Research Article| Volume 100, ISSUE 6, P988-995, June 2006

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# Clinical co-morbidities in obstructive sleep apnea syndrome treated with mandibular repositioning appliance

Open ArchivePublished:November 14, 2005

## Summary

### Introduction

Intraoral mandibular repositioner appliances (IOMRAs) are designed to enlarge pharyngeal airway space advancing the mandible and increasing genioglossus tone during sleep. Obstructive sleep apnea syndrome (OSAS) treatment with IOMRAs is beneficial, but there is a lack of studies in the literature defining the target population more inclined to respond to this treatment.

### Methods

We contacted by telephone 188 previously treated patients with IOMRA, detecting 20 not improved patients (Study Group). Twenty improved patients of the remaining 168 were randomly paired according to gender, age, apnea, and hypopnea index as Control Group. Both groups answered questionnaires for diagnosis of sleep disorders, depression, anxiety, and the Epworth sleepiness scale. We did a descriptive and inferential statistical analysis. The inferential analysis was divided into two steps: univariate analysis using Fischer exact test and a multiple inferential analysis using a stepwise regression model.

### Results

Although the final model included only insomnia, we concluded that the presence of gastric, neurological and rheumatic diseases also tended to be associated with the self-perception of non-improvement. The association between the accumulation of gastric, neurological, and rheumatic diseases and insomnia and improvement demonstrated that an increase in one of these diseases correspond to a two-fold increase in the chance of non-improvement.

### Conclusions

Insomnia was the most important factor compromising the success of OSAS treatment with IOMRAs, and the isolated presence of gastric, neurological and rheumatic diseases, but especially their combination, reduces the perception rate of well-succeeded treatment with IOMRAs.

## Introduction

The installation of intraoral devices for the treatment of obstructive sleep apnea syndrome (OSAS) has become an important therapy, and has the objective to prevent collapse of the base of the tongue against the lateral and posterior walls of the pharynx during sleep, an event increasing the critical occlusal pressure.
• Marklund M.
• Franklin M.D.
• Sahlin C.
• et al.
The effects of a mandibular advancement device on apneas and sleep in patients with obstructive sleep apnea.
• Meyer Jr, J.B.
• Knudson R.C.
The sleep apnea syndrome. Part II: treatment.
• Marcus C.L.
• Lutz J.
• et al.
Developmental changes in upper airway dynamics.
Intraoral devices are designed to augment pharyngeal airway space through mandibular protrusion and through an increase in the vertical dimension of the occlusion and in genioglossus muscle tonus as a consequence of the new position of the mandible.
• Marklund M.
• Franklin M.D.
• Sahlin C.
• et al.
The effects of a mandibular advancement device on apneas and sleep in patients with obstructive sleep apnea.
• Hans M.G.
• Nelson S.
• Luks V.G.
• et al.
Comparison of two dental devices for treatment of obstructive sleep apnea syndrome (OSAS).
• Lowe A.A.
• Fleetham J.
• Ryan F.
• et al.
Effects of a mandibular repositioning appliance used in the treatment of obstructive sleep apnea on tongue muscle activity.
• Lowe A.A.
• Tsuchiya M.
• et al.
Genioglossus muscle activity and inspiratory timing in obstructive sleep apnea.
• Lowe A.A.
• Gurza S.C.
• Sessle B.J.
Regulation of genioglossus and masseter muscle activity in man.
A small passive opening of the mandible increases genioglossus tonus through the activation of receptors located in the temporomandibular joint, resulting in a significant increase in the electromyographic amplitudes of the genioglossus and lateral pterygoid muscles during the use of intraoral mandibular repositioning appliances (IOMRAs).
• Robertson C.J.
Obstructive sleep apnea. Part I: diagnosis, aetiology, and current treatment.
• Yoshida K.
Effect of a prosthetic appliance for treatment of sleep apnea syndrome on masticatory and tongue muscle activity.
Mandibular repositioning by means of intraoral devices for the treatment of OSAS is simple, reversible, silent, and of low cost. This treatment modality is currently gaining considerable space in the scientific scenario; including blood pressure lowering, although further studies are still necessary to better understand the entire physiopathology of OSAS and the action of these intraoral devices on this condition.
• Haze J.J.
Overview of sleep disorders and the implication on dental practice.
• Lowe A.A.
Dental appliances for the treatment of snoring and/or sleep apnea.
• Gotsopoulos H.
• Kelly J.J.
• Cistulli P.A.
Oral appliance theraphy reduces blood pressure in obstructive sleep apnea: a randomized, controlled trial.
Various studies in the literature have demonstrated the causes of treatment failure of OSAS with continuous positive airway pressure and although there are reports citing side effects or complications with the use of IOMRAs, only few studies have reported the causes of treatment failure of OSAS with IOMRAs.
• Engleman H.M.
• McDonald J.P.
• Graham D.
• et al.
Randomized crossover trial of two treatments for sleep apnea/hypopnea syndrome: continuous positive airway pressure and mandibular repositioning splint.
• Neill A.
• Whyman R.
• Bannan S.
• et al.
Mandibular advancement splint improves indices of obstructive sleep apnoea and snoring but side effects are common.

