- Email: [email protected]
Relationship of Retinal Vascular Caliber with Optic Disc and Macular Structure
Relationship of Retinal Vascular Caliber with Optic Disc and Macular Structure LAURENCE S. LIM, SEANG MEI SAW, NING CHEUNG, PAUL MITCHELL, AND TIEN Y. WONG ● PURPOSE:
To examine the relationships of retinal vascular caliber with optic disc, macular, and retinal nerve fiber layer (RNFL) characteristics as measured with optical coherence tomography (OCT). ● DESIGN: Observational cross-sectional study. ● METHODS: This study included a subset of healthy children enrolled in the Singapore Cohort Study of the Risk Factors of Myopia (SCORM). Optic disc, macular, and RNFL morphology were measured with Stratus OCT 3. Digital retinal photography was performed and retinal arteriolar and venular caliber measured using validated imaging software. ● RESULTS: One hundred and four children (mean age 11.51 ⴞ 0.52 years; 50% male) were included. In multivariate analyses, smaller horizontal integrated rim width and rim area were associated with narrower retinal arterioles and venules (all P < .05), and shorter horizontal rim length was associated with narrower venules (P ⴝ .04). Optic disc diameter was not associated with arteriolar or venular caliber. Larger vertical cup-to-disc ratios and cup-to-discarea ratios were associated with narrower venules but not arterioles (P ⴝ .01 and P ⴝ .003, respectively). A thinner average RNFL measurement was associated with narrower arterioles and venules, and smaller total macular volume was associated with narrower venules. ● CONCLUSIONS: Thinner optic disc rims and RNFL measurements were associated with narrower retinal arterioles and venules, and larger cup-to-disc ratios with narrower venules. These findings suggest that retinal vessel caliber varies systematically with morphologic differences in the optic nerve head, retina, and macula. (Am J Ophthalmol 2009;148:368 –375. © 2009 by Elsevier Inc. All rights reserved.)
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ARIATIONS IN RETINAL VASCULAR CALIBER, MEA-
sured quantitatively from retinal images, have been linked to several major eye diseases, including diabetic retinopathy, age-related macular degeneration
Accepted for publication Apr 8, 2009. From the Singapore National Eye Centre, Singapore (L.S.L., T.Y.W.); Singapore Eye Research Institute (L.S.L., S.M.S., T.Y.W.); Department of Community, Occupational and Family Medicine, National University of Singapore, Singapore (S.M.S.); Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Victoria, Australia (N.C., T.Y.W.); and the Centre for Vision Research, University of Sydney, Sydney, Australia (P.M.). Inquiries to Tien Y. Wong, Singapore Eye Research Institute, Singapore National Eye Centre, 11 Third Hospital Ave, #05-00, Singapore 168751; e-mail: [email protected]
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(AMD), and glaucoma.1–7 More recently, studies have begun to explore the relationships of retinal vascular caliber with morphologic changes in the retina and optic disc in generally healthy young children. Such knowledge may help us document normal anatomic relationships that may provide insights into the vascular genesis of various eye diseases. However, extant data are limited, with inconsistent findings reported among some studies.6 The Sydney Childhood Eye Study (SCES)8 showed that retinal vessels were narrower in eyes with smaller optic discs, thinner macula, and thinner retinal nerve fiber layer (RNFL) in predominantly healthy White children. These findings have yet to be verified by other studies. In addition, it remains unclear whether similar relationships are also present in other ethnic groups (eg, Asians), who may have inherently different optic nerve structures9 and retinal vascular caliber.10 In this study, we describe the relationships of retinal vascular caliber with optic disc, macular, and RNFL characteristics, as determined from optical coherence tomography (OCT), in young, healthy Asian children.
METHODS ● STUDY POPULATION:
This cross-sectional study was on a subset of participants from the Singapore Cohort Study of Risk Factors for Myopia (SCORM), which examined 1,979 children aged 7 to 9 years at baseline in 1999 and thereafter yearly in 3 schools in Singapore. The study methodology and details of the study population have been described in detail elsewhere.11,12 The main exclusion criteria included significant systemic illnesses and ocular conditions including media opacity, uveitis, or a history of intraocular surgery, refractive surgery, glaucoma, or retinal disease. The study sample included 104 Chinese children who were randomly selected from 561 children in the Western school during the 2005 examination for OCT measurements.13 For the purposes of this study, all ocular measurements from the right eye were included in the analysis. ● OPTICAL COHERENCE TOMOGRAPHY MEASUREMENTS:
OCT was performed with the Stratus OCT 3 (Carl Zeiss Meditec, Dublin, California, USA) and all images were analyzed with the included software (version 4.1 software).
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All scans were performed by a trained ophthalmologist in a dim room with pupil dilation to ⱖ5 mm, and fixation was monitored throughout.13 Cycloplegia was achieved with 3 drops of 1% cyclopentolate 5 minutes apart, and scans were performed only after an interval of at least 30 minutes after the third drop. Demographic data, axial length (AL), and refraction were entered into the system prior to scanning and analysis. Optic disc measurements were performed using the fast optic disc scan protocol, which consists of a set of 6 linear scans along 6 equidistant diameters spaced 30 degrees apart. Optic disc parameters measured included the disc diameter, cup diameter, disc area, cup area, rim area, cup-to-disc-area ratio, vertical and horizontal cup-to-disc ratios, cup area, and cup volume. RNFL thickness was measured using the RNFL thickness scan algorithm consisting of 512 A scans centered on the disc. Peripapillary RNFL thickness parameters calculated at a 3.4-mm-diameter circle using the RNFL thickness serial analysis protocol included the average RNFL thickness, superior and inferior maximum thickness, superior and inferior average thickness, and the maximum-minimum RNFL thickness. Retinal thickness was measured as the distance between the first signal from the vitreoretinal interface and the signal from the anterior boundary of the retinal pigment epithelial layer. The fast macular scanning protocol was used, with 6 6-mm lines in a radial spoke pattern centered over the fovea acquired automatically. Each linear scan is composed of 128 equally spaced A scans. The topography of the macular thickness map generated by the software consists of 3 concentric rings with diameters of 1-mm, 3-mm, and 6-mm. The innermost 1-mm circle is designated the fovea, the area between the 1-mm and 3-mm rings the inner macula, and the area between the 3-mm and 6-mm rings the outer macula. The parameters measured were the minimum foveal thickness; average foveal thickness; inner and outer macular thickness in the temporal, superior, nasal, and inferior quadrants; the foveal volume; inner and outer macular volume in the temporal, superior, nasal, and inferior quadrants; and the total macular volume (TMV). The inner and outer macular thickness and volumes in the temporal, superior, nasal, and inferior quadrants were averaged to obtain average inner and outer macular thickness and volumes. All scans were repeated 3 times and the results averaged. ● RETINAL VASCULAR CALIBER MEASUREMENTS:
The methods for obtaining digital fundal photographs and for measuring retinal vascular caliber from these photographs have been described in earlier publications from SCORM.14 –16 Retinal photographs centered on the optic disc were obtained with a digital fundal camera (Canon CR6-NM45, EOS-D60 6.3 mega-pixel; Canon Inc, Lake Success, New York, USA) through a dilated pupil. A computer-based program was then used to measure the
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caliber of all retinal vessels located between one-half and 1 disc diameter from the optic disc margin. A pair of indices, the central retinal arteriolar and venular equivalents (CRAE and CRVE), representing the average arteriolar and venular calibers for each eye, was then calculated using formulae described previously.17,18 Correction of CRAE and CRVE for ocular magnification was performed using the Bengtsson formula.19,20 All retinal measurements were performed by a single grader who was masked to the subjects’ identity and other measured parameters. Remeasurement of 50 images 2 weeks later showed high reproducibility, with intraclass correlation coefficients of 0.85 for arteriolar caliber and 0.97 for venular caliber.21 ● OTHER STUDY PROCEDURES: Cycloplegic refraction was performed with an autokeratorefractometer (model RK5; Canon Inc Ltd, Tochigiken, Japan). Five consecutive readings were obtained with 1 of 2 calibrated autokeratorefractometers and averaged. AL measurements were performed with a contact ultrasound A-scan biometry machine (Echoscan model US-800, probe frequency of 10 mHz; Nidek Co Ltd, Tokyo, Japan), with 1 drop of 0.5% proparacaine for topical anesthesia. Measurements were repeated until the standard deviation (SD) was ⬍0.12 mm and the average of 6 measurements taken. Height was measured with children standing, without shoes. Weight in kilograms was measured using a standard portable weighing machine calibrated before the beginning of the study. Blood pressure (BP) was measured on the school premises according to a standard protocol. After 5 minutes of rest, BP was measured in a seated position using an automated sphygmomanometer (Omron Healthcare Inc, Bannockburn, Illinois, USA) with appropriate cuff size. The cuff size was selected to ensure that the bladder spanned the circumference of the arm and covered at least 75% of the upper arm without obscuring the antecubital fossa. Three separate measurements were taken and averaged for analysis. Mean arterial blood pressure (MABP) was defined as two-thirds of the diastolic BP plus one-third of the systolic BP.11,22 The parents of the subjects completed several questionnaires asking about father’s education level, classified as no formal education, primary school education, secondary school education, pre-university education or diploma, and tertiary/university education. ● STATISTICAL ANALYSIS:
Demographic characteristics and differences in study variables between the children included and excluded from OCT measurements were performed using t test or 2, as appropriate. Linear regression models were constructed with CRAE or CRVE as the dependent variable to estimate the differences in CRAE and CRVE for each SD change in the OCT parameters, adjusted initially for age and gender, and additionally for body mass index, birth weight, MABP, and father’s education as an indicator of overall socioeconomic status.
