Evaluation of peripheral anterior synechia formation following gonioscopy-assisted transluminal trabeculotomy surgery

To quantitatively assess the development of peripheral anterior synechia (PAS) formation rate and PAS locations on gonioscopic examination following gonioscopy-assisted transluminal trabeculotomy (GATT) surgery and investigate the surgical outcomes. A total of 35 eyes from 31 patients with open angle glaucoma who underwent GATT or combined GATT and phacoemulsification surgery were analyzed. Presence of PAS was assessed on gonioscopy in nasal, temporal, superior and inferior quadrants at months 1, 3 and 6 following surgery. Surgical outcomes were also noted. Frequencies of PAS formation were 38.3%, 25.3%, 17.0% and 19.1% at postoperative 1 month, 34.0%, 26.4%, 17% and 22.6% at postoperative 3 months and 32.3%, 25.8%, 16.1% and 25.8% at postoperative 6 months, in nasal, temporal, superior and inferior quadrants, respectively. The highest amount of PAS involvement was 3 clock hours in the study which was identified only in nasal and inferior quadrants. Frequency of PAS formation did not significantly differ between nasal, temporal, superior and inferior quadrants at all time points (p > 0.05). No significant differences of mean IOP levels were observed between patients who developed PAS and who did not develop PAS at postoperative 1 month (p = 0.72), 3 months (p = 0.21) and 6 months (p = 0.59). The mean IOP and mean number of antiglaucoma medications decreased from 31.5 ± 7.2 mmHg and 3.6 ± 0.6 at baseline to 13.8 ± 3.1 mmHg and 1.6 ± 1.3 at postoperative 6 months, respectively (p < 0.001, for both). Cumulative success rate (95% confidence interval) was 74.3% (69.9–78.6%) at the end of the study. Mild to moderate degrees of hyphema occurred in all cases postoperatively. Although PAS formation was observed to be relatively higher in nasal quadrant, PAS frequency was not statistically different between the angle quadrants.


Introduction
Glaucoma is a leading cause of irreversible vision loss worldwide. Patients with glaucoma may show no symptoms until the late stage of the disease leading to a delayed disease diagnosis. Elevated intraocular pressure (IOP) is an essential risk factor for the development and progression of glaucoma [1]. Previous large scaled trials have demonstrated the benefit of IOP lowering either with medications or surgery to prevent progression of glaucoma [2,3]. Conventional filtration surgeries, both trabeculectomy and glaucoma drainage devices, have been shown to be very effective procedures in controlling IOP in advanced glaucoma cases. However, these procedures may lead to significant intraoperative or postoperative complications, including suprachoroidal hemorrhage, choroidal detachment, hypotony, bleb related problems which may eventually result in surgical failure and visual compromise [4].
Gonioscopy-assisted transluminal trabeculotomy (GATT) surgery has been developed by Grover et al. [5]. In brief, this surgical technique is a conjunctival sparing procedure involving an ab interno trabeculotomy approach to circumnavigate Schlemm's canal using either a blunt-tip suture or an illuminated microcatheter [6]. GATT surgery has been shown to be efficacious in both primary and secondary forms of open angle glaucoma (OAG) so far. Studies have revealed good IOP control with reduced number of glaucoma medications after GATT procedure [7][8][9][10][11].
Development of peripheral anterior synechia (PAS) formation has been reported following both ab interno and ab externo trabeculotomy procedures [12][13][14]. Presence of PAS may have a chance to occlude the cleavage plane in these eyes leading to decreased aqueous outflow. Hence, it is important to assess PAS formation after GATT surgery. Thereby, we focus on evaluation of PAS in the present study with the aim of to bring additional awareness of PAS formation during clinical examinations after GATT procedure. There is limited literature data with specific reference to quantitative analysis of PAS formation following GATT surgery. There have been no previous studies except for a study by Matsuo et al. [15] evaluating PAS formation following microhook ab interno trabeculotomy with the use of Gonioscope GS-1 device. In the present study, we quantitatively assessed the rate and locations of PAS development following GATT surgery and investigated the surgical outcomes.

