Delhi Journal of Ophthalmology Editorial Board Editor-in-Chief Kirti Singh Official Journal of Delhi Ophthalmological Society Volume 33 Number 1 January-March, 2023 DJO Associate Editors Annu Joon Devesh Kumawat Divya Jain Mainak Bhattacharyya Arshi Singh Khushboo Chawla Priya Saraf Shweta Viswanath Assistant Editors Akanksha Ankita Bhardwaj Anjali Mehta Bhupesh Charu Khurana Deepanjali Arya Himshika Aggarwal Gunjan Budhiraja Jatinder Bali Jatinder Bhalla Jigyasa Sahu Manisha Agarwal Neha Chawla Neha Rathi Nisha Choudhary Palak Gupta Pooja Bansal Priyadarshi Gupta Priyanka Golhait Prachi Dave Rahul Mayor Rajat Jain Ritu Aurora Shipra Sharda Shruti Bhattacharya Siddharth Baindur Suma Ganesh Sumit Grover Siddharth Madan Tanvi Gaonkar V.Krishna Vaibhav Khanna Vaibhav Nagpal Vineet Sehgal Section Editors Arun Nrayanswami Bhavna Chawla George L. Spaeth Milind Pandeya Sonal Dangda Satish Kotta M. Vanathi Rajesh Sinha Ruchi Goel Vinod Kumar International & Emeritus Editor A. K. Grover Atul Kumar Bithi Chowdhary Deepak Verma Jolly Rohtagi J.S.Titiyal N.P. Singh Mahipal S. Sachdev M.D. Singh M. Vanathi Namrata Sharma Pawan Goyal Pradeep Sharma Praveen Vashisht Rakesh Bhardwaj Ramanjeet Sihota Ritu Arora Rajender Khanna Sarita Beri Suneeta Dubey S.C. Dadeya Advisory Board Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 i
Contents Editorial Salute to Giants Who Took Ophthalmology to Terra Incognita ..............................................................1 Kirti Singh Guest Editorial Innovations and Indigenization in Ophthalmology – My Contribution ...................................................3 S. C. Gupta Review Articles Artificial Intelligence: A Review of Objective Grading and Quantification of Posterior Capsular Opacification.............................................................................................................................. 9 Saurabh Kushwaha, Rajat Chaudhary, Uma Devi The Role of Pedigree Charting and Analysis in Ophthalmology ............................................................18 Ria Ratna, Shailja Tibrewal Original Articles Analysis of Retinal Nerve Fiber Layer Thickness in Glaucoma Suspects and Glaucoma by Spectral Domain Optical Coherence Tomography and its Correlation with Visual Field Parameters ..................................................................................................................25 Samruddhi N. Chanekar, Ugam P. S. Usgaonkar, Shekhar O. Akarkar Changes in Tear Film after Phacoemulsification and Manual Small Incision Cataract Surgery in Tertiary Care Hospital: A Prospective Study ......................................................................... 31 Shruti Shirwadkar, Chhaya Shinde, Rahul Waghmare, Amol Ganvir, Abhilasha Yadav, Sanyukta Joshi, Monisha Apte NIST: Needle Incision Sub‑Tenon’s Anesthesia........................................................................................36 Megha Nair, Shivraj Tagare, Rengaraj Venkatesh, Vellam Ramakrishnan Vivekanandan Case Reports Managing Extramacular Circumscribed Choroidal Hemangioma with Green Laser and Anti‑Vascular Endothelial Growth Factor Injection in Times of the Unavailability of Photodynamic Therapy 39 Dhaivat Shah, Deepanshu Agrawal, Maradula Gangawar, Amit C. Porwal, Rini Sukhwal Recurrent Hyphema after Cataract Surgery: A Diagnostic Dilemma.....................................................42 Aakanksha Sharma, Kritika Katoch, Pankaj Sharma Complex Microphthalmia due to a Homozygous Novel Variant in SIX Homeobox 6 Gene...................45 Mayank Nilay, Amita Moirangthem Pictorial CME Multimodal Imaging in Rare Case of Bilateral Macular Coloboma........................................................50 Shivangi Singh, Shivraj Tagare Photo Essay Cutting‑Edge Care: Innovative Approaches to Cataract Surgery Counseling ........................................53 Akshay Wagh, Shivraj Tagare, Swati Upadhaya, Rengaraj Venkatesh Photo Snippet on Complications following Pterygium Surgery ............................................................55 Josephine S. Christy, Megha Nair ii Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023
Omnibus Humans Omnibus Humanus ..................................................................................................................................58 V. S. Gurunadh Theme Sections Kitchen Ophthalmic Surgeon: Polishing Surgical Skills at Home.......................................................... 60 John Davis Akkara, Anju Kuriakose Calculating the Power of Toric Intraocular Lens using Total Corneal Astigmatism Measured by a Swept‑Source Optical Coherence Tomography‑Based Device: An Observation which Changed our Practice Pattern .................................................................................65 Sanjay Chaudhary, Alka Pandey, Anju Sharma, Rahil Chaudhary, Hema Mehra, Nishtha Khurana, Divya Vermani, Ritu Nagpal Frequency Based Phacoemulsification, and Calibrated Phacoemulsification Probe Tip: A Journey of Innovations ........................................................................................................................70 Taru Dewan Micropulse Laser Transscleral Cyclophotocoagulation (MP‑TSCPC) for Glaucoma Management: An Overview.....................................................................................................................73 Vineet Sehgal Clustered Regularly Interspersed Short Palindromic Repeats Gene Editing: Precision Medicine and Newer Therapies for Retinal Dystrophies........................................................................76 Mayank Bansal Cover Image Central picture has been taken by Kirti Singh People pics are from wikipedia 1. HERMANN LUDWIG FERDINAND VON HELMHOLTZ: 1821-1894, German scientist and philosopher, who made ground-breaking contributions to physiology, optics, electrodynamics, mathematics, and meteorology. 2. ALLVAR GULLSTRAND: 1862-1930, Swedish Ophthalmologist, recipient of the 1911 Nobel Prize for Physiology or Medicine for his research on the eye as a light-refracting apparatus. devised the Gullstrand slit lamp, a valuable diagnostic tool that facilitates detailed study of the eye. 3. ALBRECHT VON GRAEFE: 1828–1870, German Ophthalmologist, is the founder of modern ophthalmology. he made significant contributions to the field of ophthalmology including; describing sudden visual loss due to retinal artery embolism; optic retinitis; iridectomy in angle closure, normal tension glaucoma & Von Graefe knife 4. HANS GOLDMAN: 1899-1991, Swiss ophthalmologist. Goldmann’s major contribution to ophthalmology was in the development and refinement of instruments, including the slit lamp, Goldmann’s perimeter, Goldmann’s tonometer, Goldmann’s indirect gonio lens, Goldmann-Weekers Dark Adaptometer, fluorophotometer. 5. DOUGLAS MORAY COOPER LAMB ARGYLL ROBERTSON:1837–1909, Scottish surgeon and ophthalmologist, famous for noting the association of an intact accommodation reflex with absent light reflex in certain spinal disease, later attributed to tertiary syphilis Argyll Robertson pupils 6. GERHARD RUDOLF EDMUND MEYER-SCHWICKERATH: 1920-1992, German Ophthalmologist and researcher. His work has had an immeasurable impact on ophthalmology, however, the highlight of Dr. Meyer-Schwickerath’s pioneering work can be attributed to his experiments on light coagulation, as these principles continue to be key aspects of modern phototherapy. 7. PERCY LAVON JULIAN:1899-1975, American research chemist, was the first to synthesize the natural product physostigmine and a pioneer in the industrial large-scale chemical synthesis of the human hormones progesterone and testosterone from plant sterols such as stigmasterol and sitosterol. Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 iii
DOS Executive Members 2022-2023 Dr. Subhash C. Dadeya DOS Office Bearers Executive Members DOS Representative to AIOS Ex-Officio Members Dr. Pawan Goyal Dr. Rohit Saxena Vice President Dr. Rajendra Prasad President Dr. Jitender Singh Bhalla Secretary Dr. Sandhya Makhija Joint Secretary Dr.Alkesh Chaudhary Treasurer Dr. Kirti Singh Editor Dr. Jitender Bali Library Officer Dr. J.S. Titiyal Dr. M. Vanathi Dr. Namrata Sharma Dr. O. P. Anand Dr. Gagan Bhatia Dr. Vivek Gupta Dr. Vivek Kumar Jain Dr. Prafulla Maharanaa Dr. Amar Pujari Dr. Bhupesh Singh Dr. Pankaj Varshney iv Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023
Editorial “Eyes are the windows of the soul,” the quote ascribed to the biblical verse of “The lamp of the body is the eye. If therefore your eye is good, your whole body will be full of light (Matthew 6) reflects the deep belief of arcane secrets hidden inside the eye. Seekers, who nourished their zeal to visualize the secrets in the interiors of the eye, are the ones on whose shoulders rest the various innovations that helped evolve ophthalmology. The phenomenal growth of ophthalmology over the past century to emerge as a precise, efficient science for restoring quality vision has been due to these efforts. What separated the innovators among the seekers was, perhaps, the traits like keen observation coupled with a razor-sharp mind uncluttered by dogmas, extensive reading, and perseverance in the face of all odds, with deafness to the words such as give up, accept, and follow the status quo. Let me qualify my statement by recalling the ground-breaking work of some oft-sung heroes. Thomas Young read the manuscript of Leonardo da Vinci’s 16th-century drawing of glass shells filled with water neutralizing eye power. A high myope himself, he innovated to devise the first homemade contact lens based on this drawing, three centuries later. Hermann von Helmholtz studied the published works of Purkinje and von Brucke on light rays reflected from the retina. He, then, built on Charles Babbage’s basic contraption to devise the first‑ever direct ophthalmoscope in 1851, which he aptly named the eye mirror (Augenspiegel). Albrecht von Graefe put this tool to immediate use to demystify many diseases by visualizing optic disc excavation in glaucoma, central artery occlusion, and papilledema in the next few years when most physicians hesitated to use it. His von Graefe knife was a masterly tool, which simplified cataract surgery. Building on the optical principles of von Helmholtz, the mathematics genius, Allvar Gullstrand, calculated the pathway of light rays and image creation to become the first ophthalmologist to win the Nobel Prize in 1911. He then went on to expand his discovery to devise the most essential tool of ophthalmology, the “slit lamp” in collaboration with Carl Zeiss. For this visualization of the eye, he was given the title of “a gentleman with the lamp.” The physiologist Hans Goldmann put his knowledge of physics and optics to not only simplify the slit lamp but also standardized perimetry and tonometry.[1] His ingenious use of prisms in contact lenses made gonioscopy and fundus biomicroscopy possible. Figure 1 shows the early models of keratometer and slit lamp to emphasize how much of effort and modifications have occurred to reach the current models. The narrative linked to intellect, resilience, and the ability of some innovators to convert serendipitous observations into wondrous machines are stories worth reproducing. I recall here two such impressive stories of the discovery of (a) light photocoagulation and (b) the first antiglaucoma drug. Gerhard Meyer-Schwickerath stumbled on a serendipitous observation of a medical student’s narrative of vision loss induced after watching the solar eclipse in June 1945. Correlating this with Plato’s description of solar blindness in ancient Greece, Schwickerath used his knowledge of diathermy to design the first light photocoagulation machine in 1946. The story of how retinal detachment patients wearing dark sunglasses would wait on the roof of his clinic, for spells of continuous sunlight.[2] When the sun designed to grant them this, they would call the doctor in his clinic, who would then rush up to pivot his machine, capture the sunrays to aim them into the eyes of the supine patient – This was how the first noninvasive retinal treatment was performed, on the rooftops of a hospital. Capricious sunlight was soon to be supplanted by xenon photocoagulator in collaboration with Littman, and the rest, of course, is history. The development of a head-mounted, binocular indirect ophthalmoscope at the same time by Charles Schepens added to the success of these retinal therapies by enlarging the field of work and freeing up of hands to perform sophisticated retinal surgery. Physostigmine discovery was the serendipitous observation of Scottish missionaries of a tribal custom in Old Calabar of Nigeria named “Ordeal of innocence.” This strange custom to determine guilt by force-feeding of Calabar beans to an accused, followed by death (guilty) or vomiting (innocent), was found perplexing. Samples of beans were brought back and planted in Edinburgh, where toxicologists working on them isolated physostigmine as the active alkaloid in 1855. Argyll Robertson reported the miotic effect of eserine (physostigmine) almost a decade later and utilized it to conduct iridectomy (the only surgery then for glaucoma). Discovery of its incidental Salute to Giants Who Took Ophthalmology to Terra Incognita © 2023 Delhi Journal of Ophthalmology | Published by Wolters Kluwer - Medknow 1
Singh: Salute to giants who took ophthalmology to terra incognita effect in breaking angle‑closure attack led to its use as the first antiglaucoma drug in 1876, and a drug for blinding glaucoma had been found! However, the process of extraction from Calabar beans was laborious, and the much-in-demand drug was always in short supply. Chemical synthesis of it was made possible by Percy Julian, a chemist of colored race in the United States of America, in 1931. Furthermore, the serendipitous discovery of the steroid stigmasterol, as a byproduct of physostigmine synthesis, made Percy Julian use it as the raw material to synthesize cortisone and progesterone, the wonder drugs of that time. Percy Julian went on to hold 100 patents and minimized the lifelong racial discrimination faced by him in the phrase “There is no such thing as can’t.”[3] These stories emphasize the importance of innovations in ophthalmology, and this issue of the Delhi Journal of Ophthalmology, with the theme of “I innovations(instrumental)” seeks to detail a few of these innovative devices, which improve surgical as well as clinical outcomes. Elegant devices in microincision vitreous surgery, economically viable novel intravitreal drug delivery systems, calibrated phacotips, and frequency‑modulated phacoemulsification systems are few such innovations detailed. New algorithms dictate quality surgical outcomes such as the role of posterior corneal astigmatism in the prediction of cataract surgery outcomes and microsurgical skill stations using kitchen equipment. The fascinating world of gene modulation has now taken steps toward fruition with gene-editing techniques like CRISPR (clustered regularly interspaced short palindromic repeats). It is indeed heartening to realize that innovators and innovations still happily populate the ophthalmic fraternity in the 21st century as much as they did in the previous one. The salute to all the innovators has been aptly said by von Graefe, who inscribed these immortal words on the cup presented to von Helmholtz: To the creator of a new science, to the benefactor of mankind, in thankful remembrance of the invention of the ophthalmoscope. Kirti Singh1,2 1 Editor in Chief, DJO, 2 Guru Nanak Eye Centre, Maulana Azad Medical College and Associated Hospital, New Delhi, India. E‑mail: [email protected] References 1. Gloor BR. Hans Goldmann (1899‑1991). Eur J Ophthalmol 2010;20:1-11. 2. Meyer-Schwickerath GR. Physikalische grundlagen der diathermishen augenoperationen. Ber Zusk Dtsch Ophthl Ges 1948;54:315‑9. 3. Ravin JG, Higginbotham EJ. The story of Percy Lavon Julian: Against all odds. Arch Ophthalmol 2009;127:690‑2. This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. How to cite this article: Singh K. Salute to giants who took ophthalmology to terra incognita. Delhi J Ophthalmol 2023;33:1-2. Access this article online Quick Response Code: Website: https://journals.lww.com/djo DOI: 10.4103/DLJO.DLJO_60_23 Figure 1: (a) Early keratometer (b) Early slit lamp in Elliott museum in Stanley Medical College, Chennai (self‑taken) a b 2 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023
Guest Editorial The Beginning – 1972 All my innovations and indigenization were rooted in meeting my personal requirement and demand for such devices from my colleagues from time to time. In the 1st year of postgraduation in the Eye Department of MAMC and Irwin Hospital (now GNEC), I needed an ophthalmodynamometer for my thesis work, which could raise and maintain the intraocular pressure (IOP) to a desired level during central field charting on Bjerrum screen. Since none was available in the market, I decided to develop one. Around the same time, Prof. S.R.K Malik procured a monoocular indirect ophthalmoscope from Germany, costing around Rs. 2000/-. Dr. B Patnaik found it to be very useful and requested every postgraduate student to buy one, but it was too expensive for most students. Looking at the demand for this simple instrument, I designed the INDOSCOPE [Figure 1], which I could offer for Rs. 250/- only, and that too including a +16 D spherical condensing lens. I offered the first piece to Dr. Patnaik as a gift, but he insisted on buying it. Later, Prof. A K Gupta, when he was the head of the Ophthalmology Department at Rohtak Medical College, asked all his P G students to buy one INDOSCOPE. When I took the INDOSCOPE to the AIOS conference for sale, not many people were convinced that such a simple and low-cost device could actually work. Thus, the need for a MODEL EYE [Figure 2] to demonstrate the working of INDOSCOPE was created. This MODEL EYE later on (with some modification) became popular as a teaching and training device for practicing indirect ophthalmoscopy and retinoscopy. Innovations and Indigenization in Ophthalmology – My Contribution © 2023 Delhi Journal of Ophthalmology | Published by Wolters Kluwer - Medknow 3 Figure 1: Indoscope Figure 2: Model-i
Gupta: Innovations and indigenization in ophthalmology - My contribution 4 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 Figure 5: Eyeball Stand Figure 7: Aspheric Lenses (20D, 78D & 90D) Figure 3: Phaco-i Figure 6: Diagnostic Strips Figure 4: Laser-i Figure 8: 20D Aspheric Lens
Gupta: Innovations and indigenization in ophthalmology - My contribution Later on, more TEACHING & TRAINING DEVICES like Phaco Practice Eye [Figure 3], Laser Practice Eye [Figure 4] and Eyeball Stand [Figure 5] were developed: Necessity is the mother of all Innovations – 1975 When I came into private practice in 1975, I found that many of the daily requirements for diagnostic instruments and surgical supplies were not available in the Indian market and were being imported at an exorbitant price. I started making Indian substitutes for my own use and later for marketing. Some of the initial devices were diagnostic strips [Figure 6], slit‑lamp aspheric lenses [Figure 7], and indirect ophthalmoscope with 20D aspheric lens [Figure 8]. Gonioscopes Knowing my interest and ability to play with optics, Prof. N N Sood of R P CENTRE called me over and gave me a Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 5 Figure 9a: Gonioscopes (single, two, three & four mirror) Figure 10: Digital Camera based Fundus Camera Figure 9b: Three Mirror Gonioscopes Figure 11: Smartphone based Fundus Camera Figure 12: Retinal Image from Smartphone Fundus Camera
Gupta: Innovations and indigenization in ophthalmology - My contribution four-mirror and a three-mirror gonioscope to study optics and develop them. With the help of friends in the optics industry, I was able to develop the gonioscopes indigenously [Figure 9a and 9b]. 6 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 Figure 13: Clean room @ Madhu Instruments Figure 14: Packaging area @ Madhu Instruments Figure 15a: Iris Retractors Figure 15b: Capsule Hooks Figure 16: Preloaded Capsular Tension Ring Figure 17: Capsular Tension Rings Figure 18: Capsule Support Segment
Gupta: Innovations and indigenization in ophthalmology - My contribution Portable Digital Fundus Camera In 2005, Prof. Amod Gupta met me at the American Academy of Ophthalmology (AAO) and asked me to have a look at the newly introduced RetCam – a digital widefield fundus camera and work on it to develop a digital fundus camera. I bought a commercially available one-megapixel digital camera and Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 7 Figure 20: Suction Trephine Figure 21: Fixed Depth Trephine Figure 22: Corneal Trephine Figure 19: Trephine Punch - Vacuum & Non Vacuum Figure 23: Artificial Anterior Chamber Figure 24: Temporary Keratoprosthesis Figure 25: Intraocular Magnet Figure 26: Irrigating Lens Set
