Scleroderma-like disorders.

Fibrosing disorders comprise a wide spectrum of heterogeneous diseases characterized by sclerosis of the dermis, subcutis, and sometimes the underlying soft tissues and bone. The hallmark of this group of diseases is skin thickening as in systemic sclerosis with a different distribution pattern and for this reason they have also been referred to as "scleroderma-like" disorders. These diseases may have a different clinical course ranging from a benign disease with a localized cutaneous involvement, to a widespread, systemic, life-threatening disease. Some of them are associated with autoantibodies and/or autoimmune conditions. An accurate recognition of these scleroderma-like diseases is important for the institution of the most appropriate treatment.

Neurocognitive dysfunction in the eosinophilia-myalgia syndrome.

The eosinophilia-myalgia syndrome (EMS), a multisystem disorder associated with ingestion of L-tryptophan-containing products, causes sclerodermatous skin changes, cardiopulmonary disease, and a range of peripheral neurologic complications. Many EMS patients also report cognitive difficulty in association with the disease. To determine the frequency of objective neurocognitive impairment in EMS patients with subjective complaints of cognitive difficulty and to assess the relationship of neurocognitive loss with demographic features, degree of peripheral eosinophilia, and psychiatric diagnosis, we compared 24 EMS patients with 32 age- and education-matched healthy controls, using a comprehensive neuropsychological test battery. EMS patients additionally underwent a psychiatric interview and rheumatologic evaluation. Sixty-two percent (15 of 24) of the EMS patients demonstrated neurocognitive deficits. Compared with healthy controls, EMS patients demonstrated significant impairment on tests of verbal memory, visual memory, conceptual reasoning, and motor speed. Cognitively impaired EMS patients did not differ from those without cognitive impairment on demographic markers, degree of peripheral eosinophilia, presence of peripheral neuropathy, or frequency of concurrent psychiatric disorder, including major depression. These data support the hypothesis that EMS is associated with an encephalopathy in addition to its previously recognized peripheral neuropathy and other rheumatologic manifestations.

Toxic oil syndrome and eosinophilia-myalgia syndrome: May 8-10, 1991, World Health Organization meeting report.

In May 1991, researchers and clinicians from throughout the world met at a workshop sponsored by the Regional Office for Europe of the World Health Organization in collaboration with the Fondo de Investigación Sanitaria, Spain, and the U.S. Food and Drug Administration, National Institutes of Health, National Institutes of Mental Health, and Centers for Disease Control and Prevention to share information about two very similar diseases--toxic oil syndrome and eosinophilia-myalgia syndrome. In this paper the interpretation of conference proceedings is presented, current knowledge of the two disorders is summarized, and some possible areas for future research are mentioned. Toxic oil syndrome and eosinophilia-myalgia syndrome have many similarities. Both are related to consumer products that were presumed to be safe but have been found to have numerous trace contaminants, many of which remain to be identified, including the etiologic agents of both disorders. Both illnesses affect patients clinically by causing intense, incapacitating myalgias and a marked peripheral eosinophilia. Other rheumatologic manifestations are common in both, including arthralgias, sicca syndrome, scleroderma-like skin changes, carpal tunnel syndrome, and joint contractures. No clinical or laboratory feature has been found to be pathognomonic of either disease, and accurate diagnosis rests on the clinical judgment of the attending physician. Deaths have occurred in both diseases, and the cumulative mortality for each is approximately 2.5% for the first 2 years. Long-term complications include pulmonary hypertension, peripheral neuropathies, and joint contractures. Although treatment with corticosteroids has resulted in significant symptomatic relief in persons with either disorder, it does not alter the clinical course or long-term outcome. Research into the etiologic agents, preferred treatments, and ways to avoid similar problems in the future is needed.

Dyspnea and pulmonary function in the L-tryptophan-associated eosinophilia-myalgia syndrome.

