May-June, 2022 Vol, 28 No. 3

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 51 DOS TIMES Figure 2: Normal Pattern ERG. Figure 3: Normal Flash ERG. N95 N35 P50 The first studies of pattern ERG recording in glaucomatous eyes by May et al[7], Wanger et al[8] all reported a significant reduction in amplitude of PERG as compared to normal reference values as well as opposite eyes of the same patient. Ringens PJ[9] et al further reported an increase in latency in PERG in glaucoma along with a decrease in amplitude. Weinstein GW et al[10] found a selective reduction in the second negative wave (N-95) of PERG in glaucomatous patients and concluded that this wave (N-95) is related to early optic nerve dysfunction. This opinion was further strengthened by Arai M et al[11] whose study concluded that decrease in amplitude of the second negative wave (N-95) is a warning sign of development of glaucoma in ocular hypertensives. The most comprehensive reports of PERG abnormalities in glaucoma came from Holder et al[12] who concluded that the N-95 component is generated by the retinal ganglion cell layer and that the P-50 component is generated by he inner and outer retinal layers and macula. Following this, studies were directed at establishing correlation between PERG and other regularly conducted tests of glaucoma. Neoh C et al reported significant correlation between PERG amplitude (P50 and N-95) and the global indices (mean deviation and corrected pattern standard deviation) of Humphrey’s visual field analyzer.[13] This however could not find support from Hood CD et al who conducted a study of PERG in glaucoma patients of visual field defects.[14] They measured not only the amplitude of N-95 but also the N-95/P-50 ratio and their relationship with the global indices of automated perimetry. The amplitude of P-50 was measured from the trough of N-35 to the peak of P-50. Similarly the amplitude of N-95 was measured from the peak of P-50 to the trough of N-95. The study concluded that significant reduction in amplitude of N-95 as well as N-95/P-50 ratio (normal 1.2-1.9) is seen in glaucomatous eyes but no linear relationship could be established with perimetric field loss. In order to bridge the gap between electrophysiological tests and perimetry multifocal recordings introduced by Sutter and Tran were employed. This allows simultaneous recording of ERG from 100 regions within the visual field. This is based on the assumption that PERG analyses only the central 15 degrees of the visual field whereas the common field defects beyond this central zone can only be assessed by multifocal recording. However Klistorner et al reported that though generalized reduction in amplitude of multifocal ERG across the visual field is observed in glaucoma, no localized ganglion cell loss corresponding to visual field defects could be identified.[6] To summarize, PERG is a useful tool for early detection of glaucoma preceding the appearance of visual field defects. However the correlation of PERG with visual fields is difficult to ascertain. The main problem of PERG is not its interpretation but the process of recording itself. It requires refractive correction, clear ocular media, good patient co-operation for proper placement of electrodes because even a small reduction in the quality of the retinal image quality can cause significant reduction in the amplitude of PERG leading to erroneous results. Photopic Negative Response in Glaucoma The conventional flash electroretinogram recorded with corneal electrodes in response to flash stimuli by Ganzfield stimulator has not received much attention in glaucoma. This is because it was believe that the components of Flash ERG originate from the photoreceptors and bipolar cells of the retina which are not much affected in glaucoma. Thus use of Flash ERG was limited to detection of diseases like retinitis pigmentosa, cone dystrophy, ischaemic retinal vein occlusions etc. Recent interest in Flash ERG has been generated due to the identification of a new wave named Photopic Negative Response (PhNR) which is believed to originate from the retinal ganglion cell layer and hence may be useful in detecting early nerve dysfunction in glaucoma. The components of the conventional Flash ERG are: 1. A small negative ‘a’ wave believed to originate from the photoreceptors 2. A large positive ‘b’ wave believed to originate from the Muller’s cells and bipolar cells 3. A non-specific ‘c’ wave originating from the retinal pigment epithelium Flash ERG recorded under photopic conditions specified by

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 52 DOS TIMES International Society for Clinical Electrophysiology of Vision (ISCEV) identifies a new component named photopic negative response (PhNR) 1. PhNR is the negative wave following the ‘b’ wave 2. The amplitude of PhNR is measured from the baseline to the trough of the wave Figure 4: Photopic Negative Response (PhNR). Photopic negative response has been measured in rat eyes after optic nerve transection and intravitreal injection of tetradoxin which is a blocker of the neural activity of the retinal ganglion cells.[15,16,17,18] PhNR was found to be strongly attenuated in these eyes as compared to normals. About 56% reduction in amplitude was found after optic nerve transection and about 57% reduction was seen 30 minutes after intravitreal injection of tetradoxin. This study by Li et al demonstrated that PhNR depends on the integrity of retinal ganglion cell layer and hence may have a role to play in glaucoma detection.[19] In addition, it has been reported that the PhNR is selectively attenuated in eyes with optic nerve atrophy induced by trauma, compression, inflammation, gene mutation, and ischemia.[20,21,22] Colotto A et al reported significant reduction in amplitude of PhNR (average 62%) in POAG as compared to normals.[23] Similarly, Vishwanathan S et al[24], in a study of 62 normals, 18 POAG patients and 7 POAG suspects demonstrated that the amplitude of PhNR was greatly reduced in the POAG group as well as the suspect group in comparison to normals. They also found that the amplitude of PhNR correlated significantly with the Mean Deviation of the visual fields and the cup:disc ratio of the optic nerve head. Shigeki M et al reported a decrease in PhNR/b wave ratio in glaucomatous eyes with an increase in visual field defects.[25] The amplitude of PhNR and PhNR/b wave ratio correlated significantly with the retinal nerve fibre layer thickness (RNFLT), the rim area of the optic disc and the cup/ disc area ratio when expressed logarithmically. However, Jones AL et al reported a reduction in amplitude of PhNR in glaucoma but not in ocular hypertensives when compared to normals.[26] 23 POAG patients, 13 ocular hypertensive patients and 22 controls were included in their study in which they recorded PERG and PhNR according to ISCEV standardized conditions. Compared to controls, both POAG and OHT groups showed significant reduction in the amplitudes of PERG N95 as well as PhNR. In the POAG group, some correlation was found between the amplitudes of PERG N95, PhNR, optic disc topography and retinal nerve fibre layer thickness. No significant correlation was seen in the OHT group. They concluded that the modest correlation between the structural and electrophysiological measures in glaucoma suggest that they identify different aspects of the pathological process. Similar results were reported by Zasshi et al who recorded PhNR in cases of normal tension glaucoma and found significant reduction in amplitude as compared to normals but no correlation could be found between PhNR amplitude and visual field defects or cup:disc ratio.[27] Interestingly, Claus et al did not find any significant reduction in the amplitude of PhNR even in the presence of advanced glaucoma. They studied 18 cases of advanced glaucoma and 9 controls but demonstrated that the amplitude of the negative response was not significantly reduced in glaucomatous eyes as compared to normals.[28] Todorova MG et al reported that it is the latency rather than the amplitude of PhNR which is affected in glaucoma. They studied 15 patients of high tension glaucoma (HTG), 15 patients of normal tension glaucoma (NTG) and 15 normals and observed an increase in latency in HTG and NTG group as compared to normals but the latency delay was more sensitive for HTG than for NTG.[29] Thus, we see that being a relatively newer investigative tool, the behaviour of PhNR in glaucoma is still under debate and studies are still being conducted to establish its role in glaucoma diagnosis. Different schools of thought also exist regarding the method of recording of PhNR. Conventionally, PhNR is described by recording visual response to a red flash (650nm) on a blue background (450nm). This is presumed to relate to the long (L) and medium (M) wavelength sensitive cone pathways. It is known that the blue or short (S) wavelength sensitive cone pathway is the earliest to be affected in glaucoma. This pathway which is investigated using short wavelength automated perimetry (SWAP) can be assessed electrophysiologically using S-cone PhNR. A blue flash on a yellow background is used as stimulus to obtain this response which is known as the S-cone PhNR. Drasdo et al compared the sensitivity of S-cone PhNR and L&M cone PhNR with PERG in early POAG.[30] It was seen that the amplitude of both L&M PhNR and S cone PhNR were reduced in glaucoma as compared to normals but the latter was the more sensitive test providing the most statistically significant results. They concluded that the extensive damage to the S cone bipolar and ganglion cells which occur in early POAG owing to a pressure related mechanism is actually detected by S cone PhNR. However, Wakili N et al conducted a pilot study in 10 patients of asymmetrically advanced glaucoma between the two eyes using white flash on a white background. Comparison was done

