Anneclaire V. M. T. Vroegop, MD, Antwerp University Hospital (UZA), Wilrijkstraat 10, 2650 Edegem, Antwerp, Belgium. Tel.: 32 (0)3 821 34 36; fax: 32 (0)3 821 42 71; e-mail: email@example.com
The aim of this study was to assess the value of drug-induced sleep endoscopy (DISE) using a custom-made simulation bite in maximal comfortable protrusion (MCP) of the mandible, in the prediction of treatment outcome for obstructive sleep apnea (OSA) with a mandibular advancement device (MAD). Two hundred patients (74% male; age 46 ± 9 years; apnea–hypopnea index [AHI] 19 ± 13 h−1 sleep; body mass index [BMI] 27 ± 4 kg m−2) with sleep-disordered breathing underwent DISE with a simulation bite in MCP. One hundred and thirty-five patients with an established diagnosis of OSA commenced MAD treatment. The associations between the findings during DISE with simulation bite and treatment outcome were evaluated. Treatment response was defined as a reduction in AHI following MAD treatment of ≥ 50% compared to baseline. Overall MAD treatment response in the studied population was 69%. The results of this study demonstrated a statistically significant association between a positive effect of the simulation bite on the upper airway patency during DISE and treatment response with MAD (P <0.01). The results of this study suggest that the use of a simulation bite in maximal comfortable protrusion (MCP) of the mandible, as used during DISE in patients with OSA, tends to be effective in predicting treatment response of MAD treatment.
Obstructive sleep apnea (OSA) is a syndrome characterized by recurrent episodes of apnea and hypopnea during sleep, caused by repetitive upper airway (UA) collapse and often resulting in decreased oxygen blood levels and arousal from sleep (American Academy of Sleep Medicine Task Force, 1999). Continuous positive airway pressure (CPAP) therapy is considered the treatment gold standard, but oral appliance therapy has gained a foothold as main alternative (Gagnadoux et al., 2009; Marklund et al., 2012). Mandibular advancement devices (MADs) are currently the most common class of oral appliances used to treat OSA and custom-made MADs are to be preferred and recommended over prefabricated devices (Vanderveken et al., 2008). MADs are worn intra-orally during the night and mechanically protrude the mandible, commonly with a design to gradually protrude the mandible applying a mechanical advancing mechanism (Dieltjens et al., 2012ab; Gagnadoux et al., 2009). The aim is to prevent UA collapse and increase the cross-sectional airway dimensions, and thereby reduce snoring and obstructive sleep apneas (Tsuiki et al., 2004). Marklund et al. have shown that custom-made MADs also reduce OSA symptoms in the long term (Marklund and Franklin, 2007). Furthermore, MAD treatment can be a rescue therapy in patients with mild to severe OSA who are reluctant or non-responding to CPAP, or fail to use CPAP (Kushida et al., 2006; Lam et al., 2011; Petri et al., 2008).
The mechanism by which MADs counteract obstructive sleep apnea is still a subject of research. Improved insight into the mechanism of action could contribute to identification of the complex of factors determining treatment outcome (Chan et al., 2010). Predictors of treatment outcome are of importance in selecting patients who might benefit from MAD treatment (Petri et al., 2008). Various anthropometric and polysomnographic predictors have been described in the literature, including lower apnea–hypopnea index (AHI), lower body mass index (BMI), lower age, female gender and supine-dependent OSA (Marklund et al., 2004). Using cephalometry, Tsuiki et al., (2004) concluded that an anteriorly titrated mandibular position reduced obstructive sleep apnea severity, enlarged the velopharynx and diminished the curvature of the anterior velopharyngeal wall in good responders. Functional imaging using computational fluid dynamics on computerized tomography (CT) images of head and neck could be of predictive value in predicting treatment success, with a decrease in UA resistance and an increase in UA volume correlating with both clinical and objective improvement (De Backer et al., 2007). The role of flow–volume curves has also been described, although it was suggested that this functional assessment could be of improved predictive value when combined with a structural assessment of the UA with imaging modalities (Chan et al., 2011). In daily clinical practice, there is only a limited ability to preselect suitable patients for MAD treatment with criteria based on individual elements associated with UA behaviour.
