http://informahealthcare.com/cot ISSN: 1556-9527 (print), 1556-9535 (electronic) Cutan Ocul Toxicol, Early Online: 1–5 ! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/15569527.2015.1004079
RESEARCH ARTICLE
Peripapillary choroidal thickness in patients with chronic obstructive pulmonary disease
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Muammer Ozcimen1, Yasar Sakarya1, Ercan Kurtipek2, Taha T. Bekci2, Sertan Goktas1, Rabia Sakarya1, Halil I. Yener3, Lutfi S. Demir4, Erkan Erdogan1, Ismail S. Ivacik1, Ismail Alpfidan1, and Abdulkadir Bukus1 1
Department of Ophthalmology and 2Department of Chest Medicine, Konya Training and Research Hospital, Konya, Turkey, 3Department of Ophthalmology, Medicana Hospital, Konya, Turkey, and 4Department of Public Health, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey Abstract
Keywords
Objective: To evaluate the peripapillary choroidal thickness of patients with chronic obstructive pulmonary disease (COPD) via enhanced depth imaging optical coherence tomography (EDI-OCT). Materials and methods: A total of 80 patients with COPD (80 eyes) and 50 control subjects (50 eyes) were enrolled. Choroidal scans and the retinal nerve fiber layer (RNFL) thickness were obtained for all eyes using OCT. Results: The average peripapillary choroidal thickness measurements of the COPD group (147.58 ± 53.53 lm) were lower than the control group (160.84 ± 44.73 lm) (p ¼ 0.068). Inferior segment thicknesses were significantly thinner than the other segments (p50.05). Subfoveal choroidal thickness and RNFL thickness measurements of the COPD group were also lower than those of the control group (p ¼ 0.111). Conclusion: Hypoxia in COPD seems to affect the choroidal thickness. Thinning of the choroid may be attributed to increased vascular resistance and reduced blood flow in patients with COPD. The possible effects of the disease to the eye may be clarified through the role of the choroidal vasculature in the blood supply of the anterior optic nerve head.
Choroid, hypoxia, optical coherence tomography, pulmonary disease
Introduction Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammatory response of the lungs to noxious particles and gases resulting in progressive airflow limitation1. Today, it is accepted as a systemic disease that affects all bodily systems2 and by 2020 is predicted to become the third greatest cause of death worldwide3. Tissue hypoxia, smoking and inflammatory cytokines are responsible in the development of the systemic effects of COPD4,5. As pulmonary function gets worse and as the disease progresses, the risk of alveolar hypoxia and consequent hypoxemia increases6. Choroid is a highly vascular membrane that covers most of the posterior of the eye between the retina and sclera, supplies oxygen and nourishment to the uvea and outer layers of the retina. A functionally normal choroidal vasculature is essential for retinal function; thinning of the choroid and loss of the vascular tissues often leads to photoreceptor damage and vascular dysfunction. Optical coherence tomography is a non-invasive, noncontact imaging modality used to acquire high-resolution, Address for correspondence: Dr Muammer Ozcimen, MD, Department of Ophthalmology, Konya Training and Research Hospital, 42090 Meram, Konya, Turkey. Tel:+905324563540. Fax:+903323236723. E-mail: [email protected]
History Received 10 November 2014 Revised 22 December 2014 Accepted 31 December 2014 Published online 18 February 2015
cross-sectional scans of the retina7. It has become a valuable tool for the diagnosis and management of chorioretinal disease. Choroidal imaging with EDI-OCT, is defined by Spaide et al.8 and has given the opportunity to investigate the effects of many ocular diseases and associated physiological changes of the choroid layer9–11. A variety of ocular pathologies may have primary or associated pathology located in the peripapillary choroidal region12,13. Analysis of the thickness of the peripapillary choroid in patients with COPD may help us in explaining the pathophysiology, following disease progression and measuring the response to therapy. However, no study has yet measured the peripapillary choroidal thickness in patients with COPD. The purpose of this study is to establish the thickness of the peripapillary choroid in patients with COPD.