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 53 DOS TIMES between the two eyes of the same patient. They concluded that the amplitude of PhNR was reduced significantly in glaucoma even if a white stimulus on white background is used.[31] Gotoh Y et al recorded PhNR in 10 patients of optic nerve atrophy induced by various etiologies by providing a white stimulus on a white background.[32] They found significant reduction in amplitude of PhNR in cases of optic atrophy as compared to normals. From this they concluded that even a white stimulus on a white background may elicit PhNR as long as the recordings arise from the photopic system. The main advantage of this test over Pattern ERG is that it can be recorded even in patients with poor co-operation and hazy ocular media. The only requirement is the presence of a dilated pupil. Conclusion Glaucoma is a slowly progressive disease which might lead to irreversible loss of vision if not detected and treated early. Unfortunately, there is no single test which might enable the clinician to diagnose or rule out glaucoma with complete certainty. Diagnosis of glaucoma is based on a comprehensive assessment of the patient’s history, clinical examination findings and investigation results. Thus electrophysiological tests like PVEP, PERG, PhNR may serve as a useful adjunct in the diagnosis of glaucoma. References 1. Sommer A, Katz J, Quigley HA, Miller NR, Robin AL, Richler NC. Clinically detectable nerve fibre atrophy precedes the onset of visual field defects. Arch Ophthalmol 1999;109:77-83. 2. Krogh E. Visual evoked response in intraocular hypertension. Acta Ophthalmol 1980;58:929-32. 3. Atkin A, Brodis- Wollner I, Podos SM. Flicker threshold and pattern VEP latency in glaucoma and ocular hypertension. Invest Ophthalmol Vis Sci 1983;24:1524-8. 4. Grippo M.Latency of visual evoked potential in glaucoma and ocular hypertension. Arch Ophthalmol 1985;22:445-67. 5. Horn FK, Jonas JB, Budde WM, Junnemann AM. Monitoring glaucoma progression with visual evoked potentials of the blue-sensitive pathway. Invest Ophthalmol Vis Sci 2002;43:1828-34. 6. Klistorner, Alexander, Graham. Multifocal Pattern electroretinogram does not demonstrate localized field defects in glaucoma. Documenta Ophthalmologica 2000;100:155-66. 7. May IG, Ralston JV, Reed JL, Vandyk HJ. Loss in pattern elicited electroretinograms in optic nerve dysfunction. Am J Ophthalml 1982;93:418-22. 8. Wanger P, Persson HE. Pattern reversal electroretinogram in ocular hypertension. Doc Ophthalmol 1983; 61:27-31. 9. Ringen PJ, Vijfvinkel-Bruinenga S, Vanlith GH. The pattern elicited electroretinogram. A tool in early detection of glaucoma. Ophthalmologica 1986;192:171-5. 10. Weinstein GW, Arden GB, Hitchings RA, Ryan S, Calthorpe CM, Odom JV. The pattern ERG in ocular hypertension and glaucoma. Arch Ophthalmol !988;106(7):923-8. 11. Arai M, Yoshimora N, Sakaue H, Chihara E, Honda Y. A 3 year follow-up study of ocular hyoertension by pattern ERG. Ophthalmologica 1993;207(4):187-195. 12. Holder GE. Significance of abnormal pattern ERG in anterior visual pathway dysfunction. Br J Ophthalmol 1987;71:166-171. 13. Neoh C, Kaye SB, Brown M, Ansons AM, Wishart P. Pattern electroretinogram and automated perimetry in patients with glaucoma and ocular hypertension. Br J Ophthalmol 1994;78:359-62. 14. Hood DC, Li Xu, Thienprassidhi P. The pattern electroretinogram in patients with confirmed field defects. Invest Ophthalmol Vis Sci 2005;46:2411-8. 15. Frishman LJ, Shen FF, Du L, et al. The scotopic electroretinogram of macaque after retinal ganglion cell loss from experimental glaucoma. Invest Ophthalmol Vis Sci. 1996;37:125–141. 16. Viswanathan S, Frishman LJ, Robson JG, Harwerth RS, Smith EL, 3rd. The photopic negative response of the macaque electroretinogram: reduction by experimental glaucoma. Invest Ophthalmol Vis Sci. 1999;40:1124–1136. 17. Narahashi T. Chemicals as tools in the study of excitable membranes. Physiol Rev. 1974;54:813–889. 18. Ohkuma M, Kawai F, Horiguchi M, Miyachi E. Patch-clamp recording of human retinal photoreceptors and bipolar cells. Photochem Photobiol. 2007;83:317–322. 19. Li B, Barnes G, Holt W. The decline of the photopic negative response in the rat after optic nerve transaction. Documenta Ophthalmologica 2005;111:23-31. 20. Viswanathan S, Frishman LJ, Robson JG, Walters JW. The photopic negative response of the flash electroretinogram in primary open angle glaucoma. Invest Ophthalmol Vis Sci. 2001;42:514–522. 21. Gotoh Y, Machida S, Tazawa Y. Selective loss of the photopic negative response in patients with optic nerve atrophy. Arch Ophthalmol. 2004;122:341–346. 22. Rangaswamy NV, Frishman LJ, Dorotheo EU, et al. Photopic ERGs in patients with optic neuropathies: comparison with primate ERGs after pharmacological blockade of inner retina. Invest Ophthalmol Vis Sci. 2004;45:3827–3837. 23. Colotto A, Falsini B, Salgarello T, et al. Photopic negative response of the human ERG: losses associated with glaucomatous damage. Invest Ophthalmol Vis Sci. 2000;41:2205–2211. 24. Vishwanathan S, Frishman LJ, Robsn JG, Waller JW. The photopic negative response of the flash electroretinogram in primary open angle glaucoma. Invest Opthalmol Vis Sci. 2001; 42: 514-22. 25. Shigeki M, Gotoh Y, Toba Y, Ontaki A, Kaneko Mi, Kurosaka. Correlation between Photopic Negative Response and Retinal Nerve Fibre Layer Thickness and Optic Disc Topography in Glaucomatous Eyes. Invest Opthalmol Vis Sci. 2008; 49: 2201-07. 26. Jones AL, North RV, Aldebasi YH, Morgan JE, Drasdo N. Comparison of Electrophysiological and Structural Nerve Head Changes in Ocular Hypertension and Primary Open Angle Glaucoma. Inv Ophthalmol Vis Sci 2003;44:39-46. 27. Zasshi NG.Photopic negative response in eyes with normal tension glaucoma. Japanese J Ophthahmol 2002;106:345-67. 28. Cursiefen Claus, Korth Mathias, Horn Folkert. The negative response of the flash electroretinogram in glaucoma. Documenta Ophthalmologica 2001;103:1-12. 29. Todorova MG, Palmowski Wolfe AM, Flanmer J, Orgul S. Photopic negative response to long duration stimuli in the mfERG of open angle glaucoma patients. J European Association for Vision and Eye Research 2006; 10:45-51.

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 54 DOS TIMES 30. Drasdo N, Alsedbasi Morgan J,Yh,Chiti Z, Morlock KE, North R. The s-cone PhNR and pattern electroretinogram in primary open angle glaucoma. Inv Ophthalmol Vis Sci 2001;42:1266-71. 31. Wakili N, Horn FK, Junemann AGM, Korth M. The photopic negative response of the White-on White Flash Electroretinogram in assymetrical glaucomas. Inv Ophthalmol Vis Sci 2002;43:534-8. 32. Yasutaka Goto. Photopic Response of Eyes with Normal Tension Glaucoma. Journal of Japanese Opthalmological Society. 2004; 106 (8); 481-87. Dr. J.L.Goyal, MD, DNB Professor and HOD Department of Ophthalmology School of Medical Sciences and Research Sharda University, Greater Noida, UP Corresponding Author:

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 55 DOS TIMES Trabeculectomy with Collagen Implant for the Treatment of Glaucoma: A Prospective Study Shams Mohammed Noman[1], DCO, FCPS, Tanima Roy[2], FCPS 1. Associate prof, Bangabandhu Sheikh Mujib Medical University, Bangladesh. 2. Consultant, Ceitc.Chittagong. Glaucoma is the second leading cause of blindness worldwide. Trabeculectomy introduced by cairns 1968, remains the “gold standard” surgical option for reduction of IOP. However, episcleral fibrosis and subconjunctival scarring are the major causes of surgical failure. Conjunctival scarring that consist of linear collagen deposition can cause blockage of aqueous outflow by creating adhesions between conjunctiva and episclera and between scleral flap and underlying tissues.[2,3] MMC and 5-FU are the most commonly used adjunctive for the inhibition of fibroblast proliferation to prevent scarring. But these are cytotoxic causing non selective cell death and wound healing with thin avascular epithelium.[4] So use of anti metabolites increases the risk of post operative wound leak, hypotony, blebitis and endopthalmitis.[5] Collagen implant is a biocompatible and biodegradable highly porous structure consisting > 90% atelocollagen and < 10% glycosaminoglycans. It is designed to be used at the time of trabeculectomy to promote wound healing without MMC.[4] The implant is placed directly over the scleral flap and influences the healing process by forcing fibroblasts and myofibroblasts to grow into the pores and secrete connective tissue in the form of a loose matrix reducing scar formation and wound contraction. Purpose: To evaluate the efficacy and safety of Trabeculectomy with collagen implant in patients with medically uncontrolled glaucoma. Methods: This is prospective, non randomized, interventional case series. 76 eyes of 76 patients with medically uncontrolled glaucoma were enrolled. Detailed ocular examination was done in each subject & details were recorded. Conventional fornix based Trabeculectomy with subconjunctival collagen (Ologen) implantation was performed in all patients. Preoperative data included age, gender, best corrected visual acuity (BCVA), intraocular pressure (IOP), glaucoma type, number of preoperative glaucoma medications were recorded. Post operative IOP, number of post operative glaucoma medications & post operative complications were recorded. Each patient was followed up for at least 6 months. Results: Mean pre operated IOP was 34.21±12.5 with 2.3 number of IOP lowering medications (range 2-3). Post operative IOP, after 3 month 13.85±5.42mm of Hg (p value 0.060) after 6 month 16.42±6.42 mm of Hg (p value .056). Mean IOP lowering medications and IOP reduction after 6 months were 0.17 (P=<.001)) and 17.79 mmHg respectively. Complete success at month 3 was 97.36%, and at the last visit was 88.15%. Postoperative complications within one month were hyphema (n-3), shallow anterior chamber (n-1), wound leak (n-2). All were improved with conservative management gradually. 3 patients developed cataract with in 3 months. Conclusion: Filtration surgery with collagen implantation is a safe and effective treatment to control IOP non responsive to topical antiglaucoma medications. This theoretically improves surgical success over trabeculectomy performed without the adjunctive use of antifibrotic agents. Since published data regarding this implant and its role in trabeculectomy is limited, this study was conducted to find more information about this new material and its effect on trabeculectomy surgery. Methods This is prospective, non randomized, interventional case series that was done in the glaucoma department of Chittagong Eye Infirmary and Training Complex, Bangladesh from January 2010 to july 2012. 6x1 mm circular collagen were used for the implant. CEITC hospital review board approved the study following Helsinki declaration. 76 eyes of 76 patients with the different types of glaucoma not controlled and/or not tolerating the medications requiring trabeculectomy were enrolled. Those patient needing cataract surgery, combined procedure was done (trabreculectomy with collagen implant + implantation of posterior IOL) Informed consent was taken after detail explanation about the implant and operation. No patient lost for follow up. For each patient the following data were collected preoperatively: age, gender, type of glaucoma, BCVA, IOP (as measured the day before surgery) and number of preoperative anti glaucoma

