Sep-Oct 2023

CONTENTS PAGE NO. TITLE 06 From the President’s DESK 07 From the DESK of Chief Editor Subspeciality 08 18 41 47 51 56 67 72 75 An Overview of Lamellar Keratoplasty Techniques Keratoconus ‘kunji’ (Notes) Extended Resection with Limbal Conjunctival Autograft Versus Conventional Conjunctival Autograft for Recurrent Pterygium Topical Insulin: The Emerging Game Changer in Ocular Surface Diseases (OSD) Follicular Conjunctivitis - An Overview Predictive Analysis of Ultrasound Biomicroscopy Guidance in Cases of Anterior Staphyloma Undergoing Sclero-Corneal Transplantation - A Pilot Study Evolution of Corneal Cross-Linking Patient Satisfaction in Modern Eye Care System: A Perspective Importance of Posterior Segment Screening Before Corneal Refrective Surgery Cornea Beyond Ophthalmology

www.dosonline.org/dos-times DOS Times Volume 29, Number 5, September-October 2023 DOS EXECUTIVE MEMBERS (2021-2023) 01 Dr. Om Prakash Anand Dr. Prafulla Kumar Maharana Dr. Rajendra Prasad President Prof. Rohit Saxena Vice President Dr. Gagan Bhatia Dr. Amar Pujari Dr. Jatinder Singh Bhalla Secretary Dr. Vivek Gupta Dr. Bhupesh Singh Dr. Sandhya Makhija Joint Secretary Dr. Vivek Kumar Jain Dr. Pankaj Varshney Dr. Alkesh Chaudhary Treasurer Prof. Kirti Singh Editor Dr. Jatinder Bali Library Officer DOS Office Bearers Executive Members Dr. Pawan Goyal Prof. Namrata Sharma Ex-Officio Members

Know Your Editor Editor Chief Editor DOS Times Dr. Jatinder Singh Bhalla MS, DNB, MNAMS Hony. General Secretary Delhi Ophthalmological Society DDU Hospital, Hari Nagar Dr. Prafulla Kumar Maharana, MD Associate Professor of Ophthalmology Dr. Rajendra Prasad Centre for Ophthalmic Sciences, AIIMS, New Delhi DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times 02 Section Editor - Retina & Uvea Prof. (Col) Sanjay Kumar Mishra, HOD, Dept of Ophthalmology (vitreo retina surgeon), Army Hospital (R&R) Section Editor - Retina & Uvea Dr. Alkesh Chaudhary MBBS, MS, FMRF Head Consultant M.D. Eye Care & Laser Centre Section Editor - Uvea & Ocular Inflammatory Disorders Dr. Naginder Vashisht MD, FRCS, FICO Director & Senior Consultant Ophthalmology, Kailash Eye Care, Patel Nagar, New Delhi Senior Consultant Ophthalmology, Artemis Hospitals, Gurugram Section Editor - Retina & Uvea Dr. Raghav Malik, MS Fellowship Cataract & Refractive Surgery Associate Consultant Dept of Cataract, Cornea & Refractive Services, CFS, New Delhi Section Editor - Uvea & Ocular Inflammatory Disorders Dr. Prateek Kakkar (Retina Specialist), MD Ex-Senior Resident (Vitreo-retina, AIIMS, New Delhi) Section Editors - Retina & Uvea Dr. Deepankur Mahajan MBBS, MD (AIIMS), FICO, FAICO (Retina and Vitreous) Consultant Ophthalmologist and Vitreoretina Specialist, New Delhi Section Editor - Uvea & Ocular Inflammatory Disorders Dr. Aman Kumar MD, Senior Resident Vitreo-Retina, Uvea, ROP services Dr. R P Centre for Ophthalmic Sciences, AIIMS, New Delhi Section Editor - Retina & Uvea Dr. Rushil Kumar Saxena Dept of Vitreoretina Dr. Shroff’s Charity Eye Hospital, New Delhi Section Editor - Retina & Uvea Dr. Ankur Singh Assistant professor Dept of Ophthalmology University College of Medical Sciences and GTB Hospital, Delhi Section Editor - Retina & Uvea Dr. Abhishek Jain D.O., D.N.B., FAICO RBM Eye Institute, Delhi ADK Jain eye hospital, Bhagpat Section Editor - Cornea & External Eye Disease Dr. Sameer Kaushal Senior Consultant & Head (Ophthalmology) Artemis Hospital and PL Memorial Eye Clinic, Gurgaon Section Editor - Cornea & External Eye Disease Dr. Abha Gour Senior Consultant Cornea and Anterior Segment Dr. Shroffs Charity Eye Hospital, New Delhi

www.dosonline.org/dos-times DOS Times Volume 29, Number 5, September-October 2023 03 Section Editor - Ocular Surface Dr. Rajat Jain MBBS, MS (Gold Medalist), FICO (UK) Fellow- Cornea and Anterior Segment- LVPEI Hyderabad Section Editor - Cataract & Comprehensive Ophthalmology Dr. Ritin Goyal Director & Cornea, Cataract and LASIK surgeon at Goyal Eye Group of Eye Centers. Section Editor - Refractive Surgery Dr. Manpreet Kaur MD, Assistant Professor Cornea, Cataract & Refractive Surgery Services Dr. R P Centre for Ophthalmic Sciences AIIMS, New Delhi Section Editor - Ocular Surface Dr. Jaya Gupta Consultant Cornea Cataract & Refractive Surgery The Healing Touch Eye Care Centre, New Delhi Section Editor - Cataract & Comprehensive Ophthalmology Dr. Wangchuk Doma Venu Eye Institute and Research Centre Section Editor - Refractive Surgery Dr. Pranita Sahay, MD (AIIMS), FRCS (Glasgow), DNB, FICO, FICO (Cornea), FAICO (Ref Sx) Consultant, CFS, New Delhi Section Editor - Ocular Surface Dr. Abhishek Dave Consultant Cornea, Cataract & Refractive Surgery - CFS, New Delhi Section Editor - Ocular Surface Dr. Amrita Joshi Assistant Professor Department of Ophthalmology Army Hospital (R&R) Section Editor - Cataract & Comprehensive Ophthalmology Dr. Amit Mehtani MBBS, MS, DNB DDU HOSPITAL Section Editor - Ocular Surface Dr. Neeraj Verma MS (Ophthal) Senior Consultant Centre For Eye Care Kirti Nagar, New Delhi Section Editor - Cornea & External Eye Disease Dr. Ritu Nagpal MD Senior Research Associate Consultant, Eye7 Hospitals, Lajpat Nagar, New Delhi Section Editor - Cornea & External Eye Disease Dr. Parul Jain MBBS, MS, FICO, FAICO, MRCSEd Associate Professor GNEC, Maulana Azad Medical College Dr. Jyoti Batra Consultant, Oculoplasty and Ocular Oncology, ICARE Eye Hospital and Post graduate Institute, Noida Section Editor - Oculoplasty & Asthetics Section Editor - Oculoplasty & Asthetics Dr. Rwituja Thomas Grover Consultant Oculoplastics, Orbit, Ocular Oncology and Aesthetics services, Vision Eye Centres, New Delhi Section Editor - Oculoplasty and Orbit Dr. Sanjiv Gupta Lotus Eye Center, Naraina Vihar, New Delhi Dr. Anuj mehta Consultant and Professor Vardhman Mahavir Medical College and Safdarjung Hospital Section Editor - Oculoplasty & Asthetics Section Editor - Glaucoma Dr. Kiran Bhanot MS, DNB Senior Consultant & Hod GGS Hospital & Indira Gandhi Hospital, Dwarka, New Delhi Section Editor - Glaucoma Dr. Suneeta Dubey Head - Glaucoma Services Medical Superintendent Chairperson - Quality Assurance Dr. Shroff’s Charity Eye Hospital New Delhi, India Section Editor - Glaucoma Dr. Prathama Sarkar Consultant in Eye7 Chaudhary Eye Centre Section Editor - Glaucoma Dr. Kanika Jain MBBS, MS, DNB Senior Resident, Dept of Ophthalmology, DDU Hospital, Hari Nagar, New Delhi. Section Editor - Glaucoma Dr. Shweta Tripathi DNB, MNAMS, FMRF Senior Consultant Glaucoma Services Indira Gandhi Eye Hospital and Research Centre, Lucknow

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times 04 Prof. Swati Phuljhale Dr. R P Centre for Ophthalmic Sciences, AIIMS, New Delhi Section Editor - Strabismus Dr. Gunjan Saluja Ex SR Strabismus, Oculoplasty and Neuro-Ophthalmology services, Dr. R P Centre, AIIMS, New Delhi Section Editor - Strabismus Dr. Suraj Singh Senjam Community Ophthalmology Dr. R P Centre for Ophthalmic Sciences, AIIMS, New Delhi Section Editor - Community Ophthalmology Dr. V Rajshekhar MS, FICO Professor & Consultant Dept of Ophthalmology VMMC & Safdarjung Hospital, New Delhi Section Editor - Community Ophthalmology Dr. Digvijay Singh Affiliation, Noble Eye Care, Gurugram Section Editor - Residents Corner Dr. Vineet Sehgal MBBS, MD Fellowship in Glaucoma Senior Consultant & Incharge Glaucoma Sharp Sight Eye Hospitals Section Editor - Residents Corner Dr. Sima Das Head, Oculoplasty and Ocular Oncology Services Incharge, Medical Education Dr. Shroff’s Charity Eye Hospital New Delhi Section Editor - Ocular Oncology Dr. Arpan Gandhi Dr. Shroff’s Charity Eye Hospital New Delhi Section Editor - Ocular Pathology and Microbiology Prof. Bhavna Chawla Professor of Ophthalmology Dr. R P Centre, AIIMS, New Delhi Section Editor - Ocular Oncology Dr. Paromita Dutta Associate Professor Guru Nanak Eye Centre Maharaja Ranjit Singh Marg New Delhi Section Editor - Strabismus Dr. Sumit Monga, Senior Consultant. Pediatric, Strabismus and Neuro-Ophthalmology Services, CFS group of Eye Hospitals, Delhi-NCR Section Editor - Neuro-Ophthalmology Dr. Amar Pujari Assistant Professor Dr. R P Centre for Ophthalmic Sciences, AIIMS, New Delhi Section Editor - Neuro-Ophthalmology Dr. Rebika Dhiman Assistant Professor Strabismus and NeuroOphthalmology services, Dr. R P Centre, AIIMS, New Delhi Section Editor - Neuro-Ophthalmology Dr. Simi Gulati I/C and Specialist Charak palika hospital (ndmc) Moti bagh, New Delhi Section Editor - Glaucoma Dr. Dewang Angmo MD, FRCS, FICO Dr R P Centre for Ophthalmic Sciences AIIMS Section Editor - Glaucoma Dr. Kavita Bhatnagar Professor & Head, Dept of Ophthalmology, AIIMS, Basani Phase-2, Jodhpur Section Editor - Glaucoma

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times 06 From the President's DESK Dr. Rajendra Prasad MBBS, MD DOS TIMES Dear Friends It is with pleasure that we are towards the end of this year 2023, and I hope that during this year we have been able to meet the needs of our members in terms of educational, scientific and DOS awareness activities. I am most grateful to our teachers, our seniors, colleagues, friends and our executive members for their continued support towards the progress of our society. This year has been quite good one, most of the scientific events have been highly successful, IDOS and DOS midterm conference were grand success attracting an increasing number of delegates specially the younger delegates, those who are naturally taking the lead in the progress of our society. There has been steadily increasing numbers of faculty participation, delegate registration, free paper, video, submissions from the younger authors, which is a good trend. We also have successfully conducted sequence of subspecialty evening CMEs, DOS sports events and many other extracurricular activities with huge participation of our members. We have been trying to follow the line up of people who have provided guidance for our society in the past; with different vision and different strengths towards the progress of our society with highest level of sprits and commitment. We have also been able to push through all the plans we had committed while taking over this executive term in 2022 and have been trying our best to fulfill the responsibility and working for the betterment of the society. DOS annual conference is scheduled for 9-11 February 2024 and we will do our best to make it a grand success and continue our programs that strengthen our professionalism  through education, training and resources. DOS times is one of the educational resource along with DJO quite popular amongst the ophthalmic fraternity for publication of innovation, research work, original articles and case reports. This issue of DOS Times brings together original research articles on fundamental topics of corneal disorder providing a unique concept and scientific discussion on the subject. We have been able to achieve the task with the help of editorial board and authors and production team and our thanks and appreciation are extended to them for their contribution. “Progress lies not in enhancing what is, but in advancing towards what will be.” Dr. Rajendra Prasad President DOS

www.dosonline.org/dos-times DOS Times Volume 29, Number 5, September-October 2023 07 DOS TIMES From the DESK of Chief Editor Dr. Jatinder Singh Bhalla, MS, DNB, MNAMS Secretary Delhi Ophthalmological Society “Of all the senses, sight must be the most delightful.” Respected Seniors and Friends, Ophthalmology is a dynamically evolving specialty. Recent times have dynamically changed the subject with the introduction of microsurgical techniques, high tech introduction in diagnostics and therapeutics, and division of subspecialties in ophthalmology. Of the 36 million people who are blind worldwide, Corneal causes account for 12.7 million cases of blindness and/or visual impairment making it one of the world’s leading causes of avoidable blindness. Most who are corneal blind live in low and middle-income countries, where the condition goes beyond not being able to see. It also creates obstacles to staying in school, maintaining employment, and providing for one’s family. Navigating these challenges takes an emotional and financial toll, leading to cycles of poverty and reductions in life expectancy, often by as much as onethird. Fortunately majority of corneal blindness is avoidable. Reducing the incidence of corneal blindness involves multipronged approach-strengthening public health program, timely hospitalization, safety measures in work place, proper/timely management of corneal infection and increasing the availability of donor corneal tissue and trained keratoplasty surgeons. The current issue is focused on Cornea & has Excellent articles by esteemed Authors from all across the country- An overview of lamellar keratoplasty techniques, notes on keratoconus, Extended resection with limbal conjunctival autograft versus conventional conjunctival autograft for recurrent pterygium, Role of topical insulin in ocular surface diseases, Overview of follicular conjunctivitis, Predictive analysis of UBM in cases of anterior staphyloma undergoing sclero-corneal transplantation and evolution of corneal cross-linking. DH lawrence quoted “what the eye doesn’t see and the mind doesn’t know, doesn’t exist”. Dr HS Dua famously commented - take a moment to pause and think of what we see, is all that is needed to allow the eye to see what the mind does not know. I hope this information provided in this DOS Times will also be greatly valued by the clinicians who like to refresh their clinical acumen with the latest in published literature. The DOS Midterm Conference achieved many parameters of success. It was a matter of immense satisfaction to be able to organise a great Academic Meeting in difficult circumstances due to NMC Guidelines & Traffic restrictions due to G 20 Meet rehearsals. Credit to the hard work done by whole Executive. Highest ever number of Registrations (1500), 375 Faculty talks, 612 Free papers/ Interesting cases, 202 Wetlab Registrations, Live Surgeries from multiple centres, enthusiastic submissions for IFFA, Successful Quiz Programme. WET LAB: DOS SSTI was a jewel in the crown. Packed halls, Vibrant Trade, Power packed Science & Great talks by esteemed faculty. “What I Love Most About Reading: It Gives You The Ability To Reach Higher Ground. And Keep Climbing.” Wish you happy reading. Dr. Jatinder Singh Bhalla, MS, DNB, MNAMS Chief Editor - DOS Times, Consultant & Academic Incharge (Ophthalmology) DDU Hospital, Hari Nagar

