BASICS
DESCRIPTION
- Eosinophilia-myalgia syndrome (EMS) is a rare syndrome presenting acutely with severe myalgia and elevated eosinophil count, with the subsequent development of chronic musculoskeletal and neurologic symptoms.
- It was initially linked to epidemic exposure to contaminants in preparations of the amino acid supplement L-tryptophan (1), but there are also pre- and postepidemic cases with no known link to supplement use (2). Most of these cases were diagnosed between 1989 and 1991, but several sporadic cases have since been described (3), some with associations to other supplements, particularly 5-hydroxytryptophan (5-HTP), a serotonin precursor used worldwide in the treatment of depression, insomnia, and a variety of other psychiatric disorders.
EPIDEMIOLOGY
- In the initial epidemic cohort
- Age range: 17 to 81 years; mean, 49 years. Most patients were 35 to 60 years.
- 97% were Caucasian.
- 84% were females.
Incidence
The 1989 to 1991 epidemic resulted in 1,543 U.S. cases reported to the CDC. The rate of new cases since the November 1989 recall of L-tryptophan supplements is extremely low. New cases have potentially been linked to other nutritional supplements, including 5-HTP, l-lysine, and niacin. However, some patients who meet the criteria for EMS have no history of any supplement use. á
Prevalence
EMS is rare. Among reported cases, complete remission is unusual: 90% continue to report chronic symptoms even 4 years after diagnosis. á
ETIOLOGY AND PATHOPHYSIOLOGY
- The precise disease mechanisms in EMS are unknown (4). Elevated levels of cytokines (interleukin [IL]-2, interferon [IFN]-╬│) may play a role. Findings in biopsy specimens of muscle and skin include:
- Inflammatory (leukocytic) infiltrates
- Capillary endothelial hyperplasia
- Fibrosis of fascia and skin
- The precise cause of EMS remains controversial. One hypothesis is that a contaminant in L-tryptophan and other supplements initiates the inflammatory process; one of the best characterized example of these is 1,1-ethylidenebis (L-tryptophan), known as EBT. Alternatively, it has been suggested that high doses of L-tryptophan itself (and possibly other supplements, particularly 5-HTP) may generate toxic metabolites that are sufficient to induce the syndrome (5). Another implicated contaminant is 4,5-tryptophan-dione, found in preparations of the tryptophan metabolite 5-HTP (6).
Genetics
Genes in the major histocompatibility complex (MHC) have been implicated in the development of the disease, with some HLA subtypes conferring protection and others increasing susceptibility (7). However, testing for these subtypes is of limited clinical usefulness. á
GENERAL PREVENTION
Avoidance of supplements of unknown purity is the only known means of prevention. High supplement doses may also increase risk. á
COMMONLY ASSOCIATED CONDITIONS
Toxic oil syndrome (TOS), which is thought to be caused by ingestion of contaminated rapeseed oil, shares many of the clinical and pathologic features of EMS (8). The dermatologic findings in EMS are indistinguishable from those found in a more common entity, eosinophilic fasciitis (EF; also called Shulman syndrome or diffuse fasciitis with eosinophilia) (9). However, EF generally lacks significant myalgia and visceral involvement is minimal. Finally, there are distinct similarities between EMS and systemic sclerosis (SSc), although EMS is not associated with Raynaud phenomenon or SSc-specific autoantibodies. á
DIAGNOSIS
- The CDC criteria for the syndrome include all of the following (10):
- Incapacitating myalgias
- Blood eosinophil count >1 times 1,000/╬╝L (but may be >10 times this level)
- No evidence of infection or neoplasm that would otherwise explain symptoms.
- In 2001, new evidence-based criteria were proposed, which called for diagnosis by recognition using syndromic patterns (11)[B]:
- Pattern 1: abrupt onset with development of eosinophilia, myalgia, and one of: rash, edema, pulmonary involvement, or neuropathy
- Pattern 2: combined manifestations of fasciitis + neuropathy +myalgias in a 24-month period) OR (any three of fasciitis, neuropathy, myalgias, or eosinophilia in a 6-month period
- These patterns must occur in the absence of other explanations of symptoms.
