Persistent Hiccups after Subthalamic Nucleus Deep Brain Stimulator Implantation for Parkinson’s Disease: Case Report and Literature Review

Abstract

Hiccups are mediated by a reflex arc that consists of afferent, central, and efferent components. The structures involved in the central component have not been fully elucidated, although several brainstem structures have been implicated, including the subthalamic nucleus (STN). Accordingly, Parkinson’s disease (PD), a disease defined by the loss of dopaminergic neurons in the STN, has an interesting, although unspecified, relationship to hiccups. Hiccups have been described in association with PD and the use of dopaminergic medications. Interestingly, deep brain stimulation (DBS) of the STN appears to be implicated in the pathogenesis of hiccups as well. There have been sporadic reports of hiccups occurring in conjunction with STN-DBS. We present a case of hiccups occurring after STN-DBS for PD in a 65-year-old man. STN-DBS significantly improved his PD symptoms; however, he developed persistent and daily hiccups. As of writing, 24 months after surgery, the patient experiences hiccups several times per day with no associated gastrointestinal complaints and with significant improvement in his PD symptoms. This report describes the case details and summarizes the existing literature describing hiccups in patients undergoing surgical treatment for PD.

Introduction

Parkinson’s disease (PD) is a neurodegenerative disease defined by the loss of dopaminergic neurons in the substantia nigra pars compacta [1]. The disease is classically associated with movement disorders, including bradykinesia, tremor, and postural abnormalities, although non-motor symptoms are frequently present as well [1]. Pharmacological treatment focuses on dopamine replacement; additionally, deep brain stimulation (DBS) was approved by the Food and Drug Administration in 2002 for the treatment of PD.

Hiccups have been documented in PD and in patients undergoing medical management of PD, although the mechanism of hiccups in these populations has not been elucidated. Compared to medical management, descriptions of hiccups in association with DBS are relatively rare [2, 3].

This report concerns a patient with PD who developed intermittent daily episodes of hiccups after subthalamic nucleus (STN) placement of DBS electrodes. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000531570).

Case Report

The current case involves a 65-year-old male with a 12-year history of PD. Past medical/surgical history included tonsillectomy, vasectomy, C5-6 cervical discectomy and fusion (secondary to a fall), remote history of migraines, intracranial orthostatic hypotension, celiac disease (biopsy confirmed), occasional symptoms of esophageal reflux (exacerbated by amantadine), borderline B12, vitamin D, and testosterone deficiencies, recent diagnosis of intermediate-grade prostate cancer, and colonoscopic removal of multiple small adenomas.

His significant manifestations of PD included a prominent left arm resting tremor with less significant tremor in the other limbs, bradykinesia, festination, retropulsion, hypomimia, mild dysphagia, hypophonia, and moderate orthostatic hypotension. Aside from the Parkinsonian features, physical exam was remarkable for pedal and pretibial edema, which was largely controlled with pressure support stockings, and an unusual pattern of hyperpigmentation (predominantly involving the dorsolateral aspect of both feet). Preoperative medications included carbidopa/levodopa 25/100 mg q 2 h while awake. Entacapone 200 mg q 4 h while awake, amantadine 100 mg q 8 h, vitamin D 4,000 IU daily, and B complex one daily.

DBS surgery was performed awake using microelectrode recording. Targeting of the STN was chosen based on indirect targeting and then manually adjusted to target the dorsolateral segment. The STN was implanted bilaterally in a single stage using directional leads.

Immediate postoperative course following electrode implantation was without complication, apart from a single episode of vomiting on postoperative day #1, likely related to analgesic use (APAP/hydrocodone). Postoperative imaging demonstrated appropriate lead placement with no adverse findings.

The patient experienced dramatic lesional relief of his Parkinson’s symptoms with resolution of the tremor, improved gait and posture, and stronger voice; however, he developed new onset of frequent hiccups. The initial improvement in Parkinson’s symptoms waned over the next week despite resumption of his preoperative medications, but he continued to experience brief bouts of hiccups one to several times daily. The pulse generator was placed 2 weeks after lead placement. Initial programming 4 weeks from lead implantation and subsequent follow-up programming 2 weeks later (Table 1) resulted in substantial and incremental improvement in the Parkinson’s symptoms, allowing for elimination of amantadine and entacapone and reduction of carbidopa/levodopa to four times daily. The hiccups began after electrode implantation, 2 weeks prior to pulse generator implantation, and 4 weeks prior to turning on the stimulator. There was no change in the pattern once the stimulator was turned on.

Table 1.