We reviewed the pulmonary history, dyspnea ratings, and pulmonary function test results in 16 patients with L-tryptophan-induced eosinophilia myalgia syndrome to determine the correlation between reported pulmonary complaints and pulmonary function abnormalities. All patients reported pulmonary symptoms. Dyspnea, seen in 14 of 16 (87 percent) patients, was the most common symptom. The severity of dyspnea was graded by the baseline dyspnea index and the oxygen cost diagram. Pulmonary function testing including maximal static inspiratory and expiratory pressures were measured. The DCO was diminished in 12 of 16 (75 percent) patients. The MSIP was decreased in seven out of ten (70 percent) and the MSEP was decreased in nine out of ten (90 percent) of those patients tested. There was a statistically significant correlation between the severity of dyspnea as graded by the BDI and OCD, and the decrease in DCO. These results and a review of the literature of the pulmonary manifestations of EMS lead us to conclude that patients with EMS have a high prevalence of dyspnea, and it appears to be caused by both lung parenchymal involvement, as well as respiratory muscle weakness.

Pulmonary manifestations of the eosinophilia-myalgia syndrome associated with tryptophan ingestion.

Pulmonary manifestations are not infrequent in the L-tryptophan-induced eosinophilia-myalgia syndrome (EMS). However, previous reports have not described the results of longitudinal pulmonary function, exercise testing, high-resolution computerized tomographic (HRCT) scanning of the chest, or detailed bronchoalveolar lavage (BAL) analysis. We report six patients with EMS who had dyspnea. The diffusing capacity for carbon monoxide was decreased in five patients tested. Exercise testing with arterial blood gas sampling in three patients was consistent with pulmonary vascular or parenchymal disease. Serial exercise testing in two of these patients demonstrated marked improvement temporally associated with corticosteroid treatment. In four patients, HRCT scanning of the chest was abnormal. One of these patients showed no abnormality on routine chest roentgenogram. Two patients undergoing BAL exhibited increased eosinophils in the lavage fluid; a third had elevated lymphocytes. Serial measurements of fibroblast proliferation-stimulating-activity in samples of BAL fluid obtained from serial examinations in two patients exhibited heightened pretreatment activity that returned to the normal range following corticosteroid therapy. In these two patients, increased proportions of T-suppressor/cytolytic (CD8+) cells were observed in the BAL fluid. Despite aggressive immunosuppressive therapy, one of the patients died of respiratory failure. Another remains markedly dyspneic with pulmonary hypertension. Of the remaining four patients, two exhibited resolution of pulmonary symptoms after systemic corticosteroid therapy, and two experienced partial improvement.

Neurologic, MR imaging, and MR spectroscopic findings in eosinophilia myalgia syndrome.

BACKGROUND AND PURPOSE: Eosinophilia myalgia syndrome (EMS), a multisystemic disease induced by exposure to L-tryptophan, may result in serious CNS abnormalities. The purpose of this study was to determine the pattern of neurologic characteristics, MR imaging abnormalities, and brain neurometabolites in EMS. METHODS: Sixteen patients with EMS and CNS abnormalities (CNS-EMS) and 12 control subjects underwent evaluation, including medical and neurologic examination, proton MR spectroscopy, and MR imaging. RESULTS: Neurologic findings that were increased in CNS-EMS included minor depression (100%), amnesia (88%), and intermittent confusion (38%), although fatigue (31%), motor disorders (31%), recurrent headache (19%), major depression (13%), and dementia (6%) also occurred, but at a lesser significance. Self-reported disability was markedly increased in CNS-EMS. MR imaging findings included subcortical focal lesions, focal lesions in deep white matter, cortical atrophy, ventricular dilatation, and diffuse and periventricular white matter abnormalities. MR spectroscopic findings established two distinct spectral patterns: 1) increased choline-containing compounds, decreased N-acetylaspartate, and increased lipid-macromolecules, consistent with inflammatory cerebrovascular disease; and 2) increased glutamine, decreased myo-inositol, and decreased choline, consistent with acute CNS injury or metabolic encephalopathy. CONCLUSION: Neurologic abnormalities, self-reported disability, brain lesions, and MR spectroscopic abnormalities are common in CNS-EMS. The pattern of cerebral lesions and neurometabolites is consistent with widespread inflammatory cerebrovascular disease. However, a subgroup of patients with CNS-EMS have neurometabolic changes consistent with a metabolic encephalopathy identical or similar to hepatic encephalopathy. The neurologic abnormalities in EMS and related hypereosinophilic syndromes should be interpreted cautiously, with the recognition that both cerebrovascular injury and secondary metabolic encephalopathies may be involved.

