pii: jc- 00070-15
http://dx.doi.org/10.5664/jcsm.5480
S CI E NT IF IC IN VES TIGATIONS
Improvement of Cognitive and Psychomotor Performance in Patients with Mild to Moderate Obstructive Sleep Apnea Treated with Mandibular Advancement Device: A Prospective 1-Year Study Tea Galic, DMD1; Josko Bozic, MD2; Renata Pecotic, MD, PhD3,4; Natalija Ivkovic, MSc, RN3; Maja Valic, MD, PhD3,4; Zoran Dogas, MD, PhD3,4 Study of Dental Medicine, 2Department of Pathophysiology, 3Split Sleep Medicine Center, and 4Department of Neuroscience, University of Split School of Medicine, Split, Croatia
1
Study Objectives: This study aimed to provide the evidence on effect of mandibular advancement device (MAD) therapy on long-term cognitive and psychomotor performance, excessive daytime sleepiness, and quality of life in patients with mild to moderate obstructive sleep apnea (OSA). Methods: A total of 15 patients with mild to moderate OSA were treated with MAD therapy and they were followed up after 3 mo and 1 y of therapy. The patients were tested on three different tests of cognitive and psychomotor performance using the computer-based system Complex Reactionmeter Drenovac (CRD-series) at baseline and at the time of follow-up, and the 36-Item Short Form Health Survey (SF-36) questionnaire and Epworth Sleepiness Scale were used to assess their quality of life and excessive daytime sleepiness, respectively. Results: The mean apnea-hypopnea index (AHI) decreased significantly from 22.9 ± 5.9 events/h at baseline, to 9.7 ± 4.5 events/h after 1 y of MAD therapy (p < 0.001). There was significant improvement on all three CRD-series tests used after 1 y of MAD therapy, considering total test solving time (TTST) and minimal single task solving time (MinT), whereas total number of errors committed during the tests (TE) remained unchanged. Self-reported measures, excessive daytime sleepiness, and three domains of quality of life, social functioning, general health perception, and health change following MAD therapy showed significant improvements after 1 y of MAD therapy. Conclusions: This study demonstrates significant improvements in cognitive and psychomotor performance, particularly in the domain of perceptive abilities, convergent thinking (constructing and solving simple mathematical tasks) and psychomotor reaction times, excessive daytime sleepiness, and quality of life in patients with mild to moderate OSA following MAD therapy. Keywords: obstructive sleep apnea, oral appliances, mandibular advancement device, cognitive, psychomotor, sleepiness, quality of life Citation: Galic T, Bozic J, Pecotic R, Ivkovic N, Valic M, Dogas Z. Improvement of cognitive and psychomotor performance in patients with mild to moderate obstructive sleep apnea treated with mandibular advancement device: a prospective 1-year study. J Clin Sleep Med 2016;12(2):177–186.
I N T RO D U C T I O N
BRIEF SUMMARY
Current Knowledge/Study Rationale: The mandibular advancement device (MAD) is an approved, effective modality of treatment in patients with mild to moderate obstructive sleep apnea (OSA). However, the effect of MAD treatment on cognitive and psychomotor performance has not been sufficiently established. The aim of this study was to assess the effect of MAD treatment on cognitive and psychomotor performance and subjective measures, excessive daytime sleepiness, and quality of life. Study Impact: This study demonstrates that MAD therapy in patients with mild to moderate OSA is associated with improvement in cognitive and psychomotor performance. Furthermore, there was considerable improvement of well-being following MAD therapy.
Obstructive sleep apnea (OSA) is the most prevalent sleep related breathing disorder caused by repetitive partial or complete interruptions of breathing during sleep, resulting in intermittent hypoxemia, sympathetic excitation, and sleep fragmentation.1–4 Patients with the disorder are known to suffer excessive daytime sleepiness, leading to more motor vehicle accidents.3,5,6 OSA is also associated with the range of significant medical consequences such as obesity, hypertension, type 2 diabetes, depression, psychological and cognitive consequences, and a lower self-reported quality of life.3,4,6–8 The precise mechanisms of neurocognitive impairment associated with OSA are still unknown.8 In some studies, impaired neurocognitive performance is associated with increased apnea-hypopnea index (AHI) and intermittent hypoxia,7–10 whereas sleep fragmentation, sleep deprivation, and excessive daytime sleepiness might be additional mechanisms underlying the cognitive impairment in OSA.10 In addition to excessive daytime sleepiness, increased sympathetic excitation and increased plasma cortisol levels may contribute to impaired neurocognitive performance, particularly in memory, learning, attention, and executive function.10–12
The usual treatment for OSA is continuous positive airway pressure (CPAP), showing beneficial effects in many health outcomes.1,2,6,13,14 More recently, however, other therapeutic options have been proven to be effective treatment for OSA, including oral appliances (OA) that modify the upper airway.13–16 According to the American Academy of Sleep Medicine (AASM) and the European Sleep Research Society (ESRS) guidelines, OA are indicated in patients with mild to moderate OSA with an AHI greater than 10 events/h and lower than 177
Journal of Clinical Sleep Medicine, Vol. 12, No. 2, 2016
T Galic, J Bozic, R Pecotic et al. MAD and Cognitive/Psychomotor Performance in OSA
Neuroscience, University of Split School of Medicine, Split, Croatia. They were matched with the patients with OSA for age, sex, and BMI. Potential subjects were excluded if they scored > 10 on the ESS, which was used to evaluate daytime sleepiness. The STOP (abbreviation for Snoring, Tiredness, Observed apnea and high blood Pressure) questionnaire, a concise and easy-to-use screening tool for OSA with high sensitivity and specificity for determining the risk for OSA, has been used as a screening tool.25 Subjects with a STOP questionnaire25 score ≥ 2 were excluded from the study due to the risk for the development of OSA. Other assessments consisted of the same cognitive and psychomotor performance testing as those performed in the study group. The reference group was assessed only once to compare their baseline values with those of the study group of patients with OSA before therapy. These assessments consisted of the same measurements as those conducted for the study group.
30 events/h (10 ≤ AHI ≤ 30), as well as for those patients who do not tolerate or comply with CPAP.1,2,12,14 Of the available OA used for OSA therapy, mandibular advancement devices (MAD) are the most common, which work by advancing the mandible, thus enlarging the upper airway space and thereby preventing the collapse of the upper airway during sleep.13–16 It has been demonstrated that MAD therapy improves the sleep assessment parameters in patients with mild to moderate OSA and reduces subjective symptoms and excessive daytime sleepiness.13–21 However, although some previous studies have reported improvement of neurocognitive function after treatment of OSA with CPAP,6,8,12,22 there is still limited evidence for the efficacy of MAD therapy on cognitive and psychomotor functions.6,17,22,23 The aim of this study is thus to investigate the potential benefits of MAD therapy in patients with mild to moderate OSA over the course of 1 y, specifically assessing its effect on long-term cognitive and psychomotor performance and quality of life. We hypothesize that these functions will be improved following MAD therapy.
Sleep Assessment
All patients attended a full-night, in-laboratory polysomnography (Alice 5LE or Alice PDX, Philips Respironics, Eindhoven, Netherlands) or polygraphy (PolyMesam, MAP, Martinsried, Germany) before therapy and at the end of the 3-mo and 1-y treatment period. Each patient was recorded on the same device at baseline and at the two follow-up intervals. Polysomnography recordings included electroencephalography, electrooculography, mental and tibial electromyography, electrocardiography, nasal airflow, pulse oxymetry, thoracic and abdominal movements, and snoring intensity; the polygraphy recorded nasal flow, thermistor signal, pulse oxymetry, electrocardiography, thoracic and abdominal movements, and snoring intensity.1,2,13 All data were manually scored and evaluated in accordance with the published AASM guidelines by the same certified sleep physician who was blind to the subject’s involvement in the study, time point of the study, and MAD compliance. Participants whose sleep studies lasted fewer than 4 h were not accepted and, in such cases, were repeated. A diagnosis of OSA was defined and performed in accordance with the guidelines established by the AASM and ESRS.1,2,13
METHODS
Patients
This study was approved by the Ethics Committee of the University of Split School of Medicine and was undertaken in agreement with the principles of the Declaration of Helsinki. All study participants provided written informed consent. Two types of participants were selected: patients with OSA who met the study criteria (described next) and subjects who would serve as the reference group.24 Patients with newly diagnosed OSA from the Split Sleep Medicine Center in Split, Croatia, were prospectively recruited to the study. Inclusion criteria were mild to moderate OSA (10 ≤ AHI ≤ 30), at least six to eight healthy teeth without movement in each jaw, and a forward jaw protrusion ability of at least 5 mm. Patients were excluded for any of the following reasons: abnormal dentition, known temporomandibular joint disorder, acute periodontal disease, or history of psychiatric, neurological, and respiratory disease. Additional exclusion criteria were regular use of sedatives, narcotics or psychoactive medications, and alcohol abuse. Patients unable to understand the purpose of the study also were excluded. Demographic and anthropometric characteristics, i.e., age, sex, body mass index (BMI), neck circumference, and Epworth Sleepiness Scale (ESS) score, were abstracted from the initial physical examination at the baseline visit in the sleep clinic. Of the 33 patients screened, 11 of them failed to fulfill the dental inclusion criteria, one patient was excluded due to temporomandibular joint disorder, and three patients subsequently rejected their participation. A total of 18 patients were prospectively enrolled in the study between June 2012 and January 2013, but three of them failed to finish the study protocol. The subjects for the reference group were recruited from a pool of healthy subjects that were tested on the Complex Reactionmeter Drenovac (CRD-series) in the Department of Journal of Clinical Sleep Medicine, Vol. 12, No. 2, 2016
Oral Appliance
An adjustable, semirigid, removable MAD (Silensor-sl, Erkodent, Pfalzgrafenweiler, Germany) was individually designed and fabricated for each patient enrolled in the study. The same experienced dentist treated all patients; a dental technician fabricated all the appliances. The initial advancement of the mandible was set at 50% of the maximum protrusion; subsequent adjustments were performed throughout a 4-w period until the improvement or resolution of the subjective symptoms was achieved, or until further advancement of the mandible resulted in discomfort. After this acclimation period, no further changes in mandibular advancement were allowed. However, none of the patients required a subsequent visit to the dental office. The final mean mandibular advancement was set at 7.0 ± 1.6 mm, representing 68.8 ± 5.6% of maximum possible protrusion. Patients were advised to use the MAD each night for as long as it was tolerable, and to self-monitor on 178
T Galic, J Bozic, R Pecotic et al. MAD and Cognitive/Psychomotor Performance in OSA
Self-Reported Measures: Excessive Daytime Sleepiness and Quality of Life
a daily basis using their personal sleep diary, recording bedtime, wake-up time, and the number of hours that the appliance was used.
Subjective daytime sleepiness was evaluated by the Epworth Sleepiness Scale (ESS), a self-administrated questionnaire, which was validated in Croatian language.25 An ESS score higher than 10 represented the presence of excessive daytime sleepiness.25,32 Patients with OSA also completed a quality of life questionnaire, the 36-Item Short Form Health Survey (SF-36), a questionnaire with 36 items that measures eight multi-item dimensions: physical functioning, role limitations due to physical problems, role limitations due to emotional problems, social functioning, mental health, energy and vitality, pain, and general health perception. There is an additional item on changes in patients’ health over the follow-up period. For each dimension item, scores were coded, summed, and transformed on to a scale from 0 (worst possible health) to 100 (best possible health).33,34 Two summary scores of physical (Physical Component Summary-PCS) and emotional well being (Mental Component Summary-MCS) were calculated, which can replicate the results of the SF-36. Furthermore, the PCS and MCS were standardized such that a mean score of 50 and a standard deviation of 10 reflect the mean score of the population.34,35 All self-reported measures were assessed at baseline and at the time of the 3-mo and 1-y follow-up.
