Purpose
To determine whether there is a significant correlation among the peripapillary retinal nerve fiber layer (RNFL) thickness, foveal thickness, total macular volume, and severity of obstructive sleep apnea syndrome.
Design
Prospective study.
Methods
We studied 124 consecutive subjects who underwent polysomnography. Optical coherence tomography (OCT) was used to measure the peripapillary RNFL, foveal thickness, and total macular volume. The Pearson correlation coefficient was used to determine the relationship between the apnea-hypopnea index and OCT and other parameters. Multiple regression analysis was used to determine the independent factors for the RNFL sectors that were the most strongly correlated with the apnea-hypopnea index.
Results
The apnea-hypopnea index was significantly and negatively correlated (right eye, r = −0.31, P = 0.0004; left eye, r = −0.39, P < 0.0001) with the nasal RNFL thickness (Pearson correlation analysis). The foveal thickness and total macular volume were not correlated. The intraocular pressure, body mass index, plaque score, and incidence of hypertension were negatively correlated, and the lowest oxygen saturation and mean oxygen saturation were positively correlated with the nasal RNFL thickness in the left eye. Multiple regression analysis showed that the apnea-hypopnea index and age were independent contributors to the nasal RNFL thickness in the left eye (apnea-hypopnea index, standard regression coefficient, −0.30, t value, −2.76, P = 0.007; age, −0.24, −2.36, 0.02, respectively). The nasal RNFL thickness in both eyes decreased significantly based on the severity of the obstructive sleep apnea syndrome.
Conclusion
Exacerbation of obstructive sleep apnea syndrome may produce unique retinal neurodegenerative disorders that decrease the nasal RNFL thickness.
The association of arteriosclerotic diseases with obstructive sleep apnea syndrome has been identified recently and may be a possible risk factor for macroangiopathies, such as hypertension, coronary artery disease, and cerebrovascular disease or microangiopathic disorders such as renal disease.
In ophthalmology, obstructive sleep apnea syndrome is associated with glaucoma and optic neuropathy. Previous studies have reported that patients with obstructive sleep apnea syndrome had a high incidence of glaucoma. However, the prevalence of glaucoma in patients with obstructive sleep apnea syndrome was similar to that in the general Caucasian population. Optic neuropathy associated with glaucoma is characterized by decreased retinal nerve fiber layer (RNFL) thickness. Early detection of decreased RFNL thickness offers an opportunity to detect glaucoma in its early stages. It has also been reported that patients with glaucoma can lose 40% of retinal ganglion cell axons before a measurable visual defect becomes evident. Optical coherence tomography (OCT), a noninvasive imaging technique, provides reproducible, high-resolution, cross-sectional imaging of the RNFL. OCT is used for diagnosis and follow-up of various ophthalmologic disorders, including glaucoma. Previous studies have found that the RNFL thickness levels in patients with obstructive sleep apnea syndrome decreased compared with control subjects. However, it remains unclear whether the severity of obstructive sleep apnea syndrome is related to the RNFL thickness. The purpose of the current study was to determine whether there is a significant correlation between the RNFL thickness of the optic nerve head, the foveal thickness, and the total macular volume as determined by Stratus OCT (Carl Zeiss Meditec, Dublin, CA) and the severity of obstructive sleep apnea syndrome in Japanese patients. We also compared the carotid arteriosclerotic parameters obtained from high-resolution B-mode ultrasonography and serum arteriosclerotic risk factors.
Methods
The institutional review board of Toho University Sakura Medical Center approved the current study. Design of this study was prospective, and all participants provided informed consent according to the Declaration of Helsinki. We studied 147 consecutive patients who underwent standard overnight polysomnography at the Department of Cardiovascular Center of Toho University Sakura Medical Center between April 1, 2007, and March 1, 2010.
Sleep Study
Patients underwent polysomnography performed over a minimum of 6 hours in a quiet private room in our hospital. Electroencephalography, submental electromyography, electro-oculography, nasal and oral airflow measured using thermistors, and pulse oximetry measurements were recorded using a standard technique. The apnea-hypopnea index (times/hour) was calculated and used as an indicator of the severity of obstructive sleep apnea syndrome. An apneic event was defined as cessation of airflow for at least 10 seconds with effort to breathe. A hypoapneic event was defined as a minimal 30% reduction in thoracoabdominal movement or airflow compared with baseline lasting at least 10 seconds with 4% or greater oxygen desaturation. The severity of obstructive sleep apnea syndrome was graded according to the following apnea-hypopnea index values: normal to mild, less than 15; moderate, 15 or higher to less than 30; severe, 30 or higher to less than 60; and very severe, over 60. The lowest oxygen saturation during sleep (lowest SpO2) and the average oxygen saturation during sleep (mean SpO2) also were calculated.