Materials and methods This was a prospective observational study which was conducted under a protocol approved by the Konya Selcuk University Medical Faculty Ethics Committee and was in accordance with the ethical standards stated in the 1964 Declaration of Helsinki. Written informed consent was obtained from all participants. Eighty patients with COPD with at least 5 years of disease duration without any history of
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eye disorders other than mild cataracts were enrolled (COPD group). We used the spirometry for COPD diagnosis. According to the spirometry results, forced expiratory volume in 1 second/forced expiratory vital capacity (FEV1/ FVC) less than 70% and reversibility test negative patients were enrolled to the study. The control group (n ¼ 50) was chosen from subjects without any evidence of previous or current COPD and was consisted of age and sex-matched healthy patients having a history of smoking to avoid the possible effect of smoking on peripapillary choroidal thickness14. All subjects underwent a standardized measurement before hospitalized in which, height and weight were taken and body mass index (BMI) was calculated (weight in kg divided by height in m2). Only the participants with the BMI which is in normal (healthy weight) category (ranged from 18.5 to 25 kg/m2) were included in the study. Exclusion criteria included: history of previous laser and intraocular surgery, glaucoma, optic neuropathy, amblyopia, significant cataracts and spherical equivalent refractive errors (RE) more than ± 3.0 diopters, axial length (AL) exceeding 25 mm, choroidal neovascularization or myopic atrophy, clinically relevant opacities of the optic media and low-quality images due to unstable fixation. Participants with systemic diseases, such as diabetes, hypertension or cardiovascular disease were also not included in the study. All participants underwent a thorough ophthalmic evaluation, which included slitlamp biomicroscopy, intraocular pressure (IOP) measurement, fundus examination, a RE examination and AL measurements. Demographic and clinical data were collected for each subject. Blood gas analysis were performed for patients with COPD and oxygen saturation was measured by pulse oximetry in both groups. The participants in the study were asked not to smoke and consume any caffeine-containing drinks for at least 24 h before the OCT measurements. All participants were examined with dilated pupils using an enhanced depth imaging system (EDI; Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany). For measurements of peripapillary choroidal thickness, a 360-degree 3.4 mm diameter peripapillary circle scan was performed using the standard protocol for retinal nerve fiber layer (RNFL) assessment, as previously described15. The participants
Cutan Ocul Toxicol, Early Online: 1–5
underwent the OCT examinations in the morning to avoid the diurnal variation in choroidal thickness measurements16,17. Keratometry readings and the refraction were entered into the software program to estimate optical magnification and, therefore, to allow for more accurate comparisons across individuals. The images were viewed and measured with the supplied Heidelberg Eye Explorer software (version 5.3; Heidelberg Engineering) by two independent graders. The choroidal thickness was measured manually from the outer portion of the hyperreflective line corresponding to the retinal pigment epithelium (RPE) to the inner surface of the sclera (Figure 1) at the temporal, superotemporal, superior, superonasal, nasal, inferonasal, inferior and inferotemporal segments. For EDI-OCT of subfoveal region, foveal-centered vertical and horizontal two line scans were performed in an assay of 100 frames, 30 and high resolution. The subfoveal choroidal thickness (SFCT) was calculated by obtaining a mean measurement of vertical and horizontal scans’ thicknesses. The RNFL thickness was also determined using the same peripapillary circle scan. Only the right eye of each study participant was assessed. The data were processed and statistically analyzed using a commercial analytical software program (SPSS 15.0; SPSS, Inc., Chicago, IL). The t-test for independent samples was used for comparing variables between groups. A one-way analysis of variance was used to determine whether average choroidal thickness differed among each of the eight peripapillary regions. When the analysis showed significant differences among the groups, post-hoc analysis utilizing the least significant difference (LSD) t-test method was used to analyze the variance. The reproducibility of choroidal thickness measurements between graders was calculated via intraclass correlation coefficients. Statistical significance was considered when p50.05. All parameters are expressed as mean ± standard deviation.
Results Seventy-three participants with COPD (7 were excluded from the study because of the inability to identify the choroid–scleral junction precisely) and 50 controls were included in the study. Data from all cases are summarized in Table 1.
Figure 1. Images from 360 3.4 mm diameter peripapillary circle scans. (A) EDI-OCT of patient with COPD, (B) EDI-OCT of control participant.
OCT in chronic obstructive pulmonary disease
DOI: 10.3109/15569527.2015.1004079
Table 1. Demographic and clinical data of patients with COPD and controls.
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Patients with COPD (n ¼ 73)
Controls (n ¼ 50)
Age (years) 65.60 ± 8.08 63.02 ± 5.62 Gender (male/female) 45/28 29/21 Disease duration (years) 11.98 ± 6.19 _ Smoking status (pack-year) 41.02 ± 22.85 38.22 ± 19.33 Spherical equivalent (D) 0.76 ± 0.28 0.72 ± 0.35 Axial length (mm) 22.40 ± 1.44 22.89 ± 1.28 Mean RNFL thickness (mm) 98.47 ± 13.77 103.25 ± 7.26 IOP 15.90 ± 3.43 14.72 ± 3.37 SBP (mmHg) 124.86 ± 10.57 122.40 ± 10.70 DBP (mmHg) 77.73 ± 7.72 75.70 ± 8.51 MBP (mmHg) 92.18 ± 9.87 91.02 ± 9.24 MOPP (mmHg) 76.28 ± 8.90 76.30 ± 8.64 pH 7.41 ± 0.41 _ PaO2 (mmHg) 55.61 ± 10.79 _ PaCO2 (mmHg) 42.92 ± 8.14 _ SO2 (mg/L) 87.00 ± 8.70 91.21 ± 4.35 BMI 22.90 ± 1.75 22.30 ± 1.81
p Value 0.053 _ _ 0.478 _ 0.057 0.044 0.061 0.211 0.179 0.311 0.744 _ _ _ 0.002 0.068
D ¼ diopter; RNFL ¼ retinal nerve fiber layer; IOP ¼ intraocular pressure; DBP ¼ diastolic blood pressure; SBP ¼ systolic blood pressure; MB ¼ mean blood pressure; MOPP ¼ mean ocular perfusion pressure; pH ¼ power of hydrogen; PaO2 ¼ partial pressure of oxygen in the blood; PaCO2 ¼ partial pressureof carbon dioxide in the blood; SO2 ¼ oxygen saturation; COPD ¼ chronic obstructive pulmonary disease; p value ¼ represents significance. Table 2. Average peripapillary choroidal thickness at different segments with 360 3.4 mm diameter peripapillary circle scans. Average choroidal thickness Segment
Patients with COPD (n ¼ 73)
Controls (n ¼ 50)
p Value
T ST S SN N IN I IT Average
149.45 ± 48.04 166.31 ± 64.82 159.79 ± 53.42 164.58 ± 62.94 155.90 ± 44.31 131.63 ± 35.97 125.53 ± 53.63 127.45 ± 41.38 147.58 ± 53.53
161.54 ± 47.82 170.18 ± 39.04 176.22 ± 50.87 178.34 ± 42.12 168.32 ± 40.81 146.04 ± 41.77 143.54 ± 38.58 142.54 ± 40.58 160.84 ± 44.73
0.172 0.681 0.090 0.149 0.118 0.043 0.032 0.048 0.068
T ¼ temporal; ST ¼ Superotemporal; S ¼ Superior; SN ¼ Superonasal; N ¼ nasal; IN ¼ Inferonasal; I ¼ Inferio;, IT ¼ Inferotemporal. p value represents significance. Bold values represent significance.