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 56 DOS TIMES medications used. The operative data included date of operation, surgical technique, and presence of any intraoperative complications. Postoperative IOP, number of postoperative glaucoma medications and postoperative complications were also recorded. At each postoperative visit, the examination included measurement of BCVA, IOP measurement, slit-lamp biomicroscopy, assessment of cell and flare, bleb evaluation and funduscopy. Post operatively subjects were examined on day 1, day 7,1,3 & 6 month. In some cases more close follow up were needed. IOP measurement was performed using the Goldmann applanation tonometry. A primary outcome measure was success, as defined by the following criteria: (1) complete success defined as having an IOP of 21 mmHg or less without antiglaucoma medication; and (2) qualified success defined having an IOP of 21 mmHg or less, with antiglaucoma medication. Hypotony was defined as an IOP< 6 mmHg. Flat anterior chamberwas defined as iridocorneal touch or the depth of anterior chamber less than one corneal thickness centrally. Figure 1: A piece of Ologen. Table 1: Percentage Distribution of Age & Gender of operated patients. Table 2: Visual acuity before and after operation. Pre operatively 50% patients (n-38) had poor visual acuity </=3/60, about 22.36 % patients (n-17) had border line visual acuity (6\36-6\60) and 27.63% patients (n-21) presented with good VA. After 1 month 50% of patients had ‘‘good” VA between 6/6-6/18, after 6 month 63.15% (n-48) patients had “good” BCVA (table 2). Male Female Total Age group N % N % N % 11-20 8 10.52 3 3.94 11 14.60 21-30 7 9.21 3 3.94 10 13.51 31-40 12 15.78 5 6.57 17 20.27 41-50 12 15.78 4 5.26 16 20.62 51-60 5 6.57 3 3.94 8 12.16 61+ 12 15.78 2 2.63 14 18.91 Total 56 73.64 20 26.36 76 100 Mean Age 45.03 ±7.5 Visual Acuity Initial VA (Presenting) Affected Eye (Post Operative) 1 month (Post Operative) 3 Months (Post Operative) 6 Months N=76 Percentage N=76 Percentage N=76 Percentage N=76 Percentage 6/6-6/24 21 27.63 38 50.00 46 60.52 48 63.15 6/36-6/60 17 22.36 16 21.05 12 15.78 10 13.15 3/60-NPL 38 50.00 22 28.94 18 23.68 18 23.68 Total 76 100 76 100 76 100 76 100 Surgical Technique Surgeries were done by single surgeons. After peribulbar anesthesia & proper draping, fornix based incision was given around 12’O Clock. Triangular, superficial scleral flap (4x4mm) was produced facing apex towards 12’O clock position. 2x1 mm deep sclerectomy & a peripheral iridectomy was performed thereafter. Scleral flap was closed with a single suture (10/O nylon). Ologen was placed over the apex of the triangular flap beneath the conjunctiva after making the operation area dry. Conjunctiva was closed like a wing with 2 sutures by 10/O nylon. Post operatively all patients were treated with Atropin 1%, 3 times daily for 2 weeks, Moxifloxacin 4 times daily for 1 week & Prednisolone acetate eye drop 6 times daily for 3 weeks then tapered gradually. Statistical analysis was done with windows SPSS. Pre operative & demographic data & IOP comparison were analyzed with students T test. Surgical failure success & complications were analyzed with the χ2 test. With long rank test, Kaplan-Meier survival analysis for surgical success were calculated. P values < 0.05 were taken as statistically significant. Results In this prospective study 76 patients with mean age of 45.03 ±7.5 (range 11-80 years) were enrolled. There were 56 males and 20 females. For the better understanding the results, the total patients (N=76) were categorized into 6 age groups. The most of the patients belonged to three age groups that is (31-40), (41-50) and 60+years groups. The percentage of patient into these groups are 20.27 (n=16), 20.62 (n=16), 18.91 (n=18) respectively.

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 57 DOS TIMES Table 3: Types of glaucoma. Table 4: Pre and postoperative anti glaucoma medication. Table 5: Types of Surgery. Figure 2: Percentage Distribution of Diagnosis of Treated Patient’s. 36.84% patients (n-28) were presented with primary angle closure glaucoma (PACG) Primary open angle glaucoma (POAG) was diagnosed in 16 patients (21.05%). Glaucomatocyclitic crisis was found in 10 patients (13.15%). 8 patients (10.52) presented with Steroid induced glaucoma, 7.89% (n-6) presented with neovascular glaucoma, 7.89% (n-6) with Secondary glaucoma and, 2.63% (n-2) with normal tension glaucoma. (table-3). 38.15% (n-29) patients used 3 medications preoperatively. 2.63% (n-2) used 3 drugs postoperatively. Mean preoperative and postoperative IOP lowering medication were 2.3 (range 2-3) and 0.17 respectively. (table-4) 90.78% (n-69) patients underwent trabeculectomy with collagen implantation. 6.57% (n-5) patients underwent trabeculectomy with collagen implantation and posterior chamber lens implantation. 2 patients underwent re-trabeculectomy with collagen implant. (table-5) Preoperative Postoperative Medications Number Percentage Number Percentage Medication (1) 6 7.89 7 9.21 Medication (2) 41 53.94 Medication (3) 29 38.15 2 2.63 Total 76 100 9 11.84 mean 2.3 0.17 Types of Diagnosis Frequency Percentage PACG 28 36.84 POAG 16 21.05 GCC 10 13.15 Steroid Induced Glaucoma 8 10.52 NVG 6 7.89 Secondary Glaucoma 6 7.89 NTG 2 2.63 Total 76 100 Types of Surgery Frequency Percentage Trab+Collagen 69 90.78 Trab+Collagen+PCL 5 6.57 Retrab+Collagen 2 2.63 Total 76 100 IOP (mmHg) Preoperated IOP Operated Eye 1 month Operated Eye 3 month Operated Eye 6 month Frequency Percentage Frequency Percentage Frequency Percentage Frequency Percentage 0-10 Mean 34.21 ±12.50 28 36.84 Mean 16.71 ±6.38 25 32.89 Mean 13.85 ±5.42 14 18.42 Mean 16.42 ±6.42 11-20 14 18.42 40 52.63 49 64.47 53 69.73 21-30 12 15.78 5 6.57 2 2.63 7 9.21 31-40 23 30.26 1 1.31 0 0 0 0 41-50 09 11.86 2 2.62 0 0 2 2.64 51+ 18 23.68 0 0 0 0 0 0

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 58 DOS TIMES Figure 3: Comparison of IOP at Preoperative & follow up visits. Table 7: Comparison between IOP pre and post operatively in different type of glaucoma Table 8: Post operative complication. Mean pre operated IOP 34.21±12.50 mm of Hg (range 4-58) Mean postoperative IOP was 16.71±6.38 mm of Hg (range 4-48) on month 1, 13.85±5.42 mm Hg (range 4-28) on month 3, 16.42±6.42 mm of Hg (range 4-50) at month 6. Differences of preoperative and postoperative IOP at month 6 was statistically significant (P=0.50) Mean IOP reduction at the end of month 3 and at the last visit were 20.36 mm Hg (59.5%) and 17.79 mm Hg (52%) respectively. (table-6) Postoperative complication includes hyphema in 3 patients, shallow anterior chamber in 1 patient and wound leak in 2 eyes. All 3 occurred with in 1 month. 6.75% (n-5) patients develop cataract with in 3 months. (table-8) Based on our definitions for success, at month 3 complete success was 97.36, qualified success 2.63% at the last visit complete success was 88.15%, Qualified success was 9.21%. 2.64% are failed. (table-9) In PACG Mean pre operated IOP 37.85±13.07 mm of Hg, 18.21±11.76 mm of Hg in month 1, 16.28±10.90 mm of Hg in month 3, 18.07±11.13 mm of Hg in month 6. In steroid induced glaucoma mean pre operated IOP 45.00±13.04 mm of Hg, 20.75±6.40 mm of Hg in month 1, 15.50±4.75 mm of Hg in month 6. In POAG mean pre operated IOP 34.12±8.77, After 6 month 13.62±3.36 mm of Hg. In NVG pre operative IOP 41.3±8.4 mm of Hg, 21.3±20.9 mm of Hg in month 1, After 6 month IOP was 26.6±18.27 mm of Hg. (table-7) Diagnosis Initial Mean IOP Mean & Standard Deviation of IOP 1 Month Mean & Standard Deviation of IOP 3 Months Mean & Standard Deviation of IOP 6 months PACG 37.85± 13.07 18.21± 11.76 16.28± 10.90 18.07± 11.13 GCC 19.40± 2.27 11.80± 2.39 11.20± 2.85 15.20± 7.13 Steriod Induced 45.00± 13.04 20.75± 6.40 15.25± 4.65 15.50± 4.75 POAG 34.12± 8.77 15.25± 3.08 13.75± 3.71 13.62± 3.36 NVG 41.3±8.4 21.3±20.9 21.3±5.16 26.6± 18.27 Diagnosis Initial Mean IOP Mean & Standard Deviation of IOP 1 Month Mean & Standard Deviation of IOP 3 Months Mean & Standard Deviation of IOP 6 months NTG 18 12 16 16 Secondary Glaucoma 36±3.57 16±7.79 14.6±2.00 13.3±2.06 IOP (mmHg) Preoperated IOP Operated Eye 1 month Operated Eye 3 month Operated Eye 6 month Frequency Percentage Frequency Percentage Frequency Percentage Frequency Percentage Total 76 76 100 76 100 76 100 Table 6: Initial IOP operated and Non-operated eye. Mean pre operated IOP 34.21 ±12.50 mm of Hg (range 4-58) Mean postoperative IOP was 16.71±6.38 mm of Hg (range 4-48) on month 1, 13.85 ±5.42 mmHg (range 4-28) on month 3, 16.42±6.42 mm of Hg (range 4-50) at month 6. Differences of preoperative and postoperative IOP at month 6 was statistically significant (P=0.50) Mean IOP reduction at the end of month 3 and at the last visit were 20.36 mm Hg (59.5%) and 17.79 mm Hg (52%) respectively. (table-6) With in 1 month With in 3 months With in 6 months Frequency Percentage Frequency Percentage Frequency Percentage Hyphema 3 4.05 0 0 0 0 Shallow AC 1 1.35 0 0 0 0 Wound leak 2 2.70 0 0 0 0 Cataract 0 0 5 6.75 0 0

