Multimodal Imaging of Constrictive Pericarditis Induced by Long-term Pergolide Treatment for Parkinson's Disease.

We herein report the first case of constrictive pericarditis (CP) induced by long-term pergolide treatment for Parkinson's disease that was assessed using multimodal imaging in a 72-year-old patient with leg edema and dyspnea. The patient was correctly diagnosed with CP using multimodal imaging and successfully treated with pericardiectomy. The treatment history of Parkinson's disease and pathological findings of the removed pericardium suggested that long-term pergolide was the cause of CP. Properly recognizing pergolide as the cause of CP and accurately diagnosing CP using multimodal imaging may contribute to the early detection and treatment of pergolide-induced CP.

Dexfenfluramine and Pergolide Cause Heart Valve Disease via Valve Metabolic Reprogramming and Ongoing Matrix Remodeling.

Several clinical reports indicate that the use of amphetaminic anorectic drugs or ergot derivatives could cause valvular heart disease (VHD). We sought to investigate whether valvular lesions develop in response to long-term oral administration of these drugs and to identify drug-targeted biological processes that may lead to VHD. Treatment of New Zealand White rabbits with pergolide, dexfenfluramine, or high-dose serotonin for 16 weeks induced valvular alterations characterized by extracellular matrix remodeling. Transcriptome profiling of tricuspid valves using RNA sequencing revealed distinct patterns of differentially expressed genes (DEGs) that clustered according to the different treatments. Genes that were affected by the three treatments were functionally enriched for reduced cell metabolism processes. The two drugs yielded more changes in gene expression than serotonin and shared most of the DEGs. These DEGs were mostly enriched for decreased biosynthetic processes, increased cell-matrix interaction, and cell response to growth factors, including TGF-ß, which was associated with p38 MAPK activation. Treatment with pergolide specifically affected genes involved in homeostasis, which was corroborated by the activation of the master regulator of cell energy homeostasis, AMPK-α, as well as decreased levels of metabolism-related miR-107. Thus, both pergolide and dexfenfluramine may cause VHD through valve metabolic reprogramming and matrix remodeling.

Fecal strongyle egg counts in horses with suspected pre-clinical pituitary pars intermedia dysfunction before and after treatment with pergolide.

Pituitary pars intermedia dysfunction (PPID) has been associated with diminished immune response in aged horses. This prospective study hypothesised that this may result in increased strongyle egg shedding in affected animals and that horses treated with pergolide would have reduced fecal egg counts (eggs per gram, EPG) compared to placebo-treated animals. Adrenocorticotropic hormone (ACTH) concentrations and EPG were tested in 48 horses. There were no significant differences in baseline EPG between horses with pre-clinical PPID and healthy controls. There was no significant difference in EPG between horses with PPID after treatment with pergolide and placebo-treated animals. Using EPG as a marker of immune function, these results did not support a proposed decrease in immune function in horses with pre-clinical PPID.

[Drug-induced valve heart disease]. / Valvulopathies médicamenteuses.

Drug-induced valve heart disease. Numerous reports have shown an unquestionable association between fibrotic valve heart disease (VHD) and the following drugs: ergot alkaloids (methysergide and ergotamine), ergot-derived dopaminergic agonists (pergolide and cabergoline) and drugs metabolized into norfenfluramine (fenfluramine, dexfenfluramine and benfluorex). These drugs have a common pharmacological action on a specific serotonin receptor - the 5HT2B receptor leading to VHD. All four valves can be affected, but the mitral and aortic valves are predominantly involved. Echocardiography is the method of choice to detect these VHD and evaluate its severity. The most characteristic feature is restriction of valve motion, mainly responsible for regurgitation. Histological examination is typical, but rarely available. Drug-induced VHD may be severe, requiring cardiac surgery. The subsequent course is not well documented, varies from one patient to another, with the possibility of regression, stabilisation or deterioration.

