Obstructive Sleep Apnea in Children

Number: 0752

Policy

1. Diagnosis

   1. Aetna considers nocturnal polysomnography (NPSG) for children and adolescents younger than 18 years of agemedically necessary when performed in a healthcare facility for any of the following indications:

      1. To diagnose obstructive sleep apnea syndrome (OSAS) and differentiate it from snoring
      2. To evaluate hypersomnia
      3. Suspected narcolepsy (with MSLT)
      4. Suspected parasomnia
      5. Suspected restless leg syndrome
      6. Suspected periodic limb movement disoder
      7. Suspected congenital central alveolar hypoventilation syndrome
      8. Suspected sleep related hypoventilation due to neuromuscular disorders or chest wall deformities.

   2. Aetna considers NPSG for children medically necessary when performed in a healthcare facility after an adenotonsillectomy or other pharyngeal surgery for OSAS when any of the following is met (study should be delayed 6 to 8 weeks post-operatively):

      1. Age younger than 3 years; or
      2. Cardiac complications of OSAS (e.g., right ventricular hypertrophy); or
      3. Craniofacial anomalies that obstruct the upper airway; or
      4. Failure to thrive; or
      5. Neuromuscular disorders (e.g., Down syndrome, Prader-Willi syndrome and myelomeningocele); or
      6. Obesity; or
      7. Prematurity; or
      8. Recent respiratory infection; or
      9. Severe OSAS was present on pre-operative PSG (a respiratory disturbance index of 19 or greater); or
      10. Symptoms of OSAS persist after treatment.

   3. Aetna considers the use of abbreviated or screening techniques, such as videotaping, nocturnal pulse oximetry, unattended home PSG, or facility based, daytime, abbreviated cardiorespiratory sleep studies (daytime nap PSG, Pap Nap testing) experimental and investigational for diagnosis of OSAS in children because their effectiveness for this indication has not been established.

   4. Aetna considers measurements of circulating adropin concentrations, plasma pentraxin-3 or TREM-1 levels experimental and investigational for obstructive sleep apnea in children.
      
      
   5. Aetna considers measurement of DNA methylation levels experimental and investigational for the diagnosis and prognosis of OSA because the effectiveness of this approach has not been established.

2. Treatment

   Aetna considers the following treatments for OSAS in children with habitual snoring medically necessary when the apnea index is greater than 1 on a NPSG.

   1. Aetna considers adenoidectomy and/or tonsillectomy medically necessary for treatment of OSAS in children.  Childhood OSAS is usually associated with adenotonsillar hypertrophy, and the available medical literature suggests that the majority of cases will benefit from adenotonsillectomy.

   2. Aetna considers continuous positive airway pressure (CPAP) medically necessary for treatment of OSAS in children when any of the following is met:

      1. Adenoidectomy or tonsillectomy is contraindicated; or
      2. Adenoidectomy or tonsillectomy is delayed; or
      3. Adenoidectomy or tonsillectomy is unsuccessful in relieving symptoms of OSAS.

         Aetna considers CPAP medically necessary for treatment of tracheomalacia.

   3. Aetna considers oral appliances or functional orthopedic appliances medically necessary in the treatment of children with craniofacial anomalies with signs and symptoms of OSAS. 

   4. Aetna considers oral appliances or functional orthopedic appliances experimental and investigational for treatment of OSAS in otherwise healthy children.  There is insufficient evidence that oral appliances or functional orthopedic appliances are effective in the treatment of OSAS in healthy children.

   5. Aetna considers uvulopalatopharyngoplasty (UPPP) medically necessary for the treatment of OSAS in children with neuromuscular disorders who are deemed to be at high risk for persistent upper airway obstruction after adenotonsillectomy alone. Aetna considers UPPP experimental and investigational for the treatment of OSAS in otherwise healthy children. 
      
      
   6. Note on orthodontic treatment: Expenses associated with orthodontic treatments (such as rapid maxiallary expansion) are considered dental in nature and are not covered under Aetna's medical plans. Please check benefit plan descriptions. See CPB 0082 - Dental Services and Oral and Maxillofacial Surgery: Coverage Under Medical Plans.
      
      

   7. Aetna considers the following interventions experimental and investigational for obstructive sleep apnea in children because their effectiveness for this indication has not been established (not an all-inclusive list):

      1. Cautery-assisted palatal stiffening procedure (CAPSO);
      2. Chiropractic/osteopathic manipulation;
      3. Expansion sphincter pharyngoplasty;
      4. Flexible positive airway pressure;
      5. Hypoglossal nerve stimulation;
      6. Injection snoreplasty;
      7. Laser-assisted uvuloplasty (LAUP);
      8. Lingual tonsillectomy;
      9. Mandibular distraction osteogenesis;
      10. Maxillary expander;
      11. Midline/partial glossectomy;
      12. Nasal surgery;
      13. Pillar palatal implant system;
      14. Pre-fabricated myofunctional appliances (e.g., Myobrace/MyOSA);
      15. Repose system;
      16. Somnoplasty or Coblation;
      17. Transpalatal advancement pharyngoplasty;
      18. Uvulectomy.

Background

Obstructive sleep apnea syndrome (OSAS) is a disorder of breathing in which prolonged partial upper airway obstruction and/or intermittent complete obstruction occurs during sleep disrupting normal ventilation and normal sleep patterns.  The signs and symptoms of OSAS in children include habitual snoring (often with intermittent pauses, snorts, or gasps) with labored breathing, observed apneas, restless sleep, and daytime neurobehavioral problems.  Nocturnal enuresis, diaphoresis, cyanosis, mouth breathing, nasal obstruction during wakefulness, adenoidal facies, and hyponasal speech may also be present.  Daytime sleepiness is sometimes reported but hyperactivity can frequently occur.  Case studies report that OSAS in children can lead to behaviors easily mistaken for attention-deficit/hyperactivity disorder as well as behavioral problems and poor learning; however, most case studies have relied on histories obtained from parents of snoring children without objective measurements, control groups, or sleep studies.  Severe complications of untreated OSAS in children include systemic hypertension, pulmonary hypertension, failure to thrive, cor pulmonale, and heart failure. 

History and physical examination have been shown to be sensitive but not specific for diagnosing OSAS in children.  Primary snoring is often the presenting symptom reported by parents, and should warrant careful screening for OSAS.  Primary snoring is defined as snoring without obstructive apnea, frequent arousals from sleep or abnormalities in gaseous exchange.  It is estimated that 3 % to 12 % of children are habitual snorers but only 2 % will be diagnosed with OSAS.  Although surgical treatment has been shown to improve quality of life, it is not without risks (e.g., bleeding, velopharyngeal insufficiency, post-obstructive pulmonary edema).  Thus, clinicians must be able to distinguish between primary snoring and OSAS.  Primary snoring among children without obstructive sleep apnea is usually considered a benign condition although this has not been well evaluated.

Nocturnal polysomnography (NPSG) remains the gold standard diagnostic test to differentiate primary snoring from OSAS in children.  It is the only diagnostic technique that is able to quantitate the ventilatory and sleep abnormalities associated with sleep-disordered breathing and can be performed in children of any age. A polysomnogram (PSG) is a sleep study that is performed in a facility/laboratory setting and requires an overnight stay. PSG is designed to capture multiple sensory channels including blood pressure, brain waves, breathing patterns and heartbeat as an individual sleeps. It can also record eye and leg movements and muscle tension which can be useful in diagnosing parasomnias. A PSG performed at a facility will record a minimum of 12 channels which involves at least 22 wire attachments to the individual. Sensors that send electrical signals to a computer are placed on the head, face, chest and legs. This test is attended by a technologist and the results are evaluated by a qualified physician. A PSG may be performed in conjunction with a positive airway pressure (PAP) machine to determine the titration of oxygen flow. 

