The Relationship Between Corneal Hysteresis and Progression of Glaucoma After Trabeculectomy

Supplemental Digital Content is available in the text. Purpose: The purpose of this study was to investigate the association of corneal hysteresis (CH) measured with Ocular Response Analyzer on the progression of glaucoma after trabeculectomy. Materials and Methods: Twenty-four eyes of 19 patients with primary open-angle glaucoma underwent trabeculectomy. A series of visual fields (Humphery Field Analyzer 24-2 SITA-standard) were measured starting after 6 months after trabeculectomy (4.2±5.0 y, mean±SD). The mean total deviation (mTD) of the 52 test points were calculated. In addition, the mTD was divided into the following areas: central area (within central 10 degrees), superior area and inferior area: mTDcentre, mTDsuperior, and mTDinferior, respectively. The relationship between each area’s progression rate of mTD and the 7 variables of baseline age, central corneal thickness, baseline mTD, mean intraocular pressure (IOP), SD of IOP divided by the mean IOP, the difference between baseline IOP obtained before the initiation of any treatment, mean IOP, and CH were analyzed using the linear mixed model, and the optimal model was selected using the model selection method with the second ordered Akaike Information Criterion. Results: In the optimal model for mTD progression rate, only CH was selected with the coefficient of 0.11. The optimal model for the mTDcentre progression rate included mean IOP with the coefficient of −0.043 and CH with the coefficient of 0.12, and that for mTDinferior included only CH with the coefficient of 0.089. There was no variable selected in the optimal model for the mTDsuperior progression rate. Conclusion: CH is a useful measure in the management of glaucoma after trabeculectomy.

G laucoma is one of the leading causes of blindness worldwide. 1, 2 The disease is a progressive and irreversible optic neuropathy that can result in irrevocable visual field (VF) damage. Numerous previous studies have suggested that progression of glaucomatous VF damage can be controlled by appropriately reducing intraocular pressure (IOP). [3][4][5][6][7][8][9] Medical IOP reduction is the primary treatment for primary open-angle glaucoma (POAG); however, surgery may be further needed not in a few cases. Trabeculectomy, first reported by Cairns, 10 is one of the most representative surgeries for glaucoma worldwide, being supported by many previous studies demonstrating the effectiveness of its IOP reduction on the suppression of VF progression. [11][12][13][14][15][16] In contrast, it is also true that VF progression cannot be completely halted in all cases by merely reducing IOP. 17,18 For instance, in the Collaborative Normal-Tension Glaucoma Study Group (CNTGS), VF damage progressed in 20% of cases despite a 30% reduction in IOP. 19 VF progression cannot be completely halted even after successful trabeculectomy. Aoyama and colleagues have reported that 8.3% of patients with normal-tension glaucoma showed VF progression defined by both the Advanced Glaucoma Intervention Study (AGIS) 3 VF defect score and the mean deviation slope analysis, even with the very strict definition for successful IOP reduction (IOP < 10 mm Hg). 16 The identification of eyes at high risk of progression despite a reduction in IOP after trabeculectomy remains unclear. A possible reason may be the influence of central corneal thickness (CCT) on the tonometry measurements, including Goldmann applanation tonometry (GAT). The measurement of IOP is underestimated in eyes with thin cornea. [20][21][22][23][24][25][26][27][28][29][30][31][32] Furthermore, previous studies have suggested that CCT itself is associated with the progression of glaucoma. 7,33 However, variations in CCT account for only ≤ 12% of the measured variation in GAT-IOP 30,34 and hence correction nomograms that adjust GAT-IOP solely based on CCT are neither valid nor useful in individual patients. 35 Many recent studies suggested that another biomechanical property of the cornea termed corneal hysteresis (CH)-measured with the Ocular Response Analyzer (ORA; Reichert Ophthalmic Instruments, Depew, NY) 36 -has a significant effect on the development and progression of glaucoma. [36][37][38][39][40][41][42] We have also recently investigated the usefulness of CH on the severity 43 and progression of glaucoma, 44 in comparison to other variables including CCT. Consistent with another previous study, 40 the results suggested that the effect of CH on the severity and progression of glaucoma was much larger than that of CCT. 43,44 However, these studies investigated the effect of CH on the progression of glaucoma without surgical treatment. Very low IOP can be expected after trabeculectomy, and a considerable change can be associated with the biomechanical property of cornea after trabeculectomy. [45][46][47] Hence, the relationship between CH and progression of glaucoma after trabeculectomy should be investigated, in particular in relation with CCT and IOP control.
The purpose of this study was to investigate the possible association of CH with the long-term progression of glaucoma after trabeculectomy, in relation with CCT and IOP control. In addition, the clinical factors related to VF progression in superior and inferior hemifields may not be identical. For instance, previous studies have reported that the inferior VF is predominantly affected in nonarteritic anterior ischemic optic neuritis. 48 We have recently reported that smoking habitat was found to be related to progression predominantly in the inferior VF, suggesting that ischemia may be related to VF damage in the inferior hemifield. 49 Thus, we also investigated the effect of CH on VF progression after trabeculectomy, in the superior and inferior hemifields, separately.