Ocular perfusion pressure (OPP) is expressed as the difference between the mean blood pressure (MBP) and the intraocular pressure (IOP), which is considered as a substitute for the venous pressure. Mean OPP was calculated as: 2/ 3(MBP - IOP)18. Mean blood pressure was calculated as: MBP ¼ DBP + [1/3(SBP - DBP)]. No significant correlations were found between the choroidal thickness and mean ocular perfusion pressure (MOPP) and IOP. The average peripapillary choroidal thickness of the COPD group (147.58 ± 53.53 lm) was lower than the control group (160.84 ± 44.73), but did not reveal significance (p ¼ 0.068). The choroidal thicknesses at different segments are shown in Table 2. The post-hoc analysis utilizing LSD t-test demonstrated that, for peripapillary choroid, the inferonasal, inferior and inferotemporal thicknesses were significantly thinner than the
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Table 3. Post-hoc analysis of the peripapillary choroidal thickness of patients with COPD at eight segments using least significant difference (LSD) t-test. Segment T ST S SN N IN I IT
T
ST
S
SN
N
IN
I
– – – – – – – 0.048 – – – – – – 0.225 0.444 – – – – – 0.076 0.839 0.574 – – – – 0.449 0.222 0.648 0.308 – – – 0.037 50.001 0.001 50.001 0.005 – – 0.005 50.001 50.001 50.001 50.001 0.474 – 0.010 50.001 50.001 50.001 0.001 0.624 0.822
IT – – – – – – – –
T ¼ temporal; ST ¼ Superotemporal; S ¼ Superior; SN ¼ Superonasal; N ¼ nasal; IN ¼ Inferonasal; I ¼ Inferior; IT ¼ Inferotemporal. Bold values represent significance.
Table 4. Post-hoc analysis of the peripapillary choroidal thickness of controls at eight segments using least significant difference (LSD) t-test. Segment T ST S SN N IN I IT
T – 0.315 0.088 0.051 0.430 0.072 0.037 0.027
ST
S
SN
N
IN
I
– – – – – – – – – – – – 0.482 – – – – – 0.342 0.805 – – – – 0.828 0.358 0.244 – – – 0.005 50.001 50.001 0.010 – – 0.002 50.001 50.001 0.004 0.771 – 0.001 50.001 50.001 0.003 0.684 0.907
IT – – – – – – – –
T ¼ temporal; ST ¼ Superotemporal; S ¼ Superior; SN ¼ Superonasal; N ¼ nasal; IN ¼ Inferonasal; I ¼ Inferior; IT ¼ Inferotemporal. Bold values represent significance.
temporal, superotemporal, superior, superonasal and nasal thicknesses in both groups (p50.05, Tables 3 and 4) except between inferonasal and temporal segments of control group (p ¼ 0.072, Tables 3 and 4). However, no statistically significant difference was noted among the inferonasal, inferior and inferotemporal thicknesses. None of the other segments demonstrated any significant differences with each other. The variation trend of peripapillary choroidal thickness is illustrated in Figure 2. Intraclass correlation coefficients showed agreement between the two graders (p50.001) and ranged from moderate (0.68, superotemporal) to very high (0.93, inferotemporal). Subfoveal choroidal thickness measurements of the COPD group (249.16 ± 55.35 lm) were lower than the control (264.48 ± 47.95 lm) group; but did not show any statistical significance (p ¼ 0.111). We did not find a difference in SFCT measurements of horizontal and vertical line scan of all eyes (p ¼ 0.539 and p ¼ 0.647 in COPD and controls, respectively). Peripapillary choroidal thickness was significantly correlated to SFCT in all segments (p50.001). Average RNFL thickness was significantly lower in COPD patients (p ¼ 0.044) and peripapillary choroidal thickness was significantly correlated to RNFL thickness in all segments except temporal (p ¼ 0.120) and inferior segments (p ¼ 0.089) in the COPD group. However, peripapillary choroidal thickness did not correlate to RNFL thickness in controls.
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Cutan Ocul Toxicol, Early Online: 1–5
Figure 2. Variation trend of peripapillary choroidal thickness. The superotemporal segment had the thickest choroidal thickness, while the inferior segment had the thinnest thickness. (A) patients with COPD, (B) controls.
