eMedicine Specialties > Rheumatology > Systemic Rheumatic Disease

Eosinophilia-Myalgia Syndrome

Author: Thomas A Medsger Jr, MD, Gerald P Rodnan Professor of Medicine, Director, Scleroderma Research Program, Department of Medicine, University of Pittsburgh School of Medicine
Coauthor(s): Mohammed Mubashir Ahmed, MD, Associate Professor, Department of Medicine, Division of Rheumatology, University of Toledo College of Medicine; Eisha Mubashir, MD, Fellow in Rheumatology, Department of Medicine, Fellow, Center of Excellence for Arthritis and Rheumatology, Louisiana State University Health Sciences Center, Shreveport; Shrilekha Sairam, MD, MBBS, Fellow, Department of Internal Medicine, Division of Rheumatology, University of Texas at Galveston
Contributor Information and Disclosures

Updated: Oct 15, 2009

Introduction

Background

In October 1989, the health department in New Mexico was notified of 3 patients with an unexplained acute illness characterized by intense myalgias and peripheral blood eosinophilia. Within weeks, a nationwide outbreak of this disease occurred. The disorder was termed eosinophilia-myalgia syndrome (EMS). In November 1989, for the purpose of nationwide surveillance, the US Centers for Disease Control and Prevention (CDC) defined this syndrome as requiring all of the following criteria: (1) incapacitating myalgias, (2) a blood eosinophil count greater than 1000 cells/µL, and (3) no evidence of infection (eg, trichinosis) or neoplastic conditions that could account for these findings.

Shortly thereafter, two case-control studies initiated by the health departments in New Mexico and Minnesota confirmed a strong association between the use of a specific brand of L-tryptophan and the development of EMS. Analyses of implicated lots of L-tryptophan identified many contaminants. The best-characterized of these is 1,1-ethylidenebis (L-tryptophan) (EBT), a tryptophan dimer. With the recall of L-tryptophan from the market in November 1989, a precipitous fall in the frequency of EMS was observed.

A new approach to constructing a criterion standard for validating diagnostic criteria for a disorder was proposed using EMS as the sample disease.¹ Case reports of patients with and without EMS were reviewed and judged by an external panel of clinical experts, thus providing independent validation of the criterion standard case reports. The proposed criteria included two EMS disease onset patterns (acute and subacute).

Contaminated L-tryptophan may not be the only cause of EMS. According to one estimate, 14% of EMS cases were not related to L-tryptophan. Non–L-tryptophan–related cases were more likely to be associated with peripheral edema, rash, sclerodermalike skin changes, alopecia, neuropathy and lower mean eosinophil count, fewer pulmonary symptoms, and a better prognosis than L-tryptophan cases.

A review of toxic oil syndrome (TOS) cases that affected many thousands of Spanish patients in the early 1980s and were associated with adulterated rapeseed oil reveals that TOS shares many clinical and histopathological features with EMS. Furthermore, recent biochemical data have suggested a link between EMS and TOS. A common toxic metabolite (4-aminophenol) causes the release of dangerous carbonyl species.²

In an unusual experiment, an investigator injected himself subcutaneously with quinolinic acid, an L-tryptophan metabolite, resulting in peripheral blood eosinophilia and dermal and subcutaneous inflammatory lesions resembling those of eosinophilic fasciitis and increased transforming growth factor beta-1 (TGFB1) deposition.³ Because increased serum quinolinic acid concentrations have been recorded in eosinophilic fasciitis, these data support a relationship between EMS and eosinophilic fasciitis. This finding is not surprising considering the similar clinical findings in these two disorders.

Patients with fibromyalgia syndrome (FMS) and related disorders disproportionately ingested over-the-counter L-tryptophan–containing products, but it is unknown if these individuals were predisposed to EMS. In one study, peripheral blood mononuclear cells (PBMC) from 6 of 7 patients with EMS and other functional somatic syndromes, when incubated with peak E, produced type II (profibrotic) cytokines (compared with 3 of 24 controls).⁴

Pathophysiology

The pathogenesis of EMS remains unknown. The 3 major pathological findings observed in persons with EMS include (1) capillary endothelial cell hyperplasia, with evidence of swelling and necrosis; (2) an inflammatory cell infiltration, including monocytes, histiocytes, lymphocytes, macrophages, and plasma cells, and, occasionally, eosinophils in nerve, muscle, and surrounding connective tissue (eg, the subdermal fascial layer [fasciitis]); and (3) increased fibrosis, mostly in the fascia but also occasionally in skin.