MATERIALS AND METHODS
This study was approved by the Research Ethics Committee of the Graduate School of Medicine and Faculty of Medicine at the University of Tokyo. Written informed consent was given by participants for their information to be stored in the hospital database and used for research. This study was performed in accordance with the tenets of the Declaration of Helsinki.

Subjects
The study population consisted of 24 eyes of 19 POAG patients. All study participants underwent trabeculectomy and had at least 5 subsequent VF measurements starting after at least 6 months after trabeculectomy between 2003 and 2018 at the University of Tokyo Hospital. All subjects underwent complete ophthalmic examinations, including biomicroscopy, gonioscopy, IOP measurement, funduscopy, refraction, best-corrected visual acuity measurements, and axial length measurements, as well as ORA and VF testing [Humphrey Field Analyzer (HFA); Carl Zeiss Meditec Inc., Dublin, CA]. IOP measurement was conducted at each of patients' visit (∼3 mo interval), whereas VF measurement was performed approximately once every 2 visits. ORA measurement was carried out once in the observation period.
POAG was defined as (1) presence of typical glaucomatous changes in the optic nerve head such as a rim notch with a rim width ≤ 0.1 disc diameters or a vertical cup-to-disc ratio of > 0.7 and/or a retinal nerve fiber layer defect with its edge at the optic nerve head margin greater than a major retinal vessel, diverging in an arcuate or wedge shape and (2) gonioscopically wide open angles of grade 3 or 4 based on the Shaffer classification. Exclusion criteria were: (1) age below 20 years; (2) possible secondary ocular hypertension in either eye; (3) visual acuity ≤ 0.5 LogMAR. 50 Thus, the diagnosis of POAG was made irrespective of the presence of glaucomatous VF change, so that patients with a large range of glaucomatous damage were enrolled in the study, including those without measurable VF damage. Subjects with other systemic or ocular disorders that could affect the VF results were carefully excluded. IOP measurements were performed using GAT. Eyes with surgical intervention, including needling bleb revision and reoperation of trabeculectomy during the VF observation period were excluded; however, those with these surgical procedures performed at least 6 months before the initiation of the VF observation period were included. Eyes with cataract were carefully excluded, except for clinically insignificant cataract. Being extracted from patients' history in the clinical charts, baseline IOP was measured twice on different days without any antiglaucomatous medication or surgical treatment including laser treatment, and the average value was calculated. Mean IOP was calculated as the mean value of the all IOP record during the observation period. The difference between baseline IOP and mean IOP was calculated (ΔIOP).

VF Data
VF testing was performed using the HFA with the 24-2 or 30-2 program (SITA-Standard and Goldmann III target). All participants were subjected to near-refractive correction and had previous experience in VF examinations. Unreliable VFs defined as fixation losses > 20%, or false-positive responses > 15% were excluded, 51 following the manufacturer's recommendation. The mean total deviation (mTD) of the 52 test points in the 24-2 HFA VF test pattern was calculated. In addition, the VF was divided into the following 3 areas: central area (central 12 points within 10 degrees), superior area and inferior area. The mTD was calculated for each area (Fig. 1, mTD centre , mTD superior , and mTD inferior ).