Valvulopathies médicamenteuses. Les valvulopathies médicamenteuses sont dues à un effet agoniste de certains médicaments sur les récepteurs cardiaques sérotoninergiques 5-HT2B. Les substances associées à leur survenue sont le méthysergide, l'ergotamine, la fenfluramine, la dexfenfluramine, le pergolide, la cabergoline, le benfluorex et l'ecstasy. Les valvulopathies médicamenteuses sont caractérisées par la présence d'une fibrose engainant les valves cardiaques. Elles sont à l'origine de fuites valvulaires essentiellement du coeur gauche, parfois associées à des sténoses valvulaires. Les atteintes polyvalvulaires sont fréquentes. L'échographie Doppler cardiaque est l'examen diagnostique clé car la clinique est peu sensible et peu spécifique. Les signes échographiques sont un épaississement valvulaire, une rétraction valvulaire et un mouvement valvulaire restrictif systolo-diastolique. Les formes frustes sont fréquentes. L'aspect anatomopathologique est caractéristique, mais rarement disponible. Les formes graves sont rares et peuvent nécessiter un remplacement valvulaire. L'évolution des valvulopathies médicamenteuses est mal connue, variable d'un patient à l'autre, avec possibilité de diminution, de stabilisation ou d'aggravation.

Effectiveness of risk minimization measures for cabergoline-induced cardiac valve fibrosis in clinical practice in Italy.

On June 2008, the European Medicines Agency (EMA) introduced changes to the Summary of Product Characteristics (SPC) for cabergoline and pergolide, to reduce the risk of cardiac valvulopathy in users of these drugs. To assess the effectiveness of EMA recommendations in Italian clinical practice, we retrospectively reviewed medical charts of patients with degenerative Parkinsonism treated with cabergoline in three large Italian clinics between January 2006 and June 2012. The prevalence and the severity of cardiac valve regurgitation were assessed in patients who stopped cabergoline therapy prior to June 2008 or continued therapy after that date. In addition, the proportion of patients undergoing echocardiographic examination in each cohort was evaluated. A total of 61 patients were available for evaluation. The proportion of patients who underwent a baseline echocardiographic examination increased from 64 % in the period before the 2008 SPC changes to 71 % among those who continued treatment after that date. However, only 18 and 29 % of patients underwent at least two echocardiographic examinations during the pre-SPC and cross-SPC change period, respectively. No severe cardiac valve regurgitation was documented in any of the study patients using cabergoline either prior or after 26th June 2008. Our findings show that the 2008 changes to the SPC resulted in an increase in physicians' awareness of cabergoline-induced valvulopathy risk in Italy. However, only a small percentage of patients underwent serial echocardiography. Further efforts are needed to achieve better compliance with the prescribing guidelines for cabergoline treated patients in clinical practice.

[Severe punding in Parkinson's disease]. / Punding sévère au cours d'une maladie de Parkinson.

BACKGROUND: Punding is a stereotypical behavior characterized by an intense fascination with repetitive handling and examining of mechanical devices or arranging common objects. This condition, which is different from both obsessive-compulsive disorder and mania, is still underestimated in patients with Parkinson's disease and may have deleterious social consequences on patients and their families. CASE REPORT: We report the case of severe punding in a 23-year-old parkinsonian woman, who presented, a few days following a rise in the dose of pergolide up to 2,5 mg/(d), frequent and daily unusual repetitive behavior, characterized by ceaseless sewing, disassembly and reassembly of phones, and coloring of drawings. These behaviors were associated with a common peak of dose dyskinesia and were responsible for a considerable reduction in duration of sleep with negative impact on the quality of life of her parents. These symptoms significantly improved immediately after switching pergolide to an equivalent dose of ropinirole (12 mg/(d). DISCUSSION: Punding has only recently come to the attention of physicians through the first report in a parkinsonian patient, triggered by dopaminergic replacement therapy. The phenomenon was thought to be related to excessive dopaminergic stimulation of the limbic and associative pathways. The current mainstay of treatment is the reduction in the dose of dopaminergic medication or changing the presumed responsible drug, often a dopaminergic agonist. In this article, the authors review the epidemiology, pathophysiology and management of this curious phenomenon.

Reversible Hypotony and Choroidal Effusion Following the Use of Pergolide for Parkinson's Disease.