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times DOS TIMES 08 Figure 1: Pictorial representation of corneal layers and overview of various techniques of lamellar keratoplasty.[10] An Overview of Lamellar Keratoplasty Techniques Nashra Alma[1], MBBS, Pooja Jain[1], MS, FICO, Parul Jain[2], FRCS, MRCS(Ed), Vinay R Murthy[1], MNAMS, FAEH, Roopashri Matad[1], FRCS, FCED 1. Prabha Eye Clinic and Research Centre Jayanagar, Bangalore. 2. Guru Nanak Eye Centre, Maharaja Ranjeet Singh Marg, New Delhi. Introduction The world’s first successful allogenic penetrating keratoplasty was performed by Zirm in 1905.[1] Since then, penetrating keratoplasty has been the gold standard for corneal transplantation. However, with penetrating keratoplasty having a high incidence of complications like expulsive choroidal haemorrhage, endophthalmitis, retinal detachment, graft rejection, graft failure, the paradigm has now shifted towards lamellar keratoplasty.[2] Lamellar keratoplasty aims at replacing only the diseased layers as opposed to the full cornea.[3] Anton Elschnig performed the first Anterior Lamellar keratoplasty in 1914.[4] Endothelial keratoplasty was first performed in 1956 by Charles.[4] Pneumo-dissection and visco-dissection techniques were performed by Archila and Melles which brought about advances in DSEK.[5] The advent of the revolutionary Anwar’s Big Bubble technique in 2002 lead to an increase in popularity of DSEK.[6] Melles invented the technique of Descemetorrhexis which brought about DMEK in 2006.[7] The discovery of Dua’s layer by Dua et al in 2013 has revolutionized Lamellar Keratoplasty techniques.[8] Modern day surgical techniques and instruments such as microkeratome, femtosecond laser, intraoperative OCT, aseptic techniques, potent corticosteroids have dramatically improved the success of corneal transplantation.[9]

www.dosonline.org/dos-times DOS Times Volume 29, Number 5, September-October 2023 DOS TIMES 09 Types/Classification Indications of Anterior Lamellar Keratoplasty Indications of Posterior Lamellar Keratoplasty Optical Therapeutic Tectonic Refractive Ocular Surface Reconstruction • Corneal opacities, scars( e.g trauma, chemical injury, corneal ulcer) • Corneal dystrophies (e.g lattice, granular, macular dystrophy) • Keratoconus • Infective Corneal Ulcers • Descmetocele • Corneal stromal melts (e.g rhematoid arthritis • Corneal ectasias (e.g pellucid marginal degeneration) • Post lasik keratectasia • In combination with amniotic/mucous membrane grafts( e.g in chemical injuries/ sjs Congenital Endothelial Dystrophies Post- Surgiery/Procedure • Descemet’s membrane breaks due to birth trauma • Ice syndrome • Fuch’s endothelial dystrophy • Congenital hereditary endothelial dystrophy • Pseudophakic bullous keratopathy • Aphakic bullous keratopathy failed graft

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times DOS TIMES 10 Techniques Anterior Lamellar Keratoplasty 1) Bowman’s Membrane Transplant Bowman’s membrane is an acellular layer located between epithelium and anterior stroma. Its thickness is about 10-12 microns and comprises condensed collagen fibres of the anterior stroma. It does not have the ability to regenerate following any insult.[11] Indications: Keratoconus and persistent subepithelial haze following surface ablation procedures.[11] Preparation of donor Bowman’s layer: 1. Manual method[12]: Trypan blue is used to stain the Bowman’s layer after epithelial debridement. The stained Bowman’s layer is then peeled off from the underlying stroma using non- toothed forceps. 2. Air dissection[4,13]: Air is injected into Donor cornea which ‘dissects’ the Bowman’s layer from underlying stroma. The ‘scroll’ of Bowman’s layer is then placed in 70% ethanol which removes any epithelial cell remanent. 3. Femtosecond laser[11]: It is used to prepare the Bowman’s lenticule with greater precision and accuracy as compared to manual/air dissection which leads to a smoother but thicker Bowman’s lenticule. Surgical method: 1. Inlay technique[12]: Used commonly in Keratoconus patients. The ‘scroll’ of Bowman’s layer is inserted via a glide into mid-stroma of recipient cornea through a ‘pocket’ which is created using manual dissection. The ‘scroll’ unrolls and stays in place without the need of any sutures/tissue glue. 2. Overlay technique[12]: Used in patients with persistent subepithelial haze (e.g., post surface ablation procedures) or anterior stromal scarring (e.g., healed keratitis). The Bowman’s layer is positioned on the exposed anterior corneal stroma after epithelial debridement of recipient bed and is ‘stuck on’ the recipient by allowing it to air dry followed by bandage contact lens application. Figure 2[12]: Surgical Method of Bowman’s membrane dissection using McPherson’s forceps. Advantages[11]: 1. Suture-less technique, therefore, astigmatism induced is minimal, and hence better visual outcomes. 2. Chances of rejection considerably lower as graft is acellular. 3. Lesser incidence of postoperative steroid induced cataract, glaucoma as need for topical steroids reduced due to the acellular nature of graft. 4. Less invasive. Disadvantages[4,11]: 1. Steep learning curve as procedure is technically difficult to perform. 2. Improper dissection of donor may lead to pockets of stromal tissue remaining on Bowman’s layer, therefore the grafthost interface may not be smooth interfering with optical quality of graft. 3. Intrastromal cavitation of recipient cornea.

www.dosonline.org/dos-times DOS Times Volume 29, Number 5, September-October 2023 DOS TIMES 11 4. Increased backscattering of light due to different refractive indices of donor and host cornea. 2) Superficial Anterior Lamellar Keratoplasty (SALK) Involves removal of anterior stroma (< 160 microns stromal depth of involvement)[4] Indicated in anterior stromal pathologies e.g., macular/lattice/ granular dystrophy, keratitis, keratoconus. Figure 3[14]: Pictorial representation of SALK where only layers up to anterior stroma are removed. Surgical technique[14]: 1. Recipient preparation: • Host cornea marked with a 8 or 12 pronged radial marker using gentian violet with centration on optical axis. This helps in placing the cardinal sutures at 6 o’ clock, 12 o’ clock, 3 o’clock and 9 o’clock hours. • The size of cornea to be replaced is measured using callipers and is partially trephined depending upon the depth of corneal pathology. Stromal dissection methods: a) Manual: (i) Closed dissection: Intrastromal pocket created with Paufique knife and stromal dissection done with Crescent knife/Desmarre’s lamellar dissector. Dissection is carried out keeping the dissector parallel to plane of cornea in order to prevent perforation. A side to side sweeping movement is carried out while moving forward and dissecting from limbus to limbus. A dry dissection is carried out in order to detect any perforations. (ii) Open dissection: Done in a similar fashion, however, the difference being that the anterior lip of separated lamellar tissue is retracted with help of forceps and dissection is done under direct visualisation. b) Automated[15]: An automated microkeratome is used to prepare the recipient as well as donor cornea. It has various ranges of heads e.g., 120,180,250,350 microns which gives the corresponding lamellar cut. 2. Donor preparation: • The donor corneal button is mounted on an artificial chamber and dissected manually with the help of Crescent’s blade. • The button is trephined from endothelial side with size being more than 0.5mm than host corneal button. • The donor lenticule is then sutured onto the recipient bed using interrupted sutures with 10-0 nylon. Advantages[16]: 1. Reduced incidence of cataract, glaucoma 2. Maintained structural integrity Disadvantages[16]: 1. Alters the corneal topography with induction/worsening of astigmatism. 2. Improper/manual dissection can lead to interface irregularities and hence interface haze reducing the optical quality of donor. 3. Technically demanding procedure. Complications[14]: 1. Perforation of cornea can occur inadvertently during dissection. Dissection can be carried out from the diagonally opposite end after reforming anterior chamber with air. In case perforation is too large, the procedure has to be converted into penetrating keratoplasty. 2. Double chamber in cases of perforation. 3. Graft infection. 4. Recurrence of primary pathology e.g., stromal dystrophies. 5. Graft rejection can occur although the incidence is lesser compared to penetrating keratoplasty. 6. Graft vascularisation common in ocular surface disorders e.g., chemical burns, Stevens-Johnson syndrome. 3) Deep Anterior Lamellar Keratoplasty (DALK) Removal of all layers of cornea baring the Descemet’s membrane and Endothelium. Figure 4[17]: Pictorial representation of DALK where layers up to Posterior stroma are removed. Methods of recipient corneal dissection[15]: Along with the above-mentioned dissection methods mentioned for SALK, there are additional techniques used for the dissection of lamellar layers. They include the use of air, saline, viscoelastic substances to create a plane of cleavage between the Descemet’s membrane and Posterior stroma. (i) Saline/viscoelastic substances[15]: Involves injection of saline/viscoelastic substances into deep stroma to create a plane of cleavage between Descement’s membrane and Posterior stroma, thus facilitating smooth and easy method of dissection.

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times DOS TIMES 12 (ii) Air[17]: Involves the Anwar’s Big Bubble technique. A 30-gauge needle is used to inject air into deeper layers of stroma after partial trephination of recipient cornea. (iii) Femtosecond laser assisted[19]: Used to create customized trephination patterns in both donor and host cornea. Precise ‘cuts’ enables a precise fit of donor and host cornea, thereby Figure 5[18]: Differentiating features of Type 1 and Type 2 Big Bubbles. Figure 7[19]: Diagrammatic representation of various ‘cuts’ (a) Top hat (b) Mushroom (c) Zig-zag (d) Christmas tree (e) Traditional. Figure 6[18]: Physical appearance of Host after Anwar’s big bubble dissection. enabling faster visual recovery, minimal astigmatism and better wound healing. Advantages[19] of DALK: 1. Retains the normal host endothelium, hence lesser chances of graft rejection/failure. 2. Reduced astigmatism as number of sutures required lesser compared to Penetrating Keratoplasty. 3. Non-invasive, hence chances of endophthalmitis, cataract, retinal detachment is lesser. 4. Donor cornea does not require to have good endothelial count. 5. Stronger corneal wound. Disadvantages of DALK[19]: 1. Steeper learning curve as compared to PK. 2. Technically more demanding surgical procedure. 3. Interface irregularity can lead to suboptimal visual outcomes. 4. Pseudo-chamber/Double anterior chamber due to retention of viscoelastic substances/perforation. Complications[16,19]: 1. Perforation of host Descemet’s membrane. Small sized perforations are tamponaded with air at the end of surgery. Larger perforations have to be sutured directly to donor stroma with 11-0 Nylon. 2. Pseudo-anterior chamber: Perforation of Descemet’s membrane leads to aqueous leak in between the donor and host cornea. Managed by injecting air into anterior chamber. 3. Stromal rejection: Stromal edema and vascularisation. 4. Urrets- Zavalia syndrome. Posterior Lamellar Keratoplasty 1) Posterior Lamellar Keratoplasty • Transplantation of Endothelium-Descemet’s membrane with posterior stroma. • Indicated in endothelial pathologies e.g., Fuch’s Endothelial

www.dosonline.org/dos-times DOS Times Volume 29, Number 5, September-October 2023 DOS TIMES 13 Dystrophy, ICE syndrome, Congenital Hereditary Endothelial Dystrophy. • Technique[20] first described in 1998 by Melles. In this technique, the recipient corneal pocket is first created at the limbus. A trephine is inserted into anterior chamber and the central posterior lamellae are excised. The donor graft 1. Preparation of recipient bed: • A 9 mm external scleral tunnel is created 2 mm from the superior limbus using a guarded diamond knife and a crescent’s blade. • The stromal pockets are extended by a stromal dissector until mid-pupillary margin. The dissection is completed 360 degrees via a Devers dissector. • Terry trephine is inserted into the deep lamellar pocket created and using back pressure provided by viscoelastic injected into the anterior chamber, the posterior stroma along with endothelium is trephined, hence, leading to entry of anterior chamber. • Cindy’s scissors are used to complete the resection of recipient tissue. 2. Preparation of Donor cornea: • Corneoscleral button mounted onto artificial chamber to enable resection of tissues until 150 microns of posterior stromal tissue remains. The dissection can be carried out with the help of a microkeratome or manually using Crescent’s blade. • The posterior corneal button is ‘punched’ out from endothelial side and separated from the anterior layers. • The donor tissue is then placed with endothelial side facing down on an Ousley spatula which is coated with viscoelastic. • After filling the anterior chamber with air, the Ousley spatula containing the donor corneal button is then inserted into the stromal pocket created, in a plane level to the iris and raised anteriorly till the donor corneal surface touches the recipient stromal bed. • The donor graft is secured to the recipient bed with the help of positive pressure provided by the air bubble. is placed into position via the limbal pocket created without the use of sutures. 2) Deep Lamellar Endothelial Keratoplasty (DLEK) Technique[21]: Involves the replacement of posterior stroma and endothelium. Figure 8[22]: Steps of DLEK surgery. • The scleral wound is sutured and Balanced Salt Solution is injected into anterior chamber replacing the air bubble. • The donor graft by the action of endothelial pump, ‘sticks’ onto the recipient stromal bed, hence making this a sutureless technique. 3) Descement’s Stripping Endothelial Keratoplasty (DSEK)/Descement’s Stripping and Automated Endothelial Keratoplasty (DSAEK) • The diseased Descemet’s membrane and Endothelium are replaced. • Common indications: Fuch’s endothelial dystrophy, Congenital Hereditary Endothelial Dystrophy, Pseudophakic/Aphakic Bullous Keratopathy. Technique[23]: 1. Preparation of Donor cornea: • The donor cornea should be of good quality with minimum Figure 9[17]: Steps of DSEK/DSAEK Surgery.