ORA (CH) Data
ORA records 2 applanation measurements, before and after application of an air puff. The cornea resists the air puff because of its viscoelastic property, which results in a measurement difference between the 2 applanation pressures. This difference is called CH. 52 All ORA data had a quality index of > 7.5 as recommended by the manufacturer. The ORA measurement was performed thrice on the same day within 3 months from the last VF measurement, and the average value was used for analysis.

CCT Data
CCT was derived from the CorvisST tonometry (Oculus, Wetzlar, Germany) measurement. It was considered reliable according to the "OK" quality index displayed on the CorvisST tonometry monitor. The average value of 3 measurements was used for analysis.

Statistical Analysis
Univariate analyses between the mTD progression rate and the 7 variables of baseline age, CCT, baseline mTD, mean IOP, SD of IOP divided by the mean IOP (SD/mean IOP), ΔIOP and CH were performed using the linear mixed model in which patients were treated as a "random effect." Subsequently, as a primary analysis, a multivariate analysis using the linear mixed model was performed to examine the relationship between the progression rate of mTD and the aforementioned 7 variables where both the intercept and slope was explained using the 7 variables. The optimal model was selected using the model selection method with the second ordered Akaike Information Criterion (AIC), from 2 7 combinations. The AIC is a well-established statistical measure used in model selection, and the AIC is its corrected type, providing an accurate estimation especially when the sample size is small. 53 In a linear regression model, the degree of freedom decreases as the number of variables increases. Hence, model selection methods should be used when the number of variables is large. 54,55 As subanalyses, similar analyses were performed using the regional progression rates of mTD centre , mTD superior , and mTD inferior .
All statistical analyses were performed using the statistical programming language R (version 3.1.3; The R Foundation for Statistical Computing, Vienna, Austria).
As shown in Table S3 (Supplemental Digital Content 1, http://links.lww.com/IJG/A402), in the optimal model for the mTD progression rate, only CH was selected with the coefficient of 0.12 (SE: 0.054). The remaining 6 variables (baseline age, CCT, baseline mTD, mean IOP, SD/mean IOP and ΔIOP) were not included in this model.
The variables selected in the optimal models for the mTD centre progression rate, were mean IOP with the coefficient of −0.043 (linear mixed model, SE: 0.024) and CH with the coefficient of 0.12 (linear mixed model, SE: 0.066).
There was no variable selected in the optimal model for the mTD superior progression rate.
The only variable selected in the optimal models for the mTD inferior was CH with the coefficient of 0.089 (linear mixed model, SE: 0.040).

DISCUSSION
In the current study, the relationship between CH and VF progression after trabeculectomy was investigated in 24 eyes of 19 POAG patients. The results showed that ORA-CH was useful when analyzing the mTD progression rate; rapid mTD progression rate with low CH. The remaining variables (ie, baseline age, CCT, baseline mTD, mean IOP during the followup period, SD/mean IOP during the follow-up period and baseline IOP before treatment were not included in the optimum model for the mTD progression rate. In addition, in the current study, this analysis was iterated by dividing the VF into 3 regions: central 10 degrees, superior and inferior hemifields outside 10 degrees. Consequently, CH and mean IOP were shown to be related to VF progression in the central region, whereas CH was related to VF progression in the outer inferior hemifield. In contrast, none of the investigated variables were included in the optimum model for the progression rate in the outer superior hemifield. We recently reported the usefulness of CH in the analysis of mTD progression in glaucomatous eyes without trabeculectomy, 44 in which the mean CH value was 9.2 mm Hg. Previous reports have suggested that CH increases after trabeculectomy. 46,47 Nonetheless, a very similar average CH value was observed in the current study (9.2 and 9.4 mm Hg in the current and the previous studies, respectively). This may be because the change in CH after trabeculectomy is largely dependent on the change of IOP, 46 whereas the mean IOP values were similar between our previous and current studies (13.5 vs. 12.1 mm Hg, respectively). Of note, the mean IOP, 17 as well as the fluctuation of IOP, is may be influential for the progression of VF, 17 whereas the values of the SD of IOP were similar between our previous and current studies (1.6 vs. 1.9 mm Hg). Previous studies have suggested that IOP is less variable after trabeculectomy. 17 However, this finding was not observed in the current study. Moreover, in the current study, ΔIOP was not related to VF progression. As shown in many previous studies, [3][4][5][6][7][8][9]19,[56][57][58] there is no doubt that high IOP is a risk factor for the progression of glaucoma. In contrast, the current results suggested that the mean IOP was not significantly related to the progression of mTD. However, this finding does not deny the importance of IOP in the management of glaucoma since, in the current study, IOP was well controlled in all eyes through trabeculectomy. This result is consistent with our previous findings from a multicentre study, in which real-world clinical data were analyzed, and there was no relationship identified between the mean IOP and progression of glaucoma. 59 It should also be noted that in the previous study, 59 it was suggested that the SD of IOP was significantly related to the progression of mTD. However, this finding was not observed in eyes with a mean IOP < 15 mm Hg. Although in the current study the mean IOP value was at this level, the SD of IOP was not significantly related to the progression of VF.
Furthermore, CCT and AL have been reported to influence the progression of VF, 60,61 and these values were very similar between our previous and current studies (531 vs. 533 μm and 25.1 vs. 25.2 mm, respectively). In contrast, the baseline mTD value (−6.8 vs. −13.5 dB, respectively) and age were very different between the 2 studies (63.2 vs. 54.8 y, respectively). These differences may reflect differences in the nature of the 2 studies. Despite these differences, similar tendencies were observed in these studies: CH was significantly related to the progression of mTD in both studies, whereas mean IOP, SD of IOP, baseline mTD and CCT were not. This observation indicates the usefulness of CH in the management of glaucoma both in eyes without trabeculectomy and after trabeculectomy.
We recently reported different patterns of VF damage 62 and progression rate between POAG and primary angle-closure glaucoma, 63 agreeing with other previous reports. [64][65][66][67] This implies the presence of different pathologic mechanisms in the development of superior and inferior VF damages. Indeed, inferior VF is predominantly affected in nonarteritic anterior ischemic optic neuritis. 48 In addition, smoking was found to be related to progression predominantly in the inferior VF. 49 The current study suggested that CH was significantly related to VF progression in the inferior hemifield, unlike in the superior hemifield. Previous studies suggested that superior VF damage is more attributed to elevated IOP than that occurring in the inferior hemifield. 65 As described above, the effect of IOP on the progression of VF was no longer observed because of the nature of the current study. However, CH was significantly related to VF progression in the inferior hemifield. The primary reason for the relationship between CH and the progression of glaucoma remains unclear. However, daily life activities such as postural change, 68 eyelid blinking, 69 ocular pulsatility due to ocular hemodynamics, 70 Valsalva maneuver 71 and eye movement exert stress to eyes and may lead to deformation. 72 An eye with high hysteresis is more likely to absorb these external strains with the damping capacity, and indeed we recently reported a significant relationship between the damping capacity and progression of VF. 61 In addition, the cornea and sclera are continuous collagenous structures of an eye with similar biomechanical characteristics, 73 because embryologically, the sclera and Bruch membrane are both derived from the neural crest. 74 Our results suggest that the VF progression in the inferior hemifield is related not only to elevated IOP, but also other factors, such as CH.
In contrast to the outer VF regions, the mean IOP was significantly related to VF progression in the central 10 degrees. The number of retinal ganglion cells corresponds to the area is much larger than those of the outer regions. 75 Indeed, this region usually maintains visual sensitivity until the last stage of glaucoma. 76 The reason for the significant effect of the mean IOP in this region-despite the probable larger number of remaining retinal ganglion cells-is unclear. However, this may be attributed to treatment decision bias, as the indication of trabeculectomy was decided mainly using the tendency in the entire VF with the HFA 24-2 test. This area is directly related to the deterioration of the quality of life in patients with glaucoma. [77][78][79] Thus, the inclusion of CH in the optimal model for the progression rate in this region suggests further usefulness of CH in the management of glaucoma. Furthermore, the importance of this region can be more emphasized after trabeculectomy, since only this area may remain in the last stage of the disease. 76 A limitation of the current study is the lack of CH measurement before trabeculectomy. Further studies including this parameter are warranted. Another limitation of the current study is the effect of antiglaucoma eye drops on corneal biomechanical properties. This is because it has been reported that anti-IOP agents can change the cornea's biomechanical properties. [80][81][82][83][84] In conclusion, the current results suggested that CH is a useful measure in the management of glaucoma, even after trabeculectomy.