Delhi Journal of Ophthalomology

Current trends in Management of amblyopia

Collagen Cross Linking using Riboflavin/UVA treatment for corneal ectasia

Wave front guided correction for irregular cornea

Refractive lens exchange

NPCB Strategies for the (2007-2012)

Stem Cells- In ophthalmology and other fields

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S OCIET Y DELHI Editor Dr. Rajpal MO AL LO H G T I C Delhi

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Editorial Board: DJO Advisor : Chief Editor : Prof Rajvardhan Azad Dr. Rajpal Insan

Associate Editors: Tanuj Dada, Ajay Aurora, Viney Gupta, International Scientific Coordinator : Ashok Garg Rajesh Sinha, Kirti Singh, Arun Sangal Managing Editors : Rohit Saxena, Subhash Dadeya, M Vanathi, Vishnu Gupta, Punita K Sodhi International Advisory Board: Deputy Editor: Subrata Mandal, Anand Aggarwal, Shibal I Howard Fine (USA) Bhartiya, Rajender Khanna, Nita Gurha, Aditya Insaan, Tushar Mateen Ahmed (USA) Aggarwal, Anuj Mehta Samuel Ibrahim (Japan) Assistant Editors: Rajeev Garg, Bhawna Chawla, Meenakshi Boris Malyugin (Russia) Thakkar, Parijat Chandra, Tinku Bali Razdan, Piyush Kapoor, Mark J. Terry (USA) Sangeeta Abrol, Sarita Beri, Hemali Sharma ,Vandana Dhankar P. Muthusamy (Malaysia)

Senior Executive Editor: Lalit Verma, Sudhant Bharti, Namarata Sharma, Amit Khosla, Sanjay Chaudhary, B.P. Guliani, Rishi Mohan, Alkesh Chaudhary, Angshuman Goswam, Rajiv Gupta, Sanjeev Gupta, Rajendra Prasad,. Anita Sethi, Cyrus M. Shroff

Contributing Editors: Harinder Sethi, Prashant Naithani, Shashwat Ray, Nikhil Pal, Shalini Mohan, Noopur Gupta, .Sumi Gupta, Sulabh Goel, Rasheena Bansal, Thirumalesh, Rajesh, Siddarth, Sumeet Khanduja, Neha Khanduja, Sourabh Dileep Patwardhan Book Review Editors: Punita K. Sodhi. Abstract Review Editors: Ashu Agarwal, Ritika Sabharwal, Nishant Taneja, Charu Mittal, Sunil Kumar, Rajeev Sudan, Monica Insaan, Neera Agarwal,Vandana Dhankar

Section editors: Cornea: Anita Panda, Radhika Tandon, Ritu Arora, Ashok Sharma . Refractive surgery: Mahipal S Sachdev, Rajender Prasad Cataract: Abhay Vasavada, Sanjay Chaudhary, J S Titiyal, Anil Tara Glaucoma: Ramanjit Sihota, Harsh Kumar, Usha Raina, Usha Yadava, Devender Sood, JKS Parihar, JC Das Retina: Atul Kumar, YR Sharma Ocular Trauma: Brig. Vats, Parihar, B B Shukla, DK Mehta , Brig. Boparai, N. Chandra Oculoplasty: Ashok Grover, Sushil Kumar, Mandeep Bajaj, Neelam Pushkar, Archana Sood, Usha Kim Squint and Neuroophthalmolgy: Vimla Menon, Pradeep Sharma, Kamlesh, P.K Pandey, Gopal Das, Achal Srivastava,, J. L. Goyal Uvea and ocular inflammation: SP Garg, Vaishali Gupta, Pradeep Venkatesh ,Virender Sangwan, Rajpal Pediatric Ophthalmology: S. Ghose, S Khokhar, Anju Rastogi Ocular Genetics and Biochemistry. Jasbir Kaur, Rima Dada, Suma Ganesh, Sujata Mohanty Medical Ethics: Madan Mohan, TD Dogra, Rajendra Prashad Ocular Pharamacology: T Velpandian, Alok K Ravi Ocular Microbiology: Geeta Satpathy, Niranjan Nayak Community Ophthalmology: GVS Murthy, P Vashisht, Rajkumar, Monica, R Jose, A.S Rathore, Manoj Kumar Dhingra Ocular Anaesthesia: Ravinder Panday, Renu Sinha MO AL LO H G T I C Delhi

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Senior Academic Executive Editor Regional Editors: S. Ghose, Chief, R.P. Centre Sarita Beri-Lady Hardinge Medical College Hari Mohan, Mohan Eye Institute Brig D. P. Vats Army hospital (R & R), Delhi Cantt Gopal Das-Guru Tegh Bahadur Hospital S.C. Gupta, Medical Director, Zia Chaudhary- Guru Nanak Eye Centre Venu Eye Institute & Research Centre Ruchi Goel- Guru Nanak Eye Centre Harbans Lal, Sir Gangaram Hospital Dr.Barun K.Nayak, Editor I.J.O Rajiv Mohan-Mohan Eye Institute Amod Gupta, PGI Chandigarh Devendra Sood - Glaucoma Imaging Centre Sandeep Saxsena, KGMC Lucknow Neeraj Sanduja-Delhi Retina Centre, Daryaganj Sandeep Mittal, Medical College & Hospital, Meerut B Patnaik Indian Institute of Ophthalmology, New Delhi M.C. Agarwal-Deen Dayal Upadhyay Hospital Shrikant, BHU Varanasi Yogesh Gupta-Hindu Rao Hospital N. Shroff, Shroff Eye Centre Abhishekh Chandra, BHU B. Ghose, Director Prof. Guru Nanak Eye Centre K.P.S. Malik, HOD, Safdarjung Hospital Prashant Bhushan, BHU P. D'souza, HOD Lady Harding Medical College S.N Jha -Ganga Ram Hospital V.P. Gupta, HOD, Guru Tegh Bahadur Hospital Anil Mehta- ESI Hospital, Basai Darapur A.K Khurana, Medical Colllege & Hospital, Rohtak Kamaljeet Singh, Allahabad Santosh Honovar-LV Prasad Ajit Babu-LV Prasad National Advisory Board: H.C. Agarwal-Max Eye Hospital RB Jain, JL Goyal, R K Bhandari, A K Gupta, Harbans Lal, Rishi Mohan, G Mukherjee, PN Nagpal, Ramanjit Sihota, Abhey Anil Tara- Venu Eye Centre Vasavada, Meenakshi Thakkar, Om Prakash, P.K.Sahu, Jolly Dinesh Garg- Dayanand Medical College & Hospital, Rohatgi, Upreet Dhaliwal, Gaurav Y. Shah, Amar Agarwal, SPS Ludhiana Grewal, Indu Singh, Daljit Singh, Lingam Gopal, Madan Mohan, P.K. Khosla, V.K. Dada, H.K. Tiwari, N.N. Sood, Sanjiv Malik, S Anuradha Sharma-Aravind Eye Hospital, Madurai Natrajan, Amar Agarwal, Vinod Biala

General Information: Delhi Journal of Ophthalmology (DJO), once called Visiscan, is brought out by the Delhi Ophthalmological Society. The journal aims at providing a platform to its readers for free exchange of ideas and information in accordance with the rules laid out for such publication. The Editorial team desires at providing the clinicians with well researched, fully referenced up to date information in ophthalmology Contribution Methodology: Delhi Journal of Ophthalmology (DJO) is a quarterly journal. Author/Authors must have made significant contribution in carrying out the work and it should be original. It should be accompanied by a letter of transmittal. The article can be sent by email to the Editor and the hard copy mailed. Articles received will be sent to reviewers whose comments will be e-mailed to the Author(s) within 4-6 weeks. The identity of the authors and the reviewers will not be revealed to each other by the editorial team. The contributors shall be responsible for statements in his /her/their work including the changes made during editing. Detailed instructions to the contributors and for advertisements are included at the end of the journal. Request for reprints or any queries should be addressed to the Editors office by email or post Editorial Process: The DJO has Dr. Rajpal Insan as its Editor who is assisted by a team of renowned ophthalmologists and an illustrious advisory board. The reviewers, who are leaders in their respective fields, form the back bone of the journal by setting standards for the published work Editorial Office: Dr.Rajpal Insan Professor of Ophthalmology Vitreo Retina Unit, Room No. 480, Dr. R.P. Centre, AIIMS, New Delhi - 110 029, Tel. No. +91-11-26588500, 700, 26589900, Extn. 3180, 3188. Fax No. +91-11-26589380, 26588919, e-mail : [email protected], [email protected] Published by: Dr. Rajpal, Editor DJO, on behalf of Delhi Ophthalmological Society, Delhi Printed by: Seagulls, 264 F.I.E. Patparganj, Delhi-92, Tel. 42141055, 22156963, [email protected] Page design by: Dr. Rajpal Insan, Sajan Insan, Sach Kahoon Press Secretarial Assistance: Ghanshyam, Mrs. Anju Vohra, Sunita, Vandana, Ajay Sharam From Darkness to Light

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S OCIET Y DELHI Delhi Ophthalmological Society DOS Executive

PRESIDENT SECRETARY TREASURER

Dr. Lalit Verma, MD Dr. Namrata Sharma Dr. Sanjay Chaudhary Ph.: (O) 41644000 (R) 26263636 Ph.: (O) 26588852, (R) 95120-2572892 Ph.: (O) 23278423, (R) 23275893 (M): 9811299934 (M): 9810856988 (M): 9871411227 E-mail: [email protected] E-mail: [email protected] E-mail: [email protected]

VICE-PRESIDENT SECRETARIAT JOINT SECRETARY

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Dr. Rajpal LIBRARY OFFICER Dr. Mahipal S. Sachdev Ph.: (O) 26588500 EXTN. 3180 Ph.: (O) 41644000, (R) 26146409 (R) 26193600 (M): 9818598899 Dr. Vinay Garodia (M): 9810046017 E-mail: [email protected] Ph.: (O) 41731777 (M):9811084552 E-mail: [email protected] E-mail: [email protected] Dr. Harbansh Lal EXECUTIVE MEMBER Ph.: 28741412,(R) 28743988 (M): 98106-49942 Dr. Alkesh Chaudhary Dr. Sanjeev Gupta E-mail:[email protected] Ph.: (O) 29228101,(R) 29228924 Ph.: (O) 65293455,(M): 9810075900 (M): 9810077200 E-Mail: [email protected] Dr. Dinesh Talwar E-Mail: [email protected] Ph.: (O)41644000, (R) 26961109 Dr. Rajendra Prasad (M): 9810302298 Dr. Zia Chaudhary Ph.: (O) 26895259,(M): 9810046823 [email protected] Ph.: (O) 22259613, (M): 9810645168 E-Mail: [email protected] E-Mail:[email protected] DOS REPRESENTIVE TO AIOS Dr.Anita Sethi Dr Angshuman Goswami Ph.: (O) 41644000,(R)26932798 Dr. B.P. Guliani Ph.: (O) 95120-4266642, (R)22619848 (M): 9810199636 Ph.: (O) 26198126, (R) 2143569 (M): 9810093809 E-Mail: [email protected] (M): 9810302294 E-Mail: [email protected] E-mail: [email protected] Dr.Cyrus M. Shroff Dr. Rajiv Gupta Ph.: (O) 41633999,(R) 26462449 Dr. Kamlesh Ph.: (O) 22520480, (R) 22622855 (M): 9811204241 Ph.: (O) 23234622, (R) 24648373, (M): 9810243257 E-Mail: [email protected] (M): 9811240575 E-Mail: [email protected] MO AL LO H G T I C Delhi

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Contents of DJO

Editorial 09

Major Review Current trends in Management of amblyopia 11-16 Pradeep Sharma, Shailesh GM

Major Review Collgen Cross Linking using Riboflavin/UVA 17-19 treatment for corneal ectasia - an overview Vanathi M, Sanjay Kai, A Panda, S Khokar

Major Review Refractive lens exchange : current perspectives 20-26 I Howard Fine, Richard, S. Hoffman, Mark Packer

Major Review Wavefront guided correction of the irregular cornea 27-32 Jorge L. Aliò, Robert Montes - Micò

Major Review Neuroprotecion - an uprising wave in Glaucoma Management 33-37 Aparna Rao, Viney Gupta, Tanuj Dada, Ramanjit Sihota

Minor Review Role of sem cell culture in ocular diseases 38-43 Rajpal, R.V. Azad, Aul Kumar, Jasbir Kaur, Parul Saxena

Original Article Intravitreal Bevacizumab (Avastin) for CNV in young patients 44-49 Subrata Mandal, Zahir Abbas, Satpal Garg, Rajpal Vohra, Pradeep Venktesh, Rajesh Sinha, T. Velpandian

Original Article Interaction of p-n-o with extracted intraocular foreign bodies 50-54 Dependra Vikram Singh, Yograj Sharma, Rajeev Sharma

Original Article An insight into Indigenous Ophthalmic Medicinal Plant Drugs 55-59 N. Srikanth, Praveen Bansal, Jasbir Kaur, Renu Bansal and Rajpal Insan

Case Report Localized invasive aspergillosis of eyelid in an immunocompetent patient 60-63 Neelam Pushker, Rachna Meel, Seema Sen, Mandeep S Bajaj, Mridula Mehta, Seema Kashyap

Clinical Challenges Pituitary adenoma mimicking as primary chronic angle closure glaucoma 64-66 Viney Gupta, Tanuj Dada , Ramanjit Sihota

Journal Abstracts Rajpal Insan 67-69

Community ophthalmology National Program for Control of Blindness and 70-73 Strategies for the Eleventh Plan Five year plan (2007-2012) Dr A.S. Rathore, Dr Manoj Kr Dhingra, Dr R Jose

Instrument Review The Multifocal Electroretinogram 74 Rajvardhan Azad, Urmimala Ghatak, Bhuvan

Forthcoming Events 75

Training Programme 76 DearEditorial members of the DOS family I would like to express my humble gratitude to all DOS members for the faith they have shown in me by unanimously appointing me as the Editor of the prestigious society. This has been possible with the grace of God and blessings of my revered THE MASTER Hazoor Maharaj Gurmeet Ram Rahim Singh Ji of Dera Sacha Sauda and I dedicate this issue at his feet. My purpose as Editor of the Delhi Journal of Ophthalmology will be to bring to you a peer reviewed journal of academic excellence with contributions from all over the country and the globe. I would encourage participation from the entire DOS family to make this journal a success, so that it can one day become indexed... I have arisen from a very humble background and it has been a uphill task to reach up to here facing tremendous opposition from all quarters and words of encouragement from a few. But I have worked in good faith keeping faith in God and tried to amalgamate all in a single thread of love. In my epic journey from being no-one to someone, I would like to put to word some special people who have encouraged me and helped me to take on this challenging task. I am grateful to Prof. R V Azad who has been instrumental in changing my life for the better. Special thanks to Dr. Tanuj Dada who has initiated me into the quest for eternal bliss through spirituality, which is our ultimate (but forgotten) goal in this life. I am also thankful to Dr. Lalit Verma and Dr. Namrata Sharma for their tremendous timely support without which this issue may not have been in your hands. This issue of the DJO is the first one under my tenure as its Editor. With due respect, I tender my apology for any of the shortcomings that might have crept into while making the final manuscript as this is also a learning process for me. Please feel free to give your critical comments which will be most welcomed. The issue begins with an update on management of amblyopia with the latest treatment algorithms which have been tested in multicentric, randomized controlled trials, even though the basic aim of treatment remains the same. The article by Vanathi M et al delves to highlight the latest in the management of keratoconus by collagen cross linking. This treatment is currently being actively researched world over as a potential means to halt progression of this relentless disease though many questions still remain unanswered. The article by Alio et al attempts to solve the upcoming problems of irregular corneal astigmatism through the use of wavefront guided refractive corneal surgery. Then, Fine et al bring to highlight the principles and technique of refractive lens exchange and the ideal candidates for the same. Dada et al briefly delve onto the topic of neuroprotection in glaucoma, which as you all know is going to be the next big thing in glaucoma management once we are able to decipher the basic pathomechanisms involved in retinal ganglion cell death. AS Rathore et al highlight the major practical issues in ophthalmology that we are facing today and bring together the government policy over the 11th five year period to tackle these pressing issues in Ophthalmology. Rajpal et al highlight the very basics of stem cells in ophthalmology vis a vis other specialties of medicine and their potential in the treatment of various ocular disorders. Mandal et al throw light on management of various retinal disorders with the use of bevacizumab, which might become the “molecule of the century”. Dear colleagues, I hope that you find the present issue of the DJO both interesting and intriguing. It should serve the basic purpose of enhancing your clinical skills as well as provide a basic framework to incorporate new procedures in ones armamentarium. I am thankful to Prof. S. Ghose for providing necessary help for DJO. Special thanks to Prof. L.P. Aggarwal, who was the founder of Dr. R.P. Centre for Ophthalmic Sciences

So, enjoy reading------and I sincerely look forward to hearing from you!

Dr Rajpal Insan Professor, Vitreo-Retinal Services R.P. Centre for Ophthalmic Sciences Editor DJO E mail: [email protected], [email protected] Telephone- 011-26589380, 26588919 CURRENT TRENDS IN MANAGEMENT OF AMBLYOPIA DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 MAJOR REVIEW Current Trends in the Management of Amblyopia Shailesh GM, Pradeep Sharma

Strabismus & Neuro Ophthalmology Services, Dr. R.P. Centre for Ophthalmic Sciences, AIIMS, New Delhi

Abstract: Amblyopia is defined as a unilateral or bilateral diminution of vision caused by form vision deprivation and/or abnormal binocular interaction. Amblyopia which affects about 1-5% of the general population is a common cause of visual impairment in children. Series of articles published by PEDIG (Pediatric Eye Disease Investigator Group) were studied and also inputs from the experience at our tertiary care hospital was also taken into account to know the current concepts and its practical implications in the management of amblyopia. Various modalities of treatment for amblyopia are emerging: Refractive correction alone, Occlusion, Atropine penalization, Combined occlusion and optical penalization and use of levodopa including the technological advances in the monitoring of compliance to occlusion therapy. Although occlusion still remains the main modality of treatment, other forms of treatment can also be used to enhance or replace the treatment effectiveness of amblyopia. The role of active home vision exercises is emphasized.

Key words: Amblyopia, Occlusion, Part time, Full time, Atropine penalization, Levodopa, Active home vision exercises.

Amblyopia is a developmental disorder of the central stimulus (form) vision deprivation or abnormal visual pathways, which affects about 1-5% of the general binocular interaction. 1,2 population. It is of importance because it leads to a a) Stimulus (form) vision deprivation: Cataract or significant cumulative ocular morbidity, considering Aphakia the man-years involved that an amblyopic suffers from ² childhood throughout his life. Uncorrected refractive error (hypermetropia, myopia, astigmatism) Amblyopia is defined as a unilateral or bilateral ² diminution of vision caused by form vision deprivation Corneal opacification and/or abnormal binocular interaction. The vision in ² Vitreous hemorrhage the affected eye is two Snellen lines below the normal, ² Ptosis or prolonged bandage with no abnormality detected in the ocular media or ² visual pathways by the clinical examination. The vision ! Abnormal binocular interaction: (Abnormal is fully reversible, if treated in time. And this makes it rivalry between the two eyes) important for all the custodians of sight to ensure that ² Strabismus amblyopia be not only detected early but also be ² Asymmetric cataract, monocular cataract managed early and as effectively as possible. Or else, we ² would have to shoulder the guilt of all the children who Anisometropia (hypermetropia, myopia or grow up amblyopic and become needlessly unfit for astigmatism) most technical and professional jobs. Successful ² Aniseikonia Management would depend on early detection of Stereopsis is correlated with binocularly driven cells, amblyopia as well as elucidating its etiology. whereas amblyopia is correlated with competitive loss The causes of amblyopia could be those causing either of monocularly driven cells. Different types of amblyopia may have different involvements of the Address for correspondence:- visual functions. Prof. Pradeep Sharma MD Detection of Amblyopia: Professor of Ophthalmology, While a gamut of different visual functions like visual Dr. R.P. Centre for Ophthalmic Sciences, acuity, contrast sensitivity, mesopic vision, reading AIIMS, New Delhi-110029 (India) speed, reflex times, and visual fields can be evaluated to