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times DOS TIMES 14 endothelial count of atleast 2500-3000 cells per cubic millimetre. • Methods of dissection: After mounting the donor corneoscleral button on an artificial chamber, the posterior corneal layers can be dissected by one of the following methodsManual dissection with Crescent’s blade (DSEK), Automated microkeratome dissection (DSAEK), Femtosecond laser dissection (FLS-DSAEK). • Donor lenticule should be 3mm lesser than white to white diameter of recipient bed. 2. Preparation of Recipient bed: • A corneo-scleral/corneal incision is made. • The diseased Descemet’s membrane along with Endothelium is ‘stripped’ off by performing a Descemetorrhexis. The area to be stripped is marked on the epithelial surface with the help of trephine and a reverse Sinskey’s hook is used to score the edge of Descemet’s to initiate Descemetorrhexis. The Descemet’s membrane is then scrapped with a scrapper. • The anterior chamber is filled with air/continuous irrigation of balanced salt solution/ viscoelastic to aid in the process. 3. Inferior peripheral Iridectomy is done before inserting the transplant to prevent pupillary block glaucoma. 4. Methods of insertion of donor graft[4,17,24]: • ‘Taco’ technique[24]: Graft folded in a 60:40 ratio and inserted into anterior chamber through the scleral wound with a non-toothed forceps. However, there were incidences of graft unfolding endothelial side up and the endothelial cell loss was as high as 34-51%. • Busin glide[24]: Helps in inserting the donor lenticule endothelial side down and ensuring uncurling of lenticule with stromal side facing up. The rate of endothelial cell loss was reduced to 25%. • Sheets glide technique[24]: Graft placed on an intraocular lens Sheets glide endothelial side down along with a drop of high density viscoelastic. The sheets glide is placed into scleral wound reaching the other end of anterior chamber and is either pushed with Sinskey’s hook or pulled into anterior chamber with specially designed forceps. The rate of endothelial cell loss is as low as 9%. 5. Ensuring proper unrolling of graft[25]: • The stromal side of graft lenticule is marked with either a ‘F’ or ‘S’ in ink and proper orientation of the alphabet written ensures that the graft has unrolled in the correct orientation i.e., with stromal side up. 6. Tamponade[25]: • Once the graft has unrolled in the correct orientation in the anterior chamber, the graft is ‘tamponaded’ with air to ensure the stromal side of donor lenticule is in apposition with recipient bed. The air is maintained for atleast 10 mins before allowing some amount of air to escape to prevent occurrence of pupillary block and raised IOP consequently. • The scleral wound is sutured and patient is asked to maintain supine position to allow the tamponade effect of air bubble. Figure 10[26]: Post-operative AS-OCT showing DSEK graft in apposition with host bed.

www.dosonline.org/dos-times DOS Times Volume 29, Number 5, September-October 2023 DOS TIMES 15 Advantages[26]: 1. Less invasive. 2. Faster visual recovery. 3. Lesser induced astigmatism. 4. Structurally stronger globe. 5. Corneal Innervation intact. 6. Anterior topography unaltered. Disadvantages & Complications[26]: 1. Chances of endothelial rejection. 2. Graft detachment/dislocation into posterior chamber. 3. Suboptimal visual acuity due to interface irregularities. 4. Hyperopic shift . 5. Thicker graft compared to DMEK. 6. Improper unfolding of graft. 4) Descement’s Membrane Endothelial Keratoplasty (DMEK) • Transplantation of only Descemet’s membrane and endothelium as opposed to DSEK/DSAEK which includes posterior stroma as well. • Indications: Similar as in DSEK/DSAEK. • Selection of donor graft: 1. Endothelial cell counts of atleast 2000-3000 cells per cubic millimetre. 2. Donor age > 50 years (easier dissection as attachment is not as strong in age > 50 years). Technique[27]: • Preparation of recipient bed is similar as in cases of DSEK/ DSAEK. • Preparation of donor lenticule: Methods of dissection: 1. Submerged Cornea Using Backgrounds Away (SCUBA) technique where the donor lenticule is manually dissected with the donor cornea being submerged in BSS/Optisol solution using forceps. 2. Pneumatic dissection • The donor lenticule can be stained with Trypan Blue for better visualisation. • The ‘no-touch’ technique is used to load the lenticule into a glass injector/Intraocular lens injector/Jones tube. • Corneo-scleral/corneal wound and paracentesis ports are placed similar to DSEK/DSAEK. • The donor Descemet’s membrane is injected with pupil being constricted and anterior chamber is made shallow. Scleral wound is sutured to ensure ‘scroll’ remains in anterior chamber. • After lenticule is injected, it is unrolled with the help of either air bubbles/fluid/tapping of cornea to ensure the donor graft remains oriented with the endothelial side down. • Once graft has assumed the correct orientation, it is secured with the help of air bubble as in DSEK/DSAEK and supine position of patient is to be encouraged. Advantages[28]: 1. Superior visual outcomes compared to DSEK/DSAEK. 2. Lower rate of rejection. 3. Smaller scleral incision size. 4. Other advantages similar to DSEK/DSAEK. Disadvantages & Complications[28]: 1. Graft displacement/dislocation. 2. Improper unrolling of graft. 3. Steeper learning curve. 4. Perforation of graft. 5. Graft rejection. 6. Secondary glaucoma. 5) Pre-Descement’s Endothelial Keratoplasty (PDEK) • Transplantation of Dua’s layer, Descemet’s membrane and endothelium. • The Dua’s layer is present anterior to the Descemet’s membrane and is approximately 10 microns in thickness comprising mainly of collagen fibres. • Indications: Similar like in DSEK/DSAEK/DMEK. 1. Preparation of donor: Refer to Figure-11 Figure 11[29]: Big bubble dissection technique in PDEK. 2. Preparation of recipient: Descemetorrhexis done like in DSEK/DSAEK/DMEK. • The graft lenticule is injected and secured with air bubble after ensuring correct orientation of graft. Advantages[4,29]: 1. Endothelial loss lesser compared to DMEK. 2. Dua’s layer confers strength to the graft.

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times DOS TIMES 16 Figure 12[24]: Comparison of different techniques of posterior lamellar keratoplasty. 3. Can be done in donor < 50 years thus higher endothelial counts. 4. Easier manipulation as graft is thicker compared to DMEK. 5. Faster visual recovery compared to DMEK. 6. Easier unfolding compared to DSEK/DSAEK. Disadvantages[4,29]: 1. Steep learning curve. 2. Graft unfolding improperly. 3. Graft dislocation into posterior segment especially in post vitrectomy/aphakic eyes. 4. Graft perforation in cases where type 2 bubble is formed inadvertently. Conclusion Lamellar keratoplasty techniques despite its steep learning curve, retain the optical, therapeutic, tectonic advantages of penetrating keratoplasty while at the same time eliminating/ reducing the various disadvantages associated with it. References 1. McGhee C, Crawford A, Patel D. A brief history of corneal transplantation: From ancient to modern. Oman Journal of Ophthalmology. 2013;6(4):12. doi:10.4103/0974-620x.122289. 2. Gurnani B, Kaur K. Penetrating Keratoplasty. [Updated 2023 May 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-Available from: https://www.ncbi.nlm.nih.gov/ books/NBK592388/. 3. Koizumi N, Kinoshita S. Lamellar keratoplasty [Internet]. 2010 [cited 2023 Jun 30]. Available from: https://www.sciencedirect.com/topics/ medicine-and-dentistry/lamellar-keratoplasty. 4. Dua, H., Singh, N. and Said, D. (2018) ‘Lamellar keratoplasty techniques’, Indian Journal of Ophthalmology, 66(9), p. 1239. doi: 10.4103/ijo.ijo_95_18. 5. Tandon R, Singh R, Gupta N, Vanathi M. Corneal transplantation in the modern era. Indian Journal of Medical Research. 2019;150(1):7. doi: 10.4103/ijmr.ijmr_141_19 6. Anwar M, Teichmann KD. Big-bubble technique to Bare Descemet’s membrane in anterior lamellar keratoplasty. Journal of Cataract and Refractive Surgery. 2002;28(3):398–403. doi:10.1016/s0886- 3350(01)01181-6. 7. Melles, Gerrit R. J. MD, PhD*; Wijdh, Robert H. J. MD; Nieuwendaal, Carla P. MD. A Technique to Excise the Descemet Membrane from a Recipient Cornea (Descemetorhexis). Cornea 23(3): p 286-288, April 2004. 8. Dua HS, Freitas R, Mohammed I, Ting DSJ, Said DG. The preDescemet’s layer (Dua’s layer, also known as the dua-fine layer and the pre-posterior limiting lamina layer): Discovery, characterisation, clinical and surgical applications, and the controversy. Progress in Retinal and Eye Research. 2023;101161. doi: 10.1016/j. preteyeres.2022.101161. 9. Moramarco A, di Geronimo N, Airaldi M, Gardini L, Semeraro F, Iannetta D, et al. Intraoperative Oct for lamellar corneal surgery: A user guide. Journal of Clinical Medicine. 2023;12(9):3048. doi:10.3390/jcm12093048 . 10. Zhong, Wei & Montana, Mario & Santosa, Samuel & Isjwara, Irene & Huang, Yu-Hui & Han, Kyu-Yeon & O’Neil, Christopher & Wang, Ashley & Cortina, Maria & Cruz, Jose & Zhou, Qiang & Rosenblatt, Mark & Chang, Jin-Hong & Azar, Dimitri. (2017). Angiogenesis and lymph angiogenesis in corneal transplantation–A review. Survey of Ophthalmology. 63. 10.1016/j.survophthal.2017.12.008. 11. Sharma, B. et al. (2018) ‘Bowman’s layer transplantation: Evidence to date’, Clinical Ophthalmology, Volume 12, pp. 433–437. doi:10.2147/ opth. s141127. 12. Parker, J.S., Dockery, P.W. and Melles, G.R.J. (2020) ‘Bowman Layer Transplantation—a review’, Asia-Pacific Journal of Ophthalmology, 9(6), pp. 565–570. doi:10.1097/apo.0000000000000336. 13. Zaman S, Ibrar H, Sanaullah J, P S M, Mazhar I, Fawad R. Treatment of advance keratoconus using donor Bowman Layer: The zaman technique of Bowman Layer Transplantation (Type I & Type II). International Journal of Clinical and Experimental Ophthalmology. 2022;6(1):015–25. doi:10.29328/journal.ijceo.1001045. 14. Chaudhuri, Z. and Vanathi, M. (2012) ‘Cornea & External Diseases, chapter 6.10.2.1, Anterior Lamellar Keratoplasty’, in Postgraduate ophthalmology. New Delhi, India: Jaypee Brothers Medical Publishers, pp. 688–690. 15. Sharma, N. and Vajpayee, R.B. (2007) ‘Automated Lamellar Therapeutic Keratoplasty’, DOS Times. Edited by J.S. Titiyal, 13(4), pp. 413–415. 16. Espandar L, Carlson AN. Lamellar Keratoplasty: A Literature Review. Journal of Ophthalmology 2013; 2013:1–8. https://doi. org/10.1155/2013/894319. 17. Vanathi, M. and Ashar, J.N. (2012) ‘Cornea & External Diseases, Posterior Lamellar Keratoplasty, Chapter 6.10.2.2’, in Z. Chaudhuri (ed.) Postgraduate ophthalmology. New Delhi, India: Jaypee Brothers Medical Publishers, pp. 694–699. 18. Dua H, Katamish T, Said DG, Faraj LA. Differentiating type 1 from type 2 big bubbles in&nbsp; deep anterior lamellar keratoplasty. Clinical Ophthalmology. 2015;1155. doi:10.2147/opth. s81089. 19. Farid, M. and Steinert, R.F. (2010) ‘Femtosecond laser-assisted corneal surgery’, Current Opinion in Ophthalmology, 21(4), pp. 288– 292. doi: 10.1097/icu.0b013e32833a8dbc.

