Micropulse Transscleral Cyclophotocoagulation Results in Secondary Glaucoma

The aim of this study was to analyze the long-term outcome of first session of micropulse transscleral cyclophotocoagulation (MP-CPC) for refractory glaucoma developed after vitreoretinal surgery combined with silicone oil implantation. The inclusion criteria of this consecutive case series were: patients with secondary glaucoma in the refractory stage who underwent MP-CPC between 2018 and 2021, vitreoretinal surgery combined with silicon oil implantation, and at least a 24-month follow-up period after MP-CPC. Success was defined as the baseline eye pressure reduced at least 20%, and it should be ranged between 10 to 20 mmHg without further MP-CPC at the end of the follow-up. For this retrospective study, 11 eyes of 11 patients were selected. The reduction in IOP was found to be significant (p = 0.004) at the end of the follow-up time, and the success rate was 72% according to our results. The change in the number of antiglaucoma agents in the administered eyedrops was not significant compared to the baseline values. At the end of the follow-up period the change in BCVA values was not significant (p = 0.655). Our results confirm significant IOP lowering effect of this subthreshold method preserving visual performance safely even in eyes with previous vitrectomy surgery with a silicone oil implantation.


Introduction
Glaucoma is a disease that leads to the progressive apoptosis of retinal ganglion cells, causing irreversible damage to the retinal nerve fiber layer and the optic nerve head. Secondary glaucoma is a heterogenous group of different conditions, such as uveitis, neovascularization in proliferative diabetic retinopathy or central retinal vein occlusion (CRVO), and iatrogenic causes. Iatrogenic secondary open-angle glaucoma includes cases in which a substance (e.g., silicon oil) used in the surgical treatment of a pre-existing disease (e.g., retinal detachment) leads to higher intraocular pressure. The term refractory glaucoma is usually used in cases where the intraocular pressure is uncontrollably high despite maximum eyedrop therapy or when surgical methods (e.g., cyclodestructive procedures or filtration surgery) fail to reduce the intraocular pressure.
Silicon oil implanted in the vitreous cavity can cause an increase in intraocular pressure in several ways: pupillary block glaucoma in aphakic eyes, overfilling of silicon oil, silicon oil migrating into the anterior chamber, and secondary chronic open or closed angle glaucoma [1]. The migration of emulsified silicon oil into the anterior chamber may cause trabecular meshwork occlusion and early postoperative intraocular pressure (IOP) elevation. Macrophages of the trabecular meshwork can phagocyte the silicon oil globules, and they may cause trabeculitis, which manifests as a late IOP elevation. In the long term, silicon oil can cause major structural changes in the trabecular meshwork, which may later become permanent. Risk factors for IOP elevation following pars plana vitrectomy (PPV) combined with silicon oil implantation include preoperative intraocular hypertension, high myopia, pseudophakia, and the use of low viscosity silicon oil during surgery [2,3]. Management is difficult because, apart from topical or systemic IOP decreasing drugs,  The aim of this preliminary study was to analyze the long-term outcome of MP-CPC for refractory glaucoma developed after vitreoretinal surgery combined silicone oil implantation for complicated posterior segment disease.

Materials and Methods
It is a retrospective analysis of a consecutive case series. Medical records of 11 patients were analyzed; the data were extracted from Medsol system. Institutional Review Board approval was obtained for all study protocols (SE RKEB 193/2022). The inclusion criteria of this consecutive case series were: (1) patients who underwent MP-CPC between 2018 and 2021; (2) vitreoretinal surgery combined with silicon oil (1300 cst) implantation for complicated posterior segment disease; (3) at least 24-month follow-up period after MP-CPC; (4) no eye surgery was performed over a year before MP-CPC. Initially, we collected records of 13 patients, two of them were excluded. One patient was unable to attend follow-up visits after 9 months due to the COVID pandemic while the other patient had missed visits after 12 months due to pregnancy.
