Haryana Journal of Ophthalmology Jan-April 2024 Vol.XVI (No.1)

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 1 Vol. XVI (No. 1) For private circulation only Haryana Journal of Ophthalmology JAN - APR 2024 LET THERE BE LIGHT www.haryanaophthalmologicalsociety.com ISSN NO. 2322-0309 THEME ISSUE | Investigative Modalities ISSUE HIGHLIGHTS RHO-Kinase Inhibitors-an Insight into the New Drug Modality Steroid Induced Glaucoma: an Avertable Iatrogenic Disease Uveitic Glaucoma Molecular Biomarkers in Diabetic Retinopathy and ARMD Journal of Haryana Ophthalmological Society

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Vol. XVI (No. 1) | ISSN NO. 2322-0309 i EDITORIAL BOARD EDITORIAL SENIOR ADVISORY BOARD SUBSPECIALITY EDITORS EDITOR-IN-CHIEF: Dr. Deependra Vikram Singh ASSOCIATE EDITORS Dr. Gautam Yadav Dr. Gunjan Budhiraja Dr. Ishwar Singh Dr. C.S.Dhull Dr. A.K.Khurana Dr. S.V. Singh Dr. J.P.Chugh Dr. Sunandan Sood Dr. R.S.Chauhan Dr. Virender Sangwan Dr. Manisha Nada Dr. Manisha Rathi Dr. Sumit Sachdeva Dr. Arvind Morya Dr. Rajan Gupta Dr. Ashok Rathi Dr. Deepa Gupta Dr. Ashu Aggarwal Dr. Vikas Mittal Dr. Vishal Arora Dr. Jayeeta Bose Dr. Sameer Kaushal Dr. Chirakshi Dhull Dr. Suwarn Chetan Dr. Praveen Monga Dr. Deepak Mittal Dr. Anju Bajaj Dr. Manpreet Kaur Dr. Parveen Rewri Dr. Neha Adalakha Dr. Mainak Bhattacharya Dr. Narottama Sindhu Dr. Himani Jhangod Dr. Raja Rami Reddy Dr. Chekitaan Singh Dr. Ruchi Mittal Dr. Rohan Chawla Dr. Sumeet Khanduja Dr. Raj Anand Dr. Vikas Thukral Dr. Neebha Passi Dr. Puneet Jain Dr. Neelam Pushkar Dr. Abhilasha Dr. Parthopratim Roy Dr. Prachi Jain Dr. Manisha Aggarwal Dr. Jitender Phogat Dr. Prabhjyot Kaur Dr. Satya Karna Dr. Swati Dr. Sachin Kedar Dr. Priyamvada Yadav Dr. Shilpa Goel Dr. Yuvika Bansal Dr. Sohan Lal Bansal Dr. Reena Gupta Dr. Rajan Gupta Dr. M.L.Bagla Dr. Rajat Mathur Cataract and Refractive Cornea Anterior Segment Glaucoma Posterior Segment Orbit and Oculoplasty Ocular Oncology Uvea and Medical Retina Neuro ophthalmology Paediatics and Strabismus Social Media Community Ophthalmology Dr. S.S. Pandav Dr. Urmil Chawla Dr. Satanshu Mathur Dr. Yog Raj Sharma Dr. Amod Gupta Dr. Jagat Ram Dr. M.R. Dogra Dr. Pradeep Venkatesh Dr. Ashok Garg Dr. Kapil Vohra Dr. Ajay Sharma Dr. Narinder Kumar Taneja Dr. I. M. Rustagi Dr. J.L.Goyal Dr. R.L.Sharma Dr. Sushmita Kaushik Dr. Karamjeet Dr. Rajeev Tuli Dr. Rajeev Sudan Dr. Ramandeep Dr. Vishali Gupta Dr. Sudesh Arya Dr. Pradeep Sharma Dr. Rohit Saxena Dr. Jatinder Bali Dr. R.K.Bansal Dr. Subina Narang Dr. Arvind Tenagi Dr. Markanday Ahuja Dr. Sandhya Gaur Dr. Awaneesh Upadhyay Dr. Chirakshi Dhull Dr. Mainak Bhattacharya Dr. Prabhjot Kaur EDITORIAL BOARD | JAN-APR 2024

Vol. XVI (No. 1) | ISSN NO. 2322-0309 ii OFFICE BEARERS HOS | JAN-APR 2024 OFFICE BEARERS HOS Patrons Collegium for HOS Prof. S V Singh Dr. Kapil Vohra Immediate Past President President Chairman Scientific Committee AIOS Managing Committee Members NZOS Managing Committee Members Dr. Manisha Nada Dr. Markandey Ahuja Manisha Rathi Dr. Narinder Kumar Taneja Dr. Inder Mohan Rustagi Dr. Rajat Mathur Dr. Inder Mohan Rustagi Vice President Editor Journal Joint Secretary Dr. Praveen Arora Deependra Vikram Singh Dheeraj Gupta Past President General Secretary Treasurer Dr. Rajinder S Chauhan Dr. Inder Mohan Rustagi Rajan Gupta Dr Aayush Singhal – Hissar Dr Parveen Kumar Monga - Hissar Dr Ravi Vohra – Ambala Dr Jaspreet Aggarwal – Ambala Dr. Rajat Mathur – Ambala Dr Neebha Anand– Rohtak Dr Madan Lal bagla – Dabwali Dr Ashwani Nagar- Rohtak Dr Yavika – Sirsa Dr Malhip Bansal – Sirsa Dr A.K. Khurana – Rohtak Dr Adwin Ranga – Bhiwani Dr Parikshik Dhir – Bhiwani Dr Narinder Taneja – Bhiwani Dr Vikash Thukral – Faridabad Dr Manoj Mehta – Faridabad Dr Ashwani Bakshi – Faridabad Dr Prachi Jain – Rewari Dr Ramesh Kumar – Rewari Dr Anil Gupta – Panipat Dr B.K. Gupta – Panipat Dr Vishal Arora – Gurgaon Dr Suwarnchetan – Gurgaon Dr Hitender Ahuja – Gurgaon Dr Sanjay Jain – Gurgaon Dr R. N. Yadav – Gurgaon Dr S.S. Maan – Gurgaon Dr Simmi Talwar – Yamuna Nagar Dr Mukesh Goyal – Narnaul Dr Rajesh Garg – Yamuna Nagar Dr Avinash Sharma – Mahendrgarh Dr Aparna Singhal - Agroha Dr Harsh Raj Nehra – Bahadurgarh Dr Mankeet Kaur – Mewat Dr Rajesh Saini - , Kurukshetra Dr Vedpal – Sonipat Dr Suresh Arya – Sonipat Dr Sunil Khandiya – Karnal Dr Adviti Arora – Karnal Dr. Deepak Garg – Kaithal

Vol. XVI (No. 1) | ISSN NO. 2322-0309 iii MEET THE HOS EXECUTIVES | JAN-APR 2024 MEET THE HOS EXECUTIVES

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 1 MESSAGE FROM GENERAL SECRETARY INDEX Editorial Board Office Bearers HOS Meet the executive Contents Editorial Message Message from Associate Editor Message from President Message from Gen Secretary Remembering the Life and Legacy of Padma Bhushan Dr. Sengamedu Srinivasa Badrinath RHO-kinase inhibitors-an insight into the new drug modality Steroid Induced Glaucoma: an avertable Iatrogenic Disease Uveitic Glaucoma Conjunctivitis-23, Is it a COVID-19 type epidemic of the Eye? Molecular Biomarkers in Diabetic retinopathy and age related macular degeneration Dr. Prerna Garg, Dr. Julie Pegu, Dr. Suneeta Dubey, Dr. Monica Gandhi Dr Samiksha Choudhary MS, Fellow (Glaucoma & IOL), Dr Swarnali Sen (MS, FSN), Dr Jasleen Dhillon (MS, DNB), Dr Ramanjit Sihota (MD, FRCS, FRCOphth) Dr Tripti Johri DOMS, DNB, FGAS, Dr Varun Saini, MS, DNB, Dr Chirakshi Dhull, MD, DNB, FICO Kritika MBBS, Kanav Gupta MS FVR, Brij Kumar Gupta MS, Isha Gupta MD Thirumalesh MB MD, Aayesha khanum MBBS, Suresh K Pandey MBBS, MS, Vidushi Sharma MD, FRCS GUEST EDITORIAL REVIEW ARTICLE i ii iii 1-3 4 5 6 7-8 9-13 14-21 22-26 27-33 34-38 39-45 Page No.

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 2 Retrospective Study to Observe utility of household item for visual rehabilitation on the patients who had no hopes of getting their vision back Our experience with AURO-KPRO (Boston type 1) Assessing Knowledge, Attitude and Practice Regarding Conjunctivitis Among Primary Health Care Professionals Surgeon’s view point: MIGS – ‘Where we stand today’ Oxygen cylinder related ocular emergencies during second wave of Covid-19 pandemic in India Combined Retinal Vascular Occlusion as the Presenting Clinical Sign of SLE Topiramate induced angle closure in a one- eyed patient Dr. Ashwini Kumar Dr V.SHANKAR NAG MBBS.MS, Dr.Siva rama Krishna MBBS,DNB, Dr Madhu Uddaraju MBBS,MS Dr Bhailume Prajakta V, Dr. Maxwell Silva, Dr. Pargaonkar Nachiket, Dr. Malcolm Silva Dr Mainak Bhattacharyya – MS, DNB, FICO, Dr Ankush Mahajan- MS, Dr. Suneeta Dubey – MS, Glaucoma fellow (Wills Eye Institute, Philadelphia), Prof Tanuj Dada - MD, Dr Vanita Pathak-Ray MBBS, FRCS(Ed), FRCOphth (Lon) Mainak Bhattacharyya MS, DNB, FICO (Glaucoma), Gunjan Budhiraja DO, DNB, FICO, FELLOW (Cornea), Awaneesh Upadhyay DNB, Fellow (Retina), Shreyans Jain MD, FICO, FRCS, FRCOpth, Zakia Anwer MD, Deependra V Singh MD FASRS, Sandhya Gaur MD Foram Desai MS FMRF FAICO FICO, Kruti Shah DOMS, MS Commentary ORIGINAL ARTICLE SURGEON’S VIEW POINT CASE REPORTS 46-53 54-59 60-65 66-76 77-80 81-84 85-87

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 3 A hidden hemangioma “It takes two to Tango and three for remarkable creations!” Behind our SRK FORMULA Information for Authors Copyright Transfer Form HOS Membership Form Shipra Sharda MS, Smriti Dabas MS, Deependra V Singh MD Dr. Tarun Gupta MS, FAICO IMAGE UNDER LENS PEEK INTO HISTORY 88-89 90-91 92-96 97 98

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 4 EDITORIAL Deependra Vikram Singh, MD FASRS FORMERLY EDITORIAL OFFICE MEDICAL DIRECTOR Senior Registrar (Vitreo Retinal Surgery) AIIMS Senior Research Associate (Retina) AIIMS Eye-Q Superspecialty Eye Hospitals Sheetla Hospital, New Railway Rd, near DSD Collage, Subhash Nagar, Gurugram, Haryana 122001 Email id- drdeependravsingh@gmail.com Retina Services Chief Vitreo-retinal Surgeon Eye-Q Super Speciality Eye Hospitals Respected Seniors and dearest colleagues, Greetings from editorial team! Let me share the most exciting news first; we have finalized our contract and all formalities in teaming up with Wolter Kluwer publishers and all our subsequent issues will be now be published with them. This couldn’t have been possible without guidance and rich support from our dynamic secretary Prof. Inder Mohan Rustagi and the whole executive. We would be launching Journal’s new website along with the manuscript submission portal very soon. My gratitude to our motivated readers, innovative and committed authors, learned reviewers and the dynamic editorial team that helps and inspires us bring another exciting issue from Haryana Journal of Ophthalmology. This issue is focused on Glaucoma and is enriched by 3 excellent review articles on rock inhibitors, uveitis associated and steroid induced glaucoma. These 3 topics have been aptly chosen by our associate editor, Dr. Mainak. The topics are not only of great interest to postgraduate students but also a handy resource material for practicing ophthalmologists. Surgeon’s view point is our trademark panel discussion and dissects the MIGS, much talked about surgery for glaucoma. The expert panel has put forward their insightful view points stemmed from their vast experience to help us. I am sure this section will help all the colleagues who are adopting MIGS or have been referring cases for glaucoma surgery. Indian ophthalmology has been blessed to have visionary and legendary leaders who had not only created apex training and educational institutes but also influenced the life of thousands of bright minds who would carry on the baton of advocacy and compassionate care. Guest editorial remembering “Chief” sculptor of Sankar Netralaya Chennai, Dr. Sengamedu Srinivasa Badrinath Sir by Dr. Pandey et al is an inspiration for all of us. The issue also shares few interesting case reports besides an interesting read on Molecular Biomarkers by Dr. Thirumalesh et al who is steering research at Narayan Nethralaya, Bangalore. The journal is now attracting submissions from lot of bright and innovative authors from all over India and our editorial team has put great efforts in compiling these articles and making them fit into this issue. Of course, the constant support and help from previous editors, patrons and current executive keeps us inspired. We hope all of you will enjoy reading all the articles. Please do send us your inputs and feedbacks that help us improvise and progress. Keep driving us with your fantastic submissions Sincerely Dr. Deependra, Editor in Chief EDITORIAL MESSAGE | JAN-APR 2024 EDITORIAL MESSAGE

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 5 MESSAGE FROM ASSOCIATE EDITOR | JAN-APR 2024 MESSAGE FROM ASSOCIATE EDITOR MESSAGE FROM ASSOCIATE EDITOR Dr. Mainak Bhattacharyya ASSOCIATE EDITOR Associate Editor Haryana Journal of Ophthalmology EyeQ Super Speciality Eye Hospital, Gurugram, India 122001 Email id- drmainakb@gmail.com Dear Readers, It gives us immense pride to bring to you all this ‘special focus issue’ on glaucoma. The idea here is to raise awareness about this disease entity that is plagued much by lack of awareness and misconceptions. We have come a long way in preventing glaucoma blindness in the past two decades with newer diagnostic tools that allow early detection and timely intervention, as well as the advancement in our surgical techniques to the more recent minimally invasive procedures as well as newer drugs for better control of the intra-ocular pressure. This issue features an extensive review of the relatively newer anti-glaucoma medication rho-kinase inhibitor. My own experience has been fairly good with unexpectedly good response in secondary glaucoma and other clinical situations where response to conventional AGM is relatively weaker. Although dose related hyperaemia still remains a concern with its use. There’s an expert panel discussion on the most exciting addition to the armamentarium of glaucoma surgeons in recent years ie MIGS. We bring experiences from our panel of experts who are pioneers of MIGS in India and give a panoramic view on its future role in India. We have a very topical write up on glaucoma induced by steroid use and abuse. It is undeniably an indispensable drug but one that should be used judiciously and with constant monitoring of IOP especially in younger individuals. This is a topic very close to my heart and it feels very sad to see people using OTC steroids for months and years before realising the irreparable damage it has caused them. This issue also features a comprehensive review on post uveitic glaucoma, a lesser understood and relatively difficult to treat secondary glaucoma. We hope we’ll be able to contribute in our small way in raising awareness about this disease as we approach the World glaucoma week focussed on global glaucoma awareness. Also, looking forward to hear your feedback on the contents of this issue and urging fellows and residents across all specialities to contribute their research in any form to our upcoming issues. Sincerely yours Dr Mainak Bhattacharyya Senior Consultant and Head of Department Glaucoma Services EyeQ Super Speciality Eye Hospital, Gurugram, India 122001 drmainakb@gmail.com

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 6 PRESIDENT’S MESSAGE Dr. Markanday Ahuja PRESIDENT, HOS President Haryana Ophthalmological Society Former Vice Chancellor of. Baba Mast Nath University and Gurugram University, Director, Vision Clinic Email id- markandayahuja@gmail.com I am happy to note that Editorial team led by Dr. Deependra Singh is coming up with a new edition of HOs Journal which is a special issue on Glaucoma. Glaucoma, as we all know is a group of eye conditions that can cause blindness. We in India have more than one million cases per year. The important point is that treatment can help but the condition can’t be cured. With the advent of new technologies for Glaucoma the diagnosis and treatment though early still continues to haunt the ophthalmologist. Glaucoma has always been challenging irrespective of the times; new or old. I am sure this special edition on Glaucoma will definitely help to satiate the hunger to learn the issues and challenges in day to day practice. Ever since Dr. Deependra has taken over the responsibility of HOS Journal, it is showing a perceptive change in format, content and intent. I personally feel intent has always been more important than the content and will is more important than skill. We have colleges and Universities to teach us the skill but probably there are no Universities to teach the will. Dr. Deependra has shown the will. It is the result of that strong will that HOS Journal has got its ISSN registration. Tough disease like Glaucoma need tough minds to deal with them. If I go back to Mahabharata we find that the most skilled of warriors Arjuna when it came to biggest battle of his life lost control over his mind and body and became unwilling to fight. Have we ever thought that a person who had never lost the battle in his life lost the battle of life in the initial stages? This happened because Dronacharya his teacher had trained him in martial art but not in mental art. Then came the role of Lord Krishna who gave mental training to Arjuna through the message of Gita which ultimately helped Arjuna and his brothers to win the battle. Through this message I also call upon the Editorial team to include and introduce a column for the training of will/mind which will go a long way in the training of young professionals as they tread through the tough roads of clinical practice. The new team of HOS is all set with positivity, vigor and vitality to realize the dreams of one and all. Wishing all the best for release of this issue of HOS Journal. I wish that this issue of Journal will be liked and appreciated by one and all. Dr. Markanday Ahuja President Haryana Ophthalmological Society Former Vice Chancellor of. Baba Mast Nath University and Gurugram University, Director, Vision Clinic 2478, Sector 1 Main Rd, Sector-1, Rohtak, Haryana 124001 9896553294, markandayahuja@gmail.com MESSAGE FROM PRESIDENT | JAN-APR 2024 MESSAGE FROM PRESIDENT