www.dosonline.org/dos-times DOS Times Volume 29, Number 5, September-October 2023 DOS TIMES 17 20. Singh NP, Said DG, Dua HS. Lamellar keratoplasty techniques. Indian J Ophthalmol. 2018 Sep;66(9):1239-1250. doi: 10.4103/ijo. IJO_95_18. PMID: 30127133; PMCID: PMC6113816. 21. Terry, M. Deep lamellar endothelial keratoplasty (DLEK): pursuing the ideal goals of endothelial replacement. Eye 17, 982–988 (2003). https://doi.org/10.1038/sj.eye.6700614. 22. Terry MA. Deep lamellar endothelial keratoplasty (DLEK): pursuing the ideal goals of endothelial replacement. Eye 2003; 17:982–8. https://doi.org/10.1038/sj.eye.6700614. 23. Descemet Stripping Endothelial Keratoplasty - EyeWiki. Descemet Stripping Endothelial Keratoplasty - EyeWiki n.d. https://eyewiki. aao.org/Descemet_Stripping_Endothelial_Keratoplasty. 24. Price, M.O. et al. (2017) ‘Ek (DLEK, DSEK, DMEK): New frontier in cornea surgery’, Annual Review of Vision Science, 3(1), pp. 69–90. doi:10.1146/annurev-vision-102016-061400. 25. Terry MA. Deep lamellar endothelial keratoplasty (DLEK): pursuing the ideal goals of endothelial replacement. Eye 2003; 17:982–8. https://doi.org/10.1038/sj.eye.6700614. 26. Feldman BH, Hong A, Arede PV, Woodward MA, Bunya VY. Descemet stripping endothelial keratoplasty [Internet]. 2023 [cited 2023 Jun 29]. Available from: https://eyewiki.aao.org/Descemet_ Stripping_Endothelial_Keratoplasty. 27. Giebel, A.W. (2013) ‘DMEK’, International Ophthalmology Clinics, 53(1), pp. 1–14. doi:10.1097/iio.0b013e31827744c4. 28. Bunya VY, Woodward MA, DeMill DL, Syed ZA. Descemet Membrane Endothelial keratoplasty [Internet]. 2023 [cited 2023 Jun 29]. Available from: https://eyewiki.org/Descemet_Membrane_ Endothelial_Keratoplasty. 29. Agarwal, A. and Narang, P. (2017) ‘Pre-Descemet’s endothelial keratoplasty’, Indian Journal of Ophthalmology, 65(6), p. 443. doi: 10.4103/ijo.ijo_324_17. Dr. Nashra Alma, MBBS Prabha Eye Clinic and Research Centre Jayanagar, Bangalore. Corresponding Author:

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times DOS TIMES 18 Keratoconus ‘kunji’ (Notes) Damini Sharma, B Opt, Jaya Mishra, B Opt, Neha Mohan, MS, FICO, FLVPEI, Rajat Jain, MS, FICO, FLVPEI Jain Eye Hospital and LASER Centre, AG-152, Shalimar Bagh, Delhi. Disclaimer: This article is by no means an exhaustive review, but is written in a manner for the clinicians to understand and apply in daily clinical practice and for students to understand and reproduce the topic in exams. This will serve as an excellent ready reckoner for optometrists, clinicians and ophthalmologist for an effective diagnosis and step-wise management of varied presentations and severity of Keratoconus. For detailed reading, the author recommends article 1 stated in the reference section. Definition Keratoconus is defined as a centrally placed, eccentrically displaced, non-inflammatory thinning of the cornea. It usually is bilateral but asymmetrical. Epidemiology[2-5] 1. Age of presentation – usually 2nd decade 2. Usually bilateral asymmetrical. Only 2-4% are unilateral.[1] 3. Progression is asymmetric; Very rare to progress after 40 years of age 4. Corneal thinning - central or paracentral cornea, most commonly infero-temporally[6] 5. Etiology a. Unknown b. Usually sporadic c. Genetics - no association, no specific gene or allele found, no specific HLA association d. Clinical prevalence of KC in 1st degree relatives was only 3.34% in one study[7] 6. Risk factors or associations (most common): a. Most common - Eye rubbing induced microtrauma in Allergic eye disease[8,9] b. Downs Syndrome (Trisomy 21)[10,11] 7. Ocular Associations (Others)[12] a. Retinitis Pigmentosa b. Retinopathy of prematurity c. Aniridia d. Corneal dystrophies- Granular, PPMD, Fuchs’, Macular Biochemistry[13-15] a. Decreased total amount of protein in the cornea b. Up regulation of degradative enzymes found - matrix metalloproteinase, acid esterase, acid phosphatase c. Ratio of dermatan sulphate to keratin sulphate is increased d. Increased amount of Interleukin 1 found in keraocytes Clinical Features (Table-1) a. History I. Teens or twenties age group at presentation II. Progressive visual blur III. Frequent change of glasses IV. Distortion induced eyebrow pain, headache V. Late stages - (increased irregular astigmatism) i. Vision not improving with glasses ii. Poor repeatability of refraction iii. Visible ‘ghost’ images b. Clinical Examination - Torch light examination/ Retinoscopy/Opthalmoscopy signs/Slit Lamp I. Scissor reflex II. Oil droplet reflex - central round reflex like an oil droplet in distant direct ophthalmoscopy (Figure-1a) III. Rizzutti’s sign - conical reflection on the nasal cornea when torch light is shone temporally. (Figure-1b) IV. Munson Sign - corneal protrusion may cause angulation of the lower lid on downgaze (advanced cases) (Figure-1c) Figure 1: Clinical Examination of the eye in Keratoconus showing Oil droplet reflex (a), Rizutti’s sign (b) and Munson Sign (c).

www.dosonline.org/dos-times DOS Times Volume 29, Number 5, September-October 2023 DOS TIMES 19 Stage Name Signs Symptoms 1. Subclinical • Suspicious topography • normal slit-lamp findings • ~ 6/6 VA achievable with spectacle correction None or slight blurring of vision 2. Mild • Scissor reflex’ • Charlouex’s oil droplet reflex (Figure-1a) • mild, localised corneal steepening and thinning • increasing keratometric differences between inferior and superior cornea • increases in corneal aberrations (particularly comalike aberrations) • mild changes in refractive error • reduction of spectacle BCVA. • Frequent change of glasses • K ~ 48-52D Mild blurring or slightly distorted vision 3. Moderate • Increase in severity of signs those in stage 2 • significant corneal thinning • Vogt’s striae • Fleischer’s ring • < 6/6 spectacle BCVA • ~ 6/6 spectacle BCVA with contact lenses • increased refractive changes • increased visibility of corneal nerves • K ~ 52-58D Moderate blurring or slightly distorted vision 4. Severe • Increase in severity of signs those in stage 3 • severe corneal thinning and steepening • corneal scarring • < 6/7.5 VA with contact lens correction • Rizzuti’s sign (Figure-1b) • Munson’s sign (Figure-1c) • corneal opacities • Increased incidence of corneal hydrops • K ~ 52-58D Severe blurring and distorted vision, and monocular polyopia (typically reported as ‘ghost’ images) Table 1: Signs and symptoms based on keratoconus severity. VA, visual acuity; BCVA, best corrected visual acuity; D, dioptres. (Jacinto Santodomingo-Rubido, Contact Lens and Anterior Eye, https://doi.org/10.1016/j.clae.2021.101559) c. Subclinical Keratoconus vs Forme Fruste Keratoconus[16,17] This is an entity that requires special mention i. Forme Fruste Keratoconus - no corneal topography or slit lamp abnormalities, but keratoconus in the fellow eye ii. Subclinical Keratoconus - cornea with no detectable abnormalities based on slit lamp examination, but inferior corneal steepening/asymmetry with unaffected visual acuity 1. Increased central epithelial to stromal thickness ratio 2. Asymmetric superior-nasal epithelial thinning 3. Asymmetrically displaced anterior and posterior corneal apex 4. Corneal thinning 5. Loss of corneal volume 6. Extreme caution in any laser vision corrective procedure on the cornea

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times DOS TIMES 20 e. Tomography: Specifications of three Scheimpflug topographers and their comparison is shown in the Figure-3. For explanation, we have used the Pentacam in this article below which is usually considered the gold standard tomographer. Figure 2: Different Videokeratography patterns as seen in Keratoconus.[26] Figure 3: Comparison of different Scheimpflug based topographers in the diagnosis and management of Keratoconus. Early Detection - Investigations a. Early detection is important for: i. Improved patient outcomes through more frequent review ii. To monitor disease progression iii. Timely interventions when indicated iv. Ultimately reducing the need for corneal transplantation. b. Autorefractometer - Poor repeatability of cylinder error and axis measurements c. Corneal Thickness Profile i. Epithelial thinning at the corneal apex (cone), surrounded by an annulus of epithelial thickening ii. Epithelial thickening is due to an epithelial remodelling response in order to provide a smooth optical surface over an increasingly irregular and steep anterior stroma[18-20] iii. However, Epithelial thickness metrics should still be considered in conjunction with other clinical measures in the diagnosis of keratoconus[21] d. Topography: Placido topographers are the most commonly used i. Principle: projection of a series of illuminated mires onto the cornea and calculates corneal curvature depending upon the distortion and size of the mires.[22] ii. Rabinowitz criteria a. Most commonly used b. 4 quantitative video-keratographic indices for screening keratoconic patients[23] i. Central corneal power > 47.2 D ii. Inferior-superior dioptric asymmetry over 1.2 D iii. Sim-K astigmatism >1.5 D iv. Skewed radial axes >21° iii. Maeda and Klyce[24] - eight indices to diagnose keratoconus. 1. KPI- keratoconus prediction index - value > 0.23 is indicative of keratoconus. 2. KCI% is derived using a binary decision-making tree that was input from the KPI and four other indices and a value >0 is indicative of keratoconus. iv. KISA Index[25] - Rabinowitz and Rasheed - 1. KISA% index is derived from the product of four indices: a. K-value - an expression of central corneal steepening b. I-S value - an expression of the inferior-superior dioptric asymmetrywhich quantifies the degree of regular corneal astigmatism (Sim K1-Sim K2) c. Skewed radial axis (SRAX) index, an expression of irregular astigmatism occurring in keratoconus. d. KISA >100% in an eye with no other pathology - patient is very likely to have clinically detectable keratoconus. e. KISA - 60 to 100% - keratoconus suspects - useful for screening refractive surgery candidates. 2. Different Topographic patterns are depicted in Figure-2[26] i. Pentacam- different interpretations available 1. 4-Map - Typical print showing the anterior saggital curvature map, anterior and posterior elevation maps and corneal thickness map. (Figure-4) 2. Belin-Ambrósio enhanced ectasia display (BAD) 1 - (Figure-5,6) a. Multivariate Index b. Integrates anterior elevation, posterior elevation & the pachymetric data c. Complete overview of the corneal shape d. Quick and effective screening tool for refractive patients e. It calculates the difference in elevation values between the standard BFS and the enhanced BFS which differentiates between normal and ectatic corneas

www.dosonline.org/dos-times DOS Times Volume 29, Number 5, September-October 2023 DOS TIMES 21 Figure 4: Typical Pentacam 4-map showing the anterior saggital curvature map, anterior and posterior elevation maps and corneal thickness map. This map is most commonly used. Figure 5: Belin-Ambrósio enhanced ectasia display (BAD) of a normal cornea. The inferior map is all green in a normal cornea.

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times DOS TIMES 22 3. Others: (details beyond the scope of this article) a. Belin-Ambrósio enhanced ectasia display 2 b. BAD II c. BAD III d. Pachymetric progression index (PPI) e. Ambrósio relational thickness f. Index of surface variance (ISV) Figure 6: Belin-Ambrósio enhanced ectasia display (BAD) of a Keratoconiccornea. The inferior map is all yellow/redin a moderate/severe keratoconus. Figure 7: Aberrometry data taken from the Pentacam showing an increased vertical coma, a finding found most commonly in Keratoconus. g. Index of vertical asymmetry (IVA) h. Keratoconus index (KI) i. Central keratoconus index (CKI) j. Index of height asymmetry (IHA) k. Index of height decentration (IHD) f. Aberrometry[27-32]: data is considered together with other corneal parameters such as pachymetry and posterior corneal aberrations (Figure-7)

www.dosonline.org/dos-times DOS Times Volume 29, Number 5, September-October 2023 DOS TIMES 23 i. Anterior corneal higher order aberrations (A-HOA): 1. most useful of all aberrometry data 2. specifically important in differentiating normal eyes from sub-clinical, form fruste, or emerging keratoconus 3. vertical coma (C(3,-1)), the root mean square error (RMS) of horizontal and vertical coma, and the RMS of 3rd radial order (which includes vertical coma) are most important 4. For a 6 mm corneal diameter - indicative of keratoconus a. vertical coma < ~-0.17 µm b. RMS coma > ~0.275 µm c. 3rd order RMS > ~1.80 µm. ii. Posterior corneal higher order aberrations (P-HOA): 1. Data significantly altered in Posterior keratoconus 2. Although P-HOA increase considerably with moderate to advanced keratoconus compared to healthy controls, data does not significantly enhance the ability to differentiate normal corneas from subclinical keratoconus compared to anterior corneal HOA data alone Classification 1. Morphological (Buxton) classification:[33] It classifies the disease based on the shape and position of the cone into: a. Oval keratoconus: cone affects one/two corneal quadrants, most commonly inferior quadrant b. Nipple keratoconus: cone diameter ≤ 5 mm and located in the central/paracentral cornea c. Globe keratoconus: cone affects a large region of the anterior cornea (>75%). 2. Keratometric classification[34] categorises keratoconus into four grades based on the magnitude of the cornea’s central corneal power: a. Mild (<45 D) b. Moderate (between 46 D and 52 D) c. Advanced (between 53 D and 59 D) d. Severe (>59 D). 3. Hom’s classification[35] Classifies keratoconus into four grades based on clinical signs: a. Preclinical- no keratoconus signs are detected b. Mild cases- display mild corneal thinning and scissors reflex c. Moderate- indicates poor visual quality and corneal thinning without corneal scarring d. Severe keratoconus - the presence of scars, unreliable refraction and severe corneal thinning. 4. Amsler-Krumeich classification 36 a. Most frequently applied in clinical practice b. Uses a number of morphological and clinical features and classifies into: 5. Belin ABCD grading system[37,38] (Figure-8): This grading system in included in the Pentacam system and grades Keratoconus based on four variables: a. Anterior and posterior corneal radius Table 2 Grade 1 Corneal Steepening, Refraction > -5D; Mean central K < 48D Grade 2 NO Corneal Scar, Corneal Thickness > 400 micron; Refraction > -8D; Mean central K < 53D Grade 3 NO Corneal Scar, Corneal Thickness > 300 micron; Refraction > -10D; Mean central K < 55D Grade 4 Central Corneal Scar, Corneal Thickness > 200 micron; Refraction unreliable; Mean central K > 55D b. Curvature of the 3.0 mm central zone of the thinnest corneal location c. Thinnest pachymetry d. Distance best corrected visual acuity

