oatmeal, rye, barley, brown rice, buckwheat, bulgur, millet, and quinoa.
Consume fish, especially oily fish, at least twice a week (about 8 ounces/week). Oily fish such as salmon, mackerel, and sardines are rich in the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Consumption of these fatty acids is linked to reduced risk of sudden death and death from coronary artery disease.
Limit daily intake of saturated fat (found mostly in animal products) to less than 7% of total calories, trans fat (found in hydrogenated fats, commercially baked products, and many fast foods) to less than 1% of total calories, and cholesterol (found in eggs, dairy products, meat, poultry, fish, shellfish) to less than 300 mg per day. Choose lean meats and vegetable alternatives (such as soy). Select fat-free and low-fat dairy products. Grill, bake, or broil fish, meat, and skinless poultry.
Use little or no salt in your foods. Reducing salt can lower blood pressure and decrease the risk of heart disease and heart failure.
Cut down on beverages and foods that contain added sugars (corn syrups, sucrose, glucose, fructose, maltrose, dextrose, concentrated fruit juice, honey.)
If you consume alcohol, do so in moderation. The AHA recommends limiting alcohol to no more than 2 drinks per day for men and 1 drink per day for women.

[See In-Depth Report #43: Heart-healthy diet.]

Stress. The effects of mental stress on heart disease are controversial. Stress can affect the heart when it activates the sympathetic nervous system (the automatic part of the nervous system that affects many organs, including the heart). Some studies suggest an association between acute stress and a higher risk for serious cardiac events, such as heart rhythm abnormalities and heart attacks, in people with heart disease. However, not all studies report strong evidence that stress has any effect on the heart, particularly in people without any history of heart disease. [See In-Depth Report #31: Stress.]

Depression. Depression increases the severity of heart attack and may even worsen a patient's response to medication for heart disease. Although people with heart disease may become depressed, this does not explain entirely the link between the two problems. Data suggest that depression itself may be a risk factor for heart disease as well as its increased severity.

A number of studies indicate that depression has biologic effects on the heart, including blood clotting and heart rate. One study, for example, reported an association between depression and a greater risk for death from heart problems even in people without a history of heart disease. Even mild depression, which includes feelings of hopelessness experienced over many years, may harm the heart. A 2007 study suggested that depressive symptoms (fatigue, loss of appetite) may be a sign of thickening arteries, the early stage of coronary artery disease. [See In-Depth Report #8: Depression.]

Benefits of Moderate Drinking. Several studies have found heart protection from moderate intake of alcohol (one or two glasses a day). Moderate alcohol consumption can help boost HDL levels. Alcohol may also prevent blood clots and inflammation. Although red wine is most often cited for healthful properties, any type of alcoholic beverage appears to have similar benefit.

Adverse Effects of Heavy Drinking. By contrast, heavy drinking harms the heart. In fact, heart disease is the leading cause of death in alcoholics. Evidence suggests that people who consume more than three drinks a day have abnormal blood clotting factors. Heavy alcohol consumption can raise blood pressure, and binge drinking may increase the risk for hemorrhagic stroke (caused by bleeding in the brain). Large doses of alcohol can trigger irregular heartbeats, which can be dangerous in people with existing heart disease.

Pregnant women and people who can't drink moderately should not drink at all.

Homocysteine and Vitamin B Deficiencies. Deficiencies in the B vitamins folate (known also as folic acid), B6, and B12 have been associated with a higher risk for heart disease in some studies. Such deficiencies produce higher blood levels of homocysteine, an amino acid that has been associated with a higher risk for heart disease, stroke, and heart failure. Researchers have been studying whether vitamin B supplements can reduce homocysteine levels and, consequently, heart disease risks.

Several major 2006 studies indicated that while B vitamin supplements do help lower homocysteine levels, they have no effect on heart disease outcomes. The studies, published in the New England Journal of Medicine, examined patients who had either recently had a heart attack or suffered from diabetes or heart disease. Results showed a similar number of heart attacks and strokes among patients who took B vitamins and those who received placebo. Some experts think that homocysteine may be a marker for heart disease rather than a cause of it.

Click the icon to see the benefits of vitamin B.

Click the icon to see the food sources of vitamin B.

C-Reactive Protein. C-reactive protein is a product of the inflammatory process. Evidence increasingly suggests that high levels may predict future heart disease. It is not known if the protein plays any causal role or whether it is simply a marker for other factors in the disease process.

C. pneumoniae and Other Infectious Organisms. Some microorganisms and viruses have been under suspicion for triggering the inflammation and damage in the arteries that contribute to heart disease. The strongest evidence to date supports a possible role from Chlamydia (C.) pneumoniae (a non-bacterial organism that causes mild pneumonia in young adults). C. pneumoniae has been detected in plaques in the arteries of patients with heart disease. In some studies, evidence of previous infection has been associated with a higher risk for heart events.

Other studies also suggest that cytomegalovirus (CMV), a common virus, may have similar effects. Many people, however, have been infected with these organisms, and no clear association has been found with any of these infections.(H. pylori, the bacteria that causes peptic ulcers, has also been studied for heart effects, but evidence is very weak on any link.)

Erectile Dysfunction. Recent research suggests that erectile dysfunction may be a warning sign of coronary artery disease, even in men who are not considered at risk for the condition. Some studies indicate that men with erectile dysfunction have higher levels of C-reactive protein and more symptoms of atherosclerosis than men without erectile problems.

Periodontal Disease. A number of studies support an association between periodontal disease and cardiovascular disorders. According to a 2003 major analysis, periodontal (gum) disease is associated with a 20% higher risk for ischemic stroke and heart disease. (The added risk may be even higher in adults under 65.) Recent evidence is pointing to the inflammatory response as the common element.

Click the icon to see an image of gum disease.

Anemia. Anemia has adverse effects on the heart and increases the severity of cardiac conditions, including heart failure and heart attacks. A 2002 study suggested that anemia may even be a risk factor for heart disease itself. Blood transfusions after a heart attack improve survival rates in elderly patients who are anemic.

Iron Overload. An inherited disease called hemochromatosis, in which the intestinal tract absorbs too much iron from food, has been associated with atherosclerosis and heart attack. About 10% of Caucasians carry the gene for this condition. There is no strong evidence that excess iron levels in people without hemochromatosis can contribute to heart disease.

Sleep Apnea. Obstructive sleep apnea is a condition in which tissues in the upper throat collapse at intervals during sleep, thereby blocking the passage of air. It has been strongly associated with high blood pressure and obesity, but is also associated with heart disease and heart attacks, regardless of these risk factors. Some evidence suggests that obstructive apneas cause an increase in stiffness and inflammation in the arteries.

Some inborn or natural conditions are not risk factors themselves but have been associated with a higher incidence of heart disease or its consequences:

Factors Before Birth and In Infancy. Low weight at birth and in the womb has been associated with later heart disease in a few studies. Some suggest, however, that this may just reflect poor nutrition in the mother, which appears to affect life-long risk.

Seasonal Differences. More deaths from heart disease occur in December and January, and the fewest in the summertime. Although lower temperatures and snow shoveling may play a role in some cases, more winter deaths have been reported even in warm regions. Holiday stress or fewer daylight hours have been suggested as other reasons for these higher winter rates.

Physical Characteristics. Male pattern baldness, hair in the ear canals, and creased earlobes are associated with a higher risk for heart disease in Caucasian males.

Click the icon to see an image of an ear lobe crease.

Diagnosis

Many tests can diagnose possible heart disease. The choice of which (and how many) tests to perform depends on the patient's risk factors, history of heart problems, and current symptoms. Usually the tests begin with the simplest and may progress to more complicated ones.

Doctors routinely check for high blood pressure and unhealthy cholesterol levels in all older adults. Specific tests are also important in people who may have risk factors or symptoms of diabetes. Doctors may also test for homocysteine, the protein albumin, and blood clotting factors, especially fibrinogen.

An electrocardiogram (ECG) measures and records the electrical activity of the heart. Between 25 - 50% of people who suffer from angina or have silent ischemia, however, have normal ECG readings. The waves measured by the ECG correspond to the contraction and relaxation pattern of the different parts of the heart. Specific waves seen on an ECG are named with letters:

The electrocardiogram (ECG, EKG) is used extensively in the diagnosis of heart disease, from congenital heart disease in infants to myocardial infarction and myocarditis in adults. Several different types of electrocardiogram exist.

P. The P wave is associated with the contractions of the atria (the two chambers in the heart that receive blood from outside).
QRS. The QRS is a series of waves associated with ventricular contractions. (The ventricles are the two major pumping chambers in the heart.)
T and U. These waves follow the ventricular contractions.

The most important wave patterns in diagnosing and determining treatment for heart disease and heart attack are called ST elevations and Q waves.

A depressed or horizontal ST wave suggests some blockage and the presence of a heart disease, even if there is no angina present. (This finding, however, is not very accurate, particularly in women, and can occur without heart problems).
ST elevations and Q waves are the most important wave patterns in diagnosing and determining treatment for a heart attack. They suggest that an artery to the heart is blocked, and that the full thickness of the heart muscle is damaged. ST segment elevations do not always mean the patient has a heart attack. And, some heart attack patients do not have elevated ST segments. Other factors are important in making a diagnosis.

The primary value of exercise stress tests is not to detect coronary artery disease but to help determine the severity and predict the outcome of an existing heart condition. It is considered for the following people:

Patients with possible or probable angina and low or intermediate risk for adverse heart events.
Selected adults who do not have symptoms of heart disease but are at moderate risk to high risk for developing heart disease (a 10 - 20% chance within 10 years). Moreover, heart blockage without angina (silent ischemia) may suggest a more severe condition, at least in men.

Basic Procedure. A stress test (exercise tolerance test) monitors the patient's heart rhythms, blood pressure, and clinical status. It can tell how well the heart handles work and if parts of the heart have decreased blood supply. A typical stress test involves:

The patient walks on a treadmill or rides a stationary bicycle. Exercise continues until the heart is beating at least 85% of its maximum rate, until symptoms of heart trouble occur (changes in blood pressure, heart rhythm abnormalities, angina, fatigue), or the patient simply wants to stop.
For patients who cannot exercise, the doctor may administer dobutamine or arbutamine, which are drugs that simulate the stress of exercise.
An ECG is used to monitor heart rhythms during a stress test. (An echocardiogram or more advanced imaging technique may also be used to visualize the actions of the heart and blood flow.)

More than 25% of patients stop exercising before they reach their own maximum limits because of fear of a heart event. Patients should be reassured that the activities performed in the test under the guidance of a professional are safe.

Interpreting Results. To accurately assess heart problems, experts look at a number of findings derived from the ECG and other tools during exercise. They include:

Exercise capacity. This is a measure of a person's capacity to reach certain metabolic rates.
Heart rate and ST waves. On ECGs, doctors specifically look for abnormalities in part of the wave tracing called an ST segment. A certain type of ST segment depression may suggest the presence of heart disease. However, gender, drugs and other medical conditions can affect the ST segment. Using a measurement that adjusts the ST segment to heart rate improves accuracy.
Dukes Treadmill Score. This important score uses the number of minutes a patient can exercise and other factors that are present in patients with exercise-limiting angina.
Heart rate recovery.
Chronotropic index. This is the percentage of the heart-rate reserve that is used during the exercise. A result of 80% or less suggests a significant risk for serious heart problems in most patients.
Changes in systolic blood pressure.

Using these and other measures, doctors can determine risk fairly accurately, particularly for men of any age with chronic stable angina. The test has limitations, however, and some are significant. For example, a 2002 study indicated that in patients with suspected unstable angina the chances for a future adverse heart event remain high even if the exercise test shows low risk. In addition, for many reasons, the test is less accurate in women, and an echocardiogram may be a more accurate procedure for them. About 10% of patients, particularly younger people, will have false positive test results. In such cases, test results indicate abnormalities when there are no heart problems.

An echocardiogram is a noninvasive test that uses ultrasound images of the heart. This test is more expensive than an ECG, but it can be very valuable, particularly when used with a stress test, to detect the location and extent of heart muscle damage. It appears to be more accurate for women than ECG stress tests, but at this time it is not routinely recommended as a replacement for most women.

Computed tomography (CT) scans used alone or with ECG may be used to detect calcium deposits on the arterial walls, which are strong indicators of current and future coronary artery disease. The presence of calcium does not always signify narrowing of the arteries. But, the absence of calcification in the arteries indicates the patient has no risk for heart disease.

Advanced CT techniques are improving accuracy:

Click the icon to see an image of a CT scan.

Electron Beam Computed Tomography. Electron beam computed tomography (EBCT) is a CT technique that scans the heart so quickly that the motion of the heart appears frozen. This procedure identifies calcification and stratifies cardiac risk accurately.
Multidetector Computed Tomography. Another CT technique called multidetector computed tomography (MDCT) is able to take pictures of the entire heart in 1 millimeter slices in the time it takes for a patient to hold one breath. A 2006 study indicated that MDCT tends to have a high “false-positive” rate (indicating disease when it is not actually there), but for some patients the test may be helpful in ruling out coronary artery disease.

Some expert groups recommend CT scans in selected patients who have an intermediate risk (10 - 20% chance of heart disease within 10 years). For some of these patients, EBCT may be preferred over exercise stress testing, but most experts recommend a stress test as the main diagnostic tool. In general, the use of these expensive imaging tests is probably not very helpful for people at low or high risk. (For people with high risk, the additional information from these tests would not add much value.) More research is needed to determine the benefits of CT scanning in specific individuals.

Radionuclide procedures use imaging techniques and computer analyses to plot and detect the passage of radioactive tracers through the region of the heart. Such tracing elements are typically given intravenously. Radionuclide imaging is useful for diagnosing and determining:

Severity of unstable angina when less expensive diagnostic approaches are unavailable or unreliable
Severity of chronic coronary artery disease
Success of surgeries for coronary artery disease.
Whether a heart attack has occurred

Various imaging techniques may be used with radionuclide procedures, including:

Planar scintigraphy uses a special overhead camera and is the oldest scanning technique.
Single-photon emission computed tomography (SPECT) uses a camera that rotates around the patient and takes pictures of "slices" of the heart. It is more accurate than planar imaging in precisely locating problems in the arteries.
Positron-emission tomographic (PET) scanners employ multiple rings that surround the patients, which detect and record atomic particles (photons) that are emitted by the tracer elements (such as radioactive oxygen, nitrogen, or carbon). It is more expensive and less widely available than SPECT.

Myocardial Perfusion (Blood Flow) Imaging Test (also called the Thallium Stress Test). This radionuclide test is typically used with an exercise stress test to determine blood flow to the heart muscles. It is a reliable measure of severe heart events. It may be useful in determining the need for angiography if CT scans have detected calcification in the arteries. About a minute before the patient is ready to stop exercising, the doctor administers a radioactive tracer into the intravenous line. (Tracers include thallium, technetium, or sestamibi.) Immediately afterwards, the patient lies down for a heart scan, usually with a planar scintigraphy or with SPECT. If the scan detects damage, more images are taken 3 or 4 hours later. Damage due to a prior heart attack will persist when the heart scan is repeated. Injury caused by angina, however, will have resolved by that time.

Radionuclide Angiography. This is a technique for visualizing the chambers and major blood vessels of the heart. It uses an injected radioactive tracer and can be performed during exercise, at rest, or with use of stress-inducing drugs. It is an excellent test for assessing the heart's pumping action and for determining the severity of coronary artery disease. It is an alternative to echocardiograms in certain situations.

Click the icon to see an internal view of the heart.

Magnetic Resonance Angiography (MRA). MRA is a very promising noninvasive imaging technique that can provide three-dimensional images of the major arteries to the heart and identify disease with high accuracy. Experts believe this approach will eventually be a good alternative to angiography.

Click the icon to see an image of a MRI.

Angiography is an invasive test. It is used for patients who show strong evidence for severe obstruction on stress and other tests, and for patients with acute coronary syndrome.

A narrow tube is inserted into an artery, usually in the leg or arm, and then threaded up through the body to the coronary arteries.
A dye is injected into the tube, and an x-ray records the flow of dye through the arteries.
This process provides a map of the coronary circulation, revealing any blocked areas.

Click the icon to see an image of dye in the coronary artery.

Major complications include stroke, heart attacks, and kidney damage. These risks are very low (about 0.1%), however, if the procedure is done in an experienced medical center (one that performs at least 300 of these operations every year). Allergic reactions can also occur. The procedure is expensive, and between 10 - 30% of patients who have this procedure have normal results.

When heart cells become damaged, they release different enzymes and other molecules into the bloodstream. Elevated levels of such markers of heart damage in the blood or urine may help predict a heart attack in patients with severe chest pain and help determine treatment. Some of these factors include:

Troponins. The proteins cardiac troponin T and I are released when the heart muscle is damaged. Both are proving to be among the best diagnostic indications of heart attacks. They help to identify many individuals with ACS who might otherwise be misdiagnosed.
Creatine kinase myocardial band (CK-MB). CK-MB has been a standard marker, but the MB fraction is not as accurate as troponin levels, since elevated levels can appear in people without heart injury.
Myoglobin. Myoglobin is a protein found in heart muscles. It is released early in the injured heart, and it may be useful in combination with CK-MB and the troponins.
Newer biomarkers, including C-reactive protein (CRP), homocysteine, B-type natriuretic peptide (BNP), urinary albumin, and fibrinogen.

Several 2006 studies that evaluated how well biomarkers predict risk of heart events concluded that they do not provide much more useful information than standard risk factors (high blood pressure, unhealthy cholesterol levels, diabetes). At this time, most experts feel that these standard disease risk factors provide the best predictors of the likelihood of developing coronary artery disease, heart attack, or stroke.

Managing Heart Disease

The approach for managing any degree of coronary artery disease involves lifestyle changes. Depending on severity and individual conditions, patients may need one or more medications, surgery, or both.

Healthy diet, regular exercise and quitting smoking if you are a smoker may prevent heart disease. Follow your health care provider's recommendations for treatment and prevention of heart disease.

Experts have come up with a mnemonic device (ABCDE) for remembering 10 factors that are fundamental for management of stable angina and coronary artery disease:

A. Aspirin and anti-angina drugs

B. Blood pressure and beta-blockers

C. Cholesterol-lowering drugs (typically statins) and cigarettes (stopping)

D. Diet and diabetes control

E. Exercise and education

Unstable angina is now usually classified with non-Q myocardial infarction as acute coronary syndrome (ACS) in professional discussions of treatments. ACS usually requires more aggressive treatments, including surgery. [ACS is more fully discussed in In-Depth Report #12: Heart attack and acute coronary syndrome.]

Click the icon to see an image about angina.

Anti-Clotting Medications

Anti-clotting drugs that inhibit or break up blood clots are used at every stage of heart disease. They are generally classified as either antiplatelets or anticoagulants. All anti-clotting therapies carry the risk of bleeding, which can lead to dangerous situations, including stroke.

A thrombus is a blood clot that forms in a vessel and remains there. An embolism is a clot that travels from the site where it formed to another location in the body. Thrombi or emboli can lodge in a blood vessel and block the flow of blood in that location depriving tissues of normal blood flow and oxygen. This can result in damage, destruction (infarction), or even death of the tissues (necrosis) in that area.

Antiplatelet Drugs. These drugs prevent formation of blood platelets. Platelets are very small disc-shaped blood cells that are important for blood clotting.

Aspirin. Aspirin is an antiplatelet. It is the most common anti-clotting drug. Nearly anyone with existing heart disease or at risk for it is advised to take a low-dose aspirin every day.
Thienopyridines. Clopidogrel (Plavix) and ticlopidine (Ticlid) are thienopyridines, another type of anti-platelet drug.
Glycoprotein IIb/IIIa Inhibitors. These powerful blood-thinning drugs include abciximab (ReoPro, Centocor), eptifibatide (Integrilin), tirofiban (Aggrastat), and lamifiban. They are administered intravenously in the hospital and are used after angioplasty surgery and stent placement.

Click the icon to see an image about blood.

Anticoagulants. Anticoagulants help thin blood and include:

Heparin
Warfarin (Coumadin)
Direct thrombin inhibitors

Aspirin. Aspirin is known as a nonsteroidal anti-inflammatory drug (NSAID). It stops blood platelets, which are major clotting factors, from sticking together to form a blood clot. A daily low-dose aspirin (75 - 325 mg) is usually the first choice for preventing heart disease in high-risk individuals. Aspirin can prevent by 25 – 50% the risk of heart attacks and death in people with existing heart disease and a history of heart attack. It also reduces the risk for stroke. According to a 2006 review, aspirin works equally well for both men and women.

Click the icon to see an image about stomach ulcers.

Side effects from prolonged use of aspirin may include stomach ulcers and bleeding. (There may be a slight increased risk for bleeding-related strokes, which are very uncommon, however. Furthermore, this risk may be outweighed by protection against the more common type of stroke, which is caused by artery blockage.)

Clopidogreland Ticlopidine. Clopidogrel (Plavix) and ticlopidine (Ticlide) are anti-platelet drugs known as thienopyridines. When taken with aspirin, these drugs can significantly reduce the risk for heart attack and stroke in patients with acute coronary syndrome (unstable angina or early signs of heart attack). The combination of aspirin and a thienopyridine is essential for patients who have a drug-eluting stent. According to a 2007 American Heart Association advisory, patients who have a drug-eluting stent must take both aspirin and a thienopyridine for at least 1 year after the stent is inserted. Many experts recommend clopidogrel instead of ticlopidine because ticlopidine has been associated with dangerous blood disorders, particularly thrombocytopenia.

Clopidogrel is also recommended for patients who are undergoing angioplasty. For patients having coronary bypass surgery, it should be withheld for at least 5 -7 days prior to surgery because of a significant bleeding risk. Researchers are investigating whether clopidogrel and aspirin together are better than aspirin alone in reducing the risks following coronary bypass surgery. A 2006 study suggested that for some patients with heart disease, clopidogrel plus aspirin does not work better than aspirin alone for preventing a first heart attack or stroke.

Click the icon to see an image of the developmental process of atherosclerosis.

Click the icon to see an image about atherosclerosis.

Anticoagulants are drugs that prevent or delay blood coagulation and the formation of blood clots. Heparin has been the standard anticoagulant, but a number of drugs are now available that are proving to be better choices in many cases.

Standard (Unfractionated) Heparin. The heparin referred to as unfractionated heparin has been the standard for years and is used alone or in combination with aspirin for managing unstable angina. It is no longer the recommended first choice, however, for this patient group. It must be intravenously administered and monitored with frequent blood tests. The major complication is thrombocytopenia (a severe drop in platelets). This condition is extremely serious and can become life-threatening, particularly with bleeding in various body tissues. Alternatives include low-molecular weight heparin and direct thrombin inhibitors.

Low-Molecular Weight Heparin. Enoxaparin (Lovenox), dalteparin (Fragmin), tinzaparin (Innohep) are drugs known as low-molecular weight heparins (LMWHs). Many doctors now recommend these drugs over standard heparin for patients with unstable angina (unless bypass surgery is being planned). They have similar rates of survival, recurring angina, and bleeding as standard heparin. However, they pose lower risks for heart attack, repeat angioplasties, and thrombocytopenia. They require injections but do not require the ongoing monitoring that standard heparin does. Patients may even be able to self-administer LMWHs as people with diabetes do insulin.

Warfarin. Warfarin (Coumadin) is an oral anticoagulant. It prevents clots by inhibiting vitamin K. Warfarin is used with aspirin after a heart attack to prevent another one and to prevent blood clots in patients with atrial fibrillation. Warfarin is also proving to be more effective than aspirin for preventing heart attacks in patients with acute coronary syndromes. Warfarin therapy poses a dangerous risk for bleeding and blood coagulation must be monitored with frequent blood tests.

Direct Thrombin Inhibitors (DTIs). Direct thrombin inhibitors are a more recent group of anti-coagulants. The first DTI was hirudin, a natural substance derived from the saliva of leeches. New forms include argatroban (Novastan), bivalirudin (Angiomax), danaparoid (Orgaran), lepirudin (Refludan), desirudin (Revasc), and ximelagatran (Exanta). Many of these drugs are used along with warfarin and may be good options for patients who develop thrombocytopenia with heparin use. DTIs may prove to be superior to standard heparin for patients with acute coronary syndrome.

Other Medications

Nitrates have been used in the treatment of angina for over 100 years. These drugs release nitric oxide, thereby relaxing the smooth muscles in blood vessels. Many nitrate preparations are available. The most commonly used are nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate. Nitrates can be absorbed from the gastrointestinal tract (oral tablet), skin (ointment or patch), or from under the tongue (sublingual tablet or spray).

Rapid Acting Nitrates. Rapid-acting nitrates are used to treat acute attacks. Nitroglycerin is the most widely used drug for this purpose. It can be administered under the tongue (sublingually or as a spray) or pocketed between the upper lip and gum (buccally) and can relieve angina within minutes. The procedure for taking nitroglycerin during an attack is as follows:

At the onset of an angina attack, the patient administers one sublingual or buccal tablet or one metered dose of the spray.
If the pain is not relieved within 5 minutes the patient takes a second dose; a third can be taken after another 5 minutes if symptoms persist.
If pain continues after a total of three doses in 15 minutes, the patient should go immediately to the nearest emergency room.

Nitroglycerin is very volatile so its potency can be easily lost. Patients should take the following precautions:

Keep no more than 100 tablets on hand, stored in their original container.
When first opened, the cotton filler should be discarded, and the cap screwed on tightly immediately after each use.
A supply should always be kept close at hand in case of an attack, with the rest kept in a cool dry place.

Intermediate to Long-Term Nitrates. Sublingual tablets of isosorbide dinitrate have a somewhat slower onset of action than nitroglycerin and are useful for preventing exercise angina. Ointments, patches, and oral tablets are used for longer-term prevention of angina attacks:

Transdermal patches are applied in the morning to any hair- or injury-free area on the chest, back, stomach, thigh, or upper arm. Hands should be washed after each patch or ointment application, and sites of application should be rotated to avoid skin irritation.
Nitroglycerin ointment is applied by measuring out an even amount on an applicator paper and then placing, not rubbing or massaging, it on the chest, stomach, or thigh. Any ointment that remains from the previous application should be removed.

Long-acting forms may lose their effectiveness over time, so doctors generally schedule nitrate-free breaks to prevent tolerance. Some concern exists that nitrate-free periods might increase the risk for angina and adverse heart events. One large study, however, found no increased danger when patients used a nitroglycerine patch with scheduled breaks. The use of high blood pressure drugs known as ACE inhibitors may help prevent tolerance to nitrates.

Side Effects. Nitrates have many side effects, some of which can be serious.

Common side effects of nitrates include headaches, dizziness, nausea and vomiting, blurred vision, fast heartbeat, sweating, and flushing on the face and neck. Low blood pressure and dizziness can be relieved by lying down with the legs elevated. These effects are significantly worsened by alcohol, beta-blockers, calcium channel blockers, sildenafil (Viagra), and certain antidepressants. The doctor may prescribe medicines to lessen these side effects. Patients should contact their doctor if these side effects are persistent or severe.

Serious side effects requiring immediate medical help include fever, joint or chest pain, sore throat, skin rash (especially on the face), unusual bleeding or bruising, weight gain, and swelling of the ankles.

Withdrawal. Withdrawal from nitrates should be gradual. Abrupt termination may cause angina attacks.

Beta-blockers are useful for preventing angina attacks and reducing high blood pressure. They reduce the heart's oxygen demand by slowing the heart rate and lowering blood pressure. They are recognized for reducing deaths from heart disease and from heart surgeries, including angiography and coronary bypass. Beta-blockers are the drugs of choice for older patients with stable angina and may also be beneficial for people with silent ischemia. They are, however, less useful for the treatment of Prinzmetal’s angina. Beta-blockers are often prescribed along with other drugs such as nitrates, calcium channel blockers, or statins. A 2006 study suggested that beta-blockers and statins may help stabilize coronary artery disease and prevent the development of heart attacks.

Specific Beta-blockers. Beta-blockers include propranolol (Inderal), carvedilol (Coreg), bisoprolol (Zebeta), acebutolol (Sectral), atenolol (Tenormin), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol-XL), and esmolol (Brevibloc). A nasal spray form of propranolol appears to be very helpful in reducing exercise-induced angina attacks.

Side Effects. Beta-blocker side effects include fatigue, lethargy, vivid dreams and nightmares, depression, memory loss, and dizziness. They can lower HDL (“good”) cholesterol. Beta blockers are categorized as non-selective or selective. Non-selective beta blockers such as carvedilol and propranolol can narrow bronchial airways. These beta-blockers should not be used by patients with asthma, emphysema, or chronic bronchitis.

Patients should never abruptly stop taking these drugs. The sudden withdrawal of beta-blockers can rapidly increase heart rate and blood pressure. The doctor may advise a patient to slowly decrease the dose before stopping completely.

Calcium channel blockers reduce heart rate and slightly dilate the blood vessels of the heart, thereby decreasing oxygen demand and increasing oxygen supply. They also reduce blood pressure. CCBs vary chemically, however, and although some are helpful, others may even be dangerous for certain patients with angina.

Click the icon to see an image of the anterior heart arteries.

Long-acting nifedipine (Adalat, Procardia) and nisoldipine (Sular) and newer CCBs, such as amlodipine (Norvasc) and nicardipine (Cardene), may be beneficial for some patients with angina. They can be considered alone for patients who cannot tolerate beta-blockers, but may provide the best results when used in combination with a beta-blocker. Studies suggest that they reduce the need for repeat angioplasties. Their effects on other outcomes, including mortality rates and heart attack, are less clear.
Short-acting CCBs, including short-acting forms of verapamil, diltiazem, nifedipine, and nicardipine, are helpful for many patients with Prinzmetal's angina. However, short-acting forms of certain CCBs, such as nifedipine and nisoldipine, have been associated with severe and even dangerous side effects, including an increase in heart attacks and sudden death in some patients with unstable angina. They also increase the risk for adverse effects in patients with stable angina. Short-acting CCBs are, therefore, not used for stable or unstable angina.

There is no strong evidence that any calcium channel blockers improve survival rates. Overdose can cause dangerously low blood pressure and slow heart beats. Patients with heart failure have a higher risk for death with these drugs and should not take them. No one taking any calcium channel blocker should withdraw abruptly because such action could dangerously increase the risk of high blood pressure. Note: Grapefruit and Seville oranges boost the effects of CCBs, sometimes to toxic levels. (Regular oranges do not appear to pose any hazard.)

Angiotensin converting enzyme (ACE) inhibitors are important heart-protective drugs, particularly for people with diabetes and high blood pressure. They reduce the production of angiotensin, a chemical that causes arteries to narrow, and so are commonly used to lower blood pressure. They may also reduce risk for heart attack, stroke, complications of diabetes, and death in patients at high risk for heart disease.

ACE inhibitors include captopril (Capoten), ramipril (Altace), enalapril (Vasotec), quinapril (Accupril), benazepril (Lotensin), perindopril (Aceon), and lisinopril (Prinivil, Zestril).

Side Effects. Side effects of ACE inhibitors are uncommon but may include an irritating cough, excessive drops in blood pressure, and allergic reactions. In the past, doctors sometimes avoided giving aspirin to patients who were taking ACE inhibitors because the combination was believed to cause kidney problems. But, a 2005 study of patients with both coronary artery disease and heart failure found that taking aspirin and ACE inhibitord together is safe. The researchers also noted that taking aspirin with an ACE inhibitor can significantly reduce the risk of death for older patients with CAD and heart failure. [See In-Depth Report #14: High blood pressure.]

In 2004, the National Cholesterol Education Program issued updated recommendations on how to control cholesterol levels. These guidelines emphasize that patients should lower their LDL (“bad”) cholesterol and recommend that more people take LDL-lowering medication. Lowering LDL cholesterol and raising HDL (“good”) cholesterol can significantly reduce the risks of heart disease. Several different types of drugs (statins, bile-acid binding resins, niacin, and fibrates) are used to treat cholesterol. [See In-Depth Report #23: Cholesterol.]

Statins are the most important of these drugs. Brands include lovastatin (Mevacor), pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), atorvastatin (Lipitor), and rosuvastatin (Crestor). A major analysis of over 200 studies found that statins reduced the risk for heart problems by 60% and stroke by 17%. A 2005 review found that the more that statins lower LDL, the more they reduce CAD and other heart disease risks.

An important 2006 study found that aggressive treatment with statins may have the potential to reverse coronary artery disease. In the study, rosuvastatin reduced fatty plaque in the arteries in addition to improving LDL and HDL cholesterol levels. However, a follow-up 2007 study of rosuvastatin indicated that while the drug slowed the rate of atherosclerotic progression, it did not reverse heart disease. Future studies will continue to investigate this issue.

Side effects of statins may include stomach upset, headaches, skin rashes, muscle aches, sexual dysfunction, drowsiness, dizziness, nausea, constipation, and peripheral neuropathy (numbness or tingling in the hands and feet).

The main safety concern with statins is an uncommon condition called myopathy, which can cause muscle and joint pain and possible muscle damage. Doctors will immediately stop statin therapy if myopathy occurs. Patients should talk to their doctor about any unusual muscle discomfort or weakness, or if their urine becomes brown-colored. Statins can also affect the liver, particularly at higher doses, so patients taking these drugs should receive regular liver function tests.

Click the icon to see an image of cholesterol.

Influenza Vaccinations (Flu Shots). Evidence suggests influenza vaccinations help protect against adverse heart events (including after heart surgeries), stroke, and death from all causes in the elderly. Still, studies suggest that only two-thirds of at risk people are vaccinated, mostly because of unwarranted fears of ineffectiveness or adverse effects.

Antibiotics. Researchers have investigated antibiotics for treating patients with heart disease and past infection of the bacteria Chlamydia pneumoniae. Results from several recent large-scale clinical trials suggest that antibiotic treatment provides no benefit in preventing heart attack or other cardiac events in patients with coronary artery disease. In addition, a 2006 study indicated that short-term treatment with the antibiotic clarithromycin may increase the risk for death in patients with coronary artery disease. While it is still possible that C. pneumoniae may play a role in triggering inflammatory responses associated with ACS, antibiotic therapy is no longer considered appropriate for treatment or prevention of heart disease.

Ranolazine (Ranexa) was approved in 2006 for treatment of chronic angina. It is recommended for patients who have not responded to other angina drugs. Ranolazine is taken in combination with amlodipine, beta blockers, or nitrates. The drug appears to work better in men than in women

Gene Therapy and Angiogenesis. Proteins known as growth factors are being investigated for their ability to grow new blood vessels for supplying oxygen to the heart. After promising small trials, two large studies of genetically engineered forms of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF [GenerX]) failed to detect any benefits. Studies on therapies that actually genetically encode these proteins are underway.

Testosterone Supplements. Some trials using testosterone supplements or patches have reported improved exercise-induced blood flow in the coronary arteries and improvement in angina in some cases. Supplements of this male hormone, however, may increase the risk for prostate cancer. Experts suggest that testosterone be used only in older men with significant deficiencies in testosterone.

Selective Estrogen-Receptor Modulators (SERMs). Selective estrogen-receptor modulators (SERMs), including raloxifene (Evista), have been designed to produce the benefits of estrogen without its risks. They are thought to act like estrogen in some tissues but behave like estrogen blockers (antiestrogens) in others. Raloxifene may have some heart benefits, although it poses a risk for deep vein blood clots, which may have long-term implications for patients with heart problems. A major study is underway to determine its effects on the heart.

Surgery

Surgery is usually recommended for patients who have:

Unstable angina that does not respond promptly to medical treatment
Severe recurrent episodes of angina that last more than 20 minutes
Acute coronary syndrome
Severe coronary artery disease (severe angina, multi-artery involvement, evidence of ischemia), particularly if abnormalities are evident in the left ventricle of the heart, the main pumping chamber

Atherosclerosis is a disease of the arteries in which fatty material is deposited in the vessel wall, resulting in narrowing and eventual impairment of blood flow. Severely restricted blood flow in the arteries to the heart muscle leads to symptoms such as chest pain. Atherosclerosis shows no symptoms until a complication occurs.

Researchers have been investigating whether surgery offers any advantages if used as an early treatment for mild angina. A major analysis in 2003 reported that the use of angioplasty in patients with mild heart blockage did not reduce the risk for heart attack or death over the long term. A landmark 2007 study found that angioplasty was no better than drug therapy for preventing heart attack and stroke in patients with stable coronary artery disease. (For more information, see Angioplasty and Stents.)

Two effective surgical procedures for heart patients are:

Coronary artery bypass grafting (commonly called bypass or CABG)
Percutaneous coronary intervention (commonly called angioplasty or PCI), usually with coronary artery stent placement

Click the icon to see an image about bypass grafting.

Each of these procedures is described below.

Studies have generally reported similar survival rates with either procedure. There are some differences, however, and decision often depends on individual conditions. Patients considering surgery should discuss all options and risks with their doctor. No surgical procedure cures coronary artery disease, and patients must continue to rigorously maintain a healthy lifestyle and any necessary medications. For some patients, lifestyle changes and medications may be able to control the disease without surgery or angioplasty.