PURPOSE: To alert clinicians of the possibility of reversible drug-induced occult hypotony and choroidal effusion following the long-term use of pergolide. METHODS: Annotations were made while the case was observed. The clinical records of the patient were reviewed retrospectively. RESULTS: A 74-year-old Caucasian male with primary open-angle glaucoma presenting with reduced vision in both eyes and an inflamed right eye. Examination revealed bilateral hypotony, right anterior chamber inflammation, and right choroidal effusion. The right intraocular inflammation resolved completely after a short course of topical and oral antibiotics in addition to topical steroids. Nevertheless, the bilateral hypotony and right choroidal effusion persisted. Only the discontinuation of pergolide allowed the complete resolution of the patient's presenting symptoms and signs. CONCLUSIONS: Pergolide is known to cause pericardial and pleural effusion, and generalized oedema. However, its association with choroidal effusion and hypotony has never been reported.

The effect of dopamine agonists on cognitive functions in non-demented early-mild Parkinson's disease patients.

The effect of dopamine agonists (DAs) on cognition in Parkinson's disease (PD) is not yet completely established. Previous papers reported a worsening effect on some cognitive functions with some DAs, but not with others, suggesting that DAs may differently affect cognition in PD patients according to their pharmacological characteristics. We set out to test the effect of rotigotine and cabergoline on cognitive functions in a group of forty non-demented early-mild PD patients (H &Y <2). Subjects were randomly divided into two groups and evaluated in a randomized cross-over study using neuropsychological tests; at the same time, motor function was monitored under three different treatment conditions: DA (rotigotine or cabergoline), L-dopa, and off therapy. Rotigotine and cabergoline were chosen because while they share a mixed D1 and D2 receptor profile, the former is non-ergolinic and the latter ergolinic. No significant differences were found in cognitive function between the basal condition and the DA treatments. On the basis of the present data, which we compare with previous findings regarding pramipexole IR and pergolide, we hypothesize that combined stimulation of both dopamine receptor families, as occurs with rotigotine, cabergoline, L-dopa and pergolide, may preserve cognitive functions more than pure D2 family stimulation.

The treatment of restless legs syndrome and periodic limb movement disorder in adults--an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses: an American Academy of Sleep Medicine Clinical Practice Guideline.

A systematic literature review and meta-analyses (where appropriate) were performed to update the previous AASM practice parameters on the treatments, both dopaminergic and other, of RLS and PLMD. A considerable amount of literature has been published since these previous reviews were performed, necessitating an update of the corresponding practice parameters. Therapies with a STANDARD level of recommendation include pramipexole and ropinirole. Therapies with a GUIDELINE level of recommendation include levodopa with dopa decarboxylase inhibitor, opioids, gabapentin enacarbil, and cabergoline (which has additional caveats for use). Therapies with an OPTION level of recommendation include carbamazepine, gabapentin, pregabalin, clonidine, and for patients with low ferritin levels, iron supplementation. The committee recommends a STANDARD AGAINST the use of pergolide because of the risks of heart valve damage. Therapies for RLS secondary to ESRD, neuropathy, and superficial venous insufficiency are discussed. Lastly, therapies for PLMD are reviewed. However, it should be mentioned that because PLMD therapy typically mimics RLS therapy, the primary focus of this review is therapy for idiopathic RLS.

Valvular heart disease in patients exposed to pergolide: insights from the clinical presentation.

PURPOSE: The aim of this study was to determine whether the presence of symptoms would aid in the detection of valvular heart disease (VHD) in those exposed to pergolide. METHODS: Utilizing a prospective, cross-sectional study design, patients with an exposure to pergolide were asked regarding the presence or absence of chest pain, shortness of breath or lower extremity edema through a questionnaire. Echocardiograms were obtained on the same day as the questionnaire and were blinded to all staff involved in the study. The sensitivity, specificity, positive and negative predictive value of the reported symptoms towards the outcome moderate or severe valvular regurgitation were obtained. Using the area under the receiver-operating characteristic curve, we also ascertained whether a relationship existed between symptoms, pergolide dose and presence of VHD. To understand the associations between symptoms and echocardiographic covariates, a logistic regression analysis was performed adjusted for age and gender. RESULTS: The sensitivity, specificity, positive and negative predictive value of symptom presentation and total dose was sufficiently low that it did not aid in the determination whether significant valvular regurgitation was present. Multivariable analysis noted a significant association with indexed left atrial volume (p = 0.011), estimated pulmonary artery pressure (p = 0.047) and shortness of breath. CONCLUSIONS: The presence or absence of symptoms does not help guide whether valvular regurgitation is present or absent in individuals exposed to pergolide. Therefore, echocardiography is needed to confirm or refute pergolide-associated VHD.