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 7 REPORT FROM HONORARY GENERAL SECRETARY Dr. Inder Mohan Rustagi HON GENERAL SECRETARY HOS Haryana Ophthalmological Society MBBS; MS; FAICO ; PGDHHM Triveni Hospitals Pvt Ltd, 207/13; Subhash Nagar ; old railway road GURUGRAM; HARYANA; 122001 Email id- imrustagi1970@gmail.com Contact no. +91-9810093892 Dear HOS Members Greetings from desk of Honorary General Secretary! Please find the secretary report for year 2023-24 1. UNANIMOUS ELECTION OF VICE PRESIDENT DONE FOR 23-24 DR PARVEEN ARORA. GBM APPROVED IT 2. At present Membership has grown to 1037/1048 and out of this more than 650 are AIOS MEMBERS 3. Website of our society http://www.haryanaophthalmologicalsociety.com IS SECURE; a. DIGITAL DETAILS OF MEMBERS ARE NOW LIVE AND DYNAMIC WITH ALL DETAILS. b. ABSTRACT ONLINE. c. STILL MEMBERS HAVE NOT UPDATED THEIR DATA. APPEAL to all to do the needful please. 4. 17TH Annual conference HOS was held at Hissar at Royal palm resorts Hissar; 21-22nd jan 23 a. Organizing Sec Dr. Praveen rewri and Org Chairman Dr S S KHURANA ; UNDER THE PRESIDENCY OF DR S B JAIN ALONG WITH DR PRAVEEN MONGA AND DR G P S MANN . . b. ATTENDED BY MORE THAN 300 DELEGATES AND MORE THAN 30 NATIONAL FACULTIES PARTICIPATED AND DELIBERATED. TEAM HAS SUBMITTED THEIR BALANCE SHEET BY PENNY PENNY AND DELIGHTED THAT INSPITE OF SUCH A BIG EXPENDITURE; SAVED 69944 RS. A BIG LOUD APPLAUSE FOR THEM . c. BEST PAPER SLECTED OF DR SUPREME GOEL AND SENT for AIOS ; d. 4 orations in annual Conference in names of i. Dr Narinder Taneja .. ii. Dr SN Saxena iii. Late Sh Dr JL Sharma iv. Late Sh Dr S K Lall e. BY DR LALIT VERMA ; DR ROHIT SHETTY, DR JYOTIRMAY BISWAS &DR MAHIPAL SACHDEV 5. Journal of the society is a regular feature. Dr DEEPENDRA V SINGH IS THE EDITOR Journal. a. Issues with vibrant articles were brought out by Editor journal. b. We have tied up with WOLTER Kluwer AND HOPEFULLY IN 1- 2 YEARS ; OUR OWN JOURNAL HJoO will be indexed. 6. Credit Hours have been awarded for all our conferences by Haryana Medical Council. a. FOR 17 TH ANNUAL CONFERENCE ; 3 CME credit hours ISSUED VIDE LETTER NO HMC/2023/165 DATED 13.1.23. MESSAGE FROM GENERAL SECRETARY | JAN-APR 2024 MESSAGE FROM GENERAL SECRETARY

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 8 MESSAGE FROM GENERAL SECRETARY | JAN-APR 2024 MESSAGE FROM GENERAL SECRETARY b. Aios ARC SYMPOSIUM DONE IN THS YEAR . 5/3/23 GURGAON BY HOS AND GOS .. DR INDER MOHAN / DR DEEPENDRA / DR VISHAL ARORA .: 2 CME CREDIT HOURS LETTER DATED 3.3.23 HMC/2023/615 . c. 24 TH SEPTEMBER 23 ; SFOS : DIAGNOSTICS IN OPHTHALMOLOGY UNDER PATRONAGE OF DR PARVEEN ARORA .AND D R MAHIP ROY BANSAL . 3 CME CREDIT HOURS HMC/2023/3042 DATED 19.9.23. 7. CME are regular features of our society to update the knowledge of the members virtual CME Most of the CME by distt societies are held under the aegis of HOS . Various CME like a. 12.3.23 GURUGRAM GLAUCOMA WALK .BY GOS /HOS /IMA b. 15.3.23 WORLD GLAUCOMA WEEK BY MAX GURGAON c. 15.3.23 GLAUCOAM QUIZ BY HOS WITH RIO d. 01.04.23 INDOCONCLAVE BY AOS e. 08.06.23 DRY EYE BY SFOS AT SIRSA f. 10.06.23 ; RTM ON ADVANCEMENT IN IOL BY SFOS g. 14.6.23 PEARLS IN OPHTHALMOLOGY BY ROS h. 29.07.23 SFOS .. RAYNER ADVANACED IOL i. 13.8.23 ACOIN HARYANA BY ROS j. 3.9.23 I PLEDGE : NATIOANAL EYE DONATION FORTNIGHT BY AEDH / GOS /HOS IN GURGAON k. 11.17.9.23 POS : CLINICAL PERSPECTIVES ON GLAUACOMA l. 9.9.23 SFOS : MYOPIA m. 28.9.23 RECENT ADVANCES CME BY GOS n. 29.9.23 POS :NEW GENERATION IOLS o. 14.11.23 WORLD DIABETES DAY BY ROS /RIO p. 25.11.23 .. NEWER GENERATION IOL BY KARNAL EYE SURGEON SOCIETY. q. 15.12.23 NEWER GENERATION IOL GOS 8. LDP Programme a. THIS YEAR ..DR AYUSH SINGHAL COMPLETED HIS LDP AIOS. b. DR SUMEET KHANDUJA IS BEING SENT for LDP THIS TIME. 9. NATIONAL LEVEL QUIZ BIG Q ORGANISED BY DR BAWANKULE . a. OUT OF 670 TEAMS ALL OVER INDIA; TWO TEAMS FROM RIO ROHTAK MADE IT TO FINAL 10 TEAMS ON 12.4.23 . b. DR SURENDER KUMAR /DR ROHAN MADAN UNDER DR NADA c. DR HARSHWARDHAN CHILKOTI AND SUPREME GOEL UNDER DR RS CHAUHAN BEGGED 1ST & 3 RD PRIZE RESPECTIVELY. d. A BIG APPLAUSE FOR THEM. 10. WE HOS ARE NOW GST COMPLIANT SOCIETY. Thankful to all HOS executives; patrons; members and I bow my head in gratefulness THANKS

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 9 Remembering the Life and Legacy of Padma Bhushan Dr. Sengamedu Srinivasa Badrinath Suresh K Pandey MBBS, MS1 , Vidushi Sharma MD, FRCS2 ARTICLE INFORMATION AFFILIATION OF ALL AUTHORS: ABSTRACT 1. SuVi Eye Institute & Lasik Laser Center C 13 TALWANDI, KOTA, RAJ. 324 005, INDIA 2. SuVi Eye Institute & Lasik Laser Center C 13 TALWANDI, KOTA, RAJ. 324 005, INDIA Corresponding author Dr. Suresh K. Pandey Consultant – Past President, Kota Division Ophthalmological Society (KDOS) Past Vice President, Indian Medical Association (IMA) KOTA Director, SuVi Eye Institute & Lasik Laser Center C 13 TALWANDI, KOTA, RAJ. 324 005, INDIA Email - suresh.pandey@gmail.com NA Article received Article accepted Article on line Keywords Presented at January 2024 January 2024 February 2024 NA NA REMEMBERING THE LIFE AND LEGACY OF PADMA BHUSHAN DR. SENGAMEDU SRINIVASA BADRINATH Fig 1: Padma Bhushan Dr. Sengamedu Srinivasa Badrinath GUEST EDITORIAL | JAN-APR 2024 The passing of Dr. Sengamedu Srinivasa Badrinath (on November 21, 2023, marked the profound loss of an extraordinary educator, a true visionary, and a pioneer ophthalmologist who founded Sankara Nethralaya, Chennai. He is survived by his wife, Dr Vasanthi Iyengar, and their two sons, Ananth and Seshu Badrinath. His departure from this world leaves a void that can never be filled, but his remarkable contributions and the lives he touched will remain etched in our hearts and minds forever. Dr. Badrinath led an extraordinary life dedicated to service, visionary leadership, and the advancement of ophthalmology, and training young ophthalmologists by establishing Sankara Nethralaya at Chennai. As a visionary ophthalmologist, he trained thousands of fellows in retinal surgery.1,2 As an educator, he selflessly imparted knowledge to numerous ophthalmologists (visited from India and various other countries) who would become renowned ophthalmologists/retinal specialists themselves. As a humanitarian, he treated all patients with dignity and compassion, regardless of social status or means. Dr. Badrinath’s life is a perfect example of Live, Love, Learn, and Leave a Legacy. His legacy challenges us to lead lives uplifted by optimism and oriented toward others’ welfare. By overcoming obstacles, sharing knowledge generously, and serving humanity, we carry forward the ethos at the heart of Dr. Badrinath’s

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 10 monumental contributions to ophthalmology and society. He showed us the power of living benevolently, affirming that we uplift our shared human condition when we lift others. We consider very fortunate to meet Dr. S.S. Badrinath a few times at Sankara Nethralaya and while working at the Centre for Ocular Therapeutics and Biodevices, Storm Eye Institute, Medical University of South Carolina, Charleston, USA. He visited the USA few times and addressed the group “Friends of Sankara Nethralaya”. While addressing a group of doctors and others in the USA, he shared the work done by Sankara Nethralaya and deeply inspired all participants to help and contribute to eliminating preventable blindness in India. THE EARLY YEARS: A FOUNDATION OF EXCELLENCE Dr. Sengamedu Srinivasa Badrinath’s remarkable journey began with humble origins, hailing from a remote place in Tamil Nadu, India. Born on February 24, 1940, in Triplicane, Chennai, he embarked on a path that would shape his life and revolutionize the field of ophthalmology. With an unwavering determination to make a difference, Dr. Badrinath’s academic prowess was evident from an early age. His exceptional intellect and dedication propelled him to the top of his class at Madras Medical College, where he graduated with distinction in 1964. This early achievement foreshadowed the remarkable career that lay ahead. Driven by his thirst for knowledge and desire to push the boundaries of his field, Dr. Badrinath embarked on his academic journey, starting with his internship and a year of internal medicine residency at Grasslands Hospital in New York, halfway across the world. Dr. Badrinath traveled to Manhattan in the late 1960s passionately and enthusiastically to pursue specialized training at the prestigious Manhattan Eye, Ear, and Throat Hospital, New Your, USA. Amidst impeccable state-of-the-art facilities and world-renowned surgeons, he learned everything he could about his chosen specialty- retinal surgery. Though far from home, Dr. Badrinath remained grounded in his mission to gain expertise in ophthalmology to someday serve the visually impaired in India. His humble beginnings served not to limit his ambitions but to motivate his quest for excellence. Despite limited means, this early dedication to mastering ophthalmology would provide the foundation for his pioneering career in improving eye care for the underprivileged across India. Dr. Badrinath sought a fellowship opportunity to further refine his expertise with Dr. Charles L. Schepens, widely regarded as the father of modern retinal surgery, at the Retina Services of the Massachusetts Eye and Ear Infirmary in Boston, Massachusetts, USA. Working under the guidance of this esteemed pioneer in the field, Dr. Badrinath gained invaluable knowledge and skills that would shape his future contributions to ophthalmology. Driven by his unwavering commitment to excellence, Dr. Badrinath’s GUEST EDITORIAL | JAN-APR 2024 Remembering the Life and Legacy of Padma Bhushan Dr. Sengamedu Srinivasa Badrinath dedication was acknowledged through his achievement of becoming a fellow of the Royal College of Surgeons of Canada in 1969 and a diplomate of the American Board of Ophthalmology in 1970. These accolades were a testament to his exceptional skills and expertise in the field, setting the stage for his illustrious career. After completing his ophthalmology studies and acquiring valuable experience in the United States, Dr. Badrinath returned to India in 1970. With the constant support from his wife, Dr. Vasanthi Iyengar, Dr. Badrinath embarked on building up his medical practice in Chennai and making further phenomenal contributions to eye care. He worked as an ophthalmology consultant for six years at the esteemed Voluntary Health Services institution. From 1970 to 1972, he practiced at H.M. Hospital in Chennai, and then from 1973 to 1978, he served as an ophthalmologist at Vijaya Hospital, further expanding his patient base. Eventually, he established a thriving private practice focused on ophthalmology and the emerging field of vitreoretinal surgery. Throughout this early stage of his career, Dr. Badrinath published over 60 papers in prestigious peerreviewed journals, demonstrating his dedication to generating new knowledge, techniques, and advancements in the field of ophthalmology These formative years laid the foundation for Dr. Badrinath’s future pioneering achievements in Indian eye care. THE GENESIS OF SANKARA NETHRALAYA AT CHENNAI Jagadguru Kanchi Sri Chandrasekarendra Saraswathi Nethra Nilayam (JKCN) inspired Dr. S.S. Badrinath that led him to establish Sankara Nethralaya in collaboration with the spiritual headquarters of Sankara Math. This remarkable initiative took shape in 1978, when Dr. Badrinath, alongside a group of dedicated philanthropists, founded the Medical & Vision Research Foundations in Madras (now Chennai). As a unit of the Medical Research Foundation, Sankara Nethralaya became a charitable, not-for-profit eye hospital. Fig 2: Jagadguru Kanchi Sri Chandrasekarendra Saraswathi Nethra Nilayam (JKCN) inspired Dr. Badrinath’s that led him to

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 11 GUEST EDITORIAL | JAN-APR 2024 establish Sankara Nethralaya at Chennai. What set Sankara Nethralaya apart was its commitment to inclusivity and impartiality. It became India’s first eye hospital that welcomed individuals from all walks of life, regardless of socioeconomic status, and provided affordable and excellent care. This revolutionary approach fostered a culture of compassionate healing, transforming the landscape of Indian healthcare across various dimensions, including clinical service, research innovation, and professional education. The Sankara Nethralaya institution was built, keeping the patient at the center of all decisions. “This life is to help others,” Dr. S.S. Badrinath often remarked, exemplifying his philosophy of purposeful living. Under the guidance of Dr. Badrinath’s principles and unwavering perseverance, Sankara Nethralaya emerged as an enduring embodiment of care without compromise. It set a benchmark for accessible excellence in eye care, ensuring that every individual, whether rich or poor, could receive world-class treatment and compassionate care. Dr. Badrinath’s pioneering medical feats and systemic reforms touched countless afflicted lives. Throughout an incredible journey fueled by service-oriented values imparted in youth, his enduring legacy continues to heal, teach, and push frontiers so that others may live free of distress. The impact of Sankara Nethralaya extended beyond its immediate reach. By revolutionizing the approach to eye care and embracing inclusivity, Dr. Badrinath’s visionary hospital became a beacon of hope and inspiration for the entire nation. It served as a testament to the power of combining medical expertise with compassion, ultimately raising the standards of eye care delivery in India. Under the exceptional leadership of Dr. Badrinath, Sankara Nethralaya flourished as a sanctuary of healthcare, providing affordable excellence regardless of patients’ financial circumstances. It stood as a guiding light of hope for destitute villagers burdened by treatable blindness and offered solace to scientists tirelessly battling life-altering eye diseases. With its cutting-edge facilities and compassionate teams, the institution worked tirelessly to transform despair into joy. At its core, Sankara Nethralaya empowered lives by treating various eye diseases and restoring vision, ultimately restoring livelihoods that would have otherwise been lost due to a lack of accessible, high-quality care. Dr. Badrinath’s humanistic vision and servant leadership elevated the institution beyond being a mere ophthalmic powerhouse. It symbolized optimism for countless individuals shrouded in darkness, addressing their material and emotional needs and enabling them to look forward with renewed clarity. Dr. Badrinath’s unwavering dedication to innovation and quality propelled Sankara Nethralaya to become a global leader in eye care. Pioneering new ophthalmic technologies, such as the microkeratome for safer Lasik procedures, and cost-effective intraocular lenses, transformed cataract surgeries and positively Remembering the Life and Legacy of Padma Bhushan Dr. Sengamedu Srinivasa Badrinath impacted the lives of millions in India. However, it was not just about the technology; Sankara Nethralaya, guided by Dr. Badrinath’s vision, became a place where people from diverse backgrounds united to overcome suffering and find solace. His enduring legacy is a foundation built on hope, compassion, and selfless dedication to eradicating needless blindness, leaving an indelible mark on the field of eye care. Dr. Badrinath’s profound legacy at Sankara Nethralaya inspires future generations of ophthalmologists, vision scientists, and researchers reminding them of the transformative potential in the pursuit of accessible excellence and compassionate healing. PIONEERING RESEARCH IN OPHTHALMOLOGY BY ESTABLISHING MEDICAL RESEARCH FOUNDATION Dr. Badrinath established the Medical Research Foundation at Sankara Nethralaya. This pioneering research hub became a nucleus for important research in ophthalmology that improved the lives of millions suffering from visual impairments. Aligned with Dr. Badrinath’s vision, the center seamlessly blended scientific research with clinical practice. Under his astute guidance, luminaries like Dr. Lingam Gopal, Dr. J. Biswas, and many others collaborated at the foundation. Their efforts established India’s premier ophthalmic research institution under Dr. Badrinath’s leadership. Significant milestones included creating an ocular genetics lab with an automated DNA sequencer. The center achieved remarkable breakthroughs, gaining global recognition in prestigious scientific journals like Nature. Innovations in ophthalmic diagnostics, ocular micro-surgeries, and publishing the outcome of the complex vitreoretinal cases became a signature of the Medical Research Foundation. His influence fostered research excellence and deep empathy among the brilliant scientists he mentored, transforming the eye care landscape. Fig 3: Dr . Badrinath was supported by his wife Dr Vasanthi. Sankar Nethralya, Chennai. did pioneer work in Ophthalmology by introducing several cutting-edge ophthalmic techology.

