EuroInf: a multicenter comparative observational study of apomorphine and levodopa infusion in Parkinson's disease.

Subcutaneous apomorphine infusion (Apo) and intrajejunal levodopa infusion (IJLI) are two treatment options for patients with advanced Parkinson's disease (PD) and refractory motor complications, with varying cost of treatment. There are no multicenter studies comparing the effects of the two strategies. This open-label, prospective, observational, 6-month, multicenter study compared 43 patients on Apo (48.8% males, age 62.3 ± 10.6 years; disease duration: 14 ± 4.4 years; median H & Y stage 3; interquartile range [IQR]: 3-4) and 44 on IJLI (56.8% males, age 62.7 ± 9.1 years; disease duration: 16.1 ± 6.7 years; median H & Y stage 4; IQR, 3-4). Cohen's effect sizes (≥0.8 considered as large) were "large" with both therapies with respect to total motor, nonmotor, and quality-of-life scores. The Non-Motor Symptoms Scale (NMSS) with Apo showed moderate improvement, whereas sleep/fatigue, gastrointestinal, urinary, and sexual dimensions of the NMSS showed significantly higher improvement with IJLI. Seventy-five percent on IJLI improved in their quality-of-life and nonmotor symptoms (NMS), whereas in the Apo group, a similar proportion improved in quality of life, but 40% in NMS. Adverse effects included peritonitis with IJLI and skin nodules on Apo. Based on this open-label, nonrandomized, comparative study, we report that, in advanced Parkinson's patients, both IJLI and Apo infusion therapy appear to provide a robust improvement in motor symptoms, motor complications, quality-of-life, and some NMS. Controlled, randomized studies are required.

Non-motor Parkinson's: integral to motor Parkinson's, yet often neglected.

Non-motor symptoms are a key component of Parkinson's disease, possibly representing a clinical biomarker of its premotor phase. The burden of non-motor symptoms can define a patient's health-related quality of life. Non-motor symptoms substantially increase the cost of care-requiring increased hospitalisation and treatment-and pose a major challenge to healthcare professionals. However, clinicians often regard non-motor symptoms and their management as peripheral to that of the motor symptoms. Here, we address the clinical issues and unmet needs of non-motor symptoms in Parkinson's disease.

Non motor subtypes and Parkinson's disease.

Non motor symptoms (NMS) represent a significant burden in Parkinson's disease (PD) with numerous studies highlighting the importance of NMS both in "pre-motor" phase of PD as well as throughout the course of disease. In part this has led the international Parkinson and Movement Disorder Society (IPMDS) task force to attempt a re-definition of PD incorporating NMS and not base the diagnosis solely on motor symptoms. While motor subtypes within PD have been recognized and researched, recent clinical and neurobiological research suggests the existence of discrete non motor subtypes in PD, particularly in untreated (drug naïve) and early PD patients. Several independent observers have reported specific "clusters of NMS dominant PD" using a data driven approach in early and untreated PD patients while others have reported on the burden of NMS in untreated PD and specific NMS dominant phenotypes in untreated or treated PD using observational case series based data. In this review we report on specific NMS dominant phenotypes of PD as described in the literature using clinical observational studies and address pathophysiological concepts. A proposal for several NMS subtypes are reported combining clinical reports with, where possible, evidence base supporting probable biomarkers.

Infusion Therapies and Development of Impulse Control Disorders in Advanced Parkinson Disease: Clinical Experience After 3 Years' Follow-up.

