Meningitis

Diagnosis
Early diagnosis and treatment are very important. Classic signs of meningitis include sudden onset of fever, headache and stiff neck. These signs are often accompanied by other symptoms, such as nausea, vomiting, sensitivity to light (photophobia), and altered mental status. Older children and adults may experience a skin rash. In young children, the signs may be more subtle and my include inactivity, irritability, vomiting, or poor feeding.

If meningitis is suspected, samples of blood or cerebrospinal fluid are collected and sent to the laboratory for testing. It is important to know the specific cause of meningitis because the severity of illness and the treatment will differ depending on the cause. In the case of bacterial meningitis, for example, antibiotics can help prevent severe illness and reduce the spread of infection from person to person.
Bacterial Meningitis

If bacteria are present, they can be grown (cultured). Growing the bacteria in the laboratory is important for confirming the presence of bacteria and for identifying the specific type of bacteria that is causing the infection.
Viral Meningitis

The specific causes of meningitis may be determined by tests used to identify the virus in samples collected from the patient.
Fungal Meningitis

To confirm fungal meningitis, specific lab tests can be performed, depending on the type of fungus suspected.

Risk Factors of Meningitis

The most effective way to protect you and your child against certain types of meningitis is to complete the childhood vaccine schedule. The risk of meningitis increases by not following the recommended vaccine schedule. Other factors that can increase your risk of meningitis include:

* Age.
o Viral meningitis occurs mostly in children younger than age 5.
o Before the availability of effective vaccines, bacterial meningitis was most commonly diagnosed in young children. Now, as a result of the protection offered by current childhood vaccines, bacterial meningitis is more commonly diagnosed among pre-teens and young adults.
* Community setting.
o Infectious diseases tend to spread quickly wherever larger groups of people gather together. As a result, college students living in dormitories, military personnel and children in childcare facilities are at an increased risk.
* Pregnancy.
o Pregnant women are at an increased risk of catching listeriosis. The bacteria that cause listeriosis, listeria bacteria, can also cause meningitis. The unborn baby of a pregnant woman with listeriosis is also at risk.
* Working with animals.
o Dairy farmers, ranchers, and other people who work with domestic animals are at an increased risk of contracting listeriosis. The bacteria that cause listeriosis, listeria bacteria, can also cause meningitis.
* Weakened immune system.
o There are certain diseases, medications and surgical procedures that may weaken the immune system and increase risk of meningitis.

Signs & Symptoms

Meningitis infection is characterized by a sudden onset of fever, headache, and stiff neck. It is often accompanied by other symptoms, such as

• Nausea
• Vomiting
• Photophobia (sensitivity to light)
• Altered mental status

Bacterial Meningitis

The symptoms of bacterial meningitis can appear quickly or over several days. Typically they develop within 3-7 days after exposure.

Infants younger than one month old are at a higher risk for severe infection. In newborns and infants, the classic symptoms of fever, headache, and neck stiffness may be absent or difficult to notice. The infant may appear to be slow or inactive, irritable, vomiting or feeding poorly. In young children, doctors may also look at the child’s reflexes, which can also be a sign of meningitis.

Although the early symptoms of viral meningitis and bacterial meningitis may be similar, later symptoms of bacterial meningitis can be very severe (e.g., seizures, coma). For this reason, if you think you or someone else may have meningitis, see a physician as soon as possible.

Viral Meningitis

Viral meningitis is an infection of the meninges (the covering of the brain and spinal cord) that is caused by a virus. Enteroviruses, the most common cause of viral meningitis, appear most often during the summer and fall in temperate climates.

Viral meningitis can affect babies, children, and adults. It is usually less severe than bacterial meningitis and normally clears up without specific treatment. The symptoms of viral meningitis are similar to those for bacterial meningitis, which can be fatal. Because of this, it is important to see a healthcare provider right away if you think you or your child might have meningitis.

Symptoms of viral meningitis in adults may differ from those in children:

Common symptoms in infants

• Fever
• Irritability
• Poor eating
• Hard to awaken

Common symptoms in adults

• High fever
• Severe headache
• Stiff neck
• Sensitivity to bright light
• Sleepiness or trouble waking up
• Nausea, vomiting
• Lack of appetite

The symptoms of viral meningitis usually last from 7 to 10 days, and people with normal immune systems usually recover completely.

Fungal Meningitis

Symptoms of fungal meningitis are similar to symptoms of other forms of meningitis; however, they often appear more gradually. In addition to typical meningitis symptoms, like headache, fever, nausea, and stiffness of the neck, people with fungal meningitis may also experience:

• Dislike of bright lights
• Changes in mental status, confusion
• Hallucinations
• Personality changes

Treatment

Bacterial Meningitis

Bacterial meningitis can be treated with a number of effective antibiotics. It is important that treatment be started early in the course of the disease. If bacterial meningitis is suspected, initial treatment with ceftriaxone and vancomycin is recommended. Appropriate antibiotic treatment of the most common types of bacterial meningitis should reduce the risk of dying from meningitis to below 15%, although the risk is higher among the elderly.

Viral Meningitis

There is no specific treatment for viral meningitis. Antibiotics do not help viral infections, so they are not useful in the treatment of viral meningitis. Most patients completely recover on their own within 7 to 10 days. A hospital stay may be necessary in more severe cases or for people with weak immune systems.

Fungal Meningitis

Fungal meningitis is treated with long courses of high dose antifungal medications. This is usually given using an IV line and is done in the hospital. The length of treatment depends on the status of the immune system and the type of fungus that caused the infection. For people with immune systems that do not function well because of other conditions, like AIDS, diabetes, or cancer, there is often a need for longer treatment.

Prostate Cancer

Basic Information About Prostate Cancer

Cancer is a disease in which abnormal cells in the body grow out of control. Cancers are usually named after the part of the body where the abnormal cell growth begins. Prostate cancers are cancer cells from the prostate. When prostate cancer cells spread to other parts of the body, they are called metastases.

What Is the Prostate?

The prostate is a part of the male reproductive system, which includes the penis, prostate, and testicles. The prostate is located just below the bladder and in front of the rectum. It is about the size of a walnut and surrounds the urethra (the tube that empties urine from the bladder). The job of the prostate is to produce fluid that makes up a part of semen. As men age, the prostate tends to increase in size. This can cause the urethra to narrow and decrease urine flow.


This diagram shows the location of the prostate, in front of the rectum and just below the bladder.

Symptoms
Different people have different symptoms for prostate cancer. Some men do not have symptoms at all.

Some symptoms of prostate cancer are—

* Difficulty starting urination.
* Weak, or interrupted flow of urine.
* Frequent urination, especially at night.
* Difficulty emptying the bladder completely.
* Pain or burning during urination.
* Blood in the urine or semen.
* Pain in the back, hips, or pelvis that doesn't go away.
* Painful ejaculation.

If you have any symptoms that worry you, be sure to see your doctor right away. Keep in mind that these symptoms may be caused by conditions other than prostate cancer.

Risk Factors

Research has found risk factors that increase your chances of getting prostate cancer. These risk factors include—

* Age: The older a man is, the greater his risk for getting prostate cancer.1
* Family history: Certain genes (the functional and physical units of heredity passed from parent to offspring) that you inherited from your parents may affect your prostate cancer risk. Currently, no single gene is sure to raise or lower your risk of getting prostate cancer. However, a man with a father, brother, or son who has had prostate cancer is two to three times more likely to develop the disease himself.1
* Race: Prostate cancer is more common in some racial and ethnic groups than in others, but medical experts do not know why.

Researchers are trying to determine the causes of prostate cancer and whether it can be prevented. They do not yet agree on the factors that can influence a man's risk of developing the disease, either positively or negatively. Some of the factors under study include—1 2 3 4

* Vitamins, minerals, and herbal supplements.
* Diets high in animal fat, especially polyunsaturated fat.
* Men's hormone levels.
* Environmental agents (pesticide residues on foods, and industrial and occupational exposures).

Screening

Prostate cancer screening means looking for cancer before it causes symptoms. This helps to find cancer at an early stage when it may be easier to treat.

Tests that are commonly used to screen for prostate cancer are—

* Digital rectal exam (DRE): A doctor or nurse will insert a gloved, lubricated finger into the rectum to feel the prostate. This allows the examiner to estimate the size of the prostate and feel for any lumps or other abnormalities.
* Prostate specific antigen test (PSA): The PSA test is a blood test that measures the level of PSA in the blood. PSA is a substance made by the prostate. The levels of PSA in the blood can be higher in men who have prostate cancer. The PSA level may also be elevated in other conditions that affect the prostate.

As a rule, the higher the PSA level in the blood, the more likely a prostate problem is present. But many factors, such as age and race, can affect PSA levels. Some prostate glands produce more PSA than others. PSA levels also can be affected by—

* Certain medical procedures.
* An enlarged prostate.
* A prostate infection.