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 12 GUEST EDITORIAL | JAN-APR 2024 Remembering the Life and Legacy of Padma Bhushan Dr. Sengamedu Srinivasa Badrinath PIONEERING RESEARCH IN OPHTHALMOLOGY BY ESTABLISHING MEDICAL RESEARCH FOUNDATION In addition to the hospital and research center, Dr. Badrinath established renowned educational institutions to fulfill his vision for Sankara Nethralaya. In 1985, he founded the Elite School of Optometry, which emerged as a premier institution for optometry education and research. The school focuses on academic excellence and the importance of service to the visually disadvantaged. Dr. Badrinath also created the Medical Research Foundation’s Sankara Nethralaya Academy in 2010. an institution dedicated to providing specialized training and continuing education for healthcare professionals in the field of ophthalmology. The academy offered a wide range of programs, including specialized courses, workshops, and conferences, designed to enhance the knowledge and skills of ophthalmologists, optometrists, and other eye care professionals. Through its comprehensive and interdisciplinary approach, the Sankara Nethralaya Academy fostered a culture of continuous learning and professional development, ensuring that healthcare providers stayed at the forefront of advancements in eye care. THE CHARITABLE ARM TO DELIVER COMPASSIONATE EYE CARE TO ALL Dr. Badrinath’s commitment extended beyond conventional medicine. He ardently believed that quality healthcare is a fundamental human right. To fulfill this vision, he established the Medical Research Foundation Trust within Sankara Nethralaya to deliver compassionate eye care to all. Dr. Badrinath and a team of devoted volunteers continuously raised money for patients who could not afford treatment to ensure no one went without essential care due to lack of means. Their charitable efforts provided a vital lifeline to numerous financially struggling individuals, enabling them to access medical care that would otherwise be out of reach. While the hospital offered subsidized treatment, he introduced mobile teleophthalmology units and eye surgery vans to provide accessible or affordable care in remote rural villages. Through the Medical Research Foundation Trust and outreach initiatives, Dr. Badrinath enabled Sankara Nethralaya to fully embody his vision as a sanctuary for any in need. It is a testament to his humanism, uplifting lives through compassion beyond medical excellence alone. THE GUIDING LIGHT FOR NEXT GENERATIONS: DR. BADRINATH’S LEGACY Reflecting on the extraordinary life of Dr. S.S. Badrinath, we are moved by his profound humanitarian contributions to society and ophthalmology. His teachings were not merely words but an unwavering commitment to improving humanity. The Sankara Nethralaya revolutionized compassionate healthcare in India and set global benchmarks in clinical excellence and service to the underprivileged. His impact extends beyond Sankara Nethralaya’s walls, inspiring medical institutions worldwide to emulate his ethical, egalitarian healthcare example. His vision sparked positive change in domains spanning education, community upliftment, and rural empowerment through the broader Sankara movement. But above all, Dr. Badrinath ignited a spark in the hearts and minds of almost everyone who came into his contact. He awakened our intrinsic humanity and compelled us to pursue lives of purpose through selfless service. Fig 4: Dr. S.S. Badrinath was conferred Life-Time Achievement Award by Madras City Ophthalmological Association. Dr. S.S. Badrinath’s message to his students was about providing compassionate eye care to each and every patient. According to him “one can cross the ocean of life only by performing selfless service to humanity.” He was a real Karma Yogi. The departure of Dr. Badrinath is a big loss to the ophthalmic fraternity. Dr. Badrinath’s passing should not be seen as the end of an era but as a promise for a generation of young ophthalmologists to become ophthalmic (as well as retinal) surgeons inspired by his example to seek to understand their patients and to unravel the causes of blindness, for which as yet there are no answers. Such souls are indeed immortal and his teachings will keep living through thousands of his fellows and students.

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 13 GUEST EDITORIAL | JAN-APR 2024 Remembering the Life and Legacy of Padma Bhushan Dr. Sengamedu Srinivasa Badrinath REFERENCES Raman R, Rajan M, Natarajan S, Biswas J. A living legend with an extraordinary vision who changed the perspective of ophthalmology in India-Padma Bhushan Dr. Sengamedu Srinivasa Badrinath. Indian J Ophthalmol. 2022 Apr;70(4):1080-1082. doi: 10.4103/ijo.IJO_564_22. PMID: 35325988; PMCID: PMC9240520. Gopal, Lingam. A phenomenon called “Dr. S. S. Badrinath”. Indian Journal of Ophthalmology 72(1):p 6-7, January 2024. | DOI: 10.4103/IJO.IJO_3166_23 1. 2. Financial disclosure Conflict of Interest Acknowledgements Copyright Transfer None None Nil Copyright transfer form signed by corresponding author on behalf of all co-authors FOOTNOTES AND DISCLOSURES

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 14 RHO-KINASE INHIBITORS- AN INSIGHT INTO THE NEW DRUG MODALITY Dr. Prerna Garg MS, FSCEH (Glaucoma)1 , Dr. Julie Pegu MS 1 Dr. Suneeta Dubey MS, Glaucoma Fellow (Wills Eye Institute)1 , Dr. Monica Gandhi MS1 ARTICLE INFORMATION AFFILIATION OF ALL AUTHORS: ABSTRACT 1. Department of Glaucoma, Dr. Shroff’s Charity Eye Hospital, New Delhi Corresponding author Dr. Prerna Garg Consultant – Department of Glaucoma Dr. Shroff’s Charity Eye Hospital, New Delhi Email - prer.11@gmail.com Glaucoma is a progressive disease characterized by the gradual death of the retinal ganglion cells leading to visual deterioration, the only treatment being reduction in intraocular pressure. In primary open-angle glaucoma, there is a marked loss of trabecular meshwork cells leading to the fusion and thickening of trabecular lamellae and a significant increase in electrondense plaques leading to an increase in the outflow resistance through the conventional pathway (responsible for 80-85% of the outflow). Rho kinase inhibitors are a new class of drugs that act by decreasing this outflow resistance and thus increasing the aqueous humor outflow. Few agents of this class (eg. Netarsudil) also act as Norephinephrine uptake inhibitors and thus further decrease the intraocular pressure by decreasing the aqueous secretion as well as the episcleral venous pressure. This article discusses the pathophysiology as well as the various clinical trials of this group of drugs. It also discusses in brief a new combination drug (Netarsudil+Latanoprost) which has recently been FDA approved. A new side effect- Reticular corneal edema, noted with these drugs quite frequently has also been described. Article received Article accepted Article on line Keywords Presented at NA NA NA Glaucoma, outflow resistance, Rho kinase inhibitors, Netarsudil, ROCKET trials, reticular corneal edema NA INTRODUCTION Glaucoma is a multifactorial disease leading to a chronic progressive optic neuropathy characterized by apoptosis of retinal ganglion cells, thinning of retinal nerve fiber layer, and hence gradual deterioration of visual field and function. Currently, the only modifiable factor to halt its progression is the lowering of intraocular pressure (IOP). Since the 1800s, multiple drug formulations have been used for its treatment. They act either by decreasing the aqueous humor formation (α2 agonists, β blockers, Carbonic anhydrase inhibitors) or by increasing the outflow either by the conventional route (nonselective α agonists, parasympathomimetics) or uveoscleral route (prostaglandin analogs) (Figure 1). Newer drug molecules are now being investigated to expand the glaucoma therapy armamentarium. These include Rho kinase (ROCK) inhibitors, adenosine receptor agonists, prostanoid receptor agonists, and small interfering RNA. Here we will be discussing in detail the Rho kinase inhibitors. RHO AND RHO KINASES a) The Rho kinases - RhoA, RhoB, and RhoC are small G-proteins that are active when bound to guanosine triphosphate (GTP) and inactive when bound to guanosine diphosphate (GDP). b) They are activated by several secreted cytokines, including endothelin-1 (ET-1), thrombin, angiotensin II, lysophosphatidic acid, and transforming growth factor (TGF)-b, or via integrin activation. (1) c) They regulate cell morphology, polarity, proliferation, adhesion, motion, cytokinesis, and apoptosis along with smooth muscle contraction and neurite elongation. Figure 1. Timeline of antiglaucoma medications in current use REVIEW ARTICLE | JAN-APR 2024

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 15 Figure 2. ROCK protein kinases d) The effectors of the Rho family are the Rho kinases, ROCK1 and ROCK2. These 2 serine/threonine kinase isoforms are Rho GTP binding proteins. ROCK1 and ROCK2 contain an N-terminal kinase domain that phosphorylates target proteins, followed by a coiled-coil region with a Rho-binding domain and a domain with similarity in structure to pleckstrin, and then finally a cysteine-rich autoinhibitory domain toward the C terminus that limits kinase activity via intramolecular interactions (Figure 2). (2) PATHOPHYSIOLOGY OF RHO-KINASE/ ROCK INHIBITORS AThe Trabecular Meshwork (TM) is composed of arrays of collagen beams covered by endothelial-like cells, with loose extracellular matrix occupying the spaces between the cells of the adjacent beams. The outermost, juxtacanalicular (JCT) or cribriform region has no collagenous beams, it rather has several cell layers immersed in a loose web of extracellular matrix fibrils. This endothelial layer has significant morphologic characteristics, which distinguish it from the rest of the endothelium in both the TM and the Schlemm’s canal. The surface is bumpy due to protruding nuclei, cyst-like vacuoles, and finger-like projections bulging into the canal. These finger-like projections have been described as endothelial tubules with patent lumens. (3) Studies suggest that resistance to flow is maximum in the JCT region and/or the inner wall of Schlemm’s canal, although the exact location of the major resistance barrier is not clear. The inner wall endothelium has numerous small pores and giant vacuoles ranging from 0.5-2 µm and is in a dynamic state intermittently opening and closing depending on IOP. A hydrodynamic interaction known as “funneling” exists between the pores and the extracellular matrix in the JCT that makes inner wall pore density an important determinant of outflow resistance. (4) In primary open-angle glaucoma (POAG), there is a marked loss of trabecular meshwork cells leading to fusion and thickening of trabecular lamellae and a significant increase in electron-dense plaques compared with age-matched controls. This increases the outflow resistance through the conventional pathway. Under normal circumstances in adults, the bulk of aqueous humor exits the eye through this pathway. The Rho kinase inhibitors act by decreasing this outflow resistance. The cytoskeleton of the inner wall endothelium is composed primarily of actin filaments, intermediate filaments, and microtubules. Actin filaments along with myosin, are involved in cell contraction and motility, phagocytosis, pinocytosis, and cell adhesion. Intermediate filaments are composed of vimentin and desmin, according to immunocytochemical studies of cultured human trabecular cells. In maintaining and modulating the cell shape, anchorage, and motility, these three cytoskeletal networks act in concert, and changes in each network can induce radical changes in the other two. (5) Myosin light-chain phosphorylation plays a pivotal role in the actin–myosin interactions modulating the formation of stress fibers, focal adhesions, and cellular contraction. This is triggered by the small GTPase Rho, which activates members of the Rhoassociated kinase family (Figure 3). Rho kinase also phosphorylates Lin-11/Isl-1/Mec-3 kinase that then inhibits cofilin-mediated actin-filament disassembly leading to an increase in actin filament density, rigidity, and stability. (6) Other cytoskeletal effects of Rho kinase include a) Depolymerization of intermediate filaments and modulation of microtubule dynamics and polarity b) Increase in the contractile state and stiffness of cells c) Regulation of a variety of cell processes, particularly those involving movement and smooth muscle contraction Trabecular meshwork cells have been shown to express both ROCK1 and ROCK2. Inhibiting Rho kinases leads to alteration in the stress fibers and focal adhesions. A decrease in stress fibers leads to a decrease in the stiffness of cells. Less stiff cells can form more pores, thus decreasing the funneling effect and decreasing REVIEW ARTICLE | JAN-APR 2024 Figure 3. Pathophysiology of Rho kinase RHO-KINASE INHIBITORS- AN INSIGHT INTO THE NEW DRUG MODALITY

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 16 They have been tried in Fuchs corneal dystrophy and endothelial decompensation following cataract surgery. iii)Diabetic retinopathy and macular edema- It has been shown that ROCK pathways promote leukocyte adhesion to microvascular structures, through increased levels of activated Intercellular Adhesion Molecule-1 (ICAM-1) and expression of other downstream proteins. Treatment with ROCK inhibitor intravitreal injections would be able to reduce the adhesion of leukocytes to microvascular structures, allowing for a decrease in the effects of diabetic retinopathy and macular edema. (10) Clinical trials in early phases are ongoing to assess the efficacy of ROCK inhibitors in macular edema due to diabetic retinopathy or retinal vein occlusions and in neovascular age-related macular degeneration. iv) Rock inhibitors are being investigated for the role that Rho kinase plays in the myopia scleral remodeling pathway. CLINICAL TRIALS OF RHO KINASE INHIBITORS Pre-clinical trials: a) The first specific Rho kinase inhibitors to be investigated for their effects on outflow were Y-27632 and Fasudil. These agents significantly increased the outflow facility in enucleated porcine eyes and live rabbits while leaving the inner wall endothelium intact. APPLICATION OF RHO KINASE INHIBITORS IN OPHTHALMOLOGY i)Glaucoma- Rho kinase inhibitors are effective in reducing IOP by decreasing the TM outflow resistance. Few of these agents like Netarsudil have been found to exhibit norepinephrine transporter (NET) inhibitory action too, resulting in the blocking of the norepinephrine reuptake and thus increasing adrenergic activity at the alpha-adrenergic receptors. This results in vasoconstriction, decreasing the aqueous humor inflow as well as the episcleral venous pressure (EVP). As we all know, a decrease in EVP by 1 mm Hg decreases the IOP by 1 mm Hg, thus increasing the efficacy of this drug due to its multimodal mechanism of action. Rho kinase inhibitors also offer neuroprotection in glaucoma patients by enhancing axonal regeneration and increasing ocular blood flow. They inhibit the extracellular growth inhibitors which limit the regeneration of CNS axons when injured. (7) Also, they have been found to decrease the post-trabeculectomy scarring by inhibiting the smooth muscle actin expression and thus, the myofibroblast trans-differentiation (Fig 5). (8) ii)Cornea- In 2009, Okumura et al found that the use of a selective ROCK inhibitor, Y-27632, increased corneal endothelial cell proliferation, increased cell adhesion, and decreased cell apoptosis. It enhanced the rate of wound healing and accelerated the recovery of corneal transparency. (9) REVIEW ARTICLE | JAN-APR 2024 Figure 4. Timeline of Rhokinases and its inhibitors RHO-KINASE INHIBITORS- AN INSIGHT INTO THE NEW DRUG MODALITY outflow resistance. Changes in focal adhesions, release the attachments between the Schlemm’s canal cells and the JCT, expanding the spaces in the JCT and decreasing the magnitude of the funneling effectoutflow resistance. Changes in focal adhesions, release the