Gupta: Innovations and indigenization in ophthalmology - My contribution attached a 78 D aspheric lens in front of the camera lens [Figure 10]. A warm white Light Emitting Diode (LED) was placed just below the camera lens to act as the illuminating light source. I could get fairly good-quality retinal pictures with a 60° field of view. The quality of images further improved when the digital camera was replaced by a smartphone camera [Figure 11 and 12]. Organized Manufacturing Setup – 1999 In 1999, I moved the Research and Development, manufacturing and sales to Okhla Industrial Area, New Delhi, in a much more organized manufacturing setup under the company name “Madhu Instruments” [Figure 13 and 14]. It was an important step to control quality and reach out to a maximum number of surgeons needing these innovative devices. Since then, many hard-working professionals have joined our team, and processes have been established that have helped me speed up the innovations and make availability of all these devices in the Indian and international markets. Some of the devices developed in the last 20 years are as under. Cataract & IOL Useful products for difficult cases in cataract surgery were developed. Some of them are Iris Retractors & Capsule Hooks [Figure 15a and 15b], Preloaded CTR & Capsular Tension Rings [Figure 16 & 17] & Capsule Support Segment [Figure 18]. Keratoplasty & Cornea Many speciality trephines, which were not available in India were developed to support our cornea surgeons. Some of them are Trephine Punch - Vacuum & Non Vacuum [Figure 19], Suction Trephine [Figure 20]. Fixed Depth Trephine [Figure 21], Corneal Trephine [Figure 22] & Artificial Anterior Chamber [Figure 23]. Vitreo Retina Useful products for vitreo retina surgery were also developed like Temporary Keratoprosthesis [Figure 24], Intraocular Magnet [Figure 25], Irrigating Lens Set [Figure 26], Silicone Band [Figure 27] & Vitrectomy Lens Set [Figure 28]. Acknowledgement I would like to express my sincere gratitude to my teachers, colleagues, and ophthalmic industry friends for their never-ending guidance and encouragement. These innovations and this journey would not have been possible without their support. I am grateful to all of those at Madhu Instruments with whom I have had the pleasure to work during each innovation. Without their efforts, it would not have been possible to convert my ideas into functional devices and make them easily available to the ophthalmic community. Nobody has been more important to me in the pursuit of this journey than the members of my family. Most importantly, I wish to thank my loving and supportive wife, Madhu, and my children for taking forward my dream as their career. S. C. Gupta Formerly Director, Venu Eye Institute and Research Centre, New Delhi Visiting Consultant, Synergy Eye Care, New Delhi, India. E‑mail: [email protected] This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. How to cite this article: Gupta SC. Innovations and indigenization in ophthalmology – My contribution. Delhi J Ophthalmol 2023;33:3‑8. Access this article online Quick Response Code: Website: https://journals.lww.com/djo DOI: 10.4103/DLJO.DLJO_28_23 8 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 Figure 28: Vitrectomy Lens Set Figure 27: Silicone Band
Abstract Review Article Introduction In the past few years, artificial intelligence (AI) application has emerged as an effective diagnostic tool in health care services in almost all specialties.[1] In ophthalmology, AI‑assisted automated screening and diagnosis of retinal diseases such as diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, and glaucoma has been widely utilized in recent years.[2] However, to diagnose ocular anterior segment diseases, functional and structural assessment, investigations like slit-lamp biomicroscopy, corneal topography, tomometry, perimetry, optical coherence tonometery (OCT), etc., needs to be done. Diagnosis of anterior segment diseases largely depends on ophthalmologists professional acumen and experience, which is observers biased, time-consuming, and prone to human errors. Cataract remains the leading cause of blindness worldwide,[3] and cataract surgery is the most common ophthalmic surgical procedure performed in the world.[4] Lens epithelial cells that remain in the capsular bag postcataract surgery have the potential to migrate, proliferate and transform into fibro epithelial sheet, to produce Elschnigs pearls and capsular fibrosis leading to PCO.[5] This leads to a gradual progressive loss of transparency of the posterior capsule, causing scattering of light and visual deterioration on encroachment onto the visual axis. PCO remains the most common complication postcataract surgery.[6] With improvised and modernized surgical and cortical cleanup techniques, the incidence of PCO has reduced, but it still remains considerable and varies In ophthalmology, artificial intelligence (AI)‑assisted system is being widely used for screening and diagnosis of posterior segment diseases such as diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, and glaucoma. However, anterior segment disease’s diagnosis is largely dependent on clinical examination and hence is more observers biased and prone to human errors. Cataract is the leading cause of blindness worldwide and cataract surgery is the most common ophthalmic surgical procedure performed in the world. With improvised surgical techniques the incidence of PCO has reduced, but it remains the most common complication after cataract surgery. Neodymium-doped yttrium aluminum garnet (Nd: YAG) laser capsulotomy is accepted as the standard, safe, effective, and noninvasive treatment for PCO. Nd: YAG capsulotomy rate varies as per patients desire, surgeon assessment, geographical variability, equipment availability, and financial factors. Various imaging modalities like Slit lamp Schiempflug imaging, optical coherence tonometery, or pentacam in conjunction with several AI‑assisted automated systems have been used in the past and provide semiquantitative evaluation of PCO. A more reliable, reproducible, and valid method is required for objective and quantitative grading of PCO and hence, standardization of treatment. Here, we systematically reviewed several PCO imaging modalities, various existing AI algorithms, steps in building AI models and matrix evaluation in AI diagnosis of PCO. This review would provide both ophthalmologists and computer scientists with a detailed and exhaustive summary on the application of AI systems in objective grading and quantification of PCO, challenges, and future prospects. Keywords: Artificial intelligence, deep learning, machine learning, ophthalmic diseases, posterior capsular opacification Address for correspondence: Dr. Saurabh Kushwaha, Department of Ophthalmology, Army College of Medical Sciences, Delhi Cantt, New Delhi ‑ 110 010, India. E‑mail: [email protected] This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. For reprints contact: [email protected] How to cite this article: Kushwaha S, Chaudhary R, Devi U. Artificial intelligence: A review of objective grading and quantification of posterior capsular opacification. Delhi J Ophthalmol 2023;33:9‑17. Artificial Intelligence: A Review of Objective Grading and Quantification of Posterior Capsular Opacification Saurabh Kushwaha1 , Rajat Chaudhary1 , Uma Devi2 1 Department of Ophthalmology, Army College of Medical Sciences, New Delhi, India, 2 Department of Pharmaceutical Sciences, Institute of Pharmacy, Chhatrapati Shahu Ji Maharaj University, Kanpur, Uttar Pradesh, India Access this article online Quick Response Code: Website: https://journals.lww.com/djo DOI: 10.4103/DLJO.DLJO_7_23 Submitted: 25‑Feb‑2023 Accepted: 25‑Mar‑2023 Published: 05-Jul-2023 © 2023 Delhi Journal of Ophthalmology | Published by Wolters Kluwer - Medknow 9
Kushwaha, et al.: Artificial intelligence application in objective grading and quantification of posterior capsular opacification widely.[7‑12] Neodymium-doped yttrium aluminum garnet (Nd: YAG) laser capsulotomy remains the most effective treatment for PCO, which creates an central opening in the opacified posterior capsule to clear the visual axis.[13,14] Nd: YAG capsulotomy is one of the common ophthalmic procedure and is the second most commonly built procedure in health-care sector.[15] However, procedural cost and associated complications such as retinal detachment,[16] macular edema,[17] intraocular lens(IOLs) damage subluxation of IOL, rise in intraocular pressure, and exacerbation of localized endophthalmitis.[18‑20] Nd: YAG capsulotomy rate varies as per surgeon’s assessment,[21] patient’s desire, geographical variability,[22] equipment availability, and financial factors. Although until now, various clinical scoring systems exists to evaluate the extent of PCO, which are qualitative, subjective and depends on the ophthalmologist experience and professional knowledge.[23-26] The criteria being PCO area or density;[20,27] however, no optimal quantification method has been defined till date. Slit‑lamp retroillumination images based systems have been proposed, such as the evaluation of PCO (EPCO),[28] posterior capsular opacification (POCO),[29] automated quantification of after cataract I (AQUA I)[30] and Aslam analysis (AA) system[31,32] in recent past which requires balanced and uniform illumination and consistent processing which provides a partially objective assessment of PCO.[33,34] OCT, a noninvasive technique, has been widely used in evaluating various retinal diseases,[35] nerve fiber layer thickness,[36] and anterior segment diseases.[37,38] However, OCT has been used for the grading of the severity and quantification of PCO and its characteristics.[39] Pentacam, a Scheimpflug principle-based system has now been used in the evaluation of changes in the anterior segment of the eye, including the cornea, anterior chamber, and lens.[39-41] It has been used objectively to quantify PCO using the POCO man system.[40] These illustrated imaging systems provide semiquantitative EPCO. A more reliable, reproducible, and valid method is required to assess the risk factors associated with its development and objective and quantitative grading of PCO, and hence, standardization of treatment is desirable. In this review, we systematically reviewed various existing AI (machine learning [ML] and deep learning [DL])‑assisted automated methods and their clinical application in the diagnosis of anterior segment diseases. We also introduced various existing AI algorithm, PCO imaging modalities, steps in constructing AI models and matrix evaluation in AI diagnosis of PCO. We desire that this review may provide both ophthalmologist and computer scientists a detailed, important, consequential and an exhaustive summary on application of AI system in objective grading and quantification of PCO, challenges and future prospects. Methods We did review of literature of original research and review articles through searches in PubMed and Google Scholar database using the terms “artificial intelligence” “machine learning” “deep learning” “posterior capsular opacification,” “PCO” and “ophthalmic diseases.” Articles resulting from these researches and relevant references cited in these articles were reviewed. Studies reported in English language were only included. Articles on possible clinical automated applications of AI diagnosing and grading of PCO where reviewed. Artificial Intelligence Algorithm In 1956, Darthmouth scholar John McCarthy, described AI as a general term referring to, “hardware or software that exhibits behavior which appears intelligent.”[41] AI warren’s computer to imitated human behavior, especially with the advancement in new algorithms, large database, modernize hardware, and cloud‑based services. AI can be categorized as artificial general intelligence, artificial narrow intelligence, and artificial superintelligence. AI consists of ML, DL, automated learning, computer vision, reasoning, robotics, export system, and scheduling.[42,43] [Figure 1a] DL is a subfield of ML that assimilates the underlying features in a large database using neural networks. It is usually determined on data representation using deep neural networks stimulated by the composition and function of human brain.[44-46] ML, a subset of AI was first conceptualized in 1959 by Samuel as an application of AI that “the computer should have the ability to learn using various standardized techniques, without being explicitly programmed.”[47] It provides system the ability to automatically assimilate an advancement from experience without being explicitly programmed.[48] ML, a subgroup of AI methodologically executes algorithm to fabricate the underlying interrelation between the corpus of data and information.[49] ML is considered as an artificial computer intelligence system which permits computers to learn automatically in absence of programming and human involvement. In the recent years, with the development in the field of information technology its importance has been markedly recognized in medical practice and machine translation.[44-46] One of the important feature of ML is the enhancement in the quality of prediction with progressing experience.[50] Traditional ML and DL are the two broad forms of ML. Traditional ML algorithms utilizes variables chosen by experts as inputs, usually not involving large neural networks. The algorithms included are linear regression, logistic regression, support vector machine (SVM),[51] decision tree,[52] random forest[53] [Figure 1b] etc. DL algorithm utilizes multimedia data sets such as images, sounds and videos involving the usage of large-scale neural networks such as artificial neural networks (ANNs), convolutional neural networks (CNNs)[46] and recurrent neural networks.[54] Among these, RF and SVM are the most commonly used ML algorithms in ophthalmology.[55] Table 1 illustrates the commonly used ML algorithm in ophthalmology. DL algorithm has multi-layered neural network existing between input and output layers. There has been marked improvement 10 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023
Kushwaha, et al.: Artificial intelligence application in objective grading and quantification of posterior capsular opacification in image recognition with DL. In DL algorithms, features of the input data are automatically learned in an unsupervised way alluding to manual segmenting and depicting lessons areas[53,56] [Figure 1c]. DL algorithms broadly include three assignments: classification, objective detection, and semantic segmentation, and is classified as a database into a set of predetermined groups. VGG,[57] ResNet,[58] AlexNet,[59] Inception ResNet, and GoogleNet are few existing CNN architecture used for classification tasks.[60-63] The object detection is aimed at the detection of image and location of the region of interest (ROI) using algorithms such as you only look once, Faster-R CNN and single shot Multibox detector (SSD). Using semantic segmentation algorithms, each pixel of an image is classified into a predefined set of categories. These algorithms encompass U-Net, Google deep lab, and fully convolutional network. Table 2 illustrates various CNN algorithms in the medical field. Building Artificial Intelligence Model Till date many modalities have been used for the diagnosis and qualitative and semiquantitative assessment of PCO like Scheimpflug slit lamp[65] OCT (Moreno 2005),[66,67] and Pentacam tomograms.[68] The steps in constructing an AI model include data preparation, data partition, model optimization, and data evaluation [Figure 2]. Data preparation It is important to preprocess the raw data according to the type of data and AI algorithms for better efficacy of AI prediction these includes[69,70] (a) Denoizing: Denoizing is to be carried out to transform the images from different sources to similar size and format like specular reflection removal[71] and removing uneven illumination.[72] It hence enhances the quality of raw data and improves the learning process. (b) Data segmentations: Images collected from different sources need to be consolidated and modified into a structured data. It makes AI prediction more efficient and accurate by eliminating overfilling. ROI is necessary for ML, though for DL it is Table 1: Commonly used machine learning algorithms in ophthalmology Algorithms Prediction Linear regression Uses the learned line plane or hyperplane to predict the output value Logistic regression A transformed linear regression which projects the continous results to discrete category and is based on the idea of OR Decision tree Tree constructed in topdown repetitive divide and conquers design and predicts results based on binary rules Random forest Assemble many decision trees and predicts the class by majority voting SVM Transforms the original raw data into a higher dimension using a nonlinear mapping or by a linear optimal separating hyperplane Neuronal network Inspired by structure and function of biological neurons and models the relationship between inputs and outputs organized in layers SVM: Support vector machine, OR: Odds ratio Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 11 Figure 1: (a) AI algorithm, (b) random forest algorithm, (c) workflow of deep neural network. AI: Artificial intelligence, ML: Machine learning, DL: Deep learning b c a
Kushwaha, et al.: Artificial intelligence application in objective grading and quantification of posterior capsular opacification 12 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 useful in fewer selected cases only because CNN localizes the discriminative regions. (c) Feature extraction and selection: The structured data are cleaned, selected, and extracted to enhance the AI prediction performance. Data partition The data set is randomly segregated into two independent subgroups; one is test data set and other is modelling data set. The modelling data set is further divided into training and Figure 2: Building an AI model. AI: Artificial intelligence, DL: Deep learning, DT: Decision tree, RF: Random forest, SVM: Support vector machine, ROC: Receiver operating characteristic, AUC: Area under the curve Table 2: Various convolutional neural networks algorithm in artificial intelligence medical field Algorithm Year Top five error rate Depth Principle Reference AlexNet 2012 16.4 8 Uses reLU dropout and overlap pooling Krizhevsky et al. [59] VGG 2014 7.3 19 Homogenous topology using small size kernels Simonyan and Zisserman[64] Google net 2015 6.7 22 Introduced block concept to split transform and merge idea Szegedy et al. [60] ResNet 2016 3.6 152 Residual learning by mapping based skip connections He et al., 2016a[58] Inception V3 2016 3.5 159 Has small filters to tackle the problem of representational bottleneck Szegedy et al., 2016b[62] reLU: Rectified linear units, VGG: Visual geometric group
