Ergoloid Mesylates

Pergolide is an ergot-derived dopamine agonist used in Parkinson's disease and, increasingly, in restless legs syndrome. We report a patient with a 2.5-year history of weight loss, pleuropulmonary fibrosis, and exudative pleural effusion that developed insidiously while taking this medication. The extensive and invasive workup that preceded the diagnosis highlights the difficulty in attributing such a process to a drug reaction. This is the second report of such a reaction to pergolide, which is one of the increasing number of ergot-derived compounds in common clinical use. (CHEST 2001; 120:313-316)

Key words: Parkinson's disease; pergolide; pleuropulmonary fibrosis; restless legs syndrome

Abbreviations: PD = Parkinson's disease; RLS = restless legs syndrome

The ergot-derived alkaloids comprise a large number of compounds sharing a common ring structure and include several medications frequently used for Parkinson's disease (PD) and migraine headaches, among others (Table 1). A number of these compounds have been described to produce a pleuropulmonary fibrosis syndrome,[1] in addition to retroperitoneal fibrosis.[2] The diagnosis of this drug-associated pleuropulmonary fibrosis syndrome is largely one of exclusion and is often made with some difficulty given the presence of coexisting medical problems. It is confirmed by response to withdrawal of the offending agent. Pergolide, an ergot-derived alkaloid, was introduced as an adjunct therapy for PD[3] and has subsequently been used with some success for restless legs syndrome (RLS).[4] We wish to report a case of pergolide-induced pleuropulmonary fibrosis.

CASE REPORT

A 65-year-old white man was transferred to our institution for evaluation of progressive weight loss (50 lb total), increasing dyspnea, and fatigue noted, retrospectively, to have begun [is greater than] 2 years earlier. Workup that included chest and abdominal CT, barium enema, and sigmoidoscopy had been unrevealing. Six months prior to transfer, the patient was incidentally noted to have a small right pleural effusion. The patient had worsening dyspnea, and serial chest radiographs showed an increasing right pleural effusion. One month prior to transfer, thoracentesis documented an exudative effusion, but neither pleural fluid nor pleural biopsy specimens revealed an etiology. The patient underwent a right thoracoscopy that demonstrated "multiple plaque-like lesions on the chest wall suggestive of a mesothelioma." Biopsy specimens revealed only fibrous tissue with chronic inflammation, and culture findings were negative. The patient developed fever, worsening dyspnea, and evidence on chest radiograph of a large right hydropneumothorax. Serologic workup prior to transfer included negative results on antinuclear antibodies, antinuclear cytoplasmic antibodies, antiglomerular basement membrane antibodies, cryoglobulins, rapid plasma reagin, and rheumatoid factor studies, as well as normal complement levels (C3 and C4), serum, and urine protein electrophoresis.

The patient's medical history was notable for RLS for nearly 30 years, as well as noninsulin-dependent diabetes mellitus, hypertension, and arteriosclerotic cerebral vascular disease. His medications included pergolide, 3.5 mg/d; glipizide, 20 mg/d; losartin, 25 mg once daily; and warfarin, 5 mg once daily. The pergolide was begun 3 years earlier for treatment of RLS at the recommended starting dose of 0.05 mg qd and gradually titrated upward. Social history was notable for an 8 pack-year history of tobacco use in the 1950s and for 3 months of possible asbestos exposure in 1948 while working in a warehouse unloading asbestos pipe sleeves.

On transfer to our institution, the physical examination was remarkable for a respiratory rate of 28 breaths/min on 3 L of oxygen via nasal cannula. The patient was cachectic. Lung examination revealed dullness to percussion in the lower half of the right lung field, with decreased breath sounds in the lower half of the right lung and at the left base. Laboratory data showed a WBC count of 19.6 X [10.sup.9]/L (90% segmented neutrophils, 2% lymphocytes, 5% monocytes, and 1% eosinophils); chemistry panel showed an albumin of 2.6 g/dL (reference, 3.5 to 5.3 g/dL). Urinalysis revealed no proteinuria. Chest radiograph (Fig 1, top) showed a loculated right hydropneumothorax. Thoracentesis revealed bloody fluid with pH of 7.45, lactate dehydrogenase of 590 mg/dL, and protein of 5.1 g/dL. Cytology showed no evidence of malignancy. Purified protein derivative findings were negative.

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The patient underwent bronchoscopy with transbronchial lung biopsy that showed focal intra-alveolar fibrin and no evidence of fungal forms or malignancy. BAL showed mild inflammation with reactive epithelial cells. The patient then underwent right open lung and pleural biopsy that revealed a peel surrounding the lung, and multiple white thickened plaques on the diaphragm and the mediastinal surface. Final pathology findings revealed chronic inflammation with no evidence of malignancy or asbestos-related changes.

In light of multiple studies with negative findings for malignancy and infection, alternative causes of fibrosis, pleural thickening, and exudative effusions were sought. Pergolide was considered as a causative agent and treatment was discontinued. The patient was treated with a 2-week course of corticosteroids given the inflammation present on biopsy specimens. Within several weeks, the patient had significant subjective and objective improvement in his dyspnea and exertional capacity (Table 2). The patient is now 3 years from the discontinuation of this medication with no recurrence of symptoms, with full functional recovery, and with dramatic improvements in chest radiography (Fig 1, bottom) and pulmonary function testing (Table 2).