Cognitive and Psychomotor Performance Testing
A computer-generated test, the Complex Reactionmeter Drenovac (CRD-series),26–31 covering a broad spectrum of cognitive and psychomotor functions, was used to measure cognitive and psychomotor performance.26–31 The CRD-series has been in use for more than 40 y in psychodiagnostic work, and a number of studies of their metric characteristics have been conducted, particularly the prognostic validity of the results obtained on these tests to see how they can evaluate the success in different occupations and conditions.27,29 It consists of the software and four electronic instruments. Of its 38 standard tests, three representative tests were used in this study, in order from the simplest to the most complex. Its technical design, theoretical concept on which the tests have been developed, methodology of measurement, data processing, and presentation make the CRD-series different from the standard set of instruments used in psychological practice and scientific research. CRD-series can be used for different age categories and it does not rely on language or any other specific knowledge. The software includes a test generator intended for independent creation of an unlimited number of new CRD tests. Therefore, it is possible to use the CRD-series for multiple retesting on the same subject without the possibility of memorizing the test.27,29–31 The patients were instructed to solve the tests as accurately and quickly as possible. During each testing session, each subject was assigned a new variety of tests, so any possible memorizing of the tasks was not an issue.26,27 The CRD-series tests used in this study were light signal position discrimination (CRD 311) measuring perceptive abilities, detection, identification, visual orientation and spatial visualization; simple arithmetic operations (CRD 11) measuring convergent thinking and general ability to perform in problem situations, such as constructing and solving simple mathematical tasks; and complex psychomotor coordination (eye-hand-leg) (CRD 411) measuring complex psychomotor reaction times. Testing was performed in a quiet, translucent room, between 08:00 and 10:00, at predetermined time points (prior to the MAD therapy, at the end of the 3-mo and 1-y treatment period) given in order from the simplest to the most complex. Tests were performed under the supervision of an experienced research technician who was blind to the time point of the study and MAD compliance. Prior to the official testing, patients practiced operating using the CRD-series instruments, and reached stable baseline results, without the tendency of improvement in order to avoid learning effect.26,28 Learning effect was not an issue on the re-tests after 3-mo or 1-y time periods. Three parameters were analyzed at each measurement point: total test solving time (TTST), minimum single task solving time (MinT), and total number of errors committed during the test (TE). TTST and MinT were descriptors of speed, accuracy, and mental endurance and TE was a descriptor of attention and alertness.26–28
Treatment Outcome Measures
The primary outcomes were the changes on parameters of the CRD-series tests following MAD therapy, each representing specific cognitive and psychomotor function. Secondary outcomes were the changes in self-reported measures, excessive daytime sleepiness measured with the ESS, and quality of life measured with the SF-36 questionnaire, after 1 y of MAD therapy. Sleep assessment data were obtained according to standard procedures. Treatment success was defined as AHI < 5 events/h (complete responders), or by AHI reduction ≥ 50% (partial responders) from baseline, which was considered to be clinically significant.15,19 Subjective compliance was calculated from the personal sleep diary and patients were classified as regular users if they completed at least 4 h of MAD therapy on more than 70% of the days of the week.15,19,36
Statistical Analysis
Statistical analyses were performed with MedCalc for Windows, version 11.5.1.0 (MedCalc Software, Mariakerke, Belgium). Continuous data were presented as mean ± standard deviation, whereas categorical variables were presented as whole numbers and percentages. The Mann-Whitney U test was used for baseline comparisons between the reference group and the study group. Analysis of variance for repeated measures with Bonferroni adjustment and post-hoc Tukey’s comparisons were performed to determine the differences among data obtained at baseline before therapy, and at 3 mo and 1 y following onset of MAD therapy. Differences between the number of errors in three repeated measures were estimated with the Friedman nonparametric test. The correlations between improvement in cognitive and psychomotor performance with the changes in the ESS score, AHI, and oxygen 179
Journal of Clinical Sleep Medicine, Vol. 12, No. 2, 2016
T Galic, J Bozic, R Pecotic et al. MAD and Cognitive/Psychomotor Performance in OSA
Figure 1—Study flowchart. A total of 33 patients were screened for the study, 15 of whom were not eligible for participation.
Table 1—Demographic characteristics of patients with obstructive sleep apnea and reference subjects. Variables Age (y) Height (cm) Weight (kg) BMI (kg/m2) ESS score
33 patients initially screened
11 not meeting dental inclusion criteria 1 temporomandibular joint disorder 3 refused to participate
OSA Group (n = 15) 51.2 ± 8.9 180.0 ± 7.2 91.4 ± 8.8 28.1 ± 2.7 9.9 ± 3.8
Reference Group (n = 15) 50.5 ± 9.8 182.0 ± 8.0 93.7 ± 10.6 28.4 ± 2.9 6.7 ± 2.9
Data are presented as mean ± standard deviation. AHI, apnea-hypopnea index; BMI, body mass index; ESS score, Epworth Sleepiness Scale score.
18 patients enrolled
acute myocardial infarction (n = 1) and a broken tooth not associated with MAD usage (n = 2), leaving a total of 15 patients who completed the 1-y study protocol. The detailed flowchart of the study is summarized in Figure 1; all subjects’ characteristics are presented in Table 1. There were no significant changes in diet, lifestyle, or medications used during the study based on patients’ personal reports at the time of follow-up.
Baseline assessment MAD administration and adjustment CRD testing Questionnaires
1 patient withdrew from the study due to acute myocardial infarction
Sleep Assessment Analysis
The effects of MAD therapy on sleep assessment characteristics are presented in Table 2. There was a significant decrease in AHI at 3 mo (22.9 ± 5.9 to 11.2 ± 4.9 events/h, p < 0.05) and at 1 y of MAD therapy (22.9 ± 5.9 to 9.7 ± 4.5 events/h, p < 0.001), when compared to baseline. AHI decreased ≥ 50% in 73% of patients whereas 53% and 27% of patients reached AHI < 10 and AHI < 5 events/h, respectively, after 1 y of MAD therapy. The sleep efficiency score based on polysomnographic data (9 of 15 patients, 60%) improved from 78.5 ± 17.3 % at baseline to 85.9 ± 10.5 % after 1 y of MAD therapy (p = 0.437). The self-reported compliance was 6.3 ± 1.5 h per night during the 1-y period. Thirteen of 15 patients (87%) were considered as regular users, using the MAD at least 4 h on more than 70% of the days of the week,19,36,37 whereas two patients (13%) were considered noncompliant.
3-month follow-up
2 patients withdrew from the study due to a broken tooth not associated with MAD usage
1-year follow-up
15 patients included in the follow-up analyses
Cognitive and Psychomotor Performance
The results of our study revealed differences in certain cognitive and psychomotor performances between the patients with OSA and the reference group subjects. TTST and MinT were prolonged for both, the simple (CRD 311) and complex (CRD 11 and CRD 411) tests at baseline. The total number of errors committed during testing was similar between patients with OSA and reference group subjects for complex tests (CRD 11 and CRD 411). Comparative analyses between the groups at baseline are shown in Table 3. The results of cognitive and psychomotor performance improvement following MAD therapy are presented in Table 4. In general, TTST and MinT were shorter for simple arithmetic (CRD 11) (TTST, p = 0.026 and MinT, p = 0.010) and light signal position discrimination (CRD 311) (TTST, p = 0.011 and MinT, p = 0.039) tests following MAD therapy. MinT values on complex motor coordination (CRD 411) test decreased significantly after 1 y of MAD therapy (p = 0.014), whereas TTST did not change significantly (p = 0.078). TE did not change
Eighteen patients passed the screening and were enrolled in the study. One patient withdrew before the 3-mo follow-up due to serious heart disease, and two patients withdrew before 1-y follow-up because of a broken tooth not associated with mandibular advancement device (MAD) usage. All of the remaining 15 patients completed the follow-up analyses. CRD, Complex Reactionmeter Drenovac.
desaturation index (ODI) were calculated using Pearson correlation coefficients. A value of p < 0.05 was considered statistically significant. R ES U LT S
Patient Baseline Characteristics
Eighteen patients from the OSA group who met the inclusion criteria were initially enrolled in the study. However, three patients subsequently withdrew before the follow-up visits due to Journal of Clinical Sleep Medicine, Vol. 12, No. 2, 2016
p 0.917 0.648 0.561 0.967 0.099
180
T Galic, J Bozic, R Pecotic et al. MAD and Cognitive/Psychomotor Performance in OSA
Table 2—Sleep characteristics of 15 patients with obstructive sleep apnea before and during mandibular advancement device therapy. Variables AHI (events/h) Mean SpO2 (%) Minimum SpO2 (%) ODI (events/h) Snoring time (min)
Baseline (n = 15) 22.9 ± 5.9 95.0 ± 1.7 83.6 ± 5.5 13.9 ± 6.8 225.8 ± 172.5
3 mo (n = 15) 11.2 ± 4.9 a 95.0 ± 1.1 86.0 ± 6.0 a 6.3 ± 3.9 a 143.0 ± 168.5 a
1 y (n = 15) 9.7 ± 4.5 b 95.0 ± 1.1 87.6 ± 6.2 b 7.8 ± 6.2 b 132.4 ± 139.4 b
p < 0.001 0.550 0.047 0.009 0.007
Data are presented as mean ± standard deviation. a p < 0.05, significant difference between baseline and 3 mo of treatment. b p < 0.05, significant difference between baseline and 12 mo of treatment. AHI, apnea-hypopnea index; ODI, oxygen desaturation index; SpO2, arterial oxygen saturation.
Table 3—Cognitive and psychomotor performance on Complex Reactionmeter Drenovac tests for patients with obstructive sleep apnea at baseline before mandibular advancement device therapy, and reference subjects. Test Light signal position discrimination (CRD 311)
Test Result MinT (s) TTST (s) TE
OSA Group (n = 15) 0.43 ± 0.06 36.72 ± 5.34 0
Reference Group (n = 15) 0.40 ± 0.06 33.65 ± 5.35 0
Simple arithmetic (CRD 11)
MinT (s) TTST (s) TE
2.64 ± 0.74 155.36 ± 60.82 3 (0–7)
2.29 ± 0.58 a 132.83 ± 32.94 a 3 (1–6)
Complex motor coordination (CRD 411)
MinT (s) TTST (s) TE
0.59 ± 0.18 47.87 ± 14.94 12 (0–34)
0.56 ± 0.13 45.95 ± 13.91 11 (1–29)
p 0.309 0.126 1.000 < 0.001 < 0.001 0.754 0.756 0.902 0.319
Data are presented as mean ± standard deviation. a p < 0.001, significant difference between patients with OSA and reference subjects. CRD, Complex Reactionmeter Drenovac; MinT, minimum single task solving time; OSA, obstructive sleep apnea; TE, total number of errors; TTST, total test solving time.
Table 4—Cognitive and psychomotor performance on Complex Reactionmeter Drenovac tests for patients with obstructive sleep apnea (n = 15) at baseline and after 3 mo and 1 y of mandibular advancement device therapy. Test Light signal position discrimination (CRD 311)
Test Result MinT (s) TTST(s) TE
Baseline 0.43 ± 0.06 36.72 ± 5.34 0
After 3 mo 0.42 ± 0.06 35.52 ± 4.25 0
After 1 y 0.41 ± 0.05 b 33.89 ± 4.55 b 0
p 0.039 0.011 1.000
Simple arithmetic (CRD 11)
MinT (s) TTST (s) TE
2.64 ± 0.74 155.36 ± 60.82 3 (0–7)
2.46 ± 0.65 148.98 ± 60.82 2 (0–14)
2.31 ± 0.48 b 137.09 ± 43.16 b 2 (0–7)
0.010 0.026 0.473
Complex motor coordination (CRD 411)
MinT (s) TTST (s) TE
0.59 ± 0.18 47.87 ± 14.94 12 (0–34)
0.54 ± 0.11 47.43 ± 19.42 11 (3–59)
0.51 ± 0.13 b 41.74 ± 19.57 12 (3–41)
0.014 0.078 0.935
Data are presented as mean ± standard deviation. b p < 0.05, significant difference between baseline and 12 mo of therapy. CRD, Complex Reactionmeter Drenovac; MAD, mandibular advancement device; MinT, minimum single task solving time; OSA, obstructive sleep apnea; TE, total number of errors; TTST, total test solving time.
Self-Reported Measures: Excessive Daytime Sleepiness and Quality of Life
significantly in any of the tests performed. There were no significant differences on the CRD-series tests after 3 mo of MAD therapy compared to baseline. Individual improvements after 1 y of MAD therapy in TTST and MinT for three CRD tests used in the study are shown in Figure 2 and Figure 3. There were no significant correlations between the improvement in cognitive and psychomotor performance with the changes in the ESS score, AHI, or ODI following MAD therapy (Table 5).