Echocardiography for the detection of valvulopathy associated with the use of ergot-derived dopamine agonists in patients with Parkinson's disease.

OBJECTIVE: The ergot-derived dopamine agonists, cabergoline and pergolide, are associated with valvulopathy risk. In Japan, product labels were revised in April 2007 to recommend periodic echocardiography for patients taking these dopamine agonists, however, the compliance of physicians to follow through with this recommendation is unknown. This study assessed changes in echocardiography evaluation of patients with Parkinson's disease (PD) taking cabergoline or pergolide before and after the label revision and examined the factors related with echocardiography performance. METHODS AND PATIENTS: Medical claim data from January 2005 to December 2008 were used. Patients were divided into a C-P group (prescribed either cabergoline or pergolide) or reference group (prescribed other anti-PD drugs), and further classified based on whether they were prescribed these drugs "pre-revision" or "post-revision." The Cochran-Armitage trend test was used to compare the proportion of echocardiograms obtained amongst these groups before and after the revision. The frequencies of echocardiograms performed among the treatment groups for each period were compared by Fisher's exact test. RESULTS: A total of 222 subjects (C-P, 73; reference, 149) were assessed. The proportion of C-P patients undergoing echocardiography increased from 4.8% to 27.9% after revision of product labels (p=0.001), which was higher than those in the reference group following label revisions (11.0%) (p=0.014). Prescription duration of C-P after the revision was longer in the patients with echocardiography than without echocardiography (p=0.026). CONCLUSION: Although echocardiography evaluations increased, more than 70% of PD patients prescribed cabergoline or pergolide did not undergo such assessment despite the product label recommendation. Adherence to drug safety recommendations should be facilitated with more feasible and effective measures.

Restless legs syndrome (RLS) augmentation associated with dopamine agonist and levodopa usage in a community sample.

OBJECTIVE: Assess the rate of augmentation as it occurs during standard long-term dopaminergic treatment of RLS, potential risk factors or predictors of augmentation, the relationship between treatment duration and augmentation, and the clinical impact of augmentation on subjects' health outcomes. METHODS: Two hundred sixty-six patients with dopamine-treated RLS completed a one-time online survey. All subjects were recruited by their PCP/neurologist and were 18 or older. Augmentation was assessed using NIH guidelines and an augmentation classification system was developed through this research. RESULTS: Overall, 20% of the patients were classified as having definitive or highly suggestive clinical indications of augmentation. Five factors were considered likely to reflect increased risk of developing augmentation, including more frequent RLS symptoms pre-treatment, greater discomfort with RLS symptoms before treatment, and longer treatment duration. RLS augmentation occurred at a rate of about 8% each year for at least the first 8 years of dopamine treatment. Subjects reporting definite or highly suggestive clinical indicators of augmentation had an average IRLS score of 23.6, indicating generally inadequate treatment with generally poor clinical outcomes. Only 25% of the patients reported no indications of augmentation and they were the only group to show on average a low (<15) IRLS score and good clinical outcomes. CONCLUSIONS: As currently used, long term dopaminergic treatment for an average ± SD of 2.7 ± 2.4 years produced significant augmentation problems in at least 20% of the patients and only 25% of the patients were totally free of this problem. It is important for physicians to carefully screen patients for changes in RLS symptoms for as long as they are on dopamine agents, with particular attention paid to those patients who present with the most severe RLS symptoms prior to treatment initiation. Given the marked increase in suffering with augmentation, a method for early detection and intervention would be an important contribution to the effective management and treatment of RLS.

The impact in Japan of regulatory action on prescribing of dopamine receptor agonists: analysis of a claims database between 2005 and 2008.