Before MP-CPC and in the follow-up period, all of the patients underwent routine ophthalmic examination: best corrected visual acuity (BCVA) was measured on Early Treatment Diabetic Retinopathy Study (ETDRS) chart after automatic refractometry, slit lamp examination, Goldmann applanation tonometry, funduscopy. Intra and postoperative complications were monitored.
Indications for MP-CPC were: (1) for 9 eyes, intraocular pressure ≥ 21 mmHg despite using personally tolerable eyedrops and oral acetazolamide combination (i.e., at least 3 drugs in the eyedrops (beta blocker, carboanhydrase inhibitor, and alpha-adrenergic agonist) with or without oral carboanhydrase inhibitor or prostaglandine analog eyedrop); (2) concentrically narrowed visual field when intraocular pressure < 21 mmHg for an eye of former premature patient, and this eye was managed with a combination of four drugs in the eyedrops. The reason for the visual field examination of the affected eye prior to MP-CPC was a suspected and confirmed concentric visual field narrowing due to retinopathy of prematurity and made even worse by secondary glaucoma. (3) The final indication was high intraocular pressure and severe pain in a blind eye of another former premature patient.
The treatment was performed with a Supra 810 nm diode laser (Quantel Medical) at 3 mm from the limbus with a G-probe device, skipping the 3 and 9 o'clock regions (energy: 2000 mW, duty cycle 31.3%, time: 2 × 80 s, sweeping motion: 10 s/hemisphere). After the micropulse laser treatment, all patients received steroid eyedrop therapy for 2 weeks in addition to the previously prescribed anti-glaucoma eyedrops. The patients were asked to come for control quarterly (every three months). All complications, whether intraoperative, early, or late postoperative, were recorded. Special attention was paid to whether the surgery did not result in visible laser burn or subconjunctival suffusion. Major postoperative complications were considered to be significant visual impairment associated with MP-CPC, hypotony, phthisis. Anterior segment inflammation and transient BCVA deterioration within the first 2 postoperative weeks due to inflammation were classified as mild complications. All participants were treated in accordance with the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants.
Statistical analysis was performed using IBM SPSS Statistics 25 (SPSS Inc., Chicago, IL, USA). Therapeutic answer was characterized by the eye pressure; number of medications at baseline; 3,6,9,12,15,24,36, and 48 months; and the number of MP-CPC sessions during the follow-up. The changes in the best corrected visual acuity were also analyzed. A significant visual deterioration was defined as 2 or more lines worsening in BCVA measured on ETDRS chart. Loss rate was calculated at each follow-up time point. Loss rate means the ratio of number of patients who attended a visit and number of all patients who could have been followed based on the starting date (2018-2021). Success was defined as the baseline eye pressure reduced at least 20%, and it should be ranged between 10 to 20 mmHg at the end of follow-up. If 2 measurements occurred in the given quarter, the last was included in the analysis. Success rate was calculated at each follow-up point (categorization: 0 for patients who met the criteria of success, 1 for patients with eyes that did not). Success rate is defined as number of eyes met the criteria of success at that given follow-up time point/total number of patients who could have been seen at that time. This means that (1) all patient who did not present were considered failures and, (2) due to the retrospective nature of the study, fewer patients were seen at the 36th and 48th month visits. The categorized values of eye pressure in the first 24 months were also estimated by chi-squared test. Wilcoxon signed rank test was performed to compare baseline and endpoint data of each eye. Friedman test was used to determine whether the repeated measurements of eye pressure and agent's combination in the first 8 quarters differ from the baseline. Usage of oral acetazolamide at the end of follow-up of each patient was estimated by Fisher's exact test. A p-value of < 0.05 was considered statistically significant. Datasets are deposited in Dryad database (DOI: https://doi.org/10.5061/dryad.v6wwpzh1b, accessed on 17 March 2023).

