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Myalgia and biochemical changes following intermittent suxamethonium administration. Effects of alcuronium, lignocaine, midazolam and suxamethonium pretreatments on serum myoglobin, creatinine kinase and myalgia.

One hundred gynaecological patients for laparoscopy divided into five groups were studied to determine the effects of a number of pretreatments on serum myoglobin, creatinine kinase and myalgia following intermittent suxamethonium administration. One group acted as controls, while the other groups were given intravenous pretreatments of alcuronium 2 mg, midazolam 0.15 mg/kg, lignocaine 1.5 mg/kg and suxamethonium 7 mg. Serum myoglobin was determined by radio-immunoassay. The mean increases in the control group were 167 micrograms/litre myoglobin at 20 minutes and 196 IU creatinine kinase at 24 hours; 13 out of 20 patients responded with a marked increase of serum myoglobin at 20 minutes and of creatinine kinase at 24 hours. Only alcuronium pretreatment prevented myoglobin increase at 20 minutes, abolished creatinine kinase increase at 24 hours and reduced 24-hour myalgia. The other pretreatments slightly reduced myoglobin increase at 20 minutes and 24-hour creatinine kinase but did not reduce myalgia. Only one patient in the whole study had markedly elevated serum myoglobin at 24 hours. We conclude that only non-depolarising relaxant pretreatment is effective in the reduction of some of the adverse effects of suxamethonium administration.

Adult

Eosinophilia-myalgia syndrome. A clinical case series of 21 patients. New Mexico Eosinophilia-Myalgia Syndrome Study Group.

We reviewed 21 cases of eosinophilia-myalgia syndrome to describe the range of clinical findings in these patients. Most patients were women (20 [95%]) and middle-aged (mean, 46 years) and had taken the food supplement L-tryptophan (95%). All cases involved eosinophilia (eosinophil count, greater than or equal to 2.0 x 10(9)/L) and incapacitating myalgias. Fourteen (88%) of the 16 patients tested had mild liver function abnormalities. Aldolase levels were abnormal in all patients tested. Muscle biopsies were done in five patients; four showed eosinophilic perimyositis, and one had interstitial inflammation. No physical finding was pathognomonic or universal, but muscle tenderness, tachycardia, and rash were the most common signs found during physical examinations. Seven patients were treated with prednisone, and six showed improvement in muscle pain and a decrease in eosinophilia. The cause of this disorder is still unknown.

Biopsy

Eosinophilia-myalgia syndrome in L-tryptophan-exposed patients.

OBJECTIVES: To study the incidence of eosinophilia-myalgia syndrome, the risk factors associated with the syndrome, and the clinical spectrum of illness associated with L-tryptophan use in an exposed population. DESIGN: Retrospective cohort and nested case-control studies of risk factors for eosinophilia-myalgia syndrome using inpatient and outpatient chart reviews, telephone interviews, and in-person patient interviews. Descriptive study of clinical course of L-tryptophan users. SETTING: Office practice of one psychiatrist based in a small city (population 43,467) in South Carolina. PATIENTS: Eligible subjects were all patients from the practice who used L-tryptophan during the 1989 study interval. Of these, 418 (87%) were interviewed. MAIN OUTCOME MEASURES: Clinical spectrum of illness associated with L-tryptophan use, including definite and possible cases of eosinophilia-myalgia syndrome. RESULTS: Among the 418 interviewed L-tryptophan users, we identified 47 definite cases (11%) and 68 possible cases (16%) of eosinophilia-myalgia syndrome, most of which involved patients who were using one retail brand of L-tryptophan (brand A). Among the 157 brand A users, we identified 45 definite cases (29%) and 36 possible cases (23%) of eosinophilia-myalgia syndrome, and the risk for the syndrome increased as the brand A dose increased. Fifty percent (19 of 38) of those using more than 4000 mg/day developed definite eosinophilia-myalgia syndrome, and 84% (32 of 38) developed either definite or possible eosinophilia-myalgia syndrome. On multivariate analysis, risk for definite eosinophilia-myalgia syndrome was associated with brand A dose and age of the patient; however, gender, race, and use of other medications were not associated with the syndrome. CONCLUSIONS: These results suggest that many people exposed to the agent causing eosinophilia-myalgia syndrome may develop illness, and dose of presumably contaminated L-tryptophan is the single most important predictor of eosinophilia-myalgia syndrome. The broad range of signs and symptoms reported by patients using L-tryptophan illustrates that a strict case definition may identify only about half of those affected.

