Natural History of the Eosinophilia-Myalgia Syndrome Randall C. Culpepper, MD, MPH; Ronald G. Williams, MD, MPH; Philip J. Mease, MD; Thomas D. Koepsell, MD, MPH; and John M. Kobayashi, MD, MPH

• Objective: To describe the natural history and disease progression of the eosinophilia-myalgia syndrome and to assess the therapeutic effects of orally administered steroids on the disorder as of October 1990. • Design: Case-series analysis. A cohort of 45 patients with the eosinophilia-myalgia syndrome was followed prospectively by periodic telephone interviews and medical examinations for an average of 14 months after onset of illness. • Setting: Washington state. • Patients: The cases of 47 patients were reported to the Washington State Department of Health from 1 July to 12 December 1989. Two patients were unavailable for follow-up, and the remaining 45 completed the study. • Main Results: Patients were predominantly nonHispanic white women (87%) with an average age of 49 years. Symptoms typically progressed from early onset of myalgia and fatigue to later development of neurologic and scleroderma-like skin changes. Six (13%) patients recovered completely within 2 to 5 months of symptom onset. After 14 months of illness, over half of the patients who initially presented with myalgia, fatigue, or scleroderma-like skin changes remained symptomatic. The average severity of each major symptom was measured using interviews and patient self-reports and has improved subjectively by at least 40%. Statistical analyses showed no significant difference in long-term symptom duration or severity between patients treated and those not treated with prednisone. • Conclusions: The eosinophilia-myalgia syndrome is a long-term illness characterized by progressive improvement during the first 25 weeks after symptom onset, followed by a protracted phase of symptom resolution. We could not show a clear-cut benefit of prednisone in reducing the long-term severity or duration of the disease.

1 he eosinophilia-myalgia syndrome has recently been associated with the use of products containing L-tryptophan (1-3). Clinical manifestations include myalgia, fatigue, fever, peripheral edema, alopecia, arthralgias, pulmonary interstitial disease, neurologic complications, and skin changes (4-7). As of July 1991, the Centers for Disease Control (CDC) had received reports of 1543 cases of the disorder nationally, 31 resulting in death (update briefing number 37 from the CDC on the eosinophilia-myalgia syndrome associated with L-tryptophan-containing products; 15 July 1991). The CDC has published demographic data on approximately two thirds of all reported cases (1). Although a wide range of disease severity has been reported, few studies describe the natural history of this illness (8, 9). Also, data showing, the effectiveness of oral steroids in the treatment of this syndrome have been inconsistent (2, 6, 9-11). We report the epidemiologic, clinical, and therapeutic findings for 45 patients who fulfilled the CDC diagnostic criteria for the eosinophilia-myalgia syndrome and who had symptom onset after July 1989. Methods As of 1 January 1991, the Washington State Department of Health had identified 52 patients who met the CDC case definition for the eosinophilia-myalgia syndrome and who had symptom onset as early as 1986. Forty-seven of these patients had onset of symptoms between 1 July and 12 December 1989. The other 5 patients had symptom onset before July 1989 and were excluded because it was unclear whether these patients' disorders were linked to the epidemic. Two of the remaining 47 patients could not be interviewed, and 45 patients completed the study. Data from this cohort have not been reported previously. Cases of the eosinophilia-myalgia syndrome were defined in accordance with the CDC surveillance case definition (12), features of which included an eosinophil count greater than 1 x 109/L, generalized myalgia of sufficient severity to affect activities of daily living, and absence of any infection or neoplasm that could account for the illness. Study Design

Annals of Internal Medicine. 1991;115:437-442. From the School of Public Health and Community Medicine, University of Washington, Seattle, Washington; Madigan Army Medical Center, Tacoma, Washington; the Minor and James Medical Clinic and the Washington State Department of Health, Seattle, Washington. For current author addresses, see end of text.

