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Background: Levodopa is the most effective symptomatic therapy for Parkinson's disease, but patients with advanced Parkinson's disease develop motor fluctuations with chronic oral levodopa therapy. Foslevodopa-foscarbidopa is a soluble formulation of levodopa and carbidopa prodrugs that is delivered as a 24-h/day continuous subcutaneous infusion, and we aimed to assess the safety and efficacy of this formulation in patients with advanced Parkinson's disease., Methods: A 12-week randomised, double-blind, double-dummy, active-controlled study was done at 65 academic and community study centres in the USA and Australia. Patients with levodopa-responsive advanced Parkinson's disease inadequately controlled on current therapy, including at least 2·5 h of average daily off time, were randomly assigned (1:1) to continuous subcutaneous infusion of foslevodopa-foscarbidopa plus oral placebo or to oral immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution. Randomisation was stratified by site by means of a permutated-block schedule with a block size of two. The participants, treating investigators, study site personnel, and sponsor were masked to treatment group allocation. The primary and first key secondary endpoint in the hierarchical testing strategy were change from baseline to week 12 in on time without troublesome dyskinesia and off time, respectively; both endpoints were evaluated by an intention-to-treat analysis applying a mixed model for repeated measures analysis. Safety and tolerability were assessed throughout the study. The study is completed and is listed on ClinicalTrials.gov, NCT04380142., Findings: Between Oct 19, 2020, and Sept 29, 2021, of 270 participants screened and 174 enrolled, 141 were randomly assigned and received continuous subcutaneous infusion of foslevodopa-foscarbidopa plus oral placebo capsules (n=74) or oral encapsulated immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution (n=67). Compared with levodopa-carbidopa, foslevodopa-foscarbidopa showed a significantly greater increase in on time without troublesome dyskinesia (model-based mean [SE] 2·72 [0·52] vs 0·97 [0·50] h; difference 1·75 h, 95% CI 0·46 to 3·05; p=0·0083) and a significantly greater reduction in off time (-2·75 [0·50] vs -0·96 [0·49] h; difference -1·79 h, -3·03 to -0·54; p=0·0054). Hierarchical testing ended after the first secondary endpoint. Adverse events were reported in 63 (85%) of 74 patients in the foslevodopa-foscarbidopa group versus 42 (63%) of 67 in the levodopa-carbidopa group, and incidences of serious adverse events were similar between the groups (six [8%] of 74 vs four [6%] of 67, respectively). The most frequent adverse events in the foslevodopa-foscarbidopa group were infusion site adverse events (erythema 20 [27%]), pain 19 [26%]), cellulitis (14 [19%]), and oedema (nine [12%]), most of which were non-serious and mild-moderate in severity. The only system organ class that had more than one serious adverse event in the foslevodopa-foscarbidopa group was infections and infestations (catheter site cellulitis [one [1%]] and infusion site cellulitis [one [1%]). Adverse events led to premature discontinuation of study drug in 16 (22%) of 74 participants in the foslevodopa-foscarbidopa group versus one (1%) of 67 participants in the oral levodopa-carbidopa group., Interpretation: Foslevodopa-foscarbidopa improved motor fluctuations, with benefits in both on time without troublesome dyskinesia and off time. Foslevodopa-foscarbidopa has a favourable benefit-risk profile and represents a potential non-surgical alternative for patients with advanced Parkinson's disease., Funding: AbbVie., Competing Interests: Declaration of interests MJS received honoraria or consultation fees from Allergan, Abbott, AbbVie, Acorda, Medtronic, Merz Therapeutics, Neurocrine Pharmaceuticals, Sunovion, and Teva. JA is a study investigator and has received honoraria from AbbVie, Allergan, Teva, US World Meds, Medtronic, and Abbot; he is an investigator in studies sponsored by AbbVie, Biogen, Acadia, Northwestern University, Neuroderm, Massachusetts General Hospital, and AstraZeneca. He is also a scientific advisor for AbbVie. VSCF receives a salary from NSW Health; has received unrestricted research grants from the Michael J Fox Foundation, AbbVie and Merz; has been on Advisory Boards for AbbVie, Allergan, Ipsen, Merz, Praxis, Seqirus, Stada, Teva, and UCB; he receives royalties from Health Press. TEK has received funding from Stada, AbbVie, UCB Pharma, Seqiris, and Teva. KK has served as a consultant for AbbVie and has participated in AbbVie speakers’ bureaus. IL is a member of the