May-June, 2022 Vol, 28 No. 3

CONTENTS PAGE NO. TITLE 08 07 From the DESK of Chief Editor From the President’s DESK 10 From the DESK of Managing Editor Subspecialty Glaucoma 11 29 50 Electrophysiology in Glaucoma 16 35 55 Trabeculectomy with Collagen Implant for the Treatment of Glaucoma: A Prospective Study 20 23 The Spectrum of Angle Closure Glaucomas 40 43 Correlation of Structural Damage with Functional Changes in Glaucoma - A Mini Review 62 Istent Inject: An Update on A Novel MIGS Device in India 68 Landmark Trials in Glaucoma Inter-Rater Variability of the Non-Simultaneous Stereo Disc Photography Using A Monocular Fundus Camera Interpretation of OCT Maps in Glaucoma Evaluation of Biophysical Parameters of Lamina Cribrosa in Patients of Ocular Hypertension Using OCT Steroids in Vernal Keratoconjunctivitis - A Double Edged Sword? Artificial Intelligence in Glaucoma Normal Tension Glaucoma Simplified: A Review Article

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 DOS EXECUTIVE MEMBERS (2021-2023) 03 Dr. Pawan Goyal President Dr. Om Prakash Anand Prof. Jeewan S. Titiyal Prof. Subhash C. Dadeya Dr. Prafulla Kumar Maharana Dr. Rajendra Prasad Vice President Dr. Gagan Bhatia Prof. M. Vanathi Prof. Namrata Sharma Dr. Amar Pujari Dr. Jatinder Singh Bhalla Secretary Dr. Vivek Gupta Dr. Bhupesh Singh Dr. Sandhya Makhija Joint Secretary Dr. Vivek Kumar Jain Dr. Pankaj Varshney Dr. Alkesh Chaudhary Treasurer Prof. Kirti Singh Editor Dr. Jatinder Bali Library Officer DOS Office Bearers Executive Members DOS Representative to AIOS Ex-Officio Members

Know Your Editor Managing Editor DOS Times Chief Editor DOS Times Dr. Jatinder Singh Bhalla MS, DNB, MNAMS Hony. General Secretary Delhi Ophthalmological Society DDU Hospital, Hari Nagar Dr. Prafulla Kumar Maharana, MD Associate Professor of Ophthalmology Dr. Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 04 Section Editor - Retina & Uvea Prof. (Col) Sanjay Kumar Mishra, HOD, Dept of Ophthalmology (vitreo retina surgeon), Army Hospital (R&R) Section Editor - Retina & Uvea Dr. Alkesh Chaudhary MBBS, MS, FMRF Head Consultant M.D. Eye Care & Laser Centre Section Editor - Uvea & Ocular Inflammatory Disorders Dr. Naginder Vashisht MD, FRCS, FICO Director & Senior Consultant Ophthalmology, Kailash Eye Care, Patel Nagar, New Delhi Senior Consultant Ophthalmology, Artemis Hospitals, Gurugram Section Editor - Retina & Uvea Dr. Raghav Malik, MS Fellowship Cataract & Refractive Surgery Associate Consultant Dept of Cataract, Cornea & Refractive Services, CFS, New Delhi Section Editor - Uvea & Ocular Inflammatory Disorders Dr. Prateek Kakkar (Retina Specialist), MD Ex-Senior Resident (Vitreo-retina, AIIMS, New Delhi) Section Editors - Retina & Uvea Dr. Deepankur Mahajan MBBS, MD (AIIMS), FICO, FAICO (Retina and Vitreous) Consultant Ophthalmologist and Vitreoretina Specialist, New Delhi Section Editor - Uvea & Ocular Inflammatory Disorders Dr. Aman Kumar MD, Senior Resident Vitreo-Retina, Uvea, ROP services Dr. R P Centre for Ophthalmic Sciences, AIIMS, New Delhi Section Editor - Retina & Uvea Dr. Rushil Kumar Saxena Dept of Vitreoretina Dr. Shroff’s Charity Eye Hospital, New Delhi Section Editor - Retina & Uvea Dr. Ankur Singh Assistant professor Dept of Ophthalmology University College of Medical Sciences and GTB Hospital, Delhi Section Editor - Retina & Uvea Dr. Abhishek Jain D.O., D.N.B., FAICO RBM Eye Institute, Delhi ADK Jain eye hospital, Bhagpat Section Editor - Cornea & External Eye Disease Dr. Sameer Kaushal Senior Consultant & Head (Ophthalmology) Artemis Hospital and PL Memorial Eye Clinic, Gurgaon Section Editor - Cornea & External Eye Disease Dr. Abha Gour Senior Consultant Cornea and Anterior Segment Dr. Shroffs Charity Eye Hospital, New Delhi

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 05 Section Editor - Ocular Surface Dr. Rajat Jain MBBS, MS (Gold Medalist), FICO (UK) Fellow- Cornea and Anterior Segment- LVPEI Hyderabad Section Editor - Cataract & Comprehensive Ophthalmology Dr. Ritin Goyal Director & Cornea, Cataract and LASIK surgeon at Goyal Eye Group of Eye Centers. Section Editor - Refractive Surgery Dr. Manpreet Kaur MD, Assistant Professor Cornea, Cataract & Refractive Surgery Services Dr. R P Centre for Ophthalmic Sciences AIIMS, New Delhi Section Editor - Ocular Surface Dr. Jaya Gupta Consultant Cornea Cataract & Refractive Surgery The Healing Touch Eye Care Centre, New Delhi Section Editor - Cataract & Comprehensive Ophthalmology Dr. Wangchuk Doma Venu Eye Institute and Research Centre Section Editor - Refractive Surgery Dr. Pranita Sahay, MD (AIIMS), FRCS (Glasgow), DNB, FICO, FICO (Cornea), FAICO (Ref Sx) Consultant, CFS, New Delhi Section Editor - Ocular Surface Dr. Abhishek Dave Consultant Cornea, Cataract & Refractive Surgery - CFS, New Delhi Section Editor - Ocular Surface Dr. Amrita Joshi Assistant Professor Department of Ophthalmology Army Hospital (R&R) Section Editor - Cataract & Comprehensive Ophthalmology Dr. Amit Mehtani MBBS, MS, DNB DDU HOSPITAL Section Editor - Ocular Surface Dr. Neeraj Verma MS (Ophthal) Senior Consultant Centre For Eye Care Kirti Nagar, New Delhi Section Editor - Cornea & External Eye Disease Dr. Ritu Nagpal MD, Senior Research Associate Dr. R P Centre for Ophthalmic Sciences, AIIMS, New Delhi Section Editor - Cornea & External Eye Disease Dr. Parul Jain MBBS, MS, FICO, FAICO, MRCSEd Associate Professor GNEC, Maulana Azad Medical College Dr. Jyoti Batra Consultant, Oculoplasty and Ocular Oncology, ICARE Eye Hospital and Post graduate Institute, Noida Section Editor - Oculoplasty & Asthetics Section Editor - Oculoplasty & Asthetics Dr. Rwituja Thomas Grover Consultant Oculoplastics, Orbit, Ocular Oncology and Aesthetics services, Vision Eye Centres, New Delhi Dr. Anuj mehta Consultant and Professor Vardhman Mahavir Medical College and Safdarjung Hospital Section Editor - Oculoplasty & Asthetics Section Editor - Glaucoma Dr. Kiran Bhanot MS, DNB Senior Consultant & Hod GGS Hospital & Indira Gandhi Hospital, Dwarka, New Delhi Section Editor - Glaucoma Dr. Suneeta Dubey Head - Glaucoma Services Medical Superintendent Chairperson - Quality Assurance Dr. Shroff’s Charity Eye Hospital New Delhi, India Section Editor - Glaucoma Dr. Prathama Sarkar Consultant in Eye7 Chaudhary Eye Centre Section Editor - Glaucoma Dr. Kanika Jain MBBS, MS, DNB Senior Resident, Dept of Ophthalmology, DDU Hospital, Hari Nagar, New Delhi. Section Editor - Glaucoma Dr. Shweta Tripathi DNB, MNAMS, FMRF Senior Consultant Glaucoma Services Indira Gandhi Eye Hospital and Research Centre, Lucknow Dr. Kavita Bhatnagar Professor & Head, Dept of Ophthalmology, AIIMS, Basani Phase-2, Jodhpur Section Editor - Glaucoma

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 06 Prof. Swati Phuljhale Dr. R P Centre for Ophthalmic Sciences, AIIMS, New Delhi Section Editor - Strabismus Dr. Gunjan Saluja Ex SR Strabismus, Oculoplasty and Neuro-Ophthalmology services, Dr. R P Centre, AIIMS, New Delhi Section Editor - Strabismus Dr. Suraj Singh Senjam Community Ophthalmology Dr. R P Centre for Ophthalmic Sciences, AIIMS, New Delhi Section Editor - Community Ophthalmology Dr. V Rajshekhar MS, FICO Professor & Consultant Dept of Ophthalmology VMMC & Safdarjung Hospital, New Delhi Section Editor - Community Ophthalmology Dr. Digvijay Singh Affiliation, Noble Eye Care, Gurugram Section Editor - Residents Corner Dr. Vineet Sehgal MBBS, MD Fellowship in Glaucoma Senior Consultant & Incharge Glaucoma Sharp Sight Eye Hospitals Section Editor - Residents Corner Dr. Sima Das Head, Oculoplasty and Ocular Oncology Services Incharge, Medical Education Dr. Shroff’s Charity Eye Hospital New Delhi Section Editor - Ocular Oncology Prof. Bhavna Chawla Professor of Ophthalmology Dr. R P Centre, AIIMS, New Delhi Section Editor - Ocular Oncology Dr. Paromita Dutta Associate Professor Guru Nanak Eye Centre Maharaja Ranjit Singh Marg New Delhi Section Editor - Strabismus Dr. Sumit Monga, Senior Consultant. Pediatric, Strabismus and Neuro-Ophthalmology Services, CFS group of Eye Hospitals, Delhi-NCR Section Editor - Neuro-Ophthalmology Dr. Amar Pujari Assistant Professor Dr. R P Centre for Ophthalmic Sciences, AIIMS, New Delhi Section Editor - Neuro-Ophthalmology Dr. Rebika Dhiman Assistant Professor Strabismus and NeuroOphthalmology services, Dr. R P Centre, AIIMS, New Delhi Section Editor - Neuro-Ophthalmology Dr. Simi Gulati I/C and Specialist Charak palika hospital (ndmc) Moti bagh, New Delhi Section Editor - Glaucoma

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 07 DOS TIMES From the President’s DESK Dr. Pawan Goyal MBBS, MS The field of glaucoma has witnessed lot of changes in the past decade in terms of better understanding of pathophysiology of various glaucomatous diseases. There is upcoming of new anti-glaucoma medications minimally invasive surgeries. All this translates to patient care. This special issue of DOS Times on the subspecialty “Glaucoma” includes articles based on some of the pertinent topics of the subject by renowned experts. Our aim is to keep the readers well versed and updated with the upcoming developments in their respective subspecialities, thereby helping in improved patient care. Dr. Pawan Goyal President, DOS Chairman Goyal Eye Institute, Delhi

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 08 DOS TIMES From the DESK of Chief Editor Dr. J S Bhalla, MS, DNB, MNAMS Secretary Delhi Ophthalmological Society Glaucoma is a multifactorial progressive optic degenerative neuropathy characterised by apoptosis of retinal ganglion cells. It is a combination of vascular, genetic, anatomical & immune factors. It poses a significant public health concern as it is the second leading causes of blindness after cataract and this blindness is irreversible. People over 60 years of age, family member of those already diagnosed with glaucoma, steroids use, diabetic, hypertensive, high myope and ocular trauma. It is primarily of two types- primary and secondary glaucoma which are further subdivided into open and dose angle glaucoma. Thams et al have predicted increase in number that would increase exponentially from 76 million in 2020 to 111.8 million by 2040. This increase will mostly attributable to Asia and Africa. Individuals from Asia will be responsible for the increase of 18.8 million (79.8%) POAG cases and nine million (58.4%) PACG cases from 2013 to 2040, individuals from Africa will contribute to 10.9 million (130.8%) increase in glaucoma cases from 2013 to 2040. Glaucoma is not easily detected and can go undiagnosed there by aptly referred to as silent thief of sight. It is diagnosed after a thorough history taking, intraocular pressure measurement by applanation tonometry, gonioscopy, disc evaluation, central corneal thickness, perimetry. Thorough, meticulous examination and investigation must be done while diagnosing a patient of glaucoma. Even in experienced hands, sometimes the diagnosis of glaucoma may be a dilemma. Glaucoma is one of most evolving subspecialty in ophthalmology with advances in imagingASOC, UBM and development/introduction of new surgical technique/pharmacotherapyMIGS, ROCK inhibitors. Trabeculectomy has unequivocally stood the test of time and remains the undefeated gold standard surgery for controlling IOP. Then, Along came Glaucoma drainage devices, providing an option for those patients with failed trabeculectomy. In the last decade various Minimally Invasive Glaucoma Surgeries(MIGS) and MIGS plus procedures have gained popularity. Recently, with the introduction of i-stent, Kahook Dual Blade in India, the interest in MIGS has grown manifold . There are many reasons of delayed care in glaucoma patients. Lack of awareness amongst the population at large and the asymptomatic nature of the disease in its early stages and the lack of trained glaucoma specialists in most parts of our country creates a gap in medical care of glaucoma patients. Despite treatment, about 15% of glaucoma patients may become blind in atleast one eye within 20 years. This issue aims at discussing about early and appropriate diagnosis and management of glaucoma and also the latest developments in the field of glaucoma. This special issue on ‘’Glaucoma’’ will focus on discussing important aspects- of glaucoma by eminent stalwarts from the country & abroad. The articles on objective evaluation of structural parameters like lamina cribrosa & their correlation with functional changes make for interesting read. We are witnessing a period of renaissance in glaucoma with the advent of newer implants. Newer addition in Treatment armamentarium like I stent inject & other MIGS devices provide information about future trends. Electrophysiology in Glaucoma article tells us that this diagnostic modality also has potential. Article on Landmark trials provide us with knowledge about how to make our management more scientific.

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 09 DOS TIMES I am sure that this will help general ophthalmologists/residents and fellows to clear some doubts in diagnosis, management and progression of glaucoma and try to decrease the prevalence of blindness caused by this ever evolving disease. Dr. Jatinder Singh Bhalla, MS, DNB, MNAMS Chief Editor - DOS Times, Consultant & Academic Incharge (Ophthalmology) DDU Hospital, Hari Nagar

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 10 DOS TIMES It’s a great pleasure on my part to bring out this special edition of DOS Times “Glaucoma”. In our previous edition we had focused on recent advances and general ophthalmology. This edition is a special edition focusing on one of the important causes of blindness in India. The articles in this volume covers the entire spectrum of glaucoma; starting from basic classification to advanced treatment options. Articles on emerging concepts such as artificial intelligence in Glaucoma and newer investigation tools will be extremely useful to the readers. In the end, there is an article compiling all the recent and important trials to update the readers on various aspects of glaucoma. A special thanks to the section editors Dr. Kanika Jain, Dr. Simi Gulati, Dr. Prathama Sarkar, Dr. Suneeta Dubey and Dr. Kavita Bhatnagar for helping us in improving the quality of the articles significantly. In the end I would like to repeat my previous words. Change is an essential part of improvement over time. In spite of all our efforts there will definitely be scope for improvement in future. I would request the readers of this edition to convey us through whatever possible means their valuable suggestions and help us improve further. Dr. Prafulla Kumar Maharana, MD Managing Editor DOS Times, Associate Professor of Ophthalmology Cornea Cataract & Refractive Services Dr. Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi Email : [email protected] Dr. Prafulla Kumar Maharana, MD From the DESK of Managing Editor

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 11 DOS TIMES Inter-Rater Variability of the NonSimultaneous Stereo Disc Photography Using A Monocular Fundus Camera Sushma Tejwani, D.O, PhD, Jyoti Matalia, DO, DNB Narayana Nethralaya-2, Narayana Health City Campus, Bommasandra, Hosur Road, Bangalore, India. Introduction Glaucoma is the second most common cause of blindness worldwide[1] and a leading cause of blindness in India & other developing countries.[2] It is characterized by gradual damage of the optic nerve, visual fields loss and eventual irreversible blindness. Early diagnosis & optimal treatment is the only way to minimize visual loss due to glaucoma. Detection of optic nerve head damage is important for both the diagnosis and monitoring progression of glaucoma. Optic nerve head changes & visual field changes are the characteristic changes of glaucomatous optic neuropathy. Over the years, there have been several imaging devices that attempted to evaluate the optic nerve head and nerve fibre layer.[3,4,5] In spite of a wide variety of machines being available for quantitative assessment for glaucoma diagnosis & management such as automated perimeters, imaging techniques; stereo-photographic evaluation of the optic disc remains the gold standard.[6] It is the clinical appearance of the optic nerve head, that leads to the suspicion of glaucoma, requiring further confirmation by the above mentioned tests. However, the decision of labelling a patient as glaucoma or no glaucoma primarily depends on the clinical correlation of the disc changes with these tests. Further, the evaluation of the optic nerve head includes evaluation of the cup to disc ratio, thickness of the rims, detection of nerve fibre layer defects etc. There is significant variability and inconsistency reported, even among glaucoma specialists in evaluating optic discs. Stereo disc photography has been used to document structural abnormalities and longitudinal changes in glaucomatous eyes for decades.[7] Disc photographs are highly reproducible and record a natural colour image of the retina.[3] The Preferred Practice Pattern[8] states that the optic disc appearance can be recorded photographically or using an image analyser for glaucoma patients. Three-dimensional images of the optic nerve head can be obtained using both monocular fundus cameras and stereo-fundus cameras. Monocular imaging is not suitable for three-dimensional estimation as this system does not allow for a change in the vantage point from which the retinal surface is viewed.[9] We describe a technique, wherein the third dimensional component of disc photography can be achieved using a regular monoscopic fundus camera, thereby providing the benefit of stereo disc photography to a larger population. The principal behind non-simultaneous stereo photography is the fusion of two images taken at different angles. In this technique, Figure 1 : The diagram-representing concept of separation of images for non-simultaneous stereoscopic images with the fundus camera. we use the regular fundus camera that gives us the monoscopic image, but instead of taking the picture in a straight angle, it is taken at two lateral angles with a separation of 25-30 degrees, to provide the depth, to achieve a stereoscopic image as described in Figure 1. Validation of this method of assessing optic disc photographs taken on a regular monocular fundus camera might indicate an economical and useful option. In this study inter-observer variability and agreement between two glaucoma specialists was studied in an attempt to validate this technique of evaluating the optic nerve with a monocular fundus camera. Materials & Methods It was a retrospective cohort study wherein disc photographs of patients seen in the glaucoma clinic of a tertiary eye care centre from July 2018 to April 2020 were analysed. Optic disc photographs of subjects (glaucoma patients/suspects) above 18 years seen in glaucoma clinic were studied. Poor quality photographs as reported by any of the observers were excluded. Also, patients having any other pathology that could affect the

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 12 DOS TIMES Figure 3 : Cumulative frequency for estimation of Cup Disc ratio by two observers. Figure 2 : a) Setting for 20-degree field on Topcon fundus camera; b) The stereo-viewer used to evaluate the disc by fusing the two images using the prisms; c) The position of the joystick for the first photograph; d) The position of the joystick 25-30 degrees away and locked to click the second photograph. optic nerve like myopia of more than 6 dioptre, neurological problems, optic disc pits, congenital disc malformations, vascular disorders of retina causing neovascularisation of disc or collaterals were excluded. Technique The photographs were obtained by a single experienced technician trained to obtain the photographs using Topcon fundus camera (TRX 50 EX Retinal camera) as 20-degree field images with a dilated pupil of more than 5 mm and patient looking straight into the camera. The photographer captured a non-simultaneous stereo-pair of each eye with manual lateral movement of the camera, with 20 degree field image setting (Figure 2a). The digital photographs obtained at two different angles, 25-30 degrees apart, were then placed side by side, on a computer screen. The stereo-viewer (Screen-VU stereoscope Portland, OR 97202) was used by observers to evaluate the disc photographs (Figure 2b). The third dimension was perceived by fusing the two photographs by adjusting the prisms of the stereo-viewer. The joystick was locked at two positions to click the photographs as shown in figure 2c and 2d. Though it is difficult to ensure the exact amount of separation, we confirmed the stereoscopic images with the separation obtained. When we were imaging the optic nerve, the farthest position where the optic disc is clearly visible, was taken as the point for locking. The technique was taught to the single ophthalmic photography technician before starting the study and the nonsimultaneous stereo pair photographs were checked for the first hundred patients for the quality and stereo effect. Evaluation Two ophthalmologists, (A & B) independently viewed each stereo-pair using the stereo-viewer. They were masked to the clinical details of the patients and to the other examiner’s observations. Both eyes of each patient were assessed as two separate photographs, and not sequentially to avoid bias. Any photograph reported to be of sub-standard quality for assessment by any of the observers was discarded. All photographs were judged for the following characteristics: 1) Vertical cup: disc (CD) ratio 2) Thinnest neuro-retinal rim (NRR) 3) ISNT ruled followed or not followed 4) Presence or absence of glaucoma (Normal or Abnormal) While the first three parameters are self-explanatory, the fourth parameter that is the presence or absence of glaucoma was judged by each ophthalmologist on the overall assessment of the nerve including the three parameters and other signs as disc hemorrhage, peri-papillary atrophy, size of the disc, entry and slope of the optic nerve head in any given photograph. Statistical Analysis The findings of both the observers were tabulated. Inter-observer variability was calculated with intraclass correction (ICC) and Kappa coefficient of agreement using MedCalc software. Since CD ratio is a continuous variable, the agreement was determined using ICC, however the other parameters were non-continuous variables hence inter rater variability was determined by calculating kappa coefficient. Results There were 406 stereo disc photographs, which were collected from the glaucoma clinic for glaucoma patients and suspects. After excluding, the discs of subjects with problems other than glaucoma and substandard quality images 377 eyes of 220 patients were included in the study. Two ophthalmologists independently rated the discs with the help of the stereo-viewer for each parameter analysis. ICC with two way model, consistency type, for judging the CD ratio using the single measure method was 0.9449 with 95% confidence interval (CI) being 0.9329 to 0.9548; and with the average measure method was 0.9717 with 95% CI being 0.9653 to 0.9769. Figure 3 depicts the cumulative frequency for estimation of CD ratio by two observers.