In this case-series analysis, each patient's referring physician supplied information on the case history, physical examination, laboratory results, diagnostic findings, and treatment regimens. In addition, 15 patients were examined by one of the investigators, and the medical records of the remaining patients were evaluated. Forty-five patients were interviewed by the investigators four times by telephone during the 12 months after initial diagnosis. The initial interview was conducted after the case was reported to the Washington State Department of Health (November 1989 to January 1990). The second and third interviews were done during the weeks of 3 March and 8 May 1990, and the final interview was done during the week of 1 October 1990. Because signs such as residual skin thickening and subtle changes in functional respiratory capacity may remain undis-

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Table 1. Demographic and Clinical Characteristics of Patients with the Eosinophilia-Myalgia Syndrome by Patient Group Characteristic

Gender, % Women Men Race, % White Other Age, % < 35 years 35 to 59 years > 60 years Symptom or sign, % Myalgia Arthralgia Cough or dyspnea Edema Rash Alopecia Paresthesias or weakness Scleroderma-like skin changes

Patient Group Washington Centers for Disease Control State (n = 972) (/i = 45) 84 16

87 13

97 3

98 2

13 65 22

18 56 26

100 73 59 59 60 28 27 32

100 60 80 93 80 76 76 42

covered using telephone interviews, physical examinations by the investigators or referring physicians were used to confirm patient reports. In interviews, patients answered questions about their history of L-tryptophan use, symptom onset and resolution, and the severity of each symptom at its worst stage and at the time of each interview. Information was collected on all treatments provided to each patient and on the patient's subjective assessment of the most effective therapy for his or her myalgia, fatigue, edema, pulmonary symptoms, and overall illness. The severity index for each major symptom was quantitatively represented by the patients' self-report of discomfort on a visual analog pain scale (13). The indices of discomfort for each symptom were scored on a scale from 0 to 100 on which 0 indicated absence of a symptom and 100 indicated extreme symptom severity. The information from the first interview was repeated to the patients during subsequent interviews and was used as a benchmark to confirm data from previous selfreports. To maximize comparability, the same questionnaire was used for each follow-up interview. Statistical Analysis Demographic data and symptom frequencies were analyzed by descriptive statistics. Symptom progression and comparisons of disease characteristics between the two treatment groups were analyzed using the Student /-test if the two sample variances were homogeneous. If the variances differed, the Wilcoxon rank-sum test was used. The relative treatment effect of prednisone was analyzed using the Kaplan-Meier technique (survival analysis), and P values were calculated using the algorithm of Lee and Desu and the Statistical Package for the Social Sciences (14) software. The primary end point of the survival analysis was the percent of patients remaining symptomatic over time, considering the presence or absence of prednisone treatment. Results Forty-five patients in the state of Washington who had the eosinophilia-myalgia syndrome and who had disease onset between 1 July and 12 December 1989 were studied. No new cases have been described in 438