BACKGROUND: Use of the ergot-derived dopamine receptor agonists (cabergoline and pergolide) is associated with an increased risk of cardiac valvulopathy. Pergolide was withdrawn from the US market in 2007 because of the risk of valvular heart disease, while the European Medicines Agency (EMA) required a reduction in the maximum daily dosage of cabergoline and pergolide from 6 mg/day to 3 mg/day in 2008. In Japan, the package inserts of both drugs were revised in April 2007 to request that physicians conduct periodic ultrasonic cardiography (UCG) examinations for patients taking cabergoline or pergolide. Also, through face-to-face communication with medical representatives of drug companies, physicians were informed that use of cabergoline and pergolide has increased the risk of valvulopathy. However, cabergoline and pergolide have remained in wide use, even following the regulatory actions. OBJECTIVE: The objective of this study was to assess the impact of actions, including the package insert revision in April 2007, to encourage periodic UCG. METHODS: Data on monthly claims (January 2005-October 2008) covering 330 000 patients were obtained from a Japanese database vendor. We selected patients ≥40 years of age with Parkinson's disease. The impact of the regulatory action on the proportion of patients with Parkinson's disease prescribed cabergoline or pergolide was assessed by segmented regression analysis and by a statistical model of the rates of UCG examination in patients taking/not taking cabergoline or pergolide before and after the action. We also compared the use of cabergoline and pergolide before and after the action with that of other antiparkinson drugs. RESULTS: Of 574 patients with Parkinson's disease, the proportion of patients prescribed cabergoline or pergolide did not decrease but rather tended to increase after the action when analysed by segmented regression analysis (p = 0.13). Similarly, the proportion of the prevalent and incident users of cabergoline or pergolide did not change between two 19-month periods before and after the action. The adjusted rates of UCG examination per person-year before and after the action were both 0.02 in those not prescribed cabergoline or pergolide, but 0.02 before the action and 0.09 after the action in those taking either drug. The excess UCG examination rate of cabergoline or pergolide attributable to the action was 0.08 per person-year (95% CI 0.03, 0.11). While 1 of 49 (2%) patients taking cabergoline or pergolide had a UCG up to 19 months before the action, 9 of 36 (25%) patients taking cabergoline or pergolide had a UCG up to 19 months after the action. Annual sales from 2004 to 2008 were 195, 195, 170, 110 and 75 billion yen, respectively, and the number of valvulopathy events, including incompetence of aortic/mitral/tricuspid valves and cardiac valve disease, per annual sales from 2004 to 2008 were estimated at 0.23, 0.03, 0.08, 0.25 and 0.19 per billion yen, respectively. CONCLUSIONS: Following the actions in April 2007, no decrease in the use of cabergoline or pergolide occurred, although more patients administered the drug underwent a UCG. However, those undergoing a UCG represented one-quarter of the total number prescribed cabergoline or pergolide. To mitigate the risk, additional risk management tools such as patient registration may be needed to secure careful clinical examination (including UCG examination, if necessary) for cardiac function.

A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome.

BACKGROUND: Restless legs syndrome (RLS) is a chronic disease, which is managed with palliative medications that are likely to be required for a patient's lifetime. It is, therefore, important to know the long-term consequences of these treatments. Currently, the most commonly prescribed treatment for RLS is one of the dopamine (DA) agonists. Most of what we understand about efficacy and side effects of the DA agonists are, however, derived from relatively short-term studies. This is particularly a problem since these medications produce in some patients a significant increase or augmentation of RLS symptoms known to occur during the first 2 years of treatment and perhaps even later in treatment. The primary aim of this study was to determine the long-term efficacy (10-year) for commonly used RLS medication types: dopaminergic agonists and opioids. METHODS: Records of all RLS patients treated in one tertiary care center with pramipexole, pergolide or methadone during the years 1997-2007 were reviewed. The duration and reason for any discontinuation of treatment and medication doses were recorded. RESULTS: Annual rates for discontinuing treatment persisted for up to 10 years of treatment and were fairly constant after the first year at 9% for pramipexole, 8% for pergolide, and 0% for methadone. Similarly, annual augmentation rates were fairly constant after the first year and persisted for up to 10 years at 7% for pramipexole, 5% for pergolide, and 0% for methadone. The percentage continuing on the treatment medication for over 5 years was 58% for pramipexole and 35% for pergolide. CONCLUSIONS: The DA agonists appear to have a limited period of clinical utility for many patients. Severe augmentation, while not common in any 1 year, can develop even after years on the medication. Methadone, in contrast, shows neither augmentation nor major problems with continued efficacy after the first year of treatment.