faculty of the University of California San Diego and is supported by an endowment and university funds; she also receives funds as Chief Editor of Frontiers in Neurology and as member of the Rossy PSP Toronto Center; she is an investigator in studies funded by Roche, AbbVie, Biogen, Centogene, EIP-Pharma, Biohaven Pharmaceuticals, Novartis, and United Biopharma SR–UCB; she receives funds and participates in studies from the National Institutes of Health, the Michael J Fox Foundation, the Parkinson Foundation, the Lewy Body Association, and CurePSP; she is a member of the Scientific Advisory Board for Amydis but does not receive funds. DO has received speaking honoraria from AbbVie. MAS has received consulting fees from Medtronic, and clinical trial funding from AbbVie, US WorldMeds, Sanofi, Abbott, Takeda, and Insightec. DGS is a member of the faculty of the University of Alabama at Birmingham; is supported by endowment and university funds; and is an investigator in studies funded by AbbVie, the American Parkinson Disease Association, the Michael J Fox Foundation for Parkinson Research, Alabama Department of Commerce, the Department of Defense, and NIH grants P50NS108675, R25NS079188, and T32NS095775; he has a clinical practice and is compensated for these activities through the University of Alabama Health Services Foundation; in addition, he has served as a consultant for or received honoraria from AbbVie, the Parkinson Study Group, Curium Pharma, Roche, Appello, the International Parkinson Disease and Movement Disorder Society, Theravance, McGraw Hill, Sanofi-Aventis, and Alnylam Pharmaceutics. EOV has received consulting fees from AbbVie, Acorda, Allergan, and Medtronic. RAH has served on a scientific advisory board for Inhibikase Therapeutics, Impel NeuroPharma, CereSpir, and Vivifi Biotech; he has received financial compensation for work as a consultant from AbbVie, Acadia Pharmaceuticals, Acorda Therapeutics, Adamas Pharmaceuticals, Affiris, Amneal Pharmaceuticals, ApoPharma, Aptinyx, AstraZeneca, Axovant Gene Therapies, Biomarin International, Biotie Therapies, Britannia Pharmaceuticals., Cadent Therapeutics, Cerevance, Cerevel Therapeutics, Curium, Cynapsus Therapeutics, Denali Therapeutics, Eli Lilly, Enterin, F Hoffmann-La Roche, GE Healthcare, Global Kinetics Business Consultants, Global Life Sciences Solutions, Impax Laboratories, Impel NeuroPharma, Inhibikase Therapeutics, Intec, Intrance Medical Systems, International Stem Cell Corporation (ISCO), Jazz Pharmaceuticals, Kashiv BioSciences, KeifeRx, Kyowa Kirin, Lundbeck, Merz Pharma, the Michael J Fox Foundation, Mitsubishi Tanabe Pharma America, the National Parkinson Foundation, Neuro Challenge Foundation for Parkinson's, Neurocrine Biosciences, NeuroDerm, Neuropore Therapies, Novus Biologicals, Orion, Parkinson Study Group, Perception OpCo (Cerevel Therapeutics), Pfizer, Pharma Two B, PharmaTher, Prexton Therapeutics, Regenera Pharma, Research Catalyst, Revance Therapeutics, Sanofi-Aventis, Sarepta Therapeutics, Scion NeuroStim, Seelos Therapeutics, Sio Gene Therapies, Sunovion Pharmaceuticals, Supernus Pharmaceuticals, Takeda Pharmaceuticals, Teva Pharmaceutical Industries, Tolmar Pharmaceuticals, UCB Biosciences, US WorldMeds, and Vivifi Biotech. He serves on speakers’ bureaus for AbbVie, Acorda Therapeutics, Adamas Pharmaceuticals, Amneal Pharmaceuticals, Kyowa Kirin, Lundbeck, Neurocrine Biosciences, Sunovion Pharmaceuticals, Teva Pharmaceuticals, and US WorldMeds. He has received research support from AbbVie, Adamas Pharmaceuticals, AstraZeneca, Atlantic Research–Chelsea Therapeutics, Axovant Sciences, Biogen, Biotie Therapies, Cavion, Centogene, Cerevance, Cerevel Therapeutics, Civitas Therapeutics, Cynapsus Therapeutics, Dart NeuroScience, Enterin, F Hoffman-La Roche, Global Kinetics Corporation, Impax Laboratories, Intec Pharma, Integrative Research Laboratories Sweden, Jazz Pharmaceuticals, Kyowa Kirin, Lundbeck, the Michael J Fox Foundation, National Institutes of Health, National Institute of Neurological Disorders and Stroke, Neuraly, NeuroDerm, Northwestern University, the Parkinson Study Group, Pfizer, Pharma Two B, Prexton Therapeutics, Revance Therapeutics, Sanofi US Services, Sun Pharma Advanced Research, Sunovion Pharmaceuticals, and UCB Biopharma; he holds stock in Axial Biotherapeutics and Inhibikase Therapeutics, and has received license fee payments from USF for Parkinson's Disease Diary. KB is a former employee of AbbVie, is currently employed by Harmony Biosciences, and might hold AbbVie stock or options. MFF, NF, AJ, WZR, ST, and HZ are employees of AbbVie and might hold stock or options., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