Discussion In the present study, we found that the average peripapillary choroidal thickness measurements of the COPD group were lower than the control group, but did not reveal significance. Moreover, inferior segments were significantly thinner than the other peripapillary choroid segments in both groups. Similarly, there are few published studies that have characterized the peripapillary choroidal thickness in normal participants and found the inferior quadrant to be significantly thinner than the other segments19,20. Interestingly, we found that peripapillary choroid in the inferior segments of patients with COPD was significantly thinner than those of control participants. Choroidal thinning may be indicative of decreased blood flow in the choriocapillaris21. A thinner choroid may increase vascular resistance, resulting in a decreased blood flow in the choriocapillaris, which may be more sensitive to hypoxia or to elevated IOP. The fact that thinner choroid in the inferior sector of the optic disc may be important as this thinning makes this area more susceptible to retinal and choroidal diseases. COPD may increase vascular resistance and thereby decrease blood flow in ocular structures resulting in thinning of the choroid. Choroidal thickness reflects choroidal blood flow and depends on the perfusion pressure, IOP, nitric oxide (NO) production, endogenous catecholamines and vascular autoregulation22,23. Changes in its structure would help to evaluate choroidal and thus ocular blood flow24. Endothelin-1 and NO released from the vascular endothelium play a major role in the adaptation of choroidal vascular resistance23,25. Hypoxia appears to participate in the development of endothelial dysfunction26. However, in our present study, no significant associations were detected between the peripapillary choroidal thickness and the IOP and MOPP. This can be explained by the autoregulation of choroidal blood flow that may prevent excessive changes in choroidal thickness. Additionally, COPD may affect vascular endothelium by promoting inflammation and oxidative stress27,28. Conversely, hypoxia upregulates the production of vasoconstrictive mediators, thus leading to an increased vascular tone29.
The gratifying thing is that it has been shown that stable perfusion is provided by ocular vasoconstriction30. Palombi et al.31 emphasized vascular endothelium damage in most respiratory events as a result of desaturation and reoxygenation sequence. Hypoxia may be assumed to be the cause of ganglion cell death and reduced RNFL thickness in patients with COPD in our study. Additionally, peripapillary choroidal thickness was significantly correlated to RNFL thickness in all segments in the COPD group except temporal and inferior segments, which may be because of the small sample size used. However, peripapillary choroidal thickness did not correlate to RNFL thickness in controls. Thus, in future, larger scale studies should be conducted to confirm these observations. One of the limitations of our study was that there was a relatively small number of patients enrolled; however, the design of the study with age, sex and smoking habbit-matched control group makes the results more valuable. Other limitation of the study was that we did not measure ocular blood flow. Therefore, we were not able to fully investigate the relationship between the choroidal vascular flow and the choroidal thickness in patients with COPD. In summary, this was the first study to investigate the peripapillary choroid of patients with COPD. Our results have suggested that peripapillary choroidal thickness seems to be affected by COPD-related hypoxemia, vascular and endothelial dysfunction. Given the role of the choroidal vasculature in the blood supply of the anterior optic nerve head, studying on peripapillary choroidal thickness is of great significance. Understanding the peripapillary choroidal thickness may help us to clarify the possible effects of the disease to the eye and might be useful in clinical evaluation. Further studies with larger sample sizes are needed to determine more accurately whether there is a relationship between clinical grades and choroidal thicknesses.
Acknowledgements The authors thank Serap Ozcimen, MD, from the Department of Clinical Microbiology and Infectious Diseases, Konya, Turkey, for her assistance with manuscript preparation.
DOI: 10.3109/15569527.2015.1004079
Declaration of interest The authors declare no conflicts of interest.
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References 1. Asia Pacific COPD Roundtable Group, et al. Global Initiative for chronic obstructive lung disease strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease: an Asia-Pacific perspective. Respirology 2005;10:9–17. 2. Agusti A, Soriano JB. COPD as a systemic disease. COPD 2008;5: 133–138. 3. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet 1997;349:1498–1504. 4. Vernooy JH, Ku¨c¸u¨kaycan M, Jacobs JA, et al. Local and systemic inflammation in patients with chronic obstructive pulmonary disease: soluble tumor necrosis factor receptors are increased in sputum. Am J Respir Crit Care Med 2002;166:1218–1224. 5. Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 2004;59: 574–580. 6. Rabe KF, Hurd S, Anzueto A, et al.; Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007;176:532–555. 7. Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science 1991;254:1178–1181. 8. Spaide RF, Koizumi H, Pozzoni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 2008;146:496–500. 9. Gemenetzi M, De Salvo G, Lotery AJ. Central serous chorioretinopathy: an update on pathogenesis and treatment. Eye (Lond) 2010;24:1743–1756. 10. Koizumi H, Yamagishi T, Yamazaki T, et al. Subfoveal choroidal thickness in typical age-related macular degeneration and polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol 2011;249:1123–1128. 11. Torres VL, Brugnoni N, Kaiser PK, Singh AD. Optical coherence tomography enhanced depth imaging of choroidal tumors. Am J Ophthalmol 2011;151:586–593. 12. Spraul CW, Lang GE, Lang GK, Grossniklaus HE. Morphometric changes of the choriocapillaris and the choroidal vasculature in eyes with advanced glaucomatous changes. Vision Res 2002;42: 923–932. 13. Fujiwara T, Imamura Y, Margolis R, et al. Enhanced depth imaging optical coherence tomography of the choroid in highly myopic eyes. Am J Ophthaldrserapmol 2009;148:445–450. 14. Sizmaz S, Ku¨c¸u¨kerdo¨nmez C, Pinarci EY, et al. The effect of smoking on choroidal thickness measured by optical coherence tomography. Br J Ophthalmol 2013;97:601–614.