11 CURRENT TRENDS IN MANAGEMENT OF AMBLYOPIA DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 detect the amblyopia syndrome, the simplest is the (partial waking hours) and conventional (patching the assessment of visual acuity. good eye) or inverse (patching the amblyopic eye) During infancy and pre-school years the exact assessment of visual acuity may be difficult but a qualitative assessment of relative diminution of vision of one eye can be easily made. This is done by assessing the fixation preference of either eye. Additional information is obtained by observing the ability to maintain fixation by each eye. A central, steady and maintained (CSM) fixation of each eye implies good visual acuity of each eye. A child dislikes the covering of his better eye and may peek from the side or start crying if his better eye is forcefully covered. This also helps us in knowing that one of the eyes is amblyopic. Figure 1: Child with amblyopia wearing Indirect assessment of amblyopia can be made from the spectacles and a patch (made of micropore tape) detection of amblyopiogenic conditions (see the list of causes above). This can be done by the corneal reflex test We recommend a totally opaque full-time (full waking & Bruckner's reflex (a simple test of seeing the red glow hours) patch of the good eye alternated with a similar in both eyes simultaneously by the ophthalmoscope at patching of the amblyopic eye. The alternation is done about 50 cms) a relative assessment of the two eyes depending on the age of the child as per the following indicates a strabismus (brighter glow in strabismus eye), table: a media opacity or a significant refractive error (crescentic shadow seen). The photoscreeners are based Age Ratio of patching on the Bruckner's reflex. An asymmetry of the red reflex 0-2 years 2 : 1 (2 days good eye; is studied manually by an observer or digitally analyzed 1 day amblyopic eye) to detect the causes of amblyopia like: media opacity, 3 years 3 : 1 refractive errors or strabismus. Photoscreening is described in detail at the end of this article. 4 years 4 : 1 In addition, assessment based on behavioral tests of 5 years 5 : 1 preferential looking like Teller Acuity Cards and 6 years and above 6 : 1 Cardiff Acuity Cards are available at most specialized centres, including ours. The follow-up for visual assessment to evaluate improvement of amblyopic eye, as well as a possible Use of optokinetic nystagmus (OKN) and visually deterioration of good eye due to occlusion amblyopia is evoked responses to assess visual acuity are also done at monthly intervals, except in infancy when it is possible. A special program uses the “sweep VEP”, fortnightly. whereby VEP is recorded with sequentially reducing size of the target pattern and then the visual acuity Occlusion therapy and atropine penalization: calculated exponentially by using the Fourier analysis. Apart from occlusion therapy, there is a trend towards Treatment of Amblyopia therapy with atropine penalization. In a randomized clinical trial by PEDIG (Pediatric Eye Disease After the cause has been identified and eliminated, the 3 amblyopia therapy is based on selectively stimulating Investigator Group), 419 children younger than 7 years the cortical cells responsible for the amblyopic eye. with amblyopia and visual acuity in range of 20/40 to 20/100 were assigned to receive either patching or The various methods are occlusion, penalization, atropine at 47 clinical sites in USA. Visual acuity in the pleoptics, CAM stimulator and medical treatment. amblyopic eye improved in both the groups (3.16 in the Occlusion remains an effective treatment modality till patching group, 2.84 lines in the atropine group from the now. baseline at 6 months). Improvement was faster in the Occlusion therapy: patching group initially, but at 6 months the difference in This modality is about two centuries old but is still the the visual acuity between the groups was small. Both easiest and the best. Various types of occlusion therapies treatments were well tolerated, although atropine was are practiced by different groups. It may be totally slightly better than patching. This study concluded that (figure 1) or partially opaque; full-time or part-time atropine and patching produce improvement of similar 12 CURRENT TRENDS IN MANAGEMENT OF AMBLYOPIA DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 magnitude and both are appropriate modalities for the considered as an alternative and/or supportive therapy initial treatment of moderate amblyopia in children aged in the management of amblyopia.6 3 to less than 7 years. This study used a new visual acuity In a recently developed intermittent regimen of testing protocol for children using isolated surrounded 7 4 penalization, the traditional daily application is reduced to HOTV optotypes (letters used for testing). The protocol one to three drops (depending upon iris color) of atropine was evaluated using the Baylor-Video Acuity Tester per week. The claimed advantages of this reduced (BVAT) to present isolated surrounded HOTV administration are that it offers some protection against the optotypes. At 6 sites, the protocol was evaluated for occurrence of reverse amblyopia, presents less need to testability in 178 children aged 2 to 7 years and for maintain an exact correction in the better eye, and is more reliability in a subset of 88 children. Twenty-eight percent manageable for the caregiver. Retrospective analysis have of the 178 children were classified as having amblyopia. shown intermittent regimen to be of equivalent Using the modified protocol, testability ranged from 24 effectiveness to traditional, full time atropine penalization. percent in 2-year-olds to 96 percent in 5- to 7-year-olds. A trend apparent in most recent publications is for The visual acuity protocol had a high level of testability in pharmacological (i.e. atropine) penalization to be favored 3- to 7-year-olds and excellent test-retest reliability. The over that of optical penalization. protocol has been incorporated into the multicenter Amblyopia Treatment Study and has wide potential Refractive correction in anisometropic amblyopia is a application for standardizing visual acuity testing in very important part of treatment strategy in amblyopia. children. Many patients may show improvement in visual acuity initially with glasses. In a study by PEDIG8 One fourth of Foley-Nolan5 studied Occlusion vs. atropine therapy the patients aged 7 to 17years showed improvement (n=38) in 3 to 9 yrs with mean age of 6 years. Strabismic, over a period of 24 weeks by optical correction alone. anisometropic and mixed groups were included and They suggested that this group required additional mean treatment period for atropine group was 7.2 treatment for amblyopia apart from optical correction months and 4.3 months for occlusion. Both treatment 9 alone. Chen etal studied spectacle correction alone in groups showed similar magnitude of visual sixty children with anisometropic amblyopia from 3 to 7 improvement after 4.3 months; patching group showed years age group and found that nearly half of them had improvement from 6/60 to 6/19 and atropine group resolution of amblyopia. Visual improvement occurred showed improvement from 6/50 to 6/11. Atropine from 4weeks onward and reached a plateau, after which penalization had more patient acceptance than occlusion. it improved only slowly. They concluded that there is a No occlusion amblyopia was noted in any of the groups. need for occlusion or atropine therapy if there is no Recently, a prospective randomized trial was conducted improvement in visual acuity after 4 months of spectacle at our centre (Shailesh GM, Vimla Menon , Pradeep correction alone. Sharma, Rohit Saxena. Clinical trial of occlusion vs. How old is old? To treat amblyopia: Although atropine penalization for the treatment of amblyopia. effectiveness of treatment for amblyopia decreases after Poster. AAO annual conference. Chicago, Oct 15-18: around 7 years of age, there are clinical studies which 2005) in 63 patients of anisometropic amblyopia in the show improvement in visual acuity even in older age group of ≥ 4 to 20 years with visual acuity between children. In a more recently published prospective 2- 6/60 and 6/12. 32 patients received conventional full month pilot study (Amblyopia Treatment Study, ATS- time occlusion and 31 received pharmacological 10 3) on amblyopia treatment in older children aged 10 to penalization with atropine. We found that, magnitude of 18 yrs. by PEDIG, have reported improvement in visual improvement in visual acuity was similar in both acuity in older children and adolescents. Only patching occlusion and atropine penalization groups (2.32 lines for ≥2 hours/day combined with at least 1 hour of near improvement in occlusion group, and 2.27 lines in activities was employed in patients with VA of 20/40 - atropine penalization group at 6 months of follow-up). 20/160. Improvement of 2 or more lines was observed in Maximum visual recovery occurred slightly faster in this age group. They felt the need for a randomized occlusion group (3.9 months) than in atropine group (4.6 controlled trial to determine the upper age limit for months). Parental acceptance was better for atropine which amblyopia treatment is successful. Such cases do treatment as compared to occlusion. highlight one point that specific vision tasks with Combined optical and atropine penalization (COAT) for occlusion make it more efficient as a therapeutic the treatment of strabismic and anisometropic amblyopia modality. Occlusion in poor visual acuity patients needs is also an effective treatment method when occlusion additional supervision to avoid accidental injury as the therapy initially fails. COAT is well tolerated and can be better eye is patched.

13 CURRENT TRENDS IN MANAGEMENT OF AMBLYOPIA DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

Another PEDIG8 trial in patients aged 7 to 17 years; compliance. More sophisticated means of objective amblyopia improves with eyeglasses alone in about 25 assessment is now available in the form of Occlusion percent of patients aged 7 to 17 years, although most Dose Monitor (ODM).11,12 A modified version of the patients who are initially treated with eyeglasses alone original device is used in the MOTAS study to determine will require additional treatment for amblyopia. For the dose-response characteristics of occlusion therapy in patients aged 7 to 12 years, prescribing 2 to 6 hours per amblyopic children. ODM consists of a data logging unit day of patching with near vision activities and atropine (run by a battery) and a modified, disposable occlusion can improve visual acuity even if the amblyopia has patch made of electro conductive material on its been previously treated. For patients 13 to 17 years, undersurface (see figures 3a, 3b). The logging unit prescribing patching 2 to 6 hours per day with near records duration of skin-patch contact, which can be vision activities may improve visual acuity when the retrieved later when the child comes for follow-up. condition has not been previously treated, but appears A combination of cycloplegia and patching may be to be of little benefit if amblyopia was previously treated helpful for children who resist patching. The importance with patching. Additional follow-up is being conducted of regular follow-up visits to monitor vision, behavioral to determine if improvement in visual acuity will be problems, and compliance cannot be overemphasized. sustained once treatment is discontinued. Medical treatment: Improving Compliance: Pharmacological means for treating strabismus and Glasses are well tolerated by children, especially when amblyopia can be divided into 3 categories: paralytic there is visual improvement. Accurate fitting and agents (botulinum toxin) used directly on the maintaining proper adjustment facilitate acceptance. Straps may be useful in babies. Polycarbonate lenses are break-proof with greater safety and are preferable for children, especially if they are amblyopic. Parental attitudes and peer pressure have great impact on compliance. Compliance can be enhanced by positive reinforcement that is appropriate for the specific child and environment. Children who are known to pull out glasses or occlusion patches needs elbow restraints (in the form of a taped and rolled magazine or cardboard etc; see figure 2) may be useful to improve compliance. Sophisticated elbow restraints are now a days commercially available. Potential psychological side effects should also be kept in mind. Parental diaries are currently employed in some clinical trials to access

Fig 3a (upper): showing a occlusion dose monitor Figure 2: Elbow guard (home-made), used to prevent (ODM) unit. Figure 3b (lower): showing s patch patch/glass removal from the child with temperature sensor applied on the eye 14 CURRENT TRENDS IN MANAGEMENT OF AMBLYOPIA DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 extraocular muscles to affect eye movements; autonomic and effectively so that no child is needlessly visually agents (atropine, miotics) used topically to manipulate impaired because of the neglect of the society and the the refractive status of the eye and thereby affect ophthalmologists. alignment, focus and amblyopia; and centrally acting The role of levodopa is being seen to be effective as a agents, including levodopa and citicoline, which affect 13 modulator of neural plasticity to facilitate and expedite the central visual system abnormalities in amblyopia. . the effect of occlusion and make it effective even in later Role of atropine has already been described above. age groups. However it still does not project itself as an Medical treatment has been mainly directed to modulate alternative to occlusion, but may be a useful adjunct. the neural plasticity of the visual system which is dependent on nor-adrenergic inputs. Vision Screening:

Levodopa The goal of all vision screening is to detect poor vision or risk factors that interfere with vision and normal visual High content of dopamine in retinal amacrine cells and development. It is accepted that early diagnosis and interplexiform cells of the visual cortex in addition to the treatment yield better visual outcomes. With the high basal ganglia was correlated with the altered VEP in prevalence of amblyopia in children, only 21% of Parkinson's disease and improvement (of VEP preschool-aged children and even fewer younger potentials) following dopaminergic drugs. In addition children are screened for this condition.17 Despite the improved contrast sensitivity, oscillatory potentials, availability of many screening options, many children ERG b wave and pattern-ERG were also correlated. permanently lose vision each year as a result of This laid the basis for the use of levodopa in amblyopia. amblyopia, media opacities, and treatable ocular disease Further, to reduce the peripheral side effects and processes. increase the availability of the drug in the central Photoscreening is a vision screening technique used to nervous system, drugs like carbidopa or benserazide screen for amblyogenic factors, such as strabismus, which compete with levodopa at peripheral sites were media opacities, and significant refractive errors, in 1 or added. both eyes in children. Using a camera or video system Initial trials were conducted by Gottlob et al14 with short appropriately equipped for photoscreening, images of term effect (90 min) of orally given single large dose (200 the pupillary reflexes (reflections) and red reflexes mg). Leguire et al studied doses 100-400 mg with good (Brückner test) are obtained.18 Other than having to results on vision and contrast sensitivity. This was fixate on the appropriate target long enough for the followed by continuous administration for one week (2 photoscreening, little cooperation is needed from the mg/kg) for prolonged effects. Good effect was child. Data are then analyzed later for amblyogenic observed in 70% of 20 patients. Further trials have been factors, and positive findings are noted. Children who to study the effect of lesser dosage to reduce side effects- do not pass the test may be referred for a complete eye 25 mg and 50 mg doses for 8 hour effect was found to be examination by an ophthalmologist. successful in placebo controlled trials. It is being seen Photoscreening appears to offer certain conveniences that average doses (of 0.95 mg/kg to 1.94 mg/kg) are 15 and advantages over traditional methods of vision being well tolerated. In earlier trials with 0.48 mg/kg screening, especially in its availability to screen children three times/day tried with 3 hour part time occlusion for who are the most difficult to screen but in whom the three weeks has shown 2.7 lines improvement vs 1-6 prevalence of amblyopia is higher than in the general lines on Snellen's chart in a controlled trial. pediatric population. This includes children at high risk Our institution also conducted a trial of levodopa - for eye problems, such as premature infants or children carbidopa 0.50 mg/kg three times daily in 60 amblyopes with developmental delays or a family history of eye : 30 strabismic and 30 anisometropic in a double blind problems. Photoscreening does not represent a single controlled trial, the control group receiving placebo, technique or piece of equipment. Different optical with occlusion being given full time.16 The parameters systems can be used for photoscreening. studied were visual acuity, contrast sensitivity, pattern Studies performed by different investigators using the VER and stereoacuity. We observed mild improvement same photoscreening apparatus may yield a wide range in the levodopa group during the period of therapy of results in sensitivity, specificity, and predictive values which was not sustained. We also observed that the risk when onsite interpretation is required.19 In general, it is of occlusion amblyopia is enhanced and a proper difficult to compare efficacies of various vision monitoring of the cases is mandatory to conclude, screening methods, such as stereoacuity testing, amblyopia does need to be detected and treated early autorefraction, red reflex testing, and cover testing, and

15 CURRENT TRENDS IN MANAGEMENT OF AMBLYOPIA DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 then determine if photoscreening has better positive and 3. The Pediatric Eye Disease Investigator Group. A negative predictive values. More research is needed to randomized trial of atropine vs. patching for treatment of moderate amblyopia in children. Arch Ophthalmol. Mar establish how photoscreening can be best used. 2002; 120:268-278. Photoscreening offers hope in improving vision 4. Holmes JM, Beck RW, Repka MX, Leske DA, etal. The screening rates in infants, preverbal children, and those amblyopia treatment study visual acuity testing protocol. with developmental delays who are the most difficult to Arch Ophthalmol. 2001.119:1345-53. screen. Photoscreening has not been shown to be 5. Foley-Nolan A, McCann A, O'Keefe M. Atropine superior to other vision screeningtests currently used to penalization vs. occlusion as the primary treatment for screen 4- to 5-year-olds. In older children, currently amblyopia. Br J Ophthalmol. 1997; 81:54-57. available vision screening techniques can be used 6. Kaye SB, Chen SI, Price G, Kaye LC, Noonan C, Tripathi A reliably. et al. Combined optical and atropine penalization for the treatment of strabismic and anisometropic amblyopia. J Counseling: A child with amblyopia, whether treated AAPOS. Oct 2002; 6(5):289-293. or untreated, requires care for the first decade of life and 7. Moseley M. Amblyopia: Treatment and evaluation.In: then every 1 to 2 years throughout life. Treatment in the Moseley M, Fielder A, editors. Amblyopia: A form of patching or penalization is often unpleasant for multidisciplinary approach. Oxford.Butterworth the child and a burden for the parent/caregiver; all may Heinemann; 2002: 81-104. become discouraged. In order to maintain appropriate 8. Pediatric Eye Disease Investigator Group. Randomized therapy, the ophthalmologist must be sensitive and trial of treatment of amblyopia in children aged 7 to 17 years. Arch Ophthalmol. 2005; 123:437-47. provide proper information about the illness, support and encourage the parents, teachers and others 9. Chen PL, Chen JT, Tai MC, Fu JJ, Chang CC, Lu DW. Anisometropic amblyopia treated with spectacle interacting with the patient. The importance of correction alone: Possible factors predicting success and monitoring and long-term follow-up of amblyopia time to start patching. Am J Ophthalmol. 2007; 143:54-60. should also be explained. The distance the patient must 10. Pediatric Eye Disease Investigator Group. A prospective, travel for treatment and the socioeconomic situation of pilot study of treatment of amblyopia in children 10 to <18 the parent/caregiver should be considered in the years old. Am J Ophthalmol. 2004; 137:581-583. frequency of follow-up. 11. Fielder AR, Auld R, Irwin M etal. Compliance monitoring in amblyopia therapy. Lancet. 1994; 343:547. To conclude various modalities of treatment for amblyopia are available, of which, patching still plays a 12. Simonsz HJ, Polling JR, Voorn R et al. Electronic monitoring of treatment compliance in patching for major role. Penalization with atropine is becoming amblyopia. Strabismus. 1999; 7:113-23. popular with the possible advantages of being more 13. Chatzistefanou KI, Mills MD. The role of drug treatment in acceptable to patients and their parents, and it can children with strabismus and amblyopia. Paediatr Drugs. provide for better compliance which can be monitored 2000; 2(2):91-100. by observing the dilated pupil. But it has to be 14. Gottlob I, Stangler-Zuschrott E. Effect of levodopa on individualized, as it may not work for a myope. contrast sensitivity and scotomas in human amblyopia. Occlusion therapy has the possible advantages of Invest Ophthalmol Vis Sci. 1990 Apr; 31(4):776-80. requiring a shorter treatment time, which needs to be 15. Leguire LE, Rogers GL, Walson PD, Bremer DL, McGregor determined and it provides better flexibility for part- ML. Occlusion and levodopa-carbidopa treatment for time treatment. Early detection of amblyopia by childhood amblyopia. J AAPOS. 1998. Oct; 2(5):257-64 photoscreeners in school children and ensuring 16. Bhartiya P, Sharma P, Biswas NR, Tandon R, Khokhar SK. compliance for occlusion therapy by occlusion dose Levodopa-carbidopa with occlusion in older children with amblyopia. J AAPOS. 2002 Dec; 6(6):368-72. monitor have made amblyopia treatment outcome much better. In the pursuit of treating amblyopic eye, good eye 17. Ehrlich MI, Reinecke RD, Simons K. Preschool vision screening for amblyopia and strabismus: programs, should not be neglected and it needs to be protected. methods, guidelines. Surv Opthalmol.1983; 28:145 163. 18. Cibis GW. Video vision development assessment (VVDA): References: combining the Brückner test with eccentric 1. Weber, JL; Wood, Joanne (2005). "Amblyopia: Prevalence, photorefraction for dynamic identification for Natural History, Functional Effects and Treatment". amblyogenic factors in infants and children. Trans Am Clinical and Experimental Optometry 88 (6): 365-375. Ophthalmol Soc.1994; 92:643 685. 2. Ehrlich MI, Reinecke RD, Simons K. Preschool vision 19. Ottar WL, Scott WE, Holgado SI. Photoscreening for screening for amblyopia and strabismus: programs, amblyogenic factors. J Pediatr Ophthalmol Strabismus.1995; methods, guidelines, 1983. Surv Opthalmol.1983; 28:145 32:289 295. 163.

16 COLLAGEN CROSS-AN OVERVIEW DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 MAJOR REVIEW Collagen cross-linking using Riboflavin/UVA Treatment for Corneal Ectasia - An Overview M.Vanathi MD, Sanjay Kai MD, A Panda MD, S Khokar MD

Cornea Services, Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi

Abstract: Corneal Collagen Cross-linking with Riboflavin (C3-R) is the treatment that combines the use of riboflavin and UVA irradiation to induce corneal stroma strengthening by the creation of new bridges among the collagen fibres. C3-R therapy has been described as a new treatment option for keratoconus, corneal estasia and irregular astigmatisms. The 30- minute Cross.-Linking treatment can be performed in the doctor's office. During the treatment, custom-made riboflavin eye drops are applied to the cornea, which is then activated by ultraviolet light. The process has been shown to increase the amount of collagen cross-linking in the cornea and strengthen the weak corneal structure. This method works by increasing collagen cross linking, which are the natural “anchors” within the cornea. These anchors are responsible for preventing the cornea from bulging out and becoming steep and irregular, progressing to advanced keratoconus.

Key words:Collagen crosslinking, keratoconus, ectasia.

The precise etiology of keratoconus and other ectasia is Recent animal studies have provided convincing unclear. Genetic abnormalities in the collagen and its electronmicroscopic documentation that such crosslinking, secretion of matrix metalloproteinases crosslinking does thicken the collagen fibres of the (MMPs) and other lytic enzymes, eye rubbing, allergy, rabbit cornea 5. The initial studies were started in 1990s and other factors have been suggested. Whatever the to identify the biological glues that could be activated by cause or causes, if collagen crosslinkage can increase heat or light to increase the resistance of stromal resistance to these distortions, it would be of great collagen 6. It was discovered that the gluing effect was importance because the biomechanical properties of the mediated by an oxidative mechanism associated with cornea depend on the characteristics of collagen fibres 1, 2, hydroxyl radical release. A similar mechanism of interfibril bonds 3 and their spatial-structural disposition hardening and thickening of collagen fibres has been 4. The original hypothesis was that corneal collagen can shown in corneal aging 7 and is related to active be crosslinked by riboflavin and UVA light, thereby glycosylation of age-dependent tropocollagen increasing the cornea's thickness, stiffness, and molecules. The idea to use this conservative approach to resistance to subsequent distortion, as well as to treat keratoconus was conceived in Germany in the enzymatic digestion. The possibility that a safe, 1990s by a research group at Dresden Technical inexpensive, and relatively available therapy might stop University 8. The aim was to slow or arrest progression, the progression of a disease which otherwise causes to delay or avoid recourse to perforating keratoplasty. visual distortion and may require corneal surgery with The method of corneal cross-linking using riboflavin all of its attendant risks offers exciting hope for the and UV light is technically simple and less invasive than future. other therapies proposed for keratoconus. Unlike other invasive methods , such as intrastromal rings (INTACS) Address for correspondence:- and excimer laser surgery that do not block keractectasia Dr M.Vanathi MD but merely treat the refractive effects of the disease, this Asst. Prof. of Ophthalmology Cornea Services treats and prevents the underlying pathophysiological 8 Rajendra Prasad Centre for Ophthalmic Sciences, mechanism . All India Institute of Medical Sciences, New Delhi: 110029. In animal eyes, a significant increase in corneal E-mail: [email protected] biomechanical stiffness has been found after collagen Fax: 91-011-2659818 cross linking by combined riboflavin/ultraviolet-A (UVA) treatment5. Collagen cross linking using 17 COLLAGEN CROSS-AN OVERVIEW DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 riboflavin and UVA leads to a significant increase in energy of 3mW/cm2 or 5.4J/ cm2 for5 minutes. The lamp corneal collagen diameter. This alteration is the is then turned off, the riboflavin-dextran solution is morphologic correlate of the cross linking process again instilled, and then the 5 minutes exposure leading to an increase in biomechanical stability. The repeated 5 times (total exposure 25 minutes, total cross linking effect is strongest in the anterior half of the treatment 30 minutes). After treatment the eye surface is stroma because of the rapid decrease in UVA irradiance washed with 20ml of balanced salt solution, medicated across the corneal stroma as a result of riboflavin- with 2 to 4 drops of antibiotic and cycloplegic and enhanced UVA absorption. dressed with soft contact lens. This treatment is given for In a study by Wollensack et al, twenty-three eyes of 22 five days after which the contact lens is removed and patients with moderate or advanced progressive biomicroscopic examination is done to assess epithelial keratoconus (maximum K value, 48-72 diopters) repair. Topical therapy with flurbiprofen and antibiotic underwent riboflavin and UVA treatment 8. In all treated is continued further for 20 days. eyes, the progression of keratoconus was stopped. In 16 Clinical Applications eyes (70%) regression with a reduction of the maximal  Keratoconus. keratometry readings by 2.01 diopters and of the refractive error by 1.14 diopters was found. Corneal and  Treatment of corneal melting diseases. lens transparency, endothelial cell density, and  Prevention of post lasik keratectasia or regression of intraocular pressure remained unchanged. Visual acuity the refractive effects. improvement was noted in 15 eyes (65%). 10 Gregor et al have found a significant increase in The 3 and 5-year results of the Dresden clinical study biomechanical rigidity by a factor of 4.5 in human have shown that in all treated 60 eyes the progression of corneas, as indicated by young's modulus, following 9 keratoconus was at least stopped ('freezing') . In 31 eyes riboflavin-UVA induced collagen cross linking. This there also was a slight reversal and flattening of the increase in biomechanical rigidity has also been found in keratoconus by up to 2.87 diopters. Best corrected visual porcine cornea significantly by a factor of 1.8. From acuity was found to have improved slightly by 1.4 lines. various experiments on the diameter of corneal collagen So far, over 150 keratoconus patients have received cross fibres, resistance to enzymatic digestion, and keratocyte linking treatment in Dresden. Laboratory studies have loss after riboflavin-UVA treatment it has been revealed that the maximum effect of the treatment is in suggested that cross linking and cytotoxic effects are the anterior 300 micron of the cornea. As for the corneal significantly higher in the anterior portion of the endothelium, a cytotoxic level for endothelium was cornea11, 12. This is caused by the significant increase in found to be 0.36 mW/cm which would be reached in UVA absorption by riboflavin, leading to rapid human corneas with a stromal thickness of less than 400 reduction of UVA irradiance and collagen cross linking µm. across the cornea. This anterior area of maximum cross Procedure linking constitute about 54% of cross linking volume in human cornea (300µm/550µm), resulting in higher Pre-treatment investigations include rigidity of the total cornea as compare to porcine cornea 1. Best corrected visual acuity. where this value is 35%(300µm/850µm)10. There is no 2. Intraocular pressure. evidence of increase in intraocular pressure, endothelial damage, or cataract formation following the treatment. 3. Corneal computerized topographic examination. Optical coherence tomography examination conducted 4. Endothelial count. preoperatively and 7 days and 3 months after the 5. Ultrasound pachymetry treatment showed identical retinal macular and perimacular thickness13. After topical anaesthesia with 4% xylocaine, lid speculum is inserted. A 7mm circle is marked on the Collagen cross linking may be a new way for stopping corneal epithelium with the help of a corneal marker in the progression of keratectasia in patients with which the epithelium is removed with a blunt spatula. keratoconus. The need for penetrating keratoplasty This is followed by instillation of 2 to 4 drops of a might then be significantly reduced in keratoconus. solution containing riboflavin 0.1% and 20% dextran Given the simplicity and minimal costs of the treatment, prepared immediately before the operation and placed it is well-suited for developing countries. Long-term in a 1ml syringe. After instilling another 2 to 4 drops the results are necessary to evaluate the duration of the UV lamp is turned on. The source is focused on the apex stiffening effect and to exclude long term side-effects. of the cornea, distance 10 to 12mm, to obtain a radiant 18 COLLAGEN CROSS-AN OVERVIEW DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

