- Email: [email protected]
Relationship between optic disc hemorrhage and corneal hysteresis
ARTICLE IN PRESS
Relationship between optic disc hemorrhage and corneal hysteresis Nathan M. Radcliffe, MD,* Nathaniel Tracer, BA,y Carlos Gustavo V. De Moraes, MD,z Celso Tello, MD,x Jeffrey M. Liebmann, MD,z Robert Ritch, MDx ABSTRACT Objective: To determine the relationship between optic disc hemorrhage (DH) and corneal hysteresis (CH). Methods: Consecutive patients with prior or current photographic evidence of unilateral DH who had undergone CH measurement with the Ocular Response Analyzer (ORA; Reichert, Buffalo, NY) were enrolled. Eyes with a history of corneal disease, refractive surgery, or bilateral DH were excluded. Central corneal thickness (CCT), visual field data, 5 consecutive previous intraocular pressures (IOPs), and maximum documented peak IOP were obtained by chart review. Vertical cup-to-disc ratio (VCDR), the presence of neuroretinal rim notching, number of clock hours of beta zone parapapillary atrophy (ßPPA), and eye with greater ßPPA width were determined from photographs by 2 masked expert examiners. Results: We identified and analyzed 49 patients with photographically documented unilateral DH. Compared to fellow non-DH eyes, eyes with DH had lower CH (8.7 § 1.9 vs 9.2 § 1.7; p = 0.002), higher IOP (15.6 § 3.6 vs 14.3 § 4.1; p = 0.017), and greater VCDR (0.79 § 0.13 vs 0.68 § 0.23; p < 0.001), but were similar with respect to CCT, ßPPA extent, rim notching, peak IOP, and visual field damage (all p > 0.05). Using multivariate conditional logistic regression analysis, only CH (p = 0.012) and VCDR (p = 0.004) predicted the laterality of the DH. Conclusions: Lower CH and greater VCDR are independently associated with DH. This suggests that CH may be a structural biomarker for an abnormality of the optic nerve complex that may be associated with progressive glaucoma. Eyes in which DH were detected had lower CH.
Progressive glaucomatous visual loss can lead to blindness.13 Understanding risk factors for glaucomatous progression can help the physician appropriately monitor and treat patients at higher risk. Established risk factors for glaucomatous progression include older age, elevated intraocular pressure (IOP), lower central corneal thickness (CCT), and the presence of parapapillary atrophy (PPA) or optic disc hemorrhage (DH).16 Corneal hysteresis (CH) has been reported to be a risk factor for glaucoma progression.7 CH is the difference between the air-jet pressure at inward and outward applanation and therefore is considered to be a measure of corneal viscous dampening. A low degree of CH implies that little applied energy is absorbed (dampened) by the cornea. This purported corneal biomechanical property, measured by the noncontact Ocular Response Analyzer (ORA; Reichert, Buffalo, NY), is lower in eyes with glaucoma.712 Although CH is moderately correlated with CCT,13 in one study CH was more closely associated with glaucoma progression than CCT.7 Optic DH, visible as a superficial hemorrhage within the retinal nerve fibre layer at or immediately adjacent to the disc edge, is a strong risk factor for the development and progression of glaucomatous optic neuropathy.14,1420 Though the cause of DH is unknown, spatially consistent, localized visual field progression both precedes and accelerates after DH, suggesting that DH may be a biomarker for
ongoing neuroretinal rim deterioriation.20 A number of investigations attempting to link DH and CCT, 2 strong predictors of glaucoma progression, have failed to find a relationship.14,2123 A relationship between DH and CH might suggest that corneal biomechanical properties are somehow important to glaucomatous optic neuropathy. Both DH and low CH occur in eyes with focal neuroretinal rim notching in addition to being associated with progression.9,24 In glaucoma patients with low CH, there is a greater backward bowing of the lamina cribrosa in response to transient IOP elevation.25,26 We sought to determine whether eyes with DH have lower CH.
TAGEDH1METHODSTAGEDEN Approval for this retrospective study was obtained from the Institutional Review Boards at the New York Eye and Ear Infirmary and Weill Cornell Medical College/New York Presbyterian Hospital. This study adhered to the tenets of the Declaration of Helsinki. All digital optic nerve stereophotographs of patients examined in the glaucoma practices of the authors between 8/1/2009 and 2/28/2010 were screened for the presence of prior or current DH. Both eyes of subjects with photographic evidence of unilateral DH and documented bilateral CH measurements from the ORA (Reichert) were included. Eyes with a history of corneal
© 2019 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jcjo.2019.10.007 ISSN 0008-4182 CAN J OPHTHALMOL—VOL. &, NO. &, & 2019
1
ARTICLE IN PRESS Disc hemorrhage and hysteresis—Radcliffe et al. disease or refractive surgery were excluded, as were monocular patients and patients with bilateral DH, nonglaucomatous optic neuropathy or visual field loss, or poor-quality stereophotographs. For each patient seen within the specified period, each bilateral set of optic nerve stereophotographs was evaluated by 2 authors, who were masked to CH values and other clinical patient data. For each pair of stereophotographs, the laterality (i.e., OD vs OS) of the DH and the laterality of the eye with the greatest ßPPA width were determined. The number of clock hours encompassed by ßPPA, the presence of neuroretinal rim notching, and vertical cup-to-disc ratio (VCDR) were determined for each eye. For each patient with DH, pertinent information was obtained by chart review, including baseline CCT (DGH Technology, Exton, PA), IOP measured by Goldmann applanation tonometry on the day that CH was obtained, and on 5 previous consecutive visits as well as the maximum available IOP value. Visual field data (mean deviation [MD] and pattern standard deviation [PSD]) from the Humphrey Field Analyzer II (Carl Zeiss Meditec, Dublin, CA) were obtained for 2 consecutive perimetric examinations, the most recent of which was within 6 months before and including the date the hysteresis was recorded. ORA variables included for analysis were corneal compensated IOP (IOPcc), Goldmann correlated IOP (IOPg), corneal resistance factor (CRF), and CH. Each chart was reviewed for the presence of topical hypotensive eye drop use, previous laser trabeculoplasty, and incisional surgery. Statistical analysis was performed using SPSS statistical package (SPSS, Chicago, IL). To determine which ocular characteristics (e.g., higher IOP, lower CH) were associated with DH laterality, intereye comparisons were performed for all ocular characteristics. We explored associations for DH laterality using univariate and multivariate conditional logistic regression analysis. Statistical significance was defined as a p value of <0.05.