Kushwaha, et al.: Artificial intelligence application in objective grading and quantification of posterior capsular opacification Table 3: Studies on posterior capsular opacification using artificial intelligence application Studies Imaging modalities AI application Lasa et al., 1995[65] Zeiss Scheimpflug slit lamp Computerized image analysis software Hayashi et al., 1998[87] Scheimpflug slit lamp Linear regression analysis Tetz et al., 1997[25] Scheimpflug slit lamp EPCO Pande et al., 1997[88] Slit lamp imaging with even background elimination Coaxial elimination Ursell et al., 1998[89] Slit lamp retroillumination Computerized image analysis software Friedman et al., 1999[15] Slit lamp retroillumination Computer based image acquistion and PCO grading system Barman et al., 2000[26] Digital slit lamp retroillumination POCO Buehl et al., 2002[90] Digital coaxial retroillumination AQUA I Findl et al., 2003[27] Digital retroillumination slit lamp EPCO and AQUA I Moreno-Montañés et al., 2005[67] OCT-1 PCT Aslam et al., 2005[29] Entropy score for the central area of PCO by slit lamp imaging AA system Grewal et al., 2008[68] Scheimpflug Pentacam tomogram PCOman software Mohammadi et al., 2012[91] Ten input variables assessed using retroillumination Scheimpflug slit lamp imaging QUEST algorithum and ANN algorithum Hawlina et al., 2014[66] High resolution spectral domain OCT Custom made software, written in MATLAB Alberdi et al., 2018[92] Pentacam HR‑Scheimpflug and Oculus Pentacam HR IMAGEnet 5 software Yu et al., 2018[93] RTVue-100 spectral domain OCT Spearman’s correlation analysis Kronschläger et al., 2019[94] High resolution digital retroillumination slit lamp imaging AQUA II system PCO: Posterior capsular opacification, AI: Artificial intelligence, EPCO: Evaluation of PCO, AA: Aslam analysis, AQUA I: Automated quantification of after cataract I, AQUA II: Automated quantification of after cataract II, ANN: Artificial neural network, OCT: Optical coherence tonometery, PCT: Posterior capsular thickening, MATLAB: Matrix laboratory Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 13 validation data set in almost all cases. The training data set is used to create parameter of a model and validation data set is used to determine tuning and refining of hyper parameters and building conclusion regarding the optimal final model. The test data is used to estimate the efficiency of the final model. Another widely used data partition method is cross validation method. The most adopted cross‑validation is 5‑fold cross-validation, especially in cases where sample size is small. The other commonly used ones are 10-fold cross-validation method and K-fold cross-validation method.[73‑78] Model optimization Many algorithm types[72,74,76,77,79‑84] and different data preparation methods are incorporated to prepare algorithms and produce many more models, which are then assessed on validation data set so as to get the final model which can be used for upcoming or novel data. Furthermore, based on the analysis of the validation data set and recessive operations characteristic curve (receiver operating characteristic [ROC] curve),[76] the operating threshold is determined. Data evaluation Model evaluation determines the efficacy of the final model on novel data. The commonly used tools for depicting algorithm prediction are ROC curve, sensitivity, specificity, and accuracy. Of these, area under the ROC curve (area under the curve [AUC]) is the most commonly used matrix in AI algorithm. AUC is the area under the ROC curve graphically plotted with sensitivity and false positive rate (1‑specificity) on “y” and “x” axis, respectively. AUC for an effective model ranges from 0.5 to 1; the more higher the value, the more efficient is the model.[85] A AUC value of 0.8–0.9 indicates that the model is good or excellent; 0.9 indicates that the model is outstanding and 1.0 depicts a perfect model.[86] Artificial Intelligence Application in PCO Most of the diagnostic systems for PCO were based on Scheimpflug imaging on retroillumination on slit lamp examination. However, in the recent past, OCT and Pentacam have been used for semiquantitative and objective assessment of PCO based on AI‑assisted systems. Various studies conducted to diagnose and grade PCO in the past are illustrated in Table 3. In 1995, Lasa et al. [65] used Zeiss Scheimpflug slit lamp camera and computerized image analysis software to objectively quantify PCO based on its density and thickness. The simplex system could not assess the total area of the capsular opacity and it was limited to one Meridian at a time. Hayashi et al. [87] used Scheimpflug slit‑lamp to assess single slit images of the central 3.0 mm of the posterior capsule in up to four Meridians to estimate capsular density. This study lacked reproducibility and ability to detect progression overtime. In 1997, Tetz et al. [25] introduced EPCO to quantify PCO grading based on standard retroillumination photography. After manual segmentation, observer subjectively grades the segments with an integer density score from 0 to 4. The final EPCO score is obtained as a single metric for PCO by multiplying it by fractional area coverage behind IOL. Pande et al. [88] in the year 1997 demonstrated a slit-lamp-mounted digital camera for capturing posterior capsule images. Coaxial illumination and the emerging path were obtained by making special adaption in the system. Using the same system in 1998, Ursell et al. [89] assessed
Kushwaha, et al.: Artificial intelligence application in objective grading and quantification of posterior capsular opacification 14 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 the relationship between IOL material and PCO development. The automated analysis was based on the presence of texture on the posterior capsule fixed at some unexpressed threshold. The study compared this average percent area of the posterior capsule covered by texture. The reproducibility and validity of this system were not established. In 1999, Friedman et al. [15] developed a computer-based image acquisition and PCO grading system that captures retroillumination images of the posterior capsule using a slit lamp mounted with the digital camera. The PCO grading scheme assessed two metrics of the opacity; average density of the area assigned a score from 0% to 4% area coverage of the central 4.0 mm of PCO. The results obtained were reliable and could detect small changes in the percentage area covered by PCO. Barman et al.,[26] in the year 2000, developed an automated Posterior capsular opacification (POCO) software program for the objective and quantitative assessment of PCO. High-resolution images obtained by digital retroillumination camera system were analyzed by defining a mark area, removing purkinje light reflexes, contrast enhancement, filtration, and segmentation using co‑occurrence matrix. Although the results obtained were accurate and reproducible, it provided no qualitative information. Buehl et al. [90] in the year 2002, described an AQUA I method for diagnosing PCO using a standardized digital coaxial retroillumination system. Fully automated objective PCO analysis software was used to evaluate the captured images and a PCO score was obtained from 0 to 100. The results obtained were reproducible with good quality of captured images; however, it lacked on localization of PCO. In 2003, Findl et al. [27] conducted a comparative study of PCO quantification and repeatability of the EPCO system, POCO software and AQUA I system. The POCO system was found to lack the assessment of PCO intensity. Both EPCO and AQUA I assessments correlated well with the subjective assessment. Aslam et al. [29] in the year 2005, developed a computerized analysis system referred to as AA system. It is an objective evidence-based system that measures an entropy score for the central area of PCO and assesses its progression also. Moreno-Montañés et al. [67] in the year 2005, used OCT with an A‑4 software update for quantification of PCO. Posterior capsular thickness was assessed as a tool for PCO analysis. The results were accurate and reproducible when compared to other analysis systems. However, only three points over PCO were assessed, not the full posterior capsule. Grewal et al. [68] in the year 2008, developed a method for quantification of PCO using Scheimpflug Pentacam tomogram as it can capture images in multiple meridians in a single automated scan. Images were captured with correct focus and alignment with the corneal apex with automatic release mode of the Pentacam. The major advantage was that it was flash reflection free, operator independent at automatic release mode and nearly entire area of the posterior capsule. The objective quantitative analysis system was found to be reliable and reproducible. In the year 2012, Mohammadi et al. [91] developed an ANN algorithm to make a decision tree for prediction of PCO. Ten input variables were used to prepare a QUEST algorithum which showed 87% accuracy. Hawlina et al. [66] in the year 2014, demonstrated the use of high resolution spectral domain OCT for PCO characterization and distinguished PCO into four types, namely; fibrosis, pearl, mixed types and late–postoperative capsular bag distension syndrome. An OCT imaging was considered as more accurate objective analysis when compared to slitlamp imaging because of no observer bias in capturing image. However, they lacked to have the proper software for three‑dimensional analyses of PCO types. Alberdi et al. [92] in the year 2018, proposed the use of Pentacam HR‑Scheimpflug and Oculus Pentacam HR densitometry software based on new pentacam nuclear staging software and IMAGEnet 5 software for objective quantification of PCO. In the year 2018, Yu et al. [93] conducted an objective assessment of PCO using RTVue-100 spectral domain-OCT. PCO was evaluated for its opacified area, thickness, and density and objective scores were obtained to quantify PCO. The findings were validated by comparing with the Pentacam system and were also reproducible. Kronschläger et al. [94] in 2019, developed an AQUA II system for PCO using high‑resolution digital retroillumination images. They classified PCO into six types. However, in their study, the ROI was defined as central 4.0 mm in diameter of the IOL only and purkinje reflexes generated from axial illumination leads to lost data in VEC data set. Discussion Objective and quantitative grading of PCO is significant for determining the effect of IOL designs or material, various cataract surgeries and cleanup techniques, and other pharmatherapeutic treatments. Different qualitative or semiquantitative AI‑assisted methods have been reported, which are based on Scheimpflug imaging on slit-lamp retoillumination. Recently, new methods for objective and quantitative PCO evaluation based on OCT and Pentacam have been reported. They have been found to be more reproducible, valid, and objective but are not fully objective in the terms that they are human dependent to assess PCO levels in different imaging systems. For AI models, a huge amount of data are generated in ophthalmic clinics daily that needs to be properly prepared and processed for appropriate characteristics like resolution, structural and functional features, devices used, annotations, formatting in naming, storage, description, and sources of information. AI models need to be validated for the heterogeneous population under different conditions. The performance of the AI model is also greatly influenced by the quality of data rather than the amount of data. Here, we suggest that for building a more reliable and valid AI system, Scheimpflug imaging on slit‑lamp retroillumination, OCT, and Pentacam imaging needs to be integrated together into an AI algorithm system. Further studies are required to construct the AI algorithm to evaluate sensitivity, specificity, and validity
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Fu H, Baskaran M, Xu Y, Lin S, Wong DW, Liu J, et al. A deep learning system for automated angle-closure detection in anterior segment optical coherence tomography images. Am J Ophthalmol 2019;203:37‑45. 75. Arbelaez MC, Versaci F, Vestri G, Barboni P, Savini G. Use of a support vector machine for keratoconus and subclinical keratoconus detection by topographic and tomographic data. Ophthalmology 2012;119:2231‑8. 76. Lopes BT, Ramos IC, Salomão MQ, Guerra FP, Schallhorn SC, Schallhorn JM, et al. Enhanced tomographic assessment to detect corneal ectasia based on artificial intelligence. Am J Ophthalmol 2018;195:223‑32. 77. Aloudat M, Faezipour M, El‑Sayed A. High intraocular pressure detection from frontal eye images: A machine learning based approach. Annu Int Conf IEEE Eng Med Biol Soc 2018;2018:5406‑9. 78. Jiang J, Liu X, Zhang K, Long E, Wang L, Li W, et al. Automatic diagnosis of imbalanced ophthalmic images using a cost-sensitive deep convolutional neural network. Biomed Eng Online 2017;16:132. 79. Liu X, Jiang J, Zhang K, Long E, Cui J, Zhu M, et al. Localization and diagnosis framework for pediatric cataracts based on slit-lamp images using deep features of a convolutional neural network. PLoS One 2017;12:e0168606. 80. Wang L, Zhang K, Liu X, Long E, Jiang J, An Y, et al. Comparative analysis of image classification methods for automatic diagnosis of ophthalmic images. Sci Rep 2017;7:41545. 81. Nongpiur ME, Haaland BA, Friedman DS, Perera SA, He M, Foo LL, et al. Classification algorithms based on anterior segment optical coherence tomography measurements for detection of angle closure. Ophthalmology 2013;120:48‑54. 82. Remeseiro B, Penas M, Mosquera A, Novo J, Penedo MG, Yebra‑Pimentel E. Statistical comparison of classifiers applied to the interferential tear film lipid layer automatic classification. Comput Math Methods Med 2012;2012:207315. 83. Ambrósio R Jr., Caiado AL, Guerra FP, Louzada R, Sinha RA, Luz A, et al. Novel pachymetric parameters based on corneal tomography for diagnosing keratoconus. J Refract Surg 2011;27:753‑8. 84. Sánchez Brea ML, Barreira Rodríguez N, Sánchez Maroño N, Mosquera González A, García‑Resúa C, Giráldez Fernández MJ. On the development of conjunctival hyperemia computer-assisted diagnosis tools: Influence of feature selection and class imbalance in automatic gradings. Artif Intell Med 2016;71:30‑42. 85. Hajian‑Tilaki K. Receiver operating characteristic (ROC) curve analysis for medical diagnostic test evaluation. Caspian J Intern Med 2013;4:627‑35. 86. Lantz B. Machine Learning with R: Expert Techniques for Predictive Modeling. Packt Publishing ltd; 2019. 87. Hayashi K, Hayashi H, Nakao F, Hayashi F. In vivo quantitative measurement of posterior capsule opacification after extracapsular cataract surgery. Am J Ophthalmol 1998;125:837‑43.
Kushwaha, et al.: Artificial intelligence application in objective grading and quantification of posterior capsular opacification Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 17 88. Pande MV, Ursell PG, Spalton DJ, Heath G, Kundaiker S. High-resolution digital retroillumination imaging of the posterior lens capsule after cataract surgery. J Cataract Refract Surg 1997;23:1521‑7. 89. Ursell PG, Spalton DJ, Pande MV, Hollick EJ, Barman S, Boyce J, et al. Relationship between intraocular lens biomaterials and posterior capsule opacification. J Cataract Refract Surg 1998;24:352‑60. 90. BuehlW, Findl O, MenapaceR, Georgopoulos M, Rainer G, Wirtitsch M, et al. Reproducibility of standardized retroillumination photography for quantification of posterior capsule opacification. J Cataract Refract Surg 2002;28:265‑70. 91. Mohammadi SF, Sabbaghi M, Z‑Mehrjardi H, Hashemi H, Alizadeh S, Majdi M, et al. Using artificial intelligence to predict the risk for posterior capsule opacification after phacoemulsification. J Cataract Refract Surg 2012;38:403‑8. 92. Alberdi T, Mendicute J, Bascarán L, Barandika O, Ruiz‑Ederra J. Anterior and posterior capsule densitometry levels after femtosecond laser‑assisted cataract surgery. Int J Ophthalmol 2018;11:623‑8. 93. Yu S, Lu C, Tang X, Yuan X, Yuan B, Yu Z. Application of spectral domain optical coherence tomography to objectively evaluate posterior capsular opacity in vivo. J Ophthalmol 2018;2018:5461784. 94. Kronschläger M, Siegl H, Pinz A, Feichtenhofer C, Buehl W, Hirnschall N, et al. Automated qualitative and quantitative assessment of posterior capsule opacification by automated quantification of after‑cataract II (AQUA II) system. BMC Ophthalmol 2019;19:114.
Abstract Review Article Introduction More than 50% of ocular diseases affecting the population can be directly linked to genetics.[1] Still, in everyday practice, we lack in successfully recognizing these patients, in providing them with adequate and meaningful genetic counseling, and in assisting them with appropriate support. The implications of a missed genetic diagnosis in the patient are far-reaching. It may lead to under diagnosis of systemic associations in the proband. Potentially affected family members whose vision can be saved by early intervention are also likely to be missed. For example, a diagnosis of a disorder as aniridia at an early age warrants screening for Wilms’ tumor which, if left undiagnosed, can lead to increased mortality in such patients.[2] However, the risk of Wilms’ tumor becomes extremely low if other family members are affected. The first step to enable successful recognition of these patients in the clinic includes obtaining a detailed family history and a medical history of the patient. Pedigree charting (PC) remains to be the universal, well-understood, and fastest technique to obtain and record the same. The eye remains to be the most accessible and easy to visualize organ of the human body in which genetic phenomena such as variable expression and X‑linked inheritance can be seen even in the absence of a molecular diagnosis. Cases with skewed lyonization can be observed directly in the fundus of female carriers of X‑linked disorders such as retinitis pigmentosa and ocular albinism. It is the second most common organ after the brain to be involved in genetic disorders and has aided in the discovery of important revelations such as mitochondrial inheritance via the study of Leber’s hereditary optic neuropathy and first the human cancer gene RB1. Most monogenic and polygenic disorders follow the laws of inheritance laid out by Gregor Mendel. Recurrence risk estimation and family counseling is easier in such cases. However, multifactorial disorders, which are much more prevalent, are caused due to an interplay between several genetic alterations and environmental factors. The inheritance pattern for such In the age of fast-evolving medicine, as we understand disease pathology and the role of genetic mutations in causation more clearly, advancement in treatment methodologies such as gene therapy is gaining pace. Most eye disorders, especially in the pediatric population are attributable to a genetic etiology. In the current scenario, apart from the clinical assessment and management, an ophthalmologist is expected to provide genetic counseling and appropriate testing for the above. This includes the provision of an accurate diagnosis, prognostication of the course of the disease, estimating the risk to the family members, and outlining the systemic implications if any. However, to understand the genetic etiology of any disorder, careful analysis of generations of family history, their medical records, and deducing patterns of inheritance called “pedigree analysis” remains at the core of these discoveries. Although genetic disorders account for most of the diseases encountered in ophthalmic practice, the familial inheritance pattern is seldom sought. This article aims to deliver a basic introduction to pedigree charting and analysis with specific examples in ophthalmology. It sheds light on the symbols used to create a pedigree chart and step‑by‑step instructions for its construction. It also aims to teach the art of deducing inheritance patterns with important tips and tricks for easy interpretation. Nonspecific and atypical pedigrees that are hard to deduce have also been discussed while highlighting various advantages and shortcoming of using this method. Keywords: Genetic counseling, hereditary disorders, pedigree charting Address for correspondence: Dr. Shailja Tibrewal, Dr. Shroff’s Charity Eye Hospital, 5027, Kedar Nath Lane, Daryaganj, New Delhi ‑ 110 002, India. E‑mail: [email protected] This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. For reprints contact: [email protected] How to cite this article: Ratna R, Tibrewal S. The role of pedigree charting and analysis in ophthalmology. Delhi J Ophthalmol 2023;33:18‑24. The Role of Pedigree Charting and Analysis in Ophthalmology Ria Ratna1 , Shailja Tibrewal1,2 1 Department of Ocular Genetics, Dr. Shroff’s Charity Eye Hospital, New Delhi, India, 2 Department of Paediatric Ophthalmology, Dr. Shroff’s Charity Eye Hospital, New Delhi, India Access this article online Quick Response Code: Website: https://journals.lww.com/djo DOI: 10.4103/DLJO.DLJO_25_23 Submitted: 25-Mar-2023 Accepted: 25-Apr-2023 Published: 05-Jul-2023 18 © 2023 Delhi Journal of Ophthalmology | Published by Wolters Kluwer - Medknow
