AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

In October 1989, the health department in New Mexico was notified of 3 patients with an unexplained acute illness characterized by intense myalgia and peripheral blood eosinophilia. These 3 patients had ingested preparations containing L-tryptophan (LT). Within weeks, a nationwide outbreak of this disease occurred. The disease 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 according to 3 criteria. These criteria are (1) a blood eosinophil count greater than 1000 cells/µL, (2) incapacitating myalgia, and (3) no evidence of infection (eg, trichinosis) or neoplastic conditions that would account for these findings.

According to the CDC definition, consumption of L-tryptophan was not required for the diagnosis of EMS. Shortly thereafter, 2 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 development of EMS. Analysis of implicated lots of LT 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 was observed in the incidence of EMS.

However, contaminated L-tryptophan may not be the only cause of EMS. According to one estimate, 14% of EMS cases were not related to LT. Non–LT-related cases were more likely to be associated with symptoms of peripheral edema, rash, sclerodermalike skin change, alopecia, neuropathy and lower mean eosinophil count, fewer pulmonary symptoms, and a better prognosis compared with the LT cases. A review of toxic oil syndrome (TOS) cases that affected many thousands of Spaniards in the early 1980s and were associated with adulterated rapeseed oil reveals that TOS shares many clinical and histopathological features with EMS.

Pathophysiology

The pathogenesis of the disease remains unknown. The 3 major pathological findings observed in persons with EMS are (1) endothelial cell hyperplasia in the capillaries, with evidence of swelling and necrosis; (2) an inflammatory cell infiltrate of predominantly monocytes, histiocytes, lymphocytes, macrophages, and plasma cells and occasionally eosinophils in nerve, muscle, and connective tissue, including the subdermal fascial layer (fasciitis); and (3) increased fibrosis, mostly in the fascia.

Some evidence shows that the levels of cytokines such as interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-5 (IL-5), interferon gamma, and granulocyte-monocyte colony stimulating factor (GMCSF) are increased in the serum of some patients with EMS. McKinley and colleagues found that 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. Eosinophilia does not develop in EBT-treated animals, and the precise role of this contaminant in the pathogenesis of eosinophilia-myalgia syndrome remains uncertain.

Evidence also shows that overloads of tryptophan supplements inhibit histamine degradation by increased formation of formate and indolyl metabolites, several of which inhibit the degradation of histamine, thereby potentiating its effects. Excessive histamine activity is known to induce blood eosinophilia and myalgia. Furthermore, patients with hypothalamic-pituitary-adrenal axis dysregulation who do not have EMS also manifest greatly increased sensitivity to incurred tryptophan and histamine. Histamine disequilibrium appears to be a final common pathway for syndromes characterized by eosinophilia with myalgia.

Frequency

United States

By July of 1991, 1543 cases were reported to the CDC. However, estimates indicate that 5,000-10,000 people actually have EMS.

International

Reports indicate that EMS occurs 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 the attack rates for EMS among users of L-tryptophan to be 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 causes, including ascending polyneuropathy, cardiopulmonary disease, and superimposed infection.
• Of the patients with acute illness, 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 (range 17-81 y, mean 49 y).

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The clinical manifestations of EMS vary greatly. Typically, an abrupt onset of incapacitating myalgia occurs, with development of muscle cramps, dyspnea, 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 myalgia, and cramps.

• Early features of EMS, ie, the acute symptoms observed in the first 3-4 months, include the following:
• • Myalgia: Patients complain of generalized, severe, incapacitating myalgia that tends to worsen over weeks. The shoulders, back, and legs are affected most commonly. Relapses after complete resolution appear common. Muscle weakness is usually not observed at this early stage. Muscle cramps involving the legs and abdominal muscles occur within weeks and may persist for years. Movement, exercise, or change in position may incite a spasm.
  • Edema: Peripheral edema involving the extremities, facial edema, and periorbital edema occur in more than half the patients. This occurs approximately 1 month after disease onset.
  • Arthralgia: Arthralgia of the large joints is common; however, arthritis is rare.
  • Alopecia: Nonscarring alopecia is observed frequently during the acute illness. Then, it improves gradually.
  • Skin rash: This typically occurs approximately 3 weeks after the onset of myalgia and lasts for an average of 3 months. The types of skin 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 changes (eg, thickening of the skin): These changes occur in approximately one third of the patients. The distribution and character of these changes resemble those seen in eosinophilic fasciitis, with involvement of the forearms, arms, and legs. In distinction from scleroderma, digital involvement and Raynaud phenomenon are rare in patients with EMS.
  • Pulmonary symptoms (eg, nonproductive cough, dyspnea, or both): Pulmonary symptoms are observed commonly and usually manifest within 2-3 weeks of the onset of myalgia. These symptoms are self-limited in the majority of patients and last approximately 13 weeks.
  • Neurological symptoms (eg, paresthesias, numbness, burning sensation): These symptoms occur in approximately one third of patients.
  • Gastrointestinal symptoms (eg, dyspepsia, dysphagia, diarrhea): These symptoms have been described in patients with EMS.
• At the end of 1 year, more than half the patients have persistent chronic symptoms, including the following:
• • Myalgia with remissions and relapses
  • Muscle weakness
  • Fatigue described as "profound" (40% of patients)
  • Muscle cramps
  • Joint pain
  • Paresthesias, numbness
  • Memory loss, difficulty concentrating
  • Difficulty communicating (eg, word finding and word substitution problems)
  • Persistent sclerodermalike skin changes
  • Persistent dyspnea
• No new symptoms are noticed in patients after the first 6 months to 1 year.
• 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