Positive airway pressure (PAP) titration study is used to set the right level of PAP which can be administered as continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BPAP) once individual tolerance and optimal levels are determined by a sleep technologist. PAP titration may be performed in conjunction with a PSG as part of a split night study if the diagnosis of moderate or severe OSA can be made within the first two hours of recorded sleep and at least three hours of PAP titration, including the ability of PAP to eliminate respiratory events during both rapid eye movement (REM) sleep and non-REM sleep, is demonstrated. If this is not possible, a second night in the sleep center may be necessary for the CPAP titration study.

It should be noted that interpretation of NPSG values in children with OSAS is not unanimously agreed upon in the literature (Sargi and Younis, 2007) and only a limited number of studies designed to establish normal values for sleep-related respiratory variables in children have been reported.  However, based on normative data, an obstructive apnea index of 1 is frequently chosen as the threshold of normality.  Other normative values reported in the literature for children aged 1 to 15 years include: central apnea index 0.9; oxygen desaturation, 89 %; baseline saturation, 92 %; and PETCO2 (end-tidal carbon dioxide pressure) greater than 45 mm Hg for less than 10 % of total sleep time (Verhulst, 2007; Uliel, 2004; Schechter, 2002).

Studies have shown that abbreviated or screening techniques, such as videotaping, nocturnal pulse oximetry, and daytime nap PSG tend to be helpful if results are positive but have a poor predictive value if the results are negative. Facility based, daytime, abbreviated, cardiorespiratory sleep studies (PAP NAP testing) uses a therapeutic framework that includes mask and pressure desensitization, emotion focused therapy to overcome aversive emotional reactions, mental imagery to divert the individual’s attention from mask or pressure sensations and physiological exposure to PAP therapy during a 100 minute nap period which is purported to enhance PAP therapy adherence.  

Home/portable monitoring sleep testing is a sleep study performed in the home utilizing portable monitoring (PM) devices that are designed to be used by an individual without supervision of a sleep technologist. PM devices measure fewer parameters than a laboratory based sleep study and are therefore not recommended for assessment of sleep disorder in the pediatric population. Unattended home PSG in children was evaluated by 1 center (Jacob, 1995) and produced similar results to laboratory studies; however, the equipment was relatively sophisticated and included respiratory inductive plethysmography, oximeter pulse wave form and videotaping.  Unattended home studies in children using commercially available 4-  to  6-channel recording equipment has not been studied.  Portable monitoring based only on oximetry is inadequate for identifying OSAS in otherwise healthy children (Kirk, 2003).

Actigraphy is a technique for monitoring body movement during sleep to detect sleep disorders by using a portable device known as an actigraph, which is worn on the individual’s wrist or ankle. An example of an actigraph device is the Actiwatch.

Prescreening devices or procedures purportedly predict pretest probability of obstructive sleep apnea (OSA) prior to performing a sleep study. Examples of prescreening techniques include, but may not be limited to, acoustic pharyngometry and SleepStrip.

According to the American Academy of Pediatrics guideline on the diagnosis and management of childhood OSAS (2002), complex high-risk patients should be referred to a specialist with expertise in sleep disorders.  These patients include infants and children with any of the following: craniofacial disorders, Down syndrome, cerebral palsy, neuromuscular disorder, chronic lung disease, sickle cell disease, central hypoventilation syndrome, and genetic/metabolic/storage diseases. 

Treatment of OSAS in children depends on the severity of symptoms and the underlying anatomic and physiologic abnormalities.  Childhood OSAS is usually associated with adenotonsillar hypertrophy, and the available medical literature suggests that the majority of cases (75 % to 100 %) will benefit from adenotonsillectomy (the role of adenoidectomy alone is unclear). Tonsillectomy and/or adenoidectomy are procedures that are performed for airway obstruction, especially in children. Tonsillectomy is the surgical removal of the tonsils, which are a collection of lymphoid tissue covered by mucous membranes located on either side of the throat. An adenoidectomy is the surgical removal of the adenoid glands. The adenoids are masses of lymphoid tissue located at the back of the nose in the upper part of the throat.

Other causes of pediatric OSAS include obesity, craniofacial anomalies, and neuromuscular disorders.  Obese children may have less satisfactory results with adenotonsillectomy, but it is generally considered the first-line therapy for these patients as well.  If the patient is not a candidate for adenotonsillectomy, other treatment options include weight loss (if patient is obese) and continuous positive airway pressure (CPAP).  Nocturnal masks for CPAP or procedures for mask respiration are effective in children, but are only used in exceptional cases, such as when adenotonsillectomy is delayed, contraindicated, or when symptoms of OSAS remain after surgery. 

Severely affected children may require uvulopalatopharyngoplasty (UPPP) or tracheostomy to relieve their obstruction; however, neither have been well studied in children and is rarely indicated.  Tracheostomy is a surgical procedure in which an opening is created through the neck into the windpipe (trachea) and a tube placed through this opening to provide an airway. Uvulopalatopharyngoplasty (UPPP) is the surgical revision of the posterior soft palate and adjacent tissue to relieve partial obstruction of the nasopharyngeal airway that causes OSA.

The success of pharmacological treatment of OSAS in children has not been evaluated in controlled clinical trials (Erler and Paditz, 2004).

A Cochrane review (2007) on oral appliances and functional orthopedic appliances for OSA in children 15 years old or younger reported that there is insufficient evidence to state that oral appliances or functional orthopedic appliances are effective in the treatment of OSAS in children.  Oral appliances or functional orthopedic appliances may be helpful in the treatment of children with craniofacial anomalies that are risk factors of apnea.

In a meta-analysis of mandibular distraction osteogenesis, Ow and Cheung (2008) concluded that mandibular distraction osteogenesis is effective in treating craniofacial deformities, but further clinical trials are needed to evaluate the long-term stability and to compare the treatment with conventional treatment methods, especially in cases of OSA or class II mandibular hypoplasia.

Pang and Woodson (2007) evaluated the effectiveness of a new method (expansion sphincter pharyngoplasty [ESP]) to treat OSA.  A total of 45 adults with small tonsils, body mass index (BMI) less than 30 kg/m2, of Friedman stage II or III, of type I Fujita, and with lateral pharyngeal wall collapse were selected for the study.  The mean BMI was 28.7 kg/m2.  The apnea-hypopnea index (AHI) improved from 44.2 +/- 10.2 to 12.0 +/- 6.6 (p < 0.005) following ESP and from 38.1 +/- 6.46 to 19.6 +/- 7.9 in the uvulopalato-pharyngoplasty group (p < 0.005).  Lowest oxygen saturation improved from 78.4 +/- 8.52 % to 85.2 +/- 5.1 % in the ESP group (p = 0.003) and from 75.1 +/- 5.9 % to 86.6 +/- 2.2 % in the uvulopalato-pharyngoplasty group (p < 0.005).  Selecting a threshold of a 50 % reduction in AHI and AHI less than 20, success was 82.6 % in ESP compared with 68.1 % in uvulopalato-pharyngoplasty (p < 0.05).  The authors concluded that ESP may offer benefits in a selected group of OSA patients.  These findings need to be validated by studies with larger sample sizes and long-term follow-up.