HISTORY
- Core acute symptoms, which can last 3 to 6 months, include severe myalgias and muscle cramping, low-grade fever, fatigue, edema, alopecia, paresthesias/dysesthesias, and a variety of skin eruptions. Dry cough and dyspnea, suggesting pneumonitis, are common but generally resolve within a few weeks of the onset of myalgias.
- Chronic symptoms, which are of indefinite duration, may resemble other myopathic, neuropathic, or rheumatologic diseases. >50% of EMS patients will suffer from episodic myalgias, arthralgias, generalized weakness, fatigue, neuropathic pain, cognitive deficits, exercise intolerance, and skin changes that may resemble scleroderma.
PHYSICAL EXAM
- Musculoskeletal: shows proximal muscle tenderness. There is no objective weakness, but pain-limited restriction in the limb range of motion is present.
- Neurologic: can include ascending motor paralysis, stocking-glove sensory neuropathy, compression neuropathies, and encephalitis
- Dermatologic: various nondiagnostic macular and plaque eruptions, urticaria, and, late in the disease, persistent skin thickening that resembles scleroderma
DIFFERENTIAL DIAGNOSIS
- Inflammatory myopathies, particularly polymyositis, dermatomyositis
- Infectious myositis
- Viral: HIV, coxsackievirus, influenza, dengue, others
- Parasitic: especially trichinosis, but also including cysticercosis and trypanosomiasis
- Multifocal bacterial pyomyositis
- Lyme myositis
- Nonspecific viral myalgias and arthralgias and drug-induced myopathies (including statin-induced and steroid myopathies)
- Polymyalgia rheumatica
- Fibromyalgia
- Hypothyroid myopathy
- Osteomalacia (vitamin D deficiency)
- Eosinophilic fasciitis
- Systemic sclerosis
- TOS
- Hypereosinophilic syndromes (HES)
- Churg-Strauss syndrome
- Eosinophilic pneumonias
- Polyarteritis nodosa
DIAGNOSTIC TESTS & INTERPRETATION
The mainstay of diagnostic evaluation is the presence of eosinophilia, coupled with the absence of markers for infection, malignancy, or other systemic disease which might suggest alternative diagnoses. á
Initial Tests (lab, imaging)
- CBC with differential: Absolute eosinophil count >1,000/╬╝L is key for diagnosis of acute phase.
- May show mild to moderate leukocytosis
- ESR: elevated in 1/3 of patients; generally <50 mm/hr
- Mild to moderate transaminase elevations are common.
- Creatine kinase (CK): only elevated in 10%
- Serum aldolase: elevated in 50% of patients
- Antinuclear antibodies (ANA): nonspecific elevation, speckled pattern
- Liver function tests (LFTs)
- A chest radiograph is recommended because patients frequently present with chest symptoms. Findings may include infiltrates and pleural effusions.
Follow-Up Tests & Special Considerations
An MRI of the brain may demonstrate findings consistent with CNS vasculitis. á
Diagnostic Procedures/Other
The electromyogram/nerve conduction velocity (EMG/NCV) may show mixed myopathic and neuropathic changes, with evidence of both demyelination and axonal degeneration. á
Test Interpretation
Biopsy findings are generally nondiagnostic, but they may help exclude other disease entities: á
- Muscle biopsy findings are nonspecific, with findings of inflammatory infiltrates, atrophy, and denervation.
- Skin biopsy findings may show dermal cellular infiltrates, eosinophilic fasciitis, and fibrosis.
TREATMENT
- There is no specific treatment for EMS. Care is supportive.
- There is no evidence to support the use of prednisone or other steroids.
