Practical use of apomorphine infusion in Parkinson's disease: lessons from the TOLEDO study and clinical experience.

Subcutaneous apomorphine infusion is a device-aided therapy for Parkinson's disease that can be considered when motor fluctuations become persistent and are no longer adequately controlled by oral/transdermal medication. Apomorphine infusion is less invasive than enteral levodopa, deep brain stimulation or focused ultrasound, and is often indicated even when neurosurgical approaches are contraindicated. This article aims to provide practical guidance for doctors and nurses initiating and treating patients with apomorphine infusion, and is based on both trial data and clinical experience from movement disorders specialists. A post hoc analysis of data from the TOLEDO randomized clinical trial of apomorphine infusion was conducted along with an analysis of 'real world' experience from 13 movement disorders specialists using a questionnaire that focused on starting patients on apomorphine infusion. Practical guidelines for starting treatment with apomorphine infusion are provided taking into consideration the regional disparities in healthcare. Apomorphine infusion is straightforward to administer but to be successful it requires concordance from the patient and family, and clinical support from an experienced team of doctors and nurses, particularly in the early months of treatment.

Healthcare resource utilization and device-aided therapy discussions with eligible patients across the Parkinson's disease continuum: Revelations from the MANAGE-PD validation cohort.

INTRODUCTION: Device-aided therapy may improve the quality of life (QoL) for people with advanced Parkinson's disease (PD) and poorly controlled symptoms with oral therapy. MANAGE-PD is a validated tool classifying patients based on symptom control and advanced treatment eligibility. This study focused on patient/caregiver reported outcomes and healthcare resource utilization among patients grouped by MANAGE-PD categories. METHODS: Device-aided therapy-naïve patients receiving oral treatments were identified from the Adelphi Parkinson's Disease Programme. Patients were categorized (category 1 to 3) using MANAGE-PD. PD-specific QoL (PDQ-39), care partner burden (ZBI), satisfaction with current treatment, healthcare resource utilization, associated healthcare costs, and future treatment discussion with providers were measured. Categories were compared using ANOVA, t-test, chi square and adjusted regression analyses. RESULTS: Of the analytical sample (n = 2709), 18.9% were inadequately controlled on current therapy and potentially eligible for device-aided therapies (category 3). As expected, they had worse patient/caregiver reported outcomes versus patients in categories 1 or 2. However, the degree of difference in healthcare resource utilization, including: greater number of hospitalizations, emergency room (ER) visits and consultations, higher likelihood of being recipients of respite care, and greater PD treatment burden, was unexpected. Importantly, of patients in category 3 and their care partners, >40% did not report discussions with providers about device-aided therapies. CONCLUSION: MANAGE-PD category 3 patients had significantly higher burden on healthcare resources versus patients well-controlled with oral treatment or requiring only oral medication adjustments; yet almost half had no discussion on device-aided therapies with providers. Device-aided therapies may be considered in these patients.

Tools and criteria to select patients with advanced Parkinson's disease for device-aided therapies: a narrative review.

This article provides an overview of the various screening and selection tools which have been developed over the past 25 years to identify patients with Parkinson's disease (PD) possibly eligible for device-aided therapies (DATs). For the available screening tools, we describe the target therapies (subtypes of DAT), development methods, validation data, and their use in clinical practice. In addition, the historical background and potential utility of these screening tools are discussed. The challenges in developing and validating these tools are also addressed, taking into account the differences in population, the local health care organization, and resource availability.

Infusion Therapies in the Treatment of Parkinson's Disease.

Oral levodopa is the gold-standard therapy for treating Parkinson's disease (PD) but after a few years of treatment the therapeutic window narrows, and patients often experience various treatment-related complications. Patients in this advanced PD stage may benefit from alternative therapy, such as continuous intrajejunal delivery of levodopa-carbidopa intestinal gel (LCIG; or carbidopa-levodopa enteral suspension), continuous intrajejunal delivery of levodopa-carbidopa-entacapone intestinal gel, or continuous subcutaneous apomorphine infusion. Consideration and initiation of infusion therapies in advanced PD are suggested before the onset of major disability. The present review summarizes clinical evidence for infusion therapy in advanced PD management, discusses available screening tools for advanced PD, and provides considerations around optimal use of infusion therapy.

