Myalgia eosinophilia associated with tryptophan
Overview
n 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 (LT). 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/µL, (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. Analysis of implicated lots of LT identified many contaminants. The best-characterized of these is 1,1-ethylidenebis (L-tryptophan) (EBT), a tryptophan dimer. 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. According to one estimate, 14% of EMS cases were not related to LT. Non–LT-related cases were more likely to be associated with symptoms of peripheral edema, rash, sclerodermalike skin change, alopecia, neuropathy and lower mean eosinophil count, fewer pulmonary symptoms, and a better prognosis compared with the LT cases. 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.
Symptoms
he 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
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
Diagnosis
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: o 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. o 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. o Arthralgia: Arthralgia of the large joints is common; however, arthritis is rare. o Alopecia: Nonscarring alopecia is observed frequently during the acute illness. Then, it improves gradually. o 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. o 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. o 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. o Neurological symptoms (eg, paresthesias, numbness, burning sensation): These symptoms occur in approximately one third of patients. o 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: o Myalgia with remissions and relapses o Muscle weakness o Fatigue described as "profound" (40% of patients) o Muscle cramps o Joint pain o Paresthesias, numbness o Memory loss, difficulty concentrating o Difficulty communicating (eg, word finding and word substitution problems) o Persistent sclerodermalike skin changes o 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