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times DOS TIMES 24 Figure 8: Belin ABCD grading system to establish grading and progression of Keratoconus. Management Decision making is based on: 1. Visual Acuity 2. Progression 3. Stage of the Disease 4. Keratometry 5. Pachymetry The various treatment options with their principle, advantages and patients indicated and other comments are described in table-3. The Five point management algorithm for keratoconus has been lucidly explained by Shetty et al. (Figure-9) The authors follow their own algorithm which is a slight modification of the above with basic principles in management being the same. (Figure-10)

www.dosonline.org/dos-times DOS Times Volume 29, Number 5, September-October 2023 DOS TIMES 25 S No Management Technique Principle Patients Indicated Goals/Objectives/ Advantages Comments 1. Glasses[35] • Correct the refractive error due to ectasia induced myopia and astigmatism • Very early Keratoconus • disease not extending to the central 3-4 mm of the cornea • give better vision with glasses • Routine glass prescription 2. Soft Contact Lenses[39-40] • Similar to glasses • Correct the refractive error due to ectasia induced myopia and astigmatism • Very early Keratoconus • disease not extending to the central 3-4 mm of the cornea • Patients who do not want to wear glasses • Routine CL dispensing based on spectacle number 3. Rigid Gas Permeable (RGP) Contact Lens[41-43] • reliably corrects high levels of corneal irregular astigmatism • regular front surface • neutralization by the tear lens • Moderate-severe KC with irregular astigmatism and asymmetrical corneas • greatest level of adaptability • Three strategies o apical clearance o apical touch o three-point touch • Apical touch – more corneal flattening and scarring • Three-point touch technique- • Latest technique • provides lens support (corneal bearing) at three points along each meridian, including light apical touch and heavier paracentral corneal touch • Provides good vision in mild to moderate KC • Moves with movement of the eyeball, esp with every blink • CL rests on the cornea - CL fitting changes with KC progression and change in topography • Potential to induce apical scarring 4. Corneo-scleral Lenses[44-46] • Corneo-scleral lenses - any rigid contact lens with shared bearing between the peripheral cornea and conjunctiva overlying the sclera, irrespective of the overall lens diameter • Moderate-severe KC with irregular astigmatism and asymmetrical corneas • Patients intolerant to RGPs • improved comfort due to the reduced lens edge-eyelid interaction • enhanced stability and centration with larger optical zones • consistent vision across a range of pupil diameters • particularly useful for inferiorly located cones - when other contact lens options (i.e., • disadvantage - increased potential for corneal hypoxia due to reduced tear exchange • anterior corneal flattening is observed immediately after lens removal. Therefore, a lensfree period is required prior to corneal imaging

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times DOS TIMES 26 S No Management Technique Principle Patients Indicated Goals/Objectives/ Advantages Comments soft, corneal rigid, piggyback or hybrid lenses) fail to provide an acceptable visual outcome • oxygen delivery is enhanced in corneoscleral designs compared to sealed scleral lenses, due to tear exchange and a thinner post-lens fluid reservoir which minimises corneal oedema to assess disease progression 5. Scleral Contact Lens[47-50] • any rigid lens that vaults the cornea entirely, including the limbus, and rests upon the conjunctival tissue overlying the sclera • advanced keratoconus when other lens modalities typically fail to achieve a physiologically acceptable fit • can delay or eliminate the need for a corneal graft in corneas with minimal central scarring • larger lenses (23 mm diameter) – difficult to fit in asian eyes • modification – mini-scleral lenses (16 mm diameter) – better for Indian eyes • provides the BEST visual quality in patients of KC irrespective of any other • medical/surgical treatment in KC • No movement of the lens with every blink – more comfortable to wear • No change of CL fitting with progression of KC as the CL rests on the Sclera and not on the cornea • Fluid lake between the CL and the cornea acts as cushion and helps in longer wear times • Decreased chances of infection as compared to Corneal lenses due to absence of contact • Need fluid replacement at about 5-7 hrs after use

www.dosonline.org/dos-times DOS Times Volume 29, Number 5, September-October 2023 DOS TIMES 27 S No Management Technique Principle Patients Indicated Goals/Objectives/ Advantages Comments 6. Collagen Cross Linking (CXL)[51-54] • Increases biomechanical stability and rigidity of the cornea • attempt to prevent keratoconus progression • Progressive Keratoconus cases • Established for minimum pachy more than 450 micron (epi off) • Performed in India with pachy more than 400 micron (epi-on) • arrest progression in Keratoconus • Conventional Protocol - Dresden Protocol o Central 7-8 mm epi off o 0.1% riboflavin solution o UV-A light ay 370 nm o 3mW - 30 min radiation • Modifications (in thin corneas): o Epi-on CXL o DSAEK Lenticule assisted CXL o SMILE Lenticule assisted CXL o Contact Lens assisted CXL o CXL + hypoosmolar riboflavin 7. Athens Protocol/Bharat Protocol– PTK + Topography guided PRK + CXL[55-58] • Epithelial removal with PTK • Photorefractive keratectomy (PRK) - excimer laser to modify the shape of the anterior central cornea by removing a small section of stromal tissue by vaporization • Simulatenous CXL done • Mild-moderate keratoconus • Keratoconus patients who have poor vision with glasses • Keratoconus patients with significant irregular astigmatism induced distortion which causes eyepain • Because the corneal epithelium is thinner at the apex of the cone, PTK blunts the cone at the apex • Treats irregular astigmatism to make the cornea more regular • Better acceptance of glasses • Decreased visual distortion induced eyepain • Decreased dependence on contact lens • Athens protocol on Alcon Platform • Bharat Protocol on Nidek Platform • Cretan Protocol (thin corneas where only PTK is done to just blunt the cone – no additional stromal ablation done) • Propreitory software used • Topography/ aberrometry data incorporated in the exzimer laser machine • Simultaneous Accelerated CXL – 9mW power used for 10 min for radiation 8. Intra Corneal Ring Segments (ICRS)[56-61] • implantation of one/ two PMMA segments into the corneal stroma • reshape the irregular surface • mild to moderate Keratoconus • central transparent corneas • minimum midperipheral thickness of 450 μm at the site of incision • better UCVA and BCVA • reduction in high-order corneal aberrations • more regular corneal shape that facilitates the fitting of contact lenses

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times DOS TIMES 28 S No Management Technique Principle Patients Indicated Goals/Objectives/ Advantages Comments 9. Phakic IOl (Toric ICL)[59-62] • mild-moderate cases of stable keratoconus with low levels of irregular corneal astigmatism • to correct spectacle number in KC • usually done after disease and refraction has been stabilized • correctable to reasonable refraction with glasses • patients non-tolerant to rigid contact lens • removal of high refractive error • attain spectacle free vision • usually performed in conjunction with other surgery like CXL/Intacs • quality of vision is inferior to that of rigid/sclera CL 10. Bowman Transplantation[63-65] • bowman breaks are postulated to be a cause of KC - Bowman Transplantation corrects that • Increase the thickness in very thin and advanced KC • Vision obtained with sclera lens • Reduces the need of PKP/DALK in future • Advanced KC cases with minimal thickness less than 380-390 micron – not amendable with CXL • Central clear cornea • Increase the corneal thickness of the thinned out cornea in advanced KC • Future stabalisation of KC with CXL if required • Reduces the need of DALK/PKP in future • Historically - one manually as a surgical procedure • Femtosecond LASER assisted Bowman Transplantation – o to create a pocket in graft and host using a femto LASER o insert the bowman + anterior stroma in the lamellar pocket in the host 11. Deep Anterior Lamellar Keratoplasty[66-68] • replace diseased recipient stroma with donor corneal stroma • host descemet membrane and corneal endothelium retained • advanced KC patients who are not eligible for CXL, other procedures described above • CL in-tolerant patients • Patients who want easier and cheaper solution to INTACS, Athens protocol, Bowman Transplant, etc • Patients with history of corneal hydrops – excluded • faster visual rehabilitation due to faster wound recovery and, consequently, fewer wound healingrelated problems (vs PKP) • cheaper alternative to other newer advanced procedures • surgery limited to few corneal surgeons in the country • intra-op - chances of conversion to PKP are there • long-term – safe surgery with a good and stable long-term outcome • other Modifications of Anterior Lamellar Keratoplasty:

www.dosonline.org/dos-times DOS Times Volume 29, Number 5, September-October 2023 DOS TIMES 29 S No Management Technique Principle Patients Indicated Goals/Objectives/ Advantages Comments o Femto assisted DALK o Tuck-in Keratoplasty (when peripheral thinning is also associated) 12. Penetrating Keratoplasty[69-70] • replace the host cornea with a full thickness graft • diseased cornea removed and replaced with normal cornea • all indications of those in DALK • Patients with history of corneal hydrops • traditional and time-tested treatment for advanced Keratoconus • cheaper alternative to other newer advanced procedures • provides acceptable/good vision with glasses after surgery • all efforts shall be made to reserve this as the last option • long-term follow-up period and medications required Table 3: Various treatment options with their principle, advantages and patients indicated and other comments. Figure 9: Five-point-management-algorithm-for-keratoconus given by Shetty et al.

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times DOS TIMES 30 Figure 10: Authors algorithm for latest in Keratoconus management. We shall use these principles outlines in the case examples below. Case 1: (Figure-11)

www.dosonline.org/dos-times DOS Times Volume 29, Number 5, September-October 2023 DOS TIMES 31 Demography 33 year, male Complaints Decrease vision, frequent change in glasses, night glare, eye pain UCVA 6/18 BCVA 6/9 (-4.00/-1.5 x 140) Severity of KC Mild- Thinnest pachy- 477 micron; Kmax – 45.7 Post-op UCVA 6/9 Post-op BCVA 6/6 (-3.5/-1 X120) Treatment options: 1. Spectacles for better vision. (KC mostly in inferior cornea, central area less involved for now) 2. RGP/Scleral Lens for BEST vision 3. Repeat Pentacam after 6 months – if progressing – plan CXL/C3R 4. Athens/Bharat Protocol for correction of the surface irregularity and better vision without glasses (as thickness is good) Author’s recommendation – Surface regularization with Athens/Bharat Protocol – followed by glasses Figure-12 shows the comparison of the pre-op and the post-op anterior saggital curvature after Bharat Protocol. The difference map which signifies the actual ablation area and amount and it shows a more regular central 5.5mm of the cornea leading to a better vision, less spectacle number and decreased symptoms.

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times DOS TIMES 32 Demography 40 year, female Complaints Decrease vision even with glasses, frequent change in glasses, night glare, eye pain UCVA 6/12 BCVA 6/9 ( Severity of KC Moderate- Thinnest pachy- 442 micron; Kmax – 55.4 Treatment options: 1. Spectacles for better vision. (not a good option here as KC mostly involves the central area) 2. RGP/Scleral Lens for BEST vision 3. Repeat Pentacam after 6 months – if progressing – plan CXL/C3R 4. Athens/Bharat Protocol for correction of the surface irregularity and better vision without glasses (as thickness is good) 5. INTACS + CXL – regular astigmatism – will have better results as compared to irregular astigmatism 6. Toric ICL – if the KC is stable – Toric ICL can be done as the astigmatism is regular – It shall provide similar vision as that with glasses Author’s recommendation – Surface regularization with Athens/Bharat Protocol – followed by glasses or Toric ICL for spectacle removal once cornea is stable (usually after 1 year) Figure-14 shows the comparison map after Bharat Protocol showing the more regular central 5.5mm of the cornea and an appearance of a bow-tie pattern signifying a better anterior topographic surface and hence a better vision, less spectacle number and decreased symptoms. Case 2: (Figure-13)

www.dosonline.org/dos-times DOS Times Volume 29, Number 5, September-October 2023 DOS TIMES 33 Post-op UCVA 6/6p Post-op BCVA 6/6 (-1.00 cyl x 2) Case 3: (Figure-15)

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times DOS TIMES 34 Post-op UCVA 6/12 Post-op BCVA 6/6 (+2.00 cyl x 50) Demography 25 year, male Complaints Decrease vision even with glasses, frequent change in glasses, night glare, eye pain, poor quality of vision UCVA 3/60 BCVA 6/36 (-1.00/+3.75 x 30) Severity of KC Moderate- Thinnest pachy- 416 micron; Kmax – 55.1 Treatment options: 1. Spectacles for better vision. (not a good option here as KC mostly involves the central area) 2. RGP/Scleral Lens for BEST vision 3. Repeat Pentacam after 6 months – if progressing – plan CXL/C3R – to stop the progression 4. Cretan Protocol + CXL for correction of the surface irregularity and better vision without glasses – since the corneal thickness is less, Athens/Bharat Protocol is not preferred 5. INTACS + CXL – as mid-peripheral thickness is good 6. DALK – if the patient is not ready to wear contact lens or undergo Cretan/INTACS; reserved as the last option Author’s recommendation – Surface regularization with Cretan Protocol – followed by glasses/ Scleral Contact Lens Figure-16 shows the comparison map after Cretan Protocol showing the more regular central 5.5mm of the cornea and an appearance of a bow-tie pattern. There is significant improvement in the topography in-spite of only the PTK and no additional stromal ablation. This is possibly explained by the fact that the some superficial stroma is getting ablated in a fixed depth PTK leading to a more regular anterior ocular surface.

www.dosonline.org/dos-times DOS Times Volume 29, Number 5, September-October 2023 DOS TIMES 35 Case 4: (Figure-17) Demography 26 year, female Complaints Decrease vision even with glasses, frequent change in glasses, night glare, eye pain, poor quality of vision UCVA 6/60 BCVA 6/12 (-4.5/-1.75 x 122) Severity of KC Moderate– Thinnest pachy- 468 micron; Kmax – 55.1 Treatment options: 1. Spectacles for better vision. (not a good option here as KC mostly involves the central area) 2. RGP/Scleral Lens for BEST vision 3. Repeat Pentacam after 6 months – if progressing – plan CXL/C3R – to stop the progression 4. Athens/Bharat Protocol + CXL for correction of the surface irregularity and better vision without glasses – since the corneal thickness is good, Athens/Bharat Protocol is preferred 5. INTACS + CXL – as mid-peripheral thickness is good Author’s recommendation – Surface regularization with Athens/Bharat Protocol – followed by glasses/ Scleral Contact Lens Figure-18 shows the comparison map after Bharat Protocol showing the more regular central cornea and a better vision, less spectacle number and decreased symptoms.