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 13 DOS TIMES Correlation coefficient (r) of the CD ratio was calculated to be 0.9461 with p<0.0001 with 95% CI being 0.9343 to 0.9557. Weighted kappa for inter-rater agreement for determining the thinnest rim in a given disc by each observer was 0.838 with a standard error of 0.034 (95% CI 0.771 to 0.906) (Table 1). Observer A Observer B Inferior Nasal Superior Temporal Inferior 33 0 3 3 39 (10.3%) Nasal 0 6 1 2 9 (2.4%) Superior 1 1 27 3 32 (8.5%) Temporal 4 0 7 286 297 (78.8%) 38 (10.1%) 7 (1.9%) 38 (10.1%) 294 (78.0%) 377 Observer A Observer B AB N Superior AB (No ISNT) 142 20 162 (43.0%) N (ISNT) 11 204 215 (57.0%) 153 (40.6%) 224 (59.4%) 377 S No. Factors Agreement ICC / kappa value 95% Confidence intervals Level of agreement 1 Vertical Cup : Disc ratio (Intra class correlation) 0.94 0.93-0.95 Very good 2 Thinnest Neuro-retinal rim determination ( k value) 0.838 0.77-0.90 Very good 3 ISNT rule followed or not followed (k value) 0.83 0.74-0.84 Very good 4 Presence or absence of glaucoma (k value) 0.727 0.66-0.80 Good Observer A Observer B AB (Glaucoma) N (No Glaucoma) Superior AB (Glaucoma) 116 23 139 (36.9%) N (No Glaucoma) 25 213 238 (63.1%) 141 (37.4%) 236 (62.6%) 377 Table 1 : Inter-rater agreement (kappa) for determining the thinnest rim. Abbreviations: AB – Abnormal i.e. not following ISNT rule, N- Normal i.e. following ISNT rule Table 4 : Summary of results. Abbreviations: AB – Abnormal, N- Normal Inter-rater agreement for whether the disc is following ISNT rule or not, showed the weighted kappa of 0.831 with a standard error 0.029 with (95% CI 0.774 to 0.888) (Table 2). Table 2 : Inter-rater agreement (kappa) for whether disc is following ISNT rule or not. Table 3 : Inter-rater agreement (kappa) for assigning the disc as Normal or Abnormal. Kappa coefficient for assigning the disc as normal and abnormal was 0.727 with a standard error of 0.037 (95% CI 0.655 to 0.799) (Table 3) Significance of Kappa value was considered poor for value less than 0.21, fair between 0.21-0.4, moderate for 0.41 to 0.6, good for 0.61 to 0.8 and very good for 0.81 to 1.0. Table 4 summarizes the results and explains the significance for each factor. Post hoc analysis for sample size calculation using Medcalc for the correlation coefficient of 0.5 with alpha error and beta error of 0.01was done and that showed a minimal sample size of 82, hence sample size was adequate to determine the agreement. The inter-observer variability for estimating CD ratio, checking ISNT rule and detecting the thinnest rim using the non-

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 14 DOS TIMES simultaneous disc photographs with stereo viewer was very good, and the ability to judge the disc as normal or glaucomatous was found to be good in this study population. Discussion In this study, two ophthalmologists studied the optic disc photographs taken on a monocular fundus camera with a stereo-viewer and compared the results. Studies done previously have focused on agreement for estimating cup disc ratio and designating a disc as glaucoma or normal. However in this study, two more parameters that is detecting the thinnest rim and whether the nerve follows ISNT rule were also studied in addition the CD ratio and the ability to differentiate normal from glaucoma amongst the Indian eyes. Varma et al studied the intra-observer and inter-observer agreement between glaucoma specialists under monoscopic and stereoscopic conditions, in estimating vertical cup-todisc ratios and in assessing whether a disc had glaucomatous damage. Inter-observer agreement in estimating vertical cupto-disc ratio was moderate (stereoscopic median weighted kappa, 0.67); individual experts differed by as much as 0.2 disc diameters (DD) monoscopically and 0.16 DD stereoscopically. The observers estimated larger vertical cup-to-disc ratios when evaluating the same discs under stereoscopic conditions than under monoscopic conditions showing better estimation of glaucomatous discs with stereoscopic photography than monoscopic photography.9 Their study confirms the ability of experts to reliably evaluate the optic disc within themselves and emphasizes the need for developing standardized methods for inter-observer evaluation of the optic disc in glaucoma.[9] There was good agreement (kappa=0.727) between observers in assessing if a disc was normal or glaucomatous. In the current study, two more parameters in addition to these mentioned above were studied, and noted good to very good agreement between observers for these. An older study, done by Lichter et al demonstrated that interobserver agreement in estimating cup to disc ratio was better with stereoscopic than monoscopic photographs.[5] Abrams et al studied the agreement between optometrists, general ophthalmologists and third year residents in assessing the simultaneous stereo-photographs of the optic nerve heads viewed with a stereo-viewer and they found significant variability between the three groups in their ability to identify glaucomatous damage. They used a simultaneous stereoscopic fundus camera with the stereo base set to 3.0 mm and the photographs were viewed using an Asahi stereo- viewer. Interobserver agreement among experts for assessing glaucomatous damage was moderate (Kw= 0.56- 0.68) and similar to that of ophthalmologists and residents but significantly better than for optometrists.[10] Ophthalmologists and residents had higher sensitivity (78%) in identifying glaucomatous optic nerve damage than did optometrists (56%). The specificity for all three groups was relatively poor (range, 47%-60%).They found a fair to moderate inter-observer agreement, which shows there is limited consistency among observers in differentiating glaucomatous discs from normal discs.[10] Shuttleworth et al studied a 112 disc photographs using a Discam digital stereo camera and the images were viewed with a hand- held stereo- viewer. They found a small systematic bias between the two observers for both horizontal and vertical cup to disc ratio. Inter-observer variation was similar but slightly larger than the intra-observer variation. For horizontal CDR the ICC = 0.89 and the 95% tolerance limit for change = 0.14 (19% of range). For vertical CDR the ICC = 0.90 and the 95% tolerance limit for change = 0.14 (16% of range). Their study showed optic disc assessment using a stereo camera to be reliable and better than clinical disc evaluation.[6] Stereoscopic methods of photographic optic disc assessment are considered to be better than monoscopic methods while simultaneous fixed angle stereo images show less variation than pseudo stereo images (sequential or non-fixed angle).[6,11] Current study showed similar results with non-simultaneous stereo disc pairs thereby suggesting that with an appropriate technique and a welltrained technician these images may serve an equally good tool as simultaneous stereo images. We do agree that while taking the photograph, there is no clear cut marking on the machine for measuring the 15-degree of separation, but the results show that the technique demonstrated a good separation to allow stereoscopic images between 25-30 degree difference, and the single trained technician took all the images. In a study by Sung et al, they evaluated the intra-observer agreement, inter-observer agreement, and the agreement between a digital stereo optic disc camera (Discam) and Heidelberg retina tomograph (HRT) in measuring area cup-disc ratio (ACDR) and radial cup-disc ratio (RCDR) by two observers. They evaluated 78 eyes and found that the inter-observer agreement between the two observers was substantial (ICC = 0.79).[12] In our study, this sequential, non-simultaneous method of photography seem to be a good option for documentation for glaucoma patients, as it proved to have good inter-observer agreement for given criteria of differentiating normal and glaucomatous discs. Jampel et al studied a series of 164 stereo- photographs taken 26 months apart to determine whether the appearance of the optic disc had changed. They found poor agreement amongst the three glaucoma specialists who independently assessed disc change over time.[13] Coleman et al conducted a similar study value of obtaining follow-up stereoscopic photographs on glaucoma suspects in identifying progressive optic nerve damage. They found poor sensitivity and specificity consistently for serial stereoscopic photographs than for drawings.[14] There have been studies indicating that the training improves agreement between observers[15] and there are certain programs like Matchedflicker software that could improve the agreement further.[16] Clinical and photographic methods of evaluating the optic nerve head does involve some degree of subjective variation. Stereoscopic disc photography has long been the gold standard for optic disc evaluation.[6] In developing countries, most eye care centres may not have a stereoscopic fundus camera or software, although a monoscopic fundus camera might be a part

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 15 DOS TIMES of their armamentarium or within their reach. This technique can be of use in peripheral eye care centres where there is a shortage of specialists and equipment. Trained technicians can obtain the images and forward to glaucoma specialists, who can make a diagnosis after viewing the images with a stereoviewer. In summary, this simple method of taking the optic disc photographs non-simultaneously, using the monocular fundus camera, offers an effective screening tool in assessing glaucoma with reasonable certainty, and may be used for documentation and follow up of glaucoma patients. References 1. Quigley HA. Br J Ophthalmol. Number of people with glaucoma worldwide. 1996 May; 80 (5):389-93. Review. 2. Tielsch JM, Katz J, Singh K et al. Am J Epidemiol. A population-based evaluation of glaucoma screening: the Baltimore Eye Survey. 1991 Nov 15; 134(10):1102-10. 3. Thylefors B, Négrel AD, Pararajasegaram R et al. Bull World Health Organ. Global data on blindness. 1995; 73(1):115-21. Review. 4. Martinello M, Favaro P, Muyo Nieto GD et al. 3-D retinal surface inference: stereo or monocular fundus camera. Conf Proc IEEE Eng Med Biol Soc. 2007; 2007:896-9. 5. Lichter PR. Trans Am Ophthalmol Soc. Variability of expert observers in evaluating the optic disc. 1976; 74:532-72. 6. Shuttleworth GN, Khong CH, Diamond JP. Br J Ophthalmol. A new digital optic disc stereo camera: intra-observer and inter-observer repeatability of optic disc measurements. 2000 Apr; 84(4):403-7. 7. Varma R, Steinmann WC, Scott IU. Expert agreement in evaluating the optic disc for glaucoma. Ophthalmology. 1992 Feb; 99(2):215-21. 8. Abrams LS, Scott IU, Spaeth GL et al. Ophthalmology. Agreement among optometrists, ophthalmologists, and residents in evaluating the optic disc for glaucoma. 1994 Oct; 101(10):1662-7. 9. Krohn MA, Keltner JL, Johnson CA. Comparison of photographic techniques and films used in stereophotogrammetry of the optic disk. Am J Ophthalmol. 1979 Nov; 88(5):859-63. 10. Boes DA, Spaeth GL, Mills RP et al. J Glaucoma. Relative optic cup depth assessments using three stereo photograph viewing methods. 1996 Feb; 5(1):9-14. 11. Sung VC, Bhan A, Vernon SA. Br J Ophthalmol. Interobserver and intra-observer variability in the detection of glaucomatous progression of the optic disc. Agreement in assessing optic discs with a digital stereoscopic optic disc camera (Discam) and Heidelberg retina tomograph. 2002 Feb; 86(2):196-202. 12. Jampel HD, Friedman D, Quigley Het al. Am J Ophthalmol. Agreement among glaucoma specialists in assessing progressive disc changes from photographs in open-angle glaucoma patients. 2009 Jan; 147(1):39-44. 13. Coleman AL, Sommer A, Enger C et al. J Glaucoma. Inter-observer and intra-observer variability in the detection of glaucomatous progression of the optic disc. 1996 Dec; 5(6):384-9. 14. Breusegem C, Fieuws S, Stalmans I, Zeyen T. Agreement and accuracy of non-expert ophthalmologists in assessing glaucomatous changes in serial stereo optic disc photographs. Ophthalmology. 2011 Apr;118(4):742-6. 15. Schaefer JL, Meyer AM, Rodgers CD, Rosenberg NC, Leoncavallo AJ, Lukowski ZL, Greer AB, Martorana GM, Zou B, Shuster JJ, Jay Katz L, Schuman JS, Kass MA, Sherwood MB. Comparing glaucomatous disc change using stereo disc viewing and the Matched Flicker programme in glaucoma experts and trainees. Br J Ophthalmol. 2018 Mar;102(3):358-363. Dr. Sushma Tejwani, D.O, PhD Narayana Nethralaya-2, Narayana Health City Campus, Bommasandra, Hosur Road, Bangalore, India. Corresponding Author:

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 16 DOS TIMES Abstract: Methods: The study was conducted at our outpatient department of the territory hospital, consisting of 55 patients with a confirmed diagnosis of ocular hypertension and age-matched healthy volunteers. All the patients underwent enhanced depth SD-OCT imaging and lamina cribrosa biophysical parameters were measured in horizontal B-scan images spaced equidistantly across the vertical diameter of the optic disc and translaminar pressure gradient calculated based on BMI. Results: Mean LCT in OHT is 266.53±63.02µm, and in healthy individuals 216.28±34.25µm. Mean TLPG in OHT is 14.68±3.45 mmHg/mm, and in a healthy individual is 11.13±2.19 mmHg/mm. Conclusion: This study presents the profile of LC in OHT, and healthy controls. The current data may enable the clinical application of various indices for understanding the physiology, detection, and management of glaucoma. Shortly, we expect to have an enhancement of techniques like adaptive compensation which may help in better visualization of the LC below the vessels, hence, escalating the precision of LC thickness measurements and the effect of biomechanical parameters on LC. Evaluation of Biophysical Parameters of Lamina Cribrosa in Patients of Ocular Hypertension Using OCT Vinay D, MBBS, DOMS, DNB, Amit Mehtani, MBBS, MS, DNB, Himani Anchal, MBBS, MS, Ropfuleno Peseyie, MBBS, DOMS, Jatinder Singh Bhalla, MS, DNB, MNAMS DDU Hospital New Delhi. Introduction Glaucoma is an optic neuropathy marked by irreversible loss of the retinal ganglion cells resulting in the functional visual field (VF) deficits and is the second leading cause of blindness worldwide. Early detection is essential to retard disease progression and retain maximal vision.[1] Over the last decade, the prevalence of glaucoma in India has been reported by various studies like Vellore Eye Survey[2], Andhra Pradesh Eye Disease Study.[3,4] Aravind Comprehensive Eye Survey[5] and Chennai Glaucoma Study.[6,7,8,9] Based on the available data, from these studies, the estimates are that there are approximately 11.2 million persons aged 40 years and older with glaucoma in India, of which Primary open angle glaucoma is estimated to affect 6.48 million persons and an estimated number with primary angle-closure glaucoma is 2.54 million. Loss of vision in glaucoma occurs due to damage to retinal ganglion cell axons. This damage is believed to initiate at the level of the lamina cribrosa (LC), a network of connective tissue beams that provide structural and nutritional support to the retinal ganglion cell axons as they traverse the optic nerve head (ONH) to the brain. The resulting glaucomatous damage is characterized by distinctive changes in the ONH and patterns of visual field loss. Clinically, the disease is monitored by examining ONH morphology for signs of glaucomatous optic neuropathy, which if untreated will be recognized as a progressive deepening and enlarging of the cup and thinning of the neuroretinal rim.[10] Optical coherence tomography (OCT) is an imaging technology implemented in clinical eye care for examining tissue structure, and is used for early glaucoma detection. Lamina cribrosa is a sieve-like structure situated in the scleral canal of the optic nerve head. It is composed of interweaving collagen fibers, frequently arranged tangentially around the canals, 40-220µ in diameter, through which the ganglion cell axons pass and form the optic nerve. Astrocyte processes form an intimate web around these axons within the canals.[11] The lamina cribrosa provides a pathway for the retinal ganglion cell axons, the central retinal vein to exit the eye, and the central retinal artery to enter the eye.[12] It also functions as a barrier between the intraocular space and the extraocular space.[13] It also provides structural support to the optic nerve head by withstanding any intraocular pressure related mechanical strain or local deformities.[14] Numerous physiological processes like aging alter the structural stiffness of both the sclera and the lamina cribrosa.[15] Racial differences are also known to alter the extent of age-related stiffness of the sclera at the posterior pole.[16] Neural tissue pressure anterior to the LC is determined by the intraocular pressure (IOP), while neural tissue pressure posterior to the LC is determined by the cerebrospinal fluid (CSF) pressure (CSFP) in the subarachnoid space. The pressure difference across the LC is known as the translaminar pressure difference (TLPD= IOP ‐ retrobulbar CSFP), and the gradient of pressure across the LC is known as the translaminar pressure gradient (TLPG=TLPD/LC thickness). The translaminar pressure gradient is a biomechanical parameter. Posterior deformation of the lamina cribrosa (LC)

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 17 DOS TIMES is thought to play an intermediary role in the development of optic nerve damage induced by IOP-related stress. Because optic nerve axons pass through the LC pores, LC deformation may impose stress and insult on these axons, ultimately leading to the death of retinal ganglion cells through various mechanisms, including blockade of axonal transport. Deformation of lamina cribrosa due to a difference in translaminar pressure gradient has been implicated as a cause factor of glaucomatous damage and hence we conducted a study to image lamina cribrosa using SD-OCT and evaluate various morphometric parameters of lamina cribrosa and correlate the same with translaminar pressure gradient and types of primary open angle glaucoma. Materials and Methods It’s a cross-sectional study where patients with ocular hypertension, and age matched healthy volunteers attending the outpatient department of ophthalmology in the institution, meeting the inclusion and exclusion criteria. Each patient provided written informed consent to participate and was approved by an institutional ethical committee. Study Subjects Each participant underwent comprehensive ophthalmic examinations, including visual acuity and refractive error assessment, slit-lamp biomicroscopy, Goldmann applanation tonometry, gonioscopy, and dilated stereoscopic examination of the optic disc, Other ophthalmic examinations included scanning of the circumpapillary RNFL and the optic nerve head (ONH) using spectral-domain (SD) optical coherence tomography (Huvitz HOCT-1F instrument macular cube 512 x 128 combination scan mode and optic disc cube 200 x 200 scan mode) and standard automated perimetry (30-2 SITA-standard with an Optopol PTS 2000 field analyzer). Other parameters like height, weight, BMI, and systolic and diastolic blood pressures were measured, and ICP was calculated according to the equation ICP=(0.44×BMI)+(0.16×DBP)–(0.18×age)–1.91.[17] The following patients were excluded with high refractive errors, with media opacity precluding posterior segment assessment, advance open angle glaucoma patients, open angle glaucoma patients on advanced glaucoma therapy, and juvenile open angle glaucoma patients. Patients with secondary open angle glaucoma and primary & secondary angle closure glaucoma. Patients with other retinal pathology like CRAO, Retinal Detachment. Patients with high astigmatism >4.5D. Measurements of Lamina Cribrosa Thickness and Trans Laminar Pressure Gradient Lamina cribrosa thickness (LCT): Distance between the anterior and posterior borders of the hyper-reflective region visible beneath the ONH in the center of the BMO reference line. Bruch’s Membrane opening (BMO): The termination points of Bruch’s membrane (BM) and it seems as a high-reflection and high-contrast line in EDI-OCT. BMO represents the true position of the optic disc. Lamina cribrosa depth (LCD): Defined as the distance from the plane defined by Bruch’s membrane opening to the anterior surface of the lamina cribrosa at the center. Anterior Lamina Cribrosa Insertions: The most commonly used measure was the anterior lamina cribrosa insertion depth, the vertical distance between the anterior laminar insertion to the scleral wall, and the reference plane connecting the Bruch’s membrane openings. This same measurement was alternatively referred to as the “peripheral lamina cribrosa depth”. Lamina cribrosa curvature index (LCCI): Calculated by dividing the lamina cribrosa curve depth (LCCD) by the width (W) of the ALCS reference line and multiplying by 100 (LCCI=(LCCD/W) X 100) or as the difference between the mean lamina cribrosa depth and the anterior lamina cribrosa insertion depth. The translaminar pressure gradient is calculated using this formula TLPG=TLPD/LC thickness. Figure 1: Measurements of BMO, LCT & LCD. Statistical Analysis The collected data were transformed into variables, coded, and entered in Microsoft Excel. Data were analyzed and statistically evaluated using the SPSS-PC-25 version. Quantitative data were expressed in mean±standard deviation and depending on normality distribution differences between three comparable groups were tested by ANOVA test or Kruskal Wallis H test followed by posthoc test. Qualitative data were expressed in percentage and statistical differences between the proportions were tested by the chi-square test or Fisher’s exact test. P’ value less than 0.05 was considered statistically significant. Results This cross-sectional study included 55 healthy individuals, and 55 OHT who met inclusion and exclusion criteria. Table 1 summarizes the clinical characteristics of included subjects. Mean LCT in OHT is 266.53±63.02µm, and in healthy individuals 216.28±34.25µm. Mean TLPG in OHT is 14.68±3.45 mmHg/ mm, and in a healthy individual is 11.13±2.19 mmHg/mm.

