eMedicine Specialties > Dermatology > Connective Tissue Diseases

Eosinophilia-Myalgia Syndrome

Author: Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Coauthor(s): Nicole Quartarolo, MD, Staff Physician, Department of Dermatology, UMDNJ-New Jersey Medical School; Vinay Arya, MD, Staff Physician, Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medicine
Contributor Information and Disclosures

Updated: May 21, 2008

Introduction

Background

Eosinophilia-myalgia syndrome (EMS) was first recognized in 1989 in New Mexico in 3 patients who had an illness with a unique array of symptoms, including peripheral blood eosinophilia and severe myalgias. All 3 patients had ingested sleeping aids containing L-tryptophan. In the ensuing weeks, a nationwide epidemic of EMS became apparent; this epidemic was correlated with the use of over-the-counter compounds containing L-tryptophan. In response, the US Food and Drug Administration ordered a recall of all single-entity products containing L-tryptophan.

In 1989, the Centers for Disease Control and Prevention (CDC) issued the following case definition for EMS: (1) a peripheral eosinophil count of at least 1.0 X 109 cells/L, (2) a generalized myalgia at some point during the illness that is severe enough to affect the patient's ability to perform his or her usual daily activities, and (3) no evidence of infection or neoplasm that could explain either the eosinophilia or the myalgia.

EMS may be related to the toxic oil syndrome in Spain. They are linked by a common toxic metabolite (4-aminophenol) and may be further associated by the concomitant release of potentially hazardous carbonyl species.1

The eMedicine Rheumatology article Eosinophilia-Myalgia Syndrome may be helpful.

Pathophysiology

EMS is an illness characterized by pruritus, cutaneous lesions, edema, sclerodermoid changes, and joint pain, in addition to dramatic myalgia and eosinophilia. In the early phase of the disease, most patients have muscle aches; cough; dyspnea; macules, papules, or urticarial skin lesions; intense pruritus; constitutional symptoms, such as fatigue, fever, and weight loss; and persistent, incapacitating myalgias. This phase lasts weeks to months and is followed by a chronic phase characterized by sclerodermoid skin changes, neuropathy, neurocognitive deficits, continued myalgia, and muscle cramps. Other less common chronic manifestations involve the pulmonary, cardiac, and gastrointestinal systems.

The exact cause of EMS remains unknown; however, its histopathologic pattern is well described. The most prominent pathogenic feature of the disease is the widespread inflammatory reaction. Besides the marked eosinophilia, a considerable accumulation of inflammatory mediators is present in the tissues; these mediators include cytokines, lymphocytes, mononuclear cells, and eosinophils. This cell-mediated immune response is ultimately responsible for the widespread tissue injury, in addition to the fibrosis of the skin and the connective tissue that pervades muscles, nerves, and other organs. In fact, examination of muscle biopsy specimens reveals a dramatic inflammatory infiltrate that is predominantly composed of mononuclear cells and activated T cells.

Cytokines are implicated in several aspects of the disease. Three cytokines, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 3 (IL-3), and interleukin 5 (IL-5) have been shown to promote the growth and the maturation of eosinophils and to induce the conversion of normal eosinophils to hypodense eosinophils. Hypodense eosinophils are activated cells with increased survival and an increased capacity for cytotoxicity, and their release of inflammatory mediators, such as leukotrienes, is increased. In particular, IL-5 activity is shown to be elevated in sera from patients with EMS. Therefore, in EMS, IL-5 may play a substantial role in the growth and the stimulation of eosinophils and in their conversion to the hypodense, cytotoxic form.

The exact role of the eosinophils in the pathogenesis of EMS is uncertain, but products of the activated eosinophils, particularly the toxic granule proteins (ie, major basic protein, eosinophil-derived neurotoxin), are implicated in tissue injury. The serum and urine levels of both major basic protein and eosinophil-derived neurotoxin are dramatically increased in patients with EMS; these findings are evidence of continuous eosinophil degranulation. Also, eosinophils themselves, along with major basic protein, probably contribute to the debilitating fibrosis in EMS because they stimulate fibroblast-activating agonists, such as transforming growth factor-beta (TGF-b).

TGF-b is a powerful inducer of collagen synthesis and is implicated in the pathogenesis of several fibrotic conditions, including EMS. Fibroblasts isolated from patients with EMS demonstrate elevated expression of TGF-b, along with other genes that code for extracellular matrix components. In fact, skin and fascia from patients with EMS demonstrate excessive deposition of collagen, fibronectin, and other extracellular matrix components.

In addition to the striking fibrosis of the integument, the perimysium, and the perineurium, fibrosis and inflammation of the blood vessels lead to occlusive microangiopathy. The occlusion of the blood vessels may lead to tissue ischemia, which may also contribute to the tissue injury seen in EMS.