Washington since 12 December 1989, and no deaths have been reported. The demographic characteristics of our cohort (Table 1) were similar to those of other cases in the United States reported to the CDC (1) and to those of other studies (4, 8, 9). Patients were predominantly non-Hispanic white women (87%) ranging in age from 17 to 81 years (mean, 49 years). All patients reported use of products containing L-tryptophan before disease onset. The duration of exposure to L-tryptophan ranged from 2 weeks to 9 years (median, 6 months). The daily dose of L-tryptophan ranged from 500 mg to 11 500 mg (median, 1250 mg). We found no dose-response relation between the amount of L-tryptophan consumed and the severity of subsequent illness. We compared the clinical features of our cohort with those of all cases reported to the CDC (Table 1). Symptoms commonly included myalgia (100%), fatigue (96%), peripheral edema (93%), cough or dyspnea (80%), rash (80%), scleroderma-like skin changes (such as skin thickening and leathery changes) (42%), and paresthesias or weakness (76%). Eosinophil counts ranged from 1000 to 27 200 cells/ mm 3 (mean, 5153 cells/mm 3 ). Additional laboratory data were not reported in detail but were similar to those of other studies (2, 5, 6, 9). No clinical or laboratory evidence suggested that our patients may have had a primary connective tissue disease. Clinical Progression of Disease The clinical features common to all patients were myalgia and eosinophilia. Early features in most patients included fatigue, cough, dyspnea, cramps, arthralgia, rash, alopecia, and edema. The progression of clinical illness is shown in Figure 1. When follow-up ended, more than half of the patients still exhibited the most persistent symptoms (myalgia, fatigue, and scleroderma-like skin changes), suggesting that the true median duration of these symptoms would be greater than indicated by our results. Patients typically presented first with myalgia and fatigue, followed within several weeks (median, 16 days) by cough or dyspnea, or both. After 1 year of illness, patients generally experienced persistent myalgia and fatigue lasting longer than any other symptom. Frequently, myalgias were first reported in specific muscle groups (such as the shoulder, back, or legs) as a generalized aching pain and subsequently as episodic cramping in the extremities. Several patients reported relapses of myalgia after nearly complete symptom resolution. Relapses often occurred after periods of intense aerobic exercise done without proper reconditioning. Fatigue was profound in 19 (43%) patients who reported a most severe symptom level of 100 points. Of 44 patients with fatigue, 82% reported a most severe fatigue level of 80 to 100 points. Pulmonary symptoms were usually characterized by cough or dyspnea or both and were generally of shorter duration, starting early in the third week of illness and lasting for approximately 13 weeks (range, 1 to 65 weeks). Eleven patients (24%) were diagnosed as hav-

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ing interstitial lung disease, and three developed pulmonary hypertension as shown by cardiac catheterization. One patient is considered for heart-lung transplant because of persistent pulmonary systolic pressures of 80 to 90 mm Hg. Thirty-six patients (80%) developed a diffuse, nonspecific rash on the trunk and extremities beginning 0 to 18 weeks after illness onset (median, 3 weeks). The rash was typically erythematous and was described as either small, discrete papular eruptions or large, nonspecific macular lesions occurring most often on the face, neck, and extremities. The rash lasted for an average of 3 months and was accompanied by periods of severe pruritus. Nonscarring alopecia also occurred early in the course of the illness in 74% of patients and showed gradual improvement. Peripheral edema usually occurred within the first month of illness (median, 27 days), beginning within 0 to 138 days of disease onset. Treatment with prednisone or furosemide was reported to have been the most effective treatment for edema by 15 of 27 patients and 7 of 10 patients, respectively, and may have decreased the median duration of this symptom (190 days). Neurologic symptoms, comprising peripheral paresthesia, numbness, or weakness, or a combination, often appeared within the first month of illness (median, 41 days; range, 0 to 198 days). Sixteen of the 34 patients (47%) reporting neuropathies remained symptomatic 12 months after illness onset (median duration, 246 days). Symptoms in these patients were generally improved and consisted of diffuse paresthesias in a stocking-glove distribution. As of October 1990, 15% of patients had described onset of mild neurocognitive symptoms such as difficulty with concentration, memory loss, and word-finding and word substitution problems. These symptoms worsened progressively throughout the second 6 months of illness. At the time of publication, more patients have reported similar symptoms.

Scleroderma-like skin changes appeared later in the disease course (median, 80 days) in 42% of patients and, with the exceptions of myalgia and fatigue, lasted longer than the other symptoms (median, 247 days). These changes included leathery, dry, thickened skin, often accompanied by changes in pigmentation, distributed primarily over the extremities, neck, and face. The trunk was generally unaffected. Of 19 patients reporting scleroderma-like changes, 12 (63%) had these changes 1 year after illness onset. One year after illness onset, myalgias had resolved in 42% of patients and had improved by an average of 72% in the remainder. Other symptoms and signs usually improved by at least 40%. A few patients reported waxing and waning of symptoms (for example, myalgia and fatigue) during the course of their illness. Seven patients (16%) had less than 50% (range, 0% to 43%) overall improvement from their most severe stage of illness. This group did not differ substantially from the remainder of the cohort in severity of illness or therapeutic regimens used.

