Abstract
Study Objectives:
Several studies have reported an association between obstructive sleep apnea (OSA) and neuro-otologic diseases, such as Ménière’s disease or sudden sensorineural hearing loss (SSNHL). However, the exact relationship between OSA and those diseases has not been fully evaluated. Therefore, the aim of this study was to investigate the prospective link between OSA and Ménière’s disease or SSNHL.
Methods:
We used a nationwide cohort sample of data for 2002–2013 representing approximately 1 million patients. The OSA group (n = 942) included patients diagnosed between 2004 and 2006; the comparison group was selected using propensity score matching (n = 3,768). We investigated Ménière’s disease and SSNHL events over a 9-year follow-up period. Survival analysis, log-rank test, and Cox proportional hazards regression models were used to calculate incidence, survival rate, and hazard ratios for each group.
Results:
In the OSA group, the incidences of Ménière’s disease and SSNHL were 7,854.4 and 7,876.3 person-years, respectively. Cox proportional hazards analysis revealed no overall association between patients with OSA and the risk of subsequent Ménière’s disease or SSNHL. In a subgroup analysis, female and middle-aged patients with OSA were independently associated with a two-fold higher incidence of subsequent Ménière’s disease, compared to those without OSA. However, we could not find any significant association between patients with OSA and SSNHL even in the subgroup analysis.
Conclusions:
Our findings suggest that female or middle-aged patients with OSA are associated with an increased incidence of Ménière’s disease. However, there was no association between OSA and SSNHL.
Citation:
Kim J-Y, Ko I, Cho B-J, Kim D-K. Association of obstructive sleep apnea with the risk of Ménière's disease and sudden sensorineural hearing loss: a study using data from the Korean National Health Insurance Service. J Clin Sleep Med. 2019;15(9):1293–1301.
Keywords: sleep, obstructive sleep apnea, otology, Ménière’s disease, sudden sensorineural hearing loss
BRIEF SUMMARY
Current Knowledge/Study Rationale: Although obstructive sleep apnea (OSA) is known to contribute to serious systemic problems, such as cardiovascular events or neurocognitive deterioration, its association with the development of neuro-otologic diseases has not been fully determined. This study aimed to investigate the link between OSA and subsequent neuro-otologic diseases, such as Ménière’s disease or sudden sensorineural hearing loss (SSNHL) using a nationwide representative cohort sample.
Study Impact: Female as well as middle-aged patients with OSA were found to have a two-fold risk to develop Ménière’s disease; however, we did not discover any link between OSA and SSNHL. Further studies are needed to confirm these findings and to explore the underlying pathophysiological mechanisms.
INTRODUCTION
Obstructive sleep apnea (OSA) is a very common disorder in middle-aged adults, affecting 24% of men and 9% of women.1 It is characterized by repetitive episodes of apnea and/or hypopnea and various degrees of hypoxia caused by upper airway collapse during sleep. This may cause potentially serious consequences, including excessive daytime sleepiness, neurocognitive deterioration, and cardiovascular diseases.2–4 In addition, psychiatric comorbidities have been frequently reported in patients with OSA. The quality of life in these patients is adversely affected by those comorbidities because they lower the adherence to continuous positive airway pressure (CPAP) therapy.5–7
Recently, there has been an increase in reports of OSA comorbidity with neuro-otologic diseases, such as Ménière’s disease or sudden sensorineural hearing loss (SSNHL).8–13 Although the role of OSA in the etiology of neuro-otologic diseases remains controversial, it is clear that dizziness and/or auditory symptoms such as tinnitus disturb the sleep of the affected patients. Clinicians may also have experienced patients who say their dizziness and/or hearing symptoms are less noticeable when they sleep well. One prospective study found in patients with Ménière’s disease a low frequency of deep sleep stages and an elevated arousal index.8 Another prospective study demonstrated that CPAP therapy for OSA patients with Ménière’s disease is beneficial in the management of their vestibular and auditory symptoms.9 In addition, one national cohort study using the Taiwan National Health Insurance Database described that male patients with SSNHL had a higher proportion of prior OSA than individuals in a control group without SSNHL.10 However, whether OSA affects neuro-otologic diseases, such as Ménière’s disease or SSNHL, is still unclear.