First described in 1991 by Croft and Pringle, sleep nasendoscopy or drug-induced sleep endoscopy (DISE) can be used to identify the level of snoring and UA collapse (Croft and Pringle, 1991). This technique has shown its value in optimizing the selection of patients for surgical UA interventions and its validity and reliability have been demonstrated in the literature (Berry et al., 2005; Hessel and de Vries, 2003; Kezirian et al., 2010). A so-called “chin-lift” manoeuvre can be added to the DISE procedure, whereby the mandible is actively guided forward by “grasping” it and advancing it to a maximal protruded position. In the literature, the effect of a lesser mandibular protrusion, up to 5 mm, was suggested to improve patient selection for MAD treatment (Battagel et al., 2005; Johal et al., 2005). It has been demonstrated recently that DISE, completed with a jaw thrust manoeuvre, shows a relevant influence on the location of treatment recommendation, especially when considering MAD treatment or tongue base interventions (Eichler et al., 2012). A possible criticism of the reported study is that a non-reproducible and non-titratable mandibular protrusion manoeuvre has been performed during DISE, also not accounting for vertical opening while closing the mouth (Vanderveken, 2012).
In our clinic, the concept of DISE with the addition of a simulation bite is applied (Vanderveken et al., 2011). This is a custom-made bite registration representing the patient's maximal comfortable protrusive (MCP) position, constructed by the dental sleep professional prior to DISE. In the present study, the prognostic value of the DISE procedure with simulation bite in MCP is assessed in terms of treatment outcome with MAD.
Two hundred consecutive adult patients with sleep-disordered breathing (SDB), referred for oral appliance treatment, were included in the study. Baseline characteristics are shown in Table 1.
Table 1. Patient characteristics at baseline
All subjects (n =200)
BMI, body mass index; AHI, apnea–hypopnea index; SD, standard deviation.
Age in years (mean ± SD)
46 ± 9
Height in cm (mean ± SD)
176 ± 9
Weight in kg (mean ± SD)
84 ± 14
BMI in kg m−2 (mean ± SD)
27 ± 4
AHI, per hour sleep (mean ± SD)
19 ± 13
The reported study was conducted in accordance with the institutional guidelines of the ethical committee and all patients gave written informed consent.
The diagnosis of SDB was to be based on polysomnography (PSG), with OSA being defined as an AHI > 5 h−1 sleep. For this purpose, a standard full-night PSG was performed (Brain RT software; OSG, Rumst, Belgium). Sleep recordings were scored manually in a standard fashion by a qualified sleep technician (American Academy of Sleep Medicine Task Force, 1999). The sleep technician had no knowledge of DISE prediction results. Based on AHI the following levels of OSA severity are defined: mild sleep apnea with a score of 5 < AHI ≤ 15, moderate sleep apnea scored 15 < AHI ≤ 30 and severe sleep apnea with AHI > 30 events h−1 sleep (American Academy of Sleep Medicine Task Force, 1999).
Drug-induced sleep endoscopy (DISE) with simulation bite
The actual procedure of DISE with simulation bite was preceded by the registration of a specific simulation bite, custom-made for each individual patient (Fig. 1). This novel procedure has been described extensively by our group (Vanderveken et al., 2011). A dedicated registration fork was made in the dental technical laboratory (Ostron Blue; GC Europe, Leuven, Belgium). The upper arch was covered with a bite-registration material (Futar D; Kettenbach GmbH & Co, Eschenburg, Germany) and placed against the upper tooth arch. After curing, the patient was instructed to protrude the mandible forward towards the maximal comfortable protrusion (MCP). These measurements were repeated three times, measured and averaged. This averaged position was then recorded with the lower arch of the fork using the same bite-registration material, resulting in the simulation bite in MCP. The thickness of the simulation bite was 6 mm.