Because many factors can affect PSA levels, your doctor is the best person to interpret your PSA test results.

Should I Get Screened for Prostate Cancer?

Not all medical experts agree that screening for prostate cancer will save lives. Currently, there is not enough evidence to decide if the potential benefits of prostate cancer screening outweigh the potential risks.

Potential benefits of prostate cancer screening include—

* Screening can detect cancers early.
* Treatment for prostate cancer may be more effective when it is found early.

Potential risks of prostate cancer screening include—

* False positive test results (indicating that you have prostate cancer when in fact you do not) that lead to further tests and can cause anxiety.
* Treatment of some prostate cancers that may have never affected a man's health even if left untreated.
* Treatment may lead to serious side effects such as impotence (inability to keep an erection) and incontinence (inability to control the flow of urine, resulting in leakage).

CDC and other federal agencies follow the prostate cancer screening guidelines set forth by the U.S. Preventive Services Task Force,External Web Site Icon which state that there is insufficient evidence to recommend for or against routine screening for prostate cancer using PSA or DRE.

Informed Decision Making

Given the uncertainty about the benefit of screening, CDC supports informed decision making. Informed decision making occurs when a man—

* Understands the nature and risk of prostate cancer.
* Understands the risks of, benefits of, and alternatives to screening.
* Participates in the decision to be screened or not at a level he desires.
* Makes a decision consistent with his preferences and values.

CDC has developed materials about prostate cancer screening which are designed to promote discussions between men and physicians and to help men make informed decisions about prostate cancer screening.

Diagnosis

If your prostate specific antigen test (PSA) or digital rectal exam (DRE) is abnormal, doctors may do additional tests to find or diagnose prostate cancer.

* Transrectal ultrasound: A probe the size of a finger is inserted into the rectum, and high-energy sound waves (ultrasound) are bounced off the prostate to create a picture of the prostate called a sonogram. This test may be used during a biopsy.
* Biopsy: A small piece of tissue is removed from the prostate and looked at under a microscope to see if there are cancer cells.
o Gleason score: This score is determined when the biopsy is looked at under the microscope. If there is a cancer, the score indicates how likely it is to spread. The score ranges from 2–10. The lower the score, the less likely it is that the cancer will spread. For more information, visit the National Cancer Institute's (NCI) Prostate Cancer.

For more information about diagnosis, visit NCI's Prostate Cancer Detection and Diagnosis.

Staging

If prostate cancer is diagnosed, tests are done to find out if cancer cells have spread within the prostate or to other parts of the body. This process is called staging. Whether the cancer is only in the prostate, or has spread outside the prostate, determines your stage of prostate cancer. The stage of prostate cancer tells doctors what kind of treatment is needed.

Treatment

Different types of treatment are available for prostate cancer. You and your doctor will decide which treatment is right for you. Some common treatments are—

* Active surveillance (watchful waiting): This consists of closely monitoring the patient's prostate cancer by performing the PSA and DRE tests regularly, and treating it only if and when the prostate cancer causes symptoms or shows signs of growing.
* Surgery (radical prostatectomy): Prostatectomy is surgery to remove the prostate completely. Radical prostatectomy removes the prostate as well as the surrounding tissue.
* Radiation therapy: Radiation destroys cancer cells, or prevents them from growing, by directing high-energy X-rays (radiation) at the prostate. There are two types of radiation therapy—
o External radiation therapy: A machine outside the body directs radiation at the cancer cells.
o Internal radiation therapy (brachytherapy): Radioactive seeds or pellets are surgically placed into or near the cancer to destroy the cancer cells.
* Hormone therapy: This treatment uses drugs, surgery, or other hormones to remove male sex hormones or block them from working, which prevents cancer cells from growing.

Other therapies used in the treatment of prostate cancer that are still under investigation include—

* Cryotherapy: Placing a special probe inside or near the prostate cancer to freeze and kill the cancer cells.
* Chemotherapy: Using special drugs to shrink or kill the cancer. The drugs can be pills you take or medicines given through an intravenous (IV) tube, or, sometimes, both.
* Biological therapy: This treatment works with your body's immune system to help it fight cancer or to control side effects from other cancer treatments. Side effects are how your body reacts to drugs or other treatments. Biological therapy is different from chemotherapy, which attacks cancer cells directly.
* High-intensity focused ultrasound: This therapy directs high-energy sound waves (ultrasound) at the cancer to kill cancer cells.

For more information, visit the National Cancer Institute's (NCI) Prostate Cancer Treatment Option Overview.External Web Site Icon This site can also help you find a doctor or treatment facilityExternal Web Site Icon that works in cancer care. Visit Facing Forward: Life After Cancer TreatmentExternal Web Site Icon for more information about treatment and links that can help with treatment choices.
Clinical Trials

If you have prostate cancer, you may want to take part in a clinical trial. Clinical trials are research studies that help find new treatment options. Visit the NCI and National Institutes of Health (NIH) sites listed below for more information about finding clinical trials.

* Introduction to Clinical TrialsExternal Web Site Icon (NCI)
* Search for Clinical TrialsExternal Web Site Icon (NCI)
* ClinicalTrials.govExternal Web Site Icon (NIH)

Complementary and Alternative Medicine

Complementary medicine is a group of medicines and practices that may be used in addition to the standard treatments for cancer. Alternative medicine means practices or medicines that are used instead of the usual, or standard, ways of treating cancer. Examples of complementary and alternative medicine are meditation, yoga, and dietary supplements like vitamins and herbs.

Complementary and alternative medicine does not treat prostate cancer, but may help lessen the side effects of the cancer treatments or of the cancer symptoms. It is important to note that many forms of complementary and alternative medicines have not been scientifically tested and may not be safe. Talk to your doctor before you start any kind of complementary or alternative medicine.

For more information about complementary and alternative medicine, visit NCI's Complementary and Alternative Medicine.External Web Site Icon
Which Treatment Is Right for Me?

Choosing which kind of treatment is right for you may be hard. If you have prostate cancer, be sure to talk to your doctor about the treatment options available for your type and stage of cancer. Doctors can explain the risks and benefits of each treatment and their side effects.

Source : www.cdc.gov

Hazards to Outdoor Workers: UV Radiation

Overview

Ultraviolet (UV) rays are a part of sunlight that is an invisible form of radiation. UV rays can penetrate and change the structure of skin cells. There are three types of UV rays: ultraviolet A (UVA), ultraviolet B (UVB), and ultraviolet C (UVC). UVA is the most abundant source of solar radiation at the earth's surface and penetrates beyond the top layer of human skin. Scientists believe that UVA radiation can cause damage to connective tissue and increase a person's risk for developing skin cancer. UVB rays penetrate less deeply into skin, but can still cause some forms of skin cancer. Natural UVC rays do not pose a risk to workers because they are absorbed by the Earth's atmosphere.

Sunlight exposure is highest during the summer and between 10:00 a.m. and 4:00 p.m. Working outdoors during these times increases the chances of getting sunburned. Snow and light-colored sand reflect UV light and increase the risk of sunburn. At work sites with these conditions, UV rays may reach workers' exposed skin from both above and below. Workers are at risk of UV radiation even on cloudy days. Many drugs increase sensitivity to sunlight and the risk of getting sunburn. Some common ones include thiazides, diuretics, tetracycline, doxycycline, sulfa antibiotics, and nonsteroidal anti-inflammatory drugs, such as ibuprofen.

Workers at increased risk of UV damage include lifeguards, construction workers, agricultural workers, landscapers, gardeners, and other outdoor workers.

Risks of UV Radiation

Sunburn | Skin Cancer

Sunburn

Sunburn is an often painful sign of skin damage from spending too much time outdoors without wearing a protective sunscreen. Years of overexposure to the sun lead to premature wrinkling, aging of the skin, age spots, and an increased risk of skin cancer. In addition to the skin, eyes can get burned from sun exposure. Sunburned eyes become red, dry, and painful, and feel gritty. Chronic exposure of eyes to sunlight may cause pterygium (tissue growth that leads to blindness), cataracts, and perhaps macular degeneration, a leading cause of blindness.

Symptoms

Unlike a thermal burn, sunburn is not immediately apparent. Symptoms usually start about 4 hours after sun exposure, worsen in 24-36 hours, and resolve in 3-5 days.

Symptoms may include:

• Red, warm, and tender skin
• Swollen skin
• Blistering
• Headache
• Fever
• Nausea
• Fatigue

The pain from sunburn is worse 6-48 hours after sun exposure. Skin peeling usually begins 3-8 days after exposure.

First Aid

There is no quick cure for minor sunburn:

• Symptoms can be treated with aspirin, acetaminophen, or ibuprofen to relieve pain and headache and reduce fever.
• Drinking plenty of water helps to replace fluid losses.
• Cool baths or the gentle application of cool wet cloths on the burned area may also provide some comfort.
• Workers with sunburns should avoid further exposure until the burn has resolved.
• Additional symptomatic relief may be achieved through the application of a topical moisturizing cream, aloe, or 1% hydrocortisone cream.
• A low-dose (0.5%-1%) hydrocortisone cream, which is sold over the counter, may be helpful in reducing the burning sensation and swelling and speeding up healing.