Considerations for Choosing Angioplasty with Stent Placement. Angioplasty has the following advantages for most patients. It is:

Less invasive than bypass. (Although a minimally invasive variation of bypass surgery may reduce this distinction.)
Less expensive than bypass. (Although the postoperative need for more medications and the high risk for repeat procedures to reopen the artery may reduce the long-term difference in cost between the two procedures.)
Life-saving emergency procedure for many patients with heart attacks. (The use of bypass after a heart attack has much higher mortality rates than when it is used electively and its use is controversial in heart attack patients.)

It has the following disadvantages:

The blood vessels can close up again (restenosis) so that patients require additional procedures. (New blood thinning drugs, coronary stent coatings, and radiation treatments may help to significantly reduce restenosis rates. However, there is also some indication that stents, especially drug-eluting stents, may increase the risk for blood clots.)
It is not as appropriate as bypass for many patients with angina (people with diabetes, elderly patients, or those with multi-vessel blockage). Increasingly, however, angioplasty is proving to be as safe and as effective as bypass in many high-risk patients. Patients should be sure to discuss with their doctors the relevant risks and benefits of angioplasty and bypass.

Considerations for Choosing Bypass. Bypass is usually the appropriate procedure in patients with high-risk conditions, such as:

Multi-vessel blockage. (In one report comparing surgery to angioplasty in patients with two or three blocked vessels, the mortality rate 1 year after bypass was 0.8% and after angioplasty was 2.5%. About 80% of patients in the study were men.)
Diabetes. (Bypass produces significantly higher survival rates in these patients. Some experts believe angioplasty should rarely, if ever, be used in this population.)
Being elderly.
Certain structural features, such as a left main artery narrowed by 50% or more or a very long diseased portion of the artery.

Considerations for Women. Studies have reported higher mortality rates in women than in men after any heart surgery. Some experts theorize that on average women may be older and sicker when they have a heart operation. A 2002 study, however, suggested that when women with acute coronary syndromes are given the same aggressive and early treatment as men are, their survival rates are equal or even better.

In addition to angioplasty and bypass procedures, a number of other procedures are available or under investigation for coronary artery disease. They include:

Atherectomy
Myocardial Laser Revascularization
Enhanced External Counterpulsation (EECP)

Coronary Artery Bypass Graft Surgery

Coronary artery bypass graft surgery (CABG) is a good alternative to angioplasty for many patients, but it is very invasive. The surgery involves the following processes:

Click the icon to see an animation about CABG.

The chest is opened, and the blood is rerouted through a lung-heart machine.
The heart is stopped during the procedure.
Large blood vessels supply the grafts, which are used to reroute the blood. The blood vessel grafts are transplanted in front of and beyond the blocked arteries, so the blood flows through the new vessels around the blockage.
The standard grafts now use arteries taken from the chest wall. Studies are reporting that with such grafts arteries remain open in 90% of cases after 15 years.
In general, patients with triple bypass procedures stay in the hospital for 5 days. Those with one-vessel bypass may be able to go home in 3 days.

Click the icon to see an illustrated series detailing a heart bypass surgery.

In spite of the invasive nature of this procedure, elective bypass procedures produce better long-term survival rates than angioplasty, particularly in patients with diabetes and multi-vessel blockage. Overall mortality rates after this procedure range from 1% to slightly over 2%. The risk for stroke or heart attack after a bypass operation ranges from 1.3 - 5%. Finding a surgeon who performs at least 100 of the procedures a year helps reduce the risk for complications.

Blood clots may form in the new graft, closing it up or narrowing the treated vessel over time. Therapy with aspirin and other anti-clotting drugs help keep the graft open and working properly. For long-term prevention of closure, as well as for slowing progression of atherosclerosis, aggressive treatment with cholesterol-lowering drugs may be more beneficial than standard anti-clotting drugs.

Bleeding is also a potential complication of CABG. Anti-bleeding (also called hemorrhage-sparing) drugs are sometimes used to limit blood loss in patients who undergo this surgery. In 2006, concerns were raised about one of these drugs, aprotinin (Trasylol). Data suggested that aprotinin seriously increased the risks for kidney failure, heart failure, and stroke.

An important study, published in 2007 in the Journal of the American Medical Association, compared aprotinin with two anti-fibrinolytic drugs, aminocaproic acid (Amicar) and tranexamic acid (Cyklokapron), which are also used to control blood loss. The study of nearly 4,000 patients who had CABG found that over a 5-year period, the death rate for patients who took aprotinin was 21%, and patients had a 48% increased risk of dying. By comparison, the death rate was 16% for aminocaproic acid, 15% for tranexamic acid, and 13% for no anti-bleeding drug. Because aprotinin is more expensive as well as potentially more dangerous than other anti-bleeding drugs, experts are now recommending against its use in CABG.

Minimally invasive bypass (also called buttonhole or keyhole bypass) surgeries are exciting advances in basic bypass surgery. Studies indicate good success of these procedures for patients with disease in single vessels. They are also being investigated for multiple vessels.

One variation of minimally invasive bypass uses a four-inch incision. The surgeon works on the front of the heart while it is beating slowly. To date, there have been no differences in cardiac events or later mental complications between this so-called off-pump procedure and the standard bypass procedure.
In another variation, the heart is stopped, and the patient is put on a machine that reroutes the blood through a device that keeps it oxygenated. Fiberoptic scopes and instruments are passed through a number of finger-sized incisions. The surgeon works on all sides of the heart, guided by a video image from a tiny camera inserted through a 4-inch incision.
Some advanced heart centers now use robotic systems, which allow the surgeon to perform extremely delicate maneuvers on tiny vessels through pencil-size incisions. They are not yet used for the whole bypass process.

Eventually, minimally invasive bypass procedures may prove to be less expensive, require a shorter hospital stay, and have fewer complications than conventional coronary artery bypass surgery -- or even angioplasty. At this time, however, they are experimental procedures, performed in only a few medical centers for select candidates. Long term-success rates are unknown.

Angioplasty and Stents

Percutaneous coronary intervention (PCI), also called angioplasty, involves procedures such as percutaneous transluminal coronary angioplasty (PTCA) that help open the blocked artery.

Click the icon to see an animation about percutaneous transluminal coronary angioplasty.

A typical angioplasty procedure follows these steps:

The cardiologist threads a narrow catheter (a tube) containing a catheter into the blocked vessel.
The doctor opens the blocked vessel using balloon angioplasty, in which the surgeon passes a tiny deflated balloon through the catheter to the vessel.
The balloon is inflated to compress the plaque against the walls of the artery, flattening it out so that blood can once again flow through the blood vessel freely.
In order to keep the artery open afterwards, surgeons use a device called a coronary stent, an expandable metal mesh tube that is implanted during angioplasty at the site of the blockage. (In some cases, a stent may be used as the initial opening device instead of balloon angioplasty.)
Once in place, the stent pushes against the wall of the artery to keep it open.

Click the icon to see an animation about percutaneous transluminal coronary angioplasty.

Complications occur in about 10% of patients (about 80% within the first day). Outcomes are better in hospital settings with experienced teams and backup.

Click the icon to see an illustrated series detailing coronary artery balloon angioplasty surgery.

The most important long-term complication is reclosure (restenosis), which can lead to heart attack if not treated with a repeat procedure. Stenting and other advances have helped significantly in preventing reclosure and reducing heart attack rates. Nevertheless, a repeat procedure is still needed to restore the opening in 10 - 15% of procedures that use stents.

PCI (angioplasty) has been proven to help reduce the frequency of angina attacks. It is commonly recommended for patients who have critically blocked arteries or have already had a recent, acute heart attack. PCI can also help improve survival and prevent heart attacks in patients with acute coronary syndrome (ACS). However, doctors have been uncertain about angioplasty’s benefits for survival and heart attack prevention in lower-risk patients with stable coronary artery disease.

In 2007, a landmark study was published in the New England Journal of Medicine and presented at the 2007 meeting of the American College of Cardiology. The COURAGE study found that PCI works no better than standard heart medication (drugs to control blood pressure, lower cholesterol, and prevent blood clots) in preventing heart attack, stroke, and hospitalization in patients with stable coronary artery disease. Based on this study’s findings, experts are now recommending angioplasty only for patients who have severe heart disease. For patients with stable heart disease, drug therapy may be sufficient enough treatment and allow them to safely defer having surgery.

Angioplasty is less invasive than bypass surgery, requiring only one night in the hospital. Recuperation takes about a week. Chest pain after the procedure is very common and usually due to problems other than ischemia. Mild chest pain is even more common when a stent is used, possibly because the artery is stretched.

Reclosure of the artery during or shortly after angioplasty often occurs. A number of anti-clotting drugs are used to help prevent this.

Aspirin and the anti-platelet drug clopidogrel (Plavix) are often used to prevent reclosure during the procedure.
A high dose of the anticoagulant heparin is typically given before the operation.
Intravenous glycoprotein IIb/IIIa inhibitors, powerful drugs that block platelets, also prevent reclosure after stenting in many high-risk patients, and evidence now strongly suggests that they reduce rates of heart attack and death. Eptifibatide (Integrilin) and tirofiban (Aggrastat) are the standard drugs used during angioplasty. They may be most effective if administered during angioplasty, rather than beforehand.

All of these drugs pose a risk for bleeding complications.

Narrowing or reclosing of the artery (restenosis) can occur within a year of angioplasty or even longer in 15 - 60% of angioplasty patients. Coronary stents, anti-clotting drugs, and other advances have reduced these events significantly, but have not eliminated the problem. Theories for the cause of restenosis include:

The release of oxidants (damaging unstable particles) at the surgical site may cause injury and activate immune factors that produce cellular overgrowth in smooth muscles of the blood vessels.
Other activities, including scarring, may remodel and narrow the blood vessels. (This is most likely the reason for restenosis in patients with stents.)

Symptoms of restenosis include chest pain on exertion. (Heart attacks, however, do not usually occur with such events.) The narrowing of the artery in this case is not due to blood clots, so anti-clotting drugs are not useful. Restenosis usually requires a repeat operation. A number of approaches, mostly investigative, have been developed to prevent restenosis after angioplasty.

Drug-Coated Stents. Stents coated with the drugs sirolimus (Rapamune) or paclitaxel (Taxol) have been increasingly used in the last several years. Drug-eluting stents (as they are also called) can help prevent restenosis. However, because drug-eluting stents reduce arterial tissue growth, they can increase the risks of blood clots. In late 2006, the FDA held several meetings to discuss the increased risks of blood clots associated with drug-eluting stents. The committees found that drug-eluting stents do appear to have a small increased risk of blood clots compared to bare metal stents, but not enough research has been conducted to fully determine their risks for heart attack and death.

Five studies published in the New England Journal of Medicine in March 2007 indicated that drug-eluting stents are safe and effective for patients with coronary artery disease when they are used for FDA-approved indications. Problems have arisen when these stents are used for “off-label” purposes in patients with more complicated health problems. There is still some concern as to whether all stents (both bare metal and drug eluting) are used too frequently for patients who may be better served by drugs or bypass surgery.

In February 2007, the American Heart Association and other professional organization issued an extremely important joint advisory statement. The statement advises that all patients who have drug-eluting stents must continue to take aspirin and clopidogrel (or, rarely, ticlopidine) for at least 1 year after the stent is inserted to reduce the risk of blood clots. Clopidogrel and ticlopidine are thienopyridine drugs that, like aspirin, help prevent blood platelets from clumping together. It is very important that patients who have drug-eluting stents take both aspirin and a thienopyridine drug. If for some reason patients cannot take a thienopyridine drug, they should receive a bare metal stent instead of a drug-eluting stent.

Coronary Artery Brachytherapy. Radiation treatment called coronary artery brachytherapy (Gamma One, Beta-Cath) can slow the cell growth in the arteries that causes restenosis. With this approach, any blockage in the stent is first removed, and a tube with an inflatable balloon is inserted. The surgeon then implants a temporary device that delivers radiation. Brachytherapy has shown excellent results in preventing restenosis and significantly reducing heart events and improving survival. Brachytherapy is also showing promise in preventing restenosis in stented artery grafts that were put in place after bypass surgery and later failed. However, several 2006 studies in the Journal of the American Medical Association indicated that drug-coated stents may work better than brachytherapy in preventing restenosis in failed stents. In these studies, the drug-coated stents were inserted inside the original bare metal stents.

Medications. A number of medications are being studied for prevention of restenosis, although benefits to date have been modest. Other drugs under investigation include statins, various anti-clotting drugs, and B vitamins.

Other Procedures. Other procedures under investigation to keep the arteries open use ultrasound, "soft" x-rays, and cryotherapy (very low temperatures).

Other Treatments

Transmyocardial laser revascularization (TMLR) applies laser energy directly to areas in the heart where blockage has occurred, creating 10 - 50 tiny channels. TMLR is recommended for patients with severe angina who have not responded to surgical bypass or angioplasty procedures. TMLR is not suitable for patients who have severely damaged heart muscles. A variant called percutaneous transmyocardial laser revascularization uses a small laser (a holmium YAG laser), which is smaller than the device used in TMLR and does not require open chest surgery and a general anesthetic.

Patients report improved symptoms and exercise tolerance. Both procedures carry risks for serious complications, however, including some that can be life-threatening. It is not clear if either TMLR procedure improves survival, and, in one study, the quality of life afterwards was less than with standard heart surgeries.

A noninvasive technique called enhanced external counterpulsation (EECP) has been used successfully by over a million people in China. The technique uses an air pump that inflates and deflates pressurized cuffs around the legs, causing blood to be pushed into the heart.

EECP may help patients with angina who have not had pain relief from nitrate drugs and who do not qualify as candidates for bypass or angioplasty. In different studies, it has relieved angina in over 75% of patients who used it and reduced the need for medication. The benefits persist, and there is some evidence that it produces actual cellular changes that benefit the heart. In 2002, the FDA approved EECP for the treatment of heart failure but some insurance companies still consider its use “experimental” and will not pay for it. EECP is not recommended for patients with arrhythmia, serious heart valve problems, or peripheral artery disease.

Atherectomy procedures clear the narrowed arteries by using an approach called debulking. All of these procedures use a catheter (a thin tube) that is inserted into an artery (usually in the groin) and threaded up to the blockage. Devices are inserted through the tube to remove the plaque. They include:

Rotational atherectomy, which uses a tiny cutter spinning at 2,500 rpm
Extractional atherectomy, which "shaves" the plaque
Directional atherectomy, which slices the plaques

Although they are successful in opening arteries, they offer no advantages over standard angioplasty and are used only for special cases.

Resources

www.nhlbi.nih.gov -- National Heart, Lung, and Blood Institute
www.americanheart.org -- American Heart Association
www.acc.org -- American College of Cardiology

References

Boden WE, O'Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, et al. Optimalmedical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007 Mar 26; [Epub ahead of print]

Crouse JR 3rd, Raichlen JS, Riley WA, Evans GW, Palmer MK, O'Leary DH, et al. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. JAMA. 2007 Mar 28;297(12):1344-53. Epub 2007 Mar 25.

Eisenstein EL, Anstrom KJ, Kong DF, Shaw LK, Tuttle RH, Mark DB, et al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA. 2007 Jan 10;297(2):159-68. Epub 2006 Dec 5.

Folsom AR, Chambless LE, Ballantyne CM, Coresh J, Heiss G, Wu KK, et al. An assessment of incremental coronary risk prediction using C-reactive protein and other novel risk markers: the atherosclerosis risk in communities study. Arch Intern Med. 2006 Jul 10;166(13):1368-73.

Garcia MJ, Lessick J, Hoffmann MH; CATSCAN Study Investigators. Accuracy of 16-row multidetector computed tomography for the assessment of coronary artery stenosis. JAMA. 2006 Jul 26;296(4):403-11.

Grines CL, Bonow RO, Casey DE Jr, Gardner TJ, Lockhart PB, Moliterno DJ, et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Circulation. 2007 Feb 13;115(6):813-8. Epub 2007 Jan 15.

Kastrati A, Mehilli J, Pache J, Kaiser C, Valgimigli M, Kelbaek H, et al. Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med. 2007 Mar 8;356(10):1030-9. Epub 2007 Feb 12.

Lagerqvist B, James SK, Stenestrand U, Lindback J, Nilsson T, Wallentin L; SCAAR Study Group. Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden. N Engl J Med. 2007 Mar 8;356(10):1009-19. Epub 2007 Feb 12.

Lloyd-Jones DM, Liu K, Tian L, Greenland P. Narrative review: Assessment of C-reactive protein in risk prediction for cardiovascular disease. Ann Intern Med. 2006 Jul 4;145(1):35-42.

Maisel WH. Unanswered questions--drug-eluting stents and the risk of late thrombosis. N Engl J Med. 2007 Mar 8;356(10):981-4. Epub 2007 Feb 12.

Mangano DT, Miao Y, Vuylsteke A, Tudor IC, Juneja R, Filipescu D, et al. Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery. JAMA. 2007 Feb 7;297(5):471-9.

Mangano DT, Tudor IC, Dietzel C; Multicenter Study of Perioperative Ischemia Research Group; Ischemia Research and Education Foundation. The risk associated with aprotinin in cardiac surgery. N Engl J Med. 2006 Jan 26;354(4):353-65.

Mauri L, Hsieh WH, Massaro JM, Ho KK, D'Agostino R, Cutlip DE. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med. 2007 Mar 8;356(10):1020-9. Epub 2007 Feb 12.

Mosca L, Banka CL, Benjamin EJ, Berra K, Bushnell C, Dolor RJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation. 2007 Mar 20;115(11):1481-501.

Nicholls SJ, Tuzcu EM, Sipahi I, Grasso AW, Schoenhagen P, Hu T, et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA. 2007 Feb 7;297(5):499-508.

Rosamond W, Flegal K, Friday G, Furie K, Go A, Greenlund K, et al. Heart disease and stroke statistics--2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007 Feb 6;115(5):e69-171. Epub 2006 Dec 28.

Spaulding C, Daemen J, Boersma E, Cutlip DE, Serruys PW. A pooled analysis of data comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med. 2007 Mar 8;356(10):989-97. Epub 2007 Feb 12.

Stewart JC, Janicki DL, Muldoon MF, Sutton-Tyrrell K, Kamarck TW. Negative emotions and 3-year progression of subclinical atherosclerosis. Arch Gen Psychiatry. 2007 Feb;64(2):225-33.

Stone GW, Moses JW, Ellis SG, Schofer J, Dawkins KD, Morice MC, et al. Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents. N Engl J Med. 2007 Mar 8;356(10):998-1008. Epub 2007 Feb 12.

Wang TJ, Gona P, Larson MG, Tofler GH, Levy D, Newton-Cheh C, et al. Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med. 2006 Dec 21;355(25):2631-9.

Review Date:
4/16/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Parkinson's disease

FitSugar — Wed, 08 Oct 2008 17:35:13 -0700

In This Report

Highlights
Introduction
Symptoms
Risk Factors
Complications
Diagnosis
Treatment
Levadopa (L-dopa)
Other Medications
Surgery
Lifestyle Changes
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Approvals

In 2007, the FDA approved the first skin patch drug for treatment of Parkinson’s disease. Transdermal rotigotine (Neupro) is a dopamine agonist drug that may help improve symptoms of early-stage Parkinson’s disease. The patch is applied daily.
Rivastigimine (Exelon), an Alzheimer’s disease drug, was approved in 2006 for treatment of mild-to-moderate dementia associated with Parkinson’s disease.

Drug Withdrawal

In 2007, the FDA withdrew the dopamine agonist pergolide (Permax) from the market due to safety concerns. Several articles published in 2007 in the New England Journal of Medicine indicated that pergolide and a similar drug, cabergoline (Dostinex), are associated with heart valve problems. Cabergoline is not approved in the U.S. for treatment of Parkinson’s disease.

Dietary Supplements

In 2007, the U.S. National Institutes of Health launched a large-scale clinical trial to study whether creatine may help slow the progression of Parkinson’s disease. Creatine is a nutritional supplement that is sometimes used to enhance exercise performance.
Coenzyme Q10, an antioxidant dietary supplement, does not help improve Parkinson’s disease symptoms, according to a study published in 2007 in the Archives of Neurology.

Deep-Brain Stimulation

Deep-brain stimulation outperformed drug therapy in a randomized trial comparing these two treatment approaches. In a study published in 2006 in the New England Journal of Medicine, patients who received deep-brain stimulation had better symptom and quality of life improvement than those who were treated with only medications. However, more serious side effects were reported in the deep-brain stimulation group. Deep-brain stimulation is a surgical technique that involves implanting electrodes in a target area of the brain.

Introduction

Parkinson's disease (PD) is a slowly progressive disorder that affects movement, muscle control, and balance. Parkinson's disease is referred to as idiopathic, which means that the cause is unknown. This term distinguishes the primary disease from parkinsonism, which are the symptoms occurring from a known cause. In addition to its effects on motor control, Parkinson's disease is now recognized as a broader condition that can include cognitive and behavioral disturbances, sleep disorders, speech difficulties, and other problems.

Parkinson's disease occurs from the following process in the brain:

PD develops as cells are destroyed in certain parts of the brain stem, particularly the crescent-shaped cell mass known as the substantia nigra.

Nerve cells in the substantia nigra send out fibers to the corpus stratia, gray and white bands of tissue located in both sides of the brain.
There the cells release dopamine, an essential neurotransmitter (a chemical messenger in the brain). Loss of dopamine in the corpus stratia is the primary defect in Parkinson's disease.

Dopamine. Dopamine deficiency is the hallmark feature in PD. It is one of three major neurotransmitters known as catecholamines, which help the body respond to stress and prepare it for the fight-or-flight response. Loss of dopamine negatively affects the nerves and muscles controlling movement and coordination, resulting in the major symptoms characteristic of Parkinson's disease. Dopamine also appears to be important for efficient information processing, and deficiencies may also be responsible for problems in memory and concentration that occur in many patients.

Although it is clear that dopamine deficiency is the primary defect in Parkinson's disease, it is not clear what causes dopamine loss. The culprit is less likely to be a single cause than a combination of genetic and biologic factors, which are triggered by some environmental assault.

Other Changes. The PD disease process also appears to impair nerve endings in the heart to cause dysautonomia-- changes in the autonomic (also called sympathetic) nervous system. Such changes may impair the release of norepinephrine, a hormone that regulates blood pressure, pulse rate, perspiration, and other automatic responses to stress. Evidence suggests this may be responsible for the abrupt drops in blood pressure when standing that occur in PD. Further research is underway to determine if the loss of nerve terminals is confined to the heart or if it affects other organs as well.

Click the icon to see an animation about Parkinson's disease.

Apoptosis and Alpha Synuclein. Important research now suggests that three molecules are critical in the development of inherited PD: alpha synuclein, parkin, and ubiquitin, which all interact in the normal brain. Abnormally high levels of alpha synuclein, which is produced in dopamine-rich nerve cells, may play a central role. Normally, two other molecules, parkin and ubiquitin, are involved in the natural self-destruction of synuclein -- a natural process of programmed cell death called apoptosis. If this process goes awry, for instance, with a defective parkin gene, cell death fails to occur. If synuclein is not eliminated in these cells, it builds up and becomes toxic to dopamine. In such cases, synuclein accumulates in Lewy bodies, the deposits of fibrous tissue found in all patients with PD.

Another protein, beta amyloid, also increases the build-up of synuclein. Beta amyloid is a known factor in Alzheimer's disease, and may help explain the co-existence between Alzheimer's and Parkinson's disease in many patients.

Lewy Bodies. The fibrous deposits known as Lewy bodies are the hallmark signs of Parkinson's disease. They are found in the substantia nigra, the place in the brain where dopamine is first released. It is not clear whether Lewy bodies are the major killers of the nerve cells or whether they are simply a byproduct of the degenerative process. They are found not only in the brains of patients with Parkinson's disease but, in rare cases, may show up in cells in other parts of the body (the heart, intestine), causing severe disabling symptoms. These substances are also present in other diseases that cause dementia, such as Alzheimer's, and can occur in people without neurologic symptoms.

The Mitochondria and Oxygen-Free Radicals. Some research has observed that certain patients with PD have significantly low levels of complex I, an enzyme found in the mitochondria, sausage-like structures that are the primary source of energy within cells. Some theories suggest that low amounts of complex I may make nerve cells vulnerable to the assault of oxygen free radicals (also called oxidants). Oxidants are unstable molecules that bind to other molecules in the body. They are normally produced by the natural chemical processes in the body. If the body is subjected to environmental stresses, however, they can be over-produced. In excess, they can damage any cell, including nerve cells in the brain, and even interfere with their DNA.

NMDA Receptors. Also of interest in PD are processes that occur in an area of the brain called the subthalamic nucleus. Here, receptors known as glutamatergic N-methyl-D-aspartate (NMDA) become persistently overexcited and produce high levels of calcium ions within brain cells. This in turn leads to a cascade of events that trigger oxygen-free radicals and cell damage.

Immune Factors and the Inflammatory Response. An over-responsive immune system triggered by initial damage may also play a role in perpetuating Parkinson's disease. When the immune system becomes overactive, it produces excessive numbers of potent factors called cytokines, which cause inflammation and further injury in brain cells. Important cytokines under investigation are interleukin-1 and tumor necrosis factor.

Specific genetic factors appear to play a strong role in early-onset Parkinson's disease, an uncommon form of the disease. Research from the last several years suggests that multiple genetic factors may also be involved in late-onset Parkinson’s disease. Several important studies, published in 2005, lay the groundwork for potential genetic screening for this disease. Researchers identified the leukine-rich repeat kinase 2 (LRRK2) gene, located on a region of chromosome 12 known as PARK8, as a key gene involved in inherited forms of Parkinson’s. The researchers estimate that a single gene mutation in LRRK2 may be responsible for 5% of inherited Parkinson’s cases and about 2% of isolated cases.

Early Onset PD. The cases of genetic early-onset Parkinson's disease have most often been detected in specific family groups.

Defective genes that regulate the molecules alpha synuclein and parkin, which are important in the PD disease process, may be responsible for a number of early-onset cases. For example, genetic abnormalities the alpha synuclein protein have been detected in some early-onset Parkinson's patients of European descent.
The parkin gene may be the cause of many cases of early-onset Parkinson's in young adults. (Parkinson's cases associated with this mutation tend to progress slowly and respond well to treatment, even after years of symptoms. Dementia is also rare with this form.)

Late Onset PD. Two landmark studies published in the Journal of the American Medical Association provided the first evidence of a genetic link to late-onset Parkinson’s disease. In these 2001 studies, researchers found that regions on chromosomes 5, 6, 8, 9, and 17 were implicated with Parkinson’s. The parkin gene (located on chromosome 6) and the tau gene (located on chromosome 17) were both found in families that had late onset Parkinson’s. Parkin was previously thought to be responsible only for early-onset Parkinson’s, but this research identified it in families that had both early- and late-onset disease forms. These studies also bolstered the theory that Parkinson’s does have a genetic component and is not caused solely by environmental factors. A 2005 study found that a G2019S mutation in the LRRK gene, located on the PARK8 region of chromosome 12, was definitively associated with late-onset Parkinson’s disease in North American and European families.

Environmental toxins, infections, and other triggers can provoke excessive production in the body of oxygen free-radicals, damaging particles that may play a major role in the deterioration of nerve cells that lead to Parkinson's.

Infectious Organisms. Some research has identified immune factors that suggest a viral presence in the Lewy bodies and swollen nerve pathways of Parkinson's brains. Influenza and other potent viruses have long been known to be a cause of parkinsonism. In one well-known example, a major flu epidemic causing encephalitis in the early twentieth century left many of its victims with parkinsonism.

Environmental and Industrial Chemicals. Intense exposure to certain environmental and industrial chemicals is also being studied.

Pesticides and Herbicides. Some evidence implicates pesticides and herbicides as important factors in many cases of Parkinson's disease. A higher incidence of parkinsonism has long been noted in people who live in rural areas, particularly those who drink private well water or are agricultural workers. A large 2000 study found a strong link between high exposure to insecticides and herbicides at home and a 50 - 70% increase in risk of Parkinson's.
Other Chemicals. Intense exposure to other industrial chemicals and metals (manganese, copper, lead, iron, mercury, zinc, aluminum, and others) has also been linked with parkinsonism, a cause that is often reversible. The role of long-term exposure in the development of Parkinson's disease is unclear. High levels of iron content observed in critical parts of the brain in PD are under particular scrutiny.

Most, but not all, Parkinson's victims are elderly. Some studies indicate that the very elderly are not susceptible to the disease, indicating that the aging process itself is not the major player in the disease. Aging does appear to reduce the concentration of dopamine in structures called dopamine transporters, which carry the neurotransmitter back and forth between nerve cells. Some researchers posit that any excessive stress on these transporters might trigger Parkinson's disease in the aging, and more vulnerable, brain.

Symptoms

Parkinson's disease (PD) symptoms often start with tremor, which may occur in the following ways:

Tremors may first be only occasional, starting in one finger and spreading over time to involve the whole arm. The tremor is often rhythmic, 4 - 5 cycles per second, and frequently causes an action of the thumb and fingers known as pill rolling.
Tremors can occur when the limb is at rest or when it is held up in a stiff unsupported position. They usually disappear briefly during movement and do not occur during sleep.
Tremors can also eventually occur in the head, lips, tongue, and feet. Symptoms can occur on one or both sides of the body. In one study, 44% of patients reported experiencing internal tremors lasting less than half an hour, but occurring several times a week.

In younger patients tremor is usually predominant and often suggests a less aggressive form of the disease. Some evidence suggests that tremor in PD may occur from mechanisms in the brain that are different from those that cause other PD symptoms.

A number of PD symptoms involve motor impairment caused by the abnormalities in the brain that regulate movement:

Slowness of motion (bradykinesia) is one of the classic symptoms of Parkinson's disease. Patients may eventually develop a stooped posture and a slow, shuffling walk. The gait can be erratic and unsteady. After a number of years, muscles may freeze up or stall, usually when a patient is making a turn or passing through narrow spaces, such as a doorway.
Intestinal motility (the ability to swallow, digest, and eliminate) may slow down, causing eating problems and constipation.
Muscles may become rigid (akinesia). This symptom often begins in the legs and neck. Muscle rigidity in the face can produce a mask-like, staring appearance.
Motor abnormalities that limit action in the hand may develop in late stages. Handwriting, for instance, often becomes diminutive.
Normally spontaneous muscle movements, such as blinking, may need to be done consciously.

The traditional view of Parkinson's disease is shifting to reflect growing awareness that it is much more than a motor disease. Many non-motor components and their treatments are now under study. The following symptoms should be carefully monitored by doctors and caregivers:

Depression is the most common psychiatric problem associated with PD, affecting about 40% of patients. Because depression is a common problem in older people, it is likely not to be recognized as a symptom.
Anxiety affects about 30% of patients.
Dementia and paranoia are more common than previously understood.
Orthostatic hypotension -- some patients experience a sudden drop in blood pressure when they stand. This can cause dizziness and fainting.
Changes in sensations of temperature, hot flashes, and excessive sweating.
Daytime sleepiness and other sleep disorders are common.

Risk Factors

Parkinson's disease affects about 3% of Americans over 65 years old. Experts estimate that this percentage could double in the next 30 - 40 years. The symptoms of parkinsonism (tremor, gait disturbance, bradykinesia, and rigidity) occur in even more people, estimated to be 8 million over age 65. In a study that included very mild symptoms, parkinsonism occurred in about 15% of people 65 - 74 years of age, about 30% in those 75 - 84, and over half of people older than age 85.

The average age of onset of Parkinson's disease is 55. About 10% of Parkinson's cases are in people younger than 40 years old. Older adults are at higher risk for both parkinsonism and Parkinson's disease. There is some evidence, however, that the risk declines significantly after age 75 and that the very elderly are at low risk.

Some research indicates that men may face up to twice the risk as women. Estrogen may offer some protection for women up until menopause. A 2001 study, for example, reported a higher rate of Parkinson's disease in women who had undergone hysterectomy. Other studies suggest that the disease also progresses more rapidly in men than women. Older women seem to be more at risk for gait disturbance and men for rigidity and tremor.

People with siblings or parents who developed Parkinson's at a younger age are at higher risk for Parkinson's disease, but relatives of those who were elderly when they had the disease appear to have an average risk.

African- and Asian-Americans have a lower risk than Caucasians. Some evidence suggests that non-Caucasians may be more vulnerable to an atypical form of PD, which causes early impairment in thinking and has a poor response to levodopa, the primary PD treatment.

Increasing weight gain in middle age was associated with a higher risk of PD in a 2002 study.

Complications

Parkinson's disease (PD) is not fatal, but it can reduce longevity. The disease progresses more quickly in older than younger patients, and may lead to severe incapacity within 10 - 20 years. Older patients also tend to experience freezing and greater declines in mental function and daily functioning than younger people. If PD starts without signs of tremor, it is likely to be more severe than if tremor had been present. Having other family members with PD does not appear to have any effect on the severity of the disease.

Parkinson's disease can seriously impair the quality of life in any age group. The physical and emotional impact on the family should not be underestimated as the patient becomes increasingly dependent on their support.

Treatment advances are increasingly effective in alleviating symptoms and even slowing progression of the disease. Taking many of the medications over time, however, can produce significant side effects. Newer drugs may help reduce these occurrences.

The negative effect of overall motor and muscle impairment on daily life can be considerable. Some motor complications can be life-threatening.

Disturbed gait and unstable posture are common and serious problems in elderly patients, since they increase the risk for falling and injury. Some studies have suggested that the appearance of these symptoms early in the course of the disease predict a faster decline than having tremor as the predominant symptom.
Swallowing problems (dysphagia). The presence of dysphagia is associated with shorter survival time. Motor impairment of the muscles in the throat not only impairs swallowing but it also poses a risk for aspiration pneumonia.
Constipation is a major problem and occurs both as a result of the disease and a side effect of its treatment. Laxatives, stool softeners, and other medications may be prescribed.
Bladder control and urinary incontinence are also important complications of PD.
Speech problems occur in more than 70% of patients, by some estimates. Speech difficulty can be caused by rigidity of the facial muscles, loss of motor control, and impaired breath control. Tone can become monotonous, words may be repeated over and over, or the rate of speech may even be very fast.

Depression is extremely common, affecting up to 40% of patients with Parkinson's. PD poses multiple threats on the emotional health:

The disease process itself causes changes in chemicals in the brain that affect mood and well-being.
The complications of its symptoms have a profound impact on daily life that can be emotionally devastating without help and support.
Some drug treatments (levodopa combined with a dopamine agonist) can cause compulsive behavior, such as gambling, shopping, and increased sexuality. Patients who have pre-existing tendencies to novelty-seeking behavior, or a family or personal history of alcohol abuse, may be more likely to develop compulsive gambling. Deep brain stimulus (DBS) surgery may also increase the risk for compulsive gambling in patients who have a history of gambling.

Impaired Thinking (Cognitive Impairment). Defects in thinking, memory, language, and problem solving skills may occur early on in untreated patients or late in the course of the disease. Medications may play a role in thinking problems. In one study, for example, patients with PD were slower in detecting associations, although (unlike in Alzheimer's disease) once they discovered them they were able to apply this knowledge to other concepts. After they were taken off medication, however, they had no problems with the tasks.

Dementia. Dementia is three to six times more common in the elderly Parkinson patient than in the average older adult. It is most likely to occur in older patients who have had major depression. PD marked by muscle rigidity (akinesia), rather than tremor, and early hallucinations also increase the risk for dementia. (Visual hallucinations can also occur in about a third of patients from PD medication.) Unlike in Alzheimer's, language is not usually affected in Parkinson's related dementia.

A number of other problems associated with Parkinson's disease affect daily life:

Vision Problems. Vision is also affected, including impaired color perception and contrast sensitivity. These problems progress and can impair motor functioning.

Sleep Disorders. Excessive daytime sleepiness and other sleep disorders are common in PD, both from the disease itself and from the drugs that treat it. In general, patients have a 25% higher risk for daytime sleepiness, including suddenly falling asleep, than patients with other neurologic diseases.

Restless legs syndrome, an irresistible urge to move the calves, which often occurs at night, affects many patients. However, Parkinson's disease itself does not seem to increase the risk for RLS. Nor does RLS early in life predispose to Parkinson's later on. The common connection between RLS and Parkinson's disease may derive from iron deficiencies that can play a role in both conditions.

Many patients also suffer from nighttime leg cramps. And, some of the medications cause vivid dreams as well as waking hallucinations.

Impaired Sexuality. Although Parkinson's disease and its treatments can cause compulsive sexual behavior, the disease can also affect patients' self-esteem and inhibit sexuality. This is an area not often studied but which is important for many patients' well-being. A 2000 study reported that not only did sexual dysfunction occur, but also affectionate touching and expression of feelings were reduced, even though both partners maintained a desire for intimacy.

Worsened Sense of Smell. The sense of smell is impaired in about 70% of patients.

Osteoporosis. Parkinson’s disease may increase the risk for low bone density and osteoporosis. Both men and women are at risk. Experts recommend that patients with Parkinson’s disease get tested for osteoporosis, especially if they have problems with walking.

Diagnosis

It is difficult to diagnose Parkinson's in early stages. The disease is primarily diagnosed by its symptoms, and studies indicate that doctors make an incorrect initial diagnosis of Parkinson's disease in 8 - 35% of cases. Even neurologists have difficulties in correctly identifying the disease.

