Eosinophilia-Myalgia Syndrome

Synonyms: Sclerodermoid Myalgia; Eosinophilia Associated with Ingestion of Tryptophan
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:

• 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 findings²

It is thought that either a contaminant or a toxic metabolite of L-tryptophan causes the condition. L-tryptophan (an essential amino acid) has been used in the past as a dietary supplement for various complaints including depression, sleep problems, overeating, migraine, pain sensitivity and stress.

However, L-tryptophan may not be the only possible causative agent of EMS. 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.³

In EMS, the causative agent seems to promote a widespread inflammatory reaction. There are significant levels of eosinophils and inflammatory markers in the tissues and this immune response is thought to be the reason for the tissue damage that occurs to muscles, skin, nerves and other organs.

Early features (within first 3-4 months)²

• Myalgia 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.
• Peripheral and periorbital oedema can occur.
• Arthralgia usually affects the large joints.
• Fever
• Marked fatigue
• Skin rashes can occur including macules, papules and urticarial-type lesions.⁴ There can be associated pruritus.
• Skin involvement occurs in 60%.⁴ 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.
• 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.
• Gastrointestinal symptoms are more rare and include dyspepsia, dysphagia or diarrhoea.
• Alopecia can occur.

Chronic features (more than half have persistent symptoms after 1 year)²

• Myalgia
• Muscle weakness
• Fatigue
• Muscle cramps
• Joint pain
• Memory problems
• Expressive dysphasia
• Persistent skin changes
• Continuing respiratory symptoms
• Persistent neurological symptoms including neuropathy

These are rare and include:

• Pericarditis
• Myocarditis
• Arrhythmias
• Myocardial infarction
• Pulmonary hypertension
• Thromboembolism
• Encephalopathy
• Seizures
• Ascending polyneuropathy which can lead to respiratory arrest and death

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.²
• Liver function tests: elevated levels of bilirubin, alanine transaminase, aspartate transaminase, alkaline phosphatase, and gamma-glutamyl transferase occur in nearly half of all cases.⁴
• ESR: may be raised
• Creatine kinase: despite the myalgia creatine kinase and aldolase levels are elevated in only around 3%.⁴
• Antinuclear antibodies: these are weakly positive in about half of people but other autoantibodies are usually negative and positive results may suggest an alternative diagnosis.

Imaging

• CXR: this is often normal even in the presence of impaired respiratory function but infiltration and effusion may occur.
• MRI of the brain: this may show increased signal intensity in the occipital and parietal regions.

Other tests

• Electromyography: this can show myopathy and neuropathy.
• Skin/muscle/nerve biopsy: can show characteristic histopathological changes. Nerve biopsy can show changes including demyelination.
• Pulmonary function tests: these may be helpful if there are respiratory symptoms. They can show obstructive and restrictive defects.
• ECG/Echocardiography: changes may indicate cardiac involvement.

• Any further ingestion of L-tryptophan or other postulated causative agent must be stopped.
• Further treatment is usually symptomatic and supportive and may include analgesia and muscle relaxants.
• 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.^5,6,7
• Psychotherapy and a physiotherapy/rehabilitation programme may be required.

• From October 1989 to January 1993, 1512 cases of EMS were reported. One third of people needed hospitalization and 35 people died.⁴
• In a few people there is rapid improvement after stopping use of the offending products.
• For most patients there is improvement over about 6 months followed by a chronic course.⁷
• One study found that for 65% of patients, there was no improvement, or there was deterioration of symptoms, after 3-4 years.⁸
• Respiratory arrest due to ascending polyneuropathy is the commonest cause of death.
• The World Health Organisation 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.⁶

The Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT) is an independent scientific committee that provides advice to the Food Standards Agency, the Department of Health and other Government Departments and Agencies on matters concerning the toxicity of chemicals. They issued a statement in 2004 concerning tryptophan and EMS.⁹

COT had introduced a ban on the addition of tryptophan to foods (including supplements) in 1990 after the EMS epidemic in the USA, except in some foods for specific nutritional purposes such as infant formulas. In such cases, natural protein sources of tryptophan should be used.

L-tryptophan is available on prescription in the UK for treatment-resistant depression. It should only be initiated by specialists. Prescribing clinicians should be aware of the special warning/precaution for use related to the association between EMS and L-tryptophan products. Close monitoring is necessary with eosinophil counts and questionnaires and a unit was established by the manufacturers in 1994 to facilitate this.⁹

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.