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 17 b) Other Rho kinase inhibitors (AR-12286, Netarsudil, H-1152, Y-39983, AMA-0076) were also found to significantly decrease outflow resistance in postmortem porcine eyes and IOP in living rabbits and monkeys; maximum reductions in outflow resistance and IOP as much as 65% was achieved in these studies (Figure 5). Figure 5. Phases of a clinical trial Clinical trial results have been published in the peerreviewed literature for 4 Rho kinase inhibitors: i) SNJ-1656, ii) AR-12286, iii) Ripasudil, iv) Netarsudil All of these agents are mixed ROCK1 and ROCK2 inhibitors. SNJ-1656 – Senju Pharmaceuticals, Osaka, Japan First Rho kinase inhibitor to be studied in a clinical trial to lower IOP. It is 30 times more effective in inhibiting Rho kinase activity than Y-27632 (used in pre-clinical animal trials). Phase 1 and phase 2 trials revealed an IOP reduction of 3-3.5 mm Hg at peak and 2 mm Hg at trough. They observed conjunctival hyperemia in all subjects as a side effect. (11,12) i) AR-12286- Aerie Pharmaceuticals Phase 1 and phase 2 trials on this agent revealed a maximum reduction of 7 mm Hg with 0.5% and 3.5 mm Hg with 0.25%. However, this was abandoned because Netarsudil, also developed by Aerie Pharmaceuticals, was judged to have a longer duration of action. (13,14) ii) Ripasudil hydrochloride hydrate (K-115) Marketed as Glanatech, it was approved in Japan for the treatment of glaucoma and ocular hypertension (OHT) in September 2014. It was originally discovered by D. Western Therapeutics Institute (Aichi, Japan) and developed by Kowa Company, Ltd. Tanihara et al conducted Phase 1, Phase 2, and Phase 3 trials on this drug agent. In the phase 1 trial, they evaluated the efficacy and safety of different dose concentrations in 50 healthy male volunteers and found a reduction of 3.4, 2.2, 2.6, 4.0, and 4.3 mm Hg 2 hours after instillation with concentrations of 0.05%, 1%, 2%, 4%, and 8%, respectively. Mild conjunctival hyperemia was noticed in around 50% of the patients which resolved spontaneously within 1½ hours(15) iii) Phase 2 trials on Ripasudil: a) To identify the optimal dose- 210 POAG/ OHT patients were 0.1%, 0.2%, and 0.4% concentration twice daily (BD) and 0.4% twice daily was found to be the optimal dosing to control 24-hour IOP. (16) b) Another study found a statistically significant IOP reduction (5.2 mm Hg -0.2% and 6.4 mm Hg- 0.4%) lasting for at least 7 hours after the instillation. (17) c) A study found an additive IOP lowering of 1.4 to 2.4 mm Hg with prostaglandin analogs and 2.2 to 3.0 mm Hg with timolol. Conjunctival hyperemia (76%- mostly mild), blepharitis (21%), and allergic conjunctivitis (20%) were the most commonly reported adverse events attributed to Ripasudil monotherapy in this study. (18) d) A study specifically designed to investigate the time course of ripasudil-induced conjunctival hyperemia found peak intensity at 15 minutes after instillation and a gradual return to baseline at 120 minutes i.e. 2 hours. (19) Phase 3 trials on Ripasudil (20) revealed results similar to the phase 2 trials. Phase 4 studies- Two retrospective studies and a small, noncomparative prospective study with results reported after 3 and 12 months evaluated adjunctive treatment with Ripasudil in Japanese patients already on maximum medical therapy. They demonstrated IOP reductions ranging from 2.6 to 3.1 mmHg or approximately 15% to 16% from baseline. (21,22) Two retrospective studies suggested it is safe to use Ripasudil to lower IOP in ocular hypertensive eyes with uveitis. (23,24) iv) Netarsudil mesylate (AR-13324) Rhopressa, a Rho kinase and norepinephrine transporter inhibitor, was developed by Aerie Pharmaceuticals as one of a class of amino-isoquinoline amide Rho kinase inhibitors. It was approved for use in the United States to treat glaucoma in late 2017. Phase 1 trial- IOP lowering efficacy of Netarsudil 0.02% oncedaily dosing (OD) in the morning (AM) was assessed in 18 healthy subjects over 8 days. They concluded that it produced a substantial reduction in post-dose IOP at all time points tested reaching a maximum reduction of 6 mm Hg which was much greater than that observed historically with Xalatan (~ 3 mm Hg). (25) Phase 2 trialsa) Two studies established the optimal Netarsudil concentration in patients with IOP>21 mm Hg and <36 mm Hg. Netarsudil 0.01%, REVIEW ARTICLE | JAN-APR 2024 RHO-KINASE INHIBITORS- AN INSIGHT INTO THE NEW DRUG MODALITY

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 18 0.02%, and 0.04%, and vehicles were dosed OD AM for 7 days. Based upon mean reduction in IOP from baseline, Netarsudil 0.01% was found to be less effective than 0.02% and 0.04%, and Netarsudil 0.02% had similar efficacy and superior tolerability compared to 0.04%. Given the 24-hour efficacy and a reduced incidence of conjunctival hyperemia at 8 hours and 24 hours after dosing compared to 2 hours after dosing, it was concluded that an OD dosing of Netarsudil 0.02% at night would retain the efficacy with less chance of hyperemia occurring during the daytime. b) A double-masked, randomized dose-response study of Netarsudil vs. Latanoprost was conducted in 224 patients from 22 private ophthalmology clinics with elevated IOP ranging from 22 to 36 mm Hg. They observed that Netarsudil 0.02% was 1 mm Hg less effective than latanoprost in these patients. However, when they compared the efficacy of the two drug agents in a subgroup of patients with IOP 22-26 mm Hg, they noted that both showed similar IOP lowering efficacy. Hence, while latanoprost was more effective in patients with higher IOP, the efficacy of Netarsudil remained the same at all IOP levels. (26) c) A trial was conducted to assess the nocturnal IOP lowering of Netarsudil by 0.02%. It was dosed OD at night (PM) to 8 subjects with baseline IOP > 17 and < 30 mmHg in both eyes and compared to vehicle (4 subjects) after dosing for 7 days. Netarsudil demonstrated a statistically significant mean change from nocturnal baseline IOP of -3.5 mmHg, which was equivalent to the mean change from baseline IOP during the diurnal period (-3.5 mmHg) (Figure 6). Figure 6. Summary of phase 1 and 2 trials of netarsudil Phase 3 trials- named as ROCKET trials (Figure 7). Figure 7. ROCKET trials They were designed to confirm the safety and IOP-lowering efficacy of Netarsudil 0.02% dosed OD PM or BD over 3 months. The primary efficacy endpoint in each of the Phase 3 efficacy studies (CS301, CS302, and CS304) was mean IOP at 08:00, 10:00, and 16:00 hours at Week 2 (Day 15), Week 6 (Day 43), and Month 3 (Day 90). The assessment time points included the expected peak and trough times for Netarsudil and Timolol. The Week 2 assessment allowed for evaluation of early onset of efficacy and safety and the month 3 assessment served to establish longterm efficacy and safety. Rocket 3 trial was conducted only to assess the safety of the drug over 12 months. All the trials evaluated patients with IOP between 20 and 27 mm Hg, except Rocket 4 which also evaluated higher IOP’s from 27 to 30 mm Hg. In Rocket 1 and 2 trials, if the upper 95% confidence limit for the difference (Netarsudil – Timolol) was within 1.5 mmHg at all 9-time points and 1.0 mmHg at a majority of time points (at least 5 of 9), then Netarsudil was considered clinically non-inferior to Timolol. v) Results of the ROCKET trials (27)- a) IOP lowering efficacy- The patients with IOP ranging from 20- 30 mm Hg were divided into subgroups of IOP < 22, <23, <25, <27, and <30 mm Hg once the trials were finished. They found that with Netarsudil OD treatment, the mean change from baseline IOP was similar in each population, ranging from -3.6 to -4.9 mmHg, -3.6 to -4.8 mmHg, -3.6 to -4.7 mmHg, -3.7 to -4.7 mmHg, and -3.7 to -4.8 mmHg respectively. Treatment with timolol produced smaller mean changes from baseline IOP in the lower baseline IOP populations and larger changes in the higher baseline IOP populations, ranging from -2.8 to -4.3 mmHg, -3.5 to -4.8 mmHg, -3.8 to -5.1 mmHg, -3.9 to -5.2 mmHg, and -4.0 to -5.3 mmHg respectively. At day 90, Netarsudil 0.02% OD also demonstrated statistically significant greater efficacy relative to Timolol 0.5% BD at lower baseline IOP when comparing the proportion of subjects who achieved a ≥ 20% IOP reduction from baseline. The IOP lowering efficacy was found to be stable over 12 months. b) Safety of NetarsudilThe most common side effect noted was conjunctival hyperemia (54.4% in the OD group, 69.9% in the BD group) which was due to the vasodilatory action of this drug. However, 95% of this hyperemia was mild in intensity with the majority being investigator reported based on slit lamp examination, and only 9.9% being reported by the subjects themselves. The other side effects reported were cornea verticillata in 20% of patients and sub-conjunctival hemorrhage in 17%. Cornea verticillata is the deposition of corneal pigments in a whorl-like fashion which occurs due to lysosomal accumulation RHO-KINASE INHIBITORS- AN INSIGHT INTO THE NEW DRUG MODALITY REVIEW ARTICLE | JAN-APR 2024

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 19 of phospholipids within corneal epithelial cells in a process known as phospholipidosis. This occurs for a variety of drugs that are both cationic and amphiphilic like amiodarone, chloroquine, hydroxychloroquine, etc. It was detected after 6 weeks of dosing of Netarsudil, did not cause any visual complaints, and resolved on its own after discontinuation of the drug. Other less frequent side effects noted with the drug OD dosing were blurring of vision (7%), increased lacrimation (7%), eyelid erythema (6.8%), eye pruritis (4.1%), conjunctival edema (3.1%), eyelid edema (3.5%), punctate keratitis (3.2%), foreign body sensation (2.5%), allergic conjunctivitis (2.5%), blepharitis (2.0%), dry eye (2%) and photophobia (1.5%). c) The most frequently reported non-ocular adverse events with Netarsudil included headache (1.3% to 4.8%) and nasopharyngitis (1.4% to 3.8%). d) One side effect that was not seen in these trials was the development of reticular corneal edema – a honeycomb type of epithelial edema, which has been noted over the last year in a significant number of our patients. First described by Fernandez et al in 2018, (28) multiple case reports of this condition have surfaced over the last three years. (29,30) This has been typically noted in eyes with a compromised cornea, either post keratoplasty, after multiple ocular surgeries, or in those with underlying low-grade inflammation. e) Not much is known regarding its pathophysiology, however, it is speculated that these drugs facilitate the passage of fluid from the stroma to the epithelium, by decreasing the adhesion of intercellular junctions and increasing the permeability of tight junctions. (30) As many of these patients are on adjunctive antiglaucoma medications, carbonic anhydrase inhibitors may also play a role in the development of this side effect, by inhibiting the endothelial pump function. This however is a reversible phenomenon, on discontinuation of the agent, with no known long-term implication on the health of the cornea. f) Randomized trials are needed to study the safety and efficacy of this group of drugs in uncontrolled complex glaucoma particularly those with low endothelial cell count, as these eyes were excluded in the trials which have been previously conducted. g) There are no available data on use in pregnant/lactating women to inform any drug-associated risk; however, systemic exposure to Netarsudil from ocular administration is low. h) Safety and effectiveness in pediatric patients below the age of 18 years has not been established yet. ROCKLATAN (Netarsudil 0.02% + Latanoprost 0.005%) Observing the IOP lowering efficacy of Netarsudil 0.02%, a combination with Latanoprost 0.005% was studied with the brand name ROCKLATAN. It received FDA approval in March 2019. The phase 3 trials for this combination drug were the MERCURY 1 and 2 trials. (31) MERCURY 1 was conducted for 12 months and MERCURY 2 for 3 months. In both the trials, similar results were observed. IOP lowering effect of the combination was more than Netarsudil alone by 2-3.2 mm Hg and more than Latanoprost alone by 1.3- 2.6 mm Hg. The IOP reductions were maintained throughout the 12 months. i) Nearly twice as many Rocklatan patients achieved a 30% reduction in IOP compared to Latanoprost patients. j) Nearly 60% of Rocklatan patients achieved an IOP of ≤16 mmHg vs. 37% of Latanoprost patients. There is an ongoing MERCURY 3 trial comparing the efficacy of Rocklatan with Bimatoprost [(NCT03284853) ‘‘Safety and Efficacy Study of PG324 (Netarsudil/ Latanoprost 0.02%/0.005%) Ophthalmic Solution Compared to GANFORT (bimatoprost) Ophthalmic Solution in Open Angle Glaucoma or Ocular Hypertension’’]. Financial disclosure Conflict of Interest Acknowledgements Copyright Transfer None None Nil Copyright transfer form signed by corresponding author on behalf of all co-authors FOOTNOTES AND DISCLOSURES RHO-KINASE INHIBITORS- AN INSIGHT INTO THE NEW DRUG MODALITY REVIEW ARTICLE | JAN-APR 2024

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 20 REVIEW ARTICLE | JAN-APR 2024 Inoue T, Tanihara H. Rho-associated kinase inhibitors: a novel glaucoma therapy. Prog Retin Eye Res. 2013; 37:1e12. Loirand G. Rho kinases in health and disease: from basic science to translational research. Pharmacol Rev. 2015; 67:1074e1095. Allingham, R. R., Shields, M. B. Shields’ textbook of glaucoma. Philadelphia: Lippincott Williams & Wilkins; 2005. Cellular and molecular biology of aqueous humor dynamics;pp.1-28. Johnson M, Shapiro A, Ethier CR, Kamm RD. Modulation of outflow resistance by the pores of the inner wall endothelium. Invest Ophthalmol Vis Sci. 1992; 33:1670e1675. Tian B, Geiger B, Epstein DL, Kaufman PL. Cytoskeletal involvement in the regulation of aqueous humor outflow. Invest Ophthalmol Vis Sci. 2000; 41:619e623. Rao PV, Pattabiraman PP, Kopczynski C. Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research. Exp Eye Res. 2017; 158:23–32. McKerracher L, Winton MJ. Nogo on the go. Neuron. 2002; 36:345e348. Futakuchi A, Inoue T, Fujimoto T, et al. The effects of ripasudil (K-115), a Rho kinase inhibitor, on activation of human conjunctival fibroblasts. Exp Eye Res. 2016; 149:107e115. Okumura, N., Fujii, K., Kagami, T., Makiko, N., Kitahara, M., Kinoshita, S., & Koizumi, N. Activation of the Rho/Rho Kinase Signaling Pathway Is Involved in Cell Death of Corneal Endothelium. Investigative Opthalmology & Visual Science 2006; 57(15), 6843. Barouch FC, Miyamoto K, Allport JR, Fujita K, Bursell SE, Aiello LP, et al. Integrin-mediated neutrophil adhesion and retinal leukostasis in diabetes. Invest Ophthalmol Vis Sci. 2000; 41(5):1153–8. Tanihara H, Inatani M, Honjo M, et al. Intraocular pressure lowering effects and safety of topical administration of a selective ROCK inhibitor, SNJ-1656, in healthy volunteers. Arch Ophthalmol 2008; 126:309e315. Inoue T, Tanihara H, Tokushige H, Araie M. Efficacy and safety of SNJ-1656 in primary open-angle glaucoma or ocular hypertension. Acta Ophthalmol 2015;93:e393ee395. Williams RD, Novack GD, van Haarlem T, et al. Ocular hypotensive effect of the Rho kinase inhibitor AR-12286 in patients with glaucoma and ocular hypertension. Am J Ophthalmol 2011; 152:834e841. Kopczynski C, Novack GD, Swearingen D, van Haarlem T. Ocular hypotensive efficacy, safety and systemic absorption of AR12286 ophthalmic solution in normal volunteers. Br J Ophthalmol 2013; 97:567e572. Tanihara H, Inoue T, Yamamoto T, et al. Phase 1 clinical trials of a selective Rho kinase inhibitor, K-115. JAMA Ophthalmol 2013; 131:1288e1295. Tanihara H, Inoue T, Yamamoto T, et al. Phase 2 randomized clinical study of a Rho kinase inhibitor, K-115, in primary openangle glaucoma and ocular hypertension. Am J Ophthalmol 2013; 156:731e736. Tanihara H, Inoue T, Yamamoto T, et al. Intra-ocular pressure-lowering effects of a Rho kinase inhibitor, ripasudil (K-115), over 24 hours in primary open-angle glaucoma and ocular hypertension: a randomized, open-label, crossover study. Acta Ophthalmol 2015; 93:e254ee260. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. RHO-KINASE INHIBITORS- AN INSIGHT INTO THE NEW DRUG MODALITY REFERENCES