Baseline DISE was complemented with the use of the simulation bite and this procedure was performed by an ear–nose–throat (ENT) surgeon in a semi-dark and silent operating theatre, with the patient lying in the supine position in a hospital bed. The simulation bite is positioned intra-orally by the dental sleep professional and gently held stable, prior to the intravenous administration of sedative drugs, in order to avoid jaw clamping or waking up the patient. Artificial sleep was induced by intravenous administration of midazolam (bolus injection of 1.5 mg) and propofol through a target-controlled infusion system (2.0–2.5 μg mL−1). A fibre laryngoscope (Olympus ENF-GP, diameter 3.7 mm; Olympus Europe GmbH, Hamburg, Germany) was used for videoscopic imaging. No local anaesthetic was used for insertion of the fibre laryngoscope. During the procedure, electrocardiography and oxygen saturation were monitored continuously. The first phase of DISE contained the particular part of the sleep endoscopy including the simulation bite, assessing the UA dimensions with the simulation bite positioned intra-orally. Next, the simulation bite was removed by the dental sleep professional, allowing assessment of the UA in a baseline setting without any mandibular repositioning. After this phase, during a respiratory event, the dental sleep professional brought the mandible into the maximal protrusive position by pulling it gently forward, also referred to as a chin-lift manoeuvre. This part allowed observation of the effects of maximal protrusive positioning on the UA collapse patterns. Peroperative findings as to the presence and the level(s) of collapse were noted in the patient's medical file, using a standard scoring system (Fig. 2). The palate is defined as the particular portion of the UA at the level of the soft palate and uvula, while the oropharynx is defined by the pharyngeal region at the levels of the tonsils (above the tongue base). The tongue base is defined as the retroglossal area and the hypopharynx is defined as the UA region below the tongue base, including the tip of the epiglottis. Examples of upper airway collapse patterns are shown in Fig. 3.
When UA collapse was completely resolved (no residual collapse at any UA level) using the simulation bite, the patient was considered a “well suitable” candidate for MAD treatment. If only partial resolution was achieved (improvement, but with residual collapse at one or more UA levels) this was qualified as “partially suitable”. Patients were considered “not suitable” when UA collapsibility increased or remained unchanged with the simulation bite in situ. A similar classification was applied for the chin-lift manoeuvre.
Mandibular advancement device (MAD)
A custom-made, titratable, duobloc MAD (RespiDent Butterfly® MAD; Orthodontic Clinics NV, Antwerp, Belgium) was fitted for each patient starting MAD treatment (Fig. 4) (Dieltjens et al., 2012a). The MAD consists of two dental clips that are attached to each other with an attachment for adjustment of the mandibular protrusion in the frontal teeth area, enabling titration. Acclimatization occurred over a period of 3 months, during which the appliance was titrated to either a maximal comfortable protruded position of the mandible or a resolution of the snoring, daytime sleepiness and/or apneas as witnessed by the bed partner, based on titration instructions as provided and demonstrated by the dental sleep professional. The dental sleep professional had no knowledge of DISE prediction results.
At baseline evaluation, the Epworth Sleepiness Scale (ESS) and the Visual Analogue Scale (VAS) for snoring were assessed to evaluate daytime sleepiness and night-time snoring, respectively (Johns, 1991; Vanderveken et al., 2004). Patients with OSA at baseline and commencing MAD treatment were evaluated polysomnographically with the MAD in situ after an adaptation and titration period of 3 months, allowing “target protrusion” of the mandible, defined as the final and most effective protrusion, to be attained. An outpatient clinic appointment was scheduled to discuss the polysomnography results and the changes in subjective assessment, including the ESS and the VAS for snoring.