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 18 DOS TIMES Table 1: Clinical characteristics of OHT, and healthy individuals. Table 2: P value between different pairs for parameters. Parameters OHT Healthy Individual P value Mean age in years 52.62±12.11 57.16±11.80 0.04 SBP (mm Hg) 128.80±13.88 128.39±13.38 0.09 DBP (mm Hg) 89.34±13.57 85.01±9.61 <0.01 ICP (mm Hg) 13.60±2.26 12.32±1.99 <0.01 IOP (mm Hg) 17.54±2.72 14.73±2.04 <0.001 RNFL Thickness (µm) 80.66±11.24 97.77±8.45 <0.001 TLPD 3.94±1.38 2.41±0.60 <0.001 BMO (µm) 1670.46±231.19 1569.66±189.07 <0.01 PTT (µm) 100.76±29.94 109.34±34.15 <0.001 LCT (µm) 266.53±63.02 216.28±34.25 <0.001 LCCI 10.87±2.63 7.03±1.20 <0.001 TLPG (mmHg/mm) 14.68±3.45 11.13±2.19 <0.001 b/w group OHT & Controls DBP (mm Hg) 0.05 ICP (mm Hg) <0.01 IOP (mm Hg) <0.001 RNFL Thickness <0.001 TLPD <0.001 BMO (µm) <0.001 PTT (µm) 0.05 LCT (µm) <0.001 LCD (µm) 0.01 LCCI <0.001 TLPG (mmHg/mm) <0.001 Discussion The retinal ganglion cell axons are said to be damaged in patients with glaucoma leading to visual loss. LC is considered the main supportive element of ONH[11], and also the primary site of axonal injury in glaucoma. LC plays an important role in providing nourishment to the retinal ganglion cell axons.[12] Deformation and compression of LC enhance the optic nerve ischemia.[13] Thus, the resulting glaucomatous damage shows changes in the optic nerve head. Hence, imaging of LC morphology helps us to understand the generalized character of LC in the population and also in the detection of glaucoma. Earlier, the research on LC was mostly confined to its histology and modeling. But nowadays with advancements in the technologies like optical coherence tomography (OCT), visualization of LC has increased to a much greater extent. Studies have been done where OCT has been used to determine the changes in retinal nerve fiber layer (RNFL) and macular ganglion cell complex thicknesses; and their correlation with early detection of glaucoma and its progression.[14] If we get more knowledge about LC using OCT scans, the diagnosis and management of glaucoma would become easier. There has been the use of various new high-speed and high-resolution imaging devices. Enhanced depth imaging optical coherence tomography (EDI- OCT) and swept-source OCT (SS-OCT), are widely used nowadays to study in depth, the structure-function relationship in eyes.[15] The most commonly evaluated structural parameters are the RNFL thickness, assessed by SPL (scanning laser polarimetry) and OCT, and ONH parameters, assessed by CSLO (confocal scanning laser ophthalmoscopy). These imaging systems scan the visible part of the optic nerve, the optic nerve head (ONH), which is routinely described for documentation of the structural glaucomatous damage.[16] However, now the OCT technology has evolved tremendously, and all the structural parameters of interest can be easily measured. A recent study has shown the usefulness of SD-OCT in quantifying the cup and the rim with help of Bruch’s membrane opening (BMO) as the baseline.[18] Imaging of Bruch’s membrane (BM) is a new approach that helps to evaluate the anatomy of ONH and RNFL with precision. This is the physiological opening for axons of the retinal ganglion cells (RGCs) which are exiting the globe. Imaging by SD-OCT helps in the visualization and evaluation of the BM in high resolution. In our study, we found that • Mean age of ocular hypertension, and healthy controls were 52.62±12.11, and 57.16±11.80 years respectively. • Mean ICP in OHT is 13.6mm hg, and healthy control group is 12.32 mm hg respectively. (p value<0.01) • Mean IOP in OHT is 17.54±2.72mm hg, and healthy control is 14.73±2.04mm hg respectively. (p value<0.001) • Average RNFL thickness for healthy individuals 97.77±8.45µm, and OHT 80.66±11.24µm. (p value <0.001) • Mean TLPD in OHT is 3.94±1.38mm hg, and in healthy

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 19 DOS TIMES controls is 2.41±0.60mm hg. (p value<0.001) • Mean of BMO in OHT is 1670.46±231.19µm, and healthy individual is 1569.66±189.07µm. (p value<0.001 • Mean PTT in OHT is 100.76±29.94µm, and in healthy controls is 109.34±34.15µm. • Mean LCT in OHT is 266.53±63.02µm, and in healthy individuals is 216.28±34.25µm. (p value<0.001) • Mean LCD in OHT is 449.99±102.03µm, and in a healthy individual is 524.26±109.57µm. • LCCI in OHT is 10.87±2.63, and healthy controls is 7.03±1.20. (p value<0.001) • Mean TLPG in OHT is 14.68±3.45 mmHg/mm, and in healthy individuals is 11.13±2.19 mmHg/mm. (p value<0.001) References 1. Nadler Z, Wang B, Wollstein G, Nevins JE, Ishikawa H, Kagemann L, Sigal IA, Ferguson RD, Hammer DX, Grulkowski I, Liu JJ. Automated lamina cribrosa microstructural segmentation in optical coherence tomography scans of healthy and glaucomatous eyes. Biomedical optics express. 2013 Nov 1;4(11):2596-608. 2. Jacob A, Thomas R, Koshi SP, Braganza A, Muliyil J. Prevalence of primary glaucoma in an urban south Indian population. Indian journal of ophthalmology. 1998 Jun 1;46(2):81. 3. Dandona L, Dandona R, Mandal P, Srinivas M, John RK, McCarty CA, Rao GN. Angle-closure glaucoma in an urban population in southern India: the Andhra Pradesh Eye Disease Study. Ophthalmology. 2000 Sep 1;107(9):1710-6. 4. Dandona L, Dandona R, Srinivas M, Mandal P, John RK, McCarty CA, Rao GN. Open-angle glaucoma in an urban population in southern India: the Andhra Pradesh eye disease study. Ophthalmology. 2000 Sep 1;107(9):1702-9. 5. Ramakrishnan R, Nirmalan PK, Krishnadas R, Thulasiraj RD, Tielsch JM, Katz J, Friedman DS, Robin AL. Glaucoma in a rural population of southern India: the Aravind comprehensive eye survey. Ophthalmology. 2003 Aug 1;110(8):1484-90. 6. Vijaya L, George R, Arvind H, Baskaran M, Paul PG, Ramesh SV, Raju P, Kumaramanickavel G, McCarty C. Prevalence of angle-closure disease in a rural southern Indian population. Archives of Ophthalmology. 2006 Mar 1;124(3):403-9. 7. Vijaya L, George R, Arvind H, Baskaran M, Ramesh SV, Raju P, Kumaramanickavel G, McCarty C. Prevalence of primary angle-closure disease in an urban south Indian population and comparison with a rural population: the Chennai Glaucoma Study. Ophthalmology. 2008 Apr 1;115(4):655-60. 8. Vijaya L, George R, Paul PG, Baskaran M, Arvind H, Raju P, Ramesh SV, Kumaramanickavel G, McCarty C. Prevalence of open-angle glaucoma in a rural south Indian population. Investigative ophthalmology & visual science. 2005 Dec 1;46(12):4461-7. 9. Vijaya L, George R, Baskaran M, Arvind H, Raju P, Ramesh SV, Kumaramanickavel G, McCarty C. Prevalence of primary open-angle glaucoma in an urban south Indian population and comparison with a rural population: the Chennai Glaucoma Study. Ophthalmology. 2008 Apr 1;115(4):648-54. 10. Sigal IA, Wang B, Strouthidis NG, Akagi T, Girard MJ. Recent advances in OCT imaging of the lamina cribrosa. British Journal of Ophthalmology. 2014 Jul 1;98(Suppl 2):ii34-9. 11. Quigley HA, Hohman RM, Addicks EM, Massof RW, Green WR. Morphologic changes in the lamina cribrosa correlated with neural loss in open-angle glaucoma. American journal of ophthalmology. 1983 May 1;95(5):673-91. 12. Quigley HA. Glaucoma: macrocosm to microcosm the Friedenwald lecture. Investigative ophthalmology & visual science. 2005 Aug 1;46(8):2663-70. 13. Burgoyne CF, Downs JC, Bellezza AJ, Suh JK, Hart RT. The optic nerve head as a biomechanical structure: a new paradigm for understanding the role of IOP-related stress and strain in the pathophysiology of glaucomatous optic nerve head damage. Progress in retinal and eye research. 2005 Jan 1;24(1):39-73. 14. Wollstein G, Schuman JS, Price LL, Aydin A, Stark PC, Hertzmark E, Lai E, Ishikawa H, Mattox C, Fujimoto JG, Paunescu LA. Optical coherence tomography longitudinal evaluation of retinal nerve fiber layer thickness in glaucoma. Archives of ophthalmology. 2005 Apr 1;123(4):464-70. 15. Rolle T, Briamonte C, Curto D, Grignolo FM. Ganglion cell complex and retinal nerve fiber layer measured by fourier-domain optical coherence tomography for early detection of structural damage in patients with preperimetric glaucoma. Clinical Ophthalmology (Auckland, NZ). 2011;5:961. 16. Chauhan BC, Burgoyne CF. From clinical examination of the optic disc to clinical assessment of the optic nerve head: a paradigm change. American journal of ophthalmology. 2013 Aug 1;156(2):218-27. 17. Jonas JB, Wang NL, Wang YX, You QS, Xie XB, Yang DY, Xu L. Estimated trans‐lamina cribrosa pressure difference versus intraocular pressure as biomarker for open‐angle glaucoma. The B eijing Eye Study 2011. Acta ophthalmologica. 2015 Feb;93(1):e7-13. 18. Pollet-Villard F, Chiquet C, Romanet JP, Noel C, Aptel F. Structure-function relationships with spectral-domain optical coherence tomography retinal nerve fiber layer and optic nerve head measurements. Investigative ophthalmology & visual science. 2014 May 1;55(5):2953-62. Dr. Vinay D, MBBS, DOMS, DNB DDU Hospital New Delhi. Corresponding Author:

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 20 DOS TIMES Artificial Intelligence in Glaucoma Sujani Shroff, MS, Sathi Devi A V, DOMS Narayana Nethralaya, Bengaluru. Abstract: Glaucoma is the second most common cause of irreversible blindness. To make the diagnosis of glaucoma and recommend the appropriate treatment plan, the ophthalmologist needs to integrate clinical examination with subjective visual field testing and objective optic nerve imaging along with other tests. This can be labor intensive especially in regions having a large gap between the population to doctor ratio. In the future, this can be aided by Artificial Intelligence (AI) technology that can simulate intelligent behavior, exhibiting capabilities typically associated with the human mind, such as learning from experience, decision-making, and feature recognition. The use of AI in the field of ophthalmology has notably increased over the last decade. Glaucoma is particularly well suited for AI since the management of many ocular diseases is largely image-based and relies on pattern recognition. Introduction Glaucoma is one of the leading causes of irreversible vision loss worldwide. With a growing elderly population, the prevalence is estimated to increase from 76.0 million in 2020 to 111.8 million in 2040.[1] Although the exact pathophysiological mechanisms of the disease are not fully understood, all types of glaucoma share similar clinical features in functional damage (decrease in visual field sensitivity) and structural changes (optic disc cupping, neuroretinal rim narrowing, reduction of retinal nerve fiber layer and ganglion cell thickness).[2] With its increasing prevalence and commonly asymptomatic presentation, there is a demand for efficient and accurate glaucoma screening tools. As evaluation by specialists can be time consuming, skill dependent, prone to intra and inter observer variability and labor intensive,[3] Artificial Intelligence (AI) can provide useful insights to enhance glaucoma screening and detection.[4-6] This article aims to provide an easy read into the fundamentals of AI, understanding the applications of AI in detecting glaucomatous optic neuropathy and lastly the potential and challenges in adoption of AI into clinical practice. Fundamentals of Artificial Intelligence The term “Artificial Intelligence” was first coined in 1956 by John McCarthy and was defined as the simulation of human intelligence by machines.[7] Machine learning (ML) is a subcategory of AI which aims to develop algorithms that autonomously learn from patterns that they recognize in data without being explicitly programmed.[8] Earlier and traditional ML used complex statistical algorithms which required human programming to transform the data into adequate input features (Feature engineering). As this was time consuming and cumbersome, representation learning gained popularity as this allows the computer to recognize and analyze abstract features from raw data.[9] One of the trademark approaches of this is the use of deep learning (DL) algorithms that have intricate structures inspired by the human brain, known as artificial neural networks (ANNs). ANNs are comprised of layers of ‘neurons’, in which each layer represents a simple mathematical operation. Each layer performs computations on top of the features extracted by earlier layers, and the final output layer produces a specific outcome, such as a classification of the data. This has made it possible to train ANN with many millions or billions of parameters.[10] To accomplish this, DL must be trained to perform a specific task. This involves 3 labeled datasets- training, validation and testing. Training involves providing a dataset to the system where it will learn to predict the label by identifying the most salient features (for example: disease or healthy). The most common method used is supervised learning where the training set is fully labeled to provide the answer (or ground truth) to the question being asked. In unsupervised training, the algorithm is provided with unlabelled datasets with which it learns patterns by grouping raw data according to shared attributes. Semi supervised is a combination of both these methods. Irrespective of the method used, as the program repeats this learning process, it refines and improves until it is optimized for its desired outcome. A separate validation set is used to assess its performance. After the process of training and validation is used to identify optimal parameters, a final separate testing dataset is used to assess the performance of the best network developed using the training and validation datasets. The accuracy, sensitivity, specificity, area under the receiver operating characteristic (ROC) curve (AUCs), positive predictive value, and negative predictive value, are determined by the algorithm’s performance at predicting the testing dataset. It is imperative to keep all the 3 datasets separate to avoid bias and overestimation of performance.[11] Artificial Intelligence in Glaucoma Optic nerve images: Fundus photographs are simple, inexpensive and easy to reproduce. The earliest DL models moved away from feature engineering and attempted to calculate the vertical cup-to-disc ratio from raw images.[12] The newer models went further in classifying the images as ‘suspects’ or ‘certain’ or those that had to be referred by using predefined

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 21 DOS TIMES criteria.[13,14,15] ML algorithms using fundus photographs can help not only detect early glaucomatous optic neuropathy, but also detect and differentiate other optic neuropathies that may mimic glaucoma.[16] An AI study has also used fundus images to estimate the retinal nerve fiber layer (RNFL) thickness by using SD-OCT measurements.[17] The most recent advance is using a smartphone portable device to capture fundus images and run the novel AI software offline to denote referable glaucoma. (Medios glaucoma AI, Medios technologies, Remidio Innovative Solutions, Singapore) Optical Coherence Tomography (OCT): OCT images are less subjective and provide objective quantification of optic nerve damage by measuring RNFL thickness. However segmentation errors can limit the accuracy of OCT analysis. To overcome this, recent AI algorithms use OCT scans without automatic segmentation to detect glaucoma.[18,19] As different SD-OCT machines use different databases and variable measurements, the DL algorithms trained on one machine may have reduced reliability while analyzing data from a different machine. To overcome this problem, a transfer training can be adopted. In this, the model is pre-trained with a separate large dataset from one machine before it is trained with a smaller second training dataset from another machine to improve outcomes.[20] Standard Automated Perimetry (SAP): Visual field (VF) testing is an important tool in detecting glaucomatous optic neuropathy. However, this requires the attentive participation of the patient which can lead to large amount of errors. To overcome this, only reliable fields are included in the algorithms which in turn can compromise on real world experience. The traditional AI algorithm uses clinician grading of the VF to classify as glaucoma or non glaucoma.[21,22] To detect progression, global indices like mean deviation (MD) and pattern standard deviation (PSD) can miss subtle and focal changes while raw point-wise regression models can be very sensitive to small changes. As a trade off, region-wise regression models can strive to detect progression in separate regions.[23] An alternative option is to use an unsupervised algorithm to detect patterns of progression independently.[24] Potential of Artificial Intelligence Numerous AI strategies provide promising levels of specificity and sensitivity for structural and functional test modalities used for the detection of glaucoma. AROC values of > 0.90 were achieved with every modality. Combining structural and functional inputs has been shown to improve the diagnostic ability.[25] Other machine learning techniques utilizing complex statistical modeling have been used to detect glaucoma progression, as well as to predict future progression. In addition, AI holds promise in identifying novel risk factors and evaluating the importance of existing ones.[26] Challenges in adoption of artificial intelligence in clinical practice Universal definition of glaucoma diagnosis and progression: All studies demonstrate the performance of their AI application by comparing the results to a panel of expert clinicians or guidelines set by previous landmark studies. However, these definitions vary across each study as there is no consensus for standard. This makes it difficult to directly compare different AI applications. Data acquisition and population characteristics: Large datasets are required for training the algorithm. This is vendor and device specific. Poor quality data which is excluded is subjective and varies between different studies. Datasets trained in one set of population characteristics (like age, sex, ethnicity) may not be suitable when applied to different patient populations. Black Box decision process: As the ML algorithms recalibrate and adapt through the learning process, they become progressively more incomprehensible, even to experts. This lack of clarity regarding the algorithm is called the “Black Box,” which is a significant challenge in the clinical setting, where it is important to understand how an AI application makes its decisions in order to trust the outcome. Ethical concerns: There is an element of uncertainty when it comes to adoption of new technology especially when definitive metrics are unknown. Decisions in clinical practice are even based on ethics, and social values, personal experiences and beliefs which are subject to multiple interpretations. To convert this to an engineering solution can be challenging and debatable. Conclusion Glaucoma is a complex irreversible disease which has huge potential for screening and avoiding blindness with early detection. With rapidly evolving technology, there is hopeful anticipation for the field of AI to make a meaningful impact on clinical practice. References 1. GBD 2019 Blindness and Vision Impairment Collaborators; Vision Loss Expert Group of the Global Burden of Disease Study. Causes of blindness and vision impairment in 2020 and trends over 30 years, and prevalence of avoidable blindness in relation to VISION 2020: the Right to Sight: an analysis for the Global Burden of Disease Study. Lancet Glob Health. 2021 Feb;9(2):e144-e160. 2. Weinreb RN, Leung CK, Crowston JG, Medeiros FA, Friedman DS, Wiggs JL, Martin KR. Primary open-angle glaucoma. Nat Rev Dis Primers. 2016 Sep 22;2:16067. 3. Jampel HD, Friedman D, Quigley H, Vitale S, Miller R, Knezevich F, Ding Y. Agreement among glaucoma specialists in assessing progressive disc changes from photographs in open-angle glaucoma patients. Am J Ophthalmol. 2009 Jan;147(1):39-44.e1. 4. Ting DSW, Pasquale LR, Peng L, Campbell JP, Lee AY, Raman R, Tan GSW, Schmetterer L, Keane PA, Wong TY. Artificial intelligence and deep learning in ophthalmology. Br J Ophthalmol. 2019 Feb;103(2):167-175. 5. Salazar H, Misra V, Swaminathan SS. Artificial intelligence and complex statistical modeling in glaucoma diagnosis and management. CurrOpinOphthalmol. 2021 Mar 1;32(2):105-117. 6. Ittoop SM, Jaccard N, Lanouette G, Kahook MY. The Role of Artificial Intelligence in the Diagnosis and Management of Glaucoma. J Glaucoma. 2022 Mar 1;31(3):137-146.