References 8. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-A induced collagen crosslinking for the treatment of 1. Tuori AJ, Virtanen I, Aine E, et al. The immunohis- keratoconus. Am J Ophthalmol 2003; 135:620-627 tochemical composition of corneal basement membrane in keratoconus. Curr Eye Res 1997;16:792-801 9. Wollensak G. Crosslinking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol. 2006; 2. Cheng E, Maruyama I, Sundaraj N, et al. Expression of 17:356-60. type xii collagen and hemidesmosome associated proteins in keratoconus corneas. Curr Eye Res 2001; 22:333-340. 10. Gregor Wollensak, Eberhard Spoerl, Theo Seiler. Stress- strain measurement of human and porcine corneas after 3. Kenney MC, Nesburn AB, Burgeson RE, et al. riboflavin-ultraviolet-A-induced cross-linking. J Cataract Abnormalities of the extracellular matrix in keratoconus Refract Surg 2003; 29:837-845. corneas. Cornea 1997; 16:345-351. 11. Wollensak G, Spoerl E, Reber F, Seiler T. Keratocyte 4. Radner W, Zehetmayer M, Skorpik C, Mallinger R. cytotoxicity of riboflavin/UVA- treatment in vitro. Eye. Altered organization of the collagen in the apex of 2004; 18:718-22. keratoconus corneas. Ophthalmic Res. 1998; 30:327-332. 12. Gregor Wollensak, Eberhard Spoerl et al. Keratocyte 5. Wollensak G, Wilsch M, Spoerl E, Seiler T. Collagen fiber Apoptosis after corneal collagen cross-linking using diameter in the rabbit cornea after collagen crosslinking riboflavin/UVA treatment. 2004 ;23:43-49 by riboflavin/UVA. Cornea. 2004 ;23:503-7 13. Aldo Caporossi, Stefano Baiocchi et al. Parasurgical 6. Khadem J, Truong T, Ernest JT. Photodynamic biologic therapy for keratoconus by riboflavin-ultraviolet type a tissue glue. Cornea. 1994;13 :406-410 rays induced cross-linking of corneal collagen. J Cataract 7. Daxer A, Misof K, Grabner B, et al. Collagen fibrils in Refract Surg 2006; 32:1780-1785. human corneal stroma: Structure and aging. Invest Ophthalmol Vis Sci 1998;39:644-648

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19 REFRACTIVE LENS EXCHANGE: CURRENT PERSPECTIVES DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 MAJOR REVIEW Refractive Lens Exchange: Current Perspectives Dr. I. Howard Fine, Dr. MD, Richard Dr. S. Hoffman,MD, Mark Packer, MD, FACS (USA)

Abstract: Lens surgery has now evolved into a refractive surgery owing to improved cataract surgery outcomes as a result of lower energy, smaller incisions, and adjunctive astigmatic techniques with increased accuracy and safety. Newer generation intraocular lenses (IOLs) have revolutionized the management of presbyopia. New lenses include the Eyeonics yeonics yeonics Crystalens™,

Key words:Accomodative IOLs,Multifocal IOLs,Deformable optic IOLs

The management of presbyopia has many suboptimal Mastel Paratrap diamond keratome (Mastel Precision treatment modalities including progressive-lens Surgical Instruments, Rapid City, SD) is utilized to spectacles, bifocal contact lenses, monovision create two 1.2 mm clear corneal incisions, 30-45˚ from intraocular lenses (IOLs) and conductive keratoplasty. the temporal limbus (60-90˚ from each other) (Figure 1). There are also certain investigational modalities which One-half cc of non-preserved lidocaine 1% is instilled include scleral implants, multifocal excimer laser into the anterior chamber followed by complete ablation and corneal inserts. expansion of the anterior chamber with Viscoat®. A straight 25 gauge needle is then inserted through the In 2001, my partners and I published a paper right-handed microincision to perforate the central documenting that phaco power modulations and anterior lens capsule while simultaneously lifting a flap reduced energy input (1/10th of 1% of previously used edge to begin a capsulorhexis (Figure 2). levels) into the eye can remove cataracts, with all grades of nuclear density, and can have dramatic improvements in visual outcome, as noted by clear corneas and uncorrected visual acuities of 20/40 or better in the immediate post-operative period. This study also documented that uncorrected visual acuities were inversely proportional to the amount of energy introduced in the course of cataract surgery: The lowest levels of energy resulted in the best levels of uncorrected visual acuities, independent of patient's age or cataract density. We subsequently surveyed all the new phacoemulsification technologies and showed that once again, with utilization of these technologies, we had dramatic improvements in outcomes. We have also refined our technique for refractive lens exchange in Figure 1: Left-handed 1.2 mm clear corneal clear lenses and soft cataracts. microincision placed 45˚ from the temporal limbus The procedure is performed under topical anesthesia utilizing a Mastel Paratrap diamond knife. after appropriate informed consent. It is accompanied by preoperative measurements for IOL power and Needles routinely bent at the tip for conventional preoperative dilation along with topical antibiotics. A capsulorhexis initiation have been found to lacerate the roof of the microincision during withdrawal of the Address for correspondence:- needle. The straight unaltered 25 gauge needle is less Dr. I. Howard Fine, likely to result in this complication. After removal of the Dr. MD, Richard Dr. S. Hoffman, needle, a capsulorhexis forceps, specially designed to fit MD, Mark Packer, MD, FACS (USA) and function through a 1mm incision is then inserted

20 REFRACTIVE LENS EXCHANGE: CURRENT PERSPECTIVES DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 through the same incision and used to complete a 5-6mm maintaining infusion with the irrigating handpiece, the rhexis (Figure 3). phaco needle is removed and the aspiration handpiece is inserted to remove residual cortex and polish the posterior capsule. The irrigation & aspiration (I/A) handpieces can be alternated between the two incisions in order to gain easier access to the subincisional capsular fornix, if subincisional cortex is difficult to extract (Figure 6).

Figure 2: A straight 25 gauge needle begins the capsulorhexis by perforating the central anterior lens capsule while simultaneously lifting a flap edge.

Cortical cleaving hydrodissection with decompression is then performed in two separate distal quadrants Figure 4: The Duet System (MST Microsurgical followed by a third round of hydrodissection to prolapse Technology) beveled irrigating handpiece within the entire crystalline lens or at least one-half of it out of the left-handed microincision. the capsular bag. The microincision irrigating handpiece (Figure 4) is placed in the left-hand incision Once all the cortical matter has been removed, viscoelastic is injected into the capsular bag and into anterior chamber after removal of the aspiration hand piece and while withdrawing the irrigating handpiece (Figure 7).

Figure 3: Capsulorhexis formation utilizing an ASICO microincision capsulorhexis forceps. and the unsleeved phaco needle is inserted through the right-hand incision. Lens extraction is then performed in most cases without phaco power, utilizing high levels of Figure 5: The soft lens is carouselled in the iris vacuum while carouselling the relatively soft lens in the plane and consumed utilizing high vacuum levels. plane of the iris until it is consumed (Figure 5). Forward movement of the lens is prevented with Small amounts of ultrasound energy can be utilized the irrigating handpiece. when needed. Care should be taken to avoid directing the infusion flow towards the phaco needle tip, so as to Following this, the viscoelastic cannula is removed from prevent dislodging nuclear material from the tip. While the eye and a new 2.5mm clear corneal incision is placed 21 REFRACTIVE LENS EXCHANGE: CURRENT PERSPECTIVES DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

limited to very soft nuclei. We used equivalent or greater levels of energy than ultrasound with modulations. We put three times as much fluid through the eye and the surgeries took two to three times as long as ultrasound phacoemulsification with power modulations. As a result, at this time, laser phacoemulsification is no competition for ultrasound. Based on these studies, we concluded that cataract/lens extraction is incredibly safe and efficacious. In 2002, we published a paper in which we described our participation in FDA-monitored study of IOL Master documenting that partial coherence interferometry was as accurate as immersion ultrasound axial length Figure 6: Subincisional cortex is easily removed measurements, using the Quantel Axis-II system. The using the Duet System (MST) bimanual irrigation coefficient of correlation of these two modalities was and aspiration handpieces. (Note the Effective 0.996. During that study, we documented that 48% of Phaco Time EPT = 0 and Average Percent Phaco our patients achieved precisely the spherical equivalent Power AVG = 0 following lens removal). for which we were aiming, 92% were within a quarter of diopter of the desired spherical equivalent, and the mean absolute error was 0.21 diopters. This lead us to conclude that pre-operative measurements and calculations allow excellent results and continuum to improve. Improved cataract surgery outcomes as a result of lower energy, smaller incisions, and adjunctive astigmatic techniques with increased accuracy and safety, has lead to an evolution of lens surgery into refractive surgery. We also have to recognize that corneal refractive surgery has certain limitations like high hyperopes, higher myopes, patients with thin corneas, patients with cataracts, and also presbyopes. We also have to recognize that spherical aberration remains stable in the cornea but increases in the crystalline lens with Figure 7: Viscoelastic is injected into the capsular increasing age. Anything that is done to the cornea as a bag while maintaining infusion with the irrigating refractive surgery modality will degrade over time as handpiece. the spherical aberration in the human crystalline lens changes. between the two microincisions for IOL insertion. After When we look at the available IOLs for refractive lens IOL insertion, stromal hydration of the 2.5mm incision is exchange, we realize that options are becoming performed to make it self-sealing. Bimanual I/A is increasingly large in number and better in what they performed to remove all viscoelastic. The aspiration offer. New lenses include the eyeonics Crystalens™ handpiece is then removed and irrigation of the anterior (Aliso Viejo, CA) which is the first accommodative IOL chamber maintained. Stromal hydration of the empty that has become available in the United States (Figure 8). incision is performed to assist in closure of the With its improved 360° square posterior edge and ability microincision. The irrigation handpiece is then removed to be injected through a 2.5mm incision, this is an followed by stromal hydration of that incision. In this extremely attractive option. One hundred percent of manner, the eye is fully formed and pressurized our patients in the FDA-monitored study who were throughout the procedure avoiding hypotony and binocularly implanted with Crystalens™ were at least shallowing of the anterior chamber. 20/30 or better at all distance and 71% were 20/20 or We investigated laser phacoemulsification and although better at all distances (Figure 9). Figure 10 demonstrates we achieved excellent results, we realized that it was the stability of these results over three years. 22 REFRACTIVE LENS EXCHANGE: CURRENT PERSPECTIVES DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

Figure 9: Results for binocular implantations of the crystalens at Drs. Fine, Hoffman and Packer as part of the FDA-monitored study.

Figure 8: The eyeonics crystalens™ SE.

Figure 10: Three results of binocular implantations We have noted, however, that 15.7% of our patients, all of the crystalens. of whom were hyperopes, were more than one diopter from the desired spherical equivalent. We believe this is related to an inability to predict the final position of the optic within the eye. A small capsular bag will compress the haptics and result in a more posteriorly located optic, resulting in hyperopia, and a large bag result in an anteriorly located optic, which will result in myopia (Figure 11). We enhanced all of these patients with excellent results by implanting a piggyback IOL in the ciliary sulcus which is quite far in front of the Crystalens™ and does not appear to impede the mechanism of accommodation of the lens. We have completed quality of life surveys on Crystalens™ patients and have found that spectacle independence is achieved in 73% of our patients and that is exactly the percentage of our patients that were at least 20/25 or better at all distances. This mirrors the Figure 11: Scatterplot of intended versus achieved spherical equivalent for implantations of the experience we have had earlier with the Array crystalens™.

23 REFRACTIVE LENS EXCHANGE: CURRENT PERSPECTIVES DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

Multifocal IOLs, (Advanced Medical Optics, Santa Ana, CA). In that group of patients, 44% were at least 20/25 or better at all distances and that is the exactly the same percentage of patients who were spectacle independent. This may be what Richard Lindstrom, MD, has previously indicated as 20/”happy”, that visual acuity that will allow for complete spectacle independence. Other lenses that move in the eye include the Kellen TretraFlex (Lenstec, St. Petersburg, FL) and the HumanOptics 1CU (HumanOptics AG, Erlangen Germany), both of which have been tested in Europe, but we have had no experience within United States. Other accommodative IOLs include dual-optic IOLs. The first that has come to clinical studies in the United States is the Visiogen Synchrony™ Dual-Optic IOL Figure 13: Best corrected near and distance visual (Irvine, CA). This is a lens with a minus-powered optic acuities for the most recent implantations of the located against the posterior capsule attached by flexible Visiogen Synchrony™ Dual-Optic IOL. haptics to a plus-powered optic located more anteriorly within the capsular bag. The flexible haptics allow for greater separation between the two optics during accommodative effort on the part of the patient. This is essentially a Galilean telescope and theoretical evaluation of dual-optic lenses promises greater amplitude of accommodation than single-optic lenses that move in the eye. The early data for the Synchrony™ IOL has been good (Figures 12 and 13). This lens is also injectible through a 3.5mm incision by a new injection system. Perhaps the most promising technology for increased amplitudes of accommodation in accommodative IOLs is deformable optic IOLs. The Power Vision IOL (Power Vision, Santa Barbara, CA) has a reservoir that allows for fluid to be stored there during relaxation of accommodation. The fluid is pumped into the central Figure 14: Schematic of the Power Vision IOL.

portion of the lens during accommodation, resulting in a greater curvature of the optic and a greater plus power (Figure 14). One of the most exciting technologies is the NuLens Accommodating IOL from Herzliya, Israel. The manufacturers of this lens believe that at least eight diopters of accommodation are required for comfortable, continuous activity: one diopter for adjustment of the far plane, three diopters for near and an accommodative amplitude of twice that, resulting in a need for eight diopters of accommodation in order to avoid accommodative fatigue. The lens is based on a naturally occurring system of deformable optics which Figure 12: Summary of six month data for the Visiogen is present in the Merganser. This is a bird that flies but Synchrony™ Dual-Optic IOL. 24 REFRACTIVE LENS EXCHANGE: CURRENT PERSPECTIVES DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 also fishes for food and is able to see under water by accommodation to 4.5 diopters of accommodations forcing the anterior surface of the lens through a stiff (Figure 16). In addition, there are several injectible pupil, resulting in a marked increased curvature of the polymer IOLs on the horizon. The most promising is the lens (Figure 15). SmartIOL (Medennium, Inc., Irvine, CA), which is a hydrophobic acrylic that is designed to completely fill the capsular bag so there will be no decentration or edge effects. It is convertible, at room temperature, to a stiff rod and when it is implanted through a small incision into the eye, the thermodynamically active material reconstitutes to its original, size, shape, and dioptric power. At body temperature, it is a very flexible polymer with a high refractive index and has large amplitude of accommodation. This lens also has the advantage of being a stable gel so that if a YAG laser capsulotomy became necessary, it could be performed because the lens would not extrude into the vitreous cavity (Figure 17). A new and unusual solution is the LiquiLens (Vision Solution Technologies, Rockville, MD), which is a lens Figure 15: Illustration of the physical principle that has a fluid filled central aperture containing two behind the NuLens Accommodating IOL: The immiscible liquids, one with a lower refractive index Merganser.

The NuLens is essentially built by putting a compressible polymer between two firm plates. Accommodation results in a pressing of that polymer through the aperture in the anterior plate and an increased curvature, which theoretically can give up to 30 diopters of accommodation. The FlexOptic, by Quest Vision Technologies (Tiburon, CA), is now licensed by AMO. It has a plus-powered optic that changes shape on accommodation in addition to moving forward. The haptic is a balloon configuration and depending on the refractive index of the material, these are anywhere from 3.3 diopters of

Figure 17: Schematic drawing of the concept of the SmartIOL.

that fills the pupillary space with the patient in an upright position, and a higher refractive index fluid above that. When the patient tilts his head down, as for reading, there is a redistribution of the polymers so that some of the high-refractive index falls within the pupillary space and allows for a more plus-powered lens (Figure 18). Light adjustability, as in the Calhoun lens (Calhoun Vision, Pasadena, CA), is a technology that may be applicable to all other IOLs, either in the form of thin lens that can be piggybacked on top of other Figure 16: Schematic of the FlexOptic IOL. IOLs, or with an incorporation of the photosensitive macromers into other lenses.

25 REFRACTIVE LENS EXCHANGE: CURRENT PERSPECTIVES DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

wear bifocals, and senior citizens undergo cataract surgery. We believe that tomorrow, children will wear spectacles, and teenagers, contact lenses, but the groups that today undergo corneal refractive surgery, wear bifocals and undergo cataract surgery will all opt for refractive lens exchange. This represents a quadruple-win. Patients can enjoy a predictable refractive procedure with a rapid recovery that addresses all types of refractive errors including presbyopia and never develop cataracts. That is a significant advantage because of the changing spherical Figure 18: Demonstration of the physical aberration in so-called clinically insignificant cataracts. principles underlying the LiquiLens. The second win is that surgeons can offer these An interesting new technology from Medennium procedures without the intrusion of private or (Irvine, CA) is the Photochromatic Matrix IOL, which government insurance and establish a less disruptive would be a blue-blocking IOL under high levels of UV relationship with their patients. The third win is that light, but would revert back to a clear lens under scotopic ophthalmic industry can anticipate profits from their and mesopic conditions of illumination. research and regulatory expenses which can further expand the emerging IOL technology. Finally, the Finally, the Vision Membrane (Vision Membrane government can enjoy the decreased financial burden Technologies, Carlsbad, CA) has multiorder diffractive from their number one health-care expense, cataract optics (Figure 19) and, like other anterior chamber surgery, for the ever increasing ranks of baby boomers as more and more of these patients opt for lens exchange to address their refractive goals, ultimately reaching Medicare coverage as pseudophakes. 1. Fine IH, Packer M, Hoffman RS. Use of power modulations in phacoemulsification: Choo-choo chop and flip phacoemulsification. J Cataract Refract Surg 2001; 27(2):188-197. 2. Fine IH, Packer M, Hoffman RS. Power modulations in new technology: Improved outcomes. J Cataract Refract Surg 2004; 30:1014-1019. 3. Fine IH, Hoffman RS, Packer M. Optimizing refractive lens Figure 19: The Vision Membrane Phakic IOL. e x c h a n g e w i t h b i m a n u a l m i c r o i n c i s i o n phacoemulsification. J Cataract Refract Surg 2004; 30:550-554. multifocal IOLs, is capable of being implanted into the 4. Fine IH. Cortical cleaving hydrodissection. J Cataract anterior chamber of people who are already monofocally Refract Surg 1992; 18:508-512. implanted pseudophakes, seeking relief from 5. Packer M, Fine IH, Hoffman RS, Coffman PG, Brown LK. presbyopia. Immersion A-scan compared to partial coherence interferometry: outcome analysis. J Cataract Refract Surg It is essential to emphasize that new phacoemulsification 2002; 28 (2):239-242. and IOL technologies are expanding at a rapid rate, and 6. Hoffman RS, Fine IH, Packer M. Refractive lens exchange that any alterations to the cornea for refractive purposes with a multifocal intraocular lens. Current Opinion in will be compromised by changing spherical aberration Ophthalmology 2003; 14:24-30. of the crystalline lens as the patient ages. This leads us to 7. Packer M, Fine IH, Hoffman RS. Refractive lens exchange conclude that refractive lens exchange will be the with the Array multifocal intraocular lens. J Cataract dominant refractive procedure of the future and Refract Surg 2002; 28:421-424. addresses all components of the patients' refractive 8. McLeod SD, Portney V, Ting A. A dual optic errors, including presbyopia. accommodating foldable intraocular lens. Br J Ophthalmol Today, children with refractive errors wear spectacles, 2003; 87:1083-1085. teenagers and young adults wear contact lenses, older young adults get refractive surgery, middle aged adults

26 IRREGULAR CORNEA DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 MAJOR REVIEW Wavefront guided correction of the irregular cornea Dr. Jorge L. Alió MD, PhD, Robert Montés-Micó OD, PhD

Research, Development and Innovation Department, Ophthalmologic Institute of Alicante and the School of Medicine, University Miguel Hernández, Spain

Abstract: Irregularities in cornea can occur due to the extensive use of corneal refractive surgery. Correction of irregular astigmatism is a great challenge to refractive surgeons. Corneal wavefront guided laser may be an excellent tool for correction of irregular astigmatism induced by previous corneal refractive surgery. We have observed a significant improvement of uncorrected visual acuity, best corrected visual acuity and root mean square values of higher order aberrations. In our hands preliminary results have shown that both visual and corneal irregularity improvements are better with corneal wavefront oriented treatment ORK-W compared to topography oriented treatment.