Results
Eleven eyes of eleven patients (eight males, three females) ( Table 3) met the inclusion criteria. In all cases, the indication of MP-CPC was refractory glaucoma. At baseline, 7 patients had intraocular pressure more than 30 mmHg; one of them was blind. Three eyes were legally blind (BCVA ≤ 0.1) and another 3 eyes had 0.5 ≤ BCVA. Generally, the patients applied 3 agents (beta blocker, carboanhydrase inhibitor, and alpha-adrenergic agonist) in eyedrops, 3 patients added a prostaglandin analog, and 6 patients used an oral carboanhydrase inhibitor as well. Silicon oil was removed within 2 months to 2 years (median: 4.5 months); at the time of MP-CPC, a vitreous cavity in 4 eyes (36%) had been containing silicon oil for 1 to 10 years (median: 6.5 years). MP-CPC was performed from 8 months to 11 years after the silicon oil implantation (median: 3 years). All of the eyes underwent uncomplicated phacoemulsification and posterior chamber lens implantation either in the same session of vitrectomy (9 eyes) or before vitrectomy (2 eyes). Table 4 shows the loss and success rates at each follow-up time point, respectively.   Comorbidities of secondary glaucoma. The vitrectomies were performed between 2008 and 2019; the indications for silicon oil implantation were the following: retinal detachment with proliferative vitreoretinopathy in 5 eyes. Out of them one patient manifested rheumatoid arthritis (RA) and consecutive uveitis in both eyes. Another patient has ocular hypertension in the fellow eye. Two former premature patients suffered from retinal detachment caused by circular remnant of retinopathy of prematurity (ROP): one of them was blind for the fellow eye, the other patient's operated eye had perforating sclera injury previously. In another patient, 2 quadrants large retinal tear developed with retinal detachment 8 months after an uncomplicated phacoemulsification for congenital cataract. The next patient had a perforating cornea injury and underwent vitrectomy combined perforating keratoplasty using a temporary prosthesis. Two type 1 insulin dependent diabetic patients had severe proliferative diabetic retinopathy.
Complications. Mild acute complications, such as hyperemia or mild pain, occurred in seven and one patients, respectively. No severe complications were observed either intraoperatively or postoperatively. In the acute postoperative period, mild iritis was detected that resolved within 10 days using a steroid eyedrop. None of the patients developed a phthisis or hypotony during follow-up. No eyes became blind.
Visual acuity. Except for 2 eyes, the original visual acuity could be preserved. One line worsening in BCVA occurred in 2 eyes, one line improvement was detected in another 2 eyes, and BCVA did not change in 4 eyes. In the remaining one eye was blind at the time of MP-CPC. Significant BCVA loss occurred in 2 eyes. One of them underwent an unsuccessful pars plana vitrectomy for retinal detachment 10 years before MP-CPC. The five lines of the deterioration of BCVA is determined by not only proliferative vitreoretinopathy, but also uveitic episodes due to rheumatoid arthritis. Rheumatoid arthritis was diagnosed a year after MP-CPC. In the first 2 years of the 5-year follow-up period of MP-CPC, iridocyclitis with macular edema developed 3 times in both eyes. The patient was unable to attend control examinations due to the COVID-19 pandemic. Three lines worsening in BCVA also occurred in the fellow eye, and secondary glaucoma was detected and required a shunt implantation. The other patient's eye underwent a perforating keratoplasty combined pars plana vitrectomy for retinal detachment after a perforating cornea injury. In this case, the 5 lines of impairment in BCVA is explained by the corneal haze of the donor tissue.
Intraocular pressure. In the first 2 years, the intraocular tension could be measured regularly: in a 3-month period in the first 15 months, after said period, and in a 6-8 month period, respectively. Figure 1 shows the evolution of eye pressure during the follow-up period. Table 4 summarizes the loss rates at each follow-up time point. Seven patients could be followed for more than 3 years (40-52 months). The median values of eye pressure were all below 20 mmHg ( Figure 2). Except one eye, the others achieved the range of 20 mmHg or less with an approximately 20% reduction at the end of the follow-up period for each eye (Wilcoxon test, p = 0.004). Three patients required second session of MP-CPC, 6, 8, and 14 months after the first treatment, respectively (re-treatment rate 27%). The success rate of MP-CPC is 73% at the end of the first 2 years (based on the eye pressures collected in the first 24 months; Friedman test p-value is 0.013). Two patients achieved a 20% reduction; however, they even had an IOP above 20 mmHg (both of them had 26 mmHg with 23.50% IOP reduction). The third patient's eye pressure was under 20 mmHg, but it was only a 10% reduction (18 mmHg). Out of these 3 patients, one eye failed at the end of 48 months of follow-up. This ROP eye was blind and contained silicon oil for 10 years at the time of MP-CPC. The combination of agents in eyedrops could be reduced in one eye, and it was achieved only in the first 3 months. For oral acetazolamide, at baseline, 6 patients used oral acetazolamide while at the end of follow-up of each patient, only 1 patient applied it ( Table 3). The result is not significant (p = 0.0635), and the odds ratio is 12.00 at CI 95 1.117 to 128.9. We have to mention that at the 24-month follow-up point, no patient required oral acetazolamide. One patient required oral acetazolamide medication permanently over a year after MP-CPCP.
Life 2023, 13, x FOR PEER REVIEW 6 of 24 up period for each eye (Wilcoxon test, p = 0.004). Three patients required second session of MP-CPC, 6, 8, and 14 months after the first treatment, respectively (re-treatment rate 27%). The success rate of MP-CPC is 73% at the end of the first 2 years (based on the eye pressures collected in the first 24 months; Friedman test p-value is 0.013). Two patients achieved a 20% reduction; however, they even had an IOP above 20 mmHg (both of them had 26 mmHg with 23.50% IOP reduction). The third patient's eye pressure was under 20 mmHg, but it was only a 10% reduction (18 mmHg). Out of these 3 patients, one eye failed at the end of 48 months of follow-up. This ROP eye was blind and contained silicon oil for 10 years at the time of MP-CPC. The combination of agents in eyedrops could be reduced in one eye, and it was achieved only in the first 3 months. For oral acetazolamide, at baseline, 6 patients used oral acetazolamide while at the end of follow-up of each patient, only 1 patient applied it ( Table 3). The result is not significant (p = 0.0635), and the odds ratio is 12.00 at CI 95 1.117 to 128.9. We have to mention that at the 24-month follow-up point, no patient required oral acetazolamide. One patient required oral acetazolamide medication permanently over a year after MP-CPCP.

Discussion
Traditionally, cyclodestructive procedures are applied for otherwise non-treatable glaucoma. Transscleral CPC has a significant IOP lowering effect at 1, 5, and even 10 years. However, 51.5% of the treatments failed by the end of 10 years, and most failures occurred within the first year (40%). A high complication rate is reported in connection with this type of cyclodestructive procedure, such as a visual loss of two lines or more in 60% of patients and hypotony in 4% of eyes [8]. A subcyclo treatment uses a non-destructive laser device avoiding the side effects of the traditional transscleral procedure allowing a more precise management of the thermal effect on the targeted tissues [9].
In this retrospective preliminary study, we aimed the evaluation of IOP control using subcyclo treatment in eyes with refractory secondary open angle glaucoma caused by silicon oil implantation after vitrectomy surgery. The cases had in common that they all turned out to be complicated (e.g., complicated retinal detachment, repeated vitrectomies, former ROP patient, perforating eye injury in history, proliferative diabetic retinopathy and rheumatoid arthritis associated uveitis), and all patients underwent silicon oil implantation. Despite the fact that the silicon oil was removed, filtration surgery to reduce IOP (e.g., trabeculectomy) was not an option in these cases due to the residual emulsified silicon oil particles. Our basic aim with the MP-CPC treatment was to reduce the patients' pain by reducing the intraocular pressure and to preserve residual visual acuity by avoiding potential complications (e.g., phthisis, hypotony).