Cognitive deficits in a murine model of the eosinophilia-myalgia syndrome: a preliminary report.

The described study was to determine the effects of chronic exposure to 1,1'-ethylidenebis[L-tryptophan] (EBT), a tryptophan contaminant, on cognitive behavior of female C57BL/6 (C57) mice. EBT (also designated as "peak E" or "peak 97") is one of several compounds that are suspect in the eosinophilia-myalgia syndrome (EMS). Groups of female C57 mice (12/group) were injected IP with saline (SAL), tryptophan (TRY), EBT, or an EBT + tryptophan combination (EBT + TRY) over a 6-week period. Previous experiments established that the dosing conditions produce several characteristics of EMS, including dermal inflammation and fibrosis, increased dermal mast cells, and increased levels of quinolinic acid. The mice exposed to EBT + TRY were abnormal during the solution of a Morris water maze problem. First, they had a shorter latency to locate the submerged platform goal during the initial day of training compared to SAL or TRY mice; secondly, they did not show the systematic reduction in latency to locate the platform goal across days of training noted for SAL or TRY mice. These abnormalities occurred in the absence of altered body weight or gross motor activity during the treatment procedure, or in the animal's swim speeds at the time of testing, 3 days after termination of treatment. The results suggest that prolonged exposure to EBT + TRY can alter the reaction to a stressful environment and can alter cognitive behavior.

Eosinophilic cholecystitis as a possible late manifestation of the eosinophilia-myalgia syndrome.

We describe a case of acute acalculous cholecystitis occurring in a 43-year-old woman with a history of the eosinophilia-myalgia syndrome, associated with the ingestion of 1-tryptophan. The patient underwent a laparoscopic cholecystectomy and subsequent histological examination of the gallbladder revealed an infiltrate predominantly of eosinophils, suggesting a possible relationship to the underlying condition. This may represent a late complication of the eosinophilia-myalgia syndrome--such an association has not previously been reported in the literature. The gastrointestinal and hepatic complications of this syndrome are discussed.

Pathogenesis of L-tryptophan eosinophilia myalgia syndrome.

Taken together, these studies suggest that many different etiologic agents alone or together may initiate the common final pathways of tissue pathologic response resulting in the clinical syndrome of eosinophilia, myalgias and fasciitis. Tryptophan itself may contribute to some of the scarring features of the illness, while impure L-tryptophan, and one or more of the impurities cause the characteristic features of the illness. The altered tryptophan metabolism in EMS is secondary to inflammation.

Clinical features of eosinophilia myalgia syndrome and related disorders.

EMS, EF, and TOS are all relatively rare disorders. There are considerable data to suggest that most (if not all) of these cases may be due to toxin exposure, although the precise etiologic agent(s) has yet to be identified. It is likely that the pathogenic mechanisms responsible for disease are similar in these entities, and thus the distinctions between these illnesses may be largely semantic. Rational therapy includes the removal of an inciting agent if identified, and the application of symptom-based treatment based on the organ or tissue involved, and whether there is evidence of active inflammation is present.

Is there any relationship between eosinophilia myalgia syndrome (EMS) and fibromyalgia syndrome (FMS)? An analysis of clinical and immunological data.

The eosinophilia-myalgia syndrome (EMS) caused by intake of contaminated L-tryptophan resembles in its clinical presentation the fibromyalgia syndrome (FMS). We, therefore, analysed clinical and immunological parameters in 16 patients with chronic EMS and 100 patients with FMS in order to see whether there may be a relationship between both disorders. From 12 FMS patients and 12 controls also peripheral blood mononuclear cells (PBMC) were obtained. Myalgia and arthralgia was observed in chronic EMS in the same incidence as in patients with FMS (81%). Also antibodies to serotonin, gangliosides and phospholipids were present in both groups. In vitro stimulation of PBMC with different L-tryptophan preparations revealed in six of the 12 FMS patients but only two of the control individuals a production of type 2 cytokines (IL-5, IL-10). We, therefore, conclude that EMS may have developed in patients suffering primarily from FMS as an allergic reaction towards a more immunogenic L-tryptophan preparation.