To further investigate the relationship between OSA and neuro-otologic diseases, such as Ménière’s disease or SSNHL, we examined the association between OSA and the prospective risk of Ménière’s disease or SSNHL, using a representative sample from the National Sample Cohort 2002 to 2013 data provided by the Korean National Health Insurance Service in South Korea. This nationwide population-based dataset allowed us to trace the entire medical service utilization history of more than 1 million South Koreans and provided a unique opportunity to examine the association between OSA and the risk of Ménière’s disease or SSNHL while adjusting for clinical and demographic factors.
METHODS
Korean National Health Insurance Service
The Korean National Health Insurance Service (KNHIS) has provided mandatory health coverage to the South Korean population since 1989. A unique identification number assigned to each South Korean resident at birth prevents omission or duplication of health care data. With the integration of Medical Aid data into the KNHIS database in 2006, this database comprises the entire population of South Korea. Therefore, usage of the KNHIS database eliminates selection bias. The KNHIS database includes nearly all medical data, including the diagnostic codes according to the Korean Classification of Diseases, which are similar to those of the International Classification of Diseases.
National Sample Cohort
The present study utilized a representative sample of 1,025,340 adults from the 2002–2013 KNHIS–National Sample Cohort (NSC) in South Korea (NHIS-2018-2-258).14 This dataset accounted for approximately 2.2% of the South Korean population in 2002. Stratified random sampling was performed using 1,476 strata by age (18 groups), sex (2 groups), and income level (41 groups: 40 health insurance groups and 1 medical aid beneficiary) among the South Korean population of 46 million in 2002. Additionally, the KNHIS–NSC contains data from all health services, including hospital visits (inpatient and outpatient), medical procedures, drug prescriptions, hospital diagnoses, and demographic information (including sex, age, household income, and mortality) during the study period of 2002–2013. To date, numerous previous studies have been published using these data.15–20
Study Setting
This study was approved by the Institutional Review Board of Hallym Medical University Chuncheon Sacred Hospital (IRB No. 2016-05-052), and the need for written informed consent was waived because the KNHIS-NSC dataset consisted of de-identified secondary data for research purposes. The OSA group included all patients who received inpatient or outpatient care for an initial diagnosis of OSA between January 2004 and December 2006. To remove any potential pre-existing cases of Ménière’s disease or SSNHL, we established a washout period in the first two years (2002–2003). To further improve the accuracy of the OSA diagnosis, we defined OSA as follows: patients diagnosed with OSA more than three times between 2004 and 2006, who also underwent a sleep study. Patient records were excluded if the patients (1) were diagnosed with Ménière’s disease or SSNHL between 2002 and 2006; (2) died as a result of any cause between 2002 and 2006 or as a result of an accident after 2007; (3) were diagnosed with OSA prior to 2004; or (4) were under 18 years of age. The comparison group (four patients for every patient with OSA) was selected using propensity score matching according to age, sex, residential area, household income, and comorbidities. Additionally, we only included records in the comparison group if they satisfied all of the following conditions: (1) There was no diagnosis of snoring or sleep apnea; and (2) no sleep study was performed. Finally, records from 942 eligible patients with OSA and 3,768 patients in the comparison group were enrolled in this study.
Predictor and Outcome Variables
We only considered records with a diagnosis of Ménière’s disease or SSNHL from this dataset if they satisfied all of the following conditions: (1) the patient was diagnosed under KCD codes H81.0 (Ménière’s disease) or H91.2 (SSNHL); and (2) the patient underwent pure-tone audiometry more than three times. Table 1 presents the patient characteristics including sex, age, residence, household income, disability, and comorbidities. The study population was divided into three age groups (< 45, 45–64, > 64 years), three income groups (low: ≤ 30%, middle: 30.1–69.9%, and high: ≥ 70% of the median), and three residential areas (first area: Seoul, the largest metropolitan region in South Korea; second area: other metropolitan cities in South Korea; and third area: small cities and rural areas). The study endpoints were the death of the participant or the incidence of Ménière’s disease or SSNHL. All patients who had no events and who were alive until December 31, 2013 were tabulated after this time point. The risks of Ménière’s disease or SSNHL for the OSA and the comparison groups were compared using person-years at risk, which were defined as the duration between either the date of OSA diagnosis or January 1, 2004 (for the comparison group), and the patient’s respective endpoint. Disability and traditional risk factors, including hypertension, diabetes mellitus, and chronic kidney disease, were obtained using KCD codes. Disability and those comorbidities were defined as a diagnosis of any of these conditions in the period 2002–2006 and prior to the diagnosis of OSA.