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15. Ehrlich JR, Peterson J, Parlitsis G, et al. Peripapillary choroidal thickness in glaucoma measured with optical coherence tomography. Exp Eye Res 2011;92:189–194. 16. Usui S, Ikuno Y, Akiba M, et al. Circadian changes in subfoveal choroidal thickness and the relationship with circulatory factors in healthy subjects. Invest Ophthalmol Vis Sci 2012;53:2300–2307. 17. Tan CS, Ouyang Y, Ruiz H, Sadda SR. Diurnal variation of choroidal thickness in normal, healthy subjects measured by spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci 2012;53:261–266. 18. Maul EA, Friedman DS, Chang DS, et al. Choroidal thickness measured by spectral domain optical coherence tomography: factors affecting thickness in glaucoma patients. Ophthalmology 2011;118:1571–1579. 19. Tanabe H, Ito Y, Terasaki H. Choroid is thinner in inferior region of optic disks of normal eyes. Retina 2012;32:134–139. 20. Ho J, Branchini L, Regatieri C, et al. Analysis of normal peripapillary choroidal thickness via spectral domain optical coherence tomography. Ophthalmology 2011;118:2001–2007. 21. Querques G, Lattanzio R, Querques L, et al. Enhanced depth imaging optical coherence tomography in type 2 diabetes. Invest Ophthalmol Vis Sci 2012;53:6017–6024. 22. Rishi P, Rishi E, Mathur G, et al. Ocular perfusion pressure and choroidal thickness in eyes with polypoidal choroidal vasculopathy, wet-age-related macular degeneration, and normals. Eye 2013;27:1038–1043. 23. Fuchsja¨ger-Mayrl G, Luksch A, Malec M, et al. Role of endothelin-1 in choroidal blood flow regulation during isometric exercise in healthy humans. Invest Ophthalmol Vis Sci 2003;44: 728–733. 24. Bill A. Circulation in the eye. In: Renkin EM, Michel CC, eds. Handbook in physiology: microcirculation, Part 2. Washington DC: The American Physiological Society; 1984:1001–1035. 25. Okuno T, Sugiyama T, Kohyama M, et al. Ocular blood flow changes after dynamic exercise in humans. Eye (Lond) 2006;20: 796–800. 26. Dinh-Xuan AT, Higenbottam TW, Clelland CA, et al. Impairment of endothelium-dependent pulmonary-artery relaxation in chronic obstructive lung disease. N Engl J Med 1991;324:1539–1547. 27. Jelic S, Padeletti M, Kawut SM, et al.. Inflammation, oxidative stress, and repair capacity of the vascular endothelium in obstructive sleep apnea. Circulation 2008;117:2270–2278. 28. Toschi-Dias E, Trombetta IC, Dias da Silva VJ, et al. Time delay of baroreflex control and oscillatory pattern of sympathetic activity in patients with metabolic syndrome and obstructive sleep apnea. Am J Physiol Heart Circ Physiol 2013;304: 1038–1044. 29. McQuillan LP, Leung GK, Marsden PA, et al. Hypoxia inhibits expression of eNOS via transcriptional and posttranscriptional mechanisms. Am J Physiol 1994;267:1921–1927. 30. Morgan AJ, Hosking SL. Non-invasive vascular impedance measures demonstrate ocular vasoconstriction during isometric exercise. Br J Ophthalmol 2007;91:385–390. 31. Palombi K, Renard E, Levy P, et al. Non-arteritic anterior ischaemic optic neuropathy is nearly systematically associated with obstructive sleep apnoea. Br J Ophthalmol 2006;90:879–882.
RESEARCH ARTICLE
Peripapillary choroidal thickness in patients with chronic obstructive pulmonary disease
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Fudan University on 05/18/15 For personal use only.
Muammer Ozcimen1, Yasar Sakarya1, Ercan Kurtipek2, Taha T. Bekci2, Sertan Goktas1, Rabia Sakarya1, Halil I. Yener3, Lutfi S. Demir4, Erkan Erdogan1, Ismail S. Ivacik1, Ismail Alpfidan1, and Abdulkadir Bukus1 1
Department of Ophthalmology and 2Department of Chest Medicine, Konya Training and Research Hospital, Konya, Turkey, 3Department of Ophthalmology, Medicana Hospital, Konya, Turkey, and 4Department of Public Health, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey Abstract
Keywords
Objective: To evaluate the peripapillary choroidal thickness of patients with chronic obstructive pulmonary disease (COPD) via enhanced depth imaging optical coherence tomography (EDI-OCT). Materials and methods: A total of 80 patients with COPD (80 eyes) and 50 control subjects (50 eyes) were enrolled. Choroidal scans and the retinal nerve fiber layer (RNFL) thickness were obtained for all eyes using OCT. Results: The average peripapillary choroidal thickness measurements of the COPD group (147.58 ± 53.53 lm) were lower than the control group (160.84 ± 44.73 lm) (p ¼ 0.068). Inferior segment thicknesses were significantly thinner than the other segments (p50.05). Subfoveal choroidal thickness and RNFL thickness measurements of the COPD group were also lower than those of the control group (p ¼ 0.111). Conclusion: Hypoxia in COPD seems to affect the choroidal thickness. Thinning of the choroid may be attributed to increased vascular resistance and reduced blood flow in patients with COPD. The possible effects of the disease to the eye may be clarified through the role of the choroidal vasculature in the blood supply of the anterior optic nerve head.