If blistering occurs:

• Lightly bandage or cover the area with gauze to prevent infection.
• The blisters should not be broken, as this will slow the healing process and increase the risk of infection.
• When the blisters break and the skin peels, dried fragments may be removed and an antiseptic ointment or hydrocortisone cream may be applied.
• Seek medical attention if any of the following occur:
  • Severe sunburns covering more than 15% of the body
  • Dehydration
  • High fever (>101°F)
  • Extreme pain that persists for longer than 48 hours

Skin Cancer

Skin Cancer Types

Basal Cell

• A small raised bump that looks smooth, shiny, and translucent.
• A small, pink, crater-like growth with a raised, rolled border and an indentation in the center.
• A scar-like area that is white, yellow, or waxy.
• Reddish, irritated patches of skin.
• A sore that does not heal.
• Can usually be removed by excision or topical treatments.
• If diagnosed and treated early, basal cell cancers can be cured.

Squamous Cell

• Crusty, warty appearance.
• A raised growth with a depression in the center.
• Scaly, red patch area.
• A sore that does not heal.
• Can usually be removed by excision or topical treatments.
• If diagnosed and treated early, squamous cell cancers can be cured.

Melanoma

Changes in the size, shape, or color of moles.

• Dark mole-like appearance.
• Flat or slightly elevated discolored patch (tan, brown, red, black, blue, or white).
• Change on the skin:
• New spot developing.
• Change in size, color, or shape of existing spot or mole.
• Malignant melanoma carries significant, even fatal implications.
• Incidence of melanoma has been steadily rising, affecting people of all ages.

Symptoms

In particular, watch for:

• Irregular borders on moles (ragged, notched, or blurred edges).
• Moles that are not symmetrical (one half doesn't match the other).
• Colors that are not uniform throughout.
• Moles that are bigger than a pencil eraser.
• Sores that bleed and do not heal.
• Itchy or painful moles.
• Red patches or lumps.
• New moles.

Recommendations for Employers

Employers should take the following steps to protect workers from exposure to UV radiation:

• When possible, avoid scheduling outdoor work when sunlight exposure is the greatest
• Provide shaded or indoor break areas
• Provide training to workers about UV radiation including:
  • Their risk of exposure
  • How to prevent exposure
  • The signs and symptoms of overexposure

Recommendations for Workers

Workers should follow these recommendations to protect themselves from UV damage:

• Wear sunscreen with a minimum of SPF 15.
• SPF refers to the amount of time that persons will be protected from a burn. An SPF of 15 will allow a person to stay out in the sun 15 times longer than they normally would be able to stay without burning. The SPF rating applies to skin reddening and protection against UVB exposure.
• SPF does not refer to protection against UVA. Products containing Mexoryl, Parsol 1789, titanium dioxide, zinc oxide, or avobenzone block UVA rays.
• Sunscreen performance is affected by wind, humidity, perspiration, and proper application.
• Old sunscreens should be thrown away because they lose their potency after 1-2 years.
• Sunscreens should be liberally applied (a minimum of 1 ounce) at least 20 minutes before sun exposure.
• Special attention should be given to covering the ears, scalp, lips, neck, tops of feet, and backs of hands.
• Sunscreens should be reapplied at least every 2 hours and each time a person gets out of the water or perspires heavily.
• Some sunscreens may also lose efficacy when applied with insect repellents, necessitating more frequent application when the two products are used together.
• Follow the application directions on the sunscreen bottle.
• Another effective way to prevent sunburn is by wearing appropriate clothing.
• Dark clothing with a tight weave is more protective than light-colored, loosely woven clothing.
• High-SPF clothing has been developed to provide more protection for those with photosensitive skin or a history of skin cancer.
• Workers should also wear wide-brimmed hats and sunglasses with almost 100% UV protection and with side panels to prevent excessive sun exposure to the eyes.

Source : NIOSH

Gout

Introduction

Background

Gout is a common disorder of uric acid metabolism that can lead to deposition of monosodium urate (MSU) crystals in soft tissue, recurrent episodes of debilitating joint inflammation, and, if untreated, joint destruction and renal damage. Gout is definitively diagnosed based on the demonstration of urate crystals in aspirated synovial fluid.

Clinical Image Atlas Click to view clinical images on the features and diagnosis of gout.

Improvements in early diagnosis and the availability of definitive treatment have significantly improved the prognosis of gout, as evidenced by the declining incidence of disabling chronic tophaceous gout. However, tophaceous gout may still develop because of misdiagnosis, poor management, medication intolerances, and/or poor patient compliance.

For additional information on gout, see Medscape’s Gout Resource Center.

Pathophysiology

Although the presence of urate crystals in the soft and synovial tissues is a prerequisite for a gouty attack, the fact that urate crystals can also be found in synovial fluid in the absence of joint inflammation suggests that the mere presence of intrasynovial urate crystals is not sufficient to cause flares of gouty arthritis.

One explanation for this may lie in the observation that clumps or microtophi of highly negatively charged and reactive MSU crystals are normally coated with serum proteins (apolipoprotein [apo] E or apo B) that physically inhibit the binding of MSU crystals to cell receptors.^1,2 A gout attack may be triggered by either a release of uncoated crystals (eg, due to partial dissolution of a microtophus caused by changing serum urate levels) or precipitation of crystals in a supersaturated microenvironment (eg, release of urate due to cellular damage). From either source, naked urate crystals are then believed to interact with intracellular and surface receptors of local dendritic cells and macrophages, serving as a danger signal to activate the innate immune system.³

This interaction may be enhanced by immunoglobulin G (IgG) binding.^4,5 Triggering of these receptors, including Toll-like receptors, NALP3 inflammasomes, and the triggering receptors expressed on myeloid cells (TREMs) by MSU, results in the production of interleukin (IL)–1, which in turn initiates the production of a cascade of pro-inflammatory cytokines, including IL-6, IL-8, neutrophil chemotactic factors, and tumor necrosis factor (TNF)–alpha.⁶ Neutrophil phagocytosis leads to another burst of inflammatory mediator production.

Subsidence of an acute gout attack is due to multiple mechanisms, including the clearance of damaged neutrophils, recoating of urate crystals, and the production of anti-inflammatory cytokines including, IL-1RA, IL-10, and transforming growth factor (TGF)–beta.^7,8,9,5

Frequency

United States

Approximately 1% of the general population have gout.

International

Gout has a worldwide distribution; regional differences may reflect environmental, dietary, and genetic influences.

Mortality/Morbidity

• Gout is associated with considerable morbidity. Acute episodes of gout often lead to incapacitation.
• Untreated chronic tophaceous gout can lead to severe joint destruction.
• MSU deposition in the kidney can result in inflammation and fibrosis, leading to reduced renal function or chronic renal nephropathy.
• Hyperuricemia and gout are associated with an increased overall likelihood of mortality. Whether this is directly attributable to hyperuricemia or gout or to gout-associated diseases (eg, insulin resistance, type 2 diabetes mellitus, abdominal obesity, hypercholesterolemia, hypertension) has been much debated. Although no evidence has shown that gout or hyperuricemia causes any of these disorders, elevated urate levels have been shown to correlate with blood pressure in adolescents,¹⁰ and, among middle-aged men, hyperuricemia with gout was a significant independent risk for death due to cardiovascular disease.¹¹

Race

• Gout is slightly more prevalent in blacks than in whites.

Sex

• The prevalence of gout is 13.6 cases per 1000 men and 6.4 cases per 1000 women.
• This difference is largely a consequence of age at onset because estrogenic hormones have a mild uricosuric effect; therefore, gout is unusual in premenopausal women.

Age

• As a rule, uric acid levels are elevated for 20 years before the onset of gout.
• In men, uric acid levels rise at puberty, and the peak age of onset of gout in men is in the fourth to sixth decade of life. In women, uric acid levels rise at menopause, and peak age of onset in women is in the sixth to eighth decade of life. Gout is unlikely to present in premenopausal women or in men younger than 30 years who do not have renal insufficiency or a genetic abnormality of purine metabolism (eg, hypoxanthine-guanine phosphoribosyltransferase deficiency, phosphoribosylpyrophosphate synthetase superactivity). The higher prevalence of gout in elderly persons may also reflect an increased prevalence of metabolic syndrome, high rates of diuretic treatment for hypertension and congestive heart failure, and the use of low-dose acetylsalicylic acid. Tophi are typically detectable clinically approximately 10 years after the first gout attack.
• Cyclosporin A can cause an accelerated form of gout, even in premenopausal women, that can present after only a few years of hyperuricemia, particularly if the patient is also receiving diuretics.