Excessive daytime sleepiness measured by the ESS score was reduced significantly, both at the 3-mo (9.9 ± 3.8 to 6.0 ± 3.2, p < 0.05) and the 1-y follow-up (9.9 ± 3.8 to 6.0 ± 2.8, p < 0.05) compared to the baseline. There was no further reduction between the 3-mo and 1-y measurements. Individual ESS scores after 1 y of MAD therapy are shown in Figure 4. Across the 181
Journal of Clinical Sleep Medicine, Vol. 12, No. 2, 2016
T Galic, J Bozic, R Pecotic et al. MAD and Cognitive/Psychomotor Performance in OSA
Figure 2—Individual minimum single task solving times (MinT) at baseline and after 1 y of mandibular advancement device therapy.
Figure 3—Individual total test solving times (TTST) at baseline and after 1 y of MAD therapy.
Apnea-hypopnea index-related responders (complete and partial) are presented with filled circles and nonresponders with empty squares.
Apnea-hypopnea index-related responders (complete and partial) are presented with filled circles and non-responders with empty squares.
whole study group, seven patients (47%) experienced excessive daytime sleepiness (ESS > 10) before the MAD therapy; in 86% of these patients, excessive daytime sleepiness was resolved. Results from the quality-of-life data showed significant improvement in social functioning, general health, and a single item on changes in patients’ health over the follow-up period, after 1 y of MAD therapy, compared to the pretreatment assessment (Table 6).
daytime sleepiness and improvement of social functioning, general health and well-being. Previous studies have evaluated the effectiveness of MAD therapy in patients with mild to moderate OSA and showed improvement of AHI, snoring time, and excessive daytime sleepiness.15,16,18,20,21 The current study also demonstrated reduction in AHI ≥ 50% in 73% of patients, whereas 53% and 27% of patients reached AHI < 10 and AHI < 5 events/h, respectively, after 1 y of MAD therapy, which is in accordance to the results of other authors.15,16,18,20,21,24,37,38 Still, an ongoing challenge for sleep physicians is to estimate the efficacy of MAD therapy not only in reduction of AHI but also the improvement of subjective symptoms and the quality of life in patients with OSA. Improvement following MAD therapy in patients with OSA was obvious in speed, accuracy, and mental endurance in the problem-solving strategy, particularly in the domain of perceptive abilities, convergent thinking (constructing and
D I SCUS S I O N The results of our study on the objective parameters of cognitive and psychomotor performance showed improvement after 1 y of MAD therapy in patients with mild to moderate OSA. In addition, the MAD therapy showed a reduction of excessive Journal of Clinical Sleep Medicine, Vol. 12, No. 2, 2016
182
T Galic, J Bozic, R Pecotic et al. MAD and Cognitive/Psychomotor Performance in OSA
Figure 4—Individual Epworth Sleepiness Scale (ESS) scores at baseline and after 1 y of mandibular advancement device therapy.
Table 5—Pearson correlation coefficients between changes in cognitive and psychomotor performance, Epworth Sleepiness Scale, apnea-hypopnea index, and oxygen desaturation index. r
ΔAHI
p
r
ΔODI
p
r
ΔESS
p
CRD 311 ΔTTST (s) ΔMinT (s)
0.219 0.431 0.468 0.127
−0.001 0.996 0.481 0.164
−0.139 0.621 −0.119 0.671
CRD 11 ΔTTST (s) ΔMinT (s)
−0.284 0.306 −0.248 0.374
−0.311 0.258 −0.127 0.652
0.159 0.569 0.281 0.310
CRD 411 ΔTTST (s) ΔMinT (s)
0.029 0.916 −0.183 0.515
−0.130 0.644 −0.364 0.182
−0.469 0.178 −0.028 0.921
Data are presented as mean ± standard deviation. CRD, complex reactionmeter Drenovac; MinT, minimum single task solving time; TTST, total test solving time.
Apnea-hypopnea index-related responders (complete and partial) are presented with filled circles and nonresponders with empty squares.
Table 6—Self-reported measures-excessive daytime sleepiness and quality of life for patients with obstructive sleep apnea at baseline and after 3 mo and 1 y of mandibular advancement device therapy. Excessive daytime sleepiness ESS score Quality of life scale SF-36 dimensions Physical functioning Role limitations physical Role limitations emotional Energy/vitality Emotional well-being Social functioning Pain General health perception Health change following MAD therapy Physical Component Summary score (PCS) Mental Component Summary score (MCS)
Before Therapy (n = 15)
After 3 mo (n = 15)
After 1 y (n = 15)
p
9.9 ± 3.8
6.0 ± 3.2 a
6.0 ± 2.8 b
0.002
78.7 ± 21.4 70.0 ± 41.4 84.4 ± 30.5 61.7 ± 16.2 72.8 ± 13.9 66.7 ± 25.7 68.7 ± 25.7 57.3 ± 16.8 48.3 ± 17.6 47.1 ± 8.6 48.9 ± 7.2
76.3 ± 21.2 76.7 ± 38.3 86.7 ± 30.3 62.0 ± 19.5 68.8 ± 17.9 78.3 ± 22.9 75.0 ± 28.2 61.3 ± 17.3 58.3 ± 15.4 49.1 ± 9.5 48.8 ± 8.2
78.8 ± 16.5 83.3 ± 36.2 84.4 ± 33.0 65.3 ± 15.2 70.1 ± 16.6 81.7 ± 17.6 b 75.2 ± 23.3 64.7 ± 17.8 b 65.0 ± 15.8 b 50.6 ± 6.9 49.6 ± 9.4
0.982 0.318 0.892 0.289 0.379 0.031 0.340 0.018 0.019 0.745 0.153
Data are presented as mean ± standard deviation. a p < 0.05, significant difference between baseline and 3 mo of treatment. b p < 0.05, significant difference between baseline and 12 mo of treatment. ESS score, Epworth Sleepiness Scale score; MAD, mandibular advancement device.
solving simple mathematical tasks), and psychomotor reactions. However, attention and alertness measured by the total number of errors did not differ in patients with OSA after MAD therapy, and in comparison with the reference group. The CRD 11, which served as a measure of speed in solving simple arithmetic operations, correlates with decisions in stress situations and general ability to perform in problematic situations.27 When compared to the reference group subjects, prior to the MAD therapy, patients with OSA in our study showed the significant impairment only on the CRD 11 test. Because suboptimal speed of reaction time, thinking, and responding could be associated with the increased risk for road traffic and occupational workplace accidents, this highlights the importance of early identification and treatment of patients with OSA.23 There were no significant differences on
other two tests, complex motor coordination (CRD 311) and light signal position discrimination (CRD 411), measuring the speed of perception of one critical signal in the working environment (CRD 311) and complexly coordinated actions of patients’ extremities (CRD 411),27,28 between patients with OSA and reference group subjects. However, in terms of the efficacy of MAD therapy on cognitive and psychomotor performance, there was significant improvement following MAD therapy on both of those tests. The improvements in task time as a descriptor of speed, accuracy, and mental endurance might be of clinical significance because the reaction time and psychomotor speed is crucial in driving performance and may reduce the risk for motor vehicle accidents.6 It could also be important in an effort to reduce workplace accidents that are associated with suboptimal speed of thinking and 183
Journal of Clinical Sleep Medicine, Vol. 12, No. 2, 2016
T Galic, J Bozic, R Pecotic et al. MAD and Cognitive/Psychomotor Performance in OSA
responding.23 Paradoxically, the total number of errors were not altered, as in the study of Karanovic et al.28 Many previous studies have shown that CPAP is superior to MAD in alleviating OSA symptoms.6,20–22 This could be a potential explanation why a longer period is needed for improvement of the neurocognitive function following MAD therapy. Phillips et al.6 reported comparable neurobehavioral improvement between CPAP and MAD, whereas the improvement of OSA symptoms was greater with CPAP than MAD after 1 mo. The authors further suggested that long-term studies with an objective assessment of compliance for both devices are needed to clarify how true night-to-night residual OSA affects health outcomes. Naismith et al.23 reported improvement on the choice reaction time task after 1 mo of MAD therapy, although there were no other significant treatment effects on neuropsychological performance. Barnes et al.22 reported improvement only in executive cognitive function following 3 mo of MAD therapy with no other treatment effects on neurocognitive function. As can be seen, the majority of data about neurocognitive improvements following OSA therapy are generated in shorter studies. Because effect sizes in neurocognitive research are typically small, the current study uses a longer time period in order to detect potential improvements in other domains of functioning and, importantly, to determine the clinical significance of MAD therapy in patients with OSA.23 Because this is, to our knowledge, the first use of CRD tests in patients with OSA and there were no well-established normative data for the cognitive and psychomotor tests used, it was difficult to compare our results with those from other studies. However, CRD tests have been in use for more than 40 y, resulting in a few original scientific studies.26,28–31,39–41 There are only a few psychological tests applicable for multiple retesting on the same subjects, because the object of measurement changes during the experiment. Many psychological tests that measure capabilities, if used for multiple retesting, become tests of knowledge, thus interindividual and intraindividual variabilities of the results of the measurement diminish.27,29 Numerous studies tried to provide evidence for pathophysiological mechanisms underlying neurocognitive impairment in patients with OSA that might be irreversible or reversible. In terms of irreversible mechanisms involved in impairment of neurocognitive performance some authors proposed that it may be attributed to reduced cell neurogenesis and density of the hippocampus, the frontal cortex, and generalized gray matter.9–11,42 On the contrary, Edwards et al.11 emphasized importance of nighttime cortisol levels as a significant predictor of neurocognitive performance in patients with OSA. Reversible pathophysiological mechanisms involved in neurocognitive impairment are differentially affected by the effects of poor sleep quality, sleep fragmentation, hypoxemia, and excessive daytime sleepiness.8–10,23,42 Results of the current study indicated that patients with mild to moderate OSA reportedly had excessive daytime sleepiness. The majority of our patients (86%) who reported excessive daytime sleepiness achieved resolution of the symptoms, indicating efficacy of MAD therapy in reduction of daytime sleepiness similar to other studies.6,22,23 We recognize that in our study MAD therapy significantly improved only subjective sleepiness measured by the Journal of Clinical Sleep Medicine, Vol. 12, No. 2, 2016
ESS, whereas in some previous studies, the authors used objective measures of sleepiness determined by the maintenance of wakefulness test.12,22,23,43 We did not find any correlations between improvement of neurocognitive function and AHI or ODI either; therefore, we could only speculate whether excessive daytime sleepiness or some other proposed mechanisms could be responsible for impairments of neurocognitive performance in patients with OSA in our study. Considering those differences, it is very difficult to anticipate improvements in all aspects of neurocognitive performance following OSA therapy as reported in the previous studies.6,12,17,22,23,43 The developers of the SF-36 encourage the comparison of scores with the normative data from general population samples, which provides a better understanding of the adverse effects of OSA.34 Baseline results from the physical and mental component summary scores (PCS and MCS, respectively) of the SF-36 in our study population indicate moderate deviation from the mean of general population scores, which is in accordance with previous studies.6,22,34 Unlike recent results showing an improvement in PCS and MCS following MAD therapy, our data did not show significant improvement in this area.6,22,34 In addition, Jenkinson et al.34 reported greater deviation from the normative data than in our study population, which may be related to the recruitment of patients with more severe OSA in their sample. However, the SF-36 scores of patients with OSA in our study indicated the effects of a reduced health state compared to the general population. Additionally, the SF-36 scores indicated considerable improvements in three domains, social functioning, general health perception, and considerable improvement of well-being, following MAD therapy, with the outcome scores being close to those of the general population. Results from the previous studies showed large variations of the quality-of-life improvement, highlighting the difficulty patients have in determining the severity of their subjective symptoms.33,34 It should be noted, however, that the SF-36 is a generic quality-of-life questionnaire and, thus, may be less responsive than a disease-specific instrument.43 For a qualityof-life questionnaire to be useful in clinical trials of OSA, it should have the capacity to differentiate varying degrees of the disease.33,34 There are a few limitations of this study. The sample size was relatively small; therefore, further treatment-based studies with a larger sample size are required in order to confirm our results. Still, to the authors’ best knowledge, this is the first prospective cohort long-term study that, unlike the previous placebo-controlled or CPAP-controlled studies, followed neurocognitive functions in MAD-treated patients with OSA for as long as 1 y, which was suggested by Phillips et al.6 Also, the subjects in our study group were acting as their own control subjects in this prospective cohort study with repeated measurements. There is no scientific evidence that patients with mild to moderate OSA can spontaneously recover from their disease without lowering BMI, introducing positional therapy, sleep hygiene measures, etc., which was not the case in our study. However, our results should be confirmed in long-term randomized controlled studies with larger sample size and different severity of OSA to further establish the beneficial effect of the MAD therapy on neurocognitive function.6 184
T Galic, J Bozic, R Pecotic et al. MAD and Cognitive/Psychomotor Performance in OSA
There were no well-established normative data for the cognitive and psychomotor tests used, but we have included the reference group in order to compare the results of our study group prior to the initiation of the therapy. Furthermore, the complex motor coordination test (CRD 411), measuring complex psychomotor coordination, shows the highest possibility of the individually different effect of learning on the psychomotor component of motor coordination between the extremities.27 The CRD-series is different from the standard set of instruments used in psychological practice and scientific research because the software includes a test generator intended for independent creation of an unlimited number of new CRD tests. Therefore, it is possible to use the test series for multiple retesting on the same subject without the possibility of memorizing the test.27,29 Learning in this study could not be attributed to memorizing, because the subjects were always assigned new variations of tests, but some adaptation might have occurred over the study period.31 In conclusion, this 1-y prospective cohort study indicated improvement of OSA symptoms, cognitive and psychomotor performance, and quality of life following MAD therapy in patients with mild to moderate OSA. Further long-term randomized controlled studies with larger sample size are needed to clarify precise mechanisms underlying neurocognitive improvement as a result of MAD therapy.