This article presents an evidence-based approach to the patient with newly diagnosed Parkinson disease (PD). It includes a discussion of the current understanding of the aetio-pathogenesis of PD and of clinical features, both motor and non-motor, that assist the clinician in making this diagnosis. An approach to the management of early stage PD is discussed, including emerging evidence of the benefits of physical exercise in this condition, and issues to consider in the selection of dopaminergic medication. The newly diagnosed patient with PD is often keen to know what the future holds for them, as they face this progressive neurodegenerative condition. While currently available medical therapies are symptomatic, rather than disease-modifying, in nature, it is hoped that improved understanding of the aetio-pathogenesis of PD will pave the way for future disease-modifying therapies., (© 2021 Royal Australasian College of Physicians.)

Parkinson disease (PD) is a complex neurodegenerative disorder that can present heterogeneously with a combination of motor and non-motor symptoms. α-synuclein, a neuronal protein, can undergo aberrant conformational change resulting in the intra-neuronal accumulation of toxic oligomers that form Lewy bodies, the pathological hallmark of PD. There is evidence that pathological α-synuclein exhibits prion-like behaviour in its mode of transmission through the nervous system. The choice of initial dopaminergic treatments should be individually tailored but long term outcomes appear to be equivalent. There is level A evidence supporting the benefit of three different device-assisted therapies in treating troublesome motor fluctuations and dyskinesias. Stem cell transplantation as currently being trialled is predominantly a symptomatic therapy targeting only limited regions of the brain affected by PD, and will need to be proven to be not only as effective but as safe as currently available device-assisted therapies. New modes of treatment including active immunisation against oligomeric α-synuclein and drugs that alter cellular metabolism show some promise. The inability to effectively treat a range of non-motor, non-dopaminergic symptoms remains a major therapeutic challenge., (© 2019 AMPCo Pty Ltd.)

In Australia 1% of individuals aged over 50 years have Parkinson disease (PD). Guidance for commencing device-assisted therapies (DAT) for PD in Australia was developed based on a review of European recommendations and their relevance to the local clinical setting. An online survey and teleconference discussions were held by a group of eight local movement disorder experts to develop consensus. Referral to a movement disorder specialist and consideration of DAT is appropriate when motor fluctuations cause disability or reduced quality of life, response to treatment is inconsistent or motor fluctuations and dyskinesias require frequent treatment adjustment without apparent benefit and levodopa is required four or more times daily. Three types of DAT are available in Australia for patients with PD: continuous subcutaneous apomorphine; continuous levodopa-carbidopa intestinal gel infusion; and deep brain stimulation. All improve consistency of motor response. The most important aspects when considering which DAT to use are the preferences of the patient and their carers, patient comorbidities, age, cognitive function and neuropsychiatric status. Patients and their families need to be provided with treatment options that are suitable to them, with adequate explanations regarding the recommendations and comparison of potential device-related complications. DAT are best managed, where possible, in a specialist centre with experience in all three types of therapy. Proactive and early management of symptoms during disease progression is essential to maintain optimally motor responses and quality of life in patients with PD., (© 2017 Royal Australasian College of Physicians.)

Background: Patients with Parkinson disease (PD) commonly experience motor fluctuations and dyskinesias in response to oral dopaminergic medications. Affected patients may benefit from device-assisted therapy, such as medication infusion or deep brain stimulation surgery. This is the first Australian study of the long-term adherence to apomorphine infusion (AI) in patients with PD., Aims: To assess the adherence to AI in patients with PD in a single centre over a 10-year period and to find the reasons for discontinuation in patients who discontinued AI., Methods: This is an observational study of patients with PD treated with AI between 2004 and 2014. Outcome measures included changes in motor function and quality of life following AI, change in dose of other dopaminergic medications following AI, duration of infusion, adverse effects, reasons for cessation of AI and subsequent treatment after cessation., Results: Mean duration of AI was 21.65 months. No patient achieved apomorphine monotherapy, and the mean reduction in the levodopa-equivalent dose of other dopaminergic medications after AI was 22.7%. The benefit of AI on motor function and quality of life was rated as 'much improved' or 'better' in 83% of patients. The most common reasons for discontinuation of AI were adverse effects and inadequate motor benefit. Most patients who discontinued AI were subsequently treated with another device-assisted therapy., Conclusion: AI is an effective therapy for severe motor response complications in PD, especially in the short and medium term. However, many patients cannot be maintained on AI in the longer term., (© 2017 Royal Australasian College of Physicians.)