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times DOS TIMES 36 Case 5: (Figure-19) Post-op UCVA 6/18p Post-op BCVA 6/9 (-2.00/-2.50 x 130)

www.dosonline.org/dos-times DOS Times Volume 29, Number 5, September-October 2023 DOS TIMES 37 Demography 34 year, female Complaints Very poor vision even with glasses, severe photophobia, night glare, eye pain. Progressive decrease in corneal thickness on Pentacam in last few years UCVA 3/60 BCVA 6/60 (-0.25/-1.50 x 114) Severity of KC Advanced – Thinnest pachy- 377 micron; Kmax – 90.8 Treatment options: 1. Treatment options: 1. RGP/Scleral Lens for BEST vision 2. CXL/Athens/Bharat Protocl – NOT an option due to thin cornea 3. Femtosecond assisted Bowman Stromal Inlay – preferred to increase the thickness of the cornea and avoid a DALK/PKP 4. DALK/PK – if non affordable for Femto assisted Bowman Transplantation Author’s recommendation – Femtosecond assisted Bowman Stromal Inlay followed by Hard Contact Lenses for vision; DALK/PKP if patient not able to afford the above procedure. Figure-20 shows the clinical appearance and the anterior segment OCT taken 6 months after the Bowman Inlay Procedure. Fig 21 shows the pentacam report showing the decrease in Kmax from 90.8 to 80.2 D and increase in thickness from 377 micron to 529 micron. The cornea is now of sufficient thickness to obviate the need of DALK/PKP. This was the goal of the surgery in this patient. The patient enjoys a 6/6p vision with sclera contact lens. Post-op UCVA 6/60 Post-op BCVA 6/24p

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times DOS TIMES 38 Treatment options: 1. RGP/Scleral Lens for BEST vision 2. DALK/PK – only surgical corneal transplantation an option Author’s recommendation – Hard Contact Lenses for vision; DALK/PKP if patient not ready to wear CL or CL intolerant Conclusion The above is a summary of the latest in the management of Keratoconus. The case examples illustrated shall help the clinicians in taking appropriate management decisions. References 1. Santodomingo-Rubido J, Carracedo G, Suzaki A, et al. Keratoconus: An updated review. Contact Lens and Anterior Eye 2022; 45930:101559. 2. Krachmer JH, Feder RS, Belin MW: Keratoconus and related noninflamatory disorders. Surv Ophthalmol 1984;28:293. Case 6: (Figure-22) Demography 20 year, female Complaints Very poor vision even with glasses, severe photophobia, night glare, eye pain UCVA FC 1 m BCVA FC 2m Severity of KC Advanced – Thinnest pachy- 302 micron; Kmax – 112.2 3. Rabinowitz YS, Nesburn AB, McDonnell PJ, et al. Videokeratography of the Fellow Eye in Unilateral Keratoconus. Ophthalmology 1993;100(2):181-6. 4. Holland DR, Maeda N, Hannush SB, et al. Unilateral Keratoconis:Incidence and quantitative topographic analysis. Ophthalmology 1997;104:1409-13. 5. Lee LR, Hirst LW, Readshaw G. Clinical detection of unilateral keratoconus. Aus N Z Ophthalmol. 1995;23:129-33. 6. Romero-Jim´enez M, Santodomingo-Rubido J, Gonzalez-M, et al. The thinnest, steepest, and maximum elevation corneal locations in noncontact and contact lens wearers in keratoconus. Cornea 2013;32:332–7. 7. Wang Y, Rabinowitz YS, Rotter JI, Yang H. Genetic epidemiological study of keratoconus: evidence for major gene determination. Am J Med Genet. 2000 Aug 28;93(5):403-9. 8. Gasset AR, Hinson WA, Frias JL. Keratoconus and atopic diseases. Ann Ophthalmol. 1978 Aug;10(8):991-4.

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Clinical performance of toris K contact lens in patients with moderate to advanced keratoconus: A real life retrospective analysis. J Ophthalmol 2016;2358901. 40. Sultan P, Dogan C, Iskeleli G. A retrospective analysis of vision correction and safety in keratoconus patients wearing Toris K soft contact lenses. Int Ophthalmol 2016;36:799–805. 41. Lim L, Lim EWL. Current perspectives in the management of keratoconus with contact lenses. Eye 2020;34:2175–96. 42. Lim N, Vogt U. Characteristics and functional outcomes of 130 patients with keratoconus attending a specialist contact lens clinic. Eye 2002;16:54–9. 43. Saraç ¨O, Kars ME, Temel B, Ça˘gıl N. Clinical evaluation of different types of contact lenses in keratoconus management. Contact Lens Anterior Eye 2019;42: 482–6. 44. De Luis EB, Etxebarria Ecenarro J, Santamaria Carro A, Feijoo LR. Irregular corneas: Improve visual function with scleral contact lenses. Eye Contact Lens 2018;44:159–63. 45. Downie LE, Lindsay RG. Contact lens management of keratoconus. Clin Exp Optom 2015;98:299–311. 46. Lindsay R. Pellucid marginal degeneration. Clin Exp Optom 1993;76:219–21. 47. Ling JJ, Mian SI, Stein JD, Rahman M, Poliskey J, Woodward MA. Impact of scleral contact lens use on the rate of corneal transplantation for keratoconus. Cornea 2021;40:39–42. 48. Koppen C, Kreps EO, Anthonissen L, Van Hoey M, Dhubhghaill SN, Vermeulen L. Scleral lenses reduce the need for corneal transplants in severe keratoconus. Am J Ophthalmol 2018;185:43–7. 49. Segal O, Barkana Y, Hourovitz D, Behrman S, Kamun Y, Avni I, et

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times DOS TIMES 40 al. Scleral contact lenses may help where other modalities fail. Cornea 2003;22:308–10. 50. Rosenthal P, Croteau A. Fluid-ventilated, gas-permeable scleral contact lens is an effective option for managing severe ocular surface disease and many corneal disorders that would otherwise require penetrating keratoplasty. Eye Contact Lens 2005;31:130–4. 51. Sorkin N, Varssano D. Corneal collagen crosslinking: A systematic review. Ophthalmologica 2014;232:10–27. 52. O’Brart DPS. Corneal collagen crosslinking for corneal ectasias: A review. Eur J Ophthalmol 2017;27:253–69. 53. Beckman KA, Gupta PK, Farid M, Berdahl JP, Yeu E, Ayres B, et al. Corneal crosslinking: Current protocols and clinical approach. J Cataract Refract Surg 2019;45:1670–9. 54. Santhiago MR, Randleman JB. The biology of corneal cross-linking. 55. Kanellopoulos AJ. Ten-year outcomes of progressive keratoconus management with the Athens protocol (topography-guided partialrefraction PRK combined with CXL). J Refract Surg 2019;35:478–83. 56. Kanellopoulos AJ, Asimellis G. Keratoconus management: Longterm stability of topography-guided normalization combined with high-fluence CXL stabilization (the Athens Protocol). J Refract Surg 2014;30:88–93. 57. Kankariya VP, Dube AB, Grentzelos MA, Kontadakis GA, Diakonis VF, Petrelli M, et al. Corneal cross-linking (CXL) combined with refractive surgery for the comprehensive management of keratoconus: CXL plus. Indian J Ophthalmol 2020;68:2757–72. 58. Jain, Rajat; Shuaib, Yusra1; Mohan, Neha2; Mittal, Vikas3. Outcomes of topography-guided PRK/CXL in keratoconus using the NIDEK CXIII system—”Bharat Protocol” (Pilot study). Indian Journal of Ophthalmology 71(9):p 3203-3209. 59. Chan CCK, Sharma M, Wachler BSB. Effect of inferior-segment Intacs with and without C3-R on keratoconus. J Cataract Refract Surg 2007;33:75–80. 60. Colin J, Velou S. Implantation of Intacs and a refractive intraocular lens to correct keratoconus. J Cataract Refract Surg 2003;29:832–4. 61. El-Raggal TM, Abdel Fattah AA. Sequential Intacs and Verisyse phakic intraocular lens for refractive improvement in keratoconic eyes. J Cataract Refract Surg 2007; 33:966–70. 62. Pe˜na-García P, Sanz-Díez P, Dur´an-García ML. Keratoconus management guidelines. Int J Keratoconus Ectatic Corneal Dis 2015;4:1–39. 63. Dragnea DC, Birbal RS, Ham L, Dapena I, Oellerich S, van Dijk K, Melles GRJ. Bowman layer transplantation in the treatment of keratoconus. Eye Vis (Lond). 2018 Sep 12;5:24. 64. Mittal V, Rathod D, Sehdev N. Bowman-stromal inlay using an intraocular lens injector for management of keratoconus. J Cataract Refract Surg. 2021 Dec 1;47(12):e49-e55. 65. Mittal V, Jain N, Pandya Y, Chatterjee D. Customized BowmanStromal Inlay: An Attempt to Change the Topography of the Keratoconus Cornea. Cornea. 2023 Jun 1;42(6):739-743. 66. Melles GRJ, Lander F, Rietveld FJR, Remeijer L, Beekhuis WH, Binder PS. A new surgical technique for deep stromal, anterior lamellar keratoplasty. Br J Ophthalmol 1999;83:327–33. 67. Ang M, Mehta JS. Deep anterior lamellar keratoplasty as an alternative to penetrating keratoplasty. Ophthalmology 2011;118:2306–7. 68. Hauk L. Corneal transplantation. AORN J 2018;107:P11–4. 69. Gordon MO, Steger-May K, Szczotka-Flynn L, Riley C, Joslin CE, Weissman BA, et al. Baseline factors predictive of incident penetrating keratoplasty in keratoconus. Am J Ophthalmol 2006;142:923–30. 70. Sabater-Cruz N, Figueras-Roca M, Padr´o-Pitarch L, Tort J, CasaroliMarano RP. Corneal transplantation activity in Catalonia, Spain, from 2011 to 2018: Evolution of indications and surgical techniques. PLoS ONE 2021;16:e0249946. 71. Shetty R, Kaweri L, Pahuja N, Nagaraja H, Wadia K, Jayadev C, Nuijts R, Arora V. Current review and a simplified “five-point management algorithm” for keratoconus. Indian J Ophthalmol. 2015 Jan;63(1):46-53. Dr. Rajat Jain, MS, FICO, FLVPEI Jain Eye Hospital and LASER Centre, AG-152, Shalimar Bagh, Delhi Corresponding Author:

www.dosonline.org/dos-times DOS Times Volume 29, Number 5, September-October 2023 DOS TIMES 41 Extended Resection with Limbal Conjunctival Autograft Versus Conventional Conjunctival Autograft for Recurrent Pterygium Shreesha Kumar Kodavoor, MS, DNB, MNAMS, FGO, Ashalyne James Joseph, DNB, Ramamurthy Dandapani, MD, MNAMS The Eye Foundation, Coimbatore. Introduction A pterygium is an ocular surface fibrovascular, wing shaped encroachment onto the cornea. It is most commonly associated with chronic ultraviolet light exposure.[1,2] Nasal bulbar conjunctiva is the most common site of occurrence of pterygia. Double head pterygia has an incidence of 2.5% in tropical regions, located between 30°N and 30°S of the equator.[3,4] The main histopathological change in pterygium is elastotic degeneration of conjunctival collagen.[5] Conjunctival autograft (CAG) is the gold standard in the management of primary pterygium.[6] The primary long term outcome measure to a successful pterygium surgery is its recurrence. Recurrence rates range widely from 0%[7] to 82%.[8] Recurrent pterygium are usually difficult to manage. The main risk factors for recurrent pterygium include incomplete control of postoperative inflammation, bare sclera resection alone, excessive suturing, incomplete removal of primary pterygium, young age, high morphologic grade of pterygium, heavy vascularisation of primary pterygium and African ethinicity.[9] Recurrence is accelerated by induction of pre-inflammatory cytokines, growth factors, and different molecular biomarkers like excessive levels of stromal cell-derived factor 1, angiogenin, transcription factor Abstract: Aim: To analyse the recurrence rates and complications after extended resection with limbal conjunctival autograft (Group I) versus conventional conjunctival autograft (Group II) in recurrent pterygium cases. Materials and Methods: Retrospective analysis of 536 eyes of 520 patients was done. Extensive excision of the pterygium was done along with 1mm of normal conjunctival tissue all around and tenons was resected 0.5mm beyond the excised conjunctival margins in both groups. In Group I, a large conjunctival autograft with a thin block of limbal tissue in the graft was taken and placed on the bare sclera with limbal orientation. In Group II, conventional conjunctival autograft was taken and placed on the bare sclera. Results: Among the 265 eyes in Group I, 8 eyes (3.02%) had recurrence and among the 271 eyes in Group II, 12 eyes (4.43%) had recurrence. There was no statistically significant difference in the recurrence rates between the two groups. Other complications seen include sub conjunctival haemorrhage, graft edema, graft retraction, granuloma, dellen and graft loss. Conclusion: Extended pterygium resection with limbal conjunctival autograft or with conventional autograft seems to be effective surgical procedures in recurrent pterygium with low recurrence and encouraging results. specificity protein 1, and collagen I.[10,11,12] The histopathological changes include epithelial and stromal inflammation, stromal vascular proliferation, fibrosis and solar elastosis.[13] Recurrent pterygium frequently demonstrate a higher recurrence rate than primary pterygium.[14,15] Thus, there is a tendency to use more aggressive or combined methods for recurrent pterygium.[15,16] Current modalities for managing recurrent pterygia include conjunctival autografting, limbal conjunctival autografting, amniotic membrane grafting, mitomycin C therapy with or without CAG, P.E.R.F.E.C.T technique, Simple limbal epithelial transplantation (SLET), performed separately or in combinations.[17] Extensive resections of the pterygium should be carried out in cases of recurrent pterygium to prevent the second recurrence. Including limbus with the conjunctival autograft helps to prevent recurrence as limbal tissue acts as a barrier to conjunctival growth.[18,19] In this study, we compare the outcomes of extended resection with limbal conjunctival autograft versus extended resection with conventional conjunctival autograft for recurrent pterygium. Materials and Methods The study population was divided into two groups. Group I included a total of 265 eyes of 260 patients with recurrent pterygium who underwent extended resection with limbal