Ratna and Tibrewal: Pedigree charting and analysis multifactorial disorders is hard to decipher due to high variability within families.[3] Most diseases have a genetic component to them from increasing our genetic susceptibility or “predisposition” to disease or even to infections. For example, more than 65 candidate genes have been identified in systemic inflammation, angiogenesis, and neurogenesis pathways of diabetic retinopathy.[4] The current article aims to provide a tool to medical professionals to recognize families with hereditary disorders, gain a basic understanding of how a disease allele might be segregating within a family, and refer them for appropriate counseling and testing. The article dwells on the art and science of PC, how to interpret a pedigree with ophthalmic examples, and the uses and limitations of PC. Clinical Utility of Pedigree Charting Guide for genetic testing In the absence of a specific clinical diagnosis, medical history and analysis of the family pedigree can point toward the probable cause of the condition. In cases with an available diagnosis, it is useful to assess at-risk individuals and counsel them about the disease and its implications. This would particularly be useful in a disorder such as bilateral retinoblastoma which has 90% penetrance and is life-threatening due to tumor metastasis.[5] Once the pathogenic mutation for the family is identified, prenatal diagnosis, extended family member screening, and vigilant surveillance can be offered to high‑risk individuals in the family. Careful pedigree analysis can also help us understand if a condition is hereditary or not and decipher challenging inheritance patterns. A good example of such a scenario would be families with oculo-cutaneous albinism. Some members of the family might display the full spectrum of the disease consisting of hypopigmentation of the hair and skin and the characteristic ocular changes found in albinism such as nystagmus, reduced iris pigment with iris translucency, and reduced retinal pigment. On the other hand some family members might have just mild skin hypopigmentation and lack visual complains entirely. Genetic testing in such cases becomes important to conclude if the disorder runs in the family or is de novo in the progeny. Identification of at-risk individuals A well‑charted, multigenerational pedigree can help determine individuals in the family who are at risk of manifesting the disorder, carriers who might pass on the disorder to their offspring, or asymptomatic carriers (carrying the disease allele in case of autosomal dominant [AD] inheritance). Such individuals can then be counseled concerning the genetic test recommendations, family planning, and clinical checkups if required. A cornerstone for genetic counseling Pedigree construction and analysis is the most crucial step in a genetic counseling session. The family is explained how a detailed family history would be useful, followed by a series of questions for pedigree construction and analysis. Apart from the obvious advantage of deducing inheritance patterns and recurrence risks as mentioned earlier, another benefit of obtaining a family pedigree is rapport building. It helps the patients ease into the session, get comfortable with the counselor, and more open to answering questions about their family’s health in most cases. Another basic advantage of obtaining a detailed family history includes the ability to distinguish if a trait is genetic or influenced by environmental factors or both. Implications in research A pedigree going back several generations supported by the medical histories of several members has a strong role in research. A distinct understanding of clinically normal and affected individuals, on genetic analysis, helps distinguish gene distribution patterns and identify novel pathogenic genes by linkage analysis. Several unique populations have been identified carrying specific variants in various parts of the world and pedigree analysis has helped establish relationships between these families in some cases playing a vital role in evolutionary genetics. This sheds some light on the constricted ethnic gene pool of mutations in such populations. Deeper medical insight When PC and genetic testing lead to the diagnosis of a genetic disorder in a family, it can give more information about secondary health implications a person might suffer. For example, a tall, lean patient with a history of lens subluxation is possibly affected by a connective tissue disorder like Marfan syndrome. A genetic mutation identified in the FBN1 gene would confirm the diagnosis and other systemic medical examinations such as echocardiography for the heart may be advised in asymptomatic individuals.[6] Moreover, other family members with minor indications of being affected such as being tall and lean with hyperextensible joints can also indicate the need for testing henceforth. Such an approach has a great impact on the management of a disorder and decreases the likelihood of medical mishaps. Understanding Pedigree Charting A retrospective review of the medical ailments in the family is charted and analyzed to obtain an idea about the possible pattern of inheritance. This PC is a graphical representation of family history by taking a particular disease or character into consideration.[7] The advent of PC changed the face of genetic analysis by giving information about the probable inheritance of genes by deriving a 3–4 generational medical history of a family comprising several individuals. It is the best screening tool before recommending any genetic test. The person of interest from whom the pedigree is initiated by bringing a specific trait into notice is called the proband.[8] The pedigree represents the family members and relationships using standardized symbols. Some of the basic symbols for pedigree making are shown in Table 1. Figure 1 illustrates how a basic pedigree is initiated and how to interpret the different relationship lines. Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 19
Ratna and Tibrewal: Pedigree charting and analysis Art of Constructing a Pedigree Chart Although the technique of PC varies among professionals, most individuals prefer to first start with the proband/diseased individual drawn in the center of the page and marked with an arrow at the lower-left corner. It is followed by obtaining information about their parents (consanguinity should be specified) and siblings starting from the eldest to the youngest, making their way up to previous generations. For each couple in a pedigree, males are drawn to the left and females to the right.[7] Each individual’s name should be mentioned by their initials and age/age of death should be written below the symbols. Age of onset of symptoms and age of diagnosis for affected individuals should be mentioned where known.[7] A good, informative pedigree contains information about at least three or more generations. Clinical information about each member is obtained either verbally or by reviewing medical records. Individuals affected by the same disease within the family are labeled with the same pattern, for example, a solid color. If more than one genetic condition is affecting an individual, then a different pattern is used to denote each disease and a “key” of the same is provided at the corner of the pedigree chart explaining the inference of each pattern.[9] Some examples of good and bad pedigrees are shown in Figure 2a and b, respectively. PC can be performed by a geneticist, genetic counselor, or experienced clinicians and optometrists in the field in either a hand‑drawn pictorial pattern on paper or with the help of online tools and software such as Progeny, Cyrillic, PhenoTips, and PED6. Links to some of the online tools mentioned above are as follows: • https://www.progenygenetics.com • https://phenotips.org/. The Science of Pedigree Analysis A single affected member in a family is usually less useful to understand the inheritance pattern of a disorder. However, if multiple members are affected, it gives some clue toward the same. There are four main patterns of inheritance observed in pedigrees: autosomal recessive (AR), AD, sex‑linked, and mitochondrial inheritance.[8] To deduce a pedigree, the following points should be observed: • Number of individuals affected • Skipping of generation • Consanguinity lines • Type of distribution (vertical vs. horizontal) • The proportion of males and females (sex distribution/ bias) • Transmission of disease from male to female or male to male. The following section contains examples explaining the deduction techniques and application of these inheritance patterns using pedigree charts. (All pedigrees constructed are hypothetical examples designed by the author and are not derived from other publications/work). In the pedigree shown in Figure 3a, many individuals are affected with no sex‑linked bias, and members are affected in each generation. When “vertical” transmission of a disorder is observed, i.e., no skipping of generations occurs, it is most likely due to AD, mitochondrial, Y‑linked, or X‑linked dominant inheritance.[9] Further, when the disease is passed Table 1: Common symbols used in pedigree charting Symbol Interpretation Male Female Gender not specific/unknown Affected male Affected with two different condition 5 Number of siblings of the same gender Nonconsanguineous couple Consanguineous marriage Divorced/separated Deceased Adopted Proband P Pregnancy 20 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 Figure 1: Illustration of the different relationship lines used in a pedigree
Ratna and Tibrewal: Pedigree charting and analysis on in an un‑bias fashion affecting both males and females equally, it is more likely to be AD. Equal proportions of males and females in all the generations of the pedigree have the suspected disorder without a sex-linked bias. Thus Figure 3a is most likely to follow AD pattern of inheritance. An example of AD disease is aniridia caused by PAX6 mutations.[10] Affected children would have at least one affected parent. Each affected parent has a 50% chance of passing on the disease allele to their offspring. However, there are exceptions to this rule, as seen in the subsequent examples. Figure 3b is another example of a family with vertical transmission of a trait. We can see that there is a predominance of affected females. Whenever a sex‑linked bias is seen, observing the transmission pattern (male to females or male to males) should be the next step in evaluation. Since fathers can transmit their X chromosome only to their daughters and Y chromosome only to their sons, this characteristic enables us to decipher the inheritance pattern in sex-linked pedigrees. In the above pedigree, affected males are transmitting the disorder to only females and no male-to-male transmission is seen. Thus, it is most likely an X‑linked dominant pedigree. In X‑linked dominant pedigrees, equal probability of affected males and females exists, but affected females transmit the disorder to 50% of her offspring and affected males transmit it to all his daughters and no sons. An example is incontinentia pigmenti type 1, characterized by dermatological, ocular, dental, and neurological abnormalities.[11] Figure 4a-c depicts seemingly dominant pedigrees with noteworthy characteristics that would help the reader distinguish them during classification. In Figure 4a, individuals in all the generations are affected and more females seem to be affected than males except individuals in generation III. Also note, while the disease is seemingly being passed on from affected parents in each generation, individual III‑iii is an exception as being normal while the offspring IV-iii is affected with the disease. This could be an AD pedigree if Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 21 Figure 2: (a) A well‑constructed pedigree with a deducible mode of inheritance with all important details mentioned. Note, the generation number is mentioned for each succession in roman numerals with the eldest sibling drawn to the left and the youngest drawn to the right. Also, important details like the AOO and cause of death in case of young/sudden deaths are mentioned. The consanguinity within the family is well‑explained and the pedigree also contains a key specifying the disorder running in the family. (b) A poorly represented pedigree with improper construction technique lacking necessary information. Members of the same generation are not in the same plane, which creates confusion. Unlike an informative pedigree, it lacks age, the initials of everyone, and any details of the disorder. AOO: Age of onset a b Figure 3: (a) An autosomal dominant trait inherited directly from a parent who has the disease themselves. Multiple members in the family without skipping generations can be affected. (b) A X‑linked dominant family pedigree a b
Ratna and Tibrewal: Pedigree charting and analysis we assume the mutated gene to have “reduced penetrance.” Reduced penetrance is observed when an individual carries the mutated allele but does not express the disease or any symptoms of it throughout their lives. Hence, AD is a probable inheritance pattern here. This pedigree could also belong to mitochondrial inheritance, in which both sexes can be affected, but its distinguishing feature is that only females transmit the disease with all children affected and males do not transmit the disease.[12] This description fits the pedigree well except, as noted, some affected mothers(II‑i, II‑ii, and III-xi) are not passing on the disease trait to some of their offsprings. Also, a normal mother (III‑iii) is transmitting the disease to her offspring (IV-iii) without being affected by the disease herself. This could be due to a phenomenon called mitochondrial heteroplasmy. Each cell in the body contains multiple mitochondria, and in rare cases, only a proportion of them carry the mutated allele whereas the others have normal mitochondrial DNA.[12] Hence, the disease is expressed differently in different individuals. This is also an equally likely mode of inheritance for this pedigree. Thus, it can be deduced that the inheritance pattern in the pedigree shown in Figure 4a is either AD with reduced penetrance or mitochondrial with heteroplasmy. At this point, we realize that studying the pedigree alone may not give us a concrete answer and clinical information/diagnosis is of equal importance. In this case, a clinical diagnosis of Leber’s hereditary optic atrophy, which is a known mitochondrial disorder, helps us understand that it is most likely a mitochondrial inheritance pedigree.[13] Another, less commonly observed pedigree with the vertical transmission is Y-linked inheritance pedigrees. These are only transmitted male‑to‑male, and no females are affected. Affected fathers must pass it on to all their sons and no daughters, as depicted in Figure 4b. The Y chromosome is small and has very few disease-causing genes on it. Its main functional region called the SRY region (sex-determining regions) is mainly responsible for ‘maleness’ features such as patterned baldness, cochlear hypertrichosis etc. Mutations in the SRY region lead to a range of disorders of sexual development.[14] “Horizontal” transmission of a disorder is observed when several members of the same generation are affected with or without previously affected members in the family. Such a pattern can be observed in AR, X‑linked recessive, or AD pedigrees with incomplete penetrance. The pedigree in Figure 4c shows two generations of affected individuals without a sex‑linked bias. It could either be AR or AD. However, in non-consanguineous populations as breeding happens at random, it is less likely that all phenotypically normal individuals (I-I, I-ii, II-vii) are carriers of the same disease-causing genetic variation. Thus, the more likely explanation could be that it is an AD pedigree, and one of the proband’s paternal grandparents are asymptomatic carriers of the mutated allele (reduced penetrance) and the future generations are affected. An example of an ocular dominant disorder with reduced penetrance would be Waardenburg syndrome.[15] Let us consider the pedigree shown in Figure 5a. Here, we observe, skipping of generation, line of consanguinity, and no sex‑linked bias. A trait is more likely to be transmitted in AR‑pattern when unaffected/carrier parents pass the disease trait to affected progeny without sex‑linked bias. Consanguinity observed in families is a clue toward AR inheritance. Hence, this pedigree is most likely presenting AR inheritance, e.g., retinitis pigmentosa and albinism. 22 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 Figure 4: (a) Mitochondrial inheritance with maternal inheritance, no male transmission and incomplete penetrance. (b) Y‑linked inheritance. (c) Autosomal dominant Waardenburg syndrome showing incomplete penetrance and variable expression. Adapted from Anvesh et al.,[15] b c a
Ratna and Tibrewal: Pedigree charting and analysis A “knight’s move” pedigree is a term used to describe a family tree presenting X‑linked recessive inheritance.[16] X‑linked recessive inheritance is marked by the presence of only affected males, as they have only one copy of the X chromosome which turns out to be faulty. Male to offspring transmission is not observed and affected males are related to unaffected/normal females. These females are usually carriers of the disease-causing trait on one of their X chromosomes. Atypical X‑linked inheritance pedigree is depicted in Figure 5b, a good example being red‑green color blindness.[17] In very rare instances, females can also be affected in X‑linked recessive disorders due to a phenomenon called X‑linked inactivation (lyonization).[18] In these cases, the normal X chromosome in the complement is silenced and not transcribed; hence, only the faulty X chromosome is active, producing defective or no protein. Limitations of pedigree charting and analysis a. When it is difficult to deduce any of these inheritance patterns by looking at a pedigree, it is called a “nonspecific” pedigree. It may be due to multifactorial disorders running in a family where the manifestation of the disorder is also governed by the environment or chromosomal translocations. These disorders do not follow Mendel’s laws of inheritance. An example of a high prevalence multifactorial disorder would be high myopia, where apart from genetic predisposition (affected parents), environmental influences such as exposure to screen and history of reading at proximity also play an important role b. Factors such as incomplete penetrance, variable expression, and X‑linked inactivation as explained earlier may complicate interpretation of pedigrees due to concealed phenotypic expression of the diseases c. Conditions requiring complete clinical evaluation or biochemical tests to confirm the disease can be missed. Also, subclinical diseases with overlapping phenotypes also pose significant challenges. For example, visually insignificant congenital cataracts in seemingly unaffected family members may go unnoticed unless examined under a slit lamp d. Another example of a limitation would be a polygenic disorder with multiple modes of inheritance such as retinitis pigmentosa e. Factors such as incomplete family and medical history of proband, incorrect information, and concealing disease-related information often make accurate PC and diagnosis difficult. Nonetheless, in medicine, pedigree analysis is an essential part of a complete medical workup for a genetic disease. The information obtained is an important aid in understanding the disorder and providing the best counseling to the family. Disorders with a genetic disposition constitute most of the clinical practice; however, incorporation of PC into the routine functioning of a medical professional remains a less practiced science in most clinical setups and hence these families are not provided with holistic counseling and care. Bringing PC into regular clinical practice and advising genetic testing would ensure recognition of mutations specific to the population and accurate diagnosis of genetic disorders. Acknowledgment We are grateful to Dr. Umang Mathur (Executive Director, Dr. Shroff Charity eye Hospital), Dr.Virender Sangwan (Director of Innovations, Dr. Shroff Charity eye Hospital), and Dr. Suma Ganesh (Head of Department, Paediatric Ophthalmology, strabismus and Neuro-ophthalmology) for their constant guidance. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. References 1. Singh M, Tyagi SC. Genes and genetics in eye diseases: A genomic medicine approach for investigating hereditary and inflammatory ocular disorders. Int J Ophthalmol 2018;11:117‑34. 2. Breslow NE, Norris R, Norkool PA, Kang T, Beckwith JB, Perlman EJ, et al. Characteristics and outcomes of children with the Wilms Tumor‑Aniridia syndrome: A report from the National Wilms Tumor Study Group. J Clin Oncol 2003;21:4579‑85. 3. Van Heyningen V, Yeyati PL. Mechanisms of non-Mendelian inheritance in genetic disease. Hum Mol Genet 2004;13:R225‑33. 4. Sharma A, Valle ML, Beveridge C, Liu Y, Sharma S. Unraveling the role of genetics in the pathogenesis of diabetic retinopathy. Eye (Lond) 2019;33:534‑41. 5. Harbour JW. Molecular basis of low‑penetrance retinoblastoma. Arch Ophthalmol 2001;119:1699‑704. Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 23 Figure 5: (a) Autosomal recessive inheritance pattern. Traits include consanguinity and horizontal transmission with skipping of generations. (b) X‑linked recessive disorder with only males affected, no male‑to‑male transmission and female carriers of pathogenic gene a b
Ratna and Tibrewal: Pedigree charting and analysis 6. Sakai LY, Keene DR, Renard M, De Backer J. FBN1: The disease-causing gene for marfan syndrome and other genetic disorders. Gene 2016;591:279‑91. 7. Bennett RL, French KS, Resta RG, Doyle DL. Standardized human pedigree nomenclature: Update and assessment of the recommendations of the national society of genetic counselors. J Genet Couns 2008;17:424‑33. 8. Connor JM. Pedigree analysis. In: Encyclopedia of Genetics. USA: Gale Encyclopedia of Genetic Disorders; 2001. 9. Bull L. Genetics, mutations, and polymorphisms. In: Madame Curie Bioscience Database. Austin (TX): Landes Bioscience; 2013. Available from: https://www.ncbi.nlm.nih.gov/books/NBK6475/. [Last accessed on 2019 Sep 13]. 10. Moosajee M, Hingorani M, Moore AT. PAX6-Related Aniridia. 2003 May 20 [updated 2018 Oct 18]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2023. PMID: 20301534. 11. Fierro JA, Avina DA. Incontinentia pigmenti with neurologic and oculodental disorders. Indian J Paediatr Dermatol 2016;17:24‑6. 12. Khan NA, Govindaraj P, Meena AK, Thangaraj K. Mitochondrial disorders: Challenges in diagnosis & treatment. Indian J Med Res 2015;141:13‑26. 13. Thieme H, Wissinger B, Jandeck C, Christ‑Adler M, Kraus H, Kellner U, et al. A pedigree of Leber’s hereditary optic neuropathy with visual loss in childhood, primarily in girls. Graefes Arch Clin Exp Ophthalmol, 1999;237:714‑9. 14. Stern C. The problem of complete Y‑linkage in man. Am J Hum Genet 1957;9:147‑66. 15. Anvesh G, Raju SB, Prasad K, Sharma A, Surendra M. Rare association of waardenburg syndrome with minimal change disease. Indian J Nephrol 2018;28:226‑8. 16. Farndon P. Recognizing the common patterns of inheritance in families. InnovAiT 2008;1:561‑74. 17. Sadagopan KA, Capasso J, Levin AV. Genetics for the ophthalmologist. Oman J Ophthalmol 2012;5:144‑9. 18. Van den Veyver IB. Skewed X inactivation in X‑linked disorders. Semin Reprod Med 2001;19:183‑91. 24 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023
