# Hypoglossal Nerve Stimulation and Emerging OSA Therapies

## Introduction

As understanding of OSA pathophysiology evolves, novel therapies are emerging that target the neuromuscular mechanisms underlying airway collapse. Hypoglossal nerve stimulation (HNS) represents a paradigm shift in OSA management, offering an implantable device-based approach for patients who cannot tolerate CPAP. The OMFS surgeon should be familiar with these therapies to counsel patients comprehensively and participate in multidisciplinary OSA management.

## Hypoglossal Nerve Stimulation

### Mechanism of Action

The hypoglossal nerve (CN XII) innervates the genioglossus and other tongue protrusor muscles. During sleep, reduced neural drive to these muscles contributes to tongue base collapse and retrolingual obstruction. HNS delivers synchronized electrical stimulation to the hypoglossal nerve during inspiration. Stimulation activates the genioglossus, protruding the tongue and stiffening the retrolingual airway. The Inspire system (Inspire Medical Systems) is the FDA-approved commercially available device.

### System Components

The system consists of an implantable pulse generator (IPG) placed subcutaneously in the right infraclavicular region, a stimulation lead tunneled to the hypoglossal nerve with a cuff electrode placed on the medial branches (protrusor fibers, avoiding retrusor branches), a sensing lead placed between the external and internal intercostal muscles to detect respiratory effort, and a patient remote control that activates the device at bedtime and adjusts stimulation amplitude.

### Patient Selection Criteria

Candidates must have moderate to severe OSA with an AHI of 15 to 65, documented CPAP intolerance or failure, a BMI of 35 kg/m2 or less (expanded from the original 32 in recent studies), and absence of complete concentric collapse (CCC) at the retropalatal level on DISE, as CCC predicts poor response. Patients must be 18 years or older and not have central sleep apnea (central apnea index less than 25% of total AHI).

### Surgical Implantation

The procedure is performed under general anesthesia and typically takes 2 to 3 hours. Three incisions are made: submandibular (nerve dissection), infraclavicular (IPG), and lateral chest wall (sensing lead). Through the submandibular approach, the hypoglossal nerve is identified and the medial (protrusor) and lateral (retrusor) branches are distinguished using intraoperative nerve stimulation. A cuff electrode is placed on the appropriate nerve branches, and tongue protrusion without retraction is verified. Leads are tunneled to the IPG pocket and system function is tested intraoperatively. The device is activated approximately 1 month postoperatively to allow tissue healing.

![Diagram showing the Inspire hypoglossal nerve stimulation system components and their anatomic placement](images/hns-system-diagram.jpg)

### Outcomes

The STAR Trial (Stimulation Therapy for Apnea Reduction), the pivotal multicenter trial, demonstrated a mean AHI reduction from 29 to 9 at 12 months (68% reduction). The surgical success rate is 66 to 75% (AHI reduction greater than 50% and AHI less than 20). Five-year data show a durable response with maintained AHI reduction and high adherence (greater than 80% nightly use). Significant improvements are seen in ESS, quality of life (FOSQ), and oxygen desaturation index. Adherence rates far exceed CPAP, with a median of more than 7 hours per night.

### Complications

Tongue discomfort or abrasion is the most common complication and is managed by adjusting stimulation parameters. Lead malposition or migration may require revision surgery. Device infection occurs in 1 to 3% of cases and may require explantation. Transient tongue weakness usually resolves, and persistent hypoglossal nerve injury is rare. Battery replacement for the IPG is needed approximately every 11 years.

## Emerging Pharmacotherapy

### Targeted Drug Therapy for OSA

The atomoxetine-oxybutynin combination (AD109) targets the neuromuscular pathophysiology of OSA. Atomoxetine, a norepinephrine reuptake inhibitor, increases pharyngeal muscle tone during sleep, while oxybutynin, an antimuscarinic, reduces REM-related muscle atonia. Phase III trials show AHI reduction of 40 to 50%. Tirzepatide and semaglutide, GLP-1 receptor agonists, produce weight loss-mediated OSA improvement; the SURMOUNT-OSA trial demonstrated that tirzepatide reduced AHI by 50 to 60% with significant weight loss, and these agents are FDA-approved for weight management with growing evidence for an OSA indication. Sulthiame, a carbonic anhydrase inhibitor, stimulates respiratory drive with European trials showing AHI reduction. Dronabinol, a synthetic cannabinoid targeting vagal afferents, has limited evidence.

### Limitations

Pharmacotherapy does not address skeletal anatomy. Long-term adherence and side effect profiles are still being established. These agents are likely to be adjunctive rather than standalone treatment.

## Other Emerging Therapies

### Transoral Robotic Surgery (TORS)

TORS provides robotic-assisted tongue base reduction and epiglottoplasty, enabling precise excision of obstructive lingual tonsil and tongue base tissue. It is used as standalone or combined with palate procedures. OMFS surgeons are increasingly trained in TORS applications.