BACKGROUND: In Parkinson disease (PD), compulsive behaviors, cumulatively termed impulse control disorders (ICDs), are known to develop in patients receiving dopamine-replacement therapy with oral dopamine agonists being particularly implicated. However, the effects of continuous infusion therapies have not been explored. OBJECTIVES: We report data from a 3-year clinical observational screening of our active cohort of patients receiving apomorphine (Apo) infusion and intrajejunal levodopa infusion (IJLI) for development or attenuation of ICDs. METHODS: Forty-one patients (24 male/17 female, mean age 61.9 ± 10.9 years; PD duration 14.2 ± 4.5 years) on Apo (mean dose 106 ± 24 mg; mean duration of infusion 16 h/d) and 19 patients (13 male/6 female, mean age 58.6 ± 8.2 years; PD duration 16.2 ± 5.7 years) on IJLI (mean dose 1990 ± 807 mg; mean duration of infusion 16 h/d) were screened and observed prospectively for development of nonmotor symptoms and ICD at 3 monthly follow-ups for up to 3 years. RESULTS: In Apo group, 4 patients had preexisting ICD, and in 1 patient, ICD (binge eating) completely resolved after being started on Apo. In 3 others, ICDs continue but attenuated after Apo. However, 7 new cases of ICDs developed in the Apo group, but in only 1 (2.4%), Apo had to be discontinued. Furthermore, in 3 with binge eating, the ICDs resolved after 2 months with Apo infusion being continued. In the IJLI group, 8 patients with active ICDs showed attenuation of the behavior after IJLI initiation. At 3 years, 2 of these patients continue to have ICD. No new ICDs have developed. CONCLUSIONS: Strategies utilizing continuous drug delivery appear to have a relatively low risk of development of ICD. Apomorphine and IJLI can be used in cases with ICD if clinically indicated, with IJLI therapy possibly emerging as the most advantageous in this setting.

A Pilot Prospective, Multicenter Observational Study of Dopamine Agonist Withdrawal Syndrome in Parkinson's Disease.

Dopamine agonist withdrawal syndrome (DAWS) has been reported in patients with Parkinson's disease (PD) who rapidly decrease or stop their dopamine agonist (DA) treatment. Retrospective studies suggest a high prevalence of DAWS (14%-18%) in PD, but there are no prospective studies. We report data from the first pilot European multicenter prospective study addressing the frequency of probable DAWS (Rabinak-Nirenberg criteria) in PD patients. The self-completed Nonmotor Symptoms Questionnaire (which addresses the core features of DAWS) was administered at clinical follow-up at 1 month in 51 patients (33 male; mean age: 73.0 ± 9.9 years; PD duration: 12.2 ± 6.3 years) who had discontinued dopamine agonists. Twelve out of fifty-one patients (24%) met clinical criteria for DAWS, the most common symptoms of which were anxiety (91.7%), pain (50%), sweating (41.7%), and anhedonia (16.7%), after the withdrawal of a DA (ropinirole, pramipexole, or cabergoline). In this first prospective evaluation of DAWS in the clinic, preliminary data indicate a high rate after discontinuation of a range of DAs, particularly in the context of impulse control disorders. Larger, controlled studies are required to establish a definitive management pathway.

How Do I Examine Nonmotor Aspects of Parkinson's Disease? What Not to Miss and What to Ignore?

Nonmotor symptoms (NMS) of Parkinson's disease are a wide range of symptoms that occur well before the onset of the motor syndrome and are present right until the end of life. NMS could be classified to several types and broadly belong to dopaminergic, nondopaminergic, drug-induced subgroups and those related to motor response fluctuations. NMS are relatively under-recognized in clinical practice and can be rapidly assessed in the clinic by asking patients to complete the Non-Motor Symptoms Questionnaire (which can be downloaded from http://www.movementdisorders.org/MDS/Education/Rating-Scales/Rating-Scales-By-Disorder.htm) while they are waiting to be seen. The consultation thereafter can cover the important aspects of the symptoms that have been declared by the patient in addition to the management of the motor symptoms.

Subcutaneous apomorphine and non-motor symptoms in Parkinson's disease.

Non-motor symptoms (NMS) are now recognized to occur across all stages of Parkinson's disease (PD) and as a result there has been an increasing focus on their diagnosis, quantification and effective management. While in some subjects, NMS may be present before diagnosis, in advanced PD, NMS can contribute to hospitalization, severe disability and a shortened life expectancy. Strategies for continuous drug delivery have been reported to have a beneficial effect on NMS in PD and while the efficacy of apomorphine on motor function in PD has been confirmed in a number of studies, in addition to its possible anti-dyskinetic effect, a number of reports have also outlined the possible beneficial effect of apomorphine on NMS. This review sets out to examine the efficacy of apomorphine in non-motor aspects of PD, including its effect on neuropsychiatric and gastrointestinal symptoms, sleep (including restless legs syndrome), urinary dysfunction, pain and impulse control disorders. The analysis takes into consideration case reports, and open-label and comparative case-control studies published to date. Results of this review suggest that although data on the effect of apomorphine on NMS in PD patients are limited there is a strong suggestion of a beneficial effect that warrants further investigation in double-blind studies.