In a retrospective institutional review board-approved analysis, Wootten and Schott (2010) described their experience of treating retroglossal and base-of-tongue collapse in children and young adults with OSA using combined genioglossus advancement (Repose THS; MedtronicENT, Jacksonville, FL) and radiofrequency ablation of the tongue base.  A total of 31 patients with a mean age of 11.5 years (range of 3.1 to 23.0) were included in this analysis.  Pre-operative and post-operative polysomnographic data were evaluated for each patient.  Success of surgery was determined using the criteria of a post-operative AHI of 5 or fewer events per hour, without evidence of hypoxemia (oxygen saturation as measured by pulse oximetry), and without prolonged hypercarbia (end-tidal carbon dioxide).  Nineteen (61 %) of the 31 subjects had Down syndrome.  The overall success rate was 61 % (19 of 31) (58 % [12 of 19] success among patients with Down syndrome and 66 % [7 of 12] success among patients without Down syndrome).  Overall, the mean AHI improved from 14.1 to 6.4 events per hour (p < 0.001); the mean nadir oxygen saturation as measured by pulse oximetry during apnea improved from 87.4 % to 90.9 % (p = 0.07).  The authors concluded that pediatric OSA refractory to adenotonsillectomy that is due to retroglossal and base-of-tongue collapse remains difficult to treat.  However, most patients in this analysis benefited from combined genioglossus advancement and radiofrequency ablation.  The findings of this small, retrospective study need to be validated by well-designed studies.  furthermore, these finding are confounded by the combinational use of the Repose system and radiofrequency ablation of the tongue base.  It should be noted that the European Respiratory Society's task force on non-CPAP therapies in sleep apneas (Randerath et al, 2011) stated that nasal surgery, radiofrequency tonsil reduction, tongue base surgery, uvulopalatal flap, laser midline glossectomy, tongue suspension and genioglossus advancement can not be recommended as single interventions".

Tracheomalacia is a disorder of the large airways where the trachea is deformed or malformed during respiration.  It is associated with a wide spectrum of respiratory symptoms from life-threatening recurrent apnea to common respiratory symptoms such as chronic cough and wheeze.  Current practice following diagnosis of tracheomalacia include medical approaches aimed at reducing associated symptoms of tracheomalacia, ventilation modalities of CPAP and bilevel positive airway pressure (BiPAP) as well as surgical interventions aimed at improving the caliber of the airway.

In a prospective, randomized, controlled study, Essouri et al (2005) evaluated the efficacy of CPAP ventilation in infants with severe upper airway obstruction and compared CPAP to BiPAP ventilation.  A total of 10 infants (median age of 9.5 months, range of 3 to 18) with laryngomalacia (n = 5), tracheomalacia (n = 3), tracheal hypoplasia (n = 1), and Pierre Robin syndrome (n = 1) were included in this analysis.  Breathing pattern and respiratory effort were measured by esophageal and trans-diaphragmatic pressure monitoring during spontaneous breathing, with or without CPAP and BiPAP ventilation.  Median respiratory rate decreased from 45 breaths/min (range of 24 to 84) during spontaneous breathing to 29 (range of 18 to 60) during CPAP ventilation.  All indices of respiratory effort decreased significantly during CPAP ventilation compared to un-assisted spontaneous breathing (median, range): esophageal pressure swing from 28 to 10 cm H(2)O (13 to 76 to 7 to 28), esophageal pressure time product from 695 to 143 cm H(2)O/s per minute (264 to 1,417 to 98 to 469), diaphragmatic pressure time product from 845 to 195 cm H(2)O/s per minute (264 to 1,417 to 159 to 1,183).  During BiPAP ventilation a similar decrease in respiratory effort was observed but with patient-ventilator asynchrony in all patients.  The authors concluded that this short-term study showed that non-invasive CPAP and BiPAP ventilation are associated with a significant and comparable decrease in respiratory effort in infants with upper airway obstruction.  However, BiPAP ventilation was associated with patient-ventilator asynchrony.

An UpToDate review on "Tracheomalacia and tracheobronchomalacia in adults" (Ernst et al, 2012) states that "[c]ontinuous positive airway pressure (CPAP) can maintain an open airway and facilitate secretion drainage.  This is often initiated in the hospital during an acute illness.  The patient initially receives continuous CPAP and is gradually transitioned to intermittent CPAP as tolerated.  Patients may use intermittent CPAP as long-term therapy.  However, CPAP does not appear to have a long-term impact on dyspnea or cough.  Positive airway pressure other than CPAP (e.g., bilevel positive airway pressure) may be used instead if hypercapnic respiratory failure exists".

An eMedicine article on "Tracheomalacia Treatment & Management" (Schwartz) stated that "[s]upportive therapy is provided to most infants.  Most respond to conservative management, consisting of humidified air, chest physical therapy, slow and careful feedings, and control of infection and secretions with antibiotics.  The use of continuous positive airway pressure (CPAP) has been recommended in patients having respiratory distress and may be successful in patients requiring a short-term intervention as the disorder spontaneously resolves".  

The American Academy of Pediatrics’ practice guideline on “Diagnosis and management of childhood obstructive sleep apnea syndrome” (Marcus et al, 2012) focused on uncomplicated childhood OSAS, that is, OSAS associated with adenotonsillar hypertrophy and/or obesity in an otherwise healthy child who is being treated in the primary care setting.  The updated guideline did not mention the use of lingual tonsillectomy as a management tool for OSA in children and adolescents.

Kim and colleagues (2013) noted that OSA is a common health problem in children and increases the risk of cardiovascular disease (CVD).  Triggering receptor expressed on myeloid cells-1 (TREM-1) plays an important role in innate immunity and amplifies inflammatory responses.  Pentraxin-3 is predominantly released from macrophages and vascular endothelial cells, plays an important role in atherogenesis, and has emerged as a biomarker of CVD risk.  Thus, these researchers hypothesized that plasma TREM-1 and pentraxin-3 levels would be elevated in children with OSA.  A total of 106 children (mean age of: 8.3 ± 1.6 yrs) were included after they underwent over-night polysomnographic evaluation and a fasting blood sample was drawn the morning after the sleep study.  Endothelial function was assessed with a modified hyperemic test after cuff-induced occlusion of the brachial artery.  Plasma TREM-1 and pentraxin-3 levels were assayed using commercial enzyme-linked immunosorbent assay kits.  Circulating microparticles (MPs) were assessed using flow cytometry after staining with cell-specific antibodies.  Children with OSA had significantly higher TREM-1 and pentraxin-3 levels (versus controls: p < 0.01, p < 0.05, respectively).  Plasma TREM-1 was significantly correlated with both BMI-z score and the obstructive AHI in uni-variate models.  Pentraxin-3 levels were inversely correlated with BMI-z score (r = -0.245, p < 0.01), and positively associated with endothelial MPs and platelet MPs (r = 0.230, p < 0.01 and r = 0.302, p < 0.01).  Both plasma TREM-1 and pentraxin-3 levels were independently associated with AHI in multi-variate models after controlling for age, sex, race, and BMI-z score (p < 0.001 for TREM-1 and p < 0.001 for pentraxin-3).  However, no significant associations emerged between TREM-1, pentraxin-3, and endothelial function.  The authors concluded that plasma TREM-1 and pentraxin-3 levels were elevated in pediatric OSA, and may play a role in modulating the degree of systemic inflammation.  Moreover, they stated that the short-term and long-term significance of elevated TREM-1 and pentraxin-3 in OSA-induced end-organ morbidity remains to be defined.