Almeida FR, Lowe AA, Tsuiki S, Otsuka R, Wong M, Fastlicht S, Ryan CF. Long term compliance and side effects of oral appliances used for the treatment of snoring and obstructive sleep apnea. J Clin Sleep Med, 2005, in press.

In our clinical practice we noted that some patients report no clinical improvement except for the absence of snoring or normalization of the apnea index upon polysomnography. This observation motivated the present study in which we compared the clinical variables of two groups of patients treated with IOMRAs, one of them reporting no satisfactory clinical improvement and the other reporting that treatment was highly effective. The main hypothesis of this study was that OSAS-associated co-morbidities are the cause of patient's report of treatment failure with IOMRAs. We designed this study to investigate if associated diseases can reduce the patient feeling of improvement with IOMRAs treatment.

## Method

### Sample

A total of 188 patients of either sex ranging in age from 25 to 72 years and treated with IOMRAs (Fig. 1). All patient included in this research had two or more all night polysomnographic study. We included sleep related respiratory disorders patients with polysomnographic diagnostic of mild (5–15 events per hour), moderate (16–30 events per hour) and severe (more than 30 events per hour) OSAS and also loud snoring, during the period from 1999 to 2003.

### Polysomnography

Standard polysomnographic techniques were employed and are outlined briefly here. Surface electroencephalographic electrodes places at C3-A2 and C4-A1, a submetal electrode, and left and right electrooculograms were used to stage sleep. A finger oximeter (Criticare-Systems INC Pulse 504) recorded oxyhemoglobin saturation (SaO2). A continuous electrocardiogram recorded heart rate and rhythm. A digital polygraph (Neurotec model EQSA-400-1) recorded all physiological data throughout the night.

### Clinical data

In order to detect the presence or absence of clinical improvement after the end of the protocol, one of the authors not involved with the treatment Lucila Bizari Fernandes do Prado (LBFP) contacted the patients by telephone asking the following question: “Did your main complaint improve with the use of the IOMRA?” When the patient had difficulty understanding the question, the researcher provided a detailed explanation so that the patient could completely understand his/her health status possibly resulting from OSAS (snoring, fatigue, and sleepiness, or any other symptom that made the patient to see a sleep specialist). Twenty of the 188 patients did not show clinical improvement of the sleep related symptoms that they arrived with and comprised the Study Group. The Control Group consisted of 20 patients drawn among the remaining 168 patients with the same characteristics as the Study Group, except for the fact that they had reported clinical improvement of the sleep related symptoms after treatment. When more than one patient fulfilled the criteria of the control group the inclusion were done by drawing lots.
The two groups were matched for gender, age, body mass index (BMI), and apnea–hypopnea index (Table 1).
Table 1Demographic data and apnea–hypopnea index pre- and post treatment showing no differences between groups.
Study Group (20)Control Group (20)P
Age (yr)55.2±7.755.6±7.70.91
BMI (kg/m2)27.3±3.427.4±3.90.93
Gender4F and 16M4F and 16M
AHI pre treatment22.4±16.418.4±11.20.30
AHI post treatment4.6±3.12.8±20.17
In addition to signing a free informed consent form, the two groups were submitted at home to the Johns Hopkins questionnaire for the diagnosis of sleep disorders, the Beck Inventory for the evaluation of depression, the State-Trait Anxiety Inventory for the evaluation of anxiety, and the Epworth Sleepiness Scale for the assessment of excessive daytime sleepiness.
• Johns M.W.
Reliability and factor analysis of the Epworth Sleepiness Scale.

Biaggio AMB, Natalino L. Manual para o Inventário de Ansiedade Traço-Estado (IDATE). Rio de Janeiro: Centro Educacional de Psicologia Aplicada—CEPA; 1979.