Impact of advanced Parkinson's disease on caregivers: an international real-world study.

BACKGROUND: Caring for a partner or family member with Parkinson's disease (PD) negatively affects the caregiver's own physical and emotional well-being, especially those caring for people with advanced PD (APD). This study was designed to examine the impact of APD on caregiver perceived burden, quality of life (QoL), and health status. METHODS: Dyads of people with PD and their primary caregivers were identified from the Adelphi Parkinson's Disease Specific Program (DSP™) using real-world data from the United States, Japan and five European countries. Questionnaires were used to capture measures of clinical burden (people with PD) and caregiver burden (caregivers). RESULTS: Data from 721 patient-caregiver dyads in seven countries were captured. Caregivers had a mean age 62.6 years, 71.6% were female, and 70.4% were a spouse. Caregivers for people with APD had a greater perceived burden, were more likely to take medication and had lower caregiver treatment satisfaction than those caring for people with early or intermediate PD; similar findings were observed for caregivers of people with intermediate versus early PD. Caregivers for people with intermediate PD were also less likely to be employed than those with early PD (25.3% vs 42.4%) and spent more time caring (6.6 vs 3.2 h/day). CONCLUSIONS: This real-world study demonstrates that caregivers of people with APD experience a greater burden than those caring for people with early PD. This highlights the importance of including caregiver-centric measures in future studies, and emphasizes the need for implementing treatments that reduce caregiver burden in APD. TRIAL REGISTRATION: N/A.

Spinal cord stimulation therapy for patients with Parkinson's disease and gait problems (STEP-PD): study protocol for an exploratory, double-blind, randomised, placebo-controlled feasibility trial.

Introduction: Gait difficulties are common in Parkinson's disease (PD) and cause significant disability. These symptoms are often resistant to treatment. Spinal cord stimulation (SCS) has been found to improve gait, including freezing of gait, in a small number of patients with PD. The mechanism of action is unclear, and some patients are non-responders. With this double-blind, placebo-controlled efficacy and feasibility clinical and imaging study, we aim to shed light on the mechanism of action of SCS and collect data to inform development of a scientifically sound clinical trial protocol. We also aim to identify clinical and imaging biomarkers at baseline that could be predictive of a favourable or a negative outcome of SCS and improve patient selection. Methods and analysis: A total of 14 patients will be assessed with clinical rating scales and gait evaluations at baseline, and at 6 and 12 months after SCS implantation. They will also receive serial 18F-deoxyglucose and 18FEOBV PET scans to assess the effects of SCS on cortical/subcortical activity and brain cholinergic function. The first two patients will be included in an open pilot study while the rest will be randomised to receive active treatment or placebo (no stimulation) for 6 months. From this point, the entire cohort will enter an open label active treatment phase for a subsequent 6 months. Ethics and dissemination: This study was reviewed and approved by the Committee on Health Research Ethics, Central Denmark RM. It is funded by the Danish Council for Independent Research. Independent of outcome, the results will be published in peer-reviewed journals and presented at national and international conferences. Trial registration number: NCT05110053; ClinicalTrials.gov Identifier.

Hot and Cold Cognitive Disturbances in Parkinson Patients Treated with DBS-STN: A Combined PET and Neuropsychological Study.

Patients with Parkinson's disease (PD) often suffer from non-motor symptoms, which may be caused by serotonergic dysfunction. Deep Brain Stimulation (DBS) in the subthalamic nucleus (STN) may also influence non-motor symptoms. The aim of this study is to investigate how the cerebral 5-HT system associates to disturbances in cognition and mood in PD patients with DBS-STN turned on and off. We used psychological tests and questionnaires to evaluate cognitive function and the effects on mood from turning DBS-STN off. We applied a novel PET neuroimaging methodology to evaluate the integrity of the cerebral serotonin system. We measured 5-HT1BR binding in 13 DBS-STN-treated PD patients, at baseline and after turning DBS off. Thirteen age-matched volunteers served as controls. The measures for cognition and mood were correlated to the 5-HT1BR availability in temporal limbic cortex. 5-HT1BR binding was proportional to working memory performance and inverse proportional to affective bias for face recognition. When DBS is turned off, patients feel less vigorous; the higher the limbic and temporal 5-HT1BR binding, the more they are affected by DBS being turned off. Our study suggests that cerebral 5-HTR binding is associated with non-motor symptoms, and that preservation of serotonergic functions may be predictive of DBS-STN effects.