Methods
After obtaining institutional ethical committee approval (No: 2022-136), data of patients who underwent GATT surgery in our clinic were retrospectively collected. The study followed the principles laid out in the Declaration of Helsinki. Written informed consent was taken from each patient before study. Routine preoperative gonioscopic examination was performed in all patients to ensure the presence of an open angle with identifiable angle landmarks in all four quadrants (nasal, temporal, superior and inferior).

Patients
The ophthalmological findings of patients (≥ 18 years old) who had diagnoses of either primary OAG (POAG) or secondary OAG (SOAG) and underwent GATT procedure were examined. During preoperative evaluation, patients underwent detailed ophthalmological examinations, including best corrected visual acuity (BCVA) assessment with a standard Snellen chart, slit-lamp biomicroscopic examination, gonioscopy with a Goldmann three mirror lens, IOP measurement with applanation tonometry, and dilated fundoscopic evaluation. Central 24-2 threshold visual field test with SITA-Fast strategy using Humphrey Field Analyzer (HFA-750 i, Carl Zeiss Meditec Inc., USA) and retinal nerve fiber analysis using spectral domain optical coherence tomography (Optovue OCT V 5.1, RTVue 100-2; Optovue, Fremont, CA, USA) were also performed. Snellen visual acuities were then converted to the logarithm of the Minimum Angle of Resolution (logMAR) for statistical analysis.
Inclusion criteria in the present study were, patients to be operated with GATT surgery because of the uncontrolled IOP despite maximum medical therapy, and/or intolerance to glaucoma medications (nonadherence to treatment or ocular allergy), and/ or glaucoma progression as tested by visual field examination. The patients were also asked to follow the criteria regularly for at least 6 months. Exclusion criteria in the study were, age of lower than 18, history of previous ocular surgery (except for trabeculectomy surgery) and/or trauma, any medical condition other than OAG (such as uveitis, ectopia lentis, aniridia, albinism, high axial myopia, rheumatologic disorders and diabetes), presence of PAS in the preoperative gonioscopic evaluation and irregular follow-up shorter than 6 months.

Surgical procedure
All surgeries were performed under general anesthesia by the same experienced surgeon (MG). Details of the GATT procedure were reported in the literature previously [5]. Briefly, after providing standard surgical aseptic condition, eye was draped and lid speculum was placed. The surgeon performed surgeries by sitting on the temporal site. Two side ports were placed either in the supero-nasal or inferonasal quadrant with a 20-G microvitreoretinal blade. A temporal corneal incision was made with a 2.8 mm angled slit knife. Ophthalmic viscoelastic device (OVD) was injected into the anterior chamber. The tip of the 5-0 prolene suture was blunted with light cautery and inserted into the anterior chamber. The patient's head was tilted away from the surgeon while the microscope was oriented toward the surgeon to get proper visualization of the nasal angle with a Swan-Jacob goniolens. A 2-mm nasal goniotomy was created using a 23-G microvitreoretinal blade, and posterior wall of Schlemm's canal was exposed. Microsurgical forceps was then used to grasp and introduce the blunted tip of the prolene suture into Schlemm's canal. The suture was advanced through Schlemm's canal 360°, and distal tip of the suture was retrieved and externalized to create a 360° trabeculotomy. If suture advancement could not be made 360° where suture stopped at 180° within the canal, external part of the suture was pulled and externalized to complete a 180° trabeculotomy. Inferior trabecular meshwork was incised in cases who underwent 180° GATT. The blood in the anterior chamber and OVD was then removed from the anterior chamber using bimanual irrigation aspiration. All incisions were hydrated. In cases where combined GATT and cataract surgery was needed, GATT was performed first followed by clear corneal phacoemulsification with IOL implantation surgery.
Postoperatively, patients were ordered with topical moxifloxacin and dexamethasone 8 times a day and topical nepafenac 6 times a day during first week. Moxifloxacin was tapered to 4 times a day after one week and stopped at two weeks. Dexamethasone was tapered gradually after first week and stopped at 3 weeks. Nepafenac was tapered to 4 times a day over two weeks and stopped at 1 month. Patients were examined on the first day, first week, first month, third month and six months postoperatively. At each visit, visual acuity, IOP, complications and the number of antiglaucoma medications used were recorded. If additional IOP lowering medication is needed during follow-up, then, topical aqueous suppressants were used first. Our threshold to re-start medications and the specific agent chosen in the present study was based on the disease severity, the antiglaucoma drugs used in the contralateral eye and surgeon discretion.
Complete success was defined as IOP of 21 mm Hg or lower without use of topical antiglaucoma medication and a decrease in IOP of 20% or more from the baseline IOP. Qualified success was defined as an IOP of 21 mmHg or lower with use of topical antiglaucoma medication.

