OPTOMETRY RESEARCH PAPER

Transcription

1 C L I N I C A L A N D E X P E R I M E N T A L OPTOMETRY RESEARCH PAPER Interocular symmetry of retinal nerve fibre layer thickness in healthy eyes: a spectral-domain optical coherence tomographic study Clin Exp Optom 2014; 97: Young Hoon Hwang* MD Miryoung Song MD Yong Yeon Kim MD PhD Dong Ju Yeom MD Joo Hwa Lee MD PhD * Department of Ophthalmology, Konyang University, Kim s Eye Hospital, Myung-Gok Eye Research Institute, Seoul, Korea Department of Ophthalmology, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea Department of Ophthalmology, Korea University College of Medicine, Seoul, Korea Department of Ophthalmology, Yeoncheon-Gun Health Center and Country Hospital, Yeoncheon, Korea yongykim@korea.ac.kr Submitted: 23 December 2013 Revised: 10 May 2014 Accepted for publication: 19 May 2014 DOI: /cxo Purpose: This study was performed to investigate the interocular symmetry of peripapillary retinal nerve fibre layer (RNFL) thickness, as measured by Cirrus high-definition spectraldomain optical coherence tomography (OCT), in healthy eyes. A wide range of subject ages and refractive errors was examined. Methods: The retinal nerve fibre layer thickness was measured in 1,234 healthy eyes from 617 subjects using OCT. Interocular differences (right eye minus left eye) in global area and quadrant nerve fibre layer thicknesses were measured. The effect of age and refractive error on interocular nerve fibre layer thickness difference was also examined. Results: Means (and standard deviations) of subjects ages and average subject refractive errors were 36.4 ± 19.8 years (range: five to 80 years) and ± 2.91 D (range: to D), respectively. Cutoff limits for normal interocular nerve fibre layer thickness differences (2.5th and 97.5th percentiles of normative data) in the global area and in the superior, nasal, inferior and temporal quadrants were 9.5, 23.0, 15.6, 20.0 and 22.6 μm, respectively. Mean interocular retinal nerve fibre layer thickness differences in global area and in superior, nasal, inferior and temporal quadrants were 0.7 (p < 0.001), -3.9 (p < 0.001), 2.6 (p < 0.001), 1.1 (p = 0.007) and 3.0 (p < 0.001) μm, respectively. Interocular nerve fibre layer thickness differences were not significantly correlated with age or refractive error (average of right and left eyes, both p > 0.05). Conclusions: Significant interocular differences in peripapillary retinal nerve fibre layer thickness exist in healthy eyes, particularly in the superior quadrant. This finding should be considered when comparing retinal nerve fibre layer thickness between right and left eyes. Key words: glaucoma, myopia, optical coherence tomography, retina Detection of structural changes in the peripapillary retinal nerve fibre layer (RNFL) and optic nerve head (ONH) is important in diagnosing glaucoma. 1 3 Previous studies have reported that interocular asymmetry in retinal nerve fibre layer, optic nerve head and intraocular pressure (IOP) is an early sign of glaucomatous damage. 4 6 Further, various studies have assessed retinal nerve fibre layer thickness of the affected eye by comparing it to that of the non-affected fellow eye. 7 9 Therefore, it would be useful to know the normal range of interocular variation in retinal nerve fibre layer thickness and factors associated with interocular nerve fibre layer asymmetry. Previous optical coherence tomographic (OCT) studies in healthy eyes have shown inconsistent results in interocular nerve fibre layer thickness symmetry (Table 1) For instance, several studies have reported significant interocular differences in nerve fibre layer thickness in the superior quadrant of the retina 11,13 15,17,19 but others showed no such difference. 10,12,16 Age and myopia are both important risk factors for developing glaucoma. 