General Discussion

Summary

Eosinophilia-myalgia syndrome is a rare disorder that affects multiple organ systems of the body including the muscles, skin, and lungs. The onset of the disorder is often abrupt and the specific symptoms can vary greatly from one person to another. Common symptoms include muscle pain (myalgia), muscle weakness, cramping, skin rashes, difficulty breathing (dyspnea) and fatigue. Affected individuals have elevated levels of certain white blood cells known as eosinophils in the various tissues of the body, a condition known as eosinophilia. Eosinophilia-myalgia syndrome can potentially cause severe, disabling complications and even death.

Introduction

During the autumn of 1989, an epidemic of a new disease occurred in the United States. The illness was characterized by elevations of blood eosinophils (a type of white blood cell) and myalgia (severe muscle pain) and was termed the eosinophilia-myalgia syndrome (EMS). The disease was first recognized in October 1989 when physicians in New Mexico identified three women with similar clinical findings: all three had consumed manufactured L-tryptophan supplements prior to the onset of their illness. (L-tryptophan is an essential amino acid found naturally in various foods, and L-tryptophan can also be manufactured.) These patients’ findings were publicized by the local news media and, soon thereafter, additional cases of the same illness were identified throughout the USA and in several other countries.

Epidemiological studies were initiated within days of discovery of the epidemic in early November 1989 by state health departments in New Mexico and Minnesota, and these studies demonstrated a strong association between the consumption of manufactured L-tryptophan and the onset of EMS. A national surveillance program was initiated by the United States Centers for Disease Control (CDC) to investigate the new disease. On November 11, 1989, the United States Food and Drug Administration (FDA) issued a nationwide warning advising consumers to stop consumption of manufactured L-tryptophan food products and requested a nationwide recall of all L-tryptophan supplements sold over-the-counter.

After the removal of L-tryptophan supplements from the consumer markets, the number of new cases of EMS diminished rapidly. Nevertheless, more than 1,500 people were affected by the illness and 37 deaths were attributed to the disease. In many cases the disease struck patients in the prime of life and caused severe, debilitating neurological damage. It is likely that the toll from the disease would have been considerably greater if not for the alertness of physicians who linked the new disease to manufactured L-tryptophan, and for the epidemiological investigations by the state Departments of Health and the CDC, plus the prompt recall initiated by the FDA of products containing L-tryptophan. However, while the epidemiological and chemical investigations indicate that the epidemic of EMS was caused by contaminated L-tryptophan supplements, the precise contaminant causing the disease is still unknown.

In 1994 Congress passed the Dietary Health Supplement Education Act (DHSEA), which President Clinton signed into law. This law greatly weakened FDA’s ability to regulate dietary supplements. As a result, manufactured L-tryptophan is legally sold again.

There had been isolated cases of EMS diagnosed before the epidemic of 1989 and there have been after, as well. The isolated cases of EMS diagnosed before the epidemic of 1989 were attributed to L-tryptophan dietary supplements. The isolated cases of EMS that are currently being diagnosed are attributed to L-tryptophan or 5-HTP dietary supplements. During the time that L-tryptophan was taken off the market, the closely related dietary supplement 5-hydroxytryptophan (5-HTP) was used as a substitute, and it continues to be so used. The amino acid 5-HTP is found on the metabolic pathway that converts the essential amino acid L-tryptophan to the neurotransmitter serotonin. Because serotonin helps to regulate sleep and mood (among other things), it is thought that ingesting L-tryptophan or 5-HTP, thus purportedly improving sleep and mood, will increase this neurotransmitter.

The National Eosinophilia Myalgia Syndrome Network (NEMSN), for the past several years, has also been receiving reports from people who have developed EMS-like symptoms soon after ingesting manufactured L-tryptophan, 5-HTP, or other products containing L-tryptophan or 5-HTP, such as certain body building products, weight loss supplements, and sleep aids.

Signs & Symptoms

The symptoms and severity of eosinophilia-myalgia syndrome can vary greatly from one person to another. In most cases, the onset of the disorder is rapid.