Psychometric Properties of Clinical Indicators for Identification and Management of Advanced Parkinson's Disease: Real-World Evidence From G7 Countries.

INTRODUCTION: Standardized and validated criteria to define advanced Parkinson's disease (PD) or identify patient eligibility for device-aided therapy are needed. This study assessed the psychometric properties of clinical indicators of advanced PD and eligibility for device-aided therapy in a large population. METHODS: This retrospective analysis of the Adelphi Parkinson's Disease Specific Programme collected data from device-aided therapy-naïve people with PD in G7 countries. We assessed the presence of 15 clinical indicators of advancing PD and seven indicators of eligibility for device-aided therapy in patients classified with advanced PD or as eligible for device-aided therapy by the treating physician. Accuracy was assessed using area under the curve (AUC) and multivariable logistic regression models. Construct validity was examined via known-group comparisons of disease severity and burden among patients with and without each clinical indicator. RESULTS: Of 4714 PD patients, 14.9% were classified with advanced PD and 17.5% as eligible for device-aided therapy by physician judgment. The presence of each clinical indicator was 1.9- to 7.3-fold more likely in patients classified with advanced PD. Similarly, the presence of device-aided therapy eligibility indicators was 1.8- to 5.5-fold more likely in patients considered eligible for device-aided therapy. All indicators demonstrated high clinical screening accuracy for identifying advanced PD (AUC range 0.84-0.89) and patients eligible for device-aided therapy (AUC range 0.73-0.80). The Unified Parkinson's Disease Rating Scale (UPDRS) score, cognitive function, quality of life, and caregiver burden were significantly worse in indicator-positive patients. CONCLUSION: Specific clinical indicators of advanced PD and eligibility for device-aided therapy demonstrated excellent psychometric properties in a large sample, and thus may provide an objective and reliable approach for patient identification and treatment optimization.

Advanced Parkinson's disease (PD) refers to the stage of disease when motor complications are difficult to manage with standard therapy. Patients reaching this stage of the disease may benefit from a treatment change from pills to the so-called device-aided therapies. However, there is currently no unanimous definition of advanced PD, which makes it challenging to identify suitable candidates for device-aided therapies. There is urgent need to define specific features (or 'clinical indicators') to support healthcare professionals and patients in the identification of advanced PD as well as to define suitability for device-aided therapy. This study aimed to assess the accuracy of 15 clinical indicators and seven device-aided therapy eligibility criteria using information from a large database of 4714 patients in G7 countries. Physicians classified 14.9% of patients as having advanced PD and 17.5% were judged to be eligible for device-aided therapy. Each clinical indicator or device-aided therapy eligibility indicator was detected more frequently in patients classified as having advanced PD and in patients considered eligible for device-aided therapy, respectively. All indicators had high accuracy for identifying advanced PD and device-aided therapy-eligibility. These previously identified clinical indicators of advanced PD and device-aided therapy eligibility may provide an objective and reliable approach for patient screening and treatment optimization.

Validation and clinical value of the MANAGE-PD tool: A clinician-reported tool to identify Parkinson's disease patients inadequately controlled on oral medications.