• Gorenstein C.
Validation of a Portuguese version of the Beck Depression Inventory and the State-Trait Anxiety Inventory in Brazilian subjects.
• Gorenstein C.
Inventário de depressão de Beck: propriedades psicométricas da versão em português.
• Beck A.T.
• Ward C.H.
• Mendelson M.
• et al.
An inventory for measuring depression.
All patients in this study provided information about their general health status through the one or more of the following: (1) chart review, (2) clinical questionnaire attached to the sleep questionnaire, (3) clinical interview, and (4) phone interview. We did not have problem with this research step, because patients that reported improvement were very determined in their opinion and those that felt that they did not improved also stated their opinion vigorously and took the chance to ask for new treatment options available. We choose a phone call (made by one research (LBFP) not involved directly with the treatment) to ask the patients if they felt improvement with IOMRAs treatment because we think this procedure allows more freedom to the patient to give his/her sincere opinion far from his/her health care professional.
Insomnia was diagnosed if the patients reported that they have problem of initiating or maintaining sleep for at least 5 days per week and for more than 6 months. We grouped in the category Gastric Disease those patients with heart burning, endoscopic diagnosis of hiatus hernia, gastritis, esophagitis, and other gastric related complaints; in the category Rheumatic Disease patients with osteoarthritis, and all sort of degenerative aging-related joint disease affecting mainly the knees, lumbar column and hip joint; in the category Neurological Disease patients with headache, migraine, vertigo complaints, history of seizure or epilepsy (we did not have patients with degenerative disease, stroke, cerebelar ataxia or any other severe neurological condition); in the category Psychiatric Disease patients in treatment for or with recent history of depression, anxiety, panic disorder or other psychiatric condition.
Variables like BMI, race, educational level, rotation shift, smoking, drinking, caffeine ingestion, medications, sedatives, insufficient sleep among others were obtained mostly throughout our sleep and clinical questionnaire, but also by chart review or personal interview as mentioned above. We did not use the phone interview to collect those data, because it would take too much time and also could ensue misinformation.
To be included in the study all patients should attend two essential conditions: (1) to have a clinical and laboratorial polysomnographic diagnosis of mild (5–15 events per hour), moderate (16–30 events per hour) or severe (more than 30 events per hour) OSAS or of increased upper airway resistance syndrome according to the criteria of the American Academy of Sleep Medicine.
Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research.
; and (2) to have a follow up polysomnography at the end of IOMRAs’ titration showing less than 10 events per hour. The main complaints of these patients were snoring which disturbed the partner, fatigue, and excessive daytime sleepiness.
The IOMRAs were fabricated with two dental plates consisting of self-polymerizing acrylic resin, one for the upper arch and one for the lower arch with complete coverage of the occlusal sides of the teeth. A stainless-steel device containing a thread that permits millimeter adjustments connected the two plates in such a way that when activating the thread of the metallic device the lower plate was moved forward, promoting mandibular advancement.

### Intervention

The patients were submitted to a clinical follow-up protocol, which consisted of a weekly visit for 4 months after installation of the intraoral device. On each visit, the patient was asked about his/her clinical condition (snoring, sleepiness and fatigue) and about problems with the use of the device. The IOMRA was then adjusted to promote mandibular advancement, which was on average 0.5mm per week until the most comfortable mandible protrusive position for each patient. Satisfactory advancement of the mandible was achieved in all patients at the end of 4 months, and the adjustment procedure was discontinued when the patient reported the disappearance of snoring and clinical improvement in sleepiness and fatigue. When some symptoms persisted, the disappearance of snoring was considered to be an indicator of the efficacy of mandibular advancement with the IOMRA and adjustment was discontinued. After this adjustment period, the patients were referred to the medical teams for clinical and laboratorial polysomnographic reassessment. Control laboratorial polysomnography was performed with the IOMRA in place during the exam.