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times DOS TIMES 42 conjunctival autograft. Group II included 271 eyes of 260 patient with recurrent pterygium who underwent extended resection with conjunctival autograft during the period of 2010 to 2021. The study was retrospective in nature. In Group I, 255 patients had unilateral recurrent pterygium and 5 patients had bilateral recurrent pterygium. The follow up period ranged from 6-142 months with an average follow up of 18 months. Out of 265 eyes, 221 eyes had recurrence for the first time, 38 eyes had recurrence for the second time and 6 eyes had recurrence for the third time. The male:female ratio was 105:155. In Group II, 249 patients had unilateral recurrent pterygium and 11 patients had bilateral recurrent pterygium. The follow up period ranged from 6-139 months with an average follow up of 19.5 months. Out of 271 eyes, 232 eyes had recurrence for the first time, 34 eyes had recurrence for the second time and 5 eyes had recurrence for the third time. The male:female ratio was 112:148. All surgeries were performed by one surgeon at a tertiary eye care hospital in South India. Data retrieved from EMR (Electronic Medical Records) included patient’s age, sex, ocular medical and surgical history, visual acuity before and after surgery, surgical technique and complications. Slit lamp examination was done before the surgery and the extent of pterygium was noted and were graded [Grade 1: Normal appearance of the operated area; Grade 2: Presence of episcleral vessels in the excised area extending to the limbus, without any fibrous tissue; Grade 3: Fibrovascular tissue in the excised area reaching the limbus, not the cornea (conjunctival recurrence), Grade 4: True corneal recurrence with fibrovascular tissue on the cornea].[20] Patients with Grade 4 recurrent pterygium with true corneal recurrence were taken up for surgery. The superior conjunctiva was examined for scarring and fibrosis before the procedure. The study protocol adhered to the tenets of the Declaration of Helsinki. This study was approved by the Institutional Ethics Committee. Surgical Procedure All the surgeries were performed under topical anaesthesia (using topical 0.5% proparacaine) and infiltrative anaesthesia (using 1 cc of 2% xylocaine) was given subconjunctivally. Both blunt and sharp dissection was carried out to detach the pterygium from its corneal attachment. An extensive excision of the pterygium was done along with 1mm of normal conjunctival tissue all around (Figure-1a). 0.5mm of the tenons was resected beyond the excised conjunctival margins (Figure-1b). Corneal surface was smoothened with a crescent blade. Superotemporal conjunctival dissection was done. In Group I, limbal stem cells were included in the graft. On reaching the limbus a thin block of corneal tissue, about 0.5mm onto the cornea and approximately 100µ thickness was dissected using a crescent blade and was included in the autograft (Figure-1c). Conjunctival autograft with limbal stem cells (Figure-1e), was placed on the bare sclera with proper orientation (limbal end towards the cornea), and was fixed with fibrin glue (Tisseel, Baxter, Vienna, Austria) (Figure-1f). In Group II,conventional conjunctival autografting was done (Figure-2). Limbal stem cells were not included in the graft. No intraoperative complications were noted. Post-operatively all the patients were started on steroids (0.5% Loteprednol) 6 times a day for 4 weeks, followed by 2 times a day for 1 week and 1 time a day for 1 week, topical antibiotics (0.5% Moxifloxacin) 4 times a day for 2 weeks and preservative free tear substitutes (0.5% Carboxy methyl cellulose) for 6 weeks. Recurrence, graft edema, graft retraction, graft loss and other complications were looked for in each follow up. Recurrence was the main outcome looked for. It can be defined as a fibrovascular tissue growth of 1.5mm or more beyond the limbus onto the clear cornea with conjunctival dragging.[21] Figure 1: Extended resection with limbal conjunctival autograft (a) Extended excision of the recurrent pterygium with 1 mm of normal conjunctival tissue. (b) Resection of the tenons 0.5 mm beyond the conjunctival margins. (c) Dissection of the thin block of corneal tissue (d) Resection of the limbal conjunctival autograft. (e) Instillation of the fibrin glue over the bare sclera. (f) Placement of limbal autograft over the bare sclera with orientation of the limbal cells towards the cornea. Figure 2: Extended resection with conventional conjunctival autograft (a,b) Resection of the conventional conjunctival autograft. (c) Instillation of the fibrin glue over the bare sclera. (d) Placement of conventional autograft over the bare sclera.

www.dosonline.org/dos-times DOS Times Volume 29, Number 5, September-October 2023 DOS TIMES 43 Results A total of 536 eyes was included in the study. 265 eyes were included in Group I and 271 eyes were included in Group II. All the patient were followed up for a minimum of 6 months with an average follow up of 18 months in Group I and 19.5 months in Group II. In Group I, immediate complications like sub-conjunctival hemorrhage (Figure-3c) were seen in 152 eyes (57.35%), graft edema in 162 eyes (61.13%) and retraction of the graft (Figure-3b) was seen in 54 eyes (20.38%). Graft loss was seen in 7 eyes of which 6 had recurrence later. Recurrence (Figure-3h) occurred in a total of 8 eyes (3.02%), out of which 2 eyes had one recurrence earlier, 4 eyes had two recurrences earlier and 2 eyes had three recurrence earlier. The earliest recurrence occurred at 3 months postoperatively. Donor site complications like granuloma (Figure-3d) were seen in 5 (1.89%) eyes and 2 eyes (0.75%) had vascularization. Granuloma was also seen in the host area (Figure-3f) in 4 eyes. Severe corneal scarring occurred in 4 eyes. Dellen was noticed in 3 eyes and 1 patient developed corneal infiltrates. In Group II, immediate complications like sub-conjunctival hemmorhage were seen in 144 eyes (53.14%), graft edema Figure 3: Post-operative complications (a) Cyst. (b) Retraction of the graft. (c) Subconjunctival haemorrhage. (d) Granuloma at donor site. (e) Granuloma at graft-host junction. (f) Granuloma at the graft site. (g) Conjunctival recurrence. (h) Recurrent pterygium extending on to cornea. (i) Corneal scar. in 148 eyes (54.61%) and retraction of the graft was seen in 59 eyes (21.77%). Graft loss was seen in 6 eyes, all (100%) of

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times DOS TIMES 44 Discussion Recurrent pterygia have an aggressive growth pattern. It can cause significant conjunctival inflammation, symblepharon, corneal scarring and limbal stem cell deficiency. They have a high risk of failure and recurrence. The main aim is to reduce the recurrence and the procedure should have barrier effect and should prevent conjunctivalisation of cornea. Methods that are followed for recurrent pterygium include pterygium excision with conjunctival autograft/limbal conjunctival autograft[22], conjunctival autografting with SLET, pterygium excision with amniotic membrane graft with SLET, pterygium excision with mitomycin C[23] and also the P.E.R.F.E.C.T[24] (Pterygium Extended Removal Followed by Extended Conjunctival Transplant) technique. In our study the recurrence rate was 3.02% in Group I compared to 4.43 % in Group II. The recurrence rate was slightly lower in Group I, but there was not statistically significant difference between the two groups. Table 1: List of postoperative complications. which developed recurrence later. Recurrence occurred in a total of 12 eyes (4.43%), out of which 4 eyes had one recurrence earlier, 5 eyes had two recurrences earlier and 3 eyes had three recurrences before. The earliest recurrence occurred at 2 months postoperatively. Donor site complications like granuloma were seen in 3 eyes and 3 eyes had vascularisation. Granuloma was seen in the host area in 4 eyes. Severe corneal scarring occurred in 4 eyes. Dellen was noticed in 3 eyes and 1 patient developed corneal infiltrates. The reasons for graft loss in the two groups include undersized grafts, graft retraction and eye rubbing. Table 1 shows a comparison of the complications between the two groups. Statistical analysis was done using Fisher exact test. p value < 0.05 was considered statistically significant. No statistically significant difference was noted between any complication of Group I compared to that of Group II. Complication GROUP I Extended conjunctival resection + limbal conjunctival autograft group (n=265) GROUP II Extended conjunctival resection + conjunctival autograft group (n=271) P Value Recurrence 8 (3.02%) 12 (4.43%) 0.4957 Sub conjunctival haemorrhage 152 (57.36%) 144 (53.14%) 0.3402 Graft edema 162 (61.13%) 148 (54.61%) 0.1373 Graft retraction 54 (20.38%) 59 (21.77%) 0.7509 Graft-host junction granuloma 4 (1.51%) 4 (1.48%) >0.999 Donor site granuloma 5 (1.89%) 3 (1.11%) 0.5001 Dellen 3 (1.13%) 3 (1.11%) >0.999 Graft loss/Graft loss with Recurrence 7/6 (85.71%) 6/6(100%) >0.999 In the P.E.R.F.E.C.T technique, the pterygium excision was done with extensive removal of conjunctiva. However, this is associated with problems like pain, injury to medial rectus, which can lead to diplopia. It is also very time consuming. In our study, the extended conjunctival resection was only about 1mm behind the pterygium margins. Tenons was also resected 0.5mm behind and beyond the conjunctival margins. Too extensive conjunctival resection was avoided. This helps to avoid complications associated with P.E.R.F.E.C.T technique like pain, discomfort and diplopia. The recurrence noted with P.E.R.F.E.C.T claims to be zero[24], compared to 3.02% in the Group I and 4.43% in the Group II. The limbal epithelium is thought to function as a barrier. It helps to prevent epithelium growth of conjunctiva over cornea.[19] Previous studies have showed that usage of a conventional conjunctival autograft has higher recurrence rates compared to limbal conjunctival autograft. However, the recurrence rates were similar in the two groups in our study and there was no statistically significant difference between the

www.dosonline.org/dos-times DOS Times Volume 29, Number 5, September-October 2023 DOS TIMES 45 two groups. A study by Mashfoor et al[25] showed that Limbal conjunctival autograft (0.95% recurrence rate) was more effective than conventional conjunctival autografting (10% recurrence rate). A study by Jun Shimazaki[26] et al showed lesser recurrence rates in amniotic membrane transplantation combined with The total recurrence rate in our study was 3.73%; 3.02% in Group I and 4.43% in the Group II, which are considerably less recurrence rates in the tropical areas. We have recruited a total of 536 eyes, 265 eyes in Group I and 271 eyes in Group II, which is a large sample size compared to other previous reports on surgical management of recurrent pterygium. The results we got from this study prove that the combination of extended resection with limbal conjunctival autograft or conventional conjunctival autograft are both effective methods in the management of recurrent pterygium. The limitation of this study is that it is a retrospective study. The main advantage of this study is its large sample size, longer follow up and its comparative nature. This study, to the best of our knowledge, is one of the largest study that compared the efficacy of limbal conjunctival autograft with conventional conjunctival autografting for patients with recurrent pterygia. limbal conjunctival autograft (8.3%) than with conventional conjunctival autograft (20%). A study by Gris et al[27] showed no recurrence with limbal conjunctival autografting technique. Comparison of the outcomes of other procedures with that of our study is been illustrated in table 2. Conclusion The management of recurrent pterygia is always difficult. Extended resection with limbal conjunctival autograft and with conventional conjunctival autograft were studied. Both these methods had low and comparable recurrence rates and are therefore effective in the surgical management of recurrent pterygium. Both these methods are safe and have good results. However, a prospective study with longer durations of follow up, would give us a better idea about the efficacy of the methods. References 1. Dushku N, Reid TW. Immunohistochemical evidence that human pterygia originate from an invasion of vimentin expressing altered limbal epithelial basal cells. Curr Eye Res 1994;13:473 81. 2. Kwok LS, Coroneo MT. A model for pterygium formation. Cornea 1994;13:219 24. Author Type of Surgery No. of Eyes Follow Up (Mean) Recurrence Our study Extended resection with Limbal CAG 265 18 Months 8 (3.02%) Extended resection with CAG 271 19.5 Months 12 (4.43%) Mashfoor et al[25] Limbal CAG 105 62 months 1 (0.95%) Free CAG 100 10 (10%) Gris et al[27] Limbal CAG 7 19 months 0 (%) Mutlu et al[28] Limbal CAG 41 16 months 6 (14.6%) Lawrence W.Hirst et al[24] P.E.R.F.E.C.T 111 18 months 6 (2.7%) Raneen et al[29] CAG + Intraoperative MMC 28 26.5 months 1 (3.57%) Kenyon et al[30] CAG 41 24 months 3 (7.3%) Jun Shimazaki et al[13] Amniotic membrane transplantation with Limbal CAG 15 67 weeks 3 (20%) Amniotic membrane transplantation with CAG 12 1 (8.3%) Table 2: Comparison of our study with other studies on surgical management of recurrent pterygium.