INTRODUCTION: Making Informed Decisions to Aid Timely Management of Parkinson's Disease (MANAGE-PD) is a clinician-reported tool designed to facilitate timely identification and management of patients with advancing Parkinson's disease (PD) with suboptimal symptom control while on standard therapy. The objective of this study was to evaluate the validity and clinical value of the tool. METHODS: Driven by structured inputs from a steering committee and panel of PD experts, the tool was developed to classify patients into 3 categories. Validity and clinical value were elucidated using a two-pronged approach: (i) hypothetical patient vignettes (n = 10) developed based on the MANAGE-PD tool and rated by 17 PD specialists and 400 general neurologists (GN) and (ii) patients with PD (n = 2546) managed in real-world clinical settings. Vignette validity was based on concordance between PD experts' clinical judgement and MANAGE-PD vignette categorization. Patient-level data was used for known-group comparisons (validity) and discordant pair analysis (clinical value). RESULTS: The tool demonstrated strong validity and clinical value among PD specialists (intraclass coefficient [ICC] 0.843; Fleiss weighted kappa [ƙweighted] 0.79) and GN (ICC 0.690; ƙweighted 0.65) using patient vignettes. MANAGE-PD also demonstrated real-world validity and clinical value based on ability to identify patients with incrementally higher clinical, economic, and humanistic PD burden across categories of the tool (p < 0.01). CONCLUSIONS: MANAGE-PD demonstrated robust validity and clinical value in identifying patients with suboptimal PD symptom control. Clinical use of MANAGE-PD may complement treatment decision-making and facilitate timely and comprehensive management of patients with advancing PD.

Continuous Subcutaneous Apomorphine Infusion in Parkinson's Disease: A Single-Center, Long-Term Follow-Up Study of the Causes for Discontinuation.

(1) Background: Subcutaneous apomorphine infusion (SCAI) is one of the three main treatment options for motor fluctuations in advanced Parkinson's disease (PD). The adherence to SCAI is generally considered to be low due to adverse events and because it is perceived as a treatment option to be used for a limited period only. We evaluated the reasons for discontinuation of SCAI in relation to when patients stopped treatment. (2) Methods: We reviewed the medical records of PD patients treated with SCAI at a single center, capturing patient demographics and the reasons for cessation of SCAI. (3) Results: 101 patients were included in the analysis, with a median time on treatment of 6.34 years. The main reasons for stopping SCAI were adverse events, death, and dissatisfaction with treatment. In the first 6 years of treatment, the predominant side effects leading to discontinuation were somnolence and hallucinations. (4) Conclusions: We suggest that SCAI can be an effective long-term treatment option for advanced PD, but it requires careful patient selection, a high level of communication with the patient and carer, and rigorous monitoring of the effects of treatment and for any adverse events so they can be promptly managed.

Close relationships in Parkinson´s disease patients with device-aided therapy.

OBJECTIVES: Deep brain stimulation, continuous subcutaneous apomorphine infusion, and levodopa-carbidopa intestinal gel infusion, together called device-aided therapies (DAT), are introduced when oral and transdermal pharmacotherapy are not enough for a satisfactory control of Parkinson's disease (PD) symptoms. Solid relationships are central to an individual's well-being, but the impact of close relationships in advanced PD remains underexplored. The aim of this study was to investigate the development of close relationships between PD patients and their partners following the initiation of DAT and to examine the relationship structures in these relationships. MATERIALS AND METHODS: This was a retrospective quantitative multicenter pilot study wherein 41 couples, patients with advanced PD and their partners, retrospectively rated their relationship satisfaction before the start of DAT, after one year of DAT and at the time of the interview. The couples also answered the Experiences in Close Relationships-Questionnaire of Relational Structures (ECR-RS). RESULTS: Partners more often report changes in relationship satisfaction than patients between baseline and both 1 year after start of DAT (p = .049) and last evaluation (p = .041). The ECR-RS data reported significantly higher avoidance score for partners (p = .005) and significantly higher anxiety score for patients (p = .024). CONCLUSIONS: The close relationship wherein one part has PD and receives DAT has a high risk of being unequal. Prospective studies are needed for further clarification of the interplay between advanced PD, DAT, and close relationships, this in order to improve pre- and postinterventional support for PD patients receiving DAT, as well as their partners.

Long-term safety and efficacy of apomorphine infusion in Parkinson's disease patients with persistent motor fluctuations: Results of the open-label phase of the TOLEDO study.

