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By Alan Z. Segal, MD
Associate Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Segal reports no financial relationships relevant to this field of study. This article originally appeared in the March 2014 issue of Neurology Alert.
Synopsis: Tongue protrusion, via hypoglossal nerve stimulation, appears to have great efficacy in the treatment of obstructive sleep apnea in this uncontrolled, large case series.
Source: Strollo PJ Jr, et al. Upper-airway stimulation for obstructive sleep apnea. N Engl J Med 2014;370:139-149.
Obstructive sleep apnea (osa) is a known risk factor for stroke, myocardial infarction, and overall mortality. Continuous positive airway pressure (CPAP) continues to be the mainstay therapy for this disorder, but is plagued by adherence rates as low as 30%. CPAP is better tolerated with optimization of mask fitting, strategies such as daytime adaptation, and close follow-up and monitoring. Even with these maneuvers, however, a large proportion of patients cannot tolerate CPAP. There are alternative therapies to CPAP, including oral appliances to advance the mandible and surgeries such as uvulopalatopharyngoplasty (UPPP), but these are of modest benefit, particularly in cases of moderate-to-severe OSA. Due to these limitations and the overall prevalence and dangers of OSA, the potential benefits for upper airway (tongue) stimulation shown here are particularly exciting.
In OSA, there is excessive relaxation of pharyngeal musculature leading to airway collapse. The genioglossus muscle, responsible for tongue protrusion, is a major contributor to this loss of airway patency as the base of the tongue falls backwards into the airway. This phenomenon is frequently observed in patients with "positional apnea," who snore or obstruct when on their back but improve when turned sideways. In these patients, genioglossus function may be sufficient to push the tongue out of the airway when positioned laterally, but too weak to do so when supine. Devices designed to pull the tongue forward are uncomfortable and ineffective. Hypoglossal nerve stimulation is a more effective strategy, facilitating gengioglossus activity and tongue protrusion. This device includes an excitatory electrode placed unilaterally on the hypoglossal nerve and a sensing electrode in the chest, which monitors intercostal muscle activity and allows stimulation timed to the inspiratory phase of ventilation.
The present multicenter study included 126 patients with a history of OSA who were non-adherent to CPAP therapy. More than 900 patients were screened for the study using the apnea-hypopnea index (AHI), with the majority of exclusions due to OSA that was too mild (AHI < 20; n = 324) or too severe (AHI > 50; n = 87). The AHI scores apneas (reductions in airflow > 90%) and hypopneas (reductions in airflow > 30% accompanied by a 4% drop in oxygen saturation) throughout the duration of sleep, with the total number of events converted into an hourly rate index. In addition to requiring an AHI range of 20-50, the study excluded patients with central or mixed obstructive-central events, as well as those with positional apnea (non-supine AHI < 10). Also excluded were patients with markedly enlarged tonsils or with total airway collapse on endoscopic examination. Additionally, patients with significant comorbidities or with a body mass index (BMI) > 32 kg/m2 were excluded.
After 1 year of stimulator therapy, the AHI in study participants decreased from 29 to 9, a 68% reduction that was highly statistically significant (P < 0.001). The Oxygen Desaturation Index, defined as the number of times per hour that oxygen saturation dropped by more than 4%, decreased from 25 to 7, a 70% reduction that was also highly statistically significant. The time spent with O2 saturations < 90% was also significantly reduced. Dramatic benefits were also seen on the Epworth Sleepiness Scale and the Functional Outcome of Sleep Questionnaire, confirming that the improvements in OSA were robust and directly improved daytime alertness and cognitive function. Of note, participants did not lose weight over the course of the study (which might have been an alternative explanation for their improvement), showing a mean BMI of 28 kg/m2 at baseline and at 12 months. Following the 12-month study, a consecutive subset of patients who benefitted from the stimulator (n = 46) were randomized to an additional week with or without the device turned on. In the withdrawal group, the AHI increased from 7 to 26 in one week, compared to essentially no change in the patients continued on stimulator therapy. Serious adverse events (n = 2) requiring lead repositioning due to discomfort were rare. Nine patients required a tooth guard due to tongue abrasion.
This study represents a possible paradigm shift in the management of OSA, providing convincing evidence of the efficacy of stimulator therapy. There do remain limitations in its overall conclusions. The investigators chose patients in the "sweet spot" of OSA severity, AHI 20-50, having moderate-to-severe, but not very severe disease. Patients with milder OSA (AHI < 20) have significant OSA-associated morbidity that cannot be ignored. Patients in the very severe category (AHI > 50), not included in this study, might not be helped by hypoglossal nerve stimulation but perhaps could be treated with lower CPAP pressures, which would promote adherence.
Patients with BMI > 32 kg/m2 were excluded. This would include a subset of patients with mild-moderate obesity (BMI 30-35 kg/m2) and eliminate anyone with severe (BMI 35-40 kg/m2) or morbid (BMI > 45 kg/m2) obesity. With increasing weight, excessive neck soft tissue in obese patients contributes to airway collapse even in the presence of optimal tongue positioning. It is not clear, however, if the cutoff point used in this study represents the upper limit of efficacy for this therapy.
The study used a "permissive" definition of a positive response to therapy, using criteria of AHI < 20 and overall AHI reduction by 50%, as evidence of benefit. Patients with AHI values in the 5-20 range are treated with CPAP by many practitioners. Furthermore, successful CPAP therapy is typically considered to be "curative" when AHI is reduced into the normal range (< 5). Even with the liberal definition of treatment effect used in this study, 34% of study subjects did not achieve benefit. Given the profound reductions in mean AHI, there may have been significant inter-subject variability in treatment response.
There is a significant cost differential between CPAP therapy ($1500 for a state-of-the-art machine) and hypoglossal nerve stimulation (approximately $30,000 for the device alone, excluding surgical costs). This may be cost efficient, however, given the major expenses associated with OSA-associated morbidity and mortality, especially in patients who would not otherwise use CPAP.
Hypoglossal nerve stimulation represents a potentially exciting advance in the management of OSA. If a randomized, controlled trial confirms its efficacy, it may become the mainstay of OSA treatment.