20,21 Therefore, it is critical to investigate their effects on the differences in interocular nerve fibre layer thickness. Three previous studies showed that the interocular difference in nerve fibre layer thickness increases with age; 12,19,22 however, these studies included only children or adults within a limited age range. No study investigated interocular symmetry of retinal nerve fibre layer thickness in a population that included both children and adults. Regarding the effect of myopia on retinal nerve fibre layer thickness symmetry, we can speculate that interocular nerve fibre layer thickness asymmetry may increase with a higher degree of myopia. Little information is available on this issue. The current study was performed to evaluate interocular symmetry of peripapillary nerve fibre layer thickness profiles obtained from healthy subjects with Cirrus highdefinition spectral-domain OCT (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, California, USA). Subjects with wide ranges of age and refractive error were included to examine thoroughly how these two factors influence interocular nerve fibre layer symmetry. MATERIALS AND METHODS Participants The study protocol was approved by the Institutional Review Board of Kim s Eye Hospital, Korea and all study conduct adhered to the tenets of the Declaration of Helsinki. Healthy subjects, who visited the Kim s Eye Hospital, Seoul, Korea for a regular health 550 Clinical and Experimental Optometry 2014 Optometrists Association Australia

2 Author (year, number of subjects) Mean age (years, range) Device Mean difference in RNFL thickness (μm) Effect of age and refractive error Average Superior Nasal Inferior Temporal Age Refractive error Park and colleagues 10 (2005, 121) 43.2 (NA) Stratus OCT 3.3* * * NA NA Huynh and colleagues 11 (2007, 1,273) 6.7 (NA) Stratus OCT * -3.4* 3.8* -1.3* NA NA Budenz 12 (2008, 108) 46.0 (18 85) Stratus OCT 1.3* * NA Qian and colleagues 13 (2011, 199) 10.4 (5 18) Stratus OCT 1.2* -3.0* 8.2* NA NA Mwanza and colleagues 14 (2011, 284) 46.1 (18 84) Cirrus HD-OCT 0.5* -3.7* 1.9* 1.3* 2.6* - NA Dalgliesh and colleagues 15 (2013, 1,500) 17.3 (16 19) Cirrus HD-OCT 0.3* -4.0* 2.9* * NA NA Chen and colleagues 16 (2013, 1,529) NA (12 17) OCT-iVue * NA NA Altemir and colleagues 17 (2013, 357) 9.0 (6 13) Cirrus HD-OCT * 2.6* * - NA Lee and colleagues 18 (2013, 241) 21.4 (19 28) Cirrus HD-OCT 0.4 NA NA NA NA NA NA Al-Haddad and colleagues 19 (2014, 108) 10.7 (6 17) Cirrus HD-OCT * 2.2* * + NA Present study (2014, 617) 36.4 (5 80) Cirrus HD-OCT 0.7* -3.9* 2.6* 1.1* 3.0* - - NA : not applicable, + : significant effect, - : non-significant effect. *Significant difference at p < 0.05 Table 1. Previous study results of mean interocular differences (right eye minus left eye) in retinal nerve fibre layer (RNFL) thickness measured using optical coherence tomography (OCT) in healthy eyes. examination were enrolled. Each subject underwent a full ophthalmic examination, including assessment of visual acuity, refractive error and IOP. Additionally, the optic nerve head and fundus were examined with a 90 D lens and, for adult subjects, a 24-2 Swedish Interactive Threshold Algorithm standard automated visual field test (Humphrey Visual Field Analyzer; Carl Zeiss Meditec, Dublin, California, USA) was performed. All patients underwent peripapillary nerve fibre layer thickness measurement using the Cirrus HD-OCT. Inclusion criteria included a visual acuity of 6/9 or better, a normal IOP (less than 21 mmhg), a normal optic disc with no glaucomatous changes (that is, increased cup-to-disc ratio, neuroretinal rim narrowing), and a normal, reliable visual field (false positive/negatives less than 15 per cent, fixation losses less than 15 per cent, no significant pattern standard deviation at the less than five per cent level and normal glaucoma hemifield test results). Optical coherence tomographic measurements A 200 by 200 scan cube optic disc scan was obtained using the Cirrus HD-OCT. 23 To acquire images, the scanning laser was focused after subjects were seated and properly positioned in the chin rest. Using the iris and fundus views, the optic nerve head was aligned, so that it was the centre of the scan. Once the optic disc was centred on the live scanning laser image, data from a 6 by 6 mm square were captured. The Cirrus HD-OCT algorithm automatically