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 22 DOS TIMES 7. John McCarthy: Father of AI. IEEE Intelligent Systems. 2002 SepOct;17:84-85. Available from: https://www.computer.org/csdl/magazine/ex/2002/05/x5084/13rRUxE04ph. 8. Samuel AL. Some studies in machine learning using the game of checkers.IBM Journal of Research and Development. 1959 Jul;3(3):210- 229. doi: 10.1147/rd.33.0210. 9. Bengio Y, Courville A, Vincent P. Representation learning: a review and new perspectives. arXiv:12065538 [cs]. 2014. Available from: http://arxiv.org/abs/1206.5538. 10. Hogarty DT, Mackey DA, Hewitt AW. Current state and future prospects of artificial intelligence in ophthalmology: a review. ClinExp Ophthalmol. 2019 Jan;47(1):128-139. 11. Sengupta S, Singh A, Leopold HA, Gulati T, Lakshminarayanan V. Ophthalmic diagnosis using deep learning with fundus images - A critical review. ArtifIntell Med. 2020 Jan;102:101758. 12. Li Z, He Y, Keel S, Meng W, Chang RT, He M. Efficacy of a Deep Learning System for Detecting Glaucomatous Optic Neuropathy Based on Color Fundus Photographs. Ophthalmology. 2018 Aug;125(8):1199- 1206. 13. Phene S, Dunn RC, Hammel N, Liu Y, Krause J, Kitade N, Schaekermann M, Sayres R, Wu DJ, Bora A, Semturs C, Misra A, Huang AE, Spitze A, Medeiros FA, Maa AY, Gandhi M, Corrado GS, Peng L, Webster DR. Deep Learning and Glaucoma Specialists: The Relative Importance of Optic Disc Features to Predict Glaucoma Referral in Fundus Photographs. Ophthalmology. 2019 Dec;126(12):1627-1639. 14. Zhao R, Chen X, Liu X, Chen Z, Guo F, Li S. Direct Cup-to-Disc Ratio Estimation for Glaucoma Screening via Semi-Supervised Learning. IEEE J Biomed Health Inform. 2020 Apr;24(4):1104-1113. 15. Yang HK, Kim YJ, Sung JY, Kim DH, Kim KG, Hwang JM. Efficacy for Differentiating NonglaucomatousVersus Glaucomatous Optic Neuropathy Using Deep Learning Systems. Am J Ophthalmol. 2020 Aug;216:140-146. 16. Medeiros FA, Jammal AA, Thompson AC. From Machine to Machine: An OCT-Trained Deep Learning Algorithm for Objective Quantification of Glaucomatous Damage in Fundus Photographs. Ophthalmology. 2019 Apr;126(4):513-521. 17. Thompson AC, Jammal AA, Berchuck SI, Mariottoni EB, Medeiros FA. Assessment of a Segmentation-Free Deep Learning Algorithm for Diagnosing Glaucoma From Optical Coherence Tomography Scans. JAMA Ophthalmol. 2020 Apr 1;138(4):333-339. 18. Mariottoni EB, Jammal AA, Urata CN, Berchuck SI, Thompson AC, Estrela T, Medeiros FA. Quantification of Retinal Nerve Fibre Layer Thickness on Optical Coherence Tomography with a Deep Learning Segmentation-Free Approach. Sci Rep. 2020 Jan 15;10(1):402. 19. Asaoka R, Murata H, Hirasawa K, Fujino Y, Matsuura M, Miki A, Kanamoto T, Ikeda Y, Mori K, Iwase A, Shoji N, Inoue K, Yamagami J, Araie M. Using Deep Learning and Transfer Learning to Accurately Diagnose Early-Onset Glaucoma From Macular Optical Coherence Tomography Images. Am J Ophthalmol. 2019 Feb;198:136-145. 20. Andersson S, Heijl A, Bizios D, Bengtsson B. Comparison of clinicians and an artificial neural network regarding accuracy and certainty in performance of visual field assessment for the diagnosis of glaucoma. Acta Ophthalmol. 2013 Aug;91(5):413-7. 21. Li F, Wang Z, Qu G, Song D, Yuan Y, Xu Y, Gao K, Luo G, Xiao Z, Lam DSC, Zhong H, Qiao Y, Zhang X. Automatic differentiation of Glaucoma visual field from non-glaucoma visual filed using deep convolutional neural network. BMC Med Imaging. 2018 Oct 4;18(1):35. 22. Wen JC, Lee CS, Keane PA, Xiao S, Rokem AS, Chen PP, Wu Y, Lee AY. Forecasting future Humphrey Visual Fields using deep learning. PLoS One. 2019 Apr 5;14(4):e0214875. 23. Yousefi S, Kiwaki T, Zheng Y, Sugiura H, Asaoka R, Murata H, Lemij H, Yamanishi K. Detection of Longitudinal Visual Field Progression in Glaucoma Using Machine Learning. Am J Ophthalmol. 2018 Sep;193:71-79. 24. Mursch-Edlmayr AS, Ng WS, Diniz-Filho A, Sousa DC, Arnold L, Schlenker MB, Duenas-Angeles K, Keane PA, Crowston JG, Jayaram H. Artificial Intelligence Algorithms to Diagnose Glaucoma and Detect Glaucoma Progression: Translation to Clinical Practice. Transl Vis Sci Technol. 2020 Oct 15;9(2):55. 25. Zheng C, Johnson TV, Garg A, Boland MV. Artificial intelligence in glaucoma. CurrOpin Ophthalmol. 2019 Mar;30(2):97-103. Dr. Sujani Shroff, MS Narayana Nethralaya, Bengaluru. Corresponding Author:

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 23 DOS TIMES The Spectrum of Angle Closure Glaucomas Manish Panday, MS, FMRF Director-Glaucoma, Ratan Jyoti Netralaya, Gwalior Former Consultant, Glaucoma Services, Sankara Nethralaya, Chennai. Introduction Angle closure glaucomas remain a significant public health problem in India, especially due to its silent nature and greater risk of associated blindness. Global prevalence of Primary Angle Closure Glaucoma (PACG) was expected to be 23.36 million in 2020 and projected to be 32.04 million by 2040. Of these, 17.96 million (in 2020) and 24.50 million (in 2040) were from Asians alone.[1] Prevalence of Primary Angle Closure Disease (PACD) in population based studies from India was estimated to be close to 27.66 million.[2] Majority of affected individuals remain asymptomatic during the course of disease which is usually chronic in nature. It is essential to diagnose angle closure disease in early stages as a simple procedure such as laser iridotomy may be the only initial treatment required. Progressive synechial closure of angle can occur despite iridotomy which mandates routine gonioscopy in these eyes. These eyes are also have more propensity to develop complications after surgery such as uveal effusion and/or malignant glaucoma. Pathophysiology of Angle Closure Angle closure typically occurs due to closure of trabecular meshwork at 4 levels. i Iris: The predominant mechanism ex pupillary block ii Ciliary Body: ex Plateau Iris iii Lens: ex thick anteriorly lens/phacomorphic glaucoma iv Vectors posterior to lens: ex malignant glaucoma Angle closure may be classified as primary or secondary, the latter referring to associated ocular or systemic abnormalities responsible for angle closure. In this discussion, we would focus mainly on primary angle closure disease (PACD). Secondary closure are discussed in brief at the end. PRIMARY ANGLE CLOSURE Pupillary block constitutes the key element of primary angle closure which results from increased resistance of aqueous flow from posterior to anterior chamber at the pupillary portion of iris and anterior lens surface. This causes a forward bowing of peripheral iris resulting in closure of trabecular meshwork (‘apposition’). A proportion of these eyes develop permanent adhesion of iris to trabecular meshwork (‘synechiae’). This obstruction to outflow results in raised IOP and subsequent glaucomatous disc damage. Sometimes, this obstruction is rapid causing an acute rise of IOP with marked pain, blurred vision and a red eye (Acute Primary Angle Closure). Current Standardisation and Classification of Primary Angle Closure Disease (PACD) There was a lack of consensus in the past on standardised definitions for angle closure. Current definitions are as based on suggestions by International Society of Geographical and Epidemiological Ophthalmology (ISGEO).[3] An increased emphasis on structural (optic disc) and functional (visual field) changes in diagnosing glaucoma is done. But how much angle closure is clinically significant? By consensus, 2 quadrants (180 degrees) or more of Irido-Trabecular Contact (ITC) in dim illumination is classified as an eye having primary angle closure disease (PACD). Primary Angle closure Disease (PACD) is further classified as Primary Angle Closure Suspect (PACS), Primary Angle Closure (PAC) or Primary Angle Closure Glaucoma (PACG). PRIMARY ANGLE CLOSURE SUSPECT (PACS) An eye where 2 quadrants (180 degrees) or more of posterior trabecular meshwork cannot be seen due to ‘apposition’ of peripheral iris to trabecular meshwork under dim illumination (narrow/occludable angles) in the presence of normal intraocular pressure and no evidence of glaucomatous optic neuropathy/ visual field changes suggestive of glaucoma. PRIMARY ANGLE CLOSURE (PAC) An eye where 2 quadrants (180 degrees) or more of posterior trabecular meshwork cannot be seen have additional signs of either peripheral anterior synechiae or raised intraocular pressure or iris whorling /atrophy/distortion of radial iris pattern or glaucomflecken. Sometimes a blotchy pigmentation of angle without synechiae may be suggestive of intermittent closure. There is still no evidence of glaucomatous optic neuropathy or visual field changes suggestive of glaucoma. PRIMARY ANGLE CLOSURE GLAUCOMA (PACG) These eyes in addition develop structural (glaucomatous optic neuropathy) and/or functional (visual field) damage suggestive of glaucoma in addition to a varied combination of above features. Epidemiology and Natural History of Primary Angle Closure from India Population based studies have provided important insight into the prevalence and incidence of angle closure in India. (Figure 1) Reported prevalence differences between studies occur due to differing methodology and classification of angle closure in these studies.

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 24 DOS TIMES Figure 1: Prevalence of PACD in India. Figure 2: Note the Iris atrophic patches (yellow) and loss of pupillary ruff (white) in an eye with PACG. Vellore eye study (VES) was one of first studies to throw light on glaucoma prevalence in the south Indian population. However, VES incorporated PAC and PACG together into PACG. The actual prevalence of PACG would have been 0.5% alone. A similar prevalence of 0.5% for PACG was reported by Aravind Comprehensive Eye Survey (ACS). The Chennai Glaucoma Study (CGS), using the current ISGEO criteria reported higher rates for PACS, PAC and PACG in the urban cohort as compared to rural one. The prevalence of PACG was noted to be 0.87% in rural and 0.88% in urban cohorts. Besides this, 6.3 % were classified as PACS and 0.7% as PAC in the rural cohort as compared to 7.2 and 2.8% in urban cohorts.[4,5] The Andhra Pradesh Eye Disease Study using the ISGEO criteria reported a prevalence of 0.7% in rural and 1.8% in urban cohorts for PACG. Corresponding prevalence for PACS was 1.5% for rural and 3.5% for urban cohorts and for PAC was 0.2% in rural and 0.8% in urban cohorts.[6] The prevalence of PACS has been noted to be higher than PAC and PACG in these studies, implying that all patients of PACS do not necessarily progress to PAC and PACG and the slow rate of conversion for same. The reported incidence of conversion to PAC was noted in 11 (22%; 95% CI 9.8 to 34.2) out of 50 patients of PACS over a 5 year period (seven synechial and four appositional).[7] Eight (28.5%; 95% CI 12–45%) out of 28 patients of PAC progressed to PACG.8 Of these, two of seven had appositional and six of twenty one had synechial closure. One patient out of nine (11.1%) progressed despite laser iridotomy compared to seven out of nineteen (36.8%) who had refused same, showing the beneficial effect of Iridotomy in these PAC eyes. However none of the patients developed blindness and acute primary angle closure glaucoma in this 5 year period. Risk Factors Compared to normal eyes, eyes with angle closure may have shorter axial length, shallower anterior chambers and increased lens thickness. With increasing age, progressive thickening and forward movement of the lens contributes to narrower angles with time. This necessitates routine gonioscopy in these eyes. Demographic risk factors include increasing age, female gender, Asian ancestry and those with a history of angle closure in family. Diagnosis Diagnosis of angle closure needs a detailed history, slit lamp examination, intraocular pressure assessment with gonioscopy, optic nerve head assessment and investigations as required. History and Clinical Examination: Most primary angle closure glaucomas in Indian eyes are asymptomatic. A patient may present with intermittent attacks of redness or pain with halos and blurred vision in eyes or may present with acute onset of such symptoms. Drugs likely to precipitate angle closure such as such as adrenergic and anticholinergic agents, tri and tetracyclic antidepressants, MAO inhibitors and sulfa based such as topiramate such be recorded along with any history of angle closure in family. Clues for presence of angle closure in some cases may include corneal epithelial edema peripheral anterior chamber depth, iris changes (Figure 2) or glaucomflecken. IOP: Intraocular pressure is preferably assessed with Goldmann’s applanation tonometer. However, IOP cannot be used for diagnosis alone as significant number of people with PACG may present with normal presenting IOP. Gonioscopy: A carefully done goniosopy for diagnosis of angle closure is crucial and helps in follow up and management of these patients. Preferably, indentation gonioscopy is done in patients suspected for angle closure to differentiate appositional from synechial closure. It is first done in dim illumination with a short slit beam avoiding the pupil and then on indentation with a bright light. Careful assessment of the angle structures with their exact anatomic documentation along with iris contour, iris processes and pigmentation of the angle should ideally be done. Gonioscopy is mandatory in all known (PAC, PACG, Post YAG PI) or suspected angle closures (shallow anterior chamber,

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 25 DOS TIMES PACS, family history of glaucoma). Irido-Trabecular Contact (ITC) can be either ‘Appositional’ or ‘Synechial’. As a simple diagnostic tool, gonioscopy gives a dynamic view of angle and is able to differentiate between the two. In appositional closure the iris covers the trabecular meshwork but can be manipulated to move away using indentation gonioscopy with no evidence of synechiae. Synechial closure refers to permanent adherence of iris to trabecular meshwork. Gonioscopy is an ‘art’ and when practiced sufficiently gives information far beyond any diagnostic modality. Optic nerve head and visual fields assessment: Optic disc examination and correlation to visual fields are necessary to plan management approach. Disc assessment with a +78/90 D lens, visual fields and/or imaging of nerve fiber layer may be required Imaging of anterior segment: Anterior segment optical coherence tomography (ASOCT) and ultrasound biomicroscopy (UBM) play a key role in selected patients with angle closure along with others such as SPACImaging and Pentacam. The UBM is specifically suited to image structures posterior to the iris including ciliary body. However, a carefully done gonioscopy still remains the gold standard for diagnosis and management of angle closure glaucomas. Clinical Examples (Q1) A 50 year old male presents for general check up. He has shallow peripheral anterior chamber both eyes. Van Herrick grading was Grade 2 (Limbal chamber depth=25% of cornea thickness) both eyes. His IOP is 12 mm Hg OU. Gonioscopy shows closed angles in dim illumination opening to scleral spur on indentation with no synechiae. Optic discs are healthy. Should I do a YAG PI? (A) Assess the ‘potential’ risk of glaucoma. Assess history in first degree family members and in some cases biometric risk factors. Explain the condition to patient and risk of developing progression in some individuals. Take an informed decision to either treat with YAG PI or not and discuss with patient. YAG PI can be deferred in absence of risk factors if patient is willing for routine follow ups. (Q2) A 55 year old female presents for routine clinical examination due to decreased vision. Anterior segment evaluation showed narrow peripheral anterior chambers with early cataracts both eyes. IOP was 22 mm Hg OU. Gonioscopy showed closed angles opening on indentation to scleral spur in right eye with multiple PAS (see figure). Left eye showed closed angles opening to scleral spur on indentation with blotchy pigmentation of angle but no PAS. Optic discs are healthy both eyes. Mother had glaucoma with laser PI done in both eyes and is blind in one eye. (A) The patient has PAC both eyes. There is a strong family history of glaucoma. Despite presence of cataract, it is advisable to have a YAG PI first in both eyes and reassess the posterior segment after dilation later and decide on further investigations and possible need for anti glaucoma medications. Even if the patient later needs cataract surgery, the laser PI is preferable as first treatment modality in both PAC and PACG eyes as it deepens the anterior chamber and reduces risks from surgical complications. (Q3) A 60 year old male presents for glaucoma evaluation. He gives a history of severe, intermittent pain left eye for 2 months (left eye picture attached-showing dilated pupils with glaucomflecken). Best corrected vision is 6/6 and 6/60 in right and left eye respectively. His IOP is 12 mm Hg right eye and 50 mm Hg left eye. Gonioscopy shows closed angles in dim illumination opening to scleral spur on indentation in right eye and synechially closed angles left eye. Optic discs is healthy in right eye and shows 0.9:1 advanced cupping left eye. Should I do a YAG PI in right eye which has normal IOP?

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 26 DOS TIMES (A) The right eye has PACS and left eye is PACG. The right eye needs YAG PI and the left eye needs IOP lowering followed by definitive treatment by either YAG PI/glaucoma surgery/combined surgery as appropriate with relevant investigations for glaucoma. This is because the fellow eye (right) has a high risk of developing similar course of disease with time. Management Treatment is focussed on 3 aspects 1 IOP Control: Antiglaucoma medications are used to control IOP either for short term prior to laser or surgical procedures or for residual IOP elevation following treatment. All class of drugs can be used. Pilocarpine is contraindicated in lens induced and retrolental mechanisms as it may exacerbate shallowing of chamber angle by forward movement of lensiris diaphragm. 2 Angle Control: A laser PI is done to alleviate pupillary block. A post laser gonioscopy after washout of miotic effect is done to assess areas of synechial and appositional closures. It is important to know that despite iridotomy, non pupillary block mechanisms may cause residual angle closures. Argon laser iridoplasty may be used either as a primary procedure or when corneal edema or residual shallow anterior chamber precludes laser PI. 3 Surgery: Glaucoma surgery is required in failure of medical and/or laser treatment to control IOP or progression despite maximum tolerable therapy. Trabeculectomy/Tube shunts are one of most common glaucoma procedures done. Tube shunts are usually reserved for cases in which conventional trabeculectomy is contraindicated ex prior failed trabeculectomy(s), thinned sclera or scarred conjunctiva etc. The decision for cataract/combined surgery depends additionally on status of crystalline lens-visually significant cataract, lens vault, lens thickness and volume etc. Cataract surgery additionally helps reduce angle crowding and relative pupillary block. Goniosynechialysis has limited evidence and usually combined with lens extraction In presence of visually significant cataract, if IOP is under control in mild-moderate glaucomas, a clear corneal phacoemulsification with IOL implantation would suffice after explaining due risk of needing glaucoma surgery in future and follow ups. In advanced glaucomas with visually significant cataract, a combined cataract and glaucoma surgery would be more appropriate. Surgery needs expertise as these eyes have small bulky lenses, shallow anterior chamber, risk of corneal decompensation and malignant glaucoma. Recent interest on role of clear lens extraction (CLE) in angle closure is due to EAGLE study (Effectiveness of Early Lens Extraction for the treatment of primary angle closure glaucoma).[9] The study recruited phakic subjects aged≥50 years with newly diagnosed PAC with IOP≥30 mm Hg or PACG. The study reported a greater efficacy, better visual quality, higher reduction of medications and preventing further glaucoma surgery in CLE as compared to standard treatment. However patients with advanced glaucoma (MD worse than -15dB/Cup Disc ratios ≥0.9) were excluded. Study had certain limitations. Patients younger than 50 years, PAC with IOP< 30 mm Hg were excluded. Further studies are needed to provide predictive factors to help identify individuals likely to benefit from CLE and no change of current practice patterns are recommended based on the study. PACS When should I do a laser Iridotomy in PACS? As noted all eyes with PACS do not require laser Iridotomy. Besides 20% of angles may remain closed even after YAG PI. The decision for YAG PI in PACS often remains highly subjective. A pragmatic approach is most favourable due to a large affected population and low risk of progression. On the other hand it is impossible to predict which patient will actually comply to routine follow ups. The Zhongshan Angle Closure Prevention (ZAP) trial evaluated the efficacy and safety of prophylactic PI in PACS among Chinese subjects. At 6 years, conversion to PAC was seen in 4.19 per 1000 eye-years for eyes with LPI as compared to 7.97 per 1000 eyeyears in non-LPI eyes. So even if the risk of incident PAC was reduced by half, most conversions happened were “non sight threatening” and caused by development of “PAS” in 45/55 eyes (15/19 in LPI vs 30/36 in non-LPI). The risk reduction translates to overall annual risk reduction by 0.38% and need to treat 44 cases to prevent 1 case of new PAC over 6 years and treating 126 to prevent 1 case of visual loss due to PACG over 10 years. Hence “community based’ large scale prophylactic LPI for PACS is NOT recommended. The following can be relative indications for PI in PACS eyes o Fellow eye of an eye with primary angle closure o Confirmed family history of angle closure glaucoma o Eyes requiring frequent dilation for retinal examination ex proliferative diabetic retinopathy/ recent retinal vein occlusions among others o When follow up is impractical or a poorly compliant patient In case Iridotomy is deferred, patient is warned about symptoms and signs of acute closure and explained routine follow ups. PAC, PACG Laser peripheral iridotomy to relieve pupillary block is preferable as first line therapy for PAC and PACG after controlling IOP if high. Medical treatment should not be used as a substitution of laser in cases of PAC and PACG. After component of pupillary block has been removed, further management on lines of open angle glaucomas is done to prevent pressure induced glaucomatous optic neuropathy and visual field progression by topical hypotensive agents and/or surgery as outlined above. SECONDARY ANGLE CLOSURE Secondary angle closure occurs from known causes which may or may not be associated with pupillary block. (Figure 3)

