DOI: https://doi.org/10.21203/rs.3.rs-2802470/v1
Background
Hiccups (medically termed, “singultus”), when intractable, can cause significant medical consequences such as aspiration, malnutrition, and depression, leading to poor quality of life. Several case reports have shown that vagus nerve stimulator (VNS) implantation can help treat central idiopathic intractable hiccups. However, we present a contrary case of a patient who developed intractable singultus following VNS placement for medically refractory epilepsy.
Case presentation
We report a 71-year-old male patient with drug-resistant epilepsy who underwent VNS implantation and developed intractable hiccups shortly thereafter. The hiccups were severe and persistent, such that the patient developed a Mallory-Weiss tear, requiring intensive care, invasive intubation and mechanical ventilation, and a prolonged rehabilitation course. Despite multiple therapies including phrenic nerve block and Nissen fundoplication, the patient’s hiccups persisted and only stopped once the VNS was permanently deactivated.
Conclusions
To the best knowledge of these authors, this is the first case of hiccups as a direct consequence of VNS implantation that has been reported in the literature. The clinical impact of this report is significant given the relative unfamiliarity of hiccups as an adverse effect of VNS implantation. Neurologists and epileptologists, who present VNS implantation as a surgical option for seizure control to their patients, should be aware of the possibility of singultus development and its significant physical and emotional ramifications.
Hiccups (medically termed, “singultus”) are often benign and self-limiting, but in rare cases they can be intractable and a sign of underlying pathology. Intractable singultus is defined as hiccups persisting for > 1 month (1–3). This can result in significant and life-threatening medical consequences including insomnia, depression, malnutrition/anorexia, aspiration, pneumonia, and impaired wound healing (1, 3, 4).
There remains much to be elucidated about the pathophysiology of hiccups, the mechanism of which is complex: The hiccup reflex arc has afferent, central, and efferent components. The afferent limb is composed of the vagus and phrenic nerves, as well as T6-12 sympathetic fibers. The efferent limb consists of the diaphragm (innervated by the phrenic nerve C3-5), scalene muscles (innervated by plexal branches C5-7), glottis (innervated by the recurrent laryngeal nerve), and intercostal muscles (innervated by intercostal nerves T1-11) (1, 2, 5). The hiccup center is distributed over spinal cord segments rostral to the medulla (C3-5) in the reticular formation, the Pre-Botzinger complex and nucleus tractus solitarius in the brainstem, the hypothalamus, and the mesial temporal lobes (1, 2, 5–7).
The vagus nerve (also known as the “wandering nerve” or “vagabond nerve”) innervates multiple organs to regulate autonomic functions of the cardiovascular, respiratory, and gastrointestinal systems (8, 9). There are several case reports in the literature that show benefits of vagal nerve stimulation in treating central idiopathic intractable hiccups (1, 5, 10). This is usually achieved through vagus nerve stimulator (VNS) implantation, typically used for medically refractory epilepsy. VNS is not currently approved by the Food and Drug Administration (FDA) as a therapy for intractable hiccups, and the data is mixed regarding its efficacy to treat singultus (1, 10). Nevertheless, outcomes to date are either positive with partial or short-term hiccup resolution, or equivocal with no significant benefit from vagal nerve stimulation (10).
We present a case of intractable singultus after VNS placement in a patient with refractory epilepsy whose hiccups resolved only with VNS deactivation. To the best knowledge of these authors, this is the first case of intractable hiccups as a direct consequence of VNS implantation. This case is a significant addition to the literature given that multiple prior studies have reported the opposite association of VNS placement as a potential treatment for intractable hiccups rather than its apparent cause.