TAGEDH1RESULTSTAGEDEN We identified and analyzed 54 patients with photographically documented DH, and 49 of them met the inclusion criteria. Patients were excluded for keratorefractive surgery (n = 2), monocular status (n = 1), and bilateral DH (2 cases). Demographic data are presented in Table 1. DH occurred in the right eye in 27/49 (55.1%) of cases. Table 2 shows mean values for ocular characteristics in DH eyes compared with their nonhemorrhagic fellow eyes. Eyes with DH had lower CH (8.68 vs 9.21; p = 0.001), higher IOP (15.6 vs 14.3; p = 0.017), higher pattern standard deviation (PSD; 5.0 vs 7.1; p = 0.006), and greater VCDR (0.79 vs. 0.68; p < 0.001) than fellow non-DH eyes, but were similar with respect to ßPPA extent (measured in clock hours), rim notching, maximum documented IOP, MD, and mean IOP (all p > 0.05). ORA variables IOPcc and IOPg were similar between eyes. There were no significant differences in frequency of eye drop use, laser trabeculoplasty, or
2
CAN J OPHTHALMOL—VOL. &, NO. &, & 2019
Table 1—Demographic data of patients with unilateral disc hemorrhage Feature
Number (%)
Age (mean § SD; range), y Gender (n = 49) Male Female Race (n = 49) African origin Asian Caucasian Hispanic Diagnosis (n = 49) Chronic angle closure Glaucoma suspect Open-angle glaucoma Exfoliation syndrome
66.8 § 10.4; 32.990.5 19 (38.8) 30 (61.2) 4 (8.2) 2 (4.1) 36 (73.5) 7 (14.3) 1 (2.0) 1 (2.0) 39 (79.5) 8 (16.3)
incisional surgery between DH and non-DH eyes. The eye with the DH had a lower CH value than its fellow eye in 76% of cases and had a greater PPA maximum width in 69.4% of cases. Univariable and multivariable conditional logistic regression analyses were used to explore for associations between DH laterality and other ocular characteristics (Table 3). CH (OR = 2.98 [95% CI: 1.346.58]; p = 0.007), VCDR (OR = 2.23 [95% CI: 1.313.79]; p = 0.003), and the average of the 5 consecutive previous Goldmann IOP measurements (OR = 1.31 [95% CI: 1.011.71]; p = 0.041) predicted the laterality of the DH in the univariable model. In the multivariable analysis, only CH (OR = 4.29 [95% CI: 1.3813.33]; p = 0.012) and VCDR (OR = 2.16 [95% CI: 1.283.63]; p = 0.004) remained significant independent predictors of DH laterality. Because the variable indicating the eye with the greatest maximum PPA width was a nominal variable, it could not be entered in the conditional logistic regression analyses. In a simple logistic regression, the eye with the DH was 5 times more likely to be the eye with the
Table 2—Mean (SD) of ocular characteristics in eyes with and without disc hemorrhage Feature
No disc hemorrhage (n = 49), mean § SD; median
Disc hemorrhage (n = 49), mean § SD; median
p*
VCDR bPPA hours Maximum IOP IOP CCT MD PSD IOPg IOPcc CRF CH Notch, n (%) Surgery, n (%) Laser, n (%)
0.68 § 0.23 5.27 § 3.9 20.16 § 5.8 14.34 § 3.6 538.59 § 36.5 6.16 § 8.6; 2.45 4.96 § 4.0; 2.86 14.33 § 4.2 16.28 § 3.8 9.03 § 2.1 9.21 § 1.7 13 (26.5) 3 (6.1) 10 (20.4)
0.79 § 0.13 5.90 § 3.6 21.90 § 7.2 15.55 § 4.1 539.02 § 37.1 6.18 § 6.8; 5.70 7.06 § 4.1; 7.39 15.57 § 5.9 17.86 § 6.0 8.99 § 2.0 8.68 § 1.9 19 (38.8) 2 (4.1) 11 (22.4)
<0.001 0.085 0.101 0.017 0.790 0.395y 0.006y 0.095 0.045 0.822 0.002 0.238z 1.000z 1.000z
CCT, central corneal thickness; CH, corneal hysteresis; CRF, corneal resistance factor; IOP, intraocular pressure; IOPcc, corneal compensated IOP as measured by the Ocular Response Analyzer; IOPg, Goldmann correlated IOP; MD, mean deviation; PSD, pattern standard deviation; VCDR, vertical cup-to-disc ratio; bPPA, beta zone parapapillary atrophy. *Paired t test. y Wilcoxon signed-rank test. z McNemar x2 test.
ARTICLE IN PRESS Disc hemorrhage and hysteresis—Radcliffe et al. Table 3—Univariable and multivariable analyses of ocular characteristics predictive of disc hemorrhage using conditional logistic regression analysis Feature Univariable analysis CH VCDR Higher bPPA hours Maximum IOP IOP CCT MD PSD IOPg IOPcc Notch (1 vs 0x) Surgery (No vs Yesx) Trabeculoplasty (1 vs 0x) Multivariable analysis VCDR CH
OR
p
95% CI
2.98* 2.23y 1.24z 1.08z 1.31z 1.01z 1.00z 1.11z 1.14z 1.19z 2.00 1.50 1.20
0.007 0.003 0.100 0.131 0.041 0.787 0.941 0.059 0.123 0.058 0.166 0.657 0.763
1.346.58 1.313.79 0.961.61 0.981.19 1.011.71 0.961.06 0.941.06 0.9961.23 0.961.35 0.991.42 0.755.33 0.259.01 0.373.93
2.16y 4.29*
0.004 0.012
1.283.63 1.3813.33
CCT, central corneal thickness; CH, corneal hysteresis; IOP, intraocular pressure; IOPcc, corneal compensated IOP as measured by the Ocular Response Analyzer; IOPg, Goldmann correlated IOP; MD, mean deviation; PSD, pattern standard deviation; VCDR, vertical cup-to-disc ratio; bPPA, beta zone parapapillary atrophy. *Per one unit decrease. y Per 0.1 unit increase. z Per one unit increase. x Reference group.
maximum PPA width (OR = 5.09 [95% CI: 1.5017.23]; p = 0.009).