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 27 DOS TIMES Figure 3: Secondary Angle Closures (A) Trauma causing lens subluxation and pupillary block (B) Neovascular Glaucoma (C) Phacomorphic Glaucoma Etiology Secondary angle closure with pupillary block: -Swollen lens induced (Phacomorphic) -Anterior lens subluxation/dislocation-trauma, laxity of zonules, Marfan’s syndrome -Miotic induced secondary closure- Miotics relax the ciliary muscle, causing forward movement of iris-lens diaphragm and may precipitate angle closure. -Synechiae between iris and crystalline lens/intraocular lens/cornea/vitreous-These cause a physical obstruction to flow of aqueous from the posterior to anterior chambers and may result in ‘iris bombe’. Secondary angle closure with anterior pulling mechanism wit out pupillary block -Neovascular glaucomas -Iridocorneal endothelial syndromes -Inflammation -Post penetrating keratoplasty -Epithelial downgrowth -Aniridia Secondary angle closure with posterior pushing mechanism without pupillary block -Ciliary block glaucoma -Iridociliary cysts -Intravitreal silicon oil/gas induced -Ciliochoroidal effusions -Suprachoroidal haemorrhage -Scleral buckling Treatment of Secondary Angle Closure The treatment for secondary angle closure is directed to the cause or the primary inciting event. This itself in some cases may be the only definitive treatment required. In other cases, a prolonged event can cause a permanent damage causing raised IOP or trabecular meshwork damage/obstruction necessitating further glaucoma manouveres. A few specific conditions are described below. Phacomorphic Glaucoma: An intumescent lens causes a forward movement of iris and consequent closure of angle. This may cause an acute/subacute rise of IOP. Treated in early stages with cataract surgery usually cures the condition. In long standing cases, synechial closure of angle can occur which may warrant glaucoma procedures along with cataract surgery. Post-operative assessment of affected eye with monitoring of IOP, gonioscopy and optic disc is vital for follow ups. Always assess the “fellow eye” for risk of angle closure by routine gonioscopy and manage as per guidelines if at risk for glaucoma. Neovascular Glaucoma: The underlying cause needs to be ascertained if required on consultation with retinal surgeon. Most common causes include proliferative diabetic retinopathy and retinal vein occlusions besides others. Assess visual potential, neovascularization of iris (NVI), IOP, gonioscopy for angle status and neovascularization of angle (NVA) and fundus. Usually, if the angles are not completely synechially closed, an aggressive treatment for the precipitating cause for neovascularization with a medically controlled IOP may suffice. In eyes with poor control of IOP and a glaucoma surgery after control of the neovascular process or in eyes with poor visual potential, a cyclodestructive procedure may be required. Screening for Angle Closure As noted, not all angle closures progress. Also angle closure may progress despite a patent iridotomy. No screening tool is likely to predict progression in an individual. Modalities used to diagnose angle closure may include oblique flashlight test, VanHerick test, gonioscopy and imaging modalities. The flashlight test (Pen Light on oblique illumination) has a poor specificity to be used as screening tool. Slit lamp based determination of peripheral anterior chamber depth (Van Herick <2) has poor sensitivity. Imaging modalities besides being expensive cannot substitute gonioscopy. The best option is to use a combination of these modalities to screen for angle closure in the clinic but all treatment decisions should be done only after gonioscopy. Due to the large affected population with angle closure and poor diagnostic predictability for progression, a case based approach is best suited rather than a population based screening approach. This may apply to family screening (first degree relatives) of subjects with glaucoma/angle closure, stratifying biometrically susceptible eyes in addition to increasing age (>40 years). Conclusions Diagnosing and managing angle closure requires a proactive approach to every patient coming for an eye examination. A basic set of clinical skills including applanation tonometry, indentation gonioscopy and an optic disc assessment suffice to form a diagnosis in most subjects. Even then, it is essential to be able form a “at risk” or “those with disease” stratification for effective follow ups or treatment initiation. An improved understanding of angle closure spectrum and associated risk factors complimented by newer diagnostics and imaging systems help stratify those at need. It is also prudent to screen for angle closure patients during any outreach camps for cataract surgeries or those attending general ophthalmology clinics. References 1. Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology. 2014 Nov;121(11):2081-90.

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 28 DOS TIMES 2. George R, Ve RS, Vijaya L. Glaucoma in India: estimated burden of disease. J Glaucoma. 2010 Aug;19(6):391-7. 3. Foster PJ, Buhrmann R, Quigley HA, Johnson GJ. The definition and classification of glaucoma in prevalence surveys. Br J Ophthalmol 2002;86:238–42. 4. Vijaya L, George R, Baskaran M, et al. Prevalence of angle closure disease in a rural south Indian population. Arch Ophthalmol. 2006;124:403–409. 5. Vijaya L, George R, Arvind H, et al. Prevalence of primary angle-closure disease in an urban south Indian population and comparison with a rural population: the Chennai Glaucoma Study. Ophthalmology 2008;115:655– 60. 6. Garudadri C, Senthil S, Khanna RC et al. Prevalence and Risk Factors for Primary Glaucomas in Adult Urban and Rural Populations in the Andhra Pradesh Eye Disease Study. Ophthalmology 2010;117:1352– 1359. 7. Thomas R, George R, Parikh R, et al. Five year risk of progression of primary angle closure suspects to primary angle closure: a population based study. Br J Ophthalmol.2003;87:450–454. 8. Thomas R, Parikh R, Muliyil J et al. Five-year risk of progression of primary angle closure to primary angle closure glaucoma: a population-based study. Acta Ophthalmol. Scand. 2003: 81: 480–485. 9. Azuara-Blanco A, Burr J, Ramsay C, et al. Effectiveness of early lens extraction for the treatment of primary angle- closure glaucoma (EAGLE): a randomised controlled trial. Lancet 2016;388:1389-1397. Dr. Manish Panday, MS, FMRF Director-Glaucoma, Ratan Jyoti Netralaya, Gwalior Former Consultant, Glaucoma Services, Sankara Nethralaya, Chennai. Corresponding Author:

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 29 DOS TIMES Interpretation of OCT Maps in Glaucoma Sachin S Dharwadkar, DO, DNB, FRCS Director, Samartha clinics, Mumbai. Abstract: Optical coherence tomography has evolved significantly and so has its usage in diagnosis and management of Glaucoma. In such a scenario it is prudent to understand the limitations and its methodical use to prevent or minimise the errors that can occur in its clinical application. This article covers the necessary basics and gives a simple step wise approach to best use the technology to our advantage in management of Glaucoma. Introduction From the days of the seminal work of Huang et al and the start of the time domain Optical coherence tomography, the technology has come a long way. It has undergone a sea change in the last decade and a half and is very rapidly evolving. (Figure 1) Figure 1: Advancement in scan technology and quality, (a) Time domain macular OCT, (b) Spectral domain macular OCT (c) Spectral domain OCT with segmentation. Over the decades the main Achilles heel of glaucoma imaging (posterior segment) has been artefacts and inability to assess progression. Modern technology by using extremely fast scanning speeds (up to 90 kHz), algorithms like image averaging, Auto re scan function, Auto BMO centration and excellent tracking hardware[1] has got around most of these painful drawbacks. Imaging, thus gives us a significant lead time before the development of visual field defects in its modern day avatar. The mere usage of imaging for early diagnosis has given way to its use for assessment of progression in a robust manner. It gives us an objective assessment and quantification vis a vis visual fields which is a subjective test. OCT Angiography also has been an important value addition, albeit not as useful NFL (Nerve Fibre Layer) and Disc parameters in SD (Spectral Domain) OCT in its present form. These advances permit the assessment of progression by adding the reproducibility to imaging and reducing to near insignificance, the test re test variability.[2] Especially pre perimetric progression in green, that is more relevant and clinically significant with young patients with higher life expectancy, can be identified by this method. (Figure 2a and 2b)

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 30 DOS TIMES Figure 3: Progression maps…… CIRRUS and Spectralis. Figure 2: (a) Tracking system in various OCT machines. (b) Eg. Spectralis OCT tracking and alignment. fODi system of torsional alignment in Spectralis OCT. It is however prudent to remember the dynamic range of utility of this technology to optimise its use in patient care. Floor effect (measurements do not decrease after this level) that occurs in moderate to advanced disease (approximately 15 dB of field loss) is an important limitation.[3] From detecting changes in the Ganglion cell complex in earlier devices (GCL (Ganglion cell layer) + IPL (inner plexiform layer) + NFL), it is now possible to segment all the layers of the retina individually. This is helping a great deal in the precise measurement of the ganglion cell layer and the changes occurring therein, with reasonable accuracy. The progression assessment is relatively independent of normative data, and can give the rate of change over time, helping us find the likelihood of vision loss in lifetime: the main aim of glaucoma assessment. It is purely objective, fast and detects change earlier than visual fields. The examination results also give us an event and a trend analysis like the visual fields. (Figure 3)

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 31 DOS TIMES Figure 4: Prototype Printouts of Disc/NFL and Macula scans. Needless to say, extreme discipline and standardisation in image acquisition protocols helps greatly to this end. The issue that however still remains, is that these facilities are not available on all run of the mill machines and they come at a cost. It is important for the end user to understand advantages and more importantly, the limitations of his or her own device. This might well be the difference between its potential use and abuse in management of glaucoma. A word of caution about the normative databases is that 20% of glaucoma can be missed if only global classification followed. Sectoral classifications and more importantly close clinical correlation help significantly in early identification of disease.[4] This approach also helps us avoid the trap of “Red” (false positive) and “Green” (false negative) disease effectively. Interpretation of Scan/Printouts The unit of our interest in glaucomatous damage is the retinal ganglion cell which presents itself to scrutiny at the disc, nerve fibre layer (NFL) and the ganglion cell layer (GCL). It is important to look at this cell in its entirety rather than looking at a part like only Disc, NFL or GCL in isolation. The pattern of loss varies with the aetiology of damage, acute elevation of IOP and vascular events, each having a different pattern of damage than open angle and chronic angle closure. It is important to note here that in the current scenario it is prudent to have a machine that segments the macula (contains > 30% of all RGCs, often early involvement) in addition to the disc and RNFL scans in the armamentarium.[5] Using Disc, RNFL and macula/GCL together would increase sensitivity of detection of glaucoma vis a vis their individual usage, as also allowing effective detection of non glaucomatous changes early. A) Interpretation of the Disc/RNFL Printout All machines usually provide varying permutations of printouts. In most of the cases as the operator is not an ophthalmologist, it is prudent to have a segmented scan image on the printout to be sure about the quality of data. (in addition to the proprietary image scores) The most helpful reports in our experience are the OU reports of the Disc/RNFL scans and a combined map of the Disc, NFL and the GCL as will be shown subsequently. There are certain steps to interpretation of OCT maps which if followed can result in a flawless interpretation in quick time. Important points to be remembered before we embark on examining an OCT report are 1 Validity/applicability of normative databases in given patient-databases have limitations as to their inclusivenessethnicity, eye ball anatomy, refractive errors-can lead to faulty classifications. 2. For interpretation, use maps that show segmented images of Disc, NFL, macula and the quantitative data. The number of useful maps may differ per machine. Look at possible areas of damage rather than expecting machine to point them out. Infero/superotemporal quadrants, or clinically suspect areas. 3. OCT does not diagnose glaucoma and is an imaging tool that gives statistical significance. Clinical relevance of the data and the changes seen therein solely rests with the physician. Steps of Reading an OCT Single Exam Printout (CIRRUS) Figure 4

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 32 DOS TIMES 1. Patient data: Check Name, Age, Note Ethnicity (important for correlation to normative data) 2. Examine for scan quality a) Quality score (Proprietary, >6 is good) b) Black spots or data gaps on thickness map c) Motion artefacts on the IR image-Disc margin/vessel breaks easily seen on difference map d) Look at Tomograms-reflectance maps (AVOID false colours, Use Black and white images)- Limits of BMO, Cup delineation and NFL segmentation contour lines-all should be in order with no gaps/breaks/displacements. 3. Thickness map: understand colour codes that are different in different parts of same printout. Eg. Red (warm colours) indicates a thicker NFL in thickness map and advanced loss in statistical parameters table. The legend of the thickness maps is adjacent to it on the printout. To avoid confusion and aid in visual verification of segmentation, we feel using B/W (black and white/grayscale) for reflectance maps is better. After understanding scale and colour codes, look at Thickness map. Look carefully at the NFL bundle pattern and location (can be split/displaced from its supero/infero temporal location in small/tilted and large discs) as it affects final classification. Wedge NFL defects can also be identified on this map (wedge like defects in cool blue colours). This is raw thickness data and not compared to Normative data. 4. Deviation/Difference map: This is an en face IR (infra-red) image with overlay. Nerve head/cup boundary identification errors should be looked for and ruled out. Here patients thickness data is compared to normative data and flagged as yellow (thickness that is present in <5% normals) and red super pixels (similar values seen in <1 % normals) in areas of thinning. 5. TSNIT graph of the Neuroretinal rim: BMO–MRW (Bruch’s membrane opening-minimum rim width) distance of both eyes plotted (one continuous and one hatched line) and compared to normative data (colour coded background). It is important to look at the profiles in relation to normative data and the inter eye profile asymmetry. 6. A) TSNIT profiles of the RNFL: Data from scan circle (3.46mm) automatically centred on BMO. Data of both eyes plotted on statistically colour coded background by comparing to normative database. Normal pattern is of a classical double hump. Inter eye asymmetry and location/ height profile of the humps should be noted. B) The pie segment charts/clock hour charts below are derived from RNFL TSNIT plot. Correlate the Neuroretinal rim and NFL data and locations of thinning at this point. 7. Parameters table: located at the centre of printout, it has to be seen last. It enumerates all Disc, NFL parameters. Colour code compares it to the normative database. Values falling outside normative database flagged in gray colour. Inter eye asymmetry can be identified and numbers put in perspective here. 8. Examine the macular scans: Scans are read in same way as the NFL maps. Thickness maps, difference maps, reflectance maps, Sectoral classification and parameters table. Here again we stress the avoidance of false colours in reflectance maps to facilitate segmentation assessment. The step wise due diligence is similar to the NFL maps. Correlate the regions of thinning in Disc, NFL and the macular maps using the PANOMAP printout. (note that Panomap does not have segmented reflectance map) 9. Clinically correlate with disc and perimetry and think about alternative pathology in case of gross de correlation, from pattern of classical glaucomatous damage, usually seen as uniform thinning along the entire stretch of disc, nerve fiber layer and ganglion cell in the affected sector/area. Progression on OCT Limitation of the progression testing like floor effect in moderateadvanced disease and the need to refer the scan image on the machine console in case of outliers has to be kept in mind before embarking on interpretation of progression printouts. Unlike the perimetry, where subjectivity leads to test re test variation being common, OCT due to its objective nature and with advanced technology makes outliers a red flag. Lack of consensus about statistically v/s clinically significant progression is the main bone of contention while using imaging progression data in clinical practice. It is important to account for age related decay in each of the measured parameters and its clinical correlation before a therapeutic decision is made. The limits of these may be defined by the resolution of machine or its ability to detect change. On an average it is 0.4-0.6% of baseline thickness per year.[6,7,8] As a thumb rule for those machines that have test retest variability in the 1-2 micron range, <1 mic/yr–slow, 1-2 mic/yrMod, > 2 mic/yr is fast progressor.[9] B) Interpretation of Progression Printout: (CIRRUS)- Guided Progression Analysis (GPA) Printout Figure 5 1. Patient data, scan parameters–proprietary signal strength as per manufacturer recommendation and artefacts (black spots in the thickness maps on printout). Examine the dates of acquired baseline scans. They should be within few months of each other and not too far apart. 2. check for the alignment method in each follow up scan (R2: both translational and rotational alignment-in Cirrus) to ensure appropriate alignment of the images used for analysis. R1 (does not include rotational alignment) is not recommended for usage in analysis. 3. A) Look at the event analysis part of the printout. In the event Analysis the thickness maps and the change maps are available in the Cirrus.

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 33 DOS TIMES If the change exceeds the test re test variability the region is marked in yellow and brown super pixels, depending on the magnitude. (remember it is a statistical change, clinical significance of which is to be decided by surgeon) B) Another part of the event map in Cirrus is the RNFL thickness profile change map. Current exam compared with baselines (B1, B2) and presented as a superimposition (of curves) and changes flagged in colour code mentioned in the legend on the printout. 4. The trend analysis is represented by linear regression of CD ratio, and Average superior and inferior NFL thickness averages plotted over time. The “rate of change” values (calculated from the slope of regression line) therein, give an idea for clinical significance when correlated with history and other findings. The values that are clinically significant also vary depending on the resolution of the individual machine in question. Any outlier in this map is a red flag and a subtle suggestion to visit scan on the console to look Figure 5: 1. Baseline exam with dates (Can be selected) 2. Quality of serial scans methods of Acquisition (R1/ R2) 3. RNFL Thickness Maps And Change Maps 4. Average NFL Maps: Average, Sup, Inf NFL Thickness And Cd Ratio In Trend 5. RNFL Thickness Profile: Current TSNIT Curve With Respect To Baselines 6. NFL/ONH Summary (Colour Coded Deviation of Maps, From Baseline: Possible/Likely Loss).