INTRODUCTION: The randomized, double-blind phase (DBP) of the TOLEDO study confirmed the efficacy of apomorphine infusion (APO) in reducing OFF time in PD patients with persistent motor fluctuations despite optimized oral/transdermal therapy. Here we report safety and efficacy results including the 52-week open-label phase (OLP). METHODS: All patients completing the 12-week DBP (including those switching early to open-label treatment) were offered OLP entry. The primary objective was the evaluation of long-term safety of APO. RESULTS: Eighty-four patients entered the OLP (40 previously on APO, 44 on placebo) and 59 patients (70.2%) completed the study. The safety profile of APO was consistent with experience from extensive clinical use. Common treatment-related adverse events (AEs) were mild or moderate infusion site nodules, somnolence and nausea. Fourteen (16.7%) patients discontinued the OLP due to AEs, those involving >1 patient were infusion site reactions (n = 4) and fatigue (n = 2); hemolytic anemia occurred in one case. Reduction in daily OFF time and improvement in ON time without troublesome dyskinesia were sustained for up to 64 weeks. Pooled data for week 64 (n = 55) showed a mean (SD) change from DBP baseline in daily OFF time of -3.66 (2.72) hours and in ON time without troublesome dyskinesia of 3.31 (3.12) hours. Mean (±SD) daily levodopa-equivalent dose decreased from DBP baseline to week 64 by 543 mg (±674) and levodopa dose by 273 mg (±515). CONCLUSIONS: The safety and efficacy of APO infusion were demonstrated with long-term use for persistent motor fluctuations, allowing substantial reductions in oral PD medication.

Parkinson patients have a presynaptic serotonergic deficit: A dynamic deep brain stimulation PET study.

Patients with Parkinson's disease (PD) often suffer from non-motor symptoms, which may be caused by serotonergic dysfunction. Apart from alleviating the motor symptoms, Deep Brain Stimulation (DBS) in the subthalamic nucleus (STN) may also influence non-motor symptoms. The aim of this study is to investigate how turning DBS off affects the serotonergic system. We here exploit a novel functional PET neuroimaging methodology to evaluate the preservation of serotonergic neurons and capacity to release serotonin. We measured cerebral 5-HT1BR binding in 13 DBS-STN treated PD patients, at baseline and after turning DBS off. Ten age-matched volunteers served as controls. Clinical measures of motor symptoms were assessed under the two conditions and correlated to the PET measures of the static and dynamic integrity of the serotonergic system. PD patients exhibited a significant loss of frontal and parietal 5-HT1BR, and the loss was significantly correlated to motor symptom severity. We saw a corresponding release of serotonin, but only in brain regions with preserved 5-HT1BR, suggesting the presence of a presynaptic serotonergic deficit. Our study demonstrates that DBS-STN dynamically regulates the serotonin system in PD, and that preservation of serotonergic functions may be predictive of DBS-STN effects.

Access and Use of Device-Aided Therapies for Parkinson's Disease in Denmark.

BACKGROUND: In Denmark's five regions, there is potential inequality in access to device-aided therapy (DAT) for Parkinson's disease (PD) based on structural or socioeconomic factors. It is unclear how long DAT is maintained and affects concomitant medication. OBJECTIVES: To investigate access to DAT by comparing the proportion of patients with DBS, subcutaneous apomorphine infusion (SCAI), or levodopa/carbidopa intestinal gel (LCIG) in Danish regions 2008-2016 and describe demographics of patients, changes in use of comedication, and maintenance of DAT. METHODS: This work is a retrospective nationwide population-based registry analysis generated by combining various registries and statistics in Denmark. RESULTS: From 2008 to 2016, 612 patients started DAT. There were statistically significant differences in the number of patients starting DAT between the Capital Region (99.5 per 1,000) and both Central Jutland (66.6 per 1,000) and North Jutland (70.6 per 1,000; P < 0.05). Among DBS and LCIG patients, respectively, 4% and 42% were aged ≥70 years, 68% and 63% were men (vs. 59% in the general PD population; P < 0.05 for DBS), 73% and 63% had a partner (vs. 62% in the general PD population), and 73% and 71% had a qualifying education (vs. 63% in the general PD population; P < 0.05). Use of PD-related medication decreased significantly from 4 years before to 4 years after DAT. Eighty-one percent of the patients who started LCIG, alive 4 years later, had maintained this treatment. CONCLUSIONS: There is unequal access to DAT in the Danish regions, and political and social considerations are warranted to address structural and socioeconomic causes.

