Eosinophilia-Myalgia Syndrome

Updated: Jan 12, 2021
Author: William E Monaco, MD; Chief Editor: Herbert S Diamond, MD 


Practice Essentials

Eosinophilia-myalgia syndrome (EMS) was first identified in 1989, when approximately 1500 patients developed subacute onset of myalgias and peripheral eosinophilia. They then went on to have chronic muscle, fascia, nerve, and skin involvement. The Centers for Disease Control and Prevention (CDC) proposed a surveillance case definition that included the following[1, 2] :

  • Incapacitating myalgias
  • Peripheral eosinophil count greater than 1000/µL
  • No evidence of infection (ie, trichinosis) or neoplasm

Studies quickly linked EMS to dietary supplements that contained L-tryptophan, a supplement commonly used by patients with fibromyalgia syndrome (FMS), which was made using genetically engineered bacteria.[3, 4, 2, 5] Specifically, the analysis found an impurity identified as 1’1’-ethylidenebis[tryptophan] (EBT), in L-tryptophan manufactured by a single company.[6]  This supplement was quickly removed from the market, resulting in swift resolution of the EMS epidemic, but unfortunately there were over 30 deaths in just 6 months.

Since then, other causes of EMS have been implicated. Six other impurities in L-tryptophan have been associated with EMS, including 3-(phenylamino) alanine (PAA), which shares similar properties with 3-(N-phenylamino)-1,2-propanediol (the chemical found in rapeseed oil and implicated in the 1981 Spanish toxic oil syndrome epidemic[7] ).[8]

An investigator injected himself with quinolinic acid, an L-tryptophan metabolite, and developed peripheral eosinophilia and subcutaneous inflammatory lesions resembling eosinophilic fasciitis.[9]

Also, 14% of EMS cases occurred in patients who had not taken L-tryptophan, suggesting that other agents (eg, probiotics) can also trigger this disease.[10, 11] Since the FDA lifted the ban on L-tryptophan, rare case reports of EMS have been reported.

In 2001, new diagnostic criteria for EMS were proposed that identified the following two patterns of presentation. 

  • Abrupt onset of peripheral eosinophilia, myalgia, and at least one of the following: rash, edema, pulmonary involvement, or neuropathy.

  • One of the following occurring within 24 months of an acute illness: 1) fasciitis, neuropathy, and myalgia or muscle cramps or 2) any three or more of: fasciitis, myopathy, neuropathy, or peripheral eosinophilia

Diagnosis with the new criteria requires exclusion of trichinosis; vasculitis; and infectious, allergic, neoplastic, or connective tissue disease that could explain the patient’s symptoms.[1]


The exact pathophysiology of EMS remains unknown. It is thought to involve exposure to certain substances in a genetically susceptible host that ultimately triggers acute inflammation, eosinophil activation/degranulation, and chronic tissue fibrosis. Analysis of the deep dermis shows evidence of local fibroblast activation, increased expression, of type I and VI collagen, and elevated levels of transforming growth factor β (TGFβ). Levels of interleukin (IL)-2, IL-4, IL-5, interferon (INF) gamma, and granulocyte-monocyte colony stimulating factor (GMCSF) are increased in patients with EMS.[12, 13, 3, 14]


United States

During the initial epidemic, over 1500 cases of EMS were confirmed in the United States. However, estimates indicate that 5,000-10,000 people had this disease.[15]  Since 1991, reports of EMS are limited to case reports only, most recently in 2011.[16]


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.


By July 1991, 36 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.[17]

Of the patients with an acute presentation of EMS, 34% required hospitalization for incapacitating myalgias, muscle cramps, or pulmonary involvement.