The initial symptoms associated with eosinophilia-myalgia syndrome include breathing difficulties such as shortness of breath (dyspnea) and muscle aches, cramping and spasms. Muscle pain (myalgia) also occurs and may become progressively worse. Eventually, muscle pain may become incapacitating making it difficult to walk or perform daily activities. The muscles of the legs, back and shoulders are most often affected. Muscle spasms may be triggered by movement or exercise. Muscle weakness usually does not occur until later in the course of the disorder.

Additional symptoms that often occur during this earlier phase of eosinophilia-myalgia syndrome include cough, fever, fatigue, joint pain (arthralgia), swelling due to the abnormal accumulation of fluid (edema), and a sensation of numbness or tingling, most often in the hands, feet, arms or legs. Affected individuals may also develop a rash that can be extremely itchy (pruritus). This initial (acute) phase of the disorder usually lasts approximately 3-6 months.

After this initial phase, affected individuals experience chronic symptoms that can affect several different organ systems of the body. The skin is the organ most often affected and may slowly swell, thicken and harden (eosinophilic fasciitis). The arms and legs are most often affected. Some individuals develop small areas of hair loss (alopecia).

The central nervous system becomes involved in some cases and can cause decreased feeling (sensation) in the hands, increased sensation (hyperesthesia) in the back and arms or legs, progressive muscle weakness, bladder dysfunction, changes in mood or behavior and cognitive deficits such as memory loss, difficulty concentrating and difficulty communicating. However, the relationship between cognitive deficits or behavioral changes and eosinophilia-myalgia syndrome is controversial. Some researchers believe these problems arise from severe pain, depression and disturbances in sleep patterns associated with eosinophilia-myalgia syndrome and not from the direct, underlying effects of the disorder.

Additional symptoms can occur during the chronic phase of eosinophilia-myalgia syndrome although they occur less often than the abovementioned symptoms. Such symptoms include heart (cardiac) abnormalities including inflammation of the heart muscle (myocarditis), irregular heartbeats (arrhythmias) and palpitations. Some individuals may have gastrointestinal symptoms including nausea, vomiting, diarrhea and abdominal pain.

Muscle pain, the characteristic finding of the acute phase, also occurs during the chronic phase of the disorder, although it often comes and goes (remission and relapse). Fatigue, which can be profound, also occurs during the chronic phase. Muscle cramps and shortness of breath are also present.

Causes

Although almost all cases of eosinophilia-myalgia syndrome in the 1989 epidemic were traced back to ingestion of contaminated L-tryptophan manufactured by a single company, namely Showa Denko K.K. (Tokyo, Japan), a large petrochemical company, the precise contaminant causing the disease is still unknown.

There had been isolated cases of EMS diagnosed before the epidemic of 1989 and there have been after, as well. The isolated cases of EMS diagnosed before the epidemic of 1989 were attributed to L-tryptophan dietary supplements. The isolated cases of EMS that are currently being diagnosed are attributed to L-tryptophan or 5-HTP dietary supplements. During the time that L-tryptophan was taken off the market, the closely related dietary supplement 5-hydroxytryptophan (5-HTP) was used as a substitute, and it continues to be so used. The amino acid 5-HTP is found on the metabolic pathway that converts the essential amino acid L-tryptophan to the neurotransmitter serotonin. Because serotonin helps to regulate sleep and mood (among other things), it is thought that ingesting L-tryptophan or 5-HTP, thus purportedly improving sleep and mood, will increase this neurotransmitter.

The National Eosinophilia Myalgia Syndrome Network (NEMSN), for the past several years, has also been receiving reports from people who have developed EMS-like symptoms soon after ingesting manufactured L-tryptophan, 5-HTP, or other products containing L-tryptophan or 5-HTP, such as certain body building products, weight loss supplements, and sleep aids.

Affected Populations

Eosinophilia-myalgia syndrome was identified as an epidemic in 1989 after three people in New Mexico were identified with the disorder. The exact incidence of eosinophilia-myalgia syndrome is unknown. One estimate indicates that anywhere from 5,000-10,000 people developed the disorder during the epidemic. Most reported individuals are females and from the United States. However, eosinophilia-myalgia syndrome has been reported in other countries as well including Germany, Canada and the United Kingdom.

