Adrian Paul R. De Leon; Roongroj Bhidayasiri; Onanong Phokaewvarangkul

doi:10.14802/jmd.25045

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Letter to the editor Optimizing Device-Aided Therapies in Advanced Parkinson’s Disease: A Case Series on Continuous Subcutaneous Apomorphine Infusion in Challenging Scenarios: Adrian Paul R. De Leon^1,2, Roongroj Bhidayasiri^1,3, Onanong Phokaewvarangkul¹; Journal of Movement Disorders 2025;18(3):285-288.
DOI: https://doi.org/10.14802/jmd.25045
Published online: May 14, 2025

¹Chulalongkorn Center of Excellence for Parkinson’s Disease and Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand

²Department of Neurology, Jose R. Reyes Memorial Medical Center, Manila, Philippines

³The Academy of Science, The Royal Society of Thailand, Bangkok, Thailand

Corresponding author: Onanong Phokaewvarangkul, MD, PhD Chulalongkorn Center of Excellence for Parkinson’s Disease and Related Disorders, Department of Medicine, Faculty of Medicine, ChulalongkornUniversity and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, 1873 Rama 4 Rd., Pathumwan, Bangkok 10330, Thailand / Tel: +66-2256-4000 (ext. 70704) / E-mail: oji@chulapd.org

• Received: February 25, 2025 • Revised: April 18, 2025 • Accepted: May 12, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Dear Editor,

Globally, Parkinson’s disease (PD) is the fastest-growing neurological disorder, with the number of advanced PD (aPD) cases increasing [1]. To address motor complications (MCs), device-aided therapies (DATs), such as continuous subcutaneous apomorphine infusion (CSAI), deep brain stimulation (DBS), and levodopa-based gels, have expanded treatment options. However, selecting appropriate modalities remains challenging because of patient-related, physician-related, and treatment-related factors, especially in resource-limited areas (Figure 1A) [2].

In Thailand, only DBS and CSAI are available, but cost, invasiveness, and eligibility concerns restrict access. This article presents four aPD patients from the Chulalongkorn Center of Excellence for Parkinson’s Disease and Related Disorders selected according to previously published selection criteria where patients’ symptoms did not align with previous recommendations for CSAI but rather showed promising outcomes [3].

A 72-year-old male presented with a 10-year history of tremor-predominant PD, characterized predominantly by left-sided rest tremors, slowness, and rigidity. Despite levodopa, dopamine agonists, and rasagiline titration to a levodopa equivalent daily dosage (LEDD) of 1,720 mg, the MC improved minimally, and tremors remained refractory (Supplementary Table 1 in the online-only Data Supplement). The patient was then referred for DATs. Although DBS was recommended because of refractory tremors, the patient preferred CSAI. The CSAI was initiated, and a tremor response was observed at 1.5 mg/hr, with sustained rest tremor suppression until 7.0 mg/hr, when refractory hiccups developed. Consequently, the infusion rate was maintained at 6.8 mg/hr, resulting in the absence of tremor, mild nontroublesome dyskinesia, improved sleep, absence of psychiatric symptoms, and no recurrence of hiccups, but bradykinesia persisted (Unified Parkinson’s Disease Rating Scale Part III [UPDRS-III]: 24; tremor section: 0). The total LEDD of the oral medications was reduced to 1,420 mg (Figure 1B).

A 74-year-old female presented with a 12-year history of right-hand and leg tremors, clumsiness, and slowed movements. Despite the need for 10 doses of medications daily (LEDD: 993 mg), severe MC persisted (Supplementary Table 1 in the online-only Data Supplement). The patient was then referred for DATs. Although DBS of the globus pallidus interna is recommended for the control of severe dyskinesia, the patient selected the CSAI because of its noninvasiveness. CSAI was initiated, and dyskinesia and wearing-off symptoms improved at 3.2 mg/hr, prompting continued titration to 6.8 mg/hr for 9.5 hours (UPDRS-III score: 17; Abnormal Involuntary Movement Scale: 12). The total LEDD of the oral medications was reduced to 568 mg (Figure 1B).