Race, Sex, and Age-related Demographics

Demographic characteristics of the patients reported to have EMS were as follows:

  • 97% white
  • 84% female
  • Most were 35-60 years old (age range 17-81 years, mean 49 years)



The symptoms of eosinophilia-myalgia syndrome (EMS) vary greatly, but onset is typically acute or subacute and over the first 3-4 months most commonly consists of the following[8] :

  • Myalgias: Patients complain of generalized, severe, debilitating muscle pain and/or cramps. The shoulders, back, and legs are most commonly affected. Relapses after complete resolution are common. Weakness is an uncommon symptom early in the disease. Muscle cramps involving the leg and abdominal muscles occur early in the disease course and may persist for years

  • Edema: Peripheral edema involving the extremities and face 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: Non-scarring scalp hair loss is observed frequently during the acute illness and gradually resolves.

  • Rash: 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: Nonproductive cough and/or dyspnea usually appear within 2-3 weeks after the onset of myalgias. They are self-limited in most patients.

  • Neurological symptoms: These include parasthesias, numbness, or a burning sensations and affect up to one third of EMS patients.

  • Gastrointestinal symptoms: Rarely patients will complain of dysphagia, diarrhea, or dyspepsia.

The clinical manifestations of EMS greatly vary. Typically, there is an abrupt onset of incapacitating myalgias, 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 follow. 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.[18]

The acute inflammatory symptoms just listed typically resolve after 3-6 months, but at 1 year patients with EMS can have chronic symptoms that include the following:

  • Subjective muscle weakness
  • Spontaneous or activity-induced muscle cramps
  • Joint pain and stiffness
  • Memory loss
  • Difficulty concentrating
  • Difficulty communicating (eg, word finding and word substitution problems)
  • Scleroderma-like skin changes
  • Dyspnea on exertion

Only about 10% of patients, out of 333 surveyed 4 years since symptom onset, reported a complete recovery.[19]


Rashes occur most commonly over the face, neck, and extremities but truncal involvement is also seen. Examination of the skin in patients with eosinophilia-myalgia syndrome (EMS) may reveal the following:

  • Macules varying from small and purplish to large and brownish
  • Mucinous yellow plaques
  • Serpiginous lesions
  • Erythematous plaques

Later in the disease course, the skin may appear scleroderma-like with a woody, peau d’orange appearance similar to eosinophilic fasciitis.

Examination of the muscles will rarely reveal objective weakness early in the disease course, although later in the illness this may be present. 

Cardiopulmonary and abdominal examinations are generally normal, but hepatomegaly or findings of interstitial pneumonitis and/or a pleural effusion (i.e. pulmonary crackles, dullness to percussion, etc) may be present.

Extremities and facial exam may show edema.  Joint examination may reveal tender joints, but synovitis and effusions are absent.

Neurologic findings are typically sensory abnormalities in a stocking-glove distribution, but reports of ascending paralysis, facial palsy, and encephalitis have been reported.[8]


Although no one cause of EMS has been identified, most patients (97%) with this disease reported consuming L-tryptophan. The median exposure was 6 months, but this ranged from 2 weeks to 9 years. Doses vary from 500-11,500 mg per day, and the median dose patients consumed was 1250 mg. L-tryptophan is commonly used by patients with FMS but also is taken for insomnia, depression, and premenstrual symptoms. One specific impurity identified in L-tryptophan was 1’1’-ethylidenebis[tryptophan] (EBT).

Not every patient who consumed the specific lot of L-tryptophan from Showa Denko, a pharmaceutical company in Japan, developed EMS. There are other genetic and host factors that are required for a patient to develop EMS.[8]

Other causes include other nutritional supplements like niacin, probiotics, L-lysine, or 5 hydroxytryptophan, but patients can develop EMS without a history of drug or supplement use.





Laboratory Studies

Given the myriad different ways eosinophilia-myalgia syndrome (EMS) can present, the initial workup should be directed at identifying other possible causes. Lab tests should including a complete blood count, electrolytes, kidney function, liver function, and inflammatory markers. Other studies (eg, antinuclear antibody [ANA], anti-neutrophil cytoplasmic antibodies [ANCA] should be ordered based on the clinical presentation.

Findings may include the following[8] :

  • Leukocytosis can be mild to severe

  • Peripheral eosinophil count greater than 1000/µL, oftentimes much higher

  • Abnormal liver function study (LFT) results are common, and mild-to-moderate elevation of transaminase levels is observed in approximately 40% of patients.