Abstract Original Article Introduction Glaucomatous damage to the retinal ganglion and glial cells results in certain structural modifications which cause corresponding visual field (VF) changes.[1] Vision loss due to glaucoma is irreversible and its progression can be curtailed with early diagnosis and management. Clinical evaluation using slit-lamp biomicroscope and high-power convex lens and optic disc stereophotography are routinely used methods for the evaluation of glaucoma. However, these involve subjective assessment of optic nerve head (ONH) due to which minor changes such as notches and retinal nerve fiber layer (RNFL) loss are frequently overlooked, resulting in failure to differentiate between normal and glaucomatous disc. These methods have low sensitivity and reproducibility as it is dependent on subjective interpretation by the examiner and are subjected to interobserver variability.[2-6] These limitations are overcome by ONH and RNFL imaging. They have excellent ability to diagnose glaucoma, especially in eyes with early glaucoma that have suspicious optic disc and normal perimetry. A Cochrane review of studies done to evaluate the ability of ONH and RNFL parameters of spectral-domain optical coherence tomography (SD-OCT) has found it to have an excellent role in early diagnosis of glaucoma.[7] Purpose: The purpose of the study was to quantitatively assess the retinal nerve fiber layer (RNFL) using spectral‑domain optical coherence tomography (SD-OCT) and compare with standard automated perimetry in eyes with primary open-angle glaucoma patients and glaucoma suspects. Materials and Methods: RNFL thickness measurement by SD‑OCT and visual fields (VFs) parameters assessment was done in 160 eyes of 80 patients who were divided into three categories as 80 glaucomatous eyes, 40 glaucoma suspects, and 40 age‑ and gender‑matched normal controls. RNFL thickness values were analyzed and compared with perimetric results. One-way analysis of variance was used for the mean comparison analysis between the groups. The relationship between VF parameters and the average RNFL thickness was analyzed with the help of receiver operating characteristic curves. Results: The mean average RNFL thickness in normal controls, glaucoma suspects, and glaucoma patients was 101.58 ± 5.24, 92.35 ± 5.56, and 79.00 ± 7.97 µ, respectively (P < 0.001). There was a direct significant correlationship between average RNFL thickness and VF parameters of mean deviation and pattern standard deviation in glaucoma suspects and glaucoma patients. There was a significant association between average RNFL thickness and VF defects associated with glaucoma in glaucoma patients’ group. Conclusion: Patients with glaucoma had significantly lower RNFL quadrant measurements when compared with glaucoma suspects and normal controls. Analysis of RNFL is an excellent means for the early diagnosis of glaucoma and also aids in monitoring the progression of disease. Keywords: Glaucoma suspects, primary open‑angle glaucoma, retinal nerve fiber layer thickness, spectral‑domain optical coherence tomography, visual field parameters Address for correspondence: Dr. Samruddhi N. Chanekar, South Goa District Hospital, Margao ‑ 403 602, Goa, India. E‑mail: [email protected] This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. For reprints contact: [email protected] How to cite this article: Chanekar SN, Usgaonkar UP, Akarkar SO. Analysis of retinal nerve fiber layer thickness in glaucoma suspects and glaucoma by spectral domain optical coherence tomography and its correlation with visual field parameters. Delhi J Ophthalmol 2023;33:25‑30. Analysis of Retinal Nerve Fiber Layer Thickness in Glaucoma Suspects and Glaucoma by Spectral Domain Optical Coherence Tomography and its Correlation with Visual Field Parameters Samruddhi N. Chanekar1 , Ugam P. S. Usgaonkar2 , Shekhar O. Akarkar1 1 Department of Ophthalmology, South Goa District Hospital, Margao, Goa, India, 2 Department of Ophthalmology, Goa Medical College, Bambolim, Goa, India Access this article online Quick Response Code: Website: https://journals.lww.com/djo DOI: 10.4103/DLJO.DLJO_4_23 Submitted: 23-Feb-2023 Accepted: 22-Mar-2023 Published: 05-Jul-2023 © 2023 Delhi Journal of Ophthalmology | Published by Wolters Kluwer - Medknow 25
Chanekar, et al.: Retinal nerve fiber layer thickness in patients of glaucoma This study is done to quantitatively assess the RNFL using SD-OCT and compare with standard automated perimetry in eyes with primary open-angle glaucoma patients and glaucoma suspects. Materials and Methods This hospital-based prospective study was done at a tertiary care center from November 2018 to April 2020 (18 months). The study was done in compliance with the Institutional Ethics Committee. The census method of sampling was used for the collection of data. Informed consent was obtained from patients for enlistment in the study. The study was done as per the Declaration of Helsinki criteria for research. A total of 160 eyes (80 patients) were included in the study, of which 80 eyes (40 patients) were of glaucoma patients, 40 eyes (20 patients) of glaucoma suspects, and 40 eyes (20 patients) of normal controls. Inclusion criteria • Age: 40–70 years • Best-corrected visual acuity of 6/12 or better • Refractive error: Myopia <−3.00 D • Hypermetropia < +3.00 D • Astigmatism < ±2.00 D. • Open angles on gonioscopy (by Shaffer’s system angle grade >2) • Patients’ cooperation for VF analysis and SD-OCT. Exclusion criteria • Age <40 years and >70 years • Best-corrected visual acuity of < 6/12 • Refractive errors: Myopia ≥−3.00 D • Hypermetropia ≥+3.00 D • Astigmatism ≥ ±2.00 D. • Closed angles by gonioscopy • Secondary glaucomas/Juvenile glaucoma • Media opacities – Cataractous lens, corneal opacity, vitreous hemorrhage precluding posterior segment examination, or diminishing visual acuity <6/12 • Retinal pathology (advanced diabetic retinopathy, macular disease, ARMD) • Neurological diseases affecting VFs • Patients who underwent surgical management for glaucoma • Medications or diseases known to affect VF and RNFL thickness. All patients had a complete ophthalmologic evaluation including medical, ocular, and family history. Examination included visual acuity testing, slit-lamp examination, gonioscopy, dilated direct and indirect ophthalmoscopy, intraocular pressure (IOP) measurement using Goldmann applanation tonometry, central corneal thickness measurement, and refraction. Glaucomatous eyes were designated on the basis of dilated fundus examination. Optic-disc changes such as neuroretinal rim thinning, disc hemorrhage, inferior or superior rim notch, rim excavation, defects in nerve fiber layer, and difference of more than 0.2 in cup‑to‑disc ratio between two eyes were looked for the diagnosis of glaucoma. The cirrus high‑definition OCT (Carl Zeiss Meditec, Dublin; CA) was used for imaging for this study. Optic disc is recorded with this device in 6 mm × 6 mm cube comprising 200 B-scans each of which consists of 200 A‑scans. Analysis is performed by dividing this area into sections. The center of the optic disc is recognized automatically through the data in the cube. Acircle of 3.46 mm is formed around the disc, and RNFL thickness in peripapillary region is analyzed and compared with normative data stored in the system. RNFL thickness is obtained from the data of the scanned cube. Thinned areas are represented by cold colors, whereas dark colors are used for the thick areas. Color codes range from blue (0) to white (350 µ). Standard automated perimetry was conducted using the Humphrey field analyzer (HFA) II 24–2 program (Carl Zeiss Meditec) with a Goldmann size III (0.43°) stimulus on a 31.5 apostilb background within 1 week of OCT testing. All tests were reliable (with false positives and false negatives ≤33% and fixation losses ≤20%). For comparison, we used Humphrey global indices mean deviation (MD) and pattern standard deviation (PSD) and type of glaucomatous VF defect. Patients were classified into three categories based on Anderson’s criteria as follows: Glaucoma • Diagnostic criteria for glaucoma: Glaucomatous optic-disc changes such as cup‑to‑disc ratio ≥0.6, focal/diffuse neuroretinal rim thinning, disc hemorrhage, and RNFL thinning with corresponding VF defects with open angles on gonioscopy • Glaucomatous VF defect defined as two of the following three criteria confirmed on two consecutive fields as per the Anderson’s criteria: 1. The presence of cluster of three points on a pattern deviation probability plot with probability of <5%, one of which had a probability of <1% 2. PSD with probability of <5% 3. Glaucoma hemifield test results outside the normal limits. Patients diagnosed on above criteria receiving medical management for glaucoma were included in this category. Glaucoma suspects • IOP<21 mmHg on two consecutive measurements spaced 2 weeks apart at approximately same time of the day • Optic disc changes suggestive of glaucoma such as cup‑to‑disc ratio ≥0.6, focal/diffuse neuroretinal rim thinning, disc hemorrhage, and RNFL thinning • No evidence of VF abnormality on HFA. Normal controls were defined as those with no history of ocular/neurological/systemic diseases that might interfere with test results, IOP <21 mmHg, normal optic disc, and normal VFs. 26 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023
Chanekar, et al.: Retinal nerve fiber layer thickness in patients of glaucoma Statistical analysis The data analysis in the current study was done using the IBM SPSS Statistics for Windows version 22 (IBM Corp., Armonk, N. Y., USA). The continuous variables were showed in the form of mean ± standard deviation, and categorical variables were shown in the form of count and percent. The comparison among continuous data was done using the Student’s t-test, whereas categorical data were analyzed using the Chi-squared test. One‑way analysis of variance (ANOVA) was used for the mean comparison analysis of paired parameters between the groups. Relation between variables was investigated with Pearson’s correlation coefficient. We used receiver operator characteristic to determine the test reliability. The relationship between VF parameters and the average RNFL thickness was analyzed with the help of receiver operating characteristics (ROC) curves. Sensitivity and specificity of each test parameter were determined by obtaining the highest sensitivities, with target specificity set at 90%. P < 0.05 was considered statistically significant. Results The mean age of the patients was 58.825 ± 6.71, 54.15 ± 8.50, and 56.25 ± 7.76 in years for glaucoma patients, glaucoma suspects, and normal controls, respectively. The gender ratio was 61.25% of males and 38.75% of females. Baseline characteristics of the study population and the mean comparison analysis are summarized in Table 1. The mean average RNFL thickness in our study in normal controls, glaucoma suspects, and glaucoma patients was 101.58 ± 5.24, 92.35 ± 5.56, and 79.00 ± 7.97 µ, respectively (P < 0.001) [Table 2]. Values of area under the curve (AUC) for average RNFL thickness for comparison between glaucoma patients, glaucoma suspects, and normal controls are shown in Table 3. Similarly, AUC values for superior and inferior RNFL measurements show good diagnostic accuracy for the diagnosis of glaucoma [Table 4]. When average RNFL was compared with MD and PSD, it showed direct correlation for glaucoma patients and glaucoma suspects (P < 0.001). There was no significant relationship in normal controls [Table 5]. There is an overlap in RNFL thickness distribution among the eyes in our groups. Hence to compare VF parameters of MD and PSD against average RNFL thickness, we generated ROC curves by calculating optimal cutoff value for RNFL thickness which comes to RNFL of ≥91 µ. Results are shown in Graphs 1 and 2. The widest area under the ROC curve was obtained for both MD and PSD. AUC values of 0.968 and 0.963 for MD and PSD, respectively, against average RNFL thickness Table 1: Basic data in studied groups Glaucoma patients (n=80) Glaucoma suspects (n=40) Normal controls (n=40) t P Spherical equivalent Range −2.0–2.0 −2.0–2.5 −2.0–2.5 1.1269 0.3266 Mean±SD 0.0906±0.9746 −0.0562±1.1428 0.3±1.1715 IOP (mmHg) Range 10–26 12–20 10–16 9.692 0.001 Mean±SD 15.6±2.8357 16.25±3.3583 13.75±1.9839 MD (dB) Range −2.98–10.45 −0.43–4.12 −0.12–−1.3 212.7124 0 Mean±SD −6.6461±2.1497 −2.5235±1.1507 −0.4962±0.2796 PSD Range 1.14–4.86 0.12–2.12 −1.3–0.84 163.4925 0 Mean±SD 2.4755±0.8364 1.023±0.5716 0.192±0.39803 SD: Standard deviation, IOP: Intraocular pressure, MD: Mean deviation, PSD: Pattern SD Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 27 Graph 1: ROC curve for MD for average RNFL thickness. RNFL: Retinal nerve fiber layer, MD: Mean deviation, ROC: Receiver operating characteristics
Chanekar, et al.: Retinal nerve fiber layer thickness in patients of glaucoma Table 4: Area under curve values for inferior and superior retinal nerve fiber layer measurements for comparison between glaucoma patients, glaucoma suspects, and normal controls Inferior RNFL Superior RNFL AUC SE 95% CI AUC SE 95% CI Lower Upper Lower Upper Normal controls versus glaucoma suspects 0.854 0.040 0.775 0.933 0.855 0.041 0.775 0.934 Normal controls versus glaucoma patients 0.981 0.009 0.963 0.999 0.998 0.002 0.994 1.002 Glaucoma suspects versus glaucoma patients 0.876 0.031 0.816 0.936 0.967 0.013 0.941 0.993 AUC: Area under curve, SE: Standard error, RNFL: Retinal nerve fiber layer, CI: Confidence interval Table 2: Comparison between normal controls, glaucoma suspects, and glaucoma patients regarding retinal nerve fiber layer measurements RNFL thickness (µ) Normal controls Glaucoma suspects Glaucoma patients F P Inferior 130.15±6.39 118.3±8.94 96.63±16.16 101.514 0 Superior 124.3±7.23 113.53±6.57 95.04±8.03 219.925 0 Nasal 85.65±6.27 71.78±8.39 65.33±10.76 61.772 0 Temporal 65.63±5.76 64.13±8.71 56.74±6.88 25.955 0 Average 101.58±5.24 92.35±5.56 79.00±7.97 157.369 0 All RNFL in microns. RNFL: Retinal nerve fiber layer Table 3: Area under curve values for average retinal nerve fiber layer thickness for comparison between glaucoma patients, glaucoma suspects, and normal controls Average RNFL thickness (µ) AUC SE 95% CI Lower Upper Normal controls versus glaucoma suspects 0.889 0.036 0.819 0.959 Normal controls versus glaucoma patients 0.992 0.005 0.982 1.002 Glaucoma suspects versus glaucoma patients 0.908 0.025 0.859 0.958 AUC: Area under curve, SE: Standard error, RNFL: Retinal nerve fiber layer, CI: Confidence interval 28 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 indicate that there is a significant relationship between average RNFL thickness for MD and PSD. Table 6 shows the distribution of type of VF defect in glaucoma patients’ group. The ANOVA for the mean and PSD in these three groups of VF defects(no VF defect, single‑hemifield VF defect, and both hemifield VF defect) was significant (P = 0.000 for MD and P = 0.003 for PSD) [Table 7]. The average MD for these groups was ‑6.6461 ± 2.1497, and average pattern deviation was 2.4755 ± 0.8364. Discussion Estimation of glaucomatous damage is of paramount importance before initiating the therapy. The current protocol for the assessment of glaucomatous damage involves testing VF changes with automated perimetry and quantification of structural damage (RNFL and optic disc) with OCT. In our study, comparison between glaucoma patients, glaucoma suspects, and normal controls regarding basic data (spherical equivalent, IOP in mmHg, MD in dB, and PSD) shows that there is a statistically significant decrease in MD and significant increase in PSD in glaucoma patients with P < 0.001. In our study, we found that patients with glaucoma had significantly lower average RNFL quadrant measurements when compared with glaucoma suspects and normal controls. Furthermore, average RNFL thickness measurements in glaucoma suspects were significantly lower than normal controls. Similar findings were noted for quadrant-wise distribution of RNFL thickness, i.e., inferior, superior, nasal, and temporal quadrants. This is in similar with the study of Golzan et al.,[8] who assessed RNFL thickness in patients with glaucoma and healthy patients. In their study, glaucoma Graph 2: ROC curve for PSD for average RNFL thickness. RNFL: Retinal nerve fiber layer, PSD: Pattern standard deviation, ROC: Receiver operating characteristics
Chanekar, et al.: Retinal nerve fiber layer thickness in patients of glaucoma Table 6: Distribution of type of visual field defect in glaucoma patients group Visual field defect Number of eyes (%) Normal 4 (5.00) Generalized sensitivity 11 (13.75) Nasal step 4 (5.00) Paracentral scotoma 2 (2.50) Superior arcuate scotoma 25 (31.25) Inferior arcuate scotoma 15 (18.75) Double arcuate scotoma 19 (23.75) Total 80 (100) Table 5: Comparison of average retinal nerve fiber layer thickness with mean deviation and pattern standard deviation Average RNFL thickness (µ) (Pearson correlation coefficient) Glaucoma patients (P) Glaucoma suspects (P) Normal controls (P) MD 0.8656* (0.001) 0.7789* (0.001) 0.3589 (0.02295) PSD −0.634* (0.001) −0.7492* (0.001) −0.2865 (0.07308) *P value is significant at <0.01. RNFL: Retinal nerve fiber layer, MD: Mean deviation, PSD: Pattern standard deviation Table 7: Analysis of visual field defect in relation to mean deviation and pattern standard deviation VF parameter VF defects No field defect Single field defect Both field defect Eyes (n) 15 46 19 MD, mean±SD −4.2327±1.2241 −6.6376±1.9336 −8.5721±0.993 PSD, mean±SD 1.8827±0.536 2.4561±0.8398 2.9905±0.7142 VF parameter F-test P MD 29.3305 0 PSD 8.8477 0.0003 VF: Visual field, MD: Mean deviation, SD: Standard deviation, PSD: Pattern SD Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 29 patients had significantly lower RNFL thickness compared to normal patients (87 ± 26 µm vs. 111 ± 15 µm, P < 0.0001). Astudy done by Ajtony et al.,[9] who assessed RNFL thickness in patients with normal, preperimetric glaucoma, and primary open-angle glaucoma patients showed similar results. In their study, patients with glaucoma had a significant lower RNFL thickness as compared to preperimetric glaucoma and normal patients (77.99 ± 20.06 µm vs. 90.56 ± 10.96 µm vs. 96.48 ± 8.24 µm, P < 0.001). A study by El‑Naby et al. [10] assessed average RNFL thickness in patients of different stages of glaucoma and healthy controls. Patients with glaucoma had significantly lower average RNFL thickness as compared to healthy controls. Furthermore, our study is in accordance with that done by Mansoori et al. [11] which was conducted in Asian Indian patients to evaluate SD-OCT use for the diagnosis of early glaucoma. The study included 178 eyes (83 patients with glaucoma and 95 age‑matched healthy persons). The mean RNFL thickness in healthy controls and patients with glaucoma was 105.7 ± 5.1 and 90.7 ± 7.5 µm, respectively (P = 0.001). Multiple other studies have been done comparing RNFL measurements with conventional methods of structural and functional assessment of optic disc.[12‑17] In a study by Bowd et al.,[14] they studied 87 eyes for RNFL thickness in each quadrant and concluded that glaucoma patients have a significant RNFL thinning when compared to normal in each quadrant. They also inferred that RNFL defect in inferior quadrant had most significant correlation to the presence of glaucoma, followed by superior quadrant RNFL changes. Our study confirms the findings that inferior and superior quadrant OCT measured RNFL thickness has close relationship to glaucoma status. The correlation of RNFL with VF abnormalities has already been reported in the literature.[18,19] These studies have described the discriminating power of OCT between normal patients and patients with glaucoma.[20,21] Our study showed direct significant correlationship between average RNFL thickness and VF parameters (MD and PSD) in glaucoma suspects and glaucoma patients. No significant relationship was noted in normal controls. This is in accordance with the study of Ajtony et al.,[9] which showed a significant correlationship between MD and PSD and RNFL thickness in glaucomatous eyes. The current study compared AUC for average RNFL thickness with visual defects associated with glaucoma in glaucoma patients’ group, and it was found to be significant (0.940). Receiver operator characteristic curve to prove the accuracy of the diagnostic test has been used in various recent studies, showing similar AUC values. Williams et al. [22] used ROC curves to compare RNFL thickness with the presence of VF defects associated with glaucoma. The AUC for RNFL in patients with VF defects was 0.73 and was found to be significant. The current study also compared the association of visual hemifield defects with corresponding hemiretina to study the correlation of average RNFL measurements and VFs by automated perimetry (superior hemifield defect association with inferior hemiretina NFL thinning and vice versa). The ROC curve for inferior hemifield defects with superior RNFL thinning and superior hemifield defects with inferior RNFL thinning showed significant AUC (0.895 and 0.861, respectively). OCT can be used to detect structural changes in glaucoma. RNFL analysis has been the main thing in OCT imaging in glaucoma since its inception, although in recent years, analysis of macular and optic nerve neuroretinal rim thickness on OCT have become increasingly popular.[13] RNFL analysis has considerable diagnostic ability in early glaucoma.[23,24]