determined the vitreoretinal surface and posterior boundary of the nerve fibre layer. From these determinations, the thickness of the nerve fibre layer was calculated over the scan area. Only images without prominent involuntary saccade artefacts and a signal strength seven or more were included in the analyses. Using the built-in Glaucoma OU Analysis mode of the Cirrus HD-OCT, measurements of the thickness of the nerve fibre layer were obtained for the global area and the superior, nasal, inferior and temporal quadrants. Statistical analyses A paired t-test was performed to evaluate the significance of interocular differences in refractive error and nerve fibre layer thickness. The relationship between the interocular differences in refractive error and thickness of the nerve fibre layer was evaluated using Pearson s correlation analysis. Correlations for interocular differences in nerve fibre layer thickness with age and with average refractive error of the right and left eyes were examined to determine the effects of these two parameters on interocular nerve fibre layer differences. Commercial software (SPSS version 12.0; SPSS, Chicago, Illinois, USA) was used to perform all statistical analyses and statistical significance was defined as p less than RESULTS This study included 1,234 eyes from 617 healthy subjects (277 female). Mean (with standard deviation) of subjects ages was 36.4 ± 19.8 years (range: 5 to 80 years) and mean refractive error (average of right and left eyes) was ± 2.91 D (range: to D). Examining each eye separately, mean refractive error was ± 2.94 D (range: to D) in the right eye and ± 2.92 D (range: to D) in the left eye, a difference that was statistically significant (p < 0.001). Normal ranges of interocular differences (right eye minus left eye) in nerve fibre layer thickness were defined as those within the 2.5th to 97.5th percentiles of normative data. The cut-off limits for normal interocular nerve fibre layer thickness differences in the global area and the superior, nasal, inferior and temporal quadrants were 9.5, 23.0, 15.6, 20.0 and 22.6 μm, respectively (Table 2). Data on interocular nerve fibre Clinical and Experimental Optometry 2014 Optometrists Association Australia 551

3 layer thickness difference are shown in Table 3. Mean interocular differences in the global area and in the superior, nasal, inferior and temporal quadrants were 0.7 (p < 0.001), -3.9 (p < 0.001), 2.6 (p < 0.001), 1.1 (p = 0.007) and 3.0 μm (p < 0.001), respectively. We examined the association between interocular refractive error differences and interocular nerve fibre layer thickness differences. The amount that the right eye was more myopic than the left eye was associated with the amount that the right eye had a thinner retinal nerve fibre layer in the superior quadrant (r = 0.160, p < 0.001) and a thicker fibre layer in the temporal quadrant (r = , p < 0.001) than the left eye. The association between these two measures was not significant in any other quadrant (p > 0.05). Additionally, the interocular nerve fibre layer thickness difference was not significantly correlated with age or average refractive error of right and left eyes (p > 0.05). Percentile Global area Quadrant Superior Nasal Inferior Temporal Table 2. Percentile distribution of interocular differences (right eye minus left eye) in retinal nerve fibre layer thickness (μm). Right eye Left eye Difference p-value Global area 96.0 ± ± ± 4.4 < Quadrant Superior ± ± ± 10.2 < Nasal 67.2 ± ± ± 7.5 < Inferior ± ± ± Temporal 75.6 ± ± ± 7.9 < Right versus left eye; paired t-test. Table 3. Interocular difference (right eye minus left eye) in retinal nerve fibre layer thickness (mean ± standard deviation in μm). DISCUSSION In the present study, the cut-off limits for normal interocular differences (between the 2.5th and 97.5th percentiles of normative data) over the global area and in the nerve fibre layer thickness of retinal quadrants were 9.5 and 23.0 μm, respectively. Significant interocular differences in peripapillary nerve fibre layer thickness were found in healthy eyes, especially