Tongue neuromuscular and directhypoglossal nerve stimulation for

obstructive sleep apneaDavid W. Eisele, MDa,*, Alan R. Schwartz, MDb,

Philip L. Smith, MDb

aDepartment of Otolaryngology–Head and Neck Surgery, University of California, SanFrancisco, 400 Parnassus Avenue, Suite A-730, San Francisco, CA 94143-0342, USA

bJohns Hopkins Asthma and Allergy Center, Johns Hopkins UniversitySchool of Medicine, Bayview Circle, Baltimore, MD 21224, USA

Obstructive sleep apnea (OSA) is caused by recurrent episodes of upperairway obstruction during sleep associated with periodic arousals from sleepand oxyhemoglobin desaturations. Sleep disturbance and abnormal oxygen-ation are believed to cause the primary clinical sequelae of OSA thatinclude daytime hypersomnolence, arterial and pulmonary hypertension,and cardiopulmonary failure. Therapy for OSA is directed toward the reliefof upper airway obstruction so that the clinical manifestations of the disor-der are alleviated or prevented.

Although numerous methods have been used to restore upper airwaypatency during sleep for patients with OSA, no single treatment modalityhas been shown to provide complete reversal of upper airway obstructionduring sleep in all patients with this disorder. The cause of OSA, which isconsidered to be related to diminished genioglossus muscle activity duringsleep, is not addressed by current therapies [1]. To address this problem, theauthors conducted investigations into the effect of neuromuscular stimula-tion of the tongue muscles and direct hypoglossal nerve stimulation onupper airway patency during sleep in patients with OSA. This articlesummarizes the authors’ investigations of selective neuromuscular tongueand direct hypoglossal nerve stimulation on upper airway airflow mechanicsduring sleep in patients with OSA and the feasibility of this interventionfor the treatment of this disorder.

Otolaryngol Clin N Am36 (2003) 501–510

* Corresponding author.E-mail address: deisele@orca.ucsf.edu (D.W. Eisele).

0030-6665/03/$ - see front matter ! 2003, Elsevier Science (USA). All rights reserved.doi:10.1016/S0030-6665(02)00178-0

Neuromuscular stimulation of the tongue

Multiple prior investigations have addressed the concept of electricalstimulation of the tongue in OSA. Approaches have included attempts tostimulate the tongue with surface electrodes placed in the upper neck skin[2,3], sublingual mucosa [4,5], base-of-tongue mucosa [6], and soft palate[7]. Percutaneous wire electrodes, directed near the hypoglossal nerve, alsohave been used [8,9]. The methods used in these studies, however, lackedselectivity in stimulating the genioglossus muscle or hypoglossal nerve andinduced recurrent arousals from sleep. A generalized arousal from sleep re-sulting in pharyngeal muscle activation could have caused the improvementsin pharyngeal airway patency reported in these earlier investigations.

In light of the limitations of these studies, the authors began investi-gations into electrical stimulation of the tongue muscles with three primaryobjectives. First, methods were developed to selectively stimulate the genio-glossus muscle in volunteers and patients with OSA. Second, the e!ect ofthe selective stimulation of the genioglossus muscle on upper airway airflowdynamics during sleep was determined in patients with OSA. Third, patientswere sought for OSA treatment with an implantable electrical-stimulationsystem. Initially, methods for selective neuromuscular stimulation of thetongue muscles with transorally directed hook-wire electrodes were de-veloped. Tongue motor responses with this method were correlated withtongue motor responses resulting from selective hypoglossal nerve stimu-lation performed during open-neck surgical procedures. This correlationprovided confirmation of proper transoral electrode placement into thegenioglossus muscle based on the motor response observed with stimulation.The observed response to neuromuscular and selective hypoglossal nervestimulation of the genioglossus muscle was tongue protrusion and deviationof the tongue to the contralateral side.

Neuromuscular stimulation of the genioglossus muscle then was exam-ined during sleep in patients with OSA [10]. The level of maximal air-flow before, during, and after stimulation was measured with standardpolysomnographic recording techniques. Arousal from sleep during or afterstimulation was excluded by monitoring electroencephalography, electro-myography, the pattern of respiration, and the heart rate. All patients withOSA studied were morbidly obese with significant apnea-hypopnea indices.Neuromuscular stimulation of the genioglossus muscle resulted in an im-provement in inspiratory airflow of approximately 200 to 250 mL/s (Fig. 1).The improvement in airway patency was limited to the duration of stimu-lation of the genioglossus muscle. Importantly, the results of this study con-firmed that electrical stimulation of the upper airway could be achievedduring sleep in patients with OSA without arousal from sleep. The airway-opening effect produced by stimulation was noted to be directly relatedto genioglossus neuromuscular activation rather than global arousal fromsleep.