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 34 DOS TIMES Dr. Sachin S Dharwadkar, DO, DNB, FRCS Director, Samartha clinics, Mumbai. Corresponding Author: for errors and exclude the erroneous scan from analysis if any. Unlike fields, outliers in imaging are indicators of improper techniques or artefacts. 5. RNFL and ONH progression summary: summarises the parameters into a simple colour coded representation. Important labels are “possible loss” and “likely loss” when change exceeds test re test variability on one or multiple occasions. “Possible increase” only occurs due to artefact or pathology such as traction or edema or in segmentation errors. 6. Parameters table: it is the tabular representation of the data. The values that are outside the test re test variability are flagged in a similar colour code as in the progression summary printout. Thus in a very short time we can effectively evaluate the OCT printouts for Glaucoma diagnosis and progression in a simple and systematic manner. Clinical correlation of the OCT data after strict due diligence as above, can tremendously help in therapeutic decision making in glaucoma and is a significant value addition to visual fields tests. Needless to say that awareness of physics, individual machine limitations and possible artefacts help tremendously in getting the desired result and minimise errors in. interpretation. Acknowledgements Dr. Deepak Bhatt, UBM institute, Mumbai for the images. References 1. Reproducibility of retinal nerve fiber layer thickness measurements using eye tracker and retest function of Spectralis SD OCT in glaucomatous and healthy control eyes, Langenegger S J et al, IOVS, May 2011, Vol 52, no 6 2. Reproducibility of Retinal nerve fiber layer measurements using spectral domain optical coherence tomography. Wu h et al. Journal of Glaucoma, 2011:20(8): 470-476.) 3. Retinal nerve fiber thickness floor and corresponding functional loss in Glaucoma. Mwanza et al,J Ophthalmol. 2015 Jun;99(6):732-7. 4. Diagnostic accuracy of Spectralis and Cirrus reference database in differentiating between healthy and glaucoma eyes. Silvermann et al. 2016; 123(2): 408-414 5. Macular versus Retinal Nerve Fiber Layer Parameters for Diagnosing Manifest Glaucoma: A Systematic Review of Diagnostic Accuracy Studies, Oddone et aL, Ophthalmology 2016 May;123(5):939-49 6. Retinal nerve fibre layer imaging with Spectral domain OCT, a variability and diagnostic performance study: Leung C K et al: Ophthalmology; 2009; 116; 1257-63 7. Importance of normal ageing in estimating the rate of glaucomatous neuroretinal rim and nerve fibre layer loss. Vivana et al Ophthalmology. 2015 Dec;122(12):2392-8 8. Impact of age related change on retinal nerve fiber and macular thickness on evaluation of Glaucoma progression. Ophthalmology; 2013: 120: 2485 9. Impact of intra ocular pressure control on rates of retinal nerve fiber loss in a large clinical population. Jammal et al, Ophthalmology; 2021Jan;128(1):48-57

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 35 DOS TIMES Steroids in Vernal Keratoconjunctivitis - A Double Edged Sword? Divya Rajsrinivas, DNB, FICO, Monika Agarwal, MS, Suneeta Dubey, MS, Monica Gandhi, MS, Julie Pegu, MS Department of Glaucoma, Dr. Shroff’s Charity Eye Hospital, Daryaganj, New Delhi, India. Abstract: Vernal keratoconjunctivitis is a chronic allergic disorder affecting young males with a prevalence of 5-15%. Steroids play a critical role in the management of these patients. Long term unmonitored use of topical steroids could result in steroid induced a glaucoma. Bilateral blindness in patients with steroid induced glaucoma is not uncommon necessitating prompt recognition and early treatment. Stopping steroids or moving to steroid sparing drugs appears to be the first step towards reduction of intra-ocular pressures. Further, success of filtration surgeries appears to be quite good even in patients with Vernal Keratoconjuctivitis in recent studies. The key factor that was associated with poor response to treatment was duration of steroid therapy. Therefore, this review is aimed at describing the epidemiology and pathophysiology, enumerating the relation between steroid type and route of administration and effect, promptly identifying the side effects, and discussing the principles of medical and surgical management of steroid-induced glaucoma. Introduction Vernal keratoconjunctivitis (VKC) is a bilateral, chronic, external ocular inflammatory disorder.[1] The reported incidence of VKC in literature ranges from 0.1 to 0.5% of all ophthalmic patients and the prevalence ranged from 5% to 15% among children. VKC commonly affects children and young adult males during the early years. VKC is prevalent in warm and tropical climates.[2] VKC is mediated through type 1 IgE hypersensitivity reaction. Mast cells and eosinophils and their mediators play major roles in the clinical manifestations. The common manifestations include intense itching, redness, watering, mucoid discharge and constant rubbing of eyes. The characteristic examination findings include the presence of papillary hypertrophy of either the palpebral or the limbal conjunctiva, bulbar conjunctival pigmentation, limbal thickening, Horner Trantas dots, shield ulcers and keratoconus. Though anti- allergic medications are effective in treating VKC, severe forms do not respond to anti-allergic medications. Under these circumstances, topical steroids tend to be used as they are effective in controlling the symptoms. However, long term steroid use can predispose to development of cataract, raised IOP and glaucoma. The advent of newer alternative therapies has proven to be promising as it avoids the complications due to long term steroid abuse. Immunomodulators such as cyclosporine A and tacrolimus inhibit T cells and thereby reduce the levels of inflammatory cytokines. Therefore, they act as steroid sparing agents and aid in preventing recurrences.[3] The term steroid-induced iatrogenic glaucoma first came into existence in the 1950s with the observation of glaucoma following the use of systemic adrenocorticotropic hormones and topical or systemic steroids. The purpose of this review is to describe the risk factors, pathophysiology and management of corticosteroid induced glaucoma How Common is Steroid Abuse in India? A hospital based study from Maharashtra concluded that nearly a third of the 500 prescriptions had topical corticosteroids. Of them, 98% were very potent corticosteroids, and in 85% of cases the basis of prescribing topical steroids could not be established.[4] In another retrospective study by Gupta et al (2015) a surge in steroid induced glaucoma in paediatric patients was seen due to the increased incidence of VKC and usage of steroids. Nearly two third of children with steroid induced glaucoma were blind in one or both eyes. This is due to the fact that dexamethasone is easily available over the counter at an affordable price than tacrolimus a steroid sparing agent which can be used as an alternative in VKC.[5] These topical steroids were prescribed without counselling the parents or patients about the disease. The patients continued to use the steroids, because of the quick relief in symptoms of VKC. Injudicious use of steroids and inadequate monitoring led to steroid induced complications like ocular hypertension, glaucoma and cataract affecting vision markedly. Vision loss resulting from cataract is reversible and relatively easy to manage but glaucoma is often recognised late leaving patients with permanent visual impairment. What are the Risk Factors? When there was an increase in IOP following administration of steroids, it was indicative of the responsiveness of the trabecular outflow facility to steroids. In most instances the steroid responsiveness is noted in the first 6 weeks of initiation of steroids. Family history of primary open-angle, high myopia,

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 36 DOS TIMES diabetes mellitus and connective tissue disorders all predispose to exaggerated response to steroid administration. Extreme age group seem to be vulnerable and show an accelerated response to steroids.[6] A rapid rise and higher peak in IOP all seem to predispose to development of SIG. Ang et al (2012) described the clinical characteristics and risk factors in children with severe VKC. In most patients an increase in IOP was detected nearly 8 weeks after commencing topical corticosteroid therapy. They also observed that mixed type of VKC predisposed to development of SIG more commonly that limbal or palpebral forms. The other risk factors included limbal neovascularization in more than 3 quadrants and corneal involvement. Treatment risk factors included longer duration of corticosteroid use and topical dexamethasone 0.01% use.[7] How do you Define Steroid Induced Glaucoma and Ocular Hypertension? Steroid Induced Glaucoma 1. ONH changes characteristic of glaucoma (Vertical Cup disc ratio of more than 0.7:1 or more, inter eye asymmetry of more than 0.2/focal or diffuse neuroretinal rim thinning/ localized notching) 2. Characteristic glaucomatous field defects (Hodapp Parish Anderson criteria) 3. Open angles 4. IOP >21 mm Hg at time of diagnosis[8] Steroid Induced Ocular Hypertension 1. Subjects with a normal anterior segment with a deep anterior chamber 2. IOP >21 mm Hg on Goldman Applanation tonometry 3. Normal appearing optic disc, with intact neuroretinal rim with no evidence of glaucomatous cupping. 4. Minimum of two reliable normal visual fields, defined as pattern standard deviation (PSD) within 95% confidence limits and a glaucoma hemifield test (GHT) result within normal limits[8] How Common is Steroid Induced Glaucoma and Secondary Blindness in VKC? Nearly 85% of VKC patients tend to require steroid therapy. The reported incidence of glaucoma in patients with VKC receiving corticosteroid therapy is 2–7%.[6] Ang et al (2012) reported that incidence of steroid induced glaucoma (SIG) among VKC patients treated with steroids was 5% in the Asian population. Blindness due to steroid induced glaucoma was noted in 44% of VKC patients with SIG. Of them nearly 75% were bilaterally blind.[7] Further blindness was noted in more than a third of patients with SIG by Gupta et al.[5] They also noted a high proportion of bilateral blindness. The clinician should carefully watch for signs of ocular hypertension. If ocular hypertension is not addressed promptly can lead to glaucomatous optic neuropathy and irreversible loss of vision.[6] How do you Classify Steroids Based on Potency and IOP Responses? Highly potent: Dexamethasone 0.5% and Betamethasone 0.2% Moderately potent: Prednisolone acetate 1% Weakly potent: Loteprednol and Fluorometholone 0.1% In general, the pressure-inducing effect of steroids is directly proportional to its anti-inflammatory potency. However, the pressure-inducing potency is related to the dosage of the drug used.[9] Based on the IOP response to topical administration of betamethasone and dexamethasone, Armaly and Becker suggested three categories: 1. High responders (4 to 6% of the population)–developed an IOP greater than 31 mm Hg or a rise of more than 15 mm Hg from baseline. 2. Moderate responders (about 1/3 of the population)- developed an IOP between 25-31 mm Hg or a rise of 6-15 mm Hg from baseline. 3. Non-responders (about 2/3 of the population)–found to have an IOP less than 20 mm Hg or a rise of less than 6 mm Hg from baseline. Another factor that determines the potency of the steroid is its chemical structure. Acetates are more lipophilic and penetrate the cornea better than phosphates which are relatively hydrophilic; hence, dexamethasone acetate 0.1% can cause greater rise in IOP than other kinds of preparations.[10] What are the Routes of Steroid Administration? Exogenous corticosteroids are more likely to cause IOP elevation. The various routes are as follows (table 1). Steroid preparation IOP elevation in mm Hg(mean +- SD) Dexamethasone 0.1% 22.0±2.9 Prednisolone 1% 10.0±1.7 Dexamethasone 0.005% 8.2±1.7 Fluoromethalone 0.1% 6.1±1.4 Hydrocortisone 0.5% 3.2±1.0 Tetrahydrotriamcinolone 0.25% 1.8±1.3 Medrysone 1.0% 1.0±1.3 1. Topical therapy: This route of administration is more commonly associated with a rise in IOP when compared with the other routes. Any topical formulation applied directly to the eye or over the skin of the eyelids appear to cause an elevation in IOP.[11] 2. Periocular therapy: Periocular injections of repository corticosteroid due to their prolonged duration of action is considered to the most dangerous route of administration.

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 37 DOS TIMES Intraocular pressure elevation may occur in response any method of peri-ocular therapy be it sub conjunctival, sub tenon, or retrobulbar injection of steroids. 3. Intravitreal therapy: Intravitreal depot steroid have also shown to be associated with an elevation in IOP. Ozurdex, a slow release Intravitreal implant of dexamethasone used in the treatment of various conditions including macular edema secondary to vein occlusions and for the treatment of uveitis has been shown to cause an elevation in IOP. Previous studies have indicated that >10 mm Hg IOP increase from baseline occurs in 12.6% of patients after the first treatment and 15.4% after the second dose of Ozurdex. Intravitreal injection of triamcinolone on the contrary can increase IOP by several mm Hg in about 50% of patients, within 2 to 4 weeks after the start of treatment.[12] 4. Systemic therapy of steroids is the least likely route to causing IOP elevation. There exists a strong association between inhaled corticosteroid and the presence of ocular hypertension and the risk increased with higher dose and more puffs in patients with family history of glaucoma. However, Bernstein and Schwartz have noted in their paper that long-term systemic therapy is associated with greater increase in IOP and that longer duration of use was associated with significantly higher IOP. What are the Challenges in Paediatric Age Group? The presence of elevated IOP in children is particularly worrisome. Clinically, glaucoma is symptom-free until significant damage has been done to the eye. Children may not be able to effectively communicate about symptom changes, and in particular, measurement and monitoring of IOP in children is much more difficult than in adults. By no means should the disease reach an advanced and irreversible stage and, thus, should be prevented and treated early. What is the Underlying Pathophysiology? 1. Corticosteroids tend to decrease aqueous outflow by inhibiting degradation of extracellular matrix material in the trabecular meshwork (TM). This leads to aggregation of an excessive amount of extracellular matrix within the outflow channels which in turn causes increase in outflow resistance. Two types of ECM deposition are noted. A fingerprint-like deposition of material in the uveal meshwork and an accumulation of fine fibrillary material in the juxtacanalicular region.[13] 2. The metabolism of mucopolysaccharides could be altered resulting in their accumulation in the TM. Corticosteroids by maintaining the lysosomal membranes could reduce the release of lysosomal hyaluronidase. This can result in a relative inhibition of hyaluronate depolymerisation. As a consequence of the above mucopolysaccharides tend to accumulate resulting in retention of water (‘biological oedema’) and subsequent narrowing of the trabecular spaces.[14,15] 3. There appears to be an increase in the amounts of glycosaminoglycan, elastin, and fibronectin. To second this there has been a documented increase in the above substances in tissue culture preparations in response to dexamethasone treatment. To the contrary, the levels of tissue plasminogen activator, stromelysin, and the activity of several TM metalloproteases have been shown to fall.[16] 4. TM cells have phagocytic properties. They function to clear the outflow channels of debris. Steroids could potentially induce inhibition of phagocytosis within the meshwork. This could result in accumulation of channel debris and decreased facility of outflow thereby contributing to steroidinduced glaucoma.[17] 5. Dexamethasone caused cross-linkage of actin fibres, leading to the formation of networks within cultured human TM cells. The actin network structure was reversible following cessation of corticosteroid administration to the cultures.[18] Does Genetics Play a Role? In 1964, Becker and Hahn suggested that patient response to corticosteroids could be explained by a monogenic autosomal mechanism. Homozygotes appeared to be high responders and heterozygotes appeared to be medium responders. In dexamethasone-treated TM cells several genes tend to be upregulated. They include the following: alpha-1- antichymotrypsin, pigment epithelium-derived factor, cornea-derived transcript factor 6 and a prostaglandin D2 synthase enzyme. However, the key and exhaustively studied gene is the one representing the protein myocilin. The gene was identical to GCL1A and is now referred to as the myocilin gene.[19] The myocilin gene has been shown to be induced in human cultured TM cells after exposure to dexamethasone for 2–3 weeks. Myocilin appears to be the main factor in corticosteroid-induced ocular hypertension. First, myocilin is highly expressed in glucocorticoid exposed trabecular cells. Second, the delay in its expression of myocilin parallels the delay in the pressure rise in glucocorticoid-treated eyes. Finally, the dose required to cause the protein expression and to raise IOP appear to be similar.[13] Despite the above, there have been conflicting results in experiments aimed at altering the expression of myocilin in TM cells. Further, mice that have been genetically engineered to overexpress myocilin have not shown an increase in intraocular pressure.[20] Therefore the jury is still out on the role of myocilin in steroid induced glaucoma. Tenets of Steroid Therapy Good initial dose: Long-term moderate dosing of a steroid is more likely to result in steroid induced complications than initial treatment with high doses of a strong steroid that is tapered and switched to a lower-strength steroid. Taper once inflammation is under control: Long-term goal is either to completely eliminate steroid therapy or to find the absolute minimum maintenance dose. Move to a steroid sparing agent instead of systemic corticosteroid therapy: For chronic inflammatory conditions that require

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 38 DOS TIMES long-term maintenance therapy, corticosteroid tapering usually can be accomplished by adding an immunomodulatory agent.[21] How do you Manage Steroid Induced Glaucoma? The first and most important step is to stop the steroids. An acute elevation of IOP in response to steroids is likely to resolve in a few days. However, it may take up to 4 weeks for IOP increase due to chronic corticosteroid exposure to resolve. The response to steroid cessation depends on the type, route of administration and duration of use of steroids. Kaur et al noted resolution of SIG after cessation of steroids in nearly 44% of patients.[22] Furthermore, Ang et al observed that IOP dropped considerably after cessation of steroids when topical steroids were used for 8 weeks or less.[23] To the contrary, surgical intervention to control IOP in SIG has been reported to be as low as 16.5% in some studies and as high as 45% in other studies. The need for surgical intervention to control IOP was noted in nearly a third of patients when steroids were used for nearly 24 months.[23] This was further seconded by Ang et al who inferred that the key predictor for surgical intervention for SIG in VKC was duration of steroid therapy. They noted a 6-fold chance when steroids were continued for 18 months. Long term exposure to topical corticosteroids potentially results in permanent damage to trabecular meshwork necessitating surgical management. However, when the route of administration of steroids were systemic, medical therapy alone seemed to be effective. When cessation of steroid therapy is not possible, one can consider using a corticosteroid that is less likely to cause an increase in IOP. Alternatively, nonsteroidal anti-inflammatory drugs (NSAIDs) or steroid sparing agents like cyclosporine or tacrolimus can be employed. Cyclosporine, an immunomodulatory drug has shown to be effective in reducing steroid dependence. It modulates Th2 response thereby reducing mast cell histamine release and eosinophilic infiltration. However, cyclosporine did not modify the risk of steroid response or the need for surgery.e,f Aqueous suppressants like beta blockers and carbonic anhydrase inhibitors are very effective than prostaglandin analogues which are uncomfortable in VKC children. Trabeculectomy appears to be an effective method to treat those patients who have a persistently raised IOP following cessation of corticosteroid therapy and are refractory to medical therapy. However, the success of trabeculectomy may be questionable in eyes with conjunctival inflammation and scarring. Chronic conjunctival inflammation in VKC predisposes to long-term failure of glaucoma filtering surgeries and higher rates of repeat surgeries.[6] More certainly the success rates appear to be lower compared to when filtration surgery is performed for SIG from other causes. Ang et al noted more than 80% success in controlling IOP with trabeculectomy. They also observed that direct application of Mitomycin C 0.02% soaked in surgical sponges on to the bare sclera in the superior fornix during trabeculectomy had a substantial effect on the clinical course of VKC in their patients. Further, a general improvement of the ocular surface and reduced corneal epitheliopathy was noted with MMC which resulted in better BCVA.[23] Recently Senthil et al noted that there were no significant rates in the complete and qualified success between the surgical groups: trabeculectomy, trabeculectomy with mitomycin C and trabeculectomy with cataract surgery. The complete success rates at 5 years were 76% with trabeculectomy, 71% with trabeculectomy with mitomycin C and 66% with combined trabeculectomy and cataract surgery. They key factors that predict surgical failure include long duration of VKC and long duration of steroid.[25] More than third of the patients who underwent filtration surgery were eventually blind at last follow up. Conclusion Steroid induced glaucoma and resultant blindness is a serious problem and the clinician should take up the responsibility to educate the patients about sight-threatening complications of steroid medications. Surgical failures attributable to conjunctival inflammation is not uncommon in steroid induced glaucoma in VKC. Henceforth, every effort should be taken to raise awareness about the judicial use of steroids and to switch to steroid-sparing medications to prevent these serious complications. When steroids are indicated, prescribing a low-dose steroid and closely monitoring for side effects like elevated IOP could prevent blindness due to SIG in young children. Educating children and parents on the risk of unmonitored use of steroid medications would go a long way in preventing glaucoma and its blinding sequel in children with VKC. References 1. Buckley RJ. Allergic eye disease – a clinical challenge. Clin Exp Allergy. 1998;28(Suppl 6):39–43. 2. Choi H, Lee SB. Nonseasonal allergic conjunctivitis in the tropics: experience in a tertiary care institution. Ocul Immunol Inflamm. 2008;16(4):141–145. 3. Lambiase A, Leonardi A, Sacchetti M, et al. Topical cyclosporine prevents seasonal recurrences of vernal keratoconjunctivitis in a randomized, double-masked, controlled 2-year study. J Allergy Clin Immunol 2011;128:896–7. 4. Rathod SS, Motghare VM, Deshmukh VS, Deshpande RP, Bhamare CG, Patil JR. Prescribing practices of topical corticosteroids in the outpatient dermatology department of a rural tertiary care teaching hospital. Indian J Dermatol 2013;58:342 5. 5. Gupta S, Shah P, Grewal S, Chaurasia AK, Gupta V. Steroid-induced glaucoma and childhood blindness. Br J Ophthalmol. 2015 Nov;99(11):1454-6. doi: 10.1136/bjophthalmol-2014-306557. Epub 2015 May 22. PMID: 26002945. 6. Sihota R, Konkal VL, Dada T, Agarwal HC, Singh R. Prospective, long-term evaluation of steroid-induced glaucoma. Eye (Lond). 2008;22(1):26–30. 7. Ang M, Ti SE, Loh R, et al. Steroid-induced ocular hypertension in Asian children with severe vernal keratoconjunctivitis. Clin Ophthalmol. 2012; 6:1253-8. 8. Foster PJ, Buhrmann R, Quigley HA, et al.: The definition and classification of glaucoma in prevalence surveys. Br J Ophthalmol. 2002; 86(2): 238–42. 9. Shiono H, Oonishi M, Yamaguchi M, Sakamoto F, Umetsu A. Posterior subcapsular cataracts associated with long-term oral corticosteroid therapy. Ophthalmologic observations indicate these are frequent