3. Jordan AS, McSharry DG, Malhorta A. Adult obstructive sleep apnoea. Lancet 2014;383:736–47. 4. McNicholas WT. Sleep-related breathing disorders: nosological classification, definitions, epidemiology. In: Bassetti C, Dogas Z, Peigneux P, eds. Sleep Medicine Textbook. Regensburg, Germany: European Sleep Research Society, 2014:215–20. 5. Karimi M, Eder DN, Eskandari D, Zou D, Hedner JA, Grote L. Impaired vigilance and increased accident rate in public transport operators is associated with sleep disorders. Accid Anal Prev 2013;51:208–14. 6. Phillips CL, Grunstein RR, Darendeliler MA, et al. Health outcomes of continuous positive airway pressure versus oral appliance treatment for obstructive sleep apnea. Am J Resp Crit Care Med 2013;187:879–87. 7. Pepin JL, Borel JC, Borel AL, Levy P, Tamisier R. Sleep-related breathing disorders: comorbidities and special populations. In: Bassetti C, Dogas Z, Peigneux P, eds. Sleep Medicine Textbook. Regensburg, Germany: European Sleep Research Society, 2014:251–8. 8. Quan SF, Chan CS, Dement WC, et al. The association between obstructive sleep apnea and neurocognitive performance-the Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep 2011;34:303–14. 9. Beebe DW, Groesz L, Wells C, Nichols A, McGee K. The neuropsychological effects of obstructive sleep apnea: a meta-analysis of norm-referenced and case-controlled data. Sleep 2003;26:298–307. 10. Bucks RS, Olaithe M, Eastwood P. Neurocognitive function in obstructive sleep apnoea: a meta-review. Respirology 2013;18:61–70. 11. Edwards KM, Kamat R, Tomfhor LM, Ancoli-Israel S, Dimsdale JE. Obstructive sleep apnea and neurocognitive performance: the role of cortisol. Sleep Med 2014;15:27–32. 12. Kushida CA, Nichols DA, Holmes TH, et al. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: the Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep 2012;35:1593–602. 13. Kushida CA, Littner MR, Morgenthaler T, et al. Practice parameters for the indications for polysomnography and related procedures: an update for 2005. Sleep 2005;28:449–521. 14. Pevernagie D, Sastry M, Vanderveken OM. Sleep-related breathing disorders: treatment of respiratory sleep disorders. In: Bassetti C, Dogas Z, Peigneux P, eds. Sleep Medicine Textbook. Regensburg, Germany: European Sleep Research Society, 2014:259–74. 15. Sutherland K, Vanderveken OM, Tsuda H, et al. Oral appliance treatment for obstructive sleep apnea: an update. J Clin Sleep Med 2014;10:215–27. 16. Almeida FR, Lowe AA. Principles of oral appliance therapy for the management of snoring and sleep disordered breathing. Oral Maxillofac Sur Clin North Am 2009;21:413–20. 17. Tegelberg A, Wilhelmsson B, Erixon-Lindroth N, Lindström LH. Improved cognitive functions after treatment with an oral appliance in obstructive sleep apnea. Nat Sci Sleep 2012;4:89–96. 18. Ferguson KA, Cartwright R, Rogers R, Schmidt-Nowara W. Oral appliances for snoring and obstructive sleep apnea: a review. Sleep 2006;29:244–62. 19. Tsuiki S, Kobayashi M, Namba K, et al. Optimal positive airway pressure predicts oral appliance response to sleep apnoea. Eur Respir J 2010;35:1098–105. 20. Almeida FR, Henrich N, Marra C, et al. Patients preferences and experiences of CPAP and oral appliances for the treatment of obstructive sleep apnea: a qualitative analysis. Sleep Breath 2013;17:659–66. 21. Holley AB, Lettieri CJ, Shah AA. Efficacy of an adjustable oral appliance and comparison with continuous positive airway pressure for the treatment of obstructive sleep apnea syndrome. Chest 2011;140:1511–6. 22. Barnes M, McEvoy DR, Banks S, et al. Efficacy of positive airway pressure and oral appliance in mild to moderate obstructive sleep apnea. Am J Resp Crit Care Med 2004;170:656–64. 23. Naismith SL, Winter VR, Hickie IB, Cistulli PA. Effect of oral appliance therapy on neurobehavioral functioning in obstructive sleep apnea: a randomized controlled trial. J Clin Sleep Med 2005;1:374–80. 24. Pecotic R, Dodig IP, Valic M, Ivkovic N, Dogas Z. The evaluation of the Croatian version of the Epworth sleepiness scale and STOP questionnaire as screening tools for obstructive sleep apnea syndrome. Sleep Breath 2012;16:793–802.
A B B R E V I AT I O N S AASM, American Academy of Sleep Medicine AHI, apnea-hypopnea index BMI, body mass index CPAP, continuous positive airway pressure CRD, Complex Reactionmeter Drenovac ESRS, European Sleep Research Society ESS, Epworth Sleepiness Scale MAD, mandibular advancement device MCS, Mental Component Summary score MinT, minimal single task solving time OA, oral appliance ODI, oxygen desaturation index OSA, obstructive sleep apnea PCS, Physical Component Summary score SF-36, 36-Item Short Form Health Survey SpO2 , arterial oxygen saturation STOP, Snoring, Tiredness, Observed Apnea, High Blood Pressure TE, total number of errors committed during the test TTST, total test solving time R E FE R E N CES 1. The Report of an American Academy of Sleep Medicine Task Force. Sleeprelated breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. Sleep 1999;22:667–89. 2. Fischer J, Dogas Z, Bassetti CL, et al. Standard procedures for adults in accredited sleep medicine centres in Europe. J Sleep Res 2012;21:357–68.
185
Journal of Clinical Sleep Medicine, Vol. 12, No. 2, 2016
T Galic, J Bozic, R Pecotic et al. MAD and Cognitive/Psychomotor Performance in OSA 25. Itzhaki S, Dorchin H, Clark G, Lavie L, Lavie P, Pillar G. The effects of 1-year treatment with a Herbst mandibular advancement splint on obstructive sleep apnea, oxidative stress, and endothelial function. Chest 2007;131:740–9. 26. Petri NM, Dropulic N, Kardum G. Effects of voluntary fluid intake deprivation on mental and psychomotor performance. Croat Med J 2006;47:855–61. 27. Drenovac M. CRD-series of psychodiagnostic tests [in Croatian]. Zagreb, Croatia, AKD 1994. 28. Karanovic N, Carev M, Kardum G, et al. The impact of a single 24h working day on cognitive and psychomotor performance in staff anaesthesiologists. Eur J Anaesthesiol 2009;26:825–32. 29. Drenovac M. An analysis of some attributes of the dynamics of mental processing. Rev Psychol 2001;8:61–7. 30. Drenovac M, Petri NM. Research of effect of hyperbaric pressure on dynamics and efficiency of complex mental processing. 36th IAMPS, Split, Croatia 2000:80–9. 31. Petri NM. Change in strategy of solving psychological tests: evidence of nitrogen narcosis in shallow air-diving. Undersea Hyperb Med 2003;30:293– 303. 32. Johns MW. Daytime sleepiness, snoring, and obstructive sleep apnea. The Epworth Sleepiness Scale. Chest 1993;103:30–6. 33. Jenkinson C, Coulter A, Wright L. Short form 36 (SF-36) health survey questionnaire: normative data for adults of working age. Br Med J 1993;306:1437–40. 34. Jenkinson C, Stradling J, Petersen S. Comparison of three measures of quality of life outcome in the evaluation of continuous positive airway pressure therapy for sleep apnoea. J Sleep Res 1997;6:199–204. 35. Wright L, Harwood D, Coulter A. Health and lifestyles in the Oxford region. Oxford, UK: Health Services Research Unit, University of Oxford, 1992. 36. Vanderveken OM, Dieltjens M, Wouters K, De Backer W, Van de Heyning PH, Braem MJ. Objective measurement of compliance during oral appliance therapy for sleep-disordered breathing. Thorax 2013;68:91–6. 37. Dieltjens M, Bream MJ, Vroeqop AV, et al. Objectively measured vs selfreported compliance during oral appliance therapy for sleep-disordered breathing. Chest 2013;144:1495–502. 38. Galic T, Bozic J, Ivkovic N, Kurir Ticinovic T, Dogas Z. Effects of mandibular advancement device treatment on arterial stiffness and glucose metabolism in patients with mild to moderate obstructive sleep apnea: a prospective 1 year study. Sleep Breath 2015 May 1. [Epub ahead of print]. 39. Kajtna T, Vuleta D, Pori M, Juskin I, Pori P. Psychological characteristics of Slovene handball goalkeepers. Kinesiology 2012;2:209–17. 40. Malacko J, Doder D, Vujanovic S. The differences in the movement structures of kata, fights and mental potentials between boys and girls who train karate. Acta Kinesiologica 2010;2:28–32.
Journal of Clinical Sleep Medicine, Vol. 12, No. 2, 2016
41. Petranovic D, Taksic V, Dobrila-Dintinjana et al. Correlation of anaemia and cognitive functions measured by the complex reactionmeter Drenovac. Coll Antropol 2008;32:47–51. 42. Naismith D, Winter V, Gotsopoulos H, Hichie I, Cistulli P. Neurobehavioral functioning in obstructive sleep apnea: differential effects of sleep quality, hypoxemia and subjective sleepiness. J Clin Exp Neuropsychol 2004;26:43–54. 43. Antic NA, Catcheside P, Buchan C, et al. The effect of CPAP in normalizing daytime sleepiness, quality of life, and neurocognitive function in patients with moderate to severe OSA. Sleep 2011;34:111–9.
ACK N O W L E D G M E N T S The authors thank Jelena Baricevic for her technical assistance; Ivan Galic, DMD and Mijo Mario Vuletic, CDT for their assistance during dental examinations of patients and fabricating oral appliances. The authors also thank Darlene Garalde Intlekofer, MS, The City University of New York, New York, NY for the extensive grammar corrections. Author contributions: Dr. Galic - study design, data collection, data analysis, manuscript draft; Dr. Bozic - data analysis, manuscript draft; Ms. Ivkovic - data collection, data analysis; Dr. Pecotic - data collection, data analysis, manuscript draft; Dr. Valic - data collection, data analysis, manuscript draft; Dr. Dogas - study design, data collection, data analysis, manuscript draft.
SUBM I SSI O N & CO R R ESPO NDENCE I NFO R M ATI O N Submitted for publication February, 2015 Submitted in final revised form June, 2015 Accepted for publication July, 2015 Address correspondence to: Professor Zoran Dogas, MD, PhD, Department of Neuroscience, University of Split School of Medicine, Soltanska 2, 21000, Split, Croatia; Tel.: +385 21 557 905; Fax: +385 21 557 955; Email: [email protected]
D I SCLO S U R E S TAT E M E N T This work has been supported by the Croatian Science Foundation grant #201311-5935. The manufacturers of oral appliances and the measuring equipment had no access to or control over the study design, data collection, data analysis, data interpretation, or writing of the manuscript. This study was performed at the University of Split School of Medicine, Split, Croatia. The authors have indicated no financial conflicts of interest.
