Usefulness of Measuring Corneal Stiffness in Predicting the Reduction of Intraocular Pressure With Microhook Ab Interno Trabeculotomy

Abstract

Purpose

To investigate the predictive factors for intraocular pressure (IOP) after microhook ab interno trabeculotomy (TLO).

Methods

We included 147 eyes of 97 glaucoma patients who underwent TLO. We recorded the following preoperative parameters: systemic parameters (age, height, body mass index, systolic blood pressure, diastolic blood pressure, and history of smoking), blood examination scores, ocular parameters (preoperative Goldmann applanation tonometry [GAT]-IOP, central corneal thickness, type of glaucoma, and preoperative use of anti-glaucoma eyedrops), and Ocular Response Analyzer (ORA) parameters (corneal resistance factor [CRF], corneal hysteresis, corneal-compensated intraocular pressure). We analyzed the preoperative parameters associated with postoperative GAT-IOP. Subsequently, similar analysis was performed using a corneal visualization Scheimpflug technology instrument (Corvis ST) parameters, instead of the ORA parameters. Postoperative GAT-IOP was measured after 12 months from TLO.

Results

When ORA parameters were used, preoperative high hemoglobin (Hb), high C-reactive protein (CRP), use of brimonidine tartrate, and high CRF were significant risk factors for postoperative high GAT-IOP, in addition to type of glaucoma. When Corvis ST parameters were used, preoperative high serum Hb, high serum CRP, usage of brimonidine tartrate, high biomechanical intraocular pressure, high stress–strain index, and low time to maximal displacement of whole eye movement were significant risk factors for postoperative high GAT-IOP.

Conclusions

ORA and Corvis ST measurements suggested that stiff cornea was a risk factor for high postoperative GAT-IOP after TLO, in addition to preoperative high Hb, high CRP, and the use of brimonidine tartrate.

Translational Relevance

Stiff cornea is a risk factor for high postoperative intraocular pressure after trabeculotomy.

Introduction

Studies have shown that the principal target of glaucoma treatment is preventing visual field progression by reducing and controlling intraocular pressure (IOP), as supported by numerous clinical trials and research studies.^1–8 In the past 50 years, trabeculectomy has been the gold standard for glaucoma; however, a renewed interest has arisen in the surgical treatment of glaucoma with the development of minimally invasive glaucoma surgeries, such as microhook ab interno trabeculotomy (TLO). TLO is a surgical method used to cleave the trabecular meshwork (TM) and the inner wall of Schlemm's canal (SC), a primary site of the resistance for aqueous outflow.^9,10 The strengths of TLO include a short surgical time (<10 minutes) and low surgical cost without requiring expensive devices.¹¹ A consensus has been established that TLO could significantly reduce IOP; however, the magnitude of IOP reduction from baseline varies widely between 21.8% and 49.0% across studies.^11–17

Thus the question arises of whether the outcome of TLO can be predicted before surgery. This is clinically very important because clinicians can vary their treatment decisions and can just as easily select trabeculectomy when a favorable outcome cannot be expected with TLO. Previous studies have suggested an association between corneal biomechanical properties and the magnitude of IOP reduction after topical prostaglandin (PG) therapy¹⁸ and selective laser trabeculoplasty.¹⁹ Similarly, despite the increasing popularity of TLO, few reports have investigated the predictive factors of postoperative IOP after TLO.^20,21 These studies suggested possible predictive factors, such as age, type of glaucoma, postoperative complications, and preoperative IOP; however, the outcomes largely varied across studies. Thus the prognostic factors for the outcome of TLO have yet to be established, and we need to answer this question: What markers can be used to identify cases for which TLO should be indicated?