• Types of skin 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. Rashes commonly occur over the face, neck, and extremities. Truncal involvement is also seen.
• Sclerodermalike skin changes (although with proximal extremity involvement and without distal extremity involvement, as described above) described as woody, leathery, dry, thickened skin with a peau d'orange appearance similar to eosinophilic fasciitis occur in approximately 32% of patients. These changes appear later in the disease course (median 80 d) and tend to persist in most patients.
• Frank muscle weakness is not observed initially. However, later in the course of the illness, weakness may be present. This occurs independent of the muscle pain.
• Even though dyspnea is a common manifestation, pulmonary findings are less common. Findings vary from normal to those suggestive of interstitial pneumonitis and pleural effusion. Only a few case reports describe mild pulmonary hypertension.
• Patients may have facial and extremity edema.
• Hepatomegaly may be observed.
• Neurological examination yields findings 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.
• The majority of the 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 the disease 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, and premenstrual symptoms.
• Studies conducted during the epidemic implicated an L-tryptophan product lot manufactured by Showa Denko 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 implicated a contaminant in the product lot from Showa Denko as the cause of EMS.
  • Extensive research has failed to identify a definite cause, although a contaminant identified as "Peak E" (1,1,ethylidenebis) is most commonly associated with 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 disease. Genetic factors and various other host factors are also likely to have had a role in development of the disease.
• Clinical syndromes indistinguishable from EMS have been identified both in persons consuming other nutrition supplements (eg, 5 hydroxytryptophan, L-lysine, niacin) and in individuals without any history of drug intake.
• Similarly, the exact cause of TOS is not known.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Malignancy
Toxic oil syndrome

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Because the presenting symptoms and physical findings vary significantly, the workup is mainly directed towards identifying other causes of the patients' manifestations. Lab work is essential to differentiate EMS from other causes of myalgia, weakness, and eosinophilia.
• The presence of peripheral blood eosinophilia is an essential criterion for the diagnosis of EMS based on the CDC surveillance criteria. However, this may be missed because eosinophilia occurs early in the course of the disease and is not observed thereafter.
• • Even though the CDC criteria require an eosinophil count of at least 1000 cells/µL for diagnosis, the counts observed in patients are higher.
  • Eosinophil counts of 10,000-30,000 cells/µL are not unusual, and the bone marrow shows hyperplasia of eosinophil precursor cells.
• Lab findings commonly observed in patients with EMS include the following:
• • Leukocytosis is the most common abnormality observed in lab test results. Elevation ranges from mild to moderate.
  • An elevated creatine kinase level is uncommon; approximately 10% of patients have elevated levels. Levels that are below normal are more common.
  • Elevated aldolase levels are common and occur in approximately half the patients.
  • Abnormal LFT results are common, and mild-to-moderate elevation of transaminase levels is observed in approximately 40% of patients. Frank liver failure is not observed.
  • Mild-to-moderate elevation of the erythrocyte sedimentation rate (ESR) is observed in one third of patients. ESRs faster than 50 mm/h are rare.
  • Antinuclear antibodies with a speckled pattern in low titers are observed in approximately half the patients. The significance of this finding is uncertain.

Imaging Studies

• Chest radiograph results vary from normal to acute infiltrates.
• Pleural effusion and diffuse and bibasilar infiltrates are seen in less than one third of patients.
• MRI of the brain showed subcortical infarcts, focal lesions in deep white matter, cortical atrophy, ventricular dilatation, and diffuse and periventricular white matter abnormalities in patients with EMS. The neurologic findings included depression, amnesia, intermittent confusion, and fatigue.
• MR spectroscopic findings were consistent with widespread inflammatory cerebrovascular disease.

Other Tests

• Pulmonary function testing results and tests of the diffusing capacity of the lungs for carbon monoxide revealed a decreased diffusion capacity in approximately half the patients in one series.
• Results from electrophysiologic studies demonstrate myopathic and neuropathic changes of varying degrees.
• Results from nerve conduction studies show mixed demyelination and a pattern of axonal degeneration.

Procedures

• Histopathologic findings from various biopsy sites are helpful but not diagnostic. See Histologic Findings for detailed descriptions.

Histologic Findings

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

Muscle biopsy commonly reveals findings of inflammatory infiltrate, frequently perivascular, in the endomysium and perimysium. The inflammatory cells are predominantly lymphocytes and acid phosphatase–reactive histiocytes, with rare eosinophils. Generalized type II atrophy and denervation atrophy are not unusual; however, fiber necrosis and myofiber degeneration are uncommon.

