Hypoglossal Nerve Stimulation: From Concept to Clinical Practice

While continuous positive airway pressure (CPAP) is still the gold standard treatment for obstructive sleep apnea (OSA), it is well-established that many patients struggle with long-term adherence and tolerance.¹ The literature indicates that CPAP non-compliance rates remain as high as 34% with little improvement over the last two decades.²

As such, many alternative treatment options for OSA have emerged—including hypoglossal nerve stimulation (HGNS). Through increased clinical use, social media, and industry marketing campaigns, many patients are now aware of this option and inquiring about their candidacy with their health care provider.

This article will provide a brief overview of the history of HGNS, a refresher on the anatomy of the tongue and hypoglossal nerve, a discussion of current use of HGNS in the US, and a look ahead at emerging technologies on the horizon.

History and Evolution of HGNS

Understanding the historical development of this innovative therapy provides valuable insight into its progression and impact on addressing sleep-related breathing disorders.

The concept of HGNS emerged from early research on the role of the tongue and its musculature in the pathogenesis of OSA. Researchers discovered that decreased activity or tone of the genioglossus muscle (the primary tongue protrusor) contributed to airway collapse during sleep. This discovery led to the hypothesis that stimulating the hypoglossal nerve, which innervates the tongue muscles, could help maintain airway patency and alleviate OSA symptoms.^3-6

Initial feasibility studies with HGNS devices demonstrated the potential of this approach, showing improvements in airflow and critical closing pressure of the upper airway. These early findings paved the way for the development of more advanced HGNS systems, with the Inspire Upper Airway Stimulation system (Inspire Medical Systems, Inc.) being the first HGNS device to receive approval for the treatment of OSA from the U.S. Food and Drug Administration in 2014.^7-11

The Anatomy of the Tongue and Hypoglossal Nerve

The tongue is a crucial muscular organ in the oral cavity. It plays a vital role in speech, swallowing, and maintaining airway patency during breathing. It consists of intrinsic and extrinsic muscles that work together to facilitate its movements and positioning within the oral cavity. Knowledge of the anatomical and functional relationship between these muscles is useful in understanding the mechanism of action in HGNS.

Extrinsic muscles of the tongue

• Genioglossus: This muscle originates from the mental spine of the mandible and extends to the body of the hyoid bone. Its primary function is to protrude and depress the tongue, playing a significant role in maintaining airway patency.
• Hyoglossus: Originating from the greater cornu of the hyoid bone, this muscle aids in retracting and depressing the sides of the tongue.
• Styloglossus: Arising from the styloid process of the temporal bone, this muscle retracts and elevates the sides of the tongue.

Intrinsic muscles of the tongue

• Superior longitudinal muscle: This muscle runs along the upper surface of the tongue, enabling it to curl upward and shorten.
• Inferior longitudinal muscle: Located on the underside of the tongue, this muscle assists in retracting and shortening the tongue
• Vertical and transverse muscles: These muscles contribute to altering the tongue’s shape and size for various functions such as swallowing and speaking.

The hypoglossal nerve, also known as the twelfth cranial nerve, is responsible for the motor function of the tongue. It originates from the medulla oblongata in the brain stem and travels through the neck before branching into the tongue muscles. It has a predictable branching pattern, with specific branches responsible for innervating different tongue muscles.

Notably, the hypoglossal nerve lacks sensory function, meaning it solely controls the movement of the tongue without transmitting sensory information. This characteristic makes it an ideal target for neuromuscular stimulation to selectively activate the tongue muscles involved in maintaining airway patency.

How Inspire Works

The Inspire device is currently the only FDA-approved HGNS device for the treatment of OSA. Since its approval in 2014, it has offered a promising treatment option for individuals with OSA who have not found relief with other therapies. Before the implantation of the Inspire device, a drug-induced sleep endoscopy may be performed to evaluate the upper airway’s collapsibility and identify the potential sources of obstruction. This sedated exam provides valuable insights into the patient’s airway dynamics and aids in determining the suitability of HGNS as a treatment option.¹²

The Inspire device consists of a cuffed electrode that wraps around the hypoglossal nerve to stimulate the intrinsic tongue muscles, specifically targeting the genioglossus muscle. Additionally, it includes an implantable pulse generator (IPG) placed in a “subcutaneous pocket” below the right clavical and a respiratory sensor positioned between the ribs. The surgical procedure involves two incisions, one beneath the jaw and another on the chest to accommodate the IPG.