Clinical

History

• Acute monoarticular arthritis is the initial presentation of gout in 90% of patients.
  • In early gout, only 1 or 2 joints are usually involved. Typically, they are the smaller, lower-extremity joints. Podagra (inflammation of the first metatarsophalangeal joint) is the initial joint manifestation in 50% of cases. Eventually, it is involved in 90% of cases. Podagra is not synonymous with gout. Podagra may be observed in patients with pseudogout, sarcoidosis, gonococcal arthritis, psoriatic arthritis, and reactive arthritis.
    
    

    

    Gout. Acute podagra due to gout in an elderly man.

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    Gout. Acute podagra due to gout in an elderly man.

  • The attacks begin abruptly and reach maximum intensity within 8-12 hours. The joints are red, hot, and exquisitely tender; even a bed sheet on the swollen joint is uncomfortable. Untreated, the first attacks resolve spontaneously in less than 2 weeks.
  • A history of intermittent inflammatory arthritis, in which the joints return to normal between attacks, is typically caused by crystalline disorders and is characteristic of gouty arthritis early in its course.
  • Gout initially presents as polyarticular arthritis in 10% of patients. Elderly women, particularly women with renal insufficiency on a thiazide diuretic, can develop polyarticular arthritis as the first manifestation of gout. These attacks may occur in coexisting Heberden and Bouchard nodes. Such patients may also develop tophi more quickly, occasionally without prior episodes of acute gouty arthritis.^12,13,14
• The pattern of symptoms in untreated gout change over time.
  • The attacks become more polyarticular.
  • Although more joints may become involved, inflammation in a given joint may become less intense.
  • More proximal and upper-extremity joints become involved.
  • Attacks occur more frequently and last longer.
  • Eventually, patients may develop chronic polyarticular arthritis, sometimes nearly symmetrical, that can resemble rheumatoid arthritis. Indeed, chronic polyarticular arthritis that began as an intermittent arthritis should prompt consideration of a crystalline disorder in the differential diagnoses.
• Although gout typically causes joint inflammation, it can also cause inflammation in other synovial-based structures such as bursae and tendons.
• Tophi are collections of urate crystals in the soft tissues. They develop in more than half of patients with untreated gout and may be reported as lumps or nodules. While the classic location of tophi is along the helix of the ear, they can be found in multiple locations, including the fingers, toes, in the olecranon bursae, and along the olecranon, where they can resemble rheumatoid nodules. The finding of a rheumatoid nodule in a patient with a negative rheumatoid factor result or a history of drainage from a nodule should prompt consideration of gout in the differential diagnoses. Tophi are not commonly found during the first gout episode. They tend to develop after 10 years in untreated patients who develop chronic gouty arthritis. Tophi tend to develop earlier in women, particularly those receiving diuretics.^12,13,14
  
  

  

  Gout. Tophaceous deposits in ear.

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  Gout. Tophaceous deposits in ear.

  
  

  

  Gout. Tophaceous deposits on elbow.

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  Gout. Tophaceous deposits on elbow.

  
  

  

  Gout. Chronic tophaceous gout in an untreated patient with end-stage renal disease.

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  Gout. Chronic tophaceous gout in an untreated patient with end-stage renal disease.

• Acute flares of gout can result from situations that lead to increased levels of serum uric acid, such as the consumption of beer or liquor, overconsumption of foods with high purine content, trauma, hemorrhage, dehydration, or the use of medications that elevate levels of uric acid. Acute flares of gout also can result from situations that lead to decreased levels of serum uric acid, such as the use of radiocontrast dye or medications that lower the levels of uric acid, including allopurinol and uricosurics.
• Patients with gout are profoundly more likely to develop renal stones than are healthy individuals (by a factor of 1000); therefore, they may have a history of renal colic. Indeed, renal stones may precede the onset of gout in 40% of affected patients. While 80% of these patients may have stones composed entirely of uric acid, 20% may develop calcium oxalate or calcium phosphate stones with a uric acid core.
• Although patients with gout often have other risk factors for renal disease, including hypertension and diabetes, chronic urate nephropathy can contribute to renal insufficiency. Chronic urate nephropathy in patients with chronic tophaceous gout can result from the deposition of urate crystals in the medullary interstitium and pyramids, resulting in an inflammatory reaction that can lead to fibrotic changes. This process is characterized by hyperuricemia that is disproportional to the degree of renal impairment and is associated with a benign urinary sediment.
• Lead intoxication can damage the renal tubules, leading to impaired proximal tubular function with resultant hyperuricemia and gout.
• Because gout is frequently present in patients with the metabolic syndrome (eg, insulin resistance or diabetes, hypertension, hypertriglyceridemia, and low levels of high-density lipoproteins) and because the presence of these associated disorders can lead to coronary artery disease, these problems should be sought and treated in patients diagnosed with gout.
• Importantly, ask about a history of peptic ulcer disease, renal disease, or other conditions that may complicate the use of the medications used to treat gout.

Physical

• During an acute gout attack, examine all joints to determine if the patient's arthritis is monoarticular or polyarticular.
• Involved joints have all the signs of inflammation: swelling, warmth, erythema, and tenderness.
• The erythema over the joint may resemble cellulitis; the skin may desquamate as the attack subsides.
• The joint capsule becomes quickly swollen, resulting in a loss of range of motion of the involved joint.
• During an acute gout attack, patients may be febrile, particularly if it is an attack of polyarticular gout.
• Look for sites of infection that may have seeded the joint and caused an infectious arthritis that can resemble or coexist with acute gouty arthritis.
• The presence of tophi suggests long-standing hyperuricemia.

Causes

Gout develops in the setting of excessive stores of uric acid in the form of monosodium urate. Uric acid is an end-stage by-product of purine metabolism. Lacking uricase, humans remove uric acid primarily by renal excretion. When excretion is insufficient to maintain serum urate levels below the saturation level of 6.8 mg/dL (with some variability depending on temperature and pH), hyperuricemia may develop, and urate can crystallize and deposit in soft tissues. Ninety percent of patients with gout develop excess urate stores due to an inability to excrete sufficient amounts of normally produced uric acid in the urine (underexcretion). The remaining patients either overconsume purines or produce excessive amounts of uric acid endogenously (overproduction).

• In rare cases, overproduction of uric acid is primary, due to a genetic disorder. These disorders include hypoxanthine-guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome), glucose-6-phosphatase deficiency (von Gierke disease), fructose 1-phosphate aldolase deficiency, and PP-ribose-P synthetase variants.
• Overproduction of uric acid may also occur in disorders that cause high cell turnover with release of purines. These disorders include myeloproliferative and lymphoproliferative disorders, psoriasis, chemotherapy (tissue lysis), hemolytic anemias, pernicious anemia, ineffective erythropoiesis (as in B-12 deficiency), excessive exercise, and obesity.
• Overproduction of uric acid can occur from overconsumption of foods high in purines.
• Common causes of secondary gout due to underexcretion of uric acid include renal insufficiency, lead nephropathy (saturnine gout), starvation or dehydration, hypothyroidism, hyperparathyroidism, drugs (including diuretics and cyclosporine A), and chronic ethanol (especially beer and hard liquor) abuse. These disorders should be identified and corrected, if possible.

Individual gout flares are often triggered by acute increases or decreases in urate levels that may lead to the production, exposure, or shedding of crystals that are not coated with apo B or apo E. This can result from acute alcohol ingestion, acute overindulgence in foods high in purines, rapid weight loss, starvation, trauma, or hemorrhage. Medications that increase uric acid levels via effects on renal tubular transport include diuretics and low-dose aspirin. Gout flares can also result from agents that lower levels of uric acid, including the use of radiocontrast dyes and medications such as allopurinol or uricosurics.

Differential Diagnoses

Calcium Pyrophosphate Deposition Disease	Reactive Arthritis
Cellulitis	Rheumatoid Arthritis
Gonococcal Arthritis	Sarcoidosis
Nephrolithiasis	Septic Arthritis
Nephropathy, Uric Acid
Psoriatic Arthritis

Other Problems to Be Considered

Hypoxanthine-guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome)
Phosphoribosylpyrophosphate synthetase superactivity
Congenital fructose intolerance

Workup

Laboratory Studies

• Synovial fluid: When a patient presents with acute inflammatory monoarticular arthritis, aspiration of the involved joint is critical to rule out an infectious arthritis and to attempt to confirm a diagnosis of gout or pseudogout based on identification of crystals.
  
  

  

  Gout. Fluid obtained from a tophaceous deposit in a patient with gout.

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  Gout. Fluid obtained from a tophaceous deposit in a patient with gout.

  • The critical and essential study is synovial fluid analysis to identify urate crystals. Finding intracellular urate crystals with polarizing light microscopy firmly establishes the diagnosis of gouty arthritis.
  • Urate crystals are shaped like needles or toothpicks with pointed ends.
    