Measurement of Carotid Intima-media Thickness and Plaque Score
High-resolution ultrasonographic imaging of the carotid artery using the B-scan mode was performed using the EUB-8500 ultrasound system (Hitachi, Tokyo, Japan) with the probe frequency set to 7.5 MHz. The patients were measured while in the supine position with their heads slightly turned away from the sonographer. The procedures involved scanning the near and far walls of the carotid artery every 1 cm proximal to the carotid bulb in the longitudinal view. The intima-media thickness was defined as the average of the maximal intima-media thickness 1 cm proximal and 1 cm distal to the carotid bulb. The intima-media thickness of the thickened side of the carotid artery was used for data analyses. The plaque score was calculated as reported previously. Briefly, plaques (localized increases in intima-media thickness ≥1.1 mm) were detected by cross-sectional and longitudinal scanning of the bilateral common and internal carotid arteries. The plaque score was computed by adding the maximal thickness of each plaque in the bilateral carotid arteries.
Measurement of Laboratory Profile
Laboratory profiles were assessed using the serum total cholesterol (mg/dL), triglycerides (mg/dL), low-density lipoprotein-cholesterol (LDL-C mg/dL), high-density lipoprotein-cholesterol (HDL-C mg/dL), high-sensitivity C-reactive protein (mg/L), cystatin C (mg/L), and glycosylated hemoglobin (HbA1C %). Fasting morning blood samples were collected and stored at −70°C until needed for the appropriate assays. HbA1C was expressed according to the scale of the Japan Diabetes Society.
Other Systemic Parameters
The body mass index (kg/m 2 ) and the presence of hypertension, diabetes mellitus, or coronary artery disease was evaluated. We diagnosed hypertension in patients with blood pressure values of 140/90 mm Hg or higher or in those using antihypertensive drugs. Diabetes mellitus was defined as a fasting blood glucose level exceeding 126 mg/dL or a HbA1C exceeding 5.8%; diabetes mellitus also was considered present in patients using a hypoglycemic agent. A history of coronary artery disease was confirmed using the medical records.
OCT Measurements
OCT was performed using Stratus OCT. All patients underwent scans to measure the RNFL thickness, foveal thickness, and total macular volume. The RNFL thickness of the optic nerve head was calculated automatically using the fast RNFL algorithm. The average RNFL thicknesses in the 4 quadrants (superior, nasal, inferior, and temporal) were generated automatically in the analysis reports. The foveal thickness and total macular volume measurements were obtained using the fast macular thickness protocol. The foveal thickness and total macular volume were calculated automatically. We performed all measurements 3 times and used the average of the 3 measurements for the statistical analyses.
Measurements of Other Ocular Parameters
All patients underwent an ophthalmologic evaluation that included slit-lamp biomicroscopy, intraocular pressure (IOP) measurement by applanation tonometry, spherical refraction, gonioscopy, and fundoscopy.
Exclusion Criteria
Patients were excluded if they had histories of central apnea, glaucoma, chronic uveitis, optic neuropathy, or retinal or choroidal vascular disease or had undergone previous intraocular surgery. A total of 124 patients met the study criteria.
Statistical Analyses
The data are expressed as the means ± standard deviations for the continuous variables. The Pearson correlation coefficient was used to determine the relationship between the apnea-hypopnea index and OCT and other parameters. Multiple regression analysis was used to determine the independent factors for sectors of the RNFL thickness with the strongest correlations with the apnea-hypopnea index. Comparisons among the severities of obstructive sleep apnea syndrome were performed using 1-way analysis of variance, followed by the Bonferroni-Dunn post hoc test. P < 0.05 was considered statistically significant. The Stat View v 5.0 program (SAS Institute, Cary, NC) was used for the statistical analyses.