Choroid, hypoxia, optical coherence tomography, pulmonary disease
Introduction Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammatory response of the lungs to noxious particles and gases resulting in progressive airflow limitation1. Today, it is accepted as a systemic disease that affects all bodily systems2 and by 2020 is predicted to become the third greatest cause of death worldwide3. Tissue hypoxia, smoking and inflammatory cytokines are responsible in the development of the systemic effects of COPD4,5. As pulmonary function gets worse and as the disease progresses, the risk of alveolar hypoxia and consequent hypoxemia increases6. Choroid is a highly vascular membrane that covers most of the posterior of the eye between the retina and sclera, supplies oxygen and nourishment to the uvea and outer layers of the retina. A functionally normal choroidal vasculature is essential for retinal function; thinning of the choroid and loss of the vascular tissues often leads to photoreceptor damage and vascular dysfunction. Optical coherence tomography is a non-invasive, noncontact imaging modality used to acquire high-resolution, Address for correspondence: Dr Muammer Ozcimen, MD, Department of Ophthalmology, Konya Training and Research Hospital, 42090 Meram, Konya, Turkey. Tel:+905324563540. Fax:+903323236723. E-mail: [email protected]
History Received 10 November 2014 Revised 22 December 2014 Accepted 31 December 2014 Published online 18 February 2015
cross-sectional scans of the retina7. It has become a valuable tool for the diagnosis and management of chorioretinal disease. Choroidal imaging with EDI-OCT, is defined by Spaide et al.8 and has given the opportunity to investigate the effects of many ocular diseases and associated physiological changes of the choroid layer9–11. A variety of ocular pathologies may have primary or associated pathology located in the peripapillary choroidal region12,13. Analysis of the thickness of the peripapillary choroid in patients with COPD may help us in explaining the pathophysiology, following disease progression and measuring the response to therapy. However, no study has yet measured the peripapillary choroidal thickness in patients with COPD. The purpose of this study is to establish the thickness of the peripapillary choroid in patients with COPD.
Materials and methods This was a prospective observational study which was conducted under a protocol approved by the Konya Selcuk University Medical Faculty Ethics Committee and was in accordance with the ethical standards stated in the 1964 Declaration of Helsinki. Written informed consent was obtained from all participants. Eighty patients with COPD with at least 5 years of disease duration without any history of
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eye disorders other than mild cataracts were enrolled (COPD group). We used the spirometry for COPD diagnosis. According to the spirometry results, forced expiratory volume in 1 second/forced expiratory vital capacity (FEV1/ FVC) less than 70% and reversibility test negative patients were enrolled to the study. The control group (n ¼ 50) was chosen from subjects without any evidence of previous or current COPD and was consisted of age and sex-matched healthy patients having a history of smoking to avoid the possible effect of smoking on peripapillary choroidal thickness14. All subjects underwent a standardized measurement before hospitalized in which, height and weight were taken and body mass index (BMI) was calculated (weight in kg divided by height in m2). Only the participants with the BMI which is in normal (healthy weight) category (ranged from 18.5 to 25 kg/m2) were included in the study. Exclusion criteria included: history of previous laser and intraocular surgery, glaucoma, optic neuropathy, amblyopia, significant cataracts and spherical equivalent refractive errors (RE) more than ± 3.0 diopters, axial length (AL) exceeding 25 mm, choroidal neovascularization or myopic atrophy, clinically relevant opacities of the optic media and low-quality images due to unstable fixation. Participants with systemic diseases, such as diabetes, hypertension or cardiovascular disease were also not included in the study. All participants underwent a thorough ophthalmic evaluation, which included slitlamp biomicroscopy, intraocular pressure (IOP) measurement, fundus examination, a RE examination and AL measurements. Demographic and clinical data were collected for each subject. Blood gas analysis were performed for patients with COPD and oxygen saturation was measured by pulse oximetry in both groups. The participants in the study were asked not to smoke and consume any caffeine-containing drinks for at least 24 h before the OCT measurements. All participants were examined with dilated pupils using an enhanced depth imaging system (EDI; Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany). For measurements of peripapillary choroidal thickness, a 360-degree 3.4 mm diameter peripapillary circle scan was performed using the standard protocol for retinal nerve fiber layer (RNFL) assessment, as previously described15. The participants
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underwent the OCT examinations in the morning to avoid the diurnal variation in choroidal thickness measurements16,17. Keratometry readings and the refraction were entered into the software program to estimate optical magnification and, therefore, to allow for more accurate comparisons across individuals. The images were viewed and measured with the supplied Heidelberg Eye Explorer software (version 5.3; Heidelberg Engineering) by two independent graders. The choroidal thickness was measured manually from the outer portion of the hyperreflective line corresponding to the retinal pigment epithelium (RPE) to the inner surface of the sclera (Figure 1) at the temporal, superotemporal, superior, superonasal, nasal, inferonasal, inferior and inferotemporal segments. For EDI-OCT of subfoveal region, foveal-centered vertical and horizontal two line scans were performed in an assay of 100 frames, 30 and high resolution. The subfoveal choroidal thickness (SFCT) was calculated by obtaining a mean measurement of vertical and horizontal scans’ thicknesses. The RNFL thickness was also determined using the same peripapillary circle scan. Only the right eye of each study participant was assessed. The data were processed and statistically analyzed using a commercial analytical software program (SPSS 15.0; SPSS, Inc., Chicago, IL). The t-test for independent samples was used for comparing variables between groups. A one-way analysis of variance was used to determine whether average choroidal thickness differed among each of the eight peripapillary regions. When the analysis showed significant differences among the groups, post-hoc analysis utilizing the least significant difference (LSD) t-test method was used to analyze the variance. The reproducibility of choroidal thickness measurements between graders was calculated via intraclass correlation coefficients. Statistical significance was considered when p50.05. All parameters are expressed as mean ± standard deviation.
Results Seventy-three participants with COPD (7 were excluded from the study because of the inability to identify the choroid–scleral junction precisely) and 50 controls were included in the study. Data from all cases are summarized in Table 1.
Figure 1. Images from 360 3.4 mm diameter peripapillary circle scans. (A) EDI-OCT of patient with COPD, (B) EDI-OCT of control participant.