The associations between findings during DISE and treatment outcome were assessed. Treatment outcome was based on polysomnographic results with MAD. Treatment response was defined as a reduction in AHI following MAD treatment of ≥ 50% compared to baseline, and non-response was defined as a reduction in AHI of < 50% (Ng et al., 2012). Compliance failure was defined as a discontinuation of treatment due to medical or non-medical reasons.
Data analysis was performed using r version 2.15.0 (R Foundation for Statistical Computing, Vienna, Austria). Descriptive statistics for clinical characteristics of patients are presented as means ± standard deviation (SD). Normality of distribution was assessed using Q-Q plots. Unpaired t-tests were used to compare the maximal comfortable protrusion between responders and non-responders. Paired t-tests were used to compare measurements at baseline and at evaluation with MAD when data were distributed normally. Non-parametric tests were used in case the data were not normally distributed. Categorical data were analysed using chi-square tests. A multiple logistic regression model was built to evaluate the prognostic values of the baseline characteristics on treatment response, allowing adjustment for gender, age and BMI. Odds ratios (OR) together with confidence intervals (CI) and P-values are reported. A P-value of < 0.05 was considered significant.
A total of 200 patients (baseline characteristics outlined in Table 1) underwent DISE with simulation bite and chin-lift manoeuvre. Patient flow is depicted in Fig. 5. Fifty-two of 200 patients did not start treatment, as they were considered “not suitable”, and other treatment options could be offered. Thirteen patients were considered not to have OSA, as their AHI was below 5 h−1 sleep. As a result, 135 patients (75% male; age 46 ± 8 years; AHI 21 ± 13 h−1 sleep; BMI 27 ± 4 kg m−2) with an established diagnosis of OSA commenced MAD treatment. Twenty-five patients were lost to follow-up, as they did not attend dental control visits and the polysomnographic evaluation with MAD, despite appointment reminders. Of the 110 remaining patients, the majority of patients suffered mild OSA (53.6%), while 23 patients (20.9%) and 28 patients (25.5%) had moderate and severe OSA, respectively. PSG with MAD was performed in 103 of 110 patients and compliance failure was noted in the remaining seven cases. The reasons for non-compliance were the following: unable to tolerate the device throughout the night (two patients), choking sensations (one patient) or side effects such as tooth tenderness (one patient) and dry mouth (one patient), or a combination of thereof (one patient), and in one case, claustrophobia during MAD wear.
Upper airway collapse pattern
An overview of the UA collapse patterns in this study population is shown in the Venn diagram (Fig. 6). As noted per level, a collapse at the level of the palate was seen most frequently, followed by the tongue base and the epiglottis, while the oropharynx level was scored least frequently. There were frequently observed combinations of collapse levels, with the most frequent collapse pattern being a combination of palatal and tongue base collapse (34.4%). Multi-level collapse in general was noted in 87.2% of all patients.
Treatment response with MAD application was achieved in 71 of 103 (68.9%) patients, with a mean AHI improving from 21.4 to 8.9 h−1 sleep. ODI, ESS and VAS also decreased significantly, as shown in Table 2. A non-responder rate of 31.1% was noted (32 patients).
Table 2. Baseline versus MAD treatment outcome parameters
In the present cohort, patients marked as “well suitable” for MAD treatment, based on findings of UA patency changes during the DISE procedure with simulation bite, have a higher chance of treatment response with MAD than patients marked as only “partially suitable” or “not suitable” (OR: 4.9619, 95% CI: 1.7301–14.2311; P-value: 0.0029). The presence of palatal collapse at baseline evaluation was also associated with treatment response, albeit with a wider confidence interval (OR: 8.6822; 95% CI: 1.5643–48.1894; P-value: 0.0135). Presence of hypopharyngeal collapse at baseline evaluation showed a tendency towards an association with a less favourable treatment outcome. These associations remained significant after adjustment for gender, age, BMI, AHI and positional dependency. An overview of these findings is shown in Table 3. No statistical association was found between the effect of chin-lift manoeuvre on UA calibre and treatment response (P =0.64). The receiver operating characteristic (ROC) curve (Fig. 7) shows a high predictive value of this procedure (Fig. 6, area under the curve: 0.82). With a cut-off level of 0.50, the sensitivity is 0.91, the specificity is 0.53, the positive likelihood ratio is 1.96 and the negative likehood ratio is 0.16. Maximal comfortable protrusion did not differ between responders (mean: 8.1 mm) and non-responders (mean: 8.4 mm) (P =0.54).