DBS device settings

	Timing	Polarity	Amplitude, V/mA	Pulse width, μs	Frequency, Hz	Therapy impedance
Left STN (right arm)	Initial	C+ 2b−	2.3 mA	60	130	2,106
	24 months	C+ 2b−	3.2 mA	70	130	1,575
Right STN (left arm)	Initial	C+ 2−	2.3 mA	60	130	1,012
	24 months	C+ 2−	3.2 mA	60	130	1,012

The patient’s hiccups and reflux symptoms were treated empirically with omeprazole 20 mg daily with relief of the reflux symptoms but no reduction of the hiccups. Reflux symptoms returned after several days but resolved with elimination of the amantadine (which was also accompanied by resolution of the peripheral edema).

At the time of the writing of this report (24 months after the initial lead placement), the patient continues to experience hiccups several times daily with no relationship to other GI symptoms or meals and has been off carbidopa/levodopa for almost 6 months. Hiccups occur 1–5 times per day in no particular pattern and have no relation to meals. When they do occur, there are 1–5 hiccups (usually around 3) – this has been the pattern since the day after electrode implantation. There is no clear hiccup activity during sleep, and he has not been awakened. He continues to experience near-complete tremor arrest and significant improvement of Parkinsonism, with only minimal changes to his initial postoperative programming (Table 1).

Discussion

PD is typically associated with bradykinesia, muscle rigidity, tremor, stooped posture, and festinating gait; later stages of disease often include cognitive and neuropsychiatric dysfunction [1]; however, varied prodromal symptoms, including anosmia, gastrointestinal complaint, sleep disturbances, and autonomic dysfunction, often precede the onset of motor symptoms by several years [4]. The progression of disease reflects the hypothesis that PD pathology begins in the optic bulb and enteric nervous system, with subsequent retrograde migration to the central nervous system via the olfactory and vagus nerves, respectively [4, 5]. There is evidence that the intestinal microbiome in PD patients induces a proinflammatory environment that can increase intestinal epithelial permeability and cause oxidative stress with subsequent alpha-synuclein aggregation [4]. Hiccups are not often reported symptoms of PD, although they are relatively common complaints in PD, with up to 20% of patients reporting frequent hiccups [6].

Hiccup Pathophysiology

Hiccups are mediated by a reflex arc with afferent, central, and efferent components. The afferent limb consists of phrenic, vagal, and sympathetic (T6–12) contributions [7, 8]. The central component of the reflex arc consists of the upper cervical spinal cord and various brainstem structures. Notably, the upper brainstem structures are distinct from physiological respiratory centers [9, 10]. There is strong evidence of dorsolateral medulla involvement, as demonstrated by hiccups in lateral medullary (Wallenberg) syndrome [7, 8]. Additionally, other structures, including the midbrain, hypothalamus, reticular activating system, globus pallidus, and STN, likely contribute to the reflex [8, 9]. The efferent limb consists of phrenic, vagal, and spinal accessory innervation to the inspiratory muscles and glottis [7, 8]. Intractable hiccups can arise from dysfunction at any level of the reflex arc, and intractable hiccups have been described in several clinical conditions. Gastrointestinal conditions, such as gastroesophageal reflux disease, hiatal hernia, esophageal cancer, pancreatitis, and peptic ulceration, have been well described to cause hiccups [6]. According to Braak’s hypothesis of alpha-synuclein spread, PD patients are susceptible to hiccups due to involvement of the enteric nervous system and substantia nigra pars compacta, constituents of the hiccup reflex arc [5]. Several neurological conditions of the cervical spinal cord and brainstem have been reported in patients with intractable hiccups, including syringomyelia, Chiari malformations, neuromyelitis optica, and various vascular or space-occupying lesions [8].

It is well documented that PD patients and patients undergoing therapy with medications affecting dopamine or gamma-aminobutyric acid (GABA) have high rates of hiccups. Dopamine appears to be heavily involved in the central component of the hiccup reflex arc [11], although the exact mechanism of dopamine’s role in hiccups has not been fully elucidated. Up to 20% of PD patients report hiccups, and there are several reported cases of hiccups arising with the use of either dopaminergic or anti-dopaminergic drugs [6, 12]. Paradoxically, dopaminergic drugs have been shown to relieve or cause hiccups [11]. GABA is likewise considered critical in modulating the central limb of the reflex arc. Benzodiazepines and baclofen, both GABA receptor agonists, have also been shown to either relieve or cause hiccups [11]. Dopamine appears to be heavily involved in the central component of the hiccup reflex arc [11]; however, the exact mechanism of dopamine’s role in hiccups has not been fully elucidated, and it is not known whether the PD itself or the drugs used to treat it cause hiccups. Some PD patients experience hiccups prior to initiating medical therapy, while others experience hiccups after initiating medical therapy. Some authors posit that hiccups may even be an overlooked symptom of PD [6, 13]. It is likely that hiccups can arise in PD patients due to factors intrinsic to the disease process and extrinsic pharmacological factors [6]. Similarly, the role of DBS in the onset of hiccups has not been elucidated. Although speculative, it appears activation of STN GABA interneurons by DBS decreases STN glutamatergic output, which may disrupt “downstream” GABA, glutamate, dopamine, and acetylcholine neurotransmission between the striatum, thalamus, and cortex, thus altering several constituents of the central component of the hiccup reflex arc [14].