Assessment of postoperative PAS formation
Peripheral anterior synechia formation after surgery was evaluated at months 1, 3 and 6. Following routine ophthalmological examination, presence of PAS was assessed with a Goldmann three mirror lens in each patient under dim room light conditions. After application of topical anesthetic eye drop (0.5% proparacaine HCl) on ocular surface, concave surface of the lens was filled with a carbomer gel (Viscotears jell, Novartis, Turkey). Lens was then carefully inserted onto the patient's cornea, while the patient was looking upwards. Lens was rotated with the eye in primary position to examine the total circumference of the angle. If present, presence of PAS was noted in a quadrant base manner (nasal, temporal, superior and inferior). The extent of PAS was expressed by dividing each quadrant into three clock hours. Figure 1 shows a representative image demonstrating PAS evaluation in the study.

Statistical analysis
All data obtained from the participants were evaluated in the computer package program SPSS 13.0.1 (SPSS, Chicago, IL; license number: 9069728, KTU Trabzon). Nominal data were presented as percentages, and metric data were presented as mean ± standard deviation. The suitability of numerical data to normal distribution was evaluated with the one-sample Kolmogorov-Smirnov test. Repeated-measures analysis of variance was used to compare repeated measurements. Pearson Chi-Square test was used to analyze the difference in PAS frequency between angle quadrants. Mann-Whitney U test was used to identify any differences in IOP levels between patients who developed PAS and patients who had no PAS. Kaplan-Meier survival analysis was used to analyze the success rates with 95% confidence intervals. The statistical significance level was accepted as p < 0.05.

Results
A total of 35 eyes of 31 patients were included in the study. There were 16 females (51.6%) and 15 males (48.4%). The mean age of the patients was 68.8 ± 9.2 years (35-82 years). Clinical characteristics of the study population are given in Table 1.
Visual field evaluation could be completed in 26 patients (83.9%) due to lack of optimal patient cooperation. 22 eyes (62.9%) underwent combined GATT and phacoemulsification with intraocular lens implantation procedure, and 13 eyes (37.1%) underwent GATT alone. Two eyes had previous trabeculectomy surgery.
No sign of PAS formation on gonioscopic examination was observed in any of the patients before GATT surgery in the study.
Characteristics of PAS formation following surgery are summarized in Table 2. Frequencies of PAS formation were observed to be higher in nasal quadrant at 1, 3 and 6 months visits. One clock hour and 2 clock hours of PAS formation were observed in all quadrants at all time points. Three clock hours of PAS formation was observed only in nasal and inferior quadrants in the study. Frequency of PAS formation did not significantly differ between nasal, temporal, superior and inferior quadrants at all time points   The mean IOP at baseline was 31.5 ± 7.2 mmHg and 13.8 ± 3.1 mmHg at postoperative 6 months (p < 0.001). The mean number of antiglaucoma medication at baseline was 3.6 ± 0.6 and 1.6 ± 1.3 at postoperative 6 months (p < 0.001). The mean BCVA at baseline (0.8 ± 0.7) showed no significant change at postoperative 6 months examination (0.7 ± 0.8) (p = 0.06). Changes in IOP and BCVA are summarized in Table 3.