Adult

Eosinophilic fasciitis is clinically distinguishable from the eosinophilia-myalgia syndrome and is not associated with L-tryptophan use.

Induration of the skin develops in a majority of patients with the eosinophilia-myalgia syndrome associated with L-tryptophan, and bears striking clinical and histopathological resemblance to eosinophilic fasciitis (EF). These similarities have led to the suggestion that eosinophilia-myalgia syndrome and EF are the same disease. To study the relationship of eosinophilia-myalgia syndrome and EF, we ascertained the prevalence of L-tryptophan use in a cohort of patients with EF, and compared their clinical and laboratory findings to those of patients with eosinophilia-myalgia syndrome associated cutaneous involvement. None of 11 patients who were diagnosed as having EF between 1970 and 1989 used L-tryptophan containing preparations prior to the onset of their illness. Marked clinical and laboratory test differences were observed between patients with EF and eosinophilia-myalgia syndrome. Patients with eosinophilia-myalgia syndrome had a more acute onset, more severe symptoms, higher frequency of rash and of pulmonary, cardiac, gastrointestinal, neurologic, myopathic and thyroid involvement compared to patients with EF. Corticosteroid therapy resulted in improvement of cutaneous involvement in 88% of patients with EF but it was only partially successful in patients with eosinophilia-myalgia syndrome. Hospitalization and fatalities occurred only among patients with eosinophilia-myalgia syndrome. These observations demonstrate that eosinophilia-myalgia syndrome is a more severe disease with multisystemic involvement that can be clinically distinguished from EF. In contrast to eosinophilia-myalgia syndrome, EF is not associated with L-tryptophan ingestion.

Adrenal Cortex Hormones

The cause and pathogenesis of the eosinophilia-myalgia syndrome.

OBJECTIVE: To review recent advances in the understanding of the cause and pathogenesis of the eosinophilia-myalgia syndrome associated with ingestion of L-tryptophan. DATA SOURCES: Studies published from 1989 to 1991 were identified using a MEDLINE literature search. Additional references were selected from the bibliographies of identified articles. DATA SYNTHESIS: The eosinophilia-myalgia syndrome was epidemiologically associated with ingestion of L-tryptophan-containing preparations. Analysis of case-associated lots of L-tryptophan has revealed several chemical impurities. One of these, labeled "peak E," is an unusual dimeric form of L-tryptophan (1,1'-ethylidenebis[tryptophan]), and its presence is associated with the eosinophilia-myalgia syndrome (P = 0.022). Evidence of abnormal metabolism of tryptophan has been found in some patients with the syndrome. Eosinophil activation and the release of major basic protein and other eosinophil-derived toxic proteins into the extracellular space is a striking feature in the eosinophilia-myalgia syndrome and implicates eosinophils or their products in the pathogenesis. Mononuclear cell activation and infiltration of various affected tissues as well as fibrosis of the integument and of the connective tissue components of blood vessels, nerves, and muscles are additional frequent findings. CONCLUSIONS: Current evidence suggests that the epidemic of the eosinophilia-myalgia syndrome was caused by contaminated L-tryptophan preparations originating from a single manufacturer. Peak E or other, as yet unidentified, contaminants may trigger activation of eosinophils and inflammatory cells and increase biosynthesis of connective tissue components, resulting in the clinical and pathologic manifestations of the eosinophilia-myalgia syndrome. Further studies of the interaction of eosinophils, inflammatory cells, and fibroblasts may increase the understanding of the pathogenesis of the eosinophilia-myalgia syndrome. The insights gained from the epidemic may be applicable to more common idiopathic diseases associated with eosinophilia and fibrosis.