A 70-year-old male presented with a 15-year history of PD characterized by right-hand tremor and stiffness and was treated with levodopa/carbidopa. MCs developed, such as wearing-off for up to 10 hours daily and freezing of gait, even when a high dose of medications (LEDD: 1,970 mg) is used. Visual Hallucinations (VHs) developed but were unresponsive to quetiapine and clozapine, prompting a referral for DATs (Supplementary Table 1 in the online-only Data Supplement). Owing to uncontrolled neuropsychiatric symptoms, this patient may be unsuitable for DATs. However, the CSAI was chosen because of its reversibility, noninvasive method, and tolerability in PD patients with psychiatric symptoms. The CSAI was titrated with close monitoring of VHs. Mobility initially improved without VHs at 1.7 mg/hr until its recurrence at 2.2 mg/hr. Optimal symptom control was achieved at 2.15 mg/hr for 9.5 hours. At this dose, VHs and tremor did not recur and improved parkinsonism minimally (UPDRS-III score: 39). The total LEDD of the oral medications was reduced to 832 mg (Figure 1B).

A 74-year-old British male presented with a 7-year history of lower limb slowness, resting tremor of the left foot, and gait and balance difficulties. Severe MCs developed a partial response to levodopa/benserazide, levodopa/carbidopa controlled release, and ropinirole (LEDD: 1,800 mg) (Supplementary Table 1 in the online-only Data Supplement). The patient was then referred for DATs. Owing to anticoagulant use (apixaban 5 mg twice daily), this patient may be unsuitable for surgical DATs. However, CSAI was chosen because of its reversibility and less invasive nature. The CSAI was gradually titrated with close monitoring for abdominal bruising and ecchymosis. Motor improvement was well tolerated at 0.8 mg/hr, until minimal bruising developed at the injection sites at 2.5 mg/hr. After the steel needles were replaced with silicone needles, no recurrence of bruising was observed. At this dose, wearing-off symptoms decreased, dyskinesias did not occur, and there was no recurrence of bruising until the 1-year follow-up. (UPDRS-III score: 18) (Figure 1B).

Tremor control was achieved and sustained in patient 1, similar to findings from previous studies [4]. In contrast, the larger open-label TOLEDO trial does not report on the tremor domain [3]. The mechanism by which apomorphine improves refractory tremor is not known. However, other studies attributed its greater clinical potency to rapid penetration of the blood–brain barrier and recruitment of the serotonergic system through affinity for 5HT_1A and 5HT_2(A-C) receptors and supplementing the serotonin deficiency in the median raphe nucleus or promoting striatal dopamine release [4,5].

Severe dyskinesias and motor impairment were substantially improved and sustained in patient 2 throughout the titration, possibly due to the reduction in LEDD rather than a direct antidyskinetic effect of CSAI, as demonstrated in other studies [3].

VHs improved in patient 3 with CSAI and concomitant LEDD reduction; hence, the antipsychotic effect may be attributed to LEDD reduction rather than direct antipsychotic activity of CSAI [6]. Moreover, the EuroInf study also demonstrated decreased VHs with higher doses of CSAI [4]. VHs in PD are also attributed to decreased contrast sensitivity due to excessive retinal and cortical dopamine receptor stimulation and low D1-like receptor activity in the prefrontal cortex, impairing attention [6]. Therefore, optimization of dopaminergic activity through both a reduction in LEDD and supplementation with D1-like receptor activity in the prefrontal cortex may be associated with the control of VHs.

In patient 4, anticoagulant use, which may contraindicate brain surgery and poses risks for infusion therapy, was managed by using CSAI at a low dose. Bruising did not recur after switching to silicone needles. This finding is consistent with a study that demonstrated decreased skin reactions with the use of plastic catheters, attributed to decreased trauma to the surrounding tissue [7].

This case series presents four aPD patients where CSAI yielded acceptable outcomes despite relative contraindications, reflecting real-life scenarios. Although there are several limitations in this case series, such as the unavailability of other DATs in Thailand, an individualized approach remains key. The application of evidence-based medicine requires tailored treatment, monitoring, and informed discussions. Delivering CSAI successfully in resource-limited areas requires continuous learning and adaptation. With careful risk‒benefit assessment, CSAI remains a viable option.

Supplementary Materials

The online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.25045.

Supplementary Table 1.

The summary table outlines patient demographics

jmd-25045-Supplementary-Table-1.pdf

Notes

Ethics Statement

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1975 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all the patients included in the study.

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

This research was funded by the following grants: the Thailand Science Research and Innovation Fund of Chulalongkorn University, the Center of Excellence grants of Chulalongkorn University (CE67_015_3000_006), and the Thai Red Cross Education and Research Committee.

