Device-Aided Treatment Strategies in Advanced Parkinson's Disease

doi:10.1016/bs.irn.2017.03.001

International Review of Neurobiology

Volume 132, 2017, Pages 453-474

https://doi.org/10.1016/bs.irn.2017.03.001 Get rights and content

Abstract

With peroral levodopa treatment, a majority of patients develop motor fluctuations and dyskinesia already within a few years of therapy. Device-aided Parkinson (PD) therapies refer to deep brain stimulation (DBS), levodopa–carbidopa intestinal gel infusion (LCIG), and subcutaneous infusion of the dopamine agonist apomorphine and represent effective strategies counteracting motor fluctuations and dyskinesia. These three therapy options seem to be similarly effective in reducing “time with PD symptoms (off time)” by at least 60%–65%. The use of advanced therapy also leads to a significant reduction of dyskinesia. Recent studies also indicate that these therapies can improve a number of nonmotor symptoms in advanced PD. Altogether this results in an improved health-related quality of life in most treated patients. The side effects and complications are quite different between the three; for DBS, serious adverse events include intracranial bleeding and infection, LCIG complications relate to the infusion equipment and the establishment of the percutaneous endoscopic gastrostomy, while for apomorphine infusion the most common side effect is a formation of noduli (local inflammation) at the point of infusion. The device-aided therapies are all indicated for the treatment of motor fluctuations and/or dyskinesia when peroral/transdermal PD medications cannot be further optimized. However, the choice of device-aided therapy is made on basis of indications/contraindications, but also the patients’ symptom profile and his/her personal preferences. Therefore, it is important these treatments are discussed early, well before motor and nonmotor symptoms have deteriorated excessively.

Introduction

Levodopa therapy is the most effective treatment for Parkinson's disease (PD) medication (Olanow & Koller, 1998). However, long-term peroral levodopa intake results in clinical fluctuations and dyskinesia. Progressive loss of dopamine nerve terminals and delayed gastric emptying likely contribute to the unpredictable motor responses observed with orally dosed levodopa (LeWitt, 2014). The absorption is also compromized by other gastrointestinal abnormalities like small intestinal bacterial overgrowth and an altered gut microbiota. These abnormalities can also be responsible of nausea, early morning off and unpredictable motor and nonmotor fluctuations. Several studies show that within 2–5 year of levodopa treatment more than 50% of patients develop motor fluctuations, while the risk of dyskinesia increases by 10% per year (LeWitt, 2014, Schapira and Obeso, 2006). Three device-aided therapies constitute the main treatment strategies for advanced PD: deep brain stimulation (DBS), levodopa–carbidopa intestinal gel (LCIG), and continuous subcutaneous apomorphine infusion (CSA).

Section snippets

Deep Brain Stimulation

DBS is an established therapy for advanced PD and it has almost completely replaced ablative techniques with advantages such as reversibility, adjustability, and a lower risk of side effects (Okun, 2012). DBS is a complementary treatment option to medication with approval for several targets: the ventral intermediate nucleus of the thalamus (VIM; Zesiewicz et al., 2005), the internal globus pallidus (GPi), and the subthalamic nucleus (STN; Limousin et al., 1998, Melamed et al., 2007).

The Basics

LCIG is a gel containing levodopa and the decarboxylase inhibitor carbidopa at concentrations of 20 and 5 mg/mL, respectively. The infusion pump can be carried in a small bag around the neck or the waist and weighs about 500 g when it is loaded with a new gel-containing cartridge. The treatment response is often evaluated during a nasoduodenal phase before initiating the full procedure. During LCIG treatment, the gel is infused continuously through the abdominal wall with the help of a percutane

The Basics

The nonergot dopamine agonist apomorphine is a nonselective agonist for dopamine D₂ and—to a lesser extent—D₁ receptors, but also functions as an antagonist for α-adrenergic and 5-HT2 receptors. There is a need for studies investigating the effects of CSA in placebo-controlled blinded trials, but this is likely to change as a large multicenter study has recently been concluded. CSA is the least invasive of the device-aided therapies for advanced PD and it is entirely reversible. The apomorphine

Conclusions

The safety and efficacy of device-aided therapies have been well established. In the case of DBS, the best results are achieved based on technical knowledge of the stimulation, detailed knowledge of the basal ganglia anatomy, as well as changes in the medical therapy.