OCT in chronic obstructive pulmonary disease
DOI: 10.3109/15569527.2015.1004079
Table 1. Demographic and clinical data of patients with COPD and controls.
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Patients with COPD (n ¼ 73)
Controls (n ¼ 50)
Age (years) 65.60 ± 8.08 63.02 ± 5.62 Gender (male/female) 45/28 29/21 Disease duration (years) 11.98 ± 6.19 _ Smoking status (pack-year) 41.02 ± 22.85 38.22 ± 19.33 Spherical equivalent (D) 0.76 ± 0.28 0.72 ± 0.35 Axial length (mm) 22.40 ± 1.44 22.89 ± 1.28 Mean RNFL thickness (mm) 98.47 ± 13.77 103.25 ± 7.26 IOP 15.90 ± 3.43 14.72 ± 3.37 SBP (mmHg) 124.86 ± 10.57 122.40 ± 10.70 DBP (mmHg) 77.73 ± 7.72 75.70 ± 8.51 MBP (mmHg) 92.18 ± 9.87 91.02 ± 9.24 MOPP (mmHg) 76.28 ± 8.90 76.30 ± 8.64 pH 7.41 ± 0.41 _ PaO2 (mmHg) 55.61 ± 10.79 _ PaCO2 (mmHg) 42.92 ± 8.14 _ SO2 (mg/L) 87.00 ± 8.70 91.21 ± 4.35 BMI 22.90 ± 1.75 22.30 ± 1.81
p Value 0.053 _ _ 0.478 _ 0.057 0.044 0.061 0.211 0.179 0.311 0.744 _ _ _ 0.002 0.068
D ¼ diopter; RNFL ¼ retinal nerve fiber layer; IOP ¼ intraocular pressure; DBP ¼ diastolic blood pressure; SBP ¼ systolic blood pressure; MB ¼ mean blood pressure; MOPP ¼ mean ocular perfusion pressure; pH ¼ power of hydrogen; PaO2 ¼ partial pressure of oxygen in the blood; PaCO2 ¼ partial pressureof carbon dioxide in the blood; SO2 ¼ oxygen saturation; COPD ¼ chronic obstructive pulmonary disease; p value ¼ represents significance. Table 2. Average peripapillary choroidal thickness at different segments with 360 3.4 mm diameter peripapillary circle scans. Average choroidal thickness Segment
Patients with COPD (n ¼ 73)
Controls (n ¼ 50)
p Value
T ST S SN N IN I IT Average
149.45 ± 48.04 166.31 ± 64.82 159.79 ± 53.42 164.58 ± 62.94 155.90 ± 44.31 131.63 ± 35.97 125.53 ± 53.63 127.45 ± 41.38 147.58 ± 53.53
161.54 ± 47.82 170.18 ± 39.04 176.22 ± 50.87 178.34 ± 42.12 168.32 ± 40.81 146.04 ± 41.77 143.54 ± 38.58 142.54 ± 40.58 160.84 ± 44.73
0.172 0.681 0.090 0.149 0.118 0.043 0.032 0.048 0.068
T ¼ temporal; ST ¼ Superotemporal; S ¼ Superior; SN ¼ Superonasal; N ¼ nasal; IN ¼ Inferonasal; I ¼ Inferio;, IT ¼ Inferotemporal. p value represents significance. Bold values represent significance.
Ocular perfusion pressure (OPP) is expressed as the difference between the mean blood pressure (MBP) and the intraocular pressure (IOP), which is considered as a substitute for the venous pressure. Mean OPP was calculated as: 2/ 3(MBP - IOP)18. Mean blood pressure was calculated as: MBP ¼ DBP + [1/3(SBP - DBP)]. No significant correlations were found between the choroidal thickness and mean ocular perfusion pressure (MOPP) and IOP. The average peripapillary choroidal thickness of the COPD group (147.58 ± 53.53 lm) was lower than the control group (160.84 ± 44.73), but did not reveal significance (p ¼ 0.068). The choroidal thicknesses at different segments are shown in Table 2. The post-hoc analysis utilizing LSD t-test demonstrated that, for peripapillary choroid, the inferonasal, inferior and inferotemporal thicknesses were significantly thinner than the
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Table 3. Post-hoc analysis of the peripapillary choroidal thickness of patients with COPD at eight segments using least significant difference (LSD) t-test. Segment T ST S SN N IN I IT
T
ST
S
SN
N
IN
I
– – – – – – – 0.048 – – – – – – 0.225 0.444 – – – – – 0.076 0.839 0.574 – – – – 0.449 0.222 0.648 0.308 – – – 0.037 50.001 0.001 50.001 0.005 – – 0.005 50.001 50.001 50.001 50.001 0.474 – 0.010 50.001 50.001 50.001 0.001 0.624 0.822
IT – – – – – – – –
T ¼ temporal; ST ¼ Superotemporal; S ¼ Superior; SN ¼ Superonasal; N ¼ nasal; IN ¼ Inferonasal; I ¼ Inferior; IT ¼ Inferotemporal. Bold values represent significance.
