diagnosis and management of pergolide-induced fibrosis

12. Bucher SF, Seelos KC, Oertel WH, Reiser M, Trenkwalder C.Cerebral generators involved in the pathogenesis of restless legssyndrome. Ann Neurol 1997;41:639–645.

13. Lee MS, Choi YC, Lee SH, Lee SB. Sleep-related periodic legmovements associated with spinal cord lesions. Mov Disord 1996;11:719–722.

14. Hartmann M, Pfister R, Pfadenhauer K. Restless legs syndromeassociated with spinal cord lesions. J Neurol Neurosurg Psychiatry1999;66:688–689.

15. Brown LK, Heffner JE, Obbens EA. Transverse myelitis associ-ated with restless legs syndrome and periodic movements of sleepresponsive to an oral dopaminergic agent but not to intrathecalbaclofen. Sleep 2000;23:591–594.

16. Trenkwalder C, Bucher SF, Oertel WH. Electrophysiological pat-tern of involuntary limb movements in the restless legs syndrome.Muscle Nerve 1996;19:155–162.

17. Connor JR, Boyer PJ, Menzies SL, et al. Neuropathological ex-amination suggests impaired brain iron acquisition in restless legssyndrome. Neurology 2003;61:304–309.

18. Grol CJ. Chemistry of dopamine. In: Horn AS, Korf J, WesterinkBHC, editors. The neurobiology of dopamine. London: AcademicPress; 1979. p 7–27.

19. Campbell NR, Hasinoff B. Ferrous sulfate reduces levodopa bio-availability: chelation as a possible mechanism. Clin PharmacolTher 1989;45:220–225.

20. Youdim MB, Gassen M, Gross A, Mandel S, Grunblatt E. Ironchelating, antioxidant and cytoprotective properties of dopamine re-ceptor agonist; apomorphine. J Neural Transm Suppl 2000;58:83–96.

Diagnosis and Management ofPergolide-Induced Fibrosis

Pinky Agarwal, MD, Stanley Fahn, MD,and Steven J. Frucht, MD*

Department of Neurology, Columbia-Presbyterian MedicalCenter, Division of Movement Disorders, New York,

New York, USA

Abstract: We report on 2 patients treated with pergolide, 1of whom developed pleural fibrosis and the other retroper-itoneal fibrosis. In both cases, an extensive diagnostic eval-uation and surgical intervention were required to reach adiagnosis. Based on our experience with these patients anda review of cases of pergolide-induced fibrosis in the En-glish-language literature, we propose guidelines for the di-agnosis and management of this rare complication. © 2004Movement Disorder Society

Key words: pergolide; pleural fibrosis; retroperitoneal fibro-sis; surgery

The ergot dopamine agonist pergolide mesylate ismost commonly prescribed to treat Parkinson’s disease(PD) and restless leg syndrome (RLS). Pergolide is usedas monotherapy in patients with mild symptoms andsigns of PD and also as an adjunct to levodopa in patientswho develop motor fluctuations and dyskinesias. Likeother ergot agonists, pergolide may rarely induce fibrosisaffecting the pleural, retroperitoneal, or cardiac valvularstructures.1–14 Our experience with 2 patients who devel-oped fibrosis during treatment with pergolide promptedus to review the English-language literature to look forcommon features that could assist in the diagnosis andmanagement of this rare complication.

MATERIALS AND METHODS

We performed a Medline search using the key words“pergolide” and “fibrosis.” Only articles published inEnglish were reviewed, and publications referenced in thesearticles were also reviewed. We identified 12 studies1–7,11–15

describing 24 patients who developed symptomatic fibrosisduring the course of treatment with pergolide.

CASE SUMMARIES

Case 1

A 65-year-old man presented at age 54 with 1 year oftremor and pain in the right hand. He was diagnosed withPD and treated with pergolide, with good symptomaticbenefit. To obtain adequate relief of symptoms, the doseof pergolide was gradually increased to 7.5 mg/day.Levodopa (L-dopa) was added 5 years later because ofmotor deterioration. Eight years after the introduction ofpergolide, he developed a cough and shortness of breath.A magnetic resonance imaging scan of the chest revealeda possible mass in the left lung. A diagnostic work-upwas performed at another medical center, including anevaluation of pleural fluid (no evidence of tuberculosis ormalignancy), a bronchial biopsy (unrevealing), and aneedle biopsy consistent with pulmonary fibrosis.

Despite discontinuation of pergolide, a computed to-mography (CT) scan of the chest 1 year later showedpersistence of pleural and parenchymal fibrosis. One yearafter discontinuing pergolide, he developed severe bilat-eral leg edema and dysuria. His erythrocyte sedimenta-tion rate (ESR) was 100 mm/hr. A CT scan of theabdomen revealed thickening of the retroperitoneum,which was highly suggestive in appearance of retroper-itoneal fibrosis. The retroperitoneal mass was not acces-sible to biopsy, because it encased the abdominal aorta.An echocardiogram showed no evidence of cardiac val-vular fibrosis. A retrograde pyelogram showed stricturesof both ureters, requiring ureteral stents.