IOP lowering. Our results confirm a significant IOP lowering effect of this subthreshold method, preserving visual performance safely even in eyes with previous

Discussion
Traditionally, cyclodestructive procedures are applied for otherwise non-treatable glaucoma. Transscleral CPC has a significant IOP lowering effect at 1, 5, and even 10 years. However, 51.5% of the treatments failed by the end of 10 years, and most failures occurred within the first year (40%). A high complication rate is reported in connection with this type of cyclodestructive procedure, such as a visual loss of two lines or more in 60% of patients and hypotony in 4% of eyes [8]. A subcyclo treatment uses a non-destructive laser device avoiding the side effects of the traditional transscleral procedure allowing a more precise management of the thermal effect on the targeted tissues [9].
In this retrospective preliminary study, we aimed the evaluation of IOP control using subcyclo treatment in eyes with refractory secondary open angle glaucoma caused by silicon oil implantation after vitrectomy surgery. The cases had in common that they all turned out to be complicated (e.g., complicated retinal detachment, repeated vitrectomies, former ROP patient, perforating eye injury in history, proliferative diabetic retinopathy and rheumatoid arthritis associated uveitis), and all patients underwent silicon oil implantation. Despite the fact that the silicon oil was removed, filtration surgery to reduce IOP (e.g., trabeculectomy) was not an option in these cases due to the residual emulsified silicon oil particles. Our basic aim with the MP-CPC treatment was to reduce the patients' pain by reducing the intraocular pressure and to preserve residual visual acuity by avoiding potential complications (e.g., phthisis, hypotony).
IOP lowering. Our results confirm a significant IOP lowering effect of this subthreshold method, preserving visual performance safely even in eyes with previous vitrectomy surgery with silicone oil implantation (Table A1 in Appendix A). The reduction in IOP was found to be significant. Regarding medications, contrary to the literature data (see Table A1), the change in the number of anti-glaucoma agents in the eyedrops administered was not significant compared to the baseline values. In these complicated cases, we found it very difficult to change the existing therapy because the delicate balance of previously well-adjusted IOP values can easily be upset. The pathogenesis of secondary glaucoma is complex, and in addition to the emulsified silicone oil, several other factors are involved (e.g., autoimmune uveitis, prematurity, proliferative diabetic retinopathy, ocular trauma). We had a patient who was on continuous oral acetazolamide therapy for over one year. The odds ratio in Table 3 shows that after MP-CPC, there is a twelve-fold increase in the likelihood of getting rid of oral acetazolamide. In these cases, it was not possible to achieve a result with MP-CPC that would have led to a significant reduction or elimination of the number of eye drops used. At the same time, however, it also seems that MP-CPC could be an effective adjuvant therapy in such cases. For visual acuity, in the majority of the eyes, the change in BCVA values was not significant at the end of follow-up time; two or more lines worsening in BCVA were not detected. In two eyes, the severe visual impairment is definitely not associated with MP-CPC, and it could be explained by a difficult clinical picture. As the visual acuity in these complex cases is affected by many factors, we have not calculated a success rate for BCVA, and the change in BCVA values was not significant at the end of follow-up time. Regarding complications, we detected only mild acute complications, such as hyperemia or mild pain. No IOP spike, fibrinous reaction, or iritis was observed. We found no severe complications, such as prolonged hypotony, phthisis, cystic macular edema, or keratopathy. Severe visual deterioration in two patients can be explained by ocular pathology other than secondary glaucoma induced optic neuropathy (i.e., opacity of the donor cornea, autoimmune uveitis, and proliferative vitreoretinopathy). We cannot comment on a possible increased cataractogenesis since all of the patients underwent lens surgery several years before MP-CPC. Based on the literature data, possible complications of MP-CPC were collected in Table 2, and they occurred within the following frequency ranges regardless of the etiology (see details in Table A1): (1) severe complications: significant BCVA deterioration (4.5-44%), prolonged hypotony (1.1-13%), phthisis (2.5-5%), cystic macular edema (1.4-5%), keratopathy (1.6-18%), hyphaema (17,5%), and vitreous haemorrhage (0.3%); (2) mild complications: acute hyperemia (73%), mild pain (30%), IOP spike (10%), fibrinous reaction (0.7-3%), and iritis (1.8%). In the light of the literature data, it can be concluded that the symptoms considered as mild complications were within the known prevalence values in our study (hyperemia in 63.6% and mild pain in 9.1%).
