Related condition: toxic oil syndrome

Eosinophilia-myalgia syndrome (EMS) is a rare condition. It was first described in 1989 after 3 patients in New Mexico were found to have an illness with marked myalgia and eosinophilia. They had all taken preparations containing L-tryptophan. 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 United Kingdom. Since this epidemic, very few cases have been identified.²

The Centers for Disease Control and Prevention in the USA issued the following criteria that must be met for the diagnosis of EMS:³

• 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.

Aetiology⁴

L-tryptophan is one of 8 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 eosinophilia-myalgia syndrome (EMS) epidemic, L-tryptophan-containing dietary supplements were taken for problems such as insomnia, depression and premenstrual syndrome, and were used by bodybuilders, at doses of 1-8 g daily.⁴

The 1989 epidemic of EMS was linked (from epidemiological evidence) to a particular brand of L-tryptophan supplement, which may have been contaminated due to changes in the manufacturing process. A contaminant known as 'EBT' was found, and seems the most likely culprit. However, there are continuing uncertainties about the cause of EMS and these include:

• Contaminants other than EBT could cause EMS.
• Whether L-tryptophan itself (rather than a contaminant) can cause EMS.⁵
• There are some documented and possible EMS cases reported without a history of L-tryptophan consumption.
• It has been suggested that some cases of EMS could occur sporadically.

An outbreak of a condition with similar features occurred in Spain in 1981. It was known as toxic oil syndrome and was found to be linked to the ingestion of contaminated rapeseed oil. It affected over 20,000 people and there were in excess of 2,500 deaths.⁶

Pathophysiology

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.⁷

Presentation

Early features (within first 3-4 months)²

Myalgia, severe fatigue and rash are common presenting symptoms. In one study, about a third of patients were hospitalised initially.⁸

Early features of EMS are:^2,8

• 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, nonproductive 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.⁹ There can be associated pruritus.
• Skin involvement - occurs in 60%.⁹ 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^2,3,10

The majority of patients have persistent symptoms after 1 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, e.g. poor appetite and nausea ( less common)

Investigations⁹

Blood tests

• Full blood count: 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.³
• Liver function tests: 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): despite the myalgia, CK and aldolase levels are elevated in only around 3%.
• Autoantibodies: antinuclear antibodies may be positive; other autoantibodies are usually negative.

Imaging

• CXR: this is often normal even in the presence of impaired respiratory function but infiltration and effusion may occur.
• MRI scan of the brain: various changes found in MRI patients have been reported by Haseler et al.¹¹

Other tests

• Electromyography: this can show myopathy and neuropathy.
• Skin/muscle/nerve biopsy: histology shows various features which are described by Schwartz.⁹
• Pulmonary function tests: these may be helpful if there are respiratory symptoms.
• ECG/echocardiography: changes may indicate cardiac involvement.

Management⁹

There is no known specific treatment for eosinophilia-myalgia syndrome (EMS). Management comprises:

• Stop taking any further L-tryptophan or other possible causative agent.
• Prednisolone may be commenced and tapered off as symptoms resolve. Steroids seem to be of benefit in the short-term but not in the long-term.^3,8,10
• Further treatment is usually symptomatic and supportive and may include bedrest, 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. The following treatments have been used, with some reported benefit, according to surveys of EMS patients and their physicians:

• Nondrug treatments - heat treatments, e.g hot tubs, water aerobics, gentle physiotherapy such as stretching of muscle groups, and behavioural treatment, e.g. biofeedback.³
• Drug treatments:⁸
  • Antidepressants - amitriptyline, fluoxetine.
  • Non-steroidal anti-inflammatory drugs (NSAIDs) - aspirin, naproxen.
  • Immune modulating drugs - methotrexate, penicillamine. Ciclosporin has also been used but was reported to be of limited benefit.¹²
  • Others - furosemide, triazolam, colchicine, dantrolene, plasmapheresis.

Complications^2,9

Serious complications are rare, but have been reported, including:²

• Ascending polyneuropathy - in some cases this may lead to respiratory arrest and death.⁹
• Pneumonitis.
• Cardiomyopathy¹³ or myocarditis; myocardial infarction.
• Arrhythmias.⁴
• Encephalopathy or stroke.
• Thrombocytopenia or thromboembolic complications.