TAGEDH1DISCUSSIONTAGEDEN We found CH to be lower in eyes with DH. The observed difference in CH of 0.53 mm Hg between DH and non-DH eyes was similar in magnitude to the reported difference between eyes with normal-pressure glaucoma and POAG by Ang and colleagues and was less than the 1.6 mm Hg difference in CH between POAG and normal eyes by SullivanMee.10,11 The multivariable analysis demonstrated that this association was not dependent on IOP, level of glaucomatous field loss, or a variety of other ocular characteristics. The second consistent finding was that the eye with the greater VCDR was independently more likely to have the DH. On interocular comparison, the eye with DH had slightly higher IOP as measured by Goldmann applanation tonometry as well as through the ORA’s corneal compensated IOP. Our findings suggest that, although level of IOP and degree of glaucomatous optic neuropathy are related to DH, ocular biomechanics may be equally relevant to an eye’s susceptibility to DH. Because we used fellow eyes without DH as controls, we believe that this association exists independently of potential confounding (and bilateral) variables, including age, race, genetics, and gender. Although there are many possible reasons for an independent association between DH and CH, 2 explanations seem plausible. First, corneal biomechanical properties may provide important information about an eye’s susceptibility to glaucoma as a whole. The strongest evidence to support this comes from a human study using confocal scanning laser ophthalmoscopy in which experimentally induced IOP elevation was
found to result in greater increase in optic cup depth (and presumably greater backward laminar bowing) in patients with low CH.25 While cup shallowing in response to IOP reduction from topical ocular hypotensive treatment had previously been shown to occur in eyes with thinner corneas, in a much larger study examining CH and thickness, CCT did not predict IOP-induced optic cup deformation.25,27 CH and CCT are moderately correlated; however, our study suggests that CH may be more closely associated with active glaucoma as seen in eyes with DH.13 We found no relationship between CCT and DH. Although CCT has been proposed to relate to glaucoma risk through the hypothesis that corneal properties may be a marker for posterior segment structural integrity, a number of investigations have failed to show a relationship between the 2. To begin with, CCT does not seem to influence the development of DH or PPA.14,2123,28 Corneal thickness is unrelated to lamina cribrosa and peripapillary scleral thickness in nonglaucomatous human or monkey globes.29,30 Corneal thickness is also independent of anterior scleral thickness and axial length, though one group has reported a moderate correlation between CCT and scleral thickness in 31 patients with normal-tension glaucoma.28,3133 A retrospective evaluation of 230 primary open-angle glaucoma patients found that lower CH, but not CCT, was associated with visual field progression.7 That CH, but not CCT, may be related to laminar bowing, visual field progression, and DH raises the possibility that corneal biomechanical properties (rather than structural properties like thickness) predispose to glaucoma damage. DH may be a sign of ongoing glaucomatous neurodegeneration rather than a single event that results in future structural or functional progression.20 As DH may be the result of glaucoma damage, it is possible that reduced CH may be an indicator of glaucoma-related biomechanical stress. In support of this theory, Sun et al reported that low CH values in a series of primary angle-closure glaucoma patients partially recovered after trabeculectomy.34 This finding has been replicated in a series of POAG patients undergoing glaucoma surgery.35 That IOP and CH are negatively correlated at higher IOP levels may partially explain recovery of CH with IOP reduction; however, it is unlikely to account for the strong independent relationship between CH and DH found in this work.7,11 In this investigation, several indicators of glaucoma severity, including PSD and VCDR, were greater in DH eyes. Jonas and Xu have previously reported that DH frequency is lower in early and very advanced glaucoma and is highest in the “medium-advanced” stage.35 Because the average DH eye in this study had a VCDR of 0.8 and a PSD of 7.1 dB (compared with VCDR of 0.7 and PSD of 5.0 dB in the non-DH eye), we believe that these findings are reflective of differences in glaucoma stage between DH and non-DH eyes. VCDR was (along with CH) significantly associated with DH in the multivariable model, again confirming the previous work of Jonas et al, who reported in a multivariable analysis that neuroretinal rim area was lower in eyes with DH.36 CAN J OPHTHALMOL—VOL. &, NO. &, & 2019
3
ARTICLE IN PRESS Disc hemorrhage and hysteresis—Radcliffe et al. Consistent with a previous report, the eye with the DH more often had a greater maximum width of PPA than the fellow eye.22 PPA expands as glaucoma progresses and is associated with glaucoma progression.6,37,38 DH and PPA tend to occur near each other and are frequently present in the same eyes, and both of these conditions occur with greater frequency in the so-called normal or low-pressure glaucoma.22,3945 As DH tends to occur within regions of PPA, the relationship between PPA and CH deserves further investigation. It is possible, if not likely, that some of the patients in the present study may have had undetected DH in the fellow eye, given that up to 55% of primary open-angle glaucoma patients will have at least one DH over an average of 8 years of follow-up.46 However, because DH can be transient and such prior DHs may have been missed either eye of our study patients or in eyes of an additional cohort of patients without documented DH, we chose the current analysis. We included all eyes presenting with DH in this study, regardless of glaucoma etiology. As such, a small number of eyes had exfoliation syndrome, angle closure, or suspected glaucoma. Therefore the common feature of all eyes in this study was the topic under study, that is, the presence of DH. Despite the effect that asymmetric types of glaucoma may have on disease severity and risk of progression, we adjusted all analyses for parameters that summarize the structural and functional status of each eye (MD, PSD, VCDR). Furthermore, primary open-angle glaucoma itself is often asymmetric and the relationship between CH and CD observed in this study remained despite adjusting for these variables.4749 CH was often measured on a different date than the appearance of the DH, and the stability of CH over time is unknown. We did not find any effect of treatment on DH, and therefore it is unlikely that changes in treatment could have biased CH measurements, and if so such treatments should have masked or attenuated the effects presented in this paper. In conclusion, we have reported a new association between low CH hysteresis and DH. This suggests that CH may be a biomarker for an abnormality of the optic nerve complex that may be associated with progressive glaucoma.
6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
21. 22. 23. 24.
TAGEDH1REFERENCESTAGEDEN 25. 1. Leske MC, Heijl A, Hyman L, Bengtsson B, Dong L, Yang Z, EMGT Group. Predictors of long-term progression in the early manifest glaucoma trial. Ophthalmology. 2007;114:1965–72. 2. Nouri-Mahdavi K, Hoffman D, Coleman AL, Advanced Glaucoma Intervention Study. Predictive factors for glaucomatous visual field progression in the Advanced Glaucoma Intervention Study. Ophthalmology. 2004;111:1627–35. 3. Collaborative Normal-Tension Glaucoma Study Group. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol. 1998;126:487–97. 4. Siegner SW, Netland PA. Optic disc hemorrhages and progression of glaucoma. Ophthalmology. 1996;103:1014–24. 5. Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary
4
CAN J OPHTHALMOL—VOL. &, NO. &, & 2019
26.
27.
28.
open-angle glaucoma. Arch Ophthalmol. 2002;120:714–20. discussion 82930. Teng CC, De Moraes CG, Prata TS, Tello C, Ritch R, Liebmann JM. Beta-zone parapapillary atrophy and the velocity of glaucoma progression. Ophthalmology. 2010;117:909–15. Congdon NG, Broman AT, Bandeen-Roche K, Grover D, Quigley HA. Central corneal thickness and corneal hysteresis associated with glaucoma damage. Am J Ophthalmol. 2006;141:868–75. Luce DA. Determining in vivo biomechanical properties of the cornea with an ocular response analyzer. J Cataract Refract Surg. 2005;31:156–62. Bochmann F, Ang GS, Azuara-Blanco A. Lower corneal hysteresis in glaucoma patients with acquired pit of the optic nerve (APON). Graefes Arch Clin Exp Ophthalmol. 2008;246:735–8. Sullivan-Mee M, Billingsley SC, Patel AD, Halverson KD, Alldredge BR, Qualls C. Ocular Response Analyzer in subjects with and without glaucoma. Optom Vis Sci. 2008;85:463–70. Ang GS, Bochmann F, Townend J, Azuara-Blanco A. Corneal biomechanical properties in primary open angle glaucoma and normal tension glaucoma. J Glaucoma. 2008;17:259–62. Schroeder B, Hager A, Kutschan A, Wiegand W. [Measurement of viscoelastic corneal parameters (corneal hysteresis) in patients with primary open angle glaucoma]. Ophthalmologe. 2008;105:916–20. Touboul D, Roberts C, Kerautret J, et al. Correlations between corneal hysteresis, intraocular pressure, and corneal central pachymetry. J Cataract Refract Surg. 2008;34:616–22. Jonas JB, Stroux A, Oberacher-Velten IM, Kitnarong N, J€ unemann A. Central corneal thickness and development of glaucomatous optic disk hemorrhages. Am J Ophthalmol. 2005;140:1139–41. Drance SM, Fairclough M, Butler DM, Kottler MS. The importance of disc hemorrhage in the prognosis of chronic open angle glaucoma. Arch Ophthalmol. 1977;95:226–8. Ishida K, Yamamoto T, Sugiyama K, Kitazawa Y. Disk hemorrhage is a significantly negative prognostic factor in normal-tension glaucoma. Am J Ophthalmol. 2000;129:707–14. Jonas JB, Xu L. Optic disk hemorrhages in glaucoma. Am J Ophthalmol. 1994;118:1–8. Airaksinen PJ, Mustonen E, Alanko HI. Optic disc haemorrhages precede retinal nerve fibre layer defects in ocular hypertension. Acta Ophthalmol (Copenh). 1981;59:627–41. Jonas JB, Schiro D. Localised wedge shaped defects of the retinal nerve fibre layer in glaucoma. Br J Ophthalmol. 1994;78:285–90. De Moraes CG, Prata TS, Liebmann CA, Tello C, Ritch R, Liebmann JM. Spatially consistent, localized visual field loss before and after disc hemorrhage. Invest Ophthalmol Vis Sci. 2009;50: 4727–33. Xu L, Zhang H, Wang YX, Jonas JB. Central corneal thickness and optic disc hemorrhages: the Beijing Eye Study. Arch Ophthalmol. 2008;126:435–6. Radcliffe NM, Liebmann JM, Rozenbaum I, et al. Anatomic relationships between disc hemorrhage and parapapillary atrophy. Am J Ophthalmol. 2008;146:735–40. Kim YD, Han SB, Park KH, et al. Risk factors associated with optic disc haemorrhage in patients with normal tension glaucoma. Eye (Lond). 2010;24:567–72. Law SK, Choe R, Caprioli J. Optic disk characteristics before the occurrence of disk hemorrhage in glaucoma patients. Am J Ophthalmol. 2001;132:411–3. Wells AP, Garway-Heath DF, Poostchi A, Wong T, Chan KC, Sachdev N. Corneal hysteresis but not corneal thickness correlates with optic nerve surface compliance in glaucoma patients. Invest Ophthalmol Vis Sci. 2008;49:3262–8. Kotecha A, Elsheikh A, Roberts CR, Zhu H, Garway-Heath DF. Corneal thickness- and age-related biomechanical properties of the cornea measured with the ocular response analyzer. Invest Ophthalmol Vis Sci. 2006;47:5337–47. Lesk MR, Hafez AS, Descovich D. Relationship between central corneal thickness and changes of optic nerve head topography and blood flow after intraocular pressure reduction in open-angle glaucoma and ocular hypertension. Arch Ophthalmol. 2006;124:1568–72. Tomais G, Georgopoulos G, Koutsandrea C, Moschos M. Correlation of central corneal thickness and axial length to the optic disc and peripapillary atrophy among healthy individuals, glaucoma and ocular hypertension patients. Clin Ophthalmol. 2008;2:981–8.
ARTICLE IN PRESS Disc hemorrhage and hysteresis—Radcliffe et al. 29. Jonas JB, Hayreh SS, Tao Y. Central corneal thickness and thickness of the lamina cribrosa and peripapillary sclera in monkeys. Arch Ophthalmol. 2009;127:1395–6. 30. Jonas JB, Holbach L. Central corneal thickness and thickness of the lamina cribrosa in human eyes. Invest Ophthalmol Vis Sci. 2005;46:1275–9. 31. Oliveira C, Tello C, Liebmann J, Ritch R. Central corneal thickness is not related to anterior scleral thickness or axial length. J Glaucoma. 2006;15:190–4. 32. Shimmyo M, Orloff PN. Corneal thickness and axial length. Am J Ophthalmol. 2005;139:553–4. 33. Mohamed-Noor J, Bochmann F, Siddiqui MA, et al. Correlation between corneal and scleral thickness in glaucoma. J Glaucoma. 2009;18:32–6. 34. Sun L, Shen M, Wang J, et al. Recovery of corneal hysteresis after reduction of intraocular pressure in chronic primary angle-closure glaucoma. Am J Ophthalmol. 2009;147:1061–6. 35. Shimmyo M. Recovery of corneal hysteresis after reduction of intraocular pressure in chronic primary angle-closure glaucoma. Am J Ophthalmol. 2009;148:623. author reply 623. 36. Jonas JB, Martus P, Budde WM, Hayler J. Morphologic predictive factors for development of optic disc hemorrhages in glaucoma. Invest Ophthalmol Vis Sci. 2002;43:2956–61. 37. Xu L, Wang Y, Yang H, Jonas JB. Differences in parapapillary atrophy between glaucomatous and normal eyes: the Beijing Eye Study. Am J Ophthalmol. 2007;144:541–6. 38. Uchida H, Ugurlu S, Caprioli J. Increasing peripapillary atrophy is associated with progressive glaucoma. Ophthalmology. 1998;105:1541–5. 39. Ahn JK, Kang JH, Park KH. Correlation between a disc hemorrhage and peripapillary atrophy in glaucoma patients with a unilateral disc hemorrhage. J Glaucoma. 2004;13:9–14. 40. Sugiyama K, Tomita G, Kawase K, et al. Disc hemorrhage and peripapillary atrophy in apparently healthy subjects. Acta Ophthalmol Scand. 1999;77:139–42. 41. Kitazawa Y, Shirato S, Yamamoto T. Optic disc hemorrhage in low-tension glaucoma. Ophthalmology. 1986;93:853–7. 42. Wang XH, Stewart WC, Jackson GJ. Differences in optic discs in lowtension glaucoma patients with relatively low or high pressures. Acta Ophthalmol Scand. 1996;74:364–7. 43. Buus DR, Anderson DR. Peripapillary crescents and halos in normal-tension glaucoma and ocular hypertension. Ophthalmology. 1989;96:16–9. 44. Park KH, Park SJ, Lee YJ, Kim JY, Caprioli J. Ability of peripapillary atrophy parameters to differentiate normal-tension glaucoma from glaucomalike disk. J Glaucoma. 2001;10:95–101.
45. Krupin T, Liebmann JM, Greenfield DS, Rosenberg LF, Ritch R, Yang JW, Low-Pressure Glaucoma Study Group. The Low-pressure Glaucoma Treatment Study (LoGTS) study design and baseline characteristics of enrolled patients. Ophthalmology. 2005;112:376–85. 46. Bengtsson B, Leske MC, Yang Z, Heijl A, EMGT Group. Disc hemorrhages and treatment in the early manifest glaucoma trial. Ophthalmology. 2008;115:2044–8. 47. Crichton A, Drance SM, Douglas GR, et al. Unequal intraocular pressure and its relation to asymmetric visual field defects in low-tension glaucoma. Ophthalmology. 1989;96:1312–4. 48. Poinoosawmy D, Fontana L, Wu JX, et al. Frequency of asymmetric visual field defects in normal-tension and high-tension glaucoma. Ophthalmology. 1998;105:988–91. 49. Holst JC. A statistical study of glaucoma. Am J Ophthalmol. 1947;30:1267–75.
Footnotes and Disclosure: The authors (NMR, CGD, CT, JML, and RR) have received instrument support from Reichert, Inc. NMR has served as a consultant for New World Medical, Glaukos, Sight Sciences, Iridex, Lumenis, Alcon, Allergan, and Beaver Visitec Inc. Supported in part by the Allen Adler Research Fund of the New York Glaucoma Research Institute and by the Glaucoma Research and Education Fund of Lenox Hill Hospital, New York, NY. From the *Mt Sinai School of Medicine, New York, NY; yNYU School of Medicine, New York, NY; zVagelos College of Physicians and Surgeons, Columbia University, New York, NY; xEinhorn Clinical Research Center, New York Eye and Ear Infirmary, New York, NY. Originally received Apr. 30, 2019. Final revision Oct. 16, 2019. Accepted Oct. 24, 2019. Correspondence to Nathan Radcliffe, MD, 1101 Pelham Parkway, New York, NY 10469. [email protected]
CAN J OPHTHALMOL—VOL. &, NO. &, & 2019
5
Relationship between optic disc hemorrhage and corneal hysteresis Nathan M. Radcliffe, MD,* Nathaniel Tracer, BA,y Carlos Gustavo V. De Moraes, MD,z Celso Tello, MD,x Jeffrey M. Liebmann, MD,z Robert Ritch, MDx ABSTRACT Objective: To determine the relationship between optic disc hemorrhage (DH) and corneal hysteresis (CH). Methods: Consecutive patients with prior or current photographic evidence of unilateral DH who had undergone CH measurement with the Ocular Response Analyzer (ORA; Reichert, Buffalo, NY) were enrolled. Eyes with a history of corneal disease, refractive surgery, or bilateral DH were excluded. Central corneal thickness (CCT), visual field data, 5 consecutive previous intraocular pressures (IOPs), and maximum documented peak IOP were obtained by chart review. Vertical cup-to-disc ratio (VCDR), the presence of neuroretinal rim notching, number of clock hours of beta zone parapapillary atrophy (ßPPA), and eye with greater ßPPA width were determined from photographs by 2 masked expert examiners. Results: We identified and analyzed 49 patients with photographically documented unilateral DH. Compared to fellow non-DH eyes, eyes with DH had lower CH (8.7 § 1.9 vs 9.2 § 1.7; p = 0.002), higher IOP (15.6 § 3.6 vs 14.3 § 4.1; p = 0.017), and greater VCDR (0.79 § 0.13 vs 0.68 § 0.23; p < 0.001), but were similar with respect to CCT, ßPPA extent, rim notching, peak IOP, and visual field damage (all p > 0.05). Using multivariate conditional logistic regression analysis, only CH (p = 0.012) and VCDR (p = 0.004) predicted the laterality of the DH. Conclusions: Lower CH and greater VCDR are independently associated with DH. This suggests that CH may be a structural biomarker for an abnormality of the optic nerve complex that may be associated with progressive glaucoma. Eyes in which DH were detected had lower CH.
Progressive glaucomatous visual loss can lead to blindness.13 Understanding risk factors for glaucomatous progression can help the physician appropriately monitor and treat patients at higher risk. Established risk factors for glaucomatous progression include older age, elevated intraocular pressure (IOP), lower central corneal thickness (CCT), and the presence of parapapillary atrophy (PPA) or optic disc hemorrhage (DH).16 Corneal hysteresis (CH) has been reported to be a risk factor for glaucoma progression.7 CH is the difference between the air-jet pressure at inward and outward applanation and therefore is considered to be a measure of corneal viscous dampening. A low degree of CH implies that little applied energy is absorbed (dampened) by the cornea. This purported corneal biomechanical property, measured by the noncontact Ocular Response Analyzer (ORA; Reichert, Buffalo, NY), is lower in eyes with glaucoma.712 Although CH is moderately correlated with CCT,13 in one study CH was more closely associated with glaucoma progression than CCT.7 Optic DH, visible as a superficial hemorrhage within the retinal nerve fibre layer at or immediately adjacent to the disc edge, is a strong risk factor for the development and progression of glaucomatous optic neuropathy.14,1420 Though the cause of DH is unknown, spatially consistent, localized visual field progression both precedes and accelerates after DH, suggesting that DH may be a biomarker for
ongoing neuroretinal rim deterioriation.20 A number of investigations attempting to link DH and CCT, 2 strong predictors of glaucoma progression, have failed to find a relationship.14,2123 A relationship between DH and CH might suggest that corneal biomechanical properties are somehow important to glaucomatous optic neuropathy. Both DH and low CH occur in eyes with focal neuroretinal rim notching in addition to being associated with progression.9,24 In glaucoma patients with low CH, there is a greater backward bowing of the lamina cribrosa in response to transient IOP elevation.25,26 We sought to determine whether eyes with DH have lower CH.
TAGEDH1METHODSTAGEDEN Approval for this retrospective study was obtained from the Institutional Review Boards at the New York Eye and Ear Infirmary and Weill Cornell Medical College/New York Presbyterian Hospital. This study adhered to the tenets of the Declaration of Helsinki. All digital optic nerve stereophotographs of patients examined in the glaucoma practices of the authors between 8/1/2009 and 2/28/2010 were screened for the presence of prior or current DH. Both eyes of subjects with photographic evidence of unilateral DH and documented bilateral CH measurements from the ORA (Reichert) were included. Eyes with a history of corneal
© 2019 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jcjo.2019.10.007 ISSN 0008-4182 CAN J OPHTHALMOL—VOL. &, NO. &, & 2019
1
ARTICLE IN PRESS Disc hemorrhage and hysteresis—Radcliffe et al. disease or refractive surgery were excluded, as were monocular patients and patients with bilateral DH, nonglaucomatous optic neuropathy or visual field loss, or poor-quality stereophotographs. For each patient seen within the specified period, each bilateral set of optic nerve stereophotographs was evaluated by 2 authors, who were masked to CH values and other clinical patient data. For each pair of stereophotographs, the laterality (i.e., OD vs OS) of the DH and the laterality of the eye with the greatest ßPPA width were determined. The number of clock hours encompassed by ßPPA, the presence of neuroretinal rim notching, and vertical cup-to-disc ratio (VCDR) were determined for each eye. For each patient with DH, pertinent information was obtained by chart review, including baseline CCT (DGH Technology, Exton, PA), IOP measured by Goldmann applanation tonometry on the day that CH was obtained, and on 5 previous consecutive visits as well as the maximum available IOP value. Visual field data (mean deviation [MD] and pattern standard deviation [PSD]) from the Humphrey Field Analyzer II (Carl Zeiss Meditec, Dublin, CA) were obtained for 2 consecutive perimetric examinations, the most recent of which was within 6 months before and including the date the hysteresis was recorded. ORA variables included for analysis were corneal compensated IOP (IOPcc), Goldmann correlated IOP (IOPg), corneal resistance factor (CRF), and CH. Each chart was reviewed for the presence of topical hypotensive eye drop use, previous laser trabeculoplasty, and incisional surgery. Statistical analysis was performed using SPSS statistical package (SPSS, Chicago, IL). To determine which ocular characteristics (e.g., higher IOP, lower CH) were associated with DH laterality, intereye comparisons were performed for all ocular characteristics. We explored associations for DH laterality using univariate and multivariate conditional logistic regression analysis. Statistical significance was defined as a p value of <0.05.