MEDICATION
First Line
- Muscle relaxants
- NSAIDs
- Diuretics for peripheral edema
Second Line
Opioid analgesics á
ADDITIONAL THERAPIES
Discontinuation of medications with the potential to induce myopathy (e.g., statins, steroids) is advised. á
INPATIENT CONSIDERATIONS
Patients with EMS may require hospital admission, particularly at the onset of symptoms. á
Admission Criteria/Initial Stabilization
- Pain refractory to outpatient therapy
- Volume or electrolyte disturbances
- Rare complications include myocardial infarction, stroke, ascending motor paralysis, or encephalopathy.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patients may require close monitoring by a primary care physician. Patients may need prolonged rehabilitation services, in-home nursing care, and in severe cases, consideration of placement in a skilled nursing facility. á
DIET
Avoid nutritional supplements implicated in EMS, especially L-tryptophan and 5-HTP. High-dose amino acid and vitamin supplements of any kind are of questionable value and should not be used without physician guidance. á
PATIENT EDUCATION
Patients should be advised to modulate their activity level to prevent exacerbation of myalgias. Strenuous exercise may be contraindicated, but deconditioning should likewise be avoided. Patients may benefit from a structured support system, for which they may be directed to the National Eosinophilia-Myalgia Syndrome Network Web site: http://nemsn.org. á
PROGNOSIS
Complete recovery is estimated to occur in only 10% of patients. á
COMPLICATIONS
Complications are rare but include severe cardiac and neurologic sequelae as well as thrombocytopenia. á
REFERENCES
11 Hertzman áPA, Blevins áWL, Mayer áJ, et al. Association of the eosinophilia-myalgia syndrome with the ingestion of tryptophan. N Engl J Med. 1990;322(13):869-873.22 Sullivan áEA, Staehling áN, Philen áRM. Eosinophilia-myalgia syndrome among the non-L-tryptophan users and pre-epidemic cases. J Rheumatol. 1996;23(10):1784-1787.33 Allen áJA, Peterson áA, Sufit áR, et al. Post-epidemic eosinophilia-myalgia syndrome associated with L-tryptophan. Arthritis Rheum. 2011;63(11):3633-3639.44 Silver áRM. Pathophysiology of the eosinophilia-myalgia syndrome. J Rheumatol Suppl. 1996;46:26-36.55 Clauw áDJ, Pincus áT. The eosinophilia-myalgia syndrome: what we know, what we think we know, and what we need to know. J Rheumatol Suppl. 1996;46:2-6.66 Klarskov áK, Johnson áKL, Benson áLM, et al. Structural characterization of a case-implicated contaminant, "Peak X,"Ł in commercial preparations of 5-hydroxytryptophan. J Rheumatol. 2003;30(1):89-95.77 Okada áS, Kamb áML, Pandey áJP, et al. Immunogenetic risk and protective factors for the development of L-tryptophan-associated eosinophilia-myalgia syndrome and associated symptoms. Arthritis Rheum. 2009;61(10):1305-1311.88 Kaufman áLD, Krupp áLB. Eosinophilia-myalgia syndrome, toxic-oil syndrome, and diffuse fasciitis with eosinophilia. Curr Opin Rheumatol. 1995;7(6):560-567.99 Varga áJ, Griffin áR, Newman áJH, et al. Eosinophilic fasciitis is clinically distinguishable from the eosinophilia-myalgia syndrome and is not associated with L-tryptophan use. J Rheumatol. 1991;18(2):259-263.1010 Spitzer áWO, Haggerty áJL, Berkson áL, et al. Analysis of Centers for Disease Control and Prevention criteria for the eosinophilia-myalgia syndrome in a geographically defined population. J Rheumatol Suppl. 1996;46:73-79.1111 Hertzman áPA, Clauw áDJ, Duffy áJ, et al. Rigorous new approach to constructing a gold standard for validating new diagnostic criteria, as exemplified by the eosinophilia-myalgia syndrome. Arch Intern Med. 2001;161(19):2301-2306.
CODES
ICD10
M35.8 Other specified systemic involvement of connective tissue á
ICD9
710.5 Eosinophilia myalgia syndrome á
SNOMED
- Eosinophilia myalgia syndrome
- Eosinophilia-myalgia syndrome from tryptophan (disorder)
CLINICAL PEARLS
- Ask all patients about their use of over-the-counter vitamins and supplements.
- If suspecting EMS, first check a CBC for a markedly elevated absolute eosinophil count.
- Steroids have no role in the treatment of EMS.