186
http://dx.doi.org/10.5664/jcsm.5480
S CI E NT IF IC IN VES TIGATIONS
Improvement of Cognitive and Psychomotor Performance in Patients with Mild to Moderate Obstructive Sleep Apnea Treated with Mandibular Advancement Device: A Prospective 1-Year Study Tea Galic, DMD1; Josko Bozic, MD2; Renata Pecotic, MD, PhD3,4; Natalija Ivkovic, MSc, RN3; Maja Valic, MD, PhD3,4; Zoran Dogas, MD, PhD3,4 Study of Dental Medicine, 2Department of Pathophysiology, 3Split Sleep Medicine Center, and 4Department of Neuroscience, University of Split School of Medicine, Split, Croatia
1
Study Objectives: This study aimed to provide the evidence on effect of mandibular advancement device (MAD) therapy on long-term cognitive and psychomotor performance, excessive daytime sleepiness, and quality of life in patients with mild to moderate obstructive sleep apnea (OSA). Methods: A total of 15 patients with mild to moderate OSA were treated with MAD therapy and they were followed up after 3 mo and 1 y of therapy. The patients were tested on three different tests of cognitive and psychomotor performance using the computer-based system Complex Reactionmeter Drenovac (CRD-series) at baseline and at the time of follow-up, and the 36-Item Short Form Health Survey (SF-36) questionnaire and Epworth Sleepiness Scale were used to assess their quality of life and excessive daytime sleepiness, respectively. Results: The mean apnea-hypopnea index (AHI) decreased significantly from 22.9 ± 5.9 events/h at baseline, to 9.7 ± 4.5 events/h after 1 y of MAD therapy (p < 0.001). There was significant improvement on all three CRD-series tests used after 1 y of MAD therapy, considering total test solving time (TTST) and minimal single task solving time (MinT), whereas total number of errors committed during the tests (TE) remained unchanged. Self-reported measures, excessive daytime sleepiness, and three domains of quality of life, social functioning, general health perception, and health change following MAD therapy showed significant improvements after 1 y of MAD therapy. Conclusions: This study demonstrates significant improvements in cognitive and psychomotor performance, particularly in the domain of perceptive abilities, convergent thinking (constructing and solving simple mathematical tasks) and psychomotor reaction times, excessive daytime sleepiness, and quality of life in patients with mild to moderate OSA following MAD therapy. Keywords: obstructive sleep apnea, oral appliances, mandibular advancement device, cognitive, psychomotor, sleepiness, quality of life Citation: Galic T, Bozic J, Pecotic R, Ivkovic N, Valic M, Dogas Z. Improvement of cognitive and psychomotor performance in patients with mild to moderate obstructive sleep apnea treated with mandibular advancement device: a prospective 1-year study. J Clin Sleep Med 2016;12(2):177–186.
I N T RO D U C T I O N
BRIEF SUMMARY
Current Knowledge/Study Rationale: The mandibular advancement device (MAD) is an approved, effective modality of treatment in patients with mild to moderate obstructive sleep apnea (OSA). However, the effect of MAD treatment on cognitive and psychomotor performance has not been sufficiently established. The aim of this study was to assess the effect of MAD treatment on cognitive and psychomotor performance and subjective measures, excessive daytime sleepiness, and quality of life. Study Impact: This study demonstrates that MAD therapy in patients with mild to moderate OSA is associated with improvement in cognitive and psychomotor performance. Furthermore, there was considerable improvement of well-being following MAD therapy.
Obstructive sleep apnea (OSA) is the most prevalent sleep related breathing disorder caused by repetitive partial or complete interruptions of breathing during sleep, resulting in intermittent hypoxemia, sympathetic excitation, and sleep fragmentation.1–4 Patients with the disorder are known to suffer excessive daytime sleepiness, leading to more motor vehicle accidents.3,5,6 OSA is also associated with the range of significant medical consequences such as obesity, hypertension, type 2 diabetes, depression, psychological and cognitive consequences, and a lower self-reported quality of life.3,4,6–8 The precise mechanisms of neurocognitive impairment associated with OSA are still unknown.8 In some studies, impaired neurocognitive performance is associated with increased apnea-hypopnea index (AHI) and intermittent hypoxia,7–10 whereas sleep fragmentation, sleep deprivation, and excessive daytime sleepiness might be additional mechanisms underlying the cognitive impairment in OSA.10 In addition to excessive daytime sleepiness, increased sympathetic excitation and increased plasma cortisol levels may contribute to impaired neurocognitive performance, particularly in memory, learning, attention, and executive function.10–12
The usual treatment for OSA is continuous positive airway pressure (CPAP), showing beneficial effects in many health outcomes.1,2,6,13,14 More recently, however, other therapeutic options have been proven to be effective treatment for OSA, including oral appliances (OA) that modify the upper airway.13–16 According to the American Academy of Sleep Medicine (AASM) and the European Sleep Research Society (ESRS) guidelines, OA are indicated in patients with mild to moderate OSA with an AHI greater than 10 events/h and lower than 177
Journal of Clinical Sleep Medicine, Vol. 12, No. 2, 2016
T Galic, J Bozic, R Pecotic et al. MAD and Cognitive/Psychomotor Performance in OSA
Neuroscience, University of Split School of Medicine, Split, Croatia. They were matched with the patients with OSA for age, sex, and BMI. Potential subjects were excluded if they scored > 10 on the ESS, which was used to evaluate daytime sleepiness. The STOP (abbreviation for Snoring, Tiredness, Observed apnea and high blood Pressure) questionnaire, a concise and easy-to-use screening tool for OSA with high sensitivity and specificity for determining the risk for OSA, has been used as a screening tool.25 Subjects with a STOP questionnaire25 score ≥ 2 were excluded from the study due to the risk for the development of OSA. Other assessments consisted of the same cognitive and psychomotor performance testing as those performed in the study group. The reference group was assessed only once to compare their baseline values with those of the study group of patients with OSA before therapy. These assessments consisted of the same measurements as those conducted for the study group.
30 events/h (10 ≤ AHI ≤ 30), as well as for those patients who do not tolerate or comply with CPAP.1,2,12,14 Of the available OA used for OSA therapy, mandibular advancement devices (MAD) are the most common, which work by advancing the mandible, thus enlarging the upper airway space and thereby preventing the collapse of the upper airway during sleep.13–16 It has been demonstrated that MAD therapy improves the sleep assessment parameters in patients with mild to moderate OSA and reduces subjective symptoms and excessive daytime sleepiness.13–21 However, although some previous studies have reported improvement of neurocognitive function after treatment of OSA with CPAP,6,8,12,22 there is still limited evidence for the efficacy of MAD therapy on cognitive and psychomotor functions.6,17,22,23 The aim of this study is thus to investigate the potential benefits of MAD therapy in patients with mild to moderate OSA over the course of 1 y, specifically assessing its effect on long-term cognitive and psychomotor performance and quality of life. We hypothesize that these functions will be improved following MAD therapy.
Sleep Assessment
All patients attended a full-night, in-laboratory polysomnography (Alice 5LE or Alice PDX, Philips Respironics, Eindhoven, Netherlands) or polygraphy (PolyMesam, MAP, Martinsried, Germany) before therapy and at the end of the 3-mo and 1-y treatment period. Each patient was recorded on the same device at baseline and at the two follow-up intervals. Polysomnography recordings included electroencephalography, electrooculography, mental and tibial electromyography, electrocardiography, nasal airflow, pulse oxymetry, thoracic and abdominal movements, and snoring intensity; the polygraphy recorded nasal flow, thermistor signal, pulse oxymetry, electrocardiography, thoracic and abdominal movements, and snoring intensity.1,2,13 All data were manually scored and evaluated in accordance with the published AASM guidelines by the same certified sleep physician who was blind to the subject’s involvement in the study, time point of the study, and MAD compliance. Participants whose sleep studies lasted fewer than 4 h were not accepted and, in such cases, were repeated. A diagnosis of OSA was defined and performed in accordance with the guidelines established by the AASM and ESRS.1,2,13
METHODS
Patients
This study was approved by the Ethics Committee of the University of Split School of Medicine and was undertaken in agreement with the principles of the Declaration of Helsinki. All study participants provided written informed consent. Two types of participants were selected: patients with OSA who met the study criteria (described next) and subjects who would serve as the reference group.24 Patients with newly diagnosed OSA from the Split Sleep Medicine Center in Split, Croatia, were prospectively recruited to the study. Inclusion criteria were mild to moderate OSA (10 ≤ AHI ≤ 30), at least six to eight healthy teeth without movement in each jaw, and a forward jaw protrusion ability of at least 5 mm. Patients were excluded for any of the following reasons: abnormal dentition, known temporomandibular joint disorder, acute periodontal disease, or history of psychiatric, neurological, and respiratory disease. Additional exclusion criteria were regular use of sedatives, narcotics or psychoactive medications, and alcohol abuse. Patients unable to understand the purpose of the study also were excluded. Demographic and anthropometric characteristics, i.e., age, sex, body mass index (BMI), neck circumference, and Epworth Sleepiness Scale (ESS) score, were abstracted from the initial physical examination at the baseline visit in the sleep clinic. Of the 33 patients screened, 11 of them failed to fulfill the dental inclusion criteria, one patient was excluded due to temporomandibular joint disorder, and three patients subsequently rejected their participation. A total of 18 patients were prospectively enrolled in the study between June 2012 and January 2013, but three of them failed to finish the study protocol. The subjects for the reference group were recruited from a pool of healthy subjects that were tested on the Complex Reactionmeter Drenovac (CRD-series) in the Department of Journal of Clinical Sleep Medicine, Vol. 12, No. 2, 2016
Oral Appliance
An adjustable, semirigid, removable MAD (Silensor-sl, Erkodent, Pfalzgrafenweiler, Germany) was individually designed and fabricated for each patient enrolled in the study. The same experienced dentist treated all patients; a dental technician fabricated all the appliances. The initial advancement of the mandible was set at 50% of the maximum protrusion; subsequent adjustments were performed throughout a 4-w period until the improvement or resolution of the subjective symptoms was achieved, or until further advancement of the mandible resulted in discomfort. After this acclimation period, no further changes in mandibular advancement were allowed. However, none of the patients required a subsequent visit to the dental office. The final mean mandibular advancement was set at 7.0 ± 1.6 mm, representing 68.8 ± 5.6% of maximum possible protrusion. Patients were advised to use the MAD each night for as long as it was tolerable, and to self-monitor on 178
T Galic, J Bozic, R Pecotic et al. MAD and Cognitive/Psychomotor Performance in OSA
Self-Reported Measures: Excessive Daytime Sleepiness and Quality of Life
a daily basis using their personal sleep diary, recording bedtime, wake-up time, and the number of hours that the appliance was used.
Subjective daytime sleepiness was evaluated by the Epworth Sleepiness Scale (ESS), a self-administrated questionnaire, which was validated in Croatian language.25 An ESS score higher than 10 represented the presence of excessive daytime sleepiness.25,32 Patients with OSA also completed a quality of life questionnaire, the 36-Item Short Form Health Survey (SF-36), a questionnaire with 36 items that measures eight multi-item dimensions: physical functioning, role limitations due to physical problems, role limitations due to emotional problems, social functioning, mental health, energy and vitality, pain, and general health perception. There is an additional item on changes in patients’ health over the follow-up period. For each dimension item, scores were coded, summed, and transformed on to a scale from 0 (worst possible health) to 100 (best possible health).33,34 Two summary scores of physical (Physical Component Summary-PCS) and emotional well being (Mental Component Summary-MCS) were calculated, which can replicate the results of the SF-36. Furthermore, the PCS and MCS were standardized such that a mean score of 50 and a standard deviation of 10 reflect the mean score of the population.34,35 All self-reported measures were assessed at baseline and at the time of the 3-mo and 1-y follow-up.