Gozal and associates (2013) tested the hypothesis that concentrations of adropin, a recently discovered peptide that displays important metabolic and cardiovascular functions, are lower in OSA, especially when associated with endothelial dysfunction.  Age-, sex-, and ethnicity-matched children (mean age of 7.2 ± 1.4 years) were included into 1 of 3 groups based on the presence of OSA in an over-night sleep study, and on the time to post-occlusive maximal re-perfusion (Tmax greater than 45 seconds) with a modified hyperemic test.  Plasma adropin concentrations were assayed using a commercial enzyme-linked immunosorbent assay kit.  Among controls, the mean morning adropin concentration was 7.4 ng/ml (95 % confidence interval [CI]: 5.2 to 16.3 ng/ml).  Children with OSA and abnormal endothelial function (EF) (OSA+/EF+ group) had significantly lower adropin concentrations (2.7 ± 1.1 ng/ml; n = 35) compared with matched controls (7.6 ± 1.4 ng/ml; n = 35; p < 0.001) and children with OSA and normal EF (OSA+/EF- group; 5.8 ± 1.5 ng/ml; n = 47; p < 0.001).  A plasma adropin concentration less than 4.2 ng/ml reliably predicted EF status, but individual adropin concentrations were not significantly correlated with age, BMI z-score, obstructive AHI, or nadir oxygen saturation.  Mean adropin concentration measured after adenotonsillectomy in a subset of children with OSA (n = 22) showed an increase in the OSA+/EF+ group (from 2.5 ± 1.4 to 6.4 ± 1.9 ng/ml; n = 14; p < 0.01), but essentially no change in the OSA+EF- group (from 5.7 ± 1.3 to 6.4 ± 1.1 ng/ml; n = 8; p > 0.05).  The authors concluded that plasma adropin concentrations were reduced in pediatric OSA when endothelial dysfunction is present, and returned to within normal values after adenotonsillectomy.  They stated that assessment of circulating adropin concentrations may provide a reliable indicator of vascular injury in the context of OSA in children.  These preliminary findings need to be validated by well-designed studies.

Posadzki and colleagues (2013) critically evaluated the effectiveness of osteopathic manipulative treatment (OMT) as a treatment of pediatric conditions.  A total of 11 databases were searched from their respective inceptions to November 2012.  Only randomized clinical trials (RCTs) were included, if they tested OMT against any type of control in pediatric patients.  Study quality was critically appraised by using the Cochrane criteria.  A total of 17 trials met the inclusion criteria; 5 RCTs were of high methodological quality.  Of those, 1 favored OMT, whereas 4 revealed no effect compared with various control interventions.  Replications by independent researchers were available for 2 conditions only, and both failed to confirm the findings of the previous studies.  Seven RCTs suggested that OMT leads to a significantly greater reduction in the symptoms of asthma, congenital nasolacrimal duct obstruction (post-treatment), daily weight gain and length of hospital stay, dysfunctional voiding, infantile colic, otitis media, or postural asymmetry compared with various control interventions.  Seven RCTs indicated that OMT had no effect on the symptoms of asthma, cerebral palsy, idiopathic scoliosis, obstructive apnea, otitis media, or temporo-mandibular disorders compared with various control interventions.  Three RCTs did not perform between-group comparisons.  The majority of the included RCTs did not report the incidence rates of adverse effects.  The authors concluded that the evidence of the effectiveness of OMT for pediatric conditions remains unproven due to the paucity and low methodological quality of the primary studies.

There is also a lack of evidence regarding the clinical effectiveness of chiropractic manipulation for the treatment of sleep apnea.

The evidence on the use of midline/partial glossectomy for the treatment of OSA is not RCT-based; the data are mostly from case-series studies.

The Adult Obstructive Sleep Apnea Task Force of the American Academy of Sleep Medicine's clinical guideline on "The evaluation, management and long-term care of obstructive sleep apnea in adults" (Epstein et al, 2009) stated that " Tracheostomy can eliminate OSA but does not appropriately treat central hypoventilation syndromes (Consensus).  Maxillary and mandibular advancement can improve PSG parameters comparable to CPAP in the majority of patients (Consensus).  Most other sleep apnea surgeries are rarely curative for OSA but may improve clinical outcomes (e.g., mortality, cardiovascular risk, motor vehicle accidents, function, quality of life, and symptoms) (Consensus).  Laser-assisted uvulopalatoplasty is not recommended for the treatment of obstructive sleep apnea (Guideline)".  This guideline does not mention the use of midline glossectomy.

The American Sleep Disorders Association's practice parameters on "The surgical modifications of the upper airway for obstructive sleep apnea in adults" (Aurora et al, 2010) did not mention midline/partial glossectomy as a therapeutic option.

The European Respiratory Society task force on non-CPAP therapies in sleep apnea (Randerath et al, 2011) noted that "Nasal surgery, radiofrequency tonsil reduction, tongue base surgery, uvulopalatal flap, laser midline glossectomy, tongue suspension and genioglossus advancement cannot be recommended as single interventions".

Furthermore, an UpToDate review on “Management of obstructive sleep apnea in children” (Paruthi, 2014) states that “Tongue reduction surgery has been proposed for the management of OSA related to macroglossia (e.g., Beckwith-Wiedemann syndrome, Down syndrome).  Additional studies are needed to determine the efficacy of this procedure in such patients, especially since a case series of 13 patients with Beckwith-Wiedemann syndrome found that adenotonsillectomy was more effective than tongue reduction in relieving upper airway obstruction”.

Kerschner et al (2002) noted that children with neurologic impairment often present with airway obstruction that may require intervention.  No single method of airway intervention is universally appropriate and effective in this patient population.  These researchers examined the effectiveness of using adenotonsillectomy and UPPP in resolving obstructive apnea (OA) in patients with neurologic impairment.  These investigators performed a retrospective chart review of 15 patients with neurologic impairment and OA treated with adenotonsillectomy and UPPP between 1986 and 1998 at Children's Hospital of Wisconsin (CHW).  All patients in the series had their primary area of obstruction in the posterior oropharynx involving the soft palate, pharyngeal walls and base of tongue.  Post-operative improvement following adenotonsillectomy and UPPP was examined.  Measures of improvement were based primarily on recorded lowest oxygen saturations, but clinical parameters, flexible upper airway endoscopy and PSG were used as well.  Patient improvement was documented in 87 % of patients treated with this modality.  For the group, the mean lowest recorded oxygen saturation demonstrated a statistically significant improvement from 65 % pre-operatively to 85 % post-operatively (p = 0.005).  In long-term follow-up of these patients, 77 % (10 of 13) of those showing initial improvement have done well and have required no further airway intervention.  However, 23 % of these patients demonstrated the need for further airway intervention during follow-up.  The authors concluded that adenotonsillectomy with UPPP is worthy of consideration in certain neurologically impaired patients with moderate-to-severe OA, limited primarily to the posterior pharyngeal area.  Moreover, they stated that initial improvement may not be permanent and close long-term follow-up of patients is imperative.

