Clinical Outcomes of Micropulse Transscleral Cyclophotocoagulation in Refractory Glaucoma

This study evaluated the clinical outcomes of rst-time micropulse transscleral cyclophotocoagulation (MP-TSCPC) performed in cases of refractory glaucoma. This retrospective study analysed the patients with refractory glaucoma who underwent MP-TSCPC rom February 2018 to February 2020 at Yonsei University Severance Hospital. A total of 45 eyes of 43 Asian patients (aged 55.71±16.84 years) who underwent MP-TSCPC for the rst time, were included in this study. The mean baseline intraocular pressure (IOP) was 25.96±9.27 mmHg. The most common diagnosis was secondary glaucoma (44.4%) with a mean logarithm of the minimum angle of resolution (logMAR) visual acuity of 1.19±1.02. There was a signicant reduction (P<0.05) in IOP on 1 day 1,to 18.03±5.99 mmHg;, at 1 week, to 13.29±5.24 mmHg;, at 1 month, to 14.98±4.55 mmHg;, at 3 months, to 17.05±5.52 mmHg;, 6 months to 17.78±6.37 mmHg; and 12 months, to 16.56±5.96 mmHg. There was also a reduction (P<0.05) in the number of topical anti-glaucoma medications required to control IOP from baseline (3.69±0.63) at 1, 3, and 6 months. MP-TSCPC is an effective procedure that offers good results in reducing IOP and decreases the use of anti-glaucoma medications in patients with refractory glaucoma.


Introduction
Glaucoma is a chronic progressive optic neuropathy associated with structural damage to the optic nerve and visual eld loss, which can lead to vision loss and blindness 1 . There are many known risk factors, including elavated intraocualr pressure (IOP) 2,3 , that contribute to optic nerve damage, however, lowering IOP is the only approach known to reduce the risk of disease progression 4 .
According to literature, refractory glaucoma is de ned as a group of diseases that do not respond favorably to surgical and/or medical treatment to lower IOP 5 . Cyclodestruction procedures are often used in patients with refractory glaucoma who have failed to achieve lower IOP from ltration procedures and maximal medical therapy. Transscleral cyclophotocoagulation (TSCPC) is a cyclodestructive procedure that reduces aqueous humor production through ciliary epithelium photocoagulation 6 . Traditionally, TSCPC uses a continuous mode that delivers laser energy, and severe complications, including hypotony, phthisis bulbi and chronic in ammation, have been reported [7][8][9] .
Micropulse wave transscleral cyclophotocoagulation (MP-TSCPC) is a new technique that uses repetitive active diode laser (on cycles) micropulses interspersed with rest intervals (Off cycles). During the off cycle, nonpigmented tissue adjacent to the tissue of interest is able to "cool off", theoretically preventing the tissue from reaching the coagulative threshold and minimizing collateral tissue damage 10 .
In this study, we evaluated the e cacy and safety of MP-TSCPC performed for the rst time in cases of refractory glaucoma and compared outcomes based on prior glaucoma surgeries.