The association between corneal biomechanical properties and glaucoma is a relatively new topic. Corneal biomechanical properties have been associated with the diagnosis,²² development,²³ severity,²⁴ progression of glaucoma,^25–27 and even the effect of IOP on the rate of visual field progression.²⁵ Currently, these properties can be measured with two clinical devices. The Ocular Response Analyzer (ORA; Reichert Inc., Depew, NY, USA) measures the damping capacity of the cornea, such as corneal hysteresis (CH).²⁸ By contrast, the clinical application of an ultra-high-speed Scheimpflug camera provides detailed images of corneal deformation induced by the application of an air jet by using a corneal visualization Scheimpflug technology instrument (Corvis ST; Oculus GmbH, Wetzlar, Germany). This yields several corneal dynamic response parameters (38 with the software version 1.3r15389). We followed our patients who underwent TLO with cataract surgery for 12 months, and the association between corneal biomechanical properties measured at baseline and the postoperative outcome was investigated. Additionally, previous reports have suggested associations between IOP and systemic blood conditions, such as age, blood pressure, and various blood scores.^29–32 We also investigated their usefulness in predicting postoperative IOP after TLO.

Methods

The Research Ethics Committee of Seirei Hamamatsu General Hospital approved this study (No. 3640). Patients provided written informed consent for storing their data in the hospital database for use in research. This study was performed following the tenets of the Declaration of Helsinki.

Participants

We enrolled consecutive patients who underwent TLO combined with cataract surgery at Seirei Hamamatsu General Hospital between February 2018 and July 2019, with a minimum of 12 months of routine follow-up. Surgery was performed when patients with open-angle glaucoma and cataracts did not achieve sufficient IOP reduction with medication alone. We excluded patients who underwent previous ophthalmic surgery, such as trabeculotomy, trabeculectomy, goniosynechialysis, argon laser trabeculoplasty, selective laser trabeculoplasty, cataract surgery, and vitrectomy. After careful assessment, we also excluded eyes with other anterior and posterior segment diseases.

Data Collection

IOP was measured using the Goldmann applanation tonometer (GAT), Corvis ST, and ORA on the same day with a 15-minute interval between measurements. The order of these measurements was randomly determined. Subsequently, the axial length was measured using the optical biometer OA-2000 ver. 2C (Tomey GmbH, Nagoya, Japan) or intraocluar lens Master 700 (Carl Zeiss Meditec, Jena, Germany). In addition, the following preoperative parameters were recorded.

Systemic Parameters

Age, height, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), and history of smoking (No, Not currently, Yes) were recorded as systemic parameters.

Blood Examination Scores

White blood cell (WBC) count, red blood cell (RBC) count, hemoglobin (Hb), hematocrit (Ht), platelet (Plt) count, total protein (TP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), total bilirubin (T-bil), guanosine triphosphate (γGTP), uric acid (UA), blood urea nitrogen (BUN), creatinine (Cre), estimated glomerular filtration rate (eGFR), sodium (Na), potassium (K), chlorine (Cl), calcium (Ca), inorganic phosphate (IP), triglyceride (TG), total cholesterol (TC), blood sugar (BS), and C-reactive protein (CRP) were recorded as blood examination scores.

Ocular Parameters

Preoperative GAT-IOP, central corneal thickness (CCT), type of glaucoma (primary open-angle glaucoma [POAG], primary angle-closure glaucoma [PACG], exfoliation glaucoma [EG], and secondary glaucoma [SOAG]), and preoperative use of anti-glaucoma eyedrops (PG F2 alpha [PGF2a] analog, beta-blocker, carbonic anhydrase inhibitors [CAIs], brimonidine tartrate, or ripasudil) were recorded as ocular parameters. Additionally, postoperative GAT-IOP was also measured 12 months after operation.

ORA Parameters

Details of ORA measurement are summarized elsewhere.^28,33,34 ORA records two applanation pressure measurements: before and following the indentation of the cornea with the application of a rapid air jet. Because of the viscoelasticity of the cornea, some energy dissipates, so the air jet pressure at the second applanation (P2) during the outward movement of the cornea is lower than the pressure at the first applanation (P1), referred to as CH, the pressure difference at the two applanations (P1 − P2). CH reflects the damping capacity or energy dissipation of the cornea.^28,33,35 The corneal resistance factor (CRF) indicates the overall resistance or elastic properties of the cornea. The CRF is derived as (P1 − k × P2), where constant k is empirically determined so that CRF is maximally associated with the CCT,^33,35 but it still depends on the IOP.³⁶ Additionally, corneal compensated IOP (IOPcc) is the IOP measurement corrected with CH. CH, CRF, and IOPcc were recorded as ORA parameters.

Corvis ST Parameters

The principles of Corvis ST measurements have been described in detail elsewhere.³⁷ In brief, the high-speed Scheimpflug camera records 140 images of the cornea before and after a transient corneal indentation, which occurs within 30 ms after applying an air impulse. The corneal response is characterized by two applanations during inward and outward corneal movements, which occur before and after the maximum displacement of the corneal apex. The Corvis ST parameters examined in this study included biomechanical intraocular pressure (bIOP), PachySlope, Ambrosio relational thickness to the horizontal profile (ARTh), peak distance, highest concavity deflection amplitude (HCDefAmp), maximal displacement of whole eye movement (WEM-d), time to maximal displacement of whole eye movement (WEM-t), deformation amplitude max 1 mm (DA ratio max 1 mm), deformation amplitude max 2 mm), stiffness parameter at applanation 1 (SP-A1), stress–strain index (SSI), and biomechanical glaucoma factor (BGF) (Table 1). All parameters were calculated using the Corvis ST software version 1.6r2223.

• (1)
  “bIOP” is the estimate of IOP adjusted for CCT and age.^38,39 An updated formula was used in the latest version of the software (personal communication with Oculus):

  $$\begin{array}{ccc}\hfill \mathrm{bIOP}& =& C_{cct1}*C_{AP1}*C_{age1}+C_{cct2}*C_{age2}\hfill \\ & & +C_{DCR}+a_{19}\hfill \end{array}$$

  where C_CCT1 and C_CCT2 are parameters representing the effect of variation in CCT (mm) and C_age denotes the effect of variation in age;

  $$\begin{array}{ccc}\hfill C_{CCT1}& =& a_1*CC{T}^3+a_2*CC{T}^2+a_3*CCT+a_4\hfill \\ \hfill C_{AP1}& =& a_5*AP1+a_6\hfill \\ \hfill C_{age1}& =& a_7*Ln{\left(beta1\right)}^2+a_8*Ln\left(beta1\right)+a_9\hfill \\ \hfill Beta1& =& 0.5852*exp\left(0.0111*age\right)\hfill \\ \hfill C_{CCT2}& =& a_{10}*{CCT}^3+a_{11}*CC{T}^2+a_{12}*CCT+a_{13}\hfill \\ \hfill C_{age2}& =& a_{14}*Ln{\left(Beta1\right)}^2+a_{15}*Ln\left(Beta1\right)+a_{16}\hfill \\ \hfill C_{DCR}& =& a_{17}*highestconcavityradius+a_{18}\hfill \end{array}$$

  where the highest concavity radius is a Corvis ST parameter representing the curvature radius when the cornea is at the point of highest concavity.
• (2)“PachySlope” represents the difference in the corneal thickness from the corneal apex toward the periphery. A smaller PachySlope value indicates a relatively thin cornea in the periphery compared with the central region.
• (3)“ARTh” is the quotient of corneal thickness at the thinnest point of the horizontal meridian, and the thickness increases toward the periphery.
• (4)“Peak Distance” is the distance between nondeformed peaks under the highest concavity.
• (5)“HCDefAmp” is the pure corneal deformation under the highest concavity.
• (6)“WEM-d” is the length of the linear anterior–posterior movement of the whole eye after maximum displacement of the cornea.^40–42
• (7)“WEM-t” is the time taken for the linear anterior–posterior movement of the whole eye after maximum displacement of the cornea.^40–42
• (8)“Deformation amplitude” is the sum of whole eye movement and deflection amplitude. DA ratio max 1 mm is the ratio of deformation amplitude at the corneal apex to that at 1 mm.⁴⁰ DA ratio max 2 mm is the ratio of deformation amplitude at the corneal apex to that at 2 mm.⁴⁰
• (9)“SP-A1” is the difference between the strength of the air puff at the corneal surface and biomechanically corrected IOP divided by deflection amplitude at the first applanation.^40,43
• (10)“SSI” is a parameter related to corneal stiffness. It is a measure of the nonlinearity of stress‒strain relationship of the eye. More specifically, SSI was developed using finite element methods so that it represents corneal stiffness as a material independent from IOP and corneal geometry.⁴⁴ SSI is shown on a normalized scale, where the average value of 50-year-old eyes is equal to 1. Higher SSI values indicate stiffer and less deformable corneas.
• (11)
  “BGF” is a parameter that represents the possibility of glaucoma. It is calculated using the following formula:

  $$\begin{array}{ccc}\hfill Beta& =& 34.128+2.64\times DARatioProg-0.641\hfill \\ & & \times HCTime-0.049\times PachySlope\hfill \\ & & -0.202\times bIOP-0.036\times CCT\hfill \\ \hfill BGF& =& \frac{EXP\left(Beta\right)}{EXP\left(Beta\right)+1}\hfill \end{array}$$

  BGF ranges from 0 to 1; a higher value indicates a higher possibility of glaucoma.⁴⁵ Deformation amplitude ratio progression (DARatioProg) represents the increase in the ratio of the deformation amplitude from the corneal apex toward the periphery. Higher DARatioProg values indicate a stiffer cornea.⁴⁵ Highest concavity time refers to the timing of the highest concavity.

Table 1.

Corvis ST Parameters

Name	Description
bIOP	Corrected estimate of IOP obtained adjusted for ocular biomechanical parameters
PachySlope	The difference in corneal thickness from the corneal apex toward the periphery
ARTh	The quotient of corneal thickness at the thinnest point of the horizontal meridian and the thickness increase toward the periphery
Peak distance	The distance between nondeformed peaks under the highest concavity
HCDefAmp	Pure corneal deformation under the highest concavity
WEM-d	The time taken for the linear anterior-posterior movement of the whole eye after maximum displacement of the cornea
WEM-t	The length of the linear anterior-posterior movement of the whole eye after maximum displacement of the cornea
DA ratio max 1 mm	The ratio of deformation amplitude at corneal apex to that at 1 mm
DA ratio max 2 mm	The ratio of deformation amplitude at corneal apex to that at 2 mm
SP-A1	The difference between the strength of the air puff at the corneal surface and biomechanically corrected IOP divided by deflection amplitude at the first applanation
SSI	Material stiffness of the cornea
BGF	A parameter which represents the possibility of glaucoma

Corvis ST measurements were conducted thrice, and the average values were used for the analysis. Only reliable Corvis ST measurements were used based on the quality indicator “OK” displayed on the instrument monitor.

Statistical Analysis

The relationship between the postoperative (at 12 months) GAT-IOP and 41 preoperative parameters consisted of six systemic parameters (age, height, BMI, SBP, DBP, and history of smoking), 24 blood examination scores (WBC count, RBC count, Hb, Ht, Plt count, TP, AST, ALT, LDH, T-bil, γGTP, UA, BUN, Cre, eGFR, Na, K, Cl, Ca, IP, TG, TC, BS, and CRP), 11 ocular parameters (preoperative GAT-IOP, CCT, type of glaucoma [POAG, PACG, EG, and SOAG], and use of PGF2a analog, use of beta-blocker, use of CAIs, use of brimonidine tartrate, and use of ripasudil, and three ORA parameters (IOPcc, CH, and CRF) was investigated by using the univariate linear mixed model because we included both eyes from the same patients. The measurement of two eyes from the same patients can be highly correlated. The linear mixed model adjusts for the hierarchical structure of the data, modeling so that each patient is registered as having a random effect; that is, measurements are grouped within participants. Ignoring this measurement grouping would result in underestimating the standard errors of regression coefficients. The blood examination scores at baseline are shown in Supplementary File S1. Subsequently, the multivariate linear mixed model was used to analyze the relationship between the postoperative GAT-IOP and the 44 parameters. An optimal model for the postoperative GAT-IOP was identified through a two-stage model selection. First, 15 parameters were predetermined from 41 parameters by using the least absolute shrinkage and selection operator regression (LASSO).^46,47 Subsequently, the model selection using the second-order bias-corrected Akaike information criterion (AICc) index (all models) was conducted. We calculated the AICc values of all possible combinations of the 15 parameters (2¹⁵ patterns), and the model with the minimum AICc was identified as the optimal model. Moreover, the AICc is a corrected form of the common statistical measure of the Akaike information criterion that provides an accurate estimate even in small sample sizes.⁴⁸ Any reduction in AICc indicates an improvement of the model,^49,50 and the relative likelihood that a model with AICc_x is minimizing information loss compared with the model with the smallest AICc (AICc_min) is calculated as exp((AICc_min AICc_x)/2).⁵¹

In addition, a similar analysis was conducted by replacing the three ORA parameters with the 12 Corvis ST parameters.

Results

This study included 147 eyes of 97 patients. The types of glaucoma were POAG (117 eyes of 75 patients), PACG (18 eyes of 12 patients), EG (seven eyes of 6 patients), and SOAG (five eyes of four patients). Table 2 shows the patient demographics. The mean age (±standard deviation [SD]) of the patients was 72.9 (±8.3) years (range, 52–93 years). The GAT-IOP was 17.0 ± 4.7 (9–35) mm Hg before surgery, which was significantly decreased to 13.0 ± 3.5 (5–32) mm Hg after surgery (P < 0.001, linear mixed model). Table 2 also shows the summary of the medication scores. The score was 1.7 ± 1.7 (0–5) and 1.7 ± 1.2 (0–5) before and after surgery, respectively, which were not significantly different (P = 0.81, linear mixed model).

Table 2.

Background Demographics

Variable	Value
Systemic parameters
Age (y), mean ± SD	72.9 ± 8.3
Height (cm), mean ± SD	158.9 ± 8.9
BMI, mean ± SD	22.8 ± 3.5
SBP (mm Hg), mean ± SD	140.8 ± 25.0
DBP (mm Hg), mean ± SD	79.1 ± 14.3
Smoking status
No, eyes	109
Not currently, eyes	34
Yes, eyes	4
Ocular parameters
Preoperative GAT-IOP (mm Hg), mean ± SD	17.0 ± 4.7
CCT (µm), mean ± SD	532.5 ± 41.1
Type of glaucoma
POAG, eyes	117
PACG, eyes	18
EG, eyes	7
SOAG, eyes	5
Preoperative use of anti-glaucoma eyedrops
PGF2a
Yes	77
No	70
Beta-blocker
Yes	67
No	80
CAI
Yes	37
No	110
Brimonidine tartrate
Yes	43
No	104
Ripasudil
Yes	8
No	139
Medication scores
Before surgery	1.7 ± 1.7
After surgery	1.7 ± 1.2
ORA parameters
CH (mm Hg), mean ± SD	8.9 ± 1.6
CRF (mm Hg), mean ± SD	9.0 ± 1.6
IOPCC (mm Hg), mean ± SD	17.3 ± 5.8
Corvis ST parameters
bIOP (mm Hg), mean ± SD	13.0 ± 3.8
PachySlope, mean ± SD	30.1 ± 13.2
ARTh, mean ± SD	625.2 ± 227.5
Peak distance (mm), mean ± SD	5.0 ± 0.38
HCDefAmp (mm), mean ± SD	0.95 ± 0.14
DA ratio max 1 mm, mean ± SD	1.6 ± 0.060
DA ratio max 2 mm, mean ± SD	4.8 ± 0.66
SPA1 (mm Hg/mm), mean ± SD	102.1 ± 25.0
SSI, mean ± SD	1.2 ± 0.24
BGF, mean ± SD	0.60 ± 0.26
WEM-d (mm), mean ± SD	0.40 ± 0.10
WEM-t (ms), mean ± SD	22.2 ± 0.86

The results of univariate analysis between postoperative GAT-IOP and the values of eight systemic parameters, 24 blood examination scores, 11 ocular parameters, three ORA parameters, and the 12 Corvis ST parameters are shown in Supplementary File S2. Significant associations were observed between 18 of 58 parameters.

Table 3 shows the results of the two-stage model selection and multivariate linear mixed model analysis with 41 preoperative parameters, including ORA measured CH, CRF, and IOPcc. Among the nine variables selected with the model selection following LASSO, type of glaucoma (SOAG against POAG with coefficient = 3.66, P = 0.011, linear mixed model), high CRF (coefficient = 0.76, P < 0.001), use of brimonidine tartrate (coefficient = 1.26, P = 0.032), high Hb (coefficient = 0.52, P = 0.0026), and high CRP (coefficient = 3.39, P = 0.0071) were significant risk factors for high postoperative GAT-IOP. The EG glaucoma type was significantly associated with lower postoperative GAT-IOP (coefficient = −2.37, P = 0.046).

Table 3.

The Results of the Two-Stage Model Selection and Multivariate Linear Mixed Model Analysis With 41 Preoperative Parameters, Including ORA Measured CH, CRF, and IOPcc

Variable	Coefficient	Standard Error	P Value
Systemic parameters
SBP (mm Hg)	Not selected
DBP (mm Hg)	Not selected
Blood examination scores
WBC (µL)	Not selected
RBC (µL)	Not selected
Hb (g/dL)	0.52	0.17	0.0026
Plt (µL)	Not selected
Cre (mg/dL)	−1.67	1.56	0.29
BS (mg/dL)	Not selected
CRP (mg/dL)	3.39	1.22	0.0071
Ocular parameters
Preoperative GAT-IOP (mm Hg)	Not selected
Type of glaucoma
POAG	1	—	—
PACG	1.15	0.79	0.15
EG	−2.37	1.17	0.046
SOAG	3.66	1.42	0.011
Preoperative eye drops
Brimonidine tartrate, for yes	1.26	0.58	0.032
Ripasudil, for yes	2.01	1.14	0.080
ORA parameters
CRF (mm Hg)	0.76	0.16	<0.001
IOPCC (mm Hg)	Not selected

P values in bold suggest <0.05.

Table 4 shows the results of the two-stage model selection and multivariate linear mixed model analysis with 50 preoperative parameters, including 12 Corvis ST parameters. Among the 11 variables selected with the model selection following LASSO, preoperative high Hb (coefficient = 0.47, P = 0.0072), high CRP (coefficient = 3.15, P = 0.014), use of brimonidine tartrate (coefficient = 1.16, P = 0.048), bIOP (coefficient = 0.28, P = 0.024, linear mixed model), high SSI (coefficient = 5.51, P = 0.0019), and low WEM-t (coefficient = −0.73, P = 0.036) were significant risk factors for high postoperative GAT-IOP.

Table 4.

The Results of the Two-Stage Model Selection and Multivariate Linear Mixed Model Analysis With 50 Preoperative Parameters Including 12 Corvis ST Parameters

Variable	Coefficient	Standard Error	P Value
Blood examination scores
WBC (µL)	Not selected
Hb (g/dL)	0.47	0.17	0.0072
Cre (mg/dL)	−3.11	1.61	0.057
BS (mg/dL)	Not selected
CRP (mg/dL)	3.15	1.25	0.014
Ocular parameters
Preoperative GAT-IOP (mm Hg)	Not selected
Preoperative use of anti-glaucoma eyedrops
Brimonidine tartrate, for yes	1.16	0.58	0.048
Corvis ST parameters
bIOP (mm Hg)	0.28	0.12	0.024
Peak distance (mm)	0.52	2.50	0.83
HCDefAmp (mm)	6.72	8.32	0.42
DA ratio max 1 mm	8.52	10.12	0.40
DA ratio max 2 mm	−1.14	1.04	0.28
SPA1 (mm Hg/mm)	Not selected
SSI	5.51	1.73	0.0019
WEM-t (ms)	−0.73	0.34	0.036

P values in bold suggest <0.05.