Although the precise etiologic agent remains unknown, evidence suggests that either a chemical contaminant or a toxic metabolite of L-tryptophan is responsible for the inflammation seen in EMS (see Causes). Ultimately, the tissue injury in EMS appears to be related to a combination of factors: eosinophil-derived toxins, microangiopathy-related ischemia, fibrosis, and direct injury due to inflammatory mediators.

By applying the CDC case definition, 191 cases of EMS were retrospectively identified as pre-epidemic cases, that is, cases identified prior to July 1989.

Early epidemiological evidence linked EMS and microimpurities of L-tryptophan–containing dietary supplements. Reliance on a finite impurity from one manufacturer has been challenged as both unnecessary and insufficient to explain the etiology of EMS.2 Excessive histamine activity has been postulated because it induces blood eosinophilia and myalgia.  Correlations have been made between histamine degradation, eosinophilia, and this myopathy.3

Frequency

United States

From October 30, 1989, to January 31, 1993, a total of 1,512 cases of EMS were reported. However, only 1,345 of those fulfilled the CDC's surveillance case definition for EMS. An overwhelming majority of the cases of EMS occurred in the United States.

International

Other countries reporting cases of EMS include Germany (100 cases), Canada (12 cases), and the United Kingdom (11 cases).

Mortality/Morbidity

From October 1989 to January 1993, a total of 1,512 cases of EMS were reported. Approximately one third of patients in these cases required hospitalization, and 35 deaths were recorded.

Race

A CDC study of 1,117 patients showed that 1,046 (94%) of patients were non-Hispanic white, 19 (2%) were Hispanic, 12 (1%) were black, and 40 (4%) were from other or unknown racial or ethnic groups.

Sex

Of the 1,117 subjects in the CDC study, 927 (83%) of patients were female.

Age

The CDC study of 1,117 patients showed that patients with EMS were aged 4-85 years, with a median age of 48 years.

Clinical

History

The case definition of EMS is useful to identify patients with suspected EMS; however, to ensure a more accurate diagnosis, a more stringent set of criteria must be applied. One set of proposed classification criteria includes 4 axes: (1) the presence of a distinct acute episode with the typical signs and symptoms; (2) major physical findings, including typical involvement of organs, such as the skin, the muscles, the lungs, and the nerves; (3) characteristic laboratory values, including an eosinophil count greater than 1.0 X 109 cells/L; and (4) characteristic histopathologic features.

  • Acute episode
    • The acute episode is characterized by shortness of breath; cough; fever; debilitating fatigue; arthralgias; paresthesias; severe weakness; muscle cramps; periorbital and peripheral edema; skin hypersensitivity; and a generalized erythematous, maculopapular, or blotchy erythematous rash.
    • After this acute episode, most patients have more chronic symptoms that involve several organ systems.
  • Cutaneous involvement
    • Cutaneous involvement occurs in 60% of patients with EMS. After the initial symptoms, this is the most prominent feature of the disease.
    • In the acute phase of the disease, patients often have a diffuse eruption with pruritus and swelling.
    • Later in the disease, patients may experience skin tightening, which reflects sclerodermoid changes. However, unlike scleroderma, the fingers and the toes are almost always spared, and the Raynaud phenomenon is usually absent.
    • Patients may note an inability to tolerate even light touch. This finding tends to be more pronounced in the lower extremities than elsewhere.
    • Alopecia is also noted in more than one quarter of patients.
  • Muscular involvement
    • By definition, patients must have myalgia. This condition usually begins in the proximal muscle groups, such as those in the shoulders, the buttocks, and the thighs; then, myalgia becomes incapacitating.
    • Patients may have stiffness and aches in the affected muscles, as well as muscle cramps, particularly during exercise.
    • Patients also complain of weakness and muscle wasting that limit their ability to walk or lift heavy objects.
    • Myalgia in the jaw can lead to pain in the facial muscle or the jaw.
  • Nervous system involvement
    • Central nervous system and peripheral nervous system involvement is seen in 27% of patients, in whom disorders of these systems are the presenting features.
    • Patients may have decreased sensation, particularly in the hands, or hyperesthesia in the back and the extremities.
    • Patients may present with weakness, cognitive deficits, or bladder dysfunction.
  • Pulmonary involvement
    • Pulmonary symptoms are the major presenting complaints in the acute phase of EMS.
    • Patients report rapidly progressive shortness of breath associated with a nonproductive cough and other symptoms related to upper respiratory tract infections.
    • Patients may have chest tightness, pleuritic chest pain, or dyspnea on exertion.
  • Cardiac involvement
    • Most patients do not have heart problems; however, pericarditis, myocarditis, and cardiac arrhythmias are known complications of the disease.
    • Patients with arrhythmias may have palpitations.
  • Gastrointestinal involvement
    • Gastrointestinal problems are not common problems in this disease.
    • Some patients experience abdominal pain, nausea, vomiting, diarrhea, and weight loss.
  • Rheumatologic involvement
    • About 73% of patients have joint pain.
    • This pain can be located in the wrist, the knees, the ankles, the shoulders, the hips, the spine, or the interphalangeal and metacarpophalangeal joints.