The literature data on secondary glaucoma developed after the vitreoretinal procedure. Table A1 provides details of MP-CPC studies on secondary glaucoma previously published in the literature . The literature data are difficult to compare because the definition of success varies from study to study, the etiology is diverse, and therefore the success rates calculated at the end of follow-up period show a wide variation (from 11.0% to 95.7%; for details see Table A1). Most of the studies were retrospective; 6 studies were planned prospectively with the prospective studies being sporadic. We selected for inclusion in the discussion those publications in which we found references to MP-CPC for the treatment of secondary glaucoma, especially which developed after vitreoretinal procedure. Regarding the prospective studies, except for the study of Zbiba Barac et al., 2018 [26], and Jammal et al., 2019 [19]) were not addressed to analyze silicon oil-induced glaucoma as a different subgroup. In these studies, the success rates ranged from 52-72%; in one study the success rate was not applicable. Zbiba et al. [10] investigated only eyes with refractory stage silicon oil-induced glaucoma. Out of 33 eyes, 10 eyes contained silicon oil at the time of MP-CPC, and the follow-up was 12 months. The lowest eye pressure (16.5 mmHg) was measured at the end of the first week. After, it ranged between 19.27-19.97 mmHg. The success rate was 93.93% with a percentage of eye pressure lowering 45%.
As for the results of the retrospective studies, 2 studies were found that included vitrectomized eyes. Lim et al., 2021 [13] investigated the outcomes of MP-CPC for secondary glaucoma. Of the 43 eyes treated, 3 were vitrectomized. At the end of the mean follow-up of 28.9 months, the success rate was 39.5%. Tekeli et al., 2021 [14] compared the outcomes of primary open angle glaucoma, pseudoexfoliation, and secondary glaucoma groups, respectively. The success rates were the lowest in the secondary glaucoma group at all IOP criteria (A, B, and C), and the retreatment rate was the highest (41.2%) in this group. The data in the literature suggest that silicone oil-induced secondary glaucoma is one of the groups with the worst prognosis. As it was mentioned above, a number of other factors can make a patient's condition worse; therefore, each patient requires personalized treatment.
It is difficult to compare the results of our study with the aforementioned studies, as most of them did not include vitrectomized eyes as a separate subgroup, and where it was analyzed as a separated subgroup, it was mentioned together with several other types of secondary glaucoma. However, our success rate was lower compared to the results in Zbiba et al.'s study. It was stable through the follow-up period. The differences might arise from the long-term history of silicon oil usage and the complex pathogenesis of glaucoma, including among other autoimmune uveitis, prematurity, trauma, and severe diabetic proliferative retinopathy.
The limitations of our study are the retrospective design and the small number of patients. However, all of the patients underwent vitrectomy combined with silicone oil implantation, and the presented case series may not be representative for secondary glaucoma-induced silicone oil since many other factors are also implicated in the development of secondary glaucoma. This report should be considered as a preliminary study that requires further data validated from a greater number of patients treated in different centers.
In conclusion, the manuscript provides real-life data on an uncommon but difficultto-treat type of secondary glaucoma that develops after vitreoretinal surgery, related to silicone oil implantation but with a pathogenesis that is more complex than only silicone oil-induced. We found MP-CPC to be a safe and effective adjuvant treatment modality even in difficult cases, such as vitrectomized eyes.