Randerath and colleagues (2011) stated that in view of the high prevalence and the relevant impairment of patients with OSAS, lots of methods are offered that promise definitive cures for or relevant improvement of OSAS.  These investigators summarized the effectiveness of alternative treatment options in OSAS.  An inter-disciplinary European Respiratory Society task force evaluated the scientific literature according to the standards of evidence-based medicine.  Evidence supports the use of mandibular advancement devices in mild-to-moderate OSAS.  Maxillo-mandibular osteotomy seems to be as efficient as CPAP in patients who refuse conservative treatment.  Distraction osteogenesis is usefully applied in congenital micrognathia or mid-face hypoplasia.  There is a trend towards improvement after weight reduction.  Positional therapy is clearly inferior to CPAP and long-term compliance is poor.  Drugs, nasal dilators and apnea-triggered muscle stimulation cannot be recommended as effective treatments of OSAS at the moment.  Nasal surgery, radiofrequency tonsil reduction, tongue base surgery, uvulopalatal flap, laser mid-line glossectomy, tongue suspension and genioglossus advancement cannot be recommended as single interventions.  Uvulopalatopharyngoplasty, pillar implants and hyoid suspension should only be considered in selected patients and potential benefits should be weighed against the risk of long-term side-effects.  Multi-level surgery is only a salvage procedure for OSA patients.

The American Academy of Pediatrics’ clinical practice guideline on “Diagnosis and management of childhood obstructive sleep apnea syndrome” (Marcus et al, 2012) did not mention UPPP as a management tool.

Furthermore, an UpToDate review on “Management of obstructive sleep apnea in children” (Paruthi, 2015) states that “Uvulopalatopharyngoplasty (UPPP) is not widely used for the management of OSA in children because it is associated with significant complications, such as nasopharyngeal stenosis, palatal incompetence, and speech difficulties.  It has been successfully combined with adenotonsillectomy in children with neuromuscular disorders who are deemed to be at high risk for persistent upper airway obstruction after adenotonsillectomy alone”.

Hypoglossal Nerve Stimulation

Hypoglossal nerve stimulation technology (eg, Inspire UAS system) utilizes an implantable, programmable device that electrically stimulates the hypoglossal nerve which leads to the contraction of the genioglossus muscle. This purportedly prevents airway collapse and the development of upper airway obstruction during sleep.

Certal et al (2015) systematically reviewed the evidence regarding the safety and effectiveness of hypoglossal nerve stimulation (HNS) as an alternative therapy in the treatment of OSA. Scopus, PubMed, and Cochrane Library databases were searched (updated through September 5, 2014).  Studies were included that evaluated the effectiveness of HNS to treat OSA in adults with outcomes for AHI, oxygen desaturation index (ODI), and effect on daytime sleepiness (Epworth Sleepiness Scale [ESS]).  Tests for heterogeneity and subgroup analysis were performed.  A total of 6 prospective studies with 200 patients were included in this review.  At 12 months, the pooled fixed effects analysis demonstrated statistically significant reductions in AHI, ODI, and ESS mean difference of -17.51 (95 % CI: -20.69 to -14.34); -13.73 (95 % CI: -16.87 to -10.58), and -4.42 (95 % CI: -5.39 to -3.44), respectively.  Similar significant reductions were observed at 3 and 6 months.  Overall, the AHI was reduced between 50 % and 57 %, and the ODI was reduced between 48 % and 52 %.  Despite using different hypoglossal nerve stimulators in each subgroup analysis, no significant heterogeneity was found in any of the comparisons, suggesting equivalent effectiveness regardless of the system in use.  The authors concluded that the findings of this review showed that HNS therapy may be considered in selected patients with OSA who fail medical treatment.  They stated that further studies comparing HNS with conventional therapies are needed to definitively evaluate outcomes.

Diercks et al (2016) noted that OSA is more common in children with Down syndrome, affecting up to 60 % of patients, and may persist in up to 50 % of patients after adenotonsillectomy. These children with persistent moderate to severe OSA require CPAP, which is often poorly tolerated, or even tracheotomy for severe cases.  Hypoglossal nerve stimulation produces an electrical impulse to the anterior branches of the hypoglossal nerve, resulting in tongue protrusion in response to respiratory variation.  It supposedly allows for alleviation of tongue base collapse and improving airway obstruction.  These researchers described the first pediatric HNS; it was performed in an adolescent with Down syndrome and refractory severe OSA (AHI: 48.5 events/hour).  The patient would not tolerate CPAP and required a long-standing tracheotomy.  Hypoglossal nerve stimulation was well-tolerated and effective, resulting in significant improvement in the patient's OSA (overall AHI: 3.4 events/hour; AHI: 2.5 to 9.7 events/hour at optimal voltage settings depending on sleep stage and body position).  Five months after implantation, the patient's tracheotomy was successfully removed and he continues to do well with nightly therapy.  This was a single-case study; its findings need to be validated in well-designed studies.

Uvulopharyngopalatoplasty

An UpToDate review on “Adenotonsillectomy for obstructive sleep apnea in children” (Garetz, 2016) states that “Uvulopalatopharyngoplasty (UPPP) is not widely used for the management of OSA in children, but has been successfully combined with adenotonsillectomy in small studies of children with neuromuscular disorders who are thought to be at high risk for persistent upper airway obstruction after adenotonsillectomy alone, including children with Down syndrome or other developmental delays. Only one of these studies employed objective evaluation of improvement in OSA.  In this study, 15 children with neurologic impairments and OSA were treated with UPPP in conjunction with adenotonsillectomy.  There was a statistically significant improvement in mean oxygen saturation nadir from 65 to 85 % (p = 0.005).  In long-term follow-up, 77 % (10 of 13) of the patients did not require additional airway intervention.  Small sample size, absence of control groups, and paucity of validated outcome measures preclude analysis of the utility of this procedure in the broader pediatric population.  Potential complications include nasopharyngeal stenosis, palatal incompetence, and speech difficulties”.

Rapid Maxillary Expansion

Rapid maxillary expansion (RME) is an orthodontic treatment has been used to treat obstructive sleep apnea syndrome among children (Machado-Junior, et al., 2016). However only limited studies have evaluated this treatment for its efficacy in ameliorating obstructive sleep apnea syndrome symptoms. Therefore , there is no consensus about the benefits of using RME to treat obstrucive sleep apnea syndrome (OSAS) 