Everyday Occupations and Other Factors in Relation to Mental Well-Being among Persons with Advanced Parkinson's Disease.

This cross-sectional study investigated performed activities and the level of satisfaction with everyday occupations among people (n = 67) with advanced Parkinson's disease (PD), and how these factors and experiences of social relationships were related to mental well-being. Managing one's hygiene and physical exercises were activities that the majority still performed, whereas few were engaged in work or other productive occupations. Perceived health problems and satisfaction with everyday occupations were important factors for mental well-being since satisfaction with everyday occupations may be an important focus for occupational therapists and other health professionals when supporting mental well-being among persons with advanced PD.

EuroInf 2: Subthalamic stimulation, apomorphine, and levodopa infusion in Parkinson's disease.

OBJECTIVE: Real-life observational report of clinical efficacy of bilateral subthalamic stimulation (STN-DBS), apomorphine (APO), and intrajejunal levodopa infusion (IJLI) on quality of life, motor, and nonmotor symptoms (NMS) in Parkinson's disease (PD). METHODS: In this prospective, multicenter, international, real-life cohort observation study of 173 PD patients undergoing STN-DBS (n = 101), IJLI (n = 33), or APO (n = 39) were followed-up using PDQuestionnaire-8, NMSScale (NMSS), Unified PD Rating Scale (UPDRS)-III, UPDRS-IV, and levodopa equivalent daily dose (LEDD) before and 6 months after intervention. Outcome changes were analyzed with Wilcoxon signed-rank or paired t test when parametric tests were applicable. Multiple comparisons were corrected (multiple treatments/scales). Effect strengths were quantified with relative changes, effect size, and number needed to treat. Analyses were computed before and after propensity score matching, balancing demographic and clinical characteristics. RESULTS: In all groups, PDQuestionnaire-8, UPDRS-IV, and NMSS total scores improved significantly at follow-up. Levodopa equivalent daily dose was significantly reduced after STN-DBS. Explorative NMSS domain analyses resulted in distinct profiles: STN-DBS improved urinary/sexual functions, mood/cognition, sleep/fatigue, and the miscellaneous domain. IJLI improved the 3 latter domains and gastrointestinal symptoms. APO improved mood/cognition, perceptual problems/hallucinations, attention/memory, and the miscellaneous domain. Overall, STN-DBS and IJLI seemed favorable for NMSS total score, and APO favorable for neuropsychological/neuropsychiatric NMS and PDQuestionnaire-8 outcome. CONCLUSIONS: This is the first comparison of quality of life, nonmotor. and motor outcomes in PD patients undergoing STN-DBS, IJLI, and APO in a real-life cohort. Distinct effect profiles were identified for each treatment option. Our results highlight the importance of holistic nonmotor and motor symptoms assessments to personalize treatment choices. © 2019 International Parkinson and Movement Disorder Society.

Interdisciplinary recognizing and managing of drug-induced tardive oromandibular dystonia: two case reports.

Tardive dystonia is a risk factor in medical antipsychotic treatment. It often begins with repetitive involuntary jaw and tongue movements resulting in impaired chewing and detrimental effect on the dentition. The orofacial dysfunction may go unrecognized in a neurological setting. The diagnosis may be difficult so we suggest interdisciplinary collaboration.

Apomorphine subcutaneous infusion in patients with Parkinson's disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial.