Baseline Clinical characteristics
Among those eyes that underwent MP-TSCPC at the Severance hospital from February 2018 to February 2020, 45 eyes in 43 patients completed a minimum of 6 months follow-up. Of these, 2 patients underwent MP-TSCPC for both eyes. All patients were Korean; the average age was 55.71±16.84 years at the time of treatment; and 30 (69.8%) were male and 13 (30.2%) were female. Secondary glaucoma was the most common glaucoma type (20 eyes, 44.4%), followed by primary open angle glaucoma (19 eyes, 42.2%).
In the 45 eyes included in the study, 20 (44.4%) eyes had undergone glaucoma surgery prior to MP-TSCPC. Twelve eyes had undergone trabeculectomy, 16 eyes had undergone Ahmed glaucoma valve implantation and 8 eyes had undergone both trabeculectomy and Ahmed glaucoma valve implantation. Pseudophakia was present in 23 (51.1%) eyes, and aphakia in 6 (13.3%) eyes. The demographic and clinical characteristics of patients are summarized in table 1.
The clinical characteristics of the 8 patients who experienced failure at 6 months after MP-TSCPC are summarized in Table 3. The mean number of glaucoma medication was signi cantly reduced from baseline at 1-, 3-, and 6-month postoperative follow-up (P = 0.001, 0.002, and 0.008, respectively). The mean number of glaucoma mediation at 6 months was 3.33±0.95 (Table 2).
Loss of ≥2 lines of vision on the Snellen chart was found in 20 (44.4%) eyes, caused by deterioration of cornea edema (4 eyes), cystoid macular edema (3 eyes; 2 of these eyes had a history of macular edema before MP-TSCPC), glaucoma progression (2 eyes), vitreous hemorrhage (1 eye; this patient had a history of vitreous hemorrhage due to diabetic retinopathy), worsening of proliferative diabetic retinopathy (1 eye), relapse of choroidal neovascularization (1 eye), corneal opacity due to a persistent epithelial defect (1 eye), uveitis (1 eye), and unexplained vision loss (6 eyes).
On day 1 after MP-TSCPC, 8 eyes (24.2%) had mild postoperative in ammation in the anterior chamber. Most of these eyes responded to topical steroids and resolved in 1 week; however, in ammation persisted in 1 eye for 1 month and in 1 eye for 3 months.
Three eyes had cystoid macular edema, 1 eye had cataract progression, 1 eye had a corneal epithelial defect and 1 eye had hypotony. In the eye with hypotony (5mmHg), hypotony was nonted at 1 month and IOP was 6mmHg at 3 months. At 6 months, IOP elevated to 35mmHg, which was higher than before MP-TSCPC (22mmHg). Table 4 shows postoperative complications after MP-TSCPC. There were no incidences of severe complication such as phthisis bulbi, endophthalmitis, and sympathetic ophthalmia.
Outcomes based on prior glaucoma surgeries A subgroup analysis was conducted between eyes with and without a history of glaucoma surgery: 25 eyes had no previous glaucoma surgery versus 20 eyes had undergone glaucoma surgery including cyclodestructive procedures. The mean baseline IOP was not signi cantly different (P = 0.228) in both patient groups and did not change signi cantly at any of follow-ups. At 6 months, mean IOP was 17.41±7.35mmHg and 18.07±5.61mmHg in both groups (between groups p = 0.583). The mean reduction in IOP was 27.6% in the prior glaucoma surgery group and 34.2% in the no prior surgery group.
The mean number of glaucoma medication was not signi cantly different at baseline (P = 0.059) and did not change signi cantly at any the follow-ups.
At 6 months after MP-TSCPC, the success rates were 85.0% (17/20 eyes) for the prior glaucoma surgery group and 80.0% (20/25 eyes) for the no prior glaucoma surgery group.
The postoperative outcomes of subgroups are shown in Table 5.

Outcomes at 12 months
Of the 45 eyes that were observed for more than 6 months, 22 could be observed for up to 12 months (10 eyes in the prior glaucoma surgery group, 12 eyes in the no prior glaucoma surgery group). Of these 22 eyes, 5 eyes received repeat glaucoma surgery including repeat MP-TSCPC between 6 and 12 months after the initial MP-TSCPC (3 eyes received a second application of MP-TSCPC, 1 eye received MP-TSCPC two more times and 1 eye received ahmed valve implantation). The mean time to repeat glaucoma surgery was 7.6±0.89 months. The mean IOP was 16.56±5.96, the mean number of glaucoma medication was 3.45±1.06, and the mean visual acuity was 1.43 ± 1.04 logMAR at 12 months. The overall success rate was 68.2% at 12 months (80% in the prior glaucoma surgery group, 58.3% in the no prior group). Figure 2 illustrates the Kaplan-Meier survival curve analysis after MP-TSCPC. Survival rates between the two groups were not signi cantly different (p=0.239).