Ashok and  associates (2014) stated that RME is an orthopedic procedure routinely used to treat constricted maxillary arches and is also a potential  treatment in children presenting with sleep-disordered breathing (SDB).  These researchers evaluated the effects of RME on sleep characteristics in children.  Polysomnography was carried out in 15 children (9 boys and 6 girls) aged 8 to 13 years before expansion (T0), after expansion (T1) and after a period of 3 months after retention (T2).  Bonded rapid maxillary expander was cemented in all children.  Inter-molar distance was also measured at T0 and T2.  Non-parametric Friedman test was used for comparing the averages of sleep parameters at different time period (T0, T1, T2).  Wilcoxon signed ranks test was used for comparing the averages of inter-molar width (T0-T2); p < 0.05 were considered as significant.  All children showed an improvement in sleep parameters with an increase in sleep efficiency, decreased in arousal and desaturation index after expansion.  Total sleep time showed a statistically significant increase after expansion.  A statistically significant increase in inter-molar distance was obtained after expansion.  The authors concluded that RME is a potential additional treatment in children presenting with SDB; OSA may evolve during childhood before becoming clinically evident later in life.  The importance of these observations lies not only in the potential to treat the underlying craniofacial abnormalities, but more importantly raises the possibility that early detection and treatment of children at high risk of developing OSA may prevent the disorder.  Since maxillary constriction is a feature of chronic naso-respiratory obstruction, RME has the potential to play an important role in such a preventative strategy.  The quality of sleep of these children improved after RME, regardless of the severity of their respiratory obstruction.  The early detection and treatment of children at risk of developing OSA may prevent the sequelae of the disease.  These investigators stated that this study had several drawbacks, and thus it would be premature to make definitive conclusions about the benefit of RME on sleep characteristics in normal children, even though all patients showed an improvement in sleep parameters.  Moreover, all patients included in this sample had normal AHI.  Thus, decrease or increase in this AHI value could not be taken into consideration.  However, other than small sample size (n = 15), another drawback was the lack of the control group due to ethical reasons.

Camacho and colleagues (2017) performed a systematic review with meta-analysis for sleep study outcomes in children who have undergone RME as treatment for OSA; 3 authors reviewed the international literature through February 21, 2016.  A total of 17 studies reported outcomes for 314 children (7.6 ± 2.0 years old) with high-arched and/or narrow hard palates (transverse maxillary deficiency) and OSA.  Data were analyzed based on follow-up duration: less than or equal to 3 years (314 patients) and greater than 3 years (52 patients).  For less than or equal to 3-year follow-up, the pre- and post-RME AHI decreased from a mean ± standard deviation (M ± SD) of 8.9 ± 7.0/hr to 2.7 ± 3.3/hr (70 % reduction).  The cure rate (AHI less than 1/hr) for 90 patients for whom it could be calculated was 25.6 %.  Random effects modeling for AHI standardized mean difference (SMD) was -1.54 (large effect).  Lowest oxygen saturation (LSAT) improved from 87.0 ± 9.1 % to 96.0 ± 2.7 %.  Random effects modeling for LSAT SMD was 1.74 (large effect); AHI improved more in children with previous adenotonsillectomy or small tonsils (73 to 95 % reduction) than in children with large tonsils (61 % reduction).  For greater than 3-year follow-up (range of 6.5 to 12 years), the AHI was reduced from an M ± SD of 7.1 ± 5.7/hr to 1.5 ± 1.8/hr (79 % reduction).  The authors concluded that improvement in AHI and lowest oxygen saturation has consistently been observed in children undergoing RME, especially in the short term (less than 3-year follow-up).  Moreover, they stated that randomized trials and more studies reporting long-term data (greater than or equal to 3-year follow-up) would help determine the effect of growth and spontaneous resolution of OSA.

The American Academy of Pediatric Dentistry (AAPD) policy on “Obstructive sleep apnea” (AAPD, 2016) stated that “Although some studies have advocated the use of non-surgical interventions such as rapid maxillary/palatal expansion (RPE) or a modified monobloc appliance, these studies had small sample sizes”. Guidelines on pediatric obstructive sleep apnea from the American Academy of Pediatrics (Marcus, et al., 2012) state that rapid maxillary expansion may be effective in specially selected patients.

Furthermore, an UpToDate review on “Management of obstructive sleep apnea in children” (Paruthi, 2017) states that “Selected children with OSA may derive benefit from adjunctive therapies.  As examples, obese children with OSA may benefit from weight loss, and children with maxillary contraction may benefit from rapid maxillary expansion”. Garetz (2017) stated that RME can be used for children with OSA and narrow palate (crossbite) who have little adenotonsillar tissue, or for those with residual OSA after adenotonsillectomy.

In a review on “Oral interventions for obstructive sleep apnea”. Koretsi and colleagues (2018) stated that there is no evidence from high-quality research to support treatment with maxillary expansion (conventional or surgically assisted) in patients with OSA.

Glossectomy

In a systematic review and meta-analysis, Murphy and colleagues (2015) examined the effect of glossectomy as part of multi-level sleep surgery on sleep-related outcomes in patients with OSA.  Two independent researchers conducted the review using PubMed-NCBI and Scopus literature databases.  Studies on glossectomy for OSA that reported pre- and post-operative AHI score with 10 or more patients were included.  A total of 18 articles with 522 patients treated with 3 glossectomy techniques (midline glossectomy, lingualplasty, and submucosal minimally invasive lingual excision) met inclusion criteria.  Pooled analyses (baseline versus post-surgery) showed a significant improvement in AHI (48.1 ± 22.01 to 19.05 ± 15.46, p < 0.0001), ESS (11.41 ± 4.38 to 5.66 ± 3.29, p < 0.0001), snoring visual analog scale (VAS; 9.08 ± 1.21 to 3.14 ± 2.41, p < 0.0001), and lowest O2 saturation (76.67 ± 10.58 to 84.09 ± 7.90, p < 0.0001).  Surgical success rate was 59.6 % (95 % CI: 53.0 % to 65.9 %) and surgical cure was achieved in 22.5 % (95 % CI: 11.26 % to 36.26 %) of cases.  Acute complications occurred in 16.4 % (79/481) of reported patients.  Glossectomy was used as a standalone therapy in 24 patients.  In this limited cohort, significant reductions in AHI (41.84 ± 32.05 to 25.02 ± 20.43, p = 0.0354) and ESS (12.35 ± 5.05 to 6.99 ± 3.84, p < 0.0001) were likewise observed.  The authors concluded that glossectomy significantly improved sleep outcomes as part of multi-level surgery in adult patients with OSA.  Moreover, they stated that there is currently insufficient evidence to analyze the role of glossectomy as a stand-alone procedure for the treatment of OSA, although the evidence suggested positive outcomes in select patients.

The authors stated that this study had some several drawbacks.  There is a lack of quality research involving glossectomy with the majority of available published data drawn from small case series without control arms.  This has made it difficult to determine the true effectiveness of glossectomy.  Similar procedures vary in surgical approach, the inclusion criteria for patient selection, and types of additional procedures, and definitions of and the amount of attention paid to complications in each series, while similar, were not standardized across studies.  Additionally, many of the isolated glossectomy patients analyzed received previous palate surgery.  This made it extremely difficult to truly compare treatments and complications.  It should also be noted that AHI, while the most popular and universally reported outcome metric used for sleep medicine, has its limitations.  Moreover, they stated that future directions for research include further evaluation of isolated glossectomy and direct comparisons of glossectomy to other tongue base surgeries in multi-level surgery.