*Correspondence to: Dr. Steven J. Frucht, The Neurological Insti-tute, 710 West 168th Street, New York, NY 10032.E-mail: [email protected]

Received 25 November 2003; Accepted 14 February 2004Published online 19 May 2004 in Wiley InterScience (www.

interscience.wiley.com). DOI: 10.1002/mds.20200

PERGOLIDE-INDUCED FIBROSIS 699

Movement Disorders, Vol. 19, No. 6, 2004

TA

BL

E1.

Cli

nica

lco

urse

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sis

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700 P. AGARWAL ET AL.


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He was initially treated with tamoxifen 40 mg/day for4 weeks with no benefit. Subsequently, he was treatedwith prednisone 60 mg/day for 6 weeks with dramaticradiographic improvement of abdominal fibrosis. He wasthen treated with pramipexole without recurrence of fi-brosis and has since undergone implantation of bilateralsubthalamic nucleus stimulators.

Case 2

A 71-year-old man presented with symptoms of severeidiopathic RLS. Initial treatment with L-dopa producedno symptomatic benefit. Treatment with pergolide dra-matically improved his symptoms, although he requiredgradually increasing doses over a period of 1 year (up to5 mg/day). Two years after pergolide was introduced, hedeveloped shortness of breath. A chest radiograph re-vealed a left pleural effusion and a wedge-shaped massin the left upper lobe. Analysis of pleural fluid showed noevidence of malignancy. A fluorodeoxyglucose positronemission tomographic scan of the chest revealed lowactivity in the left chest wall, consistent with a reactiveprocess. Thorascopic examination showed homogenouswhite thickening of the pleura, and biopsy of the lungmass revealed evidence of chronic inflammation andinterstitial fibrosis with no evidence of malignancy.

Pergolide was stopped, and his dyspnea graduallyresolved. OxyContin was ineffective at relieving hissymptoms of disabling restlessness. He is currentlytreated with pramipexole, with excellent benefit and nosymptomatic or radiologic recurrence of fibrosis.

PUBLISHED LITERATURE

Clinical information on patients (including the 2 re-ported in this study) who developed serosal fibrosis dur-ing treatment with pergolide is summarized in Table 1.Patients ranged in age from 42 to 83 years, with a malepreponderance (63%). A total of 24 patients receivedpergolide as treatment for PD and 2 for RLS. The totaldaily dosage of pergolide ranged from 1 mg/day to 7.5mg/day. Patients received the drug for 11 months to 8years before symptoms began. In at least 6 patients, theESR rate was elevated, from 40 to 127 mm/hour; in theother patients the ESR was either not measured or notreported. In 1 patient (Patient 21), the ESR was normalbut C-reactive protein was elevated.

In those patients who developed pulmonary fibrosis,chest radiographs were abnormal with the exception ofPatient 13. Abdominal CT scan was abnormal in patientswho developed retroperitoneal fibrosis. Twenty-one pa-tients required an invasive procedure to secure the diag-nosis. Pergolide was discontinued in all cases, and 4patients were treated with steroids, experiencing dra-

matic benefit within several weeks of treatment. Peri-cardectomy, valve replacement and ureteral stentingwere necessary in some cases. Three patients (Patients 3,11 and 19) did not improve, despite discontinuation ofthe drug. One patient (Patient 15) died suddenly whileawaiting surgery. Further details regarding clinical fea-tures and management are summarized in Table 1.

DISCUSSION

Like its cousins bromocriptine, lisuride, and cabergoline,and related ergots methysergide, lysergic acid, and diethyl-amide ergotamine, pergolide is known to rarely triggerserosal fibrosis affecting pleural or retroperitoneal struc-tures.1–15 Recent reports of patients with fibrotic valvularheart disease7,12,15 and additional possible cases of cardiacand pulmonary fibrosis attributed to the drug10 have gener-ated concern in the minds of patients and physicians. Wechose to present our experience with 2 such patients, andreview the published literature to attempt to answer severalquestions: How do patients present with fibrotic complica-tions from pergolide?; Is fibrosis related to the dose orduration of treatment?; What happens to these patients oncethe drug is stopped?; and finally, What other treatmentoptions are available?