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 59 DOS TIMES Figure 4: Implanted Collagen During Filtration Surgery. Discussion Trabeculectomy was introduced by Cairns in 1968 and remains the most common surgical procedure for the treatment of glaucoma. The procedure is supposed to remove a portion of the trabecular meshwork, and using a partial-thickness scleral flap to cover the sclerostomy-a fistula is created between the anterior chamber and the subconjunctival space.[1,7,8] Excessive postoperative scarring causes fibrosis which obstructs the aqueous outflow significantly reducing success of trabeculectomy.[9] Both MMC and 5-FU reduce fibroblast proliferation in the sub conjunctival space as well as in the tenon capsule. So these agents are used to augment the success of trabeculectomy.[10] In 1990, MMC was applied as an anti metabolite during trabeculectomy.[9] According to different studies, the success rate of trabeculectomy with MMC with 3 months to 3 years follow-up has been reported from 62% to 93%.[11-13] This is associated with an increase in adverse effect such as, a vascular blebs, thinning of the conjunctiva, subsequent blebitis and endophthalmitis,[14] Severe hypotony could result in several complications such as choroidal detachment, gradual bleb failure, cataract and corneal oedema,and can be associated with maculopathy and loss of visual acuity[15,16] 5-FU is also associated with corneal epithelial toxicity leading to tearing, discomfort and blurred vision.[6] MMC also may cause cilliary body damage (resulting in hypotony), corneal endothelial cell damage and limbal stem cell deficiency.[17-19] These complications lead to the continued search for alternative intraoperative antiscarring treatment. One of these modalities which has been introduced during the past few years is collagen implant which is a biodegradable collagen glycosaminoglycan matrix (biodegradable within 30-90 days) which occupies subconjunctival space by its volume and guide the fibroblast growth randomly inside the matrix.[20] Our study is a nonrandomized study, so we included all ages of patients of different types of medically uncontrolled glaucoma for trabeculectomy with collagen implant. In our subcontinent primary angle closure glaucoma is the most common (36.84%). In developing country like Bangladesh PACG usually present symptomatically with severe visual loss in one or both eyes or a painful acute attack. In that case non reacting pupil and peripheral anterior synechiae are common findings. Those patient non responding to antiglaucoma medications need trabeculectomy operation. Long term postoperative inflammation, shallow anterior chamber and subsequently failed trabeculectomy, cataract formation are frequently associated with patients of primary angle closure glaucoma. In our study in PACG, after 6 month of collegen implantation, IOP was 18.07±11.13 mm of Hg with no postoperative shallow anterior chamber and no significant postoperative inflammation. Follow up for longer period is necessary. In POAG, steroid induced glaucoma, 6 month after filtration surgery with collagen implantation, IOP was well controlled. Preoperatively 50% patients visited with VA <6/60 and 27.63% with 6/6-6/18. Postoperatively 63.15% patients retain their vision within 6/6-6/18. Blurred vision is due to high IOP which induces corneal edema. 5 patients presented glaucoma with cataract so they underwent trabeculectomy with collagen implant with posterior chamber lens implantation. Dr. P. Sathyan in his retrospective non-randomized and noncomparative study in two different centre of India found success rate of trabeculectomy with collagen implant at the end of 6 months, complete success in Madurai and in Coimbatore were 70% 91.42% respectively. Reduction in antiglaucoma medications 2.68 to 1.26 (52.98%) in Madurai and 2.37 to 1 (57.80%) in Coimbatore.[21] In our study complete success at month 3 was 97.36%, at the month 6 was 88.15%. Reduction in antiglaucoma medications 2.9 to 0.17. Scott et al, account the 1 and 2 years success rate of trabeculectomy with MMC in 68 patients (85.4% and 77.9%, respectively). The mean IOP was reduced from 26.3 to 11.3 mm Hg at 1 year and to 11.9 mm Hg at 2 years.[22] Rosentreter et al found 1 year after surgery 50% reduction of IOP in trabeculectomy with MMC group and 43% reduction in trabeculectomy with ologen group.[23] In our study Mean IOP reduction at the end of month 3 and at the 6 month were 20.36 mm Hg (59.5%) and 17.79 mm Hg (52%) respectively. So these achieved success are also quite near to similar to the success rate of trabeculectomy with MMC done in many countries. To control intraocular pressure in neo vascular glaucoma is challenging. Six patients (7.89%) presented with neovascular glaucoma with 41.3±8.4 preoperative IOP. After 6 month mean IOP was 26.6±18.27 mm of Hg. In 2 patients tabeculectomy with collagen implant becomes failed with 50 intraocular pressures after 6 months of operation. Dimitris Papaconstantinou et all in their trabeculectomy with ologen study showed some complications like hypotony in 1 patient, flat anterior chamber in two patients, hyphaema in 1 eye, encapsulated bleb in 2 eyes by the end of the first postoperative month, and endophthalmitis in one eye. Flat anterior chamber with positive seidel test managed with two additional 10-0 nylon

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 60 DOS TIMES sutures were placed in the conjunctiva on the first postoperative day. 5-FU as adjuvant therapy (5 mg) was injected twice weekly via a needle in the operation site for the management of the encapsulated bleb.[14] But in contrary to their findings we did not encounter to any significant complications. In our study postoperative complication includes shallow anterior chamber in 1 patient and wound leak in 2 patient those were resolved spontaneously after giving subcunjunctival dexamethason injection followed by firm patching with Atropine1% for two days. Hyphema developed in 3 patients at immediate post operative period (1st to 3rd). This is probably due to leaking of blood from the scleral flap angle to the anterior chamber. Five patients developed cataract in which 2 are advised for cataract surgery. In comparison to MMC related complications, we did not find early postoperative complications like hypotony, or choroidal detachment, and also at the last visit no signs of bleb avascularity, blebitis, endophthalmitis or symptoms of bleb dysesthesia was found. We did not detect any collagen specific side effects, such as translocation of the implant or erosion of the conjunctiva. Collagen did not show any allergy to anybody in our study. But biodegradation is slower than the mentioned period of 60-90 days. Even in all eyes of the collagen group the implant degraded partially even at the end of 6 month after filtration surgery. So it seems the use of the collagen implant promises comparable IOP reduction after trabeculectomy and a lower risk profile in comparison with the use of anti-metabolites. Limitations of this study are short duration of follow-up, and the lack of control group of trabeculectomy with other widely accepted antifibrotic agents like MMC. Our study reveals that, trabeculectomy with implanation of an collagen implant is a safe method for penetrating filtration surgery. Conclusion In the country like Bangladesh and India due to lack of awareness, health education as well as low socioeconomic background and remoteness, frequent post operative follow up is a challenge after filtration surgery. So single safe and effective glaucoma surgery is important to combat this situation. Trabeculectomy with implantation of collagen is a new, safe and effective alternative to MMC. It has more safety margin than MMC. Longer duration of follow-up in larger number of patients is needed to observe long term affectivity of the collagen. References 1. Cairns JE (1968): Trabeculectomy. Preliminaryreport of a new method. Am J phthalmol66: 673–679.. 2 Hitchings RA, Grierson I. Clinico pathological correlation in eyes with failed fistulizing surgery. Trans OphthalmolSoc U K 1983;103(Pt 1):84-8. 3. Addicks EM, Quigley HA, Green WR, Robin AL. Histologic characteristics of filtering blebs in glaucomatous eyes. Arch Ophthalmol 1983;101(5):795-8. 4. Novelty design of ologen® Collagen Matrix toimprove surgical success rate without MMCRobert Ritch, M.D.Glaucoma Associates of New York 5. Bell RW, Habib NE & O’Brien C (1997): Long term results and complications after trabeculectomy with a single pre-operative application of 5-fluorouracil. Eye 11: 663–671. 6. Evaluation of SubconjunctivalOculusgen Implantation as an Adjunct to Trabeculectomy NaveedNilforushan, MD1 • Maryam Yadgari, MD2 Khalil GhasemiFalavarjani, MD1 • ArashEhteshamiAfshar, MD3Iranian Journal of Ophthalmology 2010;22(2):55-62 © 2010 by the Iranian Society of Ophthalmology 7. Watson PG (1981): Trabeculectomy. DevOphthalmol1: 61–70. 8. Azuara-Blanco A & Katz LJ (1998): Dysfunctional filtering blebs. Surv Ophthalmol 43: 93–126 9. Chen CW, Huang HT, Bair JS, Lee CC. Trabeculectomy with simultaneous topical application of mitomycin- C in refractory glaucoma. J OculPharmacol 1990;6(3):175-82. 10 Lee DA, Shapourifar-Tehrani S, Kitada S.The effect of 5-fluorouracil and cytarabine on human fibroblasts from Tenon’s capsule. Invest Ophthalmol Vis Sci 1990;31(9):1848-55. 11. Singh K, Egbert PR, Byrd S, et al. Trabeculectomy with intraoperative 5-fluorouracil vsmitomycin C. Am J Ophthalmol 1997;123(1):48-53. 12. Tham CC, Lai JS, Poon AS, et al. Results of trabeculectomy with adjunctive intraoperative Mitomycin C in Chinese patients with glaucoma. Ophthalmic Surg Lasers Imaging 2006;37 (1):33-41. 13. Fontana H, Nouri-Mahdavi K, Lumba J, et al. Trabeculectomy with mitomycin C: outcomes and risk factors for failure in phakic open-angle glaucoma. Ophthalmology 2006;113(6):930 14. Trabeculectomy with OloGen versus trabeculectomy for the treatment of glaucoma: a pilot study Dimitris Papaconstantinou,1 Ilias Georgalas,2 Efthimios Karmiris,1 Andreas Diagourtas,1 Chrysanthi Koutsandrea,1Ioannis Ladas,1 Michalis Apostolopoulos1 and GerasimosGeorgopoulos1 1Department of Ophthalmology, University of Athens, Greece2G.Genimatas Hospital, Athens, Greece. 15. Costa VP, Smith M, Spaeth GL, Gandham S & Markovitz B (1993): Loss of visual acuity after trabeculectomy. Ophthalmology100: 599– 612. 16. Vesti E & Raitta C (1997): A review of the outcome of trabeculectomy in open-angle glaucoma. Ophthalmic Surg Lasers 28:128–13220. 17. Hong SJ, Wu KY, Wang HZ, Lai YH. Toxic effects of mitomycin-C on cultured ciliary process cells and trabecular meshwork cell. J Ocul PharmacolTher 2001;17 (4):331-42. 18. Mietz H, Roters S, Krieglstein GK, Bullous keratopathy as a complication of trabeculectomy with mitomycin –C. Graefes Arch Clin Exp Ophthalmol 2005;243(12):1284-7. 19. Sauder G, Jonas JB, Limbal stem cell deficiency after subconjunctival Mitomycin C injection Wilkins M, Indar A, Wormald R. Intra-operative mitomycin C for glaucoma surgery. Cochrane Database Syst Rev 2005 Issue 4. Art. no.: CD002897. 20. Chen HS, Rich R, Krupin T, et al. Control of filtering bleb structure through tissue bioengineering: An animal model. Invest Ophthalmol Vis Sci 2006;47(12):5310-4. 21. Ologen in trab the Indian experience and practical tips for success Dr. P. Sathyan Chief- Glaucoma Services Aravind Eye Care system in Coimbatore India. Aeon Astron Symposium WOC 2012, Abu Dhabi , United Arab Emirates.