### Statistical analysis

Statistical analysis was divided into two parts: descriptive and inferential analysis. Descriptive analysis permitted the determination of relevant interacting factors (combination of two variables). Inferential analysis was divided into two steps: first, univariate analysis was performed to determine the association between each variable and improvement using the χ2 or Fisher exact test to identify which variables showed the strongest association with improvement upon this type of analysis.
• Agresti A.
Categorial data analysis.
Next, multiple inferential analysis was performed as follows: an intermediate model was constructed using a stepwise logistic regression model, with an entry probability of 0.15 and an exit probability of 0.25.
• Hosmer D.W.
• Lemeshow S.
Applied logistic regression.
Possible interactions suggested by the descriptive analysis, which showed an association with the variables of the intermediate model were then investigated. The variables considered to enter the final model were: BMI, race, educational level, rotation shift, working at night, smoking, drinking, caffeine ingestion, snacks at night, diseases, use of medications, sedatives, insufficient sleep, insomnia, restless leg syndrome, and periodic limb movements in sleep (PLMS).
Possible interactions effects were investigated observing the relationship between lack of improvement and each independent variable at different levels of other independent variables. We seek for changes in the odds ratio that we considered important when comparing the levels at the second independent variable but without any fixed rule due to the fact that we concern other aspect: clinical relevance of the two independent variables. Doing these we tried to exclude spurious associations, always taking in account that the sample size may not be sufficient to show relevant interactions. The combinations of variables considered to be relevant upon descriptive analysis were BMI and drinking, BMI and insomnia, drinking and gastric disease, drinking and insomnia, heart and rheumatologic disease, gastric disease and insufficient sleep, neurological and psychiatric disease, neurological disease and insufficient sleep, insufficient sleep and insomnia, and psychiatric disease and use of medications.
Since insomnia was the only variable remaining in the intermediate model ($P=0.022$), no interacting factors were investigated and therefore the final model contained only the variable insomnia.
Univariate analysis revealed a strong association between the lack of improvement and the following variables: drinking ($P=0.159$), caffeine ingestion ($P=0.206$), gastric disease ($P=0.058$), rheumatologic disease ($P=0.168$), neurological disease ($P=0.127$), and insomnia ($P=0.022$). The variable PLMS was discarded because it was only present in three individuals. Since one possible hypothesis for unsuccessful treatment is the general health status, improvement-related accumulation of the following main diseases obtained by univariate analysis was also investigated: gastric, rheumatologic and neurological diseases, and insomnia. The association between improvement and the accumulation of diseases was determined using a simple logistic regression model. Accumulation of diseases was defined as a disease index and was calculated by the following formula: disease index=gastric disease+neurological disease+rheumatologic disease+insomnia, where the presence or absence of each disease was scored as 1 or 0, respectively. The disease index construction was based on our intuition that some of the diseases studied have accumulative contribution to the lack of improvement, i.e., a person with just one of the diseases would have a better improvement when comparing with a person with two or more of the established diseases. The diseases were chosen using the univariate analysis and selecting the diseases with P-values lower than 0.20 when studying the relationship between these variables and the lack of improvement: gastric disease ($P=0.058$), rheumatologic disease ($P=0.168$), neurological disease (0.127) and insomnia ($P=0.022$).

## Results

Demographic data were not different between control and study groups substantiating our matching procedure (Table 1).
Insomnia was associated with the lack of clinical improvement when using an IOMRA ($P<0.02$; Table 2), with the expected chance of improvement being five times higher for subjects without insomnia compared to those with insomnia. Although the final model included only insomnia, univariate inferential analysis showed that the presence of gastric, neurological and rheumatic diseases also tended to be associated with the lack of improvement (Table 2).
Table 2Univariate inferential analysis of the association between diseases and improvement.
VariableP
Insomnia0.022
Gastric diseases0.058
Neurologic diseases0.127
Rheumatologic diseases0.168
Analysis of the association between the accumulation of gastric, neurological and rheumatic diseases and insomnia (disease index; Table 3) and improvement demonstrated that an increase in one of these diseases corresponded to a two-fold increase in the chance of non-improvement, i.e., the higher the disease index, the higher the proportion of patients who did not show improvement ($P=0.02$) (Table 4 and Fig. 2).
Table 3Logistic regression model using the disease index.
VariableCoefficientStandard errorPChance ratio95% confidence interval
Lower limitUpper limit
Disease index0.7610.3240.0192.1411.1354.038
Table 4Distribution of improvement according to disease index.
Disease indexImprovementTotal
YesNo
07 (78%)2 (22%)9 (100%)
16 (60%)4 (40%)10 (100%)
25 (46%)6 (55%)11 (100%)
32 (33%)4 (67%)6 (100%)
40 (0%)4 (100%)4 (100%)
Total20 (50%)20 (50%)40 (100%)

