Stimulating the Future of Treating Sleep-Disordered Breathing

Stuart MacKay, BSc(Med), MBBS(Hons), FRACS

Sleep-disordered breathing (SDB) refers to any disorder in which the patient has difficulty breathing while asleep, including obstructive sleep apnea (OSA) and central sleep apnea (CSA). OSA, which occurs because of upper airway obstruction during sleep, is far more common, with estimates of approximately 936 million people worldwide suffering from the condition.¹

“With OSA, snoring and breathing pauses and reduced airflow during the night leads to sleep fragmentation and unrefreshing sleep, which in turn impairs daytime functioning,” said Stuart MacKay, BSc(Med), MBBS(Hons), FRACS, associate professor at Illawarra ENT Head and Neck Clinic in Australia.

“Patients can feel groggy, tired, [and] sleepy and have a higher rate of motor vehicle collisions and workplace accidents. In addition, via a variety of pathophysiological pathways, but especially due to repetitive oxygen desaturation, patients with more significant sleep apnea are at risk of hypertension, arrhythmias, ischemic events, and other cardiometabolic consequences.”

A small subset of patients may have CSA, when the brain fails to send signals to breathe. CSA is less common in the general population, but there are increased rates in people with specific conditions, such as heart failure and chronic opioid use.

Although OSA and CSA have different causes, both contribute to reduced quality of life and have been linked to decreased cognition, increased cardiovascular risk, and increased mortality.¹

Continuous positive airway pressure therapy: Not suitable for all

Most sleep experts recommend continuous positive airway pressure (CPAP) as the first-line treatment for SDB, regardless of the severity of apnea. The CPAP device continuously delivers pressurized air into the upper airway, which helps keep the air passages open. Results from studies have shown that using CPAP therapy can significantly reduce the severity and morbidity associated with sleep apnea.²

The main limiting factor in the use of CPAP for OSA is the lack of compliance to therapy. The device delivers air under moderate to high pressure, which can cause a certain level of discomfort for patients. “Although it is minimally invasive, not everyone can tolerate CPAP,” said Peter M. Baptista, MD, PhD, a senior clinical consultant at the Otorhinolaryngology Unit at Clínica Universidad de Navarra in Spain. “In addition, CPAP can cause nasal obstruction and feelings of claustrophobia.”

One cohort study estimated that only 37% to 41% of patients adhered to CPAP therapy in the long term,³ which ultimately hinders the achievement of good treatment outcomes. A recent meta-analysis showed that the cardiovascular risk associated with OSA was reduced only when patients wore the device for longer than 4 hours per day.⁴

For patients with CSA, it is more than just the discomfort of CPAP that can raise problems. “With central sleep apnea, there is an interruption in the neural drive to breathe,” Sanjaya K. Gupta, MD, assistant professor of medicine at the University of Missouri-Kansas City School of Medicine, told NeurologyLive®. “There is no movement of the diaphragm, so using CPAP does not work unless the patient is making an effort to breathe.”

Alternatives to CPAP

Clinicians have used a wide range of surgical procedures in OSA, including palatopharyngoplasty, tonsillectomy, and maxillomandibular advancement.⁵ However, each surgery targets only
1 anatomical area. Results from sonographic studies have shown that OSA presents with multilevel airway collapse, which means that a single surgery may fail to resolve the complete issue.⁶

Surgery is not an option for patients with CSA. Apart from oxygen ventilation, the only other ways to manage CSA include treating the underlying heart condition that is present and cutting back
on opioid use.

Nerve stimulation for the management of sleep apnea

The search for newer, better alternatives to CPAP has resulted in 1 promising solution––nerve stimulation. By stimulating selected nerves, specific muscles that aid in airway relaxation or breathing can be made to contract. This addresses the problem of sleep apnea at a physiological level, which would reasonably be more effective and have fewer adverse effects.

For OSA, clinicians choose the hypoglossal nerve as a target for stimulation. “Hypoglossal nerve stimulation [HGNS] provides an opening of the airway at the level of both the tongue and palate,” said Baptista. Nerve stimulation causes the genioglossus muscle to contract, which moves the tongue forward. According to research by MacKay and colleagues, it is important to only stimulate the genioglossus. “Selective stimulation of the nerve fibers to the genioglossus, the main dilator of the airway, allows [the] avoidance of stimulating retrusor muscles that can compromise airway opening,” he said. “Results of such implantation are likely to improve patient and polysomnographic outcomes.”