The most common presenting symptom was dyspnea(54%). Leg edema could also occur either in one leg orboth, and cough and chest pain were not infrequent. Mostpatients gained weight (probably due to fluid accumula-tion), although 3 patients lost weight. Time from firstsymptom to diagnosis ranged from 1 to 36 months. Thetotal daily dosage of pergolide in published cases rangedfrom 1 mg/day to 8 mg/day, and duration of exposureranged from 11 months to 8 years. Thus, it would appearthat fibrosis can occur in patients treated with a low doseof pergolide for a short time, and that there may not be acompletely risk-free dose or duration of exposure.Rather, fibrosis may be an idiosyncratic event, occurringin patients who are somehow predisposed to develop it.It has also been suggested that increased serotonin levelsmay activate fibroblasts, leading to scarring.16 In patientswith pleural interstitial lung injury, an idiosyncratic im-mune reaction has also been postulated.1

In at least 6 patients, the inflammatory marker ESRwas elevated, ranging from 40 to 127 mm; the ESR wasnot reported in other cases except one in which it wasnormal. Anemia was reported in 4 patients. In thosepatients who developed pulmonary fibrosis, abnormali-ties were clearly visible on plain chest radiographs ex-cept for 1 patient (Patient 13). Abdominal CT and trans-thoracic echocardiography were very useful in definingthe extent of pathology in patients with fibrosis affectingthe retroperitoneum or cardiac valves. The time from



symptom onset to definitive diagnosis varied from 1 to36 months, suggesting that lack of awareness of thediagnosis may have contributed to the delay.

In all cases, pergolide was discontinued as soon as thediagnosis was secured. Invasive surgical procedures (peri-cardectomy, valve replacement, abdominal resection) werefrequently necessary, and most patients underwent an ex-tensive work-up to exclude malignancy. We used tamox-ifen in our first patient because of reports suggesting that itinhibits human mast cell proliferation, possibly through ionchannel modulation. It has been hypothesized that tamox-ifen might be useful in the treatment of mast cell-mediateddiseases, including mastocytosis, asthma, and pulmonaryfibrosis.17 Unfortunately, it was not effective in our patient.Prednisone acts as an anti-inflammatory agent and reducesphagocytic activity, collagen deposition, fibroblast activity,and ultimately scar formation. Response to treatment withprednisone was dramatic in 3 patients, suggesting the pos-sibility that early diagnosis and initiation of steroid treat-ment might alter the course of the illness. In most patients,the fibrotic process remits when the drug is stopped; how-ever, in some patients it does not. In our first case, despitediscontinuation of the drug, retroperitoneal fibrosis devel-oped 1 year later, which was, fortunately, extremely respon-sive to steroids. Five patients were subsequently exposed tononergot agonists without recurrence of fibrosis at lastfollow-up.

Given these facts, how should neurologists managethis rare but potentially serious complication? We rec-ommend the following strategies. All patients should becounseled about the rare possibility of fibrosis beforestarting pergolide, and all patients already taking thedrug should be informed of the possibility of this seriousadverse event. We recommend documenting this conver-sation in the medical record. It would seem prudent toavoid pergolide in any patient with a known elevatedESR, abnormal renal function, congestive heart failure,or valvular heart disease. Although the data are verylimited, it would appear that patients who develop fibro-sis from pergolide can be safely treated with nonergotdopamine agonists.

The nonergot dopamine agonists pramipexole andropinirole may be better choices than pergolide for initialfirst-line therapy in patients with PD or RLS. Given ourconcerns about pergolide-induced fibrotic complications,at our center, we no longer routinely use pergolide asfirst-line treatment in PD or RLS, instead reserving it forsituations where nonergot dopamine agonists have failedor are not tolerated. We are uncertain whether or not therare risk of pergolide-induced fibrosis is sufficient towarrant removing this valuable drug from the PD arma-

mentarium; however, this is a possibility given the avail-ability of other dopamine agonists and L-dopa.

We believe that, because the incidence of pergolide-induced fibrosis is not high, it is impractical to screenevery patient taking pergolide for fibrotic complications.However, patients who develop new dyspnea, chest pain,weight gain, or symptoms of urinary outflow obstructionshould be imaged. An elevated ESR may be an earlyindicator, although this marker is very nonspecific. Echo-cardiography and CT scan of the chest, abdomen, andpelvis are more valuable tests. Given the dramatic benefitfrom treatment with prednisone, it seems reasonable toattempt a trial of steroids in all patients who developfibrosis, especially before embarking on invasive surgi-cal procedures.

A more difficult question facing neurologists is howto manage patients who develop swelling of one orboth legs while taking pergolide. Like all dopamineagonists, pergolide can induce leg swelling, and thevast majority of these patients do not have retroperi-toneal fibrosis. Our approach in patients with signifi-cant leg swelling is to switch to another agonist or toconsider using L-dopa instead. Patients are followedweekly by telephone call or office visit, and if addi-tional symptoms such as dysuria and dyspnea developor leg swelling does not decrease, we initiate awork-up for serosal fibrosis, including CT of the chest,abdomen, and pelvis.

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diagnosis and management of pergolide-induced fibrosis

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