Eosinophilia-Myalgia Syndrome

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Related condition: toxic oil syndrome 

Eosinophilia-myalgia syndrome (EMS) is a rare condition. It was first described in 1989 after three patients in New Mexico were found to have an illness with marked myalgia and eosinophilia. They had all taken preparations containing L-tryptophan (L-TRP). An epidemic illness then became evident in the USA. In total, over 1,500 people were affected, of whom more than 30 died.[1]At the same time there were cases reported in Germany, Canada and 11 cases in the UK. Since this epidemic, very few cases have been identified.

The Centers for Disease Control and Prevention in the USA issued the following criteria that must be met for the diagnosis of EMS:

  • A peripheral eosinophil count of at least 1.0 x 109 cells/L.
  • Incapacitating myalgia.
  • No evidence of infection or neoplastic conditions that would account for these findings.

L-TRP is one of eight essential amino acids. It is also the precursor of a number of biologically important compounds including serotonin and melatonin and tryptamine. Prior to the 1989 EMS epidemic, L-TRP-containing dietary supplements were taken for problems such as insomnia, depression and premenstrual syndrome.

Toxico-epidemiological studies linked EMS to L-TRP-containing dietary supplements manufactured using genetically engineered bacteria. Initial analysis of implicated L-TRP revealed an impurity that was identified as 1'1'-ethylidenebis[tryptophan] (EBT). Removal of L-TRP from the market was followed by swift resolution of the EMS epidemic. However, the Food and Drug Administration actually lifted the ban on L-TRP in 2005, allowing L-TRP-containing products to again be available as dietary supplements. Since that time it has been recognised that some individuals possess putative immunogenetic risk and protective factors for EMS.[2]However, many experts feel that EMS is not related to taking L-TRP but rather to contaminants introduced during manufacturing.[3]


The pathophysiology is not well understood. It may involve a cell-mediated immune response, leading to a microangiopathy and release of cytokines that can induce eosinophilia and fibrosis.

The pathogenesis of EMS is thought to involve exposure to certain preparations of L-TRP in a genetically susceptible host that trigger acute inflammation and eosinophil activation and degranulation with resulting chronic tissue fibrosis. However, because EMS has been reported in individuals who have never consumed L-TRP, it is likely that xenobiotics other than L-TRP preparations can also trigger a similar immune response.[4]

EMS is characterised by subacute onset of myalgias and peripheral eosinophilia associated with chronic muscle, nerve, fascia, and skin involvement.

Early features (within first 3-4 months)

Myalgia, severe fatigue and rash are common presenting symptoms.

Early features of EMS include:

  • Myalgia - which is necessary for diagnosis. It starts proximally in the shoulders, back, gluteal region and thighs and becomes incapacitating. Stiffness, aches and cramps occur on exercise.
  • Respiratory symptoms - include shortness of breath, non-productive cough and pleuritic chest pain. Interstitial lung disease may be found.
  • Oedema - peripheral and periorbital.
  • Arthralgia - usually affects the large joints.
  • Systemic symptoms - fever, weight loss or gain.
  • Marked fatigue.
  • Skin rashes - including macules, papules and urticarial-type lesions. There can be associated pruritus.
  • Skin involvement - occurs in 60%. After early pruritus and swelling, the skin becomes thickened and feels tight with changes that look like scleroderma. Unlike scleroderma, the fingers and the toes are usually spared, and there is no Raynaud's phenomenon.
  • Alopecia can occur.
  • Neurological symptoms - can include paraesthesia, burning and numbness. A sensory/sensorimotor neuropathy can occur in a glove and stocking distribution. There may be hyperaesthesia. Ascending motor paralysis and bladder dysfunction can occur.
  • Cognitive symptoms - impaired memory, impaired concentration, or mood change.
  • Gastrointestinal symptoms are less common - these include dry mouth, dyspepsia, dysphagia and diarrhoea.

Chronic features

The majority of patients have persistent symptoms after one year, including:

  • Myalgia.
  • Muscle weakness.
  • Fatigue.
  • Muscle cramps.
  • Joint pain.
  • Memory problems including difficulty with word finding.
  • Persistent skin changes.
  • Continuing respiratory symptoms.
  • Persistent neurological symptoms including neuropathy.
  • Gastrointestinal symptoms - eg, poor appetite and nausea ( less common).

Blood tests

  • FBC: there is a marked eosinophilia; a count in excess of 1.0 x 109/L is needed to fulfil the diagnostic criteria. The eosinophilia tends to occur early in the disease and then regresses.
  • LFTs: elevated levels of bilirubin, alanine transaminase, aspartate transaminase, alkaline phosphatase, and gamma-glutamyltransferase occur in nearly half of all cases.
  • Erythrocyte sedimentation rate (ESR) may be raised.
  • Creatine kinase (CK) levels are only elevated in around 3% of cases.
  • Autoantibodies: antinuclear antibodies may be positive; other autoantibodies are usually negative.

There is no known specific treatment for EMS.

  • Any further L-TRP or other possible causative agent should be stopped.
  • Prednisolone may be of benefit in the short term.[4]
  • Further management is usually symptomatic and supportive and may include bed rest, analgesia and muscle relaxants.
  • A rehabilitation programme may be required.

Various other treatments have been used, but there is little information available regarding the evidence that they are beneficial.[4]

Serious complications are rare, but have been reported, including ascending polyneuropathy, pneumonitis, cardiomyopathy, arrhythmias and stroke

In most patients, there was slow improvement after stopping their use of L-TRP products; most patients reported improvement two years after onset of EMS. However, some patients had more rapid improvement and others experienced progression of symptoms even after stopping L-TRP.

The Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT) is an independent committee providing advice to the Food Standards Agency. They issued a statement in 2004 concerning L-TRP and EMS.[5]

  • The 2004 COT statement concluded that L-TRP as a prescription medicine has not resulted in a detectable increase in EMS, and that 220 mg L-TRP per day as a dietary supplement would not present an appreciable risk to health, providing it meets the purity criteria specified in the European Pharmacopoeia.
  • L-TRP is available on prescription in the UK for treatment-resistant depression. It should only be initiated by specialists. If any EMS-type symptoms or a raised eosinophil count develop, treatment should be stopped and the symptoms investigated.[6]

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Further reading and references

  1. Eosinophilia Myalgia Syndrome, 1989, United States; Chemical Incident Report, April 2001

  2. Okada S, Kamb ML, Pandey JP, et al; Immunogenetic risk and protective factors for the development of L-tryptophan-associated eosinophilia-myalgia syndrome and associated symptoms. Arthritis Rheum. 2009 Oct 1561(10):1305-11. doi: 10.1002/art.24460.

  3. Fernstrom JD; Effects and side effects associated with the non-nutritional use of tryptophan by humans. J Nutr. 2012 Dec142(12):2236S-2244S. doi: 10.3945/jn.111.157065. Epub 2012 Oct 17.

  4. Allen JA, Peterson A, Sufit R, et al; Post-epidemic eosinophilia-myalgia syndrome associated with L-tryptophan. Arthritis Rheum. 2011 Nov63(11):3633-9. doi: 10.1002/art.30514.

  5. COT statement on tryptophan and the Eosinophilia-Myalgia Syndrome; The Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT), August 2004

  6. British National Formulary