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 21 REVIEW ARTICLE | JAN-APR 2024 Tanihara H, Inoue T, Yamamoto T, et al. Additive intraocular pressure-lowering effects of the rho kinase inhibitor ripasudil (K115) Combined with timolol or latanoprost: a report of 2 randomized clinical trials. JAMA Ophthalmol 2015; 133: 755e761. Terao E, Nakakura S, Fujisawa Y, et al. Time course of conjunctival hyperemia induced by a Rho-kinase inhibitor anti-glaucoma eye drop: ripasudil 0.4. Curr Eye Res. 2017; 42:738e742. Inoue K, Okayama R, Shiokawa M, et al. Efficacy and safety of adding ripasudil to existing treatment regimens for reducing intraocular pressure. Int Ophthalmol 2018; 38: 93e98. Sato S, Hirooka K, Nitta E, et al. Additive intraocular pressure lowering effects of the rho kinase inhibitor, ripasudil in glaucoma patients not able to obtain adequate control after other maximal tolerated medical therapy. Adv Ther. 2016; 33:1628e1634. Inazaki H, Kobayashi S, Anzai Y, et al. Efficacy of the additional use of ripasudil, a rho-kinase inhibitor, in patients with glaucoma inadequately controlled under maximum medical therapy. J Glaucoma 2017; 26:96e100. Yasuda M, Takayama K, Kanda T, et al. Comparison of intraocular pressure-lowering effects of ripasudil hydrochloride hydrate for inflammatory and corticosteroid-induced ocular hypertension. PLoS One 2017; 12, e0185305. Yamada H, Yoneda M, Inaguma S, et al. A rho-associated kinase inhibitor protects permeability in a cell culture model of ocular disease and reduces aqueous flare in anterior uveitis. J Ocul Pharmacol Ther. 2017; 33:176e185. Levy B, Ramirez N, Novack GD, Kopczynski C. Ocular hypotensive safety and systemic absorption of AR-13324 ophthalmic solution in normal volunteers. Am J Ophthalmol 2015; 159:980-5. Bacharach J, Dubiner HB, Levy B, et al. Double-masked, randomized, dose-response study of AR-13324 versus latanoprost in patients with elevated intraocular pressure. Ophthalmology 2015; 122:302e307. Serle JB, Katz LJ, McLaurin E, et al. Two phase 3 clinical trials comparing the safety and efficacy of netarsudil to timolol in patients with elevated intraocular pressure. Am J Ophthalmol 2018; 186:116e127. Fernandez MM. Reticular Epithelial Edema in Edematous Corneas Treated with Netarsudil. Ophthalmology. 2018 Nov;125(11):1709. doi 10.1016/j.ophtha.2018.08.004. PMID: 30318038. Bhargava M, Sen S, Bhambhani V, et al. Reticular epithelial corneal edema as a novel side-effect of Rho Kinase Inhibitors: An Indian scenario. Indian J Ophthalmol. 2022 Apr;70(4):1163-1170. doi: 10.4103/ijo.IJO_2865_21. PMID: 35326007; PMCID: PMC9240559. Wisely CE, Liu KC, Gupta D, et al. Reticular Bullous Epithelial Edema in Corneas Treated with Netarsudil: A Case Series. Am J Ophthalmol. 2020 Sep; 217:20-26. doi: 10.1016/j.ajo.2020.04.002. Epub 2020 Apr 11. PMID: 32289295. Asrani S, Bacharach J, Holland E, et al. Fixed-Dose Combination of Netarsudil and Latanoprost in Ocular Hypertension and Open-Angle Glaucoma: Pooled Efficacy/Safety Analysis of Phase 3 MERCURY-1 and -2. Adv Ther. 2020; 37(4):1620-1631. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. RHO-KINASE INHIBITORS- AN INSIGHT INTO THE NEW DRUG MODALITY

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 22 STEROID INDUCED GLAUCOMA: AN AVERTABLE IATROGENIC DISEASE Dr Samiksha Choudhary MS, Fellow (Glaucoma & IOL)1 , Dr Swarnali Sen (MS, FSN)1 , Dr Jasleen Dhillon (MS, DNB)1 , Dr Ramanjit Sihota (MD, FRCS, FRCOphth)2 ARTICLE INFORMATION AFFILIATION OF ALL AUTHORS: ABSTRACT 1. Consultant Glaucoma Services, Shroff Eye Centre 2. Professor and Head Glaucoma Services, Shroff Eye Centre Corresponding author Dr. Samiksha Choudhary Consultant – Glaucoma Services, Shroff Eye Centre Email - drsamiksha21@gmail.com Steroid induced IOP elevation can occur at all age groups. 5-6% of normal patients show marked increase in IOP after steroid therapy. 30% of Glaucoma suspects and 90% POAG might have a steroid induced ocular hypertensive response. IOP can be increased by any exogenous routes of application of steroids. The pressure-inducing effect of steroids is directly proportional to anti-inflammatory potency, dosage of the drug used duration of use. Discontinuation of the steroid is the first line of management. The judicious use of steroids is advocated to make sure we find the best drug, the best concentration, the best frequency, the best route of delivery. Thus, steroid induced glaucoma is a preventable disease. Article received Article accepted Article on line Keywords Presented at NA NA NA Steroid, glaucoma, steroid induced glaucoma, pressure NA INTRODUCTION Corticosteroids are a group of anti-inflammatory drugs that are used to treat various ocular and systemic diseases. Most of these are chronic conditions which require long term treatment. With the increase in environmental pollution there has been increased incidences of ocular allergy, URI, lung diseases, skin diseases which require steroid application in some form. Steroids have been considered as the magic drug of modern medicine but it is a double-edged sword. The over-the-counter availability of this cheap drug which causes immediate relief of symptoms has led to its misuse. The use of steroids can lead to several ocular side effects. Steroid induced intraocular pressure elevation has been well documented EPIDEMIOLOGY Steroid induced IOP elevation can occur at all age groups. It has bimodal distribution. Very young (<10 years) and very old adults are at greater risk of steroid response. This accounts for one-fourth of all acquired glaucoma in children.12 Significant IOP elevations have also been reported in infants on inhalational and nasal steroids. 5-6% of normal patients show marked increase in IOP 4-6 weeks after steroid therapy. Thus 5% of the general population are steroid responders i.e their IOP increase after steroid administration. Becker and Armaly1,2,3 suggested three categories of steroid responders, based on IOP response to topical betamethasone and dexamethasone application: High responder, Moderate responder, Non-responder (table 1) Table 1 Classification of Steroid Responders ETIOPATHOGENESIS Steroid induced glaucoma is a form of open angle glaucoma. The precise Mechanism of action is unknown clearly but primarily there is reduced facility of aqueous outflow.13 (figure 1) Glucocorticoids may exert their effect through increased expression of MYOC (TIGR) gene at locus GLC1A. Steroids cause stabilisation of the lysosomal membranes and accumulation of polymerised Glycosaminoglycans (GAGs) at the trabecular meshwork6,7,8. These polymerised GAGs get hydrated causing biological oedema and increased ocular outflow resistance. Glucocorticoids increase the expression of extracellular matrix REVIEW ARTICLE | JAN-APR 2024 % population IOP rise from baseline Final IOP High responder 4-6% > 15 mm Hg >31 mm Hg Moderate responder 1/3 6-15 mm Hg 25-31 mm Hg Non responder 2/3 < 6 mm Hg < 21 mm Hg

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 23 Figure 2. Steroid Induced Ocular Hypertension caused by various routes of administration of steroids 1. Topical therapy: IOP rise can occur more frequently with topical ocular therapy than systemic therapy. IOP rise can occur by drops or ointment either applied directly to eye or over the skin of the eyelids. 2. Periocular therapy: Periocular injection of repository steroids administered subconjunctival, sub tenons, and retrobulbar are the most dangerous form of steroids because of their prolonged duration of action. A patient’s response to topical steroid therapy does not predict their response to periocular therapy.10,11 3. Intravitreal therapy: Intravitreal triamcinolone: IOP rise is a significant side effect after intravitreal triamcinolone therapy. According to a metaanalysis, percentage of IOP increase after intravitreal IVTA follows an inverted U-shaped pattern.16 (Table 2) In SCORE Study the cumulative rates of IOP elevation with IVTA (greater than 10 mm Hg above baseline within 36 months) were 2% for “standard of care” (no injection), 9% for patients treated with IVTA, 1 mg, and 45% for patients treated with IVTA, 4 mg. Patients should be monitored for 6 months for IOP management after IVTA injection. Table -2 IOP RISE AFTER IVTA INJECTION Duration of IVTA injection Percentage rise in IOP from baseline 1 week 8 % 1 month 28 % 2 month 33 % 3 month 26 % 4 month 17 % 6 month 8 % REVIEW ARTICLE | JAN-APR 2024 STEROID INDUCED GLAUCOMA: AN AVERTABLE IATROGENIC DISEASE proteins fibronectin, GAGs, laminin, elastin which increases the blockage at the trabecular meshwork. They also inhibit the phagocytic activity of the endothelial cell lining the trabecular meshwork leading to accumulation of aqueous debris Figure 1. Etiopathogenesis of steroid induced IOP rise RISK FACTORS There are a certain group of patients who are at an increased risk of steroid induced IOP rise. Patients with POAG are at increased risk. 30% of Glaucoma suspects and 90% POAG might have a steroid induced ocular hypertensive response 4 weeks after topical dexamethasone 0.01% therapy. Normal individuals classified as high responders are most likely to develop POAG. First degree relatives of POAG patients (25-30%) are also considered to be at increased risk of developing steroid responder. High Myopia or eyes with a history of Penetrating Keratoplasty, LASIK, PRK, DSEK are at increased risk of developing steroid induced IOP rise. Diagnosis of ocular hypertension is difficult in these cases because of thin CCT, ocular rigidity changes, corneal oedema, and accumulation of fluid beneath LASIK Flap. Patients with Diabetes Mellitus, Connective Tissue Disorder (Rheumatoid Arthritis), Pigment Dispersion Syndrome, Traumatic Angle Recession, Endogenous Hypercortilsolism are at increased risk of steroid induced ocular hypertension. ROUTES OF ADMINISTRATION It has been documented that IOP can be increased by any exogenous routes of application of steroids.9 (figure 2)

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 24 Ozurdex (intravitreal dexamethasone implant): 12.6% of patients show an IOP increase >10 mm Hg from baseline after the first injection and 15.4% after the second dose of Ozurdex. The ocular hypertension is transient and less severe as compared to IVTA injection as Ozurdex is a more water-soluble steroid.5 Among patients treated with the 0.7-mg insert 41.5% required IOP-lowering medication and 0.3% required incisional surgery within 36 months 3. Systemic therapy: Systemic administration of steroids is the least likely route to cause IOP elevation. It may take longer duration to elicit an IOP rise after systemic therapy. If the pressure rises, the response does not correlate with the dosage or duration of treatment. 4. Inhalational steroids: Inhaled corticosteroid can lead to a rise of intraocular pressure. Even fluticasone propionate which has an excellent safety profile has shown to raise IOP in susceptible individuals.17 The risk of IOP rise is increased with higher dose and more puffs. Inhalational steroid induced ocular hypertensive response is common in patients with family history of glaucoma. 5. Face steroid creams can raise the IOP and irreversibly damage the visual field. If the applications are discontinued, the IOP typically falls after a lag phase, but glaucomatous damage may continue nonetheless. The duration of steroid use is important in the development of glaucoma. The pressure-inducing effect of steroids is directly proportional to anti-inflammatory potency, dosage of the drug used duration of use. (Figure 3) Difluprednate is an effective topical corticosteroid, but it may cause dramatic elevation of IOP in some patients, particularly children.4 It can cause IOP increase even in those patients not previously considered to be steroid responders to other topical agents such as prednisolone acetate. Figure 3. Comparison of pressure inducing effects of Steroids with Its potency CLINICAL FEATURES Steroid induced Glaucoma mimics Primary Open Angle Glaucoma. The IOP elevation is gradual with very few symptoms. History of systemic or ocular disease, which could require chronic corticosteroid use (e.g., uveitis, collagen vascular disease, asthma, dermatitis) should be elicited in all patients having ocular hypertension. The presenting symptoms depend on the age of the patient. MANAGEMENT Discontinuation of the steroid is the first line of management. In the majority of cases, IOP typically normalizes within days of stopping the steroid. In Chronic forms IOP decrease can take 1 to 4 weeks. The duration of steroid therapy also influence the reversibility of the IOP elevation. Corticosteroids like betamethasone, prednisolone, and dexamethasone can be substituted with nonadrenal steroids like rimexolone, loteprednol etabonate, fluorometholone, and medrysone. Steroids can be replaced with other steroid sparing medications like anti metabolites, NSAIDS, immunomodulators. In rare cases where IOP does not normalise after stopping steroids, glaucoma therapy is required. Nearly all patients who develop steroid-induced iatrogenic glaucoma can be controlled with topical antiglaucoma therapy. By 6-18 months, most of the patients can be off medication. About 1–5% with intractable glaucoma may need surgery to normalize their IOP. The most commonly employed surgery in patients with virgin conjunctiva is Trabeculectomy. In cases of scarring shunt implantation or cyclodestructive procedures may be preferred. MIGS have also shown good results in these cases as the pathology is at the trabecular meshwork level. Excision in the case of sub-Tenon deposits and vitrectomy in the IVTA may be required in severe cases. Prevention is better Steroid induced glaucoma is a preventable disease. The unwarranted and irrational use of this magic drug should be avoided and self-medication should be strictly discouraged. The judicious use of steroids is advocated to make sure we find the best drug, the best concentration, the best frequency, the best route of delivery—which might be topical, peribulbar, intravitreal or systemic—and only have the patient use it as long as necessary under supervision. The patients at risk should be identified and baseline IOP measurement be done to rule out preexisting glaucoma. IOP monitoring should initially occur at 2 weeks and then every 4–6 weeks for 2–3 months, and then every 6 months after an initial response has been ruled out. After cessation of steroid therapy, most eyes are off treatment at 18 months. Supervision for long periods is essential, as the IOP may rise even after initial control following cessation of steroids. Some common ocular allergies can easily be managed by Mast cell stabilisers, Anti allergic (olopatadine, bepostastine, alcaftadine). If required short course of low potency steroids under supervision should be given. Giving a steroid free window is necessary. Immunomodulators like REVIEW ARTICLE | JAN-APR 2024 STEROID INDUCED GLAUCOMA: AN AVERTABLE IATROGENIC DISEASE

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 25 cyclosporin A and tacrolimus can be used to substitute steroids. Chronic uveitis should be managed with NSAIDS (flurbiprofen, bromfenac, nepafenac) and antimetabolites like methotrexate giving steroid free window. Thus, by following few practical and simple guidelines this iatrogenic disease can be averted. REFERENCES Armaly MF. Statistical attributes of the steroid hypertensive response in the clinically normal eye.1: The demonstration of three levels of response. Invest Ophthalmol Vis Sci 1965;14:187. Armaly MF. The heritable nature of dexamethasone induced ocular hypertension. Arch Ophthalmol 1966;75:32. Becker B. Intraocular pressure response to topical corticosteroids. Invest Ophthalmol Vis Sci 1965;4:198. Birnbaum AD, Jiang Y, Tessler HH, Goldstein DA. Elevation of Intraocular Pressure in Patients With Uveitis Treated With Topical Difluprednate. Arch Ophthalmol. 2011;129(5):664-676. doi:10.1001/archophthalmol.2011.82 Dang Y, Mu Y, Li L, Mu Y, Liu S, Zhang C, et al. Comparison of dexamethasone intravitreal implant and intravitreal triamcinolone acetonide for the treatment of pseudophakic cystoid macular edema in diabetic patients. Drug Des Devel Ther. 2014;8:1441- 1449 Francois J. Tissue culture of ocular fibroblast. Ann Ophthalmol 1975 Dec;7(12):1551-1554. Francois J. The importance of the mucopolysaccharides in intraocular pressure regulation. Invest Ophthalmol Vis Sci 1975 Mar;14(3):173-176. Francois J, Victoria-Troncoso V. Mucopolysaccharides and pathogenesis of cortisone glaucoma. Klin Monatsbl Augenheilkd 1974 Jul;165(1):5-10 Fung AT, Tran T, Lim LL, Samarawickrama C, Arnold J, Gillies M, Catt C, et al. Local delivery of corticosteroids in clinical ophthalmology: A review. Clin Exp Ophthalmol. 2020 Apr;48(3):366-401. doi: 10.1111/ceo.13702. Epub 2020 Jan 22. PMID: 31860766; PMCID: PMC7187156. Herschler J. Intractable intraocular hypertension induced by repository triamcinolone acetonide. Am J Ophthalmol 1972 Sep;74(3):501-504. Herschler J. Increased intraocular pressure induced by repository corticosteroids. Am J Ophthalmol 1976 Jul;82(1):90-93. Kaur S, Dhiman I, Kaushik S, Raj S, Pandav SS. Outcome of ocular steroid hypertensive response in children. J Glaucoma 2016 Apr;25(4):343-347. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Financial disclosure Conflict of Interest Acknowledgements Copyright Transfer None None Nil Copyright transfer form signed by corresponding author on behalf of all co-authors FOOTNOTES AND DISCLOSURES REVIEW ARTICLE | JAN-APR 2024 STEROID INDUCED GLAUCOMA: AN AVERTABLE IATROGENIC DISEASE

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 26 13. 14. 15. 16. 17. Gaballa SA, Kompella UB, Elgarhy O, Alqahtani AM, Pierscionek B, Alany RG, et al. Corticosteroids in ophthalmology: drug delivery innovations, pharmacology, clinical applications, and future perspectives. Drug Deliv Transl Res. 2021 Jun;11(3):866- 893. doi: 10.1007/s13346-020-00843-z. PMID: 32901367. Nozik RA. Periocular injection of steroids. Trans Am Acad Ophthalmol Otolaryngol 1972 May-Jun;76(3):695-705. Phulke S, Kaushik S, Kaur S,Pandav SS. Steroid-induced Glaucoma: An Avoidable Irreversible Blindness. J Curr Glaucoma Pract 2017;11(2):67-72. Rhee DJ, Peck RE, Belmont J, Martidis A, Liu M, Chang J, Fontanarosa J, et al. Intraocular pressure alterations following intravitreal triamcinolone acetonide. Br J Ophthalmol. 2006 Aug;90(8):999-1003. doi: 10.1136/bjo.2006.090340. Epub 2006 Apr 5. PMID: 16597664; PMCID: PMC1857192. Sihota, Ramanjit MD FRCS; Dada, Tanuj MD; Rai, Harminder K MD. Fluticasone propionate raises IOP in susceptible individuals. Indian Journal of Ophthalmology 52(2):p 170-1, Apr–Jun 2004. REVIEW ARTICLE | JAN-APR 2024 STEROID INDUCED GLAUCOMA: AN AVERTABLE IATROGENIC DISEASE

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 27 UVEITIC GLAUCOMA Dr Tripti Johri DOMS, DNB, FGAS1 ,Dr Varun Saini, MS,DNB1 ,Dr Chirakshi Dhull, MD, DNB, FICO2 ARTICLE INFORMATION AFFILIATION OF ALL AUTHORS: ABSTRACT 1. Glaucoma Consultant, Saini Eye hospital Pathankot, Punjab 2. Helios Eye Hospital, Rohtak Corresponding author Dr. Tripti Johri Consultant – Glaucoma Consultant, Saini Eye hospital Pathankot, Punjab Email - tripti.baffian27@gmail.com Uveitic glaucoma also known as inflammatory glaucoma is an acquired clinical entity that causes secondary glaucoma. Uveitis can be attributed to systemic causes or localised disease of the eye. Glaucoma is a considerably challenging and serious complication in these patients as it can be due to uveitis itself or with use of corticosteroids for its treatment. There are multiple mechanisms by which uveitis can lead to Ocular hypertension and glaucomatous changes, all of which are not fully apprehended to the best of our knowledge. With advent of more aggressive and comprehensive medical control of the uveitis the prognosis for uveitic glaucoma patients has drastically changed compared to a few years ago. Management is directed at diagnosis of underlying condition and appropriate management of local or systemic disease for adequate control of inflammation and deferring repeated attacks. Better medical and surgical options are available for patients suffering from uveitic glaucoma. Article received Article accepted Article on line Keywords Presented at NA NA NA Secondary glaucoma, Inflammation, Uveitis, Ocular hypertension NA INTRODUCTION Uveitic glaucoma is an acquired clinical entity that causes secondary glaucoma. Intraocular inflammation can alter both aqueous production as well as its drainage. Inflammation leads to alteration in composition of aqueous resulting in increased outflow resistance, trabecular outflow blockage by inflammatory cells and debris, pupillary block and structural changes of trabecular meshwork due to corticosteroid use [1]. The incidence of uveitis is estimated to be 38–730 people per 100,000 worldwide, and approximately 20% of patients developed ocular hypertension and many of these progressed to glaucomatous optic nerve damage [2]. PATHOGENESIS Inflammation due to uveitis leads to an imbalance in equilibrium between aqueous production and drainage [3]. Inflammation induced breakdown of the blood-aqueous barrier leads to release of inflammatory cells, proteins, debris, or fibrin in the eye which causes mechanical obstruction of trabecular meshwork and alteration of aqueous composition. This leads to increase in resistance to outflow. Glaucoma can present in either an openangle stage or a closed-angle stage [4,5]. PHYSIOLOGICAL CHANGES IN AQUEOUS COMPOSITION IN UVEITIS Intraocular inflammation induced release of inflammatory cells, proteins, prostaglandins, and cytokines into the aqueous results from increased vascular permeability [3,6]. The inflammatory cells clogs the trabecular pores resulting in dysfunction and swelling of trabecular lamellae and endothelial cells, hence disrupting aqueous outflow [7]. Prostaglandins contribute to elevated IOP by increasing the aqueous viscosity and are known to cause aqueous hypersecretion via PGE1 and PGE2 [8]. Cytokines stimulate neovascularisation and have a direct influence on aqueous humor dynamics [3]. The elevated protein content leads to aqueous sludging, causing stunted aqueous outflow [9]. ANATOMICAL CHANGES SEEN AT OUTFLOW FACILITY The morphological alteration occurs due to cellular and biochemical changes of the trabecular meshwork. On gonioscopic evaluation, uveitic glaucoma can be classified as closed or open-angle stage, an open-angle stage being more common [10,11]. The infiltration of TM with inflammatory cells and proteins, results in mechanical blockage and swelling of trabecular lamellae and endothelial cells. This leads to scarring and damage to the TM [12]. Inflammation leads to adhesions of pupillary margins with the anterior lens capsule forming posterior synechiae causing pupillary block if it extends to 360 degrees. This obstructs the passage of aqueous humor into the anterior chamber and hence forming iris bombe and causing angle closure glaucoma. The inflammatory cells and protein forms a fibrin membrane covering the pupillary margin leading to pupillary block by causing occlusio pupillae. This membrane adheres to the anterior lens capsule, hence causing occlusion of the transfer of aqueous REVIEW ARTICLE | JAN-APR 2024

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 28 humor into the anterior chamber. Iris bombe formation eventually leads to the formation of PAS, thereby, closing the angle structures. Neovascularisation induced by cytokines may be witnessed at the angle in chronic uveitis, which pulls the iris and causes angle closure. Inflammation and swelling of the ciliary body lead to its forward rotation and hence causing non-pupillary block angle closure [13,14]. OCULAR CONDITIONS ASSOCIATED WITH INFLAMMATORY GLAUCOMA Uveitic glaucoma can be idiopathic, or due to infective or systemic causes. With improvement of antimicrobial therapy, there is a drastic reduction in uveitic glaucoma due to infective pathology. The mechanism and progression of glaucoma depends on the etiology of uveitis and has been reported as more common in Fuchs heterochromic uveitis, Posner-Schlossman syndrome, herpetic uveitis, and Juvenile idiopathic arthritis (JIA) [15-19]. SIGNS AND SYMPTOMS The spectrum of symptoms ranges from blurred vision, ocular pain, redness, brow ache, redness, to other ocular disturbances like photophobia and colored halos due to corneal edema with markedly elevated IOP. The corneal examination may reveal band-shaped keratopathy, healed herpetic scars, and keratic precipitates on the endothelium (Figure 1). The anterior segment may reveal irregular pupil, iris nodule, loss of normal architecture (Figure 2), neovascularization, ectropion uvae, posterior synechiae (Figure 3), heterochromia, iris atrophy, and peripheral anterior synechiae. The lens examination may reveal pigments on the anterior lens capsule and development/progression of cataracts (Figure 4). Gonioscopy may show an open angle, or presence of PAS (Figure 5) and the degree of angle closure. Sometimes in chronic uveitis, examination also reveals features of fine vascularization in the trabecular meshwork, occasional trabecular precipitates, hypopyon, hyphaema, or fibrin deposition. Optic nerve evaluation and visual field assessment for glaucomatous damage must be done and recorded. Other possible posterior segment findings may include perivascular sheathing, cystoid macular edema, choroidal infiltrates, retinitis, or retinal detachment. Ocular Conditions Infective Conditions Systemic Conditions Fuch’s Heterochromic Iridocyclitis Viral (Herpes simplex, zoster, CMV) Juvenile Idiopathic Rheumatoid Arthritis Posner-Schlossman Syndrome Syphilis Tuberculosis Sympathetic ophthalmitis Hansen disease Sarcoidosis Behcet’s Fig 1: Old keratic pretipitates over endothelium Fig 2: Irregular pupil with loss of normal iris pattern with multiple areas of posterior synechaie (yellow arrow) iris pigments over anterior lens capsule (light blue arrow) on diffuse illumination Fig 3: Diffuse illumination showing an irregular pupil with ectropion uvea (arrow), posterior synechiae Fig 4: Multiple areas of iris pigments over anterior lens capsule, with posterior synechiae Fig 5: Gonioscopy reveals a closed angle with broad based PAS (Peripheral anterior synechaie) (arrow) 1 2 3 5 4 REVIEW ARTICLE | JAN-APR 2024 Uveitic glaucoma

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 29 MANAGEMENT OF UVEITIC GLAUCOMA The treatment uveitic glaucoma depends on various factors. The most important being a careful diagnosis of underlying etiology with the help of selective blood tests, strict control of inflammation and IOP, and constant monitoring for early glaucomatous damage and progression to initiate appropriate management. A rheumatologist’s collaboration is must to control systemic disease. The main stay of therapy is to achieve symptomatic relief, preventing glaucomatous damage and progression, reducing the recurrence of uveitis, preventing the formation of synechiae or neovascularization, and reducing the need for surgical intervention. MEDICAL MANAGEMENT The control of uveitis is necessary to minimize further complications of uveitis. An immediate and aggressive anti-inflammatory therapy prevents IOP rise and adverse events of uveitis [20]. CORTICOSTEROIDS Corticosteroids therapy is the first line of treatment for addressing non-infectious ocular inflammation. They act by inhibiting the release of arachidonic acid and subsequent production of prostaglandins, thus reducing inflammation. It can be administered through various routes like topically, peri ocularly, intravitreally, and systemically depending on the severity of inflammation. Anterior segment inflammation is addressed by the use of localized drug delivery (topical therapy), which reduces systemic side effects [21-23]. Different approaches of drug delivery like periocular, intravitreal, or systemic application are useful in posterior segment inflammation [24]. Immunosuppressive drugs such as such as methotrexate, azathioprine, cyclosporine, tacrolimus etc are reserved for refractory cases or when systemic side effects of chronic uses of corticosteroids are suspected. Most immunosuppressive agents take a minimum of 6 weeks to achieve maximum efficacy, so should be used in conjunction with corticosteroids in the beginning [24-28]. Immunomodulatory agents are biological monoclonal antibodies, which are used as third-line drugs in recent times [29]. Favourable results have been seen with the usage of Adalimumab in the treatment of treating JIA-associated and pediatric refractory panuveitis [30]. Topical cycloplegic (atropine 1%, homatropine 1%, tropicamide 1%, cyclopentolate 1%) are used as adjunct in acute uveitic episodes. They are used to relieve ciliary spasms, break acutely formed posterior synechiae, or prevent them from forming if started early in the disease process [31]. Treatment of underlying etiologies such as herpes simplex or varicella-zoster requires specific antiviral therapy along with antiglaucoma medications [32]. ANTI-GLAUCOMA TREATMENT Traditionally, beta blockers and carbonic anhydrase inhibitors (CAI) have been used as a first-line therapy to control IOP spikes in uveitic glaucoma patients. Beta-blockers are considered the drug of choice to lower the IOP elevation in patients of uveitic glaucoma that reduces production of aqueous humor [33,34]. CAIs are frequently used as 1st line management along with beta-blockers in uveitic glaucoma [32] or in cases where beta blockers are contraindicated. CAIs lead to the alteration of the ion transport mechanism in the ciliary epithelium thereby, reducing the production of aqueous humor [34]. Brimonidine is an Alpha-2 adrenergic agonist which leads to the reduction of IOP via a dual mechanism. They reduce aqueous production at ciliary epithelium and also enhance uveoscleral outflow [35,36] and their mydriatic effect is useful in preventing posterior synechiae formation in uveitic eyes [1]. The role of PGA in the management of uveitic glaucoma is controversial because of the high risk of inducing anterior uveitis, blood-aqueous barrier disruption, cystoid macular edema, and reactivation of Herpes simplex keratitis [1]. Ripasudil, a Rhoassociated protein kinase inhibitor shown to lower IOP by altering trabecular meshwork, has been approved in Japan in 2014. It has been effective in lowering IOP in approximately 50% of eyes of UG [37]. Hyperosmotic agents like glycerol and mannitol are used in acute elevation of IOP. LASER THERAPY Laser peripheral iridotomy (LPI) must be performed for eyes with a narrow anterior chamber angle susceptible to a primary acute angle closure attack [38]. An ideal peripheral iridotomy of 300– 350 microns is required to prevent acute angle-closure glaucoma [39]. SURGICAL MANAGEMENT Clinically about 30% of uveitic eyes do not respond to maximal medical therapy and require surgical intervention [40]. Inflammation-induced accelerated scarring is a challenging problem as it is associated with a higher risk of surgical failure. Adequate control of inflammation, both pre-operative and post-operative, and IOP control are desirable prior to surgical intervention for better results [41]. A quiescent phase of a minimum 3 months is considered ideal, which can be attained by the use of corticosteroid therapy. The risk of post-operative hypotony is more in uveitic glaucoma cases as chronic and relapsing intraocular inflammation leads to ciliary body impairment. Both trabeculectomy (with and without adjunctive antifibroblast medications) and aqueous drainage implants are used to control IOP [42]. Valved glaucoma drainage implants are preferred in patients with extensive conjunctival scarring, or after failed trabeculectomy [43-45]. The other significant risk factors for surgical failure are male sex, age younger than 45 years, and REVIEW ARTICLE | JAN-APR 2024 Uveitic glaucoma

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 30 non-granulomatous uveitis [46]. Trabeculectomy is considered gold standard surgery for UG with uncontrolled IOP with maximal medical therapy and in cases of angle closure with extensive PAS formation. A bleb-dependent fistula is formed that helps aqueous drainage from the anterior chamber into subconjunctival space. Various studies have shown an adequate control of IOP (< 21 mm Hg) in patients who underwent trabeculectomy [47-49]. A significant post-operactive inflammation results in failure of bleb [47]. The results of unaugmented trabeculectomy are variable and are particularly poor in young patients with UG [50,51], as a result of an accelerated wound-healing response. Trabeculectomy augmented with MMC or 5-FU has shown good surgical success rates in patients with a high risk of failure, due to its effect of minimizing scarring of the filtering bleb [51]. Glaucoma Drainage implants have been used increasingly in the treatment of uveitic glaucoma. They are especially useful in cases with unhealthy conjunctiva as primary surgery or after failed trabeculectomy surgery. Drainage devices may be valved (AGV), or non-valved (Baerveldt glaucoma implant, BGI, Molteno implant, Aurolab aqueous drainage implant AADI). A study has reported AGV to have success rates of up to 94% at 4 years follow-up in chronic UG [52]. The AGV is considered effective in reducing IOP, decreasing the number of glaucoma medications, and preserving vision [52]. Cyclophotocoagulation is used to destroy the ciliary body where aqueous humor is produced. Unfortunately, it leads to the aggravation of intraocular inflammation, and is reserved as the last step for eyes with uncontrolled IOP, pain and poor visual potential [48]. CONCLUSION Strict control of inflammation and assessing the main cause that triggers inflammation is one of the first steps in controlling the adversaries caused by intraocular inflammation. The prognosis for UG patients has drastically changed with advent of more aggressive and comprehensive medical control of uveitis. Management is directed at the diagnosis of the underlying condition and appropriate management of the local or systemic disease for adequate control of inflammation and preventing recurrent attacks. Apart from traditional trabeculectomy, various implantable drainage devices are available, which have proven to be effective and successful. Long-term large prospective studies are warranted for a better understanding of long-term results. Other glaucoma surgical options like minimally invasive glaucoma surgery (MIGS) may also be effective in these patients, but those approaches are still under evaluation. A booming role of stem cell therapy has shown effectiveness in the management of various diseases, but its role is yet to be discovered in patients with uveitic glaucoma. REFERENCES Muñoz-Negrete FJ, Moreno-Montañés J, Hernández-Martínez P, Rebolleda G. Current Approach in the Diagnosis and Management of Uveitic Glaucoma. Biomed Res Int. 2015;2015:742792. doi: 10.1155/2015/742792. Epub 2015 Oct 19. PMID: 26558280; PMCID: PMC4628996. Sng CC, Ang M, Barton K. Uveitis and glaucoma: New insights in the pathogenesis and treatment. Progress in Brain Research. 2015;221:243-269. Moorthy RS, Mermoud A, Baerveldt G, Minckler DS, Lee PP, Rao NA. Glaucoma associated with uveitis. Surv Ophthalmol. 1997 Mar-Apr;41(5):361-94. doi: 10.1016/s0039-6257(97)00006-4. PMID: 9163835. Toris CB, Pederson JE. Aqueous humor dynamics in experimental iridocyclitis. Investment in Ophthalmological Visual Science. 1987;28(3):477-481. 1. 2. 3. 4. Financial disclosure Conflict of Interest Acknowledgements Copyright Transfer None None Nil Copyright transfer form signed by corresponding author on behalf of all co-authors FOOTNOTES AND DISCLOSURES REVIEW ARTICLE | JAN-APR 2024 Uveitic glaucoma