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 61 DOS TIMES 22. Scott IU, Greenfield DS, Schiffman J, et al. Outcomes of primary trabeculectomy with the use of adjunctive mitomycin. Arch Ophthalmol 1998;116:286-91. 23. A prospective randomised trial of trabeculectomy using mitromycin C vs an ologen implant in open angle glaucoma. Rosentreter A, Schild AM, Jordan JF, Krieglstein GK, Dietlein TS. Department of Ophthalmoogy, University of Cologne, Köln, Germany, andre.rosentreter@ googlemail.com, Eye(Lond).2010Sep; 24(9):1449-57. Epub2010 Aug 20. Dr. Shams Mohammed Noman, DCO, FCPS Associate prof Bangabandhu sheikh mujib medical university, Bangladesh Corresponding Author:

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 62 DOS TIMES Istent Inject: An Update on A Novel MIGS Device in India Sahebaan Sethi, MS, DNB, FICO Arunodaya Deseret Eye Hospital, Gurugram. Introduction Glaucoma is a leading cause of irreversible blindness in the world, affecting over 65 million people.[1] The main goal in the management of glaucoma is the control of intraocular pressure (IOP), which is conventionally first attempted by the use of topical medications or laser therapy.[2] However, surgery is often required if these methods fail, to prevent vision loss. But due to the high rate of failure and complications with the traditional glaucoma procedures (e.g., trabeculectomy and glaucoma drainage devices)[3], there is need for safer and more effective glaucoma surgeries. Novel nonpenetrating and bleb-independent approaches, aim to fill this vacuum by offering a safer, less invasive method of IOP reduction associated with significantly reduced rate of complication and shorter recovery time compared to traditional glaucoma surgeries.[4] The iStent inject (Glaukos, Laguna Hills, CA), a newer trabecular microbypass stent, is a second generation of the iStent which is a smaller version of the original model (Figures 1 & 2), called the GTS400 iStent inject. iStent inject consists of two non-ferromagnetic, heparin-coated, l-shaped stents (360 μm x 230 μm) that can be inserted individually into the Trabecular Meshwork (TM) through a stainless steel insertion tube with a handheld injector (Figure 3 & 4). It is the smallest US Food and Drug Administration approved (2018) device to be ever implanted in the human body. It was launched in India only in November 2021. iStent inject is believed to be more effective, safer and has an easier learning curve due to its unique design and absence of the snorkel compared to the first generation iStent. It has a modified injector than enables the surgeon to place 2 iStents through a single entry into the eye (Figure 3 & 4). Being an ab-interno schlemm’s canal surgery, it can easily be implanted alongside phacoemulsification. Bahler et al[5] demonstrated that addition of a second iStent greatly increases the aqueous outflow, done through a laboratory test conducted on human donor eyes. The iStent inject reduces IOP by bypassing the damaged TM and restoring the physiologic mechanism of outflow. The advantage of iStent inject procedure is that it spares the conjunctiva and leaves all future options open if the patient requires a more invasive glaucoma procedure in the future. Unlike other so called MIGS procedures in the market, iStent allows for additional future trabecular procedures as well and has a faster recovery time. Figure 1: iStent inject design features (Pic Courtesy: Glaukos). Figure 3: Injector design (Pic Courtesy: Glaukos). Figure 2: iStent inject design features (Pic Courtesy: Glaukos). Figure 4: Injector distal end (Pic Courtesy: Glaukos).

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 63 DOS TIMES Outcomes of iStent Inject with Cataract Surgery Outcomes of iStent inject was first reported in 2013 by Arriola-Villalobos et al.[6] It was a prospective, uncontrolled, interventional case series in which 20 patients underwent phacoemulsification with implantation of 2 iStent injects. At 1 year follow-up, the mean post-washout reduction in IOP was by 35.7% (9.4 ± 3 mm Hg reduction, Ρ < 0.001). Mean reduction in no. of glaucoma medications was from 1.3 ± 0.6 to 0.3 ± 0.5 (Ρ < 0.001). A total of 75% patients were completely off medications even at the end 1 year with no adverse events. The conclusion was that implantation of 2 iStent inject when combined with cataract surgery seemed to be a safe & effective procedure. Another pivotal prospective, multicenter, randomized control trial of iStent inject combined with phacoemulsification vs phacoemulsification alone, followed through 24-months in 505 subjects showed 75.8% of treatment eyes vs 61.9% of control eyes experienced ≥20% reduction from baseline in unmedicated diurnal IOP (DIOP) (P = 0.005), and mean reduction in unmedicated DIOP from baseline was greater in treatment eyes (7.0±4.0 mm Hg) than in control eyes (5.4±3.7 mm Hg; P < 0.001).[7] The overall safety profile of the treatment group was favorable and similar to that in the control group throughout the 2-year follow-up. Following table summarizes major trials in the past few years and clinical results of combined iStent inject with phacoemulsification with respect to mean reduction in IOP and medications. Surgery Glaucoma Type Follow-Up (Years) IOP Reduction* Medication Reduction** 2 iStent inject+Phaco[8] Any stage OAG 2.0 5.4mm Hg, 26.6% 1.7 2 iStent inject+Phaco in Asian eyes[9] POAG 1.1 1.3±4.2mm Hg 0.6±1.0 2 iStent inject+Phaco in Australian patients[10] POAG 2.0 12.7+-3.8mm Hg, 20.6% 1.3 2 iStent inject+ Phaco[11] POAG, PXG, OHT 1.0 9 mm Hg, 36% 1.0 2 iStent inject+ Phaco[12] OAG 1.0 7 mm Hg, 34% 0.8 2 iStent inject+Phaco[13] POAG, PXG, OHT 5.0 10 mm Hg, 37% 0.1 2 iStent inject+Phaco In Saudi population[14] POAG 2.0 c 1.55,70.6% 2 iStent inject+Phaco[15] POAG 5.0 8.8mm Hg,39% 1.74,69% 2 iStent inject+Phaco[16] NTG 1.0 1.2mm Hg 1.0 2 iStent inject+Phaco[17] Any stage OAG 2.0 0.0 0 2 iStent inject+Phaco[18] Any stage OAG 1.0 2.8mm Hg,17.8% 1.3 2 iStent inject+Phaco[19] Any stage POAG 0.5 4.6mm Hg,26.6% 1.0 Surgery Glaucoma Type Follow-Up (Years) IOP Reduction* Medication Reduction** 2 iStent inject[23] POAG, PXF, ACG 3.0 10.7mm Hg 82% 2 iStent inject[15] POAG 5.0 10.7mm Hg,42% 2.24,75% 2 iStent inject[24] POAG, PG, PXG 1.0 10 mm Hg, 40% 2.0, 72% Outcomes of Standalone iStent Inject In a recent prospective report by Lindstrom et al[20] in 2020, 57 eyes with a mean IOP of 19.5±1.5mm Hg on 1 preoperative medication, underwent standalone iStent inject implants and showed a 46% reduction in IOP from baseline at month 48 without medication. In another recent report by Berdahl et al[21], 53 eyes having an unmedicated IOP of 24.9+-1.1 had a mean IOP of <=13mm Hg with one prostaglandin analogue at 60 months follow up. In a study by Anja-Maria Davis[22], role of iStent inject has been described in advanced glaucoma with uncontrolled IOP after failed trabeculectomy. Significant IOP decrease to 15.5±3.4 from 22.5±4.6 mm Hg was found after 1 year follow-up. Anti-glaucoma medications, however, needed to be maintained to achieve target pressures and to prevent glaucoma progression. Additionally, a failure rate of 27.3% makes it necessary to carefully select patients for this treatment option. No significant intraoperative or postoperative complications were reported.[22] Following table summarizes results of recent trials studying clinical outcomes of standalone iStent inject implantation in mild to moderate glaucoma patients.

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 64 DOS TIMES Surgery Glaucoma Type Follow-Up (Years) IOP Reduction* Medication Reduction** 2 iStent inject[25] OAG 1.0 12 mm Hg, 48% 1.0, 93% 2 iStent inject[26] POAG, PXG, PG 0.5 7 mm Hg, 33% 8.42 mm Hg, 35% 1.3 2 iStent inject[27] OAG 1.5 10 mm Hg, 41% 1.0 2 iStent inject[28] OAG 1.5 12 mm Hg, 48% 1.0 Comparison With Other MIGS Devices The efficacy of the first and second generation iStent implants have been compared with older and newer types of MIGS. In a retrospective review by Dorairaj et al[29], the Kahook Dual Blade® (KDB) with cataract surgery appears to offer an additional 1.5 mmHg of IOP-lowering versus the iStent implant with cataract surgery (phaco/iStent) However, in a smaller study by Lee et al., IOP-lowering effect appeared to be equal, although medication burden was reduced more in the KDB group (43.2% used ≥1 medication less in the KDB group compared to 17.2% in the iStent group).[29,30] When we compare iStent inject to Hydrus as standalone procedures, Hydrus® was found to be more effective than the iStent inject according to the COMPARE study.[31] In this study, eyes were prospectively randomized to Hydrus or to the iStent inject. At 12 months, the mean IOP decreased significantly more from the screening and baseline IOP in the Hydrus group.[31] Trabectome too has been compared to the iStent inject®, both combined with cataract surgery. One study found that in eyes with all stages and types of glaucoma, phaco/ Trabectome lowered IOP by 22.7%, which was maintained for 2 years, whereas the IOP reduction from iStent inject with cataract surgery (phaco/iStent inject) began to fade off at 6 months and became non-significant at 2 years.[17] Despite phaco/Trabectome’s IOP-lowering effect, the mean medication reduction between phaco/Trabectome and phaco/iStent inject was not statistically different.[17] Indications The indications for iStent inject is traditionally mild to moderate primary open angle glaucoma, pseudoexfoliation or pigmentary glaucoma whose medicated IOP is ≤ 30mm Hg. It’s role in advanced glaucoma or secondary open angle glaucoma, except steroid induced glaucoma is limited. It is not licensed to be used in angle closure glaucoma. And especially in presence of peripheral anterior synechiae, rubeosis or any other angle anomaly that could impair proper placement of iStent, it should be avoided. It can be used as a solo procedure in phakic or pseudophakic patients or can be combined with phacoemulsification. With a potential to reduce the burden of anti-glaucoma medications, it offers great advantage to patients who have difficulty in taking medications, have side-effects or compliance issues. Surgical Implantation Technique Paramount to any MIGS procedure is to optimize visualization at the outset. Microscope is tilted towards the surgeon by 35⁰- 45⁰ (Figure 5). Patient head is turned away from the surgeon by 35⁰-40⁰ (Figure 6). It’s important to maintain scope sterility while adjusting the oculars. Seat or table adjustments to be made according to the surgeon’s comfort. The technique of placement of the iStent inject is briefly described here. After instilling topical or local anesthesia, a temporal incision of 1.7-2.2mm is fashioned. This incision is to be slightly anterior to limbus so as to be clear corneal. The anterior chamber is then filled with cohesive viscoelastic. The iStent inserter is guided through the incision and the iStent implant is placed through the trabecular meshwork into the nasal portion of Schlemm’s canal. Correct placement of the stent is to be confirmed intraoperatively with a gonioprism. A second stent is inserted using similar technique approximately 2-3 clock-hours away from the first stent (Figure 7). Postoperatively, antibiotics are prescribed for 1 week and steroids are to be tapered over 2-3 weeks. 350 -450 Figure 5: Angulation of the microscope towards the surgeon.