The FDA expanded Inspire’s approval for use in 2023—it now specifies that the individual’s apnea hypopnea index (AHI) should be between 15 and 100, with less than or equal to 25% of events being central in nature, and BMI should be less than 40.^13-14 While the FDA indications for use have expanded, it’s important to note that insurance companies may recognize different criteria for coverage.

Inspire Outcomes and Predictors of Success

The clinical outcomes of the Inspire device have been extensively studied. HGNS is a surgical intervention, and as with any procedure, there are potential risks and complications. However, the device has been well-tolerated, with low rates of surgical and device-related complications. Patients have reported minimal impact on speech, swallowing, and daily activities, making it a favorable option for OSA treatment.

Initial feasibility studies and subsequent larger trials have demonstrated significant reductions in the apnea-hypopnea index (AHI), improvements in sleep quality and daytime sleepiness, and high patient satisfaction and adherence rates.^15–16 Long-term follow-up studies have shown sustained improvements in AHI, Epworth score, fatigue, and response rate over a period of five years, indicating the device’s efficacy and durability in managing OSA symptoms.^15–16

Researchers have also identified several patient characteristics that may predict a favorable response to HGNS therapy. Lower body mass index (BMI), less severe OSA (lower AHI), and the absence of complete concentric collapse of the soft palate on sleep endoscopy have been associated with better outcomes. Additionally, lower CPAP pressures required to maintain airway patency have been shown to correlate with a higher likelihood of success with HGNS.

Emerging HGNS Technologies

In addition to the Inspire device, other HGNS devices are being developed to address OSA. These devices offer alternative approaches to neuromuscular stimulation and have undergone clinical evaluation to assess their efficacy and safety.

LivaNova aura6000 System

Another HGNS device designed to treat OSA, the aura6000^® system (LivaNova PLC), consists of an electrode placed on the hypoglossal nerve and an IPG in the chest. The LivaNova technology utilizes six electrodes that encircle the nerve, aiming to stimulate different areas around its circumference to stiffen and flatten the tongue, reducing its collapsibility.

In an initial study involving 93 patients, the aura6000 device demonstrated a statistically significant reduction in AHI from 35 to 25 at six months. Furthermore, responders showed a substantial reduction in AHI from 35 to 8.5, indicating a positive treatment response.¹⁷

In a subsequent trial, 138 patients were implanted with the aura6000 device. Following activation, the treatment group showed a 52% success rate at four months, defined as a 50% reduction in AHI to a level less than 20. The overall success rate at 12 to 15 months was 42.5%, demonstrating the device’s potential in reducing AHI levels.¹⁸

The aura6000 system is currently undergoing further clinical evaluation in the OSPREY trial to assess its long-term efficacy and safety for the treatment of OSA.¹⁹

Nyxoah Genio Hypoglossal Nerve Stimulation Device

A bilateral HGNS system, Genio^® (Nyxoah SA) stimulates both sides of the hypoglossal nerve. The device aims to enhance tongue movement and open the airway, offering a potential solution for individuals with OSA who have not responded to conventional therapies.²⁰

The device incorporates a butterfly-shaped implantable design with electrodes that straddle or stimulate both nerves. It includes an electronic component for customization and utilizes a rechargeable battery. The surgical procedure involves a minimally invasive incision beneath the chin, and post-implantation, patients wear an adhesive patch overlying the device. Unlike traditional respiratory sensors, Genio operates on a duty cycle, alternating between on and off periods to optimize airway patency throughout the respiratory cycle.

Initial outcome studies, such as the BLAST OSA study (Bilateral Hypoglossal Nerve Stimulation for Treatment of Obstructive Sleep Apnoea), have demonstrated significant reductions in AHI, hypoxemic burden, and improvements in patient-reported outcomes, indicating the potential efficacy of the Genio device in managing OSA.