Chanekar, et al.: Retinal nerve fiber layer thickness in patients of glaucoma 30 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 Neuroretinal rim thinning in glaucoma occurs in a specific pattern following ISNT rule, breach in which could be indicative of glaucoma. Most commonly inferior and superior neuroretinal rim thinning is observed and hence AUC is on higher side for inferior followed by superior quadrant. There is a lot of advancement in image quality of SD-OCT and newer OCT tools. Certain biological factors such as age, disorders of retina, and visual pathway affect RNFL thickness, so also are acquisition artifacts which would lead to difficulty in the assessment of RNFL changes.[25] Ophthalmologist should look over all these confounding factors while interpreting the OCT report. To differentiate physiological cupping from glaucomatous changes, careful inspection of the disc for hemorrhages, baring of vessels, and notching is paramount important. In this current cross-sectional study, we did not evaluate multiple measurements per patient over time, so causal relationships were not established, although there was a strong correlation between structural and functional tests. Conclusion RNFL thickness analysis on OCT helps to identify early defects, and this can be useful as an excellent objective and quantitative method in the diagnosis and management of glaucoma. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. References 1. Hood DC, Kardon RH. A framework for comparing structural and functional measures of glaucomatous damage. Prog Retin Eye Res 2007;26:688‑710. 2. Lichter PR. Variability of expert observers in evaluating the optic disc. Trans Am Ophthalmol Soc 1976;74:532‑72. 3. Mikelberg FS, Airaksinen PJ, Douglas GR, Schulzer M, Wijsman K. The correlation between optic disk topography measured by the video-ophthalmograph (Rodenstock analyzer) and clinical measurement. Am J Ophthalmol 1985;100:417‑9. 4. Shields MB, Martone JF, Shelton AR, Ollie AR, MacMillan J. Reproducibility of topographic measurements with the optic nerve head analyzer. Am J Ophthalmol 1987;104:581‑6. 5. Caprioli J, Klingbeil U, Sears M, Pope B. Reproducibility of optic disc measurements with computerized analysis of stereoscopic video images. Arch Ophthalmol 1986;104:1035‑9. 6. Shields MB. The future of computerized image analysis in the management of glaucoma. Am J Ophthalmol 1989;108:319‑23. 7. Michelessi M, Lucenteforte E, Oddone F, Brazzelli M, Parravano M, Franchi S, et al. Optic nerve head and fibre layer imaging for diagnosing glaucoma. Cochrane Database Syst Rev 2015;2015:CD008803. 8. Golzan SM, Morgan WH, Georgevsky D, Graham SL. Correlation of retinal nerve fibre layer thickness and spontaneous retinal venous pulsations in glaucoma and normal controls. PLoS One 2015;10:e0128433. 9. Ajtony C, Balla Z, Somoskeoy S, Kovacs B. Relationship between visual field sensitivity and retinal nerve fiber layer thickness as measured by optical coherence tomography. Invest Ophthalmol Vis Sci 2007;48:258‑63. 10. El‑NabyAE, Abouelkheir HY, Al‑Sharkawy HT, MokbelTH. Correlation of retinal nerve fibre layer thickness and perimetric changes in primary open‑angle glaucoma. J Egypt Ophthalmol Soc 2018;111:7‑14. 11. Mansoori T, Viswanath K, Balakrishna N. Ability of spectral domain optical coherence tomography peripapillary retinal nerve fiber layer thickness measurements to identify early glaucoma. Indian J Ophthalmol 2011;59:455‑9. 12. Kanamori A, Nakamura M, Escano MF, Seya R, Maeda H, Negi A. Evaluation of the glaucomatous damage on retinal nerve fiber layer thickness measured by optical coherence tomography. Am J Ophthalmol 2003;135:513‑20. 13. Schuman JS, Hee MR, Puliafito CA, Wong C, Pedut‑Kloizman T, Lin CP, et al. Quantification of nerve fiber layer thickness in normal and glaucomatous eyes using optical coherence tomography. Arch Ophthalmol 1995;113:586‑96. 14. BowdC, WeinrebRN, WilliamsJM, ZangwillLM. The retinal nerve fiber layer thickness in ocular hypertensive, normal, and glaucomatous eyes with optical coherence tomography. Arch Ophthalmol 2000;118:22‑6. 15. Kaw SM, Martinez JM, Tumbocon JA, Atienza ND. Correlation of average RNFL thickness using the STRATUS OCT with the perimetric staging of glaucoma. Philipp J Ophthalmol 2012;37:19‑23. 16. Firat PG, Doganay S, Demirel EE, Colak C. Comparison of ganglion cell and retinal nerve fiber layer thickness in primary open‑angle glaucoma and normal tension glaucoma with spectral‑domain OCT. Graefes Arch Clin Exp Ophthalmol 2013;251:831‑8. 17. Elbendary AM, Mohamed Helal R. Discriminating ability of spectral domain optical coherence tomography in different stages of glaucoma. Saudi J Ophthalmol 2013;27:19‑24. 18. Leung CK, Chan WM, Chong KK, Yung WH, Tang KT, Woo J, et al. Comparative study of retinal nerve fiber layer measurement by StratusOCT and GDx VCC, I: Correlation analysis in glaucoma. Invest Ophthalmol Vis Sci 2005;46:3214‑20. 19. Kwon YH, Hong S, Honkanen RA, Alward WL. Correlation of automated visual field parameters and peripapillary nerve fiber layer thickness as measured by scanning laser polarimetry. J Glaucoma 2000;9:281‑8. 20. Budenz DL, Michael A, Chang RT, McSoley J, Katz J. Sensitivity and specificity of the StratusOCT for perimetric glaucoma. Ophthalmology 2005;112:3‑9. 21. Hoh ST, Greenfield DS, Mistlberger A, Liebmann JM, Ishikawa H, Ritch R. Optical coherence tomography and scanning laser polarimetry in normal, ocular hypertensive, and glaucomatous eyes. Am J Ophthalmol 2000;129:129‑35. 22. Williams ZY, Schuman JS, Gamell L, Nemi A, Hertzmark E, Fujimoto JG, et al. 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Abstract Original Article Introduction The Tear Film and Ocular Surface Society[1-3] defined dry eye disease as “dry eye is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.” In short, dry eye disease is an ocular surface disorder that causes discomfort and reduced vision due to tear film instability. The incidence of dry eye in India has been estimated to be around 0.42% with a male: female ratio of 1:1.22.[4,5] Background: An adequate and consistent layer of tears on the surface of the eye is essential to keep your eyes healthy, comfortable, and well. Consequences of dry eyes range from subtle but constant eye irritation to significant inflammation and even scarring of the front surface of the eye. This study was to evaluate the changes in the tear film. The aim of this study was to compare subjectively and objectively the course of surgically induced tear film changes in terms of dryness of eyes induced surgically after phacoemulsification and manual small incision cataract surgery (SICS) in tertiary care hospital. Materials and Methods: One hundred eyes of 100 patients were chosen for a prospective study. Those patients were included who had unilateral or bilateral cataracts without dry eye symptoms. By simple randomization, any abnormality in the tear film in pre‑ and postphacoemulsification and manual SICS was studied. Patients were tested for different parameters such as tear meniscus height (TMH), tear film breakup time, Schirmer test 1, and Rose Bengal staining. Eyes were tested 1 day before and 1 day, 1 month, and 3 months after surgery. Moreover, they were analyzed for possible causative factors. The association between categorical variables was analyzed using the Chi-square test. The paired t-test was used to compare the mean of quantitative variables. Preexisting ocular disease, surgery, trauma, and systemic diseases were ruled out. Results: There was no significant difference between the two groups at the end of 3 months. Fifty‑three males and 47 females between the age group of 50 and 70 years were studied prospectively for changes in tear film after cataract surgery for 2 years from January 2015 to December 2016, i.e., 24 months. Group 1 consisted of manual SICS and Group 2 consisted of phacoemulsification surgery. Among 50 patients in Group 1, there were 23 (46%) females and 27 (54%) males, and among 50 patients in Group 2, 24 (48%) females and 26 (52%) males. TMH was evaluated by image software of the slit lamp. The difference between the two gender groups was insignificant (P = 1.000). Conclusion: As any kind of incision over the cornea or ocular surface be it clear corneal or incision over the sclera like in SICS causes disturbance in the ocular surface; it causes tear film changes postoperatively. It is observed that there are definitely tear film changes seen after the surgery as microscopic ocular surface damage during any kind of incision of cataract surgery seems to be one of the causative factors causing discomfort and dry eye. But the changes at the end of three months were tear film changes have no significant difference with reference to the kind of surgery performed. Keywords: Manual small incision cataract surgery, phacoemulsification, tear film changes Address for correspondence: Dr. Shruti Shirwadkar, 102, Prakash Apartments, Dhobi Ali, Tembhi Naka, Thane West, Mumbai ‑ 400 601, Maharashtra, India. E‑mail: [email protected] This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. For reprints contact: [email protected] How to cite this article: Shirwadkar S, Shinde C, Waghmare R, Ganvir A, Yadav A, Joshi S, et al. Changes in tear film after phacoemulsification and manual small incision cataract surgery in tertiary care hospital: Aprospective study. Delhi J Ophthalmol 2023;33:31‑5. Changes in Tear Film after Phacoemulsification and Manual Small Incision Cataract Surgery in Tertiary Care Hospital: A Prospective Study Shruti Shirwadkar, Chhaya Shinde, Rahul Waghmare, Amol Ganvir, Abhilasha Yadav, Sanyukta Joshi, Monisha Apte Department of Ophthalmology, Lokmanya Tilak Municipal Medical College, Mumbai, Maharashtra, India Access this article online Quick Response Code: Website: https://journals.lww.com/djo DOI: 10.4103/DLJO.DLJO_2_23 Submitted: 23-Feb-2023 Accepted: 28-Apr-2023 Published: 05-Jul-2023 © 2023 Delhi Journal of Ophthalmology | Published by Wolters Kluwer - Medknow 31
Shirwadkar, et al.: Changes in tear film after phacoemulsification and manual small incision cataract surgery in tertiary care hospital Cataract is the leading cause of blindness in people above 50 years, according to the National Blindness and Visual Impairment Survey India 2015–19. India was the first country to launch the National Program for Control of Blindness in 1976 to reduce blindness prevalence to 0.3% by 2020. However, the estimated prevalence of blindness still stands at 1.99%. However, still, cataract surgery is the most successful and fruitful of all. Still, many patients may complain of foreign body sensation, redness, and blurring of vision.[6] After cataract surgeries, a few of the factors which can lead to the development of dry eye include prolonged use of antibiotic‑steroid eye drops, decreased tear film breakup time (TBUT) due to surface irregularity at the site of the incision, decreased mucin production from the conjunctiva secondary to incision, decreased corneal sensation due to surgical incision, decreased mucin production from the conjunctiva secondary to incision poor tear film production, stability due to surgically induced ocular inflammation, and exposure to light from the operating microscope.[7‑9] Even though these symptoms may not persist for long, proper counseling of patients regarding these symptoms preoperatively is a necessity. In our study, the aim was to evaluate the changes in tear film after phacoemulsification and manual small incision cataract surgery (SICS) in tertiary care hospital. Materials and Methods This study was a single-center, prospective comparative study of 100 patients attending an outpatient department at tertiary care hospital from January 2015 to December 2016, i.e., 2 years, operated by a single surgeon. After getting proper written informed consent, 100 eyes of 100 patients with senile cataracts were enrolled in the study. Inclusion criteria Patients with senile cataracts aged between 50 and 70 years with no prior history or evidence of dry eye syndrome were randomly selected for the study. Exclusion criteria Patients <50 or more than 70 years of age, having other kinds of cataracts like complicated and traumatic, and those who were having preoperative dry eyes were excluded from the study. Complicated surgery and prolonged surgeries were excluded. One hundred eyes of 100 patients were randomly divided into two groups: • Group 1: Out of 100, 50 eyes underwent manual SICS • Group 2: The remaining 50 patients were operated on for 2.8 mm clear corneal phacoemulsification surgery. Clinical examination included comprehensive anterior segment evaluation done under slit lamp biomicroscopy to rule out lid margins diseases and surface disorders. Tear meniscus height (TMH), TBUT, Schirmer test 1 (ST1), and Rose Bengal (RB) staining were done in all patients. Patients were evaluated using the ocular surface index (OSI) questionnaire. Technique All surgeries in both groups were performed by the same experienced surgeon. As a protocol, all patients were put on systemic and topical antibiotics a day before surgery. On the day of surgery, pupils were dilated using 0.8 mg tropicamide and 10% phenylephrine hydrochloride drops 2 h before cataract surgery. On Group 1 patients – manual SICS with the either superior or temporal sclerocorneal tunnel was performed under a peribulbar block. The incision was 6–6.5 mm in length and 1.5–2 mm from the limbus. A rigid (PMMA) Polymethyl methacrylate or foldable intraocular lens was implanted in all patients. Group 2 patients had undergone either superior or temporal clear corneal incision of 2.8 mm and were operated on by phacoemulsification technique and inserted foldable intraocular lens. A standard postoperative regime was applied to all the patients. All patients were put on a combination of steroid antibiotic drops in tapering doses for 8 weeks. Postoperative evaluation was done at 1 week, 1 month, and 3 months. At each visit, TMH, TBUT, ST1, and RB staining were done. Tear meniscus height The TMH can be used to estimate tear volume. ATMH<0.25mm is suggestive of dry eye. The precorneal tear film was observed for the presence of debris (mucous/oil droplets/debris). Tear film breakup time measurement Eyes were stained with 2% fluorescein. TBUT is the interval between the last complete blink and the first appearance of a dry spot over the cornea under a slit lamp using a cobalt‑blue filter. Three readings were taken, and the average was calculated. TBUT <10 s was considered dry eye [Figure 1]. Schirmer test 1 ST1 tests without anesthesia were done to assess the aqueous tear production (basic plus reflex secretion) and were evaluated by inserting a 5 mm × 35 mm sterile strip of Whatman No. 41 filter paper in the lower fornix at the junction of the middle and 32 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 Figure 1: TBUT (fluorescein stain). TBUT: Tear film breakup time
Shirwadkar, et al.: Changes in tear film after phacoemulsification and manual small incision cataract surgery in tertiary care hospital lateral third of the lower fornix. Wetting was measured after 5 min. Reading 10 mm or less is considered dry eye. The degree of dry eye can be graded using the amount of paper that is wet.[10] Rose Bengal stain It assesses the ocular surface damage. A sterile RB strip moistened with 4% xylocaine was applied to the inferior cul‑de‑sac. After 15 s, under red‑free light or bright light under the slit lamp, the eye was examined for staining of the cornea and conjunctiva. According to Van Bijsterveld’s scoring system, the interpretation of staining is based on intensity and location using a grading scale.[11] The nasal and temporal conjunctiva and the cornea are graded on a scale of 0–3 with a maximum possible score of 9. An additive score of 4 or more in the eye was considered a positive test [Figure 2]. Data were entered into Microsoft Excel (Windows 7; Version 2007), and analyses were done using the Statistical Package for the Social Sciences(SPSS) for Windows software (version 22.0; SPSS Inc, Chicago, IL, USA). Descriptive statistics such as mean and standard deviation (SD) for continuous variables and frequencies and percentages for categorical variables were determined. The association between categorical variables was analyzed using the Chi-square test. The paired t-test was used to compare the mean of quantitative variables at 1 week, 4 weeks, and 12 weeks by taking preoperative as the baseline. Acomparison of variables over time was analyzed using repeated measure analysis of variance. Furthermore, a comparison between the variables of both groups was made. The level of significance was set at 0.05. Results All patients were followed till 3 months postsurgery and assessed for the development of dry eye in terms of TMH, ST1, TBUT, and RB staining of the ocular surface. Out of 100 eyes of 100 patients, 53 males and 47 females between the age group of 50 and 70 years were studied prospectively for the changes in tear film after cataract surgery for 2 years from January 2015 to December 2016, i.e., 24 months. Among 50 patients in Group 1, there were 23 (46%) females and 27 (54%) males, and among 50 patients in Group 2, 24 (48%) females and 26 (52%) males. The difference between the two gender groups was insignificant (P = 1.000). TMH analysis of patients preoperatively showed all subjects had normal TMH values. From Group 1, at postoperative 1 week 21%, 1 month 28%, and 3 months 23% had low TMH, whereas from Group 2, at postoperative 1 week 19%, 1 month 26%, and 3 months 21% had low TMH pre- and postoperative dry eye test values for SICS are shown in Table 1 and Graph 1. Pre- and postoperative dry eye test values for phacoemulsification surgery are shown in Table 2 and Graph 2. The difference between Group 1 and Group 2 was statistically insignificant. Discussion Dry eye syndrome is one of the most common problems affecting the general population and can cause problems that range in severity from mildly irritating to debilitating. Any reduction in tear film causes improper visual outcome. The development of dry eye postcataract surgery could be unsatisfactory for both patients and doctors. Although there are few studies comparing both SICS and phacoemulsification techniques, it is in terms of visual outcomes postoperatively. In the literature, there are many causes of the development of dryness postcataract surgery. (1) As intact corneal innervation is important for normal tearing reflex, severing of the corneal nerves is caused due to cataract surgery which results in decreased corneal sensation resulting in reduced tear secretion. This is also called “denervation-induced dry eye.”[12,13] (2) Due to incision, there is surface irregularity or decrease of mucin production from the destruction of conjunctival goblet cells which causes tear film instability. (3) Phototoxicity due to microscope exposure. (4) Preservatives like benzalkonium chloride in postoperative drops destabilize the lipid layer of the tear film. (5) Environmental exposure to sunlight and wind causes dry eye. Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 33 Figure 2: RB stain. RB: Rose Bengal 0 5 10 15 20 25 Pre-op 1 week 4 weeks 12 weeks Percent of study subjects TBUT ST1 RB Graph 1: Comparison of TBUT, ST1, and RB in SICS. TBUT: Tear film breakup time, RB: Rose Bengal, SICS: Small incision cataract surgery, ST1: Schirmer test 1