Key words: aberrometey,, zernike polynomials, root mean square, hartmann shack sensor, tscherring aberroscope

Introduction to WAVEFRONT ABERRATION. When the wavefront shape has been obtained, Wavefront aberration is defined as the deviation using any of the previous methods, it can be between the reference wavefront that comes from a in analyzed by expanding it into sets of Zernike ideal optic system and the wavefront that originates polynomials to extract the characteristic from a measured optical system. The unit used to components of the wavefront shape. In the measure it is microns of waves and it is shown as the root Zernike polynomial expansion, the different mean square (RMS). Wavefront analysis of the eye optical aberrations may be described by terms allows to determine the optical quality of the eye by which are raised to different orders. First and evaluating the shape of its wavefront as wavefront second order terms describe tilt, astigmatism aberrations. and spherical refractive error respectively; and third, fourth and higher-orders describe There are several methods to evaluate the wavefront spherical aberration, coma and the rest of shape and are classified into the following three types: aberrations. Polynomials can be expanded up 1.- Outgoing wavefront aberrometry (Hartmann- to any arbitrary order if sufficient numbers of Shack sensor1). measurements for calculations are made. 2.- Ingoing retinal imaging aberrometry (Cross 2.- Corneal wavefront ABERRATIONS. 2 3 cylinder aberroscope , Tscherning aberroscope Videokeratoscopes have enabled the measurement of 4 and the sequential retinal ray tracing method ). the corneal shape and the determination of corneal first 3.- Ingoing feedback aberrometer (Spatially surface wavefront aberrations and their influence on 7,8 resolved refractometer5 and the optical path visual performance . To date, these methods have been difference method6). used mainly to quantify the effects of refractive surgery on corneal aberrations and visual performance. Address for correspondence:- The corneal wavefront, which is one of the components Dr. Jorge L. Alió MD, PhD, of the total ocular wavefront, can be calculated from Robert Montés-Micó OD, PhD corneal topographic height data. The corneal wavefront Research, Development and Innovation Department, can be fitted with a Zernike polynomial decomposition Ophthalmologic Institute of Alicante and the School of Medicine, in the same way that total ocular wavefront is measured University Miguel Hernández, Spain by aberrometry and fitted with the same polynomial

27 IRREGULAR CORNEA DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 decomposition. Both decompositions allow inspection prismatic component, the defocus component, the of the total ocular and corneal aberrations of the human degree of regular astigmatism, the spherical aberration, eye, considering the contribution of the cornea to the coma and the rest of the higher order aberrations. total aberrations of the eye. Figure 1 shows the procedure for calculation of the optical characteristics of the corneal surface. From a topographic map (1a) it is possible to compute the corneal wavefront aberrations of the cornea, and to differentiate between second (defocus and astigmatism) and higher-order aberrations. Figures 1b and 1c represent the total wavefront aberrations and the

Figure 1: Corneal topographic map (a) and wavefront (b,d) and higher-order aberration maps (c,f) computed for a 3- and 6-mm pupil diameters (respectively)

Using Zernike polynomial decomposition we are able to examine the optical quality of the corneal surface generating the wavefront of the anterior surface of the higher-order aberrations, respectively, for a 3-mm pupil cornea. Zernike analysis is a sophisticated analytical diameter. In the same way, figures 1d and 1e show the method which is ideal for representing surfaces of any same distribution but computed for a 6-mm pupil shape. It is based on a set of orthonormal polynomial diameter. These plots show graphically the importance developed by Zernike. Using Zernike's analysis, any of the pupil diameter to calculate the optical quality of surface can be described as the weighted sum of typical the cornea. In this specific case, the total root-mean- shapes represented by the polynomials. The series of square (RMS) of higher-order aberrations varies from polynomial is of increasing order and potentially 0.10 to 0.79 microns, showing the variation in the optical infinite. The greater the number of polynomials used, quality of the cornea as a function of considering one's the more detailed the surface representation. The pupil diameter. components chosen by Zernike are those specific for the As we have commented previously, we can compute the wavefront aberrations. The orthonormal characteristics different Zernike polynomials and separately evaluate of this mathematical approach allow the analysis of the the contribution of the different coefficients to the final individual components of the different aberrations quality of the corneal surface. Figures 2a and b represent independently of each other, quantification of the the corneal wavefront Zernike coefficients of the

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the optical quality of the cornea for a large pupil size (6- mm). 3.- Corneal wavefront as a guide for the correction of irregular astigmatism. Basis of treatment: The CSO topographer allows the analysis of the optical performance of the cornea. It measures a maximum of 6144 points of the cornea from the projection of 24 placido rings onto the cornea. The elevation data is computed from the ring positions and surface location measured from the video images. Corneal height is then translated into corneal wavefront and fitted into Zernike polynomials. These corneal aberrations do not depend on accommodation and pupil size. Corneal aberrations contribute to approximately 80 % of the total ocular aberrations in normal eyes and to an even greater value in corneas with irregular astigmatism. Corneal aberrometry is a revolutionary tool for the evaluation of quality of vision, and can be advantageously used to treat irregular astigmatism causes by a previous corneal refractive surgery. For this prospective, non-randomized pilot study, we evaluated 18 patients (18 eyes): 10 males and 8 females. Mean age of the patients was 38.5 ± 7.3 years (range 25 to 63 years). All these patients had a previous uneventful corneal refractive surgery and they were diagnosed Figure 2: Corneal topography Zernike coefficient with macroirregular or mixed (macro and micro) values computed for a 3- and 6-mm pupil diameter irregular astigmatism caused by the previous corneal (a and b, respectively) refractive surgery. We evaluated the results obtained topographic map of figure 1 computed for a 3- and 6-mm after a follow-up of 3 months. All surgical procedures pupil diameter. X-axis represents the coefficient number were performed by the same surgeon (JLA) at the (tilt, defocus, astigmatism, spherical aberration, coma, Instituto Oftalmológico de Alicante (Alicante, Spain). etc…) and the Y-axis represents the value of the The criteria for the selection of the patients were: deviation from the reference wavefront in microns irregular corneal astigmatism induced by previous (advanced or delayed, positive or negative values). corneal refractive surgery, decreased best spectacle- Large value of deviation indicates large deformation corrected visual acuity (BCVA), glare, ghost images and and poor optical quality of the corneal surface, then, distorted vision, intolerance or absence of motivation to from both graphs it is possible to observe an increase in use contact lenses. We waited for a period of 6 months to the coefficient values and consequently a reduction in confirm both the complete stabilization of the subjective refraction, the corneal topography and the tear film. Clinical Examination For each visit a comprehensive preoperative ocular examination was performed on each patient. This included previous ocular medical report, slit-lamp biomicroscopy, applanation tonometry, ultrasonic pachymetry. Subjective evaluation of quality of vision was assessed by asking the patients whether halos, glare, and monocular diplopia were reduced after surgery with best spectacle correction. Uncorrected visual acuity (UCVA) and BCVA were tested preoperatively, 1 and 3 months follow-up. Refraction 29 IRREGULAR CORNEA DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 was measured preoperatively and postoperatively under cyclopegia and using the high plus technique. Corneal topography and corneal aberration is a very important diagnostic and treatment tool and was obtained under proper tear film conditions before treatment, 1 month and 3 months after treatment. Surgical Technique Preliminary step of the procedure included obtaining the corneal topography by means of the CSO (CSO Ophtalmics, Milano, Italy). For this process, both the alignment and the stability of the pre-corneal tear film are extremely important. As mentioned above, the CSO Figure 4: Efficacy index. topographer is able to convert the elevation data in terms of Zernike Polynomials to quantify the corneal wavefront aberrometry. The root-mean-square (RMS) was used as a measure of the optical quality before and after customized corneal wavefront analysis. After capturing and analyzing corneal aberrations up to the 7th Zernike order, this data is processed by the ORK- W software (Schwind), which transforms this corneal aberration data into an adequate ablation profile. The software enables the surgeon to take an active part in the decision-making process, selecting the best solution for each patient. The software also allows the exclusion of specific aberrations according to specific surgical criteria and the choice of wide optical and transition zone. Finally, customized ablation is performed with the Schwind ESIRIS Excimer-Laser. It is a scanning spot Figure 5: Safety. Change in best spectacle-corrected laser technology with a spot of 0.8 µm and a repetition visual acuity (1 Month and 3 month after ORK-W rate of 200 Hz guided by its 330 Hz video based eye- treatment). tracking system. 2.- Safety Results: At 3 months follow up 55% patients gained one line of 1.- Efficacy BCVA, 27 % gained two lines, 11% gained 3 lines and UCVA improved in 81% of the patients, from 0.3±0.15 11% had no change (figure 5) with a safety index of 1.16 (range from 0.7 to 0.1) logarithm of minimum angle of (figure 6). The mean preoperative BCVA was 0.2 ± 0.17 resolution (logMAR) preoperatively to 0.2±0.27 (range logMAR (range 0.5 to 0.1) and mean postoperative from 0.8 to 0.00) logMAR at 3 months follow up (figure 3) with an efficacy index of 1.08 (figure 4). The mean gain of lines of postoperative UCVA was 1.81±1.5 lines.

Figure 3: UCVA and BCVA before an after Corneal Figure 6: Safety Index Aberration Oriented ablation. 30 IRREGULAR CORNEA DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

BCVA was 0.10 ± 0.23 logMAR (range 0.5 to 0.0). Then 7.-Coma-like Aberrations mean gain of lines of postoperative BCVA was 1.09± 0.7 Third order and fifth order Zernike coefficients are lines. indicators of coma-like aberrations. For a 6 mm pupil, 3.- Predictability the root mean square (RMS) of the wavefront aberration Mean preoperative SE was -0.29 D (range 1.75 D to -2.00 decreased significantly at 1 and 3 months by a factor 1.34 D; SD 1.04); at the last postoperative examination, mean and 1.38 respectively. In all cases the reduction in coma- SE was -0.20 D (range -0.50 D to -2.25; SD, 0.62) like corneal wavefront aberration was statistically significant. (Paired t-test; P<.005 for 1 and 3 months). 4.-Higher Order Aberrations 8.-Spherical-like aberration The preoperative and postoperative changes in the root Fourth order Zernike coefficients are indicators of spherical-like aberrations. The RMS values decreased significantly 1 and 3 month after surgery by a factor of 1.27 and 1.47 respectively. 4.- CASE REPORT A 33 year old white male was referred to our clinic with an ocular history of refractive surgery in both eyes. He complained of poor quality of vision, ghost images and halos especially at night in his right eye. He had a history Figure 7: Corneal Aberrometric analysis for 6 mm of moderate myopia (-3.75 1.00x 115º, 20/20 visual pupil. Change in RMS values on preoperative day, 1 acuity) before LASIK treatment. After we examined the and 3 month after ORK-W treatment.

mean square values (RMS) of the corneal higher-order wavefront aberration (total, spherical and coma-like aberrations) are shown graphically in Figure 7. All the data was analyzed for a 6 mm pupil. After ORK-W, there was a statically significant decreased in total higher order aberration. 5.-Total Higher Order Corneal Wavefront Figure 8: The bar graph above shows the magnitude (RMS) of each higher order corneal aberration (total, After ORK-W, there was statistically significant change tilt, spherical- and coma-like aberrations) for 6 mm in total higher order corneal wavefront aberration. Total pupil, before and after ORK-W treatment (1 ,3 and 6 higher order aberration reduced by a factor of 1.34 and months postop) for these patient. 1.45 at 1 month and 3 months of surgery respectively. (Paired t-test; p<0.005 for 1 and 3 months follow- up). 6.-First Order Aberrations Although ORK-W treatment does not affect directly the first order aberration, all the patients have shown statically significant changes in first order aberration. First order corneal aberration reduced by a factor of 1.62 and 1.54 at 1 and 3 month after surgery respectively. (Paired t-test; p<0.005 for 1 and 3 months follow-up).We may suggest that this improvement in first order aberration could be as a consequence Figure 9: Clinical Case. of recentration in the ablation profile. Treatment ablation profile

31 IRREGULAR CORNEA DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

Figure 10 : Clinical Case. Differential Instantaneous Map at preop ands 6 months postop. patient, his uncorrected visual acuity (UCVA) was preliminary results have shown that both visual and 20/40 with a manifest refraction of -1.75 0.75 x170º. corneal irregularity improvements are better with Corneal thickness measured by ultrasonic pachymetry corneal wavefront oriented treatment ORK-W was 482 µm. Preoperative corneal higher order compared to topography oriented treatment aberration revealed a RMS of 1.19 µm (largest (TOPOLINK)8. component was coma-like aberration with a RMS of 1.12 6.- References µm). Analysis of the RMS values shows that the major 1. Liang J, Grimm B, Goelz S, Bille JF. Objective improvement was for tilt and coma-like aberration measurement of wave aberrations of the human eye with (Figure 8). After pre-evaluation the patient underwent the use of a Hartmann-Shack wave-front sensor. J Opt Soc corneal wavefront-guided custom ablation (ORK-W) Am A 1994;11:1949-57. Figure 9 shows the ablation pattern used by the laser 2. Howland B, Howland HC. Subjective measurement of according to corneal wavefront data. The differential high-order aberrations of the eye. Science 1976;193:580-2- instantaneous map is shown in Figure 10 and demonstrates the efficacy of the treatment. At 6 months 3. Mrochen M, Kaemmerer M, Mierdel P, Krinke HE, Seiler T. Principles of Tscherning aberrometry. J Refract Surg after ORK-W treatment UCVA was 20/20 with a 2000;16:S570-1. manifest refraction of OD: -0.50 x180º (20/20). The RMS was 0.72 µm for Total HOA and 0.63µm for coma-like 4. Molebny VV, Panagopoulou SI; Molebny SV, Wakil YS, Pallikaris IG. Principles of ray tracing aberrometry. J aberrations. Refract Surg 2000;16:S572-5. 5.- CONCLUSIONS 5. Burns SA. The spatially resolved refractometer. J Refract The extensive use of corneal refractive surgery has Surg 2000;16:S566-9. increased the number of patients with corneal 6. MacRae S, Fujieda M. Slit skiascopic-guided ablation irregularities7,8. Correction of irregular astigmatism using the Nidek laser. J Refract Surg 2000;16:S576-80. remains a challenge to refractive surgeons. Irregular 7. Alió JL, Artola A, Rodriguez-Mier FA. Selective zonal astigmatism can be one of the most difficult and ablations with excimer laser for correction of irregular frustrating problems in refractive surgery. Treatment of astigmatism induced by refractive surgery. irregular astigmatism oriented by corneal wavefront Ophthalmology 2000;107:662-673. aberration has proved to be a successful technique. We 8. Alió Jl, Belda JI, Osman AA, Shalaby AM. Topography- have observed a significant improvement of guided laser in situ keratomileusis (TOPOLINK) to uncorrected visual acuity, best corrected visual acuity correct irregular astigmatism after previous refractive and RMS values of HOA. These objective results also surgery. J Refract Surg 2003;19:516-527. correlate with an improvement of patient visual 9. Alio JL, Galal A, Montalban R, Piñero D. Corneal symptoms after ORK-W treatment. wavefront guided LASIK retreatments for correction of highly aberrated corneas following refractive surgery. Corneal wavefront guided laser may be an excellent tool Accepted for publication in J Refract Surg 5-12-2006 for correction of irregular astigmatism induce by previous corneal refractive surgery. In our hands

32 GLAUCOMA MANAGEMENT DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 MAJOR REVIEW Neuroprotection --- An uprising wave In Glaucoma Management Aparna Rao, Viney Gupta, Tanuj Dada, Ramanjit Sihota

Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi 110029, India.

Abstract: Neuroprotection has recently become the buzzword for ophthalmologists worldwide. It implies enhancement of ganglion cell survival with various drugs acting at various sites thereby preventing apoptosis. A large number of drugs are currently in use as neuroprotectants and various trials are studying newer drugs which target different pathways and signaling systems leading to cell death in glaucoma. Knowledge of the cascade of events leading to apoptotic death in glaucoma would be helpful in understanding and identifying the potential sites where intervention with drugs may halt or delay the process thereby preventing ganglion cell death.

Key words: Apoptosis; neuroprotection; excitotoxicity.

“Neuroprotection” implies protection and enhancement (more so in normal or low-tension glaucoma). Several of survival of the retinal ganglion cells (RGC) which studies over the years have shown the possible existence constitute the primary cells damaged in glaucoma, of pressure independent mechanisms to cell death where the balance between retinal ganglion cell death which may be potential sites or targets in and survival is tipped more towards progressive neuroprotective therapy. destruction owing to a combination of causative factors, The concept of neuroprotection were originally the most important being intraocular pressure. Lower conceived in relation to spinal cord trauma .Then invertebrates like the leech are known for complete clinical trials proved their efficacy in treating growth and reconnections after transection of the CNS. cerebrovascular accident (CVA), Alzheimer's, But humans do not seem to share this privilege and amyotrophic lateral sclerosis (ALS or Lou Gehrig's therefore ganglion cell death in our central nervous disease), epilepsy and Huntington's disease. The system implies permanent damage beyond repair. similarity in the mechanism of apoptotic damage of ganglion cells in both Alzheimer's disease and glaucoma and the encouraging results obtained with Unlike cells of the human peripheral nervous system neuroprotectants in the field of medicine and surgery which have immense regenerative capacity, cells of the has raised the possibility that neuroprotection can apply central nervous system, including retinal ganglion cells in glaucoma too. The use of neuroprotectants is on the are incapable of regeneration after cell death. increase and is fast emerging as a potential modality of Glaucomatous optic nerve head cupping in majority of preventing irreversible damage. This article reviews the the cases is detected on perimetry after loss of more than 1 currently available drugs, their site of action and also half of the RGCs .Further, glaucoma continues to gives an insight into possible future therapies which are progress in many cases despite adequate control of IOP still emerging. To better understand how neuroprotection plays in the Address for correspondence:- prevention and treatment of glaucoma, it may help to Dr Aparna Rao review the evolution of the events that finally lead to Research associate, ganglion cell death and irreversible damage in Dr Rajendra Prasad Centre for Ophthalmic Sciences glaucoma. The factors leading to the final onslaught on All India Institute of Medical Sciences the optic nerve can be viewed as a three tier “hit” system New Delhi 110029, India. of damaging stimuli which singly or in combination FAX: 91-11 -26588919. lead to progressive ganglion cell death (Figure 1). Email: [email protected]

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6 glutamate .Glutamate interacts with three sub-types of neuronal glutamate inotropic receptors, namely, Apoptosis N-methyl-d-aspartate (NMDA), kainate; and DL- alpha-amino-3-hydroxy-5-methyl-4-isoxalone Ca+2, Na+, NO- Proteases, Free radicals, propionic acid (AMPA). In glaucoma, excess

Accumulation of Neurotrophin glutamate binds to NMDA receptors which causes

excitotoxins depletion accumulation of intracellular sodium and calcium which in turn activates a chain of reactions leading to Elevated Ischemia Genetic IOP factors active free radicals which cause ganglion cell toxicity Figure 1: Three tier “hit” system of ganglion cell and death (Figure2).

death and apoptosis in glaucoma. 3) All the above damaging stimuli and events culminate in the final destructive event whereby the cells are 1) The base of the tier comprises of damaging stimuli in irreversibly damaged and cell death subsequently the form of mechanical, vascular or genetic factors ensues by cell apoptosis 7. What actually triggers the which incite a series of cascading events that apoptotic signal for these cells to initiate their own eventually lead to ganglion cell death. Till recently, death is not known but a common mechanism may IOP was considered as the definitive cause for be free radicals associated with the tumor suppressor glaucomatous damage. But the common observation gene activating proteases and nucleases which lead of continued damage despite adequate IOP control in to cellular degradation and death. At the molecular glaucoma has now shed light on other causative level, depletion of neurotrophins or excitotoxin factors like ischemia and genetic factors which may accumulation is detected by an unknown sensor predispose the optic nerve head to glaucomatous protein that activates the tumor suppressor protein damage even under normal intraocular pressures. p53 which in turn controls the expression of bax and Mechanical forces due to elevated IOP and extra bcl-2 genes. cellular matrix deficiency lead to compression of the These events are responsible for cytochrome-c lamina cribrosa which impedes the axoplasmic flow release from the mitochondria which in turn leads to of neurotrophins to retinal ganglion cell bodies. The 2 activation of a cascade of enzymatic process vascular hypothesis suggests decreased optic nerve involving caspases that digest the cellular head perfusion and accumulation of excitatory components (Figure2). glutamate which adds on to the primary insult on the cells. Specific genes and mutations for several types 1. Neurotrophin depletion 3 of open-angle glaucoma have been identified 2. Glutamate (presynaptic recently (though polygenetic inheritance is common) neurons and Muller cells) with majority of the cases being attributed to an abnormality in the GLC1A/trabecular inducible Voltage gated channels glucocorticoid response (TIGR) gene that produces NMDA receptor myelin protein 4. In addition, apoptotic genes such as Bax and Bad have been recently identified with Sensor neuronal cell death. protein GANGLION CELL + +2 2) The next tier constitutes a step further towards Na Ca irreversible damage and is due to accumulation of p53 ---- Bax/bcl-2—cytchrome-c ----- excitotoxins and gradual neurotrophin depletion capsases—enzymatic digestion caused by the causative factors in the first tier. Neurotrophins serve as survival factors for the ganglion cells and are fed to the cells by the lateral Figure 2: Molecular mechanism of ganglion cell death geniculate nucleus. One such neurotrophins is the brain-derived neurotrophic factor (BDNF). Glaucoma blocks the retrograde flow of BDNF by Though various animal trials in the past few years have slowing axoplasmic transport with subsequent shed light on the possible mechanisms of optic nerve activation of ganglion cell death signals 5.The second damage in glaucoma, several questions still remain damaging stimulus associated with glaucoma is the unanswered. These include- release of excitotoxins, the most important of which is

34 GLAUCOMA MANAGEMENT DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

1) What is the trigger for induction of apoptosis? 5) How long does the inciting factor have to exist for 2) Why aren't all cells affected at the same time? It apoptosis to get initiated? seems that a subset of ganglion cells is damaged 6) Are the reparative mechanisms different in each initially by the inciting factor and the rest of the cells cell? die as a consequence of death of adjacent cells. Nevertheless, based on the existing knowledge of the 3) What determines the response of a cell to various various mechanisms of progressive optic nerve inciting factors? damage in glaucoma, it is possible to derive at various sites at which the ongoing process of apoptosis can be 4) Does the response differ in different people and in halted or treated.(Fig 3) different types of glaucoma?

Ocular Blood flow Genetic hypotensives enhancers modulation

Elevated IOP ischemia genetic factors

Accumulation of Neurotrophins Glutamate inhibitors Synthetic NMDA antagonists excitotoxins- depletion Neurotrophins glutamate- NMDA

NO Free radical Na channel Ca channel inhibitors Protease scavengers blockers blockers inhibitors

Sodium accumulation Calcium accumulation Nitric oxide synthase Proteases/ Free radical activation nucleases formation

Apoptosis of Therapeutic ganglion cells vaccine/genetic modulation

35 GLAUCOMA MANAGEMENT DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

Researchers are therefore now focusing on these new Glutamate inhibitors/NMDA antagonists. These neuroprotective agents which can act at various levels include drugs that either block glutamate release or of the disease process to prevent ganglion cell death 8. inhibit glutamate interaction at the NMDA receptor. Ocular hypotensive agents. Lowering IOP helps Lifarazine and riluzole have been shown to block reverse the cascade of events leading to ganglion cell glutamate before synapses, attenuating the release of excitotoxin at the NMDA receptor. NMDA antagonists death by removing the primary damaging stimulus. 10 Present-day therapy aims to achieve this, with beta include felbamate, eliprodil and Memantine. blockers, prostaglandins and alpha agonists either Memantine belongs to a class of drugs known as "open- singly or used as a combination in different cases. Alpha- channel blockers.” These attenuate glutamate release by entering and binding to NMDA receptor channels, thus 2-agonists are also believed to act as anti-apoptotic 11 agents in experimental studies by slowing down the blocking calcium entry . It blocks accumulation of neuronal loss in glaucoma and Alzheimer's disease by glutamate levels without significantly affecting normal activating a protein kinase B dependent signaling cell function. Also by virtue of its ability to rapidly block pathway. and unblock NMDA channels, memantine may help retain normal NMDA receptor function and cell survival Genetic modulators. These aim at inducing cells to in areas of reduced glutamate levels. The agent is produce anti-apoptotic proteins. The compounds currently used in the treatment of Parkinson's disease selegiline and brimonidine, and the tumor suppressor and Alzheimer's disease. gene p53, may prevent RGC apoptosis by increasing expression of the Bcl-x and bcl-2 genes. One study has Neurotrophins. The brain feeds the RGC axons with demonstrated that gene transfer to the outflow tissues of these growth factors of which the most important are the the living cat and retinal pigment epithelium and brain derived growth factor and basic fibroblast growth photoreceptors of the living rat is feasible by means of factor. Brimonidine has been proposed to up regulate herpes virus. Another study has shown that the RGC's the expression of basic fibroblast factor in experimental can be transfected with the bcl-L gene which inhibits pro- studies though such significance in a clinical scenario is apoptotic proteins. This novel form of therapeutic yet not established. eugenics and its evolution and clinical use in common Sodium channel blockers. These are thought to inhibit practice could be expected in the coming future only. sodium channel action in the events leading to cell death. FDA-approved for treating epilepsy include Blood flow enhancers/Calcium channel blockers. 9 Calcium channel blockers have been known to improve lamotrigine, topiramate &Riluzole though their use in blood flow in the central nervous system and their use in glaucoma and safety remains to be proven. CVA is a well accepted mode of treatment. Possibility of Nitric oxide inhibitors. Several studies have implicated extrapolating their beneficial effects for enhancing optic nitric oxide as the prime molecule mediating glutamate nerve head flow are therefore being studied especially in induced retinal ganglion cell death in glaucoma. The cases of low tension glaucoma. Their final efficacy in nitric oxide synthase exists in three isoforms of which these cases is yet to proven beyond doubt due to NOS-1 is found in retinal ganglion cells and many areas concerns that the resultant systemic hypotension may of the CNS. It has been postulated that the appearance of reduce optic nerve head perfusion. Nimodipine and NOS1 in reactive astrocytes in glaucoma may be due to betaxalol are the drugs which are currently being up regulation of the enzyme in glaucoma. The increased studied among this group of drugs. Studies using concentration of nitric oxide thus produced plays a n a f t i d r o f u r y l , a s e r o t o n i n S 2 r e c e p t o r major neurodestructive role by formation of free antagonist(causing vasodilatation thereby improving radicals, especially super oxide radical, causing blood flow), in treating CVA, Raynaud's phenomenon, structural and functional death of the ganglion cells. The peripheral arterial disease and LTG indicate this agent nitric oxide inhibitors prevent Nitric oxide synthase and may have potential neuroprotective benefits. Others halt the cascade of events induced by glutamate thereby under review include carbonic anhydrase inhibitors and preventing cell damage 1 0 . Examples include the Chinese herb ginkgo biloba. (Inhibition of platelet nitroglycerine, which provides oxidized nitric oxide, activation factor being the mode of action). Current and possibly ginkgo biloba. studies also show a beneficial effect of betaxalol in Free radical scavengers/antioxidants. These highly reducing calcium influx into stressed cells thereby reactive compounds are important mediators in cell slowing the death process initiated by ischemia or other degeneration. Potential free radical scavengers which inciting factors. 10 are under study include vitamins C and E, enzymes

36 GLAUCOMA MANAGEMENT DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 catalase and superoxide dismutase (SOD) and ginkgo still remains unproven. While certain answers of biloba. neuronal death and regeneration still remains Protease inhibitors. Proteases are enzymes involved in unanswered, exploring into the same could provide us the final stages which cause cell apoptosis. Owing to the with newer potential drugs which could possibly success of the protease inhibitors saquinavir, ritonavir, reverse the cascade of events leading to cell death. indinavir and nelfinavir mesylate in treating AIDS, similar agents may aid in treating glaucoma. Conclusion: To conclude, the concept of optic nerve Vaccine: A therapeutic vaccine for protecting the protection is still in its infancy. Nonetheless, research ganglion cells against autoimmune response to different into this new group of drugs, their improved safety and insults is still underway and if formulated may help the discovery of additional neuroprotective agents will protect the cells even in the late stages after the exposure undoubtedly lead us further into this promising era in to the inciting factors. glaucoma therapy and may actually become part of our Newer approaches in neuroprotection glaucoma-fighting armamentarium one day. 1) Erythropoietin: This molecule is known for its anti- apoptotic activity in human red blood cells. After References: discovery of receptors for the molecule in the retinal 1) Quigley HA, Addicks EM: Quantitative correlation of ganglion cells, intravitreal injection has been shown nerve fiber loss and visual field defects in glaucoma. to inhibit capsase-3 activation in axotomised rat Arch Ophthal 1982:100:135-146. eyes. 2) Mittag T, Schmidt KG. Mechanisms of Neuroprotection 2) Mitochondrial Modulators: Altered blood flow against glaucoma, Ophthalmologe. 2004; 101:1076-86. dynamics induce axonal energy compromise which 3) Sarfarazi M. Recent advances in molecular genetics of makes them susceptible to various insults. Agents glaucomas. Hum Mol Genet 1997; 6 : 1667-1677 which are targeted specifically at enhancing the 4) Stone EM, Fingeret JH, and Alward WLM, et al. mitochondrial function in the RGC's should Identification of a gene that causes primary open angle therefore be beneficial in preventing apoptosis. glaucoma. Science 1997; 275:668-670. Alpha-lipoic acid and nicotinamide are some 5) Nickells, RW. Retinal ganglion cell death in glaucoma: agents which can be used for this purpose. the how, the why, and the maybe. J Glaucoma 1996; 3) It has been recently observed that wallerian 5:345-356 degeneration occurs by a different apoptosis 6) Dreyer EB, Lipton SA. Excitatory amino acids in independent mechanism which is inhibited by slow glaucoma: a potentially novel etiology of neuronal loss. wallerian degeneration seen in mouse models of Invest Ophthalmol Vis Sci 1992; 33:1093 motor neuron disease. Its application to optic nerve 7) Nickells RW, Zack DJ. Apoptosis in ocular disease: A protection in human eyes is still in evolution and molecular overview. Ophthal Genetics 1996; 17:145 being investigated by Keith R Martin at the Centre 8) Update presented on glaucoma neuroprotection for Brain Repair, Cambridge University, UK. research. Ophthalmol Times. 1999; 24 : 51-54. According to him “It is becoming clear that to 9) Hubert JP, et al. Antagonism by riluzole of entry of categorize neuronal death as either apoptotic or calcium evoked by NMDA and veratridine in rat necrotic is a gross over simplification and that non cultured granule cells: evidence for a dual mechanism of apoptotic cell death pathways may be important in action. Br J Pharmacol 1994; 113:261-267 neuronal degeneration.” 10) Levin LA . Direct and indirect approaches to Despite various encouraging results on animal trials of neuroprotective therapy of glaucomatous optic the various neuroprotectants, their efficacy in reversing neuropathy. Surv Ophthalmol. 1999; 43:S98-101. the ongoing process of ganglion cell death in humans

37 STEM CELL CULTURE IN OCULAR DISEASES DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 MINOR REVIEW Role of stem cell culture in ocular diseases Dr. Rajpal *, Dr. R. V. Azad*, Dr. Atul Kumar*, Dr. Jasbir Kaur** and Parul Saxena** *Dr. R.P. Centre for Ophthalmic Sciences, AIIMS, New Delhi, India. **Ocular Biochemistry, Dr. R.P. Centre for Ophthalmic Sciences, AIIMS, New Delhi, India.

Abstract:: Stem cells are recent advances in ophthalmology, which have given newer therapeutic modalities in the management of retinal diseases, which were thought to be incurable. The potential use of stem cells in the treatment of a variety of human retinal disease remains tremendously exciting. Stem cell therapy is a new area of research in which lot of development is taking place. Although it is immature to interpret the clinical implication of the experimental research but it is important to know the various development taking place in this field. Stem cells may have some other effects like neutrotrophic or vasculotrophic effects

Key words: Stem cell, Macular degeneration

number producing populations of daughter cells (transit amplifying cells) that can proceed down through unique pathways of differentiation.

The ultimate stem cell, the fertilized egg, is formed from fusion of the haploid progeny of germinal stem cells. The fertilized egg is totipotent; from it forms all the tissues of the developing embryo.

In adults, tissue is renewed by proliferation of specialized stem cells, which divide to form one cell that remains a stem cell and another cell that begins the process of differentiation to the specialized function of a mature cell type.

There are striking similarities between tissues of malignant tumors and of developing embryos. Hence only transplantation of stem cells, without appropriate knowledge of growth factors and differentiation signals can lead to cancer.

Type of stem cells

 Embryonic stem cells  Germinal stem cells Stem cells are undifferentiated cells able to divide  Somatic progenitor cells indefinitely yet maintain the ability to differentiate into  Hematopoietic stem cells specific cell types. They are able to survive throughout the lifetime of the organisms, while maintaining their Scientists have found adult stem cells in many more tissues than they once thought possible. Certain kinds of Address for correspondence:- adult stem cells seem to have the ability to differentiate Dr. Rajpal into a number of different cell types, given the right Dr. R.P.Centre for Ophthalmic Sciences, conditions. If the differentiation of adult stem cells can AIIMS, Ansari Nagar, New Delhi-110029, India. be controlled in the laboratory, these cells may become 38 STEM CELL CULTURE IN OCULAR DISEASES DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 the basis of therapies for many serious common diseases.

An adult stem cell is an undifferentiated cell found among differentiated cells in a tissue or organ, can renew itself, and can differentiate to yield the major specialized cell types of the tissue or organ.The primary role of adult stem cells in a living organism are to maintain and repair the tissue in which they are found. The term somatic stem cell is used instead of adult stem cell. Unlike embryonic stem cells, which are defined by their origin (the inner cell mass of the blastocyst), the origin of adult stem cells in mature tissues is unknown.

CLINICAL APPLICATIONS OF STEM CELLS resting stem cell, to transit- amplifying precursor cells, to mature circulating blood cells. Until recently, most Stem cell technology is a rapidly developing field that primitive bone marrow progenitor cell was believed to combines the efforts of cell biologists, geneticists, and be pluripotent, giving rise to stromal cells and clinicians. It offers hope of effective treatment for a lymphocytic cells, as well as RBCs, WBCs. In addition to variety of malignant and non-malignant diseases. haematopoietic precursor, bone marrow also contains a mesenchyamal progenitor cell can give rise to many CLINICAL APPLICATIONS OF STEM CELLS IN other cell types such as muscle cells, astrocytes , and OCULAR DISEASES neurons,as well as stromal cells that support hematopoiesis. However, the accumulating evidence is • Stem cells have great potential value in treating eye that, not only does the bone marrow contain a pluri/ diseases characterized by irreversible loss of cells, multipotent blood forming stem cell, but it also contains such as glaucoma and photoreceptor degeneration. a cell that has the capacity to circulate to other organs Ocular diseases, such as retinitis pigmentosa and and replace different nonhaematopoietic tissues. age-related macular degeneration, reflect damage to Although these bone marrow-derived cells have specific cells that are not normally repaired or markers of the hematopoietic stem cell [HSC], it has not replaced ,they may be treated by stem cells been ruled out that this multipotent cell may be of transplantation stromal origin. Serial transplantation indicates that a • Conditions that destroy the limbal area of the single bone marrow cell may give rise to many different peripheral cornea, such as the Stevens - Johnson tissue types and suggest that a common precursor must syndrome, ocular pemphigoid, and chemical and exist, not only for stromal and hematopoietic lineages, thermal injuries, can deplete stem cells of the corneal but also other germ layer-derived cell types. It is this epithelium. The result is scarring and opacification putative totipotent bone marrow cell that has stimulated of the normally clear cornea. Standard corneal the great revival of interest in adult stem cells in the last transplantation cannot treat this form of functional few years. There are still some caveats to the generally blindness---- stem cells have potential. accepted assumption of pluripotentiality of tissue stem cells including HSCs. OCULAR STEM CELLS Lee MS..1 et al, has done recent clinical trial using adult bone marrow (BM) derived stem cells to regenerate  Limbal Stem Cells infarcted myocardium have reported success in  Conjunctival Stem Cells improving cardiac functions.1 Presuming on the basis of  Retinal Stem Cells bone marrow stem cells differentiating into  Bio-engineered Cornea myocardium is not supported by experimental data by 2 3 ROLE OF BONE MARROW-DERIVED STEM CELLS Murry. CE et alAccording to Balasam LB et al haematopoietic stem cells adopt mature haematopoietc In1917, Pappenhein postulated the existence of an fates in ischemic myocardium4. According to Anderson undifferentiated stem cell for blood cells .The DJ 4, et al these clinical observations cannot be haematopoietic or blood forming cells are located in the invalidated but raises many questions regarding bone marrow .The lineage of blood cells extends from a interpretation and emphasizes that there is a need to 39 STEM CELL CULTURE IN OCULAR DISEASES DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 establish rigorous standards by which such clinical developmental angiogenesis in both neonatal mice or 5 studies are evaluated. injury induced neovascularization. HSCs fraction, used in Otoni study not only inhibited angiogenesis when ROLE OF ADULT BONE MARROW DERIVED engineered to express an antiangiogenic, but also ENDOTHELIAL PROGENITOR [ STEM ] CELLS rescued and stabilized (e.g. matured) degenerating vessels. It was also observed that by preventing Bone Marrow derived stem Cells can contribute to vascular degeneration there is a trophic rescue effect on retinal and choroidal neovascularization. photoreceptors themselves, (50) suggesting that autologous bone marrow grafts of HSC fractions Hematopoietic Stem Cells Contains a pool of EPC containing EPC may provide trophic effects on (Endothelial Progenitor Cells) Capable of incorporating associated neural tissue that goes beyond simple into retinal vasculature has been shown. It was Grant nutrition. Such observations could provide a rational for and his colleague who first demonstrated that use of HSC in treatment of a variety of inherited retinal systemically administered HSC can function as degenerations such as retinitis pigmentosa. hemongioblasts during hypoxia stimulated retinal neovascularization There are technical challenges in using HSC for cell (In their model they have demonstrated that circulating, based therapies in the eye. (1) Stem cells are difficult to undifferentiated precursors cells can be recruited to the transfect (2) Another problem in the circulating stem cell sites of retinal neovascularization and, along with field is the issue of HSC “homing”. proliferation of local endothelial cells, can contribute to new blood vessel growth and development. The It has been reported in the literature that Lin HSCs experiments of Grant and colleagues demonstrated that contain a population of EPC that can promote circulating cells can incorporate into laser stimulated angiogenesis by targeting reactive astrocytes and retinal neovascularisation, but the role of these cells in incorporate into an established template without non irradiated host where the proliferation of local disrupting the retinal structure. Thus, if we can modify inflammatory, precursor, and endothelial cells is not genetically the autologous EPC and then transplant impaired by lethal irradiation, remains unclear. them into ischemic or abnormally vascularized retina then it may be possible to incorporate them into new This fact that EPCs contribute to pathological vessels and there by continuously delivering neovascularisation in ischemic and inflammatory therapeutic molecules to the retina for a prolonged retinopathies such as diabetic retinopathy and ARMD period of time such local delivery of pharmacological can be utilized in reducing abnormal angiogenesis. agents in physiologically meaningful doses may

7 represent a new paradigm for treating currently Recently Dorrel Ml,. et al has shown that adult bone untreatable ocular disease. marrow-derived stem cells utilize R-Cadherin to target sites of neovascularization in the developing retina. So Bone marrow-derived stem cells can exert a if we can antagonize or device a function-blocking neurotrophic rescue in retinal degeneration. antibodies to R-cadherin, the neovascularization can be stopped. Studies have suggested the role of certain Inherited degenerations of the retina affect as many as 1 adhesion molecule, such as integrin alpha 4 beta 1, may in 3500 individuals and are characterized by progressive play role in targeting circulating EPCs to sites of night blindness, visual field loss, optic nerve atrophy, abnormal angiogenesis during vascularzation of arteriolar attenuation, altered vascular permeability, tumors. and central loss of vision, often progressing to complete blindness. Most inherited human retinal degenerations Role of Bone marrow- derived stem cells as specifically affect rod photoreceptors but there is vasculotrophic rescue: concomitant loss of cones, the principal cellular component of the macula. Cone-specific survival Bone marrow-derived stem cells can exert a factors have been described and may facilitate cone vasculotrophic rescue. Experimental studies done on survival in mouse models of retinal degeneration. newborn mice by Otoni etal,.8 has shown that intravitreal HSC can target activated astrocytes, once HSC cells have also recently been reported to completely targeted to the template of activated astrocyte, the prevent retinal vascular degeneration ordinarily lineage negative HSCs participate in normal observed in mouse models of retinal degeneration, and

40 STEM CELL CULTURE IN OCULAR DISEASES DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 that the vascular rescue correlates with neuronal rescue. amniotic membrane as a carrier and can then be The inner nuclear layer remains nearly normal and the surgically transplanted to the ocular surface. These outer nuclear layer containing photoreceptors is tissue equivalents have been used successfully in significantly preserved, with the rescued cells being Conjunctival replacement. The use of Conjunctival predominantly cones. Detectable, albeit severely stem cells suggests additional future applications abnormal, electroretinogram recordings are observed in for these tissue equivalents. rescued mice at times when they are never observed in control treated, or untreated, rd/rd eyes. Large-scale CORNEAL SCARRING genomic analysis of rescued eyes revealed significant upregulation of antiapoptotic genes. These injected • Confluent sheets of cultured corneal epithelial cells, bone marrow-derived progenitor cells are never suitable for grafting, can be produced from limbal observed anywhere else except near blood vessels. The tissue taken from eye bank organ-cultured corneas, autologous bone marrow-derived EPCs may be useful although it takes longer, on average,to reach in the treatment of currently untreatable retinal confluence (1721 days) than an equivalent sample degenerative diseases as well as ones in which abnormal from a fresh eye (912 days) used for angiogenesis cause the vision loss. transplantation.Adult stem cells from relatives used to restore vision.Adult Stem Cells Used to Grow What is the precise identity of the cells exerting vasculo- New Corneas. and neurotrophic rescue in degenerating retinas? STEM CELLS AND GLAUCOMA Adult bone marrow-derived stem cells may have wide There are atleast 3 potential targets for stem cell utility in the treatment of retinal vascular diseases and therapy in glaucoma even inherited retina degeneration. • RGC • optic nerve head RETINAL STEM CELLS • trabecular meshwork. Stem cells have been discovered at the pigmented ciliary The most work has focused on replacing RGCs because margin of the adult mouse retina. The human eye their death is final common pathway for visual loss in contains about 10.000 of these cells. They can be isolated glaucoma and other optic neuropathies.Because human from eye bank eyes, even from elderly patients. Retinal RGCs are mammalian CNS neurons that cannot divide stem cells do not differentiate to form brain cells yet are and differentiate to replace other cells lost from disease, capable of producing all of the different retinal cell blindness from glaucoma is irreversible.Finding a way types. Although human brain stem cells require no to differentiate stem cells into RGCs and allow them to growth factors and grow easily and rapidly, even in connect to their appropriate targets would be a major completely defined serum-free media. Retinal stem cells step in repopulating the neurons lost in glaucoma. could lead the way for stem cell ocular therapies, such as The main issue to resolved are survival and implanting photoreceptors grown in culture into the differentiation of the stem cell maintaining the state of blind eye of an individual with retinitis pigmentosa or the surrounding microenvironment. extension of axons other retinal degenerative disorders. into the optic nerve establishment of functional connections in the lateral geniculate nucleus ANTERIOR SEGMENT STEM CELLS appropriate activation of transsynaptically connected • Limbal stem cells located in the basal limbal area are cortical targets. involved in renewal of the corneal epithelium. The RGC precursor cells introduced into the retina Limbal stem cells can be transplanted by using extend processes into the optic nerve head. autografts in cases of unilateral disease or allografts The need to establish a functional network from relatives or cadaver eyes for bilateral disease. communicating information to the brain makes the Cultured limbal stem cells can be used; a small problem of stem cell replacement of RGCs especially biopsy specimen from a healthy limbus can be complex. expanded exvivo and then grafted to an eye with Because patients lose a substantial portion of their RGCs stem cell deficiency. Adult pluripotent stem cells before developing functional deficits, there is hope that can be used for a ocular surface reconstruction. a limited amount of restoration might have a large effect Autologous Conjunctival biopsy specimens obtain on visual capability. in the superior fornix, where Conjunctival stem cells A third target for cellular repletion is the optic nerve reside, can be expanded in tissue culture by using head, which undergoes substantial remodelling and biochemical change in glaucoma.Issues to be dealt 41 STEM CELL CULTURE IN OCULAR DISEASES DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 within the region of the nerve head include excavation, inhibiting factors in amacrine cells and production of activation of astrocytes, secretion of nitric trophic factors. oxides,vascular complications,and loss of Much more needs to be known about potential sources cellularity.Progression of laucomatous optic of stem cells that could be developed in appropriate neuropathy in the presence of what appears to be conditions and that could be approved for therapy. This clinically adequate lowering of intraocular pressure includes the need to explore embryonic stem cells, and may reflect structural and functional optic nerve head even the transplantation of some types of mature cells. differentiated cells. Repopulating these cells with stem cell-derived normal Microenvironments need to be identified in which stem astrocytes and fibroblasts might be an alternate therapy cells can proliferate; differentiate; engraft; migrate; and, for glaucoma--- One that does not require complex once they are in the right state and place, shut down axonal path finding. proliferation. This may include the need to understand These include not only fetal stem cells but also cells from more about other cell types in the surrounding brain,limbus,conjunctiva, corneal endothelium , and environments and on the topographic map of the target retina. region. Another approach to improving the local environment Much more needs to be known about potential sources could come through genetic modification of cells before of stem cells that could be developed in appropriate they are introduced. conditions and that could be approved for therapy. This Successful use of such approaches will require more includes the need to explore embryonic stem cells, and work on determining which genetic modifications are even the transplantation of some types of mature needed and also on overcoming problems with gene differentiated cells. silencing that can happen not only after differentiation Microenvironments need to be identified in which stem but also in some cases in the course of passaging as they cells can proliferate; differentiate; engraft; migrate; and, are being grown for use --- STEM CELL once they are in the right state and place, shut down ENGINEERING. proliferation. This may include the need to understand more about other cell types in the surrounding CHALLENGES IN USING STEM CELLS FOR environments and on the topographic map of the target OCULAR DISEASES region.

• There are strict rules for the conditions in which REFRENCES stem cells must be grown if they are destined for 1 Lee MS, Makkar RR. Stem-cell transplantation in therapeutic use.Cells must be grown without serum myocardial infarction: a status report. Ann Intern Med and without the use of cell feeder layers, something 2004; 140:729-737. that would potentially complicate maintenance of at 2 Murry CE, Soonpaa MH, Reinecke H et al. least some stem cell types that require other cell Haematopoietic stem cells do not transdifferentiate into types in their local niche to maintain an intermediate cardiac myocytes in myocardial infarcts. Nature 2004; state of differentiation.The cells must differentiate 428:664-668. in completely defined conditions. their proliferation 3 Balsam LB, Wagers AJ, Christensen JL et al. after transplantation must be shut down. they must Haematopoietic stem cells adopt mature haematopoietic perform the desired functions while remaining fates in ischaemic myocardium. Nature 2004; 228:668-673. localized to their site of targeting. 4 Anderson DJ, Gage FH, Weissman IL. Can stem cells cross lineage boundaries? Nat Med 2001; 7:393-395. There are at least 3 different areas in which progress 5 McKay RD. Stem cell biology and neurodegenerative needs to be achieved disease. Philos Trans R Soc Lond B Biol Sci 2004; 359:851- 856. More needs to be known about precursor cells for any given cell type and about their production of essential 6 Asakura A. Stem cells in adult skeletal muscle. Trends factors, which may mean identification of stem cells that Cardiovasc Med 2003; 13:123-12 can differentiate into cell types that can live (eg. In the 7 Reh TA, Fischer AJ. Stem cells in the vertebrate retina. optic nerve head) and produce the appropriate factors. Brain Behav Evol 2001; 58:296-305. Alternatively, it may mean genetic modification of cells 8 Otani A, Dorrell MI, Kinder K et al. Rescue of retinal to achieve expression of genes encoding such factors. degeneration by intravitreally injected adult bone Desired functions include interfering with apoptosis, marrow-derived lineage negative hematopoietic stem

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cells. J Clin Invest 2004;114:765-774. 14 Espinosa-Heidmann DG, Caicedo A, Hernandez EP et al. Bone marrow-derived progenitor cells contribute to 8 Matsumoto K, Yoshitomi H, Rossant J et al. Liver experimental choroidal neovascularization. Invest organogenesis promoted by endothelial cells prior to Ophthalmol Vis Sci 2003; 44:4914-4949. vascular function. Science 2001;294:559-563. 15 Sengupta N, Caballero S, Mames RN et al. The role of 9 Shen Q, Goderie SK, Jin L et al. Endothelial cells stimulate adult bone marrow-derived stem cells in choroidal self-renewal and expand neurogenesis of neural stem neovascularization. Invest Ophthalmol Vis Sci cells. Science 2004;304:1338-1340. 2003;44:4908-4913. 10 Grant MB, May WS, Caballero S et al. Adult hematopoietic 16 Csaky KG, Baffi JZ, Byrnes GA et al. Recruitment of stem cells provide functional hemangioblast activity marrow-derived endothelial cells to experimental during retinal neovascularization. Nat Med 2002; 8:607- choroidal neovascularization by local expression of 612. vascular endothelial growth factor. Exp Eye Res 2004; 11 Wagers AJ, Sherwood RI, Christensen JL et al. Little 78:1107-1116. evidence for developmental plasticity of adult 17 Dorrell MI, Otani A, Aguilar E et al. Adult bone marrow- hematopoietic stem cells. Science 2002;297:2256-2259. derived stem cells utilize R-cadherin to target sites of 12 Krause DS, Theise ND, Collector MI et al. Multi-organ, neovascularization in the developing retina. Blood 2004; multi-lineage engraftment by a single bone-marrow- 103:3420-3427. derived stem cell. Cell 2001; 105:369-377. 18 Otani A, Kinder K, Ewalt K et al. Bone marrow-derived 13 Grant MB, Caballero S, Brown GA et al. The contribution stem cells target retinal astrocytes and can promote or of adult hematopoietic stem cells to retinal inhibit retinal angiogenesis. Nat Med 2002;8:1004-1010. neovascularization. Adv Exp Med Biol 2003; 522:37-45.