Miller and associates (2017) examined the effect of TORS base of tongue (BOT) reduction on sleep-related outcomes in patients with OSA.  Data sources included PubMed, Scopus, Embase, CINAHL, Cochrane, and Ovid.  Literature search by 2 independent authors was conducted using the afore-mentioned databases.  Studies on TORS BOT reduction as part of OSA treatment in adult patients with pre- and post-operative AHI scores were included.  Studies on TORS as treatment for diseases other than OSA were excluded.  A total of 6 articles with 353 patients treated with TORS BOT reduction met inclusion criteria.  Pooled analyses (baseline versus post-surgery) showed significant improvement in the following: AHI (44.3 ± 22.4 to 17.8 ± 16.5, p < 0.01), ESS (12.9 ± 5.4 to 5.8 ± 3.7, p < 0.01), lowest oxygen saturation (79.0 ± 9.5 to 84.1 ± 6.5, p < 0.01), and snoring VAS (9.3 ± 0.8 to 2.4 ± 2.43, p < 0.01).  Surgical success rate, defined as a greater than 50 % reduction of AHI with a post-operative AHI less than 20, was 68.4 % (95 % CI: 63.0 % to 73.5 %).  Cure rate (post-operative AHI less than 5) was 23.8 % (95 % CI: 19.1 % to 29.2 %).  The authors concluded that TORS BOT reduction decreased AHI and symptoms of sleepiness in adult patients with OSA.  It is considered successful in a majority of cases; however, these researchers stated that further studies must be performed to optimize patient selection criteria to achieve higher rates of success.  The keywords of this study included trans-oral robotic surgery, base of tongue, glossectomy, lingual tonsillectomy, obstructive sleep apnea, and sleep surgery.

Cammaroto and co-workers (2017) noted that Coblation tongue surgery and TORS proved to be the most published therapeutic options for the treatment of patients affected by OSA.  These researchers carried out a systematic review of the literature and an analysis of the data.  The mean rates of failure were 34.4 % and 38.5 %, respectively in TORS and Coblation groups.  Complications occurred in 21.3 % of the patients treated with TORS and in 8.4 % of the patients treated with Coblation surgery.  The authors concluded that TORS appeared to give slightly better results, allowing a wider surgical view and a measurable, more consistent removal of lingual tissue.  However, the higher rate of minor complication and the significant costs of TORS must also be considered. 

Montevecchi and colleagues (2017) stated that pediatric OSAS is primarily caused by adeno-tonsillar hypertrophy.  However, tongue base hypertrophy is increasingly being recognized as a cause, even after adeno-tonsillectomy.  These investigators reported 3 cases of pediatric OSAS successfully treated by TORS BOT.  In all children, these investigators were able to achieve improved retro-lingual patency while avoiding significant procedure-related morbidity.  The authors concluded that tongue base reduction by TORS appeared to be a feasible solution for the base of tongue obstruction due to lingual tonsil hypertrophy in pediatric patients.

Vicini and associates (2017) reviewed TORS for the treatment of OSAHS.  The review presented the experience of the robotic center that developed the technique with regards to patient selection, surgical method, and post-operative care.  In addition, the review provided results of a systematic review and meta-analysis of the complications and clinical outcomes of TORS when applied in the management of OSAHS.  The rate of success, defined as 50 % reduction of pre-operative AHI and an overall AHI less than 20 events/hour, was achieved in up to 76.6 % of patients with a range between 53.8 % and 83.3 %.  The safety of this approach was reasonable as the main complication (bleeding) affected 4.2 % of patients (range of 4.2 % to 5.3 %).  However, transient dysphagia (7.2 %; range of 5 % to 14 %) did compromise the QOL and must be discussed with patients pre-operatively.  The authors concluded that TORS for the treatment of OSAHS appeared to be a promising and safe procedure for patients seeking an alternative to traditional therapy.  They stated that appropriate patient selection remains an important consideration for successful implementation of this novel surgical approach requiring further research.  The keywords of this study included midline glossectomy, obstructive sleep apnea, partial glossectomy, posterior glossectomy, sleep surgery, TORS, and transoral robotic surgery.

In a retrospective study, Folk and D'Agostino (2017) compared sleep-related outcomes in OSAHS patients following BOT resection via robotic surgery and endoscopic midline glossectomy.  A total of 114 robotic and 37 endoscopic midline glossectomy surgeries were performed between July 2010 and April 2015 as part of single or multi-level surgery.  Patients were excluded for indications other than sleep apnea or if complete sleep studies were not obtained.  Thus, 45 robotic and 16 endoscopic surgeries were included in the analysis.  In the robotic surgery group there were statistically significant improvements in AHI [(44.4 ± 22.6) events/hour - (14.0 ± 3.0) events/hour, p < 0.001], ESS (12.3 ± 4.6 to 4.5 ± 2.9, p < 0.001), and O2 nadir (82.0 % ± 6.1 % to 85.0 % ± 5.4 %, p < 0.001).  In the endoscopic group there were also improvements in AHI (48.7 ± 30.2 to 27.4 ± 31.9, p = 0.06), ESS (12.6 ± 5.5 to 8.3 ± 4.5, p = 0.08), and O2 nadir (80.2 % ± 8.6 % to 82.7 % ± 6.5 %, p = 0.4).  Surgical success rate was 75.6 % and 56.3 % in the robotic and endoscopic groups, respectively.  Greater volume of tissue removed was predictive of surgical success in the robotic cases (10.3 versus 8.6 ml, p = 0.02).  The authors concluded that both robotic surgery and endoscopic techniques for tongue base reduction improved objective measures of sleep apnea; greater success rates may be achieved with robotic surgery compared to traditional methods.  Moreover, they stated that these findings were limited by the retrospective nature of this study, and further clinical studies are needed despite these encouraging results.

Measurement of DNA Methylation Levels for the Diagnosis and Prognosis of Obstructive Sleep Apnea

Chen and co-workers (2016) hypothesized that DNA methylation patterns may contribute to disease severity or the development of hypertension and excessive daytime sleepiness (EDS) in patients with OSA.  Illumina's (San Diego, CA) DNA methylation 27-K assay was used to identify differentially methylated loci (DML).  DNA methylation levels were validated by pyro-sequencing.  A discovery cohort of 15 patients with OSA and 6 healthy subjects, and a validation cohort of 72 patients with SDB.  Microarray analysis identified 636 DMLs in patients with OSA versus healthy subjects, and 327 DMLs in patients with OSA and hypertension versus those without hypertension.  In the validation cohort, no significant difference in DNA methylation levels of 6 selected genes was found between the primary snoring subjects and OSA patients (primary outcome).  However, a secondary outcome analysis showed that interleukin-1 receptor 2 (IL1R2) promoter methylation (-114 cytosine followed by guanine dinucleotide sequence [CpG] site) was decreased and IL1R2 protein levels were increased in the patients with SDB with an ODI of greater than 30.  Androgen receptor (AR) promoter methylation (-531 CpG site) and AR protein levels were both increased in the patients with SDB with an ODI of greater than 30.  Natriuretic peptide receptor 2 (NPR2) promoter methylation (-608/-618 CpG sites) were decreased, whereas levels of both NPR2 and serum C-type natriuretic peptide protein were increased in the SDB patients with EDS.  Speckled protein 140 (SP140) promoter methylation (-194 CpG site) was increased, and SP140 protein levels were decreased in the patients with SDB and EDS.  The authors concluded that IL1R2 hypo-methylation and AR hyper-methylation may constitute an important determinant of disease severity, whereas NPR2 hypo-methylation and SP140 hyper-methylation may provide a biomarker for vulnerability to EDS in OSA.