Both LCIG and CSA have been studied rather thoroughly in studies with either prospective open-label or retrospective designs. With the randomized controlled double-blinded study on LCIG, the level of evidence has improved further

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Safety and efficacy of continuous subcutaneous foslevodopa-foscarbidopa in patients with advanced Parkinson's disease: a randomised, double-blind, active-controlled, phase 3 trial
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Citation Excerpt :
DBS improves off time and dyskinesia but requires a neurosurgical intervention that is associated with potentially serious complications and is not recommended for elderly patients who might have vascular disorders.10 Reductions in off time were reported in CSAI studies, but the poor tolerability of high doses, reduced tolerability over time, and formation of subcutaneous nodules are limitations.10,11 Additionally, DBS and CSAI can rarely be used as a monotherapy for patients with advanced Parkinson's disease.12
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.
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.
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.
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.
AbbVie.
Foslevodopa/foscarbidopa subcutaneous infusion maintains equivalent levodopa exposure to levodopa-carbidopa intestinal gel delivered to the jejunum
2022, Parkinsonism and Related Disorders
Citation Excerpt :
In line with what expected by the low dose of LD administered, no clinically significant laboratory measurements, vital signs, suicidal behaviors/ideation or other systemic events were observed during the course of this study. Mild infusion site reactions were reported in subjects who received foslevodopa/foscarbidopa, which is consistent with previous reports of other medications that are delivered as a CSCI [14–16]. Data from adults and children receiving insulin as CSCI for management of diabetes, show that although adverse events associated with insulin pumps are common, the overall rates of permanent discontinuation due to those events are low [17].
The objective of this study was to compare the pharmacokinetics (PK) of levodopa (LD) from 24-h continuous subcutaneous infusion of foslevodopa/foscarbidopa to the LD pharmacokinetics from 16-h levodopa-carbidopa intestinal gel (LCIG) followed by night-time oral LD/carbidopa (CD) doses.
This was a Phase 1, open-label, randomized, 2-period crossover study conducted in 25 male and female healthy volunteers.
The LD exposures (C_max0-16, AUC_0-16 and AUC∞) following subcutaneous infusion of 700/35 mg foslevodopa/foscarbidopa over 24 h were similar (<8% difference) to those of LCIG 350/87.5 mg LD/CD administered over 16 h followed by two 100/25 mg LD/CD oral doses at 18 and 21 h after the start of LCIG delivery.
Foslevodopa/foscarbidopa subcutaneous infusion provides levodopa exposures comparable to LCIG throughout the day.
Not Applicable.
Should we start integrating genetic data in decision-making on device-aided therapies in Parkinson disease? A point of view
2021, Parkinsonism and Related Disorders
Citation Excerpt :
All these therapeutic options provide greater motor improvement than their oral counterparts. However, their side effects and complications are unique and can be substantial [6]. Therefore, we often individualize therapy according to clinical features, goals of treatment, financial state, and support environment.
Parkinson disease (PD) is a complex heterogeneous neurodegenerative disorder. Association studies have revealed numerous genetic risk loci and variants, and about 5–10% suffer from a monogenic form. Because the presentation and course of PD is unique to each patient, personalized symptomatic treatment should ideally be offered to treat the most disabling motor and non-motor symptoms. Indeed, clinical milestones and treatment complications that appear during disease progression are influenced by the genetic imprint. With recent advances in PD, more patients live longer to become eligible for device-aided therapies, such as apomorphine continuous subcutaneous infusion, levodopa duodenal gel infusion, and deep brain stimulation surgery, each with its own inclusion and exclusion criteria, advantages and disadvantages. Because genetic variants influence the expression of particular clinical profiles, factors for better or worse outcomes for device-aided therapies may then be proactively identified. For example, mutations in PRKN, LRRK2 and GBA express phenotypes that favor suitability for different device therapies, although with marked differences in the therapeutic window; whereas multiplications of SNCA express phenotypes that make them less desirable for device therapies.
The next chapter in symptomatic Parkinson disease treatments
2019, Parkinsonism and Related Disorders
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From the neuropsychiatric standpoint, apomorphine is considered to be better tolerated than oral dopamine agonists. Nevertheless, mild hallucinations (20%), as well as severe visual hallucinations (10%), have been reported, although likely less common than intermittent apomorphine delivery [42]. Furthermore, a recent long-term observational study reported cognitive decline 15 months after receiving CSAI, and hallucinations after 39.8 months [77].
Significant advances in the symptomatic treatment of Parkinson disease (PD) have occurred since the discovery of levodopa (LD). Perhaps as a testament to its unparalleled efficacy, novel formulations aiming to optimize LD delivery to obtain better bioavailability, longer duration of effect and less plasma level fluctuations remain a major focus of drug development, nearly 5 decades since it was first commercially used. In addition, alternative apomorphine delivery formulations are also in development to provide rapid-acting, needle-free agents for the management of “off” episodes in patients experiencing motor fluctuations. “Non-dopaminergic” approaches have also emerged as promising treatments targeting different pathways to enhance the modulation of dopaminergic and neuroprotective mechanisms. This paper focuses on reviewing the evidence on the latest advances in non-surgical, symptomatic motor PD treatment.
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Chapter Sixteen - Device-Aided Treatment Strategies in Advanced Parkinson's Disease