in the superior quadrant. Age and average right and left refractive error did not affect interocular nerve fibre layer thickness differences. Our conclusions on symmetry of interocular retinal nerve fibre layer thickness were made by examining a large number of subjects with the widest age and refractive error ranges. The symmetry of interocular retinal nerve fibre layer thickness has been examined previously by several studies with the time-domain Stratus OCT (Carl Zeiss Meditec, Dublin, California, USA) and the spectral-domain Cirrus HD-OCT 14,15,17 19 or OCT-iVue100 (Optovue, Inc, Fremont, California, USA) 16 (Table 1). The cut-off limit for normal interocular differences in average retinal nerve fibre layer thickness (9.5 μm) in the present study was similar to that used in previous Cirrus HD-OCT studies ( and 9.3 μm 15 ) but lower than those used in Stratus OCT studies (11.7 to 17.0 μm) This difference may be explained, in part, by the lower measurement variability of the Cirrus HD-OCT compared with the Stratus OCT. 24,25 Although the statistical significance of differences in interocular nerve fibre layer thickness has varied among studies, common findings were reported, namely, the right eye rather than the left eye, had a thinner nerve fibre layer in the superior quadrant and a thicker or similar nerve fibre layer in all other quadrants examined. 10,12 15,17,19 Previous studies found that higher levels of myopia were associated with a thinner nerve fibre layer in the superior, nasal and inferior quadrants and a thicker nerve fibre layer in the temporal quadrant. 23,26 We observed that a higher level of myopia in the right eye was associated with a thinner superior and a thicker temporal nerve fibre layer in the right eye. Therefore, differences in the interocular nerve fibre layer thickness in the superior and temporal quadrants may be due, in part, to differences in refractive error between the eyes. Although the right eye was more myopic than the left eye, the retinal nerve fibre layer thickness was greater in the nasal and inferior quadrants of the right eye. Therefore, other factors besides interocular refractive error differences, including interocular variation in topographic retinal blood vessel distributions 18,27 or retinal ganglion cell axon and glial cell densities, 14 may also contribute to the observed interocular asymmetry in retinal nerve fibre layer thickness. Recently, Lee and colleagues 18 reported that superior retinal vessels in the right eye were located more temporally than in the left eye. Given that the retinal nerve fibre layer is mainly distributed along the retinal vessels, 27 this finding can be attributed in part to the thinner superior and thicker temporal retinal nerve fibre layers in the right eye than in the left eye. Another possible cause of asymmetry in interocular nerve fibre layer thickness is measurement artefact. The retinal nerve fibre layer thickness profile measurements are influenced by scan angle 28 or 552 Clinical and Experimental Optometry 2014 Optometrists Association Australia

4 cyclotorsion. 18,29 If the OCT source light is reflected differently in the right and left eyes, measurement error may be the cause of the observed asymmetry in the interocular retinal nerve fibre layer thickness profile. Further study regarding this issue is needed. Our study included subjects with higher degrees of myopia than previous studies investigating interocular nerve fibre layer thickness symmetry As a result, refractive error differences between subjects should be considered when comparing our results with those of other studies. It may be that interocular symmetry differs with myopia but our study indicates that this is not the case (average right and left refractive error did not significantly correlated with interocular differences in retinal nerve fibre layer thickness). In addition, our cut-off limits for normal nerve fibre layer thickness symmetry were similar to those used in previous studies, 14,15 which also found a trend toward a thinner nerve fibre layer in the superior quadrant and a