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 65 DOS TIMES Figure 6: Angulating the patient’s head away from surgeon. Figure 7: iStent inject placement (Pic Courtesy: Glaukos). Safety Profile Studies have determined that iStent inject implantation is as safe as cataract surgery alone.[7] The most common adverse effects reported include stent obstruction (6.2%–13.2%) with peripheral anterior synechiae, intraocular pressure spike (5.2%– 11%), posterior capsular opacification (5.2%–11%), corneal edema (10%), rebound iritis (6%), postoperative inflammation (5.7%), mild hyphema (3.9%-5%), and vision deterioration (1%–1.3%).[7,18,31] With respect to postoperative hyphema, none of the studies reported hyphema occupying more than 10% of the anterior chamber. According to a study, between 1.6% and 5.1% of the patients required additional glaucoma surgery to control IOP.[19] No hypotony has been reported yet, as the natural episcleral back pressure of 8 to 11 mm Hg minimizes the risk.[32,33] By minimizing or removing the need for anti-glaucoma medications (AGM), iStent inject has been studied to save the patient from the deleterious effects of AGM on the ocular surface. In a prospective, multicenter trial mean OSDI score of patients who underwent iStent implanation was evaluated 3 months postoperatively and was observed to reduce from 40.1 to 17.5 (p<0.0001).[34] The study concluded that the protective effect of iStent inject to the ocular surface, by reducing burden of anti-glaucoma medications, is an additional factor to consider in benefit-to-risk ratio. Cost-Effectiveness Cost utility of iStent inject + Cataract surgery has been studied compared to cataract surgery alone with the use of anti-glaucoma medications. iStent inject with phacoemulsification had an 86% chance of being cost effective at willingness to pay threshold of €30,000 per quality adjusted life years (QALY) gained, in a study done in France.[35] In another probabilistic base case analysis[36], iStent inject® with cataract surgery was found to be cost-effective compared with cataract surgery alone over a lifetime horizon when using willingness-to-pay threshold of ¥5 000 000 per QALY. iStent inject® with cataract surgery compared to cataract surgery alone was found to increase costs (¥1 025 785 vs ¥933 759, respectively) but was more effective in increasing QALYs (12.80 vs 12.74) and avoiding blindness (0.133 vs 0.141). The differences in costs were mainly driven by costs of primary surgery (¥279 903 vs ¥121 349). The authors concluded that iStent inject® with cataract surgery is a cost-effective strategy over cataract surgery alone from the public payer’s perspective and cost-saving from the societal perspective in patients with mild-to-moderate POAG in Japan.[36] Conclusion iStent inject device implantation at the time of phacoemulsification is a safe and effective method to reduce IOP and antiglaucoma medication burden in patients with mild-to-moderate POAG and cataract. It has no vision-threatening complications and boasts of excellent safety profile, similar to cataract surgery alone. References 1. Y.-C. Tham, X. Li, T. Y. Wong, H. A. Quigley, T. Aung, and C. -Y. Cheng, “Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and metaanalysis,” Ophthalmology, vol. 121, no. 11, pp. 2081–2090. 2. D. C. Musch, B. W. Gillespie, L. M. Niziol, L. F. Cashwell, and P. R. Lichter, “Collaborative Initial Glaucoma Treatment Study G. Factors associated with intraocular pressure before and during 9 years of treatment in the Collaborative Initial Glaucoma Treatment Study,” Ophthalmology, vol. 115, no. 6, pp.927–933, 2008. 3. S. J. Gedde, L. W. Herndon, J. D. Brandt, D. L. Budenz, W. J. Feuer, and J. C. Schiffman, “Surgical complications in the Tube Versus Trabeculectomy study during the first year of follow-up,” American Journal of Ophthalmology, vol. 143, no. 1, pp. 23–31.e2, 2007. 4. H. Saheb and I. I. K. Ahmed, “Micro-invasive glaucoma surgery: current perspectives and future directions,” Current Opinion in Ophthalmology, vol. 23, no. 2, pp. 96–104, 2012. 5. C. K. Bahler, C. R. Hann, T. Fjield, D. Haffner, H. Heitzmann, and M. P. Fautsch, “Second-generation trabecular meshwork bypass stent (iStent inject) increases outflow facility in cultured human anterior segments,” American Journal of Ophthalmology, vol. 153, no. 6, pp. 1206–1213, 2012. 6. Arriola-Villalobos P, Martínez-de-la-Casa JM, Díaz-Valle D, GarcíaVidal SE, Fernández-Pérez C, García-Sánchez J, García-Feijoó J. Mid-term evaluation of the new Glaukos iStent with phacoemulsification in coexistent open-angle glaucoma or ocular hypertension and cataract. Br J Ophthalmol. 2013 Oct;97(10):1250-5. 7. Samuelson TW, Sarkisian SR, Lubeck DM, et al. Prospective, ran-

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 66 DOS TIMES domized, controlled pivotal trial of an ab interno implanted trabecular micro-bypass in primary open-angle glaucoma and cataract. Ophthalmology. Jun 2019;126(6):811-821. 8. Neuhann R, Neuhann T. Second-generation trabecular micro-bypass stent implantation: retrospective analysis after 12- and 24-month follow-up. Eye and Vision. 2020;7(1):1. 9. Hu YW J, Ang CH B, Tecson IOC, Kan Tsia-Chuen J, Yip WL L. Combined phacoemulsification and iStent inject implantation in Asian eyes. European Journal of Ophthalmology. 2022;32(1):288-295. 10. Salby AM, Skalicky SE. Combined iStent® Inject Trabecular Micro-Bypass and Phacoemulsification in Australian Patients with Open-Angle Glaucoma. Clin Ophthalmol. 2020;14:985-993 11. P. Arriola-Villalobos, J. M. Mart´ınez-de-la-Casa, D. D´ıaz-Valle et al., “Mid-term evaluation of the new Glaukos iStent with phacoemulsification in coexistent open-angle glaucoma or ocular hypertension and cataract,” British Journal of Ophthalmology, vol. 97, no. 10, pp. 1250–1255, 2013. 12. Johannes Gonnermann1 & Eckart Bertelmann1 & Milena Pahlitzsch1 & Anna-Karina B. Maier-Wenzel 1 & Necip Torun1 & Matthias K. J. Klamann1; Contralateral eye comparison study in MICS & MIGS: Trabectome® vs. iStent inject®; Graefes Arch Clin Exp Ophthalmol (2017) 255:359–365. 13. Arriola-Villalobos P, Martinez-de-la-Casa JM, Diaz-Valle D, Morales-Fernandez L, Fernandez-Perez C, Garcia-Feijoo J. Glaukos iStent inject® Trabecular Micro-Bypass Implantation Associated with Cataract Surgery in Patients with Coexisting Cataract and Open-Angle Glaucoma or Ocular Hypertension: A Long-Term Study. J Ophthalmol. 2016;2016:1056573. 14. Al Habash A, Otaif W. Surgical Outcomes of Combined 2nd-Generation Trabecular Microbypass (iStent Inject) and Cataract Surgery for the Treatment of Primary Open-Angle Glaucoma in the Saudi Population. Ophthalmol Ther. 2021 Dec;10(4):923-933. 15. Hengerer FH, Auffarth GU, Conrad-Hengerer I. iStent inject Trabecular Micro-Bypass with or Without Cataract Surgery Yields Sustained 5-Year Glaucoma Control. Advances in Therapy. 2022 Mar;39(3):1417-1431. 16. Ang, B.C.H., Chiew, W., Yip, V.C.H. et al. Prospective 12-month outcomes of combined iStent inject implantation and phacoemulsification in Asian eyes with normal tension glaucoma. Eye and Vis 9, 27 (2022). 17. Yousef AY, Strzalkowska A, Hillenkamp J, Rosentreter A, Loewen NA. Comparison of a second-generation trabecular bypass (iStent inject) to ab interno trabeculectomy (Trabectome) by exact matching. Graefe’s Archive for Clinical and Experimental Ophthalmology. Arch Clin Exp Ophthalmol. 2020;258(12):2775–2780. 18. Salimi A, Lapointe J, One-Year HP. Outcomes of second-generation trabecular micro-bypass stents (iStent Inject) implantation with cataract surgery in different Glaucoma subtypes and severities. Ophthalmol Ther. 2019;8(4):563–575. 19. Guedes RAP, Gravina DM, Lake JC, Guedes VMP, Chaoubah A. Intermediate results of iStent or iStent inject implantation combined with cataract surgery in a real-world setting: a longitudinal retrospective study. Ophthalmol Ther. 2019;8(1):87–100. 20. Lindstrom, Richard, et al. “Four-year outcomes of two second-generation trabecular micro-bypass stents in patients with open-angle glaucoma on one medication.” Clinical Ophthalmology (Auckland, NZ) 14 (2020): 71. 21. Berdahl, John, et al. “iStent inject trabecular micro‐bypass stents with topical prostaglandin as standalone treatment for open‐angle glaucoma: 4‐year outcomes.” Clinical & experimental ophthalmology 48.6 (2020): 767-774. 22. Anja-Maria Davids, Milena Pahlitzsch, Alexander Boeker et al, iStent inject as a reasonable alternative procedure following failed trabeculectomy? ;Eur J Ophthalmol2018 Nov;28(6):735-740. 23. Hengerer, Fritz H., et al. “Second-generation trabecular micro-bypass stents as standalone treatment for glaucoma: a 36-month prospective study.” Advances in therapy 36.7 (2019): 1606-1617. 24. Voskanyan L, García-Feijoó J, Belda JI, Fea A, Jünemann A, Baudouin C; Synergy Study Group. Prospective, unmasked evaluation of the iStent® inject system for open-angle glaucoma: synergy trial. Adv Ther. 2014 Feb;31(2):189-201. 25. Fea AM, Belda JI, Rękas M, Jünemann A, Chang L, Pablo L, Voskanyan L, Katz LJ. Prospective unmasked randomized evaluation of the iStent inject (®) versus two ocular hypotensive agents in patients with primary open-angle glaucoma. Clin Ophthalmol. 2014 May 7;8:875-82. 26. Klamann MK, Gonnermann J, Pahlitzsch M, Maier AK, Joussen AM, Torun N, Bertelmann E. iStent inject in phakic open angle glaucoma. Graefes Arch Clin Exp Ophthalmol. 2015 Jun;253(6):941-7. 27. Lindstrom R, Lewis R, Hornbeak DM, Voskanyan L, Giamporcaro JE, Hovanesian J, Sarkisian S. Outcomes Following Implantation of Two Second-Generation Trabecular Micro-Bypass Stents in Patients with Open-Angle Glaucoma on One Medication: 18-Month Follow-Up. Adv Ther. 2016. 28. John Berdahl MD, Lilit Voskanyan MD PhD, Jonathan S Myers MD, Dana M Hornbeak MD MPH, Jane Ellen Giamporcaro MS, L Jay Katz MD and Thomas W Samuelson MD; Implantation of two second-generation trabecular micro-bypass stents and topical travoprost in openangle glaucoma not controlled on two preoperative medications: 18-month follow-up; Clinical and Experimental Ophthalmology 2017; 45: 797–802. 29. Dorairaj SK, Kahook MY, Williamson BK, Seibold LK, ElMallah MK, Singh IP. A multicenter retrospective comparison of goniotomy versus trabecular bypass device implantation in glaucoma patients undergoing cataract extraction. Clin Ophthalmol. 2018;12:791–797. 30. Lee D, King J, Thomsen S, Hirabayashi M, Comparison AJ. Of surgical outcomes between excisional goniotomy using the Kahook Dual Blade and iStent Trabecular micro-bypass stent in combination with phacoemulsification. Clin Ophthalmol. 2019;13:2097–2102. 31. Ahmed IIK, Fea A, Au L, et al. A prospective randomized trial comparing Hydrus and iStent microinvasive glaucoma surgery implants for standalone treatment of open-angle glaucoma: the COMPARE study. Ophthalmology. 2020;127(1):52–56. 32. Outflow resistance of enucleated human eyes at two different perfusion pressures and different extents of trabeculotomy. Curr Eye Res 1989;8:1233-40. 33. Samuelson TW, Katz LJ, Wells JM, Duh Y-J, Giamporcaro JE. Randomized evaluation of the trabecular micro-bypass stent with phacoemulsification in patients with glaucoma and cataract. Ophthalmology 2011;118:459-467. 34. Schweitzer JA, Hauser WH, Ibach M, et al. Prospective Interventional Cohort Study of Ocular Surface Disease Changes in Eyes After Trabecular Micro-Bypass Stent(s) Implantation (iStent or iStent inject) with Phacoemulsification. Ophthalmol Ther. 2020 Dec;9(4):941-953.