Research results have shown that there is also palatoglossal coupling, which increases the airway space at the retropalatal level.⁷ This dilates and stabilizes the airway at multiple levels. In a recent systematic review, Baptista and colleagues reviewed 12 studies that used HGNS for OSA.⁶ They found the procedure reduced the number of apneic and hypopnea events per hour by 18 points, measured via the apnea-hypopnea index (AHI). There was also a reduction of 14.6 points in the number of oxygen desaturations measured via the oxygen desaturation index (ODI). According to MacKay, “The advantages of HGNS include the ability to avoid devices worn on the face and in the mouth, and avoidance of painful intra-oral/pharyngeal surgeries. Disadvantages include the requirement for commitment to titrations, follow-up, and ongoing device use.”

There are different types of HGNS, namely unilateral and bilateral. “Bilateral HGNS allows a higher likelihood of symmetrical tongue and, in cases of ‘coupling,’ palatal movement to improve airway patency in sleep,” MacKay told NeurologyLive®. “Advantages over currently available unilateral stimulation include [fewer] components to implant, and external stimulation rather than an implanted ‘pacemaker.’ The incision is small and relatively painless.”

In CSA, stimulation of the phrenic nerve can be just as effective. This eliminates periodic respiration by causing consistent, regular diaphragmatic contractions, which generates negative intrathoracic pressure and restores a regular breathing pattern. Last year, investigators reported the results of using a phrenic nerve stimulator over a 3-year period.⁸ The result was sustained improvement across a wide range of sleep metrics, including the AHI, ODI, central apnea index, and arousal index. More recently, a pooled meta-analysis of 5 different studies showed that phrenic nerve stimulation could effectively reduce AHI scores by approximately 26.7 events per hour, as well as reduce the ODI scores by approximately 24.¹⁶ events per hour.⁹

The nerve stimulator needs to be implanted into the patient’s body to function. Several different devices are available to treat OSA through HGNS. In general, the device consists of a sensor electrode, a pulse generator, and a stimulation electrode.¹⁰ The sensor electrode is usually implanted into the intercostal muscles, or just below the ribs. During inspiration, it gives off an electric signal that is picked up by an implantable pulse generator (IPG). The IPG is usually placed in a pocket below the clavicle, medial to the delto-pectoral groove. After receiving an electric signal, it generates a pulse that is transmitted to the stimulation electrode, which is implanted around the medial branches of the hypoglossal nerve.

The device used in CSA has a slightly different design; a sensing lead is placed in the azygous vein, behind the heart, to the level of the diaphragm to detect breathing. A pacing electrode is placed in a vein adjacent to the phrenic nerve. “The device works automatically and in concert with patients’ normal respiratory cycle,” said Gupta. “The pacing and sensing leads are plugged
into a device that looks and functions similar to a cardiac pacemaker. Once connected, the device and leads are surgically placed under the skin in the right upper chest, just below the collarbone. The device is programmed to sense the patient’s breathing and the moment when the breathing stops, the device will deliver electricity through the pacing lead to the phrenic nerve, which will stimulate the diaphragm to contract.” All this happens automatically and seamlessly, in concert with the patient’s normal respiratory cycle. No intervention is necessary on behalf of the patient to initiate therapy, they don’t have to wear a CPAP mask, and the device turns off when they get up in the morning.

Can all patients with SDB receive nerve stimulation therapy? According to most experts, the answer is no. The type of patient selected can greatly influence treatment outcomes, and establishing which sleep apnea the patient has is a key priority. HGNS will not work if the patient has CSA. Conversely, phrenic nerve stimulation only benefits those with CSA; it is not indicated for those with primarily OSA. There is a third type of sleep apnea called “treatment emergent” CSA^.11 This is primarily OSA in which a central component emerges following the use of CPAP therapy. Uncertainty remains about whether nerve stimulation can benefit this subset of patients.