TAGEDH1RESULTSTAGEDEN We identified and analyzed 54 patients with photographically documented DH, and 49 of them met the inclusion criteria. Patients were excluded for keratorefractive surgery (n = 2), monocular status (n = 1), and bilateral DH (2 cases). Demographic data are presented in Table 1. DH occurred in the right eye in 27/49 (55.1%) of cases. Table 2 shows mean values for ocular characteristics in DH eyes compared with their nonhemorrhagic fellow eyes. Eyes with DH had lower CH (8.68 vs 9.21; p = 0.001), higher IOP (15.6 vs 14.3; p = 0.017), higher pattern standard deviation (PSD; 5.0 vs 7.1; p = 0.006), and greater VCDR (0.79 vs. 0.68; p < 0.001) than fellow non-DH eyes, but were similar with respect to ßPPA extent (measured in clock hours), rim notching, maximum documented IOP, MD, and mean IOP (all p > 0.05). ORA variables IOPcc and IOPg were similar between eyes. There were no significant differences in frequency of eye drop use, laser trabeculoplasty, or
2
CAN J OPHTHALMOL—VOL. &, NO. &, & 2019
Table 1—Demographic data of patients with unilateral disc hemorrhage Feature
Number (%)
Age (mean § SD; range), y Gender (n = 49) Male Female Race (n = 49) African origin Asian Caucasian Hispanic Diagnosis (n = 49) Chronic angle closure Glaucoma suspect Open-angle glaucoma Exfoliation syndrome
66.8 § 10.4; 32.990.5 19 (38.8) 30 (61.2) 4 (8.2) 2 (4.1) 36 (73.5) 7 (14.3) 1 (2.0) 1 (2.0) 39 (79.5) 8 (16.3)
incisional surgery between DH and non-DH eyes. The eye with the DH had a lower CH value than its fellow eye in 76% of cases and had a greater PPA maximum width in 69.4% of cases. Univariable and multivariable conditional logistic regression analyses were used to explore for associations between DH laterality and other ocular characteristics (Table 3). CH (OR = 2.98 [95% CI: 1.346.58]; p = 0.007), VCDR (OR = 2.23 [95% CI: 1.313.79]; p = 0.003), and the average of the 5 consecutive previous Goldmann IOP measurements (OR = 1.31 [95% CI: 1.011.71]; p = 0.041) predicted the laterality of the DH in the univariable model. In the multivariable analysis, only CH (OR = 4.29 [95% CI: 1.3813.33]; p = 0.012) and VCDR (OR = 2.16 [95% CI: 1.283.63]; p = 0.004) remained significant independent predictors of DH laterality. Because the variable indicating the eye with the greatest maximum PPA width was a nominal variable, it could not be entered in the conditional logistic regression analyses. In a simple logistic regression, the eye with the DH was 5 times more likely to be the eye with the
Table 2—Mean (SD) of ocular characteristics in eyes with and without disc hemorrhage Feature
No disc hemorrhage (n = 49), mean § SD; median
Disc hemorrhage (n = 49), mean § SD; median
p*
VCDR bPPA hours Maximum IOP IOP CCT MD PSD IOPg IOPcc CRF CH Notch, n (%) Surgery, n (%) Laser, n (%)
0.68 § 0.23 5.27 § 3.9 20.16 § 5.8 14.34 § 3.6 538.59 § 36.5 6.16 § 8.6; 2.45 4.96 § 4.0; 2.86 14.33 § 4.2 16.28 § 3.8 9.03 § 2.1 9.21 § 1.7 13 (26.5) 3 (6.1) 10 (20.4)
0.79 § 0.13 5.90 § 3.6 21.90 § 7.2 15.55 § 4.1 539.02 § 37.1 6.18 § 6.8; 5.70 7.06 § 4.1; 7.39 15.57 § 5.9 17.86 § 6.0 8.99 § 2.0 8.68 § 1.9 19 (38.8) 2 (4.1) 11 (22.4)
<0.001 0.085 0.101 0.017 0.790 0.395y 0.006y 0.095 0.045 0.822 0.002 0.238z 1.000z 1.000z
CCT, central corneal thickness; CH, corneal hysteresis; CRF, corneal resistance factor; IOP, intraocular pressure; IOPcc, corneal compensated IOP as measured by the Ocular Response Analyzer; IOPg, Goldmann correlated IOP; MD, mean deviation; PSD, pattern standard deviation; VCDR, vertical cup-to-disc ratio; bPPA, beta zone parapapillary atrophy. *Paired t test. y Wilcoxon signed-rank test. z McNemar x2 test.
ARTICLE IN PRESS Disc hemorrhage and hysteresis—Radcliffe et al. Table 3—Univariable and multivariable analyses of ocular characteristics predictive of disc hemorrhage using conditional logistic regression analysis Feature Univariable analysis CH VCDR Higher bPPA hours Maximum IOP IOP CCT MD PSD IOPg IOPcc Notch (1 vs 0x) Surgery (No vs Yesx) Trabeculoplasty (1 vs 0x) Multivariable analysis VCDR CH
OR
p
95% CI
2.98* 2.23y 1.24z 1.08z 1.31z 1.01z 1.00z 1.11z 1.14z 1.19z 2.00 1.50 1.20
0.007 0.003 0.100 0.131 0.041 0.787 0.941 0.059 0.123 0.058 0.166 0.657 0.763
1.346.58 1.313.79 0.961.61 0.981.19 1.011.71 0.961.06 0.941.06 0.9961.23 0.961.35 0.991.42 0.755.33 0.259.01 0.373.93
2.16y 4.29*
0.004 0.012
1.283.63 1.3813.33
CCT, central corneal thickness; CH, corneal hysteresis; IOP, intraocular pressure; IOPcc, corneal compensated IOP as measured by the Ocular Response Analyzer; IOPg, Goldmann correlated IOP; MD, mean deviation; PSD, pattern standard deviation; VCDR, vertical cup-to-disc ratio; bPPA, beta zone parapapillary atrophy. *Per one unit decrease. y Per 0.1 unit increase. z Per one unit increase. x Reference group.
maximum PPA width (OR = 5.09 [95% CI: 1.5017.23]; p = 0.009).
