Eosinophilia-Myalgia Syndrome- Long Term Complications
by Luis R. Espinoza M.D.
The existence of the eosinophilia-myalgia syndrome (EMS) was clearly established in 1989 after a cluster of cases with symptoms of incapacitating myalgias and eosinophilia were reported. It was realized shortly after that EMS was a systemic disorder which may affect multiple organ systems leading to severe disability and mortality. Although sporadic cases of EMS were recognized prior to the outbreak of 1989, well-conducted epidemiological studies conclusively demonstrated that the epidemic outbreak of EMS could be traced back to the intake of L-tryptophan of certain lots from a single manufacturer. More importantly, the incidence of EMS in the United States diminished abruptly following the withdrawal of L-tryptophan containing products.
Although this review will deal with the long-term complications associated with EMS, a brief overview of the characteristics of patients who died shortly after the epidemic outbreak will be described next. As of August 10, 1991, 36 deaths related to EMS had been reported to the Centers for Disease Control, Atlanta, Georgia. Among all patients fulfilling the surveillance case definition for EMS, it was found that EMS patients who died were older, had higher absolute leukocyte and eosinophil counts, and reported a greater frequency of cough or dyspnea, neuropathy, hepatomegaly, leukocytosis, and elevated erythrocyte sedimentation rate (a marker of ongoing inflammation).
Of the 36 patients who died, 33 (92%) had neuromuscular sequelae, 29 (81%) had pulmonary complications, and 23 (64%) had cardiac manifestations. The most commonly observed disease process leading to death was progressive polyneuropathy and myopathy (24 of the 36 reported deaths) which produced complications of pneumonia and sepsis or respiratory failure due to weakness; cardiomyopathy was the underlying cause of death for 4 patients, primary pulmonary disease for 3, sudden death attributed to arrhythmia for 2, stroke for 2, and septic complications of therapy for one. It is clear from this data that EMS is a multisystemic disease, and risk factors of poor prognosis include older age and involvement of more than one organ system.
The question that remains unanswered is whether or not the clinical manifestations associated with EMS completely disappeared or ameliorated once L-tryptophan containing products were removed from the market. Our personal experience with over 20 patients diagnosed at the peak of the epidemic in 1989 suggests that most patients remained symptomatic although many have a very good outcome. To this regard I would like to summarize some of the literature on this subject published in the past 2-4 years.
Hertzman et al (Ann Int Med 1995: 851-855) attempted to describe the course of the EMS during a 2 year period. Fifteen physicians completed a structured review form to describe symptoms, physical findings, laboratory data, and responses to treatments in 205 patients with the EMS at the onset of illness and after 18 to 24 months of follow-up. This study was performed in 15 university and private clinical practice settings. A total of 205 patients entered the study. All of them had follow-up data available and met four criteria at diagnosis: eosinophil count of 1000 cells/mm3 or greater, presence of fasciitis, peripheral neuropathy, polyradiculopathy, interstitial pulmonary disease, pulmonary hypertension, or myocardial involvement; history of L-tryptophan consumption; and absence of other conditions that could account for these findings. Results showed that after 18 to 24 months, all symptoms except cognitive changes were reported to have improved in most patients. Nearly all physical findings were also reported to have improved or resolved in most patients; only peripheral neuropathy was unchanged. No evidence of ongoing inflammatory disease was reported. Prednisone was reported to be helpful in 79% of patients who received it during the acute phase of the syndrome. No other treatment was reported to be consistently beneficial. Authors conclude that 18-24 months after the onset of illness, most symptoms and physical findings in most patients with the EMS resolved or improved. Cognitive changes were reported to be worse in 32% of patients.
The outcome noted in the above discussed study would appear to suggest that EMS is a benign disease without significant morbidity, and perhaps mortality. The good outcome found may be explained on the basis of patient selection, patient referral, large number of patients studied, and other unexplained reasons.
Outcome seen in this study also contrasts with that of others. Campbell et al (Southern Med J 1995; 88: 953-958). In this case-series analysis, of 34 patients originally identified with EMS, 31 survivors were followed-up by yearly telephone interviews. A number of variables were ascertained including type, duration, and severity of symptoms and whether certain patient characteristics were associated with illness improvement. At a median of 3.6 years after onset, 3 patients (8.8%) had died. Two (5.9%) were well, 7 (20.6%) were improved, and 22 (64.7%) reported either no change or worsening overall condition compared to 1 year prior.
Musculoskeletal and neurologic symptoms predominated. The prevalence of several symptoms, including muscle cramps, joint pain, and cognitive dysfunction, increased over the course of study. Age, sex, peak eosinophil count, early prednisone use, and usual dose or duration of L-Tryptophan use were not associated with significant improvement. Authors concluded that for the majority of patients, EMS is a chronic illness having a major impact on life-style 3.6 years after onset.
Kaufman L.D. (Arthritis & Rheumatism 1994; 37:84-87) reported similar data with 57 patients with well-characterized EMS evaluated prospectively at a university hospital for 21-64 months (mean 36 months). Data revealed that 88% of the patients continue to have symptomatic disease with more than 3 clinical manifestations. Fatigue (91%), muscle cramping (75%), myalgia (70%), paresthesias with objectively demonstrated hypesthesias (62%), articular symptoms (54%), scleroderma-like skin changes (44%), and proximal muscle weakness (40%), were the more common features of chronic EMS. Cognitive symptoms were seen in 86% of patients, and tremor and myoclonus were also seen.
It is obvious that results from this study are in contrast with the previously discussed one. It is my belief that both studies are probably correct and outcome most likely reflect the clinical spectrum associated with EMS - at one end patients with milder disease (musculoskeletal involvement) and at the other end of the spectrum patients with more severe disease (multiorgan system involvement - cardiopulmonary, neurologic).
A variety of long-term complications have been described in patients with EMS (Table 1).
Of interest are the inflammatory lesions demonstrated in coronary arteries and cardiac neural structures at post-mortem studies in EMS. The inflammation is primarily lymphocytic - predominantly CD45RO+ T cells, and CD20+ B cells. These cells were prominently observed in neurovascular lesions, notably in the conduction system and the coronary chemoreceptor. These findings may explain the fatal cardiac arrhythmia seen in some patients, and not too dissimilar to those changes seen in patients with the toxic oil syndrome (adulterated oil).
It is also important to mention that a consistent finding reported over and over is the presence of neuropsychological, emotional, and neurocognitive dysfunction in a significant majority of patients with chronic EMS. Feelings of depression, tension, nervousness, fatigue, helplessness, memory loss, are present in over half of patients with EMS. Furthermore, 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 disorders, including major depression.
In conclusion, EMS is a chronic multiorgan system disorder associated with significant morbidity, and disability - both physically and emotionally.
TABLE 1. LONG-TERM CLINICAL COMPLICATIONS REPORTED IN
ASSOCIATION WITH EOSINOPHILIA-MYALGIA SYNDROME