### Expansion Sphincter Pharyngoplasty (ESP)

ESP is a modified palatopharyngoplasty that repositions the palatopharyngeus muscle laterally and anteriorly. It addresses lateral pharyngeal wall collapse better than traditional UPPP, with superior outcomes and surgical success rates of approximately 80%.

### Myofunctional Therapy

Myofunctional therapy consists of exercises targeting the oropharyngeal muscles to improve tone and coordination. It reduces AHI by approximately 50% in mild to moderate OSA. It serves as an adjunctive therapy that improves outcomes when combined with other treatments and is practiced by specially trained speech-language pathologists.

### Nasal Expiratory Positive Airway Pressure (EPAP)

Provent and Bongo devices are one-way valves that create expiratory resistance, generating positive pressure to splint the airway. They are suitable for mild to moderate OSA as an alternative for CPAP-intolerant patients.

### Oral Pressure Therapy

The Winx device creates negative oral pressure to advance the soft palate and tongue. It has seen limited adoption and was discontinued commercially, though the concept remains relevant.

![Timeline showing the evolution of OSA surgical and device-based therapies from UPPP through HNS and pharmacotherapy](images/osa-therapy-evolution.jpg)

## Comparison of Emerging OSA Therapies

| Therapy | Mechanism | AHI Reduction | Ideal Candidate | Key Limitation |
|---------|-----------|---------------|----------------|----------------|
| MMA | Skeletal expansion of pharyngeal airway | 85-100% success | Skeletal deficiency; moderate-severe OSA | Invasive; IAN paresthesia; facial change |
| Hypoglossal nerve stimulation (Inspire) | Electrical stimulation of tongue protrusors | 66-75% success | AHI 15-65; BMI ≤35; no CCC on DISE | Does not address skeletal anatomy; device cost |
| Atomoxetine + Oxybutynin | Increases pharyngeal tone; reduces REM atonia | 40-50% | Neuromuscular OSA phenotype | Long-term adherence unknown; side effects |
| GLP-1 agonists (tirzepatide, semaglutide) | Weight loss-mediated airway improvement | 50-60% | Obese OSA patients | Weight regain if discontinued; GI side effects |
| TORS | Robotic tongue base/epiglottic reduction | Variable (60-70%) | Tongue base obstruction; lingual tonsil hypertrophy | Does not address skeletal or palatal collapse |
| Expansion sphincter pharyngoplasty | Lateral repositioning of palatopharyngeus | ~80% success | Lateral pharyngeal wall collapse | Does not address retrolingual obstruction |
| Myofunctional therapy | Oropharyngeal muscle exercise | ~50% (mild-moderate) | Mild-moderate OSA; adjunctive use | Compliance-dependent; limited for severe OSA |

## The OMFS Perspective

OMFS surgeons should understand HNS indications and outcomes to counsel patients appropriately. MMA remains the most effective surgical option for moderate to severe OSA with skeletal deficiency. HNS is complementary and best suited for patients without significant skeletal deficiency who fail CPAP. Combination approaches (HNS plus skeletal surgery) are being explored for refractory cases. GLP-1 agonist-mediated weight loss may reduce the surgical burden in obese OSA patients. The OMFS surgeon's role continues to expand as part of the multidisciplinary sleep surgery team.

![Decision algorithm for selecting among CPAP, oral appliance, MMA, HNS, and pharmacotherapy based on patient factors](images/osa-treatment-selection-algorithm.jpg)

## Clinical Pearls

HNS achieves surgical success in 66 to 75% of patients with adherence rates exceeding CPAP. Complete concentric retropalatal collapse on DISE is a contraindication to HNS, and these patients may be better candidates for MMA. GLP-1 receptor agonists represent the most significant pharmacologic advance for OSA in decades. MMA remains the most effective surgical treatment and should be offered to patients with skeletal deficiency regardless of BMI. The future of OSA management is multimodal, combining skeletal surgery, neurostimulation, pharmacotherapy, and lifestyle modification.

## References

1. Strollo PJ, et al. "Upper-Airway Stimulation for Obstructive Sleep Apnea." *New England Journal of Medicine*. 2014;370(2):139-149.
2. Woodson BT, et al. "Five-Year Outcomes of Upper Airway Stimulation for Obstructive Sleep Apnea (STAR Trial)." *Otolaryngology--Head and Neck Surgery*. 2018;159(1):194-202.
3. Malhotra A, et al. "Tirzepatide for the Treatment of Obstructive Sleep Apnea (SURMOUNT-OSA)." *New England Journal of Medicine*. 2024;391(14):1288-1300.
4. Taranto-Montemurro L, et al. "The Combination of Atomoxetine and Oxybutynin Greatly Reduces Obstructive Sleep Apnea Severity." *American Journal of Respiratory and Critical Care Medicine*. 2019;199(10):1267-1276.