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times DOS TIMES 46 3. Cameron ME. Pterygium Throughout the World. Springfield, Ill, USA: Charles C Thomas; 1965. 4. Dolezalová V. Is the occurrence of a temporal pterygium really so rare? Ophthalmologica 1977;174:88 91. 5. Spencer WH. Ophthalmic Pathology: An Atlas and Textbook. 3rd ed., Vol. 1. Philadelphia: W.B. Saunders; 1985. p. 174 6. 6. Toker E, Eraslan M. Recurrence after primary pterygium excision: Amniotic membrane transplantation with fibrin glue versus conjunctival autograft with fibrin glue. Curr Eye Res 2015;41:18. 7. Al Fayez MF. Limbal versus conjunctival autograft transplantation for advanced and recurrent pterygium. Ophthalmology 2002;109:1752– 5. 8. Tan DT, Chee SP, Dear KB, Lim AS. Effect of pterygium morphology on pterygium recurrence in a controlled trial comparing conjunctival autografting with bare sclera excision. Arch Ophthalmol 1997;115:1235–40. 9. Ghiasian L, Samavat B, Hadi Y, Arbab M, Abolfathzadeh N. Recurrent pterygium: A review. Journal of Current Ophthalmology. 2021 Oct;33(4):367. 10. Nuzzi R, Tridico F. How to minimize pterygium recurrence rates: Clinical perspectives. Clin Ophthalmol. 2018;12:2347–62. 11. Kim KW, Park SH, Kim JC. Fibroblast biology in pterygia. Exp Eye Res. 2016;142:32–9. 12. Shi CS, Wu Y, Shu N, Jiang LL, Jiang B. Expression and role of specificity protein 1 and collagen I in recurrent pterygial tissues. Int J Ophthalmol. 2021;14:223–7. 13. Nassar MK, El-Sebaey AR, Abdel-Rahman MH, El-Ghonemy K, Shebl AM. Clinical, pathological, and molecular aspects of recurrent versus primary pterygium. Menoufia Medical Journal. 2014 Apr 1;27(2):386. 14. Hirst LW. The treatment of pterygium. Surv Ophthalmol 2003;48(2):145–180. 15. Kodavoor SK, Preethi V, Dandapani R. Profile of complications in pterygium surgery-A retrospective analysis. Indian Journal of Ophthalmology. 2021 Jul;69(7):1697. 16. Segev F, Jaeger-Roshu S, Gefen-Carmi N, Assia EI. Combined mitomycin C application and free flap conjunctival autograft in pterygium surgery. Cornea 2003;22(7):598–603. 17. Lam DS, Wong AK, Fan DS, Chew S, Kwok PS, Tso MO. Intraoperative mitomycin C to prevent recurrence of pterygium after excision: a 30-month follow-up study. Ophthalmology 1998;105(5):901–905. 18. Tseng SCG, Chen JJY, Huang AJW, et al. Classification of conjunctival surgeries for corneal diseases based on stem cell concept. Ophthalmology Clinics of North America 1990; 3: 595–610. 19. Shreesha Kumar Kodavoor, Preethi Venkatesh, Ramamurthy Dandapani, Gitansha Shreyas Sachdev. Recurrent Pterygium Excision with Extended Resection and Limbal Conjunctival Autograft - Our Results. International Journal of Ophthalmology & Visual Science. Vol. 6, No. 2, 2021, pp. 67-71. doi: 10.11648/j.ijovs.20210602.11. 20. Prabhasawat P, Barton K, Burkett G, et al. Comparison of conjunctival autografts, amniotic membrane grafts, and primary closure for pterygium exicision. Ophthalmology 1997; 104: 974-985. 21. Singh G, Wilson MR, Foster CS. Long term follow up study of mitomycin eye drops as adjunctive treatment of pterygia and its comparison with conjunctival autograft transplantation. Cornea 1990;9: 331 4. 22. Anduze AL. Conjunctival flaps for pterygium surgery. Annals of Ophthalmology. 2006 Sep; 38 (3): 219-23. 23. Fakhry MA. The use of mitomycin C with autologous limbalconjunctival autograft transplantation for management of recurrent pterygium. Clinical Ophthalmology (Auckland, NZ). 2011; 5: 123. 24. Hirst LW. Prospective study of primary pterygium surgery using pterygium extended removal followed by extended conjunctival transplantation. Ophthalmology 2008; 115: 1663–72. 25. Al Fayez MF. Limbal-conjunctival vs conjunctival autograft transplant for recurrent pterygia: a prospective randomized controlled trial. JAMA ophthalmology. 2013 Jan 1;131(1):11-6. 26. Shimazaki J, Kosaka K, Shimmura S, Tsubota K. Amniotic membrane transplantation with conjunctival autograft for recurrent pterygium. Ophthalmology. 2003 Jan 1; 110 (1): 119-24. 27. Gris O, Guell JL, del Campo Z: Limbal-conjunctival autograft transplantation for the treatment of recurrent pterygium. Ophthalmology 2000, 107:270– 273. 28. Mutlu FM, Sobaci G, Tatar T: A comparative study of recurrent pterygium surgery: limbal conjunctival autograft transplantation versus mitomycin C with conjunctival flap. Ophthalmology 1999, 106:817–821. 29. Management of Recurrent Pterygium With Intraoperative Mitomycin C and Conjunctival Autograft With Fibrin Glue. Raneen Shehadeh Mashor Sathish Srinivasan Corey Boimer Kenneth Lee Oren Tomkins Allan R. Slomovic. 30. Kenyon KR, Wagoner MD, Hettinger ME. Conjunctival autograft transplantation for advanced and recurrent pterygium. Ophthalmology. 1985 Nov 1; 92 (11): 1461-70. Dr. Shreesha Kumar Kodavoor, MS, DNB, MNAMS, FGO Head of the Department, Cornea services, The Eye foundation, Coimbatore. Corresponding Author:

www.dosonline.org/dos-times DOS Times Volume 29, Number 5, September-October 2023 DOS TIMES 47 Topical Insulin: The Emerging Game Changer in Ocular Surface Diseases (OSD) Avani Hariani, MS, DNB, FICO, Parul Jain, MS, Isha Gupta, MS, Gahan Reddy, MBBS Department of Ophthalmology, Guru Nanak Eye Center, MAMC, Delhi. Abstract: OSDs contribute to a major portion in an ophthalmologist’s clinic. Meticulous choice of investigations and treatment is a skill very few have mastered. The treatment options available are extensive, and many a times overwhelming to an ophthalmologist. Role of Topical Insulin in the eye has been widely researched in animals and its role in OSDs established. However, there is a paucity of human trials. After reviewing the recent advances, it appears that Topical Insulin will be the game changer in OSDs. We present a brief review of the work reported involving the use of Topical Insulin in OSDs. Keywords: Topical Insulin, Ocular surface disorders, PED, neurotrophic keratitis, diabetic keratopathy. Spectrum of Ocular Surface Disorders (OSD) The ocular surface comprises the cornea, conjunctiva, eyelids and lacrimal glands and the nerves supplying the ocular surface. The spectrum of ocular surface disorders is vast and comprises of Dry eyes and related disorders, blepharitis, meibomian gland dysfunction, lid margin abnormalities, epitheliopathies like, recurrent corneal erosions, persistent epithelial defects, neurotrophic keratopathy, limbal stem cell diseases, surface abnormalities associated with systemic diseases like diabetic keratopathy, Sjogren’s syndrome, oculocutaneous syndrome and so on. Patients suffer from persistent symptoms like visual disturbance, blurred vision, ocular discomfort, burning, foreign body sensation, photophobia which affect the physical as well as the mental quality of life (QoL).[1] Existing Therapies Management of OSDs includes a comprehensive and thorough evaluation of the lids, tear film, cornea, conjunctiva and the patient as a whole. Treatment therapies include preservative free lubrication, withdrawal of inciting factor (medication/ lid margin abnormalities), topical immunomodulators/antiinflammatory, punctal plugs, punctal inserts, bandage contact lenses, tarsorrhaphy, amniotic membrane grafts.[2] Autologous blood serum and other growth factors like recombinant human nerve growth factor (rhNGF) cenegermine have been tried. In a quest to come up with newer non-invasive, safe, easily available, cost-effective alternative to the above treatment modalities, numerous scientific researches have been done. Insulin and its Role in Eye Disease Insulin, a potent anabolic hormone has been a favourite topic for researchers due to its wound healing, anti-inflammatory and nerve regeneration properties. The growth-promoting effects of insulin appear to occur through activation of receptors for the family of related insulin-like growth factors (IGFs) IGFs have been postulated to be involved in the complex process of maintaining the ocular milieu and help in wound healing by regulating the differentiation, migration and growth of stromal keratocytes and epithelial cells.[3] Insulin is closely related to IGFs and was first demonstrated in the tear film by Rocha et al.[4] The role of topical insulin in strengthening wounds has been studied in decubitus ulcers and experimentally induced superficial skin wounds.[5] Topical Insulin in OSDs The very first study in ophthalmology in humans was done by Aynsley et al.[6] they presented 5 cases where insulin helped epithelize corneal ulcers unresponsive to treatment. This triggered a chain reaction into understanding this hormone better and utilizing it to tackle the disease based on the pathogenesis involved. We present a brief review of the recent advances in this field, so that as ophthalmologists we and our patients can benefit from the various properties of this magic molecule. Dry Eyes Disease (DED) DED is a multifactorial disorder as described by TFOS DEWS II.[7] In the ocular surface, local hyperglycemia causes the increased formation of advanced glycation end products and oxidative stress-mediated tissue damage.[8] Role of Insulin: In a study conducted in animals topical insulin preparations were demonstrated to improve the tear volume and corneal epithelial cell architecture studied on impression cytology.[9] Studies conducted on human meibomian gland epithelial cells (HMGEC), found that insulin causes a dose dependent increase in phosphatidylinositide 3-kinase/Akt (AKT) signaling in these cells which is associated with a stimulation of cell proliferation and neutral lipid accumulation.[10] Dias et al.[11] conducted a study on lacrimal gland acinar cells and found that topical

DOS Times Volume 29, Number 5, September-October 2023 www.dosonline.org/dos-times DOS TIMES 48 insulin therapy in dry eyes restores the secretory vesicle density and Rab 27b and syntaxin expression. Neurotrophic Corneal Ulcer Neurotrophic keratopathy is a condition which causes a reduction in corneal sensitivity due to abnormality in the neural innervation. If not managed promptly it may lead to persistent corneal epidefects, ulceration, and perforation. Role of Insulin: In terms of mechanism, IGF1 may play a role in neurotrophic keratopathy by promoting corneal epithelial cell migration, corneal limbal stem cell differentiation into epithelial like cells, and corneal nerve regeneration by increasing synaptogenesis.[12] Studies in diabetic mice with topical insulin has been shown to slow the loss of sub basal plexus of corneal nerves.[13] Wang et al.[14] published 6 case reports of complicated refractory neurotrophic ulcers refractory to the conventional treatment which were managed with topical insulin. In a study by Soares et al.[15] 90% of eyes affected by stage 2 and 3 of refractory neurotrophic keratopathy benefitted from using insulin drops. Diabetic Keratopathy Diabetic keratopathy has been estimated to occur in 47%-64% of diabetic patients. These patients are at a risk of developing epithelial fragility, decreased sensitivity, abnormal wound healing and corneal ulceration.[16] The causative factor include chronic hyperglycemia, corneal nerve damage and impairment on insulin action.[17] The anti-inflammatory neural feedback is damaged due to progressive peripheral nerve damage which interrupts the afferent and efferent neural signalling.[18] Role of Insulin: Insulin exerts metabolic and mitogenic effects on target tissues through the mediation of gene expression and protein synthesis.[19] Various animal studies have reported that topical insulin promotes re-epithelialization and improved corneal sensitivity in diabetic rats with keratopathy.[13] In humans, Topical insulin (1U/ml) has shown to improve the rate of epithelial healing in diabetic patients undergoing epithelial debridement to improve the view during VR surgeries.[20] To assess effects of topical insulin on the symptoms and signs of diabetics with dry eye disease, Azmi et al.[21] conducted a study with 160 participants (320 eyes) who showed a significant improvement in the OSDI score. Persistent Epithelial Defects (PEDs) In a healthy cornea, an acute epithelial defect heals within 1- 2 weeks. PED on the other hand do not show any improvement after two weeks of conventional medical treatment.[22] Etiologies include neurotrophic keratitis, chemical or thermal burns, neuroparalytic, diabetes mellitus, immune mediated, post corneal transplants. Role of Insulin: IGFs have been postulated to be involved in this complex process of corneal wound healing. The combination of substance P and IGF-1 upregulates expression of the integrin α5 chain5,6 and induces the phosphorylation of paxillin, which is required for the rearrangement of actin filaments associated with cell migration in corneal epithelial cells.[23] Diaz-Valle et al.[24] in a prospective interventional study in 21 patients with PEDs treated with topical insulin (1U/ml) reported that there was a significant decrease in the size of the PED and 81% of the patients had complete re epithelisation in 7-114 days. The same group compared Topical Insulin to the rate of epithelial healing in PED patients with autologous serum eye drops and concluded that topical insulin had better epithelization outcomes and could thus be considered as a first-line treatment.[25] Limbal Stem Cell Deficiency (LSCD) Chemical injuries cause extensive damage to the ocular surface. Immediate therapy is directed toward prompt irrigation and removal of any remaining chemical contact with the eye. Initial medical therapy is directed toward promoting reepithelialization, increasing keratocyte collagen production, minimizing collagenase activity, and controlling inflammation. Role of Insulin: Insulin secreted by the lacrimal glands has shown to promote corneal epithelial cell migration and proliferation in various studies. It directly modulates inflammatory mediators and acts upon immune cells to enhance immunocompetence.[26] Studies conducted on human aortic endothelial cells have shown that topical insulin suppressed three important inflammatory mediators: intercellular cell adhesion molecular-1 (ICAM-1), MCP-1 expression, NFκB binding and inhibition of TNF-α induction locally.[27] Not many studies have been done to assess the role of insulin in chemical injuries with LSCD. Balal et al.[28] used Topical insulin to treat 5 patients PEDs due to chemical injuries and reported a successful resolution of PED. Safety Insulin has been tried and tested on humans since aeons. Insulin in the form of topical eye has not been FDA approved. Many studies have reported the safety of topical insulin both on local ocular structures and on systemic status of an individual. A prospective RCT[29] was conducted in 80 volunteers in which subjects were given 100 U/ml crystalline porcine insulin randomized to one eye and placebo (sterile saline) to the fellow eye. Subjective ocular irritation, visual acuity, objective assessment of the eyelids, conjunctiva, cornea, anterior chamber, crystalline lens, pupil size, and intraocular pressure were evaluated and no statistically significant difference (p > 0.05) observed between insulin-treated and placebo-treated eyes. The same group conducted a study to evaluate the systemic absorption of Insulin.[30] Subjects were evaluated for 2 hours following administration of a single dose of topical insulin. No systemic absorption of insulin was observed, blood glucose levels and serum immunoreactive insulin levels were unchanged. The results of this study suggest that single-dose insulin in concentrations up to 100 U/ml formulated in saline has no detectable clinical toxicity to the anterior structures of the human eye and no systemic side-effects. Conclusion OSDs involve a game-play between various factors both at the