Drug Contamination

Effects of precurarisation on suxamethonium-induced postoperative myalgia during the first trimester of pregnancy.

Two hundred and fifty women undergoing termination of pregnancy during the first trimester under general anaesthesia were studied to determine the effects of precurarisation on suxamethonium-induced postoperative myalgia and on the need for postoperative analgesics after suxamethonium. Either alcuronium (0.03 mg/kg), atracurium (0.04 mg/kg), tubocurarine (0.05 mg/kg), vecuronium (0.01 mg/kg) or saline was administered in a double-blind manner 4 min before giving suxamethonium. An additional 50 patients were studied who received isoflurane rather than precurarisation and suxamethonium. Every pretreatment prevented fasciculations better than did saline (P less than 0.001). In the saline group, 92% of patients had fasciculations and in the other groups this ranged from 8 to 32%, respectively. On the first postoperative day, 76% of the patients in the saline group had myalgia while myalgia was manifested in 28, 54 and 34% of patients given alcuronium, tubocurarine or vecuronium, respectively (P less than 0.05). Atracurium failed in this effect with 62% having myalgia. In the isoflurane group, none of the patients complained of myalgia on the first postoperative morning. The need for analgesics was less (P less than 0.005) in the isoflurane group (8%) and in the pretreatment groups (18-27%) than in the saline group (42%). It is concluded that precurarisation with tubocurarine, vecuronium or, most effectively, with alcuronium but not with atracurium decreases suxamethonium-induced postoperative myalgia and seems to be necessary also during the first trimester of pregnancy.

Abortion, Induced

Tubular aggregates: their association with myalgia.

Three thousand consecutive muscle biopsies were reviewed for the presence of tubular aggregates and their association with clinical symptomatology. Tubular aggregates were detected in 19 patients (0.6%). Twelve of these nineteen patients had severe myalgia, and the most abundant tubular aggregates were found in biopsies of patients with myalgia. Seven patients had only myalgia as their clinical symptomatology with normal physical examination. An additional five patients with tubular aggregates and myalgia had concomitant amyotrophic lateral sclerosis (2) or neuropathy (3). The high incidence of myalgia associated with tubular aggregates in our patients and the fact that tubular aggregates originate from sarcoplasmic reticulum suggest a role played by this structure in the pathogenesis of myalgia.

Amyotrophic Lateral Sclerosis

Eosinophilia-myalgia syndrome. Natural history in a population-based cohort.

BACKGROUND: To determine the natural history of eosinophilia-myalgia syndrome, we followed up all patients with eosinophilia-myalgia syndrome reported to the Oregon Health Division, Portland, during the recent epidemic caused by contaminated tryptophan. METHODS: Patients were interviewed by telephone from 1 to 5 months after illness onset and again at least 12 months after onset. Symptoms (type, onset, and duration), overall disability, treatment, and tryptophan lot and dose were assessed for each patient. RESULTS: Information was obtained for 55 (96%) of 57 case-patients: 53 patients completed interviews and two patients had died. For the 53 patients who were interviewed, symptoms with onset more commonly during the first 3 months of illness included severe myalgias, fatigue, generalized weakness, edema, and rash. Symptoms with later onset included paresthesias, muscle cramps, extremity weakness, and alopecia. At 12 months, 41 patients (77%) continued to report fatigue, 36 (68%) weakness, and 34 (64%) myalgias; 26 patients (49%) had difficulty climbing stairs, 23 (43%) had difficulty getting up from a chair, and 15 (28%) had difficulty holding a cup. Higher doses of tryptophan were correlated with more severe disability, both initially (rs = .33) and at follow-up (rs = .42). Although most patients reported improvement in symptoms at 12 months, only 14 (26%) patients reported that they were able to perform all normal daily activities. CONCLUSIONS: Most patients with eosinophilia-myalgia syndrome in this population-based cohort are still symptomatic 1 year after onset, primarily with the complaints reported early in the illness. The association between degree of disability and daily tryptophan dose suggests that ingestion of varying amounts of contaminant may be responsible, in part, for the severity of symptoms experienced by individual patients.