Acknowledgments

We would like to express our sincere gratitude to everyone who contributed to the completing of this manuscript. We thank all the nursing staff and colleagues at the Chulalongkorn Center of Excellence for Parkinson’s Disease and Related Disorders. We also thank all the patients who participated in this study.

Author Contributions

Conceptualization: Onanong Phokaewvarangkul, Roongroj Bhidayasiri. Data curation: Adrian Paul R. De Leon. Formal analysis: Adrian Paul R. De Leon. Funding acquisition: Onanong Phokaewvarangkul, Roongroj Bhidayasiri. Investigation: Adrian Paul R. De Leon. Methodology: Onanong Phokaewvarangkul. Project administration: Adrian Paul R. De Leon. Resources: Onanong Phokaewvarangkul, Roongroj Bhidayasiri. Software: Adrian Paul R. De Leon. Supervision: Onanong Phokaewvarangkul, Roongroj Bhidayasiri. Validation: Onanong Phokaewvarangkul. Visualization: Adrian Paul R. De Leon, Onanong Phokaewvarangkul. Writing—original draft: Adrian Paul R. De Leon. Writing—review & editing: Onanong Phokaewvarangkul, Roongroj Bhidayasiri.

Figure 1.

Clinical profiles of device-aided therapies and the individual patient responses to continuous subcutaneous apomorphine infusion. A: Available evidence for the different device-aided therapies for managing symptoms of advanced PD. Green: effective; yellow: possibly effective; red: contraindicated. B: (a) Line graph demonstrating the titration of the CSAI dose in patient 1 compared with the changes in the LEDD and ON-medication UPDRS-III score. (b) Line graph demonstrating the titration of the CSAI dose in patient 2 compared with the changes in the LEDD and ON-medication UPDRS-III score. (c) Line graph demonstrating the titration of the CSAI dose in patient 3 compared with the change in LEDD, ON-medication UPDRS-III score, and hallucinations. (d) Line graph demonstrating the titration of the CSAI dose in patient 4 compared with the changes in the LEDD and ON-medication UPDRS-III score. CSAI, continuous subcutaneous apomorphine infusion; DBS, deep brain stimulation; LCIG, levodopa-carbidopa intestinal gel; UPDRS-III, Unified Parkinson’s Disease Rating Scale Part III; LEDD, levodopa equivalent daily dose.

REFERENCES

1. GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the global burden of disease study 2016. Lancet Neurol 2019;18:459–480.PubMed PMC
2. Phokaewvarangkul O, Auffret M, Groppa S, Markovic V, Petrovic I, Bhidayasiri R. What was first and what is next in selecting device-aided therapy in Parkinson’s disease? Balancing evidence and experience. J Neural Transm (Vienna) 2024;131:1307–1320.Article PubMed PDF
3. Bhidayasiri R, Chaudhuri KR, LeWitt P, Martin A, Boonpang K, van Laar T. Effective delivery of apomorphine in the management of Parkinson disease: practical considerations for clinicians and Parkinson nurses. Clin Neuropharmacol 2015;38:89–103.PubMed
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Optimizing Device-Aided Therapies in Advanced Parkinson’s Disease: A Case Series on Continuous Subcutaneous Apomorphine Infusion in Challenging Scenarios

Figure 1. Clinical profiles of device-aided therapies and the individual patient responses to continuous subcutaneous apomorphine infusion. A: Available evidence for the different device-aided therapies for managing symptoms of advanced PD. Green: effective; yellow: possibly effective; red: contraindicated. B: (a) Line graph demonstrating the titration of the CSAI dose in patient 1 compared with the changes in the LEDD and ON-medication UPDRS-III score. (b) Line graph demonstrating the titration of the CSAI dose in patient 2 compared with the changes in the LEDD and ON-medication UPDRS-III score. (c) Line graph demonstrating the titration of the CSAI dose in patient 3 compared with the change in LEDD, ON-medication UPDRS-III score, and hallucinations. (d) Line graph demonstrating the titration of the CSAI dose in patient 4 compared with the changes in the LEDD and ON-medication UPDRS-III score. CSAI, continuous subcutaneous apomorphine infusion; DBS, deep brain stimulation; LCIG, levodopa-carbidopa intestinal gel; UPDRS-III, Unified Parkinson’s Disease Rating Scale Part III; LEDD, levodopa equivalent daily dose.

Figure 1.

Optimizing Device-Aided Therapies in Advanced Parkinson’s Disease: A Case Series on Continuous Subcutaneous Apomorphine Infusion in Challenging Scenarios



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