BACKGROUND: Subcutaneous apomorphine infusion is a clinically established therapy for patients with Parkinson's disease with motor fluctuations not optimally controlled by oral medication. Open-label studies have shown that apomorphine infusion is effective in reducing off time (periods when antiparkinsonian drugs have no effect), dyskinesias, and levodopa dose, but confirmatory evidence from double-blind, controlled studies is lacking. We aimed to investigate the efficacy and safety of apomorphine infusion compared with placebo in patients with Parkinson's disease with persistent motor fluctuations despite optimised oral or transdermal treatment. METHODS: In this randomised, placebo-controlled, double-blind, multicentre trial, we enrolled patients at 23 European hospitals who had been diagnosed with Parkinson's disease more than 3 years previously and had motor fluctuations not adequately controlled by medical treatment. Patients were randomly assigned (1:1) with a computer-generated randomisation code, stratified by site, to receive 3-8 mg/h apomorphine or placebo saline infusion during waking hours (16 h a day [range 14-18 was acceptable]) for 12 weeks. The flow rate of the study drug and other oral medications could be adjusted during the first 4 weeks on the basis of individual efficacy and tolerability, after which patients entered an 8-week maintenance period. The primary endpoint was the absolute change in daily off time based on patient's diaries, and was assessed in the full analysis set, which was defined as all patients who received at least one dose of allocated study drug and had efficacy data available at any timepoint post-baseline. Safety was assessed in all patients who received at least one dose of apomorphine or placebo. All study participants and investigators were masked to treatment assignment. Both the 12-week double-blind phase and the 52-week open-label phase of this study are now complete; this paper reports results for the double-blind phase only. This study is registered with ClinicalTrials.gov (NCT02006121). FINDINGS: Between March 3, 2014, and March 1, 2016, 128 patients were screened for eligibility and 107 were randomly assigned, of whom 106 were included in the full analysis set (n=53 in both groups). Apomorphine infusion (mean final dose 4·68 mg/h [SD 1·50]) significantly reduced off time compared with placebo (-2·47 h per day [SD 3·70] in the apomorphine group vs -0·58 h per day [2·80] in the placebo group; difference -1·89 h per day, 95% CI -3·16 to -0·62; p=0·0025). Apomorphine was well tolerated without any unexpected safety signals. Six patients in the apomorphine group withdrew from the study because of treatment-related adverse events. INTERPRETATION: Apomorphine infusion results in a clinically meaningful reduction in off time in patients with Parkinson's disease with persistent motor fluctuations despite optimised oral or transdermal therapy. FUNDING: Britannia Pharmaceuticals.

Viewpoint and practical recommendations from a movement disorder specialist panel on objective measurement in the clinical management of Parkinson's disease.

Motor aspects of Parkinson's disease, such as fluctuations and dyskinesia, can be reliably evaluated using a variety of "wearable" technologies, but practical guidance on objective measurement (OM) and the optimum use of these devices is lacking. Therefore, as a first step, a panel of movement disorder specialists met to provide guidance on how OM could be assessed and incorporated into clinical guidelines. A key aspect of the incorporation of OM into the management of Parkinson's disease (PD) is defining cutoff values that separate "controlled" from "uncontrolled" symptoms that can be modified by therapy and that relate to an outcome that is relevant to the person with PD (such as quality of life). Defining cutoffs by consensus, which can be subsequently tested and refined, is the first step to optimizing OM in the management of PD. OM should be used by all clinicians that treat people with PD but the least experienced may find the most value, but this requires guidance from experts to allow non-experts to apply guidelines. While evidence is gained for devices that produce OM, expert opinion is needed to supplement the evidence base.

Understanding the role of the Parkinson's disease nurse specialist in the delivery of apomorphine therpy.

Optimal care of Parkinson's disease (PD) patients should involve a multidisciplinary team (MDT) of which a PD nurse specialist (PDNS) is a key member. The role of a PDNS is particularly prominent in the care of advanced PD patients suitable for apomorphine because, in addition to nursing skills, apomorphine treatment requires liaison, training, interaction and coordination with patients, caregivers and other members of the MDT as well as the interface with primary care physicians. The therapeutic success of apomorphine therapy depends not only upon the pharmacologic drug response, but also on how well the patient understands his/her disease and how to handle the therapy. In this respect, a PDNS is a vital member of the MDT who provides education and training, support, and is available for consultation when problems arise. In this article, we review the literature on the contribution of PDNSs in both continuous subcutaneous apomorphine infusion and intermittent subcutaneous apomorphine injection and highlight the various beneficial aspects of PDNS care, supported by scientific evidence when available. Despite a low level of published evidence, there is strong clinical evidence that the impact of PDNSs on the management of apomorphine therapy is vital and indispensable for the success of this treatment.