Aim: To determine gastric emptying, blood pressure, mesenteric artery blood flow, and blood glucose responses to oral glucose in Parkinson's disease., Methods: Twenty-one subjects (13 M, 8 F; age 64.2 ± 1.6 years) with mild to moderate Parkinson's disease (Hoehn and Yahr score 1.4 ± 0.1, duration of known disease 6.3 ± 0.9 years) consumed a 75 g glucose drink, labelled with 20 MBq (99m)Tc-calcium phytate. Gastric emptying was quantified with scintigraphy, blood pressure and heart rate with an automated device, superior mesenteric artery blood flow by Doppler ultrasonography and blood glucose by glucometer for 180 min. Autonomic nerve function was evaluated with cardiovascular reflex tests and upper gastrointestinal symptoms by questionnaire., Results: The mean gastric half-emptying time was 106 ± 9.1 min, gastric emptying was abnormally delayed in 3 subjects (14%). Systolic and diastolic blood pressure fell (P < 0.001) and mesenteric blood flow and blood glucose (P < 0.001 for both) increased, following the drink. Three subjects (14%) had definite autonomic neuropathy and 8 (38%) had postprandial hypotension. There were no significant relationships between changes in blood pressure, heart rate or mesenteric artery blood flow with gastric emptying. Gastric emptying was related to the score for autonomic nerve function (R = 0.55, P < 0.01). There was an inverse relationship between the blood glucose at t = 30 min (R = -0.52, P < 0.05), while the blood glucose at t = 180 min was related directly (R = 0.49, P < 0.05), with gastric emptying., Conclusion: In mild to moderate Parkinson's disease, gastric emptying is related to autonomic dysfunction and a determinant of the glycaemic response to oral glucose.

Tremor is a common clinical problem in middle-aged and older patients, and Parkinson disease (PD) is one of the commonest causes. Careful history-taking and physical examination is usually sufficient for diagnosis of PD; extensive investigation is generally not required. Treatment of PD should be individualised, taking into account the patient's age, lifestyle, severity of motor symptoms, level of disability, comorbidities, expectations of treatment and PD subtype (eg, akinetic rigid or tremor dominant). In PD, optimal medical therapy often involves a combination of dopaminergic medications, aiming for doses that provide adequate symptom relief without adverse effects such as dyskinesias and impulse-control disorders. Continuous dopaminergic stimulation and deep brain stimulation should be considered for patients with PD whose motor symptoms cannot be adequately controlled with oral medication, especially those aged less than 70 years.

Background and Importance: Camptocormia is characterized by abnormal flexion of the thoracolumbar spine that increases during upright posture and abates in the recumbent position and has been reported to occur in patients with Parkinson disease. Camptocormia causes significant spinal and abdominal pain, impairment of balance, and social stigma., Clinical Presentation: A 57-year-old woman with Parkinson disease developed severe camptocormia, which did not improve with trials of antiparkinsonian and muscle relaxant medications. The patient was successfully treated with bilateral globus pallidus interna deep brain stimulation surgery under general anesthesia. High-frequency neuromodulation afforded relief of camptocormia and improvement in Parkinson disease symptoms., Conclusion: Camptocormia in Parkinson disease may represent a form of dystonia and can be treated effectively with chronic pallidal neuromodulation.

Parkinson disease (PD) is a multisystem neurodegenerative disorder that affects about 1% of the population over the age of 55 years and has mean age of onset of about 60 years. The Braak hypothesis proposes that the earliest pathological evidence of PD is found in the enteric nervous system, medulla and olfactory bulb, and only subsequently progresses (over years) to the substantia nigra and cortex. Non-motor symptoms, such as constipation, hyposmia and sleep disorders, may precede typical motor features of PD by several years. No treatment has been convincingly shown to slow PD progression (ie, a neuroprotective drug remains elusive). Symptomatic benefit from dopaminergic therapy is usually maintained throughout the course of the disease. The decision as to whether to commence treatment with either levodopa or a dopamine agonist needs to be individually tailored, but long-term outcomes appear to be equivalent. Advanced PD is complicated by the loss of non-dopaminergic neurones, resulting in symptoms that are largely unresponsive to dopaminergic therapy. Treatment with apomorphine, Duodopa or deep-brain stimulation surgery may be beneficial for selected patients with advanced PD. Non-motor symptoms, such as mood disorders, cognitive impairment, autonomic dysfunction and sleep disorders, are responsible for significant morbidity. Management often requires a multidisciplinary approach.