thicker layer in other areas in the right eye. Therefore, we conclude that interocular differences in retinal nerve fibre layer thickness are not influenced by refractive error. It has been suggested that the amount of asymmetry in retinal nerve fibre layer thickness may be affected by age. 12,19,22 Budenz 12 reported that, although not strongly associated (r 2 = 0.031), interocular differences in nerve fibre layer thickness increased with age. Funaki and colleagues 22 also confirmed this finding. Among healthy children (ages six to 17 years), those older than 10 years showed more pronounced variation in the interocular difference in nerve fibre layer thickness than the younger group. 19 In contrast, we did not find a significant association between age and interocular asymmetry of nerve fibre layer thickness. Previous studies examined a relatively small number of adults 12,22 or children 19 but our study included a large number of adults and children. It may be that selection bias contributed, at least in part, to the observations in other studies of a significant correlation between age and interocular nerve fibre layer thickness difference. Given that nerve fibre layer thickness may change with advancing age, 22,30 further studies investigating longitudinal changes in nerve fibre layer symmetry are needed. Many OCT studies have evaluated retinal nerve fibre layer thickness in only one eye, with the study eye chosen at random or based on disease severity. The right or left distribution of study eyes may have affected retinal nerve fibre layer thickness results, particularly if OCT were used to obtain the measurements. Although not great in magnitude, we found that healthy eyes had a significantly thinner superior retinal nerve fibre layer in the right eye than in the left eye. Therefore, when comparing nerve fibre layer thickness between two groups, more frequent inclusion of the right eye in one group than in the other could result in an overestimation of interocular differences in the thickness of the nerve fibre layer in the superior quadrant. Future studies should consider the right/left distributions of included eyes to maximise OCT study accuracy. In conclusion, the thickness of the retinal nerve fibre layer varied significantly between the right and left eyes but age and refractive error did not affect the magnitude of these differences. Interocular asymmetry should be considered when interpreting Cirrus HD-OCT thickness measurements of the retinal nerve fibre layer. REFERENCES 1. Schuman JS, Hee MR, Puliafito CA, Wong C, Pedut-Kloizman T, Lin CP, Hertzmark E and colleagues. Quantification of nerve fiber layer thickness in normal and glaucomatous eyes using optical coherence tomography. Arch Ophthalmol 1995; 113: Budenz DL, Michael A, Chang RT, McSoley J, Katz J. Sensitivity and specificity of the StratusOCT for perimetric glaucoma. Ophthalmology 2005; 112: Medeiros FA, Zangwill LM, Bowd C, Vessani RM, Susanna R Jr, Weinreb RN. Evaluation of retinal nerve fiber layer, optic nerve head and macular thickness measurements for glaucoma detection using optical coherence tomography. Am J Ophthalmol 2005; 139: Fishman RS. Optic disc asymmetry. A sign of ocular hypertension. Arch Ophthalmol 1970; 84: Quigley HA, Enger C, Katz J, Sommer A, Scott R, Gilbert D. Risk factors for the development of glaucomatous visual field loss in ocular hypertension. Arch Ophthalmol 1994; 112: Cartwright MJ, Anderson DR. Correlation of asymmetric damage with asymmetric intraocular pressure in normal tension glaucoma (low-tension glaucoma). Arch Ophthalmol 1988; 106: Choi F, Park KH, Kim DM, Kim TW. Retinal nerve fiber layer thickness evaluation using optical coherence tomography in eyes with optic disc hemorrhage. Ophthalmic Surg Lasers Imaging 2007; 38: Mansoori T, Viswanath K, Balakrishna N. Quantification of retinal nerve fiber layer thickness after unilateral acute primary angle closure in Asian Indian eyes. J Glaucoma 2013; 22: Kupersmith MJ, Mandel G, Anderson S, Meltzer DE, Kardon R. Baseline, one and three month changes in the peripapillary retinal nerve