Criteria for the definition of the eosinophilia-myalgia syndrome.

The widely disseminated surveillance case definition of the eosinophilia-myalgia syndrome (EMS) recommended by the Centers for Disease Control in 1989 has never been validated by an appropriate challenge and has commonly been used for unintended purposes. To accurately classify patients for clinical and epidemiologic studies and to properly diagnose individual patients, an acceptable set of criteria must be established. In determining which combination of clinical and laboratory manifestations should be properly included in criteria for EMS the following elements should be considered: (1) the presence of a well delineated, documented acute episode with characteristic symptoms, signs, and laboratory abnormalities; (2) the presence of characteristic histopathological abnormalities; (3) the presence of objective evidence for involvement of the most commonly affected major organs: skin, muscle, nerve, and/or lung; and (4) the absence of premorbidities or comorbidities that could explain the components of illness on which the diagnosis is based. A preliminary set of criteria is proposed in this paper. This model requires further scrutiny, revision, and testing.

[Eosinophilia-myalgia syndrome].

Eosinophilia-myalgia syndrome (EMS) is a newly recognized disease, characterized by peripheral eosinophilia with scleroderma-like features. By July 1991, 1543 cases of EMS, including 31 fatal cases, have been reported. Although epidemiologic studies strongly suggest the association of EMS with ingestion of L-tryptophan (LT) containing a contaminant from a single manufacture, the pathogenesis of this disease is not well understood. The insight obtained from the study of EMS may be applicable to scleroderma or eosinophilic fasciitis. Recent advances in the understanding of clinical and pathologic features of EMS are reviewed.

Eosinophilia-myalgia syndrome: patient status 2-4 years after onset.

The clinical status of patients with the eosinophilia-myalgia syndrome (EMS) was studied 2-4 years after its description in 2 databases: (1) a structured review of 205 patients with EMS completed by 15 physicians 18-24 months after onset, which included symptoms, physical findings, laboratory data, and responses to treatments; (2) a self-report questionnaire completed by 344 patients with EMS 42-48 months after onset. Most patients continued to experience symptoms, but almost none experienced new signs of acute inflammation more than one year after onset of EMS. These databases, while presenting information concerning longterm outcomes of more patients with EMS than other reported sources, remain limited by patient selection and the absence of information concerning clinical symptoms before development of EMS.

Pathophysiology of the eosinophilia-myalgia syndrome.

Significant morbidity and mortality occur during the acute phase of the eosinophilia-myalgia syndrome (EMS), and many patients still have chronic manifestations of the disease. Although the precise etiologic agent or agents within implicated batches of L-tryptophan remain uncertain, histopathologic studies support a role for a cell mediated immune response underlying the pathophysiology of EMS. The cellular immune response seems to lead to a microangiopathy and release of cytokines that can induce eosinophilia and fibrosis. Such responses are most marked within the dermis, subcutis, fascia, and connective tissue in and around muscles, nerves, and other tissues. The pathophysiology of the chronic symptoms is poorly understood but may involve ischemia, neuropathy, and metabolic abnormalities.

Fibromyalgia, psychiatric disorders, and assessment of the longterm outcome of eosinophilia-myalgia syndrome.

Fibromyalgia, medical disorders associated with fibromyalgia, and various psychiatric disorders may complicate the assessment of the longterm illnesses caused by the eosinophilia-myalgia syndrome (EMS). The effect of these conditions on the evaluation of outcome in EMS is shown by the use of clinical vignettes derived from a review of medical records of patients with EMS. These observations have implications for the clinical management of patients with a history of EMS and for interpretation of studies of the longterm outcome of EMS.