Results
Table 1 shows the patients’ background factors and the results of polysomnography. The mean apnea-hypopnea index value was 33.2 ± 21.0 (times/hour).
| Mean ± Standard Deviation | Range | |
|---|---|---|
| Age (years) | 61.7 ± 10.0 | 38 to 86 |
| Men/women | 88/36 | |
| Spherical refraction (diopters) | ||
| Right eye | −0.14 ± 2.12 | −6.75 to 5.5 |
| Left eye | −0.15 ± 2.22 | −10.00 to 4.25 |
| IOP (mm Hg) | ||
| Right eye | 12.7 ± 3.1 | 7 to 23 |
| Left eye | 12.7 ± 2.9 | 7 to 20 |
| Body mass index (kg/m 2 ) | 24.9 ± 3.6 | 18.2 to 35.8 |
| HbA1C (%) | 5.8 ± 1.0 | 4.4 to 10.8 |
| Total cholesterol (mg/dL) | 187.6 ± 29.6 | 104 to 253 |
| Triglycerides (mg/dL) | 140.7 ± 77.0 | 45 to 600 |
| LDL-C (mg/dL) | 108.7 ± 26.4 | 35 to 175 |
| HDL-C (mg/dL) | 51.8 ± 14.9 | 28 to 94 |
| Cystatin C (mg/L) | 0.82 ± 0.15 | 0.53 to 1.54 |
| High-sensitivity C-reactive protein (mg/L) | 0.12 ± 0.24 | 0.004 to 2.380 |
| Intima-media thickness (mm) | 0.90 ± 0.17 | 0.6 to 1.4 |
| Plaque score | 4.6 ± 4.5 | 0.0 to 20.1 |
| Hypertension (%) | 61.3 | |
| Diabetes mellitus (%) | 26.6 | |
| Coronary artery disease (%) | 21.8 | |
| Apnea hypopnea index (times/hour) | 33.2 ± 21.0 | 0.3 to 83.3 |
| Lowest SpO2 (%) | 83.1 ± 8.0 | 58 to 96 |
| Mean SpO2 (%) | 95.2 ± 1.7 | 90 to 98 |
Table 2 shows the results of Pearson correlation analysis between the apnea-hypopnea index and OCT parameters. The apnea-hypopnea index was significantly negatively correlated (right eye, r = −0.31, t value, −3.66, P = 0.0004; left eye, r = −0.39, t value = −4.69, P < 0.0001) with the nasal RNFL thickness. The foveal thickness and total macular volume were not correlated with the apnea-hypopnea index.
| Explanatory Variable | r | t Value | P Value |
|---|---|---|---|
| Peripapillary RNFL thickness (μm) | |||
| Right eye | |||
| Average | −0.15 | −1.64 | 0.10 |
| Superior | −0.05 | −0.55 | 0.59 |
| Nasal | −0.31 | −3.66 | 0.0004 |
| Inferior | −0.08 | −0.83 | 0.41 |
| Temporal | 0.06 | 0.70 | 0.48 |
| Left eye | |||
| Average | −0.15 | −1.61 | 0.11 |
| Superior | 0.11 | 1.19 | 0.24 |
| Nasal | −0.39 | −4.69 | <0.0001 |
| Inferior | −0.17 | −1.94 | 0.05 |
| Temporal | 0.17 | 1.87 | 0.07 |
| Right eye | |||
| Foveal thickness (μm) | 0.04 | 0.41 | 0.69 |
| Total macular volume (mm 3 ) | −0.06 | −0.62 | 0.53 |
| Left eye | |||
| Foveal thickness (μm) | 0.07 | 0.81 | 0.42 |
| Total macular volume (mm 3 ) | −0.11 | −1.23 | 0.22 |
Table 3 shows the comparisons of the RNFL thickness, foveal thickness, and total macular volume in the various severity levels of obstructive sleep apnea syndrome. The nasal RNFL thickness bilaterally differed significantly (right eye, P = 0.004; left eye, P = 0.0002) among the differing severity levels of obstructive sleep apnea syndrome.