Table 1.
Characteristics of the patients investigated in the study.
Statistical Analysis
Incidence rates per 1,000 person-years for Ménière’s disease or SSNHL were obtained by dividing the number of patients with incidents of specific diseases by person-years at risk. The overall specific disease-free survival rates were determined using Kaplan–Meier survival curves for the observation period. To identify whether OSA increased the risk of occurrence of specific diseases, we used Cox proportional hazard regression analyses to calculate the hazard ratio (HR) and 95% confidence interval (CI), adjusted for the other predictor variables. All statistical analyses were performed using R version 3.5.0 (R Foundation for Statistical Computing, Vienna, Austria), using a significance level of .05.
RESULTS
The present study comprised records from 942 patients with OSA and 3,768 comparison individuals (non-OSA). A total of 7,854.4 and 7,876.3 person-years in the OSA group and 31,475.3 and 31,554.1 person-years in the comparison group were evaluated for Ménière’s disease or SSNHL events, respectively. The characteristics of the study populations for the two cohorts (the OSA group and the comparison group) are presented in Table 1. There were similar distributions of sex, age, residential area, household income, disability, and comorbidities between the two groups because each variable was matched appropriately (Table 1). In this study, we used univariate and multiple Cox regression models to analyze the HRs for the development of Ménière’s disease or SSNHL during the 9-year follow-up period. In addition, Kaplan–Meier survival curves with log-rank tests for the 9-year follow-up period are presented in Figure 1, Figure 2, and Figure 3. The overall incidences of Ménière’s disease were not significantly different between the OSA group (3.56 per 1,000 person-years) and the comparison group (2.45 per 1,000 person-years), with an adjusted HR of 1.47 (95% CI 0.96–2.27) (Table 2). Additionally, we found that there was no significant difference in the overall SSNHL incidence between the OSA group (1.40 per 1,000 person-years) and the comparison group (1.14 per 1,000 person-years), with an adjusted HR of 1.22 (95% CI 0.62–2.40) (Table 3).
Figure 1. Development of Ménière’s disease and sudden sensorineural hearing loss in the OSA and comparison groups.
CI = confidence interval, HR = hazard ratio.
Figure 2. Development of Ménière’s disease and sudden sensorineural hearing loss according to patient sex.
(A) Male. (B) Female. CI = confidence interval, HR = hazard ratio.
Figure 3. Development of Ménière’s disease and sudden sensorineural hearing loss according to patient age.
(A) < 45 years. (B) 45 to 64 years. (C) > 64 years. CI = confidence interval, HR = hazard ratio.
Table 2.
Incidence and hazard ratio of Ménière’s disease during the 9-year follow-up period.
Table 3.
Incidence and hazard ratio of sudden sensorineural hearing loss 9-year follow-up period.
Interestingly, the subgroup analysis revealed in the female OSA group a significantly higher incidence of Ménière’s disease than that in the female comparison group (Table 4). The overall incidence of Ménière’s disease in the female OSA group was 6.13 per 1,000 person-years, which was higher than the incidence observed in the comparison group (2.45 per 1,000 person-years). After adjusting for sociodemographic factors (age, residential area, and household income), disability, and comorbidities, the adjusted HR for developing Ménière’s disease among females with OSA during the 9-year follow-up period was 2.32 (95% CI 1.30–4.13). This means that female patients with OSA had an approximately two-fold higher incidence of Ménière’s disease than male patients with OSA. However, in the male population, there was no significant difference in the overall incidences of Ménière’s disease between the OSA and the comparison group. Moreover, when we calculated the HRs for the development of Ménière’s disease during the 9-year follow-up period according to the age, we observed that the prospective development of Ménière’s disease was only significantly related to OSA in the group of middle-aged patients (45–64 years; adjusted HR 2.02, 95% CI 1.09–3.76) (Table 5). We also calculated HR for the development of SSNHL during the 9-year follow-up period according to sex and age. However, we could not find any significant differences in the subsequent development of SSNHL between the OSA group and the comparison group (Table 4 and Table 5).