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370 TABLE 1. Relationship of Optical Coherence Tomography Optic Disc Parameters to Retinal Vascular Caliber Retinal Arteriolar Caliber (m)
Retinal Venular Caliber (m)
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Mean Difference (95% CI)
P value
Mean Difference (95% CI)
P value
Mean Difference (95% CI)
P value
Mean Difference (95% CI)
P value
Vertical disc diameter (0.32 mm) Vertical cup diameter (0.35 mm) Horizontal rim length (0.36 mm) Vertical integrated rim area (0.30 mm2) Horizontal integrated rim width (0.26 mm) Disc area (0.43 mm2) Cup area (0.34 mm2) Rim area (0.37 mm2) Cup-to-disc-area ratio (0.19) Horizontal cup-to-disc ratio (0.13) Vertical cup-to-disc ratio (0.11) Topographical cup area (0.32 mm2) Topographical cup volume (0.19 mm3) Average nerve width at disc margin (0.06 mm)
2.97 (⫺4.88, 10.82) ⫺3.06 (⫺10.10, 3.99) 5.53 (⫺1.58, 12.64) 7.64 (⫺0.32, 15.59) 9.12 (0.26, 17,98) 2.37 (⫺3.03, 7.76) ⫺3.47 (⫺10.86, 3.92) 6.54 (⫺0.06, 13.14) ⫺1.28 (12.93, 10.38) ⫺3.66 (⫺22.19, 14.88) ⫺16.54 (⫺38.24, 5.17) ⫺3.18 (⫺11.33, 4.97) 1.19 (⫺11.06, 13.44) 43.91 (2.93, 84.89)
.45 .39 .13 .06 .04 .39 .35 .052 .83 .70 .13 .44 .85 .04
3.16 (⫺4.98, 11.30) ⫺3.47 (⫺11.02, 4.08) 6.56 (⫺1.25, 14.38) 8.26 (⫺0.17, 16.70) 9.96 (0.67, 19.24) 3.08 (⫺2.64, 8.79) ⫺3.31 (⫺11.25, 4.63) 7.38 (0.44, 14.32) ⫺4.88 (⫺17.39, 7.63) ⫺5.44 (⫺25.22, 14.34) ⫺18.79 (⫺42.00, 4.38) ⫺3.28 (⫺11.96, 5.40) 0.82 (⫺12.23, 13.87) 48.56 (4.37, 92.75)
.44 .36 .10 .06 .04 .29 .41 .04 .44 .59 .11 .45 .90 .03
4.54 (⫺7.42, 16.50) ⫺6.70 (⫺17.09, 4.30) 10.06 (⫺0.71, 20.83) 19.31 (7.67, 30.96) 21.43 (8.40, 34.46) 3.26 (⫺4.98, 11.49) ⫺8.72 (⫺19.87, 2.44) 12.22 (2.28, 22.15) ⫺24.35 (⫺41.30, ⫺7.40) ⫺23.82 (⫺51.61, 3.97) ⫺42.31 (⫺74.54, ⫺10.07) ⫺8,73 (⫺21.05, 3.59) ⫺2.32 (⫺20.98, 16.34) 70.43 (8.16, 132.70)
.45 .24 .07 .001 .002 .43 .12 .02 .005 .09 .01 .16 .81 .03
3.35 (⫺8.62, 15.31) ⫺8.13 (⫺19.11, 2.86) 11.71 (0.34, 23.07) 21.18 (9.47, 32.89) 21.16 (9.00, 34.32) 1.44 (⫺7.01, 9.88) ⫺10.47 (⫺21.93, 0.98) 10.58 (0.39, 20.77) ⫺26.69 (⫺44.07, ⫺9.32) ⫺24.45 (⫺52.98, 4.09) ⫺44.06 (⫺77.13, ⫺11.00) ⫺8.93 (⫺21.55, 3.69) 0.96 (⫺18.19, 20.11) 89.81 (26.20, 153.42)
.58 .14 .04 .001 .002 .74 .07 .04 .003 .09 .01 .16 .92 .006
CI ⫽ confidence interval; SD ⫽ standard deviation. Adjusted for age, gender, body mass index, birth weight, mean arterial blood pressure, and father’s education.
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P value
.009 .10 .19 .10 .002 .53 0.49 (0.13, 0.85) 0.16 (⫺0.03, 0.35) 0.13 (⫺0.07, 0.33) 0.21 (⫺0.04, 0.46) 0.34 (0.13, 0.56) 0.07 (⫺0.14, 0.27) .004 .10 .13 .10 ⬍.001 .55
a
0.26 (0.03, 0.49) 0.10 (⫺0.02, 0.22) 0.09 (⫺0.04, 0.22) 0.15 (⫺0.02, 0.31) 0.13 (⫺0.01, 0.28) 0.13 (⫺0.001, 0.26) RNFL average (9.79 m) Inferior maximum (52.16 m) Superior maximum (17.43 m) Inferior average (15.55 m) Superior average (15.87 m) Maximum-minimum (16.62 m)
CI ⫽ confidence interval; RNFL ⫽ retinal nerve fiber layer; SD ⫽ standard deviation. Adjusted for age, gender, body mass index, birth weight, mean arterial blood pressure, and father’s education.
0.51 (0.17, 0.86) 0.15 (⫺0.03, 0.34) 0.15 (⫺0.04, 0.34) 0.21 (⫺0.04, 0.45) 0.38 (0.17, 0.58) 0.06 (⫺0.14, 0.27) .04 .19 .17 .11 .06 .07 0.26 (0.01, 0.51) 0.09 (⫺0.04, 0.21) 0.09 (⫺0.04, 0.23) 0.14 (⫺0.03, 0.31) 0.15 (⫺0.004, 0.30) 0.13 (⫺0.01, 0.27)
Mean Difference (95% CI)
.03 .11 .16 .08 .06 .052
Multivariate-Adjusteda
Mean Difference (95% CI) P value Mean Difference (95% CI)
RESULTS THE MEAN AGE OF THE SUBJECTS INCLUDED IN THE STUDY
RNFL Parameters (per SD increase)
P value
Mean Difference (95% CI)
P value
Retinal Venular Caliber (m)
Age- and Gender-Adjusted Multivariate-Adjusteda
Retinal Arteriolar Caliber (m)
Age- and Gender-Adjusted
TABLE 2. Relationship of Optical Coherence Tomography Retinal Nerve Fiber Layer Parameters to Retinal Vascular Caliber
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These factors had been identified as covariates associated with retinal vascular caliber in previous studies from the same cohort. All probabilities quoted are two-sided and all statistical analyses were undertaken using statistical analysis software (SPSS version 13.0; SPSS Inc, Chicago, Illinois, USA).
was 11.51 ⫾ 0.52 years, half were male, and the mean CRAE and CRVE were 154.05 ⫾ 10.87 m and 230.32 ⫾ 16.26 m, respectively. The mean spherical equivalent refraction was 0.46 ⫾ 0.48 diopters and the mean AL was 22.86 ⫾ 0.69 mm. Compared to excluded children (n ⫽ 590), children included in the study (n ⫽ 104) were more likely to be Chinese and younger. (11.51 ⫾ 0.52 years vs 12.21 ⫾ 1.12 years; P ⬍ .001) (data not shown). Table 1 summarizes the associations between optic disc parameters and retinal vascular caliber. After controlling for age and gender, thinner horizontal integrated rim width was associated with narrower retinal arteriolar and venular caliber. For every SD decrease in horizontal integrated rim width, arteriolar caliber decreased by 9.12 m (95% confidence interval [CI], 0.26, 17.98; P ⫽ .04) and venular caliber by 21.43 m (95% CI, 8.40, 34.46; P ⫽ .002) in age- and gender-adjusted models, and by 9.96 m (95% CI, 0.67, 19.24; P ⫽ .04) and 21.16 m (95% CI, 9.00, 34.32; P ⫽ .002) respectively, in multivariate-adjusted models. Shorter horizontal rim length was associated with narrower venular caliber, 11.71 m (95% CI, 0.34, 23.07) per SD decrease in horizontal rim length. Smaller rim area was associated with both narrower arteriolar and venular caliber after adjustment; 7.38 m (95% CI, 0.44, 14.32) and 10.58 m (95% CI, 0.39, 20.77) per SD decrease in rim area, respectively. Larger vertical cup-to-disc ratios and cup-to-disc-area ratios were associated with narrower venular caliber by ⫺44.06 m (95% CI, ⫺77.13, ⫺11.00) and by ⫺26.69 m (95% CI, ⫺44.07, ⫺9.32) decreases per SD increase in vertical cup-to-disc ratios and cup-todisc-area ratios, respectively, but not with arteriolar caliber in either age- and gender-adjusted or multivariate models. No significant associations were found between optic disc diameter and either arteriolar or venular caliber. Table 2 shows the relationship of RNFL thickness and macular parameters to retinal vascular caliber. Average RNFL thickness showed associations with both arteriolar and venular caliber. For every SD decrease in RNFL thickness, arteriolar caliber decreased by 0.26 m (95% CI, 0.03, 0.49; P ⫽ .03) and venular caliber by 0.51 m (95% CI, 0.17, 0.86; P ⫽ .004) in age- and gender-adjusted models, and by 0.26 m (95% CI, 0.01, 0.51; P ⫽ .04) and 0.49 m (95% CI, 0.13, 0.85; P ⫽ .009) respectively, in multivariate-adjusted models. For venular caliber, the variation was primarily in the superior quadrant. Of all the
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.02 .44 .37 .35 .21 .39 .41 .20 12.54 (2.27, 22.81) 0.08 (⫺0.12, 0.28) ⫺0.05 (⫺0.15, 0.06) 0.15 (⫺0.16, 0.46) 0.21 (⫺0.11, 0.53) 127.24 (⫺167.99, 4222.27) 80.62 (⫺111.59, 272.84) 39.68 (⫺21.35, 100.72)
DISCUSSION OUR STUDY IN A POPULATION SAMPLE OF HEALTHY
school-aged Chinese children demonstrates significant correlations between retinal vascular caliber and different optic disc, RNFL, and macular features as measured by OCT. Given the high reliability and reproducibility of both of these imaging modalities,23–26 and the absence of ocular or systemic disease in the study population, our findings likely represent physiologic relationships with a high degree of validity. We found that thinner optic disc rims and RNFL measurements were associated with narrower retinal arteriolar and venular caliber, with larger cup-to-disc ratios associated with narrower venular caliber. There are few directly comparable studies. Two studies have documented the relationship of retinal vascular caliber with more subjective assessment of optic disc parameters from fundus photographs. The Beaver Dam Eye Study27 in older adults with a mean age of 69 years reported that eyes with smaller optic discs, as documented from retinal photographs, had narrower retinal arteriolar and venular calibers using similar retinal vessel measurement process to ours. In a previous SCORM analysis, we reported that smaller vertical disc diameter, defined from retinal photographs, was associated with narrower retinal arterioles and venules.14 These results have been interpreted as being consistent with proposed mechanisms in the pathogenesis of ischemic optic neuropathy,28,29 in which small, crowded discs lead to vascular compression and predispose to ischemia. In the only other study that evaluated measurements from OCT, the SCES reported in white children that vertical and horizontal disc diameters were not correlated with arteriolar diameter, and vertical, but not horizontal, disc diameter was associated with venular diameter. Our current results are consistent with these observations, as neither disc diameter nor disc area was associated with arteriolar or venular caliber. The reasons for the discrepancy in studies using photography or OCT are not clear, but may be related to differences in study population (eg, age and ethnicity) or differences between optic disc measurements between OCT and photographic methods,30,31 with OCT tending to underestimate linear dimensions compared to photographic methods. Meyer and Howland32 have published “normalization” factors relative to the Zeiss fundus camera for optic disc measurements by the Rodenstock Optic Disc Analyzer (RODA), Topcon fundus camera, and the Heidelberg Retina Tomograph (HRT), but no similar factor for the OCT has been reported to date. The application of a “normalization” factor for the OCT is potentially illuminating, and further work to define it is warranted.