Table 4. Post-hoc analysis of the peripapillary choroidal thickness of controls at eight segments using least significant difference (LSD) t-test. Segment T ST S SN N IN I IT
T – 0.315 0.088 0.051 0.430 0.072 0.037 0.027
ST
S
SN
N
IN
I
– – – – – – – – – – – – 0.482 – – – – – 0.342 0.805 – – – – 0.828 0.358 0.244 – – – 0.005 50.001 50.001 0.010 – – 0.002 50.001 50.001 0.004 0.771 – 0.001 50.001 50.001 0.003 0.684 0.907
IT – – – – – – – –
T ¼ temporal; ST ¼ Superotemporal; S ¼ Superior; SN ¼ Superonasal; N ¼ nasal; IN ¼ Inferonasal; I ¼ Inferior; IT ¼ Inferotemporal. Bold values represent significance.
temporal, superotemporal, superior, superonasal and nasal thicknesses in both groups (p50.05, Tables 3 and 4) except between inferonasal and temporal segments of control group (p ¼ 0.072, Tables 3 and 4). However, no statistically significant difference was noted among the inferonasal, inferior and inferotemporal thicknesses. None of the other segments demonstrated any significant differences with each other. The variation trend of peripapillary choroidal thickness is illustrated in Figure 2. Intraclass correlation coefficients showed agreement between the two graders (p50.001) and ranged from moderate (0.68, superotemporal) to very high (0.93, inferotemporal). Subfoveal choroidal thickness measurements of the COPD group (249.16 ± 55.35 lm) were lower than the control (264.48 ± 47.95 lm) group; but did not show any statistical significance (p ¼ 0.111). We did not find a difference in SFCT measurements of horizontal and vertical line scan of all eyes (p ¼ 0.539 and p ¼ 0.647 in COPD and controls, respectively). Peripapillary choroidal thickness was significantly correlated to SFCT in all segments (p50.001). Average RNFL thickness was significantly lower in COPD patients (p ¼ 0.044) and peripapillary choroidal thickness was significantly correlated to RNFL thickness in all segments except temporal (p ¼ 0.120) and inferior segments (p ¼ 0.089) in the COPD group. However, peripapillary choroidal thickness did not correlate to RNFL thickness in controls.
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Figure 2. Variation trend of peripapillary choroidal thickness. The superotemporal segment had the thickest choroidal thickness, while the inferior segment had the thinnest thickness. (A) patients with COPD, (B) controls.
Discussion In the present study, we found that the average peripapillary choroidal thickness measurements of the COPD group were lower than the control group, but did not reveal significance. Moreover, inferior segments were significantly thinner than the other peripapillary choroid segments in both groups. Similarly, there are few published studies that have characterized the peripapillary choroidal thickness in normal participants and found the inferior quadrant to be significantly thinner than the other segments19,20. Interestingly, we found that peripapillary choroid in the inferior segments of patients with COPD was significantly thinner than those of control participants. Choroidal thinning may be indicative of decreased blood flow in the choriocapillaris21. A thinner choroid may increase vascular resistance, resulting in a decreased blood flow in the choriocapillaris, which may be more sensitive to hypoxia or to elevated IOP. The fact that thinner choroid in the inferior sector of the optic disc may be important as this thinning makes this area more susceptible to retinal and choroidal diseases. COPD may increase vascular resistance and thereby decrease blood flow in ocular structures resulting in thinning of the choroid. Choroidal thickness reflects choroidal blood flow and depends on the perfusion pressure, IOP, nitric oxide (NO) production, endogenous catecholamines and vascular autoregulation22,23. Changes in its structure would help to evaluate choroidal and thus ocular blood flow24. Endothelin-1 and NO released from the vascular endothelium play a major role in the adaptation of choroidal vascular resistance23,25. Hypoxia appears to participate in the development of endothelial dysfunction26. However, in our present study, no significant associations were detected between the peripapillary choroidal thickness and the IOP and MOPP. This can be explained by the autoregulation of choroidal blood flow that may prevent excessive changes in choroidal thickness. Additionally, COPD may affect vascular endothelium by promoting inflammation and oxidative stress27,28. Conversely, hypoxia upregulates the production of vasoconstrictive mediators, thus leading to an increased vascular tone29.
The gratifying thing is that it has been shown that stable perfusion is provided by ocular vasoconstriction30. Palombi et al.31 emphasized vascular endothelium damage in most respiratory events as a result of desaturation and reoxygenation sequence. Hypoxia may be assumed to be the cause of ganglion cell death and reduced RNFL thickness in patients with COPD in our study. Additionally, peripapillary choroidal thickness was significantly correlated to RNFL thickness in all segments in the COPD group except temporal and inferior segments, which may be because of the small sample size used. However, peripapillary choroidal thickness did not correlate to RNFL thickness in controls. Thus, in future, larger scale studies should be conducted to confirm these observations. One of the limitations of our study was that there was a relatively small number of patients enrolled; however, the design of the study with age, sex and smoking habbit-matched control group makes the results more valuable. Other limitation of the study was that we did not measure ocular blood flow. Therefore, we were not able to fully investigate the relationship between the choroidal vascular flow and the choroidal thickness in patients with COPD. In summary, this was the first study to investigate the peripapillary choroid of patients with COPD. Our results have suggested that peripapillary choroidal thickness seems to be affected by COPD-related hypoxemia, vascular and endothelial dysfunction. Given the role of the choroidal vasculature in the blood supply of the anterior optic nerve head, studying on peripapillary choroidal thickness is of great significance. Understanding the peripapillary choroidal thickness may help us to clarify the possible effects of the disease to the eye and might be useful in clinical evaluation. Further studies with larger sample sizes are needed to determine more accurately whether there is a relationship between clinical grades and choroidal thicknesses.
Acknowledgements The authors thank Serap Ozcimen, MD, from the Department of Clinical Microbiology and Infectious Diseases, Konya, Turkey, for her assistance with manuscript preparation.
DOI: 10.3109/15569527.2015.1004079
Declaration of interest The authors declare no conflicts of interest.
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