Physical

  • Cutaneous manifestations
    • A diffuse eruption consisting of erythematous macules and papules often develops over the trunk and the extremities. The skin may have a mottled appearance and occasionally appears ecchymotic. No palpable purpura is evident.
    • Four weeks to 4 months after the onset of myalgias, a progressive peau d'orange–type induration may develop. This process tends to start in the distal part of the lower and upper extremities and gradually moves proximally. The digits are characteristically spared. The skin classically appears firm, shiny, and hide-bound.
    • Sometimes, venous furrowing of the uplifted arm is observed.
  • Neuromuscular manifestations
    • Neuromuscular examination of patients with EMS reveals weakness and paresthesias. Some patients have cutaneous hyperesthesia (the inability to tolerate touch). This finding tends to be more pronounced in the lower extremities.
    • Muscles are often tender to palpation.

Causes

Although the consumption of L-tryptophan is not part of the definition of EMS, it is described in more than 96% of patients with EMS. Tryptophan is an essential amino acid that is present in many foods and is part of various remedies. It is used to treat insomnia, anxiety, premenstrual syndrome, and obesity. In fact, prior to 1989, millions of Americans had been ingesting products containing L-tryptophan for many years. Therefore, any hypothesis about the association between L-tryptophan consumption and EMS must address why some individuals had the syndrome while others did not. During the peak of the epidemic, 2 theories emerged: the toxic metabolite hypothesis and the contaminant hypothesis.
  • Toxic metabolite hypothesis
    • L-tryptophan is metabolized through 2 separate pathways. In one pathway, L-tryptophan is broken down to serotonin. In the other pathway, L-tryptophan is degraded into kynurenine. In this pathway, kynurenine can be metabolized to quinolinic acid, which is an endogenous neurotoxin implicated in the pathogenesis of several metabolic and neurologic conditions.
    • Metabolites of both pathways are associated with connective tissue disorders.
    • Serotonin overproduction by carcinoid tumors is associated with myalgias and arthralgias in addition to sclerodermalike skin changes.
    • Patients with EMS are noted to have abnormalities in both of these pathways. However, aberrant tryptophan metabolism by itself does not provide an adequate explanation.
  • Contaminant hypothesis
    • Because of the epidemic nature of the syndrome, an inherited alteration in tryptophan sensitivity or metabolism is unlikely to be the sole factor responsible for the development of EMS. Rather, a contaminant is implicated as a cause of the syndrome.
    • In fact, L-tryptophan from different brands of products used by patients with EMS was traced back to one manufacturer in Japan who had altered the manufacturing process of L-tryptophan before the epidemic.
    • High-performance liquid chromatography of EMS-associated L-tryptophan reveals several peaks that correspond to impurities. One particular peak was consistently found in case-associated lots. This substance was isolated, purified, and shown to be 1,1-ethylidenebis (tryptophan). Although 1,1-ethylidenebis may not be the etiologic agent, it may be a marker for another contaminant.

More on Eosinophilia-Myalgia Syndrome

Overview: Eosinophilia-Myalgia Syndrome
Differential Diagnoses & Workup: Eosinophilia-Myalgia Syndrome
Treatment & Medication: Eosinophilia-Myalgia Syndrome
Follow-up: Eosinophilia-Myalgia Syndrome
References
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Further Reading

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Keywords

EMS, L-tryptophan-induced eosinophilia-myalgia syndrome, sclerodermoid myalgia, sclerodermoid fasciitis, eosinophilia associated with ingestion of tryptophan, L-tryptophan

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Contributor Information and Disclosures

Author

Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

Nicole Quartarolo, MD, Staff Physician, Department of Dermatology, UMDNJ-New Jersey Medical School
Nicole Quartarolo, MD is a member of the following medical societies: Alpha Omega Alpha and Sigma Xi
Disclosure: Nothing to disclose.

Vinay Arya, MD, Staff Physician, Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medicine
Vinay Arya, MD is a member of the following medical societies: Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

Takeji Nishikawa, MD, Emeritus Professor, Department of Dermatology, Keio University School of Medicine; Director, Samoncho Dermatology Clinic; Managing Director, The Waksman Foundation of Japan Inc
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Director Dermatology Residency Training Program, Scott and White Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: 3M Pharmaceutical Grant/research funds Other; Graceway Pharmaceuticals Grant/research funds Other

Managing Editor

Lester F Libow, MD, Dermatopathologist, South Texas Dermatopathology Laboratory
Lester F Libow, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Texas Medical Association
Disclosure: Nothing to disclose.

CME Editor

Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital
Glen H Crawford, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Phi Beta Kappa, and Society of USAF Flight Surgeons
Disclosure: Nothing to disclose.

Chief Editor

William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System
William D James, MD is a member of the following medical societies: American Academy of Dermatology and Society for Investigative Dermatology
Disclosure: elsevier Royalty Other; american college of physicians Honoraria Other

 
 
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