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Selective direct hypoglossal nerve stimulation

Another investigation was undertaken to determine the e!ect of directhypoglossal nerve stimulation on upper airway patency in patients withOSA during sleep [11]. A tripolar half-cuff electrode (Medtronic 3990; Med-tronic, Minneapolis, MN) was used. This electrode was designed to limitthe electrical current to the nerve and to prevent nerve entrapment. Thehypoglossal nerve was exposed through an upper neck incision in patientswith OSA. Two loci of hypoglossal nerve stimulation, the distal branch tothe genioglossus muscle and the main nerve trunk, were examined. The levelof maximal inspiratory airflow before, during, and after stimulation wasmeasured during sleep with standard polysomnographic techniques. Lack ofarousal from sleep was confirmed by monitoring electroencephalography,electromyography, the respiratory pattern, and the heart rate. Electricalstimulation of the hypoglossal nerve at both stimulation loci resulted ina marked improvement in inspiratory airflow during stimulation, compared

Fig. 1. Mean maximal inspiratory airflow (VI max) levels for eight patients with OSA before,during, and after neuromuscular stimulation of the genioglossus muscle during sleep. (FromSchwartz AR, Eisele DW, Hari A, et al. Electrical stimulation of the lingual musculature inobstructive sleep apnea. J Appl Physiol 1996;81:643–52; with permission.)

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with unstimulated breaths, without patient arousal from sleep (Fig. 2). Itwas concluded from this study that airway obstruction in patients with OSAwas alleviated by hypoglossal nerve stimulation, not only when the genioglos-sus muscle was stimulated but also when the tongue retrusor muscles werecoactivated with the genioglossus muscle.

Implantable hypoglossal nerve-stimulation system

After the publication of the above-mentioned studies that confirmed thesuccess of electrical-stimulation methods for opening the airway in patientswith OSA without arousal from sleep and additional animal studies [12],a Food and Drug Administration-approved feasibility study was un-dertaken to investigate the treatment of patients with OSA with a fully

Fig. 2. Mean maximal inspiratory airflow (VI max) in five patients with OSA before, dur-ing, and after hypoglossal nerve stimulation during sleep. Filled circles indicate stimulationof the hypoglossal nerve branch to the genioglossus muscle. Open circles indicate maintrunk hypoglossal nerve stimulation. (From Eisele DW, Smith PL, Alam DS, Schwartz AR.Direct hypoglossal nerve stimulation in obstructive sleep apnea. Arch Otolaryngol Head NeckSurg 1997;123:57–61; with permission.)

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implantable hypoglossal nerve-stimulation system. This system, the Inspire I(Medtronic) (Fig. 3) consists of components that were designed to reliablypredict the onset of the inspiratory phase of respiration and to stimulate thehypoglossal nerve during inspiration. The system components include animplantable pulse generator (IPG), a respiratory pressure sensor, and a tri-polar, half-cuff peripheral nerve-stimulation electrode. The IPG containsa programmable microprocessor. Stimulus frequency, duration, and ampli-tude can be adjusted transcutaneously by the physician programmer. Theperipheral nerve lead and the respiratory pressure sensor interface withthe IPG.

Surgical implantation of the hypoglossal nerve-stimulation system isdescribed in detail elsewhere [13,14]. Briefly, the system is implanted undergeneral anesthesia through three surgical incisions: an upper lateral neckincision, a lower midline neck incision, and an infraclavicular incision. Thehypoglossal nerve is exposed by dissection through an upper neck incision.The stimulation electrode is placed on the peripheral hypoglossal nervebranch to the genioglossus muscle (Fig. 4). Proper placement on the desirednerve is confirmed by stimulation of the nerve with a hand-held pulse gen-erator and observation of tongue protrusion and deviation to the contra-lateral side. Through a midline lower neck incision, the pressure transduceris placed flush with the posterior aspect of the manubrium through a drillhole, and the transducer housing is secured to the manubrium with aminiscrew (Fig. 5). An infraclavicular pocket, superficial to the pectoralismajor muscle fascia, is created by way of an infraclavicular incision (Fig. 6).A tunneling device then is used to tunnel the nerve-electrode lead and thepressure-transducer lead to the IPG pocket. The leads then are connected tothe IPG, and the wounds are closed. The system is checked for functionalintegrity before awakening the patient from anesthesia. Further testing of

Fig. 3. Schematic diagram of Inspire I Hypoglossal Nerve Stimulation System (Medtronic,Minneapolis, MN).

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the system is deferred for 1 month to allow for adequate healing andstabilization of the implanted system.