The authors stated that this study had several drawbacks.  First, the cause-and-effect relationship could not be determined in this cross-sectional clinical study design, because inherited DNA methylation patterns (epigenotype) may affect the development of disease, and environmental stimuli may cause disease progression through DNA methylation changes.  These preliminary in-vitro experiment with peripheral blood mononuclear cell samples from 6 healthy subjects showed that gene expression and DNA methylation levels of the 4 selected genes were not altered with 4 d of IHR treatment (7 h of alternative 0 % and 21 % O2 each day) compared to normoxic conditions, indicating that these CpG sites may be the initiators of different phenotypes in OSA but not responders to IHR.  However, the authors acknowledged that they could not exclude a role for IHR for 2 reasons: (a) the treatment period was very short (4 days) compared to months/years in patients with OSA; and (b) the paradigm for IHR did not mimic exactly cyclical intermittent hypoxia as occurred in humans.  Second, DNA methylation and protein expression changes were demonstrated independently in the patients with SDB with different phenotypes (secondary outcome), but not between patients with OSA and PS (primary outcome).  Further studies with sufficiently large sample sizes are needed for the internal and external validity and the reliability of the results.  However, % time of less than 90 % SaO2 has been demonstrated to be the strongest predictor of high-sensitivity C-reactive protein variability in patients with OSA, indicating that the AHI may not reflect the true characteristic of chronic intermittent hypoxia and inflammation.  Third, gene expression levels of the selected genes were not examined in the peripheral blood mononuclear cell samples of the discovery or validation cohorts because of inadequate RNA samples.  However, their protein expressions showed corresponding changes, indicating a potential functional role of these DML in regulating gene expressions.  Fourth, hypertension-related DMLs in the discovery cohort, such as IL1R2 and SP140, were shown to be associated with the ODI and EDS, respectively, in the validation cohort.  However, these results were not unexpected, because EDS in patients with OSA is a special phenotype, characterized by younger age, higher blood pressure, and more severe hypoxic load.  These researchers also acknowledged that the study design did not allow an understanding of whether these findings were unique to these outcomes solely in the setting of OSA or whether they represented general differences in those disease states.  Fifth, the identified changes in the peripheral blood mononuclear cells may be only partly responsible for the pathogenesis of OSA, and partly mirrored differences in other relevant tissues.  These investigators stated that further investigation is needed to clarify whether these changes could be translated to neurons, endothelium, or other end-organ tissues.  Finally, verification and validation of many enriched pathways identified in the discovery phase are ongoing.  Among them, the cyclic adenosine monophosphate (cAMP)-protein kinase A signaling-cAMP response element binding protein (CREB) pathway has been reported to play an important role in sleep-wake control, hippocampal neuronal plasticity, and memory processes.

Perikleous and colleagues (2018) noted that OSA is characterized by phenotypic variations, which can be partly attributed to specific gene polymorphisms.  Recent studies have focused on the role of epigenetic mechanisms in order to permit a more precise perception about clinical phenotyping and targeted therapies.  These researchers synthesized available evidence on the relation between DNA methylation patterns and the development of pediatric OSA, in light of the apparent limited literature in the field.  They performed an electronic search in PubMed, Embase, and Google Scholar databases, including all types of articles written in English until January 2017.  Literature was apparently scarce; only 2 studies on pediatric populations and 3 animal studies were identified  Forkhead Box P3 (FOXP3) DNA methylation levels were associated with inflammatory biomarkers and serum lipids.  Hyper-methylation of the core promoter region of endothelial nitric oxide synthase (eNOS) gene in OSA children were related with decreased eNOS expression.  Furthermore, increased expression of genes encoding pro-oxidant enzymes and decreased expression of genes encoding anti-oxidant enzymes suggested that disturbances in oxygen homeostasis throughout neonatal period pre-determined increased hypoxic sensing in adulthood.  The authors concluded that epigenetic modifications may be crucial in pediatric sleep disorders to enable in-depth understanding of genotype-phenotype interactions and lead to risk assessment.  They stated that epigenome-wide association studies are needed to validate certain epigenetic alterations as reliable, novel biomarkers for the molecular prognosis and diagnosis of OSA patients with high risk of end-organ morbidity.

Maxillary Protraction Appliances

In a systematic review and meta-analysis, Ming and colleagues (2018) examined the efficacy of maxillary protraction appliances (MPAs) on improving pharyngeal airway dimensions in growing class III patients with maxillary retrognathism.  These researchers carried out an electronic search in PubMed, Cochrane Library, Web of Science, and Embase until September 2, 2017.  The assessments of methodological quality of the selected articles were performed using the Newcastle-Ottawa Scale.  Review Manager 5.3 (provided by the Cochrane Collaboration) was used to synthesize the effects of MPAs on pharyngeal airway dimensions.  Following full-text articles evaluation for eligibility, a total of 6 studies (168 treated subjects and 140 untreated controls) were included in final quantitative synthesis and they were all high-quality.  Compared to untreated control groups, the treatment groups had increased significantly nasopharyngeal airway dimensions with the following measurements: PNS-AD1 (fixed: mean difference, 1.33 mm, 95 % CI: 0.48 mm to 2.19 mm, p = 0.002), PNS-AD2 (random: mean difference, 1.91 mm, 95 % CI: 0.02 mm to 3.81 mm, p = 0.05), aerial nasopharyngeal area (fixed: mean difference, 121.91 mm2, 95 % CI: 88.70 mm2 to 155.11 mm2, p < 0.00001) and total nasopharyngeal area (fixed: mean difference, 142.73 mm2, 95 % CI: 107.90 mm2 to 177.56 mm2, p < 0.00001).  Meanwhile, McNamara's upper pharynx dimension (fixed: mean difference, 0.96 mm, 95 % CI: 0.29 mm to 1.63 mm, p = 0.005), which was highly related to post-palatal airway dimension, was also improved significantly.  However, no statistically significant differences in adenoidal nasopharyngeal area (p > 0.05) and McNamara's lower pharynx dimension (p > 0.05) existed.  The authors concluded that MPAs could increase post-palatal and nasopharyngeal airway dimensions in growing skeletal class III subjects with maxillary retrusion.  Moreover ,they stated that it may be suggested that MPAs have the potential to reduce the risk of OSAS in children with maxillary retrusion by enlarging airway space.

Pre-Fabricated Myofunctional Appliances (e.g., Myobrace/MyOSA)

Levrini and colleagues (2018) examined the efficacy of the Myobrace/MyOSA myofunctional appliance for the treatment of mild-to-moderate OSA in children, by means of the AHI.  A total of 9 children with a diagnosis of mild-to-moderate OSA were included in the study.  Participants wore the Myobrace/MyOSA myofunctional appliance for a period of 90 days.  The initial AHI, determined by means of a sleep test, was used as baseline (To), and a second AHI, computed at the end of the experimental period, was used as final data (T1).  The differences between the AHIs at To and T1 were calculated (diff AHI) and used for statistical purposes.  The level of oxygen saturation (SaO2) was also recorded before and after treatment, and their differences calculated as diff SaO2.  Statistical analysis was performed with a paired t-test and statistical significance was established at 95 % level of confidence.  A statistical significant reduction in the AHI of the studied subjects was computed at the end of the experimental period (p = 0.0425).  Although there was an improvement in the SaO2, it did not reach a statistically significant difference.  The authors concluded that the findings of this study suggested that the Myobrace/MyOSA myofunctional appliance can be an alternative to treat mild-to-moderate OSA in children.  Moreover, they stated that further studies are needed to determine the stability of the results after treatment.

The above policy is based on the following references: