Corneal Hysteresis as a Marker for Patients with Secondary Glaucoma

ABSTRACT Purpose To investigate and compare the association of corneal hysteresis (CH) in patients with secondary glaucoma to control patients and patients with primary open-angle glaucoma (POAG). Additionally, to determine the consistency of CH measurements in patients with secondary glaucoma. Methods A total of 84 patients (121 eyes) were prospectively included in this study. Twenty-three patients (46 eyes) were healthy controls, 24 patients (40 eyes) were diagnosed with POAG, and 27 patients (35 eyes) were diagnosed with a form of secondary glaucoma. CH and intraocular pressure (IOP) were measured using the Ocular Response Analyzer. Three measurements per eye were performed and used for the analysis and to determine fluctuations in CH data. One-way ANOVA with post-hoc Bonferroni analysis and Chi-Squared testing was done to determine differences between groups. Results All patients were matched for age. Patients in both POAG and secondary glaucoma groups were matched for age and IOP. All groups had similar sex and racial compositions as well as similar proportions of diabetes, hypertension, and hyperlipidemia. CH was lower (p < .05) in patients with POAG (9.32 ± 1.64) and secondary glaucoma (7.89 ± 3.18) when compared to healthy controls (11.16 ± 1.60). Fluctuations in CH measurements were minimal in all groups. Further analysis of the secondary glaucoma group revealed no differences in CH between different types of secondary glaucoma (p > .05). Conclusion Patients with secondary glaucoma have lower CH when compared to POAG or control groups. The ORA exhibits precision of CH measurements for control, POAG, and secondary glaucoma groups, making it a reliable tool in management of secondary forms of glaucoma.


INTRODUCTION
Corneal hysteresis (CH) is a biomechanical property of the cornea that represents the ability of corneal tissue to respond to the loading and unloading of a specific force, i.e. a bidirectional applanation stimulus. 13][4] A low CH value is associated with progressive optic nerve damage and has been proven as an independent risk factor for predicting the development of glaucoma. 5,6As a result, CH has been promoted as being a tool for the screening, diagnosis, and prognosis of glaucoma.
Many of the studies that have investigated CH as a potential diagnostic or prognostic marker have focused on patients with primary open angle glaucoma (POAG) or patients after ocular surgeries. 4,7However, there has not been much investigation into the role of CH as a marker for secondary glaucoma, namely, neovascular, traumatic, uveitic glaucoma, or pigmentary glaucoma, among others.This is crucial given that forms of secondary glaucoma contribute to roughly 18% of the mean prevalence of POAG in the world, which constitutes more than 10 million individuals. 8Furthermore, secondary forms of glaucoma tend to have a more rapid onset and progression than POAG often leading to complications and potentially blindness if intervention is not initiated early enough. 9herefore, the purpose of the current investigation is to study corneal hysteresis in patients with confirmed secondary glaucoma and determine its efficacy as a clinical marker by comparing it to an age-matched cohort of control patients and patients with POAG.Furthermore, the current analysis will evaluate CH in confirmed cases of secondary glaucoma to determine its efficacy a potential marker for these conditions.

MATERIALS & METHODS
The study was approved by the Institutional Review Board of Rutgers New Jersey Medical School.Written informed consent was obtained by all participants.This study was performed in accordance with the tenets of the Declaration of Helsinki

Participants
The study population consisted of a total of 84 patients (121 eyes) and were all patients of the Department of Ophthalmology & Visual Science at Rutgers New Jersey Medical School that were prospectively and consecutively enrolled.Only patients with a confirmed clinical diagnosis based on biomicroscopic examination, structure, and function testing were included.Patients with POAG or a form of secondary glaucoma were included in this study.A separate control group was also established.Twenty-three patients (46 eyes) were healthy controls, 24 patients (40 eyes) were diagnosed with POAG, and 27 patients (35 eyes) were diagnosed with a form of secondary glaucoma.Secondary glaucoma diagnoses included neovascular glaucoma, traumatic glaucoma, uveitic glaucoma, and other forms of glaucoma which included both pigmentary glaucoma and childhood glaucoma.

Data Collection
Corneal hysteresis,Goldman-correlated intraocular pressure (IOP g ), and corneal-compensated intraocular pressure (IOP cc ) measurements were acquired using the Ocular Response Analyzer (ORA; Reichert Technologies, New York, USA).Three consecutive ORA measurements during the same visit were made on the eye that was affected.The average value of the three measurements was used for analysis.Fluctuations of corneal hysteresis measurements were determined by taking the standard deviation of the three consecutive measurements per patient.This standard deviation represents the fluctuations of each CH measurement when compared to the average of the three measurements.The average of all standard deviations was taken for each group and plotted to represent the precision of CH measurements.

Statistical Analysis
All statistical analysis and graph creation was completed using GraphPad Prism software (Version 5.1).Differences in IOP cc , IOP g , CH, and fluctuations in CH measurements between control, POAG, and secondary glaucoma groups were analyzed using one-way ANOVA testing.Analysis of demographic variables (Table 1) was done using a chi-square test.Differences between subgroups of secondary glaucoma were analyzed using one-way ANOVA testing with post-hoc Bonferroni analysis.

RESULTS
Patients were separated into control, POAG, and secondary glaucoma groups.Of the patients in the secondary glaucoma group, 7 (26%) had neovascular glaucoma, 4 (15%) had traumatic glaucoma, 10 (37%) had uveitic glaucoma, 3 (11%) had childhood glaucoma and 1 (3%) had pigmentary glaucoma.Patients in the control, POAG, and secondary glaucoma groups were matched for age (Table 1).Demographic analysis of the three patient populations revealed a near-equal distribution of male and female patients and a high proportion of black and Hispanic patients when compared to white or Asian patients.No difference was observed in distribution of sex (p = 0.38), race (p = 0.46), or comorbitdities (p = 0.67) between the three populations.The majority of eyes in the POAG and secondary glaucoma groups were on two or more glaucoma medications.However, patients in the secondary glaucoma had a higher rate of glaucoma surgery when compared to patients in the POAG group (35% vs. 15%), but was not statistically significant when compared directly (p=0.06).
The average of three ORA measurements was used to determine IOP g IOP cc , and CH (Table 2).Patients in the control group did exhibit lower IOP g and IOP cc but only reached statistical significance when compared to the secondary glaucoma group.Patients in the secondary glaucoma group did exhibit higher mean (±SD) IOP cc (25.8 ± 18.2 vs. 20.6 ± 8.4) and IOP g (22.1 ± 13.4 vs. 18.6 ± 7.9) when compared to the POAG group but did not reach statistical significance (p = 0.11; p = 0.17).Measurements of CH showed that that control group had a higher CH when compared to both POAG and secondary glaucoma groups (p < .0001).Furthermore, secondary glaucoma patients had a significantly lower CH when compared to POAG (7.89 ± 3.18 vs. 9.32 ± 1.64: p = 0.02).Further analysis of CH measurements was done to determine the precision of CH as a marker for both POAG and secondary glaucoma.Standard deviation (SD) of the three measurements, a representation of fluctuation, was determined per patient and calculated for all groups (Table 2).Control, POAG, and secondary glaucoma groups exhibited low overall fluctuation and did not show any differences (0.38 ± 0.66 vs. 0.26 ± 0.34 vs. 0.33 ± 0.41; p = 0.67).The similarities in the fluctuations of CH measurements between the control, POAG, and secondary glaucoma groups are illustrated (Figure 1).Subsequent analysis of the secondary glaucoma group was conducted to determine differences in various types of secondary glaucoma (Table 3).No differences in IOP cc (p = 0.25), IOP g (p = 0.58), or CH (p = 0.33) were observed between any of the sub-groups of secondary glaucoma following one-way ANOVA testing.

DISCUSSION
To our knowledge, this is the first study that investigates and compares corneal hysteresis in patients with secondary glaucoma to those patients with POAG.Overall, both POAG and secondary glaucoma groups had lower CH when compared to the control group.When matched for age and IOP, patients with secondary glaucoma exhibited lower CH when compared to POAG (p < 0.05).However, no differences in CH were observed between subgroups of secondary glaucoma.Furthermore, fluctuations in CH in the secondary glaucoma were similar to those observed in the control and POAG groups suggesting an equivalence in the precision of the CH measurements further supporting CH as a potential diagnostic and prognostic marker for patients with secondary forms of glaucoma.
There have been many studies that have investigated corneal hysteresis in the context of POAG, showing a lower CH when compared to controls.1][12] More specifically, CH has been shown to be predictive of early changes in parts of the retina, i.e. thinning of peripapillary retinal nerve fiber layer and ganglion cell complex, both of which are first affected in glaucoma. 13Subsequent demographic analysis revealed that there are several demographic factors have also been shown to influence corneal hysteresis including the male sex, an increased age, and black ethnicity. 14,15Smoking, diabetes, and systemic lupus erythematosus have also been positively associated with CH. 16 Other investigations into corneal hysteresis before and after glaucoma surgeries have also been conducted showing usefulness with certain surgeries, e.g.trabeculectomy 3 and cataract surgery, 17 but not others, e.g.trabecular microbypass stenting. 18nlike POAG, investigations studying corneal hysteresis in forms of secondary glaucoma have been scarce.Only two studies examined this but only focused on   congenital glaucoma, showing lower CH in patients with congenital glaucoma when compared to controls. 19,20owever, when comparing these two studies, the measurements of CH for patients with congenital glaucoma were not consistent (6.3 ± 1.58 vs. 9.1 ± 1.6) suggesting the need for further investigation.Investigations into other forms of secondary glaucoma, including neovascular, uveitic, and traumatic, have yet to be studied.In the current study, neovascular, uveitic, traumatic, and other forms of secondary glaucoma are represented and analyzed (Table 3).No difference was observed between any of the subgroups of secondary glaucoma in terms of IOP cc , IOP g , and CH.However, further analysis of these groups is required given the trends in CH, most notably among patients with neovascular glaucoma.The current study is not without limitations, most notably, the small sample size.While a small sample size is not ideal, it was necessary to match patients in the POAG and secondary glaucoma groups, by both age and IOP, both of which are powerful confounding variables that undoubtedly affect a patient's glaucoma onset and development.Furthermore, the other two studies that have analyzed CH in patients with secondary glaucoma report similar total sample sizes of both 26 patients (40 eyes) and 42 patients (91 eyes), only 11 of which were confirmed with congenital glaucoma, suggesting the difficulty that comes with enrolling patients these patients into these types of studies. 19,20Another limitation was the racial demographics of our patient population.For all study groups, the majority of patients were black or Hispanic with very few being white or Asian.This may potentially have effects on our CH data since black patients have been shown to have lower values of CH when compared to whites or Asians. 16However, the purpose of the current investigation was to determine CH in secondary glaucoma patients, compare it to control and POAG CH, as well as to test the efficacy of CH as a clinical tool in secondary glaucoma.Since there were near equal distributions of black and Hispanic patients in the control, POAG, and secondary glaucoma groups this concern was largely controlled for and therefore does not affect any comparisons made between groups.Finally, another limitation is the diversity of the secondary glaucoma group in terms of its makeup.This group is made up of different secondary glaucoma types which have a different pathophysiology and different management and treatment plans.This, as well as the fact that these patients tended to have a higher rate of incisional surgery, can affect CH measurements since both of these variables can affect corneal biomechanics.Therefore, while we do show that the secondary glaucoma group had a lower CH when compared to POAG (Table 2), we do not believe that this is the essential finding of this investigation.More importantly, the use of corneal hysteresis as a clinical marker for patients with secondary glaucoma has been shown to be effective, especially when compared to the control group.The relative differences between POAG and secondary glaucoma, while interesting, are not fully conclusive.
The purpose of the current investigation was to characterize and compare secondary glaucoma patients to POAG patients in terms of CH.Overall, our analysis showed a lower CH in patients with POAG and secondary glaucoma when compared to controls.Additionally, we show no difference in the fluctuation in the distributions of CH measurements when comparing control, POAG, and secondary glaucoma patients.Given the prevalence of secondary glaucoma and its relative severity, further investigation and study into diagnostic and prognostic tools, such as CH, are essential for improving patient management.

Discloure Statement
Disclosures for Albert S. Khouri: Grant support: Allergan, NJ Health Foundation, Fund for NJ Blind; Consultant: Glaukos, Bausch & Lomb, Alcon; Speaker Bureau: Allergan, Bausch & Lomb.The rest of the authors report no potential conflicts of interest.

Figure 1 .
Figure 1.Fluctuations of CH measurements, represented as standard deviation (SD), between the control (•), POAG (○), and secondary glaucoma (◊) groups is shown.No statistical difference was observed among these groups.

Table 1 .
Demographic analysis of study population.
*Comparison was only done between POAG and secondary glaucoma groups.

Table 2 .
Corneal hysteresis in patients with POAG & secondary glaucoma.

Table 3 .
Subset analysis of corneal hysteresis in secondary glaucoma types.
Data is presented as Mean ± SD.