    

    

    Gout. Needles of urate on polarizing microscopy.

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    Gout. Needles of urate on polarizing microscopy.

  • Urate crystals are negatively birefringent, meaning that the crystals are yellow when aligned parallel to the slow ray of the compensator and that they are blue when they are perpendicular.
    
    

    

    Gout. Strongly negative birefringent, needle-shaped crystals diagnostic of gout obtained from an acutely inflamed joint.

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    Gout. Strongly negative birefringent, needle-shaped crystals diagnostic of gout obtained from an acutely inflamed joint.

  • Pseudogout crystals (calcium pyrophosphate) are rod-shaped with blunt ends.
  • Pseudogout crystals are positively birefringent. Pragmatically, this means that their colors are opposite those of gout. Thus, pseudogout crystals are blue when aligned parallel to the slow ray of the compensator and yellow when they are perpendicular.
  • Crystals need to be distinguished from birefringent cartilaginous or other debris. Debris may have fuzzy borders and may be curved, whereas crystals have sharp borders and are straight.
  • Corticosteroids injected into joints have a crystalline structure that can mimic monosodium urate crystals. They can be either positively or negatively birefringent.
  • The sensitivity of a synovial fluid analysis for crystals is 84%, with a specificity of 100%. If gout remains a clinical consideration after negative analysis findings, the procedure can be repeated in another joint or with a subsequent flare. Crystals may be absent very early in a flare.
  • While the sensitivity is inferior, urate crystals can be identified from synovial fluid aspirated from previously inflamed joints that are not currently inflamed. Such crystals are generally extracellular.
  • Minute quantities of fluid in the shaft or hub of the needle are sufficient for synovial fluid analysis.
  • Once a diagnosis of gout is established based on confirmation of crystals, joints do not need repeat aspiration with subsequent flares unless infection is suggested or the flare does not respond appropriately to therapy for acute gout.
  • In patients with acute monoarticular arthritis, send synovial fluid for Gram stain and culture and sensitivity. The culture also provides sensitivities for antibiotic management.
  • Synovial fluid should also be sent for cell count.
  • During acute attacks, the synovial fluid is inflammatory, with a WBC count greater than 2000/µL (class II fluid) and possibly greater than 50,000/µL, with a predominance of polymorphonuclear neutrophils.
  • Synovial fluid glucose levels are usually normal, whereas they may be depressed in septic arthritis and occasionally in rheumatoid arthritis. Measurement of synovial fluid protein has no clinical value.
  • Crystalline arthritis and infectious arthritis can coexist. Indeed, infectious arthritis is more common in previously damaged joints, which may occur in patients with chronic gouty arthritis.
• Serum uric acid
  • This is the most misused test in the diagnosis of gout. The presence of hyperuricemia in the absence of symptoms is not diagnostic of gout. In addition, as many as 10% of patients with symptoms due to gout may have normal serum uric acid levels at the time of their attack. Thus, the correct diagnosis of gout can be missed if the joint is not aspirated. Remember that situations that decrease uric acid levels can trigger attacks of gout. In such cases, the patient's prior medical records may reveal prior elevations of uric acid.
  • Five to eight percent of the population has elevated serum uric acid levels (>7 mg/dL), but only 5-20% of patients with hyperuricemia develop gout. Thus, an elevated serum uric acid level does not indicate or predict gout. As noted above, gout is diagnosed based on the discovery of urate crystals in the synovial fluid or soft tissues. More importantly, some patients with infectious arthritis present with a hot swollen joint and an elevated serum uric acid level and are at risk of being mismanaged if their synovial fluid is not aspirated to rule out septic arthritis.
  • Asymptomatic hyperuricemia should generally not be treated. However, patients with levels higher than 11 mg/dL and overexcretion of uric acid are at risk for renal stones and renal impairment; therefore, renal function should be monitored in these individuals.¹⁵
  • The level of serum uric acid correlates with risk for developing gout. The 5-year risk for developing gout is approximately 0.6% if the level is less than 7.9 mg/dL, 1% if 8-8.9 mg/dL, and 22% if higher than 9 mg/dL.
• Uric acid in 24-hour urine sample
  • A 24-hour urinary uric acid evaluation is generally performed if uricosuric therapy is being considered.
  • If patients excrete more than 800 mg of uric acid in 24 hours on a regular diet, they are overexcretors and thus overproducers of uric acid. These patients (approximately 10% of patients with gout) require allopurinol instead of probenecid to reduce uric acid levels.
  • Patients who excrete more than 1100 mg in 24 hours should undergo close renal function monitoring because of the risk of stones and urate nephropathy.
  • In patients in whom probenecid is contraindicated (eg, those with a history of renal stones or renal insufficiency), a 24-hour urine test of uric acid excretion does not need to be performed because the patient clearly will need allopurinol.
• Blood chemistry
  • Obtaining an accurate measure of the patient's renal function before deciding on therapy for gout is important, since the serum creatinine evaluation alone can underestimate renal dysfunction in elderly patients or in patients with low muscle mass.
  • Patients with gout are at an increased risk of developing diabetes mellitus.
  • Abnormal liver function tests need to be considered when therapy is selected.
• CBC count: The WBC count may be elevated in patients during the acute gouty attack, particularly if it is polyarticular.
• Lipids: Hypertriglyceridemia and low high-density lipoproteins are associated with gout.
• Urinalysis: Patients with gout are at an increased risk of renal stones; therefore, these patients may have a history of hematuria.

Imaging Studies

• Radiography
  • Plain radiographs may show findings consistent with gout, but these findings are not diagnostic. The most common radiographic findings early in the disease include soft-tissue swelling or an absence of abnormalities.
  • Haziness suggestive of tophi can be seen in late gout, and tophi may calcify.
  • Erosions that are not typical of rheumatoid arthritis may suggest gout.
    • Erosions with maintenance of the joint space
    • Erosions without periarticular osteopenia
    • Erosions outside the joint capsule
    • Erosions with overhanging edges
      
      

      

      Gout. Radiograph of erosions with overhanging edges.

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      Gout. Radiograph of erosions with overhanging edges.

    • Erosions with sclerotic borders, sometimes called cookie-cutter or punched-out borders
    • Erosions that are distributed asymmetrically among the joints, with strong predilection for distal joints, especially in the lower extremities
      
      

      

      Gout. Plain radiograph showing typical changes of gout in the first metatarsophalangeal joint and fourth interphalangeal joint.

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      Gout. Plain radiograph showing typical changes of gout in the first metatarsophalangeal joint and fourth interphalangeal joint.

      
      
      

      

      Gout. Plain radiograph showing chronic tophaceous gouty arthritis in the hands.

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      Gout. Plain radiograph showing chronic tophaceous gouty arthritis in the hands.

Procedures

Perform arthrocentesis to rule out an infectious arthritis and to establish a crystal-proven diagnosis of gout. Tophi also may be aspirated for crystal analysis under polarizing microscopy.

Histologic Findings

Tophi have been found in all tissues except the brain. However, monosodium urate dissolves in formalin; therefore, only the ghosts of urate crystals may be seen if formalin is used. Alcohol-fixed tissue is best for identification of urate crystals.

Treatment

Medical Care

Gout is managed in 3 stages: (1) treating the acute attack, (2) providing prophylaxis to prevent acute flares, and (3) lowering excess stores of urate to prevent flares of gouty arthritis and to prevent tissue deposition of urate crystals.

As mentioned above, asymptomatic hyperuricemia should generally not be treated. However, patients with levels higher than 11 mg/dL who overexcrete uric acid are at risk for renal stones and renal impairment; therefore, renal function should be monitored in these individuals.¹⁵

Acute gout

Options for treatment of acute gout include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and colchicine (a classic treatment that is now rarely indicated). The choice is based primarily on any concomitant health problems (eg, renal insufficiency, peptic ulcer disease).