Skin/fascia biopsy findings generally reveal normal epidermis. The dermis may be normal or may have perivascular infiltrates, with monocytes, eosinophils, and lymphocytes without fibrinoid necrosis. Fasciitis is indistinguishable from eosinophilic fasciitis. Findings vary from extensive infiltrates with lymphoplasmacytoid cells, eosinophils, and monocytes to diffuse fibrosis of connective tissue extending into dermis and epimysium. These findings differ from the findings in patients with scleroderma, with fewer collagen deposits in the dermis. Changes consistent with scleroderma have also been described in some patients with EMS.

Nerve biopsy findings show a combination of demyelination and axonal degeneration, with epineural, perineural, and perivascular cellular infiltrates.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Stopping ingestion of L-tryptophan or any other agent that may be the offending factor is key in the treatment of these patients.
• Because of the protean manifestations of the syndrome, patients are treated based on their symptoms. No drug is known to alter the course of the disease. High doses of corticosteroids may be helpful in acutely ill patients, but the response is not nearly as dramatic as in patients with pure eosinophilic fasciitis.
• Assistance with activities of daily living in either the inpatient or outpatient setting may be required because the myalgia and muscle cramps can be incapacitating.
• Based on symptoms, patients may need admission to the hospital for evaluation and treatment.

Consultations

• 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, nerve, and fascial biopsies.

Diet

• Any over-the-counter medication or herbal supplement should be avoided until further information is available.

Activity

• Bed rest may be required for the intense muscle pain and cramps during the acute phase of the illness.
• During the chronic phase of the disease, strenuous physical activity may cause muscle pain and cramps and should be avoided if these symptoms occur.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

No standard of care exists. Because the initial outbreak was sudden and widespread, only anecdotal reports and a few retrospective studies are available to aid in treatment. Furthermore, the variable presentation of the syndrome and subjective nature of the symptoms makes interpretation of these studies difficult.

For early manifestations, patients are treated according to their symptoms, with muscle relaxants, analgesics, diuretics, and vitamins.

In addition, patients are commonly treated with prednisone because inflammation has a role in the development of symptoms, especially the skin manifestations.

Chronic symptoms, such as muscle pain, spasm, weakness, neuropathy, and skin thickening, have been extremely resistant to treatment.

In a small retrospective series, treatment with prednisone showed no benefit in reducing the severity or duration of symptoms. Long-term steroid use appears to have no role in treatment.

Isotretinoin may decrease contractures and cutaneous thickening. Symptomatic treatment with muscle relaxants and analgesics may be required for prolonged periods.

Drug Category: Corticosteroids

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

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients with an acute episode may need hospitalization. A workup may be necessary to help rule out infections and neoplasms, which could mimic EMS.

Further Outpatient Care

• Because symptoms tend to be prolonged, sometimes persisting for years, treatment with muscle relaxants and analgesics may be required.
• Persistent muscle pain and spasm can interfere with activities of daily living.
• Prolonged nursing support may be required.

In/Out Patient Meds

• Treatment is based on symptoms. Persistent pain requires analgesics, including opiates. Muscle relaxants may be needed for the treatment of spasms. A prolonged course of prednisone is neither effective nor required.

Transfer

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

Deterrence/Prevention

• Active exercise may result in relapse of myalgia in some patients. These patients should refrain from prolonged strenuous activity.
• While case reports exist of patients with EMS tolerating a rechallenge with L-tryptophan from different manufacturers, the substance is best avoided.

Complications

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

Prognosis

• Most patients continue to have some symptoms 3-4 years after the acute presentation.
• In one series, only approximately 10% of the patients reported complete recovery.
• • Persistent muscle pain, fatigue, and muscle spasm were the most common complaints.
  • Subjective memory loss and word-finding difficulties were also reported in this series. These symptoms were highly resistant to any therapeutic intervention.
• Patients who had severe disease at onset, with organ involvement, neurologic involvement, and skin thickening, tended to have a worse prognosis.

Patient Education

• Patients must be advised to use caution while using over-the-counter medications and must be informed of the potential adverse effects of nutraceuticals.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to tell the patient to stop using the offending medication
• Failure to consider other diagnoses (eg, malignancy, infection)

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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• Roubenoff R, Cote T, Watson R, et al. Eosinophilia-myalgia syndrome due to L-tryptophan ingestion. Report of four cases and review of the Maryland experience. Arthritis Rheum. Jul 1990;33(7):930-8. [Medline].
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• Smith MJ, Garrett RH. A heretofore undisclosed crux of eosinophilia-myalgia syndrome: compromised histamine degradation. Inflamm Res. Nov 2005;54(11):435-50. [Medline].
• Swygert LA, Maes EF, Sewell LE, et al. Eosinophilia-myalgia syndrome. Results of national surveillance. JAMA. Oct 3 1990;264(13):1698-703. [Medline].
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Article Last Updated: Nov 17, 2006