DISCUSSION

The differential diagnosis of an exudative effusion in a patient with this history includes occult malignancy, infection (eg, tuberculosis), benign asbestos pleural effusion, and drug reaction. The patient underwent an extensive evaluation including a pleural biopsy, bronchoscopy with transbronchial biopsy, thoracoscopic and open lung biopsies, as well as multiple thoracenteses. None of these studies documented malignancy or infection. Tuberculosis seemed unlikely given the negative findings on purified protein derivative and multiple cultures. The patient had a history of a short exposure to asbestos, but had no pleural plaques and no asbestos bodies on biopsy. While this does not exclude benign asbestos pleural disease, his systemic symptoms of weight loss and malaise as well as the absence of chest wall pain in his presentation contrast with the typical presentation.[5] In addition, benign asbestos pleural effusions usually occur within 10 to 15 years of asbestos exposure. Ultimately, the diagnosis of pergolide-associated pleuropulmonary fibrosis is based on the response to the removal of the offending agent. In this patient, only pergolide treatment was discontinued and all other long-term medications were maintained.

When this patient was evaluated, there were no reports of such reactions to pergolide; however, there were reports of pleuropulmonary disease associated with other ergot derivatives.[1] Subsequently a single case report of pergolide-associated pleuropulmonary disease has been reported,a Pergolide has been described to cause retroperitoneal fibrosis,[7] which is also associated with ergot derivatives.

The first report of pleuropulmonary disease attributed to ergot derivatives was a case series in 1966 that described 27 patients receiving methysergide who developed retroperitoneal fibrosis.[8] Two of the patients developed pleural and pulmonary inflammation and fibrosis. An additional reported patient underwent a lung biopsy revealing "fibrosis around vessels and terminal bronchioles." Clinically, all three patients had episodes of pleural inflammation with friction rubs, fever, and pleural effusions. In each case, symptoms resolved with discontinuation of methysergide treatment. A similar syndrome has been reported with bromocriptine, other dopamine agonists, and ergotamines.[1] Pleuropulmonary involvement in eight patients receiving ergot derivatives other than bromocriptine was also reviewed.[1] The patterns of involvement in this series included a spectrum from interstitial pneumonitis to pleuropulmonary fibrosis with associated exudative effusions. The mean age of the patients was 70 years, with a treatment duration of 8 months to 15 years. Clinical and radiographic changes were very similar to those noted in this case. Similarly, patients in all reported series underwent extensive evaluations for malignancy and infection before suspicion was directed toward medications.

The mechanism by which the ergot derivatives produce fibrosis, either pleuropulmonary or retroperitoneal, remains obscure. There is no evidence that it is dependent on dosage or duration of use of the medication. Some questions have been raised as to whether this represents a serotonergic effect of these medications, as serotonin has been shown to be profibrotic. It is this serotonergic effect that was implicated in the valvular abnormalities associated with the use of phenteramine-fenfluramine and in the carcinoid syndrome. The relevance of this mechanism to pleuropulmonary fibrosis has yet to be proved. The causal relation between the ergots and this syndrome seems quite well established, however, with multiple cases showing regression of symptoms with withdrawal of the offending agent and, in a few instances, recurrence of symptoms when the patient was rechallenged.[1]

We report this case to draw attention to a large class of compounds, the ergot-derived alkaloids (Table 1), which are used in treatment of a growing number of diseases. The pleuropulmonary syndrome associated with their use appears to be induced by many of these compounds. The pulmonary symptoms develop insidiously, making the association with onset of use of this medication difficult. The constitutional nature of the syndrome leads to its confusion with malignancy (particularly mesothelioma) and infection. The rapid clinical improvement that results from discontinuation of the medication confirms the diagnosis.

REFERENCES

[1] Pfitzenmeyer P, Foucher P, Dennewald G, et al. Pleuropulmonary changes induced by ergoline drugs. Eur Respir J 1996; 9:1013-1019

[2] Robert M, Derbaudrenghien JP, Blampain JP, et al. Fibrotic processes associated with long-term ergotamine therapy [letter]. N Engl J Med 1984; 311:601-602

[3] Mizuno Y, Kondo J, Narabayashi H. Pergolide in the treatment of Parkinson's disease. Neurology 1995; 45:S13-S21

[4] Wetter TC, Stiasny K, Winkelmann J, et al. A randomized controlled study of pergolide in patients with restless legs syndrome. Neurology 1999; 52:944-950

[5] Robinson BWS, Musk AW. Benign asbestos pleural effusion: diagnosis and course. Thorax 1981; 36:896-900

[6] Shaunak S, Wilkins A, Pilling JB, et al. Pericardial, retroperitoneal, and pleural fibrosis induced by pergolide. J Neurol Neurosurg Psychiatry 1999; 66:79-81

[7] Jimenez-Jimenez FJ, Lopez-Alvarez J, Sanchez-Chapado M, et al. Retroperitoneal fibrosis in a patient with Parkinson's disease treated with pergolide. Clin Neuropharmacol 1995; 18:277-279

[8] Graham JR, Suroy HI, LeCompte PR, et al. Fibrotic disorders associated with methysergide therapy for headache. N Engl J Med 1966; 274:359-368

(*) From the Division of Pulmonary and Critical Care Medicine (Drs. Danoff and Terry), Department of Internal Medicine; and Division of General Internal Medicine (Dr. Flynn), Division of Molecular and Clinical Rheumatology, Program for Outpatient Education in Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; and Health Care Investment Banking (Dr. Grasso), Credit Suisse First Boston, New York, NY.

Manuscript received October 11, 2000; revision accepted November 29, 2000.

Correspondence to: John A. Flynn, MD, MBA, Johns Hopkins University, Johns Hopkins Outpatient Center, 601 North Caroline St, #7143, Baltimore, MD 21287

COPYRIGHT 2001 American College of Chest Physicians
COPYRIGHT 2001 Gale Group