  • An elevated serum creatinine kinase level is uncommon, affecting only approximately 10% of patients with EMS.Elevated aldolase levels are common and occur in approximately half of patients.

  • Mild-to-moderate elevation of the erythrocyte sedimentation rate (ESR) is observed in one third of patients.

  • Antinuclear antibodies with a speckled pattern in low titer are observed in approximately half of patients. The significance of this is uncertain.

Imaging Studies

Imaging plays no role in the diagnosis of EMS, but patients may receive chest and/or brain imaging depending on their symptoms.  Findings on such imaging may include[20] :

  • Chest radiography results vary from normal to pleural effusion and/or infiltrates.Abnormalities are seen in less than one third of patients.

  • Magnetic resonance imaging (MRI) of the brain has shown subcortical infarcts, focal lesions in the deep white matter, cortical atrophy, ventricular dilatation, and both diffuse and periventricular white matter abnormalities.The significance of these imaging findings is not clear.

Other Tests

Other tests such as pulmonary function tests (PFTs), echocardiography, and electrophysiologic studies may be performed based on the patient’s symptoms.  Again, none of these are diagnostic of EMS. Findings include the following[8] :

  • PFTs reveal a slightly decreased diffusion capacity in up to half of patients with EMS but no evidence of restrictive or obstructive lung disease.

  • Electrophysiologic studies demonstrate myopathic and neuropathic changes of varying degrees. Nerve conduction studies show mixed demyelination and a pattern of axonal degeneration.

  • Echocardiography typically shows normal left ventricular function and normal estimated pulmonary artery pressure, but pulmonary arterial hypertension is occasionally detected.


Because of the varying skin rashes and muscle symptoms EMS can cause, biopsy of skin, muscle, or full thickness (epidermis to muscle) biopsy may be required to rule out other diagnoses.[8]

Histologic Findings

No consistent findings are observed in biopsy specimens from patients with EMS; therefore, histopathologic findings are helpful but not diagnostic.

Muscle biopsy commonly reveals inflammatory infiltrates, frequently perivascular, in the endomysium and perimysium. The inflammatory cells are predominantly lymphocytes and acid phosphatase–reactive histiocytes, with rare eosinophils. In some instances, microangiopathy is present. Generalized type II myofiber atrophy and denervation atrophy are common, but myofiber necrosis and degeneration are infrequent.

Skin/fascia biopsy findings generally reveal a normal epidermis. The dermis may be normal or may have perivascular infiltrates of monocytes, eosinophils, and lymphocytes without fibrinoid necrosis. These findings differ from those in patients with scleroderma, who have more collagen deposition in the dermis.

Nerve biopsy of affected nerves shows a combination of demyelination and axonal degeneration, with epineural, perineural, and perivascular cellular infiltrates.[21, 8]



Medical Care

The first and most important step is to discontinue the L-tryptophan or other possible offending agent(s). No medication has been shown to alter the course of the disease, but high-dose steroids (eg, equivalent of prednisone 60 mg/day) may be helpful in acutely ill patients.  However, the response to corticosteroids is not as dramatic as in patients with other causes of eosinophilia like eosinophilic fasciitis.  Other care should be directed symptomatically.[8]


Depending on the clinical features, consultation with a neurologist, rheumatologist, pulmonologist, or dermatologist may be needed. Consultation with a surgeon may be necessary for muscle biopsy.


Patients should avoid all herbal supplements and other over-the-counter medication unless further information about the pathophysiology of EMS is elucidated.[8]


Activity may exacerbate the myalgias or muscle cramps. During the acute illness, patient may require bed rest if their symptoms are intense. Over the long term, strenuous activity should be avoided only if it causes symptoms to recur.



Medication Summary

[8] Aside from discontinuing offending medication(s), no standard of care exists for eosinophilia-myalgia syndrome (EMS). For early manifestations of EMS, treatment is directed symptomatically and can include analgesics, vitamins, muscle relaxants, and diuretics.