Shirwadkar, et al.: Changes in tear film after phacoemulsification and manual small incision cataract surgery in tertiary care hospital As there is no gold‑standard diagnostic test for the assessment of dry eyes, various diagnostic tests with different sensitivities and specificities are used to diagnose dry eyes. In our study, TMH, TBUT, ST1, and ocular surface staining with RB were done. Many other studies comparing the preoperative and postoperative changes in dry eye symptoms and/or dry eye test values showed significant worsening after cataract surgery.[6,14-16] In our study, TMH values were lowest at 1 month, while it showed a slight improvement at 3 months. Irrespective of the type of surgery by the end of 12 weeks, all eyes showed statistically significant deterioration of tear secretion and tear stability proved by all tear film and dry eye tests. Studies by Dodia et al.,[19] in which dryness of eyes was evaluated in three groups, namely, SICS (B), phacoemulsification in clear corneal incision (A1), and phacoemulsification in scleral tunnel incision (A2). The incidence of dry eye changes was significantly high in the A1 group (28%), which is more than twice that seen in other groups. Patients with shorter TBUT had the next highest proportion, values being 20%, 12%, and 8% in GroupA1, A2, and Group B, respectively. Mohana et al.,[18] in their study, claimed that preoperatively, the mean and SD of TMH, Schirmer’s test, TBUT, ocular surface disease index, and impression cytology were, respectively, 0.55 ± 0.166, 9.23 ± 2.112, 9.48 ± 3.212, 56.18 ± 10.926, and 208.80 ± 59.120 in patients who underwent SICS and 0.55 ± 0.170, 9.231 ± 2.117, 9.487 ± 2.489, 54.482 ± 9.001, and 237.937 ± 238.1 in patients who underwent phacoemulsification. Thus, the two groups were similar in their dry eye status. Sinha M et al. [17] concluded that in general, as compared to preoperative assessment, all of the values peaked at 1 week and then tended to decline by the end of 1 month. However, none of these parameters returned to the baseline even at the 1-month follow‑up. These findings indicate that the peak impact of cataract surgery in terms of dry eye was during the 1st week and tended to decline thereafter. He also reported that although there was a recovery in all tear film parameters by the end of 3 months, the values did not reach the preoperative values. Similar results were observed in our study. The use of filters for light, less surgical time, gentle handling of ocular tissues, and proper way of irrigating fluids over the ocular surface will reduce postoperative dryness of eyes. Conclusion After this study and also after assessing many other previous studies, we can conclude that the changes in tear film and dryness of eyes are inevitable following cataract surgery irrespective of the type of surgery. Although there was a rapid deterioration of dry eye test values in the initial 1 week Table 1: Pre- and postoperative dry eye test values for small incision cataract surgery d Preoperative 1 week 4 weeks 12 weeks P TMH (%) 0 21 28 23 <0.001* TBUT 11.36±1.60 7.78±1.80 6.63±1.42 6.20±1.45 <0.001* ST 1 20.82±5.30 11.86±1.80 10.28±1.52 9.55±1.55 <0.001* RB 2.1±0.8 2.5±0.8 2.8±1.10 2.9±1.2 0.014* P 0.014* <0.001* <0.001* TMH: Tear meniscus height, TBUT: Tear film breakup time, ST 1: Schirmer test 1, RB: Rose Bengal Table 2: Pre- and postoperative dry eye test values for phacoemulsification surgery Tests Preoperative 1 week 4 weeks 12 weeks P TMH (%) 0% 19% 26% 21% <0.001* TBUT 11.53±1.50 7.90±2.01 7.15±1.25 6.56±1.23 <0.001* - <0.001* <0.001* <0.001* ST 1 20.06+/4.60 12.14±1.150 10.10±1.70 9.30±1.80 <0.001* - <0.001* <0.001* <0.x001* RB 1.90±1.15 2.15±1.23 2.35±1.16 2.42±1.18 0.358 - 0.358 0.054 0.027 TMH: Tear meniscus height, TBUT: Tear film breakup time, ST 1: Schirmer test 1, RB: Rose Bengal 34 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 0 5 10 15 20 25 Pre-op 1 week 4 weeks 12 weeks Percent of study subjects TBUT ST1 RB Graph 2: Comparison of TBUT, ST1, and RB in phacoemulsification. TBUT: Tear film breakup time, RB: Rose Bengal, ST1: Schirmer test 1
Shirwadkar, et al.: Changes in tear film after phacoemulsification and manual small incision cataract surgery in tertiary care hospital postoperatively, irrespective of the type of surgery in our study, subsequent 4 weeks and 12 weeks follow-ups showed gradual changes. Patients should be informed preoperatively regarding dryness of eyes after surgery. Minimal exposure to the microscope and routine use of preservative-free artificial tears postoperatively to alleviate symptoms should be practiced. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. References 1. Lemp MA, Baudouin C, Baum J, Dogru M, Foulks GN, Kinoshita S, et al. The definition and classification of dry eye disease: Report of the definition and classification subcommittee of the international dry eyeworkshop (2007). Ocul Surf 2007;5:75‑922. 2. Friedman NJ. Impact of dry eye disease and treatment on quality of life. Curr Opin Ophthalmol 2010;21:310-6. 3. Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK, et al. TFOS DEWS II definition and classification report. Ocul Surf 2017;15:276‑83. 4. Sullivan DA, Rocha EM, Aragona P, Clayton JA, Ding J, Golebiowski B, et al. TFOS DEWS II sex, gender, and hormones report. Ocul Surf 2017;15:284‑333. 5. Srinivasan R, Agarwal V, Suchismitha T, Kavitha S. Dry eye after phacoemulsification. AIOC Proceedings. 2008. 6. Cho YK, Kim MS. Dry eye after cataract surgery and associated intraoperative risk factors. Korean J Ophthalmol 2009;23:65‑73. 7. Sutu C, Fukuoka H, Afshari NA. Mechanisms and management of dry eye in cataract surgery patients. Curr Opin Ophthalmol 2016;27:24‑30. 8. Li XM, Hu L, Hu J, Wang W. Investigation of dry eye disease and analysis of the pathogenic factors in patients after cataract surgery. Cornea 2007;26:S16‑20. 9. Bron AJ, Abelson MB, Ousler G, Pearce E, Tomlinson A, Yokoi N, et al. Methodologies to diagnose and monitor dry eye disease: report of the Diagnostic Methodology Subcommittee of the International Dry Eye WorkShop (2007). Ocular Surface 2007;5:108-52. 10. van Bijsterveld OP. Diagnostic tests in the Sicca syndrome. Arch Ophthalmol 1969;82:10‑4. 11. Anom‑Supradnya I, Jayanegara W, Sugiana I, Raka Widiana I. Phacoemulsification and sutureless large incision manual cataract extraction change corneal sensibility. Bali Med J 2013;2:108‑12. 12. Khanal S, Tomlinson A, Esakowitz L, Bhatt P, Jones D, Nabili S, et al. Changes in corneal sensitivity and tear physiology after phacoemulsification. Ophthalmic Physiol Opt 2008;28:127‑34. 13. Ram J, Gupta A, Brar G, Kaushik S, Gupta A. Outcomes of phacoemulsification in patients with dry eye. J Cataract Refract Surg 2002;28:1386‑9. 14. Kohlhaas M. Corneal sensation after cataract and refractive surgery. J Cataract Refract Surg 1998;24:1399‑409. 15. Kasetsuwan N, Satitpitakul V, Changul T, Jariyakosol S. Incidence and pattern of dry eye after cataract surgery. PLoS One 2013;8:e78657. 16. Saif MY, Saif AT, Saif PS, Abd El Khalek MO, Mahran W. Dry eyechanges after phacoemulsification and manual small incision cataract surgery (MSICS). Int J Ophthalmol Eye Res 2016;4:18‑19. 17. Sinha M, Sinha A, Chowdhury B. Comparative evaluation of dry eye following cataract surgery: A study from North India. IOSR J Dent Med Sci 2014;13:13‑1816. 18. Ganvit SS, Ahir HD, Sadhu J, Pandya NN. Study of the dry eye changes after cataract surgery. Int J Res Med 2014;3:142‑5. 19. Dodia K, Bapat S, Chudasama RK. Dry eye risk factors after phacoemulsification cataract surgery at a secondary care hospital. Int J Health Allied Sci 2013;2:242‑5. Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 35
Original Article Introduction A cataract is one of the most common causes of impaired vision in the world. The majority of cataract surgeries are performed under regional anesthesia such as peribulbar anesthesia, sub-Tenon’s anesthesia, and topical anesthesia.[1] Peribulbar anesthesia has more frequent associations with chemosis and subconjunctival hemorrhage than retrobulbar blocks due to the anterior spread of anesthetic agent and damage of blood vessels by needle tip. Retrobulbar anesthesia has serious complications such as retrobulbar hemorrhage, globe perforation, optic nerve injury, myotoxicity, and oculocardiac reflex; hence, this technique is almost obsolete. Topical anesthesia comprises using anesthetic drops or gel on the surface of the eye. It is quick and pain free to administer and allows patients to immediately regain their sight after surgery.[2,3] However, it neither produces akinesia nor reduces pain sensitivity related to the iris or ciliary body.[4] Epithelial and endothelial toxicity has also been found.[1] Studies have shown that topical anesthesia was associated with more pain as compared to sub-Tenon’s anesthesia immediately and 30 min after surgery. A meta‑analysis has shown that there is an increased risk of posterior capsular rupture associated with topical anesthesia as compared to sub-Tenon’s anesthesia.[1] Sub-Tenon’s anesthesia consists of injecting an anesthetic agent directly into the sub-Tenon’s space with a curved blunted needle. Around 5 mL of anesthetic agent is injected. It provides more analgesia and is found to be associated with a lower rate of posterior capsular rupture as compared to topical anesthesia.[2] Patient satisfaction was also more with sub-Tenon’s anesthesia as compared to topical anesthesia.[5] Sub-Tenon’s anesthesia would be better for providing anesthesia in cases associated with an increased risk of intraoperative complications such as mature cataracts, posterior polar cataracts, phacodonesis, and traumatic cataracts. The conventional technique of performing sub-Tenon’s anesthesia consists of dissection performed by conjunctival Abstract Background: One of the most common regional anesthesia used in cataract surgeries is sub- Tenon’s anaesthesia. Sub-Tenon’s anaesthesia consists of injecting an anaesthetic agent directly into sub-Tenons space with a curved blunted needle. Most common complications related to sub-Tenon’s anaesthesia such as subconjunctival haemorrhage and chemosis has been associated with blunt dissection of conjunctiva and Tenon’s. However, it provides akinesia, analgesia and is considered the choice of anaesthesia in complicated cataracts. Aims and Objectives: An innovative technique of sub- Tenon’s anaethesia, to reduce the existing complications associated with sub-Tenon’s anaesthesia and reducing the volume of anesthetic administered while preserving the quality of anaesthesia. Materials and Methods: An innovative technique was developed avoiding the blunt conjunctival and Tenon’s dissection and replacing it by a point entry that is of size of a needle incision into the sub-Tenon’s space using lacrimal dilator. Results: This novel technique resulted in lesser occurrences of sub conjunctival hemorrhage, chemosis and even in lowering the volume of anesthetic agent used. It gave aesthetic satisfaction to patient postoperatively. Conclusion: NIST technique prevents the complications made by dissection in the conventional technique of sub-Tenon’s anesthesia, while ensuring the quality of anesthesia. Keywords: Cataract surgery, innovative technique, sub-Tenon’s anesthesia, surgical innovation Address for correspondence: Dr. Megha Nair, Aravind Eye Hospital, Puducherry, India. E‑mail: [email protected] This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. For reprints contact: [email protected] How to cite this article: Nair M, Tagare S, Venkatesh R, Vivekanandan VR. NIST: Needle incision sub-Tenon’s anesthesia. Delhi J Ophthalmol 2023;33:36‑8. NIST: Needle Incision Sub-Tenon’s Anesthesia Megha Nair, Shivraj Tagare1 , Rengaraj Venkatesh2 , Vellam Ramakrishnan Vivekanandan3 Department of Cornea and Refractive Services, 1 Department of Retina and Vitreous Services, 2 Chief Medical Officer, 3 Department of IOL and Cataract Services, Aravind Eye Hospital, Puducherry, India Access this article online Quick Response Code: Website: https://journals.lww.com/djo DOI: 10.4103/DLJO.DLJO_26_23 Submitted: 29-Mar-2023 Revised: 15‑Apr‑2023 Accepted: 25-Apr-2023 Published: 05-Jul-2023 36 © 2023 Delhi Journal of Ophthalmology | Published by Wolters Kluwer - Medknow
Nair, et al.: Needle Incision sub‐Tenon’s Anesthesia scissors in the inferonasal quadrant to gain access to the sub-Tenon’s space under Tenon’s capsule. The viscoelastic cannula is inserted into the sub-Tenon’s space and a local anesthetic agent is injected. However, this technique has been found to have various complications such as chemosis and subconjunctival hemorrhage.[6] Keeping this in mind, to reduce the existing complications associated with sub-Tenon’s anesthesia and reduce the volume of anesthetic administered, whereas preserving the quality of anesthesia; an innovative technique was developed to avoid the blunt conjunctival and Tenon’s dissection and replace it with a point entry into the sub-Tenon’s space using the lacrimal dilator. Methods Surgical technique The equipment required to perform NIST consists of a universal wire speculum, small Hoskin’s plain forceps, curved blunt‑tipped Wescott’s spring scissors, curved blunt‑tipped Steven’s cannula/27 G viscoelastic cannula, and Wilder bent lacrimal dilator size 3, all prepared after sterilization. The patient is prepared by placing intravenous access and monitoring by pulse oximetry. After the patient is made to lie in a supine position, two drops of local anesthetic proparacaine hydrochloride 0.5% are instilled into the conjunctiva. The conjunctiva is cleansed with 5% povidone‑iodine solution and lids with 10% povidone-iodine and is allowed to act for 3 min. Universal wire speculum is placed. 2.5ml of local anesthetic, a mixture of lignocaine and hylase, is withdrawn in a 5cc syringe. To apply the block, the inferonasal quadrant is chosen as it has the advantage of being away from the usual site of surgery and away from the insertions of extraocular muscles. The fused conjunctiva and anterior Tenon’s capsule are picked up at an inferonasal point using forceps, 7–10 mm from the limbs, and midway between the insertions of the medial and inferior rectus muscles. The conjunctiva and the tenons are captured firmly by a downward motion and a small triangular space is created. A small puncture hole is made in this triangular space using the lacrimal dilator. After making a small puncture hole, the sub-Tenon’s space is accessed by inserting the viscoelastic cannula/Steven’s cannula along the contour of the globe to create a thin channel just past the equator to the posterior sub‑Tenon’s space as shown in Figure 1. 2–2.5 mL of local anesthetic is introduced into the sub-Tenon’s space gently and slowly. Injection speed is to be kept at 1 mL/3 s. The speculum is removed, and gentle pressure is applied using sterile cotton over the point of the injection site with closed eyelids for about 2–3 min. Avoid ocular massage as it can cause raised intraocular pressure (IOP). The onset of analgesia and orbicularis block takes about 1–3 min and the onset of globe akinesia by 5–7 min. Results Subconjunctival hemorrhage occurred due to the rupture of vessels while dissecting the conjunctiva and Tenon’s capsule using the conjunctival scissors. The use of a lacrimal dilator in NIST carefully avoids or minimizes the number of blood vessels getting damaged during the process of making an entry into the sub-Tenon’s space as the diameter of the nick/puncture hole created by the lacrimal dilator is point size. It also helps choose a blood vessel-free zone for puncturing the conjunctiva and tenon. The incidence of subconjunctival hemorrhage was reduced using the NIST technique. The point size puncture hole in NIST also ensures that the anesthetic agent goes entirely into the sub-Tenon’s space with minimum leakage and hence requires the use of lesser volume of anesthetic drug, thereby only causing minimal IOP rise. Discussion Although there is a changing trend of performing phacoemulsification under topical anesthesia, many surgeons prefer using regional anesthesia to perform complicated cataract surgeries such as mature and hypermature cataracts, traumatic cataracts, and cataract surgeries in phacolytic and phacomorphic glaucoma; predicting the risk of complications to take place in these cases. Advantages of sub‑Tenon’s anesthesia include good analgesia, good akinesia, avoidance of complications by sharp needle techniques, no requirement of facial blocks, safe in patients on anticoagulants and with high axial length, and minimal rise in IOP. However, sub-Tenon’s anesthesia, when performed the conventional way, using conjunctival scissors, is often associated with complications such as chemosis and subconjunctival hemorrhage. Subconjunctival hemorrhage occurs due to the tearing of small blood vessels during conjunctival or Tenon’s capsule dissection.[6] Even though it is limited to one quadrant, it can easily spread to other quadrants. Subconjunctival hemorrhage can lead to a red-looking eye Figure 1: (a) Wilder bent lacrimal dilator size 3, (b) Tenting of the conjunctiva and Tenon’s capsule by forceps, (c) Needle size incision by lacrimal dilator, (d) Administration of the anesthetic agent c d a b Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 37
Nair, et al.: Needle Incision sub‐Tenon’s Anesthesia after surgery which is cosmetically unappealing for the patient. Patients taking antiplatelets have been found to have a higher incidence of subconjunctival hemorrhage, although not statistically significant.[7] Various strategies have been tried to reduce subconjunctival hemorrhage, such as careful dissection, application of vasoconstrictor-soaked buds, and localized conjunctival cautery before dissection.[8,9] The use of a lacrimal dilator in NIST carefully avoids or minimizes the number of blood vessels getting damaged during the process of making an entry into the sub-Tenon’s space as the diameter of the nick/ puncture hole created by the lacrimal dilator is point size. Thus, the incidence of subconjunctival hemorrhage was reduced using the NIST technique. The conventional sub-Tenon’s technique included dissection of the conjunctiva and Tenon’s to form a tract for the introduction of Steven’s cannula. This was found to be a dispensable step. In the NIST technique, the size of the puncture hole created by the lacrimal dilator was sufficient enough for the introduction of the 19 G Steven’s cannula/viscoelastic cannula, allowing a smooth entry into the sub-Tenon’s space without the requirement of dissection. As dissection was completely omitted, subconjunctival hemorrhage and chemosis were close to none. This ensured esthetic satisfaction to the patient postoperatively. The local anesthetic agent is injected using a 19 G Stevens cannula with an outer diameter of 1.067 mm. The outer diameter of the cannula should be accommodated to inject the local anesthetic agent; hence, dissection of size just sufficient to fit the cannula is enough. However, the dissection using conjunctival scissors often creates a larger defect in the conjunctiva and Tenon’s capsule. The large-size defect can be a potential source of infection and may require suturing. The large-size defect in the conjunctiva and Tenon’s capsule can lead to fibrosis, making it unsuitable for taking grafts for pterygium and other surgeries in the future. A larger defect makes it difficult to perform trabeculectomy and conjunctival peritomy in vitreoretinal surgeries. The puncture hole created by Wilder lacrimal dilator size 3 in the NIST technique is of size just sufficient to accommodate the 19 G Steven’s cannula, thereby preventing the complications of dissection as used in a conventional technique. A larger defect due to dissection can lead to leakage of the local anesthetic agent into the subconjunctival space, causing chemosis and also reducing the anesthetic agent going into the sub‑Tenon’s space. This leads to insufficient anesthesia, thereby making the patient uncooperative on the table due to a lack of akinesia and analgesia. Repeated sub-Tenon’s anesthesia or injecting greater volumes of anesthetic agents cause severe positive pressure and lead to grave complications during cataract surgeries. Sub-Tenon’s anesthesia requires up to 5 mL of anesthetic agent, and injecting more than 5 mL has been shown to increase IOP.[10] The point-size puncture hole in NIST ensures that the anesthetic agent goes entirely into the sub-Tenon’s space with minimum leakage and hence requires a lesser volume of anesthetic drug. Conclusion Thus, the NIST technique prevents the complications made by dissection in the conventional technique of sub-Tenon’s anesthesia while ensuring the quality of anesthesia. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. References 1. Guise P. Sub‑Tenon’s anesthesia: An update. Local Reg Anesth 2012;5:35‑46. 2. Guay J, Sales K. Sub-Tenon’s anaesthesia versus topical anaesthesia for cataract surgery. Cochrane Database Syst Rev 2015;2015:CD006291. 3. Barequet IS, Sachs D, PrielA, Wasserzug Y, Martinowitz U, Moisseiev J, et al. Phacoemulsification of cataract in patients receiving Coumadin therapy: Ocular and hematologic risk assessment. Am J Ophthalmol 2007;144:719‑23. 4. Reddy SC, TheviT. Local anesthesia in cataract surgery. Int J Ophthalmic Res 2017;3:204‑10. 5. Rüschen H, Celaschi D, Bunce C, Carr C. Randomised controlled trial of sub-Tenon’s block versus topical anaesthesia for cataract surgery: A comparison of patient satisfaction. Br J Ophthalmol 2005;89:291‑3. 6. Kumar CM, Eid H, Dodds C. Sub-Tenon’s anaesthesia: Complications and their prevention. Eye (Lond) 2011;25:694‑703. 7. Kumar N, Jivan S, Thomas P, McLure H. Sub‑Tenon’s anesthesia with aspirin, warfarin, and clopidogrel. J Cataract Refract Surg 2006;32:1022‑5. 8. Kumar CM, Dowd TC. Complications of ophthalmic regional blocks: Their treatment and prevention. Ophthalmologica 2006;220:73‑82. 9. Gauba V, Saleh GM, Watson K, Chung A. Sub‑Tenon anaesthesia: Reduction in subconjunctival haemorrhage with controlled bipolar conjunctival cautery. Eye (Lond) 2007;21:1387‑90. 10. Sohn HJ, Moon HS, Nam DH, Paik HJ. Effect of volume used in sub‑Tenon’s anesthesia on efficacy and intraocular pressure in vitreoretinal surgery. Ophthalmologica 2008;222:414‑21. 38 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023