In a survey of PD patients experiencing hiccups, Miwa and Kondo found that half of the patients attributed hiccups to pharmacotherapy, while the other patients did not [6]. Dopamine agonists have been well documented to cause hiccups [12], and dopamine antagonists, especially chlorpromazine, are well established to relieve hiccups [6, 11]; however, hiccups have also been reported as an initial symptom prior to the diagnosis of PD and pharmacotherapy [6, 15]. Additionally, Miyaoka and Kamijima [16] reported a case of dopamine antagonist-induced hiccups, and other cases reports describe the resolution of hiccups with dopamine agonists [15]. Although there is some contradictory evidence in the literature, there is strong evidence that dopamine agonists are capable of inducing hiccups in PD patients [13].

In a pharmacovigilance database and literature review, Lertxundi et al. [13] describe 45 cases of hiccups occurring secondary to dopamine agonist administration, and the authors attribute the hiccups to dopamine agonism, particularly at the D3 receptor. Interestingly, the authors state that the treatment of hiccups in PD patients may be especially challenging because dopamine antagonists are contraindicated in this population. Dopamine appears to contribute to the development of hiccups by participating in the central component of the reflex arc.

DBS-Hiccups Cases in the Literature

The occurrence of hiccups after DBS of the STN is sparsely reported (Table 2); only one study has directly investigated the phenomenon [2], one report describes 2 cases of this event [3], and a few studies briefly cite hiccups as an adverse event of treatment [17–20]. Wu et al. [2] conducted a retrospective case control study of patients undergoing STN-DBS to identify potential risk factors for developing postoperative hiccups. The group reports that 34 out of 191 patients had postoperative transient persistent hiccups. Through binary multivariate logistic regression analysis, the authors identify four risk factors for hiccups after STN-DBS: male gender, elevated BMI, preoperative amantadine use, and white matter noninfectious peri-electrode edema. Interestingly, the focal peri-electrode white matter edema was limited to the STN, and the presence of edema was temporally correlated with the duration of hiccups, which the authors interpret as evidence of STN involvement in the hiccup reflex arc.

Table 2.

Literature review of PD surgical cases associated with intractable hiccups

Case	Demographics (age, sex)	Surgical indication	Surgery	DBS settings	Hiccup time onset	Hiccup management	Hiccup resolution	Notes
De Bie et al. [9], 1999	54 (mean), 5/7 M, 2/7 F	PD	Posteroventral pallidotomy	NA	Variable: Immediately after surgery to POD 1	NS	6/7 resolved by POD 3; 1/7 resolved by 6 months postop	Composite of 7 cases
Composite of 7 cases
Jochim et al. [3], 2015	71, M	Tremor dominant PD	STN-DBS	125 Hz; 60 μs; left: C+ 3−; 4.7 V interleaving with: 2+ 1−; 2.8 V; right: C+ 10−; 1.8V	POD 2; brief reoccurrence 5 months later		POD 12; reoccurrence resolved after 2 days	Hiccups started POD 2, DBS initiated POD 5
	57, M	Tremor dominant PD	STN-DBS	130 Hz; 60 μs; left: C+ 11−; 4.2 V; right: C+ 2−; 3.0 V	6 months post-op	Domperidone, baclofen, pantoprazole, and levetiracetam: none effective; hiccups self-limiting	Ongoing periodic episodes lasting hours-weeks over period of 16 months	History of hiatal hernia and history of H. pylori infection
Odekerken et al. [20], 2013	NS (not specified for patients with hiccups)	PD	GPi DBS or STN-DBS	NS (not specified for patients with hiccups)	NS	NS	NS	RCT comparing GPi DBS to STN-DBS; hiccups reported in 10/65 GPi patients and 2/63 STN patients, with no further information on hiccups reported
Jiang et al. [19], 2021	NS (not specified for patients with hiccups)	PD	Bilateral STN-DBS with propofol-remifentanil general anesthesia (experimental) or awake (control)	NS (not specified for patients with hiccups)	NS	NS	NS	Purpose of study was investigating effects of propofol on STN neuronal spiking; hiccups reported as side effect in 7/68 patients at 6-month follow-up, with no further information on hiccups reported
Wu et al. [2], 2022	58 (mean); 33/34 M, 1/34 F	PD	STN-DBS under general anesthesia	NS	Most commonly POD 2–3	Several approaches described: antiparkinsonian drugs, metoclopramide, chlorpromazine, drinking water, and holding breath; none effective; hiccups self-limiting	Most commonly POD 4–6	Composite of 34 cases
								Male, higher BMI, preoperative amantadine, and peri-electrode white matter edema were all risk factors for hiccups
Composite of 34 cases
Ling et al. [17], 2022	NS (not specified for patients with hiccups)	PD	STN-DBS with SedLine monitoring under propofol anesthesia	NS (not specified for patients with hiccups)	NS	NS	NS	Purpose of study was monitoring prefrontal cortex EEG during STN-DBS under propofol anesthesia; hiccups reported as side effect in 3/43 patients by POD 7, with no further information on hiccups reported
Ling et al. [18], 2022	NS (not specified for patients with hiccups)	PD	STN-DBS under general anesthesia	NS (not specified for patients with hiccups)	NS	NS	NS	Purpose of study was validating model for predicting delirium after STN-DBS; hiccups reported as side effect in 22/159 patients by POD 7, with no further information on hiccups reported