CI ⫽ confidence interval; SD ⫽ standard deviation. Adjusted for age, gender, body mass index, birth weight, mean arterial blood pressure, and father’s education. a
1.83 (⫺4.53, 8.18) 0.05 (⫺0.08, 0.18) 0.01 (⫺0.06, 0.08) 0.03 (⫺0.17, 0.22) ⫺0.002 (⫺0.20, 0.20) 81.24 (⫺109.88, 272.35) 14.12 (⫺106.03, 134.28) ⫺0.52 (⫺38.05, 37.02) Total macular volume (0.39 m ) Foveal minimum thickness (19.24 m) Foveal average thickness (35.84 m) Inner macular thickness, average (13.40 m) Outer macular thickness, average (12.80 m) Foveal volume (0.01 m3) Inner macular volume (0.02 m3) Outer macular volume (0.07 m3)
.57 .43 .78 .78 .99 .40 .82 .98
3.16 (⫺4.28, 10.61) 0.07 (⫺0.07, 0.21) 0.02 (⫺0.06, 0.09) 0.08 (⫺0.14, 0.29) 0.03 (⫺0.20, 0.27) 115.68 (⫺90.28, 321.63) 46.64 (⫺88.14, ⫺181.42) 6.04 (⫺37.17, 49.25)
.40 .32 .66 .49 .77 .27 .49 .78
12.85 (3.68, 22.01) 0.05 (⫺0.15, 0.24) ⫺0.05 (⫺0.15, 0.05) 0.20 (⫺0.09, 0.49) 0.28 (⫺0.01, 0.58) 81.03 (⫺207.91, 369.96) 112.24 (⫺67.27, 291.75) 53.58 (⫺1.73, 108.90)
.007 .65 .34 .18 .06 .58 .22 .06
P value Mean Difference (95% CI) P value Mean Difference (95% CI) P value Mean Difference (95% CI) P value Mean Difference (95% CI) Macular Parameters (per SD increase)
3
Multivariate-Adjusteda
Retinal Venular Caliber (m)
Age- and Gender-Adjusted Multivariate-Adjusteda
Retinal Arteriolar Caliber (m)
Age- and Gender-Adjusted
TABLE 3. Relationship of Optical Coherence Tomography Macular Parameters to Retinal Vascular Caliber
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macular parameters, only the TMV showed a significant positive association with venular caliber (regression estimate 12.54 m [95% CI, 2.27, 22.81]; P ⫽ .02) (Table 3).
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Besides global assessments of optic disc size such as disc diameter and disc area, topographic disc measures such as cup and rim assessments may give further information on optic nerve head hemodynamics. The SCES reported that the magnitude of association of retinal vascular caliber was generally stronger for optic cup than optic disc parameters, suggesting that nerve fiber crowding occurred primarily at the level of the lamina cribrosa.8 Eyes with smaller cup-to-disc ratios were associated with narrower retinal venular diameters but there was no association with arteriolar diameter. The lack of association with arteriolar diameter is interesting, and supports a theory of vascular compression as retinal veins are less resistant to deformation than retinal arteries, given their almost nonexistent tunica media.33 Larger cup-to-disc ratios were, however, associated with narrower venules in our study. This contrasting association is a novel finding and could imply some ethnic/racial variation. Alternatively, it could suggest that, if vascular compression is in fact occurring at the level of the lamina cribrosa, its primary effect is to cause mild compression leading to outflow limitation and venular dilation without affecting arteriolar caliber. The Singapore Malay Eye Study5 recently reported that narrower vessels were associated with larger vertical cup-to-disc ratio in adults with and without glaucoma, implicating a vascular theory of glaucoma in which vascular insufficiency contributes to optic rim loss, but our findings in healthy children indicate that at least part of the relationship in adults is physiological in origin. Our study also found that thinner optic disc rims were associated with narrower retinal vascular caliber. As cup-to-disc ratio and rim size were also found to be inversely related, vascular compression at the level of the optic nerve rim by retinal nerve fibers may also contribute to the vascular changes seen. OCT evaluation of the fellow eye of nonarteritic ischemic optic neuropathy has also demonstrated larger vertical integrated rim area than in control eyes.34 We thus speculate that eyes predisposed to nonarteritic ischemic optic neuropathy may initially manifest wider venules with no change in arteriolar caliber, and the epidemiologic associations between narrower arterioles and smaller optic disc size could be attributable to autoregulatory vasoconstriction following chronic compression that ultimately contributes to optic nerve ischemia. The average RNFL thickness was positively correlated with both arteriolar and venular caliber, similar to the observations by Cheung and associates.8 The thicker RNFL may be related to a thicker or larger optic disc rim. Alternatively, wider retinal vessels could also provide greater nutritional support for a larger volume of nerve fibers. This is consistent with vascular theories of glaucoma that emphasize the association between retinal vessel
narrowing and glaucoma damage,2,3,21as RNFL thinning is a known feature of glaucoma.35 There were no significant associations with macular parameters apart from a positive correlation between TMV and venular caliber. In the SCES, a thinner macula was associated with narrower retinal vessels.8 This relationship applied mainly to outer macular thickness, and the authors postulated that this could be because the retinal vessels usually do not extend to the central macula. Our findings may simply be an extension of this hypothesis, in which inner macular measurements are under-represented in the TMV. The greater metabolic demand from a larger macular volume may also help to explain the association with wider vessels, and may in turn contribute to the association of wider vessels with an increased prevalence of early AMD in adults4 through a variety of pathogenetic mechanisms including inflammation, oxidative stress, and endothelial dysregulation.36 –38 The strengths of our study design include in vivo assessments of retinal vascular caliber and optic nerve, RNFL, and macular parameters in healthy Asian children by independent and masked observers, high reproducibility in retinal vessel measurements, and standardized assessment of cycloplegic refraction, biometry, and anthropometric measures and BP. General limitations of our study regarding errors inherent in retinal photography and measurement,18 as well as random errors associated with the timing of photography in relation to the cardiac cycle,39 have been described previously. These random errors, however, would likely bias our results to the null. Our sample size is also relatively small, and the possibility of selection bias cannot be totally excluded, as a significant proportion of participants were excluded because of lack of OCT data. Future longitudinal studies with comprehensive OCT and retinal vessel caliber measurements in larger samples of children and adults should be conducted. In conclusion, this study documents anatomic correlations between retinal vascular caliber with optic nerve, RNFL, and macular morphology in healthy Asian children. Our findings in Asian children are generally in line with previous findings in White children, and may further contribute to the current understanding of the normal physiological variations in retinal vascular caliber and their inter-relationship to other anatomic features in the fundus. Such information could be useful in furthering our understanding of vascular theories of adult optic nerve, retinal, and macular diseases. The contrasting optic nerve head associations with retinal venular compared with arteriolar caliber will need additional studies and longitudinal observations, before any conclusions can be made about a possible hemodynamic role in these relationships.
THIS STUDY WAS SUPPORTED BY SINGAPORE’S NATIONAL MEDICAL RESEARCH COUNCIL, NMRC/0975/2005 (DR SAW) AND NMRC/STaR/0003/2008, the SingHealth Foundation, SHF/FG227P/2005 and the Singapore BioImaging Consortium C-011/2006 (Dr Wong). The authors indicate no financial conflict of interest. Involved in design and conduct of study (S.M.S., N.C., T.Y.W.); collection, management, analysis, and
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interpretation of data (L.S.L., S.M.S., N.C., P.M., T.Y.W.); and preparation, review, or approval of the manuscript (L.S.L., S.M.S., N.C., P.M., T.Y.W.). The study was approved by the Institutional Review Board of the Singapore Eye Research Institute. All study procedures were performed in accordance with the tenets of the Declaration of Helsinki as revised in 1989.
17. Knudtson MD, Lee KE, Hubbard LD, Wong TY, Klein R, Klein BE. Revised formulas for summarizing retinal vessel diameters. Curr Eye Res 2003;27:143–149. 18. Hubbard LD, Brothers RJ, King WN, et al. Methods for evaluation of retinal microvascular abnormalities associated with hypertension/sclerosis in the Atherosclerosis Risk in Communities Study. Ophthalmology 1999;106:2269 –2280. 19. Cheung N, Tikellis G, Saw SM, et al. Relationship of axial length and retinal vascular caliber in children. Am J Ophthalmol 2007;144:658 – 662. 20. Wong TY, Wang JJ, Rochtchina E, Klein R, Mitchell P. Does refractive error influence the association of blood pressure and retinal vessel diameters? The Blue Mountains Eye Study. Am J Ophthalmol 2004;137:1050 –1055. 21. Cheung N, Tong L, Tikellis G, et al. Relationship of retinal vascular caliber with optic disc diameter in children. Invest Ophthalmol Vis Sci 2007;48:4945– 4948. 22. Saw SM, Hong CY, Chia KS, Stone RA, Tan D. Nearwork and myopia in young children. Lancet 2001;357:390. 23. Tzamalis A, Kynigopoulos M, Schlote T, Haefliger I. Improved reproducibility of retinal nerve fiber layer thickness measurements with the repeat-scan protocol using the Stratus OCT in normal and glaucomatous eyes. Graefes Arch Clin Exp Ophthalmol 2009;247:245–252. 24. Tangelder GJ, Van der Heijde RG, Polak BC, Ringens PJ. Precision and reliability of retinal thickness measurements in foveal and extrafoveal areas of healthy and diabetic eyes. Invest Ophthalmol Vis Sci 2008;49:2627–2634. 25. Budenz DL, Fredette MJ, Feuer WJ, Anderson DR. Reproducibility of peripapillary retinal nerve fiber thickness measurements with Stratus OCT in glaucomatous eyes. Ophthalmology 2008;115:661– 666. 26. Patton N, Aslam TM, MacGillivray T, et al. Retinal image analysis: concepts, applications and potential. Prog Retin Eye Res 2006;25:99 –127. 27. Lee KE, Klein BE, Klein R, Meuer SM. Association of retinal vessel caliber to optic disc and cup diameters. Invest Ophthalmol Vis Sci 2007;48:63– 67. 28. Burde RM. Optic disk risk factors for nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol 1993;116: 759 –764. 29. Beck RW, Servais GE, Hayreh SS. Anterior ischemic optic neuropathy. IX. Cup-to-disc ratio and its role in pathogenesis. Ophthalmology 1987;94:1503–1508. 30. Neubauer AS, Krieglstein TR, Chryssafis C, Thiel M, Kampik A. Comparison of optical coherence tomography and fundus photography for measuring the optic disc size. Ophthalmic Physiol Opt 2006;26:13–18. 31. Ramakrishnan R, Kader MA, Budde WM. Optic disc morphometry with optical coherence tomography: comparison with planimetry of fundus photographs and influence of parapapillary atrophy and pigmentary conus. Indian J Ophthalmol 2005;53:187–191. 32. Meyer T, Howland HC. How large is the optic disc? Systematic errors in fundus cameras and topographers. Ophthalmic Physiol Opt 2001;21:139 –150.
REFERENCES 1. Cheung N, Rogers SL, Donaghue KC, Jenkins AJ, Tikellis G, Wong TY. Retinal arteriolar dilation predicts retinopathy in adolescents with type 1 diabetes. Diabetes Care 2008;31: 1842–1846. 2. Mitchell P, Leung H, Wang JJ, et al. Retinal vessel diameter and open-angle glaucoma: the Blue Mountains Eye Study. Ophthalmology 2005;112:245–250. 3. Wang S, Xu L, Wang Y, Wang Y, Jonas JB. Retinal vessel diameter in normal and glaucomatous eyes: the Beijing Eye Study. Clin Experiment Ophthalmol 2007;35:800 – 807. 4. Jeganathan VS, Kawasaki R, Wang JJ, et al. Retinal vascular caliber and age-related macular degeneration: the Singapore Malay Eye Study. Am J Ophthalmol 2008;146:954 –959. 5. Amerasinghe N, Aung T, Cheung N, et al. Evidence of retinal vascular narrowing in glaucomatous eyes in an Asian population. Invest Ophthalmol Vis Sci 2008;49:5397–5402. 6. Sun C, Wang JJ, Mackey DA, Wong TY. Retinal vascular caliber: systemic, environmental, and genetic associations. Surv Ophthalmol 2009;54:74 –95. 7. Islam FM, Nguyen TT, Wang JJ, et al. Quantitative retinal vascular calibre changes in diabetes and retinopathy: the Singapore Malay Eye Study. Eye 2008. Forthcoming. 8. Cheung N, Huynh S, Wang JJ, et al. Relationships of retinal vessel diameters with optic disc, macular, and retinal nerve fiber layer parameters in 6-year-old children. Invest Ophthalmol Vis Sci 2008;49:2403–2408. 9. Huynh SC, Wang XY, Rochtchina E, Crowston JG, Mitchell P. Distribution of optic disc parameters measured by OCT: findings from a population-based study of 6-year-old Australian children. Invest Ophthalmol Vis Sci 2006;47:3276 –3285. 10. Rochtchina E, Wang JJ, Taylor B, Wong TY, Mitchell P. Ethnic variability in retinal vessel caliber: a potential source of measurement error from ocular pigmentation?—the Sydney Childhood Eye Study. Invest Ophthalmol Vis Sci 2008; 49:1362–1366. 11. Saw SM, Tong L, Chua WH, et al. Incidence and progression of myopia in Singaporean school children. Invest Ophthalmol Vis Sci 2005;46:51–57. 12. Saw SM, Hong RZ, Zhang MZ, et al. Near-work activity and myopia in rural and urban schoolchildren in China. J Pediatr Ophthalmol Strabismus 2001;38:149 –155. 13. Luo HD, Gazzard G, Fong A, et al. Myopia, axial length, and OCT characteristics of the macula in Singaporean children. Invest Ophthalmol Vis Sci 2006;47:2773–2781. 14. Cheung N, Tong L, Tikellis G, et al. Relationship of retinal vascular caliber with optic disc diameter in children. Invest Ophthalmol Vis Sci 2007;48:4945– 4948. 15. Cheung N, Saw SM, Islam FM, et al. BMI and retinal vascular caliber in children. Obesity (Silver Spring) 2007; 15:209 –215. 16. de Haseth K, Cheung N, Saw SM, Islam FM, Mitchell P, Wong TY. Influence of intraocular pressure on retinal vascular caliber measurements in children. Am J Ophthalmol 2007;143:1040 –1042.
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33. Roggendorf W, Cervos-Navarro J. Ultra-structure of arterioles in the cat brain. Cell Tissue Res 1977;178:495–515. 34. Contreras I, Rebolleda G, Noval S, Munoz-Negrete FJ. Optic disc evaluation by optical coherence tomography in nonarteritic anterior ischemic optic neuropathy. Invest Ophthalmol Vis Sci 2007;48:4087– 4092. 35. Anton A, Moreno-Montanes J, Blazquez F, Alvarez A, Martin B, Molina B. Usefulness of optical coherence tomography parameters of the optic disc and the retinal nerve fiber layer to differentiate glaucomatous, ocular hypertensive, and normal eyes. J Glaucoma 2007;16:1– 8. 36. Hollyfield JG, Bonilha VL, Rayborn ME, et al. Oxidative damage-induced inflammation initiates age-related macular degeneration. Nat Med 2008;14:194 –198.
37. Schaumberg DA, Christen WG, Buring JE, Glynn RJ, Rifai N, Ridker PM. High-sensitivity C-reactive protein, other markers of inflammation, and the incidence of macular degeneration in women. Arch Ophthalmol 2007;125:300 – 305. 38. Evereklioglu C, Er H, Doganay S, et al. Nitric oxide and lipid peroxidation are increased and associated with decreased antioxidant enzyme activities in patients with age-related macular degeneration. Doc Ophthalmol 2003; 106:129 –136. 39. Cheung N, Islam FM, Saw SM, et al. Distribution and associations of retinal vascular caliber with ethnicity, gender, and birth parameters in young children. Invest Ophthalmol Vis Sci 2007;48:1018 –1024.
AJO History of Ophthalmology Series The Ticho House
A
beautiful landmark in Jerusalem, a museum known as the Ticho House, is the former hospital and residence of the ophthalmologist, Dr Albert Ticho (1883 to 1960) and his wife the artist, Anna Ticho (1894 to 1980). Born in what is now the Czech Republic, Albert Ticho trained in Vienna and immigrated to Palestine in 1912, soon followed by Anna. Ticho’s early work included supervising the first American Hadassah nurses in fighting trachoma. Their work was reported at a historic
conference in 1914 whose proceedings constituted the first modern medical book published in Hebrew. Ticho’s career in ophthalmology spanned an intensely eventful, historical period in the Middle East from the last years of the Ottoman Empire, through wars and mandatory British rule, to the establishment of the modern State of Israel. Provided by David M. Reifler, MD, of the Cogan Ophthalmic History Society.
PHOTO: The Ticho House, an extension of the Israel Museum, Jerusalem with the American artist, Lynn Avadenka in the foreground. Photo by Marc Sussman.
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To examine the relationships of retinal vascular caliber with optic disc, macular, and retinal nerve fiber layer (RNFL) characteristics as measured with optical coherence tomography (OCT). ● DESIGN: Observational cross-sectional study. ● METHODS: This study included a subset of healthy children enrolled in the Singapore Cohort Study of the Risk Factors of Myopia (SCORM). Optic disc, macular, and RNFL morphology were measured with Stratus OCT 3. Digital retinal photography was performed and retinal arteriolar and venular caliber measured using validated imaging software. ● RESULTS: One hundred and four children (mean age 11.51 ⴞ 0.52 years; 50% male) were included. In multivariate analyses, smaller horizontal integrated rim width and rim area were associated with narrower retinal arterioles and venules (all P < .05), and shorter horizontal rim length was associated with narrower venules (P ⴝ .04). Optic disc diameter was not associated with arteriolar or venular caliber. Larger vertical cup-to-disc ratios and cup-to-discarea ratios were associated with narrower venules but not arterioles (P ⴝ .01 and P ⴝ .003, respectively). A thinner average RNFL measurement was associated with narrower arterioles and venules, and smaller total macular volume was associated with narrower venules. ● CONCLUSIONS: Thinner optic disc rims and RNFL measurements were associated with narrower retinal arterioles and venules, and larger cup-to-disc ratios with narrower venules. These findings suggest that retinal vessel caliber varies systematically with morphologic differences in the optic nerve head, retina, and macula. (Am J Ophthalmol 2009;148:368 –375. © 2009 by Elsevier Inc. All rights reserved.)
V
ARIATIONS IN RETINAL VASCULAR CALIBER, MEA-
sured quantitatively from retinal images, have been linked to several major eye diseases, including diabetic retinopathy, age-related macular degeneration
Accepted for publication Apr 8, 2009. From the Singapore National Eye Centre, Singapore (L.S.L., T.Y.W.); Singapore Eye Research Institute (L.S.L., S.M.S., T.Y.W.); Department of Community, Occupational and Family Medicine, National University of Singapore, Singapore (S.M.S.); Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Victoria, Australia (N.C., T.Y.W.); and the Centre for Vision Research, University of Sydney, Sydney, Australia (P.M.). Inquiries to Tien Y. Wong, Singapore Eye Research Institute, Singapore National Eye Centre, 11 Third Hospital Ave, #05-00, Singapore 168751; e-mail: [email protected]
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(AMD), and glaucoma.1–7 More recently, studies have begun to explore the relationships of retinal vascular caliber with morphologic changes in the retina and optic disc in generally healthy young children. Such knowledge may help us document normal anatomic relationships that may provide insights into the vascular genesis of various eye diseases. However, extant data are limited, with inconsistent findings reported among some studies.6 The Sydney Childhood Eye Study (SCES)8 showed that retinal vessels were narrower in eyes with smaller optic discs, thinner macula, and thinner retinal nerve fiber layer (RNFL) in predominantly healthy White children. These findings have yet to be verified by other studies. In addition, it remains unclear whether similar relationships are also present in other ethnic groups (eg, Asians), who may have inherently different optic nerve structures9 and retinal vascular caliber.10 In this study, we describe the relationships of retinal vascular caliber with optic disc, macular, and RNFL characteristics, as determined from optical coherence tomography (OCT), in young, healthy Asian children.
METHODS ● STUDY POPULATION:
This cross-sectional study was on a subset of participants from the Singapore Cohort Study of Risk Factors for Myopia (SCORM), which examined 1,979 children aged 7 to 9 years at baseline in 1999 and thereafter yearly in 3 schools in Singapore. The study methodology and details of the study population have been described in detail elsewhere.11,12 The main exclusion criteria included significant systemic illnesses and ocular conditions including media opacity, uveitis, or a history of intraocular surgery, refractive surgery, glaucoma, or retinal disease. The study sample included 104 Chinese children who were randomly selected from 561 children in the Western school during the 2005 examination for OCT measurements.13 For the purposes of this study, all ocular measurements from the right eye were included in the analysis. ● OPTICAL COHERENCE TOMOGRAPHY MEASUREMENTS:
OCT was performed with the Stratus OCT 3 (Carl Zeiss Meditec, Dublin, California, USA) and all images were analyzed with the included software (version 4.1 software).
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All scans were performed by a trained ophthalmologist in a dim room with pupil dilation to ⱖ5 mm, and fixation was monitored throughout.13 Cycloplegia was achieved with 3 drops of 1% cyclopentolate 5 minutes apart, and scans were performed only after an interval of at least 30 minutes after the third drop. Demographic data, axial length (AL), and refraction were entered into the system prior to scanning and analysis. Optic disc measurements were performed using the fast optic disc scan protocol, which consists of a set of 6 linear scans along 6 equidistant diameters spaced 30 degrees apart. Optic disc parameters measured included the disc diameter, cup diameter, disc area, cup area, rim area, cup-to-disc-area ratio, vertical and horizontal cup-to-disc ratios, cup area, and cup volume. RNFL thickness was measured using the RNFL thickness scan algorithm consisting of 512 A scans centered on the disc. Peripapillary RNFL thickness parameters calculated at a 3.4-mm-diameter circle using the RNFL thickness serial analysis protocol included the average RNFL thickness, superior and inferior maximum thickness, superior and inferior average thickness, and the maximum-minimum RNFL thickness. Retinal thickness was measured as the distance between the first signal from the vitreoretinal interface and the signal from the anterior boundary of the retinal pigment epithelial layer. The fast macular scanning protocol was used, with 6 6-mm lines in a radial spoke pattern centered over the fovea acquired automatically. Each linear scan is composed of 128 equally spaced A scans. The topography of the macular thickness map generated by the software consists of 3 concentric rings with diameters of 1-mm, 3-mm, and 6-mm. The innermost 1-mm circle is designated the fovea, the area between the 1-mm and 3-mm rings the inner macula, and the area between the 3-mm and 6-mm rings the outer macula. The parameters measured were the minimum foveal thickness; average foveal thickness; inner and outer macular thickness in the temporal, superior, nasal, and inferior quadrants; the foveal volume; inner and outer macular volume in the temporal, superior, nasal, and inferior quadrants; and the total macular volume (TMV). The inner and outer macular thickness and volumes in the temporal, superior, nasal, and inferior quadrants were averaged to obtain average inner and outer macular thickness and volumes. All scans were repeated 3 times and the results averaged. ● RETINAL VASCULAR CALIBER MEASUREMENTS:
The methods for obtaining digital fundal photographs and for measuring retinal vascular caliber from these photographs have been described in earlier publications from SCORM.14 –16 Retinal photographs centered on the optic disc were obtained with a digital fundal camera (Canon CR6-NM45, EOS-D60 6.3 mega-pixel; Canon Inc, Lake Success, New York, USA) through a dilated pupil. A computer-based program was then used to measure the
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caliber of all retinal vessels located between one-half and 1 disc diameter from the optic disc margin. A pair of indices, the central retinal arteriolar and venular equivalents (CRAE and CRVE), representing the average arteriolar and venular calibers for each eye, was then calculated using formulae described previously.17,18 Correction of CRAE and CRVE for ocular magnification was performed using the Bengtsson formula.19,20 All retinal measurements were performed by a single grader who was masked to the subjects’ identity and other measured parameters. Remeasurement of 50 images 2 weeks later showed high reproducibility, with intraclass correlation coefficients of 0.85 for arteriolar caliber and 0.97 for venular caliber.21 ● OTHER STUDY PROCEDURES: Cycloplegic refraction was performed with an autokeratorefractometer (model RK5; Canon Inc Ltd, Tochigiken, Japan). Five consecutive readings were obtained with 1 of 2 calibrated autokeratorefractometers and averaged. AL measurements were performed with a contact ultrasound A-scan biometry machine (Echoscan model US-800, probe frequency of 10 mHz; Nidek Co Ltd, Tokyo, Japan), with 1 drop of 0.5% proparacaine for topical anesthesia. Measurements were repeated until the standard deviation (SD) was ⬍0.12 mm and the average of 6 measurements taken. Height was measured with children standing, without shoes. Weight in kilograms was measured using a standard portable weighing machine calibrated before the beginning of the study. Blood pressure (BP) was measured on the school premises according to a standard protocol. After 5 minutes of rest, BP was measured in a seated position using an automated sphygmomanometer (Omron Healthcare Inc, Bannockburn, Illinois, USA) with appropriate cuff size. The cuff size was selected to ensure that the bladder spanned the circumference of the arm and covered at least 75% of the upper arm without obscuring the antecubital fossa. Three separate measurements were taken and averaged for analysis. Mean arterial blood pressure (MABP) was defined as two-thirds of the diastolic BP plus one-third of the systolic BP.11,22 The parents of the subjects completed several questionnaires asking about father’s education level, classified as no formal education, primary school education, secondary school education, pre-university education or diploma, and tertiary/university education. ● STATISTICAL ANALYSIS:
Demographic characteristics and differences in study variables between the children included and excluded from OCT measurements were performed using t test or 2, as appropriate. Linear regression models were constructed with CRAE or CRVE as the dependent variable to estimate the differences in CRAE and CRVE for each SD change in the OCT parameters, adjusted initially for age and gender, and additionally for body mass index, birth weight, MABP, and father’s education as an indicator of overall socioeconomic status.
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370 TABLE 1. Relationship of Optical Coherence Tomography Optic Disc Parameters to Retinal Vascular Caliber Retinal Arteriolar Caliber (m)
Retinal Venular Caliber (m)
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Multivariate-Adjusteda
Age- and Gender-Adjusted
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Optic Disc Parameters (per SD increase)
Mean Difference (95% CI)
P value
Mean Difference (95% CI)
P value
Mean Difference (95% CI)
P value
Mean Difference (95% CI)
P value
Vertical disc diameter (0.32 mm) Vertical cup diameter (0.35 mm) Horizontal rim length (0.36 mm) Vertical integrated rim area (0.30 mm2) Horizontal integrated rim width (0.26 mm) Disc area (0.43 mm2) Cup area (0.34 mm2) Rim area (0.37 mm2) Cup-to-disc-area ratio (0.19) Horizontal cup-to-disc ratio (0.13) Vertical cup-to-disc ratio (0.11) Topographical cup area (0.32 mm2) Topographical cup volume (0.19 mm3) Average nerve width at disc margin (0.06 mm)
2.97 (⫺4.88, 10.82) ⫺3.06 (⫺10.10, 3.99) 5.53 (⫺1.58, 12.64) 7.64 (⫺0.32, 15.59) 9.12 (0.26, 17,98) 2.37 (⫺3.03, 7.76) ⫺3.47 (⫺10.86, 3.92) 6.54 (⫺0.06, 13.14) ⫺1.28 (12.93, 10.38) ⫺3.66 (⫺22.19, 14.88) ⫺16.54 (⫺38.24, 5.17) ⫺3.18 (⫺11.33, 4.97) 1.19 (⫺11.06, 13.44) 43.91 (2.93, 84.89)
.45 .39 .13 .06 .04 .39 .35 .052 .83 .70 .13 .44 .85 .04
3.16 (⫺4.98, 11.30) ⫺3.47 (⫺11.02, 4.08) 6.56 (⫺1.25, 14.38) 8.26 (⫺0.17, 16.70) 9.96 (0.67, 19.24) 3.08 (⫺2.64, 8.79) ⫺3.31 (⫺11.25, 4.63) 7.38 (0.44, 14.32) ⫺4.88 (⫺17.39, 7.63) ⫺5.44 (⫺25.22, 14.34) ⫺18.79 (⫺42.00, 4.38) ⫺3.28 (⫺11.96, 5.40) 0.82 (⫺12.23, 13.87) 48.56 (4.37, 92.75)
.44 .36 .10 .06 .04 .29 .41 .04 .44 .59 .11 .45 .90 .03
4.54 (⫺7.42, 16.50) ⫺6.70 (⫺17.09, 4.30) 10.06 (⫺0.71, 20.83) 19.31 (7.67, 30.96) 21.43 (8.40, 34.46) 3.26 (⫺4.98, 11.49) ⫺8.72 (⫺19.87, 2.44) 12.22 (2.28, 22.15) ⫺24.35 (⫺41.30, ⫺7.40) ⫺23.82 (⫺51.61, 3.97) ⫺42.31 (⫺74.54, ⫺10.07) ⫺8,73 (⫺21.05, 3.59) ⫺2.32 (⫺20.98, 16.34) 70.43 (8.16, 132.70)
.45 .24 .07 .001 .002 .43 .12 .02 .005 .09 .01 .16 .81 .03
3.35 (⫺8.62, 15.31) ⫺8.13 (⫺19.11, 2.86) 11.71 (0.34, 23.07) 21.18 (9.47, 32.89) 21.16 (9.00, 34.32) 1.44 (⫺7.01, 9.88) ⫺10.47 (⫺21.93, 0.98) 10.58 (0.39, 20.77) ⫺26.69 (⫺44.07, ⫺9.32) ⫺24.45 (⫺52.98, 4.09) ⫺44.06 (⫺77.13, ⫺11.00) ⫺8.93 (⫺21.55, 3.69) 0.96 (⫺18.19, 20.11) 89.81 (26.20, 153.42)
.58 .14 .04 .001 .002 .74 .07 .04 .003 .09 .01 .16 .92 .006
CI ⫽ confidence interval; SD ⫽ standard deviation. Adjusted for age, gender, body mass index, birth weight, mean arterial blood pressure, and father’s education.
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P value
.009 .10 .19 .10 .002 .53 0.49 (0.13, 0.85) 0.16 (⫺0.03, 0.35) 0.13 (⫺0.07, 0.33) 0.21 (⫺0.04, 0.46) 0.34 (0.13, 0.56) 0.07 (⫺0.14, 0.27) .004 .10 .13 .10 ⬍.001 .55
a
0.26 (0.03, 0.49) 0.10 (⫺0.02, 0.22) 0.09 (⫺0.04, 0.22) 0.15 (⫺0.02, 0.31) 0.13 (⫺0.01, 0.28) 0.13 (⫺0.001, 0.26) RNFL average (9.79 m) Inferior maximum (52.16 m) Superior maximum (17.43 m) Inferior average (15.55 m) Superior average (15.87 m) Maximum-minimum (16.62 m)
CI ⫽ confidence interval; RNFL ⫽ retinal nerve fiber layer; SD ⫽ standard deviation. Adjusted for age, gender, body mass index, birth weight, mean arterial blood pressure, and father’s education.
0.51 (0.17, 0.86) 0.15 (⫺0.03, 0.34) 0.15 (⫺0.04, 0.34) 0.21 (⫺0.04, 0.45) 0.38 (0.17, 0.58) 0.06 (⫺0.14, 0.27) .04 .19 .17 .11 .06 .07 0.26 (0.01, 0.51) 0.09 (⫺0.04, 0.21) 0.09 (⫺0.04, 0.23) 0.14 (⫺0.03, 0.31) 0.15 (⫺0.004, 0.30) 0.13 (⫺0.01, 0.27)
Mean Difference (95% CI)
.03 .11 .16 .08 .06 .052
Multivariate-Adjusteda
Mean Difference (95% CI) P value Mean Difference (95% CI)
RESULTS THE MEAN AGE OF THE SUBJECTS INCLUDED IN THE STUDY
RNFL Parameters (per SD increase)
P value
Mean Difference (95% CI)
P value
Retinal Venular Caliber (m)
Age- and Gender-Adjusted Multivariate-Adjusteda
Retinal Arteriolar Caliber (m)
Age- and Gender-Adjusted
TABLE 2. Relationship of Optical Coherence Tomography Retinal Nerve Fiber Layer Parameters to Retinal Vascular Caliber
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These factors had been identified as covariates associated with retinal vascular caliber in previous studies from the same cohort. All probabilities quoted are two-sided and all statistical analyses were undertaken using statistical analysis software (SPSS version 13.0; SPSS Inc, Chicago, Illinois, USA).
was 11.51 ⫾ 0.52 years, half were male, and the mean CRAE and CRVE were 154.05 ⫾ 10.87 m and 230.32 ⫾ 16.26 m, respectively. The mean spherical equivalent refraction was 0.46 ⫾ 0.48 diopters and the mean AL was 22.86 ⫾ 0.69 mm. Compared to excluded children (n ⫽ 590), children included in the study (n ⫽ 104) were more likely to be Chinese and younger. (11.51 ⫾ 0.52 years vs 12.21 ⫾ 1.12 years; P ⬍ .001) (data not shown). Table 1 summarizes the associations between optic disc parameters and retinal vascular caliber. After controlling for age and gender, thinner horizontal integrated rim width was associated with narrower retinal arteriolar and venular caliber. For every SD decrease in horizontal integrated rim width, arteriolar caliber decreased by 9.12 m (95% confidence interval [CI], 0.26, 17.98; P ⫽ .04) and venular caliber by 21.43 m (95% CI, 8.40, 34.46; P ⫽ .002) in age- and gender-adjusted models, and by 9.96 m (95% CI, 0.67, 19.24; P ⫽ .04) and 21.16 m (95% CI, 9.00, 34.32; P ⫽ .002) respectively, in multivariate-adjusted models. Shorter horizontal rim length was associated with narrower venular caliber, 11.71 m (95% CI, 0.34, 23.07) per SD decrease in horizontal rim length. Smaller rim area was associated with both narrower arteriolar and venular caliber after adjustment; 7.38 m (95% CI, 0.44, 14.32) and 10.58 m (95% CI, 0.39, 20.77) per SD decrease in rim area, respectively. Larger vertical cup-to-disc ratios and cup-to-disc-area ratios were associated with narrower venular caliber by ⫺44.06 m (95% CI, ⫺77.13, ⫺11.00) and by ⫺26.69 m (95% CI, ⫺44.07, ⫺9.32) decreases per SD increase in vertical cup-to-disc ratios and cup-todisc-area ratios, respectively, but not with arteriolar caliber in either age- and gender-adjusted or multivariate models. No significant associations were found between optic disc diameter and either arteriolar or venular caliber. Table 2 shows the relationship of RNFL thickness and macular parameters to retinal vascular caliber. Average RNFL thickness showed associations with both arteriolar and venular caliber. For every SD decrease in RNFL thickness, arteriolar caliber decreased by 0.26 m (95% CI, 0.03, 0.49; P ⫽ .03) and venular caliber by 0.51 m (95% CI, 0.17, 0.86; P ⫽ .004) in age- and gender-adjusted models, and by 0.26 m (95% CI, 0.01, 0.51; P ⫽ .04) and 0.49 m (95% CI, 0.13, 0.85; P ⫽ .009) respectively, in multivariate-adjusted models. For venular caliber, the variation was primarily in the superior quadrant. Of all the
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.02 .44 .37 .35 .21 .39 .41 .20 12.54 (2.27, 22.81) 0.08 (⫺0.12, 0.28) ⫺0.05 (⫺0.15, 0.06) 0.15 (⫺0.16, 0.46) 0.21 (⫺0.11, 0.53) 127.24 (⫺167.99, 4222.27) 80.62 (⫺111.59, 272.84) 39.68 (⫺21.35, 100.72)
DISCUSSION OUR STUDY IN A POPULATION SAMPLE OF HEALTHY
school-aged Chinese children demonstrates significant correlations between retinal vascular caliber and different optic disc, RNFL, and macular features as measured by OCT. Given the high reliability and reproducibility of both of these imaging modalities,23–26 and the absence of ocular or systemic disease in the study population, our findings likely represent physiologic relationships with a high degree of validity. We found that thinner optic disc rims and RNFL measurements were associated with narrower retinal arteriolar and venular caliber, with larger cup-to-disc ratios associated with narrower venular caliber. There are few directly comparable studies. Two studies have documented the relationship of retinal vascular caliber with more subjective assessment of optic disc parameters from fundus photographs. The Beaver Dam Eye Study27 in older adults with a mean age of 69 years reported that eyes with smaller optic discs, as documented from retinal photographs, had narrower retinal arteriolar and venular calibers using similar retinal vessel measurement process to ours. In a previous SCORM analysis, we reported that smaller vertical disc diameter, defined from retinal photographs, was associated with narrower retinal arterioles and venules.14 These results have been interpreted as being consistent with proposed mechanisms in the pathogenesis of ischemic optic neuropathy,28,29 in which small, crowded discs lead to vascular compression and predispose to ischemia. In the only other study that evaluated measurements from OCT, the SCES reported in white children that vertical and horizontal disc diameters were not correlated with arteriolar diameter, and vertical, but not horizontal, disc diameter was associated with venular diameter. Our current results are consistent with these observations, as neither disc diameter nor disc area was associated with arteriolar or venular caliber. The reasons for the discrepancy in studies using photography or OCT are not clear, but may be related to differences in study population (eg, age and ethnicity) or differences between optic disc measurements between OCT and photographic methods,30,31 with OCT tending to underestimate linear dimensions compared to photographic methods. Meyer and Howland32 have published “normalization” factors relative to the Zeiss fundus camera for optic disc measurements by the Rodenstock Optic Disc Analyzer (RODA), Topcon fundus camera, and the Heidelberg Retina Tomograph (HRT), but no similar factor for the OCT has been reported to date. The application of a “normalization” factor for the OCT is potentially illuminating, and further work to define it is warranted.
CI ⫽ confidence interval; SD ⫽ standard deviation. Adjusted for age, gender, body mass index, birth weight, mean arterial blood pressure, and father’s education. a
1.83 (⫺4.53, 8.18) 0.05 (⫺0.08, 0.18) 0.01 (⫺0.06, 0.08) 0.03 (⫺0.17, 0.22) ⫺0.002 (⫺0.20, 0.20) 81.24 (⫺109.88, 272.35) 14.12 (⫺106.03, 134.28) ⫺0.52 (⫺38.05, 37.02) Total macular volume (0.39 m ) Foveal minimum thickness (19.24 m) Foveal average thickness (35.84 m) Inner macular thickness, average (13.40 m) Outer macular thickness, average (12.80 m) Foveal volume (0.01 m3) Inner macular volume (0.02 m3) Outer macular volume (0.07 m3)
.57 .43 .78 .78 .99 .40 .82 .98
3.16 (⫺4.28, 10.61) 0.07 (⫺0.07, 0.21) 0.02 (⫺0.06, 0.09) 0.08 (⫺0.14, 0.29) 0.03 (⫺0.20, 0.27) 115.68 (⫺90.28, 321.63) 46.64 (⫺88.14, ⫺181.42) 6.04 (⫺37.17, 49.25)
.40 .32 .66 .49 .77 .27 .49 .78
12.85 (3.68, 22.01) 0.05 (⫺0.15, 0.24) ⫺0.05 (⫺0.15, 0.05) 0.20 (⫺0.09, 0.49) 0.28 (⫺0.01, 0.58) 81.03 (⫺207.91, 369.96) 112.24 (⫺67.27, 291.75) 53.58 (⫺1.73, 108.90)
.007 .65 .34 .18 .06 .58 .22 .06
P value Mean Difference (95% CI) P value Mean Difference (95% CI) P value Mean Difference (95% CI) P value Mean Difference (95% CI) Macular Parameters (per SD increase)
3
Multivariate-Adjusteda
Retinal Venular Caliber (m)
Age- and Gender-Adjusted Multivariate-Adjusteda
Retinal Arteriolar Caliber (m)
Age- and Gender-Adjusted
TABLE 3. Relationship of Optical Coherence Tomography Macular Parameters to Retinal Vascular Caliber
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macular parameters, only the TMV showed a significant positive association with venular caliber (regression estimate 12.54 m [95% CI, 2.27, 22.81]; P ⫽ .02) (Table 3).
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Besides global assessments of optic disc size such as disc diameter and disc area, topographic disc measures such as cup and rim assessments may give further information on optic nerve head hemodynamics. The SCES reported that the magnitude of association of retinal vascular caliber was generally stronger for optic cup than optic disc parameters, suggesting that nerve fiber crowding occurred primarily at the level of the lamina cribrosa.8 Eyes with smaller cup-to-disc ratios were associated with narrower retinal venular diameters but there was no association with arteriolar diameter. The lack of association with arteriolar diameter is interesting, and supports a theory of vascular compression as retinal veins are less resistant to deformation than retinal arteries, given their almost nonexistent tunica media.33 Larger cup-to-disc ratios were, however, associated with narrower venules in our study. This contrasting association is a novel finding and could imply some ethnic/racial variation. Alternatively, it could suggest that, if vascular compression is in fact occurring at the level of the lamina cribrosa, its primary effect is to cause mild compression leading to outflow limitation and venular dilation without affecting arteriolar caliber. The Singapore Malay Eye Study5 recently reported that narrower vessels were associated with larger vertical cup-to-disc ratio in adults with and without glaucoma, implicating a vascular theory of glaucoma in which vascular insufficiency contributes to optic rim loss, but our findings in healthy children indicate that at least part of the relationship in adults is physiological in origin. Our study also found that thinner optic disc rims were associated with narrower retinal vascular caliber. As cup-to-disc ratio and rim size were also found to be inversely related, vascular compression at the level of the optic nerve rim by retinal nerve fibers may also contribute to the vascular changes seen. OCT evaluation of the fellow eye of nonarteritic ischemic optic neuropathy has also demonstrated larger vertical integrated rim area than in control eyes.34 We thus speculate that eyes predisposed to nonarteritic ischemic optic neuropathy may initially manifest wider venules with no change in arteriolar caliber, and the epidemiologic associations between narrower arterioles and smaller optic disc size could be attributable to autoregulatory vasoconstriction following chronic compression that ultimately contributes to optic nerve ischemia. The average RNFL thickness was positively correlated with both arteriolar and venular caliber, similar to the observations by Cheung and associates.8 The thicker RNFL may be related to a thicker or larger optic disc rim. Alternatively, wider retinal vessels could also provide greater nutritional support for a larger volume of nerve fibers. This is consistent with vascular theories of glaucoma that emphasize the association between retinal vessel
narrowing and glaucoma damage,2,3,21as RNFL thinning is a known feature of glaucoma.35 There were no significant associations with macular parameters apart from a positive correlation between TMV and venular caliber. In the SCES, a thinner macula was associated with narrower retinal vessels.8 This relationship applied mainly to outer macular thickness, and the authors postulated that this could be because the retinal vessels usually do not extend to the central macula. Our findings may simply be an extension of this hypothesis, in which inner macular measurements are under-represented in the TMV. The greater metabolic demand from a larger macular volume may also help to explain the association with wider vessels, and may in turn contribute to the association of wider vessels with an increased prevalence of early AMD in adults4 through a variety of pathogenetic mechanisms including inflammation, oxidative stress, and endothelial dysregulation.36 –38 The strengths of our study design include in vivo assessments of retinal vascular caliber and optic nerve, RNFL, and macular parameters in healthy Asian children by independent and masked observers, high reproducibility in retinal vessel measurements, and standardized assessment of cycloplegic refraction, biometry, and anthropometric measures and BP. General limitations of our study regarding errors inherent in retinal photography and measurement,18 as well as random errors associated with the timing of photography in relation to the cardiac cycle,39 have been described previously. These random errors, however, would likely bias our results to the null. Our sample size is also relatively small, and the possibility of selection bias cannot be totally excluded, as a significant proportion of participants were excluded because of lack of OCT data. Future longitudinal studies with comprehensive OCT and retinal vessel caliber measurements in larger samples of children and adults should be conducted. In conclusion, this study documents anatomic correlations between retinal vascular caliber with optic nerve, RNFL, and macular morphology in healthy Asian children. Our findings in Asian children are generally in line with previous findings in White children, and may further contribute to the current understanding of the normal physiological variations in retinal vascular caliber and their inter-relationship to other anatomic features in the fundus. Such information could be useful in furthering our understanding of vascular theories of adult optic nerve, retinal, and macular diseases. The contrasting optic nerve head associations with retinal venular compared with arteriolar caliber will need additional studies and longitudinal observations, before any conclusions can be made about a possible hemodynamic role in these relationships.
THIS STUDY WAS SUPPORTED BY SINGAPORE’S NATIONAL MEDICAL RESEARCH COUNCIL, NMRC/0975/2005 (DR SAW) AND NMRC/STaR/0003/2008, the SingHealth Foundation, SHF/FG227P/2005 and the Singapore BioImaging Consortium C-011/2006 (Dr Wong). The authors indicate no financial conflict of interest. Involved in design and conduct of study (S.M.S., N.C., T.Y.W.); collection, management, analysis, and
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interpretation of data (L.S.L., S.M.S., N.C., P.M., T.Y.W.); and preparation, review, or approval of the manuscript (L.S.L., S.M.S., N.C., P.M., T.Y.W.). The study was approved by the Institutional Review Board of the Singapore Eye Research Institute. All study procedures were performed in accordance with the tenets of the Declaration of Helsinki as revised in 1989.
