Levodopa-induced respiratory dysfunction in Parkinson’s disease managed with subthalamic nucleus deep brain stimulation

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Neurofunction. 2024;20(2):54-58

Publication date (electronic) : 2024 September 30

doi : https://doi.org/10.52662/nf.2024.00157

So Hee Park, MD, PhD

Department of Neurosurgery, Yeungnam University College of Medicine, Daegu, Korea

Address for correspondence: So Hee Park, MD, PhD Department of Neurosurgery, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Korea Tel: +82-53-620-3790 Fax: +82-53-620-3770 E-mail: shpark123@yu.ac.kr

Received 2024 August 26; Revised 2024 September 28; Accepted 2024 October 3.

Abstract

INTRODUCTION

Since its introduction in the 1960s, levodopa has been the gold standard for the treatment of Parkinson’s disease (PD). However, long-term levodopa treatment is frequently associated with motor fluctuations and dyskinesias, which can severely impact patient quality of life [1,2]. Patients treated with levodopa therapy for 4–6 years have approximately a 40% likelihood of experiencing motor fluctuations and a nearly 40% of developing levodopa-induced dyskinesias (LID) [3]. Motor fluctuations and dyskinesias can become treatment-limiting as increasing the levodopa dose or frequency to manage disease progression can exacerbate disability or reduce quality of life of patients [4,5]. In such cases, deep brain stimulation (DBS) may provide therapeutic benefits.

LID may present as various involuntary movements, including chorea, ballism, dystonia, myoclonus, or combination of these, affecting the neck, facial muscles, jaw, tongue, hips, shoulders, trunk, and limbs or as involuntary flexion of the toes [6]. However, symptomatic respiratory disturbances as a manifestation of LID are rarely reported. Herein, we present a case of an 80-year-old man with PD who experience episodes of respiratory distress attributed to LID, which was effectively treated with DBS.

CASE REPORT

An 82-year-old man with a 12-year history of PD presented with symptoms of wearing-off that persisted despite increasing the dose and frequency of his mediation. He was diagnosed with PD at another hospital, where he had been receiving treatment before visiting our hospital. His PD initially manifested with resting tremor, bradykinesia, and rigidity in his left hand, which gradually spread to the right side. N-3-[18F]fluoropropyl-2β-carbomethoxy-3β-4-iodophenyl nortropane ([18F]FP-CIT) imaging revealed asymmetrically decreased dopamine transporter binding in the bilateral striatum, particularly in the right posterior putamen.

Several months ago, due to his symptoms of freezing of gait and wearing-off, his medication dosages were gradually escalated to benserazide/levodopa 25/100 mg 2.5 tablets four times a day, plus pramipexole SR 0.375 mg twice a day, and opicapone 50 mg once a day. Despite these adjustments, he continued to experience wearing-off symptoms and was switched to levodopa/carbidopa/entacapone 200/50/200 one tablet and levodopa/carbidopa 100/25 mg half a tablet, five times a day, along with safinamide 50 mg once a day, and Madopar dispersible tablets as needed. Despite these changes, symptoms of wearing-off remained challenging to manage, and he experienced occasional respiratory distress, which worsened after the medication change, prompting his visit to our hospital.

Regarding the respiratory distress, the patient reported feeling mildly short of breath when the medication wore off, and occasionally, more severe respiratory after taking the medication. However, these episodes were not consistent, and no clear temporal relationship between the onset of respiratory symptoms and the timing of levodopa administration was observed. He was a non-smoker with no history of primary cardiac or pulmonary disease.

Due to persistent wearing-off symptoms despite the five times daily, DBS was considered. The patient demonstrated a 64.3% improvement in Unified Parkinson’s Disease Rating Scale part III scores in the “on” state (score 15) compared to the “off” state (score 42). During a 7-day inpatient admission for off-medication testing, the patient did not report any respiratory distress. Chest X-ray and pulmonary function tests, including spirometry, showed normal results, suggesting the absence of primary pulmonary pathology (Fig. 1). Echocardiogram and cardiac 123I-mIBG showed no abnormal finding. However, about 3 days after being discharged and resuming his levodopa regimen, he again experienced episodes of respiratory disturbance.

Fig. 1.

Chest X-ray and pulmonary function test results. (A) A chest X-ray shows no significant abnormalities, indicating the absence of structural lung disease. (B) Pulmonary function tests revealed normal lung function, ruling out primary pulmonary pathology as a cause for the patient’s respiratory symptoms.

Given the patient’s symptoms, bilateral subthalamic nucleus (STN) DBS was performed (Fig. 2). Following successful DBS, which allowed for a reduction in his medication dosage, the patient experienced significant improvement in his symptoms, with no further complaints of respiratory distress.

Fig. 2.

Preoperative planning images (A) and postoperative skull (B) and chest X-ray (C) following bilateral subthalamic nucleus deep brain stimulation.

DISCUSSION

A variety of respiratory disorders have been described in association with PD. Some of these abnormalities have been suggested to have underlying mechanisms such as impaired central coordination of respiratory muscles or decreased thoracic mobility and have been shown to improve with dopaminergic therapy [7-9]. However, some respiratory disturbances occur as a consequence of levodopa therapy; these are rarely described and may be underrecognized in clinical practice (Table 1) [7,10-15].

Table 1.

A literature review of cases on respiratory dyskinesia in patients with Parkinson’s disease

Respiratory abnormalities manifesting as symptomatic dyspnea, irregularities in respiratory rate, and fluctuations in depth beginning 30 to 120 minutes after levodopa administration have been documented in a small subset of patients with PD [7,10-12]. The pattern observed is characterized by irregular tachypnea alternating with brief periods of apnea, without paradoxical chest and abdominal movement during breath, which suggests disordered central respiratory rhythm control rather than respiratory muscle chorea [12]. This phenomenon is thought to result from the degeneration of dopaminergic neuronal system, including dopamine-containing neurons in brainstem centers that control breathing. Alterations in dopaminergic receptor function in central respiratory circuits may contribute to levodopa-induced respiratory dysfunction [12]. The temporal relationship between respiratory disturbance and peak levodopa effect has led to the term “respiratory dyskinesia” to describe these abnormalities [10].

When a PD patient presents with respiratory dysfunction, a detailed medical history is crucial to differentiate levodopa-induced respiratory dyskinesia from other respiratory disorders. When the temporal relation with medication is ambiguous, a levodopa challenge test may be helpful [16,17]. To manage respiratory dyskinesia, various pharmacological interventions have been employed. The dopamine agonist tiapride has been reported to suppress abnormal respiratory patterns, and there has been a case where catechol-O-methyltransferase inhibitor was used to reduce the dose of levodopa and improve symptoms [11,16]. For these patients, STN DBS may be a valuable therapeutic option, as it allows for significant reduction in levodopa requirements, consequently minimizing LID [17].

CONCLUSION

In conclusion, respiratory disturbances in PD, although uncommon, should be recognized as a potential complication of levodopa therapy, particularly at peak doses. This case underscores the need for awareness and consideration of nonmotor symptoms in PD, which may be effectively managed through comprehensive treatment strategies, including DBS.

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