Ondine’s curse: clinical presentation with diaphragmatic pacing and spontaneous respiratory recovery. Illustrative case

Abstract

BACKGROUND

The complexity of posterior fossa surgery can often lead to rare complications due to the anatomy involved. Vestibular schwannoma resection is a common pathology in the posterior fossa, often requiring surgical intervention. Given the proximity of this space to the brainstem, cranial nerve VII/VIII complex, and posterior inferior cerebellar artery (PICA), neurovascular complications are not infrequent. A rare vascular complication from this surgical approach is a lateral medullary infarction from injury to the lateral medullary segment of the proximal PICA, leading to central hypoventilation syndrome (CHS).

OBSERVATIONS

This report presents a unique case of a 51-year-old man who underwent a retrosigmoid craniectomy for resection of a vestibular schwannoma. Following surgery, the patient was unable to be weaned off the ventilator and was noted to become apneic while he slept, a clinical picture consistent with Ondine’s curse.

LESSONS

This report discusses the anatomical considerations of this surgical corridor leading to this complication and the management of a patient with acquired Ondine’s curse and reviews the scarce literature on this uncommon cause of acquired CHS.

Central hypoventilation syndrome (CHS), or “Ondine’s curse,” is a deadly condition with multiple etiologies. Ondine, a nymph from a German fairytale who fell in love with a mortal man, placed a spell on her love after discovering his infidelity, resulting in his inability to breathe during sleep.¹ Often congenital in nature, CHS is a neurological condition associated with irregular and inadequate breathing during sleep and, in severe cases, while awake. Several reported cases of acquired CHS in the literature describe brainstem tumors,² brainstem tethering,³ skull base trauma,⁴ os odontoideum,⁵ and 1 case following posterior fossa surgery.⁶ Here, we describe a case of acquired Ondine’s curse following posterior fossa surgery for resection of a vestibular schwannoma. For the first time, we describe the need for diaphragmatic pacing with spontaneous recovery following this etiology of acquired CHS.

Illustrative Case

A 51-year-old male had a past medical history of left vestibular schwannoma, hypertension, hyperlipidemia, prediabetes, coronary artery disease status post–drug-eluting stent (previously on aspirin and clopidogrel), and heart failure with reduced ejection fraction; he presented with dizziness, tinnitus, gait instability, and left-sided hearing loss. The patient was found on magnetic resonance imaging (MRI) to have a left cerebellopontine angle mass (CPA) (Fig. 1). He presented to the hospital for surgical intervention. The patient underwent left retrosigmoid craniectomy for tumor resection with duraplasty and mesh cranioplasty. There was no significant bleeding during the case; however, there was an arterial branch of the posterior inferior cerebellar artery (PICA) that was found to be bleeding and was subsequently cauterized. Postoperatively, he had a left facial nerve palsy (House-Brackmann grade 4) and was initially unable to close his eye, which improved over the subsequent weeks.

FIG. 1.

Preoperative MRI in the axial (A) and coronal (B) planes, demonstrating a left CPA mass causing brainstem compression and expansion of the internal acoustic canal (IAC). Postoperative axial T1-weighted postcontrast MRI (C) and axial diffusion-weighted imaging (D) demonstrating gross-total resection of the left CPA mass, decompression of the brainstem, and areas of diffusion restriction in the left lateral cerebellar hemisphere and left lateral medulla.

Following the procedure, the patient was unable to be weaned off the ventilator despite several days of trialing pressure support and remained intubated postoperatively, eventually requiring tracheostomy. He continued to ambulate postoperatively with physical therapy with the use of a portable ventilator. Postoperative brain MRI demonstrated a lateral medullary infarct (Fig. 1), which was thought to contribute to the patient’s difficulty maintaining respiratory drive. Thoracic surgery was consulted and recommended diaphragmatic pacing with the placement of bilateral phrenic nerve stimulator leads, which he received on postoperative day 16. The patient eventually required gastrostomy tube placement and was eventually weaned to pressure support on the ventilator. He attended spinal cord injury rehabilitation over a 1-month period, during which he was fully weaned off respiratory support, and his tracheostomy was capped. Two months following surgery, his tracheostomy was decannulated. He did not require diaphragmatic pacing and was referred to thoracic surgery for removal of his bilateral phrenic nerve leads, which were subsequently removed 6 months after placement. Upon follow-up 17 months after surgery, the patient remained stable neurologically, without requiring the use of mechanical ventilation.