Table 3. Multiple logistic regression model (combined model with all parameters)
Multiple logistic regression
Adjusted for gender, age, BMI, AHI, supine dependency
95% CI for OR
95% CI for OR
SB, simulation bite; OR, odds ratio; CI, confidence interval; P, P-value; BMI, body mass index; AHI, apnea/hypopnea index.
Effect SB Collapse
The effect of the simulation bite per outcome category is shown in Table 4, with “predicted response” being based on the number of patients marked as “well suitable” for MAD treatment. The middle column and right column consist of the patients who were categorized as “partially suitable” and “not suitable”, respectively. The results show that in the “predicted response” group, a majority of patients were responders (83.3%).
Table 4. Prediction of treatment outcome and treatment outcome on polysomnography with the mandibular advancement device (MAD)
This study is the first to describe the effects of a custom-made simulation bite in maximal comfortable protrusion (MCP) of the mandible during DISE for the prospective prediction of MAD treatment outcome in the individual patient. The results of this study demonstrate that patients in whom UA patency improved substantially with the presence of the simulation bite in MCP during DISE are more likely to be treated successfully with MAD treatment. The described DISE technique, completed with the simulation bite, provides a reliable and reproducible mandibular position during the DISE examination. A major advantage of the reproducibility is that the simulation bite can also be used during other investigations with possible clinical utility in predicting the outcome of treatment of OSA with oral appliance therapy, such as CT, magnetic resonance imaging (MRI), awake endoscopy, cephalometry and two-dimensional (2D) videofluoroscopy (Chan et al., 2010; De Backer et al., 2007). Accordingly, Johal et al., 2011 demonstrated that significant changes occur in the pharyngeal airway of OSA patients following insertion of an oral appliance in MCP when assessed using videofluoroscopy.
The results of the present study indicate that the chin-lift manoeuvre in maximal protrusion may be clinically less relevant for therapeutic decision-making than generally considered. Manually mimicking MAD use may be indicative, to a certain extent (Eichler et al., 2012; Johal et al., 2007), but this approach does not account for the given thickness of a particular MAD, whereas each oral appliance inherently causes a certain amount of vertical mouth opening. In addition, this manoeuvre is not reproducible in terms of the degree of mandibular advancement (Vanderveken, 2012). Furthermore, both the jaw thrust (Esmarch) and chin-lift manoeuvres can be disturbing stimuli during DISE, potentially provoking arousal by awakening of the patient during the procedure.
DISE with simulation bite being of predictive value for MAD treatment outcome is a key finding, particularly as the prediction of MAD treatment outcome continues to be an important research topic throughout the field. Retrospective analysis of factors such as AHI and body position has shown that these parameters are of potential influence on treatment outcome, as are BMI, neck circumference, gender and age (Marklund et al., 2004; Mostafiz et al., 2011; Ng et al., 2012). Using cephalometry, Mostafiz et al., 2011. found a larger tongue size in complete responders to MAD treatment in relative terms. Chan et al. (2010) suggested that the palate is important in determining treatment outcome with MAD. In the present study, a statistically significant association was found between the presence of palatal collapse and treatment response with MAD, confirming these previous findings. Although the OR for this association is higher than for the association between the simulation bite effect and treatment response, the variability is higher, hindering direct clinical conclusions. Furthermore, it must be noted that, in the present study, a palatal collapse was seen most frequently as a part of a multi-level collapse (Fig. 5). In other recent literature, it was found that oropharyngeal collapse has been related to a better outcome with MAD treatment, using multi-sensory catheters to determine UA closing and the site(s) of UA collapse (Ng et al., 2006) or phrenic nerve stimulation (Bosshard et al., 2011). Comparison of these studies is limited, as mainly population sizes (Ng study: n =12; Bosshard study: n =33; present study: n =110) and evaluation technique differ (Ng study: UA catheters; Bosshard study: UA catheter; present study: DISE). Further studies combining advanced diagnostic technologies and individually tailored treatment could contribute to a better understanding of the role of the upper airway in the pathophysiology of OSA and treatment thereof (Pillar and Lavie, 2008).