Activities of Daily Living

Phenytoin reduces suxamethonium-induced myalgia.

A prospective, randomised trial was undertaken in 60 healthy adults to determine the efficacy of intravenously administered phenytoin in doses of 5 mg.kg-1 for the prevention of suxamethonium-induced fasciculations, a rise in serum K+ and myalgia. This was compared with tubocurarine pretreatment and no pretreatment (control group). Phenytoin pretreatment significantly reduced myalgia from 45% (nine patients) in the control group to 10% (two patients) (p less than 0.05). It also decreased the duration and mean intensity of fasciculations. Incidentally, phenytoin was also found to decrease significantly mean serum Na+ levels (p less than 0.001) both at 5 and 20 min after administration. Tubocurarine pretreatment (3 mg) resulted in a significant decrease in fasciculations, but myalgia, which occurred in five patients, remained the same. No significant correlation was found between muscle fasciculations, postoperative myalgia and K+ changes, but patients with myalgia had a significant decrease in mean serum Na+ levels at 5 and 20 min after suxamethonium (p less than 0.01).

Adult

Natural history of the eosinophilia-myalgia syndrome.

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 non-Hispanic 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.

Adolescent

[Use of atracurium for the prevention of fasciculations and succinylcholine myalgia in athletes undergoing orthopedic surgery].

The Authors report their clinical experience about the use of atracurium besylate in preventing succinylcholine-induced fasciculations and postoperative myalgias in fifty athletes (ASA class 1), submitted to arthroscopic meniscectomy. The patients were pretreated with atracurium 5 mg i.v. or saline solution in a double-blind fashion. After 2.5 minutes, succinylcholine 1.3 mg/kg was administered, and fasciculations were recorded on a scale ranging from 0 to 3. Twenty-four hours after surgery all subjects were questioned about myalgias occurrence, scored by a 0-3 scale. Fasciculations occurred in all patients who received saline and in 44% of those treated with atracurium. Myalgias on the postoperative day were observed in 80% of patients treated with saline solution, but only in 36% of patients who received atracurium. The difference between atracurium and saline solution was statistically significant (p less than 0.001) either for fasciculations or myalgias incidence. These findings show that atracurium 5 mg i.v. is effective in preventing succinylcholine-induced fasciculations and postoperative myalgias, and suggest atracurium as the drug of choice for this purpose, particularly in muscular subjects.

Adolescent

Central nervous system involvement in the eosinophilia-myalgia syndrome.

A patient with eosinophilia-myalgia syndrome developed progressive central nervosa system involvement that did not improve despite discontinuation of L-tryptophan therapy. Neurologic impairment was manifested initially by spastic monoparesis, which was improved by treatment with methyl-prednisolone and hydroxyurea. Recurrence of weakness was accompanied by gait ataxia, dysphagia, and complaints of a gradual decline in memory and concentration. Neuropsychological testing identified a broad pattern of cognitive deficits suggestive of a subcortical dementia, and magnetic resonance imaging demonstrated multiple high-signal lesions in the white matter. Cognitive deficits appear to be underrecognized in patients with the eosinophilia-myalgia syndrome. The response of our patient's initial symptoms to corticosteroid therapy suggests a possible role for autoimmune mechanisms in the pathogenesis of central nervous system involvement in the eosinophilia-myalgia syndrome. Neuropsychological evaluation should be performed in patients with cognitive complaints to delineate the full spectrum of central nervous system impairment associated with the eosinophilia-myalgia syndrome.