Systematic Review

To understand the relevant literature, a systematic literature review was conducted using the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines.⁷ Articles were queried that included the topic of CHS in the PubMed electronic database until November 2022. Keywords used in the search included “central,” “hypoventilation,” and “syndrome.” Further specification included use of the term “neurosurgery,” and articles were excluded if they did not include full-text manuscripts or were not written in or translated to English. Due to the high relative preference of congenital CHS and genetic link to the paired-like homeobox 2B (PHOX2B) gene, papers that focused on “congenital” CHS were also excluded. References of selected papers were subsequently examined to identify manuscripts that were potentially missed. Publications were excluded if they did not include full-text manuscripts or if the main focus was not acquired CHS. Full-text manuscripts deemed relevant to the current case yielded 21 results. The methodology used in the PRISMA schematic is outlined in Fig. 2. All publications were case reports, ranging from 1 to 3 patient reports, with the majority of papers highlighting a single case. Etiologies included infection, trauma, tumor, vascular lesions, and others (Table 1).

FIG. 2.

Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) workflow chart.

TABLE 1.

Literature review of publications meeting systematic review inclusion criteria

Authors & Year	Journal	Title	Etiology	Central Hypoventilation Resolution
Sarnoff et al., 195126	J Am Med Assoc	“Hypoventilation syndrome in bulbar poliomyelitis”	Bulbar poliomyelitis	No
Udwadia et al., 198727	Chest	“Radiation necrosis causing failure of automatic ventilation during sleep with central sleep apnea”	Radiation necrosis	No
Giangaspero et al., 19889	Clin Neuropathol	“Failure of automatic control of ventilation (Ondine’s curse) associated with viral encephalitis of the brainstem: a clinicopathologic study of one case”	Encephalitis	Yes
Valente et al., 199312	Chest	“An uncommon case of brainstem tumor with selective involvement of the respiratory centers”	Tumor	No
Auer et al., 199610	Clin Neuropathol	“Multiple sclerosis with medullary plaques and fatal sleep apnea (Ondine’s curse)”	Multiple sclerosis	No
Kraus et al., 199928	Clin Neurol Neurosurgery	“Ondine’s curse in association with diabetes insipidus following transient vertebrobasilar ischemia”	Vascular infarct	No
Manning & Leiter, 200013	Am J Respir Crit Care	“Respiratory control and respiratory sensation in a patient with a ganglioglioma within the dorsocaudal brain stem”	Tumor	Yes
Ioos et al., 200114	J Child Neurol	“Sleep disorders caused by brainstem tumor: case report”	Tumor	Yes
Schetstatsky & Fernandes, 200429	Arq Neuropsiquiatr	“Acquired Ondine’s curse: case report”	Vascular infarct	Yes
Rao et al., 200530	Acta Anaesthesiol Scand	“Ventilatory management and weaning in a patient with central hypoventilation caused by a brainstem cavernoma”	Cavernoma	Yes
Marin-Sanabria et al., 20062	J Clin Neurosci	“Snoring associated with Ondine’s curse in a patient with brainstem glioma”	Tumor	No
Matschke & Laas, 200731	Am J Forensic Med Pathol	“Sudden death due to central alveolar hypoventilation syndrome (Ondine’s curse) in a 39-year-old woman with heterotopia of the inferior olive”	Heterotypia	No
Matsuyama et al., 200932	Intern Med	“Central alveolar hypoventilation syndrome due to surgical resection for bulbar hemangioblastoma”	Hemangioblastoma	Yes
Pedroso et al., 200933	Neurol India	“Ondine’s curse after brainstem infarction”	Vascular infarct	No
Liu et al., 20113	World Neurosurgery	“Brainstem tethering with Ondine’s curse”	Encephalocele	Yes
Choi et al., 20114	J Craniofac Surg	“Paradoxical herniation in wartime penetrating brain injury with concomitant skull-base trauma”	Trauma	Yes
Campbell & Brown, 20135	Br J Neurosurg	“Case report of os odontoideum causing Ondine’s curse”	Os odontoideum	Yes
Faraji Rad et al., 20156	Iran J Otorhinolaryngol	“Sleep apnea syndrome after posterior fossa surgery: a case of acquired Ondine’s curse”	Tumor	Yes
Tanaka et al., 201634	NMC Case Rep J	“Central hypoventilation syndrome complicated with lateral medullary infarction after endovascular treatment of the vertebral artery dissecting aneurysm: a case report”	Vascular infarct	No
Zhu et al., 201835	J Neurol Neurophysiol	“Case report: Ondine’s curse syndrome secondary brainstem infarction”	Vascular infarct	No