DBS, deep brain stimulation; M, male; F, female; PD, Parkinson’s disease; STN, subthalamic nucleus; POD, postoperative day; RCT, randomized controlled trial; GPi, globus pallidus internus; NS, not specified; NA, not applicable.

Jochim et al. [3] reported 2 cases of periodic, intractable hiccups occurring after STN-DBS. The first case occurred in a 71-year-old man who developed hiccups 2 days after surgery that resolved 10 days after surgery; interestingly, hiccups recurred for a brief 2-day stint several months later and spontaneously resolved. The other patient was a 57-year-old man with a 16-month history of intermittent bouts of persistent hiccups 6 months postoperatively.

These authors posit that the rapid postoperative onset of hiccups may implicate a lesional effect, whereas the late onset in the second patient and later recurrence in the first patient may implicate a stimulation effect [3]. Nevertheless, the authors state that hiccups are a potential side effect of STN-DBS. As in their first case, the temporal relationship to the lead insertion in our case would argue in favor of lesional effect sustained at the time of lead placement rather than a result of the stimulation. Poststroke hiccups are well documented in medullary infarcts but also in various other supra- and infratentorial structures [21] and would further support the possibility of a lesional phenomenon.

The remaining reports of hiccups after STN-DBS are briefly mentioned as side effects during studies that were not investigating hiccups [17–20]. Of note, Odekerken et al. [20] reported that hiccups were more commonly associated with globus pallidus internus stimulation than when STN was the target. Additionally, other functional neurosurgical procedures for PD have been shown to cause hiccups, including a report of 5 patients developing hiccups following pallidotomy for PD [9]. Similar to PD and PD medications, it seems DBS is capable of inducing hiccups, although the underlying mechanism is not clear.

While some contribution from celiac disease or GERD cannot be excluded in the current case, these had been present for several years prior to the lead placement with no occurrences of hiccups. We also cannot entirely rule out the coincidental onset of hiccups, as Miwa and Kondo [6] have observed an increase in prevalence of hiccups among patients with PD (20% vs. 3%). Unlike the cases previously reported by Jochim et al. [3], the hiccups occur daily but are short in duration and not severe enough to warrant further pharmacologic intervention. The patient also expressed concern regarding potentially increasing bradykinesia and rigidity with chlorpromazine or haloperidol, and a trial of carbidopa/levodopa 25/250 mg for the residual freezing episodes did not change the hiccups frequency or severity. Like those cases, DBS was associated with a marked reduction in Parkinson’s symptoms.

Conclusion

PD and dopaminergic drugs have been documented to induce hiccups, although the mechanism remains unclear. We report a case of hiccups occurring after STN-DBS in a PD patient. There are relatively few descriptions of this phenomenon compared to either disease-induced or medication-induced hiccups in PD. Although the causality of our clinical observation remains to be proven, we believe that this additional case of periodic, intractable hiccups points to a rare but relevant side effect of STN-DBS in patients with PD.

Statement of Ethics

This study was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images. Ethical approval was not required for this study in accordance with local or national guidelines.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

The authors have not received funding.

Author Contributions

Michael D. Staudt and Michael E. Maddens conceptualized the study. Andrew Waack performed the literature review and drafted the manuscript. Michael E. Maddens, Nicholas J. Maddens, Adam Kuhlman, and Michael D. Staudt reviewed and edited the draft. All authors read and approved the final manuscript.

Funding Statement

The authors have not received funding.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.