## Discussion

To our knowledge, this is the first study trying to determine the causes of failure report of IOMRA treatment in well-indicated cases of OSAS. Treatment of OSAS with intraoral devices has been a matter of intensive discussion in the literature over the last two decades, with most studies trying to prove the efficacy of IOMRAs in the treatment of mild and moderate OSAS.
• Marklund M.
• Franklin M.D.
• Sahlin C.
• et al.
The effects of a mandibular advancement device on apneas and sleep in patients with obstructive sleep apnea.
• Hans M.G.
• Nelson S.
• Luks V.G.
• et al.
Comparison of two dental devices for treatment of obstructive sleep apnea syndrome (OSAS).
• Yoshida K.
Effect of a prosthetic appliance for treatment of sleep apnea syndrome on masticatory and tongue muscle activity.
• Lowe A.A.
Dental appliances for the treatment of snoring and/or sleep apnea.
• Engleman H.M.
• McDonald J.P.
• Graham D.
• et al.
Randomized crossover trial of two treatments for sleep apnea/hypopnea syndrome: continuous positive airway pressure and mandibular repositioning splint.
The present study demonstrated that both the sleep specialist and the dental surgeon should go beyond the well-established routine considerations of each specialty and perform a more complete assessment of the patient. The professional should survey the clinical history for systemic involvement, mainly gastric, neurological and rheumatic disorders and the presence of insomnia, which may compromise the self-perception of the effect of treatment with IOMRAs. In the present study, global clinical assessment of the patients permitted the identification of other factors that had a strong influence on the clinical evolution of patients treated with IOMRAs, and we should take care special attention for the diagnosis of insomnia that is highly prevalent in apnea patients.
• Krakow B.
• Melendrez D.
• Ferreira E.
• Clark J.
• Warner T.D.
• Sisley B.
• Sklar D.
Prevalence of insomnia symptoms in patients with sleep-disordered breathing.
Care of patients with sleep disorders requires a wider knowledge of these disorders on the part of the dental surgeon and successful treatment does not only depend on a good domination of the manufacturing techniques and adjustment of the intraoral devices. In addition to providing basic behavioral guidance to his/her patient, the dentist should also be able to recognize situations in which follow-up by a general or specialized clinician is necessary.
Awareness of the patient regarding his/her parallel health problems and how they may interfere with the treatment of OSAS with IOMRAs is fundamental to guarantee success and to prevent frustration for both the dental surgeon and the patient. We have already presented data showing that about 80% of the patients improve upon treatment with an IOMRA,
• Carvalho L.B.C.
• et al.
Quality of life of patients with obstructive sleep apnea syndrome treated with an intraoral mandibular repositioner.
and this study allow us to suspect that patients who do not improve probably present co-morbidities associated with the sleep related respiratory condition, as shown in Fig. 2. We have to keep in mind that OSAS patients have poor perception of their disease state, and some symptoms not related to OSAS can be far more important to them; if the sleep specialist are not aware, both patient and health professional end frustrated, and the patient lose the opportunity of seeing other health professional that would be necessary to manage his/her problem.
We also noticed in our study that the accumulation of diseases (insomnia, gastric, rheumatological, and neurological—Fig. 2) drastically reduces the chances of improvement of the OSAS patients. Although the relationship between the disease index and lack of improvement found seems to be clinically relevant, the reader should always take in account that this strategy analysis could be dangerous for those who assume these findings without regarding the limitations of the sample size and without regarding the fact that the construction of the index was based in our intuition and in the P-values encountered in univariate analysis.
The major limitation of the present study was the small number of patients in each group, a fact that might have underestimated the effects of certain co-morbidities, in addition to reducing the possible number of variables entering the multivariate logistic regression model. We therefore suggest further studies including a larger number of patients to better define the role of co-morbidities in the perception of improvement, as well as to establish treatment-associated strategies.

## Conclusions

The present study demonstrated that (1) insomnia is probably the factor that most compromises the perception of self-improvement after OSAS treatment with IOMRAs; (2) the isolated presence of gastric, neurological and rheumatic diseases, but especially their combination, reduces the perception rate of improvement after treatment with IOMRAs; (3) the health care professional involved in the treatment of OSAS should be trained to provide a more complete assessment of the patient, irrespective of his specialty, and, finally, (4) patients selected for treatment with IOMRAs should be informed that their perception of improvement does not only depend on the use of an IOMRA but also on the attention given to their global health status.

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• et al.
The effects of a mandibular advancement device on apneas and sleep in patients with obstructive sleep apnea.
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Developmental changes in upper airway dynamics.
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Comparison of two dental devices for treatment of obstructive sleep apnea syndrome (OSAS).
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Effects of a mandibular repositioning appliance used in the treatment of obstructive sleep apnea on tongue muscle activity.
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Genioglossus muscle activity and inspiratory timing in obstructive sleep apnea.
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Regulation of genioglossus and masseter muscle activity in man.
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Obstructive sleep apnea. Part I: diagnosis, aetiology, and current treatment.
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Effect of a prosthetic appliance for treatment of sleep apnea syndrome on masticatory and tongue muscle activity.
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Overview of sleep disorders and the implication on dental practice.
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Validation of a Portuguese version of the Beck Depression Inventory and the State-Trait Anxiety Inventory in Brazilian subjects.
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