Discussion
The management of refractory glaucoma is a serious challenge, and the TSCPC represents one of the various interventional alternatives for decreasing IOP in patients with refractory glaucoma 11 . However, traditional TSCPC delivers continuous high intensity laser that causes complication such as hypotony and phthisis bulbi.
Recently, MP-TSCPC has demonstrated superior e cacy in lowering IOP with less complications 8,10 because of minimal disruptions to the collateral non-pigmented epithelium, ciliary body stroma, and adjacent tissue.
Our study also demonstrated that MP-TSCPC is an effective surgical option with fewer complications for eyes with refractory glaucoma. The two most common complications were mydriasis and postoperative iritis.
The study by William et at. 12 and Emanuel et al. 13 showed higher complication rates of postoperative in ammation and hypotony. William et al. identi ed the "non-White race" as being a factor associated with a 3.6-fold higher risk of prolonged in ammation, possibly explained by a greater energy absorption due to pigment. Even though this study was conducted in Asians, the low postoperative in ammation and hypotony rate is thought to be due to the use of relatively low energy laser. The total energy delivered was lower in our study than in their study (2000 mW, 31.3% duty cycle, 100 ~ 180 seconds VS 2000 mW, 31.3% duty cycle, 120 ~ 360 seconds). These results suggest that the risk of complications of MP-TSCPC could be related to the delivered energy. Vig et al. 14 in their recent study reported very few complications using lower durations/total energy (up to 90 seconds for the 2000 mW laser).
Although there have not been many reports on the matter, mydriasis is another possible complication after MP-TSCPC, which may lead to clinical ndings such as glare or other visual discomforts 15,16 . Mydriasis occurred in 9 eyes in this study. It is possible that the iris pigmentation was more distributed than in the previous 'Caucasian' study subjects, resulting in more energy absorption by the surrounding tissues 17 . In a recent study, of the 349 patients who underwent MP-TSCPC, 4 presented with xed pupil and dilated pupils that did not react to light or accommodate after the procedure. All 4 patients had brown irises and myopia 18 .
A signi cant number of patients experienced vision changes after MP-TSCPC in our study. In total, 44.4% of patients experienced vision loss ≥ 2 lines on the Snellen chart at 6 months follow up. The relatively high rate of vision loss may be related to differences in study populations. In general, our study subjects had advanced glaucoma and complex ocular histories. Continuous visual eld loss may have accounted for some of the loss of VA of the patients in this study when no obvious adverse effect occurred. Out of the 6 eyes that had unexplained vision loss, 5 had advanced glaucoma. In one study that evaluated the outcomes of MP-TSCPC in patients with good baseline vision, there was no signi cant reduction in logMAR BCVA from baseline to 1, 3, 6, and 12 months postoperatively 19 . In contrast, the baseline mean VA was 1.19 ± 1.02 logMAR in this study.
Further, considering the recurrence of vitreous hemorrhage or cystoid macular edema in eyes with vision loss, it was not clear whether the vision loss observed in eyes after MP-TSCPC was related directly to the laser procedure or determined by the underlying disease process and the natural progression of advanced glaucoma. Moreover, because of the imprecise nature of VA measurements and poor reproducibility of Snellen VA assessment at low levels of vision, caution should be taken when interpreting apparent changes in VA. To evaluate the effect of MP-TSCPC in vision loss, research should be conducted with patients at different stages of the disease, and better baseline visual acuities should be obtained.
Many variables responsible for the extent of the postoperative IOP lowering effect have been proposed: age, sex, type of glaucoma, previous ocular surgery, and iris pigmentation 20 . In this study, postoperative IOP was not statistically different between the group with previous ocular surgery and the group without previous ocular surgery. Until recently, cyclodestructive procedures have been performed as the last option for patients with poor visual potential. In comparison with glaucoma surgery, MP-TSCPC is quick, technically easy to perform, relatively inexpensive, and minimally invasive. Therefore, MP-TSCPC could be a good alternative for invasive incisional glaucoma surgery in patients who are at a high risk of surgical complications.
However, in a study of outcomes of MP-TSCPC in Asian patients with advanced glaucoma 21 , the signi cant risk factor for failure was previous glaucoma surgery (Odds ratio = 2.33, 95%CI = 1.11-4.59, P = 0.02). This is possibly due to difference in patient characteristics. There were 4 (8.9%) eyes with neovascular glaucoma (NVG) in our study, whereas 33.8% (70 eyes) of them had NVG, although it is not known which patients were included in which group. In TSCPC, the risk of complications and failure is affected by the type of glaucoma, with patients with NVG having a signi cantly increased risk of complications and failure 22,23 . Tan et al. 10 also reported a higher failure rate in patients with NVG.
Many published studies have reported the short-term e cacy of MP-TSCPC. However, There are relatively few large-scale studies that report on the long-term e cacy of this procedure. The greatest drop in IOP was noted the rst week after MP-TSCPC and increased gradually during the rst 6 months of our study. This result is consistent with that of the retrospective study that have evaluated the long-term e cacy of MP-TSCPC for patients with advanced glaucoma 21 . In that study, the success rates of up to 70% at postoperative week 6 subsequently declined throughout the 3 years of follow-up after MP-TSCPC to 18.5% at postoperative year 3. In our study, although the sample size was small, the success rate dropped to 68.2% at 12 months. Aqino et al. observed treatment success (de ned as IOP between 6 and 21mHg and at least 30% reduction in IOP) in 75% of 24 MP-TSCPC-treated eyes after 12 months and in 52% of treated eyes after 18months 8 . Therefore, prospective studies with a larger cohort and a longer follow-up are necessary to con rm the effects of MP-TSCPC.
The limitation of our study include its retrospective nature, small sample size, and relatively short follow-up period. Due to the limited follow-up time, it may be unrealistic to determine major complications such as phthisis bulbi. Another drawback is our inclusion of only subjects with refractory glaucoma who failed to reach target IOP with maximal anti-glaucoma therapy, with or without previous glaucoma surgery. Additionally, our study analyzed patients of a single ethnic group. Therefore, caution need to be exercised in terms of generalizing our results.
Nevertheless, this study is meaningful as it is the rst to report the clinical outcomes of rst-time MP-TSCPC for the treatment of refractory glaucoma in an Asian population.
In conclusion, our data shows that MP-TSCPC is effective treatment for lowering IOP in refractory glaucoma regardless of prior glaucoma surgery. However, there were signi cant risks of visual loss and some adverse effects such as mydriasis.
Therefore, it is necessary to explain the possible complications to the patients before procedure. Further research is needed to nd the optimal laser settings for each ethnicity.

