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Eosinophilia-Myalgia Syndrome
Last Updated: August 2, 2002 |
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| Synonyms and related
keywords: EMS, eosinophilia myalgia syndrome, toxic oil
syndrome, TOS, L-tryptophan, tryptophan, polyneuropathy,
cardiopulmonary disease, superimposed infection |
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AUTHOR
INFORMATION |
Section
1 of 10 
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| Author: Shrilekha
Sairam, MD, MBBS, Fellow, Department of Internal
Medicine, Division of Rheumatology, University of Texas at
Galveston
Coauthor(s): Jeffrey
R Lisse, MD, FACP, Associate Chief, Professor,
Department of Internal Medicine, Division of Rheumatology, University
of Arizona School of Medicine
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| Editor(s): Carlos J Lozada, MD, Director of
Rheumatology Fellowship Program, Associate Professor,
Department of Medicine, Division of Rheumatology and
Immunology, Jackson Memorial Medical Center, University of
Miami School of Medicine; Francisco Talavera, PharmD,
PhD, Senior Pharmacy Editor, eMedicine; Lawrence
H Brent, MD, Chair, Program Director, Associate
Professor, Department of Medicine, Division of Rheumatology,
Albert Einstein Medical Center, Thomas Jefferson University; Alex
J Mechaber, MD, FACP, Associate Director of
Generalist Primary Care Clerkship, Assistant Professor,
Department of Internal Medicine, Division of General Internal
Medicine, University of Miami School of Medicine; and Arthur
Weinstein, MD, Director, Division of Rheumatology,
Professor of Medicine, Georgetown University Medical Center,
Department of Medicine, Washington Hospital Center |
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INTRODUCTION |
Section
2 of 10 
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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. 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/mL,
(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. 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. 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.
Frequency:
- In the US: By July of 1991, 1543 cases were
reported to the CDC. However, estimates indicate that 5,000-10,000
people actually have EMS.
- Internationally: 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).
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
- Fatigue described as "profound" (40% of patients)
- 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.
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DIFFERENTIALS |
Section
4 of 10
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Churg-Strauss
Syndrome
Eosinophilic
Leukemia
Eosinophilic
Pneumonia
Hypereosinophilic
Syndrome
Hypothyroidism
Polymyalgia
Rheumatica
Scleroderma
Trichinosis
Other Problems to be Considered:
Malignancy
Toxic oil syndrome
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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/mL for diagnosis,
the counts observed in patients are higher.
- Eosinophil counts of 10,000-30,000 cells/mL
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.
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.
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TREATMENT |
Section
6 of 10
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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.
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MEDICATION |
Section
7 of 10
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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.
Drug Name
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Prednisone (Deltasone) --
Results in prompt resolution of eosinophilia. Subjective
improvement noted in symptoms of dyspnea, myalgia, and edema
in most patients.
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| Adult Dose |
Acute illness: 20-30 mg PO
qd
Severe symptoms/organ involvement: 40-60 mg PO qd; taper over
2 wk as symptoms resolve
| Pediatric Dose |
Not established
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| Contraindications |
No absolute
contraindication; severe bacterial, viral, or fungal
infection; active peptic ulcer disease; diabetes mellitus
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| Interactions |
Coadministration with
estrogens may decrease clearance; concurrent use with digoxin
may cause digitalis toxicity secondary to hypokalemia;
phenobarbital, phenytoin, and rifampin may increase metabolism
(consider increasing maintenance dose); monitor for
hypokalemia with coadministration of diuretics
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| Pregnancy |
B - Usually safe but
benefits must outweigh the risks.
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| Precautions |
Abrupt discontinuation may
cause adrenal crisis; hyperglycemia, edema, avascular
necrosis, myopathy, peptic ulcer disease, hypokalemia,
osteoporosis, euphoria, psychosis, myasthenia gravis, growth
suppression, and infections may occur with glucocorticoid use
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FOLLOW-UP |
Section
8 of 10
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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.
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MISCELLANEOUS |
Section
9 of 10
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Medical/Legal Pitfalls:
- Failure to tell the patient to stop using the offending
medication
- Failure to consider other diagnoses (eg, malignancy, infection)
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BIBLIOGRAPHY |
Section
10 of 10
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- Belongia EA, Gleich GJ: The eosinophilia-myalgia syndrome
revisited [editorial]. J Rheumatol 1996 Oct; 23(10): 1682-5[Medline].
- Bulpitt KJ, Verity MA, Clements PJ, Paulus HE: Association of
L-tryptophan and an illness resembling eosinophilic fasciitis.
Clinical and histopathologic findings in four patients with
eosinophilia-myalgia syndrome. Arthritis Rheum 1990 Jul; 33(7):
918-29[Medline].
- Clauw DJ, Flockhart DA, Mullins W, et al: Eosinophilia-myalgia
syndrome not associated with the ingestion of nutritional
supplements. J Rheumatol 1994 Dec; 21(12): 2385-7[Medline].
- Clauw DJ, Pincus T: The eosinophilia-myalgia syndrome: what we
know, what we think we know, and what we need to know. J Rheumatol
Suppl 1996 Oct; 46: 2-6[Medline].
- Culpepper RC, Williams RG, Mease PJ, et al: Natural history of
the eosinophilia-myalgia syndrome. Ann Intern Med 1991 Sep 15;
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Harris ED, Ruddy S, Sledge CB, eds. Textbook of Rheumatology. 4th
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- Hertzman PA, Falk H, Kilbourne EM, et al: The
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- Hertzman PA: Criteria for the definition of the
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should be treated and how? Rheum Dis Clin North Am 1993 Feb;
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the eosinophilia-myalgia syndrome associated with L-tryptophan
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syndrome: May 8-10, 1991, World Health Organization meeting
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years after onset. J Rheumatol Suppl 1996 Oct; 46: 19-24;
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syndrome due to L-tryptophan ingestion. Report of four cases and
review of the Maryland experience. Arthritis Rheum 1990 Jul;
33(7): 930-8[Medline].
- Shulman LE: The eosinophilia-myalgia syndrome associated with
ingestion of L- tryptophan. Arthritis Rheum 1990 Jul; 33(7): 913-7[Medline].
- Swygert LA, Maes EF, Sewell LE, et al: Eosinophilia-myalgia
syndrome. Results of national surveillance. JAMA 1990 Oct 3;
264(13): 1698-703[Medline].
- Varga J, Uitto J, Jimenez SA: The cause and pathogenesis of the
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140-7[Medline].
| NOTE:
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Eosinophilia-Myalgia
Syndrome excerpt
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