When considering treatment that is not certain to positively affect all potentially collapsible UA levels, identifying patterns of UA collapse is a crucial element in the diagnostic work-up. Although time-consuming, DISE provides information that is less likely to be collected otherwise, especially taking into account the multi-factorial nature of UA obstruction (Berry et al., 2005; Croft and Pringle, 1991; Hessel and de Vries, 2003; Vanderveken, 2012). In evaluating the collapse patterns in the present study population, the quasi-omnipresent palatal collapse (95.4%) is remarkable, as is depicted clearly in the Venn diagram (Fig. 4). Also, multi-level collapse was noted in the majority of patients (87.2%). These findings are in accordance with recent literature (Ravesloot and de Vries, 2011).
This study has several limitations. It is obvious that assessment of the UA during DISE is based on subjective findings. Concerning the subjective nature of the observations during DISE, the presence of an inter-rater variability component is to be expected to a certain extent, although the inter-rater reliability has been labelled moderate to substantial and the test–retest reliability of DISE appears to be good, especially in the evaluation of the hypopharyngeal airway (Kezirian et al., 2010; Rodriguez-Bruno et al., 2009). Furthermore, it is not known to what extent the UA patency needs to change in order to counteract UA collapse effectively. Further studies will need to investigate such types of effect on the predictive value of the screening approach applied. In the present study a standard DISE scoring system was used, with configuration of collapse as a standard component (Fig. 2). However, the present study population was considered too small to perform proper statistical analysis assessing the associations of the combinations of level–degree–configuration with treatment response. Another important issue is the quantification of the cross-sectional upper airway areas during DISE. Although adequate quantified measurement techniques in propofol-anaesthetized subjects are described in the literature (Oliven et al., 2007, 2010), visual estimation of the upper airway during DISE is still common practice. Also in this study, no specific measurements of the cross-sectional upper airway areas were performed, which can be considered a limitation that needs to be addressed in further research on the role of DISE in predicting MAD therapy outcome. Another potential limitation of the study is the generalizability and accessibility of DISE in routine clinical practice. As DISE generally requires administration of propofol, the procedure has to be performed in a controlled setting with specialized health-care professionals. This may be cumbersome, as accessibility may not be optimal throughout all practices. Finally, another important drawback concerns the negative predictive value of the reported DISE with simulation bite procedure. Previous studies on prediction of MAD treatment outcome found negative predictive values of 78 and 45%, respectively (Dort et al., 2006; Gagnadoux et al., 2009). In the present study, the majority of patients who were considered “not suitable” for MAD treatment did not start MAD treatment. For this reason, the negative predictive value of the use of the simulation bite was difficult to assess in this study. Future research in this field should also focus on the false negative proportion, as this may constitute a large group of patients.
Ideally, patient selection is based on prospective elements. Specific diagnostic procedures that are potentially well suited for this purpose must also be feasible, easily accessible, time and cost-effective and well tolerable for the patient. At the same time, different relative anatomical and functional effects are to be expected in different patients; therefore, proper individual assessment in a setting that resembles MAD use most accurately will be necessary. The DISE approach, complemented with the use of a simulation bite in maximal comfortable protrusion, is likely to meet this criterion closely.
All authors declare no conflicts of interest (no personal of financial support, no involvement with organization(s) with financial interest in the subject matter of the paper, nor any actual or potential conflict of interest) to declare.