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 67 DOS TIMES 35. Nieland, Kaspar, et al. “A cost-effectiveness analysis of iStent inject combined with phacoemulsification cataract surgery in patients with mild-to-moderate open-angle glaucoma in France.” PLoS One 16.6 (2021): e0252130. 36. Igarashi, Ataru & Shoji, Nobuyuki & Chu, Alice & Falvey, Heather & Han, Ru & Ueyama, Maki & Onishi, Yoshie. (2022). iStent inject® and cataract surgery for mild-to-moderate primary open angle glaucoma in Japan: a cost-utility analysis. International Journal of Ophthalmology. 15. 954-961. 10.18240/ijo.2022.06.13. Dr. Sahebaan Sethi, MS, DNB, FICO Arunodaya Deseret Eye Hospital, Gurugram. Corresponding Author:

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 68 DOS TIMES Landmark Trials in Glaucoma Shivani Joshi, MBBS, Chandradevi Shanmugam, MD, Dewang Angmo, MD, DNB, FRCS, FICO, MNAMS Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India. Clinical trials are helpful in comparing the benefits and risks of new eye disease treatments. For the past few decades, there has been a greater revolution in the treatment modality for glaucoma with the availability of new advent investigative modalities and treatment options. These landmark randomized studies have greatly deepened knowledge of the disease. The following review will highlight the key findings of the medical trials in glaucoma and the impact on their clinical practice. Treatment vs no treatment trial Trial of specific drug Trial of medical vs surgical OHTS 1&2 EGPS CIGTS EMGT LoGTS AGIS CNTGS ROCKET I and II MERCURY 1 Results Medication group Observation group IOP control 22.5% 4% POAG (in 5 years) 4.4% 9.5% Results Early treatment Delayed treatment Incidence of POAG 16% 19% Time to develop POAG 6 years 7 years Structural & functional damage 5% 8% Ocular Hypertension Treatment Study 1 (OHTS)[1] Aim: • To determine if early treatment of people with topical glaucoma medications who have ocular hypertension (OHT) that is increased intraocular pressure (IOP) without any visual field changes, would prevent or delay them from developing Primary Open-Angle Glaucoma (POAG). • To determine the risk factors for developing POAG among ocular hypertensive subjects. Methodology: • It is a Prospective multicentred randomized clinical trial enrolling 1636 patients with 5 year follow up. • Patients with OHT with no glaucomatous field changes were randomized into two groups of which one group received topical glaucoma medications whereas the other group was the control group. • The medical therapy was initiated so that there was a reduction of IOP of 20% from baseline to achieve a target IOP of 24mmHg or less. • The patients were followed up every 6 months during which full ophthalmic evaluation, visual field testing, IOP measurement and disc photographs were taken. • The diagnosis of glaucoma was made when the patient developed a reproducible visual field defect or a reproducible deterioration in the appearance of the optic disc. Inclusion Criteria: • Patients with age between 40 to 80 years who has IOP of 24mmHg to 3mmHg in one eye and 21mmHg to 32mmHg in the contralateral eye were included. • The patients should have normal visual fields and normal optic disc. Exclusion Criteria: • Patients who had previous intraocular surgeries, with visual acuity <20/40 in either eye or diseases which cause visual field defect other than glaucoma were excluded from the study. Outcome Measures: • Development of reproducible visual field abnormality or disc deterioration attributed to POAG. • Risk factors found were old age, higher IOP, decreased CCT, larger vertical and horizontal cup-disc ratio, greater pattern standard deviation in the visual fields, African American race. Conclusion: • Early initiation of treatment has lead to decreased progression to POAG in patients with OHT. Ocular Hypertension Treatment Study 2 Aim: • This study was the continuation of OHTS phase 1. The aim of this study was to study the efficacy and safety of early versus late treatment initiation in preventing the progression to POAG. Methodology: • The study protocol was the same except the medication was initiated in the observation group and termed as delayed treatment group. Results:

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 69 DOS TIMES Results Early treatment Delayed treatment B/L disease 4% 6% Conclusions and relevance in practice: • Early medical treatment reduces the cumulative incidence of POAG. • The absolute effect is greatest in high risk individuals. • There are safe and effective treatment options for most ocular hypertensive patients. Early Manifest Glaucoma Trial (EMGT)[2] Aim: • To compare the effect of immediate therapy to lower the IOP versus late or no treatment on the progression of newly detected open-angle glaucoma. • To determine extent of IOP reduction attained by treatment, to explore factors that may influence glaucoma progression, and to describe the natural history of newly detected glaucoma. Methodology: • The study enrolled 255 patients who were randomized into either early intervention group, where 360 degree trabeculoplasty ha been done and they received betaxolol eye drop 5mg/ml whereas the control group did not undergo any intervention. In the treatment group if the IOP is >25mmHg or in the control group if the IOP is >35mmHg, then Latanoprost (Xalatan) eye drop was started. Inclusion Criteria: • Patients between age group of 50 to 80 years with early POAG, Normal Tension Glaucoma (NTG) and Pseudoexfoliation glaucoma with reproducible visual field changes were included in the study. Exclusion Criteria: • Patients with vision <20/40 in atleast one eye, with advanced field defects, not able to get good disc photographs or reliable visual fields, cataractous lens, mean IOP >30mmHg or any IOP >35mmHg were excluded. Follow up: • All the patients underwent two baseline investigation of IOP, visual field, disc photographs and slit lamp examination. The patients were followed up every 3 months for visual field and other investigations and every 6 monthly for disc photographs. Outcome Measures: • Perimetric progression was defined by sustained increase of visual field loss in three consecutive 30-2 Humphrey visual field test as determined from computer-based analyses,. • Optic disc progression as determined from flicker chronography and side-by-side comparisons of fundus photographs performed by masked, independent evaluators. Results: • The treatment group maintained a 25% reduction in the IOP throughout the study whereas there was no significant change in the IOP in the control group. • Progression after 6 years o Treatment group- 45% and occurred at 66 months o Control- 62% and occurred at 48 months • High risk of progression was found to be associated with old age, higher baseline IOP, pseudoexfoliation syndrome (PEX), bilateral disease and more advanced baseline visual field changes. Conclusion and relevance in practice: • Risk of progression decreased 10% with each 1mmHg IOP reduction from baseline. Thin central corneal thickness was a risk factor in POAG (IOP>21mmHg). Low blood pressure was a risk factor in normal tension glaucoma (IOP<21mmHg). Collaborative Normal Tension Glaucoma Study (CNTGS)[3] Aim: • To evaluate the role of IOP control in preventing the progression among Normal Tension Glaucoma patients. Methodology: • It is a prospective multicentred randomized study which included 145 eyes of which 5 withdrew before achieving the IOP lowering goal. It included patients with either unilateral or bilateral NTG with optic disc changes and visual field abnormality, with IOP less than or equal to 20mmHg. • The patients were then randomized into either observation group or treatment group. • In observation group one eye was just followed up till there was a progression of glaucoma whereas the other eye could receive medications except carbonic anhydrase inhibitors. • In treatment group the patients underwent interventions like medications, laser trabeculoplasty or trabeculectomy to reduce the IOP by 30%. • The patients were followed up 3 monthly during the first year and 6 monthly thereafter for 5-7 years. Outcome Measures: To evaluate visual field progression and optic disc changes. Results: • At the end of 5 years follow up, there was 80% progression free survival in the treatment group whereas 40% in the control group. • In the treated group the visual field progression was 18% whereas it is 30% in the untreated group. 35% of the control eyes and 12% of the treated eyes reached end points ( which were specifically defined criteria of glaucomatous optic disc progression or visual field loss).