Discussion

CHS is a rare neurological condition resulting in the lack of coordinated respiratory effort required for ventilation during sleep states and, in severe conditions, during awake states as well. The majority of known cases are congenital and found during infancy, with no known cure. Congenital cases are caused by a gene mutation in PHOX2B, leading to a polyalanine repeat expansion mutation, affecting neural crest cell migration and autonomic nervous system development.⁸ CHS presents when the descending anterolateral medullocervical pathway (Fig. 3), which is responsible for autonomic breathing, is affected, and therefore may include congenital or acquired etiologies.⁶ A wide array of etiologies have been attributed to acquired CHS, including neoplasms in the brainstem and fourth ventricle,² skull base trauma,⁴ os odontoideum,⁵ infections,⁹ and demyelinating diseases such as multiple sclerosis.¹⁰ In acquired cases, CHS may result from either direct injury to the anterolateral medullocervical pathway at the level of the medulla or from secondary injury due to ischemia. The vertebral artery supplies the medulla, and specifically the lateral medullary branch supplies the lateral medulla (Fig. 3). In cases such as the one presented where a large CPA tumor is resected, the lesion may be in close proximity or encapsulating this vessel, putting it at risk for injury. Any disruption of blood supply to this portion of the brainstem can cause lateral medullary syndrome, which may include impaired pain/temperature sensation of the ipsilateral face or contralateral body, ipsilateral Horner syndrome, dysphagia, nystagmus, irregular breathing, or other symptoms.¹¹ When the lateral medullary injury precisely affects the rostral medulla, the reflexive control of central respiration is affected and CHS persists. This phenomenon has been reported several times previously following tumor resection; however, these reported cases all included tumors within the brainstem^2,12–14 or fourth ventricle.⁶ To our knowledge, this is the first reported case of acquired CHS following tumor resection in the CPA. While there is a lack of consensus for diagnostic criteria of Ondine’s curse, there is agreement that the patient must demonstrate that, while they are incapable of breathing automatically, they are able to initiate their own breaths on command.

FIG. 3.

Illustration demonstrating the vascular distribution of the lateral medulla in relation to a CPA tumor. Infarction of the lateral medulla may lead to disruption of the descending anterolateral medullocervical pathway responsible for autonomic breathing, leading to CHS. CN = cranial nerve. Used with permission from ©Mount Sinai Health System.