Central Nervous System Diseases

Simultaneous development of two cases of eosinophilia-myalgia syndrome with the same lot of L-tryptophan in Japan.

A newly recognized and well-described connective tissue disease, eosinophilia-myalgia syndrome, is thought to relate to L-tryptophan ingestion. The suspect L-tryptophan made in Japan has been distributed in Japan and in the United States. Different from many case reports of eosinophilia-myalgia syndrome in the United States, it has not been reported in Japan. We describe the first case reports of two Japanese patients. Eosinophilia-myalgia syndrome developed in these patients simultaneously, during L-tryptophan treatment by the same physician using the same lot of prescribed L-tryptophan. Furthermore, both patients had the following HLA types: HLA-Aw33(w19), -B44(12), and -DR6. These findings implicate the existence of another factor in the development of eosinophilia-myalgia syndrome in addition to the suspect L-tryptophan.

Aged

A histopathologic comparison of Shulman's syndrome (diffuse fasciitis with eosinophilia) and the fasciitis associated with the eosinophilia-myalgia syndrome.

A comparison of the histopathologic features of Shulman's syndrome (diffuse fasciitis with eosinophilia) and the fasciitis associated with the eosinophilia-myalgia syndrome is presented. The study population consisted of eight biopsy specimens of seven patients with Shulman's syndrome and 11 specimens from 10 patients with eosinophilia-myalgia syndrome. Both groups exhibited inflammatory changes in the subcutaneous fat, septa, and fascia; cutaneous changes were more prominent in cases of eosinophilia-myalgia syndrome. Eosinophils and plasma cells were not consistently present in either condition; mast cells and factor XIIIa-positive cells were consistently present in the inflammatory infiltrates. Although there was overlap in the histopathologic findings, Shulman's syndrome tends to involve the subcutis alone and the eosinophilia-myalgia syndrome tends to be a pancutaneous-subcutaneous process.

Eosinophilia

Eosinophilia-myalgia syndrome: the Cleveland Clinic experience.

Eosinophilia-myalgia syndrome is a recently described clinical syndrome caused by a suspected contaminant of L-tryptophan, an essential amino acid that was manufactured and sold as a nutritional supplement. This study reports the clinical and pathological findings of 22 cases of eosinophilia-myalgia syndrome evaluated at the Cleveland Clinic and includes data for up to 1 year of follow-up (for the epidemic cases). Nineteen of the 22 cases were evaluated and followed prospectively in the time period from November 1989 to November 1990. Two of the 22 represented nonepidemic forms of the syndrome which occurred prior to the 1989 epidemic. During a review of all cases of biopsy-proven diffuse fasciitis with eosinophilia at the Cleveland Clinic since 1978, one of the 22 was retrospectively identified as having an epidemic form of the syndrome, with onset in July 1989. In this study, adverse prognosticating factors in eosinophilia-myalgia syndrome included nerve and muscle involvement, fasciitis, and weight loss. Eosinophilia-myalgia syndrome is striking in its severity and diversity, and its features are similar to those of two other unusual illnesses--toxic oil syndrome and diffuse fasciitis with eosinophilia. With the recent purification of the suspected contaminant, it is hoped that further clues to the etiology of this syndrome and similar syndromes will be uncovered.

Adult

An investigation of the cause of the eosinophilia-myalgia syndrome associated with tryptophan use.