43 INTRAVITREAL BEVACIZUMAB DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

ORIGINAL ARTICLE Intravitreal Bevacizumab (Avastin) for Choroidal Neovascularization in Young Patients

Subrata Mandal, Zahir Abbas, Satpal Garg, Rajpal Vohra, Pradeep Venkatesh, Rajesh Sinha, T Velpandian

Dr Rajendra Prasad Centre for Ophthalmic Sciences, India

Abstract: Purpose : To evaluate the efficacy and safety of intravitreal bevacizumab in young patients (<50 years) with choroidal neovascularization. Design: Prospective, noncomparative, interventional case series. Participants: Fifty eyes of 50 patients with choroidal neovascularization due to idiopathic, myopia, inflammatory, angioid streak and central serous chorioretinopathy. Methods: Patients with choroidal neovascularization received intravitreal bevacizumab (1.25 mg/ 0.05 ml). Intravitreal injection was repeated if optical coherence tomography (OCT) showed presence of fluid in the form of intraretinal edema, subretinal fluid (SRF) and/or pigment epithelial detachment (PED) at 4 weeks interval. Ophthalmic evaluations included best corrected visual acuity (BCVA), complete ophthalmic examination, OCT and fundus fluorescein angiography (FFA). Patients were followed up for a minimum period of 9 months. Main outcome measures: Assessment of changes in BCVA, OCT findings including central macular thickness, angiographic characteristics and complications. Results: The patients were followed-up for a mean period of 10.2 months. The mean number of intravitreal injection was 1.8 injections per eye. At 9 months the mean BCVA improved from 20/133 (median 20/200) to 20/50 (median 20/40) (p<0.001). The mean central macular thickness reduced from 318 µm to 238 µm (p<0.001). At final visit 30 eyes (60%) had an improvement of BCVA of 3 lines or more, 16 eyes (32%) remained stable and 4 eyes (8%) lost 3 or more lines. No significant ocular or untoward systemic side effects were observed. Conclusions: Overall results suggest that intravitreal bevacizumab (1.25mg/ 0.05ml) is safe and well tolerated in young patients with choroidal neovascularization from different etiologies. Significant number of patients showed marked improvement in visual acuity and decrease in retinal thickness on OCT. Further evaluation with longer follow up is needed to confirm long term efficacy and safety. Key words: bevacizumab, choroidal neovascularization, optical coherence tomography

Choroidal neovascularization (CNV) is a significant p l a c e b o . 6 V e r t e p o r f i n f o r c h o r o i d a l cause of central vision loss. Most common cause of CNV neovascularizationassociated with angioid streaks also is age related macular degeneration (AMD) which is does not appear to significantly alter the course of this seen in elderly. But in the younger patients of 50 years or disease with most eyes undergoing enlargement and less, CNV is related to various conditions like disciform transformation of the neovascular process.7 pathological myopia, angioid streak, trauma, inflammation, ocular histoplasmosis syndrome(POHS) Other treatment modalities in the form of transpupillary or central serous chorioretinopathy (CSR).1 Cases in thermotherapy and submacular surgery are not which it occurs without any apparent predisposing satisfactory.8, 9, 10 Most of the published studies report cause are known as idiopathic CNV.2 low patient numbers with variable visual results. Though juxtafoveal and extrafoveal CNV can be treated The expenses associated with PDT are considerably with thermal laser, it is not recommended for subfoveal high and this limits the number of centers at which CNV as it will reduce central vision immediately. treatments can be administered. The visual results of Decision to treat subfoveal CNV is difficult due to PDT are inconsistent and highly variable. The limited proven therapeutic options. Photodynamic introduction of anti-VEGF agents has resulted in a new therapy (PDT) has shown to be effective in young patient treatment option for CNV management. Because of its with CNV in many studies.3, 4, 5 But long term results of low cost and reported encouraging results, off-level use PDT in myopic CNV are not significantly different from of bevacizumab has taken front seat in the management of CNV. In this study we report the results of intravitreal Address for correspondence:- bevacizumab for choroidal neovascularization due to Dr. Subrata Mandal different etiologies in consecutive 50 young patients. Dr. Rajendra Prasad Centre for Ophthalmic Sciences All India Institute of medical Sciences Patients and methods: New Delhi-110029, India The study was a prospective, noncomparative, E-mail: [email protected] consecutive, interventional study to evaluate the

44 INTRAVITREAL BEVACIZUMAB DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 efficacy and safety of intravitreal bevacizumab in young interval. patients with choroidal neovascularization. Outcome measures: Patient Selection The primary efficacy outcome was the proportion of Fifty cases of choroidal neovascularization were eyes that had improvement (gain of 3 or more lines), enrolled for this study. The patient had CNV due to stable (within 2 lines) or moderate vision loss (loss of 3 or idiopathic (32 eyes), myopic (12 eyes), angioid streak (3 more lines) of vision at the last follow-up. eyes), inflammation (3 eyes), and CSR (2 eyes). Three patients of idiopathic CNV were previously treated with Other outcome measures were change in the mean photodynamic therapy with poor response. All other BCVA, CMT, macular volume, requirement of patients either refused or could not afford retreatment and untoward effects. photodynamic therapy. Informed consent was obtained from each eligible patient after explaining its potential risks and benefits. Inclusion criteria included patients aged 50 years or younger with CNV, OCT showing intra-retinal edema, subretinal fluid (SRF) or pigment epithelial detachment (PED) and FFA showing leakage. Patients having concurrent ocular diseases which may compromise vision were also excluded. Hypertension and history of thromboembolic event were ruled out before intravitreal injections. Only patients with a minimum follow-up of 9 months were included in this study.

Before treatment full ophthalmological examination was done. Best corrected visual acuity (BCVA) was recorded with standard Snellen chart. Color fundus photography, fluorescein angiography and fast macular scan and line Figure: 1 Aliquot (0.2 ml) made from commercially available scan by OCT (Stratus OCT, Carl Zeiss Meditec, Dublin, bevacizumab (100mg/4ml) used separately for each patient. California, USA) were done before treatment. Statistical analysis: Intravitreal Bevacizumab Injection and Follow-up The Snellen visual acuity was converted to logarithm of Assessment minimum angle of resolution (logMAR) equivalent. A 0.2 ml aliquot (figure 1) of commercially available Data were recorded on an excel spreadsheet. All the bevacizumab (25mg/ml) was prepared for each patient entries were checked for any possible keyboard error. in our centre. The aliquots were stored at 40 to 80C. Two drops of proparacaine (0.5%) was put in the eye to be For data analysis, statistical software STATA version 9.0 treated five minutes apart before injection. After (College Station, Texas, USA) was used. Data were preparing the eye with 5% povidone iodine, 1.25 mg expressed as mean (±SD) and median (range). Visual (0.05ml) of bevacizumab was injected intravitreally via and OCT parameters were compared at baseline and 4 the pars plana using 26-gauge needle. After injection weeks, 3, 6 and 9 months. Wilcoxon Signed Ranks test intraocular pressure was checked and one drop of was used for comparison of data which were not gatifloxacin eye drop was put. Eye was bandaged for 3 to normally distributed whereas paired t-test was used for 4 hours and patients were instructed to put topical normally distributed data. In this study p<0.05 has been gatifloxacin eye drop four times a day for next 4 days. considered as statistically significant. Patients were seen on next day to look for any Results: complication and then at 1 week and 4 weeks. At each visit full ophthalmological examination including From December 2005 to June 2006, 50 eyes of 50 BCVA, fundus photography and OCT was done. Blood consecutive patients of CNV were included in the study. pressure was also monitored. Intravitreal injection was There were 36 (72%) male and 14 (28%) female patients. repeated if OCT showed persistent intraretinal edema, The average age of the patients was 36.8 years with a SRF and/or PED. Fluorescein angiography was range of 15 to 50 years. repeated at 3 months interval. Retinal thickness was The Snellen BCVA at baseline ranged from counting assessed by OCT using fast macular scan at 4 weeks finger at 2 feet to 20/40, with a median of 20/200. The

45 INTRAVITREAL BEVACIZUMAB DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 mean ± standard deviation (SD) logMAR BCVA before given in this series with a mean of 1.8 injections per eye treatment was 1.02 ± 0.49 (20/210 in Snellen equivalent). (range 1 to 5). Seventeen patients required 2 injections Amongst optical coherence tomography parameters at while eight other patients required 3 injections. One baseline, the mean ± SD CMT was 318 ± 140 µm. On patient each received 4 and 5 injections. The patients fluorescein angiography all cases demonstrated either who received single intravitreal injection had final classic or predominantly classic subfoveal CNV. The visual acuity between 20/70 and 20/25 and none of the patients were followed-up for a mean period of 10.2 patients who required 3 or more intravitreal injections months (range 9 to 12 months) and all completed gained more than 20/40 visual acuity. minimum 12 weeks of follow-up. Safety and Complications Visual outcomes The injection was well tolerated by all the patients. Three The Snellen BCVA at 4 weeks ranged from 20/250 to patients complained of black floater on the day of 20/30 with median of 20/60. The mean logMAR BCVA injection. But no patients developed uveitis, vitreous was 0.533 ± 0.32 and the improvement from baseline was hemorrhage, retinal tear, retinal detachment, significant (p< 0.001). At 3, 6 and 9 months the mean endophthalmitis, cataract, other ocular toxicity or logMAR BCVA was 0.49 ± 0.32 (median 20/50) thromboembolic events. The mean blood pressure at (p<0.001), 0.51 ± 0.37 (median 20/50) (p<0.001) and 0.54 baseline and 3 months follow-up were 126/74 and ± 0.36 (median 20/50) (p<0.001) respectively. Maximum 124/74 mmHg respectively. improvement in BCVA occurred at 4 weeks after first injection. However, further improvement was observed Selected case reports in subsequent follow-up also. Twenty one patients Case 1: A 36 year-old young male presented with (42%) had final BCVA of 20/40 or more and none except diminution of vision OS. His BCVA at presentation was one had worse than 20/200 of visual acuity. At final visit 20/20 OD and 20/600 OS. Ophthalmic examination, 20 eyes (60%) had an improvement of BCVA of 3 lines or colour fundus photograph, FFA (figure 2) revealed a more, 16 eyes (32%) remained stable and four eyes (8%) diagnosis of left idiopathic subfoveal classic CNV with lost 3 or more lines (moderate visual loss). serous detachment as well as subretinal and sub-RPE bleed. Transverse OCT line scan at baseline showed Optical coherence tomographic outcomes intraretinal edema, SRF and PED. Right eye was normal. At 4 weeks follow-up 28 of 50 eyes demonstrated As he could not afford PDT, after discussion he opted for marked decreased in retinal thickness and complete intravitreal bevacizumab. After one injection BCVA resolution of SRF and/or PED. Eight weeks after improved to 20/200 but OCT showed persistent fluid. injection further 14 eyes of the remaining 22 eyes had Intravitreal bevacizumab was repeated 4 times till OCT resolution of retinal edema, SRF and/or PED. At 3 showed complete resolution of edema, SRF and PED. At months, only 5 eyes had retinal edema, SRF and/or PED and were advised repeat injection. At 6 months none except one eye had SRF. Three eyes had recurrence of retinal edema, SRF and/or PED on OCT at 8, 10 and 11 months respectively. The central macular thickness at 4 weeks, 3, 6 and 9 months were 248 ± 76 µm (median=244), 242 ±78 µm (median=238), 233 ± 76 µm (median=234)and 238±62 µm (median=232) respectively. The decrease in CMT from baseline was significant at each follow-up and maximum reduction of CMT was observed after first injection at 4 weeks. At 9 months average reduction of CMT was 80 µm (p<0.001). Repeat intravitreal injections Figure: 2 Colour fundus photograph, fluorescein angiogram Optical coherence tomography findings were used to and OCT of a 36 year-old young male showing left idiopathic decide retreatment. Intravitreal bevacizumab injection subfoveal classic CNV with serous detachment as well as was repeated at 4 weeks interval if OCT showed subretinal and sub-RPE bleed. Patient received total 4 intravitreal bevacizumab (1.25mg/0.05 ml) at 4 weeks increased retinal thickness due to edema, presence of interval. At 20 weeks follow-up, colour fundus photograph, SRF and/or PED. Total 90 intravitreal injections were fluorescein angiogram and OCT showed complete scarring and staining without leakage. 46 INTRAVITREAL BEVACIZUMAB DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

20 weeks follow-up ophthalmic examination, colour explained about the available treatment options. After fundus photograph, fundus fluorescein angiography taking informed consent intravitreal bevacizumab was showed complete scarring and staining without leakage. injected. After two intravitreal bevacizumab injections The final BCVA was 20/ 120 OS. During further follow- BCVA improved to 20/80. At 9 months he was up till 12 months no recurrence was seen. maintaining 20/80 vision and no fluid was detected on OCT though PED was persisting. Case 2: A 25 year-old female developed diminution of vision to 20/400 OD. She had myopia of -16 diopters OU. Ophthalmic examination, colour fundus photograph, FFA and OCT (figure 3) showed juxtafoveal active CNV. Intravitreal bevacizumab was injected and at 4 weeks follow-up vision improved to 20/40 with marked reduction of fluid in OCT. At 3 months follow-up FFA showed contraction of the membrane with staining and OCT also demonstrated absence of fluid. He was maintaining a vision of 20/40.

Figure: 4 Colour fundus photograph, FFA of a 42-year-old male showing juxtafoveal classic CNV secondary to angioid streak. Optical coherence tomography revealed intraretinal edema and large multiple cystoid spaces at the fovea. He received 2 intravitreal bevacizumab. At 3 months follow-up OCT demonstrated contraction of membrane with minimal edema. BCVA improved from 20/120 at baseline to 20/60 at last follow-up.

Figure: 3 Colour fundus photograph, FFA and OCT of a Discussion: 25 year-old myopic female showing juxtafoveal active CNV with serous detachment. Intravitreal bevacizumab The natural course and outcome of idiopathic CNV is was injected and at 4 weeks follow-up vision improved not well known and has not been studied in large series from 20/400 to 20/40 with marked reduction of fluid in of patients. But natural history of idiopathic CNV is OCT. At 6 months follow-up FFA showed contraction of seems to be better than that seen in AMD and thermal the membrane with staining and OCT also laser does not appear to be a suitable treatment option demonstrated absence of fluid.

Case 3: A 42-year-old male presented with diminution of vision to 20/120 OS. Ophthalmic examination, colour fundus photograph, FFA showed juxtafoveal classic CNV secondary to angioid streak (figure 4). Optical coherence tomography revealed intraretinal edema and large multiple cystoid spaces at the fovea. He received intravitreal bevacizumab. Though at 4 weeks there was marked reduction in CMT on OCT intravitreal bevacizumab was repeated. At 3 months follow-up visual acuity was 20/60 and OCT demonstrated contraction of membrane with minimal edema. He was asked for further follow-up and no recurrence was seen Figure: 5 Colour fundus photograph, FFA and OCT of a 50- in 9 months follow-up. year-old male showing a subfoveal CNV secondary to chronic Case 4: A 50-year-old male presented with sudden CSR complicated by subretinal hemorrhage and PED. After worsening of vision to finger counting at 2 feet in right two intravitreal bevacizumab injections BCVA improved eye. He was a known case of CSR for last 8 years. On from finger counting at 2 feet at baseline to 20/80 at last follw- examination he had a subfoveal CNV complicated by up. At 9 months he was maintaining 20/80 vision and no fluid subretinal hemorrhage and PED (figure 5) and was was detected on OCT though PED was persisting. 47 INTRAVITREAL BEVACIZUMAB DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

because it will diminish the central vision fluid, subretinal fluid and PED. Median visual acuity immediately.2, 8, 11 In Macular Photocoagulation improved from 20/200 to 20/80 at 8 weeks. In a recent Study (MPS), 53% (10 out of 19 eyes) of non-treated eyes study, Bashshur et al20 reported results of intravitreal lost 2 or more lines of vision.11 In study by Ho et al2 16% bevacizumab (2.5 mg/0.1ml) in 17 eyes of subfoveal (3 out of 19 eyes) of eyes had moderate vision loss in the CNV from AMD. At 12 weeks follow-up 76% of eyes had mean observation period of 87 months. complete resolution of SRF with improvement of mean BCVA from 20/252 to 20/76. Despite one report of favorable visual outcome in the natural history of myopic CNV by Avila et al12 most other reports Most of the published studies on idiopathic CNV report shows progressive deterioration of vision and emphasize low patient numbers with variable visual results. that myopic CNV should not be left untreated. Currently, there are no published studies evaluating the efficacy or safety of intravitreal bevacizumab for The introduction of photodynamic therapy (PDT) in the year idiopathic subfoveal CNV. 2000 offered the first selective treatment for CNV, allowing for closure of choroidal neovascular membranes with In a retrospective chart review of 11 eyes of 9 patients by relative sparing of the overlying retina. But results of PDT in Yamamoto et al21, the effect of intravitreal bevacizumab AMD were not satisfactory for occult or large lesions.13 for treating subfoveal CNV secondary to pathologic However, in idiopathic CNV results of PDT are better.4, 14 myopia was assessed. They reported a mean of +3.5 lines improvement in VA with 8 eyes achieving 20/50 or The study of transpupillary thermotherapy (TTT) by better vision at the last follow up. Of the total of 11 eyes Kumar et al15 showed 11 of 21 eyes (52%) eyes had one or in the study, in 6 eyes intravitreal bevacizumab was more lines improvement of vision whereas 19% of eyes used as primary treatment. showed a decline in BCVA in a mean follow-up of 5.1 months. As the TTT has not been evaluated by others for Sakaguchi et al22 in a nonrandomized, interventional the treatment of idiopathic CNV, its role is not well known. case series studied eight patients of myopic CNV with intravitreal bevacizumab (1mg). In six eyes (75%) the Surgical removal and macular translocation in idiopathic BCVA improved two or more lines and remained the CNV is possible but few eyes have been treated with these same in two eyes (25%). Out of 8 patients, two had modalities so far. In addition, they have many received prior sub-Tenon's injection of triamcinolone. disadvantages like being invasive in nature, demanding surgical expertise, surgical complication including retinal As bevacizumab has not been studied in a prospective, detachment and recurrence.8, 9, 16 randomized, clinical trial, patients should be warned about and followed closely for, potential complications. Although pathogenesis of CNV is elusive, it is well But in our series of 50 patients we did not find any case of recognized that this angiogenic disease requires uveitis, hemorrhage, endophthalmitis, thromboembolic mediators of angiogenesis. Various mediators of events or any other ocular toxicity. No preservative angiogenesis are VEGF, PEDF, angiopoietins, FGF-2, induced toxicity can occur as it is not used for nitric oxide, extracellular matrix. The most widely studied bevacizumab preparation. Systemic toxicity of mediator has been vascular endothelial growth factor intravitreal bevacizumab is also remote possibility as (VEGF), which plays a central role in the complex cascade dose is much less than systemic dose (1.25mg of vessel growth, proliferation, and hyperpermeability. intravitreal vs. 5mg/kg intravenous). Bevacizumab (Avastin, Genentech, Inc., South San In our study, at final visit 30 eyes (60%) had an Francisco, CA), a humanized anti-VEGF antibody which improvement of BCVA of 3 lines or more, 16 eyes (32%) inhibits VEGF-A protein was approved by the US Food remained stable and 4 eyes (8%) lost 3 or more lines. and Drug Administration for intravenous use to treat Results of PDT in idiopathic CNV vary from 25% of one metastatic colorectal cancer in 2004.17 After the line improvement in a recent study to 62% of 3 lines published case report of visual acuity improvement and improvement in earlier smaller series.4, 14, 23 decreased retinal thickness by intravitreal injection of bevacizumab in case of neovascular AMD18 many have Twenty one eyes (42%) had final BCVA of 20/40 or more started using it in different retinal pathologies. and none except one had worse than 20/200 of visual acuity in our series. The final BCVA of 20/40 or more was Avery et al19 retrospectively reviewed 81 eyes of 79 reported in 25%23 (2 out of 8 eyes), 30%24 (3 out of 10 patients with subfoveal CNV secondary to AMD treated eyes), and 50% eyes14 (4 out of 8 eyes) in various studies. with monthly bevacizumab injections. They found that thirty of 81 eyes at 4 weeks and additional 25 of 51 eyes at In OCT SRF was found to resolve faster than retinal edema 8 weeks exhibited complete resolution of intraretinal whereas PED resolved last. The SRF and PEDs was not 48 INTRAVITREAL BEVACIZUMAB DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 possible to measure quantitatively. Only retinal edema 11. Macular Photocoagulation Study group. Krypton laser was assessed by measuring CMT and/or macular volume. photocoagulation for idiopathic neovascular lesions. Results of a randomized clinical trial. Arch Ophthalmol In our series a mean of 1.8 injections per eye were 1990;108:832-37. administered. Bashshur et al15 administered 3 injection of 12. Avila MP, Weiter JJ, Jalkh AE, et al. Natural history of 2.50mg/0.1ml every four weeks in CNV from AMD. This choroidal neovascularization in degenerative myopia. suggests that CNV in young patients may require lesser Ophthalmology. 1984; 91:1573-81. amount of injection in comparison to CNV from AMD. 13. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: Limitation of our study is relatively short duration of two-year results of a randomized clinical trial including follow-up. Despite this, our observation strongly lesions with occult with no classic choroidal suggest that intravitreal bevacizumab in the treatment of neovascularization-verteporfin in photodynamic therapy CNV in young patients is safe and effective. report 2. Am J Ophthalmol. 2001;131:541-560. References: 14. Spaide RF, Martin ML, Slakter J et al. Treatment of idiopathic subfoveal choroidal neovascular lesions using 1. Cohen SY, Laroche A, Leguen Yet al. Etiology of choroidal photodynamic therapy with verteporfin. Am J neovascularization in young patients. Ophthalmology. Ophthalmol 2002; 116: 6268. 1996;103(8):1241-4. 15. Kumar A, Prakash G, Singh R P. Transpupillary 2. Ho AC, Yannuzzi LA, Pisicano K et al. The natural history of thermotherapy for idiopathic subfoveal choroidal idiopathic subfoveal choroidal neovascularization. neovascularization. Acta Ophthalmologica Scandinavica Ophthalmology 1995;102:782-9. 2004;82:205-208. 3. Sickenberg M, Schmidt-Erfurth U, Miller JW et all. A 16. Fujii GY, Pieramici DJ, Humayun MS, et al. Complication preliminary study of photodynamic therapy using associated with limited macular translocation. Am J verteporfin for choroidal neovascularization in pathologic Ophthalmol. 2000;130:751-62. myopia, ocular histoplasmosis syndrome, angioid streaks, and idiopathic causes. Arch Ophthalmol. 2000;118(3):327-36. 17. Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and 4. Chan WM, Lam DS, Wong TH et al. Photodynamic leucovorin for metastatic colorectal cancer. N Engl J Med. therapy with verteporfin for subfoveal idiopathic 2004 3;350(23):2335-42. choroidal neovascularization: one-year results from a p r o s p e c t i v e c a s e s e r i e s . O p h t h a l m o l o g y . 18. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical 2003;110(12):2395-402. coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for neovascular age- 5. Erdem Ergun; Michael Tittl; Michael Stur. Photodynamic related macular degeneration. Ophthalmic Surg Lasers Therapy With Verteporfin in Subfoveal Choroidal Imaging. 2005;36:331-5. Neovascularization Secondary to Central Serous Chorioretinopathy. Arch Ophthalmol. 2004;122:37-41. 19. Avery RL, Pieramici DJ, Rabena MD et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular 6. Verteporfin in Photodynamic Therapy (VIP) Study Group. degeneration. Ophthalmology. 2006;113(3):363-372. Verteporfin therapy of subfoveal choroidal neovascularization in pathologic myopia. 2-year results of 20. Bashshur ZF, Bazarbachi A, Schakal A, et al. Intravitreal a randomized clinical trial--VIP report no. 3. bevacizumab for the management of choroidal Ophthalmology 2003; 110:667-673. neovascularization in age-related macular degeneration. Am J Ophthalmol 2006; 142:1-9. 7. Saad Shaikh, Alan J. Ruby, George A. Williams. Photodynamic therapy using verteporfin for choroidal 21. Yamamoto I, Rogers AH, Reichel E, Yates P, Duker JS. neovascularization in angioid streaks. Am J of Intravitreal Bevacizumab (Avastin) as Treatment for Ophthalmology. 2003;135:1-6 Subfoveal Choroidal Neovascularization Secondary to Pathologic Myopia. Br J Ophthalmol. 2006 Jul 26 (Epub 8. Thomas MA, Dickinson JD, Melberg NS et al. Visual ahead) results after surgical removal of subfoveal choroidal neovascular membranes. Ophthalmology 1994;101:1384- 22. Sakaguchi H, Ikuno Y, Gomi F, Kamei M, Sawa M, 96. Tsujikawa M, Oshima Y, Kusaka S, Tano Y. Br J Ophthalmol. 2006 Aug 16 (Epub ahead). 9. Fujii GY, Humayun MS, Pieramici DJ et al. Initial experience of inferior limited macular translocation for 23. Lam A, Lee HC, Ho AC, Regillo CD, et al. Photodynamic subfoveal choroidal neovascularization resulting from therapy in young patients.Ophthalmic Surg Lasers causes other than age-related macular degeneration. Am J Imaging. 2006;37(3):182-9. Ophthalmol. 2001;131:90-100. 24. Rogers AH, Duker JS, Nichols N, et al. Photodynamic 10. Ruiz-Moreno JM, de la Vega C. Surgical removal of therapy of idiopathic and inflammatory choroidal subfoveal choroidal neovascularisation in highly myopic neovascularization in young adults. Ophthalmology. patients. Br J Ophthalmol 2001; 85:1041-3. 2003;110(7):1315-20.