Discussion

Our study showed that 147 eyes that underwent TLO with cataract surgery were followed up for 12 months, and the association between various ocular and systemic variables at baseline and the magnitude of IOP reduction postoperatively was investigated. Corneal biomechanical properties measured with ORA and Corvis ST were also included as ocular parameters. Consequently, IOP was reduced by an average of 4.0 mm Hg (23.5%), where preoperative high Hb, high CRP, use of brimonidine tartrate, and high CRF were significant risk factors for high postoperative GAT-IOP, in addition to the type of glaucoma when ORA parameters were used (Table 3). The significant risk factors for high postoperative GAT-IOP were preoperative high Hb, high CRP, use of brimonidine tartrate, high bIOP, high SSI, and low WEM-t when Corvis ST parameters were used (Table 4).

Higher preoperative GAT-IOP was associated with higher postoperative IOP.^20,52–56 This is compatible with the current univariate analysis (Supplementary File S2). However, preoperative GAT-IOP was not selected as a significant risk factor for high postoperative IOP in the multivariate linear mixed model analysis with preoperative parameters including Corvis ST parameters in the current study(Table 4). Instead, with the multivariate linear mixed model analysis including Corvis ST parameters, preoperative bIOP was selected as a significant risk factor for high postoperative GAT-IOP (Table 4), indicating the usefulness of bIOP, which is the estimate of IOP adjusted for age, CCT, and a corneal biomechanical property (highest concavity radius) over GAT-IOP^38,39 in predicting postoperative IOP. Conversely, CRF was a significant risk factor for high postoperative GAT-IOP in the multivariate linear mixed model analysis including ORA parameters (Table 3). Previously, CRF is an indicator of the overall resistance or the elastic properties of the cornea, depending on the IOP.³⁶ Thus CRF affected by IOP and corneal stiffness was more useful than GAT-IOP for predicting postoperative IOP.

In this study, high CRF value was a significant risk factor for high postoperative GAT-IOP with the multivariate linear mixed model analysis with preoperative parameters, including ORA parameters (Table 3). Additionally, high SSI value was a significant risk factor for high postoperative GAT-IOP in the multivariate linear mixed model analysis with preoperative parameters, including Corvis ST parameters (Table 4). Both parameters represent corneal stiffness, with a high value indicating stiff and deformation-resistant cornea. Notably, SSI represents corneal stiffness as a material independent from IOP and corneal geometry,⁴⁴ unlike CRF, indicating that corneal stiffness as a material is a risk factor for high postoperative GAT-IOP, per se. It should be worth noting that bIOP and SSI were simultaneously significant risk factors, which implies that corneal stiffness related with IOP (CRF) or in conjunction with (SSI and bIOP) are better predictive factors for postoperative GAT-IOP than preoperative GAT-IOP alone. This is in agreement with a previous study reporting that IOP measurement is influenced by corneal material properties, such as stiffness, but the association is very weak (R² = 0.0052), indicating that all our study findings cannot be explained.⁴⁴ Another hypothesis to explain the effect of corneal stiffness on postoperative GAT-IOP may be the mechanical properties of the extracellular matrix (ECM). Previous studies reported that the ECM of the cornea alternated by aging, leading to corneal tissue stiffening.^57–63 Another study reported that various ocular tissues were stiffer in glaucomatous eyes than in normal, healthy age-matched controls, including the TM, SC, cornea, sclera, and lamina cribrosa, being associated with increased ECM deposition and fibrosis,⁶⁴ which may involve the mechanotransduction processes in driving SC cell dysfunction.⁶⁵ In addition, the flow resistance is likely generated either in the ECM of the juxtacanalicular connective tissue or the basement membrane of the SC.⁶⁶ These reports would imply that those with high corneal stiffness by increased ECM deposition and fibrosis also have SC cell dysfunction, leading to high postoperative GAT-IOP due to increased outflow resistance of the SC. Besides, the high postoperative GAT-IOP in the eyes with stiff cornea may suggest that the resistance at the collector channel is also increased by such remodeling process, not only in the TM, SC, and cornea, because the TM and SC are incised in TLO.