Therapeutic hypoglossal nerve stimulation in obstructive sleep apnea

Recently, a multi-institutional, prospective trial to investigate the thera-peutic e"cacy of the Medtronic Inspire I hypoglossal nerve-stimulationsystem for OSA was completed [14]. Eight middle-aged, moderately over-weight men with moderate to severe OSA during non-rapid-eye-movement(non–REM) and REM sleep underwent implantation of the system. Nightlyunilateral hypoglossal nerve stimulation was initiated at 4 weeks after system

Fig. 4. Half-cu! stimulation electrode placement around distal branch of the hypoglossal nerveto the genioglossus muscle. (From Eisele DW, Schwartz AR, Smith PL. Electrical stimulation ofthe upper airway for obstructive sleep apnea. Op Tech Otolaryngol Head Neck Surg 2000;11:59–65; with permission.)

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implantation. Patients initiated electrical stimulation with a self-controlledprogramming unit. A pre-set delay in system activation allowed patients toinitiate sleep before the start of electrical stimulation.

Sleep and breathing patterns were examined at baseline and at 1, 3, and 6months postoperatively. Results of this clinical trial indicated that unilateralhypoglossal nerve stimulation decreased the severity of the OSA throughoutthe entire study period. Specifically, stimulation reduced the mean apnea-hypopnea indices in non-REM and REM sleep compared with baselinevalues (Fig. 7). The severity of oxyhemoglobin desaturations was reducedsignificantly. All patients were able to tolerate long-term stimulation atnight, and there were no adverse effects related to system implantation ornerve stimulation. Small, consistent increases in stimulus parameters wererequired early in the protocol to maintain therapeutic responses to stimu-lation. After 3 months, however, little further increase in stimulus intensity

Fig. 5. Pressure transducer placement through a drill hole in the manubrium. (From Eisele DW,Schwartz AR, Smith PL. Electrical stimulation of the upper airway for obstructive sleep apnea.Op Tech Otolaryngol Head Neck Surg 2000;11:59–65; with permission.)

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was required, suggesting that the nerve-electrode interface had stabilizedduring this early postoperative period. The results of this prospective studydemonstrate the feasibility and therapeutic benefit of unilateral hypoglossalstimulation in OSA.

Some system technical issues require resolution before broader applica-tion of a stimulation system for the treatment of OSA. Electrode breakageor respiratory sensor malfunction occurred in some patients, resulting incompromise of long-term stimulation. Patients who remained free fromstimulator malfunction, however, were able to continue to use the device asprimary therapy for OSA.

Fig. 6. Implantable pulse generator placement in an infraclavicular pocket superficial to thepectoralis major muscle fascia. The nerve-electrode lead and pressure-transducer lead aretunneled to the IPG pocket and connected to the IPG. (From Eisele DW, Schwartz AR, SmithPL. Electrical stimulation of the upper airway for obstructive sleep apnea. Op Tech OtolaryngolHead Neck Surg 2000;11:59–65; with permission.)

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Further studies are necessary to optimize patient-selection criteria fortherapeutic hypoglossal nerve stimulation. Patient selection may be basedon baseline di!erences in upper airway collapsibility or the site of pharyn-geal obstruction. Therapeutic responses may be augmented by the use ofmultisite stimulation, such as bilateral hypoglossal nerve stimulation, orstimulation of other combinations of upper airway and cervical muscles.Most importantly, the e!ect of electrical stimulation of the upper airway onmeasures of daytime sleepiness, performance, and cardiopulmonary func-tion must be assessed before this treatment modality can be established asa therapeutic option for OSA.

Fig. 7. Non-REM apnea-hypopnea indices for a night without stimulation (baseline) and forentire-night and continuous periods with hypoglossal nerve stimulation. Patients’ values for theentire night are the mean of values at 1, 3, and 6 months and last follow-up. (From SchwartzAR, Bennett ML, Smith PL, et al. Therapeutic electrical stimulation of the hypoglossal nervein obstructive sleep apnea. Arch Otolaryngol Head Neck Surg 2001;127:1216–23; withpermission.)

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Summary

Recent studies have shown that neuromuscular stimulation of thegenioglossus muscle and direct stimulation of the hypoglossal nerve canbe performed selectively and safely. Such stimulation, delivered below thearousal threshold, can modulate airflow during sleep in patients with OSA.The feasibility and potential of upper airway stimulation for the treatmentof OSA have been demonstrated. Further studies and stimulation-systemrefinements are presently underway, with hopes of establishing upper airwaystimulation as a therapeutic option for this challenging disorder.

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[10] Schwartz AR, Eisele DW, Hari A, et al. Electrical stimulation of the lingual musculature inobstructive sleep apnea. J Appl Physiol 1996;81:643–52.

[11] Eisele DW, Smith PL, Alam DS, Schwartz AR. Direct hypoglossal nerve stimulation inobstructive sleep apnea. Arch Otolarygol Head Neck Surg 1997;123:57–61.

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[14] Schwartz AR, Bennett ML, Smith PL, et al. Therapeutic electrical stimulation of the hypo-glossal nerve in obstructive sleep apnea. Arch Otolaryngol Head Neck Surg 2001;127:1216–23.

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