A medical and personal history should include any relevant symptoms as well as any medications taken, and information on exposure to environmental toxins.

Early Symptoms. Early treatment may help slow progression, so an early diagnosis of Parkinson's is highly desirable. Early symptoms are often mild, however, so Parkinson's disease can be missed, particularly in young adults. Repeated assessment of symptoms over time is important for improving the accuracy of diagnosis. Too often a younger person with Parkinson's may be diagnosed with mental illness, because the doctor associates the disease only with older people.

Parkinson's may be suspected in patients with the following symptoms:

Slowness and difficulty of movement. These are usually the first symptoms. The patient will be asked to walk and to get out of a chair, preferably a deep one. Early gait disturbance, however, often indicates a disease other than Parkinson's disease.
A tremor when their limb is relaxed. (As many as 25% of patients, however, will not have a tremor.)
Symptoms on one side of the body.

Later Symptoms. In later stages of Parkinson's disease, the symptoms are usually unmistakable, and the problem can often be diagnosed using simple physical tests and a medical and personal history.

The loss of smell is associated with loss of dopamine receptors in the brain. “Scratch and sniff” smell tests can help a doctor diagnose Parkinson’s disease. Smell tests can help differentiate Parkinson’s disease from other conditions with similar symptoms. Some patients with a very similar condition called multiple system atrophy will have a good initial response to levodopa, but it is not usually sustained.

Levodopa and apomorphine can confirm a diagnosis of Parkinson’s disease. If patients’ symptoms improve when they take these drugs, they likely have Parkinson’s, ruling out other neurological diseases.

According to 2006 guidelines from the American Academy of Neurology, there is not enough evidence to recommend for or against the use of imaging techniques such as computerized tomography (CT), magnetic resonance imaging (MRI), or positron-emission tomographic (PET) to diagnose PD.

When symptoms resemble Parkinson's disease but have an identifiable cause, the syndrome is known as parkinsonism. People who have parkinsonism, but not Parkinson's disease, often have additional neurologic symptoms. A number of conditions can also have similar or some of these symptoms.

Other Neurologic Conditions. Many medical conditions may cause symptoms of Parkinson's disease:

Hardening of the arteries (arteriosclerosis) in the brain can cause multiple small strokes, which can produce loss of motor control.

Click the icon to see an image of plaque in an artery.

Alzheimer's disease can be very similar. In one study 23% of people with Alzheimer's also met the criteria for Parkinson's disease. The two diseases often coexist, and research suggests that Alzheimer's and Parkinson's disease may sometimes share a common biologic origin, the accumulation of the protein alpha synuclein and Lewy bodies in the brain.
Lewy bodies variant (LBV), also called dementia with Lewy bodies, is a separate disease from both Alzheimer's and Parkinson's disease. It has similar symptoms to both but is marked by early dementia.
Encephalitis caused by influenza has been known to cause parkinsonism.
Primary progressive freezing gait is a progression condition, in which freezing gait occurs at the onset. Other Parkinson-like features, such as slow movement, often develop. Although very similar to PD, this condition does not respond to L-dopa or other PD medications.
Essential tremor, unlike the tremor of Parkinson's disease, often occurs in the head and voice and is usually worse during motion, as opposed to rest.
Progressive supranuclear palsy has similar symptoms, but involves less tremor and earlier rigidity, and it tends to affect both sides of the body symmetrically. Magnetic resonance imaging scans that measure parts of the midbrain may be a reliable method for distinguishing between PD and progressive supranuclear palsy.
Multiple system atrophy (previously called Shy-Drager syndrome) is a degenerative nerve disease that also affects movement and blood pressure and has many of the symptoms of Parkinson's disease. Some research suggests that a trial using the drug apomorphine may help differentiate between the two.
Other problems that may mimic Parkinson's disease include Wilson's disease, thyroid abnormalities, hydrocephalus, tumors, having the fragile X trait (but not the full disorder), and a number of degenerative neurologic diseases.

Drugs. Certain drugs or medications account for about 4% of all cases of parkinsonism. According to some studies, patients who experience drug-induced parkinsonism may actually be at an increased risk of developing Parkinson's disease later in life. A number of drugs can cause these symptoms, including antipsychotic and antiseizure drugs. Anyone with parkinsonism should discuss their medications with their doctor.

The American Academy of Neurology (AAN) recommends the Beck Depression Inventory or the Hamilton Depression Rating Scale to screen for depression in patients with Parkinson’s disease. The AAN recommends the MMSE and CAMCOG tests to screen for dementia. During these tests, the patient answers a series of questions.

Treatment

Drugs, physical therapy, and surgical interventions can manage Parkinson's disease. The goals of treatment for Parkinson's disease are to:

Relieve disabilities
Balance the problems of the disease with the side effects of the medications

Treatment is very individualized for this complicated disease. Patients must work closely with doctors and therapists throughout the course of the disease to customize a program suitable for their particular and changing needs. Patients should never change their medications without consulting their doctor, and they should never stop taking their medications abruptly.

The American Academy of Neurology recommends the following therapies for the initial treatment of Parkinson’s disease:

Levodopa (L-dopa). Levodopa, or L-dopa, has been used for years and is the gold standard for treating Parkinson's disease. The drug increases brain levels of dopamine. It is used in nearly all phases of the disease. The standard preparations (Sinemet, Atamet) combine levodopa with carbidopa, a drug that slows the breakdown of levodopa. Levodopa is better at improving motor problems than dopamine agonists but increases the risk of involuntary movements (dyskinesia).

Dopamine Agonists. Dopamine agonist drugs mimic dopamine to stimulate the dopamine system in the brain. These drugs include pramipexole (Mirapex), ropinirole (Requip), bromocriptine (Parlodel), and rotigotine (Neupro). The Food and Drug Administration (FDA) pulled the dopamine agonist pergolide (Permax) from the market in March 2007 over safety concerns that included potentially fatal heart valve damage.

Selegiline (Eldepryl) and rasagiline (Azilect). Selegiline is a monoamine oxidase B (MAO-B) inhibitor that may have some mild benefit as an initial therapy. However, unlike levodopa, it does not slow the progression of Parkinson’s disease. Another MAO-B inhibitor, rasagiline (Azilect), was approved in May 2006. Unlike selegiline, which needs to be taken by mouth twice a day, rasagiline needs to be taken only once a day.

Drug treatments for Parkinson disease do not consistently control symptoms. At certain points during the day, the beneficial effects of drugs wear off, and patients can experience a return of symptoms, such as uncontrolled muscular motor function, difficulty walking, and loss of energy. In 2006, the American Academy of Neurology (AAN) reviewed evidence for the various drugs used to treat “off time.” The AAN found that the following drugs had the strongest evidence for controlling off time symptoms:

Entacapone (Comtan) belongs to a class of drugs called catechol-o-methyl transferase (COMT) inhibitors. COMT inhibitors help prolong the effects of levodopa by blocking an enzyme that breaks down dopamine.
Rasagiline (Azilect) belongs to a class of drugs called monoamine oxidase (MAO) inhibitors. These drugs slow the breakdown of dopamine that occurs naturally in the brain and dopamine produced from levodopa.

The AAN also found good evidence for the dopamine agonists ropinirole (Requip) and pramipexole (Mirapex), and the COMT inhibitor tolcapone (Tasmar). Deep brain stimulation is a surgical treatment that may help improve motor fluctuations in some patients.

Both Levodopa and dopamine agonists can cause involuntary movements (dyskinesia). The AAN has not found any strong evidence to recommend any drug for treating dyskinesia. However, weak evidence suggests that the antiviral drug amantadine (Symmetrel) may help reduce stiffness and improve dyskinesia. There is also weak evidence that deep brain stimulation of the subthalamus area may be helpful.

Conditions associated with motor impairment and other symptoms of Parkinson's disease may require a variety of treatments.

Depression. Although depression is very common in PD, there have been surprisingly few controlled studies. Antidepressants used for PD include tricyclics, particularly amitriptyline (Elavil). Some studies have found that selective serotonin-reuptake inhibitors (SSRIs) -- which include fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil) -- may worsen symptoms of Parkinson's. Doctors should monitor patients taking SSRIs.

Psychotic Side Effects. Studies indicate that clozapine (Clozaril) and quetiapine (Seroquel), antipsychotic drugs used to treat schizophrenia, may be the best drugs for treating psychosis in patients with Parkinson's disease. A similar drug, olanzapine (Zyprexa), should not be used for patients with PD because it can worsen their psychotic symptoms.

Dementia. The cholinesterase inhibitor drugs donepezil (Aricept) and rivastigmine (Exelon) are used to treat Alzheimer’s disease. Studies suggest that these drugs may also help treat dementia associated with Parkinson’s disease. In 2006, rivastigimine was approved for treatment of mild-to-moderate dementia associated with Parkinson’s disease.

Daytime Sleepiness. Modafinil (Provigil), a drug used to treat narcolepsy, is proving to be very helpful for patients with sleepiness related to their disease.

Drooling. In search of a simple solution for the problem of drooling, scientists have reported that injections of very small amounts of botulinum toxin effectively reduce saliva production and drooling. In such small amounts the toxin is safe.

Voice Loss. A relatively simple procedure using collagen injections in the neck appears to be a safe and effective method of improving the voice and speech disorders caused by PD. The procedure augments the collagen in the vocal fold and works best in patients who can still initiate speech. A 2001 study reported improvements that lasted from 2 - 7 months in 61% of patients.

Erectile Dysfunction. Sildenafil (Viagra) is proving to be very helpful for men who suffer from impotence from Parkinson's disease. However, the drug may worsen orthostatic hypotension, a side effect of some PD medications.

Eventually, symptoms such as stooped posture, freezing, and speech difficulties may not respond to drug treatment. (Total unresponsiveness is unlikely, however, even after 20 years of treatment.) The following approaches may be tried:

Simply increasing the dose of levodopa or its frequency raises an unacceptable risk of the distressing side effects. Some doctors have tried hospitalizing patients, totally withdrawing the levodopa, and then re-administering it. Benefits were seen for only a few months, however, and there were some dangerous risks to the process of withdrawal, including pneumonia and blood clots in the lungs.

An embolus is a blockage of an artery in the lungs by fat, air, tumor tissue, or blood clot.

Surgical treatments, including deep brain stimulation and pallidotomy, may help some patients.
Research is ongoing to develop drugs and procedures that will manage advanced disease and possibly even reverse the process.

Levadopa (L-dopa)

Levodopa, also called L-dopa, which is converted to dopamine in the brain, remains the gold standard for treating Parkinson's disease. The standard preparations (Sinemet, Atamet) combine levodopa with carbidopa, which improves the action of levodopa and reduces some of its side effects, particularly nausea. Levodopa can also be combined with benserazide (Madopar) with similar results, but Sinemet is almost always used in America. Dosages vary, although the preparation is usually taken in three or four divided doses per day. In 2004, the FDA approved a new oral form of carbidopa-levodopa (Parcopa) that dissolves on the tongue.

In general L-dopa has the following effects on Parkinson's disease:

It is most effective against rigidity and slowness.
It produces less benefit for tremor, balance, and gait.

In many patients, levodopa significantly improves the quality of life for many years. If symptoms do not improve after 2 - 3 months, one of the following reasons may account for the failure:

Other neurologic problems may be causing the symptoms.
Some patients have abnormalities in other brain sites that do not respond to L-dopa.
Sometimes patients are so depressed they cannot tell if the drug is beneficial or not. Only a series of physical examinations by the doctor will indicate that the drug is actually helping.

Studies suggest that levodopa may help slow disease progression and protect against brain cell degeneration.

The toxic effects of levodopa with or without carbidopa are considerable.

Physical Side Effects. The physical side effects are as follows:

Low blood pressure. Low blood pressure is a common problem during the first few weeks, particularly if the initial dose is too high. The addition of extra supplements of carbidopa reduces this effect to some degree. The patient should drink lots of fluids and possibly increase salt intake to maintain normal blood pressure.
Arrhythmia. In some cases the drug may cause abnormal heart rhythms.
Gastrointestinal effects. Stomach and intestinal side effects are common even with carbidopa. Taking the drug with food can alleviate the nausea. However, proteins interfere with intestinal absorption of levodopa, and some doctors recommend not eating any protein until nighttime in order to avoid this interference. The drug can also cause gastrointestinal bleeding.
Effects in the lung. Levodopa can cause disturbances in breathing function, although it may benefit patients who have upper airway obstruction.
Hair loss.

Psychiatric and Mental Side Effects. The major adverse effects of the drug are psychiatric. Patients taking levodopa, especially in combination with other drugs, can experience:

Confusion.
Extreme emotional states, particularly anxiety.
Vivid dreams.
Visual and possibly auditory hallucinations. The drug may even unmask dementia that had not been previously noticed.
Effects on learning. L-dopa appears to have mixed effects on learning. It may improve working memory. However, some evidence suggests that it impairs areas of the brain related to other learning functions and social behavior.
Sleepiness and sleep attacks.

Levodopa causes fewer psychiatric side effects than other drugs used for Parkinson's disease, including anticholinergics, selegiline, amantadine, and dopamine agonists. Because psychiatric side effects often occur at night, if they are severe some doctors recommend reducing or stopping the evening dose.

Within 4 - 6 years of treatment with levodopa, the effects of the drug in many patients begin to last for shorter periods of time (called the wearing-off effect) and the following pattern may occur:

Patients may first notice slowness (bradykinesia) or tremor in the morning before the next dose is due.
Less commonly, some experience painful dystonia, muscle spasms that can cause sustained contortions of various parts of the body, particularly the neck, jaw, trunk, and eyes and possibly the feet.
Patients must increase the frequency of levodopa doses. This puts them at risk for dyskinesia (the inability to control muscles), which usually occurs when the drug level peaks. Dyskinesia can take many forms, most often uncontrolled flailing of the arms and legs or chorea, rapid and repetitive motions that can affect the limbs, face, tongue, mouth, and neck. Dyskinesia is not painful, but it is very distressing.
In some people, eventually L-dopa is effective only for 1 - 2 hours and most patients start to experience motor fluctuations. In about 15 - 20% of patients such fluctuations become extreme, a phenomenon known as the on-off effect, which consists of unpredictable, alternating periods of dyskinesia and immobility. Sometimes the symptoms switch back in forth within minutes or even seconds. (The transition may follow such symptoms as intense anxiety, sweating, and rapid heartbeats.)

Reasons for the Wearing-Off Effect. Debate is ongoing about the cause of the wearing-off effect and dyskinesia. Some theories suggested for these effects are:

The disease progresses beyond the ability of levodopa to control it.
Some patients become tolerant to prolonged exposure to dopamine and, at the same time, the disease is progressing.
The brain's own dopamine neurons become incapable of storing dopamine. When the levodopa wears off, little or no natural dopamine remains.
Levodopa itself accelerates the disease by producing oxygen free radicals, unstable particles that increase injuries to the brain and dopamine degradation.

Preventing the Wearing-Off Effect. To reduce the effects of fluctuation and the wearing-off effect, it is important to maintain as consistent a level of dopamine as possible. Unfortunately, levodopa is poorly absorbed and may remain in the stomach a long time. A number of strategies are being developed to take care of these problems:

Some patients take multiple small doses on an empty stomach, crushing the pills and mixing them with a lot of liquid.
A liquid form of Sinemet may produce fewer fluctuations and a prolonged "on" time compared with the tablet.
A prolonged release version of levodopa and carbidopa (Sinemet CR) is also available to control fluctuations for some people. (Some evidence suggests that there is no actual difference in symptom control between the sustained and immediate release forms, but patients on Sinemet CR tend to experience a better quality of life.)

Other Medications

Selegiline (Eldepryl, Movergan, Zelepar), also known as deprenyl, is an antioxidant drug that blocks monoamine oxidase B (MAO-B), an enzyme that degrades dopamine. Until recently, selegiline was the drug most commonly used in early-onset disease and in combination with levodopa for maintenance. A major 2002 study reported, however, that although selegiline delays the need for L-dopa by a few months, it has no effect on long-term progression.

Rasagiline (Azilect), another MAO-B inhibitor, was approved in May 2006 for the initial treatment of Parkinson’s disease. It is used alone during early-stage PD and in combination with L-dopa for moderate-to-advanced PD. Unlike selegiline, which is taken twice a day, rasagiline is taken once a day.

Other Adverse Effects. MAO-B inhibitors may have severe side effects:

One of the most important side effects is orthostatic hypotension, particularly in people taking Sinemet plus selegiline. This condition is a sudden drop in blood pressure that causes dizziness and lightheadedness when a patient stands up. Orthostatic hypotension can also occur with other Parkinson's drugs.
Can cause high blood pressure (hypertension) if combined with drugs that increase serotonin levels -- such drugs include nearly every major antidepressant. Patients suffering from depression and taking selegiline should discuss all treatment options with their doctor.
Can also cause a dangerous increase in blood pressure if patients eat foods rich in the amino acid tyramine. Patients should avoid the following foods while taking selegiline or rasagiline and for 2 weeks after stopping medication: aged cheeses, air-dried meats, pickled herring, yeast extract, aged red wines, draft beers, sauerkraut, and soy sauce

Debate over Mortality Rates. Some major studies have reported higher mortality rates in patients with advanced PD. Such findings may be due to adverse effects on the heart and blood vessels. Although other studies have not reported lower survival rates, some experts believe that, given its modest effects, selegiline may be a poorer drug choice than others, particularly in patients with risk factors for heart disease.

Dopamine agonists stimulate dopamine receptors in the substantia nigra, the part of the brain in which Parkinson's is thought to originate. Dopamine agonists are effective in delaying motor complications during the first 1 or 2 years of treatment.

Newer Dopamine Agonists. The most commonly prescribed dopamine agonists are pramipexole (Mirapex) and ropinirole (Requip). They are used either alone or in combination with L-dopa. Pramipexole appears to work better and have fewer side effects than ropinirole.

Studies still report, however, that L-dopa is superior for improving motor function. In one study, motor function was no different in disease progression among all of the drugs by the third year of treatment. Recent research suggests that L-dopa is better at improving motor disability and dopamine agonists are better at reducing motor complications. L-dopa has a higher risk for dyskinesia side effects than dopamine agonists, but dyskinesia can also occur with dopamine agonists.

Side Effects. Side effects of pramipexole and ropinirole vary but can be severe and include:

Gastrointestinal side effects (nausea and constipation). Nausea can be controlled by drugs, such as domperidone.
Headache
Orthostatic hypotension (sudden drop in blood pressure upon standing up)
Nasal congestion
Nightmares, hallucinations, and psychosis (more severe than with L-dopa for both drugs)
Sudden sleep attacks. These can be very serious, particularly if patients are driving. (Sleep attacks may occur -- although less commonly -- with other PD drugs.)

Other Dopamine Agonists.

Specific dopamine agonists that contain ergot alkaloids include bromocriptine (Parodel), pergolide (Permax), cabergoline (Dostinex), and lisuride (Dopergin). As of 2007, bromocriptine is the only ergot dopamine agonist approved for Parkinson’s treatment in the United States. In January 2007, the New England Journal of Medicine (NEJM) published two studies indicating that pergolide and cabergoline are associated with heart valve damage. In March 2007, due to these safety concerns, the FDA withdrew pergolide from the U.S. market. Cabergoline and lisuride are not approved in the U.S. for Parkinson’s disease treatment but are used for this purpose in other countries. The NEJM studies did not find any heart valve problems associated with bromocriptine or lisuride.
Rotigotine transdermal (Neupro) is a dopamine agonist that is delivered through a skin patch that is changed daily. In 2007, the FDA approved rotigotine transdermal for treatment of symptoms of early Parkinson’s disease. It is the first skin patch approved for Parkinson’s disease. Side effects are similar to those of other dopamine agonists.
Apomorphine is a dopamine agonist used as a "rescue" drug in people experiencing on-off effects severe enough to require going off L-dopa for a few days. In 2004, the FDA approved apomorphine for treating off-time episodes of Parkinson’s disease. Apomorphine is given by injection. Because it causes severe nausea and vomiting, it must be taken with an anti-nausea drug.

Catechol-O-methyl transferase (COMT) inhibitors increase concentrations of existing dopamine in the brain. Entacapone (Comtan, Stalevo) is the current standard COMT inhibitor. (Stalevo combines entacapone and levodopa into a single pill.) It improves motor fluctuations related to the wearing-off effect and has shown good results in improving on time and reducing the requirements for L-dopa. If the patient does not respond to the drug within 3 weeks, it should be withdrawn. No one should withdraw abruptly from these drugs.

Side Effects. Side effects include:

Involuntary muscle movements
Mental confusion and hallucinations
Cramps, nausea, and vomiting
Insomnia
Headache
Urine discoloration (a harmless side effect but should be reported to the doctor)
Diarrhea
Less commonly, constipation, susceptibility to respiratory infection, sweating, dry mouth

Of major concern are reports of a few deaths from liver damage in patients taking the COMT inhibitor tolcapone (Tasmar). The drug has been taken off the market in many countries and is recommended in the U.S. only for patients who cannot tolerate another other drugs. Entacapone does not appear to have the same effects on the liver and does not require monitoring. A 2003 3-year study suggested that the drug is safe and effective over the long term. Still, patients should watch out for symptoms of liver damage, including jaundice (yellowish skin), fatigue, and loss of appetite.

Jaundice is a condition produced when excess amounts of bilirubin circulating in the bloodstream dissolve in the subcutaneous fat (the layer of fat just beneath the skin), causing a yellowish appearance of the skin and the whites of the eyes. With the exception of normal newborn jaundice in the first week of life, all other jaundice indicates overload or damage to the liver, or inability to move bilirubin from the liver through the biliary tract to the gut.

Anticholinergics were the first drugs used for PD, but have largely been replaced by dopamine drugs. They are generally used only against tremor in the early stages. They are not as effective against bradykinesia and posture problems and may increase the risk for dementia in late stages. Among the many anticholinergics are trihexyphenidyl (Artane, Trihexy), benztropine (Cogentin), biperiden (Akineton), procyclidine (Kemadrin), and ethopropazine (Parisdol). Orphenadrine (Norflex) is a drug with anticholinergic properties, but is also a muscle relaxant and does not cause urinary retention.

Side effects of Anticholinergics. Anticholinergics commonly cause dryness of the mouth (which can actually be an advantage in some people who experience drooling). Other side effects are nausea, urinary retention, blurred vision, and constipation. These drugs can also increase heart rate and worsen constipation. Anticholinergics can sometimes cause significant mental problems, including memory loss, confusion, and even hallucinations. People with glaucoma should use these drugs cautiously.

Amantadine (Symadine, Symmetrel) stimulates the release of dopamine and may be used for patients with early mild symptoms. It has some benefit against muscle rigidity and slowness and may help some patients in advanced stages who are unresponsive to other drugs. It is less powerful than levodopa and may lose its effectiveness after 6 months. It may also reduce motor fluctuations brought on by levodopa, however, and these benefits appear to persist for at least a year. Large, well-conducted studies are still needed to determine its true benefits and safety.

Side Effects. Side effects are similar to those of anticholinergic drugs and also may include swollen ankles and mottled skin. It can also cause visual hallucinations. Overdose can cause serious and even life-threatening toxicity. Patients with Parkinson's should not withdraw from this drug abruptly. In rare instances, it can cause acute delirium or a life-threatening condition called neuroleptic malignant syndrome. Pregnant or nursing women should not use this drug.

Anticonvulsants. Zonisamide (Zonegran), a drug used to treat epilepsy, is showing promise in treating tremors, motor problems, and involuntary movements in patients with Parkinson’s disease.

Budipine and Other Glutamate Blockers. A number of experimental drugs are being investigated for Parkinson's disease because they block the actions of glutamate, an amino acid that is a particularly potent nerve cell killer. Some of these drugs block a receptor group to glutamate called N-methyl-D-aspartate (NMDA). Investigational NMDA antagonists include remacemide, memantine, riluzole, and budipine.

Stem Cell Transplantation. Scientists are investigating whether transplanting embryonic stem cells into the brain may help treat Parkinson’s disease. Researchers hope that the transplanted stem cells may be able to stimulate dopamine production. However, stem cell transplantation research is still in its very early stage. It will be many years before clinical trials will be conducted in humans.

Surgery

Surgical procedures are recommended for specific patients with advanced Parkinson’s disease who no longer respond to drug treatments. Surgical treatment cannot cure Parkinson's disease, but it may help control symptoms such as motor fluctuations and dyskinesia. Pallidotomy and thalamotomy are older procedures that destroy tissue in certain parts of the brain. Deep brain stimulation, the current standard surgical practice for Parkinson’s disease, has largely replaced the older operations.

In deep brain stimulation (DBS), also called neurostimulation, an electric pulse generator controls symptoms. The generator is similar to a heart pacemaker. It sends electrical pulses to specific regions of the brain. Candidates for surgery are generally patients who have responded well to levodopa drug treatment. Patients who have had PD for fewer than 16 years may experience greater benefit from DBS than patients who have had the disease longer.

Evidence indicates that DBS improves motor function and reduces dyskinesia best when the procedure targets the subthalamic nucleus (STN) of the brain. Many studies demonstrate the effectiveness of STN stimulation. Procedures that target the globus pallidus interna or ventral intermediate nucleus of the thalamus can also sometimes treat rigidity and tremors. However, there is not yet enough evidence to support stimulation of these parts of the brain.

The procedure is performed as follows:

The surgeon implants a tiny pulse generator near the collarbone, which is connected to four electrodes that have been implanted in the target area in the brain.
The generator delivers programmed pulses to this area, which the patient can turn on and off using a magnet held over the skin.
When on, the pulses suppress symptoms. Complications occur in 2 - 4% of operations. The most serious ones are bleeding in the brain and infection. Depression is common.

In a 2006 study of patients with advanced Parkinson’s disease and severe motor symptoms, patients who received DBS had better improvement in symptoms and quality of life than those who received only drug therapy. However, patients in the neurostimulation group had more serious side effects than those who were treated only with medications. Researchers are also studying whether DBS can benefit patients with earlier-stage Parkinson’s disease.

Pallidotomy and thalamotomy are surgical procedures that destroy brain tissue in regions of the brain associated with Parkinson’s symptoms such as dyskinesia, rigidity, and tremor. In these procedures, a surgeon drills a small hole in the patient’s skull and inserts an electrode to destroy brain tissue. Pallidotomy targets the global pallidus area. Thalamotomy targets the thalamus. Because these procedures permanently eliminate brain tissue, most experts now recommend deep brain stimulation instead of pallidotomy or thalamotomy.

Surgical complications may include behavioral or personality changes, trouble speaking and swallowing, facial paralysis, and vision problems. Weight gain after surgery is also common.

Scientists are investigating whether stem cells may eventually help treat Parkinson disease. Experimental surgery has shown promise using fetal brain cells rich in dopamine implanted in the substantia nigra area of the brain. Because the use of embryonic stem cells is controversial, researchers are studying alternative types of cells, including stem cells from adult brains and cells from human placentas or umbilical cords. Studies are also using gene therapies and other advanced treatments for transplanting dopamine-producing cells or nerve-protecting cells into the brain. All of this research is still in preliminary stages.

Lifestyle Changes

No special diets or natural foods have been shown to slow down the progression of Parkinson's disease, but there are some dietary recommendations.

Protein. High levels of proteins compete with levodopa for transport to the brain and reduce its effectiveness. Avoiding protein altogether is not the solution, since malnutrition can result. Most experts now recommend trying to maintain a carbohydrate-to-protein ratio of 7:1 throughout the day. This may be difficult to calculate and some doctors recommend simply keeping proteins to 12% of total daily calories.

As an aid in calculation, food labels indicate proteins in grams. One gram of protein equals four calories. Good control of protein intake may help minimize fluctuations and wearing-off and may allow some patients to reduce their daily levodopa dosage.

Fruits and Vegetables and Increasing Fiber. Eating whole grains, fresh fruits, and vegetables is the best approach for any healthy life. A diet rich in fruits and vegetables may help protect nerve cell function. Many of these foods are also often rich in fiber, which is particularly important for helping to prevent constipation.

Dietary fiber is the part of food that is not affected by the digestive process in the body. Only a small amount of fiber is metabolized in the stomach and intestine, the rest is passed through the gastrointestinal tract and makes up a part of the stool. There are two types of dietary fiber, soluble and insoluble. Soluble fiber retains water and turns to gel during digestion. It also slows digestion and nutrient absorption from the stomach and intestine. Soluble fiber is found in foods such as oat bran, barley, nuts, seeds, beans, lentils, peas, and some fruits and vegetables. Insoluble fiber appears to speed the passage of foods through the stomach and intestines and adds bulk to the stool. It is found in foods such as wheat bran, vegetables, and whole grains. Fiber is very important to a healthy diet and can be a helpful aid in weight management. One of the best sources of fiber comes from legumes, the group of food containing dried peas and beans.

People whose diets have been low in fiber should increase it gradually. It is best to obtain dietary fiber, soluble or insoluble, in the natural form of whole grains, nuts, legumes, fruits, and vegetables. If it proves difficult to do so, psyllium, a grain naturally found in India, is an excellent soluble fiber supplement (Metamucil, Fiberall, Perdiem Fiber). Fluids are particularly important in preventing constipation.

Fish Oil. Omega-3 fatty acids, which are found in oily fish, are proving to have powerful anti-inflammatory effects and may also be nerve protective.

Click the icon to see an image of foods that contain omega-3 fatty acids.

Dairy Products. A 2002 study reported a higher risk for Parkinson's disease in men (but not in women) who consumed high amounts of dairy products. This association was not linked to fats in dairy foods and high intake of calcium or protein from other sources did not increase the risk. A 2005 prospective study of men found that milk consumption in midlife was associated with increased risk of Parkinson’s disease. As with prior research, the researchers did not find that calcium itself carried a risk. They suggested that some unidentified neurotoxic contaminant in milk may be responsible.

Vitamins.

B Vitamins. Most B vitamins play important roles in the brain and central nervous system. Vitamin B6 (pyridoxine) theoretically has benefits for PD because it is necessary in the production and metabolism of dopamine. Folate deficiency may increase toxic effects against dopamine neural pathways, perhaps by increasing levels of homocysteine, an amino acid that may play a destructive role in many diseases, including heart and neurologic disorders. Some evidence suggests that L-dopa elevates homocysteine levels, so folate supplements may be particularly important for patients. Although the major food sources of B vitamins are meats and dairy products, which are high in protein, these vitamins are also found in whole grains and are added as supplements to commercial cereals.

Click the icon to see an image of the benefits of vitamin B6.

Click the icon to see an image of foods that contain vitamin B6.

Click the icon to see an image of foods that contain folate.

Vitamin E. Researchers have investigated antioxidant vitamins, especially vitamin E, for their effect on the brain. Some, but not all, studies have reported slower mental decline and lower risk for Parkinson's and Alzheimer's disease in people who ate large amounts of foods rich in vitamin E. Such foods include vegetable oils (particularly wheat germ oil), sweet potatoes, turnip greens, mangos, avocados, nuts, sunflower seeds, and soybeans. Vitamin E supplements, however, do not appear to be helpful for slowing disease progression or improving symptoms.

Both smoking and coffee drinking have been associated with lower risk for PD. Researchers are attempting to discover if these substances protect nerve cells. One interesting study suggested that the early disease process in PD produces changes in the dopamine pathway that actually protects an individual from caffeine and nicotine addiction, so that fewer patients have a history of smoking and caffeine. Research is needed to determine why these toxic substances protect against PD.

Smoking and Nicotine Replacement. Cigarette smokers appear to have a 40% lower risk for Parkinson's disease, indicating some protection by nicotine. This finding, of course, is no excuse to smoke, but such protection may help researchers develop new therapies. Studies on nicotine replacement, such as gum or patches, have been conflicting, however, with some short-term studies reporting no benefits. A 2002 study suggested that nicotine replacement may help smokers with early PD, but not nonsmokers.

Coffee Consumption. Studies have indicated that the risk for PD in coffee drinkers is about 30% lower than for non-coffee drinkers. In a 30-year study of Japanese-American men, coffee consumption was associated with a lower risk for Parkinson's disease, and the more coffee they drank, the lower their risk became. Coffee and tea can reduce fluids by increasing urination, however, and so may increase constipation in PD.

Regular use of ibuprofen may reduce the risk of Parkinson’s disease according to research presented at the 2005 annual meeting of the American Academy of Neurology. In this prospective study, people who took at least two ibuprofen tablets per week for at least 1 year lowered their risk of developing Parkinson’s by 35% compared to nonusers or irregular users. For those who took ibuprofen daily, the comparative risk was 38% lower. Other non-steroidal anti-inflammatory drugs (NSAIDS) did not appear to affect disease risk.

Generally, manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like a drug, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been a number of reported cases of serious and even lethal side effects from herbal products. Always check with your doctor before using any herbal remedies or dietary supplements.

The following dietary supplements are being studied for treatment of Parkinson's disease:

Creatine. Creatine is a nutritional supplement that is sometimes used to improve exercise performance. In 2007, the U.S. National Institutes of Health launched a large-scale clinical trial to study whether creatine can slow the progression of Parkinson’s disease. The trial will enroll patients who have been diagnosed with PD within the last 5 years and who have received levodopa therapy for no more than 2 years.

Coenzyme Q10 (Ubiquinone). Coenzyme Q10 (also called ubiquinone) is an antioxidant being studied for the treatment of Parkinson's disease. This enzyme is important for cellular energy, which may be impaired in PD. In one study, patients who took coenzyme Q10 had slower decline in daily activities and mental and motor skills compared to patients on placebo. However, a 2007 study found that small doses of coenzyme Q10 had no effect on improving Parkinson’s symptoms. Researchers are still investigating whether larger doses given over a long period of time may benefit patients.

Exercise early in adult life may help protect against later development of Parkinson’s disease. Exercise is also an important component of rehabilitation. Physical therapy is extremely important and usually includes active and passive exercise, gait training, practice in normal activities, and if needed, hot or cold treatments, water therapy, and electrical stimulation. Exercise is also essential for well-being and helps patients maintain productive years. To date, no specific approach has been proven to be better than others.

Exercise Programs. Exercise programs are defined as passive or active.

Passive exercise, mostly stretching and manipulation of muscles by a physical therapist, is aimed at preventing muscles from shortening. A passive exercise program that begins with slow and gentle exercises and becomes progressively more intense may improve mobility in patients with early and mid-stage Parkinson's disease.
Active exercises are used to help range-of-motion, coordination, and speed. Patients should continually make efforts to practice movement, even simple ones, such as marching in place, making circular arm movements, and raising the legs up and down while sitting. Patients who enjoy sports or the use of exercise equipment should continue with these activities even if their skills diminish, assuming there are no other medical conditions that would prevent participation.

Gait Training. Practicing new methods for standing, walking, and turning may help retain balance. The following tips may be helpful:

Take large steps when walking forward, raising the toes at the forward step, and hitting the ground with the heel.
Take small steps while turning.
When walking or turning, have the legs 12 - 15 inches apart to provide a wide base.
Do not wear rubber or crepe-soled shoes because they grip the floor and may cause the patient to fall forward.
Using devices that keep a rhythmic beat, such a metronome (a simple device used by musicians to keep time), may be very effective, possibly more than music itself, in helping patients to walk faster and take longer steps. One study found that setting a metronome rhythm to about 10% faster than the patient's fastest gait offers significant improvement over walking to no rhythm at all or to a rhythm that matches the gait.

Reducing Muscle Freezing. The patient should practice regular daily activities that simplify actions and reduce the incidence of muscle freezing. Most often, freezing occurs when a patient begins to move or is presented with an obstacle. The following tips may be helpful:

Rock from side to side.
If the legs feel frozen, lift the toes. This simple action may free spasm in some cases.
Hum marching tunes. In fact, music has been shown to help people move and to get out of bed in the morning. Some studies report that wearing a Walkman and turning music on in situations associated with freezing, such as crossing a street, is helpful.
Divide actions into separate events, which may prevent freezing that occurs from trying to coordinate too many physical operations at one time. For instance, when going through a doorway, approach the door, stop at the door, open it, stop, and then walk through the doorway.
A cane equipped with a laser pointer may be helpful, at least temporarily.
Simply being touched by another person can sometimes release the patient (although a patient with PD should never be pulled or pushed).

Sleep Deprivation Therapy. Sleep deprivation therapy may have a role in treating some cases of depression and some studies are finding some benefits on the depression, tremor, and rigidity experienced by patients. Scientists believe that sleep deprivation produces certain anticholinergic effects, which may improve both depression and Parkinson's symptoms.

Mental Tasks. Mental training may increase dopamine in the brain. Some studies indicate that being mentally fit may be as important for patients as being physically fit. Helpful approaches include:

Select and learn new hobbies that require finger and hand mobility, such as sewing, carpentry, fishing, or playing cards.
Practice deep breathing and relaxation exercises. These may help maintain proper speech control, control tremor, and reduce anxiety.
Both the patient and any caregivers should consider psychological therapy and support for depression and loss of motivation. If psychological therapy is too costly, inexpensive support programs and groups are widely available and can be invaluable for the patient and the family.