• Nonsteroidal anti-inflammatory drugs
  • NSAIDs are the drugs of choice in most patients with gout who do not have underlying health problems.
  • Although indomethacin is the traditional NSAID of choice for acute gout (unless the patient is elderly, because of the potential for adverse CNS effects in this age group), most NSAIDs can be used. Select an agent with a quick onset of action, but do not use aspirin because it can alter uric acid levels and potentially prolong and intensify an acute attack. Cyclooxygenase-2 (COX-2) inhibitors have been used with success.
  • Start with the highest dose for 2-3 days and taper down over approximately 2 weeks. Gout symptoms should be absent for at least 2 days before the NSAID is discontinued.
  • Avoid NSAIDs in patients who have a history of peptic ulcer disease or GI bleeding, patients with renal insufficiency, patients with abnormal hepatic function, patients taking warfarin (selective COX-2 inhibitors can be used), and patients in the intensive care unit who are predisposed to gastritis. Use NSAIDs cautiously in patients with diabetes and those who are receiving concomitant angiotensin-converting enzyme (ACE) inhibitors.
• Corticosteroids
  • Corticosteroids can be given to patients with gout who cannot use NSAIDs or colchicine. Some rheumatologists recommend corticosteroids over NSAIDs as the preferred choice for treatment of acute gout. Steroids can be given orally, intravenously, intramuscularly, intra-articularly, or indirectly via adrenocorticotropic hormone (ACTH).
  • Prednisone can be given at a dose of approximately 40 mg for 1-3 days and then tapered over approximately 2 weeks. Tapering more rapidly can result in a rebound flare.
  • Using parenteral corticosteroids confers no advantage unless the patient cannot take oral medications.
  • Intra-articular corticosteroids are particularly useful in patients with a monoarticular flare to help reduce the systemic effects of oral steroids. Ensuring that the joint is not infected prior to injecting intra-articular corticosteroids is particularly important.
  • ACTH at 40 IU IM can be given to induce corticosteroid production by the patient's own adrenal glands. Such a regimen does not depend on the patient to taper prednisone properly.
• Colchicine
  • Colchicine in acute gout
    • Although colchicine was once the treatment of choice for acute gout, it is now a second-line approach because of its narrow therapeutic window and risk of toxicity.¹⁶ When used in classic hourly dosing regimens in acute gout, colchicine causes adverse GI effects, particularly diarrhea and vomiting, in 80% of patients.
    • Dosing recommendations for colchicine in acute gout therapy have been modified in recent years because of an increased awareness of its toxicities. The most recent recommendations have been trending toward lowered daily and cumulative doses. A task force of The EULAR Standing Committee for International Clinical Studies has developed evidence-based guidelines that recommend colchicine dosing in acute gout of 0.5 mg tid (0.6 mg tid in the United States).¹⁷ An alternative regimen suggested by the New Zealand Medicines and Medical Devices Safety Authority is as follows: 1 mg loading dose followed by 0.5 (0.6) mg every 6 hours, up to a maximum of 2.5 mg/24 hours and 6 mg over 4 days.¹⁶
    • Patients with gout may be able to abort an attack by taking a single colchicine tablet at the first twinge of an attack.
    • Colchicine should not be used if the glomerular filtration rate (GFR) is less than 10 mL/min, and the dose should be decreased by at least half if the GFR is less than 50 mL/min.
    • Colchicine should also be avoided in patients with hepatic dysfunction, biliary obstruction, or an inability to tolerate diarrhea.
    • A clinical response to colchicine is not pathognomonic for gout and may occur in patients with pseudogout, sarcoid arthropathy, psoriatic arthritis, or calcific tendonitis.
    • In February 2008, the US Food and Drug Administration (FDA) ruled that intravenous colchicine can no longer be produced or shipped in the United States because of its toxicities. Because of this, intravenous colchicine is no longer advocated for the treatment of acute gout in the United States.¹⁸
  • Colchicine as a prophylaxis against recurrence of acute flares
    • Lowering uric acid with either allopurinol or probenecid can precipitate attacks of gout. When used prophylactically, colchicine can reduce such flares by 85%.¹⁹
    • The standard dose for prophylaxis is colchicine 0.6 mg bid. In patients with renal insufficiency, this dose may need to be decreased to daily or every-other-day administration.
    • Compared with the 80% risk of adverse GI effects in patients using classic hourly colchicine for the treatment of acute gout, the prophylactic dose of colchicine induces adverse GI effects in only 4% of patients.
    • Long-term use of colchicine can lead to a muscle weakness associated with elevated levels of creatine kinase due to a drug-induced neuromyopathy, particularly in patients with renal insufficiency.²⁰
    • In patients who cannot take colchicine, NSAIDs, such as indomethacin at 25 mg bid, can be used for prophylaxis. If NSAIDs are contraindicated, low doses of prednisone can be considered.
    • Prophylaxis with colchicine can be started during an acute attack.

Chronic gout

Long-term management of gout is focused on lowering uric acid levels. The goal of therapy is to lower serum uric acid levels to approximately 6 mg/dL or less.

In many cases, patients who have a first attack of gout should undergo therapy with agents that lower uric acid, given the high risk for further inflammatory attacks and the potential for destructive tophaceous deposition in the bone, synovium, and kidney, even without episodes of acute inflammation. However, some rheumatologists advocate waiting for the second attack to initiate therapy to lower uric acid levels because not all patients experience a second attack and because some patients may need to be convinced they need life-long therapy. The risk of a second attack of gout after the first attack is 62% after 1 year, 78% after 2 years, and 93% after 10 years. The decision to begin therapy depends partly on the baseline serum uric acid levels (>9 mg/dL denotes a higher risk for recurrent gouty arthritis and tophi).

Monotherapy with colchicine may help prevent flares of inflammatory arthritis but does not prevent the accumulation of uric acid in the joints, which can lead to further joint destruction. In all cases, the risks and benefits need to be judged based on the individual patient. For instance, in an elderly patient with multiple underlying medical problems and renal insufficiency, the risks of therapy to lower uric acid levels may outweigh the benefits.

Agents that lower uric acid levels should not be initiated during an acute attack. This may lead to a more intense and prolonged attack. Typically, they should be started a few weeks after the attack has resolved and with the protection of prophylactic colchicine to prevent another attack. If the patient develops a gout flare after beginning therapy with a uric acid–lowering agent, the agent should not be discontinued because this will only cause another flux in the uric acid level, which may prolong and intensify the attack.

• Probenecid
  • Some rheumatologists prefer probenecid whenever possible because it has fewer significant adverse effects than allopurinol. Probenecid can be used in most middle-aged patients with gout who are otherwise healthy.
  • Indications for the use of allopurinol instead of probenecid include renal insufficiency (GFR <50>
  • Drug interactions may occur with probenecid (see Medication).
  • Patients who use probenecid need to drink 2 L of fluid daily at the inception of therapy in order to reduce their urinary concentration and thereby reduce the risk of renal stones.
• Allopurinol
  • Allopurinol blocks xanthine oxidase and thus reduces the generation of uric acid. Therefore, it should be used in patients who overproduce uric acid and in patients at risk of tumor lysis syndrome to prevent renal toxicity during therapy for malignancies. It is the most effective urate-lowering agent. However, alcohol can interfere with the effectiveness of allopurinol.
  • Approximately 3-10% of patients taking allopurinol develop dyspepsia, headache, diarrhea, and/or pruritic maculopapular rash. Less frequently, patients taking allopurinol can develop allopurinol hypersensitivity, which carries a mortality rate of 20-30%. Features of allopurinol hypersensitivity include fever, toxic epidermal necrolysis, bone marrow suppression, eosinophilia, leukocytosis, renal failure, hepatic failure, and vasculitis. Corticosteroids are often used to treat allopurinol hypersensitivity.
  • Allopurinol hypersensitivity is more likely to occur in patients with renal insufficiency, patients who are taking a diuretic, and patients begun on 300 mg of allopurinol.²¹ Although allopurinol hypersensitivity is more common (although still rare) in patients with renal insufficiency, this effect does not appear to be dose-related.²² Thus, a slow and careful titration of allopurinol dosing sufficient to achieve uric acid levels of less than 6 mg/dL is also recommended in these patients.²³
  • Allopurinol should be discontinued in patients who develop a rash. In patients with a history of drug eruptions due to allopurinol, both oral²⁴ and intravenous²⁵ desensitization regimens can be considered.
  • In most patients, start at 100 mg per day (50 mg in patients with renal insufficiency) and adjust the dose monthly according to the uric acid level until the goal of a uric acid level of 6 mg/dL or less is achieved.
  • Beware of drug interactions. For example, allopurinol prolongs the half-life of azathioprine and 6-mercaptopurine. It enhances the bone marrow toxicity of cyclophosphamide. Patients taking concomitant ampicillin are at an increased risk of rash.
  • Once the target uric acid level is achieved and maintained for 6 months, discontinue colchicine prophylaxis.
  • Avoiding the use of medications that elevate uric acid in patients with gout is prudent. Thus, other agents are preferable to a thiazide diuretic to treat hypertension. However, if such a medication is needed, it can be used with appropriate adjustments of allopurinol or probenecid.
  • Allopurinol can be used in combination with probenecid. However, note that allopurinol increases the half-life of probenecid, whereas probenecid increases the excretion of allopurinol.