Cognitive and Psychomotor Performance Testing
A computer-generated test, the Complex Reactionmeter Drenovac (CRD-series),26–31 covering a broad spectrum of cognitive and psychomotor functions, was used to measure cognitive and psychomotor performance.26–31 The CRD-series has been in use for more than 40 y in psychodiagnostic work, and a number of studies of their metric characteristics have been conducted, particularly the prognostic validity of the results obtained on these tests to see how they can evaluate the success in different occupations and conditions.27,29 It consists of the software and four electronic instruments. Of its 38 standard tests, three representative tests were used in this study, in order from the simplest to the most complex. Its technical design, theoretical concept on which the tests have been developed, methodology of measurement, data processing, and presentation make the CRD-series different from the standard set of instruments used in psychological practice and scientific research. CRD-series can be used for different age categories and it does not rely on language or any other specific knowledge. The software includes a test generator intended for independent creation of an unlimited number of new CRD tests. Therefore, it is possible to use the CRD-series for multiple retesting on the same subject without the possibility of memorizing the test.27,29–31 The patients were instructed to solve the tests as accurately and quickly as possible. During each testing session, each subject was assigned a new variety of tests, so any possible memorizing of the tasks was not an issue.26,27 The CRD-series tests used in this study were light signal position discrimination (CRD 311) measuring perceptive abilities, detection, identification, visual orientation and spatial visualization; simple arithmetic operations (CRD 11) measuring convergent thinking and general ability to perform in problem situations, such as constructing and solving simple mathematical tasks; and complex psychomotor coordination (eye-hand-leg) (CRD 411) measuring complex psychomotor reaction times. Testing was performed in a quiet, translucent room, between 08:00 and 10:00, at predetermined time points (prior to the MAD therapy, at the end of the 3-mo and 1-y treatment period) given in order from the simplest to the most complex. Tests were performed under the supervision of an experienced research technician who was blind to the time point of the study and MAD compliance. Prior to the official testing, patients practiced operating using the CRD-series instruments, and reached stable baseline results, without the tendency of improvement in order to avoid learning effect.26,28 Learning effect was not an issue on the re-tests after 3-mo or 1-y time periods. Three parameters were analyzed at each measurement point: total test solving time (TTST), minimum single task solving time (MinT), and total number of errors committed during the test (TE). TTST and MinT were descriptors of speed, accuracy, and mental endurance and TE was a descriptor of attention and alertness.26–28
Treatment Outcome Measures
The primary outcomes were the changes on parameters of the CRD-series tests following MAD therapy, each representing specific cognitive and psychomotor function. Secondary outcomes were the changes in self-reported measures, excessive daytime sleepiness measured with the ESS, and quality of life measured with the SF-36 questionnaire, after 1 y of MAD therapy. Sleep assessment data were obtained according to standard procedures. Treatment success was defined as AHI < 5 events/h (complete responders), or by AHI reduction ≥ 50% (partial responders) from baseline, which was considered to be clinically significant.15,19 Subjective compliance was calculated from the personal sleep diary and patients were classified as regular users if they completed at least 4 h of MAD therapy on more than 70% of the days of the week.15,19,36
Statistical Analysis
Statistical analyses were performed with MedCalc for Windows, version 11.5.1.0 (MedCalc Software, Mariakerke, Belgium). Continuous data were presented as mean ± standard deviation, whereas categorical variables were presented as whole numbers and percentages. The Mann-Whitney U test was used for baseline comparisons between the reference group and the study group. Analysis of variance for repeated measures with Bonferroni adjustment and post-hoc Tukey’s comparisons were performed to determine the differences among data obtained at baseline before therapy, and at 3 mo and 1 y following onset of MAD therapy. Differences between the number of errors in three repeated measures were estimated with the Friedman nonparametric test. The correlations between improvement in cognitive and psychomotor performance with the changes in the ESS score, AHI, and oxygen 179
Journal of Clinical Sleep Medicine, Vol. 12, No. 2, 2016
T Galic, J Bozic, R Pecotic et al. MAD and Cognitive/Psychomotor Performance in OSA
Figure 1—Study flowchart. A total of 33 patients were screened for the study, 15 of whom were not eligible for participation.
Table 1—Demographic characteristics of patients with obstructive sleep apnea and reference subjects. Variables Age (y) Height (cm) Weight (kg) BMI (kg/m2) ESS score
33 patients initially screened
11 not meeting dental inclusion criteria 1 temporomandibular joint disorder 3 refused to participate
OSA Group (n = 15) 51.2 ± 8.9 180.0 ± 7.2 91.4 ± 8.8 28.1 ± 2.7 9.9 ± 3.8
Reference Group (n = 15) 50.5 ± 9.8 182.0 ± 8.0 93.7 ± 10.6 28.4 ± 2.9 6.7 ± 2.9
Data are presented as mean ± standard deviation. AHI, apnea-hypopnea index; BMI, body mass index; ESS score, Epworth Sleepiness Scale score.
18 patients enrolled
acute myocardial infarction (n = 1) and a broken tooth not associated with MAD usage (n = 2), leaving a total of 15 patients who completed the 1-y study protocol. The detailed flowchart of the study is summarized in Figure 1; all subjects’ characteristics are presented in Table 1. There were no significant changes in diet, lifestyle, or medications used during the study based on patients’ personal reports at the time of follow-up.
Baseline assessment MAD administration and adjustment CRD testing Questionnaires
1 patient withdrew from the study due to acute myocardial infarction
Sleep Assessment Analysis
The effects of MAD therapy on sleep assessment characteristics are presented in Table 2. There was a significant decrease in AHI at 3 mo (22.9 ± 5.9 to 11.2 ± 4.9 events/h, p < 0.05) and at 1 y of MAD therapy (22.9 ± 5.9 to 9.7 ± 4.5 events/h, p < 0.001), when compared to baseline. AHI decreased ≥ 50% in 73% of patients whereas 53% and 27% of patients reached AHI < 10 and AHI < 5 events/h, respectively, after 1 y of MAD therapy. The sleep efficiency score based on polysomnographic data (9 of 15 patients, 60%) improved from 78.5 ± 17.3 % at baseline to 85.9 ± 10.5 % after 1 y of MAD therapy (p = 0.437). The self-reported compliance was 6.3 ± 1.5 h per night during the 1-y period. Thirteen of 15 patients (87%) were considered as regular users, using the MAD at least 4 h on more than 70% of the days of the week,19,36,37 whereas two patients (13%) were considered noncompliant.
3-month follow-up
2 patients withdrew from the study due to a broken tooth not associated with MAD usage
1-year follow-up
15 patients included in the follow-up analyses
Cognitive and Psychomotor Performance
The results of our study revealed differences in certain cognitive and psychomotor performances between the patients with OSA and the reference group subjects. TTST and MinT were prolonged for both, the simple (CRD 311) and complex (CRD 11 and CRD 411) tests at baseline. The total number of errors committed during testing was similar between patients with OSA and reference group subjects for complex tests (CRD 11 and CRD 411). Comparative analyses between the groups at baseline are shown in Table 3. The results of cognitive and psychomotor performance improvement following MAD therapy are presented in Table 4. In general, TTST and MinT were shorter for simple arithmetic (CRD 11) (TTST, p = 0.026 and MinT, p = 0.010) and light signal position discrimination (CRD 311) (TTST, p = 0.011 and MinT, p = 0.039) tests following MAD therapy. MinT values on complex motor coordination (CRD 411) test decreased significantly after 1 y of MAD therapy (p = 0.014), whereas TTST did not change significantly (p = 0.078). TE did not change
Eighteen patients passed the screening and were enrolled in the study. One patient withdrew before the 3-mo follow-up due to serious heart disease, and two patients withdrew before 1-y follow-up because of a broken tooth not associated with mandibular advancement device (MAD) usage. All of the remaining 15 patients completed the follow-up analyses. CRD, Complex Reactionmeter Drenovac.
desaturation index (ODI) were calculated using Pearson correlation coefficients. A value of p < 0.05 was considered statistically significant. R ES U LT S
Patient Baseline Characteristics
Eighteen patients from the OSA group who met the inclusion criteria were initially enrolled in the study. However, three patients subsequently withdrew before the follow-up visits due to Journal of Clinical Sleep Medicine, Vol. 12, No. 2, 2016
p 0.917 0.648 0.561 0.967 0.099
180
T Galic, J Bozic, R Pecotic et al. MAD and Cognitive/Psychomotor Performance in OSA
Table 2—Sleep characteristics of 15 patients with obstructive sleep apnea before and during mandibular advancement device therapy. Variables AHI (events/h) Mean SpO2 (%) Minimum SpO2 (%) ODI (events/h) Snoring time (min)
Baseline (n = 15) 22.9 ± 5.9 95.0 ± 1.7 83.6 ± 5.5 13.9 ± 6.8 225.8 ± 172.5
3 mo (n = 15) 11.2 ± 4.9 a 95.0 ± 1.1 86.0 ± 6.0 a 6.3 ± 3.9 a 143.0 ± 168.5 a
1 y (n = 15) 9.7 ± 4.5 b 95.0 ± 1.1 87.6 ± 6.2 b 7.8 ± 6.2 b 132.4 ± 139.4 b
p < 0.001 0.550 0.047 0.009 0.007
Data are presented as mean ± standard deviation. a p < 0.05, significant difference between baseline and 3 mo of treatment. b p < 0.05, significant difference between baseline and 12 mo of treatment. AHI, apnea-hypopnea index; ODI, oxygen desaturation index; SpO2, arterial oxygen saturation.
Table 3—Cognitive and psychomotor performance on Complex Reactionmeter Drenovac tests for patients with obstructive sleep apnea at baseline before mandibular advancement device therapy, and reference subjects. Test Light signal position discrimination (CRD 311)
Test Result MinT (s) TTST (s) TE
OSA Group (n = 15) 0.43 ± 0.06 36.72 ± 5.34 0
Reference Group (n = 15) 0.40 ± 0.06 33.65 ± 5.35 0
Simple arithmetic (CRD 11)
MinT (s) TTST (s) TE
2.64 ± 0.74 155.36 ± 60.82 3 (0–7)
2.29 ± 0.58 a 132.83 ± 32.94 a 3 (1–6)
Complex motor coordination (CRD 411)
MinT (s) TTST (s) TE
0.59 ± 0.18 47.87 ± 14.94 12 (0–34)
0.56 ± 0.13 45.95 ± 13.91 11 (1–29)
p 0.309 0.126 1.000 < 0.001 < 0.001 0.754 0.756 0.902 0.319
Data are presented as mean ± standard deviation. a p < 0.001, significant difference between patients with OSA and reference subjects. CRD, Complex Reactionmeter Drenovac; MinT, minimum single task solving time; OSA, obstructive sleep apnea; TE, total number of errors; TTST, total test solving time.
Table 4—Cognitive and psychomotor performance on Complex Reactionmeter Drenovac tests for patients with obstructive sleep apnea (n = 15) at baseline and after 3 mo and 1 y of mandibular advancement device therapy. Test Light signal position discrimination (CRD 311)
Test Result MinT (s) TTST(s) TE
Baseline 0.43 ± 0.06 36.72 ± 5.34 0
After 3 mo 0.42 ± 0.06 35.52 ± 4.25 0
After 1 y 0.41 ± 0.05 b 33.89 ± 4.55 b 0
p 0.039 0.011 1.000
Simple arithmetic (CRD 11)
MinT (s) TTST (s) TE
2.64 ± 0.74 155.36 ± 60.82 3 (0–7)
2.46 ± 0.65 148.98 ± 60.82 2 (0–14)
2.31 ± 0.48 b 137.09 ± 43.16 b 2 (0–7)
0.010 0.026 0.473
Complex motor coordination (CRD 411)
MinT (s) TTST (s) TE
0.59 ± 0.18 47.87 ± 14.94 12 (0–34)
0.54 ± 0.11 47.43 ± 19.42 11 (3–59)
0.51 ± 0.13 b 41.74 ± 19.57 12 (3–41)
0.014 0.078 0.935
Data are presented as mean ± standard deviation. b p < 0.05, significant difference between baseline and 12 mo of therapy. CRD, Complex Reactionmeter Drenovac; MAD, mandibular advancement device; MinT, minimum single task solving time; OSA, obstructive sleep apnea; TE, total number of errors; TTST, total test solving time.
Self-Reported Measures: Excessive Daytime Sleepiness and Quality of Life
significantly in any of the tests performed. There were no significant differences on the CRD-series tests after 3 mo of MAD therapy compared to baseline. Individual improvements after 1 y of MAD therapy in TTST and MinT for three CRD tests used in the study are shown in Figure 2 and Figure 3. There were no significant correlations between the improvement in cognitive and psychomotor performance with the changes in the ESS score, AHI, or ODI following MAD therapy (Table 5).