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ORIGINAL ARTICLE Interaction of Perfluoro-n-octane with extracted intraocular foreign bodies Deependra Vikram Singh, MD, Yog Raj Sharma, MD, Rajeev Sharma, MD

Dr Rajendra Prasad Centre for Ophthalmic Sciences, India

Abstract: Background: Perfluorocarbon liquid (PFCL) s have been known to facilitate foreign body (FB) removal. Their ability to float the frequently encountered FBs in vitreoretinal practice is unknown. Methods: We preserved all intraocular foreign bodies (IOFB) removed by pars plana vitrectomy during 6 months period. All FBs were analyzed and tested with perfluoro-n-octane to assess its usefulness in FB removal. Results: Out of total 25 FBs extracted during the period 20 (80%) were nonmagnetic with size varying from 1.5 to 7.5mm. All FBs sank when placed at saline air interface and only 2 (FBs both nonmagnetic) floated when placed at the saline-PFCL interface. In second set of experiments we were unable to float any FB off the bottom of the test container. Conclusions: Higher specific gravity and larger size limit the usefulness of perfluoro-n-octane for floating and manipulating most commonly- encountered IOFBs. Further work utilizing heavier PFCLs and retinal impact measurements are needed to investigate the possible (cushion effect) protection offered by PFCLs during foreign body removal.

Key words: intraocular foreign body, Perfluorocarbon liquids, surface forces, ocular trauma.

Perfluorocarbon liquid (PFCL)s have found great utility Methods and Materials in managing complex vitreoretinal surgical procedures We preserved all intraocular foreign bodies (IOFB) 2 like retained lens fragments , dislocated intraocular removed through pars plana during 6 months period 3 4 lens , proliferative vitreoretinopathy , subretinal and from Jan 2004 to June 2004. Foreign Bodies (FB) were 5 suprachoroidal hemorrhage and giant retinal tears . preserved in a glass vial containing 2% methylcellulose High specific gravity, optical clarity, low viscosity and to prevent corrosion. All FBs were analyzed and tested. high interfacial tension are the properties that make First a permanent magnet was used to check if they are 6 them extremely popular as third hand. Perfluoro-n- magnetic (and hence metallic) and then size and specific octane is particularly favorable PFCL because of its high gravity of all FBs was measured. The largest dimension purity, refractive index different from water (easy in mm was taken as the size and specific gravity was 6 visualization) and higher vapor pressure. PFCLs have measured using Archimedes' Principle as used by been known to float various materials off the retina. The Sudhalkar et al.9 Each IOFB was weighed in air (Wa) and materials like intraocular lens and retained lens water (Ww) and specific gravity was then calculated fragments float because their density is lower than using formula Wa/ (Wa-Ww).10 All IOFBs were washed PFCL. Previous authors have reported the clinical use of with balanced salt solution (BSS) to remove 2% PFCL in facilitating removal of glass intraocular foreign methylcellulose before testing. PFCLs can facilitate FB 7 bodies (IOFB). PFCLs are also reported to be effective removal either by floating the FB off the retina or by for removal of intraretinal IOFBs by tamponading retina acting as a cushion and thus preventing retinal injury in 8 and minimizing iatrogenic tears formation. case FB drops while removing. So we decided to The purpose of our study was to confirm our clinical simulate these two clinical situations during 2 sets of impression that PFCLs do not facilitate the intraocular experiments. Testing was done in a glass test tube and a manipulation of most IOFBs that we deal with clinically. glass vial. Each FB was placed at saline-air and saline- PFCL interfaces in a glass test tube filled with 2 cc of perfluoro-n-octane (PF-OCTANE, VITREO LABS 3109, Address for correspondence:- ISELIN-08830, USA) and 1 cc of BSS to determine its Deependra Vikram Singh MD, buoyancy. Second set of experiments were performed Senior Research Associate, Vitreo Retina Services with a glass vial containing 2 cc of BSS and a FB placed at Dr. Rajendra Prasad Centre for Ophthalmic Sciences the bottom. Perfluoro-n-octane in 2 ml syringe with bent All India Institute for Medical Sciences, Ansari Nagar, 23 G needle was injected underneath each of the FBs one New Delhi-110029, India by one to check if they could be floated off the bottom of Tel: 91-11-26593193 Fax: -91-11-26588919 the vial. Results of both these sets of experiments were Email [email protected] recorded for all FBs.

50 EXTRACTED INTRAOCULAR FOREIGN BODIES DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

Results are magnetic iron FBs and their size and high specific gravity limits the role of perfluoro-n-octane in their A total of 25 FBs were extracted during the study period. removal. Investigators have reported the use of PFCL in 20 FBs were magnetic and 5 were non magnetic. All non facilitating the removal of a large glass IOFB.7 They magnetic FBs were pieces of stone. Size of FBs ranged theorized that surface forces rather than buoyancy from 1.5mm to 7.5mm. Specific gravity of magnetic FBs might explain this phenomenon. In an another ranged from 7.4 to 7.9 and of non magnetic FBs from 2.9 experimental study Sudhalkar et al have tested potential to 3.6. Table 1 lists the magnetic property, size and FB materials with specific gravity ranging from 1.1-8.7 specific gravity of extracted FBs. During first set of and varying sizes for there affinity for saline and PFCL.9 experiments all FBs sank when placed at saline-air PFCL used by them was perfluorotributylamine interface and only 2 nonmagnetic FBs floated when (specific gravity, 1.94). They concluded that for each placed at the saline-PFCL interface. In the second set of material tested there is a critical surface/volume ratio experiments we were unable to float any FB off the above which specimens floated at the saline-PFCL bottom of the glass vial. interface. The higher the specific gravity, smaller is the Cushion effect: To know the difference in velocity FB size required for floatation. The maximum size for retardation offered by PFCL (specific gravity, 1.76) as steel FB which could float was found to be 1.4 mm. As is compared to the saline (specific gravity, 1.00) a evident from our study the usual size of IOFBs that we theoretical model of a magnetic FB falling from the deal with is between 1.5 to 7.5mm and the usefulness of sclerotomy site onto the retina was devised. To simplify PFCLs in floating them off the retina is limited. the calculations FB size used was 3×2×1 mm (close to Although we were able to float 2 nonmagnetic FBs by average size of FBs we extracted) with mass of 45mg placing them at saline-PFCL interface this property of (Table 2). The distance traveled was taken as 20 mm. PFCLs is not clinically useful. IOFB once held with When a FB falls freely in a fluid, gravitational and forceps or magnet is lifted off the retina and taken out buoyant forces act against each other, with buoyant force without any effort to place it on saline-PFCL interface. resisting the free fall. Another force known as drag force To further determine the clinical usefulness of PFCLs in which depends on viscosity of the fluid also favors the manipulating IOFBs we devised a theoretical model of a buoyant force in opposing the downward movement. A FB falling onto the retina. A series of mathematical series of mathematical equations were utilized to equations were sought for to calculate the difference in calculate the velocity of given FB falling through saline 11 velocities of a given FB falling through saline and PFCL. and PFCL (Table 3). We found that the velocities The PFCLs were found to retard the velocity and hence attained by the given FB (dimensions; 3*2*1mm) on can also be expected to lessen the impact of a falling FB reaching the retina after traveling through 20 mm in onto the retina. This cushion effect can minimize the water and PFCL to be 0.55 m/s and 0.388 m/s retinal injuries sustained in case an IOFB falls during respectively with 29% reduction in velocity offered by removal. PFCL (Table 3). Although cushion effect seems to be offered by PFCLs Discussion the actual verification can only be done in vivo. Series of PFCLs are valuable and extremely useful tool for animal studies are required to elucidate the cushion complex vitreoretinal procedures.1 They have simplified effect thus offered by PFCLs. Also the actual incidence of the management of giant retinal tears5 and posteriorly FB slipping out of forceps and falling onto the retina or dislocated nucleus2 and intraocular lenses.3 Temporary optic disc during removal is expected to be low in tamponade provided due to their high specific gravity experienced hands and with increased usage of rare (1.76-2.03) has helped in reattaching retinal detachments earth intravitreal magnets. 4 with advanced proliferative vitreoretinopathy. Their This study has few limitations. First limitation is the use usefulness in facilitating IOFB removal remains to be of lighter PFCL (PF OCTANE). Heavier PFCLs like tested clinically. PFCLs can facilitate FB removal either perfluorotributylamine would have floated more by floating the FB off the retina or by acting as a cushion number of FBs. Another limitation of the study is the and thus preventing retinal injury in case FB drops while experiments being performed in vitro only. removing. Our study tested the clinical usefulness of perfluoro-n-octane in manipulating a series of foreign We conclude that most IOFBs seen by us are magnetic bodies that had been removed from the eyes of actual and are too large and heavy to be facilitated by PFCLs in patients. Perfluoro-n-octane which is most widely used removing them. Since we were also able to make 2 non in our part of world and is the preferred PFCL was magnetic FBs (heavier than PFCL) float on PFCL authors tested. We found that most (80%) of the IOFBs seen by us support the theory proposed by Sudhalkar et al9 that for

51 EXTRACTED INTRAOCULAR FOREIGN BODIES DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 small FBs surface forces (adhesive forces) might be 9. Sudhalkar HA, Johnson MW. Perfluorocarbon liquid responsible for making them float. Theoretically PFCLs manipulation of high-density intraocular foreign bodies. do retard the velocity of a falling FB and may provide Retina. 1998; 18(5):460-5. cushion effect to retina. Further animal studies with th larger variety of IOFBs are warranted to define the role of 10. Smith AW, Copper JN. Elements of Physics, 9 ed. New PFCLs in managing IOFBs. York: McGraw-Hill Book Company, 1979:156-160. References 11. Warren L, McCabe, Julian C.Smith, Peter Harriot. Flow past immersed bodies. Unit Operations of Chemical 1. Chang S. Perfluorocarbon liquids in vitreoretinal surgery. Engineering.5th ed. Singapore. McGraw-Hill ISE.1993 156- Int Ophthalmol Clin 1992; 32:153-163. 172.

2. Shapiro MJ, Resnick KI, Kim SH, Weinberg A. Decision to treat subfoveal CNV is difficult due to Management of the dislocated crystalline lens with a limited proven therapeutic options. Photodynamic perfluorocarbon liquid. Am J Ophthalmol 1991; 112:401- therapy (PDT) has shown to be effective in young 405. patient with CNV in many studies.3, 4, 5 But long term results of PDT in myopic CNV are not significantly 3. Lewis H, Sanchez G. The use of perfluorocarbon liquids in different from placebo.6 Verteporfin for choroidal the repositioning of posteriorly dislocated intraocular neovascularizationassociated with angioid streaks also lenses. Ophthalmology 1993 Jul; 100(7):1055-9. does not appear to significantly alter the course of this 4. Coll GE, Chang S, Sun J, et al. Perfluorocarbon liquid in the disease with most eyes undergoing enlargement and management of retinal detachment with proliferative disciform transformation of the neovascular process.7 vitreoretinopathy. Ophthalmology 1995; 102:630-39. Other treatment modalities in the form of transpupillary 5. Kreiger AE, Lewis H. Management of giant retinal tears thermotherapy and submacular surgery are not without buckling. Ophthalmology 1992; 99:491-98. satisfactory.8, 9, 10 Most of the published studies report low patient numbers with variable visual results. 6. Kwun RC, Chang S. Perfluorocarbon liquids in Vitreoretinal Surgery. Stephen J. Ryan, RETINA, 3rd ed. The expenses associated with PDT are considerably Singapore: Mosby, Inc, 2001: 2162-3. high and this limits the number of centers at which treatments can be administered. The visual results of 7. Ruddat MS, Johnson MW, The use of perfluorocarbon PDT are inconsistent and highly variable. The liquid in the removal of radiopaque intraocular glass. introduction of anti-VEGF agents has resulted in a new Arch Ophthalmol 1995; 113:1568-9. treatment option for CNV management. Because of its low cost and reported encouraging results, off-level use 8. Vartanyan AH, Hovhannisyan TA. Application of of bevacizumab has taken front seat in the management perfluorocarbon liquid in the removal of metallic of CNV. In this study we report the results of intravitreal intraretinal foreign bodies. Med Sci Monit. 2002 Feb; bevacizumab for choroidal neovascularization due to 8(2):CR66-71. different etiologies in consecutive 50 young patients. Required Doctors at Saha Satnam Speciality Hospital Dera Sacha Sauda (Sirsa), Haryana World Record in Blood Donation Please Contact CMO, Dr.Aditya Insan Telphone:-01666-245666, 238659

52 EXTRACTED INTRAOCULAR FOREIGN BODIES DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

Table 1 Properties of Extracted Foreign Bodies Foreign Body Magnetic Size Specific Foreign Body Magnetic Size Specific (in order of (in order of date of (mm) Gravity date of (mm) Gravity removal) removal) 1 Yes 3.6 7.6 14 Yes 2.5 7.5 2 Yes 2.7 7.8 15 No 5.7 3.0 3 No 4.1 2.9 16 Yes 3.2 7.7 4* No 2.5 3.1 17 Yes 2.2 7.5 5 Yes 6.0 7.6 18 Yes 2.8 7.5 6 Yes 5.5 7.4 19 Yes 4.0 7.8 7 Yes 1.5 7.9 20* No 2.8 3.2 8 No 7.5 3.6 21 Yes 2.7 7.6 9 Yes 3.3 7.4 22 Yes 1.8 7.7 10 Yes 1.9 7.5 23 Yes 2.8 7.8 11 Yes 2.8 7.5 24 Yes 3.5 7.5 12 Yes 4.3 7.7 25 Yes 4.5 7.4 13 Yes 3.9 7.4 * Foreign Bodies floated

Table 2 MOTION OF FOREIGN BODY THROUGH THE FLUID The equation of motion of a foreign body through Now the external force is the weight of the body in this case. any fluid is given by the following equation: - The buoyant force acting on the body will be given by the weight of the liquid displaced. du F  mg (1) m  F  F  F e e b d ma  mg dt F  e  b   P P Fb: buoyant force Where Fe  External Force g: acceleration due to gravity Fb  Buoyant Force Now for the foreign body given:- ρ: density of medium

ρp: density of particle Fd  Drag Force Dimensions: 1mm*3mm*2.0mm Now the body is approximated to a spherical body whose diameter is calculated by the following formula. (v and s The drag force is given by the following equation: - represent the volume and surface area of the particle (3) respectively) 2 C D AP vo  6vP 613 2 Fd  DP    1.64mm  sP 2(13  3 2  21) Where Vp : volume of particle, CD Drag Coefficient Sp :surface area of the particle AP Projected area of the particle measured in plane 1 2 AP  DP perpendicular to motion of particle 4  P  7.5g / cc  2.133mm2 DPvo N  Reynold's Number (  viscosity) m  volum e   P ReP   6  10  9  7500kg Drag force is the force experienced by the particle due to the  5 presence of the fluid there. This is calculated as above.  4.5  10 kg mass of the given particle Dp : diameter of the particle

d u    C u 2  A Substituting values from 2 and 3 in 1, we get: - (4)  g P  D P d t  P 2 m 53 EXTRACTED INTRAOCULAR FOREIGN BODIES DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

Table 3 Calculating velocities of given FB through Saline and PFCL

Case I: Body Falls Through Saline 3 Assuming that T ≈ 298 K   1000kg / m

Temperature of the medium assumed to be that of normal ambient temperature that is 298 Kelvin and density is assumed to be almost equal to that of water. du 2 Substituting these values into equation 4, we get: -  8.4933  C u (176.08) dt D 24  Now, CD depends on u C D  D P u  1 .95  10  3  u du  8 .499  0 .343 u dt

Substituting the value of CD found above into the differential equation we get the above first order linear equation. By solving the above equation we can find the velocity of the body after in the fluid as a function of time. Proceeding with the solution we get: - du  0.343 u  8.499 dt (As particle falls in the fluid the velocity of the 0 .343 dt 0 .343 t Integr. factor  e   e particle will change with distance traveled, that is 0 .343 t 0.343 t 0.343 t the speed with which it falls. This will correlate e du  0.343 e udt  8.499 e dt with time also) d (e 0 .343 t u )  8.499 e 0 .343 t dt u = velocity of the particle at any instant of time t e 0 .343 t u  24 .78 e 0.343 t  c

Substituting the initial condition (at t=0, u=0) to get the integration constant, we get (e 0.343 t  1) u  24 .78 e 0.343 t dx u  where x is the position of the body at any time instant t dt dx  24 .78  (1  e  0.343 t )dt e  0.343 t x  24 .78 (t  )  c 2 x is the depth of the particle from the 0.343 top of the medium in which it starts At start t  0, x  0, we get falling at any instant of time t e  0.343 t  1 x  24 .78 (t  ) 0.343

When x=20mm, from the above equation we get t=0.65 sec. Substituting this time value into the equation for u (t) we get u (0.065) = 0.55 m/sec.

Case II: Body Falls Through PFCLs (Similarly) u = 0.388 m/sec.

54 A SCIENTIFIC APPROACH DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

ORIGINAL ARTICLE

An Insight into Indigenous Ophthalmic Medicinal Plant Drugs: A Scientific Approach

N. Srikanth*ψ, Parveen Bansal **, Jasbir Kaur***, Renu Bansal **** and Rajpal Vohra*****

* Central Council for Research in Ayurveda & Siddha, Janakpuri, New Delhi, India ** Central Research Institute (Ayurveda), Punjabi Bagh, New Delhi, India. *** Ocular Biochemistry, Dr. R.P. Centre for Ophthalmic Sciences, AIIMS, New Delhi, India. **** Microbiology, Govt. Medical College, Faridkot (Punjab), India. ***** Dr. R.P. Centre for Ophthalmic Sciences, AIIMS, New Delhi, India.

Abstract: The paper highlights hidden knowledge about various ophthalmic plant drugs scattered elsewhere in various corners of ancient literatures of Ayurveda and provides the basic knowledge concerning ophthalmic drugs found in medical classics of ancient and medieval period, which forms a base for further research and validation. An attempt has also made to classify the Ayurvedic ophthalmic plants based on their mode of action with Ayurvedic pharmacological basis.