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 39 DOS TIMES though clinically unsuspected. Clin Pediatr (Phila). 1977;16:726-8. 10. Kersey JP, Broadway DC. Corticosteroid-induced glaucoma: a review of the literature. Eye (Lond). 2006;20:407-16 11. Cubey RB. Glaucoma following the application of corticosteroid to the skin of the eyelids.Br J Dermatol 1976 Aug;95(2): 207-208 12. Vedantham V. Intraocular pressure rise after intravitreal triamcinolone. Am J Ophthalmol 2005 Mar;139(3):575. 13. Wordinger RJ, Clark AF. Effects of glucocorticoids on the trabecular meshwork: towards a better understanding of glaucoma. Prog Retina Eye Res 1999; 18: 629–667. 14. Francois J. Corticosteroid glaucoma. Ann Ophthalmol 1977; 9: 1075– 1080 15. Armaly MF. Effect of corticosteroids on intraocular pressure and fluid dynamics: I. The effect of dexamethasone in the normal eye. Arch Ophthalmol 1963; 70: 482–491. 16. Snyder RW, Stamer WD, Kramer TR, Seftor REB. Corticosteroid treatment and trabecular meshwork proteases in cell and organ culture supernatants. Exp Eye Res 1993; 57: 461–468 17. Shirato S, Bloom E, Polansky J, Alvarado J, Stilwell L. Phagocytic properties of confluent human trabecular meshwork cells. Invest Ophthalmol Vis Sci 1988; 29: S125. 18. Clark AF, Wilson K, McCartney MD, Miggans ST, Kunkle M, Howe W. Glucocorticocoid-induced formation of crosslinked actin networks in cultured human trabecular meshwork cells. Invest Ophthamol Vis Sci 1994; 35: 281–294 19. Polansky JR, Fauss DJ, Chen P, Chen H, Liltjen-Drecoll E, Johnson D et al. Cellular pharmacology and molecular biology of the trabecular meshwork inducible glucocorticoid response gene product. Ophthalmologica 1997; 21: 126–139. 20. Zilling M, Wurm A, Grehn FJ, Russell P, Tamm ER. Overexpression and properties of wild-type and Tyr437His mutated myocilin in the eyes of transgenic mice. Invest Ophthalmol Vis Sci 2005; 46: 223–234. 21. Friedman NJ, Kaiser PK. Ocular pharmacology. In: Essentials of Ophthalmology. Philadelphia: Elsevier; 2007:25-32. 22. Kaur S, Dhiman I, Kaushik S, et al. Outcome of ocular steroid hypertensive response in children. J Glaucoma 2016;25:343–7. 23. Ang M, Ho C-L, Tan D, et al. Severe vernal keratoconjunctivitis requiring trabeculectomy with mitomycin C for corticosteroid-induced glaucoma. Clin Exp Ophthalmol 2012;40:e149–55. 24. Senthil S, Thakur M, Rao HL, Mohamed A, Jonnadula GB, Sangwan V, Garudadri CS. Steroid-induced glaucoma and blindness in vernal keratoconjunctivitis. Br J Ophthalmol. 2020 Feb;104(2):265-269. 25. Senthil S, Rao HL, Ali MH et al. Long-term outcomes and risk factors for failure of glaucoma filtering surgery in eyes with vernal keratoconjunctivitis and steroid-induced glaucoma. Indian J Ophthalmol. 2022 Mar;70(3):820-825. Dr. Suneeta Dubey, MS Medical Superintendent Head, Glaucoma services Dr. Shroff’s Charity Eye Hospital Corresponding Author:

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 40 DOS TIMES Normal Tension Glaucoma Simplified: A Review Article Shweta Tripathi[1], DNB, MNAMS, FMRF, J S Bhalla[2], MS, DNB, MNAMS, Shalini Mohan[3], MS, DNB, MNAMS 1. Senior Consultant Glaucoma Services, Indira Gandhi Eye Hospital and Research Centre, Lucknow. 2. Consultant Head of Glaucoma Services and Incharge Academics, DDU Hospital, New Delhi. 3. Professor, Officer Incharge Glaucoma Services, Dept of Opthalmology, GSVM Medical College, Kanpur. Abstract: Glaucoma is one of the leading causes of permanent blindness. The most significant risk factor is elevated IOP. Normal tension Glaucoma comprises of cases with normal pressure and clinical signs of Glaucoma. This article discusses the pathophysiology, symptoms and management of Normal Tension Glaucoma. Keywords: Glaucoma, IOP, Normal Tension Glaucoma. Introduction Glaucoma is the leading cause of irreversible blindness and second leading cause of blindness, leading to a huge burden of the world.[1] Glaucoma is characterised with progressive optic neuropathy, optic disc cupping and visual field loss, associated with raised intraocular pressure (IOP). Several factors contributing to glaucomatous optic Neuropathy are increased intraocular pressure (IOP), Migraine headache, family history, systemic hypertension. Glaucoma is a gradual degeneration of retinal ganglion cells (RGCs) and optic nerves axons. Retinal ganglion cells are the neuron cells of central nervous system, cell bodies of the neurons being present in the interior retina and their axons being present in optic nerve. Actual Biological basis and factors contributing to the progression of glaucoma are still not fully understood. Main reason yet known for glaucoma is the increased intraocular pressure within the eye, which is responsible for the degeneration of retinal ganglion cells and nerve cells.[2] Normal-tension glaucoma (NTG), also known as normal or low-pressure glaucoma, is defined as open-angle glaucoma with a presenting IOP in the normal range.[3] “Von Graefe” described for the first time a condition that is now referred to as normal or low-tension glaucoma. In the early 1900s, applying tonometry and ophthalmoscopy NTG was recognized as a new clinical entity. Due to the lack of understanding of the underlying pathophysiology of NTG a variety of terms, such as pseudoglaucoma, paraglaucoma, low-tension glaucoma or glaucoma without high pressure and arteriosclerotic optic atrophy have been coined. Intriguingly, we know today that glaucomatous optic disc excavation and visual field loss is found, varying with age, in 30–90% of patients with IOP within a normal range, a condition that is now named NTG. Given the complexity of the pathophysiology of NTG, probably a term like “normal tension glaucomatous optic neuropathy’’ would be more fitting.[4-7] In order to determine the role of IOP in NTG, the “Collaborative Normal-Tension Glaucoma Study” was initiated. One eligible eye of 145 subjects with NTG was randomized either to no treatment (control) or to a 30% IOP reduction from baseline. After 3 years, an overall analysis showed a survival of 80% in the treated arm and 60% in the control arm. The 5-year survival figures were 80% in the treated arm and 40% in the controls.[8] The Kaplan– Meier curves were significantly different (P=0.0018). Visual field loss appeared in both groups, 22/66 in the treated and 31/79 in the untreated group. Although the difference was statistically significant the clinical relevance seemed less impressive. It became evident that although pressure lowering of 30% can be beneficial in some patients, it did not stop the progression in all patients. Therefore, pressure alone can not explain the optic nerve degeneration in NTG as a sole factor.

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 41 DOS TIMES Normal IOP leads to mechanical damage and to stress on the axons in the lamina cribrosa Vascular dysregulation Higher than normal pressure gradient across the lamina cribrosa NTG is caused by impaired CSF circulation in the subarachnoid space of the optic nerve and this results in a toxic damage to the nerve The nutrition of the axons within the lamina cribrosa is considered to be dependent on oxygen and nutrition from the capillaries within the lamina cribrosa. Damage to axons, capillaries and astrocytes in the biomechanical paradigm is thought to be caused by lamina cribrosa deformation and IOP-related stress and strain onto axons, capillaries and astrocytes within the lamina cribrosa. Ocular perfusion was mediated by ischemia instead of mechanical compression of the optic nerve fibers. Several studies revealed that insufficient blood supply leads to retinal ganglion cell loss. While IOP exercises a force from within the eye (anteriograde) onto the lamina cribrosa, cerebrospinal fluid is the counterforce at the back side of the lamina cribrosa, The lamina cribrosa and the optic nerve axons are located between two pressure zones, intraocular pressure (IOP) and intracranial pressure (ICP). The difference between these two pressures OS translaminar pressure. Studies have found a positive correlation between the translaminar pressure and the neuroretinal rim area. Clinical Features: In the consensus report on NTG by China Wang et al[12], they described NTG afflicting 1% of the Chinese population, and that NTG comprises 70% of POAG cases. They found that patients meeting the characteristics of Flammer Syndrome (FS) have a lower intracranial pressure, leading to an increased gradient at the lamina cribosa, and a resultant decrease in perfusion of the optic nerve. Flammer syndrome, which is often associated with NTG, describes a phenotype of people having a predisposition for an altered vascular reaction to stimuli such as cold, emotional stress or high altitude. Common symptoms are: cold extremities, low blood pressure, prolonged sleep onset time[13], reduced feeling of thirst, increased sensitivity to odor and Pain. Some ocular clinical features can be summarized as below: 1. Cupping can manifest in the form of localized Neuro retinal rim thinning/focal notching. 2. In few cases shallow cupping with pallor of the disc with surrounding tissue to some extent is observed. 3. Myopics require a more careful disc evaluation as being more prone for the occurrence of NTG. The frequent coexhisting temporal crescent in myopes causes the visual field scotomas to be closer to fixation. Geijssen and Greve[14] felt that there were three distinct groups of NTG patients according to their optic disc appearance-focal ischaemic, senile sclerotic, and myopic-each with diverent prognostic and possibly aetiological significance. Levene concluded in his review that the extent of disc cupping in NTG is often greater than would be expected from the size and depth of the visual field defect present. Other authors have found no diverences in the pattern of cupping between NTG and HTG.[15] 4. Peripapillary atropy/Crescent/Halo in the form of absent RPE is more frequent association of NTGs. 5. Splinter hemorrhages indicating a uncontrolled disease process & is more commonly seen in NTG, but can occur in HTG (High Tension Glaucoma). Visual Fields: Superior dense arcuate scotoma/superior hemifield defect closer to fixation are commoner in NTG when compared to HTG. According to the most recent reports the real differences do exist in the degree of localisation and the location of the visual field defects seen in NTG and HTG. Diagnosis When the cupping/Visual Field Defect (Closer to fixation in presence of subtle disc changes) like glaucoma are discovered in the absence of an abnormally high IOP, the working diagnosis can be that of NTG. Confirmation of the diagnosis of NTG is only made after ruling out other causes of glaucomatous cupping/Visual Field Loss. Differential Diagnosis 1. Physiological Cupping 2. Burnt Out Glaucoma 3. Past Event of any Heamodynamic Crisis 4. Large optic disc Drusen 5. Anterior ischemic optic neuropathy 6. Intracranial Tumors Neurological Evaluation of the NTG Patient 1. If the disc/field correlation is not Established-that is, have Pathophysiology[9-11]

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 42 DOS TIMES pale discs without glaucomatous cupping 2. Visual Field Patterns obeying the Vertical Meridian with neurological defects. 3. If the patient is young and the aforementioned causes of cupping is excluded. Management 1. IOP lowering Treatment Options: Target is to lower IOP by approximately 25% which can be achieved by Antiglaucoma medications PG analogues the 1st Drug of Choice. 2 NON IOP Lowering Treatment Options: CaChannel Blockers along with some Neuroprotective Agents can be considered. References 1. Zhang, N., Wang, J., Li, Y. et al. Prevalence of primary open angle glaucoma in the last 20 years: a meta-analysis and systematic review. Sci Rep 11,13762 (2021). https://doi.org/10.1038/s41598-021- 92971-w. 2. Kumarasamy N, Lam F, Wang A, Theoharides T (2006) Glaucoma: Current and developing concepts for inflammation, pathogenesis and treatment. European Journal of Inflammation 4(3): 129-137. 3. Lee BL, Bathija R, Weinreb RN. The definition of normal-tension glaucoma. J Glaucoma. 1998 Dec;7(6):366-71. [PubMed] 4. Grewe R. [The history of glaucoma]. Klin Mon Augenheilkd. 1986;188:167–9. 5. Graefe AV. Über die Iridectomie bei Glaucom und über den glaucomatösen Prozess. Albrecht Von Graefes Arch Klein Exp Ophthalmol. 1857;3:456. 6. Klein BE, Klein R, Sponsel WE, et al. Prevalence of glaucoma. The Beaver Dam Eye Study. Ophthalmology. 1992;99:1499–504. 7. Cho HK, Kee C. Population-based glaucoma prevalence studies in Asians. Surv Ophthalmol. 2014;59:434–47. 8. Collaborative Normal-Tension Glaucoma Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am J Ophthalmol. 1998;126:498–505. 9. 9.Drance S, Anderson DR, Schulzer M. Risk factors for progression of visual field abnormalities in normal-tension glaucoma. Am J Ophthalmol. 2001;131:699–708. 10. Flammer J, Mozaffarieh M. What is the present pathogenetic concept of glaucomatous optic neuropathy? Surv Ophthalmol. 2007;52:S162– 73. 11. Killer HE, Pircher A. Normal tension glaucoma: review of current understanding and mechanisms of the pathogenesis. Eye (Lond). 2018 May;32(5):924-930. doi: 10.1038/s41433-018-0042-2. Epub 2018 Feb 19. PMID: 29456252; PMCID: PMC5944657. 12. Wang NL (2019) The expert consensus on the diagnosis and treatment of normal tension glaucoma in China (2019 Edition). Chin J Ophthalmol 55: 329- 332. 13. Ayoub G, Luo Y, Lam DMK (2021) Normal tension glaucoma: Prevalence, etiology and treatment. J Clin Res Ophthalmol 8(1): 023-028. DOI: https://dx.doi.org/10.17352/2455-1414.000088. 14. Geijssen HC, Greve EL. Vascular concepts in glaucoma. Curr Opin Ophthalmol 1995;6:71–7. 15. King D, Drance SM, Douglas G, et al. Comparison of visual field defects in normal-tension glaucoma and high-tension glaucoma. Am J Ophthalmol 1986;101:204–7. Dr. Shweta Tripathi, DNB, MNAMS, FMRF Senior Consultant Glaucoma Services, Indira Gandhi Eye Hospital and Research Centre, Lucknow. Corresponding Author:

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 43 DOS TIMES Correlation of Structural Damage with Functional Changes in Glaucoma - A Mini Review Prerna Garg[1], MS, Suneeta Dubey[2], MS 1. Consultant, Glaucoma Department, Dr. Shroff’s Charity Eye Hospital, New Delhi, India. 2. Medical Superintendent, Chairperson- Quality Assurance, Head- Glaucoma Services, Dr. Shroff’s Charity Eye Hospital, New Delhi, India. Abstract: Prompt diagnosis of glaucoma in its early stages is now possible with technological advances like OCT. With increase in life expectancy, managing this disease and slowing its rate of progression is of prime importance. This can be possible only by better diagnostic modalities. Glaucoma can be diagnosed either by detecting the structural changes on OCT or the functional defects on Standard Automated perimetry. Instead of using them as separate modalities, correlating these structural functional changes would greatly increase their sensitivity and specificity. Multiple maps relating the visual field defects to the optic nerve sectors have been developed over the years, most popular being the Garway-Heath map, and based on these maps various OCT machines have now introduced softwares which integrate the two reports into a single, easy to understand format. Keywords: Glaucoma, structure function, OCT, SAP, FORUM software. Background Glaucoma is a chronic condition that causes progressive retinal ganglion cell (RGC) loss resulting in typical structural changes in optic nerve head (ONH) and retinal nerve fibre layer (RNFL) along with deterioration of visual function. Evaluating structural and functional changes is now a usual routine in glaucoma management, with their correlation being one of the most important aspects to adequately grade the severity and course of the disease. Structural characteristics of the ONH and RNFL include both qualitative (direct ophthalmoscope/90 D examination) and semiquantitative (disc photographs) clinical assessment methods as well as quantitative imaging techniques like Heidelberg Retinal Tomography (HRT) and Optical Coherence Tomography (OCT). With the advancement of OCT and introduction of Spectral-domain (SD) OCT, measurement and quantification of neuroretinal rim area or RNFL thickness and, more recently, of macular and ganglion cell complex thickness is possible. Standard automated perimetry (SAP) has been the preferred method to evaluate the corresponding functional loss in glaucoma. Newer instruments like short wavelength automated perimetry (SWAP), microperimetry, fundus tracking perimetry have also been used to assess the visual function, however, SAP remains the gold standard. Most of the studies suggest that structural changes precede functional changes, however, the evidence for this is still lacking. In some eyes, structural and functional glaucomatous losses may become apparent simultaneously, or functional loss may appear without recognition of any structural damage. In Ocular Hypertension Treatment Study (OHTS), 34 percent of patients showed changes in visual field before showing any structural changes in optic disc and 7 percent developed changes in optic disc and visual field simultaneously. Numerous maps relating visual field regions to ONH sectors have been developed over the years like Wirtschafter et al.- 1982,[1] Yamagishi et al.- 1997,[2] Anton et al.- 1998,[3] Weber et al.- 1990,[4] Garway-Heath et al.- 2000,[5] Garway-Heath et al.- 2002.[6] The most complete and most popular of these is the map by Garway-Heath et al. Based on this map, Hood and Kardon described a linear model to relate RNFL thinning on OCT to sensitivity losses in different visual field point groupings.[10] Combining structural and functional tests improves the diagnostic ability to detect glaucoma as well as study the progression of the disease. We will also be discussing about a new software based on Hood-Kardon model, the “FORUM Glaucoma Workplace 2.0”, which integrates the structural and functional test results to monitor glaucoma for clinical use. Structural Damage in Glaucoma Glaucoma is characterized by an irreversible loss of ganglion cells, the axons of which form the optic nerve. Ganglion cells are located in three retinal layers- dendrites in inner plexiform layer (IPL), cell bodies in ganglion cell layer (GCL), and their axons in retinal nerve fiber layer (RNFL). Therefore, these three layers are affected in glaucoma typical visual field defects. The RNFL fibres are particularly thick in the superotemporal and inferotemporal quadrants of the disc. These regions have long been known to be particularly vulnerable to glaucomatous damage (Figure 1).