Speech Therapy. Speech therapy may help those who develop a monotone voice and lose volume, particularly in combination with medications. There are no well-conducted studies comparing specific speech therapies, but the Lee Silverman Voice Treatment (LSVT) appears to be an example of an effective technique. It has five major components:

Focus on the voice ("think loud/think shout")
High effort (pushes patients to overcome limitations)
Intensive treatment (16 sessions in 1 month)
Calibration (learning to know and accept the amount of effort needed to produce normal sound so it becomes automatic)
Quantification (continuous feedback to objectively document success)

LSVT may help swallowing as well as speech.

Equipment and Devices. A number of devices can be helpful for maintaining stability and preventing falls. The following are some examples:

Rails installed where the patient needs support in getting up or down, such as along the bed and in the bathroom.
Walkers with locking wheels. (Walkers do not appear to be helpful for freezing.)
Chairs with straight backs, firm seats, and arm rests.
Firm mattresses and satin sheets or less expensive sheets with high thread counts. (These are useful for helping patients slide out of bed.)

Resources

www.ninds.nih.gov -- National Institute of Neurological Disorders and Stroke
www.aan.com -- American Academy of Neurology
www.apdaparkinson.org -- American Parkinson's Disease Association
www.pdf.org -- Parkinson's Disease Foundation
www.parkinson.org -- National Parkinson Foundation
www.michaeljfox.org -- Michael J. Fox Foundation for Parkinson's Research
www.wemove.org -- Worldwide Education and Awareness for Movement Disorders
www.parkinsonsaction.org -- Parkinson's Action Network

References

Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schafer H, Botzel K, et al. A randomized trial of deep-brain stimulation for Parkinson's disease. N Engl J Med. 2006 Aug 31;355(9):896-908.

Murata M, Hasegawa K, Kanazawa I. Zonisamide improves motor function in Parkinson disease: a randomized, double-blind study. Neurology. 2007 Jan 2;68(1):45-50.

Schade R, Andersohn F, Suissa S, Haverkamp W, Garbe E. Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl J Med. 2007 Jan 4;356(1):29-38.

Schupbach WM, Maltete D, Houeto JL, du Montcel ST, Mallet L, Welter ML, et al. Neurosurgery at an earlier stage of Parkinson disease: a randomized, controlled trial. Neurology. 2007 Jan 23;68(4):267-71. Epub 2006 Dec 6.

Storch A, Jost WH, Vieregge P, Spiegel J, Grelich W, Durner J, et al. Randomized, double-blind, placebo-controlled trial on symptomatic effects of coenzyme Q10 in Parkinson disease. Arch Neurol. 2007 July;64.

Voon V, Thomsen T, Miyasaki JM, de Souza M, Shafro A, Fox SH, et al. Factors associated with dopaminergic drug-related pathological gambling in Parkinson disease. Arch Neurol. 2007 Feb;64(2):212-6.

Watts RL, Jankovic J, Waters C, Rajput A, Boroojerdi B, Rao J. Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease. Neurology. 2007 Jan 23;68(4):272-6. Epub 2007 Jan 3.

Zanettini R, Antonini A, Gatto G, Gentile R, Tesei S, Pezzoli G. Valvular heart disease and the use of dopamine agonists for Parkinson's disease. N Engl J Med. 2007 Jan 4;356(1):39-46.

Review Date:
6/4/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Sickle cell disease

FitSugar — Wed, 08 Oct 2008 17:35:29 -0700

In This Report

Highlights
Introduction
Risk Factors
Symptoms
Diagnosis
Outlook
Complications
Treatment
Prevention and Lifestyle Ch...
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Screening for Sickle Cell Disease

The United States Preventive Services Task Force’s 2007 guidelines recommend that all newborn infants be screened for sickle cell disease. (In the United States, most states require hospitals to perform this test.) Early detection of sickle cell disease ensures that babies will be given treatment to prevent infections. Sickle cell disease is an inherited condition. About 1 in 375 African-American babies are born with sickle cell disease, but children of other ethnicities are also at risk.

Infections and Sickle Cell Disease

Children with sickle cell disease are highly susceptible to many life-threatening infections, including those caused by the pneumococcus bacterium. Pneumococcal vaccinations are an important protection against this bacterium. Research published in 2007 in Clinical Infectious Diseases indicates that the introduction of the pneumococcal conjugate vaccine has helped reduce by 90% the rate of pneumococcal infections in children with sickle cell disease. Four doses of this vaccine are given from age 2 - 15 months. A second type of pneumococcal vaccine, pneumococcal saccharide, is given when the child reaches 2 years of age.
Daily antibiotics given from age 2 months through 5 years can help prevent many other types of bacterial infections, such as meningitis and blood infections.

Introduction

Blood has two major components:

Plasma is a clear yellow liquid that contains proteins, nutrients, hormones, electrolytes, and other substances. It constitutes about 55% of blood.
White and red blood cells and platelets make up the balance of blood. The white cells are the infection fighters for the body, and platelets are necessary for blood clotting. The important factors in anemia, however, are red blood cells.

Red blood cells (RBCs), also known as erythrocytes, carry oxygen throughout the body to nourish tissues and sustain life. Red blood cells are the most abundant cells in our bodies. Men have about 5.2 million red blood cells per cubic millimeter of blood, and women have about 4.7 million red blood cells per cubic millimeter of blood. To understand red blood cells and their role in anemia, it is useful to know certain facts about them.

Hemoglobin and Iron. Each red blood cell contains about 280 million hemoglobin molecules. Hemoglobin is a complex molecule and the most important component of red blood cells. It is composed of protein (globulin) and a molecule (heme), which binds to iron.

In the lungs, the heme component binds to oxygen in exchange for carbon dioxide. The red blood cells carry the oxygen to the body's tissues, where the hemoglobin releases the oxygen in exchange for carbon dioxide, and the cycle repeats. The oxygen is used in the mitochondria, the power source within all cells.

Structure and Shape. Red blood cells are extremely small and look something like tiny, flexible inner tubes. This unique shape offers many advantages:

It provides a large surface area to absorb oxygen and carbon dioxide.
Its flexibility allows it to squeeze through capillaries, the tiny blood vessels that join the arteries and veins.
Abnormally shaped or sized erythrocytes are typically destroyed and eliminated.

Blood Cell Production (Erythropoiesis). The actual process of making red blood cells is called erythropoiesis. (In Greek, erythro means "red" and poiesis means "the making of things.") The process of manufacturing, recycling, and regulating the number of red blood cells is complex and involves many parts of the body:

The body carefully regulates its production of red blood cells so that enough are manufactured to carry oxygen but not so many that the blood becomes thick or sticky (viscous).
Most of the work of erythropoiesis occurs in the bone marrow.
If the body needs more oxygen (at high altitudes, for instance), the kidney triggers the release of erythropoietin (EPO), a hormone that increases production of red blood cells in the bone marrow.
The lifespan of a red blood cell is 90 - 120 days. The liver and spleen remove old red blood cells from the blood.
When old red blood cells are broken down for removal, iron is returned to the bone marrow to make new cells.

Sickle cell disease occurs from genetic changes which causes a portion of the hemoglobin molecules to be abnormal:

Hemoglobin A (HbA). HbA is the hemoglobin molecule found in normal red blood cells during childhood and adulthood. People without sickle cell anemia have primarily this type of hemoglobin in their blood cells.
Hemoglobin S (HbS). HbS (S is for sickle) is the abnormal variant of hemoglobin A, which occurs in sickle-red blood cells and is the primary characteristic of the disease. The difference between hemoglobin A (HbA) and hemoglobin S (HbS) lies in only one protein out of about 300 that are common to both. This protein lies along an amino-acid chain called beta-globin, where even a tiny abnormality has disastrous results.

Hemoglobin is the most important component of red blood cells. It is composed of a protein called heme, which binds oxygen. In the lungs, oxygen is exchanged for carbon dioxide. Abnormalities of an individual's hemoglobin value can indicate defects in red blood cell balance. Both low and high values can indicate disease states.

Hemoglobin F (HbF) is a form of hemoglobin that is produced during fetal development in the womb. (The F in HbF stands for fetal.) It is usually present for only a short time after birth. Normally, most HbF is later replaced by HbA, although some HbF may persist throughout life. Importantly, HbF is able to block the sickling action of red blood cells. Infants who have inherited sickle cell disease do not develop symptoms of the illness while they still have HbF present in their blood. People with the sickle cell gene who continue to carry some fetal hemoglobin are better protected, therefore, from severe forms of the disease. This knowledge is being used as the basis for therapies used in treating sickle cell disease.

The symptoms and problems of sickle cell disease are a result of the hemoglobin S (HbS) molecule:

When the sickle hemoglobin molecule loses its oxygen, it forms rigid rods called polymers that change the red blood cells into a sickle or crescent shape.
These abnormally sickle-shaped cells are both rigid and sticky. They stick to the walls and cannot squeeze through the capillaries. Blood flow through tiny blood vessels becomes slowed or stopped throughout the body. This deprives tissues and organs of oxygen.
In the immediate setting, oxygen deprivation (hypoxia) can cause severe pain (the sickle cell crisis). Over time, it leads to gradual destruction in organs and tissues throughout the body.

Click the icon to see an image of sickle cells.

In a vicious cycle, oxygen deprivation in cells leads to more polymerization and increased production of sickle cells. The higher the concentration of sickle hemoglobin and the more acidic the environment, the faster the sickle cell process.
Cell dehydration (not enough water molecules) is another major destructive factor in the sickling process of red blood cells. Dehydration increases the density of hemoglobin S within the cell, thereby speeding up the sickling process.
Sickle cells also have a shorter life span (10 - 20 days) than that of normal red blood cells (90 - 120 days). Every day the body produces new red blood cells to replace old ones, but sickle cells become destroyed so fast that the body cannot keep up. The red blood cell count drops, which results in anemia. This gives sickle cell disease its more common name, sickle cell anemia.

The severity of sickle cell disease generally depends on a number of factors:

The extent of oxygen loss. Prolonged oxygen deprivation contributes to the severe pain experienced as a sickle cell crisis. It also produces both short- and long-term organ damage. The lungs are specifically critical targets of the disease process. Because they supply oxygen, they can restore the sickle molecules to a normal form. Unfortunately, once the process occurs, the lungs become major sites for sickle cell damage, particularly for dangerous acute episodes of chest pain.
The acidity of the environment. The lower the better. The organs most seriously affected are those with an acidic environment (such as the spleen and bone marrow).
The concentration of hemoglobin S within the cell. The lower the better.
The amount of a protective hemoglobin F (for fetal). The more the better.

Risk Factors

Sickle cell disease is inherited. People at risk for inheriting the gene for sickle cell descend from people who are or were originally from Africa and parts of India and the Mediterranean. The sickle cell gene also occurs in people from South and Central America, the Caribbean, and the Middle East. The high incidence of the sickle cell gene in these regions of the world is due to the sickle cell's ability to make red blood cells resistant to the malaria parasite:

People who inherit just a single gene are referred to as having the sickle trait. These people are protected against malaria and do not develop sickle cell disease. About 40% of people in certain parts of Africa and about 9% of African-Americans have the trait.
Those who inherit both copies of the HbS gene develop sickle cell disease. They are not protected from malaria, however. In fact, malaria is more serious in these individuals. An estimated 1 in 500 African-Americans and 1 in 1,000 - 1,400 Hispanic Americans are born with sickle cell disease.

The sickle cell gene for hemoglobin S (HbS) is the most common inherited blood condition in America. About 72,000 Americans -- mostly African-Americans -- have sickle cell disease. The risk for inheriting sickle cell disease from parents with the sickle cell gene is as follows:

One parent has only one copy of the sickle cell gene and the other parent has two normal hemoglobin genes, and the child inherits a healthy gene from each parent. The child will not inherit either the disease or the trait.
The child inherits one copy of the sickle cell gene. The child has the trait (HbS) only. The other, healthy hemoglobin gene overrides HbS and blocks the development of sickle cell disease. Such people lead normal lives.
The child inherits the hemoglobin S gene from both parents (HbSS). The child develops the full-blown disease. (If each parent has one copy of the gene, the child has a 25% chance of acquiring the disease.)
The child inherits one hemoglobin S gene and one abnormal hemoglobin gene from other causes (such as one form called HbSC). Such children may develop a form of sickle cell disease. It is often a milder variant, but children can experience severe symptoms. They are also at risk for some of the complications of sickle cell disease, although their risks for serious problems are lower than in children with the full-blown disease.

Symptoms

General Symptoms in Infants. In infants, symptoms do not usually appear until late in the baby's first year. Most commonly, they include:

Fever
Swelling of the hands and feet
Pain in the chest, abdomen, limbs, and joints
Nosebleeds and frequent upper respiratory infections

General Symptoms in Childhood. Pain is the most common complaint. It can be acute and severe or chronic, usually from orthopedic problems in the legs and low back. Other symptoms include:

Anemia
Fatigue
Irritability
Jaundice (yellowish discoloration of the skin and eyes)
Bedwetting

Additional Symptoms in Adolescence or Adulthood. Symptoms of childhood continue in adolescence and adulthood. In addition, patients may experience:

Delayed puberty (in young teenagers)
Severe joint pain
Progressive anemia
Leg sores
Gum disease

The hallmark of sickle cell anemia is a group of devastating symptoms known collectively as a sickle cell crisis (also sometimes known as a vaso-occlusive crisis). Sickle cell crises are episodes of pain that occur with varying frequency and severity in different patients and are usually followed by periods of remission. Severe sickle cell pain has been described as being equivalent to cancer pain and more severe than postsurgical pain. It most commonly occurs in the lower back, leg, abdomen, and chest, usually in two or more locations. Episodes usually recur in the same areas.

The risk for a sickle cell crisis is increased by any activity that boosts the body's requirement for oxygen, such as illness, physical stress, or being at high altitudes. In more than half the cases, however, the trigger is unknown. Acute chest syndrome is a particularly serious complication of sickle cell crisis. It occurs in the lungs and can be extremely serious and even life threatening.

Diagnosis

Prenatal diagnosis of sickle cell disease is now possible for women who may be at risk for having a child with the disease. A positive result for sickle cell disease, however, poses extremely difficult questions even for parents who are not opposed to abortion.

A genetic test known as preimplantation genetic diagnosis (PGD) may prove to determine the presence or absence of the sickle cell mutation in embryos (fertilized eggs) before they are implanted in the mother during assisted fertilization techniques. This genetic tool may eventually help avoid the often emotionally devastating effects of abortion.

In the United States, most hospitals screen newborn babies for sickle cell disease. To perform the test, a blood sample is taken from the baby's heel using a simple needle prick. Early detection of sickle cell disease can help reduce the risk for life-threatening infections and increase the odds for survival. Babies who are diagnosed with sickle cell disease are given daily antibiotics to help prevent infections.

Unfortunately, no tests can definitely determine which children are at highest risk for a stroke and, therefore, would be candidates for ongoing blood transfusions. The following are diagnostic tools currently used or under investigation:

Transcranial Doppler (TCD) ultrasonography measures the speed of blood flow in the brain and is the most sensitive method to date for identifying children at risk for stroke. However, high-risk children are still vulnerable to stroke even if the TCD screening diagnosed normal blood flow velocities.
The use of follow-up magnetic resonance imaging (MRI) to detect small blockages in blood vessels may help confirm high risk in patients identified by TCD ultrasound.
Some patients may need to undergo angiography, an invasive diagnostic technique useful for detecting aneurysms.
Researchers are also beginning to uncover possible genetic markers that may eventually be used to help identify sickle cell patients at higher risk for stroke.

Outlook

New and aggressive treatments for sickle cell disease are prolonging life and improving its quality. As recently as 1973, the average lifespan for people with sickle cell disease was only 14 years. Currently, life expectancy for these patients can reach 50 years and over. Early studies showed that women had a greater risk for death from sickle cell disease than men, but experts now believe this was due to high mortality during pregnancies before the mid-1970s. Women with sickle cell disease now actually live longer than their male counterparts.

The damage and durability of sickle cell disease occurs because the logjam that sickle cells cause in the capillaries slows the flow of blood and reduces the supply of oxygen to various tissues. Not only does pain occur when body tissues are damaged by lack of oxygen, but serious and even life-threatening complications can result from severe or prolonged oxygen deprivation. Sickle cell disease is referred to in some African languages as "a state of suffering," but the disease has a wide spectrum of effects, which vary from patient to patient. In some people, the disease may trigger frequent and very painful sickle cell crises that require hospitalization. In others, it may cause less frequent and milder attacks.

Children with sickle cell disease are very susceptible to infections, usually because their damaged spleens are unable to protect the body from bacteria. A recent study suggested that signs of impaired lung function occur even in very early years. As medical progress has increased the lifespan of children with sickle cell disease, older patients are now facing medical problems related to the long-term adverse effects of the disease process. The most serious dangers are acute chest syndrome, long-term damage to major organs, stroke, and complications during pregnancy such as high blood pressure in the mother and low birth weight.

Complications

There is still no cure for sickle cell disease other than experimental transplantation procedures, but treatments for complications of sickle cell have prolonged the lives of many patients who are now living into adulthood.

The hallmark of sickle cell disease is the sickle cell crisis (also sometimes known as a vaso-occlusive crisis), which is an episode of pain. It is the most common reason for hospitalization in sickle cell disease. The pattern may occur as follows:

In general, the risk for a sickle cell crisis is increased by any activity that boosts the body's requirement for oxygen, such as illness, physical stress, or being at high altitudes. In more than half of episodes, however, the trigger is unknown.
Episodes typically begin at night and last 3 - 14 days, accelerating to a peak over several days and then declining.
The pain is typically described as sharp, intense, and throbbing. Severe sickle cell pain has been described as being equivalent to cancer pain and more severe than postsurgical pain. Shortness of breath is common.
Pain most commonly occurs in the lower back, leg, hip, abdomen, or chest, usually in two or more locations. Episodes usually recur in the same areas. Pain in the bones (usually occurring symmetrically on both sides) is common because blood obstruction can directly damage bone and because bone marrow is where red blood cells are manufactured.
The liver or spleen may become enlarged, causing pain in the upper right or upper left sides of the abdomen. Liver involvement may also cause nausea, low-grade fever, and increasing jaundice.
Males of any age may experience prolonged, often painful erections, a condition called priapism.

Episodes cannot be predicted, and they vary widely among different individuals. In one study, nearly 40% of patients reported no painful episodes over a 5-year period. About 5% of patients experienced severe and frequent episodes (more than three a year). They sometimes become less frequent with increasing age. Generally, people can resume a relatively normal life between crises. Most patients are pain-free between episodes although pain can be chronic in some cases.

Acute chest syndrome (ACS) occurs when the lungs are deprived of oxygen during a crisis. It can be very painful, dangerous, and even life threatening. It is a leading cause of illness among sickle cell patients and is the most common condition at the time of death. At least one whole segment of a lung is involved, and the following symptoms may be present:

Fever of 101.3°F degrees (38.5°C) or above
Rapid or labored breathing
Wheezing or cough
Acute chest pain

Pain often lasts for several days. In about half of patients, severe pain develops about 2 - 3 days before there are any signs of lung or chest abnormalities. Acute chest syndrome is often accompanied by infections in the lungs, which can be caused by viruses, bacteria, or fungi. Pneumonia is often present. A dull, aching pain usually follows, which most often ends after several weeks, although it may persist between crises.

Air is breathed in (inhaled) through the nasal passageways, and travels through the trachea and bronchi to the lungs.

Causes of Acute Chest Syndrome. Primary causes of acute chest syndrome include:

Infection. Infection from viruses or small atypical organisms (Chlamydia and Mycoplasma) is the most common cause of the oxygen deprivation that leads to acute chest syndrome.
Blockage of blood vessels. Blockage in the blood vessels (called infarction) that cuts off oxygen in the lungs is another important cause of acute chest syndrome. Blockage may be produced by blood clots or fat embolisms. (Fat embolisms are particles formed from fatty tissue in the bone marrow that enter and travel through the blood vessels.)
Asthma. Asthma can increase the frequency and pain of acute chest syndrome episodes in children, according to an important 2006 study. The researchers recommended that all children with sickle-cell disease who have frequent acute chest syndrome attacks should be evaluated for asthma.

In about 45% cases, the cause cannot be established. Some cases of acute chest syndrome may result from treatments of the crisis, including from administration of opioids (which reduce oxygen) or excessive use of intravenous fluids. Other lung diseases may also trigger ACS.

Severity of Acute Chest Syndrome. The mortality rates for ACS are around 2% in children and 4% in adults. The syndrome and its long-term complications are the major causes of death in older patients. The condition is four times more deadly in adults than in children. The longer a patient survives, the greater is the damage done by repetitive sickle cell crises in the chest and lungs.

The following destructive effects can occur:

Damage in the chest area from recurrent episodes increases susceptibility to invading infections, even those that are ordinarily not harmful. Infections frequently clear up if they are limited to small areas of the lung, but if they spread, they can progress very quickly and become life threatening.
Lung damage over time can lead to obstruction in the airways in lungs, causing asthma-like conditions.

Infections are common and an important cause of severe complications in sickle cell patients. Before early screening for sickle cell disease and the use of preventive antibiotics in children, 35% of infants with sickle cell died from infections. Fortunately, with screening tests for sickle cell now required for newborns in most states, and with the use of preventive antibiotics in babies who are born with the disease, this terrible mortality rate has dropped significantly.

Infections in Infants and Toddlers with Sickle Cell Disease. The most common organisms causing infection in children with sickle cell disease include:

Streptococcus pneumoniae (can cause blood infections or meningitis)
Haemophilus influenza (a cause of meningitis)

Such infections pose a grave threat to infants and very young children with sickle cell disease. They can progress to fatal pneumonia with devastating speed in infants, and death can occur only a few hours after onset of fever. The risk for pneumococcal meningitis, a dangerous infection of the central nervous system, is also significant.

Infections in Children and Adults. Infections are also common in older children and adults with sickle cell disease, particularly respiratory infections such as pneumonia, kidney infections, and osteomyelitis, a serious infection in the bone. (The organisms causing them, however, tend to differ from those in young children.) Infection-causing organisms include:

Chlamydia and Mycoplasma pneumoniae. These are the important infections in acute chest syndrome (see above).
Gram-negative bacteria. This group of bacteria mostly infects hospitalized patients and can cause serious pneumonias and other infections.

About 30% of patients with sickle cell disease have pulmonary hypertension. Pulmonary hypertension is a serious and potentially deadly condition that develops when pressure in the arteries of the lungs increases. It is an often unrecognized complication and cause of death in sickle cell disease. Many doctors recommend that all adults with sickle cell disease undergo echocardiographic testing to identify if they are at risk for pulmonary hypertension and require treatment.

Researchers are developing new types of tests that may help with early identification of pulmonary hypertension. For example, some studies indicate that a simple blood test for the hormone brain natriuretic peptide (BNP) could help identify patients with sickle cell pulmonary hypertension. Higher levels of BNP are associated with increased pressure in the pulmonary (lung) arteries. A blood test measuring levels of the enzyme lactate dehydrogenase (LDH) may also help identify patients at risk for pulmonary hypertension, as well as leg ulcerations and priapism (persistent and painful erection of the penis). Echocardiography or other tests would still need to be performed to confirm results from these blood tests.

The primary symptom of pulmonary hypertension is shortness of breath, which is often severe. Pulmonary hypertension can be very serious and life threatening in the short- and long-term. If pulmonary hypertension develops suddenly it can cause respiratory failure, which is life threatening. Over time, pulmonary hypertension may cause a condition called cor pulmonale, in which the right side of the heart increases in size. In some cases, this enlargement can lead to heart failure.

Click the icon to see an image of cor pulmonale.

After acute chest syndrome, stroke is the most common killer of patients with sickle cell disease who are older than 3 years old. Between 8 - 10% of patients suffer strokes, typically at about age 7. Patients may also suffer small strokes that may not be immediately noticeable. However, patients who have many of these small strokes may over time start behaving differently or have worsening mental functioning.

Strokes are usually caused by blockages of vessels carrying oxygen to the brain. Patients with sickle cell disease are also at high risk for stokes caused by aneurysm, a weakened blood vessel wall that can rupture and hemorrhage. Multiple aneurysms are common in sickle cell patients, but they are often located where they cannot be treated surgically.

Click the icon to see an image of stroke.

Anemia is a significant characteristic in sickle cell disease (which is why the disease is commonly referred to as sickle cell anemia).

Severe worsening of anemia. Children, adolescents, and possibly young adults may experience what is called splenic sequestration. This happens when a large amount of the sickled red blood cells collect in the patient's spleen. Symptoms may include pain in the right abdomen below the ribs and a large mass (the swollen spleen) may be felt.

Chronic Anemia. Because of the short lifespan of the sickle red blood cells, the body is often unable to replace red blood cells as quickly as they are destroyed. This causes a particular form of anemia called hemolytic anemia. Most patients with sickle cell disease have a hemoglobin levels of 8 g/dL, much lower than people without sickle cell anemia. Chronic anemia reduces oxygen and increases the demand on the heart to pump more oxygen-bearing blood through the body. Eventually, this can cause the heart to become dangerously enlarged, with an increased risk for heart attack and heart failure.

On occasion, patients may experience what is called an aplastic crisis. This happens when the cells in the bone marrow that are normally trying to make new red blood cells suddenly stop working. This sudden stopping is often triggered by a virus called human parvovirus B19.

The kidneys are particularly susceptible to damage from the sickling process. Persistent injury can cause a number of kidney disorders, including infection. Problems with urination are very common, particularly uncontrolled urination during sleep. Patients may have blood in the urine, although this is usually mild and painless and resolves without damaging consequences. Kidney failure is a major danger in older patients and accounts for 10 - 15% of deaths in sickle cell patients. Renal medullary carcinoma is an aggressive, rapidly destructive tumor in the kidney that is rare but can occur as a result of sickle cell disease.

Click the icon to see an image of kidney anatomy.

A reported 38 - 42% of males, including children, with sickle cell disease suffer from priapism. Priapism causes prolonged and painful erections that can last from several hours to days. Experts think that priapism in sickle cell disease may be caused by the destruction of red blood cells and subsequent reduction of nitric oxide. If priapism is not treated, partial or complete impotence can occur in 80% of cases.

Click the icon to see an image of the male reproductive anatomy.

Enlargement of the liver occurs in over half of sickle cell patients, and acute liver damage occurs in up to 10% of hospitalized patients. Because sickle cell patients often need transfusions, they have been at higher risk for viral hepatitis, an infection of the liver. This risk, however, has decreased since screening procedures for donated blood have been implemented.

About 30% of children with sickle cell disease have gallstones, and by age 30, 70% of patients have them. In most cases, gallstones do not cause symptoms for years. When symptoms develop, patients may feel overly full after meals, have pain in the upper right quadrant of the abdomen, or have nausea and vomiting. Acute attacks can be confused with a sickle cell crisis in the liver. Ultrasound is usually used to confirm a diagnosis of gallstones. If the patient does not have symptoms, no treatment is usually necessary. If there is recurrent or severe pain from gallstones, the gallbladder may need to be removed. Minimally invasive procedures (using laparoscopy) reduce possible complications. [For more information, see In-Depth Report #10: Gallstones.]

Click the icon to see an image of cholithiasis.

The spleen of most adults with sickle cell anemia is nonfunctional due to recurrent episodes of oxygen deprivation that eventually destroy it. Injury to spleen causes problems in immune function and increases the risk for serious infection. A very serious anemic condition called acute splenic sequestration crisis (sudden spleen enlargement) can occur if the damaged spleen suddenly becomes enlarged from trapped blood.

Click the icon to see an image of an enlarged spleen.

In some children with sickle cell disease, excessive production of blood cells in the bone marrow causes bones to grow abnormally, resulting in long legs and arms or misshapen skulls. Sickling that blocks oxygen to the bone can also cause bone loss and pain. Sickling that affects the hands and feet of children causes a painful condition called hand-foot syndrome. A condition called avascular necrosis of the hip occurs in about half of adult sickle cell patients when oxygen deprivation causes tissue death in the bone. Eventually adult patients may require surgery to remove diseased and dead bone tissue. Joint replacement may be required in severe cases. X-rays are not very useful for detecting early disease in the bones. MRI may be important.

Click the icon to see an image of the blood supply to bone.

Leg sores and ulcers occur in up to 10% of sickle cell patients and usually affect patients older than 10 years.

Women with sickle cell disease who become pregnant are at higher risk for complications, but serious problems have dropped significantly over the past decades. One study reported a higher risk for premature birth and low birth weight in the baby, and a higher risk for infections and hospital visits in the mother after delivery. Pain crises occurred in nearly half of the women, and nearly 60% required transfusions. The study also reported, however, that, in general, the outcome for pregnancy is favorable. Still, pregnancy during sickle cell is high-risk and carries a mortality rate of about 1%.

Older children and adult patients with sickle cell are subject to other medical problems, including impaired physical development, gum disease, and scarring and detachment of the retina.

Treatment

Research is ongoing toward identifying the biologic and chemical activities that promote or protect against the sickle cell process. Currently, experimental treatments focus on the basic processes that cause the red blood cells to sickle in the first place. There are three basic modes of treatment:

Stimulation of production of healthy fetal hemoglobin in order to inhibit the sickling process
Blocking dehydration in the cells
Transplantation of bone marrow or stem cells from healthy donors so that normal hemoglobin is produced rather than hemoglobin S

Hemoglobin F (HbF), also called fetal hemoglobin, is the form of hemoglobin in the fetus and small infants. Most HbF is later replaced by the hemoglobin that is present in the growing child and adult, although some HbF may persist. Fetal hemoglobin is able to block the sickling action of red blood cells so that infants with sickle cell disease do not develop symptoms of the illness while they still have hemoglobin F. Adults who have sickle cell disease but still retain high levels of hemoglobin F generally have mild disease.

Studies now suggest that the severity of sickle cell disease can be reduced by using drugs that stimulate production of HbF. Even increases as modest as 4% may have significant benefits for these patients.

Hydroxyurea. Hydroxyurea (Droxia, Hydrea) destroys cells in the bone marrow, which results in an increase in special cells that can produce HbF. It is currently the only drug in general use to prevent acute sickle cell crises.

Hydroxyurea is used to treat adults and adolescents with moderate-to-severe recurrent pain (occurring three or more times a year). Hydroxyurea reduces sickling crises and pain, priapism, the number of transfusions, and life-threatening complications in this group. The benefits appear to be long-lasting. Hydroxyurea is not a cure-all. Not all patients respond to hydroxyurea, and the best candidates for the treatment are not yet clear. Small studies have reported no protection from damage in the spleen or bones and joints. Effects on stroke and complications in the eye or kidney are not yet known.

Hydroxyurea is still being investigated in young people. To date, the response to the drug in children and teenagers with sickle cell disease is similar to the response in adults, and few severe adverse effects are being reported. Recent research also suggests that hydroxyurea is safe and beneficial for infants. A 2005 study indicated that long-term hydroxyurea treatment can improve height, weight, and spleen function, and reduce episodes of acute chest syndrome. Patients in the study started the treatment as babies, and most patients took the drug for at least 4 years. The drug was given by mouth in a flavored liquid form.

Side effects include gastrointestinal problems, headache, drowsiness, and skin and nail changes. In rare cases, there have been reports of hallucinations and seizures. The drug may also cause leg ulcers and gangrene in some patients. Patients should handle hydroxyurea with care and wash their hands before and after touching the bottle or capsules. Household members who are not taking hydroxyurea (such as caregivers) should wear disposable gloves when handling the medicine or its bottle.

Cytidine Analogues. Cytidine analogues increase HbF production by affecting the genes that regulate it. Decitabine is one such drug that was developed to treat leukemia and other blood malignancies. Early studies are suggesting that it significantly increases HbF production, even in patients in whom treatment with hydroxyurea failed. Only minor toxic side effects have been reported to date.

Butyrates. Butyrates are natural fatty acids, the end-products of fermented carbohydrates in the intestinal tract that are also metabolized from fiber. One derivative, arginine butyrate, has been under investigation for some time in sickle cell for its role in stimulating production of HbF. Because its actions are different from hydroxyurea, experts hope the two drugs may eventually be used in combination. However, arginine butyrate is difficult to administer, and different forms that might make it simpler to use are needed.

General Guidelines for Managing a Sickle Cell Crisis. The basic objectives for managing a sickle cell crisis are control of pain and rehydration by administration of fluids. Oxygen is typically given for acute chest syndrome. Effective pain medications are available to help reduce the severe pain of sickle cell crises.

Accurate and continually updated assessment of pain determined by patient input and participation is at the crux of effective care for children with sickle cell disease. Often, however, patients are not given the treatment they require.

Many patients, their families, and even doctors are hesitant to use opioids aggressively because of fear of addiction. This fear, however, is nearly always unwarranted. Addiction occurs in only about 1 - 3% of patients with sickle cell disease who are taking opioids.
Many patients use emergency rooms of large hospitals for treating acute pain. Waiting times are long, and there is no single health care provider who knows the patient and can offer consistent assessment and management of pain.
Many doctors do not understand the nature of sickle cell pain. For example, early phases of sickle cell crisis can cause severe pain before test results confirm a diagnosis of a crisis. In such cases, health professionals may question the patient's self-reporting and withhold appropriate pain medication.
Patients may behave normally (talking on the phone, sleeping) and not appear to be in pain, but have actually developed coping behaviors to allow them to function in spite of severe pain.
Children and adults report pain differently, with children tending to report less pain than they actually feel. (One way of determining the severity of pain that a child feels is to show pictures of faces demonstrating degrees of pain and asking the child to point to the one that best expresses his or her experience.)

Adult patients and parents of children with the disease should insist on aggressive pain-relief treatment. If doctors show any reluctance to administer medications after the onset of pain, patients or caregivers should not hesitate to seek a more responsive health care professional.

All patients should have a treatment plan that helps guide them and their families during a pain episode. Plans should outline which medicines to take and when to seek medical help. Patients and families should learn to recognize symptoms early and begin managing with an appropriate amount of pain medication.

Opioids. Severe pain should be treated with strong painkillers, usually opioids. Opioids are generally given orally to adults and adolescents and intravenously to children. Nevertheless, there are exceptions. Studies indicate that oral medications are also effective in children.

Morphine is often used for frequent or prolonged episodes of pain. Unfortunately, its effectiveness is not as long-lasting in sickle cell patients as it is in other patients with severe pain, such as those with cancer.
The opioid meperidine (Demerol) is also used for sickle cell crises. Meperidine is not as powerful as morphine, however, and, if used for prolonged periods, may cause twitches, tremors, and disturbed mental states including seizures.
Some newer synthetic opioids such as fentanyl (Duragesic) or hydromorphone(Dilaudid) have a rapid onset and possibly fewer side effects than morphine. Fentanyl can be applied using a patch, which may help some patients who have difficult receiving intravenous drugs. It takes 12 hours to be effective, however.
Oral drugs, such as methadone, oral morphine, codeine, and oxycodone, are useful for home management of chronic pain and for transitional treatments between the hospital and home. Tramadol (Ultram) is a potent oral painkiller that has opioid-like properties but is not as addictive. (Dependence and abuse have been reported, however.) It may be very useful for sickle cell patients who need painkillers outside the hospital. It has minimal effects on respiratory function and has a low potential for addiction.

Possible side effects of opioids are vomiting and nausea, itching, constipation, itching, skin rashes, and problems urinating. If the patient vomits or becomes nauseated, the doctor may prescribe prochlorperazine (Compazine). Devices have been developed to allow patients to administer their own painkillers as needed.

Anti-Inflammatory Drugs. Because of the potentially serious side effects of opioids, doctors are constantly searching for safer and easier ways of reducing the severity of pain of sickle cell crises. Because experts believe that inflammation is a major contributor to the pain of sickle cell disease, drugs that reduce inflammation are being studied:

Prescription-strength NSAIDs include diflunisal (Dolobid) and ketorolac (Toradol). Ketorolac may be particularly helpful in relieving bone pain, and may be effective for individuals who cannot tolerate opioids. In one study, it was superior to meperidine and had fewer side effects. Studies have suggested, however, that when used as first-line therapy in an acute crisis, ketorolac is effective only in about half of episodes.
Corticosteroids are powerful anti-inflammatory drugs that are commonly used to treat pain caused by inflamed muscles and joints. Such drugs include methylprednisolone (Medrol) and dexamethasone (Decadron, Hexadrol). Studies suggest that using these drugs along with opioids may help some sickle cell patients. Because steroids can suppress the body's infection fighters, they should not be given to patients with bacterial infections or any serious medical complication.

Epidural Anesthesia. An epidural analgesia (injection of an anesthetic into the spinal fluid) may be very effective for pain that is unresponsive to the usual therapies.

Initial Management. Acute chest syndrome can be fatal and must be treated immediately. Basic treatments include the following:

Supplementary oxygen -- this is critical and life saving.
Administration of fluids -- overhydration should be avoided to reduce the risk of fluid in the lungs.
Pain relievers
Bronchoscopy (a diagnostic procedure involving insertion of a tube into the lower airways) may be needed to identify infection.