Levels of the cytokines interleukin (IL)–2, IL-4, IL-5, interferon gamma, and granulocyte-monocyte colony stimulating factor (GMCSF) are increased in the serum of some patients with EMS. Serum soluble IL-2 receptor (sIL-2R) levels were elevated in 7 patients with EMS compared with controls. Injection of EBT in rodents caused inflammation in the dermis, fascia, and perimysium. In addition, EBT stimulates fibroblast proliferation and collagen synthesis in vitro, but eosinophilia does not develop in EBT-treated animals. The precise role of this contaminant in the pathogenesis of EMS remains uncertain.

It may be unnecessary to implicate L-tryptophan impurities in the development of EMS. Excessive oral ingestion of tryptophan supplement inhibits histamine degradation by increasing formation of formate and indolyl metabolites, several of which block the degradation of histamine, thereby potentiating its effects. Increased histamine activity is known to induce peripheral blood eosinophilia and myalgia.⁵ Furthermore, patients with hypothalamic-pituitary-adrenal axis dysregulation who do not have EMS also manifest greatly increased sensitivity to ingested tryptophan and histamine. Histamine disequilibrium appears to be a final common pathway for syndromes characterized by eosinophilia with myalgia.

Frequency

United States

By July 1991, 1543 EMS cases in the United States had been reported to the CDC.⁶ However, estimates indicate that 5,000-10,000 people actually had this disease.

International

EMS also occurred in other parts of the world, including the United Kingdom, France, Israel, Japan (12 patients), western Germany (69 patients), and Canada (10 patients). Cohort studies performed during the epidemic estimated that the attack rate of EMS among users of L-tryptophan was 0.5%-9%, depending on the product lot of the L-tryptophan ingested. Since the epidemic of 1989-1991, only a few new cases have been reported.

Mortality/Morbidity

• By July 1991, 31 deaths were attributed to EMS. The mortality rate ranged from 2% in national surveillance data to 6% in some cohorts. Most deaths were the result of neurogenic complications such as ascending polyneuropathy, cardiopulmonary disease, or superimposed infection.
• Of the patients with an acute presentation of EMS, 34% required hospitalization for incapacitating myalgia, muscle cramps, or pulmonary involvement.

Race

• Of the patients reported to have EMS, 97% were white.

Sex

• Eighty-four percent of patients were female.

Age

• EMS occurred most commonly in people aged 35-60 years (age range 17-81 years, mean 49 years).

Clinical

History

The clinical manifestations of eosinophilia-myalgia syndrome (EMS) greatly vary. Typically, there is an abrupt onset of incapacitating myalgia, muscle cramps, dyspnea, peripheral edema, low-grade fever, fatigue, and skin rashes. These acute inflammatory symptoms resolve in 3-6 months, and variable degrees of neuropathy, myopathy, and skin thickening occur. Three to 4 years after the acute illness, patients report persistent chronic fatigue, intermittent myalgias, and muscle cramps, but no new manifestations appear after that time.