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 31 Kok H, Barton K. Uveitic glaucoma. Ophthalmological Clinical North America. 2002;15(3):375-387. Freddo TF, Patterson MM, Scott DR. Influence of mercurial sulfhydryl agents On aqueous outflow pathway in enucleated human eyes. Investigative Ophthalmology & Visual Science. 1984;25:278-285. Roth M, Simmons RJ. Glaucoma associated with precipitates on the trabecular meshwork. Ophthalmology. 1979;86:1613-1619. Chiang TS, Thomas RP. Ocular hypertension following infusion of prostaglandin E1. Archives of Ophthalmology. 1972;88:418- 420. Epstein DL, Hashimoto JM, Grant WM. Serum obstruction of aqueous outflow in enucleated eyes. American Journal of Ophthalmology. 1978;86:101-105. Panek WC, Holland GN, Lee DA, Christensen RE. Glaucoma in patients with uveitis. British Journal of Ophthalmology. 1990;74:223- 227. Krupin T, Feite ME. Glaucoma associated with uveitis. In: Ritch R, Shields MB, Krupin T, editors. The Glaucomas. CV Mosby: St Louis; 1989. pp. 1205-1223. Oguz E, Alasehirli B, Pehlivan Y, Onat AM, Oztuzcu S, Ozkara E, Kisacik B, Camci C, Demiryürek AT. Association between Rhokinase (ROCK2) gene polymorphisms and Behçet’s disease. Transl Res. 2012 Dec;160(6):428-34. doi: 10.1016/j.trsl.2012.08.002. Epub 2012 Aug 30. PMID: 22939913. Brooks AMV, Grant G, Young T, Newton A, Gillies WE. Cyclitic glaucoma. Australian New Zealand Journal of Ophthalmology. 1989;17:1.57-1.1164. Pavlin CJ, Easterbrook M, Harasiewicz K, Foster FS. An ultrdsound biomicroscopic analysis of angle-closure gbducomd secondary to ciliochoroidal effusion in IgA nephropathy. American Journal of Ophthalmology. 1993;116:341-345. Renfro L, Snow JS. Ocular effects of topical and systemic steroids. Dermatologic Clinics. 1992;10:505-510. Kimura SJ, Hogan MJ, Thygeson P. Fuch’s syndrome of heterochromic cyclitis. A.M.A. Archives of Ophthalmology. 1955;54:179- 186. Hirose S, Ohno S, Matsuda H. HLA Bw 54 and glaucomocyclitic crisis. Archives of Ophthalmology. 1985;103:1837-1839. Matsuda K, Izawa Y, Mishima S. Prostaglandins and glaucomatocyclitic crisis. Japan Journal of Ophthalmology. 1975;19:368- 375. Foster CS, Havrlikova K, Baltatzis S, Christen WG, Merayo-Lloves J. Secondary glaucoma in patients with juvenile rheumatoid arthritis-associated iridocyclitis. Acta Ophthalmol Scand. 2000 Oct;78(5):576-9. doi: 10.1034/j.1600-0420.2000.078005576.x. PMID: 11037918. Becker B. Intraocular pressure response to topical steroids. Invest Ophthalmology. 1965;4:198-205. Yaylali V, Ozbay D, Tatlipinar S. Efficacy and safety of rimexolone 1% versus prednisolone acetate 1% in the control of postoperative inflammation following phacoemulsification cataract surgery. International Ophthalmology. 2004;25:65-68. Rothova A. Corticosteroids in uveitis. Ophthalmology Clinics of North America. 2002;15:389-394. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. REVIEW ARTICLE | JAN-APR 2024 Uveitic glaucoma

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 32 Friedman DS, Holbrook JT, Ansari H, Alexander J, Burke A, Reed SB, Katz J, Thorne JE, Lightman SL, Kempen JH; MUST Research Group. Risk of elevated intraocular pressure and glaucoma in patients with uveitis: results of the multicenter uveitis steroid treatment trial. Ophthalmology. 2013 Aug;120(8):1571-9. doi: 10.1016/j.ophtha.2013.01.025. Epub 2013 Apr 16. PMID: 23601801; PMCID: PMC3720698. Sen HN, Vitale S, Gangaputra SS, Nussenblatt RB, Liesegang TL, Levy-Clarke GA, Rosenbaum JT, Suhler EB, Thorne JE, Foster CS, Jabs DA, Kempen JH. Periocular corticosteroid injections in uveitis: effects and complications. Ophthalmology. 2014 Nov;121(11):2275-86. doi: 10.1016/j.ophtha.2014.05.021. Epub 2014 Jul 11. PMID: 25017415; PMCID: PMC4254355. Jones NP. The Manchester Uveitis Clinic: The first 3000 patients, 2: Uveitis Manifestations, Complications, Medical and Surgical Management. Ocular Immunology and Inflammation. 2015;23(2):127-134. Larkin G, Lightman S. Mycophenolate mofetil. A useful immunosuppressive in inflammatory eye disease. Ophthalmology. 1999;106:370-374. Hesselink DA, Baarsma GS, Kuijpers RW. Experience with cyclosporine in endogenous uveitis posterior. Transplantation Proceedings. 2004;36:372-377. Durrani K, Papaliodis GN, Foster CS. Pulse IV cyclophosphamide in ocular inflammatory disease: Efficacy and short-term safety. Ophthalmology. 2004;111:960-965. Goldstein DA, Fontanilla FA, Kaul S. Long-term follow-up of patients treated with short-term high-dose chlorambucil for sightthreatening ocular inflammation. Ophthalmology. 2002;109:370-377. Ku WN, Lin CJ, Tsai YY. The rescue effect of adalimumab in the treatment of refractory pediatric panuveitis complicated with steroid-induced glaucoma. Taiwan Journal of Ophthalmology. 2018;8(3):164-167. Kulkarni A, Barton K. Uveitic glaucoma. In: Shaarawy TM, Sherwood MB, Hitchings RA, Crowston JC, editors. Glaucoma Volume I. 2nd ed. St. Louis, MO: Saunders Ltd.; 2015. Siddique SS, Suelves AM, Baheti U, Foster CS. Glaucoma and uveitis. Surv Ophthalmol. 2013 Jan-Feb;58(1):1-10. doi: 10.1016/j. survophthal.2012.04.006. PMID: 23217584. Ohno S, Ichiishi A, Matsuda H. Hypotensive effect of carteolol on intraocular pressure elevation and secondary glaucoma associated with endogenous uveitis. Ophthalmologica. 1989;199:41-45. Dailey RA, Brubaker RF, Bourne WM. The effects of timolol maleate and acetazolamide on the rate of aqueous formation in normal human subjects. American Journal of Ophthalmology. 1982;93:232-237. Sponsel WE, Paris G, Trigo Y, Pena M, Weber A, Sanford K, McKinnon S. Latanoprost and brimonidine: therapeutic and physiologic assessment before and after oral nonsteroidal anti-inflammatory therapy. Am J Ophthalmol. 2002 Jan;133(1):11-8. doi: 10.1016/ s0002-9394(01)01286-7. PMID: 11755835. Toris CB, Camras CB, Yablonski ME. Acute versus chronic effects of brimonidine on aqueous humor dynamics in ocular hypertensive patients. American Journal of Ophthalmology. 1999;128:8-14. Kusuhara S, Katsuyama A, Matsumiya W, Nakamura M. Efficacy and safety of ripasudil, a Rho-associated kinase inhibitor, in eyes with uveitic glaucoma. Graefe’s Archive for Clinical and Experimental Ophthalmology. 2018 Apr;256(4):809-814. Ramdas WD, Pals J, Rothova A, Wolfs RCW. Efficacy of glaucoma drainage devices in uveitic glaucoma and a meta-analysis 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. Uveitic glaucoma REVIEW ARTICLE | JAN-APR 2024

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 33 of the literature. Graefe’s Archive for Clinical and Experimental Ophthalmology. 2019;257(1):143-151. DOI: 10.1007/s00417-018- 4156-9. Epub: 2018 Oct 11. PMID: 30310971; PMCID: PMC6323086. Agraval U, Qi N, Stewart P, Luo X, Williams G, Rotchford A, et al. Optimum size of iridotomy in uveitis. Clinical & Experimental Ophthalmology. 2015;43(7):692-696. Kalin-Hajdu E, Hammamji K, Gagne S, Harasymowycz P. Outcome of viscodilation and tensioning of Schlemm’s canal for uveitic glaucoma. Canadian Journal of Ophthalmology. 2014;49(5):414-419. Sung VC, Barton K. Management of inflammatory glaucomas. Current Opinion in Ophthalmology. 2004;15:136-140. Netland PA, Denton NC. Uveitic glaucoma. Contemporary Ophthalmology. 2006;5:1-26. Da MA et al. Management of uveitic glaucoma with Ahmed glaucoma valve implantation. Ophthalmology. 1999;106:2168- 2172. Ceballos EM, Parrish RK, Schiffman JC. Outcome of Baerveldt glaucoma drainage implants for the treatment of uveitic glaucoma. Ophthalmology. 2002;109:2256-2260. Kuchtey RW, Lowder CY, Smith SD. Glaucoma in patients with ocular inflammatory disease. Ophthalmology Clinics of North America. 2005;18:421-430. Shimizu A, Maruyama K, Yokoyama Y, Tsuda S, Ryu M, Nakazawa T. Characteristics of uveitic glaucoma and evaluation of its surgical treatment. Clinical Ophthalmology. 2014;8:2383-2389. Hill RA, Nguyen QH, Baerveldt G, Forster DJ, Minckler DS, Rao N, Lee M, Heuer DK. Trabeculectomy and Molteno implantation for glaucomas associated with uveitis. Ophthalmology. 1993 Jun;100(6):903-8. doi: 10.1016/s0161-6420(93)31556-3. PMID: 8510904. Hoskins DH, Hetherington J, Shaffer RN. Surgical management of the inflammatory glaucomas. Perspect Ophthalmol. 1977;1:173-181. Stavrou P, Misson GP, Rowson NJ, Murray PI. Trabeculectomy in uveitis: Are antimetabolites necessary at the first procedure? Ocul Immunol Inflamm. 1995;3(3):209-16. doi: 10.3109/09273949509069114. PMID: 22823243. Stavrou P, Murray PI. Long-term follow-up of trabeculectomy without antimetabolites in patients with uveitis. American Journal of Ophthalmology. 1999;128:434-439. Wright MM, McGehee RF, Pederson JE. Intraoperative mitomycin-C for glaucoma associated with ocular inflammation. Ophthalmic Surgery and Lasers. 1997;28:370-376. Bao N, Jiang ZX, Coh P, Tao LM. Long-term outcomes of uveitic glaucoma treated with Ahmed valve implant in a series of Chinese patients. International Journal of Ophthalmology. 2018;11(4):629-634. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. Uveitic glaucoma REVIEW ARTICLE | JAN-APR 2024

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 34 Conjunctivitis-23, Is it a Covid-19 type epidemic of the Eye? Kritika MBBS1 , Kanav Gupta MS, FVR1 , Brij Kumar Gupta MS1 , Isha Gupta MD1 ARTICLE INFORMATION AFFILIATION OF ALL AUTHORS: ABSTRACT 1. NC Medical College & Hospital, Israna Corresponding author Dr. Kanav Gupta Assoc Prof., Dept. of Ophthalmology, NC Medical College and Hospital, Israna; Panipat. Telephone No. 9728700332 Email - kanavg@hotmail.com Nowadays many patients are visiting Ophthalmology OPD with complaints of red eye associated with swelling, discharge, and watering. The spike in the number of these cases is increasing day by day. More than 50 percent of cases per day are presenting with this similar complaint. Is this a new fire in the forest? Is this Conjunctivitis-23? Who to blame for this spike in cases of conjunctivitis in 2023? Is it rain or flood? Is it an unhygienic environment? Can we beat this Conjunctivitis-23? We can beat Conjunctivitis-23 and stop its spread by frequent handwashing, and avoid sharing towels, and linens of the affected individual. Kala chashma will not protect against the spread of Conjunctivitis-23. So, let’s fight against this epidemic of Conjunctivitis-23 as we did against Covid-19. Article received Article accepted Article on line Keywords Presented at November 2023 December 2023 February 2024 Conjunctivitis, viral, bacterial, allergic, Covid-19 NA INTRODUCTION Conjunctivitis and other eye diseases have been rising sharply in North India this time in 2023. Delhi and the surrounding areas have reported numerous cases of conjunctivitis amid the heavy rains and floods. More than 50 percent of the daily Outpatient Department (OPD) patients are reporting conjunctivitis. It has been seen that out of these 90 percent of cases are coming with adenoviral conjunctivitis. Though there is a rise in cases during this time every year but this time the rise is alarming. Is it a new epidemic like Covid-19? Is this spike in cases an indicator of Conjunctivitis-23? Will this “kala chashma” act as a shield from conjunctivitis-23? Conjunctivitis, also referred to as pink eye or an eye infection, is a contagious disease that causes inflammation of the conjunctiva, the translucent layer that covers the white part of the eye and the inner part of the eyelids. [1] The epithelial covering of the conjunctiva acts as a barrier against infection. The disruption of this barrier leads to conjunctivitis. [2] The major cause of conjunctivitis, particularly in adults, is a virus (adenovirus), [3,4] followed by bacterial allergies, chemical agents, or foreign objects lodged in the eye. However, due to India’s high population density, humidity, and occasionally inadequate or unsanitary living conditions, viral and bacterial conjunctivitis are the main reasons for the rise of conjunctivitis cases. [3,5] The high humidity levels have also led to an influx of patients with pink eyes and watery discharge into OPD. [6] Conjunctivitis is typically spread by direct or indirect touch. Direct transmission does occur via droplets from an infected person’s cough or sneeze. It can spread inadvertently through the sharing of personal objects like towels, cosmetics, pillows, or contact lenses. The disease “Conjunctivitis or eye flu gets communicated by contaminated fingers or by contaminated items”. It typically spreads more quickly in social settings. [7] The virus causing this epidemic has been found to stay for a long duration on surfaces. Therefore, if a person with conjunctivitis touches a surface and a subsequent person touches the same surface and subsequently touches his eye, conjunctivitis will spread to the new individual. Since it is not an airborne illness, staring at someone with eye flu will not cause it to spread. ‘Kala chashma’ does not provide a shield against the transmission of ocular infection. Conjunctivitis can only manifest itself if a person comes into contact with the secretion or watery discharge coming from an infected individual’s eyes. Conjunctivitis has distinct symptoms that make it reasonably easy to diagnose. Increased tear production, thick yellow discharge that crusts over the eyelashes, especially after sleeping; itchy, burning, or irritated eyes and redness in the inner or white part of the eye. [8-11] Severe form of illness includes blurred vision, severe pain, and an increased sensitivity to light. [12] Patients with pink eyes should avoid rubbing or touching them too much. They should wash their hands to get rid of the germs on their hands, avoid sharing towels, and linens, and should stay at home to prevent infection spread. [13] REVIEW ARTICLE | JAN-APR 2024

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 35 3. Hot dry environment. 4. Genetic predisposition. 5. Asthma/eczema. Viral conjunctivitis1. Exposure to infected individuals. 2. Active infection with herpes simplex virus. 3. Prior infection with herpes simplex virus. 4. Acute chicken pox. Symptoms: 1. Pink or red eye. 2. Swelling of the conjunctiva and/or eyelids. 3. Watering 4. Foreign body sensation 5. Itching, irritation, and/or burning 6. Discharge (pus or mucus) 7. Crusting of eyelids or lashes, especially in the morning Warning Symptoms: 1. Extreme pain 2. Diminished vision 3. Photophobia DIAGNOSIS: The most common symptom of conjunctivitis is redness and swelling but it also has some specific symptoms related to the cause. A thorough history should be taken at first which should include the onset and duration of symptoms which should include impairment of vision, itching, watering, type of discharge, history of contact lens wear, exposure to chemical agents, and contact with a patient of conjunctivitis. An ophthalmic examination should be performed to determine the type of discharge and to know the severity of conjunctivitis. Sometimes the cause is difficult to diagnose without laboratory examination of discharge and proper treatment is done following diagnosis. Discharge samples undergo microbiological evaluation. Recurrent conjunctivitis cases, cases with severe discharge and unresponsive to treatment undergo conjunctival cultures. [19] Cultures are taken before starting treatment and if started stop before 48 hours and take culture. [20] Nucleic acid amplification techniques may be used in diagnosing viral infections. Polymerase chain reaction (PCR) tests for detection of viruses are also available. Rapid antigen testing techniques which can be used for adenoviruses testing reported to be 89% sensitive and up to 94% specific. [20] Patients with allergic conjunctivitis can be diagnosed with a skin scratch test or intradermal injection of common allergens, and assays for detecting serum IgE levels. REVIEW ARTICLE | JAN-APR 2024 Conjunctivitis-23, Is it a COVID-19 type epidemic of the Eye? As there are many causes of red eye and all forms of conjunctivitis lead to red eye so it is very important to detect the type of conjunctivitis for proper treatment. This article highlights the predisposing factors, causes, signs, symptoms, diagnosing criteria, factors essential for the prevention of conjunctivitis, and treatment options for conjunctivitis. METHOD OF LITERATURE SEARCH: A systematic literature search was undertaken using Medline, PubMed, Google Scholar, and Cochrane. The following keywords were used; “conjunctivitis,” “viral,” “bacterial,” “allergic,” and “Covid-19.” All relevant articles including review articles, original articles, case series, and case reports were reviewed. The search was conducted in July 2023. We have mostly selected publications listed in the last 20 years but did not exclude the older publications, which are commonly referenced. Causes of Conjunctivitis: 1. Bacterial 2. Viral 3. Allergens 4. Chemical or dust particle induced 5. Other (contact lens, fungi, parasite) Bacterial causes1. Staphylococcus 2. Hemophilus Influenza 3. Gonococcal 4. Chlamydial Hemophilus influenza was found to be the most common cause of bacterial conjunctivitis in young children and on the contrary in adults the cause was found to be staphylococcus. [14] Viral causes1. Adenovirus 2. Herpes simplex virus 3. Varicella zoster virus 4. Molluscum contagiosum 5. Enterovirus The most common type of infectious conjunctivitis is considered to be viral in etiology. Adenovirus is responsible for 90% of cases of viral conjunctivitis. [15,16] Other forms of viruses are less frequent causes of conjunctivitis. [17] Among the adenoviral group HAdV-D species members have the strongest association with viral conjunctivitis. [18] PREDISPOSING FACTORS: Causes of Conjunctivitis: 1. Environmental allergens. 2. Outdoor air pollution.