TAGEDH1DISCUSSIONTAGEDEN We found CH to be lower in eyes with DH. The observed difference in CH of 0.53 mm Hg between DH and non-DH eyes was similar in magnitude to the reported difference between eyes with normal-pressure glaucoma and POAG by Ang and colleagues and was less than the 1.6 mm Hg difference in CH between POAG and normal eyes by SullivanMee.10,11 The multivariable analysis demonstrated that this association was not dependent on IOP, level of glaucomatous field loss, or a variety of other ocular characteristics. The second consistent finding was that the eye with the greater VCDR was independently more likely to have the DH. On interocular comparison, the eye with DH had slightly higher IOP as measured by Goldmann applanation tonometry as well as through the ORA’s corneal compensated IOP. Our findings suggest that, although level of IOP and degree of glaucomatous optic neuropathy are related to DH, ocular biomechanics may be equally relevant to an eye’s susceptibility to DH. Because we used fellow eyes without DH as controls, we believe that this association exists independently of potential confounding (and bilateral) variables, including age, race, genetics, and gender. Although there are many possible reasons for an independent association between DH and CH, 2 explanations seem plausible. First, corneal biomechanical properties may provide important information about an eye’s susceptibility to glaucoma as a whole. The strongest evidence to support this comes from a human study using confocal scanning laser ophthalmoscopy in which experimentally induced IOP elevation was
found to result in greater increase in optic cup depth (and presumably greater backward laminar bowing) in patients with low CH.25 While cup shallowing in response to IOP reduction from topical ocular hypotensive treatment had previously been shown to occur in eyes with thinner corneas, in a much larger study examining CH and thickness, CCT did not predict IOP-induced optic cup deformation.25,27 CH and CCT are moderately correlated; however, our study suggests that CH may be more closely associated with active glaucoma as seen in eyes with DH.13 We found no relationship between CCT and DH. Although CCT has been proposed to relate to glaucoma risk through the hypothesis that corneal properties may be a marker for posterior segment structural integrity, a number of investigations have failed to show a relationship between the 2. To begin with, CCT does not seem to influence the development of DH or PPA.14,2123,28 Corneal thickness is unrelated to lamina cribrosa and peripapillary scleral thickness in nonglaucomatous human or monkey globes.29,30 Corneal thickness is also independent of anterior scleral thickness and axial length, though one group has reported a moderate correlation between CCT and scleral thickness in 31 patients with normal-tension glaucoma.28,3133 A retrospective evaluation of 230 primary open-angle glaucoma patients found that lower CH, but not CCT, was associated with visual field progression.7 That CH, but not CCT, may be related to laminar bowing, visual field progression, and DH raises the possibility that corneal biomechanical properties (rather than structural properties like thickness) predispose to glaucoma damage. DH may be a sign of ongoing glaucomatous neurodegeneration rather than a single event that results in future structural or functional progression.20 As DH may be the result of glaucoma damage, it is possible that reduced CH may be an indicator of glaucoma-related biomechanical stress. In support of this theory, Sun et al reported that low CH values in a series of primary angle-closure glaucoma patients partially recovered after trabeculectomy.34 This finding has been replicated in a series of POAG patients undergoing glaucoma surgery.35 That IOP and CH are negatively correlated at higher IOP levels may partially explain recovery of CH with IOP reduction; however, it is unlikely to account for the strong independent relationship between CH and DH found in this work.7,11 In this investigation, several indicators of glaucoma severity, including PSD and VCDR, were greater in DH eyes. Jonas and Xu have previously reported that DH frequency is lower in early and very advanced glaucoma and is highest in the “medium-advanced” stage.35 Because the average DH eye in this study had a VCDR of 0.8 and a PSD of 7.1 dB (compared with VCDR of 0.7 and PSD of 5.0 dB in the non-DH eye), we believe that these findings are reflective of differences in glaucoma stage between DH and non-DH eyes. VCDR was (along with CH) significantly associated with DH in the multivariable model, again confirming the previous work of Jonas et al, who reported in a multivariable analysis that neuroretinal rim area was lower in eyes with DH.36 CAN J OPHTHALMOL—VOL. &, NO. &, & 2019
3
ARTICLE IN PRESS Disc hemorrhage and hysteresis—Radcliffe et al. Consistent with a previous report, the eye with the DH more often had a greater maximum width of PPA than the fellow eye.22 PPA expands as glaucoma progresses and is associated with glaucoma progression.6,37,38 DH and PPA tend to occur near each other and are frequently present in the same eyes, and both of these conditions occur with greater frequency in the so-called normal or low-pressure glaucoma.22,3945 As DH tends to occur within regions of PPA, the relationship between PPA and CH deserves further investigation. It is possible, if not likely, that some of the patients in the present study may have had undetected DH in the fellow eye, given that up to 55% of primary open-angle glaucoma patients will have at least one DH over an average of 8 years of follow-up.46 However, because DH can be transient and such prior DHs may have been missed either eye of our study patients or in eyes of an additional cohort of patients without documented DH, we chose the current analysis. We included all eyes presenting with DH in this study, regardless of glaucoma etiology. As such, a small number of eyes had exfoliation syndrome, angle closure, or suspected glaucoma. Therefore the common feature of all eyes in this study was the topic under study, that is, the presence of DH. Despite the effect that asymmetric types of glaucoma may have on disease severity and risk of progression, we adjusted all analyses for parameters that summarize the structural and functional status of each eye (MD, PSD, VCDR). Furthermore, primary open-angle glaucoma itself is often asymmetric and the relationship between CH and CD observed in this study remained despite adjusting for these variables.4749 CH was often measured on a different date than the appearance of the DH, and the stability of CH over time is unknown. We did not find any effect of treatment on DH, and therefore it is unlikely that changes in treatment could have biased CH measurements, and if so such treatments should have masked or attenuated the effects presented in this paper. In conclusion, we have reported a new association between low CH hysteresis and DH. This suggests that CH may be a biomarker for an abnormality of the optic nerve complex that may be associated with progressive glaucoma.
6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
21. 22. 23. 24.
TAGEDH1REFERENCESTAGEDEN 25. 1. Leske MC, Heijl A, Hyman L, Bengtsson B, Dong L, Yang Z, EMGT Group. Predictors of long-term progression in the early manifest glaucoma trial. Ophthalmology. 2007;114:1965–72. 2. Nouri-Mahdavi K, Hoffman D, Coleman AL, Advanced Glaucoma Intervention Study. Predictive factors for glaucomatous visual field progression in the Advanced Glaucoma Intervention Study. Ophthalmology. 2004;111:1627–35. 3. Collaborative Normal-Tension Glaucoma Study Group. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol. 1998;126:487–97. 4. Siegner SW, Netland PA. Optic disc hemorrhages and progression of glaucoma. Ophthalmology. 1996;103:1014–24. 5. Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary
4
CAN J OPHTHALMOL—VOL. &, NO. &, & 2019
26.
27.
28.
open-angle glaucoma. Arch Ophthalmol. 2002;120:714–20. discussion 82930. Teng CC, De Moraes CG, Prata TS, Tello C, Ritch R, Liebmann JM. Beta-zone parapapillary atrophy and the velocity of glaucoma progression. Ophthalmology. 2010;117:909–15. Congdon NG, Broman AT, Bandeen-Roche K, Grover D, Quigley HA. Central corneal thickness and corneal hysteresis associated with glaucoma damage. Am J Ophthalmol. 2006;141:868–75. Luce DA. Determining in vivo biomechanical properties of the cornea with an ocular response analyzer. J Cataract Refract Surg. 2005;31:156–62. Bochmann F, Ang GS, Azuara-Blanco A. Lower corneal hysteresis in glaucoma patients with acquired pit of the optic nerve (APON). Graefes Arch Clin Exp Ophthalmol. 2008;246:735–8. Sullivan-Mee M, Billingsley SC, Patel AD, Halverson KD, Alldredge BR, Qualls C. Ocular Response Analyzer in subjects with and without glaucoma. Optom Vis Sci. 2008;85:463–70. Ang GS, Bochmann F, Townend J, Azuara-Blanco A. Corneal biomechanical properties in primary open angle glaucoma and normal tension glaucoma. J Glaucoma. 2008;17:259–62. Schroeder B, Hager A, Kutschan A, Wiegand W. [Measurement of viscoelastic corneal parameters (corneal hysteresis) in patients with primary open angle glaucoma]. Ophthalmologe. 2008;105:916–20. Touboul D, Roberts C, Kerautret J, et al. Correlations between corneal hysteresis, intraocular pressure, and corneal central pachymetry. J Cataract Refract Surg. 2008;34:616–22. Jonas JB, Stroux A, Oberacher-Velten IM, Kitnarong N, J€ unemann A. Central corneal thickness and development of glaucomatous optic disk hemorrhages. Am J Ophthalmol. 2005;140:1139–41. Drance SM, Fairclough M, Butler DM, Kottler MS. The importance of disc hemorrhage in the prognosis of chronic open angle glaucoma. Arch Ophthalmol. 1977;95:226–8. Ishida K, Yamamoto T, Sugiyama K, Kitazawa Y. Disk hemorrhage is a significantly negative prognostic factor in normal-tension glaucoma. Am J Ophthalmol. 2000;129:707–14. Jonas JB, Xu L. Optic disk hemorrhages in glaucoma. Am J Ophthalmol. 1994;118:1–8. Airaksinen PJ, Mustonen E, Alanko HI. Optic disc haemorrhages precede retinal nerve fibre layer defects in ocular hypertension. Acta Ophthalmol (Copenh). 1981;59:627–41. Jonas JB, Schiro D. Localised wedge shaped defects of the retinal nerve fibre layer in glaucoma. Br J Ophthalmol. 1994;78:285–90. De Moraes CG, Prata TS, Liebmann CA, Tello C, Ritch R, Liebmann JM. Spatially consistent, localized visual field loss before and after disc hemorrhage. Invest Ophthalmol Vis Sci. 2009;50: 4727–33. Xu L, Zhang H, Wang YX, Jonas JB. Central corneal thickness and optic disc hemorrhages: the Beijing Eye Study. Arch Ophthalmol. 2008;126:435–6. Radcliffe NM, Liebmann JM, Rozenbaum I, et al. Anatomic relationships between disc hemorrhage and parapapillary atrophy. Am J Ophthalmol. 2008;146:735–40. Kim YD, Han SB, Park KH, et al. Risk factors associated with optic disc haemorrhage in patients with normal tension glaucoma. Eye (Lond). 2010;24:567–72. Law SK, Choe R, Caprioli J. Optic disk characteristics before the occurrence of disk hemorrhage in glaucoma patients. Am J Ophthalmol. 2001;132:411–3. Wells AP, Garway-Heath DF, Poostchi A, Wong T, Chan KC, Sachdev N. Corneal hysteresis but not corneal thickness correlates with optic nerve surface compliance in glaucoma patients. Invest Ophthalmol Vis Sci. 2008;49:3262–8. Kotecha A, Elsheikh A, Roberts CR, Zhu H, Garway-Heath DF. Corneal thickness- and age-related biomechanical properties of the cornea measured with the ocular response analyzer. Invest Ophthalmol Vis Sci. 2006;47:5337–47. Lesk MR, Hafez AS, Descovich D. Relationship between central corneal thickness and changes of optic nerve head topography and blood flow after intraocular pressure reduction in open-angle glaucoma and ocular hypertension. Arch Ophthalmol. 2006;124:1568–72. Tomais G, Georgopoulos G, Koutsandrea C, Moschos M. Correlation of central corneal thickness and axial length to the optic disc and peripapillary atrophy among healthy individuals, glaucoma and ocular hypertension patients. Clin Ophthalmol. 2008;2:981–8.