• Early features of EMS, observed during the first 3-4 months, include the following:
  • Myalgias: Patients complain of generalized, severe, incapacitating muscle pain that tends to worsen over weeks. The shoulders, back, and legs are affected most often. Relapses after complete resolution are common. Muscle weakness is usually not observed at this early stage. Muscle cramps involving the leg and abdominal muscles occur within weeks and may persist for years. Movement, exercise, or change in position may trigger muscle spasm.
  • Edema: Peripheral edema involving the extremities, facial edema, and periorbital edema occur in more than half of patients, typically 3-4 weeks after disease onset.
  • Arthralgias: Pain in large joints is common, but true arthritis is rare.
  • Alopecia: Nonscarring scalp hair loss is observed frequently during the acute illness and then resolves gradually.
  • Skin rash: Cutaneous manifestations develop approximately 3 weeks after the onset of myalgia and last for an average of 3 months. The types of rash seen in patients with EMS include macules varying from small and purplish to large and brownish, urticaria, mucinous yellow plaques, dermatographism, serpiginous lesions, and erythematous plaques. Severe pruritus is prominent in some patients.
  • Skin thickening: These findings occur in approximately one third of the patients. They resemble those seen in eosinophilic fasciitis, with skin thickening and subcutaneous induration affecting the forearms, arms, and legs. Patches of skin thickening resembling morphea are occasionally observed. In contrast with systemic sclerosis, digital skin thickening and Raynaud phenomenon are rare in patients with EMS.
  • Pulmonary symptoms (eg, nonproductive cough, dyspnea, or both): Pulmonary symptoms are observed commonly and usually appear within 2-3 weeks after the onset of myalgias. These complaints are self-limited in most patients and last less than 3 months.
  • Neurological symptoms (eg, paresthesias, numbness, burning sensations): Approximately one third of patients report these symptoms.
  • Gastrointestinal symptoms (eg, dyspepsia, dysphagia, diarrhea): These problems have been described in some patients with EMS.
• At the end of 1 year, more than half of patients with EMS have persistent chronic symptoms, including the following:
  • Myalgias with remissions and relapses
  • Muscle weakness (based on history)
  • Fatigue often described as "profound" (40% of patients)
  • Spontaneous or activity-induced muscle cramps
  • Joint pain and stiffness
  • Paresthesias, including numbness, tingling, and burning sensations
  • Memory loss, difficulty concentrating
  • Difficulty communicating (eg, word finding and word substitution problems)
  • Sclerodermalike skin changes
  • Dyspnea upon exertion
• No new symptoms have been noted after the first 6 months to 1 year after disease onset.
• Analysis of self-reported answers to questionnaires from 333 patients 4 years after the acute illness shows that most patients continued to have symptoms (as described above) and only 10% reported full recovery.

Physical

• Skin rashes: These include macules varying from small and purplish to large and brownish, urticaria, mucinous yellow plaques, dermatographism, serpiginous lesions, and erythematous plaques. Rashes commonly occur over the face, neck, and extremities. Truncal involvement is also seen.
• Sclerodermalike skin changes: These include woody, leathery, dry, thickened skin with a peau d'orange appearance similar to eosinophilic fasciitis. These changes appear later in the disease course (after several months) and tend to persist in most patients.
• Muscle weakness: Definite muscle weakness is not observed initially. However, later in the course of the illness, weakness may be present. Muscle weakness is independent of myalgias.
• Pulmonary findings: Objective pulmonary findings are uncommon. Findings vary from normal to those suggestive of interstitial pneumonitis and pleural effusion. Only a few case reports describe mild pulmonary hypertension.
• Facial and extremity edema
• Hepatomegaly
• Neurological findings: These are consistent with sensory or sensorimotor involvement in a glove-stocking distribution. Ascending motor paralysis, compression neuropathies, facial palsy, and encephalitis have been described.

Causes

• No specific etiologic agent has been found for EMS.
• Most individuals identified as having EMS during the acute outbreak consumed L-tryptophan (97%) prior to the development of the syndrome.
  • Patients with EMS were exposed to L-tryptophan for 2 weeks to 9 years, with a median exposure of 6 months. The daily dose varied from 500-11,500 mg, with a median dose of 1250 mg.
  • No correlation was observed between the development of EMS and the duration or dose of L-tryptophan use.
• L-tryptophan is an essential amino acid found in many foods and has been available over the counter since 1974. It has been used for insomnia, depression, premenstrual symptoms, and other complications.
• Studies conducted during the epidemic implicated an L-tryptophan product lot manufactured by Showa Denko, a pharmaceutical company in Japan.
  • Administration of L-tryptophan from this lot induced inflammation of subcutaneous fascia and perimysium in mice.
  • The temporal clustering of the disease and a report of a patient not developing EMS when rechallenged with a different lot of L-tryptophan imply a contaminant in the product lot from Showa Denko as the cause of EMS.
  • Extensive research has failed to identify a precise cause, although a contaminant identified as "Peak E" (1,1,ethylidenebis) is most commonly associated with the development of EMS.
• Consumption of L-tryptophan manufactured by the implicated producer did not always result in disease. In one study, 44% of the persons who used the implicated lot did not develop EMS. Genetic and other host factors are also likely to have played a role in the precipitation of EMS.
• Clinical syndromes indistinguishable from EMS have been identified both in persons consuming other nutritional supplements (eg, 5 hydroxytryptophan, L-lysine, niacin) and in individuals without any history of drug intake.
• The exact cause of TOS is not known.

• Search for CME/CE on This Topic »

• Eosinophilia-Myalgia Syndrome (Dermatology)
• Eosinophilia (Hematology)