An obvious indication for HGNS is for patients who are unable to tolerate CPAP. However, before clinicians consider this procedure, the patient must be evaluated for other factors. “Patients should see credentialed sleep surgeons for a thorough assessment and discussion of treatment options if they cannot tolerate or adhere to CPAP or other devices long-term,” advised MacKay.

In a recent review study, Baptista highlighted 3 key factors that must be considered during patient selection.¹² These include the severity of OSA, body mass index (BMI), and the severity of airway collapse at the palatal level. “If patients have [a] very high BMI (> 35) or concentric palatal collapse, HGNS is best avoided,” said Baptista. Obesity is a predictor for poor OSA treatment outcomes regardless of the type of treatment. In terms of severity of airway collapse at the palatal level, HGNS relaxes the palatal and retrolingual musculature, but if there is concomitant collapse in the posterior or lateral pharynx, this technique may not be effective. To ascertain the exact area of collapse, drug-induced sleep endoscopy can serve as a valuable diagnostic tool.

Nerve stimulation is a relatively expensive technique compared to CPAP and may not be financially feasible for patients with mild OSA. The FDA recommends using this technique for patients with moderate to severe apnea with an AHI score between 15 and 65.¹³

For phrenic nerve stimulation, the severity of apnea and the proportion of central events are the main considerations. “We generally target patients with moderate to severe sleep apnea where at least 80% of the events are central in nature,” says Gupta.

Risks of nerve stimulation

Implantable nerve stimulation seems to be a reasonably safe method of treatment. In their meta-analysis, Baptista’s team analyzed the number of adverse events related to HGNS. Serious events were documented in 6% of all patients, for whom there was a requirement for surgical repositioning of the device or the replacement of electrodes.⁵ Minor adverse effects were reported by almost 60% of all patients, including discomfort from electrical stimulation and tongue abrasion due to constant movement. Although these effects were common during the first year of treatment, they reduced in subsequent years.

The meta-analysis for phrenic nerve stimulation showed serious adverse events in 3.9% of all patients. These included hematoma, migraine, and atypical chest pain, which necessitated the removal of the device. Minor adverse effects were reported in about 5.3% of all patients, including device discomfort, dislocation of leads, and lead failure.⁹ The more severe adverse effects may be avoided by refinements in surgical technique, whereas discomfort mostly resolves with time as the patient gets used to the device.

The future of nerve stimulation for SDB

As the use of nerve stimulators continues to rise, the onus is now on making these devices more efficient and increasing their capabilities. Baptista believes that future research must focus on finding ways to circumvent lateral airway collapse at the palatal level. “We are just at the very beginning,” he said. “In a few years, there will be devices that are much smaller and perhaps capable of stimulating a specific group of fibers that allow airway opening.”

Research into nerve stimulation therapy still has a long way to go. Although prospective studies have illustrated the therapy’s standalone efficacy, there is no research comparing the use of this therapy to CPAP, which is still the gold standard for OSA. Longitudinal studies are also needed to assess secondary outcomes. “We still do not know if phrenic nerve stimulation can reduce morbidity and mortality rates,” Gupta pointed out.

According to Mackay, “Areas that represent the most exciting future investigation are patient preferences, combination therapies, further refinement of implantation and titration techniques, miniaturization of devices, and endophenotyping outcomes in low muscle hyporesponsive-type OSA patients.”

Most physicians are aiming for a more accurate diagnosis and evaluation, prior to wider acceptance of current treatment strategies. “For patients with an appropriate indication, the phrenic nerve pacing procedure can be life-changing,” stated Gupta. However, nerve stimulation has yet to gain wide acceptance. One main barrier, especially in the case of CSA, is the lack of a proper diagnosis. “CSA patients lack traditional symptoms such as snoring and daytime somnolence,” said Gupta, who feels that the only way to improve diagnostic accuracy is to maintain a high index of suspicion. “If you have a patient with heart failure, atrial fibrillation, or stroke who continues to complain of fatigue despite optimal medical therapy, consider the possibility of CSA,” he advised. A sleep study or polysomnogram is the best diagnostic test for sleep apnea and clinicians should recommend it to such patients.