ARTICLE IN PRESS Disc hemorrhage and hysteresis—Radcliffe et al. 29. Jonas JB, Hayreh SS, Tao Y. Central corneal thickness and thickness of the lamina cribrosa and peripapillary sclera in monkeys. Arch Ophthalmol. 2009;127:1395–6. 30. Jonas JB, Holbach L. Central corneal thickness and thickness of the lamina cribrosa in human eyes. Invest Ophthalmol Vis Sci. 2005;46:1275–9. 31. Oliveira C, Tello C, Liebmann J, Ritch R. Central corneal thickness is not related to anterior scleral thickness or axial length. J Glaucoma. 2006;15:190–4. 32. Shimmyo M, Orloff PN. Corneal thickness and axial length. Am J Ophthalmol. 2005;139:553–4. 33. Mohamed-Noor J, Bochmann F, Siddiqui MA, et al. Correlation between corneal and scleral thickness in glaucoma. J Glaucoma. 2009;18:32–6. 34. Sun L, Shen M, Wang J, et al. Recovery of corneal hysteresis after reduction of intraocular pressure in chronic primary angle-closure glaucoma. Am J Ophthalmol. 2009;147:1061–6. 35. Shimmyo M. Recovery of corneal hysteresis after reduction of intraocular pressure in chronic primary angle-closure glaucoma. Am J Ophthalmol. 2009;148:623. author reply 623. 36. Jonas JB, Martus P, Budde WM, Hayler J. Morphologic predictive factors for development of optic disc hemorrhages in glaucoma. Invest Ophthalmol Vis Sci. 2002;43:2956–61. 37. Xu L, Wang Y, Yang H, Jonas JB. Differences in parapapillary atrophy between glaucomatous and normal eyes: the Beijing Eye Study. Am J Ophthalmol. 2007;144:541–6. 38. Uchida H, Ugurlu S, Caprioli J. Increasing peripapillary atrophy is associated with progressive glaucoma. Ophthalmology. 1998;105:1541–5. 39. Ahn JK, Kang JH, Park KH. Correlation between a disc hemorrhage and peripapillary atrophy in glaucoma patients with a unilateral disc hemorrhage. J Glaucoma. 2004;13:9–14. 40. Sugiyama K, Tomita G, Kawase K, et al. Disc hemorrhage and peripapillary atrophy in apparently healthy subjects. Acta Ophthalmol Scand. 1999;77:139–42. 41. Kitazawa Y, Shirato S, Yamamoto T. Optic disc hemorrhage in low-tension glaucoma. Ophthalmology. 1986;93:853–7. 42. Wang XH, Stewart WC, Jackson GJ. Differences in optic discs in lowtension glaucoma patients with relatively low or high pressures. Acta Ophthalmol Scand. 1996;74:364–7. 43. Buus DR, Anderson DR. Peripapillary crescents and halos in normal-tension glaucoma and ocular hypertension. Ophthalmology. 1989;96:16–9. 44. Park KH, Park SJ, Lee YJ, Kim JY, Caprioli J. Ability of peripapillary atrophy parameters to differentiate normal-tension glaucoma from glaucomalike disk. J Glaucoma. 2001;10:95–101.
45. Krupin T, Liebmann JM, Greenfield DS, Rosenberg LF, Ritch R, Yang JW, Low-Pressure Glaucoma Study Group. The Low-pressure Glaucoma Treatment Study (LoGTS) study design and baseline characteristics of enrolled patients. Ophthalmology. 2005;112:376–85. 46. Bengtsson B, Leske MC, Yang Z, Heijl A, EMGT Group. Disc hemorrhages and treatment in the early manifest glaucoma trial. Ophthalmology. 2008;115:2044–8. 47. Crichton A, Drance SM, Douglas GR, et al. Unequal intraocular pressure and its relation to asymmetric visual field defects in low-tension glaucoma. Ophthalmology. 1989;96:1312–4. 48. Poinoosawmy D, Fontana L, Wu JX, et al. Frequency of asymmetric visual field defects in normal-tension and high-tension glaucoma. Ophthalmology. 1998;105:988–91. 49. Holst JC. A statistical study of glaucoma. Am J Ophthalmol. 1947;30:1267–75.
Footnotes and Disclosure: The authors (NMR, CGD, CT, JML, and RR) have received instrument support from Reichert, Inc. NMR has served as a consultant for New World Medical, Glaukos, Sight Sciences, Iridex, Lumenis, Alcon, Allergan, and Beaver Visitec Inc. Supported in part by the Allen Adler Research Fund of the New York Glaucoma Research Institute and by the Glaucoma Research and Education Fund of Lenox Hill Hospital, New York, NY. From the *Mt Sinai School of Medicine, New York, NY; yNYU School of Medicine, New York, NY; zVagelos College of Physicians and Surgeons, Columbia University, New York, NY; xEinhorn Clinical Research Center, New York Eye and Ear Infirmary, New York, NY. Originally received Apr. 30, 2019. Final revision Oct. 16, 2019. Accepted Oct. 24, 2019. Correspondence to Nathan Radcliffe, MD, 1101 Pelham Parkway, New York, NY 10469. [email protected]
CAN J OPHTHALMOL—VOL. &, NO. &, & 2019
5