| Apnea hypopnea index (times/hour) | <15 | 15≤ to <30 | 30≤ to <60 | >60 | P Value |
|---|---|---|---|---|---|
| Peripapillary RNFL thickness (μm) | |||||
| Right eye | |||||
| Average | 100.1 ± 15.7 | 97.0 ± 10.6 | 98.7 ± 10.3 | 93.1 ± 8.5 | 0.22 |
| Superior | 117.1 ± 20.4 | 115.8 ± 16.8 | 119.4 ± 18.4 | 112.5 ± 15.9 | 0.56 |
| Nasal | 73.9 ± 16.1 | 73.0 ± 16.5 | 70.7 ± 15.6 | 56.8 ± 13.8 | 0.004 |
| Inferior | 127.4 ± 24.9 | 123.9 ± 18.8 | 125.4 ± 17.9 | 121.9 ± 17.4 | 0.81 |
| Temporal | 81.1 ± 21.7 | 75.9 ± 16.2 | 79.0 ± 14.6 | 81.7 ± 15.9 | 0.59 |
| Left eye | |||||
| Average | 98.6 ± 14.0 | 94.2 ± 10.5 | 95.6 ± 11.2 | 91.0 ± 12.3 | 0.19 |
| Superior | 116.0 ± 21.1 | 115.3 ± 21.1 | 121.5 ± 19.4 | 117.9 ± 20.9 | 0.54 |
| Nasal | 74.7 ± 16.2 | 66.2 ± 16.1 | 64.3 ± 14.2 | 53.8 ± 9.3 | 0.0002 |
| Inferior | 127.9 ± 23.4 | 119.9 ± 15.0 | 124.8 ± 21.3 | 113.7 ± 20.6 | 0.10 |
| Temporal | 74.7 ± 18.0 | 72.0 ± 13.8 | 76.1 ± 16.7 | 81.9 ± 23.7 | 0.28 |
| Right eye | |||||
| Foveal thickness (μm) | 171.2 ± 25.3 | 158.9 ± 22.3 | 163.6 ± 28.8 | 172.3 ± 32.6 | 0.36 |
| Total macular volume (mm 3 ) | 6.9 ± 0.5 | 6.8 ± 0.4 | 6.7 ± 0.4 | 6.8 ± 0.4 | 0.57 |
| Left eye | |||||
| Foveal thickness (μm) | 161.1 ± 21.9 | 158.9 ± 22.3 | 158.7 ± 23.4 | 166.0 ± 27.8 | 0.71 |
| Total macular volume (mm 3 ) | 6.8 ± 0.4 | 6.7 ± 0.4 | 6.7 ± 0.4 | 6.6 ± 0.3 | 0.45 |
Table 4 shows the results of the Pearson correlation analyses between the nasal RNFL thickness in the left eye and all parameters. The IOP (r = −0.18, t value, −2.13, P = 0.04); body mass index (r = −0.25, t value = −2.87, P = 0.005); HDL-C (r = 0.23, t value = 2.63, P = 0.01); plaque score (r = −0.18, t value = −2.00, P = 0.04); incidence of hypertension (r = −0.23, t value = −2.60, P = 0.01); lowest SpO2 (r = 0.26, t value = 2.99, P = 0.003); and mean SpO2 (r = 0.27, t value = 3.15, P = 0.002) were correlated significantly with the nasal RNFL thickness in the left eye. The patients’ ages (r = −0.17, t value = −1.91, P = 0.06) tended to be correlated with the nasal RNFL thickness in the left eye but did not reach significance.
| Explanatory Variable | r | t Value | P Value |
|---|---|---|---|
| Age (years) | −0.17 | −1.91 | 0.06 |
| Spherical refraction: | |||
| Left eye (diopters) | 0.09 | 1.03 | 0.31 |
| IOP: left eye (mm Hg) | −0.18 | −2.06 | 0.04 |
| Body mass index (kg/m 2 ) | −0.25 | −2.87 | 0.005 |
| HbA1C (%) | −0.11 | −1.22 | 0.23 |
| Total cholesterol (mg/dL) | 0.08 | 0.83 | 0.41 |
| Triglycerides (mg/dL) | −0.12 | −1.33 | 0.19 |
| LDL-C (mg/dL) | −0.01 | −0.07 | 0.95 |
| HDL-C (mg/dL) | 0.23 | 2.63 | 0.01 |
| Cystatin C (mg/L) | −0.09 | −1.04 | 0.30 |
| High-sensitivity C-reactive protein (mg/L) | −0.05 | −0.53 | 0.60 |
| Intima-media thickness (mm) | −0.13 | −1.47 | 0.15 |
| Plaque score | −0.18 | −2.00 | 0.04 |
| Hypertension + = 1, − = 0 | −0.23 | −2.60 | 0.01 |
| Diabetes mellitus + = 1, − = 0 | −0.03 | −0.36 | 0.72 |
| Coronary artery disease + = 1, − = 0 | −0.14 | −1.54 | 0.13 |
| Lowest SpO2 (%) | 0.26 | 2.99 | 0.003 |
| Mean SpO2 (%) | 0.27 | 3.15 | 0.002 |
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