Discussion
In the present study, we investigated the characteristics of PAS formation following GATT surgery in patients with OAG. Although PAS formation was observed to be relatively higher in nasal quadrant, PAS frequency was not statistically different between the angle quadrants. Moreover, involvement of PAS formation in clock hours was relatively larger in both nasal and inferior quadrants. To the best of our knowledge, this is the first study assessing the characteristics of PAS formation specifically after GATT procedure.
We quantitatively evaluated PAS formation after GATT surgery in the present study. PAS frequencies were observed to be higher in nasal quadrant at all time points. But difference of PAS formation rate between quadrants did not reach a statistically significant level at each time point. We believe that this result was possibly due to relatively lower number of patients included in our study. Higher rate of PAS frequency in nasal quadrant might depend on surgical maneuvers during surgery, including goniotomy, placement of suture tip into Schlemm's canal and advancement of the suture in the canal via nasal region. Matsuo et al. [15] have used a specialized instrument (microhook tip) to incise the inner wall of the Schlemm's canal making approximately 180°-240° ab interno trabeculotomy along temporal and nasal regions. Similar to our findings, they demonstrated a significant PAS formation rate within trabeculotomy incision following that procedure. The authors have also proposed that shallowing of anterior chamber with subsequent iridotrabecular contact following surgery may play a role in the development of PAS out of trabeculotomy incision [15]. But as opposed in that study, we did not observe PAS formation out of trabeculotomy region at least in our cases who received 180° GATT procedure. Surgical technique in that study is differed slightly from GATT in some aspects. Matsuo et al. [15] have used the microhook tip to strip out trabecular meshwork where in GATT, a suture is used to cleave trabecular meshwork. Although the authors have suggested generalization of their findings in all trabeculotomy-related glaucoma procedures, we think that abovementioned contradictory findings need to be further investigated.
Apart from higher PAS frequency in nasal quadrant in our study, another observation was relatively wider PAS involvement in nasal and inferior quadrants. We think that hyphema induced inflammation might cause broader PAS development especially in inferior quadrant in our cases. Since we detected hyphema during early postoperative period, presence of higher amount of broad PAS in inferior quadrant suggests the influence of early postsurgical inflammation. As most of collector channels are located in inferonasal portion of the iridocorneal angle [16], it should be borne in mind that presence of high amount of PAS in nasal and inferior quadrants may further impede aqueous outflow, thereby reducing the effect of GATT surgery.
One may think that presence of PAS may have a chance to impact IOP lowering effect of surgery by decreasing aqueous outflow, thereby reducing surgical efficacy. In the present study, we also analyzed IOP levels between patients who developed PAS and who did not show PAS formation in order to reveal a potential influence of PAS formation on IOP control. We observed no significant differences of IOP levels at each time point. This result may indicate that PAS occurrence may not affect the IOP status.
GATT has been shown to be an effective treatment option for OAG patients with different disease severity [6][7][8]11]. When combined with cataract surgery, GATT procedure could be more efficacious in reducing IOP and number of antiglaucoma medications [17]. Furthermore, sight-threatening complications have been reported to be lower following GATT as compared with traditional filtrating surgeries [18,19]. Compatible with the previous literature data, GATT surgery effectively lowered IOP and antiglaucoma medications in our study. We observed a 74.3% of cumulative surgical success rate at the end of the study. This success rate could be related to the definition of surgical success based on IOP values and IOP decrease from baseline in the present study. Since this type of success definition may not be applied to all OAG patients with regard to reaching a target IOP to control disease progression in each case. For such reasons, this result should be interpreted carefully. Furthermore, as most of our cases underwent combined surgery, additional IOP lowering effect of cataract surgery via increased trabecular outflow might have contributed higher surgical success [17].
Another ongoing debate regarding GATT procedure is cannulating Schlemm's canal < 180° or > 180°. It has been well demonstrated that most of the collector channels are located in the inferonasal quadrant, thus cleavage of trabecular meshwork only through inferior quadrant with the so called hemi-GATT technique may result in similar surgical outcomes as with 360° GATT [20]. Actually, this was supported by the notion that maximal surgical effect could be obtained just with 120° trabecular meshwork removal following excisional goniotomy with the kahook dual blade [20]. Another study has found similar surgical success rates either with < 180° GATT or > 180° GATT [21]. Circumferential cannulation of Schlemm's canal was done in 65.6% of our patients where 180° could be achieved in 34.3%. All but one case who received 180° GATT in the present study showed surgical failure at the end of the follow-up. Although it was not the primary aim of the present study, our results may suggest comparable surgical success rates between 180° versus 360° GATT. We believe that this issue still needs further investigation. Furthermore, as inferior trabecular meshwork was incised in cases who underwent 180° GATT, this might have possibly affected higher PAS frequency in nasal angle and broad PAS formation in inferior angle.
