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Pericardial, Retroperitoneal, and Pleural Fibrosis Induced by Pergolide

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Pericardial, Retroperitoneal, and Pleural Fibrosis Induced by Pergolide J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.66.1.79 on 1 January 1999. Downloaded from J Neurol Neurosurg Psychiatry 1999;66:79–81 79 SHORT REPORT Pericardial, retroperitoneal, and pleural fibrosis induced by pergolide S Shaunak, A Wilkins, J B Pilling, D J Dick Abstract 1992, the emergence of motor fluctuations led Three patients with Parkinson’s disease to the introduction of pergolide, and the dose are described who developed pericardial, of this was gradually increased to a maximum retroperitoneal, and pleural fibrosis asso- of 1mg/day. 1n 1994, 2 years after the ciated with pergolide treatment. Surgical introduction of pergolide, the patient devel- intervention was required in all three oped left flank pain with weight loss, and was cases, either to reach a tissue diagnosis or found to have a mild anaemia (haemoglobin for potentially life threatening complica- 10.4 g/dl), with indices suggesting iron defi- tions. Symptoms emerged on average 2 ciency, and an ESR of 40 mm/h. Upper gastro- years after the institution of treatment, intestinal endoscopy and barium enema gave and were suYciently non-specific to cause negative results. Seven months later right sided significant delays in diagnosis in all cases. chest pain and a non-productive cough devel- The erythrocyte sedimentation rate (ESR) oped; investigations confirmed persistent anae- was raised in the two patients in whom it mia, an ESR of 55 mm/h, and bilateral pleural was measured. Serosal fibrosis is a rarely thickening on chest radiography and CT. Lung reported adverse eVect of pergolide treat- function tests showed a reduction in total lung ment, although it is well described with capacity of 36% with no fall in transfer factor, other dopamine agonists. We suggest that consistent with pleural fibrosis without paren- patients with Parkinson’s disease who chymal involvement. receive pergolide treatment should be Seven months later the patient presented regularly monitored for the development with exertional dyspnoea, paroxysmal atrial of such complications. fibrillation, and signs of gross right ventricular (J Neurol Neurosurg Psychiatry 1999;66:79–81) failure. Echocardiography suggested pericar- dial thickening, with a dyskinetic septum but Keywords: pergolide; Parkinson’s disease; ergot; serosal relatively good left ventricular function. Dig- fibrosis oxin and diuretics were added without benefit. http://jnnp.bmj.com/ Constrictive pericarditis was suspected, and Dopamine agonists such as pergolide and bro- this was confirmed at cardiac catherisation mocriptine are widely used in the management where right atrial pressure was found to be of Parkinson’s disease to treat motor fluctua- raised with equalisation of right and left tions during chronic levodopa therapy. In addi- ventricular pressures in diastole. At explora- tion, the early use of these drugs as mono- tion, the heart was encased in thick, calcified pericardium, with tight bands around the therapy is increasingly advocated, particularly on September 25, 2021 by guest. Protected copyright. in younger patients, to delay or reduce the superior and inferior vena cavae. Total pericar- development of late motor fluctuations and dectomy with freeing of the vena cavae was dyskinesia. Although fibrotic reactions are well performed, with an immediate fall in right documented after bromocriptine therapy,1–4 atrial pressure to normal values, and resolution Department of there are relatively few reports of these compli- of the patient’s cardiac failure. Subsequently, Neurology, Norfolk and pergolide was stopped, and the patient is Norwich Hospital, cations arising during treatment with per- golide. We describe three patients who devel- currently maintained on a combination of Brunswick Road, levoopa/benserazide and tolcapone. Norwich NR1 3SR, UK oped pronounced serosal fibrosis after S Shaunak treatment with pergolide, which in one case A Wilkins was life threatening, and review the literature CASE 2 J B Pilling on this condition. D J Dick This 61 year old man was diagnosed with Par- kinson’s disease in 1990 at the age of 53, and Correspondence to: Case reports initially treated with a levodopa/benserazide Dr S Shaunak, Department CASE 1 preparation (Madopar 125, 0.5 g/day). Per- of Neurology, Addenbrookes Hospital, Hills Road, This 63 year old man presented in 1976 at the golide was introduced 2 years later and the Cambridge, CB2 2QQ, UK. age of 41 with asymmetric tremor and rigidity. dose increased over the course of 12 months to A diagnosis of Parkinson’s disease was made a total of 3 mg/day. Two years after the Received 28 May 1998 and and therapy with a levodopa/benserazide introduction of pergolide, the