Excessive daytime sleepiness measured by the ESS score was reduced significantly, both at the 3-mo (9.9 ± 3.8 to 6.0 ± 3.2, p < 0.05) and the 1-y follow-up (9.9 ± 3.8 to 6.0 ± 2.8, p < 0.05) compared to the baseline. There was no further reduction between the 3-mo and 1-y measurements. Individual ESS scores after 1 y of MAD therapy are shown in Figure 4. Across the 181
Journal of Clinical Sleep Medicine, Vol. 12, No. 2, 2016
T Galic, J Bozic, R Pecotic et al. MAD and Cognitive/Psychomotor Performance in OSA
Figure 2—Individual minimum single task solving times (MinT) at baseline and after 1 y of mandibular advancement device therapy.
Figure 3—Individual total test solving times (TTST) at baseline and after 1 y of MAD therapy.
Apnea-hypopnea index-related responders (complete and partial) are presented with filled circles and nonresponders with empty squares.
Apnea-hypopnea index-related responders (complete and partial) are presented with filled circles and non-responders with empty squares.
whole study group, seven patients (47%) experienced excessive daytime sleepiness (ESS > 10) before the MAD therapy; in 86% of these patients, excessive daytime sleepiness was resolved. Results from the quality-of-life data showed significant improvement in social functioning, general health, and a single item on changes in patients’ health over the follow-up period, after 1 y of MAD therapy, compared to the pretreatment assessment (Table 6).
daytime sleepiness and improvement of social functioning, general health and well-being. Previous studies have evaluated the effectiveness of MAD therapy in patients with mild to moderate OSA and showed improvement of AHI, snoring time, and excessive daytime sleepiness.15,16,18,20,21 The current study also demonstrated reduction in AHI ≥ 50% in 73% of patients, whereas 53% and 27% of patients reached AHI < 10 and AHI < 5 events/h, respectively, after 1 y of MAD therapy, which is in accordance to the results of other authors.15,16,18,20,21,24,37,38 Still, an ongoing challenge for sleep physicians is to estimate the efficacy of MAD therapy not only in reduction of AHI but also the improvement of subjective symptoms and the quality of life in patients with OSA. Improvement following MAD therapy in patients with OSA was obvious in speed, accuracy, and mental endurance in the problem-solving strategy, particularly in the domain of perceptive abilities, convergent thinking (constructing and
D I SCUS S I O N The results of our study on the objective parameters of cognitive and psychomotor performance showed improvement after 1 y of MAD therapy in patients with mild to moderate OSA. In addition, the MAD therapy showed a reduction of excessive Journal of Clinical Sleep Medicine, Vol. 12, No. 2, 2016
182
T Galic, J Bozic, R Pecotic et al. MAD and Cognitive/Psychomotor Performance in OSA
Figure 4—Individual Epworth Sleepiness Scale (ESS) scores at baseline and after 1 y of mandibular advancement device therapy.
Table 5—Pearson correlation coefficients between changes in cognitive and psychomotor performance, Epworth Sleepiness Scale, apnea-hypopnea index, and oxygen desaturation index. r
ΔAHI
p
r
ΔODI
p
r
ΔESS
p
CRD 311 ΔTTST (s) ΔMinT (s)
0.219 0.431 0.468 0.127
−0.001 0.996 0.481 0.164
−0.139 0.621 −0.119 0.671
CRD 11 ΔTTST (s) ΔMinT (s)
−0.284 0.306 −0.248 0.374
−0.311 0.258 −0.127 0.652
0.159 0.569 0.281 0.310
CRD 411 ΔTTST (s) ΔMinT (s)
0.029 0.916 −0.183 0.515
−0.130 0.644 −0.364 0.182
−0.469 0.178 −0.028 0.921
Data are presented as mean ± standard deviation. CRD, complex reactionmeter Drenovac; MinT, minimum single task solving time; TTST, total test solving time.
Apnea-hypopnea index-related responders (complete and partial) are presented with filled circles and nonresponders with empty squares.
Table 6—Self-reported measures-excessive daytime sleepiness and quality of life for patients with obstructive sleep apnea at baseline and after 3 mo and 1 y of mandibular advancement device therapy. Excessive daytime sleepiness ESS score Quality of life scale SF-36 dimensions Physical functioning Role limitations physical Role limitations emotional Energy/vitality Emotional well-being Social functioning Pain General health perception Health change following MAD therapy Physical Component Summary score (PCS) Mental Component Summary score (MCS)
Before Therapy (n = 15)
After 3 mo (n = 15)
After 1 y (n = 15)
p
9.9 ± 3.8
6.0 ± 3.2 a
6.0 ± 2.8 b
0.002
78.7 ± 21.4 70.0 ± 41.4 84.4 ± 30.5 61.7 ± 16.2 72.8 ± 13.9 66.7 ± 25.7 68.7 ± 25.7 57.3 ± 16.8 48.3 ± 17.6 47.1 ± 8.6 48.9 ± 7.2
76.3 ± 21.2 76.7 ± 38.3 86.7 ± 30.3 62.0 ± 19.5 68.8 ± 17.9 78.3 ± 22.9 75.0 ± 28.2 61.3 ± 17.3 58.3 ± 15.4 49.1 ± 9.5 48.8 ± 8.2
78.8 ± 16.5 83.3 ± 36.2 84.4 ± 33.0 65.3 ± 15.2 70.1 ± 16.6 81.7 ± 17.6 b 75.2 ± 23.3 64.7 ± 17.8 b 65.0 ± 15.8 b 50.6 ± 6.9 49.6 ± 9.4
0.982 0.318 0.892 0.289 0.379 0.031 0.340 0.018 0.019 0.745 0.153
Data are presented as mean ± standard deviation. a p < 0.05, significant difference between baseline and 3 mo of treatment. b p < 0.05, significant difference between baseline and 12 mo of treatment. ESS score, Epworth Sleepiness Scale score; MAD, mandibular advancement device.
solving simple mathematical tasks), and psychomotor reactions. However, attention and alertness measured by the total number of errors did not differ in patients with OSA after MAD therapy, and in comparison with the reference group. The CRD 11, which served as a measure of speed in solving simple arithmetic operations, correlates with decisions in stress situations and general ability to perform in problematic situations.27 When compared to the reference group subjects, prior to the MAD therapy, patients with OSA in our study showed the significant impairment only on the CRD 11 test. Because suboptimal speed of reaction time, thinking, and responding could be associated with the increased risk for road traffic and occupational workplace accidents, this highlights the importance of early identification and treatment of patients with OSA.23 There were no significant differences on
other two tests, complex motor coordination (CRD 311) and light signal position discrimination (CRD 411), measuring the speed of perception of one critical signal in the working environment (CRD 311) and complexly coordinated actions of patients’ extremities (CRD 411),27,28 between patients with OSA and reference group subjects. However, in terms of the efficacy of MAD therapy on cognitive and psychomotor performance, there was significant improvement following MAD therapy on both of those tests. The improvements in task time as a descriptor of speed, accuracy, and mental endurance might be of clinical significance because the reaction time and psychomotor speed is crucial in driving performance and may reduce the risk for motor vehicle accidents.6 It could also be important in an effort to reduce workplace accidents that are associated with suboptimal speed of thinking and 183
Journal of Clinical Sleep Medicine, Vol. 12, No. 2, 2016
T Galic, J Bozic, R Pecotic et al. MAD and Cognitive/Psychomotor Performance in OSA
responding.23 Paradoxically, the total number of errors were not altered, as in the study of Karanovic et al.28 Many previous studies have shown that CPAP is superior to MAD in alleviating OSA symptoms.6,20–22 This could be a potential explanation why a longer period is needed for improvement of the neurocognitive function following MAD therapy. Phillips et al.6 reported comparable neurobehavioral improvement between CPAP and MAD, whereas the improvement of OSA symptoms was greater with CPAP than MAD after 1 mo. The authors further suggested that long-term studies with an objective assessment of compliance for both devices are needed to clarify how true night-to-night residual OSA affects health outcomes. Naismith et al.23 reported improvement on the choice reaction time task after 1 mo of MAD therapy, although there were no other significant treatment effects on neuropsychological performance. Barnes et al.22 reported improvement only in executive cognitive function following 3 mo of MAD therapy with no other treatment effects on neurocognitive function. As can be seen, the majority of data about neurocognitive improvements following OSA therapy are generated in shorter studies. Because effect sizes in neurocognitive research are typically small, the current study uses a longer time period in order to detect potential improvements in other domains of functioning and, importantly, to determine the clinical significance of MAD therapy in patients with OSA.23 Because this is, to our knowledge, the first use of CRD tests in patients with OSA and there were no well-established normative data for the cognitive and psychomotor tests used, it was difficult to compare our results with those from other studies. However, CRD tests have been in use for more than 40 y, resulting in a few original scientific studies.26,28–31,39–41 There are only a few psychological tests applicable for multiple retesting on the same subjects, because the object of measurement changes during the experiment. Many psychological tests that measure capabilities, if used for multiple retesting, become tests of knowledge, thus interindividual and intraindividual variabilities of the results of the measurement diminish.27,29 Numerous studies tried to provide evidence for pathophysiological mechanisms underlying neurocognitive impairment in patients with OSA that might be irreversible or reversible. In terms of irreversible mechanisms involved in impairment of neurocognitive performance some authors proposed that it may be attributed to reduced cell neurogenesis and density of the hippocampus, the frontal cortex, and generalized gray matter.9–11,42 On the contrary, Edwards et al.11 emphasized importance of nighttime cortisol levels as a significant predictor of neurocognitive performance in patients with OSA. Reversible pathophysiological mechanisms involved in neurocognitive impairment are differentially affected by the effects of poor sleep quality, sleep fragmentation, hypoxemia, and excessive daytime sleepiness.8–10,23,42 Results of the current study indicated that patients with mild to moderate OSA reportedly had excessive daytime sleepiness. The majority of our patients (86%) who reported excessive daytime sleepiness achieved resolution of the symptoms, indicating efficacy of MAD therapy in reduction of daytime sleepiness similar to other studies.6,22,23 We recognize that in our study MAD therapy significantly improved only subjective sleepiness measured by the Journal of Clinical Sleep Medicine, Vol. 12, No. 2, 2016
ESS, whereas in some previous studies, the authors used objective measures of sleepiness determined by the maintenance of wakefulness test.12,22,23,43 We did not find any correlations between improvement of neurocognitive function and AHI or ODI either; therefore, we could only speculate whether excessive daytime sleepiness or some other proposed mechanisms could be responsible for impairments of neurocognitive performance in patients with OSA in our study. Considering those differences, it is very difficult to anticipate improvements in all aspects of neurocognitive performance following OSA therapy as reported in the previous studies.6,12,17,22,23,43 The developers of the SF-36 encourage the comparison of scores with the normative data from general population samples, which provides a better understanding of the adverse effects of OSA.34 Baseline results from the physical and mental component summary scores (PCS and MCS, respectively) of the SF-36 in our study population indicate moderate deviation from the mean of general population scores, which is in accordance with previous studies.6,22,34 Unlike recent results showing an improvement in PCS and MCS following MAD therapy, our data did not show significant improvement in this area.6,22,34 In addition, Jenkinson et al.34 reported greater deviation from the normative data than in our study population, which may be related to the recruitment of patients with more severe OSA in their sample. However, the SF-36 scores of patients with OSA in our study indicated the effects of a reduced health state compared to the general population. Additionally, the SF-36 scores indicated considerable improvements in three domains, social functioning, general health perception, and considerable improvement of well-being, following MAD therapy, with the outcome scores being close to those of the general population. Results from the previous studies showed large variations of the quality-of-life improvement, highlighting the difficulty patients have in determining the severity of their subjective symptoms.33,34 It should be noted, however, that the SF-36 is a generic quality-of-life questionnaire and, thus, may be less responsive than a disease-specific instrument.43 For a qualityof-life questionnaire to be useful in clinical trials of OSA, it should have the capacity to differentiate varying degrees of the disease.33,34 There are a few limitations of this study. The sample size was relatively small; therefore, further treatment-based studies with a larger sample size are required in order to confirm our results. Still, to the authors’ best knowledge, this is the first prospective cohort long-term study that, unlike the previous placebo-controlled or CPAP-controlled studies, followed neurocognitive functions in MAD-treated patients with OSA for as long as 1 y, which was suggested by Phillips et al.6 Also, the subjects in our study group were acting as their own control subjects in this prospective cohort study with repeated measurements. There is no scientific evidence that patients with mild to moderate OSA can spontaneously recover from their disease without lowering BMI, introducing positional therapy, sleep hygiene measures, etc., which was not the case in our study. However, our results should be confirmed in long-term randomized controlled studies with larger sample size and different severity of OSA to further establish the beneficial effect of the MAD therapy on neurocognitive function.6 184
T Galic, J Bozic, R Pecotic et al. MAD and Cognitive/Psychomotor Performance in OSA
There were no well-established normative data for the cognitive and psychomotor tests used, but we have included the reference group in order to compare the results of our study group prior to the initiation of the therapy. Furthermore, the complex motor coordination test (CRD 411), measuring complex psychomotor coordination, shows the highest possibility of the individually different effect of learning on the psychomotor component of motor coordination between the extremities.27 The CRD-series is different from the standard set of instruments used in psychological practice and scientific research because the software includes a test generator intended for independent creation of an unlimited number of new CRD tests. Therefore, it is possible to use the test series for multiple retesting on the same subject without the possibility of memorizing the test.27,29 Learning in this study could not be attributed to memorizing, because the subjects were always assigned new variations of tests, but some adaptation might have occurred over the study period.31 In conclusion, this 1-y prospective cohort study indicated improvement of OSA symptoms, cognitive and psychomotor performance, and quality of life following MAD therapy in patients with mild to moderate OSA. Further long-term randomized controlled studies with larger sample size are needed to clarify precise mechanisms underlying neurocognitive improvement as a result of MAD therapy.