Therapeutic Approaches Cases were evaluated to determine whether an association existed between prednisone treatment and disease course. Twenty-eight patients (group 1) were treated with prednisone, and 17 (group 2) were not. Three patients in group 2 did not receive any medication for their illness, whereas others were given various medications including corticosteroids, cytotoxic agents (cyclophosphamide or methotrexate), nonsteroidal antiinflammatory drugs, muscle relaxants, vitamin B6, narcotics, diuretics, and H2 antagonists. The dose and duration of prednisone therapy varied but typically

Figure 1. Progression of clinical characteristics of patients with the eosinophilia-myalgia syndrome as of October 1990. Median number of days to symptom onset shown by white bars. Duration of characteristics indicated by solid bars. More than 50% of patients remained symptomatic, with myalgia, fatigue, and scleroderma-like skin changes at the durations shown (indicated by asterisks). 15 September 1991 • Annals of Internal Medicine Downloaded From: http://annals.org/ by a Penn State University Hershey User on 02/19/2016

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consisted of high initial doses (40 to 60 mg/d), gradually tapered during 4 months (range, 2 weeks to 12 months). Survival analysis comparing the two groups showed no statistically significant differences (P > 0.2) for duration of myalgia, fatigue, pulmonary symptoms, edema, rash, paresthesias, scleroderma-like skin changes, or overall illness (Figure 2). Also, patient self-reports of overall disease severity at the most severe stage of illness did not differ significantly between the two treatment groups (P > 0.2). Only one of the eight predictors shown in Table 2 suggested that the prednisone-treated group may have had more severe disease. Twenty-nine percent of patients in the steroid-treated group were hospitalized, compared with only 6% of the untreated patients (P = 0.07). Comparisons between the two groups for age; number of days ill; number of days missed from work; maximum eosinophil count; duration of L-tryptophan exposure; dose of L-tryptophan; and most severe degree of myalgia, fatigue, pulmonary symptoms, edema, and overall illness, however, showed no significant differences. Although 20 of 28 patients (71%) reported that prednisone was the "most effective treatment" overall, there was no statistically significant association between prednisone treatment and overall disease duration (Figure 2). Two of the three untreated patients have completely recovered, and the condition of the third has improved significantly. The demographic and disease characteristics of these three patients did not differ from those of other patients in the cohort. All patients with pulmonary interstitial disease and pulmonary hypertension were treated with prednisone and reported subjective improvement. One patient,

however, did not show improvement in pulmonary arterial pressures as indicated by cardiac catheterization. It is uncertain what the long-term outcome of these patients would have been had they not been treated with prednisone. Discussion The eosinophilia-myalgia syndrome is a chronic multisystem disease, the clinical features of which range from moderate myalgia and fatigue to a severely progressive, sometimes fatal, disease with polyneuropathy, scerloderma-like skin changes, neurocognitive dysfunction, and pulmonary hypertension. Clinical findings, with the exception of myalgias and arthralgias, were reported more frequently in this study than in data from the CDC (Table 1). This feature may be the result of the period during which the information was collected. The national data were derived from CDC surveillance case reports submitted early in the epidemic. Information on patients who developed symptoms after completion of the case report may have been missed. Also, these surveillance reports were not always completed by trained personnel, and, therefore, accurate patient responses may not have been obtained. In particular, the differences between true sclerodermalike skin disease and nonspecific skin changes or neuropathies and paresthesias may not have been detected. In contrast, patients from Washington state were followed for up to 12 months after the initial national surveillance data were collected. Consequently, disease characteristics of the eosinophilia-myalgia syndrome may be more closely approximated by our data than by those obtained from the CDC reports. As in other published reports (3, 4, 8, 9, 12, 15, 16),

Figure 2. Proportion of patients with continued illness stratified by treatment with oral steroids. Each step on the curves represents resolution of illness for one patient. Four of 28 patients treated and 2 of 17 patients not treated with oral steroids recovered. There was no significant difference between the two treatment groups for the overall duration of illness (P > 0.2) as of 15 October 1990. Proportions were estimated using the survival analysis method of Berkson and Gage. (EMS = the eosinophiliamyalgia syndrome.) 440