A 71-year-old male presented to the clinic with epilepsy, first diagnosed at the age of 2 years. For many years, his seizures were controlled with medication. However, one year after a fall resulting in traumatic brain injury, seizures recurred and failed to respond to multiple anti-seizure medications including levetiracetam, phenytoin, clobazam, and topiramate. The patient subsequently underwent surgery with VNS implantation with satisfactory seizure reduction at the age of 54. Unfortunately, soon after, the patient developed hiccups that persisted despite medical treatment, resulting in a Mallory-Weiss tear that required intensive care unit (ICU) admission with intubation and ventilation followed by a month-long rehabilitation. The patient then underwent a Nissen fundoplication followed by two phrenic nerve blocks that led to only transient resolution for 13 months. Subsequently, VNS was turned off, which was followed by complete hiccup resolution as of recent follow-up appointments at the time of this publication.
Hiccups can be attributed to almost 4000 hospitalizations per year in the United States (4, 11).
When severe and intractable, they have a devastating impact on one’s physical and mental health. Multiple peripheral and central etiologies have been identified for intractable singultus (4, 12, 13), but vagal nerve stimulation has never been among them; rather, several cases have highlighted VNS implantation as a potential therapy for hiccups (1, 10).
VNS was FDA-approved as an adjuvant therapy for medically refractory epilepsy in 1997 (8, 14). It is overall well-tolerated with relatively few side effects, the most common of which are laryngeal (e.g. hoarseness, dysphonia) due to the vagus nerve’s effect on vocal cord motion and supraglottic muscle tension (15). Other side effects include bradyarrhythmias (from parasympathetic stimulation of the atrioventricular node) (8), cardiac syncope and asystole (16), respiratory problems (cough, dyspnea, sleep disordered breathing) (17, 18), surgical or hardware complications (infection, lead malfunction, vocal cord palsy) (19), Horner syndrome (20), and dysphagia and/or aspiration (21). However, intractable singultus has not previously been recognized as a potential complication of VNS to the best knowledge of the authors.
The exact mechanism of how hiccups are triggered is unknown, although there are likely multiple ways to stimulate the reflex arc given its wide distribution via the autonomic nervous system. Any process that irritates or damages part of the hiccup reflex or nerves of the autonomic system including the vagus and phrenic nerves can lead to singultus (1). We hypothesize that VNS may lead to uninhibited activity of the vagus nerve, a key component of the hiccup reflex, causing intractable singultus. However, more research is needed to understand why in some cases this stimulus can lead to hiccup resolution, whereas in our patient, it triggered new onset hiccups. Hiccups can also be seen in strokes of the brainstem (22) and it has been shown that VNS modulates central parasympathetic activity and may lead to post-stimulus brainstem plasticity (23). Given that the vagus nerve nucleus lies within the nucleus ambiguus in the brainstem, this may be another potential mechanism.
Intractable singultus can be incredibly distressing for patients and negatively impact their health and quality of life. We present the first known report of hiccups as a direct consequence of VNS, an established therapy for medically refractory epilepsy and an off-label treatment for intractable singultus in several prior case reports. Our results demonstrate that the relationship between vagal nerve stimulation and hiccups remains to be further clarified. Providers recommending or prescribing VNS for seizures should be aware of hiccups as a rare but possible side effect, and those considering VNS for the treatment of singultus should exercise caution that VNS may trigger or worsen the hiccups. Additional research is merited to better understand the complex phenomenon of hiccups and how vagal nerve stimulation modulates its pathogenesis.
vagus nerve stimulator
Food and Drug Administration
intensive care unit
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Written consent for publication was obtained from the patient for publication using our institutional consent form. A copy of this form is available for review by the editor of this journal.
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The authors declare that they have no competing interests.
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Authors’ contributions
Initial manuscript concept: AM. Initial manuscript draft and revisions: SR. Literature search: SR. Manuscript edits, revisions, and comments: SR, AM. All authors reviewed the manuscript prior to submission. The author(s) read and approved the final manuscript.
Acknowledgements
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Authors’ information
Department of Neurology, Boston Medical Center, Boston, MA, USA
Susan Zhang Recio & Myriam Abdennadher
Corresponding Author
Myriam Abdennadher