The device has shown promising outcomes in reducing AHI and improving daytime symptoms, offering an alternative for individuals intolerant to or failing CPAP therapy. The recent completion of the open-label DREAM study demonstrated that the device met its co-primary endpoints, indicating substantial reductions in AHI and the oxygen desaturation index, as well as high responder rates.²¹ These results underscore the potential of hypoglossal nerve stimulation as a viable treatment modality for OSA. Nyxoah submitted the fourth and final module for its pre-market application for Genio to the FDA in early July.²²

Exploration of Ansa Cervicalis Stimulation

Emerging research is exploring the potential of stimulating the ansa cervicalis, a nerve in the neck that innervates the strap muscles supporting the voice box. This concept, known as tracheal tug, aims to induce tracheal tug, which can limit airway collapsibility and potentially mitigate OSA. Preliminary studies have shown that combined stimulation of the hypoglossal nerve and ansa cervicalis results in improved air flow and airway opening, suggesting a potential direction for future neuromuscular interventions in OSA treatment.²³

Hypoglossal nerve stimulation continues to revolutionize the landscape of OSA treatment. With one FDA-approved device on the U.S. market, another potentially on the way, and several more devices commercially available in Europe, HGNS is a promising therapeutic option for OSA—particularly in patients who cannot tolerate or comply with CPAP therapy. As we gain experience and the technology is further developed, we are learning the characteristics unique to individual patients that predict success with this form of therapy.

Sidebar

Three HGNS Takeaways From Philly Sleep

Dr. Huntley delivered two lectures on the latest developments in hypoglossal nerve simulation at the 2024 Philadelphia Sleep Conference—one for the Physician track and one for the Tech/RT track. Here are three key topics he addressed during the presentation and live Q&A sessions that followed:

Adjusting Stimulation with Age and Weight

When asked about adjusting stimulation with age and weight, Dr. Huntley mentioned that increasing the voltage and amount of stimulation is possible as individuals get older or heavier. However, the long-term impact on outcomes remains unclear. Age is a predictor of improved success, possibly due to a less collapsible airway, while weight is a predictor of decreased success. Anecdotally, adjusting stimulation levels, such as bumping up voltage in specific situations like after consuming alcohol, may help control symptoms.

Criteria for Full-Night Efficacy Study

Dr. Huntley highlighted the importance of assessing device usage and sleep patterns during a home study to determine full-night efficacy. The criteria for a full-night efficacy study include assessing usage data from the device, aligning it with the hypnogram from the home study, and ideally capturing at least four hours of usage. Multiple nights of home sleep testing are preferred to gather comprehensive data, and it’s beneficial to observe a combination of supine and non-supine sleep patterns.

Appropriate Patient Selection Criteria

Dr. Huntley emphasized the importance of patient selection criteria based on factors such as the severity of OSA and the patient’s BMI. He explained that HGNS is an effective treatment option for OSA, but it is not for everyone. The success of HGNS is influenced by factors such as BMI, critical closing pressure of the airway, airway collapse pattern, age, and gender.

Call to Action

Learn More About HGNS

If you want to take a deeper dive into HGNS, you can purchase the 2024 Philadelphia Sleep Conference recording to watch all of the presentations, including Dr. Huntley’s. Respiratory therapists and sleep technologists can earn up to 10 continuing education credits.

Dr. Huntley is the associate professor of Otolaryngology-Head & Neck Surgery and Sleep Medicine and the Associate Residency Program Director at Thomas Jefferson University. He is a board-certified and fellowship-trained sleep specialist. One of two sleep surgeons with Jefferson Health to pioneer the use of hypoglossal nerve stimulation with the FDA-approved Inspire device, Dr. Huntley is internationally recognized as one of the most experienced surgeons to perform this innovative, minimally invasive procedure.

Disclosure: Dr. Huntley has disclosed research support from Nyxoah and Inspire and a consulting role for Nyxoah. These affiliations are with companies specializing in hypoglossal nerve stimulation, which is the focus of this discussion.

References

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