Observations

Treatment Strategies for CHS

The foundation of treatment for a patient with CHS is assuring adequate ventilation and oxygenation during both the sleeping and awake states.¹⁵ To this end, positive-pressure ventilation via tracheostomy remains the mainstay of treatment for CHS. Other modes of ventilation, such as noninvasive positive-pressure ventilation and negative-pressure ventilation, have been suggested in the pediatric population who experience the congenital form of CHS, but these modes of ventilation have not been explored in adult patients with acquired CHS.^16,17 Patients with CHS such as this patient are able to make use of portable ventilators to remain mobile and maintain a reasonable quality of life. Patients with long-term tracheostomies are at risk of decannulation, infection in the trachea or around the tube, damage to the trachea, or long-term complications like tracheomalacia and trachea-esophageal fistulas, which can all lead to subsequent respiratory decompensation.¹⁸

Given the high level of ventilatory dependence required by patients with CHS, phrenic nerve stimulators have been used to successfully manage respiratory insufficiency. Phrenic nerve stimulators have been used for the past 50 years to provide diaphragmatic pacing in adult patients with CHS.¹⁹ This involves the placement of bilateral electrodes on the phrenic nerve to receive electrical stimulation through a battery-operated external transmitter (Fig. 4).²⁰ Phrenic nerve stimulator placement is not uncommon in patients with respiratory paralysis due to brainstem or high cervical spinal cord lesions, leading to malfunction of the respiratory control centers or interruption of neurons above the phrenic nerve cell bodies.²⁰ Diaphragmatic pacing can be complicated by failure of the pacing device, fibrosis of the phrenic nerve, and obstructive apnea from asynchrony between skeletal muscle contraction in the upper airway and the paced inspiration.^21–23 Careful monitoring is required to attain full pacing in patients with CHS.

FIG. 4.

Illustration demonstrating the configuration of a bilateral diaphragmatic pacer, including contact of electrodes with the bilateral phrenic nerve, controlled by an external pacemaker. Diaphragmatic pacing may be an effective treatment strategy for CHS. Used with permission from ©Mount Sinai Health System.

The use of pharmacological agents to induce metabolic acidosis and increase respiratory drive, such as acetazolamide and medroxyprogesterone, has been suggested, but these agents have overall not been shown to be effective in the management of CHS.⁶

Resolution of Respiratory Paralysis Following CHS

Resolution of respiratory paralysis after acquired CHS occurs in the minority of cases. Although the degree of ventilatory assistance required varies from patient to patient, patients with CHS often require lifelong respiratory support.¹⁶ In congenital cases, patients are often able to maintain adequate ventilation while awake as their respiratory system matures but still depend on respiratory support at night.²⁴ The use of diaphragmatic pacing in patients with CHS has shown some promise in assisting with the resolution of respiratory paralysis. Diaphragmatic pacing has been tested as a tool to avoid diaphragmatic amyotrophy in patients with amyotrophic lateral sclerosis, where spontaneous breathing recovery was possible with moderate success.²⁵ In CHS, some patients have been reported to develop some degree of spontaneous respiration after weeks or months of diaphragmatic pacing, but this degree of respiration was considered insufficient for adequate ventilation.²¹ Other cases describing acquired Ondine’s curse after tumor surgery demonstrated a spontaneous recovery of breathing after prolonged hospitalization and respiratory support.^6,12 Across all etiologies, the majority of cases show patients partly or fully recovering from central hypoventilation, which may be due to a redundancy in descending respiratory pathways that allow for such recovery.

Lessons

The case presented here is unique in both etiology and disease course. Acquired CHS is an uncommon, but significant outcome and has only been reported as a sequela of posterior fossa surgery in a small number of instances. Diaphragmatic pacing through phrenic nerve stimulation is not novel in the treatment of patients with brainstem and high cervical pathology; however, here we demonstrate that this treatment can be used to expedite a patient’s discharge from the hospital to a rehabilitation center, which may speed up recovery following surgery.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Schupper, Devarajan, Shrivastava. Acquisition of data: Schupper, Devarajan, Lee, Perez. Analysis and interpretation of data: Schupper, Devarajan, Perez, Shrivastava. Drafting of the article: Schupper. Critically revising the article: Schupper, Devarajan, Lee, Shrivastava. Reviewed submitted version of manuscript: Schupper, Lee, Perez, Shrivastava. Approved the final version of the manuscript on behalf of all authors: Schupper. Statistical analysis: Schupper. Administrative/technical/material support: Devarajan. Study supervision: Perez, Shrivastava.