Eosinophilia–myalgia syndrome is a rare, sometimes fatal neurological condition linked to the ingestion of the dietary supplement L-tryptophan. The risk of developing EMS increases with larger doses of tryptophan and increasing age. The presence of eosinophilia is a core feature of EMS, along with unusually severe myalgia (muscle pain).
Signs and symptoms
The initial, acute phase of EMS, which last for three to six months, presents as trouble with breathing and muscle problems, including soreness and spasm, but which may also be intense. Muscle weakness is not a feature of this phase, but some people experience muscle stiffness. Additional features can include cough, fever, fatigue, joint pain, edema, and numbness or tingling, usually in the limbs, hands and feet.
The chronic phase follows the acute phase. Eosinophilic fasciitis may develop, primarily in the limbs. Central nervous system signs may appear, including numbness, increased sensation, muscle weakness, and sometimes cardiac or digestive dysfunction. Fatigue is present to some degree, while the muscle pain (which may be extremely intense) and dyspnea continue in this phase. In total, more than 1,500 cases of EMS were reported to the CDC, as well as at least 37 EMS-associated deaths. After preliminary investigation revealed that the outbreak was linked to intake of tryptophan, the U.S. Food and Drug Administration (FDA) recalled tryptophan supplements in 1989 and banned most public sales in 1990, with other countries following suit.
Subsequent epidemiological studies suggested that EMS was linked to specific batches of L-tryptophan supplied by a single large Japanese manufacturer, Showa Denko. It eventually became clear that recent batches of Showa Denko's L-tryptophan were contaminated by trace impurities, which were subsequently thought to be responsible for the 1989 EMS outbreak. The L-tryptophan was produced by a bacterium grown in open vats in a Showa Denko fertilizer factory. While a total of 63 trace contaminants were eventually identified, only six of them could be associated with EMS. The compound EBT (1,1'-ethylidene-bis-L-tryptophan, also known as "Peak E") was the only contaminant identifiable by initial analysis, but further analysis revealed PAA (3-(phenylamino)-L-alanine, also known as "UV-5"), and peak 200 (2[3-indolyl-methyl]-L-tryptophan). Two of the remaining uncharacterized peaks associated with EMS were later determined to be 3a-hydroxy-1,2,3,3a,8,8a-hexahydropyrrolo-[2,3-b]-indole-2-carboxylic acid (peak C) and 2-(2-hydroxy indoline)-tryptophan (peak FF). These were characterized using accurate mass LC–MS, LC–MS/MS and multistage mass spectrometry (MS<sup>n</sup>). The last of the six contaminants (peak AAA/"UV-28", being "the contaminant most significantly associated with EMS" No consistent relationship has ever been firmly established between any specific trace impurity or impurities identified in these batches and the effects of EMS. While EBT in particular has been frequently implicated as the culprit, there is no statistically significant association between EBT levels and EMS. While critics of this theory have argued that this hypothesis fails to explain the near-absent reports of EMS prior to and following the EMS outbreak, this fails to take into account the sudden rapid increase in tryptophan's usage immediately prior to the 1989 outbreak, and ignores the strong influence of the EMS outbreak's legacy and the extended FDA ban on later usage of tryptophan. A major Canadian analysis located a number of patients that met the CDC criteria for EMS but had never been exposed to tryptophan, which "brings causal interpretations of earlier studies into question". Other studies have highlighted numerous major flaws in many of the epidemiological studies on the association of tryptophan with EMS, which cast serious doubt on the validity of their results. As the FDA concluded, "other brands of L-tryptophan, or L-tryptophan itself, regardless of the levels or presence of impurities, could not be eliminated as causal or contributing to the development of EMS".
At the time of the outbreak, Showa Denko had recently made alterations to its manufacturing procedures that were thought to be linked to the possible origin of the contaminants detected in the affected lots of tryptophan. A key change was the reduction of the amount of activated charcoal used to purify each batch from >20 kg to 10 kg. The reduction in the amount of activated carbon used and the introduction of the fifth generation Bacillus amyloliquefaciens strain were both associated with the development of EMS, but due to the high overlap of these changes, the precise independent contribution of each change could not be determined (although the bypass of the reverse-osmosis filtration for certain lots was determined to be not significantly associated with the contaminated lots of tryptophan). While Showa Denko claimed a purity of 99.6%, it was noted that "the quantities of the known EMS associated contaminants, EBT and PAA, were remarkably small, of the order of 0.01%, and could easily escape detection". Since the initial ban on L-tryptophan, a normal metabolite of the compound in mammals, 5-hydroxtryptophan (5-HTP) has become a popular replacement dietary supplement.
Regulatory response
The FDA loosened its restrictions on sales and marketing of tryptophan in February 2001,
Treatment
Treatment is withdrawal of products containing L-tryptophan and the administration of glucocorticoids. Most patients recover fully, remain stable, or show slow recovery, but the disease is fatal in up to 5% of patients.
See also
- Toxic oil syndrome