Other Treatments. Other treatments include:

High-dose intravenous corticosteroids (usually dexamethasone) may hasten recovery from acute chest syndrome and reduce the duration of hospitalization. They are also important if fat embolisms develop.
Antibiotics that specifically target the organisms ( Chlamydia, Mycoplasma) that commonly trigger acute chest syndrome. Such antibiotics include erythromycin, azithromycin, clarithromycin, and various tetracyclines.
Transfusions are important early on for rapid improvement in severe cases, especially if fat embolisms have developed.

To increase oxygen levels in children hospitalized for acute chest syndrome, a simple breathing technique known as incentive spirometry may also be beneficial. A spirometer is a hand-held plastic device commonly used by asthma patients to measure their lung capacity and by patients after surgery to increase intake of oxygen. Patients with sickle cell disease are asked to inhale and exhale into this device every 2 hours during the day and when wake at night until their chest pain subsided. This device forces more air into the lungs, and may help prevent the serious drop in oxygen levels and the risk for infection caused by acute chest syndrome. Spirometry leads to slower rates of collapsed lung tissue and infections. This very inexpensive and simple treatment might have beneficial long-term effects.

General Approach to Treating Infections. Fever in any sickle cell patient should be considered an indication of infection. Temperatures over 101°F in children warrant a call to the doctor. Adults with sickle cell should call the doctor if they have a have fever over 100°F and any signs of infection, including chest pain, productive cough, urinary problems, or any other symptoms. Some approaches for treating infections include:

Hospitalization for infections. When sickle cell patients develop infections, they are nearly always hospitalized immediately and treated with intravenous or high-dose injections of antibiotics in order to prevent septicemia, the dangerous spread of the infection throughout the body. Antibiotics called cephalosporins [cefotaxime (Claforan), ceftriaxone (Rocephin), or cefuroxime (Ceftin)] are typically used. Repeated hospitalizations are very disruptive for both children and adults. Studies have found that older children whose fever is below 38.5°C (101°F) and who have no serious infection or other complications may not need hospitalization. Children who have indications of serious complications of infection (higher fevers, pain, a history of pneumonia, and signs of dehydration) should remain in the hospital.
Treatment of osteomyelitis. If osteomyelitis, an infection in the bone, occurs, a 6-week antibiotic course is needed, most of it intravenous. An accurate diagnosis of osteomyelitis is sometimes difficult to make, because bone damage from sickling can cause similar symptoms. It should be strongly considered in children with signs of pain and swelling in the legs, a high white blood cell count, high fever, and high levels of a test that measures so-called sedimentation rates. It is important, however, to confirm the presence of an actual infection before administering antibiotics, because the antibiotic treatment required for osteomyelitis is so intensive and prolonged. The most common cause of osteomyelitis in children is Salmonella.
Treatment of urinary tract infections. Urinary tract infections may be difficult to manage and can be a serious problem for pregnant women with sickle cell disease. Doctors should take a urine culture before beginning antibiotic treatment and another culture 1 - 2 weeks after treatment to be sure the infection has cleared up.

Bosentan (an endothelin receptor antagonist) and other drugs are used to treat this condition. Investigational therapies include nitric oxide, L-arginine (which converts to nitric oxide), blood transfusions, warfarin, vasodilators, and sildenafil (Viagra). Hydroxyurea does not appear to help.

Folic acid and possibly iron supplements are often given to help treat the anemia that occurs in patients with sickle cell disease. (Patients who are given multiple transfusions may experience iron overload, and iron supplements should be avoided in such cases. Also, folic acid can mask pernicious anemia, which is caused by deficiency of vitamin B12 and is more common in African-Americans than other populations.)

Kidney damage in patients with sickle cell disease can cause bleeding into the urine. Mild episodes can usually be treated with bed rest and fluids. Severe bleeding may require transfusions. ACE inhibitors are drugs commonly used to control high blood pressure and are proving to be important for preventing hypertension and kidney failure in sickle cell patients. Such drugs include captopril (Capoten), enalapril (Vasotec), quinapril (Accupril), benazepril (Lotensin), and lisinopril (Prinivil, Zestril).

Priapism causes prolonged and painful erections that can last from several hours to days. It is best to relieve this problem within 12 hours. Relief within 36 hours is important to avoid permanent impotence. Pain relief and intravenous fluids are the initial steps. Exchange transfusions may be used to reduce the hemoglobin S and sickling that cause this condition. Drugs used to prevent priapism include terbutaline and phenylephrine, which help restrict blood flow to the penis. Hormonal treatments such as leuprolide (Lupron) and diethylstilbestrol may prevent repetitive and prolonged episodes of priapism in severely affected teenage boys with sickle cell disease. A surgical procedure that implants a shunt to redirect blood flow is sometimes performed. Inflatable penile implants may help maintain potency without causing priapism. Researchers are also investigating other treatments including inhaled nitric oxide, arginine, and sildenafil (Viagra).

The spleen is often removed (splenectomy) in children who have one or two acute splenic sequestration crises. Transfusion therapy is an alternative for preventing acute splenic sequestration in high-risk patients. At this time there are no studies comparing overall survival and benefits between the two approaches.

Leg ulcers are difficult to treat. Simple treatment with a moist dressing usually provides the best results. To treat mild ulcers, the leg should be gently washed with cotton gauze soaked in mild soap or a solution of one tablespoon of household bleach to one gallon of water. A dressing soaked in diluted white vinegar may be applied every 3 - 4 hours.

More severe ulcers require debridement, which is the removal of injured tissue until only healthy tissue remains. Debridement may be accomplished using chemical (enzymes), surgical, or mechanical (irrigation) means. Hydrogels (Nu-Gel, Intrasite Gel, Scherisorb, Clearsite, Duoderm, Geliperm) are helpful in healing ulcers and are noninvasive and soothing. Topical antibiotics, saline or zinc oxide dressings, or cocoa butter or oil are also used depending on severity. The leg should be elevated. Bed rest for a week or more is sometimes required for severe ulcers.

Skin grafts and transfusions have been helpful in some extreme cases. In one promising study administering arginine butyrate for many weeks improved ulcer healing by 10-fold. (This drug is also under investigation for other beneficial effects in patients with sickle cell disease.)

Women who are pregnant should be treated at a high-risk clinic. They should take folic acid in addition to multivitamins and iron. Standard treatment is given for sickle cell crises, which may occur more frequently during pregnancy. The benefits of transfusions to prevent crises during pregnancy are not yet clear and experts recommend them only for women who experience frequent complications during pregnancy.

Women with sickle cell disease should talk to their doctors before becoming pregnant. Sexually active women should use contraception at all times.

At this time, the only true cure for sickle cell disease is bone marrow or stem cell transplantation. The bone marrow nurtures stem cells, which are early cells that mature into red and white blood cells and platelets. By destroying the sickle cell patient's diseased bone marrow and stem cells and transplanting healthy bone marrow from a genetically-matched donor, normal hemoglobin may be produced. Clinical studies using a few carefully selected patients have reported very successful results.

Up to 80 - 85% of patients who meet criteria for receiving a transplant receive remain disease free. Unfortunately, only about 7% meet the criteria for transplantation, including those who:

Are age 16 or younger (generally considered the better candidates, but patients in their 20s have had successful transplants)
Have severe symptoms but no long-term organ or neurologic damage
Have a genetically matched brother or sister who will donate their marrow

Complications. Bone marrow transplant carries its own dangers and limitations. About 10% of those who have bone marrow transplants die from the treatment. Some complications include:

In patients who do not receive a bone marrow donation from a matched sibling, the transplanted cells from a donor (called allogeneic grafts) may attack the patient's own tissues, a potentially fatal condition called graft-versus-host disease (GVHD). Drugs that destroy bone marrow and suppress immunity must be administered before the procedure so that the body's immune system does not attack the transplanted tissue. Still, this does not always prevent the problem.
Other very serious complications include bleeding, pneumonia, and severe infection.
Those who live but are not cured face long-term problems caused by the drugs used in transplantation and by the disease itself.
Even in those who are cured, long-term consequences may include a higher risk for cancer and infertility.

The use of umbilical cord blood and cells from placentas is showing promise for providing healthy stem cells to patients who do not have genetically matched donors for bone marrow transplant. Cord blood has certain advantages over stem cell transplantation, including the capacity to produce more cells quickly. Because immune factors in cord blood are immature, the risk and severity of graft-versus-host disease may be reduced.

Early clinical trials are also reporting some success with a process called partial chimerism, in which a mixture of the patient's and a donor's bone marrow is used. The procedure has far fewer side effects because all the bone marrow is not destroyed. Although some sickle blood cells remain, small studies indicate that the patients are still free of the typical infections and pain of the disease.

Transfusions are often critical for treating sickle cell disease. In some cases, they may be given on a regular basis to prevent stroke or other life-threatening complications of the disease. Ongoing transfusions can reduce episodes of pain and acute chest syndrome. They can also help improve height and weight in children with sickle cell disease. Regular transfusions, however, can have severe side effects. Normal hemoglobin levels for patients with sickle cell disease are around 8 g/dL. Doctors will try to keep the hemoglobin level no higher than 10 g/DL after transfusion.

Transfusions may be required by sickle cell patients either for specific episodes (used only for specific events) or as chronic transfusions (ongoing transfusions).

Episodic Transfusions. Episodic transfusions are needed in the following situations:

To manage sudden severe events, including acute chest syndrome, stroke, widespread infection (septicemia), and multi-organ failure.
To manage severe anemia, usually caused by splenic sequestration (dangerously enlarged spleen) or aplasia (halting of red blood cell production, most often caused by parvovirus). Transfusions are generally not required for mild or moderate anemia.
Before major surgeries. Some evidence suggests that a conservative transfusion regime is as effective as aggressive transfusions in these cases, but more research is needed. Transfusions are generally not required for minor surgeries.

Chronic Transfusions. Chronic (on-going) transfusions are used for:

Stroke Prevention. Chronic transfusions are also used to prevent first or recurrent strokes. Evidence shows that regular (every 3 - 4 weeks) blood transfusions can reduce the risk of a first stroke by 90% in high-risk children. The objective of such transfusions is to reduce hemoglobin S concentrations to less than 30% of total hemoglobin. In addition, studies indicate that as many as 90% of patients who have experienced a stroke do not experience another stroke after 5 years of transfusions. In 2004, the National Heart, Lung, and Blood Institute (NHLBI) issued a clinical alert strongly advising doctors against terminating regular transfusions for high-risk children.
Pulmonary hypertension and chronic lung disease
Heart failure
Chronic kidney failure and severe anemia
Unusually severe and protracted episodes of pain

Chronic blood transfusions carry their own risks, including iron overload, alloimmunization (an immune response reaction), and exposure to bloodborne pathogens. Still, data from large-scale trials suggest that the risks for stroke outweigh the risks associated with transfusions. Researchers are working on ways to reduce the side effects associated with transfusion treatment.

Kinds of Transfusions. Transfusions may be either simple or exchange.

Simple Transfusion. Simple transfusions involve the infusion of one or two units of donor blood to restore blood volume levels and oxygen flow. It is used for moderately severe anemia, severe fatigue, and nonemergency situations when there is a need for increased oxygen. It is also used for acute chest syndrome.
Exchange Transfusion. Exchange transfusion involves drawing out the patient's blood while exchanging it for donor red blood cells. It can be done as manual procedure or as automatic one called erythrocytapheresis. Exchange transfusions should be used promptly if there is any evidence that the patient's condition is deteriorating. It prevents stroke and also may be used in patients with severe acute chest syndrome and to reduce the risk of iron overload in patients who require chronic transfusion therapy. Studies suggest that it may improve oxygenation and reduce hemoglobin S levels. Exchange transfusion may also reduce the risk of heart failure and help prevent fat embolism, a life-threatening condition in which fatty tissue from the bone marrow travels to blood vessels in the lungs and cuts off oxygen.

Iron Overload and Chelation Therapy. Iron overload increases risk for complications, including liver cancer and heart failure. A liver biopsy accurately determines whether excess iron levels are present. A non-invasive test called a superconducting quantum interference device (SQUID) should be used if available.

Chelation therapy is used to remove excess iron stores in the body that can harm the liver, heart, and other organs. The drug deferoxamine (Desferal) is commonly used during such therapy. Unfortunately, deferoxamine has some severe side effects and must be used with a pump for about 12 hours each day. Many patients do not continue treatment. In 2005, the drug deferasirox (Exjade) was approved for the treatment of transfusion-related iron overload in patients ages 2 and older. It is taken once a day by mouth. Patients mix the pills in liquid and drink the mixture. This new treatment may make chelation therapy much easier and less painful for patients.

Other Complications of Transfusion Therapy.

Immune reactions. An immune reaction may occur in response to donor blood. In such cases, the patient develops antibodies that target and destroy the transfused cells. This reaction, which can occur 5 - 20 days after transfusion, can result in severe anemia and may be life-threatening in some cases. It can be generally prevented with careful screening and matching of donor blood groups before the transfusion.
Hyperviscosity. With this condition, a mixture of hemoglobin S and normal hemoglobin causes the blood to become sticky. The patient is at risk for high blood pressure, altered mental status, and seizures. Careful monitoring can prevent this condition.
Transmission of viral illness. Before widespread blood screening, transfusions were highly associated with a risk for hepatitis and HIV. This complication has decreased considerably.

Nitric oxide, a soluble gas, is a natural chemical in the body that relaxes smooth muscles and expands blood vessels. Hemoglobin removes nitric oxide. Because sickle cells release hemoglobin, patients with the disease are deficient in nitric oxide. This lack of nitric oxide constricts blood vessels and causes pain in sickle cell diseases. In adult patients, men may be more susceptible to this effect than women. Some studies indicate that inhaling nitric oxide may slow the disease process and improve symptoms in acute sickle cell crises. It is difficult to administer, however. More studies are needed. (Nitric oxide is not the same substance as nitrous oxide, the so-called laughing gas used in dentistry.)

Sickle cell disease can cause red blood cells to break apart. This process is called hemolysis. Hemolysis causes a lack of the amino acid arginine. Arginine is involved in producing nitric oxide. Recent research suggests that a lack of arginine may contribute to the development of pulmonary hypertension, a leading cause of death in patients with sickle cell disease. Pulmonary hypertension causes high blood pressure in the arteries that carry blood to the lungs.

A 2005 study found that patients with sickle cell who had low levels of arginine were 3.6 times more likely to die than patients with high arginine levels. Most patients in the study died from pulmonary hypertension. Scientists are working on developing a blood test that could measure amino acid levels and help identify patients at greatest risk of death. They are also working on developing drugs that could block arginase, a protein in cells that is released during hemolysis, which consumes arginine. There is no evidence indicating that arginine nutritional supplements are helpful or harmful for patients with sickle cell disease. Patients should talk to their doctor before taking these or other supplements.

Researchers are studying the mechanisms behind cell membrane damage, dehydration, and potassium loss in order to develop drugs that will inhibit these processes. Drugs under investigation include those that specifically block the Gardos channel, which is an important route for potassium loss and dehydration. Researchers are also studying specific types of mineral supplements, such as magnesium pidolate and zinc sulfate. Initial studies have shown promising results for zinc’s efficacy in preventing red blood cell dehydration, but more research is needed.

Prevention and Lifestyle Changes

No o proven methods prevent either sickle cell crises or long-term complications of sickle cell disease. By taking precautions and aggressively managing problems that occur, however, patients are now living longer, with a better quality of life.

To prevent or reduce the severity of long-term complications, a number of precautions may be helpful:

Have regular physical examinations every 3 - 6 months.
Have periodic and careful eye examinations.
Have sufficient rest, warmth, and increased fluid intake. (These are critical precautions for reducing oxygen loss and the risk for dehydration.)
Avoid conditions, such as crowds, that increase risk for infections.
Avoid excessive demands on the body that would increase oxygen needs (physical overexertion, stress). Low impact exercise (leg lifts, light weights) may be useful and safe for maintaining strength, particularly in the legs and hips, but patients should consult their doctor about any exercise program.
Avoid high altitudes if possible. If flying is necessary, be sure that the airline can provide oxygen.
Do not smoke, and avoid exposure to second-hand smoke. Both active and passive smoking may promote acute chest syndrome in patients with sickle cell disease.

Vaccinations. Everyone with sickle cell disease should have complete regular immunizations against all common infections. Children should have all routine childhood vaccinations. The following are important vaccinations for everyone with sickle cell disease:

Pneumococcal vaccines. All sickle cell patients should be vaccinated with the pneumococcal vaccine. There are two types of pneumococcal vaccines; the choice between them depends on the age of the patient. Infants and children less than 2 years of age should receive 4 doses of the pneumococcal conjugated vaccine (Prevnar) between 2 - 15 months of age. (This vaccine has helped reduce the rate of serious pneumococcal disease by more than 90%.) The pneumococcal polysaccharide vaccine should be administered at age 2 years or older, repeated after 3 - 5 years for patients younger than age 10, or in 5 years for patients older than age 10.
Vaccination against Haemophilus influenza, the major cause of childhood meningitis, starting at age 2 months.
Influenza vaccines should be given every winter, starting at age 6 months.
Meningococcal vaccination for patients age 5 and older.
Hepatitis B vaccine. Anyone starting transfusion therapy should receive this vaccine.

Tuberculosis skin testing should be performed every year.

Antibiotics. In addition to regular immunizations, preventive (prophylactic) antibiotics are the best approach for protection against pneumonia and other serious infections among children with sickle cell disease. Babies diagnosed with sickle cell are given daily antibiotics, starting at 2 months of age and continuing through 5 years of age. Penicillin is usually the antibiotic given, unless a child is allergic to it.

Many patients stop taking their antibiotics or the parents stop giving them to their children. Doctors are concerned about developing bacterial resistance to common antibiotics and researchers warn that patients might experience breakthrough infections as resistance becomes more frequent.

Foods. Good nutrition, while essential for anyone, is critical for patients with sickle cell disease. Some dietary recommendations include:

Fluids are number one in importance. The patient should drink as much water as possible each day to prevent dehydration.
Diet should provide adequate calories, protein, fats, and vitamins and minerals. Patients and families should discuss vitamin and mineral supplements with their doctors and nurses.
Studies on omega-three fatty acids, found in fish and soybean oil, suggest that they might make red blood cell membranes less fragile, and possibly less likely to sickle, although no studies have proven this definitively. Fish and soy products have health benefits in any case. In one small study, fish oil supplements reduced the frequency of painful episodes over the course of a year.

Vitamins. Patients should take daily folic acid and vitamin B12 and B6 supplements. Vitamin B6 may have specific anti-sickling properties. Some experts recommend 1 mg folic acid, 6 microgram vitamin B12, and 6 mg vitamin B6. Foods containing one or all of these vitamins include meats, oily fish, poultry, whole grains, dried fortified cereals, soybeans, avocados, baked potatoes with skins, watermelon, plantains, bananas, peanuts, and brewer's yeast. Of note, folic acid can mask pernicious anemia, which is caused by deficiency of vitamin B12 and is more common in African-Americans than other populations.

Click the icon to see an image of vitamin B6 sources.

Note on Iron. Although sickle cell disease is often referred to as anemia, patients should avoid iron supplements or iron rich foods when receiving multiple transfusions, which increase the risk for iron-overload.

In assessing the seriousness of this disease, no one should underestimate its emotional and social impact. For the family, nothing is more heartbreaking than watching their child endure extreme pain and life-threatening medical conditions. The patient endures not only the pain itself but also the emotional strain from unpredictable bouts of pain, fear of death, and lost time and social isolation at school and work. Academic grades among patients average less than C, even in children with a low frequency of hospitalization (averaging 17 days a year).

These problems continue over the years, and both children and adults with sickle cell disease often suffer from depression. The financial costs of medical treatments combined with lost work can be very burdensome.

Any chronic illness places stress on the patient and family, but sickle cell patients and caregivers often face great obstacles in finding psychological support for the disease. Communities in which many sickle cell patients live generally lack services that can meet their needs, and professionals who work in their medical facilities are often overworked. In a study comparing patients with different kinds of long-term illnesses, those with sickle cell disease gave the lowest scores to their doctors and other professional caregivers for compassion, and were least satisfied with their medical care.

It is very important for patients and their caregivers to find emotional and psychological support. No one should or can endure this life-long disease alone. Unfortunately, studies indicate that most patients do not receive even basic supportive care that could help reduce the anxiety and intensity of pain that occurs when a sickle cell crisis erupts.

The following are some measures that some people find helpful in dealing with this disease:

Stress Reduction. Stress reduction techniques and relaxation methods appear to be helpful. Breathing and mediation techniques may be very helpful.
Cognitive-Behavioral Therapy. Studies suggest that cognitive behavioral therapies that teach coping skills can result in less negative thinking and even less pain. Coping skills refer to the patient's ability to respond to symptoms, such as pain.
On-Line Support Help. Computer on-line services are now valuable sources of support groups and access to research. They are particularly valuable for patients who cannot easily leave home or for patients who are ill.
Support Associations. Parent and professional support associations still offer the best and least expensive sources of help.

Other important factors are those that help maintain positive attitudes including spirituality, humor, or having important life goals (such as having children or pursuing a career).

Resources

www.sicklecelldisease.org -- Sickle Cell Disease Association of America
www.nhlbi.nih.gov -- National Heart, Lung, and Blood Institute (NHLBI)
www.scinfo.org -- Sickle Cell Information Center
www.sicklecellsociety.org -- Sickle Cell Society (UK)
www.sicklecell-info.org -- NHLBI Comprehensive Sickle Cell Centers
www.clinicaltrials.gov -- Find clinical trials

References

Adams RJ, Brambilla D; Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) Trial Investigators. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N Engl J Med. 2005 Dec 29;353(26):2769-78.

Al Hajeri AA, Fedorowicz Z, Omran A, Tadmouri GO. Piracetam for reducing the incidence of painful sickle cell disease crises. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD006111.

Bernaudin F, Socie G, Kuentz M, et al Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood. 2007 Oct 1;110(7):2749-56. Epub 2007 Jul 2.

Dunlop RJ, Bennett KC. Pain management for sickle cell disease. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD003350.

Fathallah H, Atweh GF. Induction of fetal hemoglobin in the treatment of sickle cell disease. Hematology Am Soc Hematol Educ Program. 2006:58-62.

Halasa NB, Shankar SM, Talbot TR, et al. Incidence of invasive pneumococcal disease among individuals with sickle cell disease before and after the introduction of the pneumococcal conjugate vaccine. Clin Infect Dis. 2007 Jun 1;44(11):1428-33. Epub 2007 Apr 18.

Hankins JS, Wynn LW, Brugnara C, Hillery CA, Li CS, Wang WC. Phase I study of magnesium pidolate in combination with hydroxycarbamide for children with sickle cell anemia. Br J Haematol. 2008 Jan;140(1):80-5. Epub 2007 Nov 7.

Lee MT, Piomelli S, Granger S, et al. Stroke Prevention Trial in Sickle Cell Anemia (STOP): extended follow-up and final results. Blood. 2006 Aug 1;108(3):847-52.

Mehta SR, Afenyi-Annan A, Byrns PJ, Lottenberg R. Opportunities to improve outcomes in sickle cell disease. Am Fam Physician. 2006 Jul 15;74(2):303-10.

Singh PC, Ballas SK. Drugs for preventing red blood cell dehydration in people with sickle cell disease. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003426.

Tanabe P, Myers R, Zosel A, et al. Emergency department management of acute pain episodes in sickle cell disease. Acad Emerg Med. 2007 May;14(5):419-25. Epub 2007 Mar 26.

U.S. Preventive Services Task Force. Screening for Sickle Cell Disease in Newborns: U.S. Preventive Services Task Force Recommendation Statement. AHRQ Publication No. 07-05104-EF-2, September 2007. Agency for Healthcare Research and Quality, Rockville, MD.

Review Date:
3/11/2008
Reviewed By:
A.D.A.M. Editorial Team: David Zieve, MD, MHA, Greg Juhn, MTPW, David R. Eltz, Kelli A. Stacy, ELS. Previously reviewed by Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital (1/1/2008).

A.D.A.M. Copyright

adam.com

Crohn's disease

FitSugar — Wed, 08 Oct 2008 17:35:24 -0700

Overview

Signs and Symptoms
What Causes It?
Risk Factors
What to Expect at Your Provider's Office
Preventive Care
Treatment Options
Other Considerations
Supporting Research

HEALTH GUIDE REFERENCE FROM A.D.A.M

Crohn's disease is a chronic inflammatory bowel disease that causes ongoing inflammation of the intestinal tract. It is similar to ulcerative colitis, another inflammatory bowel disease. However, while ulcerative colitis usually is confined to the innermost layer of the large intestine and rectum, Crohn's disease can occur anywhere in the intestine, often in patches surrounded by healthy tissue, and can spread deeper into the tissues. Symptoms include chronic bloody or watery diarrhea, abdominal pain, fever, and loss of appetite. Symptoms tend to wax and wane, with the disease becoming active or going into remission several times during the person's lifetime.

Crohn's disease can cause intestinal obstructions, ulcers (most often in the lower part of the small intestine, the large intestine, or the rectum), fistulas (hollow passages from one part of the intestine to another), and anal fissures (a crack in the anus or the skin around the anus that can lead to infection). In addition, people with Crohn's disease are at risk of malnutrition, because their intestine cannot absorb all the needed nutrients from their diet.

Crohn's disease affects 2 - 7 out of 100,000 people and researchers believe that these numbers are growing. It develops mostly between the ages of 15 - 40, although children and older adults may also develop the condition. There is no cure for Crohn's disease. Medication and strict diets can help control the condition. Some people with the condition will require surgery to remove part of the digestive tract at some point in their lives. However, surgery does not cure the disease.

Signs and Symptoms

The most common signs and symptoms of Crohn's disease are diarrhea and abdominal pain. The symptoms can range from mild to severe.

Diarrhea (with or without blood)
Abdominal pain and bloating
Fatigue
Poor appetite
Weight loss
Fever
Nausea and vomiting
Floating stools (which is caused by poor digestion of fat)

Crohn's disease can also be associated with other medical conditions, including arthritis, osteoporosis, eye infections, blood clots, liver disease, and skin rashes.

What Causes It?

No one is sure what causes Crohn's disease. Theories include a faulty immune system response triggered by bacteria or a virus; genetics, since about a quarter of people who have Crohn's disease also have a close relative with the disease; and a diet high in saturated fat and processed foods, since Crohn's disease is more common in the developed world. It is likely that several factors may be involved in the disease.

Risk Factors

Jewish heritage (three to six times more likely than the general population)
European (particularly Scandinavian) ancestry
Family history of inflammatory bowel disease
Cigarette smoking
Living in an industrialized country (particularly an urban area)
Diet high in sugar and saturated fat and low in fruit and vegetables

What to Expect at Your Provider's Office

Your doctor will perform a thorough physical exam as well as a series of tests to diagnose Crohn's disease. Blood tests may reveal anemia (due to a significant loss of blood) and a high white blood cell count (a sign of inflammation somewhere in the body). Stool samples may indicate whether there is bleeding or infection in the colon or rectum.

The following procedures may be also helpful in distinguishing between ulcerative colitis, Crohn's disease, and other inflammatory conditions.

Colonoscopy -- A colonoscopy, in which a long, flexible, lighted tube with a camera is used to take pictures of the colon, can reveal any inflammation, bleeding, or ulcers along the entire colon wall. This procedure usually requires sedation. A sigmoidoscopy is similar but is used to examine the rectum and lower part of your colon. It can be done without sedation, but may miss inflammation higher in the colon or the small intestine.
Capsule endoscopy -- In this test, you swallow a small capsule with a camera in it, and the camera takes pictures as it passes through the length of your digestive tract. The capsule then passes out of the body through your stool. The test is generally safe, but if there is an intestinal obstruction the capsule may become trapped. Your doctor will run other tests to make sure you do not have an obstruction before using this procedure.
Barium enema -- This procedure examines the large intestine with an x-ray. It involves being given barium (a dye) as an enema, which coats the lining of your large intestine and rectum. It is generally not as reliable a test as colonoscopy.
CT scans -- This imaging technique allows your doctor to look at the entire intestine and can help locate intestinal obstructions or fistulas.

Preventive Care

Although there is no known way to prevent Crohn's disease, the condition can usually be managed with a combination of medication, diet, and lifestyle changes. Exercise can help prevent the stress and depression that often accompany Crohn's disease, and quitting smoking can reduce symptoms. Eating a diet rich in fruit and vegetables can also help lessen symptoms.

Treatment Options

The primary goal in treating Crohn's disease is to control acute flares of the disease and to maintain remission for as long as possible. The specific type of treatment often depends on how severe the symptoms are. For example, people with mild-to-moderate symptoms are usually treated with medications that reduce swelling and suppress the immune system. More severe cases may require surgery.

Many people with inflammatory bowel diseases use complementary and alternative remedies in addition to prescription medications. Preliminary studies indicate that lifestyle changes, dietary adjustments (such as eating a rich variety of fruits and vegetables and avoiding saturated fat and sugar), and specific herbs and supplements may be useful additions to treatment.

Lifestyle

Stress

Many people with Crohn's disease report that stress makes their symptoms worse. Relaxation techniques and mind-body exercises, such as yoga, tai chi, and meditation, are worth considering, particularly when used in addition to other forms of treatment. In addition, studies suggest that hypnosis may improve immune function, increase relaxation, decrease stress, and ease feelings of anxiety.

Exercise

Exercise is helpful for those with Crohn's disease, both in terms of maintaining health and reducing stress. Although exercise is considered safe for people with Crohn's disease, anyone with a chronic illness should talk to their doctor before starting a new exercise or fitness regimen. It is especially important for people with Crohn's disease to drink water before exercising and during exercise to prevent dehydration. Extreme changes in body temperature during exercise should also be avoided.

Smoking

Cigarette smoking is a risk factor for Crohn's disease and studies have shown that it may worsen symptoms. If you smoke, you should quit.

Drug Therapies

Although medications cannot cure Crohn's disease, they can reduce symptoms and help you control your condition. Sometimes, they can induce remission of the disease for a period of time. Medications commonly used to treat Crohn's disease include:

Sulfasalazine (Azulfidine) -- An older drug that reduces inflammation during acute flare-ups and is usually taken with folic acid. Side effects include abdominal discomfort, nausea, and lowered sperm count. Sulfasalazine can be effective, but newer drugs are available.
Mesalamine (Asacol, Rowasa) -- This drug reduces inflammation during acute flare-ups and helps prevent recurrences, and generally has fewer side effects that sulfasalazine.
Corticosteroids (such as budesonide, prednisone, and prednisolone) -- These drugs can reduce inflammation throughout your body but have many side effects, including acne, and an increased risk of infection, osteoporosis, high blood pressure, excessive hair growth, diabetes, and disorders of the eye including glaucoma and cataracts. Corticosteroids also suppress your body's production of the hormone cortisol and cannot be stopped abruptly. They are not for long-term use, but may be used to control flares.
Immune system suppressors -- These medications decrease inflammation by suppressing the immune system. They are sometimes used in combination with steroids to reduce the dose of the steroid medication. These drugs can take several months to work, and all may have significant side effects. Drugs include azathioprine (Imuran), methotrexate (Rheumatrex), infliximab (Remicade), and cyclosporine. Newer drugs in this class that have fewer side effects, such as adalimumab (Humira), are being tested.
Antibiotics -- Antibiotics may be prescribed to help treat fistulas and ulcers. Ciproflaxin (Cipro) and metronidazole (Flagyl) are most commonly used.
Antidiarrheal medications (such as diphenoxylate, loperamide, or psyllium) -- Medications used to treat diarrhea must be used only under medical supervision and with extreme caution. They can slow down the normal movements of the gastrointestinal tract and, in severe cases, may cause a complication known as toxic megacolon.

Surgical Procedures

Although surgery will not cure Crohn's disease, three out of four people with the condition will eventually have resections (parts of their colons removed) to close fistulas or to remove a severely damaged part of your intestine. In some cases laparoscopic surgery (which uses a smaller incision) can be done, leading to fewer complications and shorter hospital stays. Strictureplasty, in which a balloon is inserted into the intestine and expanded, is sometimes done when the intestine has become too narrow from scar tissue.

Complementary and Alternative Therapies

People with Crohn's disease often cannot absorb all the nutrients their bodies need, due to damage in the intestine, or they find it difficult to eat because of abdominal pain and nausea. Some medications may also lower needed nutrients in the body. For example, sulfasalazine reduces the body's ability to absorb folate while corticosteroids can reduce levels of calcium. Making sure that you get enough nutrients is a crucial part of treating Crohn's disease. People with significant malnourishment, severe symptoms, or those awaiting surgery may require parenteral (intravenous) nutrition.

Nutrition

Although diet cannot cause or cure Crohn's disease, some studies suggest that people who eat foods high in saturated fat and sugar or who eat processed foods may be more likely to develop the disease. Certain foods may also reduce symptoms and make recurrences of the disease less likely.

Eating fruits and vegetables, lowering fat, and eliminating sugar may reduce the risk of developing Crohn's disease. Although a low-fiber diet is one of the risk factors for developing Crohn's disease, some people with Crohn's disease find that fiber makes symptoms worse. If fiber bothers you, steam or bake your vegetables rather than eating them raw, and avoid high fiber fruits such as apples.
Certain foods may aggravate symptoms of Crohn's disease – most often, dairy products, fats, and spicy foods. People with Crohn's disease may want to avoid these foods.
Eat five or six smalls a day.
If symptoms are severe, an elemental diet may be recommended. Elemental formulas are liquid diets that contain only the basic building blocks of food and need not be broken down into smaller substances along the digestive tract. Some people find it difficult to stick to an elemental diet, but after a period of time, often other foods can be reintroduced. One study suggests that adding omega-3 fatty acids to an elemental diet may boost its nutritional content and make it more likely that people with Crohn's disease will adhere to it.

Vitamins and Minerals

Because of decreased appetite, malabsorption, chronic diarrhea, side effects of medication, and surgical removal of parts of the digestive tract, many people with Crohn's disease have vitamin and mineral deficiencies. In particular, people with Crohn's disease may lack adequate vitamin D, B12, and K, plus folic acid, calcium, and zinc. Your doctor may recommend that you take a multivitamin daily.

Zinc (25 mg), folic acid (800 mcg), vitamin B12 (800 mcg) -- These vitamins are used by the body to repair cells in the intestine. In addition, drugs such as sulfasalazine and methotrexate may case levels of folic acid in the body to drop, requiring supplementation.

Vitamin D (1,000 IU per day) -- is necessary to maintain strong bones. People with Crohn's disease, especially those who take corticosteroids, often have low levels of vitamin D and are at risk for osteoporosis.

Fish oil (2.7 g per day) -- Omega-3 fatty acids found in fish oil may help fight inflammation and reduce the chances of recurrence, but studies have been mixed. The study with the most positive results used a special type of fish oil – "enteric-coated free-fatty-acid form" – that is not sold commercially. Some researchers suggest that measuring the blood levels of different types of fatty acids may help determine if fish oil would be useful. Do not take high doses of a fish oil supplement if you take blood-thinning medication.

Saccharomyces boulardi (250 mg three times per day to 500 mg four times per day) -- One small study indicated that this type of "good" bacteria helped people with Crohn's disease reduce the incidence of diarrhea. However, other studies have shown mixed results.

N-acetyl glucosamine -- Preliminary research suggests that N-acetyl glucosamine supplements or enemas may improve symptoms of inflammatory bowel disease, but more studies are needed to know whether glucosamine would have any effect on Crohn's disease.

Glutamine (400 mg four times per day) -- is an amino acid found in the body that that helps the intestine function properly. While there is no evidence that glutamine specifically helps reduce symptoms of Crohn's disease, it may be beneficial for overall intestinal health. Glutamine is best taken on an empty stomach. Do not take glutamine is you are diabetic or have seizures.

Herbs

Because of the presence of inflammation and the nature of the disease, Crohn's disease should not be treated with herbs alone. However, herbs may be a useful complement to traditional medical treatment. Remember that herbs can trigger side effects and can interact with other herbs, supplements, or medications. For these reasons, herbs should be taken with care, under the supervision of a health care provider.

The evidence for using herbs to treat Crohn's disease is mostly lacking. Among the herbs that have been used traditionally to treat inflammation within the digestive tract are:

Slippery elm (Ulmus fulva) is a demulcent (protects irritated tissues and promotes their healing). Take 60 -320 mg per day. One tsp. powder may be mixed with water and drunk three to four times a day.
Marshmallow (Althaea officinalis) is a demulcent and emollient; drink one cup of tea three times per day. To make tea, steep 2 - 5 g of dried leaf or 5 g dried root in one cup boiling water. Strain and cool. Avoid marshmallow if you have diabetes.
Cat's claw (Uncaria tomentosa, 250 mg per day) is an anti-inflammatory.
Boswellia (Boswellia serrata, 1,200 mg three times per day for up to 8 weeks) has anti-inflammatory properties, and a few small studies suggest that it may be effective in treating Crohn's disease. However, more research is needed to be sure. Bsowellia may interact with other drugs and supplements, so talk to your doctor before taking it.