fiber layer in acute optic neuritis: relation to baseline vision and MRI. J Neurol Sci 2011; 308: Park JJ, Oh DR, Hong SP, Lee KW. Asymmetry analysis of the retinal nerve fiber layer thickness in normal eyes using optical coherence tomography. Korean J Ophthalmol 2005; 19: Huynh SC, Wang XY, Burlutsky G, Mitchell P. Symmetry of optical coherence tomography retinal measurements in young children. Am J Ophthalmol 2007; 143: Budenz DL. Symmetry between the right and left eyes of the normal retinal nerve fiber layer measured with optical coherence tomography (an AOS thesis). Trans Am Ophthalmol Soc 2008; 106: Qian J, Wang W, Zhang X, Wang F, Jiang Y, Wang W, Xu S, and colleagues. Optical coherence tomography measurements of retinal nerve fiber layer thickness in chinese children and teenagers. J Glaucoma 2011; 20: Mwanza JC, Durbin MK, Budenz DL. Interocualr symmetry in peripapillary retinal nerve fiber layer thickness measured with the Cirrus HD-OCT in healthy eyes. Am J Ophthalmol 2011; 151: Dalgliesh JD, Tariq YM, Burlutsky G, Mitchell P. Symmetry of retinal parameters measured by spectral-domain OCT in normal young adults. J Glaucoma [Epub ahead of print]. 16. Chen L, Huang J, Zou H, Xue W, Ma Y, He X, Lu L, and colleagues. Retinal nerve fiber layer thickness in normal Chinese students aged 6 to 17 years. Invest Ophthalmol Vis Sci 2013; 54: Altemir I, Oros D, Elía N, Polo V, Larrosa JM, Pueyo V. Retinal asymmetry in children measured with optical coherence tomography. Am J Ophthalmol 2013; 156: Jee D, Hong SW, Jung YH, Ahn MD. Interocular retinal nerve fiber layer thickness symmetry value in normal young adults. J Glaucoma [Epub ahead of print]. 19. Al-Haddad C, Antonios R, Tamim H, Noureddin B. Interocular symmetry in retinal and optic nerve parameters in children as measured by spectral domain optical coherence tomography. Br J Ophthalmol 2014; 98: Marcus MW, de Vries MM, Montolio FG, Jansonius NM. Myopia as a risk factor for open-angle glaucoma: A systematic review and meta-analysis. Ophthalmology 2011; 118: Leske MC, Connell AM, Wu SY, Hyman LG, Schachat AP. Risk factors for open-angle glaucoma: the Barbados Eye Study. Arch Ophthalmol 1995; 113: Funaki S, Shirakashi M, Funaki H, Yaoeda K, Abe H. Relationship between age and the thickness of the retinal nerve fiber layer in normal subjects. Jpn J Ophthalmol 1999; 43: Hwang YH, Yoo C, Kim YY. Myopic optic disc tilt and the characteristics of peripapillary retinal nerve fiber layer thickness measured by spectraldomain optical coherence tomography. J Glaucoma 2012; 21: Leung CK, Cheung CY, Weinreb RN, Qiu Q, Liu S, Li H, Xu G and colleagues. Retinal nerve fiber layer imaging with spectral-domain optical coherence tomography: a variability and diagnostic performance study. Ophthalmology 2009; 116: Hong S, Kim CY, Lee WS, Seong GJ. Reproducibility of peripapillary retinal nerve fiber layer thickness with spectral domain cirrus high-definition Clinical and Experimental Optometry 2014 Optometrists Association Australia 553

5 optical coherence tomography in normal eyes. Jpn J Ophthalmol 2010; 54: Kang SH, Hong SW, Im SK, Lee SH, Ahm MD. Effect of myopia on the thickness of the retinal nerve fiber layer measured by Cirrus HD optical coherence tomography. Invest Ophthalmol Vis Sci 2010; 51: Hood DC, Fortune B, Arthur SN, Xing D, Salant JA, Ritch R, Liebmann JM. Blood vessel contributions to retinal nerve fiber layer thickness profiles measured with optical coherence tomography. J Glaucoma 2008; 17: Hong S, Kim CY, Seong GJ. Adjusted peripapillary retinal nerve fiber layer thickness measurements based on the optic nerve head scan angle. Invest Ophthalmol Vis Sci 2010; 51: Hwang YH, Lee JY, Kim YY. The effect of head tilt on the measurements of retinal nerve fibre layer and macular thickness by spectral-domain optical coherence tomography. Br J Ophthalmol 2011; 95: Lee JY, Hwang YH, Lee SM, Kim YY. Age and retinal nerve fiber layer thickness measured by spectral domain optical coherence tomography. Korean J Ophthalmol 2012; 26: Clinical and Experimental Optometry 2014 Optometrists Association Australia