Patients enrollment
This retrospective study included patients with refractory glaucoma who underwent a single rst-time MP-TSCPC at the glaucoma center in Severance hospital from February 2018 to February 2020. Approval for this study was obtained from the Severance Institutional Review Board, which provided a waiver informed consent for the retrospective review of existing patient records (IRB number:4-2020-1200). The methods used in this study adhered to the Declaration of Helsinki.
Patients with refractory glaucoma is de ned as those who have failed to reach target IOP using maximal topical antiglaucoma medication, and/or dependent on oral carbonic anhydrase inhibitors, with or without previous glaucoma surgery and poor surgical prognosis 24,25 . Pre-and postoperative clinical data, including age, sex, type of glaucoma, BCVA, IOP, treatment history, and medication, were recorded. Patients who did not undergo at least 6 months of follow-up were excluded.

Surgical procedure
All procedures were performed under retrobulbar or sub-Tenons anesthetic block (4% lidocaine and 0.5% bupivacaine). The laser probe was placed at the peri-limbal area at 1mm from the corneo-scleral limbus with the probe perpendicular to the surface of the globe. The laser setting was 2000mW with a duty of 31.3%. The laser was applied throughout 180° for 90 seconds in eyes with no previous glaucoma surgery and 60 seconds in eyes with previous glaucoma surgery to avoid the previous sites of prior glaucoma surgery ( ltering and drainage implant areas). The procedure was repeated for the other hemi-eld. The 3 and 9 o'clock areas were avoided due to the potential of damaging the long posterior ciliary nerves and arteries.
The dose of topical glaucoma medications and acetazolamide was gradually tapered depending on the patients' individual needs after the procedure.
Postoperatively, patients were prescribed levo oxacin 0.5% and umetholone 0.1% 4 times daily during the rst week, followed by a tapering course.

Follow-up
Data were collected at follow-up visits on 1 day, 1 week, 1 month, 3 months, 6 months, and 12 months after the procedure. Anterior segment examination, anterior chamber reaction, postoperative IOP, BCVA, postoperative complication, and the number of glaucoma medication at each follow-up were recorded.

Outcome measures
The primary outcome was surgical success, de ned as IOP of 6-21mmHg or more than 20% reduction in IOP from baseline, without any further glaucoma surgeries. Failure was de ned as IOP <6mmHg or >21mmHg, and <20% reduction in IOP, or received further glaucoma surgeries. Further glaucoma surgeries included repeat MP-TSCPC, continuous-wave diode TSCPC, trabeculectomy, or glaucoma tube shunt implantation.
A subgroup analysis was performed between eyes with and without history of glaucoma surgery.

Statistical analysis
Statistical analysis was performed using SPSS, version 22.0 (IBM Corp., Armonk, NY, USA). The post-treatment values were compared with the baseline values using the paired t-test or Wilcoxon signed-rank test. A Mann-Whitney U test was used to compare variables between each group. Kaplan-Meier survival analysis was used to determine the cumulative success. BCVA was converted from Snellen visual acuity to logarithm of the minimum angle of resolution (logMAR) eqivalents. A p value less than 0.05 was considered statistically signi cant.

Declarations Data Availability Statement
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.     Data are expressed as the mean ± standard deviation. IOP = intraocular pressure; BCVA = best corrected visual acuity; logMAR = logarithm of minimal angle of resolution. * P-value for Mann-Whitney test. Figure 1 Rates of the success through the follow-ups. At 6 months, the overall success rate is 82.2%. This rate drops to 68.2% at 12 months.