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 44 DOS TIMES Figure 1: A schematic model showing the regions of the disc most vulnerable to local glaucomatous damage as reported by Hood et al.[11] SVZ- 45°-90°, IVZ- -45°- -90°, MVZ- -38°- -69°. Figure 2: 24’2c pattern introduced by Zeiss with 10 extra points in the central 10° as shown in blue. They are known as Superior vulnerability zone (SVZ) and Inferior vulnerability zone (IVZ) respectively. SVZ corresponds with superotemporal GCL on the posterior pole outside the central 8 degrees of macula, whereas a portion of IVZ corresponds to inferotemporal GCL within central 8 degrees of the macula, a region known as macular vulnerability zone (MVZ).[8] The ganglion cells in this zone of macula are the first to be affected in glaucoma corresponding to inferotemporal RNFL defect in early glaucoma. The axons from ganglion cells in the superior part of central 8 degrees and a portion of inferonasal area (papillomacular bundle) correspond to temporal area of the ONH. This area is less vulnerable to glaucomatous damage with the inferonasal area last to be damaged (central isle of relative preservation). Normal RNFL thickness ranges from 100-160 µm, when it decreases below 50 µm it is characterized as RNFL atrophy. The RNFL consists of axons of RGC’s and non-neural components like glial cells, blood vessels. The axonal portion decreases in a linear fashion with decrease in visual sensitivity, however, the residual portion remains constant. The residual RNFL thickness in the arcuate regions is, on an average, about one-third of the normal thickness of that region. Various imaging technologies have been introduced for an objective assessment of RNFL. These include scanning laser polarimetry, HRT, OCT. OCT, by consensus, has now become the imaging modality of choice for the diagnosis and structural follow-up of glaucoma on imaging. With the introduction of SD-OCT in 2006, the whole paradigm of glaucoma diagnosis has been refined. SD-OCT offers a much higher resolution (5µm), faster scanning speed (26,000-70,000 scans/second), greater depth penetration and lesser motion artifacts. Using artificial intelligence, various modern day segmentation protocols have been updated, allowing subcomponent analysis in the diagnosis of glaucoma. Hence along with the papillary and circumpapillary measures, it also analyses the macular RNFL, GCL-IPL and total macular thickness. It has long been known that mild macular damage occurs in early glaucoma, however, without any way to objectively quantify the damage in earlier years, it was ignored to a great extent. With the help of SD-OCT, immense work has been done in this field by Donald C. Hood and his colleagues.[7,8,11] They reported that the average thickness of the GCL has a doughnut appearance with little or no RGC’s at the centre of the fovea and maximum thickness at 5°, thicker along the horizontal meridian in the nasal as compared to the temporal retina. As glaucoma progresses, along with pRNFL thinning, there is also a gradual thinning in the macular GCL. In their studies they found significant GCIPL thinning in the inferotemporal region of central 8° of macula in patients with MD better than -1.5 dB on SAP, indicating macular damage starting in early glaucoma.[11] These RGC’s corroborated to the arcuate fibres entering the disc at the inferotemporal region from -38° to -65°, a region termed by them as the MVZ. Functional Damage in Glaucoma SAP is the gold standard to diagnose functional changes in glaucoma by evaluating the visual field. The different field tests include: • 30-2 – 74 points 6° apart • 24-2 – 54 points 6° apart • 10-2 – 68 points 2° apart • Macula test- central 5 degrees- 16 points 2° apart • 24c-2 – Newer test in HFA 3 incorporating 10 points in the central 10° of 24-2 (Figure 2).[23]

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 45 DOS TIMES Figure 3: Map showing the different zones corresponding to the ONH sectors. Newer instruments like Microperimetry (MP) and Fundus tracking perimetry (Compass, Centervue, Padua, Italy) are also being used to assess the functional changes. MP, which is also known as fundus perimetry, assesses visual sensitivity while directly examining the ocular fundus. Its results are relatively independent of eye movements and directly related to the stimulated area. Therefore, the visual field (VF) sensitivities measured by MP are supposed to have better spatial localization. Fundus tracking perimetry employs continuous retinal imaging through infrared light source and adjusts the location of retinal stimulation to compensate for eye movements during the test. This has recently been shown to reduce test-retest variability and improve discrimination between people with and without glaucoma. However, most of the studies have found similar structure function relationship when compared with SAP.[12,13] Hence SAP remains the gold standard for assessing the functional changes in glaucoma. On SAP total deviation (TD) data can be a better indicator of widespread damage than pattern deviation (PD) data Early macular damage can occur either as local deep defects or widespread shallow defect on macular VF.[14] These would correspond to a relatively focal pRNFL loss or a generalised pRNFL thinning respectively. To correlate the widespread defects adequately, TD should be considered, as it better represents that kind of damage. The PD, by removing the mean, corrects for diffuse losses due to cataracts or a small pupil. This “correction” will also obscure a true widespread loss due to glaucoma, as pointed out by Artes et al in the case of widespread damage seen on visual fields (VF) in the OHTS investigation.[15] Therefore, even if TD is abnormal and PD is normal, OCT must be done to look for changes in GCL and RNFL thickness. 24-2 vs 10-2 field tests- which is preferred The macular region (i.e. ±8° from fixation) covers less than 2% of the retinal area, but contains over 30% of the RGCs. As stated above, early glaucomatous damage to the macula is relatively common, and involves defects that are deep and local or shallow and widespread. Schiefer et al reported that over 50% of eyes with mild to moderate glaucoma had defects within the central ±3°.[16] Traynis et al showed that in patients with early glaucoma (MD ≥ 6 dB), 16% of the hemifields classified as normal on 24-2 were abnormal with 10’2 testing.[17] The 24-2 test, does not adequately test the macular region, as the 6° grid has only four points within central 8°. When these four points are displaced to take into account the anatomical position of the RGCs, they fall outside of the macular region most affected by glaucoma. However, it would be too tedious for the patients to get both 24-2 and 10-2 tests done. Certain instances when a 10-2 should also be done include- Patients who present abnormalities on inferotemporal and temporal pRNFLT and GCIPL thickness. Any of the 4 central test points or 8 paracentral test points depressed <0.5% on the 24-2 VF.[18] Any of the 12 central/paracentral test points depressed <5% on the 24-2 VF test with corresponding GCIPL defect on OCT.[18] What is Affected First-Structure or Function? It has been a long known fact that structural changes precede functional loss. 40–50% of the nerve fibers are lost before development of the visual field defects. RNFL thinning can be seen in 60% with red-free photography, 6 years before appearing of the visual field defects. However, recently it has been proven that structural changes do not always precede functional changes, infact they go hand in hand. Since SAP documents the defects in a logarithmic dB scale, the functional changes are detected only after substantial number of RNFL fibres are lost.[9] In some cases where RNFL thickness/ganglion cell density is more than normal, the functional changes on SAP may occur before structural changes are seen on OCT. Also, sometimes in early stages of glaucoma, RGC’s may be structurally intact but being dysfunctional may lead to altered visual sensitivity and field defect in that location. In principle, when axons are lost there has to be some corresponding loss of some component of visual function simultaneously, but the detection of either the structural or the functional loss will depend on the sensitivity of the methods available for their measurement. Linking Structure and Function to Aid in Detection of Glaucomatous Damage For several decades, researchers have recognized that a relationship exists between the anatomical integrity of the optic nerve and visual function in patients with glaucoma. Numerous attempts have been made to map such structurefunction correlates. One of the most complete maps was that published by Garway-Heath (Figure 3).[20] This was based on a non-quantitative method of assessing RNFL through fundus photography. In this map, the centre of the 24-2 pattern grid was aligned to the fovea on the RNFL images, and

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 46 DOS TIMES the two images were digitally added. A circle, approximately 6° (the size of an average ONH) was generated on the grid, aligned as closely as possible to the ONH margins and divided into 30° reference sectors. The mirror image, about the horizontal meridian of the RNFL photo was taken. Then, the points adjacent to the edge of the RNFL defect or prominent bundle were identified and traced back to the ONH. This is a population map because it is designed to be a reasonable representation of the ‘Average Eye’. Hood et al. described a linear model to relate RNFL thinning as measured by OCT, to sensitivity losses in the different visual field point groupings based on this map. They plotted the RNFL thickness in the superior and inferior arcuate sectors of the disc against their respective SAP sensitivity loss (dB units), and found that the RNFL thickness becomes asymptotic for sensitivity losses > 10 dB.[10] This is known as the “FLOOR EFFECT” i.e. for sensitivity loss > 10 dB, the RNFL thickness remains same. Structure-Function Correlation in Different Stages of Glaucoma Histological studies in humans and primates have indicated that large numbers of RGCs may be lost before statistically significant abnormalities appear on SAP. In a study of cadaver eyes, Kerrigan-Baumrind et al estimated that at least 25%–35% of RGCs would have to be lost for a significant visual field defect to appear.[21] These studies suggest that reliance on SAP in early glaucoma will likely lead to an underestimation of the amount of glaucomatous damage. This is expected, since SAP data is presented using a logarithmic dB scale. This scale compresses the range of losses in early stages of the disease while expanding the range in later stages (Figure 4).[22] In contrast, OCT can detect structural damage as well as the rate of change in these early stages much more accurately. Figure 4: Scatter plot by Medeiros et al showing the relationship between SAP MD and the estimated number of RGC’s.[22] In advanced stages, SAP is more sensitive to small changes in the number of RGCs that would not produce detectable changes in RNFL thickness due to the floor effect described previously. Medeiros et al found that disease severity had a significant effect on the diagnostic ability of SAP pattern standard deviation (PSD), which for a specificity of 80%, had a sensitivity of 85% in eyes with 70% loss of neuroretinal rim area compared to a sensitivity of only 40% in eyes with 10% loss of neuroretinal rim area.[23] Individual-Specific Structure-Function Maps Garway Heath map, the most commonly used map for correlating structure-function is a population average map. It does not take into account the individual factors which can affect the mapping of visual field locations onto the ONH sector. Most important of these factors is the Fovea-Bruch’s Membrane Opening (FoBMO) centre axis. It is the angle between the fovea and the BMO center relative to the horizontal axis of the image acquisition frame and an interindividual variation ranging from +6° to -17° has been found.[24] Due to this large variation, rim measurements in a given ONH sector would not precisely refer to the same anatomical location among different individuals, resulting in errors in mapping the visual field to ONH sectors. Other factors which can lead to interindividual variability include the ONH size, axial length and position of major retinal vessels. Combined Structure-Function Index (CSFI) It represents the estimated percentage of RGC’s lost compared to an age-matched healthy eye. Although direct quantification of RGCs isn’t yet possible in vivo, empirical formulas are described that allow RGC counts to be estimated from perimetric threshold-sensitivity values as well as from the OCT RNFL thickness measurements. Medeiros et al have recently reported a method of combining the RGC estimates from OCT and SAP.[25] This has been used to develop a combined structure–function index (CSFI). Therefore, an eye with a CSFI of 100% will have an estimated RGC count equal to that expected for age, whereas an eye with a CSFI of 50% will have an estimated RGC count half that expected for age. FORUM Glaucoma Workplace 2.0 Various OCT systems have now developed softwares that integrate the structure and function data into a single report format. One such software is the FORUM glaucoma workplace (Carl Zeiss Meditec Inc., Dublin, CA) developed in 2013 which combines data from Humphrey Field Analyzer and CIRRUS OCT. It maps the anatomical relationship between visual field test points in the Humphrey 24-2, 30-2 or 10-2 test and regions of the RNFL/GCL, based on the Garway-Heath map. The Combined Report consists of two to three pages. The first page summarizes the combined data from the HFA and CIRRUS, while the rest of the pages provide further detail. Depending on the type of test data available, different combined reports can be generated. These may include fundus photos and ganglion cell analyses. In this, the OCT display is flipped along the horizontal axis to correspond to the orientation of the visual field data. Similar software’s are also provided by the Spectralis OCT and Topcon OCT systems.

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 47 DOS TIMES Figure 5: As can be seen, VFA is normal with only few non specific points abnormal, whereas on OCT there is thinning of ST RNFL in R/E and thinning of ST and IT RNFL in L/E. Suggestive of Pre-perimetric glaucoma Figure 6: In this we can see, generalized depression of field in R/E with 2-3 abnormal points on PD adjacent to the blind spot s/o enlargement of blind spot (not fulfilling Anderson’s criteria). Few Examples of Application of FORUM SOFTWARE at our Hospital 1. 33/M, on GAT- IOP R/E- 22, L/E- 14, B/E Disc suspect R/E0.7, L/E- 0.5. (Figure 5) 2. 51/M, Myopic, IOP- R/E 14, L/E 12 (GAT), C:D- R/E- 0.7, L/E-0.8. (Figure 6)

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 48 DOS TIMES Corresponding OCT shows borderline bipolar thinning of RNFL with borderline GCIPL thinning. In L/E, VFA shows a dense, macular sparing superior paracentral scotoma with OCT showing borderline thinning of RNFL in inferonasal and superotemporal quadrants and ONL in inferotemporal quadrants and GCL-IPL thinning ONL. Hence, diagnosis in this patient is R/E- pre-perimetric glaucoma and L/E- Moderate glaucoma. 3. 43/M, GAT- R/E-19, L/E-18, C:D- 0.9 B/E, GonioscopyB/E synechial closure with PI, L/E H/O Trabeculectomy. Figure 7: This is a combined 10-2 and GCA report showing advanced visual field loss with only temporal central field left in both eyes. Corresponding GCA shows GCIPL outside normal limits in all quadrants. Suggestive of Advanced glaucoma B/E Conclusion Glaucoma, since many decades, has been diagnosed only on the basis of functional visual field defects on SAP. In the last 10-20 years, it has been possible to detect structural damage by glaucoma early in its course with the discovery of OCT. Hence, it makes sense to correlate the structural damage on OCT with the functional defects on SAP. However, it is difficult to estimate the exact point at which one test might perform better than the other for monitoring an individual patient. Hence combining these two approaches is advisable so that one can evaluate progression and measure rates of change throughout all stages of the disease. References 1. Wirtschafter JD, Becker WL, Howe JB, Younge BR. Glaucoma visual field analysis by computed profile of nerve fiber function in optic disc sectors. Ophthalmol. 1982;89:255–267. 2. Yamagishi N, Anton A, Sample PA. Mapping structural damage of the optic disk to visual field defect in glaucoma. Am J Ophthalmol. 1997;123:667–676. 3. Anton A, Yamagishi N, Zangwill L. Mapping structural to functional damage in glaucoma with standard automated perimetry and confocal scanning laser ophthalmoscopy. Am J Ophthalmol. 1998;125:436– 446. 4. Weber J, Dannheim F, Dannheim D. The topographical relationship between optic disc and visual field in glaucoma. Acta Ophthalmol (Copenh) 1990;68:568–574. 5. Garway-Heath DF, Poinoosawmy D, Fitzke FW, Hitchings RA. Mapping the visual field to the optic disc in normal tension glaucoma eyes. Ophthalmology. 2000;107:1809–1815. 6. Garway-Heath DF, Holder GE, Fitzke FW, Hitchings RA. Relationship between electrophysiological, psychophysical, and anatomical measurements in glaucoma. Invest Ophthalmol Vis Sci. 2002;43:2213– 2220. 7. Hood DC. Improving our understanding, and detection, of glaucomatous damage: an approach based upon optical coherence tomography (OCT). Prog Retin Eye Res. 2017;57:46–75.

www.dosonline.org/dos-times DOS Times - Volume 28, Number 3, May-June 2022 49 DOS TIMES 8. Hood DC, Raza AS, de Moraes CGV, et al. Glaucomatous damage of the macula. Prog Retin Eye Res. 2013;32:1–21. 9. Malik R, Swanson WH, Garway-Heath DF. ‘Structure-function relationship’ in glaucoma: past thinking and current concepts. Clin Exp Ophthalmol. 2012;40:369–380. 10. Hood DC, Kardon RH. A framework for comparing structural and functional measures of glaucomatous damage. Prog Retin Eye Res. 2007;26:688–710. 11. Hood DC, Raza AS, de Moraes CGV, Johnson CA, Liebmann JM, Ritch R. The nature of macular damage in glaucoma as revealed by averaging optical coherence tomography data. Trans. Vis. Sci. Tech. 2012;1:1–15. 12. Rao HL, Januwada M, Hussain RSM, et al. Comparing the structure-function relationship at the macula with standard automated perimetry and microperimetry. Invest Ophthalmol Vis Sci 2015;56:8063–8. 13. Montesano G, Rossetti LM, McKendrick AM, et al. Effect of fundus tracking on structure–function relationship in glaucoma. British Journal of Ophthalmology Published Online First: 02 March 2020. doi: 10.1136/bjophthalmol-2019-315070 14. Hood DC, Slobodnick A, Raza AS, et al. Early glaucoma involves both deep local, and shallow widespread, retinal nerve fiber damage of the macular region. Invest Ophthalmol Vis Sci. 2014;55:632–649. 15. Artes PH, Chauhan BC, Keltner JL, et al. Ocular Hypertension Treatment Study Group. Longitudinal and cross-sectional analyses of visual field progression in participants of the Ocular Hypertension Treatment Study. Arch Ophthalmol. 2010; 128: 1528–1532. 16. Schiefer U, Papageorgiou E, Sample PA, et al. Spatial pattern of glaucomatous visual field loss obtained with regionally condensed stimulus arrangements. Invest Ophthalmol Vis Sci. 2010;51(11):5685– 5689. 17. Traynis I, De Moraes CG, Raza AS, Liebmann JM, Ritch R, Hood DC. Prevalence and nature of early glaucomatous defects in the central 10° of the visual field. JAMA Ophthalmol. 2014;132(3):291‐297. doi:10.1001/jamaophthalmol.2013.7656 18. Park H-YL, Hwang B-E, Shin H-Y, et al. Clinical clues to predict the presence of parafoveal scotoma on humphrey 10-2 visual field using a humphrey 24-2 visual field. Am J Ophthalmol. 2016;161:150–159. 19. Epshtein D. ZEISS Humphrey Field Analyzer: today and tomorrow. 2019. Available at: https://newgradoptometry.com/wpcontent/uploads/2019/02/ZEISS-HFA-of-Today-and-TomorrowWhite-Paper. pdf. Accessed August 7, 2019. 20. Garway-Heath DF, Poinoosawmy D, Fitzke FW, Hitchings RA. Mapping the visual field to the optic disc in normal tension glaucoma eyes. Ophthalmology. 2000;107:1809–1815. 21. Kerrigan-Baumrind LA, Quigley HA, Pease ME, et al. Number of ganglion cells in glaucoma eyes compared with threshold visual field tests in the same persons. Invest Ophthalmol Vis Sci. 2000;41:741– 748. 22. Medeiros, F., Tatham, A., & Weinreb, R. (2014). Strategies for improving early detection of glaucoma: the combined structure–function index. Clinical Ophthalmology, 611. doi:10.2147/opth.s44586 23. Medeiros FA, Zangwill LM, Anderson DR, et al. Estimating the rate of retinal ganglion cell loss in glaucoma. Am J Ophthalmol. 2012;154:814–824.e1. 24. Chauhan BC, Burgoyne CF. From clinical examination of the optic disc to clinical assessment of the optic nerve head: a paradigm change. Am J Ophthalmol. 2013;156:218–227.e2. 25. Medeiros FA, Lisboa R, Weinreb RN, et al. A combined index of structure and function for staging glaucomatous damage. Arch Ophthalmol. 2012;130:1107–1116. Dr. Prerna Garg, MS Consultant, Glaucoma Department Dr. Shroff’s Charity Eye Hospital Delhi Corresponding Author:

DOS Times - Volume 28, Number 3, May-June 2022 www.dosonline.org/dos-times 50 DOS TIMES Electrophysiology in Glaucoma J.L.Goyal, MD, DNB Professor of Ophthalmology, School of Medical Sciences and Research, Sharda University, Greater Noida, UP. Introduction Glaucoma is a multifactorial optic neuropathy characterized by progressive loss of retinal ganglion cells and their nerve fibres leading to characteristic loss of visual function. Significant loss of ganglion cells inevitably leads to visual disability but there is an inbuilt redundancy in the visual system which allows a large number of neurons to be lost without becoming manifest in standard tests of visual function. The techniques like routine testing of IOP, automated perimetry and optic nerve fibre layer photography fail to detect early glaucomatous damage. Ocular hypertensive eyes with no clinically manifest visual field loss or change in the appearance of the optic nerve head may have lost about 30% of the their axons.[1] To summarize, early diagnosis of glaucoma remains a challenge to the clinician. It is conceivable that early nerve damage can be detected only by a test which is sensitive to its dysfunction before structural changes occur. Electrophysiological evaluation of optic nerve and retinal ganglion cell layer is one such diagnostic modality. Visual Evoked Potential in Glaucoma Pattern Visual Evoked Potential is recorded in response to reversing checker board stimulus where the background illuminance is kept constant. The potential of the optic nerve is recorded using surface electrodes placed on the occipital cortex. Pattern VEP has the following components 1. A small negative wave the trough of which has a latency of around 75ms (N-75) 2. A large positive wave the peak of which has a latency of around 90-110ms (P-100) 3. A negative wave the trough of which has a latency of around 130-140ms (N-135) N135 N75 P100 Figure 1: Normal Pattern VEP. Early reports of Pattern VEP recording in glaucomatous eyes have come from Krogh et al[2] who artificially elevated IOP in experimental animal eyes. Recording of VEP was done prior to and after the elevation of IOP. Transient VEP amplitude drop was observed in response to elevated IOP. Atkin A et al reported an increase in latency of the positive wave (P-100) in glaucoma patients and ocular hypertensives as compared to normals.[3] They also found that the latency in glaucomatous eyes was increased as compared to ocular hypertensives. But this conclusion could not find support from Grippo TM et al who opined that there is not much change in latency of P-100 in glaucoma or ocular hypertension.[4] Further the increase in latency could not correlate with the perimetric field loss. Thus they came to the conclusion that VEP is an indicator of retinal ganglion cell death rather than damage. Hence it is of little use in detecting early nerve dysfunction. Horn FK et al suggested that VEP with blue on yellow pattern stimulation may be useful in detecting early glaucomatous damage.[5] This is based on the assumption that the short wavelength sensitive nerve pathway or the blue wave sensitive pathway is the earliest to be affected in glaucoma. Hence this S-cone VEP may pick up early changes not evident on conventional VEP. Further, to bridge the gap between electrophysiology and perimetry multifocal recordings were introduced by Sutter and Tran. This allows simultaneous recording of VEP from 100 different points within the visual field. Klistorner et al reported generalized reduction in amplitude and increase in latency of VEP across the visual field. Moreover areas of scotoma in the visual field showed more change in VEP amplitude and latency as compared to other areas.[6] To summarize, conventional Pattern VEP can detect only established glaucoma but newer modifications like S-cone VEP and multifocal VEP may be used to diagnose early disease and monitor progression. Pattern Electroretinogram in Glaucoma Pattern electroretinogram is recorded in response to reversing checkerboard stimulus (reversal rate<6 pps) where the mean luminance is kept constant. The retinal potential is recorded with the help of corneal electrodes like gold foil electrode or H-K electrodes. The waveform of pattern ERG shows the following components; 1. A small negative wave the trough of which is obtained at around 35ms (N-35) 2. A large positive wave the peak of which is obtained at around 45-60ms (P-50) 3. A large negative component the trough of which lies at around 90-100ms (N-95)