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our patients were predominantly middle-aged, non-Hispanic white women who took L-tryptophan for varying periods and in a wide range of doses. Many patients had been using L-tryptophan for an extended period but presented with clinical symptoms during the same relatively brief interval as patients who had recently begun taking L-tryptophan. This observation is consistent with data from earlier epidemiologic studies (17, 18) that suggest that a contaminant was responsible for the epidemic. A structure for such a contaminant has been proposed and identified as l,l'-ethylidenebis[tryptophan] (19). Such a contaminant could initiate an autoimmune reaction in the host either as a direct effect of the toxic compound or indirectly by formation of an abnormal L-tryptophan metabolite (20). This "contaminant hypothesis" would explain the temporal clustering of cases in this epidemic, but it does not easily explain the more rare and episodic cases that occurred before July 1989. One possibility is that the contaminant has been present in subthreshold concentrations for a long period, producing occasional pathologic findings unassociated with any identifiable cause. Another theory suggests that a possible cofactor, such as individual variations in tryptophan metabolism (6, 21), may play a role in determining which persons will become ill. We found that the long-term progression of the eosinophilia-myalgia syndrome is characterized during the first 4 to 6 months by severe illness followed by a steady decrease in severe myalgia, pulmonary complications, rash, and edema. This stage is followed by a sustained period of protracted symptom resolution characterized by persistence of less severe myalgia, fatigue, peripheral neurologic symptoms, and scleroderma-like skin changes. There are striking similarities between the eosinophilia-myalgia syndrome and the toxic-oil syndrome reported in Spain in 1981 (22, 23). Features common to both syndromes include eosinophilia, myalgia, pulmonary changes, neuropathic changes, arthritis, alopecia, rash, edema, and scleroderma-like skin changes. Persons with the toxic-oil syndrome typically presented with more severe pulmonary symptoms and evidence of pulmonary edema. The case fatality rate for both syndromes is approximately 2%. Long-term outcome studies of the toxic-oil syndrome showed resolution of myalgia, rash, edema, and pulmonary edema in less than 1 year but longer durations for neuropathies and scleroderma-like skin changes (23, 24). These similarities suggest that patients with the eosinophilia-myalgia syndrome will follow the same long-term course seen in patients with the toxic-oil syndrome and can expect steady improvement of early symptoms with possible prolongation of late sequelae, including paresthesias, myalgias, schleroderma-like skin changes, and neurocognitive dysfunction. The possibility of a similar, environmentally induced immunologic process (25) remains to be elucidated. The nature of this epidemic did not allow for randomization of treatment groups. Our analysis did not control for other medications used concurrently. Further, the dosage and tapering schedules varied widely among the patients. The two groups were similar, however, in dis-

Table 2. Comparison of Patient Groups by Steroid Treatment Variable

Patients* P Treated with Untreated Value Steroids (n = 17) (n = 28)

Age, y Hospitalized, % Work days missed, n Days ill, n Maximum eosinophil count, cells/mm* Dose of L-tryptophan used, mgld Duration of L-tryptophan use, d Duration from illness onset to L-tryptophan cessation, d

48 29 26 362

50 6 30 350

>0.2 0.07 >0.2 >0.2

5717

4260

0.11

1499

1745

0.17

434

558

>0.2

46

36

>0.2

* Values are expressed as means.