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 36 REVIEW ARTICLE | JAN-APR 2024 Conjunctivitis-23, Is it a COVID-19 type epidemic of the Eye? Differentiation between Infectious and Non-Infectious Conjunctivitis: Infectious conjunctivitis presents with the following clinical signs and symptoms: eye discharge, conjunctival congestion, sticking eyelashes, foreign body sensation, chemosis, and a history of contact with conjunctivitis patient. [21] Non-infectious conjunctivitis presents with itching and redness mainly. [22] The main findings are the presence of papillae in the superior or inferior tarsal conjunctiva accompanied by severe itching. [23,24] Differentiation between Bacterial and Viral Conjunctivitis: Bacterial conjunctivitis involves one eye followed by the involvement of the second eye within 24-48 hours, however, a viral etiology should be considered if the second eye gets infected after 48 hours with an accompanying swollen periauricular lymph node. The second eye in viral cases is clinically less severe and the complaints involve itching and irritation along with serous discharge. A papillary or pseudomembranous conjunctival reaction strongly implies a bacterial origin for conjunctivitis, but a follicular conjunctival reaction is more likely to reflect a viral etiology. [25,26] In a meta-analysis, it was found that a combination of three indicators, bilateral mattering of the eyelids, lack of itching, and no previous history of conjunctivitis, were found to be good predictors for bacterial conjunctivitis. [27] It was also seen that “gluing of the eyelids” upon waking up in the morning was associated with bacterial etiology. [28] PREVENTION: When you have conjunctivitis: • Avoid social gatherings. • Frequent hand washing with soap for at least 20 seconds. • Wash hands after touching eyes or putting eyedrops. • Use alcohol scrub if handwash is not available. • Avoid touching or rubbing your eyes. • Keep your towels, linens, and handkerchiefs separate. • Clean your eyes with wet cotton or cloth and through it after use. • Stop wearing contact lenses. • Do not use public pools. When you are around an infected individual- • Wash your hands after coming in contact with the individual. • Don’t touch your eyes without washing your hands. • Don’t use his towels and linens. How to prevent reinfection- • Wash your clothes properly with hot water after infection. • Clean your glasses after infection. • Through away the brushes used around the eye during the infection period. • Don’t use contact lens used during the infection period. • Prevention of exposure to allergens. TREATMENT: The goal behind the treatment of conjunctivitis is to improve patient comfort, shorten the duration of illness, and prevent the spread of infection. For comfort, patients should be instructed to do cold compresses and use lubricants such as artificial tears which can help reduce some of the inflammation and dryness produced by conjunctivitis. Cold, moist compresses can relieve swelling and irritation in the lids. Artificial tears act as a barrier, dilute numerous allergens, and clear the ocular surface of several inflammatory mediators. Decongestants typically have vasoconstriction action and the capacity to control itching and watering. Mast cell stabilizers prevent sensitized mast cells from degranulating after exposure to certain antigens and can help manage pruritus associated with seasonal allergies. Antibiotic drops can also be used in treatment as they prevent subsequent bacterial infections, shorten the duration of illness, and also prevents spread. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat allergic conjunctivitis. Steroids are used cautiously in selected cases as in cases of pseudomembranes or subepithelial infiltrates. SUMMARY: Conjunctivitis is one of the most common complaints with which people visit Ophthalmology OPD. The reason for conjunctivitis can be bacterial, viral, or allergic. Depending upon the cause the treatment varies and it usually resolves within 7-14 days without any long-term side effects. It can be a self-limiting to visionthreatening condition depending upon the severity. So adequate and timely measures should be taken.

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 37 REVIEW ARTICLE | JAN-APR 2024 Conjunctivitis-23, Is it a COVID-19 type epidemic of the Eye? REFERENCES Alfonso SA, Fawley JD, Alexa Lu X. Conjunctivitis. Prim Care. 2015; 42:325-45. Callaghan RJ. The Pathogenesis of Staphylococcus aureus Eye Infections. Pathogens. 2018; 7:9. Azari AA, Barney NP. Conjunctivitis: a systematic review of diagnosis and treatment. JAMA. 2013; 310:1721-9. O’Brien TP, Jeng BH, McDonald M, Raizman MB. Acute conjunctivitis: truth and misconceptions. Curr Med Res Opin. 2009; 25:1953–61. Hovding G. Acute bacterial conjunctivitis. Acta Ophthalmol. 2008; 86:5-17. https://mausam.imd.gov.in/chandigarh. Boyd K. Conjunctivitis: What is pink eye? Am Acad Ophthalmol. 2023. Leibowitz HM. The red eye. N Engl J Med. 2000; 343:345-51. Mahmood AR, Narang AT. Diagnosis and management of the acute red eye. Emerg Med Clin North Am. 2008; 26:35-55. Puri LR, Shrestha GB, Shah DN, Chaudhary M, Thakur A. Ocular manifestations in herpes zoster ophthalmicus. Nepal J Ophthalmol. 2011; 3:165-71. Liesegang TJ. Herpes zoster ophthalmicus natural history, risk factors, clinical presentation, and morbidity. Ophthalmol. 2008. Narayana S, McGee S. Bedside diagnosis of the ‘Red Eye’: a systematic review. Am J Med. 2015; 128:1220–4. Scott IU. Viral conjunctivitis. Drugs and diseases. 2023. Hovding G. Acute bacterial conjunctivitis. Acta Ophthalmol. 2008; 86:5–17. Stenson S, Newman R, Fedukowicz H. Laboratory studies in acute conjunctivitis. Arch Ophthalmology. 1982; 100:1275–7. Fitch CP, Rapoza PA, Owens S, Murillo-Lopez F, Johnson RA, Quinn TC, et al. Epidemiology and diagnosis of acute conjunctivitis at an inner-city hospital. Ophthalmology. 1989; 96:1215–20. Newman H, Gooding C. Viral ocular manifestations: a broad overview. Rev Med Virol. 2013; 23:281–94. Singh G, Zhou X, Lee JY, Yousuf MA, Ramke M, Ismail AM, et al. Recombination of the epsilon determinant and corneal tropism: human adenovirus species D types 15, 29, 56, and 69. Virology. 2015; 485:452–9. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. Financial disclosure Conflict of Interest Acknowledgements Copyright Transfer None None Nil Copyright transfer form signed by corresponding author on behalf of all co-authors FOOTNOTES AND DISCLOSURES

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Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 39 MOLECULAR BIOMARKERS IN DIABETIC RETINOPATHY AND AGE RELATED MACULAR DEGENERATION Thirumalesh MB MD1 , Aayesha khanum MBBS1 ARTICLE INFORMATION AFFILIATION OF ALL AUTHORS: ABSTRACT 1. Vitreo retinal Services, Narayana Nethralaya Corresponding author Dr. Thirumalesh M B Consultant – Vitreo Retina and Translational scientist Narayana Nethralaya, Bangalore Email - thirumaleshmb@gmail.com NA Article received Article accepted Article on line Keywords Presented at January 2024 January 2024 February 2024 Diabetic Retinopathy, Agre-related macular degeneration, Molecular biomarkers NA BIOMARKERS IN DIABETIC RETINOPATHY The prevalence of diabetes mellitus is increasing at an alarming rate, and one of its most devastating consequences is diabetic retinopathy (DR). Numerous studies have emphasized the critical role of optimal diabetes management in preventing the development and progression of DR [1,2]. However, it has been observed that factors such as duration of diabetes, glycemic control, and blood pressure regulation can only account for approximately 15% of the variation in DR manifestation [1,2,3,4]. For example, some patients with well-managed blood sugar levels may exhibit early signs or rapidly advancing stages of DR despite seemingly good control over glucose levels. Conversely, other individuals with subpar glycemic control might not display any symptoms for several years [5]. This discrepancy highlights the need for further investigation into understanding the underlying mechanisms responsible for DR initiation and advancement. By gaining greater insights into these molecular pathways driving DR development and identifying new biomarkers associated with disease progression, clinicians will be better equipped to diagnose this condition at earlier stages while also monitoring its clinical course more effectively. It is important to note that multiple factors contribute to the pathogenesis of DR, such as genetic, epigenetic, and environmental influences playing significant roles. Breakdown of the proper functioning across various components of the retinal neurovascular unit, such as pericyte loss, inflammation, neovascularisation, blood retinal barrier breakdown have their role in pathogenesis [6]. Among this inflammation is the most salient process driving the cycle [7, 8]. REVIEW ARTICLE | JAN-APR 2024 PATHOPHYSIOLOGY OF DIABETIC RETINOPATHY Vascular endothelial dysfunction Neuronal dysfunction Inflammation, including vascular leakage and edema Thrombosis and fibrinolysis Lipid deposition Basement membrane thickening and fibrosis Cell growth dysregulation/ death Disturbed balance between pro and anti angiogenic factors Changes in cell signalling, e.g. PKC, polyol pathway, AGE-related, PPARα, WNT Molecular changes, including modifications of telomeres and DNA While proinflammation is generally homeostatically protective, it can be deleterious if chronic. Its complex interplay between various molecular mediators and recruitment and activation of leukocytes [9,10]. Inflammation and proinflammatory molecules lead to microvasculature damage and further vascular ischemia.

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 40 REVIEW ARTICLE | JAN-APR 2024 Molecular Biomarkers in Diabetic retinopathy and age-related macular degeneration Vascular damage and ischemia increases vascular permeability and hence these process are closely linked with progression of diabetic retinopathy [11]. Progressive ischemia creates progressive vascular compromise in the diabetic microcirculation further ensuing widespread autoregulatory disturbance. This leads to further release of substances compensating for such dysregulation, clinically recognizable as the progression from background DR (BDR) to proliferative diabetic retinopathy (PDR). There is associated dysregulation of immune and angiogenesis factors in the diabetic microenvironment. Widespread breakdown of the blood–retinal barrier, resulting in protein exudation and leukocyte migration leads to diabetic macular edema. At the proliferative stage of retinopathy there is neovascularization, a consequence of nonperfusion and tissue hypoxia. Classifying biomarkers on basis of function (12,13) Mechanisms Molecular biomarker Angiogenesis Pro-inflammatory/angiogenic- VEGF, PGF, IGF1, CTGF, stem cell factor, MCP-1, MIF, SDF-1, fractalkine Anti-inflammatory/antiangiogenic- PEDF, IP10, MIG Anti-inflammatory/proangiogenic- EPO Blood coagulation Thrombin P-Selectin D-Dimer Cell viability Heme oxygenase 1 (HO-1) Hyperglycemia Serum glycated hemoglobin (HbA1c) Advanced glycation end products (AGEs) Inflammation Tumor necrosis factor alpha (TNF-α) Interferon-induced protein-10 Monocyte chemoattractant protein-1 (MCP-1) Lipocalin 1 (LCN1) Interleukin-1 receptor antagonist (IL-1ra) Matrix metallopeptidase 9 (MMP9) Interleukin-8 (IL-8) Interleukin-6 (IL-6) Kallistatin Complement factor B (CFB) Complement factor H (CFH) Alpha-2-macroglobulin (A2M) Pentraxin-3 (PTX3) Anti-inflammatory- IL-10 Vascular adhesion molecules VCAM-1, ICAM-1, Eselectin, sVAP Innate immune response cells Retinal endothelial cells with toll-like receptors Transcription factors HIF-1, NF-ĸB Lipid accumulation in the retina Apolipoprotein A1 (ApoA1) Apolipoprotein B (ApoB) Neurogenesis Nerve growth factor (NGF) Semaphorin 3A (Sema3A) Brain derived neurotrophic factor (BDNF) Oxidative stress 8-Hydroxy-2′-deoxyguanosine (8-OHdG) Reduced hydrogen sulfide (H2S) Kallistatin Photoreceptor degradation Cystatin C Vitamin deficiency Homocysteine To subclassify various biomarkers (basis of compartments) Vitreous and Aqueous Humor Biomarkers In diabetic retinopathy there is shift towards a pro-angiogenic environment, consistent with that several proangiogenic mediators are upregulated, whereas some anti angiogenic mediators are downregulated. A recent analysis on 138 vitreous samples from eyes with diabetic retinopathy identified more than 1350 distinct proteins, 230 proteins being more abundant in patients with PDR than NPDR, including angiogenic factors and inflammatory mediators, complement and coagulation cascade proteins, protease inhibitors, apolipoproteins, immunoglobulins, proteins involved in ROS production, and cell adhesion molecules [14]. Aqueous humor might serve as a better tool in terms of relative ease and safety of sample withdraw compared to vitreous. Proteins released from diabetic retina diffuse from the vitreous humor into the aqueous. It helps to characterize the ocular biomarker profile of diabetic patients and helps monitor their response to therapy. Serum and Plasma Biomarkers High concentrations of soluble VCAM, ICAM, E-selectin, glycoprotein 130, serum amyloid A, pentraxin 3, and IL6 have been associated with onset of microvascular complication in diabetic retinopathy [15,16]. High levels of TNF-α and soluble TNF receptors 1 and 2 (TNFR-1 and TNFR-2, respectively), have been found in serum of patients with DR, and they have been associated with disease progression and with an increased risk of developing PDR and DME [17]. Development

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 41 of retinal hard exudates and DME have been associated with high serum levels of CRP [18]. Increased levels of apolipoprotein B (APO-B) and decreased levels of apolipoprotein A (APO-A) correlate to DR severity, whereas a high APO-B/APO-A ratio is positively associated to increased risk of developing DME [19]. The only validated biomarker for the prediction of DR onset and progression remains to be glycated hemoglobin (HbA1c), solidifying that a good glycemic control is effective in reducing the risk of DR and its complications [20]. Molecular biomarkers in Age related macular degeneration Age-related macular degeneration (AMD) is the main cause of irreversible blindness in the elderly. A biomarker is an indicator of normal biological and pathogenic processes, or pharmacologic responses to a therapeutic intervention [21]. Molecular markers (biomarkers) in AMD are less often used; rather, imaging exams such as color fundus photography (CFP), fundus autofluorescence (FAF), optical coherence tomography (OCT), fluorescein angiography and ICG are the selected options for its diagnosis, prognosis, and assessment of the therapeutic efficacy. The molecular biomarkers in AMD is a lesser explored area and their association and translatability in clinical practice much less. Pathogenesis in AMD Molecular biomarkers in AMD REVIEW ARTICLE | JAN-APR 2024 Molecular Biomarkers in Diabetic retinopathy and age-related macular degeneration BIOMARKER TYPE MECHANISM C-reactive protein (CRP) Systemic inflammatory marker non-specific serum marker for subclinical inflammation (22) CRP may enhance NF-kB nuclear translocation and induce secretion of pro-inflammatory cytokine interleukin 8 (IL-8) (23) Important activator of the classical complement pathway and the pathogenesis of AMD is thought to involve the activation of the complement pathway (24,25) Carboxyethylpyrrole (CEP) and CEP antibody titres End product of lipid oxidation a protein generated from free radical induced oxidation of docosahexaenoate (DHA)-containing lipids levels (26)

Vol. XVI (No. 1) | ISSN NO. 2322-0309 Page no. 42 REVIEW ARTICLE | JAN-APR 2024 Molecular Biomarkers in Diabetic retinopathy and age-related macular degeneration Nε -carboxymethyllysine (CML) Advanced glycation end product Nε -carboxymethyllysine (CML)- a marker of protein damage and advanced glycation end products (27) Pentosidine Advanced glycation end product a marker of protein damage and advanced glycation end products (27) Vascular endothelial growth factor (VEGF) Angiogenic Proangiogenesis (28,29) Interleukin-6 (IL-6) Inflammatory marker Acute phase reactant Induce the growth and differentiation of T cells and maturation of B cells Dictates the transition from acute to chonic inflammation by changing the nature of leucocyte infiltrate (from polymorphonuclear neutrophils to monocyte/macrophages) (30) Interferon γ-Inducible Protein 10 (IP-10) Chemokine IP-10 is a chemoattractant for activated T lymphocytes- role in effect T cell generation and trafficking to sites of tissue inflammation (31) Eotaxin-1 (CCL11) and Eotaxin-2 (CCL24) Chemokine Potent chemoattractant in eosinophil and other inflammatory cell recruitment (32) Homocysteine Amino acid in the blood Higher levels in neovascular AMD vs. the dry form of AMD. (33, 34, 35) Annexin A5 (ANXA5), Protein S100-A9 (calgranulin B) Heat shock proteins, alpha-crystallin A chain Circulating antibodies Play a role in AMD via autophagy compromise and downstream activation of the inflammasome (36) Serum Cholesterol High-risk genotypes had higher serum levels of Apo-A1 and HDLC with lower levels of triglycerides compared to controls (37) It is crucial to perform a thorough molecular analysis and molecular characterisation. To categorize the ocular and systemic biomarkers using metabolomics, preteomics and genomics. Precision medicine in AMD will be made possible by such thorough characterization, which will aid in the development of pharmacomics and the understanding of the molecular causes in each unique patient. REFERENCES Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in Type 2 diabetes. N. Engl. J. Med. 359(15), 1577–1589 (2008). The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med. 329(14), 977–986 (1993). 1. 2. Financial disclosure Conflict of Interest Acknowledgements Copyright Transfer None None Nil Copyright transfer form signed by corresponding author on behalf of all co-authors FOOTNOTES AND DISCLOSURES

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