Other therapeutic options

• Nonrecombinant urate-oxidase (uricase) is used in Europe to prevent severe hyperuricemia induced by chemotherapy in patients with malignancies, as well as in selected patients with treatment-refractory gout. Recently, the FDA approved recombinant Aspergillus flavus uricase for the prevention of tumor lysis syndrome. However, it is highly immunogenic and may cause anaphylaxis.²⁶ A polyethylene-glycol linked uricase is currently being evaluated. In theory, short-term use of such agents in patients with severe tophaceous could debulk the total-body urate load, allowing for maintenance with probenecid or allopurinol.
• Patients with allopurinol hypersensitivity can often tolerate oxypurinol, which is a metabolite of allopurinol.²⁷ It is available on a "compassionate use" basis. Cross-reactivity with allopurinol can occur.
• Benzbromarone is an effective uricosuric agent that may eventually become available. However, it can cause fulminant hepatotoxicity.
• Febuxostat, a nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol in patients with gout. Febuxostat is administered orally and is metabolized mainly in the liver. In contrast, allopurinol and its metabolites are excreted primarily by the kidney. Therefore, febuxostat can be administered in patents with renal insufficiency, with no dosage adjustment. Its efficacy and side-effect profile otherwise appears similar to that of allopurinol.²⁸
• The angiotensin receptor blocker losartan and the triglyceride-lowering agent micronized fenofibrate have moderately potent uricosuric effects. They should therefore be considered in patients with gout who also require treatment for hypertension and hypertriglyceridemia.²⁶
• Vitamin C, with its uricosuric effect, may reduce the serum concentration of uric acid.²⁹
• In an open-label pilot study of 10 patients with refractory acute gout treated with the IL-1 antagonist anakinra, pain was substantially reduced in all patients within two days, without side effects. Clinical signs of inflammation had disappeared in 9 of 10 patients by the third day of treatment.³⁰

Surgical Care

• In patients with gout that is diagnosed and treated early, orthopedic surgery is usually unnecessary. In patients with untreated gout or gout that is treated late in the disease course, orthopedic repair may be necessary.
• Tophi should not be surgically removed unless they are in a critical location or drain chronically.
• In patients undergoing arthroscopy, the presence of white lesions, sometimes on an erythematous base, should prompt consideration of gout.

Consultations

Rheumatologists should be involved in the care of patients with gout. They can establish the diagnosis with arthrocentesis and synovial fluid analysis for crystals. They also are skilled in the management of this disorder.

Diet

• Diet modifications can improve the serum uric acid levels by only 1 mg/dL and are rarely able to lower uric acid levels sufficiently to prevent further attacks and accumulation of urate.
• Patients with gout should avoid beer and hard liquor because they elevate levels of uric acid and therefore can precipitate attacks of gout. Indeed, heavy drinkers are much more likely to have recurrent gout attacks, even with allopurinol therapy. Moderate wine intake is not associated with an increased gout flares.³¹
• Particularly because of the association of gout with atherosclerosis, the diagnosis of gout may be a good time to advise a low-cholesterol, low-fat diet if otherwise appropriate for the patient. While such a diet may help uric acid levels, such advice should be given primarily to help prevent atherosclerosis.
• Weight reduction in patients who are obese can improve hyperuricemia.

Activity

Patients with gout should avoid using the inflamed joint during an acute attack. Otherwise, they should be active.

Medication

Acute inflammation due to gout can be treated with NSAIDs, corticosteroids, or, rarely, colchicine. NSAIDs are generally the drugs of choice unless the patient has a risk factor that contraindicates these agents. Ultimately, gout is treated by decreasing tissue stores of uric acid with allopurinol or probenecid. Because agents that lower uric acid can precipitate attacks of gout, low-dose colchicine is used as prophylaxis when such therapy is initiated.

Nonsteroidal anti-inflammatory drugs

These agents as a class are the drugs of choice to treat acute inflammation of gout in patients who can safely take these medications.

Indomethacin (Indocin)

The traditional NSAID used to treat acute inflammation in gout, although other NSAIDs can be used effectively. These agents block cyclooxygenase and, thereby, the generation of prostaglandins. Use maximum level of NSAID and taper over approximately 2 weeks, depending on patient's response.

• Dosing
• Interactions
• Contraindications
• Precautions

Adult

50 mg PO tid or qid for 1-3 d, depending on response, and begin tapering

Pediatric

Not established

• Dosing
• Interactions
• Contraindications
• Precautions

Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase the INR when taking anticoagulants (patients on anticoagulants should consider alternative therapy); phenytoin levels may be increased when administered concurrently

• Dosing
• Interactions
• Contraindications
• Precautions

Documented hypersensitivity, patient on anticoagulation, GI bleeding, renal insufficiency, thrombocytopenia

• Dosing
• Interactions
• Contraindications
• Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; GI toxicity may include nausea, dyspepsia, abdominal pain, diarrhea, and bleeding; reversible leukopenia may occur (discontinue if persistent leukopenia, granulocytopenia, or thrombocytopenia occurs)

Anti-inflammatory agents

Colchicine is now considered a second-line agent in the treatment of acute gout flares because of its narrow therapeutic window. More often, it is used at a lower dose as a prophylactic agent to prevent flares of gout when adding agents that lower uric acid.

Colchicine (Colcrys)

Inhibits microtubules and thereby may inhibit phagocytosis, neutrophil mobility, and chemotaxis. Also may inhibit generation of prostaglandins.

Corticosteroids

These agents are potent and effective anti-inflammatory drugs that can be used to treat acute gout in patients who cannot tolerate NSAIDs or colchicine. Steroids can be given PO, IM, IV, intra-articularly, or indirectly via ACTH. The short-burst therapy of corticosteroids necessary to treat an acute flare of gout is generally well tolerated and not associated with the chronic adverse effects associated with long-term steroid use. In many patients, a short course of steroids is a safer option than NSAIDs and colchicine. In patients with only 1 or 2 involved joints, intra-articular corticosteroids are a safe and effective treatment option.

Prednisone (Deltasone, Orasone, Meticorten)

Can be given PO to abort an attack of gout. No intrinsic advantage to treating with IV corticosteroids exists unless the patient cannot take medications PO. The advantage of intra-articular steroids is that they reduce the systemic effects of PO steroids, but care must be taken to make sure the joint is not infected. ACTH also can be used to induce the patient's own adrenal gland to produce corticosteroids.
Steroid dose packs that clearly label the dose to be taken each day can be convenient for some patients.

Uricosuric agents

Uricosuric agents lower uric acid levels by increasing net renal excretion of uric acid. They are better tolerated than allopurinol but are less effective and cannot be used in all circumstances. These agents increase the risk of renal stones. These agents should not be started during an attack of acute gouty arthritis. The goal of therapy is to lower serum uric acid to approximately 5-6 mg/dL without causing renal stones.

Xanthine oxidase inhibitors

These agents prevent the generation of uric acid and thereby reduce the tissue stores of uric acid. Allopurinol is more likely to be effective than uricosuric agents but carries an increased risk for significant adverse effects. Allopurinol should not be started during an attack of acute gouty arthritis. The goal of therapy is to lower the serum uric acid level to approximately 5-6 mg/dL.

Source : Medscape

Autism

Screening and Diagnosis

Photo: Parent discussing medical issues with physicianDiagnosing autism spectrum disorders (ASDs) can be difficult, since there is no medical test, like a blood test, to diagnose the disorders. Doctors look at the child’s behavior and development to make a diagnosis.

ASDs can sometimes be detected at 18 months or younger. By age 2, a diagnosis by an experienced professional can be considered very reliable.[1] However, many children do not receive a final diagnosis until much older. This delay means that children with an ASD might not get the help they need.

Diagnosing an ASD takes two steps:

1. Developmental Screening

Developmental screening is a short test to tell if children are learning basic skills when they should, or if they might have delays. During developmental screening the doctor might ask the parent some questions or talk and play with the child during an exam to see how she learns, speaks, behaves, and moves. A delay in any of these areas could be a sign of a problem.

All children should be screened for developmental delays and disabilities during regular well-child doctor visits at:
* 9 months
* 18 months
* 24 or 30 months
* Additional screening might be needed if a child is at high risk for developmental problems due to preterm birth, low birth weight or other reasons.

In addition, all children should be screened specifically for ASDs during regular well-child doctor visits at:
* 18 months
* 24 months
* Additional screening might be needed if a child is at high risk for ASDs (e.g., having a sister, brother or other family member with an ASD) or if behaviors sometimes associated with ASDs are present


It is important for doctors to screen all children for developmental delays, but especially to monitor those who are at a higher risk for developmental problems due to preterm birth, low birth weight, or having a brother or sister with an ASD.

If your child’s doctor does not routinely check your child with this type of developmental screening test, ask that it be done.

If the doctor sees any signs of a problem, a comprehensive diagnostic evaluation is needed.

2. Comprehensive Diagnostic Evaluation

The second step of diagnosis is a comprehensive evaluation. This thorough review may include looking at the child’s behavior and development and interviewing the parents. It may also include a hearing and vision screening, genetic testing, neurological testing, and other medical testing.