Homeopathy

Although few studies have examined the effectiveness of specific homeopathic therapies, professional homeopaths may consider the following remedies for the treatment of Crohn's disease symptoms (such as diarrhea) based on their knowledge and experience. Before prescribing a remedy, homeopaths take into account a person's constitutional type -- your physical, emotional, and psychological makeup. An experienced homeopath assesses all of these factors when determining the most appropriate treatment for each individual.

Mercurius -- for foul-smelling diarrhea that may have streaks of blood accompanied by a sensation of incomplete emptying. This remedy is most appropriate for individuals who tend to feel exhausted following bowel movements, experience fluctuations in body temperature, perspire frequently, and have a thirst for cold fluids.
Podophyllum -- for explosive, gushing, painless diarrhea that worsens after eating or drinking. Exhaustion often follows bowel movements, and the individuals for whom this remedy is appropriate may experience painful cramps in the lower legs and feet.
Veratrum album -- for profuse, watery diarrhea accompanied by stomach cramps, bloated abdomen, vomiting, exhaustion, and chills. The diarrhea tends to worsen as a result of eating fruit. The individual for whom this therapy is appropriate tends to crave cold liquids.

Acupuncture

Acupuncture has long been used in Traditional Chinese Medicine to treat inflammatory bowel disease. One study in Germany found that acupuncture and moxibustion were effective specifically for treating Crohn's disease. Acupuncturists treat people with inflammatory bowel disease based on an individualized assessment of the excesses and deficiencies of qi located in various meridians. Moxibustion (a technique in which the herb mugwort is burned over specific acupuncture points) is used because its effect is thought to reach deeper into the body than using needles alone.

Other Considerations

Pregnancy

Women who are in remission at the time of conception generally have normal pregnancies and healthy babies. However, women with active disease are more prone to miscarriages, spontaneous abortions, and stillbirths. Symptoms often get worse during pregnancy. For this reason, women with active Crohn's disease who are or wish to become pregnant should continue medications under the guidance of their doctor. Corticosteroids or sulfasalazine are considered relatively safe during this time.

Pregnant women should avoid high doses of vitamins. An obstetrician can provide instructions regarding taking multivitamins during pregnancy. The herbs cat's claw (Uncaria tomentosa) and turmeric (Curcuma longa) are not recommended during pregnancy or breastfeeding.

Prognosis and Complications

A number of complications can develop from Crohn's disease. Many can be successfully treated.

Narrowing of the colon, which may cause obstruction
Perforation of the colon
Abscesses (pus-filled pockets of infection) in the colon
Toxic megacolon (grossly swollen colon that may rupture)
Fistulas (abnormal hollow passages that lead from one part of the intestine to another, or to other organs)
Infection of the blood (sepsis)
Colon cancer
Nutritional problems (including weight loss and reduced muscle mass)
Joint pain and arthritis
Osteoporosis (bone loss)
Gallstones
Eye infections/inflammation
Mouth ulcers, gum inflammation, and dental cavities
Liver damage
Blood clots
Depression and anxiety
Anemia

Although there is no cure for Crohn's disease, many people with the disease lead active lives by controlling their symptoms with medication. Over time, however, Crohn's disease is less responsive to treatment. Within 10 years of diagnosis, 71% of people will need surgical removal of the affected intestine, and many experience at least one relapse in any 10-year period.

Supporting Research

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Review Date:
3/18/2007
Reviewed By:
Steven D. Ehrlich, N.M.D., private practice specializing in complementary and alternative medicine, Phoenix, AZ. Review provided by VeriMed Healthcare Network.

A.D.A.M. Copyright

adam.com

Smoking

FitSugar — Wed, 08 Oct 2008 17:34:57 -0700

In This Report

Highlights
Introduction
Nicotine Addiction
Health Risks
Secondhand Smoke
Smoking Bans
Quitting Smoking
Symptoms of Withdrawal
Failure to Quit
Lifestyle Changes
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Smoking and Your Health

Smoking may worsen knee osteoarthritis in men. A study published in the Annals of Rheumatic Disease found that male smokers have more pain and cartilage loss than men who do not smoke. Previous studies have not found such a link.
Smoking greatly increases the risk of age-related macular degeneration. An Australian study reports that smokers are four times more likely to develop the eye condition than those who have never smoked. Smokers also developed the condition at an earlier age.
Analysis of several studies suggests that smoking cigarettes and, in some cases, cigars or pipes, may reduce the risk of Parkinson's disease. However, smoking causes many other serious health conditions and should not be considered a means for preventing Parkinson's.
A small study suggests that infants who are breastfed just after their mother smokes sleep less than those whose mothers did not smoke.

Smoking Cessation

Certain genes may make it easier for you to quit smoking. Researchers at Duke University have identified more than 200 genes that distinguish those who have successfully kicked the habit. It is the first time such genes have been identified. The findings could lead to new smoking cessation therapies that target a person's specific genetic makeup.

Smoke Free Zones

More and more households in the United States are banning smoking. The U.S. Centers for Disease Control and Prevention (CDC) reports that 75% of households now forbid smoking at any time or place in the home.

Smoking in the Movies

Teens who see actors smoke on screen are more likely to become established smokers, according to an updated study in the Archives of Pediatric Adolescent Medicine. Study authors say the likelihood of smoking increases with exposure to movies that depict such behavior.

Introduction

More than 20% of adults in the United States smoke, according to a 2006 report by the U.S. Centers for Disease Control and Prevention (CDC). More than 80% of them smoke every day. Although smoking had steadily declined among adults in recent years, the trend now appears to have stalled. Between 2004 and 2005, the CDC says there was no observable change in smoking rates among U.S. adults.

The addictive effects of tobacco have been well documented. Tobacco is considered to be a mood and behavior altering substance that is psychoactive and abusable. Tobacco is believed to be as potentially addictive as alcohol, cocaine, and morphine. Tobacco and its various components increase the risk of cancer (especially in the lung, mouth, larynx, esophagus, bladder, kidney, pancreas, and cervix), heart attacks, strokes, and chronic lung disease.

The younger children start smoking, the more likely they will smoke as an adult. Smoking is often immediately addictive. According to the American Cancer Society, the earlier you start smoking, the more likely you are to develop long-term nicotine addiction.

In the past, advertising was responsible for encouraging some teens to smoke. New regulations have made it much more difficult for advertisers to promote smoking to young people. However, scenes that show people smoking are still common in movies and television shows, often in a positive light. This may be a major influence on the attitude toward smoking in children and adolescents. An updated study in the Archives of Pediatric Adolescent Medicine found that adolescents that watch movies that portray smoking are more likely to become established smokers.

To prevent children from smoking, parents should not smoke, and they should tell their child that they disapprove of smoking. Schoolchildren who believed that both their parents strongly disapproved of smoking were less than half as likely to smoke as those kids whose parents did not show as much disapproval towards smoking. Other research has supported these findings.

Children whose parents closely monitor their television and music-listening habits are less likely to drink, use drugs, and smoke cigarettes.

Neglected children, or children with absentee parents, were four times as likely to abuse drugs, drink, and smoke as children living with parents who were regularly present and who offered a structured lifestyle.

In a 2002 study, children who regularly attended religious services were also less likely to smoke.

Doctors can have a major effect on young people. However, in one survey, less than half of teenagers had ever been asked by their doctors if they smoked or were counseled not to smoke, even though most teen smokers said they would admit to it if asked.

More American men smoke than women. The following chart details the rate of current smoking in the United States among adults aged 18 years and over, grouped by age and sex:

While the number of adults over 65 who smoke is lower than those in other age groups, older adults usually have smoked for a long time (about 40 years) and tend to be heavier smokers, according to the American Lung Association. Because of this, older smokers are more likely to have smoking-related illnesses.

Caucasian students (under age 18) are more likely to smoke than Hispanics and African-Americans. In 2005, the rate of smoking was highest among American Indians and Alaskan natives. Hispanics and Asians had the lowest rates.

In general, the rate of smoking is highest in the Midwest and South and lowest in the Northeast and West. Utah has the lowest rate of smoking in the United States.

A major U.S. government study reported that people who have not graduated from high school or received their General Education Development (GED) certificate tend to have higher smoking rates than those who attended college.

Higher rates of cigarette smoking have been reported among adults who have earned a GED and those with a 9 – 11 grade education. The lowest rates are seen among those with advanced college degrees.

People with low self-esteem and adolescents with behavioral problems have a higher risk for smoking. Men and women with mental disorders are 50% more likely to smoke than those without such illness.

For example, depression and schizophrenia are known risk factors for smoking. Both may actually have biologic effects that are responsible for this higher risk.

Smoking is much more common among persons with disabilities than those without emotional, mental, or physical limitations. A 2007 Centers for Disease Control study found that the rate of smoking is nearly 50% higher among persons with disabilities. The CDC survey included those with mental illness and drug and alcohol addictions in the disabled group.

Evidence now strongly supports the idea that genes play a role in a person's dependence on nicotine. Researchers are now targeting specific genes that may be responsible for nicotine dependence. So far, research has been shown that there is a common genetic vulnerability to both nicotine and alcohol dependence.

Some studies suggest that the cheaper it is to buy cigarettes and smoke, the more widespread smoking will be. For example, states that have low taxes on cigarettes have a high proportion of smokers. Making it more expensive to smoke may reduce the number of smokers.

Nicotine Addiction

Nicotine is the chemical in cigarettes that makes them addictive. Higher levels of nicotine in a cigarette can make it harder to quit smoking. A report by the Massachusetts Department of Health found that the amount of nicotine in cigarettes has steadily increased over the last 6 years. Higher nicotine levels were found in all cigarette categories, including “light" brands. Massachusetts is one of several states that require tobacco manufacturers to submit yearly reports regarding cigarettes.

Some researchers feel nicotine is as addictive as heroin. In fact, nicotine has actions similar to heroin and cocaine, and the chemical affects the same area of the brain.

Depending on the amount taken in, nicotine can act as either a stimulant or a sedative. Cigarette smoking has definite immediate positive effects. For example, it can:

Boost mood and relieve minor depression
Suppress little fits of anger
Enhance concentration and short-term memory
Produce a modest sense of well-being

Most smokers have a special fondness for the first cigarette of the day because of the way brain cells respond to the day's first nicotine rush. Nicotine, particularly taken in the first few cigarettes of the day, increases the activity of dopamine, a chemical in the brain that elicits pleasurable sensations, a feeling similar to achieving a reward.

Over the course of a day, however, the nerve cells become desensitized to nicotine. Smoking becomes less pleasurable, and smokers may be likely to increase their intake to get their "reward." A smoker develops tolerance to these effects very quickly and requires increasingly higher levels of nicotine.

A smoker may "forget" their craving for nicotine if a part of the brain called the insula becomes damaged. A 2007 study published in the journal Science found that smokers with brain damage to this area were 136 times more likely to forget their addiction to nicotine. The findings may one day lead to new drugs that better help a person quit.

Smokeless tobacco, also called spit tobacco, includes chewing tobacco (dip and chew), tobacco powder (snuff), as well as flavored tobacco lozenges. These products also contain nicotine. There are two forms of spit tobacco.

These products allow tobacco to be absorbed by the digestive system or through mucous membranes. Smokeless tobacco contains at least 28 cancer-causing substances. Smokeless tobacco is not a safe substitute for smoking cigarettes or cigars. According to the National Institutes of Health, chewing on an average-size piece of chewing tobacco for 30 minutes can deliver as much nicotine as smoking three cigarettes.

Although research is inconsistent, some evidence suggests that smokeless tobacco produces a 50-fold increase in the risk of oral cancer, gingivitis, and tooth loss.

Health Risks

Smoking -- even just a few cigarettes a day -- has been linked to many serious health risks. Some are listed below.

According to the American Lung Association, smoking is directly responsible for about 90% of the deaths due to lung cancer. Smoking is also responsible for the majority of deaths due to chronic obstructive pulmonary disease (COPD), which includes emphysema and chronic bronchitis.

A study in the July 2006 American Journal of Respiratory and Critical Care Medicine showed that smokers with asthma who give up smoking can improve their lung function in as little as 1 week. The small study involved 21 smokers with asthma. Ten of them quit smoking for 10 weeks, while the others continued to smoke. After just a week, lung function test scores in those who stopped smoking improved considerably. In less than 2 months, lung function scores among those who stopped smoking improved by more than 15%.

Study authors say their findings show that there is a “reversible component to the harmful effects of smoking on the airways in asthma.”

All forms of tobacco raise heart attack risk. Smoking, chewing tobacco, and being exposed to secondhand smoke greatly increase the risk of a heart attack. In some cases, the risk of heart problems in people who smoke or are exposed to smoke may be three times greater, according to a study published in the journal Lancet. However, the study also found that the risk of a heart attack among those who stopped smoking slowly decreased over time.

Smoking has a negative affect on a man's sexuality and fertility. Heavy smoking is frequently cited as a contributory factor in impotence because it decreases the amount of blood flowing into the penis. One study noted that among men with high blood pressure, smoking caused a 26-fold increase in impotence.

Smoking impairs sperm motility, reduces sperm lifespan, and may cause genetic changes that can affect a man's offspring. One 2002 trial found that men or women who smoke have lower success rates with fertility treatments. An earlier study reported that men who smoke also have lower sex drives and less frequent sex.

Studies have linked cigarette smoking to many reproductive problems. Continuing to smoke during pregnancy may also cause health problems in the baby.

Negative effects of smoking on female fertility include:

Greater risk for infertility. Women at greatest risk for fertility problems are those who smoke one or more packs a day and who started smoking before age 18.
Earlier menopause. Women who smoke tend to start menopause at an earlier age than nonsmokers, perhaps because toxins in cigarette smoke damage eggs.
Pregnancy complications. Women who smoke have a greater risk for ectopic pregnancy and miscarriage.

Click the icon to see an image of an ectopic pregnancy.

Effects on Unborn Child. Smoking during pregnancy increases the risk for stillbirth, prematurity, and low birth weight in their babies. Women who smoke during pregnancy have lower levels of folate, a B vitamin that is important for preventing birth defects.

Children of mothers who smoke during pregnancy may also be at increased risk for obesity and diabetes.

Some women have particular genes that may make them especially likely to deliver low birth weight infants if they smoke, although newborns of all female smokers have a greater risk for low weight. The good news is that women who quit before becoming pregnant or even during the first trimester reduce the risk for a low birth weight baby to that of women who never smoked.

Women who want to become pregnant should make every attempt to quit and should use smoking cessation aids before they try to conceive. After birth, if new mothers cannot quit, they should at least be sure not to smoke in the same room as their infant.

Smoking and Breastfeeding. Smoking right before breastfeeding may interrupt the child's sleep patterns. A small study found that such infants sleep less than other infants, and that their sleep time dropped significantly as levels of nicotine in breast milk increased.

Smoking has many harmful effects on bones and joints:

Smoking can keep new bone from forming. Women who smoke are at high risk for loss of bone density and osteoporosis.

Click the icon to see an image of osteoporosis.

Postmenopausal women who smoke have a significantly greater risk for hip fracture than those who do not.
Men who smoke may have more severe symptoms of knee arthritis, according to a study published in the Annals of Rheumatic Disease.
Smokers are more apt to develop degenerative disorders and injuries in the spine.
Smokers have more trouble recovering from surgeries, including knee or hip replacements. A 2006 study published in the Journal of Bone & Joint Surgery suggests that smoking delays tendon-bone healing, which may lead to a slower recovery after rotator cuff repair surgery.
Smokers whose jobs involve lifting heavy objects are more likely to develop low back pain than nonsmokers.
Smoking may increase the risk of rheumatoid arthritis in some older women. A 2006 study in Annals of the Rheumatic Diseases showed that smoking nearly doubled the risk of rheumatoid arthritis in postmenopausal women who did not have the most established genetic risk factor for the disease, a genotype called HLA-DRB1 SE.

Click the icon to see an image of rheumatoid arthritis.

Smoking may increase the risk of developing diabetes. Researchers involved in the Insulin Resistance Atherosclerosis Study (IRAS) looked at the relationship between smoking and diabetes and found that 25% of smokers who started the trial with normal blood sugar had diabetes 5 years later compared to 14% of nonsmokers. The results were published in Diabetes Care.

A study released in 2006 supports earlier beliefs that smokers have a higher risk of developing glucose intolerance, a condition that precedes diabetes. The study, published in the British Medical Journal, involved 4,572 people. The findings suggest that chemicals in smoke could affect the pancreas. The pancreas is the organ that produces insulin, which helps control blood sugar (glucose) levels.

Smoking increases acid production in the stomach. It also reduces blood flow and production of compounds that protect the stomach lining.

Diverticulitis. One study suggested that smoking was a major risk factor in diverticulitis, a condition in which small bumps develop in the wall of the colon. In addition, smokers were at risk for complications from diverticulitis, including bleeding and abscess. Diverticulitis mostly affects people over age 50.

Inflammatory Bowel Disease. Smoking has mixed effects on inflammatory bowel disease. Inflammatory bowel disease is the collective term for ulcerative colitis and Crohn's disease. Smokers have been shown to have lower than average rates of ulcerative colitis, but higher than average rates of Crohn's disease. Smokers with Crohn's disease who quit are said to have less severe symptoms.

Click the icon to see an image of inflammatory bowel disease.

Peptic Ulcers. Results of studies on the effect of smoking on ulcers are mixed. Some evidence suggests that smoking delays the healing of gastric and duodenal ulcers. One study reported that after ulcers healed, about half of smokers relapsed after a year, and that all heavy smokers relapsed after 3 months. Other studies, however, have found no increased risk for ulcers in smokers. Smoking does not appear to increase susceptibility to Helicobacter pylori (H. pylori), the bacteria that causes many peptic ulcers.

Click the icon to see an image of peptic ulcers.

Hepatitis and Cirrhosis. Smoking is linked to increased liver scarring (cirrhosis) caused by either excessive drinking or chronic hepatitis B or C viruses.

Cyanide, a chemical found in tobacco smoke, interferes with thyroid hormone production. Smoking triples the risk for developing thyroid disease, particularly hyperthyroidism and hypothyroidism. Women smokers with subclinical hypothyroidism (a symptom-free condition in which the thyroid gland is mildly underactive) have a higher risk for developing full-blown hypothyroidism than their nonsmoking peers. Smoking has also been linked to goiter, a swelling of the thyroid that occurs in people who do not get enough iodine.

Click the icon to see an image of the thyroid.

Smokers are at increased risk for heart and circulatory problems and delayed wound healing after surgery. In one study, patients who were able to cut down or quit smoking 6 - 8 weeks prior to knee or hip replacement surgery were much less likely to suffer complications.

The following age-related conditions occur at higher rates in smokers than nonsmokers:

Cataracts. Quitting smoking reduces your chances of needing cataract surgery in the future, although not to the level seen with nonsmokers.

Click the icon to see an image of a cataract.

Age-related macular degeneration (AMD). AMD is a leading cause of blindness in older people. An Australian study, published in 2007 found that the condition is four times more likely in persons who smoke than those who have never done so. Symptoms of macular degeneration include a loss of central vision, which makes it difficult to read.
Gum disease and tooth loss. A government study found that more than half of the cases of severe gum disease in adults in the United States may be due to cigarette smoking.
Wrinkles. Studies confirm that smokers are nearly five times more likely to develop more and deeper wrinkles as they age compared to nonsmokers.
Baldness and premature gray hair. Certain chemicals in smoke break down in hair cells, which leads to hair damage.
Hearing loss, particularly high-frequency hearing loss. Some experts believe that losing the ability to hear high pitched sound in smokers may be due to a decrease in blood flow to the cochlea, the part of the ear that carries sound to the brain.
Incontinence. One study of 600 women indicated that smokers and former smokers are twice as likely to develop incontinence as women who never smoked.

Secondhand Smoke

Secondhand smoke is produced by a burning cigarette or other tobacco product. An estimated 4 million children a year get sick from being around secondhand smoke. Parental smoking has been shown to affect the lungs of infants as early as the first 2 - 10 weeks of life, and such abnormal lung function could persist throughout life.

Exposure to secondhand smoke in the home increases the risk for asthma and asthma-related emergency room visits in children who have existing asthma.

Parental smoking is believed to increase the risk for lower respiratory tract infections (such as bronchitis or pneumonia) by 50%. Environmental exposure to smoke is thought to be responsible for 150,000 - 300,000 such cases every year.

Smoking Bans

Smoking bans have spread across the country. By October 2007, at least 22 states and the District of Columbia have passed some type of law banning smoking in almost all public places and workplaces, including restaurants and bars. The date an individual state's ban takes effect varies greatly; some do not take effect until 2008 or 2009.

As of January 1, 2006, nine states were considered "smoke-free" -- California, Connecticut, Delaware, Massachusetts, Maine, New York, Rhode Island, Vermont, and Washington.

Quitting Smoking

It's never too late to quit smoking. According to the American Cancer Society, about half of all smokers who keep smoking will die from a smoking-related disease. Quitting has immediate health benefits.


Time after last cigarette	Physical Response
20 minutes	Blood pressure and pulse rates return to normal.
8 hours	Levels of carbon monoxide and oxygen in the blood return to normal.
24 hours	Chance of heart attack begins to decreases.
48 hours	Nerve endings start to regrow. Your ability to taste and smell increases.
72 hours	Bronchial tubes relax and the lungs can fill with more air.
2 weeks to 3 months	Improved circulation; lung function increases up to 30%.
1 to 9 months	Decreased rates of coughing, sinus infection, fatigue, and shortness of breath; regrowth of cilia in the airways, increasing the ability to clear mucus and clean the lungs and reducing the chance of infection; overall energy level increases.
Long-Term Effects	After a year, the risk of dying from heart attack and stroke is reduced by up to 50%.

According to the National Institutes of Health, about 40% of smokers who want to quit make a serious attempt to do so each year, but fewer than 5% actually succeed. A June 2006 report published by the NIH says that the available smoking cessation products and therapies are greatly underused. If more smokers asked for or were offered such help, the agency says quit rates could double or triple.

Some people have certain genes that make quitting easier. Researchers at Duke University have identified more than 200 genes that distinguish those who have successfully kicked the habit. It is the first time such genes have been identified. The findings could lead to new smoking cessation therapies that target a person's specific genetic makeup.

Methods of quitting smoking include counseling and support groups, nicotine patches, gums, lozenges, and sprays, smoking cessation pills, and slowly cutting back on the number of cigarettes smoked (incremental reduction).

About 4% of smokers who quit without any outside help succeed. Nevertheless, most people try to quit alone, and many have reported activities that can help the process of withdrawal. The primary obstacle in trying to quit alone is making the behavioral changes necessary to eliminate the habits associated with smoking. Excellent books, tapes, and manuals are available and are strongly recommended to help people who want to quit without other assistance.

Nicotine replacement therapy involves the use of products that provide low doses of nicotine that do not contain the contaminant found in smoke. The goal of therapy is to relieve cravings for nicotine and ease the symptoms of withdrawal.

In general, nicotine replacement therapy benefits moderate-to-heavy smokers the most. However, it does appear somewhat helpful for light smokers (people who smoke fewer than 15 cigarettes a day).

Nicotine Patches. Nicotine patches deliver nicotine through the skin. This is called transdermal nicotine delivery. It is effective in reducing symptoms during withdrawal. Nicotine patches are available over the counter.

Patches may work in different ways:

Step-Down Approach. Patches that use this method include NicoDerm CQ. The patches come in three strengths (21, 14, and 7 mg). You use the strongest dose first and reduce it gradually over a period of 8 - 10 weeks. A 21 mg patch is about equal to 15 cigarettes. A heavy smoker may need to wear two patches at first.
Single-Step Approach. The single-step patch (Nicotrol) can be taken off after 16 hours and replaced 8 hours later. It can be used for only 6 weeks.

Patches are applied and used in similar ways:

A single patch is worn each day and replaced after 24 hours.
To avoid skin irritation it is applied to different hairless locations above the waist and below the neck each day.
People can wear the patches for 24 hours, but some have reported odd dreams and have disliked the sensation of the patch during the night. People who wear the patch all the time, however, have fewer withdrawal symptoms and slightly better abstinence rates than those who take it off at night.
Patches should be stored and discarded safely, particularly in homes with small children. Small children have been poisoned and gotten sick from wearing, chewing, or sucking on nicotine patches. There have been no reports of death from children who have been poisoned.
The FDA recommends using the patches for 3 - 5 months, although some studies suggest that using them for 8 weeks achieves the maximum benefits.

Children should not come in contact with the patches, even while the smoker is wearing them. If the child has worn the patch, the affected skin should be washed right away. Urgent medical care may be required if the child has eaten nicotine or worn a patch for a prolonged time.

Nicotine Gum. Nicotine gum (Nicorette) is available over the counter and has helped many people quit. Some prefer it to the patch because they can control the nicotine dosage, and chewing satisfies the oral urge associated with smoking.

Tips for using the gum:

If you are just starting to quit, chew 1 - 2 pieces each hour. A smoker should not chew more than 20 pieces a day.
The goal is to stop using the gum by 6 months, but about 3% of people continue to use it long after they have quit smoking.
The gum must be chewed slowly until it develops a peppery taste. It is then tucked between the gum and cheek where it is stored so that the nicotine can be absorbed.
Coffee, tea, soft drinks, and acidic beverages may interfere with nicotine absorption, so people should wait at least 15 minutes after drinking before chewing a piece of gum.

Some people prefer other methods or cannot use the gum for the following reasons:

They find the gum unpleasant tasting.
Side effects specific to the gum may include upset stomach, mouth ulcers, hiccups, and throat irritation.
They are embarrassed by chewing gum.
They wear dentures.

Long-term dependence may be a problem with the gum. Although such dependence is probably safer than smoking, research is needed to confirm this, and experts recommend people chew gum for no more than 6 months.

The Nicotine Inhaler. The nicotine inhaler resembles a plastic cigarette holder. It comes with a number of nicotine cartridges, which are inserted into the inhaler and "puffed" for about 20 minutes, up to 16 times a day. The dose is gradually decreased. It requires a prescription in the United States. Several studies have reported that the inhaler triples abstinence rates (between 17 - 28%) compared with placebo (6 - 9%) after 6 months. It has some specific advantages over other nicotine replacement products:

The inhaler provides varying doses of nicotine on demand (as opposed to continuously with the patch or the gum) and is relatively fast-acting. Blood nicotine levels peak about 20 minutes after using the inhaler, comparable to the gum and faster than the 2 - 4 hours seen with the patch.
It satisfies oral urges.
Most of the nicotine vapor is delivered in the mouth, not into the lung airways (although some people experience mouth or throat irritation and cough).

Using a combination of the inhaler and the patch may be particularly effective. In one study, the combination led to an abstinence rate of over 60% after 6 weeks. While this percentage dropped off over time, it was still a large improvement over the use of the inhaler and a placebo patch.

The Nicotine Nasal Spray. The nasal spray satisfies immediate cravings by providing doses of nicotine rapidly and thus may play a useful role in conjunction with slower-acting nicotine replacement therapies. (Nicotine levels peak within 5 - 10 minutes after administering the spray). The spray can irritate the nose, eyes, and throat, so it may not be suitable for those with allergies or sinus infections. Most people, however, can tolerate the side effects, which usually go away within the first few days.

Nicotine Lozenge. A nicotine lozenge (Commit) is available over the counter. It is made from pressed tobacco and comes in two strengths for heavier or lighter smokers. In a large 2002 study, 15 - 18% of smokers who used it remained smoke free, compared to 6 - 10% who were given a dummy lozenge. Side effects included heartburn, hiccups, nausea, headaches, and cough. The Commit lozenge also contains phenylalanine, a chemical that certain people may need to avoid.

Facts about Nicotine Replacement Therapy:

Not cheating on the very first day of nicotine-replacement use increases the chance of quitting permanently by tenfold.
The more cigarettes a patient smokes, the higher the dose of nicotine replacement may be required at the start.
Adding a counseling program may boost the effect of any nicotine replacement program.
Do not smoke while using nicotine replacement. It can cause nicotine to build up to toxic levels.
Nicotine replacement helps prevent weight gain while it is being used, but people are still at higher risk for gaining weight when they stop all nicotine.

Side Effects. Side effects of any nicotine replacement product may include headaches, nausea, and other gastrointestinal problems. People often experience sleeplessness in the first few days, particularly with the patch, but the insomnia usually passes. Patients using very high doses are more likely to have symptoms. Reducing the dose can prevent them.

Special Concerns for Specific Individuals. There has been some concern that the patch might be harmful for people with heart or circulatory disease, but studies are finding that it poses no danger for these individuals. In fact, it may help reduce angina attacks brought on by exercise. However, unhealthy cholesterol levels (lower HDL levels) caused by smoking remain abnormal with use of the nicotine patch. HDL levels improve when all nicotine is stopped.

Nicotine replacement may not be completely safe in pregnant women, although it has been used successfully in this group without ill effect. There is an increase in heart rates in unborn children of women who use the patch as compared with those who smoke.

Keep all nicotine products away from children. Nicotine is a poison. All nicotine products should be kept safely away from small children. A parent should call a physician or a poison control center immediately if a child has been exposed to a nicotine replacement product, even for a short duration. Parents should also call the doctor if a small child has been exposed to a nicotine product and has any symptoms, including stomach upset, irritability, headaches, a rash, or fatigue.

Warnings Against Long-Term Use. No one should use nicotine replacement therapies as a long-term substitute for smoking. Any nicotine replacement therapy should be temporary. In one study, use of nicotine gum for more than a year was associated with insulin resistance, an abnormality that occurs in diabetes. Some studies have now suggested that nicotine itself may have properties that increase the risk for cancer, independent of carcinogenic chemicals in smoke. More studies are needed.

Bupropion (Zyban, Wellbutrin) is a type of antidepressant that is also an FDA-approved product for smoking cessation. It differs from most other antidepressants because it increases the effects of dopamine, the brain chemical that appears to play a strong role in nicotine addiction. Using Zyban along with nicotine replacement therapy may help you better control cigarette smoking cravings. Zyban does not contain nicotine. In most cases, Zyban is taken a week or two before quitting, and must be taken for 7 - 12 weeks. The usual maintenance dose is 150 mg tablet twice a day. No single dose should be higher than 150 mg.

Side effects of bupropion include gastrointestinal problems, headaches, insomnia, dry mouth, and irritation. In very rare cases, seizures have occurred, although usually in people who exceeded the recommended dose or who already had risk factors for seizures.

A newer drug called varenicline (Chantrix) may significantly reduce cigarette cravings and work better than Zyban. A study in the Archives of Internal Medicine found that almost 50% of those who took varenicline successfully quit. Varenicline mimics some effects of nicotine on the brain, but blocks others. Previous studies published in the Journal of the American Medical Association showed that Chantrix works twice as well as Zyban and quadruples one’s chances of successfully quitting. The FDA approved Chantrix as a smoking cessation aid in May 2006. It is for use in cigarette smokers age 18 and older. It should not be combined with nicotine replacement therapy.

The tricyclic antidepressant nortriptyline (Pamelor, Aventyl) may help reduce nicotine action. Quit rates with either of these medicines are as high as 30%. Long-term abstinent rates are more than twice those of placebo. Most other antidepressants, including fluoxetine (Prozac), have no additional benefits for smokers.

Nortriptyline has been specifically studied for helping smokers. It is best to start taking the medication 10 - 28 days before your intended quit date. Studies have reported quit rates of 14 - 24%. Side effects of nortriptyline include dry mouth and changes in taste. It should be noted that in rare cases, tricyclics can have serious side effects, and overdose can be deadly. Tricyclics may pose a danger for some patients with certain types of heart disease.

Smokers who use outside help have the best record for quitting, with success rates of 25 - 35%. Those who are counseled in addition to using nicotine replacement and Zyban have the best chance. Brochures, audio tapes, and other self-help materials are often ineffective when used alone, but may be helpful in conjunction with a counseling program.

Types of behavioral approaches:

Problem Solving or Coping Strategies. Smokers more likely to quit smoking when they learn thinking (cognitive) and behavioral techniques for breaking the link between certain cues and smoking, stress management techniques, and ways to handle the symptoms of withdrawal and the urge to relapse. The more intense the counseling program, the better. Smokers should look for programs that offer the following:

Session lengths of 20 - 30 minutes
Four to seven sessions
A 2-week program
Additional 2 weeks or more of follow-up contact

Scheduled Reduction. Scheduled reduction is a gradual way to stop smoking.

Divide the number of minutes per day that you are awake by the number of daily cigarettes you smoke. The number you get is how long you wait between smokes.
Week 1: Set up a schedule with time intervals based on this result and using a timer, smoke only at those intervals. If the "cigarette appointment" is missed by more than 5 minutes, you must skip that cigarette.
Week 2: Reduce the number of cigarettes you smoke by one-third and recalculate your time between smokes based on the lower number.
Week 3: Reduce the count again.
Week 4: Quit smoking

Those who are unable to smoke during working hours could try calculating the intervals based on the usual smoking times of the day.

The Staged Approach. The intent of the staged approach is to plan quitting interventions customized for each individual rather than imposing some general method for quitting. The approach takes the smoker through six stages with behavioral interventions at each point:

Pre-contemplation
Contemplation
Preparation
Action
Maintenance
Termination

Although some studies report this approach is significantly more effective than non-staged methods, an analysis of 23 trials did not find the staged approach to be any more effective than other methods. Most studies, however, were weak, and better research is needed on this approach.

People who follow this approach do not proceed from one stage to another in a simple, step-by-step fashion. They actually cycle or spiral back and forth, so that they may move from stage 1 to 2 to 3, and then back to 2 again. They may stay in maintenance mode for years and then fall back to stage 2. Remember that this is normal -- if you tried quitting in the past and didn't stick with it, don't consider yourself a failure. Just try again.

Stage 1: Pre-Contemplation.

People at this stage have no plans or desire to stop smoking. They aren't even considering quitting. People at this stage are generally unaware of the specific benefits that quitting can bring. Or, they may simply have "failed" in the past and have given up. There's no point in talking about how to start a cessation program at this stage. Instead, it is important to think about how quitting will help you feel better, have more confidence, or live longer. The benefits must be identified before a person will consider quitting. If you are at this stage, a good activity is to ask several friends or family members why they quit.

Stage 2: Contemplation.

A person at this stage is thinking, "I think I should probably quit, but I need help getting started." People at this stage know that quitting is good for them, but it seems like a daunting task or they don't think they can pull it off. Some may have tried and failed in the past. It's important for people at this stage to consider some of the truths and falsehoods of quitting. If you are at this stage, write down (brainstorm) all your potential roadblocks -- the things that you believe make quitting difficult -- and learn strategies for overcoming or side-stepping those hurdles. People at this stage might benefit from making a pledge, contract, or other commitment that they are going to get more active in the near future. The goal is to identify the roadblocks and ways to overcome these hurdles, and make a commitment to quitting.

Stage 3: Preparation.

Smokers at this stage are ready to quit. The goal of this stage is to create a specific action plan that takes all factors into account, so that quitting is successful. People at this stage need to know what methods work and what support exists to help them. If you are at this stage, you should consider some backup plans -- what to do when the urge to smoke hits you.

Stage 4: Action!

People at this stage have just quit. This stage is where the most behavioral change occurs. It requires significant commitment and energy. If you are at this stage, keep talking to friends and family for inspiration. Review your backup plans. Reward yourself for small achievements. Having a fellow smoker quit with you can be a huge support as you both get through this stage.

Stage 5: Maintenance.

People at this stage have been smoke-free at least 6 months. The goal now is to prevent relapse. If you are at this stage, continue to be wary of roadblocks and keep reminding yourself of the benefits you have gained. Think about what you have found most enjoyable about being smoke-free.

Hypnosis. Although rigorous studies are lacking, some people report successful cessation from smoking when hypnosis is given in individual sessions. The process is effective only if you trust the therapist and can feel completely at ease in the vulnerable and passive state necessary for hypnotic suggestion.

During a typical session, the hypnotherapist will use various techniques (such as imagery, silent counting) to put you in a relaxed state.

When you are very relaxed, but not asleep, the hypnotherapist quietly suggests motivations for not smoking. The hypnotherapist should also reinforce a positive self-image while you are in deep relaxation. This helps many people avoid the depression that accompanies withdrawal.

The sessions usually takes about 1 hour.

You should be taught methods of self-hypnosis to use at home, and follow-up once to reinforce what you've learned.

Acupuncture and Acupressure. The acupuncture technique for quitting smoking usually uses very tiny curved staples inserted into three different points around the edge of the ear. The procedure is painless. You will be told to press each staple in a certain order for a few seconds whenever the craving for a cigarette occurs. The acupuncturist may also use acupuncture points elsewhere on the body. There are no side effects except for some soreness if the acupuncture staple is pressed too hard.

A related technique called acupressure involves simply pressing select points on the body when a craving hits. Some studies have reported good quit rates with acupuncture, but few rigorous studies have been conducted using this approach.

Aim to Quit Completely

Everyone who quits should aim to quit completely. Most people who return to smoking "cheat" in the first few weeks. Quitting completely is essential to regain good health and reverse bad effects caused by smoking. Reducing smoking, even by half, does not eliminate the risk for cancer and other health problems. Although smokers take in less smoke and nicotine, the body is still unable to heal itself from the ongoing intake of toxins. It should also be noted that changing to low-tar cigarettes is not a solution. In fact, smokers of these cigarettes tend to inhale deeper, perhaps even increasing health risks.