Table 4.
Inner ear functions by sex among the sample patients.
Table 5.
Hazard ratios of inner ear functions by age among the sample patients.
DISCUSSION
In the present longitudinal study, we examined the association between neuro-otologic diseases, such as Ménière’s disease or SSNHL among sociodemographically matched individuals extracted from a nationwide 9-year longitudinal cohort database of 1,025,340 South Korean patients. We observed no overall association between OSA and an increased incidence of Ménière’s disease or SSNHL. Although 9 years may not be a long enough period to develop Ménière’s disease or SSNHL, we found that female as well as middle-aged patients with OSA were associated with a higher risk of developing Ménière’s disease compared to those without OSA. Specifically, our findings revealed an approximately two-fold higher incidence of Ménière’s disease in female or middle-aged patients with OSA compared to that in participants without OSA after adjusting for sociodemographic characteristics, disability, and comorbidities of the patients.
Ménière’s disease is a disorder of the inner ear that is also known as idiopathic endolymphatic hydrops but its etiology remains unknown.21 This condition is characterized by sudden episodes of extreme dizziness (vertigo), a roaring, buzzing, or other sounds sound in the ears (tinnitus), a feeling of pressure or fullness in the ears, and fluctuations in hearing. Episodes are often associated with nausea and vomiting, and they can severely disrupt activities of daily living. To date, the possibility that OSA might affect Ménière’s disease remains controversial. However, several reports suggest an effect of sleep deprivation on the vestibular function.22–24 One study describes that patients with OSA had a higher rate of abnormalities on vestibular function tests, including caloric tests, saccadic eye movement latency, and smooth-pursuit movements.22 Other studies also report a higher rate of nystagmus, canal paresis, and a significant decay of vestibulo-ocular reflex gain in patients with moderate-to-severe OSA.23,24 Moreover, a recent nationwide population-based study in Taiwan shows that sleep apnea is significantly associated with a higher incidence of vertigo (adjusted HR 1.71, 95% C: 1.48–1.97).25 However, that study included various diseases causing vertigo and had a relatively short observation period of 5.99 years. In addition, we suggest that vascular problems may be another potential mechanism for the development of Ménière’s disease in OSA patients. Several studies described that vascular events could modify inner-ear homeostasis and trigger Ménière’s disease.26–28 Interestingly, one recent study showed that oxidative stress is involved in the degeneration of the blood labyrinthine barrier in Ménière’s disease.29 This report supports our vascular hypothesis, because it is well-known that the blood labyrinthine barrier is critical in the maintenance of inner-ear homeostasis and the intermittent hypoxic events in OSA increase oxidative stress.
The present study is the first to investigate the risk of Ménière’s disease in patients with OSA using a relatively long follow-up period (9 years) and a large population-based national database. In the subgroup analyses for sex and age, we found that among females with OSA, the adjusted HR for Ménière’s disease was 2.32 (95% CI 1.30–4.13). Additionally, only the group of patients aged 45–64 years exhibited a significant relationship between Ménière’s disease and OSA, with an adjusted HR of 2.02 (95% CI 1.09–3.76). Consistent with the results of our study, a previous prospective study found that OSA was found in approximately 15% and periodic limb movement disease in 9% of patients with Ménière’s disease.8 Moreover, another study reported that the results of audiometric tests and the dizziness handicap inventory were significantly improved in Ménière’s disease patients after CPAP therapy.9 However, it remains unclear why only female and middle-aged patients exhibit a significantly increased risk of Ménière’s disease. A United States epidemiological study demonstrated that Ménière’s disease is roughly equally distributed between the age of 40 and 80 years with a peak at an age of 60 years.30 A United Kingdom population-based study revealed a similar mean age of 55.4 ± 13.7 years at the time of Ménière’s disease diagnosis31 Additionally, those epidemiological studies show a slightly higher prevalence in females than in males.30,31 Thus, we consider the neuro-otologic organs of female and middle-aged patients as more vulnerable to hypoxia.