ease severity and demographic and illness characteristics. An evaluation of the benefit of prednisone in this syndrome, although complicated by possible confounding factors, may provide a better understanding of the role of steroids in the treatment of similar disorders. We found no clear-cut benefit of prednisone therapy in the reduction of long-term symptom severity or duration. Orally administered steroids may, however, relieve the most severe early manifestations of the disorder as well as those associated with periodic exacerbations. The degree of symptom severity (for example, pulmonary interstitial disease, severe myalgia) should guide indications for prednisone therapy. We cannot recommend continuous long-term steroid therapy after the most severe manifestations of the disorder have improved. Acute exacerbations, however, may benefit from short periods of steroid treatment. We continue to evaluate this cohort with serial examinations, magnetic resonance imaging scanning, and neuropsychologic assessments. This and other continued follow-up of patients with the eosinophilia-myalgia syndrome will further characterize the natural long-term progression of the disease and will define more accurately the role of prednisone therapy in the treatment of similar, environmentally induced toxic syndromes. Acknowledgments: The authors thank the patients for their cooperation and Dr. Margot Krauss, Dr. Mark Oberle, and Dr. Mart Mannik for support and technical assistance. Requests for Reprints: Randall C. Culpepper, MD, MPH, Great Lakes Naval Hospital, OHPMD Code 037, Great Lakes, IL 60088. Current Author Addresses: Dr. Culpepper: Great Lakes Naval Hospital, OHPMD Code 037, Great Lakes, IL 60088. Dr. Williams: Commander, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland 21702-5011. Dr. Mease: Minor and James Medical Clinic, 515 Minor Avenue, Seattle, WA 98104. Dr. Koepsell: School of Public Health and Community Medicine, University of Washington, SC-37, Seattle, WA 98195. Dr. Kobayashi: Washington State Department of Health, Communicable Disease Epidemiology, 1610 N . E . 150th Street, Seattle, WA 98155-7224.

References 1. Swygert LA, Maes EF, Sewell LE, Miller L, Falk H, Kilbourne EM. Eosinophilia-myalgia syndrome: results of national surveillance. JAMA. 1990;264:1698-703.

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2. Hertzman PA, Blevins WL, Mayer J, Greenfield B, Ting M, Gleich GJ. Association of the eosinophilia-myalgia syndrome with the ingestion of tryptophan. N Engl J Med. 1990;322:869-73. 3. Eosinophilia-myalgia syndrome—New Mexico. MMWR. 1989;38: 765-7. 4. Clinical spectrum of eosinophilia-myalgia syndrome—California. MMWR. 1990;39:89-91. 5. Kilbourne EM, Swygert LA, Philen RM, Sun RK, Auerbach SB, Miller L, et al. Interim guidance on the eosinophilia-myalgia syndrome. Ann Intern Med. 1990;112:85-7. 6. Silver RM, Heyes MP, Maize J C , Quearry B, Vionnet-Fuasset M, Sternberg EM. Scleroderma, fasciitis, and eosinophilia associated with the ingestion of tryptophan. N Engl J Med. 1990;322:874-81. 7. Flannery MT, Wallach PM, Espinoza LR, Dohrenwend MP, Moscinski LC. A case of the eosinophilia-myalgia syndrome associated with use of an L-tryptophan product. Ann Intern Med. 1990; 112: 300-1. 8. Kaufman LD, Gruber BL, Gregersen PK. Clinical follow-up and immunogenetic studies of 32 patients with eosinophilia-myalgia syndrome. Lancet. 1991;337:1071-4. 9. Philen RM, Eidson M, Kilbourne EM, Sewell M, Voorhees R. Eosinophilia-myalgia syndrome. A clinical case series of 21 patients. Arch Intern Med. 1991;151:533-7. 10. Clauw DJ, Nashel DJ, Umhau A, Katz P. Tryptophan-associated eosinophilic connective-tissue disease. JAMA. 1990;253:1502-6. 11. Varga J, Peltonen J, Vitto J, Jimenez S. Development of diffuse fasciitis with eosinophilia during L-tryptophan treatment: demonstration of elevated Type I collagen gene expression in affected tissues. Ann Intern Med. 1990;112:344-51. 12. Eosinophilia-myalgia syndrome and L-tryptophan-containing products—New Mexico, Minnesota, Oregon, and New York, 1989. MMWR. 1989;38:785-8. 13. Callahan LF, Brooks RH, Summey JA, Pincus T. Quantitative pain assessment for routine care of rheumatoid arthritis patients, using a pain scale based on activities of daily living and a visual analog pain scale. Arthritis Rheum. 1987;30:630-6.

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