Create a List

Write down 10 reasons to quit. In addition to health reasons, the list might include having better smelling hair, clothes, and breath; having fewer wrinkles; enjoying the taste of food; and saving money. Read the list often during the quitting process to help stay motivated.

Decide on a Specific Quit Date

Some people find it helpful to choose a particular date to quit when little or no stress is anticipated for at least the first 3 days. Women affected by PMS should avoid quitting right before their menstrual cycle. It may help to write out a quit contract, putting the date on paper, and getting a friend to sign it. Discard all smoking paraphernalia on the eve before the quit date, and make plans to stay busy on the day itself, and especially at night, when the urge to smoke will be high.

Make an Oath

Take an extreme oath. For example, "If I smoke one more cigarette my dog will die." Although this seems absurd, some people, even well-educated individuals, who have failed all other methods have reported that they quit completely and successfully after taking such an oath.

Let the Body and Mind Heal During Withdrawal

Retreat from the world when cravings become overwhelming. Take naps, warm baths or showers, meditate, or read novels.
Help your body get rid of nicotine. Drink plenty of water, eat fresh fruits, vegetables, whole grains, and fiber-rich foods. Carrots, apples, and celery are good munching foods.
When cravings occur, hold your breath as long as possible or take a few deep rhythmic breaths.
Use meditation or relaxation and deep breathing exercises. In fact, taking deep breaths when the urge to smoke occurs is a good stopgap measure.

Get Family and Friends Involved

Tell all your friends and family that you've already quit, so you'll be embarrassed if they catch you smoking.
Pay a family member or friend if they catch you smoking. The amount should be large enough ($5 - 20) to be a deterrent, but not so large as to be ridiculous.
If your partner or friend smokes, try persuading them to quit or, at the very least, not to smoke around you and others.

Exercise

Studies continue to show that smokers who exercise can greatly increase their ability to quit smoking while reducing their risk for weight gain. Move the muscles when cravings occur. Dance, run, walk, jump up and down, stretch, do push-ups. Yoga is an excellent exercise program for quitting. Older people and anyone with health problems should consult their health care provider before starting such a program.

Maintain a Healthy Diet

Eat plenty of fresh, crunchy fruits and vegetables. This is also a useful way of satisfying oral cravings without adding many calories.
Drink plenty of water and healthy beverages.
Moderate intake of coffee or tea may be helpful. A small study suggested that drinking caffeinated beverages (such as coffee or tea) while on nicotine replacement may enhance energy expenditure and may help prevent weight gain. Moderate coffee intake may also have antidepressant properties. Avoid caffeine in the evening, however, since sleep disturbances can be a problem during withdrawal.

Change Daily Habits

Change your daily schedule, particularly eating times, as much as possible. Eat at different times or eat many small meals instead of three large ones. Sit in a different chair or even a different room.
If you smoke after eating, find other ways to end a meal. Play a tape or CD, eat a piece of fruit, get up and make a phone call, or take a walk (a good distraction that burns calories as well). For example, if you normally have a cigarette with coffee, drink tea instead or use a different cup.
Substitute oral habits by eating celery, chewing sugarless gum, sucking on a cinnamon stick, or carrying worry beads.
Go to public places and restaurants where smoking is prohibited or restricted.
Set short-term quitting goals and reward yourself when they are met.
Every day put the money normally spent on cigarettes in a jar and buy something pleasurable at the end of a predetermined period of time.
Find activities that focus the hands and mind but are not taxing or fattening: Computer games, solitaire, knitting, sewing, whittling, and crossword puzzles.

Denormalization is the idea that smoking is no longer normal. This concept of denormalization is best instituted by laws and local regulations making smoking inaccessible in public places, raising prices, and putting stricter limitations on cigarette advertising.

Increasing taxes on cigarettes may be one of the most important methods for reducing smoking in the population, particularly in younger people.

Evidence is suggesting that banning smoking in work and public places may be leading to a higher quit rate than in places where smoking is permitted.

Denormalization can also work on a personal level. A British study showed that when one spouse makes healthy changes, including quitting smoking, the other one follows. In couples where smoking continues, it usually continues in both.

Symptoms of Withdrawal

After you quit smoking, you with have some withdrawal symptoms. Such symptoms generally peak in intensity 3 -5 days after you quit, and usually disappear after 2 weeks, although some may persist for several months.

The symptoms of withdrawal include both physical and mental difficulties.

Physical Symptoms.

Tingling in the hands and feet
Sweating
Intestinal disorders (cramps, nausea)
Headaches
Sore throat, coughing, and signs of a cold

Withdrawal symptoms should be treated accordingly, just as you would with physical symptoms due to an illness or disease.

Mental and Emotional Symptoms. Tension and craving build up during periods of withdrawal, sometimes to a nearly intolerable point. Nearly every moderate-to-heavy smoker experiences more than one of the following strong emotional and mental responses to withdrawal:

Temper tantrums, intense needs, feelings of dependency, and a state of near paralysis
Insomnia
Mental confusion, vagueness, or difficulty concentrating
Irritability, restlessness, impatience, or anger
Anxiety
Depression

The first signs of nicotine withdrawal seem to appear within 30 minutes of a smoker’s last cigarette. The findings, published in Psychopharmacology, are believed to be the first to show just how early nicotine withdrawal occurs. The study involved 50 people who smoked a pack of cigarettes daily. Half refrained from smoking for 4 hours, while the others smoked as usual. After 30 minutes, those who did not have a cigarette craved one and did more poorly on tasks requiring attention than those in the smoking group. Within 3 hours, the non-smoking group showed increases in anxiety, sadness, and difficulty concentrating.

Depression is common during withdrawal and over the long term. In the short term, it may mimic the feelings of grief felt when a loved one is lost. A smoker should plan on a period of actual mourning in order to get through the early withdrawal depression.

There is a significant association between cigarette smoking and a susceptibility to depression. People who are prone to depression face a 25% chance of becoming depressed when they quit smoking, and this increased risk persists for at least 6 months. What's more, depressed smokers have a very low level of success. Only about 6% remain smoke-free after a year. There are strong reasons for this:

Smoking may be masking depression, which can become severe even after the early stages of withdrawal have passed.
For some smokers, the future physical damage incurred by smoking is an abstraction, which fails to motivate quitting when measured up against the very real emotional pain triggered by nicotine withdrawal.
Not only does the smoker suffer, but the negative emotions often harm relationships with friends and family, who might even urge the ex-smoker to take up cigarettes again.

People who suffer from depression while quitting might do better using a combination of emotionally supportive therapy (as opposed to behavioral therapy), nicotine replacements, and antidepressants, such as bupropion (Zyban). If severe depression lasts beyond the withdrawal period, professional help should be sought as soon as possible.

Quitting smoking does increase the risk for weight gain. But, kicking the habit of smoking may cause more weight gain than previously thought. A study in Health Services Research found that the average weight gain among former smokers was about 21 pounds, rather than the 5 - 15 pounds commonly cited. But, fear of weight gain shouldn’t stop a person from quitting smoking. Instead, the study authors encourage weight-control measures after quitting. To come up with a new average, the scientists re-analyzed data from the 1998 Lung Health Study of 5,887 American smokers. That study found that those who quit smoking gained about 12 pounds.

Smoking uses up calories -- about 200 a day according to one study. Burning calories helps you lose weight. After quitting, the body's metabolism slows down, and food is digested better. Insulin levels increase, enabling the body to process more sugar for energy. When you quit smoking, you may snack more frequently.

How to Keep the Weight Off After Smoking. Exercise is very helpful in controlling weight. To burn the same amount of calories as you did while smoking, you need only take an extra 15-minute daily walk and eliminate 100 calories a day from meals. Just a moderate increase in physical activity can help keep weight gain to a minimum.

Nicotine replacement therapy can help protect against weight gain. See the section on "Quitting Smoking" in this report.

Failure to Quit

Biologic, psychological, behavioral, and cultural factors all play a role in nicotine addiction, making smoking one of the hardest addictions to beat. About half of people who quit return to smoking. Even after years of not smoking, some ex-smokers still have occasional cravings for cigarettes.

Some experts suggest that, in addition to depression, there are three major areas responsible for the inability to quit:

Mental performance. Nicotine improves concentration and thinking. Quitting smoking temporarily impairs one's mental performance.
Stress. Although smoking many not reduce stress, stopping certainly increases it.
Weight gain. Quitting smoking can cause you to gain weight. Studies are mixed on whether weight gain is permanent in most smokers or not. Certainly, it is a major factor in relapse. [See "Weight Gain" section in this report.]

How well a person does in the first 2 weeks is critical to their success. Smokers should not be shy about seeking all the help they can during this period. Although withdrawal symptoms can be intense, treatments are available to reduce them.

Attempts to quit are never a waste of time, since the amount of smoking is reduced during these periods. People who keep trying still have a 50 - 50 chance of finally quitting.

Researchers have been trying to discover individual risk factors or sets of behaviors that can help predict why specific people fail to quit. Some factors include:

Being female
Being a heavy smoker
Inhaling deeply
Being a long-term smoker
Having severe withdrawal symptoms

Among many studies, however, only one found a single consistent factor for failure to quit:

Cheating during the first 2 weeks of withdrawal, even with the patch, nearly guarantees that a person will smoke again in 6 months.

Studies show that women have a harder time trying to quit smoking and have less success with abstinence programs than men. There are many proposed reasons for this:

Nicotine has different effects on mood in women compared to men. Women who quit may have greater anxiety and stress than men who quit.
Women are not as physically dependent on nicotine as men, but they are more addicted to the actual behavior of smoking, which is the more powerful deterrent to quitting. This may be the reason why nicotine replacement, which only reduces cravings, tends not to be as effective in women.
Women may fear weight gain after quitting more than men.
Certain phases in the menstrual cycle may reduce the response to drugs that are used to help women quit smoking.
Men may be less supportive than women in helping their partners to quit.
Women trying to quit may miss the feeling of control associated with smoking more than men.

On the positive side, evidence suggests that when women quit, their lung function seems to improve more rapidly than in men who quit.

Lifestyle Changes

Smokers and former smokers should immediately begin to implement a healthier lifestyle and change any other behaviors that might be damaging their health.

Everyone should also maintain a healthy diet, with foods rich in whole grains and fruits and vegetables (particularly dark colored ones). Avoid saturated fats and instead choose monounsaturated fats, which are found in olive oil or fats from oily fish. Two studies have indicated that eating fish more than twice a week might help limit the tobacco damage in people who do not smoke more than a pack and a half a day.

Even with a healthful diet, however, smoking reduces the levels of a number of vitamins, importantly vitamin C. Some research suggests that supplementation of folic acid, a B vitamin, and the antioxidants vitamins E and C and selenium may improve lung function or reduce the damage done by cigarette smoke. Studies have shown that daily vitamin E supplements are associated with reduced risk for prostate cancer among smokers and that higher levels of vitamin E are linked to a lower risk for lung cancer. The best way of achieving healthy levels of important nutrients is from healthy foods.

Click the icon to see an image of the benefits of vitamin E.

Click the icon to see an image of the sources of vitamin E.

Women who are pregnant and continue to smoke must be sure to take appropriate vitamins, particularly folic acid. In this way, they might reduce the increased risk of fetal injury and death, although they do not eliminate that risk.

Regular exercise reduces a smoker's risk of heart disease (although still not to the level of a nonsmoker). Exercise does not lower a smoker's risk for lung cancer or emphysema.

If you smoke, you should be screened for any smoking-related disorders. Have your cholesterol and blood pressure checked regularly. Women should have annual Pap smears to detect cervical cancer. All older adults should be screened for colon cancer. Computed tomography (CT) screening programs, which are becoming increasingly available, may detect lung cancer at an early stage. Ask your health care provider if you should have this test, and if your insurance will cover it.

Resources

www.cancer.org -- American Cancer Society
www.lungusa.org -- The American Lung Association

References

Alati R, Al Mamun A, O'Callaghan M, Najman JM, Williams GM. In utero and postnatal maternal smoking and asthma in adolescence. Epidemiology. 2006 Mar;17(2):138-44.

Amin S, Niu J, Guermazi A, et al. Cigarette smoking and the risk for cartilage loss and knee pain in men with knee osteoarthritis. Ann Rheum Dis. 2007 Jan;66(1):18-22. Epub 2006 Dec 7.

Breslau N., Novak SP, Kessler RC. Psychiatric disorders and stages of smoking. Biological Psychiatry. 55(1):69-76, 2004.

Centers for Disease Control and Prevention (CDC). Tobacco use among adults -- United States, 2005. MMWR. 2006 Oct 27;55(42):1145-8.

Centers for Disease Control and Prevention (CDC). Annual smoking-attributable mortality, years of potential life lost, and productivity losses -- United States, 1997-2001. MMWR. 2005;54:625-628.

Centers for Disease Control and Prevention (CDC). State-specific prevalence of smoke-free home rules -- United States, 1992-2003. MMWR. 2007 May 25;56(20):501-4.

Chaudhuri R, Livingston E, McMahon AD, et al. Effects of smoking cessation on lung function and airway inflammation in smokers with asthma. Am J Respir Crit Care Med. 2006 Jul 15;174(2):127-33.

Dobson R. Smoking may increase abdominal obesity. BMJ. 2005 Sep 17;331(7517):596.

Eisenberg D, Quinn BC. Estimating the effect of smoking cessation on weight gain: an instrumental variable approach. Health Services Research. 2006 July 6; (early online version).

Galatz LM, Silva MJ, Rothermich SY, Zaegel MA, Havlioglu N, Thomopoulos S. Nicotine delays tendon-to-bone healing in a rat shoulder model. J Bone Joint Surg Am. 2006 Sep;88(9):2027-34.

Health, United States, 2005, with Chartbook on Trends in the Health of Americans. Hyattsville, Md. National Center for Health Statistics; 2005.

Hendricks P, Ditre J, Drobes D, Brandon T. The early time course of smoking withdrawal effects. Psychopharmacology. 2006;187(3): 385-396.

Houston TK, Person SD, Pletcher MJ, Liu K, Iribarren C, Kiefe CI. Active and passive smoking and development of glucose intolerance among young adults in a prospective cohort: CARDIA study. BMJ. 2006 May 6;332(7549):1064-9.

Linn-Rasker SP, van der Helm-van Mil AHM, van Gaalen FA, et al. Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles. Ann Rheum Dis. 2006;65:366-371.

Li YF, Langholz B, Salam MT, Gilliland FD. Maternal and grandmaternal smoking patterns are associated with early childhood asthma. Chest. 2005 Apr;127(4):1232-41.

Mennella JA, Yourshaw LM, Morgan LK. Breastfeeding and smoking: short-term effects on infant feeding and sleep. Pediatrics. 2007 Sep;120(3):497-502.

Naqvi NH, Rudrauf D, Damasio H, Bechara A. Damage to the insula disrupts addiction to cigarette smoking. Science. 2007 Jan 26;315(5811):531-4.

Nides M, Oncken C, Gonzales D, et al. Smoking cessation with varenicline, a selective alpha4beta2 nicotinic receptor partial agonist: results from a 7-week, randomized, placebo- and bupropion-controlled trial with 1-year follow-up. Arch Intern Med. 2006 Aug 14-28;166(15):1561-8.

Oncken C, Gonzales D, Nides M, Rennard S, Watsky E, Billing CB, Anziano R, Reeves K. Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist, varenicline, for smoking cessation. Arch Intern Med. 2006 Aug 14-28;166(15):1571-7.

Ritz B, Ascherio A, Checkoway H, et al. Pooled analysis of tobacco use and risk of Parkinson disease. Arch Neurol. 2007 Jul;64(7):990-7.

Sargent JD, Stoolmiller M, Worth KA, et al. Exposure to smoking depictions in movies: its association with established adolescent smoking. Arch Pediatr Adolesc Med. 2007 Sep;161(9):849-56.

Teo KK, Ounpuu S, Hawken S, et al. Tobacco use and risk of myocardial infarction in 52 countries in the INTERHEART study: a case-control study. Lancet. 2006 Aug 19;368(9536):647-58.

The Health Consequences Of Smoking: A Report Of The Surgeon General. Atlanta, GA: US Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, US Dept of Health and Human Services; 2004.

Tonnesen P, Mikkelsen K, Bremann L. Nurse-conducted smoking cessation in patients with COPD using nicotine sublingual tablets and behavioral support. Chest. 2006 Aug;130(2):334-42.

Uhl GR, Liu QR, Drgon T, Johnson C, Walther D, Rose JE. Molecular genetics of nicotine dependence and abstinence: whole genome association using 520,000 SNPs. BMC Genet. 2007 Apr 3;8:10.

Wagena EJ, Knipschild P, Zeegers MP. Should nortriptyline be used as a first-line aid to help smokers quit? Results from a systematic review and meta-analysis. Addiction. 2005;100:317-326.

Review Date:
10/8/2007
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital

A.D.A.M. Copyright

adam.com

Systemic lupus erythematosus

FitSugar — Wed, 08 Oct 2008 17:35:17 -0700

In This Report

Highlights
Introduction
Causes
Risk Factors
Symptoms
Complications
Diagnosis
Treatment
Treatment for Cutaneous and...
Treatment for Severe SLE...
Lifestyle Changes
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Systematic Lupus Erythematosus (SLE)

SLE is an autoimmune disease that causes a chronic inflammatory condition. The inflammation triggered by SLE affects many organs in the body, including skin, joints, kidneys, lung, and nervous system. Women, especially African-American and Asian women, are at highest risk for developing SLE.

Symptoms and Diagnosis

Not all patients with SLE experience the same symptoms. The most common symptoms are joint pain, skin rash, and fever. Symptoms can develop slowly or appear suddenly. Many patients with SLE have “flares,” in which symptoms suddenly worsen and then disappear for long periods of time. Diagnosing SLE is complicated because symptoms vary widely and can resemble other conditions. A doctor will base an SLE diagnosis on certain specific criteria including symptom history and the results of blood tests for antinuclear antibodies.

Treatment

No drug can cure SLE, but many different drugs can help control symptoms and relieve discomfort. The choice of drugs depends on the severity of the condition as well as other factors. Patients with mild SLE may be helped by nonsteroidal anti-inflammatory drugs (NSAIDs) while patients with more severe SLE may require corticosteroids or immunosuppressants. Researchers are working to develop new drugs and treatments for SLE.

Living with SLE

Patients can make lifestyle changes to help cope with SLE. These include:

Avoid excessive sunlight exposure, and wear sunscreen (ultraviolet light is the one of the main triggers of flares).
Get plenty of rest (fatigue is another common SLE symptom).
Engage in regular light-to-moderate exercise to help fight fatigue and heart disease, and to keep joints flexible.

Introduction

Systemic lupus erythematosus (SLE) is a chronic, often life-long, autoimmune disease. It can be mild to severe, and affects mostly women. SLE may affect various parts of the body, but it most often manifests in the skin, joints, blood, and kidneys. SLE was first described in 1828. Its very name helps define the disease:

Systemic is used because the disease can affect organs and tissue throughout the body.
Lupus is Latin for wolf. It refers to the rash that extends across the bridge of the nose and upper cheekbones and was thought to resemble a wolf bite.
Erythematosus is from the Greek word for red and refers to the color of the rash.

Lupus has many different symptoms. Common ones include:

Fatigue
Joint pain or swelling
Skin rashes

Causes

Systemic lupus erythematosus is a complex disorder that occurs as a consequence of a number of independent processes and factors.

Environmental factors, such as viruses, exposure to chemicals, or sunlight trigger inflammatory or immune activity. This immune activation may begin as an appropriate response to an unwanted "invader." But, because of a combination of genetic factors, an individual with lupus develops an ongoing immune response that does not shut itself off appropriately. This leads to waxing and waning flares of inflammation that can involve various organs of the body, depending on specific features of this self-perpetuating immune response in individual patients.

The exact combination of genes that predispose individuals to SLE may differ somewhat from patient to patient, but probably share certain common features which tend to impair the ability of the body to get rid of immune-triggering particles and which tend to prolong or increase the degree of immune responsiveness to these triggers.

A major characteristic of lupus is that it is an autoimmune response in which immune factors, called autoantibodies, attack the person's own cells. Some autoantibodies are normal in a well-balanced immune system, and serve various roles to help the body dispose of wastes, protect from infectious invaders, and to keep blood vessels clear. In healthy people, autoantibodies tend to be well-regulated and well "masked," or covered up, until needed. Therefore, it is probably the high activity and high detectability of autoantibodies that makes lupus unique, not the fact that they exist.

The Normal Immune System Response. The inflammatory process is a byproduct of the activity of the body's immune system, which fights infection and heals wounds and injuries:

When an injury or an infection occurs, white blood cells are mobilized to rid the body of any foreign proteins, such as a virus.
The masses of blood cells that gather at the injured or infected site produce factors to fight any infections.
In the process, the surrounding area becomes inflamed and some healthy tissue is injured. The immune system is then called upon to repair wounds by clotting any bleeding blood vessels and initiating fiber-like patches to the tissue.
Under normal conditions, the immune system has special factors that control and limit this inflammatory process.

The Infection Fighters. B cells and T cells are two important components of the immune system that play a role in the inflammation associated with lupus. Both B cells and T cells belong to a family of immune cells called lymphocytes. Lymphocytes help fight infection.

B cells and T cells are involved in the immune system's response to infection. Antigens are foreign bodies (such as bacteria and viruses) that stimulate the immune system to produce autoantibodies. When a T cell recognizes an antigen it will produce chemicals (cytokines) that cause B cells to multiply and release many immune proteins (antibodies). These antibodies circulate widely in the bloodstream, recognizing the foreign particles and triggering inflammation in order to rid the body of the invasion.

An antigen is a substance that can provoke an immune response. Typically antigens are substances not usually found in the body.

For reasons that are still not completely understood, both the T cells and B cells become overactive in lupus patients. In lupus, a complex interaction between activated immune cells and an impaired antigen-elimination process leads to a greater than normal range of what the antibodies recognize. Eventually, antibodies are made that recognize more of the body's own tissues in a stronger or more persistent manner than is healthy, and inflammatory responses are mounted in these tissues.

Autoantibodies. In the majority of patients with SLE, antinuclear antibodies (ANA) are detectable. Such autoantibodies may be present in individuals up to 7 years prior to their developing symptoms of lupus. Some subtypes of ANA are found in lupus patients and only rarely in people without lupus. These include:

Anti-ds DNA. An autoantibody called anti-double stranded DNA (anti-ds DNA) may play an important role in some lupus patients.
Anti-Sm antibodies. This antibody is found most often in lupus patients of African descent and is almost never detected in people without lupus.
Anti-Ro (SSA) and Anti-La (SSB)
Antiphospholipid antibodies

Cytokines. Most immune cells secrete or stimulate the production of powerful immune factors called cytokines. In small amounts, cytokines are indispensable for maintaining the balance of the body during immune responses, including:

Infections
Injuries
Tissue repair
Blood clotting
Clearing of debris from inflamed blood vessels
Other aspects of healing.

If overproduced, however, they can cause serious damage, including dangerous levels of inflammation and cellular injury. Specific cytokines called interferons and interleukins play a critical role in SLE by regulating the secretion of autoantibodies by B cells.

Complement. Another immune factor of high interest in SLE is the complement system. This is comprised of more than 30 proteins and is important for defending and regulating the immune response. Inherited deficiencies in certain complement components (C1q, C1r, C1s, C4, and C2) have long been associated with SLE.

Researchers estimated that 20 - 100 different genetic factors may be involved in the alterations of the immune system set point that could make a person susceptible to SLE.

Research published in 2003 identified a particular set of genes, now commonly called the "interferon signature," that is activated by interferon in patients with severe lupus. This discovery may help doctors identify patients at particular risk for severe disease before they develop symptoms.
A genetic risk factor for lupus in African-American women has been identified.
Other research has identified defects in genes that regulate apoptosis, the natural process by which cells self-destruct.
An abnormal gene identified in some patients with SLE promotes the build-up of immune complexes that can cause kidney damage. HLA (human leukocyte antigen) is a protein that presents antigens to T cells by holding them up from the surface of macrophages or other antigen-presenting cells. Among the types of HLA associated with lupus are HLA-DR2, -DR3, -A1, -B8, and DMA-0104.

In genetically susceptible people, there are various external factors that can provoke an immune response. Possible SLE triggers include colds, fatigue, stress, chemicals, sunlight, and certain drugs.

Viruses. Blood tests reveal that patients with SLE are more likely to have been exposed to certain viruses than the general population. These viruses include the Epstein-Barr virus (the cause of mononucleosis), cytomegalovirus, and parvovirus-B1.

Results from a 2005 study, conducted by researchers at the National Institute of Environmental Health Sciences, suggested a strong association between Epstein-Barr virus (EBV) and increased risk of lupus, particularly for African-Americans. The association was not as strong for whites, but increased with age (patients over 50 years of age had four times higher risk).

The researchers also observed that a genetic variation in CTLA-4, a protein that helps regulate T cell immune system response, appeared to modify the risk of lupus associated with EBV-IgA antibodies. Therefore, an individual’s CTLA-4 genotype could determine the immune system’s responsiveness in fighting repeat episodes of EBV infection.

Click the icon to see an image of mononucleosis.

Some research suggests that different viruses may imprint specific types of SLE. For instance cytomegalovirus may affect blood vessels and cause problems such as Raynaud's phenomenon or blood abnormalities, but may not affect the kidney as much. These are speculations, however, and not a proven association.

Sunlight. Ultraviolet (UV) rays found in sunlight are important SLE triggers. When they bombard the skin, they can alter the structure of DNA in cells below the surface. The immune system may perceive these altered skin cells as foreign and trigger an autoimmune response against them. UV light is categorized as UVB or UVA depending on the length of the wave.

UVB are short waves (280 - 320 nm). The shorter the wavelengths, the more damage they do.
UVA are longer waves (320 - 400 nm). Some research suggests that UVA wavelengths in the longest range, known as UVA1 (340 - 400 nm), may actually repair DNA and normalize immune responses.

Chemicals. Clusters of SLE cases have occurred in populations with high exposure to certain chemicals. Chlorinated pesticides and crystalline silica are two suspects. A number of other chemicals are under investigation. However, it is very difficult to determine a causal role for any specific chemicals. (Silicone breast implants have been under intense scrutiny as a possible trigger of autoimmune diseases, including SLE. The weight of evidence to date, however, finds no support for this concern.) Some drugs have been associated with a temporary lupus syndrome (drug-induced lupus), which resolves when these drugs are stopped.

Hormones. Cytokines, major immune factors that are active in SLE, are directly affected by sex hormones. In general, estrogen enhances antibody production, and testosterone reduces antibody production, although their exact role in SLE may be more complicated than that since there are various ways in which each hormone might influence various immune cells. Women with SLE may have lower levels of several active male hormones (androgens), and some men who are affected by SLE may also have abnormal androgen levels.

Premature menopause, and its accompanying symptoms (such as hot flashes), is common in women with SLE. Hormone replacement therapy (HRT), which is used to relieve these symptoms, increases the risk for blood clots and heart problems. It is not clear whether HRT triggers SLE flares. Women should discuss with their doctors whether HRT is an appropriate and safe choice. Guidelines recommend that women who take HRT use the lowest possible dose for the shortest possible time. Women with SLE who have active disease, antiphospholipid antibodies, or a history of blood clots or heart disease should not use HRT.

Oral Contraceptives. Female patients with lupus used to be cautioned against taking oral contraceptives (OCs) due to the possibility that estrogen could trigger lupus flare-ups. However, recent evidence indicates that OCs are safe, at least for women with inactive or stable lupus. Women who have been newly diagnosed with lupus should avoid OCs. Lupus can cause complications in its early stages. For this reason, women should wait until the disease reaches a stable state before taking OCs. In addition, women who have a history of, or who are at high risk for, blood clots (particularly women with antiphospholipid syndrome) should not use OCs. The estrogen in OCs increases the risk for blood clots.

Risk Factors

The number of people diagnosed with lupus has more than tripled over the past four decades. Some experts believe this may simply indicate a greater degree of doctor training in recognizing the syndrome.

About 90% of lupus patients are women, most diagnosed when they are in their childbearing ages. Hormones may be an explanation. After menopause, women are only 2.5 times as likely as men to contract SLE. Flares also become somewhat less common after menopause in women who have chronic SLE.

African-Americans are three to four times more likely to develop the disease than Caucasians and to have severe complications. Hispanics and Asians are also more susceptible to the disease.

A family history plays a strong role in SLE. A brother or sister of a patient with the disorder has 20 times the risk as someone without an immediate family member with SLE.

The disease is rare in childhood. When it does occur, it is often associated with thrombotic thrombocytopenia purpura, a condition resulting from abnormally low levels of blood platelets. SLE in children may also be caused by certain medications, including minocycline and zafirlukast.

Rheumatoid Arthritis. Studies have investigated the relationship among hormones, SLE, and rheumatoid arthritis, another autoimmune disease. Higher levels of estrogen are associated with SLE, while lower levels are associated with rheumatoid arthritis. Some research suggests that some patients, in fact, progress from one disease to the other, and that such transitions occur during major hormonal shifts, such as the onset of menopause or pregnancy.

Rheumatoid arthritis is a systemic autoimmune disease that initially attacks the lining, or synovium, of the joints.

Many prescription drugs can cause lupus-like skin symptoms. In one study, the most common drugs causing these symptoms were high blood pressure (hypertension) medications, including hydrochlorothiazide, angiotensin-converting-enzyme inhibitors, and calcium-channel blockers. About 40 different drugs have been linked to lupus onset. Anyone diagnosed with cutaneous lupus erythematosus should be sure to tell their doctors all the medications (including herbs and supplements) that they are taking.

Smoking. Smoking may be a risk factor for triggering SLE and can increase the risk for skin and kidney problems in women who have the disease.

Symptoms

SLE symptoms may develop slowly over months or years, or they may appear suddenly. Symptoms tend to be worse during winter months, perhaps because prolonged exposure to sunlight in the summer causes a gradual build-up of factors that trigger symptoms months later.

The most common symptom is joint pain, which occurs in about 90% of patients with SLE. Characteristics of this symptom vary widely:

It is often accompanied by swelling and redness.
It can last from hours to months.
It may be mild or severe.
It can occur in one joint, move from one to another, or flare erratically.
Pain often occurs in the morning and improves during the day, only to return later when the patient tires.
The joints most affected are fingers, wrists, elbows, knees, and ankles. (Joints in the spine and neck are not affected.)

Children may experience these symptoms as growing pains, and, in all patients, they may be the only symptoms for many years.

Fever occurs in 90% of patients with SLE and is usually caused by the inflammatory process of the disease, not by infection. It is low-grade except during an acute lupus crisis.

Three-quarters of patients with SLE have skin inflammation and skin lesions (ulcers, rashes, or other injured areas). About half of these lesions are photosensitive; that is, they are aggravated by ultraviolet (UV) radiation from sunlight, even from light coming through a window. (UV radiation may even trigger systemic flares in patients with SLE.)

A number of different skin conditions have been described in patients with SLE.

Discoid Lupus Erythematosus. About 20% of patients have discoid lesions. In such cases, the condition is often known as discoid lupus erythematosus (DLE). Patients with this condition may have the following skin abnormalities:

Discoid means coin-shaped, so these lesions are round and raised. They are also scaly. Untreated, the margins gradually extend outward as the center dries out and shrivels, causing severe scarring. If discoid lesions appear on the scalp, they can plug hair follicles and cause irreversible hair loss. Discoid lesions can also appear on the upper body.

Lupus, discoid -- view of lesions on the chest: This close-up picture of the neck clearly shows the typical rounded appearance of discoid lupus. The whitish appearance is caused by scaling. The two dark spots are biopsy sites and are not part of the disease.

A butterfly-shaped rash across the face may accompany this condition. This rash causes little scarring, although spidery, branching lines of swollen capillaries (the tiniest blood vessels) may appear.

Click the icon to see an image of systemic lupus erythematosus.

Most patients with this condition have only a limited skin disorder. In only about 10% of cases does discoid lupus develop into full-blown SLE.

Subacute Cutaneous Lupus Erythematosus. Subacute cutaneous lupus erythematosus (SCLE) can cause skin lesions on parts of the body that are exposed to sunlight. These lesions do not cause scarring.

Vasculitis. Patients with SLE sometimes develop inflammation in the blood vessels (vasculitis) that may have the following effects on the skin:

Red welts may form across large areas of the body.
Sometimes deep red bumps may appear, particularly on the leg, where they may ulcerate.
In some people, reddish-purple lesions appear on the pads of fingers and toes or near the nails of fingers and toes.
Lesions caused by vasculitis may ulcerate or blister if they erupt on mucous membranes in the mouth, nose, or vagina and can be painful if they occur on the throat.
Vasulitis can attack blood vessels in almost any other organ, including the brain, the heart, and the gastrointestinal tract.

Click the icon to see an image of vasculitis.

Other symptoms include:

Fatigue
Loss of appetite, nausea, and weight loss
Chest pain
Bruising
Menstrual irregularities
Thought and concentration disturbances
Personality changes
Sleep disorders, such as restless legs syndrome and sleep apnea
Dryness of the eyes and mouth
Brittle hair or hair loss

Hair loss or breakage may also occur in about half of patients with SLE during severe flares or after pregnancy or severe illness. In such cases, hair grows back.

Raynaud's phenomenon is a condition in which cold or stress can cause spasms in impaired blood vessels, resulting in pain in fingers and toes. It occurs as part of the inflammatory response in blood vessels, which can narrow them and reduce circulation. In extreme cases, gangrene can result.

Click the icon to see an image of Raynaud's phenomenon.

A number of conditions may resemble SLE:

Scleroderma: Hardening of the skin caused by overproduction of collagen
Multiple sclerosis: Fatigue, heaviness or clumsiness in the arms and legs
Rheumatoid arthritis: Inflammation of the lining of the joints
Sjögren syndrome: Characterized by dry eyes and dry mouth
Mixed connective tissue disorder: Similar to SLE, but milder
Myositis: Inflammation and degeneration of muscle tissues
Rosacea: Flushed face with pus-filled blisters
Seborrheic dermatitis: Sores on lips and nose
Lichen planus: Swollen rash that itches, typically on scalp, arms, legs, or in the mouth
Dermatomyositis: Bluish-red skin eruptions on face and upper body
Lyme disease: Bulls-eye rash, joint inflammation, and flu-like symptoms

Complications

Systemic lupus erythematosus (SLE) is one of the most serious rheumatic diseases. According to a 2002 government study, the annual number of deaths has risen from 879 - 1,406 since 1979. About a third of these deaths occur in people aged 15 - 44 years, mostly women. Such numbers may be underestimates, since SLE can affect so many organs that a cause of death in some people with SLE may not be directly attributed to the condition. A primary cause of death among patients with lupus is atherosclerosis, a disease of the coronary blood vessels resulting from accelerated buildup of plaque.

SLE is unpredictable and varies greatly form one individual to the next. Severity also appears to differ among ethnic groups and countries. In European and North American patients with SLE for example, overall 5-year survival rates are 93 - 95%, while in Asia or Africa they are considerable lower (60 - 70%). Other research indicates that African-American and Hispanic American patients suffer greater organ damage than Caucasian patients. Genetic factors appear to have some influence on specific effects of SLE on organ damage among ethnic groups. However, the poorer outlook among minority groups and in underdeveloped nations is probably due to less access to good health care.

Mild SLE. About 20 - 30% of cases are mild. For many of these patients, the only symptoms may be the skin rashes of discoid lupus erythematosus (DLE) or subacute cutaneous lupus erythematosus (SCLE) with or without joint aches. The number and intensity of symptoms in mild cases often decrease over time, as does the likelihood of major organ involvement. These skin conditions, however, are not absolute insurance against more severe disease, and patients with mild SLE should be tested for organ involvement.

Widespread SLE. Most commonly, SLE is a chronic, life-long disease, alternating between periods of symptom relapse, (called flares), and remission. The disease may begin in any of the various systems of the body and progress unpredictably to others. The following are typical patterns:

Symptom relapses, or flares, occur on the average of two or three times a year.
Between flares, most patients with SLE function at about 90% of normal capacity.

The degree of severity depends on different factors:

Severity of the inflammatory response
Frequency of episodes
The degree of organ or system involvement

Vital organs or systems, such as lungs, kidneys, nervous system, joints skin, and others are affected in 50 - 75% of patients with SLE. Infections followed by kidney failure are the chief causes of death in patients with SLE.

Because of more effective and aggressive treatment, the prognosis for SLE has improved markedly over the past two decades. Long-term progress of the disease is affected greatly by treatment in the initial acute phase of the disease, so a speedy and accurate diagnosis is all-important. The 10-year survival rate with treatment is now 85 - 95%, and many people have a normal life span. SLE that develops later in life is generally less serious than SLE that strikes in childhood.

Almost 85% of patients with SLE experience problems associated with abnormalities in the blood.