Prognosis^4,8,10

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

Studies on patients with EMS found that:

• From October 1989 to January 1993, 1,512 cases of EMS were reported. One third of people needed hospitalisation and 37 people died.^4,9
• For most patients there is improvement over a period of several months, followed by a chronic course.¹⁰
• One study found that a significant proportion of patients had persisting symptoms 3 years after onset of EMS.³
• The World Health Organization reported a cumulative mortality of around 2.5% in the first two years for both toxic oil syndrome and the EMS epidemic related to L-tryptophan ingestion.¹⁴

Current recommendations for use of tryptophan and 5-hydroxy-L-tryptophan

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 tryptophan and eosinophilia-myalgia syndrome (EMS):⁴

• The COT banned tryptophan in foods (including supplements) in 1990 - except in some foods for specific nutritional purposes, such as infant formulas, where natural protein sources of tryptophan must be used.
• The 2004 COT statement concluded that tryptophan as a prescription medicine has not resulted in a detectable increase in EMS, and that 220 mg tryptophan 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-tryptophan 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.¹⁵

5-hydroxy-L-tryptophan (5-HTP) is a precursor in the biosynthesis of serotonin from L-tryptophan. 5-HTP can be purchased as a dietary supplement. An impurity has been identified in 5-HTP; its significance is unknown.¹⁶

A Cochrane review on the effectiveness of L-tryptophan and 5-HTP for depression found that, from limited data (two small trials only) they are more effective than placebo. However, their use was not recommended because of the possible link with EMS.¹⁶

Document references

1. Chemical Incident Report from the Chemical Incident Response Service. April 2001. Page 9-10. Health Protection Agency
2. Medsger TA et al; Eosinophilia-Myalgia Syndrome, eMedicine, Oct 2009
3. Campbell DS, Morris PD, Silver RM; Eosinophilia-myalgia syndrome: a long-term follow-up study. South Med J. 1995 Sep;88(9):953-8. [abstract]
4. The Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT); COT statement on tryptophan and the Eosinophilia-Myalgia Syndrome. August 2004
5. Smith MJ, Garrett RH; A heretofore undisclosed crux of eosinophilia-myalgia syndrome: compromised Inflamm Res. 2005 Nov;54(11):435-50. [abstract]
6. Sanchez-Porro Valades P, Posada de la Paz M, de Andres Copa P, et al; Toxic oil syndrome: survival in the whole cohort between 1981 and 1995. J Clin Epidemiol. 2003 Jul;56(7):701-8. [abstract]
7. Silver RM; Pathophysiology of the eosinophilia-myalgia syndrome. J Rheumatol Suppl. 1996 Oct;46:26-36. [abstract]
8. Hertzman PA, Clauw DJ, Kaufman LD, et al; The eosinophilia-myalgia syndrome: status of 205 patients and results of treatment 2 years after onset. Ann Intern Med. 1995 Jun 1;122(11):851-5. [abstract]
9. Schwartz RA; Eosinophilia-Myalgia Syndrome, eMedicine, Dec 2009
10. Culpepper RC, Williams RG, Mease PJ, et al; Natural history of the eosinophilia-myalgia syndrome. Ann Intern Med. 1991 Sep 15;115(6):437-42. [abstract]
11. Haseler LJ, Sibbitt WL Jr, Sibbitt RR, et al; Neurologic, MR imaging, and MR spectroscopic findings in eosinophilia myalgia AJNR Am J Neuroradiol. 1998 Oct;19(9):1687-94. [abstract]
12. Clauw DJ, Alloway JA, Katz P; Use of cyclosporin A in the eosinophilia myalgia syndrome. Ann Rheum Dis. 1993 Jan;52(1):81-2.
13. Finsterer J, Stollberger C; Neuromuscular disorders associated with apical hypertrophic cardiomyopathy. Acta Cardiol. 2009 Feb;64(1):85-9. [abstract]
14. Philen RM, Posada M; Toxic oil syndrome and eosinophilia-myalgia syndrome: May 8-10, 1991, World Health Organization meeting report. Semin Arthritis Rheum. 1993 Oct;23(2):104-24. [abstract]
15. British National Formulary; 59th Edition (March 2010) British Medical Association and Royal Pharmaceutical Society of Great Britain, London (link to current BNF)
16. Shaw K, Turner J, Del Mar C; Tryptophan and 5-hydroxytryptophan for depression. Cochrane Database Syst Rev. 2002;(1):CD003198. [abstract]

Internet and further reading

• National eosinophilia-myalgia syndrome network. A non-profit organization offering educational information and peer support to those with EMS
• Solomon J, Schwarz M; Drug-, toxin-, and radiation therapy-induced eosinophilic pneumonia. Semin Respir Crit Care Med. 2006 Apr;27(2):192-7. [abstract]

Acknowledgements