Regression of cardiac valvulopathy related to ergot-derived dopamine agonists.

AIMS: In a previous echocardiographic prevalence study we reported a significant increase in the frequency of heart valve regurgitation in patients with Parkinson's disease taking the ergot-derived dopamine agonists pergolide and cabergoline versus controls. We followed-up our original cohort of patients to ascertain whether valvulopathy regressed after discontinuation of treatment and/or its incidence increased over time. METHODS: Prospective follow-up of 101 patients treated with ergot-derived dopamine agonists included in the prevalence study: 53 given pergolide and 48 cabergoline (64% male; 66.4 ± 8.7 years of age, 11.5 ± 5.9 years of disease, 21.8 ± 5.9 months of follow-up); 55 stopped treatment while 46 continued. The main outcomes measures, were: echocardiographic quantification of regurgitant valve disease, abnormal leaflet, or cusp thickening and measurement of mitral valve tenting area. RESULTS: Valve abnormalities regressed in about one third of patients with significant multivalvular and in about half of the patients with monovalvular regurgitation who withdrew; no progression was observed in remaining patients. Patients continuing ergot-derived dopamine agonists showed progression of cardiac valvulopathy: seven new cases with three to four regurgitation grade of any valve occurred during follow-up; this regarded also patients who had been on pergolide for many years. CONCLUSION: Owing to the persistence of risk of heart valve damage over time and the lack of its mid-term reversibility in many patients, we believe that pergolide and cabergoline should be prescribed only when therapeutic alternatives with a better risk/benefit ratio are unavailable and the patient has access to echocardiography.

Compulsive singing associated with a dopamine agonist in Parkinson disease.

OBJECTIVE: To describe a patient with Parkinson disease in whom compulsive singing developed without other types of pathologic behavior after starting treatment with pergolide. MATERIAL: An 82-year-old woman with Parkinson disease was given pergolide (250 microg/d), without modifying the doses of other medications. RESULTS: She started to hum the same melody and often sang songs repeatedly. Pergolide was discontinued, and the episodes of repetitive humming and singing were markedly decreased. CONCLUSIONS: Our observations suggest that a dopamine agonist may contribute to compulsive singing in Parkinson disease.

Cardiac surgery in a patient with retroperitoneal fibrosis and heart valvulopathy, both due to pergolide medication for Parkinson's disease.

Retroperitoneal fibrosis is best described as a chronic inflammatory process which may be idiopathic, but can rarely be brought about by medications, such as pergolide, used for treating Parkinson's disease. Pergolide can produce a fibrotic process in heart valves, resulting in valve insufficiency in up to 25% of cases. Herein we describe the case of a 68-year-old man who received pergolide for 2 years for Parkinson's disease. The patient developed retroperitoneal fibrosis resulting in renal failure from ureteral obstruction necessitating ureteral stenting, as well as significant aortic and mitral valve insufficiency. He successfully underwent surgery for combined aortic valve, mitral valve and ascending aorta replacement because of severe valve insufficiency and dilated (d = 5.8 cm) ascending aorta. Retroperitoneal fibrosis improved with pergolide cessation and corticosteroid treatment. This is the second case reported in the literature, of a patient who had double valve and ascending aorta replacement surgery because he suffered from this rare but serious adverse effect of dopamine agonists used for managing Parkinson's disease.

Drug-induced fibrotic valvular heart disease.

The initial association between the development of valvular heart disease and drugs stems from observations made during the use of methysergide and ergotamine for migraine prophylaxis in the 1960s. Since then, the appetite suppressants fenfluramine and dexfenfluramine, the dopamine agonists pergolide and cabergoline, and more recently, the recreational drug ecstasy (3,4 methylenedioxymethamphetamine; MDMA) have been implicated. Results from clinical trials show that drug dose and treatment duration affect both the risk of developing the disease and its severity. The natural history of the disease remains unclear, although regression of valvular lesions after the end of treatment has been reported. Interference with serotonin metabolism and its associated receptors and transporter gene seems a likely mechanism for development of the drug-induced valvular heart disease. Physicians need to balance the benefits of continued therapy with these drugs against possible risks. Further investigation is needed to assist with treatment decisions. Continued vigilance is necessary because several commonly prescribed treatments interact with serotonergic pathways.