Abstract

Introduction

Section snippets

Deep Brain Stimulation

The Basics

The Basics

Conclusions

Parkinsonism & Related Disorders

Parkinsonism & Related Disorders

Parkinsonism & Related Disorders

Parkinsonism & Related Disorders

The Lancet. Neurology

Parkinsonism & Related Disorders

The Lancet. Neurology

The Lancet Neurology

Parkinsonism & Related Disorders

Revue Neurologique

Basal Ganglia

Parkinsonism & Related Disorders

The Lancet Neurology

Pallidal vs subthalamic nucleus deep brain stimulation in Parkinson disease

Archives of Neurology

Effect and safety of duodenal levodopa infusion in advanced Parkinson's disease: A retrospective multicenter outcome assessment in patient routine care

Journal of Neural Transmission

Body weight gain rate in patients with Parkinson's disease and deep brain stimulation

Movement Disorders

Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease

Stereotactic and Functional Neurosurgery

Mechanism of action of deep brain stimulation

Neurology

Infections and hardware salvage after deep brain stimulation surgery: A single-center study and review of the literature

Stereotactic and Functional Neurosurgery

Risk factors for hemorrhage during microelectrode-guided deep brain stimulator implantation for movement disorders

Neurosurgery

Surgical site infections after deep brain stimulation surgery: Frequency, characteristics and management in a 10-year period

PloS One

Hardware-related complications of deep brain stimulation: A ten year experience

Acta Neurochirurgica

Motor and non-motor outcomes of continuous apomorphine infusion in 125 Parkinson's disease patients

Parkinsonism & Related Disorders

Surgical and hardware complications of deep brain stimulation. A seven-year experience and review of the literature

Acta Neurochirurgica

Clinical and neuropsychological follow up at 12 months in patients with complicated Parkinson's disease treated with subcutaneous apomorphine infusion or deep brain stimulation of the subthalamic nucleus

Journal of Neurology, Neurosurgery, and Psychiatry

A randomized trial of deep-brain stimulation for Parkinson's disease

New England Journal of Medicine

Levodopa/carbidopa intestinal gel therapy for advanced Parkinson disease: An early toxic effect for small nerve fibers?

Muscle & Nerve

Quality of life in Parkinson's disease improved by apomorphine pump: The OPTIPUMP cohort study

Journal of Neurology

A randomized trial of focused ultrasound thalamotomy for essential tremor

The New England Journal of Medicine

Risks of common complications in deep brain stimulation surgery: Management and avoidance

Journal of Neurosurgery

Levodopa-carbidopa intestinal gel in advanced Parkinson's disease: Final 12-month, open-label results

Movement Disorders

Pallidal versus subthalamic deep-brain stimulation for Parkinson's disease

New England Journal of Medicine

Hardware-related complications of deep brain stimulation: A review of the published literature

Stereotactic and Functional Neurosurgery

Bilateral subthalamic nucleus stimulation for Parkinson's disease: A systematic review of the clinical literature

Neurosurgery

Two-year follow-up of subthalamic deep brain stimulation in Parkinson's disease

Movement Disorders

Remarks on the surgery of the central nervous system

BMJ

Effect and time course of deep brain stimulation of the globus pallidus and subthalamus on motor features of Parkinson's disease

Clinical Neuropharmacology

Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson's disease: A prospective study using single-dose challenges

Movement Disorders

Advanced stages of PD: Interventional therapies and related patient-centered care

Journal of Neural Transmission

Intraduodenal levodopa-carbidopa intestinal gel infusion improves both motor performance and quality of life in advanced Parkinson's disease

Journal of Clinical Neuroscience

Integrated safety of levodopa-carbidopa intestinal gel from prospective clinical trials

Movement Disorders

Levodopa therapy for Parkinson's disease: Pharmacokinetics and pharmacodynamics

Movement Disorders

Electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease