Retinal nerve fiber loss precedes measurable optic nerve head (ONH) and visual field damage and is observed in 60% of eyes approximately six years before any detectable visual field defects in glaucoma.1 Examination of the ONH and its surrounding retinal nerve fiber layer (RNFL) is considered essential in the diagnosis as well as monitoring of glaucoma. Damage to the optic disc is associated with an abnormal appearance of the RNFL. Recent advances in glaucoma research have sought to develop objective methods to measure these structures for early diagnosis of glaucoma.
Optical coherence tomography (OCT) is a new optical technique for real-time, quantitative, objective, high-resolution measurements and cross-sectional imaging of the retina from which the RNFL is calculated.2 Attempts have been made by several investigators34 to measure RNFL thickness in normal and glaucomatous eyes using OCT. Some studies suggest that OCT may be superior to scanning laser polarimetry (SLP) and Heidelberg retinal tomography (HRT) for detecting a specific pattern of reduction in the average and focal RNFL thickness as well as the disc parameters.56
White on White (W/W) perimetry is a generally accepted method for monitoring visual field damage in glaucoma patients and suspects. Glaucoma patients suffer a loss of about 40% of their retinal ganglion cells before this loss is picked up on W/W perimetry.7 Short-wave automated perimetry (SWAP) detects functional abnormalities of certain ganglion cells which have an increased susceptibility to glaucomatous damage in the early stages of the disease.8 Clinically detectable changes in SWAP and RNFL may precede field defects in W/W perimetry in progressive glaucoma; these are predictive of the onset and location of future W/W perimetry defects and correlate with early structural damage to the optic nerve.9 These defects are larger and the rate of progression is greater in SWAP than in W/W perimetry.
Several studies have confirmed a correlation between RNFL and visual field loss in SWAP. The prevalence of SWAP deficits in ocular hypertensive eyes with normal W/W perimetry visual fields is 8 to 30%.10 Short-wave automated perimetry shows a specificity of 93%11 to 100%.12
The aim of the study was to measure the RNFL thickness by OCT in eyes with glaucoma and in ocular hypertensives and to compare the results with that of age-matched normal eyes and to correlate the findings with global indices of visual fields in ocular hypertensives.
Materials and Methods
A total of 90 eyes (30 consecutive normal, 30 ocular hypertensive and 30 glaucomatous eyes) of individuals (age range 30 to 70 years) attending the glaucoma service of our hospital, between May and December 2003 were enrolled in this cross-sectional study. The study was approved by the Institutional Review Board of our Institute. All 90 eyes had open angles with best corrected visual acuity (BCVA) of 20/40 or better with clear lenses. Other inclusion criteria were
- Normal eyes: No history of ocular surgery or laser treatment, intraocular pressure (IOP) of 21mmHg or less, normal slit-lamp examination, cup disc (CD) ratio 0.2 to 0.4, symmetrical cupping and normal W/W perimetry on Humphrey field analyzer (HFA) 30-2 with Swedish interactive threshold algorithm (SITA) fast strategy.
- Ocular hypertension: IOP greater than 24mmHg on a diurnal day curve before treatment on at least two separate occasions with normal HFA 30-2 W/W perimetry (SITA fast test strategy) and normal SWAP (full threshold test strategy) visual fields and CD ratio of 0.2 to 0.4.
- Glaucoma: IOP greater than 24mmHg and an abnormal W/W perimetry that fulfilled the minimum criteria for glaucomatous visual field defects, namely, a cluster of three or more non-edge points in a location typical for glaucoma, all of which were depressed on pattern deviation plot at P < 5% level and one of which was depressed at P < 1% level, ONH or RNFL defects characteristic of glaucomatous excavation, notching, focal or diffuse atrophy of RNFL, vertical CD ratio more than 0.6 or disc asymmetry more than 0.2 between the two eyes.
A detailed medical and surgical history was elicited from the patients, all of whom underwent a complete ophthalmic examination that included slit-lamp biomicroscopy, visual acuity testing with refraction, ONH examination, applanation tonometry, gonioscopy, HFA perimetry and OCT evaluation of RNFL. Informed consent was obtained from all participants before their inclusion in the study by providing details of the study.
Exclusion criteria for all groups included a BCVA worse than 20/40, abnormal findings on slit-lamp examination, angle abnormalities on gonioscopy, any other intraocular eye diseases, diseases affecting visual fields (pituitary lesions, demyelinating diseases, diabetes mellitus, the acquired immunodeficiency syndrome) or secondary causes of IOP increase (pseudoexfoliation, corticosteroid use, iridocyclitis, trauma) and any pathological condition, including retinal, that could affect the visual fields. Patients with lens opacities greater than one according to the Lens Opacity Classification System (LOCS III) were excluded.13
W/W perimetry was performed with HFA (Zeiss Humphrey Systems, Model 750) by using SITA-fast test strategy 30-2 program W / W and SWAP 30-2(Full Threshold test strategy) program. Patients were allowed to dark adapt for 3 to 5 min while SWAP was switched on. A reliable test was defined as having fewer than 20% false-positive or false-negative scores and fewer than 33% fixation losses.
Normal visual field indices were defined as Mean Deviation (MD) and Corrected Pattern Standard Deviation (CPSD) within 95% confidence limits and glaucoma hemifield test within normal limits.
Perimetry and OCT examinations were performed on the same day.
Optical coherence tomography was performed by using Stratus OCT, model 3000(Carl Zeiss Meditec Inc, Dublin, CA, USA). The results were analyzed with Version 4.0.1 software. After dilatation to a minimum of 5 mm, a patch was placed over the other eye. Three hundred and sixty degrees circular scans with a diameter of 3.4 mm, centered on the optic disc were performed using the Fast RNFL thickness protocol. Scan acquisition time was one second at each sitting.
The RNFL thickness was defined as the number of pixels between the anterior and posterior edges of the RNFL. Each scan consisted of 100 individual A-scan samples evenly distributed along a circle circumference. Three circular scans, each 3.4 mm in diameter centered on the optic disc, were obtained from each test eye. The best quality, properly aligned scan was chosen for analysis. Average RNFL thickness was calculated globally and separately for superior, inferior, temporal and nasal quadrants. Good quality OCT scans were defined as scans with a signal-noise ratio > 40dB.
The parameters compared were average RNFL thickness of the entire circumference of the optic disc and quadrant thickness consisting of superior (46 to 135 degrees), nasal (136 to 225 degrees), inferior (226 to 315 degrees) and temporal (316 to 345 degrees) quadrant areas between the three groups. Paired comparisons for all significant mean defects were conducted. To evaluate the strength of the association of SWAP or W/W perimetry, correlations between RNFL thickness and visual field parameters were assessed by correlation coefficients (Pearson's r) and significance calculated using the Student t-test. Data were reported as mean ± standard deviation (SD). A P value of less than 0.05 was considered statistically significant.
Ninety eyes (30 normal, 30 ocular hypertensive and 30 glaucomatous) were enrolled. There was no difference between the groups with regard to gender, race and age. Mean age of the patients was 52.32±10.11 years. The mean age of patients in the glaucoma group was 53.77±15.24 years, in the ocular hypertension group was 48.64±11.52 years and in normal subjects was 51.20±6.8 years. The mean vertical CD ratio was 0.28, 0.34 and 0.78 in normal, ocular hypertensive and glaucomatous eyes respectively. The RNFL thickness was greatest in the superior and inferior quadrants and thinner in the nasal and temporal quadrants in the normal group [Fig. 1]. The RNFL profile demonstrated the "double hump" pattern. These results are consistent with those of earlier studies.5
The RNFL thickness in glaucomatous eyes differed significantly from normal eyes in all parameters (P < 0.001). Representative OCT recordings in patients with ocular hypertension and glaucoma are depicted in [Figs 2 and 3] respectively.
Mean RNFL thickness was 52.95±31.10 mm in glaucomatous eyes, 82.87±17.21 mm in ocular hypertensives and 94.26±12.36 mm in normals [Table 1]. In the ocular hypertensive group, RNFL was thinner in the nasal (61.5±19.91 mm), inferior (107.87±25.79 mm) and temporal (54±14.45 mm) quadrants when compared to normals (P < 0.001). The RNFL was thinner in glaucomatous eyes in the superior (73.45±39.57 mm), nasal (53.67±33.54 mm), inferior (64.41±43.68 mm) and temporal (46.67±21.95 mm) quadrants when compared to normals (P < 0.001). Mean RNFL was significantly thinner in ocular hypertensives (82.87±17.21 mm; P=0.008) and in glaucomatous eyes (52.95±31.10 mm; P < 0.001), than in normals (94.26±12.36 mm).
With reference to global indices in ocular hypertensives: on W/W perimetry, mean deviation (MD) was -2.25±1.69 and pattern standard deviation (PSD) was 2.32±1.54; on SWAP, MD was -5.32±4.49, PSD was 3.83±1.59 and CPSD was 2.84±1.85 [Table 2]. The SWAP MD and PSD values were significantly larger (P < 0.001) than the values obtained with W/W perimetry. In the ocular hypertensive group, the mean RNFL showed weak correlation only with MD on W/W perimetry (r=+0.41, P =0.022). In ocular hypertensives mean RNFL did not show any statistically significant correlation with global indices of SWAP; MD (r=+0.20, P=0.957), PSD(r=-0.26, P=0.125) or CPSD (r=-0.32, P=0.015) [Table 2].
With reference to global indices in glaucoma subjects: on W/W perimetry, MD was -5.54±5.82 and PSD was 4.74±2.82. In the glaucoma group mean RNFL showed correlation only with PSD (r= -0.355), correlation with MD was (r=+0.151).
Optical coherence tomography helps in obtaining objective and reproducible measures of RNFL thickness and detects focal defects independent of the visibility of RNFL. Sommer et al.14 in a 10-year follow-up study, reported that RNFL thinning is a sensitive indicator of the extent of glaucomatous damage and that RNFL loss precedes measurable ONH and visual field damage approximately six years before any detectable visual field defects. Thus, the possibility of detecting these defects in areas of physiological decreased visibility is enhanced when OCT, rather than a conventional method, is used.
In our study, the mean thickness of the RNFL in glaucomatous patients and in ocular hypertensive patients was significantly less than in normals [Table 1]. Hoh et al.15 reported that the mean RNFL thickness measured with OCT was significantly less in glaucomatous eyes (56.9±21.5 mm) than in ocular hypertensive (83.70±16.57 mm) and normal (90.86±14.17 mm) eyes; although RNFL thickness tended to be greater in normal than in ocular hypertensive eyes, this difference was not statistically significant.
Guedes et al.16 reported that the inferior RNFL was the only parameter in which a statistically significant difference was observed between normal subjects and glaucoma suspect groups. Pieroth et al.3 reported a specificity of 81% and sensitivity of 65% in detecting focal defects solely through statistical analysis of OCT measurements and also noted that focal RNFL defects are located in the inferotemporal and superotemporal regions of the RNFL. In our study, in glaucomatous eyes, the RNFL thickness in the inferior quadrant was 64.41±43.68 mm and that in the superior quadrant was 73.45±39.57 mm, which was significantly thinner than in normals, wherein RNFL thickness in the inferior quadrant was 120.15±14.32 mm (P < 0.001) and in the superior quadrant was 116.19±19.97 mm (P < 0.001). In the group clinically assessed as ocular hypertensives, RNFL thickness in the inferior quadrant was 107.87±25.79 mm and in the superior quadrant was 106.25±33.54 mm, which was significantly thinner (P < 0.001) than the values observed in normals, suggesting an early damage.
Sample et al.12 reported the greatest prevalence of SWAP abnormalities in high-risk ocular hypertensives, lowest in low-risk ocular hypertensives and intermediate in medium-risk ocular hypertensive patients. Johnson et al.10 reported that localized SWAP sensitivity loss is prevalent in ocular hypertensive eyes, being 5 to 8% in eyes with a CD ratio less than 0.3, 12 to 23% in eyes with a CD ratio between 0.3 to 0.6 and 20 to 43% for CD ratio greater than 0.6; these workers opined that this sensitivity loss was predictive of the subsequent glaucomatous visual field loss that is observed with W/W perimetry.
Teesalu et al.1718 demonstrated that among patients with glaucoma, 38% of apparently normal W/W perimetry hemifields were classified as abnormal using SWAP hemifield data while 52% were classified as abnormal using HRT data, thus suggesting that eyes with seemingly healthy W/W perimetry hemifields may, in fact, already be affected by glaucoma. Mok et al.7 reported that RNFL assessments by OCT correlate well with SWAP test results in early glaucoma damage. Subjects with abnormal SWAP values had thinner RNFLs than those with normal SWAP values. Therefore, assessment of RNFL by OCT may be as sensitive as SWAP in early detection of glaucoma and before a specific W/W perimetry defect has occurred.
Soliman and associates1 reported a significant correlation (correlation coefficient r = 0.557) between average RNFL thickness and mean deviation on W/W perimetry. Parisi et al.19 and Zangwill et al.20 have also reported a significant correlation between average RNFL thickness and MD. Kanamori et al.21 showed that the highest correlation coefficient in all parameters was 0.729 at the average RNFL thickness, suggesting that average RNFL thickness was most useful for monitoring glaucoma. Localized RNFL defects can be clinically detected if more than 50% of the thickness of RNFL is lost. Therefore ocular hypertensive patients may have an impaired function of ganglion cells despite clinically normal-looking RNFL.17
In our study, all patients clinically classified as ocular hypertensives showed diffuse thinning of RNFL in all quadrants, except superiorly, when compared to normals (P < 0.001) as demonstrated by OCT only. Global indices on SWAP showed larger MD (P < 0.001) and PSD (P < 0.001) when compared to W/W perimetry.
It has also been suggested17 that while SWAP may, in some cases, show functional damage even before RNFL loss is clinically detected, there are other patients in whom glaucomatous RNFL abnormalities can be detected despite normal SWAP and W/W perimetry visual fields. The SWAP shows a specificity of 93 to 100% in glaucoma suspects and RNFL assessment and SWAP combination analysis yields 100% sensitivity.9 Therefore a combination of SWAP and RNFL may help in improving the adequacy of our therapeutic decisions.
The results of our study indicate that patients classified as ocular hypertensives on the basis of conventional diagnostic techniques (tonometry and disc examination) show early changes in SWAP global indices and diffuse thinning of RNFL in all quadrants. Therefore a combination of SWAP and OCT may be a useful diagnostic tool to detect damage in high-risk ocular hypertensives.
Source of Support:
Conflict of Interest:
1. Soliman MA, Van Den TJ, Ismaeil AA, Dejong LA, De Smet MD. Retinal nerve fiber layer analysis: Relationship between optical coherence tomography and red- free photography Am J Ophthalmol. 2002;133:187–95
2. Huang D, Swanson EA, Lin CP, Schuman JS, Stinson WG, Chang W, et al Optical coherence tomography Science. 1991;254:1178–81
3. Pieroth L, Schuman JS, Hertzmark E, Hee MR, Wilkins JR, Coker J, et al Evaluation of focal defects of nerve fiber layer using optical coherence tomography Ophthalmology. 1999;106:570–9
4. Bowd C, Weinreb RN, Williams JM, Zangwill LM. The retinal nerve fiber layer thickness in ocular hypertensive, normal and glaucomatous eyes with optical coherence tomography Arch Ophthalmol. 2000;118:22–6
5. Bowd C, Zangwill LM, Berry CC, Blumenthal EZ, Vasile C, Sanchez-Galeana C, et al Detecting early glaucoma by assessment of retinal nerve fiber layer thickness and visual function Invest Ophthalmol Vis Sci. 2001;42:1993–2003
6. Zangwill LM, Bowd C, Berry CC, Williams J, Blumenthal EZ, Sanchez-Galeana CA, et al Discriminating between normal and glaucomatous eyes using the Heidelberg Retina Tomograph, GDx nerve fiber analyzer and optical coherence tomograph Arch Ophthalmol. 2001;119:985–93
7. Mok KH, Lee VW. Nerve fiber analyzer and short wavelength automated perimetry in glaucoma suspects Ophthalmology. 2000;107:2101–4
8. Sample PA, Bosworth CF, Blumenthal EZ, Girkin C, Weinreb RN. Visual function-specific perimetry for indirect comparison of different ganglion cell populations in glaucoma Invest Ophthalmol Vis Sci. 2000;41:1783–90
9. Polo V, Larrosa JM, Pinilla I, Perez S, Gonzalvo F, Honrubia FM. Predictive value of short wavelength automated perimetry: A 3 year follow up study Ophthalmology. 2002;109:761–5
10. Johnson CA, Brandt JD, Khong AM, Adams AJ. Short wavelength automated perimetry in low, medium and high-risk ocular hypertensive eyes Arch Ophthalmol. 1995;113:70–6
11. Wild JM, Moss ID, Whitaker D, O'Neill EC. The statistical interpretation of blue-on-yellow visual field loss Invest Ophthalmol Vis Sci. 1995;36:1398–410
12. Sample PA, Taylor JD, Martinez GA, Lusky M, Weinreb RN. Short-wavelength color visual fields in glaucoma suspects at risk Am J Ophthalmol. 1993;115:225–33
13. Chylack LT Jr, Wolfe JK, Singer DM, Leske MC, Bullimore MA, Bailey IL, et al The Lens Opacities Classification System III. The Longitudinal Study of Cataract Study Group Arch Ophthalmol. 1993;111:831–6
14. Sommer A, Katz J, Quigley HA, Miller NR, Robin AL, Richter RC, et al Clinically detectable nerve fiber layer atrophy precedes the onset of glaucomatous field loss Arch Ophthalmol. 1991;109:77–83
15. Hoh ST, Greenfield DS, Mistlberger A, Liebmann JM, Ishikawa H, Ritch R. Optical coherence tomography and scanning laser polarimetry in normal, ocular hypertensive and glaucomatous eyes Am J Ophthalmol. 2000;129:129–35
16. Guedes V, Schuman JS, Hertzmark E, Wollstein G, Correnti A, Mancini R, et al Optical coherence tomography measurement of macular and nerve fiber layer thickness in normal and glaucomatous human eyes Ophthalmology. 2003;110:177–89
17. Teesalu P, Airaksinen PJ, Tuulonen A. Blue-on-yellow visual field and retinal nerve fiber layer in ocular hypertension and glaucoma Ophthalmology. 1998;105:2077–81
18. Teesalu P, Vihanninjoki K, Airaksinan PJ, Tuulonen A. Hemifield association between blue -on yellow visual field and optic nerve head topographic measurements Graefes Arch Clin Exp Ophthalmol. 1998;236:339–45
19. Parisi V, Manni G, Centofanti M, Gandolfi SA, Olzi D, Bucci MG. Correlation between optical coherence tomography, pattern electroretinogram and visual evoked potentials in open angle glaucoma patients Ophthalmology. 2001;108:905–12
20. Zangwill LM, Williams J, Berry CC, Knauer S, Weinreb RN. A comparison of optical coherence tomography and retinal nerve fiber layer photography for detection of nerve fiber layer damage in glaucoma Ophthalmology. 2000;107:1309–15
21. Kanamori A, Nakamura M, Escano MF, Seya R, Maeda H, Negi A. Evaluation of the glaucomatous damage on retinal nerve fiber layer thickness measured by optical coherence tomography Am J Ophthalmol. 2003;135:513–20