Most common complication after surgery was the presence of hyphema in all our cases which resolved spontaneously during early postoperative period without further surgical intervention. We also observed a 20% rate of IOP spike during postoperative two weeks, which was successfully controlled with medical therapy. Presence of IOP spike following GATT is an important situation and needs prompt intervention, since it could be associated with increased risk of future surgical failure. Inflammatory response, use of steroids and prolonged hyphema, could induce IOP spikes after GATT procedure [22]. We believe that absence of massive and prolonged hyphema and early tapering of steroids with additional use of nonsteroidal anti-inflammatory drugs might have contributed good control of IOP spikes with subsequent surgical success in our study. Furthermore, we detected mild to moderate degrees of hyphema in our patients; however, it is plausible to think that the amount of hyphema might also have association with PAS formation in our study. As hyphema mostly collects inferiorly, it could have caused broad PAS formation in inferior portions of the angle in the present study.
There could be several other factors related to PAS development after GATT surgery in our study. Higher levels of pro-inflammatory cytokines have been shown in patients with exfoliation syndrome [23]. Higher degrees of early postoperative inflammation have been documented in cases with pseudoexfoliation compared to that without pseudoexfoliation following cataract surgery [24]. Approximately 66% of our patients had pseudoexfoliation glaucoma; therefore, this might have an influence on PAS rate in the present study. Furthermore, as most of the cases in our study underwent combined phacoemulsification and GATT procedure, combined surgical effect might have a chance to contribute PAS formation rate via increased inflammation [25].
The current study has some limitations: The study included relatively lower number of patients with a shorter follow-up, and we did not perform ocular biometry, especially anterior chamber depth of the patients, so we could not exclude the effect of anterior chamber depth variations on PAS development. Also, we did not explore the influence of additional cataract surgery on PAS formation. Furthermore, there were 2 eyes that underwent previous trabeculectomy surgery before GATT in our study. Although no PAS was detected on preoperative gonioscopy in these eyes before GATT, eyes are often prone to develop PAS after trabeculectomy [26], thereby there is a possibility that history of trabeculectomy may have a chance to induce PAS formation following GATT surgery.
In conclusion, present study firstly investigated the PAS formation specifically following GATT procedure. PAS frequency was observed to be not statistically different between nasal, temporal, superior and inferior angle portions. PAS formation tended to occur more frequently in nasal quadrant after surgery. Surgical maneuvers in nasal quadrant during GATT could be a reason of frequent PAS formation in nasal angle. PAS involvement in clock hours were also observed to be wider in both nasal and inferior quadrants. However, we could not exhibit a statistically significant difference in the frequency of PAS formation between iridocorneal angle quadrants which might be related to relatively lower number of patients in the study. Presence of hyphema might have a chance to induce broad PAS formation in inferior angle region. PAS formation also seems not to have an influence on IOP control. The present study would have an impact on daily clinical practice regarding a better conception of clinical outcomes following GATT surgery. Furthermore, as preoperative gonioscopic evaluation is prerequisite for patients who underwent GATT, postoperative gonioscopic examinations would bring additional awareness regarding PAS while investigating the surgical outcomes of GATT procedure. Clinicians could modify their surgical approach regarding intraocular manipulations and hyphema control, modulate postoperative treatment regimen regarding inflammation control, and also, they can perform sequential gonioscopic analysis considering the results of this study. We believe that further studies with longer follow-up are needed in order to validate the results of the current work and better ascertain the effect of GATT surgery on PAS development.
Author contributions All authors contributed to the study conception and design. Material preparation, data collection were performed by MG, and analysis was performed by AT, HO, FTB and DU. The first draft of the manuscript was written by MG and AT, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding The authors declare that no funds, grants or other support were received during the preparation of this manuscript.

Conflict of interest
The authors have no relevant financial or non-financial interest to disclose.
Ethical approval This study was performed in line with the principles of Declaration of Helsinki. Approval was granted by the Ethics Committee of Karadeniz Technical University, Faculty of Medicine (2022 -136).

Consent to participate
Informed consent was obtained from all individual participants included in the study.