BACKGROUND: The eosinophilia-myalgia syndrome is a newly recognized illness that has been associated with the consumption of tryptophan products. It is not known whether the cause is related to the tryptophan itself or to chemical constituents introduced by the manufacturing process. METHODS: To describe the epidemiology of the eosinophilia-myalgia syndrome further and elucidate a possible association with the manufacturing process, we conducted surveillance for the syndrome in Minnesota, a community survey of tryptophan use in Minneapolis-St. Paul, and a case-control study to assess potential risk factors, including the use of tryptophan from different manufacturers. We performed high-performance liquid chromatography on tryptophan samples to identify other chemical constituents. RESULTS: The prevalence of tryptophan use increased from 1980 to 1989 and was highest among women. Among the subjects for whom the source of the tryptophan was known, 29 of 30 case patients (97 percent) and 21 of 35 controls (60 percent) had consumed tryptophan manufactured by a single company (odds ratio, 19.3; 95 percent confidence interval, 2.5 to 844.9; P less than 0.001). This company used a fermentation process involving Bacillus amyloliquefaciens to manufacture tryptophan. Analysis of the manufacturing conditions according to the retail lot demonstrated an association between lots used by case patients and the use of reduced quantities of powdered carbon in a purification step (odds ratio, 9.0; 95 percent confidence interval, 1.1 to 84.6; P = 0.014), as well as the use of a new strain of B. amyloliquefaciens (Strain V) (odds ratio, 6.0; 95 percent confidence interval, 0.8 to 51.8; P = 0.04). There was a significant correlation (r = 0.78, P less than 0.001) between the reduced amount of powdered carbon used during manufacturing and the use of the new bacterial strain. High-performance liquid chromatography of this company's tryptophan demonstrated one absorbance peak (peak E) that was present in 9 of the 12 retail lots (75 percent) used by patients and 3 of 11 lots (27 percent) used by controls (odds ratio, 8.0; 95 percent confidence interval, 0.9 to 76.6; P = 0.022). CONCLUSIONS: The outbreak of the eosinophilia-myalgia syndrome in 1989 resulted from the ingestion of a chemical constituent that was associated with specific tryptophan-manufacturing conditions at one company. The chemical constituent represented by peak E may contribute to the pathogenesis of the eosinophilia-myalgia syndrome, or it may be a surrogate for another chemical that induces the syndrome.

Adolescent

Differential effects of neuromuscular blocking agents on suxamethonium-induced fasciculations and myalgia.

The effect of pretreatment with suxamethonium, gallamine or pancuronium on suxamethonium-induced fasciculations and myalgia was studied in a controlled, randomized and double-blind clinical trial. Both fasciculations and myalgia were assessed on a four-point rating scale. There was no significant correlation between fasciculations and postoperative muscle pain at 24, 48 or 72 h, and pretreatment with suxamethonium had no significant effect on fasciculations or myalgia. Gallamine had a more marked effect on fasciculations than pancuronium, and the decrease in the fasciculation score was statistically significant. In contrast, pancuronium had a greater effect on myalgia, and decreased postoperative muscle pain significantly at 24 and 48 h. These differences may reflect the differential activity of gallamine and pancuronium at the neuromuscular junction. Pretreatment had little or no effect on plasma potassium concentrations.

Adolescent

Attenuation of suxamethonium myalgias. Effect of midazolam and vecuronium.

We studied the incidence of fasciculations and postoperative myalgias in 100 female outpatients who had laparoscopy under thiopentone, N2O, isoflurane anaesthesia. Four groups of 20 patients each were pretreated with saline (group 1), tubocurarine 0.05 mg/kg (group 2), vecuronium 0.006 mg/kg (group 3), or midazolam 0.025 mg/kg (group 4), followed by suxamethonium 1.5 mg/kg. Group 5 received only vecuronium 0.1 mg/kg as relaxant (no suxamethonium). Fasciculations were graded, and postoperative myalgias rated on the first and third postoperative days. In groups 1-5 the incidence of fasciculations was 95, 15, 25, 95 and 0%; the incidence of myalgias on the first day after operation was 70, 45, 65, 75 and 60%, and on the third day after operation 20, 5, 20, 20, and 5%, respectively. We conclude that pretreatment with vecuronium, but not midazolam, decreases the incidence of fasciculations after suxamethonium (p less than 0.05) and that in this patient population, postoperative myalgias appear to be unrelated to the use of suxamethonium.

Adult