Abstract Case Report Introduction Circumscribed choroidal hemangioma (CCH) is a congenital benign vascular tumor of the choroid which appears as a subtle orange–red round or oval mass, commonly found at the posterior pole with associated pigmentary changes. The diagnosis is either incidental or occurs when it causes symptoms such as exudative retinal detachment or macular edema. Treatment modalities for CCH include photodynamic therapy (PDT), laser photocoagulation, transpupillary thermotherapy (TTT), external beam plaque radiotherapy, intravitreal anti-vascular endothelial growth factor (VEGF) injection, and oral propranolol (nonselective beta blocker).[1,2] We describe a case of CCH with exudative foveal detachment successfully managed with laser photocoagulation and intravitreal anti-VEGF injection, due to the nonavailability of verteporfin dye used in PDT. Case Report A 37‑year‑old healthy male patient presented in the outpatient department with a complaint of seeing black spots gradually increasing in size in the left eye in the past 2 months. Best‑corrected visual acuity (BCVA) right eye was 20/20 and the left eye was 20/200. On examination, the left eye fundus examination [Figure 1a] revealed oval orange slightly elevated mass superonasal to the optic nerve head with overlying pigmentation and subretinal fluid (SRF), which Circumscribed choroidal hemangioma (CCH), an orange–red, well‑circumscribed benign neoplasm of choroidal vasculature. Ancillary tests for diagnosis are fundus fluorescein angiography, indocyanine green angiography, optical coherence tomography (OCT), OCT angiography, and ultrasound or magnetic resonance imaging. It is usually associated with cystoid macular edema, subretinal fluid (SRF), subretinal fibrosis, or retinoschisis. Choroidal hemangioma needs treatment, when it is associated with visual symptoms and exudative retinal detachment. Photodynamic therapy is the first‑line treatment, but currently, there is an unavailability of verteporfin dye. We are reporting an interesting case of a 37‑year‑old male diagnosed with CCH at our center, who presented with significant visual symptoms due to associated SRF at the macula. He was managed with high-duration low-power green laser photocoagulation and anti-vascular endothelial growth factor injection yielding to the resolution of SRF and an improvement in visual outcome. Keywords: Anti‑vascular endothelial growth factor, choroidal hemangioma, fundus fluorescein angiography, laser photocoagulation, optical coherence tomography, optical coherence tomography angiography, subretinal fluid Address for correspondence: Dr. Dhaivat Shah, Choithram Netralaya, Shriram Talawadi, Dhar Road, Indore, Madhya Pradesh, India. E‑mail: [email protected] This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. For reprints contact: [email protected] How to cite this article: Shah D, Agrawal D, Gangawar M, Porwal AC, Sukhwal R. Managing extramacular circumscribed choroidal hemangioma with green laser and anti-vascular endothelial growth factor injection in times of the unavailability of photodynamic therapy. Delhi J Ophthalmol 2023;33:39-41. Managing Extramacular Circumscribed Choroidal Hemangioma with Green Laser and Anti-Vascular Endothelial Growth Factor Injection in Times of the Unavailability of Photodynamic Therapy Dhaivat Shah, Deepanshu Agrawal, Maradula Gangawar, Amit C. Porwal, Rini Sukhwal Department of Ophthalmology, Choithram Netralaya, Shriram Talawadi, Indore, Madhya Pradesh, India Access this article online Quick Response Code: Website: https://journals.lww.com/djo DOI: 10.4103/DLJO.DLJO_6_23 Submitted: 23-Feb-2023 Accepted: 18‑Apr‑2023 Published: 05-Jul-2023 © 2023 Delhi Journal of Ophthalmology | Published by Wolters Kluwer - Medknow 39
Shah, et al.: Managing extramacular circumscribed choroidal hemangioma with laser and anti‐VEGF injection was noted to gravitate to the macula. The optical coherence tomography (OCT)-macula [Figure 1b] revealed SRF, and the OCT done at the level of the mass lesion [Figure 1c] showed a large dome-shaped elevation of the Retinal Pigment Epithelium (RPE) and associated SRF and hyperreflective deposits. Fluorescein angiography (FFA) [Figure 1d] showed early hyperfluorescence with staining in late phases and minimal leakage. No focal leaks were noted at the macula. The OCT angiography (OCTA) (6 × 6) scan [Figure 1e and f] showed irregular and dilated vessels in the choroidal slab. On the basis of these findings, a diagnosis of CCH was established. PDT, which is the first-line treatment, is currently unavailable due to supply chain issues due to global geopolitical tensions. Hence, we went ahead with a combination therapy of low-power high-duration green laser photocoagulation over the lesion, followed by an intravitreal anti-VEGF (bevacizumab) injection 24 h later. Scatter laser photocoagulation technique over the tumor surface was used with a spot size of 200 μm, duration of 4 ms, and power varying from 100 to 150 mW. We followed up with the patient monthly for the next 3 months, monitoring the BCVA, mass size, and SRF on OCT. At 3 months postprocedure, the patient had an improved BCVA of 20/40. There was a near total reduction in SRF on the fundus photo [Figure 2a], and the mass lesion had overlying chorioretinal atrophic patches (laser marks) [Figure 2b]. The findings were correlated with OCT‑macula [Figure 2c]. The OCT at the mass [Figure 2d] lesion revealed alterations at the RPE level, correlating with the laser scars. The patient was last seen at 6-month follow-up visit, where he was symptomatically better with a maintained visual acuity and no evident increase in the size of CCH. Discussion Choroidal hemangioma is a benign, congenital, vascular tumor usually found in adults around the fourth to sixth decade of life. It is usually asymptomatic but can have symptoms such as decrease of vision, floaters, and metamorphopsia due to secondary changes such as SRF and macular edema.[1-3] Various ancillary tests have been described to diagnose CCH, such as OCT, OCTA, FFA, indocyanine angiography, magnetic resonance imaging, and B-scan ultrasonography. These tests help diagnosing and differentiating CCH from other posterior segment disorders such as amelanotic choroidal melanoma, choroidal metastasis, and choroidal osteoma.[1] Symptomatic CCH needs prompt treatment. The most promising treatment accepted worldwide today is PDT, as it 40 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 Figure 1: (a) Fundus photo showing an elevated orange mass superonasal to the optic nerve head with an associated SRF at the macula (b) An OCT line scan across the macula reveals the presence of SRF. (c) OCT line scan at the level of mass lesion revealing a dome‑shaped lesion with reflective deposits and SRF at RPE. (d) Late phase FFA with hyperfluorescence at the lesion. (e and f) OCTA (Choroidal slab) (6 × 6) at the level of mass lesion revealing irregular and dilated choroidal vessels. OCT: Optical coherence tomography, SRF: Subretinal fluid, OCTA: OCT angiography, FFA: Fluorescein angiography c d b f a e Figure 2: (a) Fundus photo showing significant reduction in SRF at the macula (b) Fundus photo revealing laser marks on the surface of the mass lesion (c) OCT line scan at macula revealing a marked reduction in SRF level (d) OCT line scan at the mass lesion showing retinochoroidal adhesions, RPE alterations, and reduced SRF. OCT: Optical coherence tomography, SRF: Subretinal fluid c d a b
Shah, et al.: Managing extramacular circumscribed choroidal hemangioma with laser and anti‐VEGF injection resolves both subretinal and intraretinal fluid with minimal side effects.[4,5] Anti‑VEGF can lead to a reduction in tumor‑associated exudation by depleting endothelial fenestrae and altering intercellular adhesion molecules. SRF responds well, but the tumor does not reduce in size.[6] Laser photocoagulation is effective in treating choroidal hemangiomas with the resolution of SRF reported in 62%–100% of the cases, while the recurrence of SRF is >40%–50%. It has been found to cause shrinkage in tumor size.[7] Seldom case reports described in the literature have combined both entities to gain the advantage of tumor size reduction by laser and aiding the SRF resolution with anti-VEGF injection.[8] Our case responded well with the therapy, yet we believe a larger case series are required to put forward this therapy as a preferred line of treatment. Conclusion In cases of extra-macular CCH where the cost of treatment or unavailability of PDT dye/TTT is a concern, combination therapy of high-duration low-power green laser photocoagulation along with anti-VEGF injection can be of immense value. Patient consent Obtained. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. References 1. Sen M, Honavar SG. Circumscribed choroidal hemangioma: An overview of clinical manifestation, diagnosis and management. Indian J Ophthalmol 2019;67:1965‑73. 2. Mashayekhi A, Shields CL. Circumscribed choroidal hemangioma. Curr Opin Ophthalmol 2003;14:142-9. 3. Krohn J, Rishi P, Frøystein T, Singh AD. Circumscribed choroidal haemangioma: Clinical and topographical features. Br J Ophthalmol 2019;103:1448‑52. 4. Porrini G, Giovannini A, Amato G, Ioni A, Pantanetti M. Photodynamic therapy of circumscribed choroidal hemangioma. Ophthalmology 2003;110:674‑80. 5. Robertson DM. Photodynamic therapy for choroidal hemangioma associated with serous retinal detachment. Arch Ophthalmol 2002;120:1155‑61. 6. Mandal S, Naithani P, Venkatesh P, Garg S. Intravitreal bevacizumab (avastin) for circumscribed choroidal hemangioma. Indian J Ophthalmol 2011;59:248‑51. 7. Duquesne N, Bouchard O, Jean‑Louis B, Bievelez B, Grange JD. Argon laser photocoagulation of circumscribed choroidal hemangiomas. J Fr Ophtalmol 2002;25:42‑7. 8. Karimi S, Nourinia R, Mashayekhi A. Circumscribed choroidal hemangioma. J Ophthalmic Vis Res 2015;10:320‑8. Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 41
Case Report Introduction Anterior chamber hemorrhage (hyphema) is usually the result of trauma to the eye. Spontaneous hyphema is a rare occurrence. The most common cause of nontraumatic hyphema was rubeosis iridis. Spontaneous hyphema is also reported in cases of leukemia, bleeding disorders, and with the use of some drugs. This condition must be recognized timely to manage and prevent its complications, such as glaucoma and corneal blood staining.[1] Corneal blood staining can result due to long-standing hyphema with increased intraocular pressure (IOP).[2] The major cause of postoperative hyphema is direct trauma mostly to the iris. The next cause of hyphema is indirect trauma like coughing, sneezing, vomiting, and squeezing of the eye during dressing leading to the rupture of fine blood vessels.[3] Early diagnosis and treatment are important as they can lead to severe complications leading to irreversible vision loss. We, herein, report a case of hyphema after uneventful cataract surgery, which is later diagnosed as chronic lymphoid leukemia (CLL). It is a lymphoproliferative disorder characterized by monoclonal B-cell proliferation. Ocular involvement in CLL can be due to leukemic infiltrate or as a consequence of compromised immune function, hyperviscosity, thrombocytopenia, and anemia. Case Report A 71‑year‑old female patient was presented in the outpatient department of ophthalmology with complaints of diminution of vision in both her eyes for 1 year. Diminution of vision was more in the left eye. It was painless and progressive in nature. There was no history of ocular trauma, ocular surgery, colored halos, floaters, and flashes of light. There was no history of any medical illness or any drug intake. On examination, the visual acuity of the patient was the perception of light with accurate projection of rays in the left eye and 6/24 in the right eye. The pupils and iris were normal. The anterior chamber was shallow with Van Herick Grade 2. There was an intumescent cataract in the left eye and a posterior subcapsular cataract with nuclear sclerosis grade two in the right eye. The posterior segment was not visible due to media haze in the left eye, while it was normal in the other eye. IOP was 21 mm of Hg in both eyes. General physical examination was normal, and the patient was posted Abstract The ophthalmological examination plays a very important role in diagnosing several systemic diseases. The eye manifestations do not even help the physician to reach a certain diagnosis; however, sometimes, these are the only manifestations of the disease raising suspicion of a specific systemic disease. In this case report, a postcataract surgery patient presented with a persistent hyphema for 1 week. It raised suspicion of systemic coagulation abnormality in an otherwise healthy patient. Further investigations revealed the underlying diagnosis of chronic lymphoid leukemia (CLL). CLL is a monoclonal disorder affecting the blood and bone marrow, which is characterized by the proliferation and accumulation of mature but functionally incompetent lymphocytes. Keywords: Coagulation, hyphema, leukemia Address for correspondence: Dr. Pankaj Sharma, Zonal Hospital Dharamshala, Kangra, Himachal Pradesh, India. E‑mail: [email protected] This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. For reprints contact: [email protected] How to cite this article: Sharma A, Katoch K, Sharma P. Recurrent hyphema after cataract surgery: A diagnostic dilemma. Delhi J Ophthalmol 2023;33:42-4. Recurrent Hyphema after Cataract Surgery: A Diagnostic Dilemma Aakanksha Sharma1 , Kritika Katoch1 , Pankaj Sharma2 1 Department of Ophthalmology, Zonal Hospital Dharamshala, Kangra, Himachal Pradesh, India, 2 Department of Obgy, Zonal Hospital Dharamshala, Kangra, Himachal Pradesh, India Access this article online Quick Response Code: Website: https://journals.lww.com/djo DOI: 10.4103/DLJO.DLJO_3_23 Submitted: 23-Feb-2023 Accepted: 27‑Mar‑2023 Published: 05-Jul-2023 42 © 2023 Delhi Journal of Ophthalmology | Published by Wolters Kluwer - Medknow
Sharma, et al.: Recurrent hyphema after cataract surgery: A diagnostic dilemma for cataract surgery of the left eye. The patient’s fasting blood sugar was 96 mg/dl, and her blood pressure was 130/70 mmHg. Small incision cataract surgery of the left eye was done. The intraoperative course of the surgery was uneventful, and the eye was patched. On the first postoperative day, the eye patch was removed. Full chamber hyphema was noted on examination. There was no history of pain or trauma to the eye. On further examination, the patient’s cornea was clear, IOP was 20 mmHg, and blood pressure was 136/70 mmHg. Strict bed rest was advised for the patient with the propped-up position. The patient was started on antibiotics, steroid eye drops, and cycloplegics. IOP was monitored 4 hourly. On the second postoperative day, hyphema was settled; however, IOP was 26 mmHg [Figure 1]. The cornea was clear, and the intraocular lens was in the capsular bag. The patient was started on 0.5% timolol and was discharged on request. On the 6th postoperative day, the patient came to the outpatient department for routine follow-up. There was no history of pain in the eye, any oral drug intake, or trauma to the eye. Again, there was dispersed hyphema. No corneal staining was noticed. IOP was 21 mmHg. The patient was admitted, and strict bed rest with a propped‑up position was ensured. Again, hyphema was settled. After 2 days, there was rebleed with full chamber hyphema. Then, the patient was investigated for the cause. The coagulation profile of the patient was normal; however, the total leucocyte count was 197,000 cu/mm3 with lymphocyte predominance. The peripheral blood smear revealed leukocytosis with small mature lymphocytes in the majority with the presence of smudge cells. These smudge cells are more fragile than normal lymphocytes that are disrupted during the process of being spread on a glass slide. The possibility of CLL was kept, and flow cytometry was advised for characterization. Later on, the patient was referred for further management to a tertiary institute. On follow-up, we found that the patient was diagnosed as a case of CLL and managed for primary illness. Discussion Hyphema is the collection of blood in the anterior chamber of the eye. Most commonly, trauma is the cause of hyphema. Other causes of hyphema include uveitis, leukemia, hemophilia, von Willebrand disease, sickle cell disease, and the use of anticoagulant medications and intraocular surgery.[1] Neovascularization of the eye, most commonly associated with diabetes mellitus, also predisposes the patient for the occurrence of hyphema. These vessels are very thin and fragile, which rupture easily with changes in the IOP. Thus, the preoperative examination should rule out neovascularization of the eye to avoid any postoperative surprises as it become difficult to look for neovascularization because of hyphema settles inferiorly or disappears. Postoperative hyphema has become a less common entity with advancements in cataract surgery as clear corneal incision is preferred nowadays. It may result from intraoperative iris injury or due to a sudden increase in IOP rupturing the fine iris vessels. Postoperative hyphema is more common with glaucoma surgery than cataract surgery. Most of the cases respond to medical management; only a few cases need surgical management. The goal of management is to prevent rebleeding which will increase the chances of complications. Treatment begins with patient education cautioning that activity should be restricted to decrease the chances of rebleed. The head should remain elevated at least 45° even during sleep so as to allow the blood to settle in the anterior chamber. Patients should be asked to avoid nonsteroidal anti‑inflammatory drug analgesics that increase the risk of a rebleed. The potent topical steroid should be prescribed for associated inflammation. Cycloplegics such as atropine 1.0% or cyclopentolate 1.0% can be prescribed if patients have ciliary spasms or are photophobic. Associated ocular hypertension should be managed using aqueous suppressants. Prostaglandins and miotics should be avoided in these patients. If necessary, carbonic anhydrase inhibitors can be used; however, these should be avoided if sickle cell disease is suspected. In certain conditions, anterior chamber wash should be done to prevent corneal staining and glaucomatous changes in the eye, which can lead to structural damage to the eye. In patients posted for cataract surgery, we always enquire about any tooth extraction or surgery to rule out bleeding tendencies. In our case, it could not rule out bleeding tendency. Later on, even the coagulation profile was also normal. It was raised total leukocyte count which raised the suspicion of underlying hematological disorders, and on further investigation, CLL was diagnosed. In lymphoid leukemia, neoplastic B-cells escape apoptosis and continue to divide within the lymph nodes. They then infiltrate the spleen and bone marrow, causing splenomegaly. The splenomegaly leads to increased sequestration of red blood cells and platelets, leading to anemia and thrombocytopenia. Patients are more susceptible to autoimmune hemolytic anemia (positive Coombs test) and autoimmune thrombocytopenia. In these patients with thrombocytopenia, bleed/bruises and petechiae can be seen on physical examination. The majority of the patients with CLL remain asymptomatic. Treatment is determined by the patient’s symptoms and signs, and the clinical stage. Treatment modalities include chemotherapy with steroids and cytotoxic Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 43 Figure 1: Showing hyphema
Sharma, et al.: Recurrent hyphema after cataract surgery: A diagnostic dilemma agents, immunotherapy, and allo- or auto-transplantation of bone marrow with total body irradiation.[4] Conclusion There are very few incidences of hyphema postcataract surgery. Most of the cases result in patients on anticoagulant drugs or due to intraoperative trauma. Sometimes, the cause is not evident posing a diagnostic dilemma. Thus, rare causes like leukemia should be kept in mind to diagnose certain life-threatening systemic illnesses. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. References 1. Chen EJ, Fasiuddin A. Management of traumatic hyphema and prevention of its complications. Cureus 2021;13:e15771. 2. Krauthammer M, Mandelblum J, Spierer O. Corneal blood staining after complicated cataract surgery. Case Rep Ophthalmol 2018;9:421‑4. 3. Mathur KN, Awasthy P, Mathur JS. Hyphaema after cataract operation. J All India Ophthalmol Soc 1964;12:119‑22. 4. Buchan J, McKibbin M, Burton T. The prevalence of ocular disease in chronic lymphocytic leukaemia. Eye (Lond) 2003;17:27‑30. 44 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023