17. Knudtson MD, Lee KE, Hubbard LD, Wong TY, Klein R, Klein BE. Revised formulas for summarizing retinal vessel diameters. Curr Eye Res 2003;27:143–149. 18. Hubbard LD, Brothers RJ, King WN, et al. Methods for evaluation of retinal microvascular abnormalities associated with hypertension/sclerosis in the Atherosclerosis Risk in Communities Study. Ophthalmology 1999;106:2269 –2280. 19. Cheung N, Tikellis G, Saw SM, et al. Relationship of axial length and retinal vascular caliber in children. Am J Ophthalmol 2007;144:658 – 662. 20. Wong TY, Wang JJ, Rochtchina E, Klein R, Mitchell P. Does refractive error influence the association of blood pressure and retinal vessel diameters? The Blue Mountains Eye Study. Am J Ophthalmol 2004;137:1050 –1055. 21. Cheung N, Tong L, Tikellis G, et al. Relationship of retinal vascular caliber with optic disc diameter in children. Invest Ophthalmol Vis Sci 2007;48:4945– 4948. 22. Saw SM, Hong CY, Chia KS, Stone RA, Tan D. Nearwork and myopia in young children. Lancet 2001;357:390. 23. Tzamalis A, Kynigopoulos M, Schlote T, Haefliger I. Improved reproducibility of retinal nerve fiber layer thickness measurements with the repeat-scan protocol using the Stratus OCT in normal and glaucomatous eyes. Graefes Arch Clin Exp Ophthalmol 2009;247:245–252. 24. Tangelder GJ, Van der Heijde RG, Polak BC, Ringens PJ. Precision and reliability of retinal thickness measurements in foveal and extrafoveal areas of healthy and diabetic eyes. Invest Ophthalmol Vis Sci 2008;49:2627–2634. 25. Budenz DL, Fredette MJ, Feuer WJ, Anderson DR. Reproducibility of peripapillary retinal nerve fiber thickness measurements with Stratus OCT in glaucomatous eyes. Ophthalmology 2008;115:661– 666. 26. Patton N, Aslam TM, MacGillivray T, et al. Retinal image analysis: concepts, applications and potential. Prog Retin Eye Res 2006;25:99 –127. 27. Lee KE, Klein BE, Klein R, Meuer SM. Association of retinal vessel caliber to optic disc and cup diameters. Invest Ophthalmol Vis Sci 2007;48:63– 67. 28. Burde RM. Optic disk risk factors for nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol 1993;116: 759 –764. 29. Beck RW, Servais GE, Hayreh SS. Anterior ischemic optic neuropathy. IX. Cup-to-disc ratio and its role in pathogenesis. Ophthalmology 1987;94:1503–1508. 30. Neubauer AS, Krieglstein TR, Chryssafis C, Thiel M, Kampik A. Comparison of optical coherence tomography and fundus photography for measuring the optic disc size. Ophthalmic Physiol Opt 2006;26:13–18. 31. Ramakrishnan R, Kader MA, Budde WM. Optic disc morphometry with optical coherence tomography: comparison with planimetry of fundus photographs and influence of parapapillary atrophy and pigmentary conus. Indian J Ophthalmol 2005;53:187–191. 32. Meyer T, Howland HC. How large is the optic disc? Systematic errors in fundus cameras and topographers. Ophthalmic Physiol Opt 2001;21:139 –150.
REFERENCES 1. Cheung N, Rogers SL, Donaghue KC, Jenkins AJ, Tikellis G, Wong TY. Retinal arteriolar dilation predicts retinopathy in adolescents with type 1 diabetes. Diabetes Care 2008;31: 1842–1846. 2. Mitchell P, Leung H, Wang JJ, et al. Retinal vessel diameter and open-angle glaucoma: the Blue Mountains Eye Study. Ophthalmology 2005;112:245–250. 3. Wang S, Xu L, Wang Y, Wang Y, Jonas JB. Retinal vessel diameter in normal and glaucomatous eyes: the Beijing Eye Study. Clin Experiment Ophthalmol 2007;35:800 – 807. 4. Jeganathan VS, Kawasaki R, Wang JJ, et al. Retinal vascular caliber and age-related macular degeneration: the Singapore Malay Eye Study. Am J Ophthalmol 2008;146:954 –959. 5. Amerasinghe N, Aung T, Cheung N, et al. Evidence of retinal vascular narrowing in glaucomatous eyes in an Asian population. Invest Ophthalmol Vis Sci 2008;49:5397–5402. 6. Sun C, Wang JJ, Mackey DA, Wong TY. Retinal vascular caliber: systemic, environmental, and genetic associations. Surv Ophthalmol 2009;54:74 –95. 7. Islam FM, Nguyen TT, Wang JJ, et al. Quantitative retinal vascular calibre changes in diabetes and retinopathy: the Singapore Malay Eye Study. Eye 2008. Forthcoming. 8. Cheung N, Huynh S, Wang JJ, et al. Relationships of retinal vessel diameters with optic disc, macular, and retinal nerve fiber layer parameters in 6-year-old children. Invest Ophthalmol Vis Sci 2008;49:2403–2408. 9. Huynh SC, Wang XY, Rochtchina E, Crowston JG, Mitchell P. Distribution of optic disc parameters measured by OCT: findings from a population-based study of 6-year-old Australian children. Invest Ophthalmol Vis Sci 2006;47:3276 –3285. 10. Rochtchina E, Wang JJ, Taylor B, Wong TY, Mitchell P. Ethnic variability in retinal vessel caliber: a potential source of measurement error from ocular pigmentation?—the Sydney Childhood Eye Study. Invest Ophthalmol Vis Sci 2008; 49:1362–1366. 11. Saw SM, Tong L, Chua WH, et al. Incidence and progression of myopia in Singaporean school children. Invest Ophthalmol Vis Sci 2005;46:51–57. 12. Saw SM, Hong RZ, Zhang MZ, et al. Near-work activity and myopia in rural and urban schoolchildren in China. J Pediatr Ophthalmol Strabismus 2001;38:149 –155. 13. Luo HD, Gazzard G, Fong A, et al. Myopia, axial length, and OCT characteristics of the macula in Singaporean children. Invest Ophthalmol Vis Sci 2006;47:2773–2781. 14. Cheung N, Tong L, Tikellis G, et al. Relationship of retinal vascular caliber with optic disc diameter in children. Invest Ophthalmol Vis Sci 2007;48:4945– 4948. 15. Cheung N, Saw SM, Islam FM, et al. BMI and retinal vascular caliber in children. Obesity (Silver Spring) 2007; 15:209 –215. 16. de Haseth K, Cheung N, Saw SM, Islam FM, Mitchell P, Wong TY. Influence of intraocular pressure on retinal vascular caliber measurements in children. Am J Ophthalmol 2007;143:1040 –1042.
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33. Roggendorf W, Cervos-Navarro J. Ultra-structure of arterioles in the cat brain. Cell Tissue Res 1977;178:495–515. 34. Contreras I, Rebolleda G, Noval S, Munoz-Negrete FJ. Optic disc evaluation by optical coherence tomography in nonarteritic anterior ischemic optic neuropathy. Invest Ophthalmol Vis Sci 2007;48:4087– 4092. 35. Anton A, Moreno-Montanes J, Blazquez F, Alvarez A, Martin B, Molina B. Usefulness of optical coherence tomography parameters of the optic disc and the retinal nerve fiber layer to differentiate glaucomatous, ocular hypertensive, and normal eyes. J Glaucoma 2007;16:1– 8. 36. Hollyfield JG, Bonilha VL, Rayborn ME, et al. Oxidative damage-induced inflammation initiates age-related macular degeneration. Nat Med 2008;14:194 –198.
37. Schaumberg DA, Christen WG, Buring JE, Glynn RJ, Rifai N, Ridker PM. High-sensitivity C-reactive protein, other markers of inflammation, and the incidence of macular degeneration in women. Arch Ophthalmol 2007;125:300 – 305. 38. Evereklioglu C, Er H, Doganay S, et al. Nitric oxide and lipid peroxidation are increased and associated with decreased antioxidant enzyme activities in patients with age-related macular degeneration. Doc Ophthalmol 2003; 106:129 –136. 39. Cheung N, Islam FM, Saw SM, et al. Distribution and associations of retinal vascular caliber with ethnicity, gender, and birth parameters in young children. Invest Ophthalmol Vis Sci 2007;48:1018 –1024.
AJO History of Ophthalmology Series The Ticho House
A
beautiful landmark in Jerusalem, a museum known as the Ticho House, is the former hospital and residence of the ophthalmologist, Dr Albert Ticho (1883 to 1960) and his wife the artist, Anna Ticho (1894 to 1980). Born in what is now the Czech Republic, Albert Ticho trained in Vienna and immigrated to Palestine in 1912, soon followed by Anna. Ticho’s early work included supervising the first American Hadassah nurses in fighting trachoma. Their work was reported at a historic
conference in 1914 whose proceedings constituted the first modern medical book published in Hebrew. Ticho’s career in ophthalmology spanned an intensely eventful, historical period in the Middle East from the last years of the Ottoman Empire, through wars and mandatory British rule, to the establishment of the modern State of Israel. Provided by David M. Reifler, MD, of the Cogan Ophthalmic History Society.
PHOTO: The Ticho House, an extension of the Israel Museum, Jerusalem with the American artist, Lynn Avadenka in the foreground. Photo by Marc Sussman.
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