Association of l‐tryptophan and an illness resembling eosinophilic fasciitis: clinical and histopathologic findings in four patients with eosinophilia‐myalgia syndrome

Abstract

The Centers for Disease Control has recently reported an association between the use of oral Ltryptophan preparations and a disease marked by severe myalgia, peripheral eosinophilia, and neuromuscular and cutaneous abnormalities. They have labeled the condition eosinophilia-myalgia syndrome. We report here the clinical and histopathologic findings in 4 patients who developed an illness resembling eosinophilic fasciitis following the initiation of oral L-tryptophan supplementation.L-tryptophan has gained popularity as an empiric therapy for a variety of pain and sleep disorders, including insomnia, premenstrual syndrome, fibromyalgia (11, and depression. and over the last decade, its recommendation by practitioners and use by the general public have become extensive. Recently. the Centers for Disease Control (CDC) has received numerous reports suggesting a possible relationship between the oral consumption of commercial preparations of I>-tryptophan and the development of a syndrome marked by eosinophilia. severe myalgia, fever, skin changes, and respiratory symptoms, with onset weeks to years after initiation of L-tryptophan use ( 2 4 ) . The CDC has issued a health alert advising consumers to discontinue the use of this dietary supplement. They provided a provisional case-definition of eosinophilia-myalgia syndrome (EMS), but they did not include definitive morphologic findings. The precise role of L-tryptophan (or a contaminant in the L-tryptophan preparation) in the development of the syndrome is unknown, but the temporal relationship between the use of these preparations and the onset of EMS was sufficient to warrant this immediate warning by the CDC.Eosinophilic fasciitis (EF) was originally described by Shulman in 1974 ( 5 ) and further characterized by Rodnan and coworkers the following year (6,7). Although recognizing a similarity between EF and idiopathic scleroderma, Rodnan and other investigators have postulated that EF is a clinically distinct entity, differentiated from scleroderma by the pattern and appearance of the skin involvement, the presence of eosinophilia, the absence of Raynaud's phenomenon, an elevation in the erythrocyte sedimentation rate (ESR) and gamma globulin level, the rapidity with which contractures develop, the responsiveness to corticosteroid treatment, and the characteristic biopsy findings of deep fasciitis with perivascular infiltrates sparing skin and muscle. Over 200 case reports have followed the original description; however, the etiology of EF has remained an enigma.In this report, we describe 4 patients whose clinical and laboratory findings fit the CDC's provisional criteria for the diagnosis of EMS and who developed an illness that clinically resembled eosinophilic fasciitis. In response to the CDC's health alert, their cases were retrospectively reviewed and it was discovered that all 4 were taking L-tryptophan before and during the disease course. This probable associa-

A murine model of the eosinophilia-myalgia syndrome induced by 1,1'-ethylidenebis (L-tryptophan).

“…In the of 206±62 to 110±24 and 131±35 nM after 3 and 6 d current study, we demonstrate that significant dermal and subrespectively (P < 0.001 compared with saline concutaneous inflammation and fibrosis occur when female uinolinic acid returned toward baseline by 2 wk of C57BL/6 mice are administered synthetic EBT by intraperitoosure (180±55 nM; P = NS compared with saline neal injection. EBT appears to be capable ofinducing lesions of and continued to rise to levels that were significantly the dermis and subcutis, including the fascia and perimysium, compared with baseline or saline-treated control ani-consistent with those seen in patients with EMS (2,3,7,8,11). …”

“…In addition to eosinophilia and myalgia, many EMS patients developed scleroderma-like skin changes frequently accompanied by fasciitis (2,3,7,8), peripheral neuropathy (9-I 1 ), and pneumonitis ( 12). Remarkably similar clinical and histological changes were observed in patients affected by the toxic oil syndrome (TOS) that occurred in Spain in 1981 (13).…”

Hyaluronan homeostasis and its role in pain and muscle stiffness

“…Another histochemical study showed that the acid mucopolysaccharide deposits in EMS patients were almost exclusively made of HA 42 . Biopsies from EMS did not show myonecrosis or vessel destruction, and creatinine kinase levels were also normal 39,41 . Taken together, these findings suggest that the severe myalgia associated with EMS was not due to tissue necrosis but could potentially be caused by ischemia associated with the accumulation of HA.…”

“… 38 Although the pathogenesis of this disease is still poorly understood, cutaneous and muscle biopsies of patients with EMS showed accumulation of acid mucopolysaccharide deposits in the fascial and perimysial regions, specifically around the arterioles and small arteries, without evidence of arteritis. 39 , 40 Perineural fibrosis and loss of microvasculature were noted on histopathological studies of EMS patients. 39 Focal perifascicular atrophy was also reported in the progression of the disease.…”

Meno’s paradox and medicine

“…demic of low vitamin D levels does not cause increased levels of skeletal fragility and unexplained fractures. The diagnosis of EMS also appears to have been originally suggested as the result of an abduction, as researchers tried to make sense of a number of patients who presented with strange and unexplained symptoms (Bulpitt et al 1990;Hertzman et al 1990). Research into the historical processes by which these patterns were identified may be useful in contemporary conversations about how to diagnose disease.…”