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 70 DOS TIMES • Risk factors for progression were found to be female gender, migraine, disc hemorrhage at presentation and probably racial and genetic predisposition. Conclusion and relevance to clinical practice: • The beneficial effect of IOP reduction on progression of visual change in NTG was only found when the impact of cataracts on visual field progression was removed. The rate of progression without treatment is highly variable. There are factors independent from IOP leading to progression in NTG. European Glaucoma Preventing Study (EGPS)[4] Aim: • To evaluate the efficacy of reduction of IOP by dorzolamide in preventing or delaying POAG in patients affected by ocular hypertension (OHT). • To study the natural history of OHT and the risk factors involved in the conversion to POAG. Methodology: • It was a multicentric double masked placebo controlled randomized trial. The patients were randomized into either study group with Dorzolamide therapy or into the control group where placebo was given. The patients were followed up every 6 monthly upto 5 years. Inclusion Criteria: • It included patients between 30 to 80 years with Intraocular pressure (IOP) between 22 and 29mmHg in atleast one eye, with no prior treatment, with open angles on gonioscopy and two normal visual fields and norma optic discs. Exclusion Criteria: • The patients with visual acuity <20/40 in either of the eyes and those with previous intraocular surgery or co-existing ocular comorbidities were excluded from the study. Outcomes: • The outcome measures were number of patients who progressed to POAG which included either visual field or optic disc changes or both. The safety end point was an IOP of more than 35 mmHg on 2 consecutive examinations. Results: • The mean IOP reduction and the percentage reduction in the IOP was significantly higher in the Dorzolamide group. • Probability of developing POAG was 13.4% in the Dorzolamide group versus 14.1% in the control group which was not statistically significant. Conclusions and relevance to clinical practice: • The study failed to prove any protective role of Dorzolamide medical therapy in the conversion of OHT patients with moderate risk to POAG at 5 years of follow up. Low-Tension Glaucoma Treatment Study (LoGTS)[5] Aim: • To evaluate the visual field stability in low-pressure glaucoma patients randomized to intraocular pressure reduction in both eyes with topical twice daily brimonidine tartrate 0.2% versus twice-daily timolol maleate 0.5%. • To test if topical brimonidine in NTG has a neuroprotective benefit, comparing to timolol which has similar IOPlowering effect. Methodology: • It is multicentred, double masked randomized clinical trial. The patients were randomized into either Brimonidine monotherapy or Timolol monotherapy. The patients were followed up with 24-2 Humphery full threshold perimetry, tonometry every 4 months and annual optic disc photography. Inclusion Criteria: • Low-pressure glaucoma patients with 30 years of age or older were included in the study. Exclusion Criteria: • Patients with untreated IOP of 21mmHg or more, advanced visual field loss were excluded from the study. Outcome Measures: • To measure the progression of visual field loss. Results: • 27.9% had unilateral field loss. Visual field mean deviation for all eyes was -5.4+/-4.7 decibels. Disc haemorrhage was present at baseline in 29 patients (32 eyes) Conclusion and relevance to clinical practice: • Brimonidine and Timolol lower the IOP to a similar level in NTG. • Brimonidine has a higher risk of ocular allergy, systemic adverse events and non-compliance compared with timolol. • Brimonidine may reduce visual field progression in NTG compared to timolol. ROCKET TRIAL - Rho Kinase Elevated IOP Treatment Trial 1 and 2 (ROCKET-1 and ROCKET-2)[6] Aim: • To evaluate the efficacy and ocular and systemic safety of Netarsudil 0.02% ophthalmic solution, a rho-kinase inhibitor and norepinephrine transporter inhibitor, in patients with open-angle glaucoma and ocular hypertension. Study Design: • In ROCKET-1 trial patients were randomized to receive either Netarsudil 0.02% once daily (OD) or Timolol 0.5% twice a day(BD). Whereas in ROCKET-2 trial, patients were randomized into either Netarsudil 0.02% BD group or Timolol 0.5% BD group. Results: • Netarsudil 0.02% OD and Netarsudil 0.02% BD was noninferior to Timolol 0.5% BD. The most frequent adverse event was conjunctival hyperemia.

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 71 DOS TIMES Conclusion and relevance to clinical practice: • Once-daily dosing of Netarsudil 0.02% was found to be effective and well tolerated for the treatment of patients with ocular hypertension and open-angle glaucoma. MERCURY Trial[7] Aim: • To compare the ocular hypotensive efficacy and safety of a fixed-dose combination (FDC) of the Rho kinase inhibitor netarsudil and latanoprost vs monotherapy with netarsudil or latanoprost Methodology: • It is a randomized, double-masked clinical trial which included adults with open-angle glaucoma or ocular hypertension (unmedicated intraocular pressure >20 and <36 mm Hg ) The patients were randomized to receive once-daily Netarsudil/Latanoprost FDC, netarsudil 0.02%, or latanoprost 0.005% for up to 12 months. The primary efficacy endpoint was mean IOP at 8:00 AM, 10:00 AM, and 4:00 PM at 2nd week, 6th week and at 3rd month respectively. Conclusion: • Patients who receive once-daily Netarsudil/Latanoprost FDC demonstrated superior IOP reductions to Netarsudil and Latanoprost with acceptable ocular safety. Collaborative Initial Glaucoma Treatment Study (CIGTS)[8] Aim: • Determine if glaucoma is better treated by initial medical therapy or filtration surgery Methodology: • A total of 607 patients with newly diagnosed open angle glaucoma were randomised to either medication group or trabeculectomy (with or without 5-fluorouracil). • In medication group the patients received medical therapy in a step ladder pattern, more medications were added if the IOP did not reach the target, argon laser trabeculoplasty and finally trabeculectomy. • In trabeculectomy group initial trabeculectomy was done and if there was a failure, they underwent argon laser trabeculoplasy and finally started on medications. • The patients were followed up at 3rd and 6th month and then subsequently every 6 monthly. If patients have undergone trabeculectomy, their follow up was done on day 1, week 1 and 1 month. In all visits, examination like IOP, slit lamp evaluation and visual field evaluation was done. Inclusion Criteria: • The study included newly diagnosed cases of primary open angle glaucoma, pseudoexfoliation glaucoma and pigmentary glaucoma with IOP of more than 20 mmHg with 3 contiguous points abnormal with p <2% in 24-2 Humphrey visual field analysis with GHT outside normal limits with disc changes, or IOP between 20 and 26mmHg with 2 contiguous abnormal points with p <2% and disc changes or IOP >27mmHg with optic disc changes. Exclusion Criteria: • Patients with use of glaucoma medications for more than 14 days and if less than 14 days then if they had a history of use within 3 weeks of randomization. • Patients with other disorders which could cause a visual field or disc changes and CIGTS visual field score of more than 16 in either eye were excluded from the study. Outcome Measures • The primary outcome measured was the worsening of the visual field in terms of worsening of the visual field score. • The secondary outcome was IOP, visual acuity and healthrelated quality of life. Results: • Though both groups had a significant lowering of IOP from the baseline, there was significant lowering of IOP in the surgical group compared to medication group. • The visual field score was maintained in the surgery group. The visual field score improved initially in the medication group but later became comparable to the surgery group. There was initial worsening in the surgery group which partly was due to the development of cataract. The percentage of patients with significant visual field loss was similar in both groups. • Patients in the surgery group suffered a 3-letter vision loss after the intervention. At the 5 years follow up, more percentage of patients in the surgical group had 15 letters or more reduction in the visual acuity compared to the medication group (3.9% vs 7.2%). • Cataract formation increased after trabeculectomy. 17.3% of them developed a cataract in the surgery group, whereas 6.2% in the medication group developed a cataract. Conclusion and relevance to clinical practice: • IOP reduction was greater with surgery than with medical therapy but the quality of life is worse with surgical group. Trabeculectomy was associated with cataract formation and worsening of visual acuity. Advanced Glaucoma Intervention Study (AGIS)[9] Aim: • To determine if advanced, medically uncontrolled open angle glaucoma is better treated by initial argon laser trabeculoplasty or trabeculectomy. Methodology: • It was a prospective randomized control trial in which 591 patients (789 eyes) were randomized into two groups. • One group underwent trabeculectomy first followed by Argon laser trabeculoplasty and if there was a failure would undergo a second trabeculectomy (TAT group). • The second group underwent the Argon laser trabeculoplasty,

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 72 DOS TIMES then a trabeculectomy and finally another trabeculectomy if there was a failure (ATT group). Antifibrotics was used only in eyes with previous surgery. • Patients were followed up at week 1, week 4, 3rd month, 6th month and then every 6 monthly for 5 years. Patients with open angle glaucoma with IOP not controlled with medications were recruited in the study. Inclusion Criteria: • Patients with open angle glaucoma with uncontrolled IOP and between age group of 35 to 80 years were included in the study. Outcomes: • The primary outcome seen was the reduction in the vision, which can be either the visual acuity or a significant reduction in the visual field. • The secondary outcomes were failure of treatment, number of glaucoma medications used, IOP and time to treatment failure. Results: • In both black and white patients throughout 7-year followup, the mean decrease in intraocular pressure was greater in eyes assigned to TAT, and the cumulative probability of failure of the first intervention was greater in eyes assigned to ATT. • The factors associated with the failure of ALT included higher baseline IOP and younger age group whereas the factors associated with failure of trabeculectomy was younger age, diabetes mellitus, higher baseline IOP and postoperative complication like severe inflammation and high IOP. Conclusion and relevance to clinical practice: • The ATT sequence was better for blacks whereas the TAT sequence was better for Caucasians. References 1. Gordon MO, Beiser JA, Brandt JD, Heuer DK, Higginbotham EJ, Johnson CA, et al. The Ocular Hypertension Treatment Study: Baseline Factors That Predict the Onset of Primary Open-Angle Glaucoma. Arch Ophthalmol. 2002 Jun 1;120(6):714–20. 2. Leske MC, Heijl A, Hyman L, Bengtsson B. Early manifest glaucoma trial: Design and baseline data. Ophthalmology. 1999 Nov 1;106(11):2144–53. 3. Anderson DR. Collaborative Normal Tension Glaucoma Study. Curr Opin Ophthalmol. 2003 Apr;14(2):86–90. 4. Results of the European Glaucoma Prevention Study. Ophthalmology. 2005 Mar 1;112(3):366–75. 5. Krupin T, Liebmann JM, Greenfield DS, Rosenberg LF, Ritch R, Yang JW. The Low-pressure Glaucoma Treatment Study (LoGTS): Study design and baseline characteristics of enrolled patients. Ophthalmology. 2005 Mar 1;112(3):376–85. 6. Serle JB, Katz LJ, McLaurin E, Heah T, Ramirez-Davis N, Usner DW, et al. Two Phase 3 Clinical Trials Comparing the Safety and Efficacy of Netarsudil to Timolol in Patients With Elevated Intraocular Pressure: Rho Kinase Elevated IOP Treatment Trial 1 and 2 (ROCKET-1 and ROCKET-2). Am J Ophthalmol. 2018 Feb 1;186:116–27. 7. Asrani S, Robin AL, Serle JB, Lewis RA, Usner DW, Kopczynski CC, et al. Netarsudil/Latanoprost Fixed-Dose Combination for Elevated Intraocular Pressure: Three-Month Data from a Randomized Phase 3 Trial. Am J Ophthalmol. 2019 Nov 1;207:248–57. 8. Musch DC, Lichter PR, Guire KE, Standardi CL. The collaborative initial glaucoma treatment study: Study design, methods, and baseline characteristics of enrolled patients. Ophthalmology. 1999 Apr 1;106(4):653–62. 9. The advanced glaucoma intervention study (AGIS): 7. the relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol. 2000 Oct 1;130(4):429–40. Dr. Dewang Angmo MD, DNB, FRCS, FICO, MNAMS Associate Professor of Ophthalmology Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India. Corresponding Author:

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