Related Disorders

Symptoms of the following disorders can be similar to those of eosinophilia-myalgia syndrome. Comparisons may be useful for a differential diagnosis.

Eosinophilic fasciitis is a rare disorder characterized by inflammation of the tough band of fibrous tissue beneath the skin (fascia). The arms and legs are most often affected. Inflammation is caused by the abnormal accumulation of certain white blood cells including eosinophils in the fascia. Eosinophilic fasciitis eventually causes the skin to swell and slowly thicken and harden (induration). The disorder most commonly affects middle-aged adults. The exact cause of eosinophilic fasciitis is unknown. Some researchers believe that eosinophilic fasciitis is a variant of scleroderma (systemic sclerosis), an autoimmune connective tissue disorder characterized by hardening of the skin. Eosinophilic fasciitis commonly afflicted EMS patients. (For more information on this disorder, choose “eosinophilic fasciitis” as your search term in the Rare Disease Database.)

Toxic oil syndrome is a rare disorder that occurred in Spain in the early 1980s. Affected individuals developed a variety of symptoms including shortness of breath (dyspnea), cough, chest pain, headaches, and fever. Additional symptoms occurred in some cases including abdominal pain, difficulty swallowing (dysphagia), nausea, a skin rash, itching (pruritus), a rapid heartbeat (tachycardia), an abnormally enlarged liver (hepatomegaly) and an abnormally enlarged spleen (splenomegaly). Eventually, affected individuals develop severe muscle pain and cramps. Affected individuals also had abnormally high levels of eosinophils (a type of white blood cell) in the body (eosinophilia). Toxic oil syndrome was caused by rapeseed oil, which was intended for industrial use, but fraudulently sold as olive oil. Researchers believe that toxins found in the rapeseed oil (as part of the refinement process), such as fatty acid compounds (anilides), caused the symptoms of the disorder. However, as with EMS, the cause of the toxic oil syndrome remains a mystery.

Eosinophilic disorder is a general term for any disorder characterized by infiltration of the skin and tissue by a certain type of white blood cell called eosinophils, including disease resulting from arthropod bites, infections, and drug reactions. Churg-Strauss syndrome, hypereosinophilic syndrome and eosinophilic cellulitis are examples of disorders characterized by elevated levels of eosinophils. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)

Diagnosis

EMS is a syndrome with multiple clinical presentations and variable severity. The first clinical reports showed that most patients developed profound eosinophilia and severe myalgias. Further, other symptoms included joint pains, weakness or fatigue, difficulty breathing or cough, rash, headache, peripheral edema (swelling), fever and abnormal tingling sensations. Most patients also showed an elevation of an enzyme called serum aldolase, which is an indicator of muscle damage. About one-half of the patients had abnormal liver function tests.

Clinical and histopathological findings of EMS overlap those of eosinophilic fasciitis a fibrotic syndrome characterized by tender swelling and hardening of subcutaneous tissues especially in arms and legs.

There are no medical tests to definitively diagnose EMS. Many physicians lack knowledge of EMS, and therefore, patients may be diagnosed with diseases that have overlapping symptoms, such as fibromyalgia, chronic fatigue syndrome, lupus, arthritis, fasciitis, and other autoimmune or neuromuscular disorders with similar symptoms. Criteria for the diagnosis have been described that are useful.

Standard Therapies

Treatment

There are no peer-reviewed guidelines for the standard of care of EMS patients. Because of the variety and diversity of how EMS manifests, patients are treated based on their individual symptoms and may be prescribed muscle relaxants, analgesics, and diuretics.

High doses of corticosteroids may help reduce inflammation, However, most researchers have concluded that this course of treatment does not reduce the severity or duration of EMS symptoms.

In the acute phase, patients who have intense muscle pain and cramps may need to limit or avoid strenuous physical activity. Some patients have required hospitalization. In the chronic phase, patients who keep as physically active as possible seem to do better than others.