patient devel- in revised form 4 August 1998 preparation (Madopar 250, 1.25 g/day) was oped marked oedema of the left leg, associated Accepted 10 August 1998 instituted with good symptomatic relief. In with urinary frequency, nocturia, and loin pain; J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.66.1.79 on 1 January 1999. Downloaded from 80 Shaunak, Wilkins, Pilling, et al the ESR was raised at 57 mm/h, and there was Serosal fibrosis is a recognised complication mild impairment of renal function. A nuclear of treatment with ergot derivatives, including lymphangiogram was normal, but CT of the methysergide, lysergic acid diethylamide abdomen disclosed a severe left hydronephro- (LSD), and ergotamine.5 In addition, some sis and appearances consistent with retroperi- reports have linked the use of bromocriptine toneal fibrosis. Retrograde ureterography and cabergoline, also ergot derivatives, with the showed an 8 cm stricture in the left mid-ureter, development of pleuropulmonary and retro- which was stented, and steroids were started at peritoneal fibrosis,1–4 6 and with constrictive a dosage of 20 mg/day. The patient’s loin pain pericarditis3 in patients with Parkinson’s dis- and urinary symptoms subsequently resolved, ease. These reactions seem to occur more with a concomitant fall in the ESR, although he commonly in men than women, may occur has required low dose maintenance steroids after short term and low dose therapy, and are since. Pergolide was withdrawn, and the patient often irreversible after withdrawal of the drug, is now maintained on an levodopa/benserazide although a degree of regression may be seen.5 preparation alone. Recent imaging has shown In many of the reported cases, inflammatory an atrophic, non-functioning left kidney, with markers such as the ESR and C reactive evidence of mild pelvicalyceal dilatation on the protein have been raised,1–4 and these findings right. may be of diagnostic value. Such complications of pergolide therapy, CASE 3 however, are rarely described, although they This 70 year old man developed Parkinson’s may be expected on theoretical grounds given disease in 1991 at the age of 62, and was that pergolide is also an ergot derivative. There initially treated with levodopa/benserazide are two published reports of retroperitoneal (Madopar 125, 375 mg/day) and selegiline. fibrosis after pergolide treatment,78butwecan Pergolide was introduced 4 years later for find no other cases of constrictive pericarditis motor fluctuations, to a maximal dose of 3.75 or pleural fibrosis associated with this drug in mg/day. Eighteen months after the introduc- the literature. The manufacturers and the tion of pergolide, the patient complained of Committee on Safety of Medicines have right shoulder pain and mild exertional dys- received the following additional reports of pnoea. Routine haematological investigations cardiac and pulmonary toxicity after pergolide were unremarkable, although the ESR was not therapy since the launch of the drug in 1991: measured. haemopericardium one, constrictive pericardi- Within 6 months the pain had become more tis one (fatal outcome), pericarditis (non- severe, involving the anterior chest wall and specified) one, pulmonary fibrosis one, pleural root of the neck, and the patient complained of eVusion one, lung infiltration one, and dys- increasing dyspnoea. Physical examination pnoea nine (personal communication). now showed reduced air entry at the base of the The mechanism of fibrosis induced by ergot right lung, and chest radiography showed derivatives is poorly understood, although it thickening of the pleura of the right lung, which has been suggested that there may be an was confirmed on CT. A percutaneous biopsy idiosyncratic immune response, with the drug was performed, but histology was inconclusive, acting as a hapten.9 Pathological studies of and open pleural biopsy was therefore under- drug induced pleural fibrosis have shown a http://jnnp.bmj.com/ taken. Histological examination of the pleura dense fibrotic reaction, with minimal inflam- showed dense fibrous tissue and cytokeratin matory infiltrate.5 However, a mononuclear cell positive mesothelial tissue without mitoses, and infiltrate has been reported in biopsied cases of the appearances were thought to be those of ergot induced retroperitoneal fibrosis, occa- benign pleural fibrosis. Pergolide was subse- sionally with eosinophilia and vasculitis, but quently discontinued, and the patient is without evidence of complement or immune managed on levodopa alone. There has been complex deposition.10 no clinical or radiological resolution of his res- Patients with Parkinson’s disease treated on September 25, 2021 by guest. Protected copyright. piratory disease. with ergot derived dopamine agonists, includ- ing relatively recently introduced drugs such as Discussion pergolide and cabergoline,
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