In some cases, the primary care doctor might choose to refer the child and family to a specialist for further assessment and diagnosis. Specialists who can do this type of evaluation include:
* Developmental Pediatricians (doctors who have special training in child development and children with special needs)
* Child Neurologists (doctors who work on the brain, spine, and nerves)
* Child Psychologists or Psychiatrists (doctors who know about the human mind)

Source : www.cdc.gov

Current H5N1 Situation

Assessment of Current Situation

The highly pathogenic avian influenza A (H5N1) epizootic (animal outbreak) in Asia, Europe, the Near East, and Africa is not expected to diminish significantly in the short term. It is likely that H5N1 virus infections among domestic poultry have become endemic in certain areas and that sporadic human infections resulting from direct contact with infected poultry and/or wild birds will continue to occur. So far, the spread of H5N1 virus from person-to-person has been very rare, limited and unsustained. However, this epizootic continues to pose an important public health threat.

There is little pre-existing natural immunity to H5N1 virus infection in the human population. If H5N1 viruses gain the ability for efficient and sustained transmission among humans, an influenza pandemic could result, with potentially high rates of illness and death worldwide. No evidence for genetic reassortment between human and avian influenza A virus genes has been found to date, and there is no evidence of any significant changes to circulating H5N1 virus strains to suggest greater transmissibility to or among humans. Genetic sequencing of avian influenza A (H5N1) viruses from human cases in Vietnam, Thailand, and Indonesia shows resistance to the antiviral medications amantadine and rimantadine, two of the medications commonly used for treatment of influenza. This leaves two remaining antiviral medications (oseltamivir and zanamivir) that should still be effective against currently circulating strains of H5N1 viruses. A small number of oseltamivir resistant H5N1 virus infections of humans have been reported. Efforts to produce pre-pandemic vaccine candidates for humans that would be effective against avian influenza A (H5N1) viruses are ongoing. However, no H5N1 vaccines are currently available for human use.

Research suggests that currently circulating strains of H5N1 viruses are becoming more capable of causing disease (pathogenic) in animals than were earlier H5N1 viruses. One study found that ducks infected with H5N1 virus are now shedding more virus for longer periods without showing symptoms of illness. This finding has implications for the role of ducks in transmitting disease to other birds and possibly to humans as well. Additionally, other findings have documented H5N1 virus infection among pigs in China and Vietnam; H5N1 virus infection of cats (experimental infection of housecats in the Netherlands, isolation of H5N1 virus from domestic cats in Germany and Thailand, and detection of H5N1 viral RNA in domestic cats in Iraq and Austria); H5N1 virus infection of dogs (isolation of H5N1 virus from a domestic dog in Thailand); and isolation of H5N1 viruses from tigers and leopards at zoos in Thailand). In addition, H5N1 virus infection in a wild stone marten (a weasel-like mammal) was reported in Germany and in a wild civet cat in Vietnam. Avian influenza A (H5N1) virus strains that emerged in Asia in 2003 continue to evolve and may adapt so that other mammals may be susceptible to infection as well.

Notable findings of epidemiologic investigations of human H5N1 cases include:

• Thailand, 2004: An investigation concluded that probable limited human-to-human spread of influenza A (H5N1) had occurred in a family as a result of prolonged and very close contact between an ill child and her mother in a hospital. Transmission did not continue beyond one person.
• Vietnam, 2004: While the majority of known human H5N1 cases have begun with respiratory symptoms, one atypical fatal H5N1 case in a child in southern Vietnam presented with fever, diarrhea and seizures, and was initially diagnosed as encephalitis. The etiology was identified retrospectively as H5N1 virus through testing of cerebrospinal fluid, fecal matter, and throat and serum samples. Further research is needed to ascertain the implications of such findings.
• Vietnam, 2005: Investigations suggest transmission of H5N1 viruses to two persons through consumption of uncooked duck blood.
• Azerbaijan, 2006: Investigations revealed contact with H5N1-infected wild dead birds (swans) as the most plausible source of infection in several cases in teenagers involved in removing feathers from the birds.
• Indonesia, 2006: WHO reported evidence of limited human-to-human spread of H5N1 virus. In this situation, 8 people in one family were affected, with 7 deaths. H5N1 virus was isolated from 7 cases. The first family member is thought to have become ill through contact with infected poultry. This person then infected six family members. One of those six people (a child) then infected another family member (his father). No further spread outside of the exposed family was documented or suspected.
• Vietnam, 2006: A study reported a correlation between high H5N1 viral concentration and elevated inflammatory cytokine levels in fatal cases. The authors concluded that early antiviral treatment is needed to suppress H5N1 viral replication to prevent the inflammatory response that appears to be implicated in the pathogenesis of H5N1 virus infection.

Human H5N1 Cases

(WHO) has reported human cases of avian influenza A (H5N1) in Asia, Africa, the Pacific, Europe and the Near East. Indonesia and Vietnam have reported the highest number of H5N1 cases to date. Overall mortality in reported H5N1 cases is approximately 60%. The majority of cases have occurred among children and adults aged less than 40 years old. Mortality was highest in cases aged 10-19 years old. Studies have documented the most significant risk factors for human H5N1 infection to be direct contact with sick or dead poultry or wild birds, or visiting a live poultry market. Most human H5N1 cases have been hospitalized late in their illness with severe respiratory disease. A small number of clinically mild H5N1 cases have been reported. The current cumulative number of confirmed human cases of avian influenza A/(H5N1) is available on the WHO Avian Influenza website. Despite the high mortality, human cases of H5N1 remain rare to date.

Clusters of Human H5N1 Cases

Clusters of human H5N1 cases ranging from 2-8 cases per cluster have been identified in most countries that have reported H5N1 cases. Nearly all of the cluster cases have occurred among blood-related family members living in the same household. Whether such clusters are related to genetic or other factors is currently unknown. While most people in these clusters have been infected with H5N1 virus through direct contact with sick or dead poultry or wild birds, limited human-to-human transmission of H5N1 virus cannot be excluded in some clusters.

Animal H5N1 Cases

Since December 2003, avian influenza A (H5N1) virus infections in animals have been reported in Asia, Africa, the Pacific, Europe and the Near East. View the update on avian influenza in animals from the World Organization for Animal Health Web site.

Bird Import Ban

There is currently a ban on the importation of birds and bird products from H5N1-affected countries. The regulation states that no person may import or attempt to import any birds (Class Aves), whether dead or alive, or any products derived from birds (including hatching eggs), from the specified countries. For more information, see Embargo of Birds from Specified Countries.

Travel

Updated Information for Travelers about Avian Influenza A(H5N1) is available at the CDC Travelers’ Health Web site. Also see Guidelines and Recommendations - Interim Guidance about Avian Influenza A (H5N1) for U.S. Citizens Living Abroad.

CDC Response

CDC is working with WHO and other international partners to monitor the situation closely. In addition, CDC continues to work with WHO and the National Institutes of Health (NIH) on development of a vaccine for influenza A (H5N1). For more information view CDC's Response to Avian Influenza.

• Also see Updated Interim Guidance for Laboratory Testing of Persons with Suspected Infection with Avian Influenza A (H5N1) Virus in the United States for CDC’s domestic H5N1 surveillance recommendations.

The World Health Organization has additional resources and information on avian influenza A H5N1, including

• Recommendations and laboratory procedures for detection of avian influenza A(H5N1) virus in specimens from suspected human cases (pdf 165K, 28 pages)
• WHO guidelines for investigation of human cases of avian influenza A(H5N1) (pdf 115K, 18 pages)
• Collecting, preserving and shipping specimens for the diagnosis of avian influenza A(H5N1) virus infection Guide for field operations (pdf 2.36M, 83 pages)

Background on the Current Outbreaks

Highly pathogenic avian influenza A (H5N1) virus is an influenza A virus subtype that occurs mainly in birds and is highly contagious among birds, causing high mortality among domestic poultry. Outbreaks of highly pathogenic H5N1 among poultry and wild birds are ongoing in a number of countries. Currently, there are two different groups (or clades) of H5N1 viruses circulating among poultry (clade 1, and clade 2 viruses). At least three subgroups or subclades of clade 2 H5N1 viruses have infected humans to date: subclades 2.1, 2.2, and 2.3 viruses. H5N1 virus infections of humans are rare and most cases have been associated with direct poultry contact during poultry outbreaks. While the H5N1 virus does not now infect people easily, infection in humans is very serious when it occurs; so far, more than half of people reported infected have died. Rare cases of limited human-to-human spread of H5N1 virus may have occurred, but there is no evidence of sustained human-to-human transmission.

Nonetheless, because all influenza viruses have the ability to change, scientists are concerned that H5N1 viruses one day could be able to infect humans more easily and spread easily from one person to another. Because H5N1 viruses have not infected many humans worldwide, there is little or no immune protection against them in the human population and an influenza pandemic (worldwide outbreak of disease) could begin if sustained H5N1 virus transmission occurred. Experts from around the world are watching the H5N1 situation very closely and are preparing for the possibility that H5N1 viruses may begin to spread more easily from person to person.

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NOTE: The World Health Organization (WHO) maintains situation updates and cumulative reports of human cases of avian influenza A (H5N1)