SSNHL is characterized by sudden-onset sensorineural hearing loss of at least 30 dB in three sequential frequencies over 3 days or less.32 Although it has a high spontaneous recovery rate (32% to 65%), the possible causes and the pathogenesis of SSNHL remain unknown. For this reason, SSNHL continues to be one of the most controversial and challenging issues in the field of neuro-otology. Previously, some studies described the association between sleep-related problems and SSNHL. One study, revealing that male but not female patients with SSNHL were more likely to have prior OSA than controls, demands further thought and study.10 Additionally, a significantly decreased expression of several circadian clock genes was found in patients with SSNHL.33 However, in the present study, we observed no significant difference in the overall incidence of SSNHL between the OSA group and the comparison group, with an adjusted HR of 1.22 (95% CI 0.62–2.40). Even in the subgroup analyses for sex and age, we did not detect any significant relationship between SSNHL and OSA. Consistent with our findings, another study also showed no significant difference in SSNHL prevalence between OSA and control groups.34 However, 9 years may not be a long enough period to develop SSNHL in terms of vascular problem. Thus, if the cohort period was longer, a meaningful correlation may be found between OSA and SSNHL.
Our study has several strengths. First, this was a cohort study that utilized a nationwide population-based dataset, which enabled us to effectively analyze all events for Ménière’s disease or SSNHL. Second, our cohort had a relatively long follow-up period. Third, to improve diagnostic accuracy, we defined OSA as having at least three OSA diagnostic codes. Finally, a prior study validating the KNHIS–NSC data found similar prevalence of 20 major diseases in each year;therefore, the reliability of the KNHIS–NSC data used in the present study was defined as fair to good.35 However, the present study has some notable limitations. We were unable to access other specific health data, including body mass index, lipid profiles, and information regarding behavioral risk factors such as smoking or alcohol consumption. Therefore, these possibly confounding factors could not be controlled in this study. Moreover, this database does not provide information from medical charts or polysomnography data. Thus, we could not determine OSA severity or self-reported excessive daytime sleepiness as assessed with measures such as the Epworth Sleepiness Scale. In addition, it is possible that some patients with OSA may have been included in the comparison group because polysomnography was not performed on this group. Furthermore, positive airway pressure or oral appliances used as a treatment for OSA are not covered under KNHIS, so this information was unavailable in the dataset used. Finally, because this was a retrospective cohort study, we could not directly examine and analyze the mechanisms underlying the relationship between OSA and Ménière’s disease or SSNHL. Future clinical studies investigating a wider range of factors, diagnostic criteria, and disease severity can provide additional evidence for the link between OSA and Ménière’s disease or SSNHL.
In conclusion, the present study investigated a possible link between OSA and the development of Ménière’s disease or SSNHL during a 9-year follow-up period. We found that female or middle-aged patients with OSA had a higher risk of Ménière’s disease, but not SSNHL. Therefore, this study provides new insights into the effects of OSA on neuro-otologic disorders.
DISCLOSURE STATEMENT
All authors have read and approved the manuscript. This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT; NRF-2017M3A9E8033231) and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number HI17C2412). The funding source had no role in the design and conduct of this study and did not influence the analyses, interpretation of the data, or decision to submit the results. The authors report no conflicts of interest.
ABBREVIATIONS
- CI
confidence interval
- CPAP
continuous positive airway pressure
- HR
hazard ratio
- KNHIS
Korean National Health Insurance Service
- NSC
National Sample Cohort
- OSA
obstructive sleep apnea
- SSNHL
sudden sensorineural hearing loss
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