Our study showed that high Hb was associated with high postoperative GAT-IOP. Previous studies have provided evidence for increased blood viscosity caused by the increased Hb concentration,^6,28,33 indicating that the blood vessels with high Hb is predisposed to occlusion, which may contribute to the increase in episcleral venous pressure and IOP elevation subsequently. It may support this speculation that high blood viscosity was positively associated with the development of cerebral infarction.^5,8,21,38

Moreover, high CRP was also a significant risk factor for high postoperative GAT-IOP. Previous clinical trials have shown that an increased CRP value indicates an increased risk of developing atherosclerotic vascular disease.^67,68 Systemic inflammation may cause blood vessel occlusion, which may contribute to the increased in episcleral venous pressure and IOP elevation subsequently.

Furthermore, brimonidine tartrate use was relevant to high postoperative GAT-IOP. Brimonidine tartrate has vasoconstrictive properties.^69,70 Brimonidine tartrate use may cause increased episcleral venous pressure because of vasoconstrictive properties, leading to elevated postoperative IOP. In addition, brimonidine tartrate can cause follicular conjunctivitis with poor IOP control.⁷¹ Although the mechanism was unclear, it was speculated that the follicular conjunctivitis increased conjunctival and episcleral blood flow, which might result in IOP elevation.^72–74 Such an effect of the use of brimonidine tartrate may have lasted even after TLO. By contrast, ripasudil had IOP-lowering effects on the surgical outcomes of TLO.^75,76 However, ripasudil use was not significantly associated with GAT-IOP (Supplementary File S2, Table 3). Our study consisted of eyes with multiple eyedrop users. A further study is needed to investigate the effect of these eyedrops on the outcome of TLO in detail, preparing eyes with single eyedrops.

Several epidemiological studies have suggested a positive correlation between systemic blood pressure and IOP,^32,77–82 which is compatible with the current univariate analysis, where high SBP was associated with high postoperative GAT-IOP (Supplementary File S2). In the present multivariate analysis, SBP was not selected for a significant risk factor for high postoperative GAT-IOP (Table 3). Also, previous studies have suggested possible predictive factors of postoperative IOP after TLO, such as age and type of glaucoma.^20,21 High BMI, dyslipidemia, low high-density lipoprotein cholesterol, and high blood pressure are risk factors for elevated IOP.^29–32,83 Nevertheless, no significant association was observed between these values and postoperative GAT-IOP in this study, indicating that ORA and Corvis ST parameters are more useful than various proposed risk factors, such as SBP and age, as predictive factors of postoperative IOP after TLO.

This study has limitations. First, the sample size was relatively small, and further validation of the current result is required in a larger dataset. Second, this study is retrospective in design. A future study is needed to confirm our results in a prospective study. Finally, this study included relatively small numbers of eyes with EG, PACG, and SOAG (n = 5-18), compared to POAG (n = 117). A further study should be conducted shedding light on the effect of disease type, preparing a larger number of eyes in each disease type.

In conclusion, ORA and Corvis ST measurements indicated that stiff cornea was a risk factor for high postoperative GAT-IOP after TLO in addition to preoperative high Hb, high CRP, and use of brimonidine tartrate. This information is useful for clinicians when deciding the indication of TLO in patients with glaucoma.