Prednisone is commonly prescribed for the acute inflammatory phase. However, most published articles conclude that treatment with corticosteroids is not beneficial in reducing the severity or duration of the acute symptoms. Long-term steroid treatment has no role.

Chronic symptoms such as muscle pain, spasm, weakness, neuropathy, and skin disease are treated symptomatically.


Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Prednisone (Sterapred)

Results in prompt resolution of eosinophilia. Subjective improvement noted in symptoms of dyspnea, myalgia, and edema in most patients.



Further Outpatient Care

Because symptoms of EMS tend to be prolonged, sometimes persisting for years, intermittent treatment with muscle relaxants and analgesics may be required.

Further Inpatient Care

Patients who are acutely ill with EMS may require hospitalization for supportive care, inpatient workup for infections, auto-immune diseases, neoplasms, and other mimics of EMS, and consideration of corticosteroid therapy.

Inpatient & Outpatient Medications

Treatment is based on symptoms. Persistent pain requires analgesics. Muscle relaxants may be needed for the treatment of muscle spasms. A prolonged course of prednisone is neither effective nor indicated.


Incapacitating myalgias may require transfer to a skilled nursing facility or rehabilitation unit for assistance with activities of daily living.


Exercise may result in relapse of myalgias in some patients, and they should be advised to avoid any activities that cause or worsen symptoms.  Patients should avoid L-tryptophan and other possible causative medication(s) or supplement(s).


Serious and life-threatening complications (eg, ascending polyneuropathy, cardiomyopathy, myocarditis, myocardial infarction, encephalopathy, stroke, thrombocytopenia) have been reported, but they occur only rarely.


Most patients (90%) continue to have some symptoms 3-4 years after the acute presentation. These are likely due to permanent tissue damage that occurred in the acute phase of the disease.  Persistent muscle pain, fatigue, and muscle spasm were the most common residual complaints.  Subjective memory loss and word-finding difficulties were also reported in this series. These symptoms were not responsive to any therapeutic intervention.  Patients who had severe disease at onset with internal organ involvement, neurologic findings, and skin thickening tended to have a worse prognosis[28].

Patient Education

Patients should be advised that over-the-counter medications are not subjected to rigorous testing for short- or long-term side effects. Their use could result in as yet unknown adverse health consequences.


Questions & Answers


What is eosinophilia-myalgia syndrome (EMS)?

What are the diagnostic criteria for eosinophilia-myalgia syndrome (EMS)?

What is the pathophysiology of eosinophilia-myalgia syndrome (EMS)?

What is the prevalence of eosinophilia-myalgia syndrome (EMS) in the US?

What is the global prevalence of eosinophilia-myalgia syndrome (EMS)?

What is the mortality and morbidity associated with eosinophilia-myalgia syndrome (EMS)?

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What are the differential diagnoses for Eosinophilia-Myalgia Syndrome?


What is the role of lab testing in the workup of eosinophilia-myalgia syndrome (EMS)?

What is the role of imaging studies in the workup of eosinophilia-myalgia syndrome (EMS)?

What is the role of pulmonary function tests (PFTs) in the workup of eosinophilia-myalgia syndrome (EMS)?

What is the role of electrophysiologic testing in the workup of eosinophilia-myalgia syndrome (EMS)?

What is the role of echocardiography in the workup of eosinophilia-myalgia syndrome (EMS)?

What is the role of biopsy in the workup of eosinophilia-myalgia syndrome (EMS)?

Which histologic findings are characteristic of eosinophilia-myalgia syndrome (EMS)?


How is eosinophilia-myalgia syndrome (EMS) treated?

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Which dietary modifications are used in the treatment of eosinophilia-myalgia syndrome (EMS)?

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What is the role of medications in the treatment of eosinophilia-myalgia syndrome (EMS)?

Which medications in the drug class Corticosteroids are used in the treatment of Eosinophilia-Myalgia Syndrome?


What is included in long-term monitoring of eosinophilia-myalgia syndrome (EMS)?

When is inpatient care indicated for the treatment of eosinophilia-myalgia syndrome (EMS)?

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