3. Jordan AS, McSharry DG, Malhorta A. Adult obstructive sleep apnoea. Lancet 2014;383:736–47. 4. McNicholas WT. Sleep-related breathing disorders: nosological classification, definitions, epidemiology. In: Bassetti C, Dogas Z, Peigneux P, eds. Sleep Medicine Textbook. Regensburg, Germany: European Sleep Research Society, 2014:215–20. 5. Karimi M, Eder DN, Eskandari D, Zou D, Hedner JA, Grote L. Impaired vigilance and increased accident rate in public transport operators is associated with sleep disorders. Accid Anal Prev 2013;51:208–14. 6. Phillips CL, Grunstein RR, Darendeliler MA, et al. Health outcomes of continuous positive airway pressure versus oral appliance treatment for obstructive sleep apnea. Am J Resp Crit Care Med 2013;187:879–87. 7. Pepin JL, Borel JC, Borel AL, Levy P, Tamisier R. Sleep-related breathing disorders: comorbidities and special populations. In: Bassetti C, Dogas Z, Peigneux P, eds. Sleep Medicine Textbook. Regensburg, Germany: European Sleep Research Society, 2014:251–8. 8. Quan SF, Chan CS, Dement WC, et al. The association between obstructive sleep apnea and neurocognitive performance-the Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep 2011;34:303–14. 9. Beebe DW, Groesz L, Wells C, Nichols A, McGee K. The neuropsychological effects of obstructive sleep apnea: a meta-analysis of norm-referenced and case-controlled data. Sleep 2003;26:298–307. 10. Bucks RS, Olaithe M, Eastwood P. Neurocognitive function in obstructive sleep apnoea: a meta-review. Respirology 2013;18:61–70. 11. Edwards KM, Kamat R, Tomfhor LM, Ancoli-Israel S, Dimsdale JE. Obstructive sleep apnea and neurocognitive performance: the role of cortisol. Sleep Med 2014;15:27–32. 12. Kushida CA, Nichols DA, Holmes TH, et al. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: the Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep 2012;35:1593–602. 13. Kushida CA, Littner MR, Morgenthaler T, et al. Practice parameters for the indications for polysomnography and related procedures: an update for 2005. Sleep 2005;28:449–521. 14. Pevernagie D, Sastry M, Vanderveken OM. Sleep-related breathing disorders: treatment of respiratory sleep disorders. In: Bassetti C, Dogas Z, Peigneux P, eds. Sleep Medicine Textbook. Regensburg, Germany: European Sleep Research Society, 2014:259–74. 15. Sutherland K, Vanderveken OM, Tsuda H, et al. Oral appliance treatment for obstructive sleep apnea: an update. J Clin Sleep Med 2014;10:215–27. 16. Almeida FR, Lowe AA. Principles of oral appliance therapy for the management of snoring and sleep disordered breathing. Oral Maxillofac Sur Clin North Am 2009;21:413–20. 17. Tegelberg A, Wilhelmsson B, Erixon-Lindroth N, Lindström LH. Improved cognitive functions after treatment with an oral appliance in obstructive sleep apnea. Nat Sci Sleep 2012;4:89–96. 18. Ferguson KA, Cartwright R, Rogers R, Schmidt-Nowara W. Oral appliances for snoring and obstructive sleep apnea: a review. Sleep 2006;29:244–62. 19. Tsuiki S, Kobayashi M, Namba K, et al. Optimal positive airway pressure predicts oral appliance response to sleep apnoea. Eur Respir J 2010;35:1098–105. 20. Almeida FR, Henrich N, Marra C, et al. Patients preferences and experiences of CPAP and oral appliances for the treatment of obstructive sleep apnea: a qualitative analysis. Sleep Breath 2013;17:659–66. 21. Holley AB, Lettieri CJ, Shah AA. Efficacy of an adjustable oral appliance and comparison with continuous positive airway pressure for the treatment of obstructive sleep apnea syndrome. Chest 2011;140:1511–6. 22. Barnes M, McEvoy DR, Banks S, et al. Efficacy of positive airway pressure and oral appliance in mild to moderate obstructive sleep apnea. Am J Resp Crit Care Med 2004;170:656–64. 23. Naismith SL, Winter VR, Hickie IB, Cistulli PA. Effect of oral appliance therapy on neurobehavioral functioning in obstructive sleep apnea: a randomized controlled trial. J Clin Sleep Med 2005;1:374–80. 24. Pecotic R, Dodig IP, Valic M, Ivkovic N, Dogas Z. The evaluation of the Croatian version of the Epworth sleepiness scale and STOP questionnaire as screening tools for obstructive sleep apnea syndrome. Sleep Breath 2012;16:793–802.
A B B R E V I AT I O N S AASM, American Academy of Sleep Medicine AHI, apnea-hypopnea index BMI, body mass index CPAP, continuous positive airway pressure CRD, Complex Reactionmeter Drenovac ESRS, European Sleep Research Society ESS, Epworth Sleepiness Scale MAD, mandibular advancement device MCS, Mental Component Summary score MinT, minimal single task solving time OA, oral appliance ODI, oxygen desaturation index OSA, obstructive sleep apnea PCS, Physical Component Summary score SF-36, 36-Item Short Form Health Survey SpO2 , arterial oxygen saturation STOP, Snoring, Tiredness, Observed Apnea, High Blood Pressure TE, total number of errors committed during the test TTST, total test solving time R E FE R E N CES 1. The Report of an American Academy of Sleep Medicine Task Force. Sleeprelated breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. Sleep 1999;22:667–89. 2. Fischer J, Dogas Z, Bassetti CL, et al. Standard procedures for adults in accredited sleep medicine centres in Europe. J Sleep Res 2012;21:357–68.
185
Journal of Clinical Sleep Medicine, Vol. 12, No. 2, 2016
T Galic, J Bozic, R Pecotic et al. MAD and Cognitive/Psychomotor Performance in OSA 25. Itzhaki S, Dorchin H, Clark G, Lavie L, Lavie P, Pillar G. The effects of 1-year treatment with a Herbst mandibular advancement splint on obstructive sleep apnea, oxidative stress, and endothelial function. Chest 2007;131:740–9. 26. Petri NM, Dropulic N, Kardum G. Effects of voluntary fluid intake deprivation on mental and psychomotor performance. Croat Med J 2006;47:855–61. 27. Drenovac M. CRD-series of psychodiagnostic tests [in Croatian]. Zagreb, Croatia, AKD 1994. 28. Karanovic N, Carev M, Kardum G, et al. The impact of a single 24h working day on cognitive and psychomotor performance in staff anaesthesiologists. Eur J Anaesthesiol 2009;26:825–32. 29. Drenovac M. An analysis of some attributes of the dynamics of mental processing. Rev Psychol 2001;8:61–7. 30. Drenovac M, Petri NM. Research of effect of hyperbaric pressure on dynamics and efficiency of complex mental processing. 36th IAMPS, Split, Croatia 2000:80–9. 31. Petri NM. Change in strategy of solving psychological tests: evidence of nitrogen narcosis in shallow air-diving. Undersea Hyperb Med 2003;30:293– 303. 32. Johns MW. Daytime sleepiness, snoring, and obstructive sleep apnea. The Epworth Sleepiness Scale. Chest 1993;103:30–6. 33. Jenkinson C, Coulter A, Wright L. Short form 36 (SF-36) health survey questionnaire: normative data for adults of working age. Br Med J 1993;306:1437–40. 34. Jenkinson C, Stradling J, Petersen S. Comparison of three measures of quality of life outcome in the evaluation of continuous positive airway pressure therapy for sleep apnoea. J Sleep Res 1997;6:199–204. 35. Wright L, Harwood D, Coulter A. Health and lifestyles in the Oxford region. Oxford, UK: Health Services Research Unit, University of Oxford, 1992. 36. Vanderveken OM, Dieltjens M, Wouters K, De Backer W, Van de Heyning PH, Braem MJ. Objective measurement of compliance during oral appliance therapy for sleep-disordered breathing. Thorax 2013;68:91–6. 37. Dieltjens M, Bream MJ, Vroeqop AV, et al. Objectively measured vs selfreported compliance during oral appliance therapy for sleep-disordered breathing. Chest 2013;144:1495–502. 38. Galic T, Bozic J, Ivkovic N, Kurir Ticinovic T, Dogas Z. Effects of mandibular advancement device treatment on arterial stiffness and glucose metabolism in patients with mild to moderate obstructive sleep apnea: a prospective 1 year study. Sleep Breath 2015 May 1. [Epub ahead of print]. 39. Kajtna T, Vuleta D, Pori M, Juskin I, Pori P. Psychological characteristics of Slovene handball goalkeepers. Kinesiology 2012;2:209–17. 40. Malacko J, Doder D, Vujanovic S. The differences in the movement structures of kata, fights and mental potentials between boys and girls who train karate. Acta Kinesiologica 2010;2:28–32.
Journal of Clinical Sleep Medicine, Vol. 12, No. 2, 2016
41. Petranovic D, Taksic V, Dobrila-Dintinjana et al. Correlation of anaemia and cognitive functions measured by the complex reactionmeter Drenovac. Coll Antropol 2008;32:47–51. 42. Naismith D, Winter V, Gotsopoulos H, Hichie I, Cistulli P. Neurobehavioral functioning in obstructive sleep apnea: differential effects of sleep quality, hypoxemia and subjective sleepiness. J Clin Exp Neuropsychol 2004;26:43–54. 43. Antic NA, Catcheside P, Buchan C, et al. The effect of CPAP in normalizing daytime sleepiness, quality of life, and neurocognitive function in patients with moderate to severe OSA. Sleep 2011;34:111–9.
ACK N O W L E D G M E N T S The authors thank Jelena Baricevic for her technical assistance; Ivan Galic, DMD and Mijo Mario Vuletic, CDT for their assistance during dental examinations of patients and fabricating oral appliances. The authors also thank Darlene Garalde Intlekofer, MS, The City University of New York, New York, NY for the extensive grammar corrections. Author contributions: Dr. Galic - study design, data collection, data analysis, manuscript draft; Dr. Bozic - data analysis, manuscript draft; Ms. Ivkovic - data collection, data analysis; Dr. Pecotic - data collection, data analysis, manuscript draft; Dr. Valic - data collection, data analysis, manuscript draft; Dr. Dogas - study design, data collection, data analysis, manuscript draft.
SUBM I SSI O N & CO R R ESPO NDENCE I NFO R M ATI O N Submitted for publication February, 2015 Submitted in final revised form June, 2015 Accepted for publication July, 2015 Address correspondence to: Professor Zoran Dogas, MD, PhD, Department of Neuroscience, University of Split School of Medicine, Soltanska 2, 21000, Split, Croatia; Tel.: +385 21 557 905; Fax: +385 21 557 955; Email: [email protected]
D I SCLO S U R E S TAT E M E N T This work has been supported by the Croatian Science Foundation grant #201311-5935. The manufacturers of oral appliances and the measuring equipment had no access to or control over the study design, data collection, data analysis, data interpretation, or writing of the manuscript. This study was performed at the University of Split School of Medicine, Split, Croatia. The authors have indicated no financial conflicts of interest.
186