Anemia. About half of patients with SLE are anemic. Causes include:

Iron deficiencies resulting from excessive menstruation
Iron deficiencies from gastro-intestinal bleeding caused by some of the treatments
A specific anemia called hemolytic anemia, which destroys red blood cells
Anemia of chronic disease

Hemolytic anemia can occur with very high levels of the anticardiolipin antibody. It can be chronic or develop suddenly and be severely (acute).

Antiphospholipid Syndrome. Between 34 - 42% of patients with SLE have antiphospholipid syndrome (APS). This is a specific set of conditions related to the presence of autoantibodies called lupus anticoagulant and anticardiolipin. These autoantibodies react against fat molecules called phospholipids, and so are called antiphospholipids. Their actions have complex effects that include causing narrowing and abnormalities of blood vessels.

Patients who have APS have a very incidence of blood clots, which most often occur in the deep veins in the legs (32%). Blood clotting, in turn, puts patients at higher risk for stroke (13%) and pulmonary embolism (clots in the lungs) (9%).

This picture shows a red and swollen thigh and leg caused by a blood clot (thrombus) in the deep veins in the groin (iliofemoral veins). Such a clot prevents normal return of blood from the leg to the heart.

About 22% of patients have thrombocytopenia -- a reduction in blood platelets that can cause bleeding.
The effects on blood vessels have also been associated with confusion, headaches, and seizures. Leg ulcers can also develop.
Patients with APS who become pregnant have a high incidence of pregnancy loss, especially in the late term.

Not all patients with APS carry both of the autoantibodies, and they can also wax and wane and so have varying effects. APS also occurs without lupus in about half of patients with the syndrome.

Thrombocytopenia. In thrombocytopenia, antibodies attack blood platelets. In such cases, blood clotting is impaired, which causes bruising and bleeding from the skin, nose, gums, or intestines. (This condition can also occur in APS, but it is not considered to be one of the standard features of the syndrome.)

Neutropenia. Neutropenia is a drop in the number of white blood cells. Patients with SLE often neutropenia, but the condition is usually harmless unless the reductions are so severe that they leave the patient vulnerable to infections.

Acute Lupus Hemophagocyte Syndrome. A rare blood complication of SLE that occurs primarily in Asians is called acute lupus hemophagocytic syndrome. It is generally of short duration and characterized by fever and a sudden drop in blood cells and platelets.

Lymphomas. Patients with SLE and other autoimmune disorders have a greater risk for developing lymph system cancers such as Hodgkin’s disease and non-Hodgkin’s lymphoma (NHL). A 2005 study reported that patients with SLE were over seven times more likely to develop NHL than healthy patients.

Heart disease is a primary cause of death in lupus patients. The immune response in SLE can cause inflammation and other damaging effects that can cause significant injury to the arteries and tissues associated with the circulation and the heart. In addition, SLE treatments (particularly corticosteroids) affect cholesterol, weight, and other factors that can also affect the heart. For decades, experts questioned the extent to which the drugs used to treat SLE contributed to the high rate of atherosclerosis in such patients. Numerous studies now suggest that something about the disease process itself, possibly the chronic inflammation of the blood vessels, probably lies at the root of this dangerous problem. In any event, patients with SLE, have a higher chance for the following conditions, which put them at risk for heart attack or stroke:

Atherosclerosis, or plaque buildup in the arteries
Increased stiffness in the arteries
Unhealthy cholesterol and lipid (fatty molecules) levels
High blood pressure, most likely because of kidney injury and corticosteroid treatments
Congestive heart failure
Pericarditis, an inflammation of the tissue surrounding the heart (occurs in about 30% of patients)
Myocarditis, an inflammation of the heart muscle itself (rare)

Click the icon to see an image of pericarditis.

Abnormalities in the valves of the heart (rare)
Blood clots

The risk for cardiovascular disease, heart attack, and stroke is much higher than average in younger women with SLE. The risks decline as such women age.

SLE affects the lungs in about 60% of patients:

Recurrent inflammation of the membrane lining the lung (pleurisy) is the most common problem.
In some cases, fluid accumulates, a condition called pleural effusion, and can cause stabbing localized pain that worsens when coughing, sneezing, laughing, or taking a deep breath.
Inflammation of the lung itself in SLE is called lupus pneumonitis. It can be caused by infections or by the SLE inflammatory process. Symptoms are the same in both cases: fever, chest pain, labored breathing, and coughing. Rarely, lupus pneumonitis becomes chronic and causes scarring in the lungs, which reduces their ability to deliver oxygen to the blood.
A very serious and also rare condition called pulmonary hypertension occurs when high pressure develops in the vessels supplying blood to the lungs.

Click the icon to see an image of primary pulmonary hypertension.

The kidneys are a crucial battleground in SLE because it is here that the debris left over from the immune attacks is most likely to be deposited. About 50% of patients with SLE exhibit inflammation of the kidneys (called lupus nephritis).This condition occurs in different forms and can vary widely in severity.

Click the icon to see an image of the kidney.

Proliferative nephritis is a serious variant of lupus nephritis. It occurs when the inflammatory process causes widespread damage and scarring in the blood vessels of the kidneys, which filters waste products, water, and salts out of the blood. The condition is associated with high blood pressure and kidney deterioration.
Membranous lupus nephritis is another variant that is often associated with a good outlook. In some cases, however, if the kidney is persistently exposed to high protein levels, the disorder can progress to fatal end-stage kidney (renal) disease.

Serious complications occur eventually in about 30% of patients. If kidney injury develops, it almost always occurs within 10 years of the onset of SLE, rarely after that.

Nearly all patients with SLE report some symptoms relating to problems that occur in the central nervous system (CNS), which includes the spinal cord and the brain. Most of these symptoms are minor and some, such as headache, may be related to depression rather than the disease itself. CNS involvement is more likely to occur in the first year, usually during flare-ups in other organs. Symptoms vary widely and may be indistinguishable from psychiatric or neurologic disorders or from the side effects of some medications used for SLE. Central nervous system symptoms are usually mild, but there is little effective treatment available for them. CNS symptoms get worse as the disease progresses.

The most serious CNS disorder is inflammation of the blood vessels in the brain, which occurs in 10% of patients with SLE. Fever, seizures, psychosis, and even coma can occur. Other CNS side effects include:

Irritability
Emotional disorders (anxiety, depression)
Mild impairment of concentration and memory
Migraine and tension headaches
Problems with the reflex systems, sensation, vision, hearing, and motor control

Infections are a common complication and a major cause of death in all stages of SLE. The immune system is indeed overactive in SLE, but it is also abnormal and reduces the ability to fight infections. Patients are not only prone to the ordinary streptococcal and staphylococcal infections, but they are also susceptible to fungal and parasitic infections (called opportunistic infections), which are common in people with weakened immune systems. They also face an increased risk for herpes, salmonella, and yeast infections. Corticosteroid and immunosuppressants, treatments used for SLE, also increase the risk for infections, thereby compounding the problem.

About 45% of patients with SLE suffer gastrointestinal problems, including nausea, weight loss, mild abdominal pain, and diarrhea. Severe inflammation of the intestinal tract occurs in less than 5% of patients and causes acute cramping, vomiting, diarrhea, and, rarely, intestinal perforation, which can be life-threatening. Fluid retention and swelling can cause intestinal obstruction, which is much less serious but causes the same type of severe pain. Inflammation of the pancreas can be caused by the disease and by corticosteroid therapy.

Arthritis caused by SLE almost never leads to destruction or deformity of joints. The inflammatory process can, however, damage muscles and cause weakness. Patients with SLE also commonly experience reductions in bone mass density (osteoporosis) and have a higher risk for fractures, whether or not they are taking corticosteroids (which can increase the risk for osteoporosis). Women who have SLE should have regular bone mineral density scans to monitor bone health.

Click the icon to see an image of osteoporosis.

Inflamed blood vessels in the eye can reduce blood supply to the retina, resulting in degeneration of nerve cells and a risk of hemorrhage in the retina. The most common symptoms are cotton-wool-like spots on the retina. In about 5% of patients sudden temporary blindness may occur.

In one study, 40% of patients with SLE quit work within 4 years of diagnosis, and many had to modify their work conditions. Significant factors that predicted job loss included high physical demands from the work itself, a more severe condition at the time of diagnosis, and lower educational levels. People with lower income jobs were at particular risk for leaving them.

Women with lupus who conceive face high-risk pregnancies. It is important for women to understand the potential complications and plan accordingly. The most important advice is to avoid becoming pregnant when lupus is active.

Research suggests that the following factors predict a successful pregnancy:

Disease state at time of conception. Experts strongly recommend that women wait to conceive until their disease state has been inactive for at least 6 months.
Kidney (renal) function. Women should make sure that their kidney function is evaluated prior to conception. Poor kidney function can worsen high blood pressure and cause excess protein in the urine. These complications increase the risk for preeclampsia and miscarriage.
Lupus-related antibodies. Antiphospholipid and anticardiolipin antibodies can increase the risks for preeclampsia, miscarriage, and stillbirths. Anti-SSA and anti-SSB antibodies can increase the risk for neonatal lupus erythematosus, a condition that can cause skin rash and liver and heart damage to the newborn baby. Levels of these antibodies should be tested at the start of pregnancy. Certain medications (aspirin, heparin) and tests (fetal heart monitoring) may be needed to ensure a safe pregnancy.
Medication use during pregnancy. Women with active disease may need to take low-dose corticosteroids, but women with inactive disease should avoid these drugs. Steroids appear to pose a low risk for birth defects, but can increase a pregnant woman’s risks for gestational diabetes, high blood pressure, infection, and osteoporosis. For patients who need immunosuppressive therapy, azathioprine (Imuran) is an option. Methotrexate (Rheumatrex) and cyclophosphamide (Cytoxan) should not be taken during pregnancy.

Pregnancy Risks

Women with lupus are 20 times more likely to die during pregnancy than women without the disease. The risk for maternal death is due to the following serious conditions that can develop during pregnancy:

Miscarriages. About 25% of lupus pregnancies result in miscarriage. The risk is highest for patients with antiphospholipid antibodies, active kidney disease, or high blood pressure.
Blood clots. Women with lupus have a 6 times greater risk for developing deep vein thrombosis (blood clots) than women without the disease.
Clotting complications. Low blood platelet count and anemia are also risks. Women with lupus are 3 times more likely to need a transfusion during pregnancy than women without lupus.
Infections. Blood infections (sepsis), pneumonia, and urinary tract infections are more common in pregnant women with lupus.
Preeclampsia. Women with lupus are three times more likely than healthy women to develop preeclampsia (pregnancy-related high blood pressure), which can be potentially life threatening.

Birth Complications

Pre-term birth. Women with lupus are 2.5 times more likely to have pre-term labor than women without lupus. Pre-term labor increases the risk for giving birth to low-weight babies.
Stillbirths. A 2005 study reported that the risk of still births was 10 times greater for women who had not yet been diagnosed with lupus, and 4 times greater for women with diagnosed lupus, compared with healthy women. This suggests that lupus may have a pre-disease state.
Caesarean section. Thirty-seven percent of women with lupus require a C-section compared with 22% of women without the disease.

Despite these obstacles, many women with lupus have healthy pregnancies and deliver healthy babies. To increase the odds of a successful pregnancy, it is important for women to plan carefully before becoming pregnant. Be sure to find knowledgeable doctors with whom you can communicate and trust. Experts recommend that pregnant women with lupus assemble an interdisciplinary health care team that includes a rheumatologist, high-risk obstetrician, and (for patients with kidney disease) a nephrologist.

Diagnosis

No single test can confirm or rule out SLE. A number of tests are required before SLE can be diagnosed definitively. The first symptoms of SLE can resemble one of many syndromes or disorders, including rheumatoid arthritis, Still's disease, rheumatic fever, Lyme disease, multiple sclerosis, thrombotic thrombocytopenia purpura, cryoglobulinemia, Weber-Christian disease, viral infections, vasculitis, psychosis, and other conditions. Other autoimmune disorders, such as Sjögren syndrome or scleroderma, may even be present at the same time as SLE.

1. Characteristic rash across the cheek

2. Discoid lesion rash

3. Photosensitivity

4. Oral ulcers

5. Arthritis

6. Inflammation of membranes in the lungs, the heart, or the abdomen

7. Evidence of kidney disease

8. Evidence of severe neurologic disease

9. Blood disorders, including low red and white blood cell and platelet counts

10. Immunologic abnormalities

11. Positive antinuclear antibody (ANA)

Note: A patient must experienced four of the criteria before a doctor can classify the condition as SLE. These criteria, proposed by the American College of Rheumatology, are not to be relied upon solely for diagnosis, however.

Methods for measuring the antibodies involved with SLE vary, and the range of results can be bewildering. Repeat tests may be needed.

Antinuclear Antibodies (ANAs). A primary test for SLE checks for antinuclear antibodies (ANA), which attack the cell nucleus.

High levels of ANA are found in more than 98% of patients with SLE. A number of other conditions, however, also cause high levels of ANA, so a positive test is not a definite diagnosis for SLE:

Antinuclear antibodies may be strongly present in other autoimmune diseases (such as scleroderma, Sjögren syndrome, or rheumatoid arthritis).
They also may be weakly present in about 20 - 40% of healthy women.
Some drugs can also produce positive antibody tests, including hydralazine, procainamide, isoniazid, and chlorpromazine.

A negative ANA test makes a diagnosis of SLE unlikely but not impossible. High or low concentrations of ANA also do not necessarily indicate the severity of the disease, since antibodies tend to come and go in patients with SLE.

In general, the ANA test is considered a screening test:

If SLE symptoms are present and the ANA test is positive, other tests for SLE will be administered.
If SLE symptoms are not present and the test is positive, the doctor will look for other causes, or the results will be ignored if the patient is feeling healthy.

ANA Subtypes. In some cases, doctors may test for specific ANA subtypes.

Anti-double stranded DNA (Anti-ds DNA) is usually found only in patients with SLE. It may play an important role in injury to blood vessels found in SLE, and high levels often indicate kidney involvement. Anti-ds DNA levels tend to fluctuate over time and may even disappear.
Anti-Sm antibodies are also usually found only with SLE. They are more constant and are more likely to be detected in African-American patients. Although the antibody is not usually seen in lupus patients, its confirmed presence almost always indicates SLE.
When the ANA is negative but the diagnosis is still strongly suspected, a test for anti-Ro (also called anti-SSA) and anti-La (also called anti-SSB) antibodies may identify patients with a rare condition called ANA negative, Ro lupus. These autoantibodies may be involved in the sun-sensitive rashes experienced by patients with SLE and are also found in association with neonatal lupus syndrome, in which a pregnant mother's antibodies cross the placenta and cause inflammation in the developing child's skin or heart.

Antibodies to SR Proteins. An advance in diagnosing SLE has been the detection of antibodies to molecules called SR proteins, which are carried by most patients. The test accurately detects lupus in 50 - 70% of patients who test positive for these antibodies.

Antiphospholipid Antibodies. In patients with SLE in whom blood abnormalities are suspected, tests may be able to detect the presence of the two major antiphospholipid antibodies:

A quarter to a half of patients with SLE may have these antibodies. They attack blood-clotting regulator proteins that stick to phospholipids, fatty compounds found in cell membranes throughout the body. Antiphospholipid antibodies increase the risks for blood clots and may be responsible for narrowing of (and irregularities in) blood vessels. Antiphospholipid antibodies are linked with miscarriages and other pregnancy complications, strokes, heart attacks and blood clots in almost any part of the body, including kidneys, legs, lungs, and eyes.
The test for the lupus anticoagulant antibody measures the time it takes blood to clot. A longer than normal blood clotting time indicates a higher chance for clotting in the body and, therefore, the presence of lupus anticoagulant.
An ELISA test (enzyme-linked immunosorbent assay) is performed to detect the anticardiolipin antibody.

As with the ANA, these antibodies also have a tendency to appear and disappear in a single patient. Patients who have these autoantibodies as well as blood clotting problems or frequent miscarriage are diagnosed with antiphospholipid syndrome (APS), which often occurs in SLE but can also develop independently.

Complement. Blood tests of patients with SLE often show low levels of serum complement, a protein in the blood that aids the body's infection fighters. Individual proteins are termed by the letter "C" followed by a number. Common complement tests measure C3, C4, C1q, and CH50. There is some evidence that complete deficiencies of C1q may be a key factor in the inability of the immune system to contain the autoimmunity process. Complement levels are especially low if there is kidney involvement or other disease activity.

LE Cell Tests. The first blood test ever used for SLE called LE (lupus erythematosus) cell test is positive in only about half of patients with SLE and is no longer used that often.

Blood Count. White and red blood cell and platelet counts are usually lower than normal and, depending on severity, are used to determine complications, such as anemia or infection.

Click the icon to see an image of the formed elements of blood.

If a skin rash is present, the doctor may take a biopsy (a tissue sample) from the margin of a skin lesion. A test known as a lupus band detects antibodies known as immunoglobulin G (IgG), which are located just below the outer layer of the tissue sample. They are present in about 80% of patients with active SLE and in 30 - 40% of those with inactive disease. The biopsy will not differentiate between systemic and discoid lupus, but it can rule out other diseases. Tests for other antibodies will rule out or confirm discoid lupus and subacute cutaneous lupus.

Kidney Damage and Lupus Nephritis. Kidney damage in patients already diagnosed with SLE may be detected from the following tests:

Blood tests that measure creatinine, a protein metabolized in muscles and excreted in the urine. High levels suggest kidney damage, although it can also be present with normal creative levels.
Tests for detecting anti-ds DNA antibodies and complement. High levels of anti-ds DNA and low levels of complement C3 suggest kidney damage. (It should be noted, however, that some patients with severe kidney damage show low levels of anti-ds DNA.) Testing for anti-C1q antibodies now appears to be an even more reliable indicator of lupus nephritis.
Urine analysis. Urine analyses should be performed at 4- to 6-month intervals to check for signs of kidney involvement.
A kidney biopsy. This may be performed to determine if lupus nephritis is present when less invasive tests indicate kidney involvement. It is not absolutely accurate but it helps determine treatment. Electron microscopy (very high-powered electronic microscopes) may be especially important in obtaining critical information on the degree of kidney damage.

Lung and Heart Involvement. A chest x-ray may be performed to check lung and heart function. An electrocardiogram and an echocardiogram are administered if heart disease is suspected.

Click the icon to see an image of an electrocardiogram.

Central Nervous System Complications. SLE occurring in the central nervous system (CNS) can be difficult to diagnose because its symptoms are easily confused with other psychiatric and neurologic conditions.

Tests of the cerebrospinal fluid (CSF) for elevated levels of autoantibodies are the most reliable ways to detect CNS complications caused by a faulty immune system.
Additional tests, including electroencephalograms (EEGs), magnetic resonance imaging (MRI), computed tomography (CT), or x-rays may be useful when blood vessel blockage in the brain is suspected.
If the doctor suspects that CNS symptoms are caused by infection, especially for patients who are receiving immunosuppressant therapy, a lumbar puncture should be performed.

Osteoporosis. To detect early osteoporosis in patients with SLE whose disease has lasted more than 3.5 years, experts recommend an imaging test called dual energy x-ray absorptiometry (DEXA) to measure bone mineral density.

Treatment

No treatment cures systemic lupus erythematosus, but many therapies can suppress symptoms and relieve discomfort. Treatment of SLE varies depending on the extent and severity of the disease.

Only three drugs are FDA-approved for the treatment of lupus:

Prednisone
Aspirin
Hydroxychloroquine

However, none of these drugs are the current standard of care. In everyday practice, numerous other drugs are commonly used. Researchers are conducting numerous clinical studies and drug investigations. Genetic research in lupus is progressing very rapidly, and hopefully new drugs will be approved in the future. There are also different drugs available to treat some of the conditions associated with lupus.

Less intensive treatments may be effective for symptoms of mild lupus. They include:

Creams and sunblocks for rashes
Nonsteroidal anti-inflammatory drugs for fever, arthritis, and headache
Antimalarial drugs for pleurisy, mild kidney involvement, and inflammation of the tissue surrounding the heart

More aggressive treatment is needed if there is serious disease progression, as evidenced by:

Hemolytic anemia
Low platelet count with an accompanying rash (thrombocytopenia purpura)
Major involvement in the lungs or heart
Significant kidney damage
Acute inflammation of the small blood vessels in the extremities or gastrointestinal tract
Severe central nervous system symptoms

The primary approach to treating severe SLE is to suppress the immune factors, most often first with corticosteroids and other immunosuppressant drugs. Investigational drugs and procedures are also showing promise.

The major complications of the disease must be treated as separate problems, keeping in mind the specific aspects of SLE. They are discussed elsewhere in this report.

Treatment for Cutaneous and Mild SLE

Creams. Steroid creams are often used for skin lesions. However, many patients with discoid lupus do not respond to steroids, particularly if they have eruptions that are caused by sun sensitivity. A cream derived from vitamin A (Tegison) may help some lesions that do not clear up with steroid creams.

Sun Protection. Sun protection is essential. Patients should always use sunblock creams (not just sunscreens) and always wear hats and clothing made of tightly woven fabrics.

Common NSAIDs. NSAIDs block prostaglandins, the substances that dilate blood vessels and cause inflammation and pain. There are dozens of NSAIDs.

Over-the-counter NSAIDs include aspirin, ibuprofen (Motrin, Advil), naproxen (Aleve), ketoprofen (Actron, Orudis KT).
Prescription NSAIDs include ibuprofen (Motrin), naproxen (Naprosyn, Anaprox), diclofenac (Voltaren), tolmetin (Tolectin), ketoprofen (Orudis, Oruvail), dexibuprofen (Seractil).

For people with lupus, NSAIDs may help relieve:

Joint pain and swelling
Muscle pain

Side Effects. Regular, long-term use of NSAIDs can cause ulcers and gastrointestinal bleeding, which can lead to anemia. To avoid these problems, it’s best to take NSAIDs with food or immediately after a meal. Long-term use of NSAIDs (with the exception of aspirin) can also increase the risk for heart attack and stroke.

Other NSAID side effects may include:

Upset stomach
Dyspepsia (burning, bloated feeling in pit of stomach)
Drowsiness
Skin bruising
High blood pressure
Fluid retention
Headache
Rash
Reduced kidney function

Patients who have kidney problems associated with lupus (lupus nephritis) should be especially cautious about using NSAIDs. Experts recommend that patients with lupus who take NSAIDs on a regular basis should have their liver and kidney function tested every 3 - 4 months.

An ulcer is a crater-like lesion on the skin or mucous membrane caused by an inflammatory, infectious, or malignant condition. Patients can take certain medicines to suppress the acid in the stomach causing the erosion of the stomach lining. Endoscopic therapy can be used to stop bleeding from the ulcer.

Long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) is the second most common cause of ulcers. Ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs) are more likely to bleed than those caused by the bacteria Helicobacter pylori.

Those at high risk for bleeding include people over age 60, anyone with a history of ulcers or gastrointestinal bleeding, patients with serious heart conditions, people who abuse alcohol, and those who take medications such as anticoagulants (blood thinners) and corticosteroids.

Proton-pump inhibitor (PPI) drugs may help prevent and heal ulcers caused by NSAIDs. PPIs include omeprazole (Prilosec), esomeprazole (Nexium), and lansoprazole (Prevacid).

A doctor may prescribe antimalarial drugs for discoid lupus (skin sores) or mild lupus when skin problems and joint pains are the predominant symptoms:

Hydroxychloroquine (Plaquenil) is the most common antimalarial drug used for lupus. This drug is effective as maintenance therapy to reduce flares in patients with mild or inactive disease. Hydroxychloroquine may help protect against blood clots in people with antiphospholipid syndrome, high cholesterol levels, and bone loss.
Other antimalarial drugs include chloroquine (Aralen) or quinacrine (Atabrine).

Treatment may start initially with high doses in order to accumulate high levels of the drug in the bloodstream. It is not known exactly why antimalarials work. Some researchers believe they inhibit the immune response, and others think they interfere specifically with inflammation.

A 2006 study suggested that anti-malarial drugs work best in patients who have genetic predispositions to certain types of immune-fighting proteins. The study found that patients who had genetic variations causing abnormally high levels of tumor necrosis alpha (TNF-alpha) and abnormally low levels of interleukin-10 (IL-10) responded best to these drugs.

Side Effects. Side effects of antimalarials may include:

Skin rash
Change in skin color (yellow in the case of quinacrine)
Gastrointestinal problems
Headache
Hair loss
Muscle aches
Eye damage

The most serious is damage to the retina, although this is very uncommon at low doses. Eye damage after taking hydroxychloroquine is reversible when caught in time and treated, but it is not reversible if the damage develops after taking chloroquine. An eye exam is advisable about every 6 months.

Antimalarials may also be used in combination with other anti-SLE drugs, including immunosuppressants and corticosteroids. It should be noted that smoking significantly reduces the effectiveness of antimalarial drugs.

Treatment for Severe SLE

Severe SLE is treated with corticosteroids, also called steroids, which suppress the inflammatory process. Steroids can help relieve many of the complications and symptoms, including anemia and kidney involvement.

Oral prednisone (Deltasone, Orasone) is usually prescribed. Other drugs include methylprednisolone (Medrol, Solumedrol), hydrocortisone, and dexamethasone (Decadron).

Some people need to take oral prednisone for only a short time; others may require it for a long duration. An intravenous administration of methylprednisolone using "pulse" therapy for 3 days is proving useful for flare-ups in the joints. Combinations with other drugs, particularly immunosuppressants, may be beneficial.

Regimens vary widely, depending on the severity and location of the disease. Most patients with SLE can eventually function without prednisone, although some may have to choose between the long-term toxicity of corticosteroids and the complications of active disease.

Side Effects of Long-Term Oral Corticosteroids. Unfortunately, serious and even life-threatening complications have been associated with long-term steroid use. The bone-thinning condition osteoporosis is a common and particularly severe long-term side effect of prolonged steroid use. Medications that can prevent osteoporosis include calcium supplements, parathyroid hormone, alendronate etidronate, risedronate, or hormone replacement therapy in post-menopausal women. Vitamin C and E may help reduce the risk of cataracts.

Other side effects associated with prolonged use of oral steroids include:

Cataracts
Glaucoma
Diabetes
Fluid retention
Susceptibility to infections
Weight gain
High blood pressure
Acne
Excess hair growth
Wasting of the muscles
Menstrual irregularities
Irritability
Insomnia
Psychosis

Withdrawal from Long-Term Use of Oral Corticosteroids. Long-term use of oral steroid medications suppresses secretion of natural steroid hormones by the adrenal glands. After withdrawal from these drugs, this so-called adrenal suppression persists and it can take the body a while (sometimes up to a year) to regain its ability to produce natural steroids again. A few cases of severe adrenal insufficiency have occurred when patients switched from oral to inhaled steroids, which, in rare cases, has resulted in death.

No one should stop taking any steroids without consulting a doctor first, and if steroids are withdrawn, regular follow-up monitoring is necessary. Patients should discuss with their doctors measures for preventing adrenal insufficiency during withdrawal, particularly during stressful times, when the risk increases.

Drugs known as immunosuppressants are often used, either alone or with corticosteroids for very active SLE, particularly when kidney or neurologic involvement or acute blood vessel inflammation is present. These drugs suppress the immune system by damaging cells that grow rapidly, including those that produce antibodies. About a third of patients take immunosuppressants at some point in the course of the disease.

Specific Immunosuppressants. The most common immunosuppressants are:

Cyclophosphamide (Cytoxan) used to be considered the gold standard of treatment for lupus kidney disease (lupus nephritis). Cyclophosphamide is given intravenously and is sometimes used in combination with corticosteroids or other drugs. It has been used for lupus since the 1970s. Side effects are very severe and include nausea, vomiting, hair loss, infertility, and infections.
Mycophenolate mofetil (CellCept) is now becoming the new standard. Many recent studies have shown that CellCept works better than cyclophosphamide and causes far fewer severe side effects (diarrhea is the main side effect). Unlike cyclophosphamide, it is taken by mouth. Most doctors now recommend CellCept as a first-line treatment for newly diagnosed patients with mild or moderate lupus kidney disease. It may not be appropriate for patients with kidney failure or rapidly progressing kidney disease.
Azathioprine (Imuran) has the lowest toxicity, but is less effective than other immunosuppressants.
Cyclosporine (Sandimmune) has been used for years, mostly for SLE associated with kidney involvement. High blood pressure is common, however, with this drug.

The most frequent side effects of immunosuppressants include:

Stomach and intestinal problems
Skin rash
Mouth sores
Hair loss

Serious side effects of immunosuppressants include:

Low blood cell counts
Anemia
Menstrual irregularity
Early menopause
Ovarian failure
Infertility
Herpes zoster (shingles)
Liver and bladder toxicity
Increased risk of cancer

In general, immunosuppressants should not be used alone unless corticosteroids are ineffective or inappropriate. Grapefruit juice has an enzyme that may enhance the effects of some immunosuppressants.

Monoclonal Antibodies (MAbs). A MAb is a laboratory-made protein that targets specific immune cells, such as B cells. B cell over-activation has been identified as a key component of the lupus disease process. Promising MAbs in development for SLE treatment include:

Epratuzumab is being investigated for treatment of moderate-to-severe lupus. It is currently in Phase III trials.
Belimumab (Lymphostat-B) is also in Phase III trials.
Rituximab (Rituxan), a lymphoma cancer and rheumatoid arthritis drug, has shown good results in early trials in improving lupus symptoms. Researchers think it may affect how T cells and B cells interact. However, in December 2006 the FDA warned of several cases of progressive multifocal leukoencephalopathy (PML) in patients with lupus who took this drug. PML is a life-threatening brain infection. Some patients developed PML as late as 12 months after their last dose of rituximab. Two patients with lupus died from PML.

Intravenous Immunoglobulins. Intravenous immunoglobulins (IVIG) are sometimes used for patients who have not responded to other SLE treatments. Immunoglobulins are antibodies produced by immune system B-lymphocyte cells. IVIG is a blood product that contains these antibodies.

Dehydroepiandrosterone (DHEA). Dehydroepiandrosterone (DHEA) is a natural steroid hormone that is produced by the adrenal glands and converted into estrogen and androgen. The synthetic equivalent of DHEA, prasterone (Prestara), is being investigated as a potential treatment for SLE. Several clinical trials have indicated promising, although mixed, results for prasterone’s effect on preventing bone mineral density loss in women who take prednisone. Prasterone is still in the drug development stage and it is not clear when, or if, it will be commercially available.

Autologous Stem Cell Transplantation. Some patients with severe lupus have achieved at least short-term remission after undergoing autologous transplantation of stem cells and high-dose drug therapy to suppress the damaging immune factors. Stem cells are the early forms for all blood cells in the body. An autologous transplant is one in which marrow or blood cells used are the patient's own. (The advantage to an autologous transplant is that the patient's own cells are not at risk for rejection by the immune system.)

The procedure first removes the cells from the patient, who then receives high-dose immunotherapy. The stem cells are then reintroduced. Early results of small studies are encouraging, especially for treatment of antiphospholipid syndrome. Evidence suggests that these re-introduced stem cells do not repeat the original autoimmune errors. A 2006 study in the Journal of the American Medical Association indicated that autologous stem cell transplantation can help boost the immune system and lead to remission. Patients in the study had severe lupus that was resistant to standard treatments. Results were long-lasting. Researchers calculated that patients had a 50% chance of remaining disease-free after 5 years.

UVA-1 Phototherapy. A promising treatment uses ultraviolet A-1 (UVA-1) radiation, long UVA wave lengths that do not promote sunburn and may actually block inflammatory immune factors. Small studies have suggested that UVA-1 phototherapy may have some benefits for lowering disease activity in SLE.

Plasmapheresis. Plasmapheresis is a process in which the fluid part of the blood, called plasma, is removed from blood cells. The procedure involves first taking blood from the patient. The plasma, which contains the inflammatory antibodies and other immunologically active substances, is discarded and replaced with other fluids. The blood is then returned. Plasmapheresis is not useful for routine management of patients but may have some benefits for patients who do not respond to standard treatments or in specific cases, such as lupus patients with hemolytic anemia.


Infections, Inflammation, or Hypertension in the Lungs	Preventive Measures. Immunizations with inactive viruses and preventive antibiotics should be considered for patients with SLE who are at high risk for infection. Treating Infections. Lung infections need to be treated aggressively with antibiotics. However, antibiotic drugs such as penicillin or the sulfa drugs may cause sensitivity rashes that can be confused with SLE rash. Treating Lung Inflammation. While inflammation of the lung (pneumonitis) resembles pneumonia, it is not an infection but is a result of the autoimmune process. This condition needs to be treated with corticosteroids or immunosuppressants, but only if the doctor is sure infection is not present. Treating Pulmonary Hypertension. Pulmonary hypertension is very serious. Drugs known as prostacylins -- which include epoprostenol, iloprost, and treprostinil -- are standard drugs. Bosentan (Tracleer) is the first oral drug approved for pulmonary hypertension. An inhaled iloprost formulation (Ventavis) was approved in 2004. Sildenafil (Viagra, Revatio) may also be used for this condition. Lung transplantation may be required.
Bleeding and Clotting Disorders	Antiphospholipid Syndrome and Clotting Disorders. Hydroxychloroquine or aspirin may help prevent blood clots in women with antiphospholipid syndrome (APS). (Aspirin does not appear to be protective in men who carry the autoantibodies responsible for APS.) In patients who have experienced blood clots, treatment with the anticoagulant warfarin (Coumadin) is advisable. This blood-thinning drug may be needed lifelong. Scientists are investigating other treatment options, including autologous stem cell transplantation. The procedure has shown promise in studies for treating lupus-associated APS, but it is still experimental. Excess Bleeding from Thrombocytopenia (Drop in Blood Platelets). Treatments that may be effective for thrombocytopenia include combinations of a corticosteroid and either danazol (a male hormone) or the antimalarial hydroxychloroquine. Immunosuppressants or intravenous immunoglobulin IgG may be helpful in some patients. Surgical removal of the spleen may be advisable if bleeding disorders are a serious problem, but this option should be considered carefully, because the spleen provides one line of defense against infection. (Abnormal spleen function, in any case, appears to be fairly common in SLE.)
Kidney Disease	Drugs. Mycophenolate mofetil (CellCept), a newer drug, can help treat kidney disease associated with SLE and has fewer side effects than other immunosuppressants. It is taken by mouth. Recent studies suggest that it works better than cyclophosphamide. CellCept may be best for patients with mild-to-moderate lupus kidney disease and may not be appropriate for patients with advanced kidney disease. Intravenous cyclophosphamide is the most effective drug at this time for proliferative lupus nephritis, and, in combination with a steroid, has been shown to control advanced kidney disease in 60 - 90% of patients. It has severe side effects, including nausea, vomiting, hair loss, and infertility. Steroids are also useful for treating active kidney disease and for managing milder forms of nephritis. Procedures. Kidney transplant or dialysis should be considered for patients with SLE with severe kidney damage. For unknown reasons, SLE does not generally recur in the transplanted kidneys. Studies are conflicting, however, over whether SLE transplant patients have higher organ-rejection rates than other kidney-transplant recipients. Both transplantation and dialysis have potentially serious complications. Plasmapheresis. It is not clear if plasmapheresis is beneficial for SLE kidney disease.
Osteoporosis	Treatments for osteoporosis include calcium, vitamin D, bisphosphonates, parathyroid hormone, and selective estrogen-receptor modulators (SERMs). [For more information, see In-Depth Report #18: Osteoporosis.]
Heart Disease	The need for aggressive treatment of high blood pressure often accompanies kidney disease. SLE is also accompanied by high cholesterol levels, which requires diet changes and drug therapies. [For more information, see In-Depth Reports #3: Coronary artery disease; #14: High blood pressure; #23: Cholesterol; and #43: Heart healthy diet.]

The spleen is an organ that helps produce and maintain red blood cells. It also aids the body's immune system by producing white blood cells that destroy harmful substances in the body. Removal of the spleen makes a person more susceptible to infection.

Click the icon to see an illustrated series detailing kidney transplant.

Lifestyle Changes

People with SLE should try to maintain a healthy and active lifestyle. Light-to-moderate exercise, interspersed with rest periods, is good for the heart, helps fight depression and fatigue, and can help keep joints flexible.

Patients should minimize their exposure to crowds or people with contagious illnesses. Careful hygiene, including dental hygiene, is also important.

It is very important that patients with SLE avoid excessive exposure to sunlight. Simple preventive measures include avoiding overexposure to ultraviolet rays and wearing protective clothing and sunblocks. There is some concern that allergy shots may cause flare ups in certain cases. Patients who may benefit from them should discuss risks and benefits with an SLE specialist. In general, patients with SLE should use only hypoallergenic cosmetics or hair products.

Chronic stress has profound physical effects and influences the progression of SLE. Getting adequate rest of at least 8 hours and possibly napping during the day may be helpful. Maintaining social relationships and healthy activities may also help prevent the depression and anxiety associated with the disease.

Resources

www.lupus.org -- Lupus Foundation of America
www.lupusny.org -- SLE Foundation of America
www.niams.nih.gov -- National Institute of Arthritis and Musculoskeletal and Skin Diseases
www.rheumatology.org -- American College of Rheumatology
www.lupusresearchinstitute.org -- Lupus Research Institute

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Review Date:
1/21/2008
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

A.D.A.M. Copyright

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