Key words:

In spite of great technological advances in the field of there is no cure for many of the diseases. For instance, ophthalmic medicine and surgery, conservative therapy problems retained with management of conditions such still continues to be mainstay for reversible ailments. as Retinitis pigmentosa, Glaucoma, Degenerative Researchers are relentlessly in quest to identify plants neuro-ophthalmic lesions, chronic allergic disorders of with medicinal properties. Often they are successful, adnexa etc. have remained unsolved since decades. proverbially, in turning over a new leaf. Apart from these problems of management, adverse ocular effects of synthetic medicaments are creating Tremendous advancements made in the science of considerable amount of discomfort and morbidity to the ophthalmology in recent years have opened a new era in patient, has become a challenge to the ophthalmologist. the history of medicine. Scientists and scholars of modem ophthalmology have attracted most of the Owing to the difficulties mentioned above, it is a mankind who are anxious about maintenance of juncture that the need for such drugs which could prolonged and healthy vision. At the same time, there effectively tackle the above problems without any are numerous challenging problems, existing before adverse effects. modern ophthalmologists, which require special Ever since dawn of history man has been in pursuit of attention to develop untrodden fields of medical new substances that could cure illness and promote knowledge hidden in various treasuries. health and longevity. Ayurveda, one such science that Modern ophthalmology is incomplete in spite of philosophises in not merely treating the illness but tremendous research and utilization of advancements of counter balancing the disequilibria that result in disease. various sciences viz. biotechnology, bio-medical It is the traditional system of medicine holds out to the engineering etc. It is true that, there is surgery to manage world, the promise of healthy long life. many of ophthalmic problems; if there is no surgery The happiest part of history of medicine is the origin of Indian ophthalmology (2000 B.C.). Susruta, the father of Address for correspondence:- Indian ophthalmology and author of Susruta Salmhita Dr. N. Srikanth, has contributed many chapters on clinical Assistant Director (Ayurveda), Central Council for ophthalmology, ocular surgery, principles of ocular Research in Ayurveda & Siddha (Department of pharmacology, and therapeutics in his text. AYUSH, Ministry of Health & Family Welfare, From historical point of view it is evident that plants, Govt. of India), 61-65, Institutional Area, 'D' Block, metals, minerals and animal products extremely used in Janakpuri, New Delhi 110058, India alleviating the wide range of ocular conditions. History 55 A SCIENTIFIC APPROACH DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 of ophthalmic use of natural products of medicinal value indigenous ophthalmic drugs found in medical classics can be traced from remote past in pre-early Christian of ancient and medieval period which forms a base for Era. For instance Atharvaveda furnishes many references further research and revalidation . A special attention to the use of different natural products as topica1 has also been made to classify these drugs based on their ophthalmic medicaments-Anjanas varied pharmacological actions on visual system and adnexa. For instance, Caksusya Drugs-drugs used in Objectives and Methodology improving visual acuity, visual fields and colour vision, The present work aims at exposition of hidden Naktandhyahara Drugs- drugs prescribed to manage knowledge about various single ophthalmic drugs various conditions presenting with night blindness of scattered elsewhere in various corners of ancient varied aetiology, Netrasulahara Drugs advocated for the literature and to impart the basic knowledge concerning alleviation of painful ophthalmic conditions and so on .

Pharmacological actions & specific ophthalmic uses of Indigenous Ophthalmic Drugs

1. DRUGS USEFUL IN THE MANAGEMENT OF OPHTHALMIC CONDITIONS IN GENERAL Actions (in Sanskrit) Sanskrit name Botanical name Netramayahara Gunija Abrus precatorius Nayanaaya Satavari Asparagus racemosus Netraroganut Darvl Berberis aristata Nayanamayaghna Caksusya Cassia absus Netravikarahara Aparajita Clitorea tematea Pavana-pitta-kapha Amalaki Emblica officinalis pradusta netraroga Netrarogahara Patola Trichosanthus dioica Netragadahrt Kadali Musa paradisiaca Aksirogaghna Sarala Pinus roxburghii Nayanamayanasana Mulaka Raphanus sativus Asesaksirogahara Lodhra Symplocos racemosa Aksirogapaha Tagara candani Ervatamica divaricata Netrarogahara Amlika Tamarindus indica Netramayaghna Hartaki Terminalia chebula Aksirogaghna Krsnagaru Aquilaria agallocha Caksuroganasana Tagara Veleriana wallichii

2. DRUGS USEFUL IN PAINFUL OPHTHALMIC CONDITIONS

Actions (in Sanskrit) Sanskrit name Botanical name Netraruja Darvi Berberis aristata Netrarujahara Bhrngaraja Eclipta alba Aksiruja Krsnaagaru Aquilaria agallocha Aksiruja Jati Jasminum grandiflorum Netrabadha Nimba Azadirachta indica Asruvedanahara Sigru Moringa oleifera Netrarsulapaha Misreya Foeniculum vulgare Nayanartinasana Karanja Derris indicia Nayanarujahara Mulaka Raphanus sativus Aksirukhara Manjistha Rubia cordifolia Asrutodasambhavam Amlika Tamarindus indica Rogan Samayati Netrarujapaharini Haritaki Terminalia chebula Netravyathahara Guduci Tinospora cordifolia 3. DRUGS ALLEVIATIVE OF FACTORS (DOSAS) RESPONSIBLE FOR DISORDERS OF VISION AND ADNEXA Actions (in Sanskrit) Sanskrit name Botanical name Aksidosahara Darvi Berberis aristata Drstidosaghna Sveta marica Moringa concanensis Drstidosanasana Tagara Veleriana wallichii 4. DRUGS USEFUL IN ACUTE VISUAL DISTURBANCES AND CONGESTION Actions (in Sanskrit) Sanskrit name Botanical name Asrudrstiprasadanam Nirmali Strychnos potatorum Netra-prasadanam Nlrmali Strychnos potatorum Drsti-prasadanam Iksu Saccharum officinarum 56 A SCIENTIFIC APPROACH DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

5. DRUGS CONDUCIVE TO VISION AND ADNEXA Actions (in Sanskrit) Sanskrit name Botanical name Aksihita Jalapippalika Phyla nodiflora Netrahita Bibhitaka Terminalia belarica Aksihita Nirgundi Vitex negundo 6 DRUGS USEFUL IN ALLERGIC CONDITIONS OF THE EYE Actions (in Sanskrit) Sanskrit name Botanical name Kanduhara Guduci Tinospora cordifolia Darvi Berberis aristata Netrakaanduhara Punarnava Boerhaavia diffusa Aksikandu Amlika Tamarindus indica Netrasothakandu Nimba Azadirachta indica vyathapaha

7 DRUGS CONDUCIVE TO EYE ORGAN (Action In Sanskrit NETRYA, NETRA HITA) Lasuna Allium sativum Kumari Aloe vera Satavari Asparagus racemosus Darvi (rasanjana) Berberis aristata Latakasturi Abelmoschus moschatus Nimba Azadirachta indica Kantakari (anjana) Solanum verginianum

8. DRUGS EFFECTIVE IN IMPROVING VISUAL ACUITY AND DISORDERS VISION (Action In Sanskrit --CAKSUSYA)

Sanskrit name Botanical name Lavanga Syzygium aromaticum Caksusya Cassia absus Karpura Cinnamomum camphora Aparajita Clitorea tarnatea I Jiraka Cuminum cyminum Amalaki Embelica officinalis Hingu Ferula narthex Yastimadhu Glycyrrhiza glabra Jati Jasminum grandiflorum Jivanti Leptadenia reticulata Jalapipplika Phyla nodiflora Karavellaka Momordica charantia Sigru Moringa oleifera Karavlra Nerium oleander Mudagaparni Vigna trilobata Karanja Derris indica Nirmali Strychnos potatorum Lodhra Symplocos racemosa Masaparni Teramnus labialis Bibhitaki Terminalia bellirica Haritaki Terminalia chebula Guduci Tinospora cordifolia Draksa Vitis vinifera 9. DRUGS USEFUL IN THE MANAGEMENT OF NIGHT-BLINDNESS OF VARIED AETIOLOGY Actions (in Sanskrit) Sanskrit name Botanical name Naktandhyahara Agastya Susbania grandiflora Bhrngaraja Eclipta alba Jivanti Leptadenia reticulata Tuvaraka (taila) Hyydnocarpus laurifolia Ratrandhya Satavari Asparagus recemosusNisandhahara Punarnavii (kanji) Boerhaavia diffusa Naktandhyanasinl Darvi Berberis aristata 10. DRUGS EFFECTIVE IN INFLAMMATORY OPHTHALMIC CONDITIONS Actions (in Sanskrit) Sanskrit name Botanical name

57 A SCIENTIFIC APPROACH DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

Navanetrakopa Caksusya Cassia absus Netrakopanut Karavira Nerium oleander Navadrkkopam Amalaki Emblica officinalis Navadrkprasamanam Sigru Moringa oleifera 11. DRUGS EFFECTIVE IN BLINDNESS OF VARIED AETIOLOGY Actions (in Sanskrit) Sanskrit name Botanical name Andhya Gunja Absus precatorius 12. DRUGS EFFECTIVE IN MANAGING SWELLING OF THE EYELID AND LID-MARGIN Actions (in Sanskrit) Sanskrit name Botanical name Anjananamilka Darvi Berberis aristata

13. DRUGS USEFUL IN MANAGING CORNEAL ULCERS AND OPACITY, EPIPHORA & LACRIMATION Actions (in Sanskrit) Sanskrit name Botanical name Netrapuspa Punarnava (ghrta) Boerhaavia diffusa Aparajita Clitorea ternatea Nayanapuspahrt Karanja Derris indica Netrasrava Punarnava (ksaudra) Boerhaavia diffusa Sukra Karpura Cinnamomum camphora Sukraroga Atasi Linum usitatissimum

14. DRUGS EFFECTIVE IN INFECTIVE AND INFLAMMATORY CONDITIONS OF LIDS, CONJUNCTIVA\ Actions (in Sanskrit) Sanskrit name Botanical name Pilla Tuvaraka Hydnocrpus laurifolia Pillavartma Guduci Tinospora cordifolia Pillanasana Tagara Veleriana wallichii

15. DRUGS EFFECTIVE IN DEGENERA TIVE CONDITIONS OF CONJUNCTIVA,.PTERYGIUM ETC. Actions (in Sanskrit) Sanskrit name Botanical name Armahara Guduci Tinospora cordifolia Armahara Tuvaraka Hydnocarpus laurifolia 16. DRUGS EFFECTIVE IN MANAGEMENT OF VISUAL DISORDERS Actions (in Sanskrit) Sanskrit name Botanical name Kaca Guduci Tinospora cordifolia Tuvaraka Hydnocarpus laurifolia Nili Karavellaka Momordica charantia Tuvaraka Hydnocarpus laurifolia Nilima Agastya Susbania grandiflora

17. DRUGS EFFECTIVE IN MANAGING OCULAR INFLAMMATORY CONDITIONS Actions (in Sanskrit) Sanskrit name Botanical name Netrasopha Karavira Nerium oleander Netraharsa Sigru Moringa oleifera

18. DRUGS USEFUL IN SPECIFIC INFLAMMATORY CONDITIONS OF THE EYE Actions (in Sanskrit) Sanskrit name Botanical name

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Pittaraktaksirogaghna Amalaki Embelica officinalis Slesmabhisyandanasana Sigru Moringa oleifera Pittabhisyandanasana Amalaki Embelica officinalis Darvi Berberis aristata Paripurita-nayana Karavellaka Momordica charantia Pittaja netraroga Candana Santalum album Vatabhisyanda Kantakari Solanum verginianum Patalagata roga Dronapuspi Leucas cephalotes Raktabhisyandanasana Nirmall Strychnos potatorum Vataja timira Amlika Tamarindus indica 19. DRUGS USEFUL IN MANAGING SUB-CONJUNCTIVAL HAEMORRHAGE & OTHER HAEMORRHAGIC CONDITIONS OF THE EYE Actions (in Sanskrit) Sanskrit name Botanical name Arjuna-nasana Nirmali Strychnos potatorum

20. DRUGS USEFUL IN DISORDERS OF SCLERA AND CORNEA Actions (in Sanskrit) Sanskrit name Botanical name Shuklagata roga Bibhitaki Terminalia bellirica Sukla & Krsnagata roga Guduci Tinospora cordifolia

21. DRUGS USEFUL IN MANAGING CATARACT Actions (in Sanskrit) Sanskrit name Botanical name Linganasa Guduci Tinospora cordifolia

Conclusion 3. Srikanth, N., 2000. The Actions and Uses of Every country has its traditional cure for its disease. Indigenous Ophthalmic Drugs, Chaukhamba These prescriptions have evolved based on Sanskrit Prathisthan, Delhi, geographical conditions, flora, fauna, and mineral 4. Srikanth N, Ancient Ocular Therapeutics An resources. India is one of the richest nations in the integrated approach., Ayur Medline Vol.I, April, world in terms of natural resources of medicinal valu 1999, richest nations in the world in terms of natural 5. Srikanth, N. and Hosmath, R.P., 1996, management resources of medicinal value. These natural resources of Glaucoma with indigenous drugs - a clinical still as potent and effective as they were thousands study, submitted to Bangalore University., years ago. A vast number of indigenous drugs coupled 6. Srikanth, N., 1999, Management of open angle with innumerable claims of their varied uses as glaucoma - a case report, Ayur Medicine Vol. II, described above, in alleviating wide range of page 96 ophthalmic affections calls for scientific validation for 7. Srikanth N, The potent Anti-glaucoma drug: their attributes and principles. Scientists of various Mahatriphalaghrita : A Pharmacological profile, disciplines, ophthalmologists, and research scholars Aryavaidyan, Vol.XIV No.2, pp. 87-94, Jan.2001) may utilize the knowledge of ancient heritage for the 8. Srikanth N, A report on clinical trials in Diabetic development of safe, cost-effective, quality assured Retinopathy, Ayur Medline Vol. III pp. 53-55, Dec. and clinically proven ophthalmic drugs to promote the 2000, 1. Srikanth N,.Hazra J,.Chopra K.K, A sustainable utilization of indigenous ophthalmic drugs Comprehensive Clinical Report on Role Of An for the benefit of mankind. Indigenous drug Manjistha (Rubia cordifolia) in References painful ophthalmic conditions, Ayurved 1. A n o n y m o u s 1 9 9 6 , P h a r m a c o l o g i c a l Mahasammelan Patrika,Vol.IX pp.58-64, Sept. 2000) Investigations of Certain Medicinal Plants and 2. Sushruta, 1979,Sushruta Samhita, Uttarasthana, Compound Formulations Used in Ayurveda &Sidda Chowkhambha Sanskrit Series, Varanasi. Vagbhata CCRAS, New Delhi ,1976 ,Astanga Samgraha, Sutra sthana, Telugu 2. Anonymous ,1978, Ayurvedic Formulary of India, Academy, Hyderabad Vol-1, Ministry of health and Family welfare , Govt . of India.

59 IMMUNOCOMPETENT PATIENT DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

CASE REPORT Localized invasive aspergillosis of eyelid in an immunocompetent patient

Neelam Pushker, Rachna Meel, Seema Sen, Mandeep S Bajaj, Mridula Mehta, Seema Kashya

Dr. Rajendra Prasad Centre for Ophthalmic Sciences All India Institute of Medical Sciences, New Delhi 110 029, INDIA Abstract: Orbital aspergillosis is an uncommon but serious infection. It usually arises from the paranasal sinuses and secondarily infects the orbit. Isolated involvement of the eyelid without involvement of the orbit or sinuses has never been reported before. We report a case of isolated adnexal invasive aspergillosis in an immunocompetent patient. Key words : Aspergillosis , sinus ,

A 30 years old female patient hailing from Bihar presented in the OPD with a slowly growing mass lesion in the right lower lid since two years. On examination, she had a non-tender mass in the right lower lid extending from the medial canthus to the lateral canthus (Fig.1).

Fig2: CT scan( Axial cut) showing lesion in the preseptal area

Fig1: Right lower lid mass lesion (after on the affected side. A CT-scan of head and orbit (Fig.2) incisional biopsy) showed a heterogeneous mildly enhancing mass lesion involving the subcutaneous tissue and the tissues The overlying skin had no signs of inflammation, overlying the inferior orbital rim and infiltrating the however the lesion was adherent to the skin on periorbital fat planes. The para-nasal sinuses were palpation. The edges of the mass were ill defined, the normal. An incisional biopsy was taken for a definitive surface was smooth and consistency very firm, almost diagnosis, which showed multiple epitheliod rubbery. There was no complaint of watering and the granulomas with central necrosis, and multiple hyphae lacrimal drainage system was freely patent on syringing. that stained with Gomori Methamine stain suggestive of The best-corrected visual acuity was 6/6 in both the eyes Aspergillus. The patient was investigated for various and there was no restriction of extraocular movements risk factors for Mycosis including a total leucocytic count, absolute neutrophil count and blood sugar for Address for correspondence:- diabetes. Chest X ray was done to rule out involvement Dr. Neelam Pushker of the lungs. Apart from a history of working with the Assistant Professor cattle and in the fields, which could have subjected her Dr. R.P. Centre for Ophthalmic Sciences All India Institute of Medical Sciences, to heavy exposure of the fungus, no other risk factors New Delhi 110 029, INDIA were found. Our patient was immunocompetent. After Ph. : +91-11-26588500 ext. 3020 Fax: +91-11-26588919 a baseline investigation for the renal functions Email: [email protected]

60 IMMUNOCOMPETENT PATIENT DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 (electrolytes and urea, creatinine) and sensitivity testing, the patient was started on intra venous Amphotericin B. Amphotericin B was started at 0.25mg/kg body weight and increased to 1 mg/kg body weight daily (in 5% dextrose very slowly over a period of 6 hrs). Intravenous Dexamethasone and Avil injections had to be given prior to the Amphotericin B injection in order to prevent chills and rigors during the infusion. Also the mass was excised in toto through a sub-ciliary skin incision. Intraoperatively the mass was found to be strongly adherent to the septum which was breeched at places in order to be able to remove the mass completely. The mass was very rubbery in consistency and was difficult to cut even with a surgical blade. The mass was sent for Fig5: CT scan(Axial cut) After 6 weeks of histo-pathological examination and fungal cultures. A Amphotericin-B therapy Veinflon (18 gauge) was left in the surgical wound for local irrigation with Amphotericin B (Fig.3). At the end of 6 weeks the patient was clinically free of the disease (Fig.4) and a repeat CT scan did not show any evidence of residual or recurrent pathology (Fig. 5). The culture from the sample that was taken during the surgery did not grow any fungus even at three weeks. The patient has been discharged on oral Itraconazole 200mg bid. She will be reviewed every 4 weeks and a CT scan will be repeated if there is any any clinical evidence of recurrence. If no clinical or radiological recurrence is seen by the end of 3 months, all treatment will be stopped and patient will be kept on 3 monthly follow up for another year. Fig3:Post operatve picture with venflon left in the wound for irrigation with Amphotericin-B Discussion Local irrigation with Amphotericin B 1mg/ml/dose Orbital aspergillosis is a relatively uncommon except in certain parts of the world where it is endemic, as in was done once daily for a week, when secondary 1 bacterial infection started developing and the veinflon Sudan. had to be removed. Systemic Amphotericin B was Aspergillus is a ubiquitous fungus found particularly in continued till a cumulative dose of 2.5 grams was soil and decaying vegetation. It is however the most 2 reached. Renal functions were repeated bi-weekly till common fungal contaminant of the paranasal sinuses. the patient was on Amphotericin B. The patient tolerated A variety of conditions have been known to increase the the medicine well and the renal functions were never risk of infection by this fungus. deranged during the treatment. Host factors that increase the risk of aspergillosis include immunocompromised states like diabetes mellitus, AIDS, conditions associated with deficient phagocytosis as in neutrophil dysfunction or neutropenia, 3 , 4 hematological malignancies, administration of steroids or immunosuppressants, and chronic granulomatous diseases or prolonged granulocytopenia as in transplant recipients. Prolonged occlusive dressings as in patients of burns or post- exenteration provide warm, moist conditions with loss of tissue integrity ideal for Aspergillus growth. 5 Environmental factors that lead to excessive exposure to Fig.4: Patient at the end of 6 weeks of Amphotericin-B Therapy fungal spores as in yard work, compost heaps and

61 IMMUNOCOMPETENT PATIENT DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 construction projects have also been implicated in side effects of therapy with Amphotericin-B. causing aspergillosis.6, 7 Itraconazole has been used at dose ranging from 200 to Aspergillosis is also known to occur in absence of any 1000mg daily alone or in combination with 29, 30,31 risk factors in healthy immunocompetent individuals. Amphotericin-B in cases of invasive Aspergillosis. Immunocompetent people have been reported to present with intracranial involvement, necrotising otitis Conclusion 10,11,12 media and endophthalmitis. Therefore absence of Invasive aspergillosis in immunocompetent patients is a risk factors does not exclude a fungal etiology. rare disease, where it usually remains limited to the Aspergillus infection is now known to present in four paranasal sinuses or sometimes involves the orbit. It 13,14 different patterns. In immunocompetent cases it may rarely reaches the brain or disseminates widely. Several present as allergic Aspergillus sinusitis or a sinonasal cases of localized sino-orbital aspergillosis have been aspergilloma. Both are saprophytic form of infection reported in literature. characterized by lack of tissue invasion and necrosis. Invasive aspergillosis of lid alone with normal paranasal Occasionally tissue destruction may result from sinuses and no local or systemic risk factors has not associated inflammation rather than tissue invasion.9,15 been reported before. The patient was managed on lines Both may respond well to local treatment.9 of localised sino-orbital aspergillosis with complete On the other hand, Aspergillus characteristically causes resolution of the disease. Further follow up is however tissue invasion in the immunocompromised. Tissue required to know the chances of recurrence and invasion may present as granulomatous inflammation prognosis in such a case. and fibrosis or cause diffuse vascular invasion, thrombosis and tissue necrosis (fulminant References: aspergillosis). There are a few reports on aspergillosis in 1. Rudwan MA, Sheikh HA. Aspergilloma of paranasal immunocompetent patients. The cases reported were sinuses-a common cause of unilateral proptosis in Sudan. 16,17 18,19 Clin Radiol 1976;27:497-502. primarily involving sinuses or lungs. However, Cerebral aspergillosis and disseminated aspergillosis 2. Stammberger H, Jakse R, Beaufort F. Apergillosis of the have also been reported .20,21 para nasal sinuses: X-ray diagnosis, histopathology, and clinical aspects. Ann Otol Rhinol Laryngol 1984 Our patient was immunocompetent and had an isolated involvement of preseptal lid tissue without any sinus 3. Bennett JE. Aspergillus species. In Mandell GL, Douglas involvement. RG, Bennett JE (eds): Principles and Practice of Infectious Diseases, New York, Churchill Livingstone. 1990, pp1958- Aspergillus has characterstic appearance under the 1962 microscope. It is haematoxophilic with 45 degree branching septate hyphae that stain with Gomori 4. Decker CF, Parenti DM. Invasive aspergillosis in patients 22 with HIV infection: report of two patients and a review of methamine and periodic acid schiff stains. Aspergillus the literature. J Acquir Immune Defic Syndr 1991;4:603- may take up to 3 weeks for growing on fungal culture 606. medium at 30 degrees temperature and humidity of 45%. 23 Pathological examination is mandatory to 5. Khardori N, Hayat S, Rolston K, et al. Cutaneous 24 Rhizopus and Aspergillus infections in five patients with establish a diagnosis of invasive aspergillosis. cancer. Arch Dermatol 1989;125:952-956. The prognosis of invasive sino-orbital aspergillosis in immunocompetent patients is significantly worse than 6. Ismail MA, Abdel-Sater MA. Mycoflora inhabiting water 25,26 closet environments. Mycoses 1994;37:53-57. other forms of aspergillosis. There is no uniformly accepted guideline for treatment. 7. Sarubbi FA, Kopf HB, Wilson MB, et al. Increased recovery of Aspergillus flavus from respiratory Management involves radical surgical debridement and specimens during hospital construction. Am Rev Respir antifungal therapy locally and systemically. Though Dis 1982;125:33-38. Amphotericin-B has been the main stay in the treatment of aspergillosis, Itraconazole has also been reported to 8. Boes B, Bashir R, Boes C, et al. Central nervous system be effective.27 Literature review suggests a response rate aspergillosis. Analysis of 26 patients. J Neuroimaging 1994;4:123-129. of only of 40-60 % to different drugs. 28 Amphotericin-B is given in a dose of 0.5-1.5 mg /kg body weight up to a 9. Brown P, Demaerel P, McNaught A, et al. Neuro- cumulative dose of 2.5 to 3 grams. Renal functions ophthalmological presentation of non-invasive derangement and electrolyte dysfunction are known A s p e r g i l l u s s i n u s d i s e a s e i n t h e n o n -

62 IMMUNOCOMPETENT PATIENT DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

immunocompromised host. J Neurol Neorosurg 21. Raja NS, Singh NN. Disseminated invasive aspergillosis Psychiatry 1994;57:234-237. in an apparently immunocompetent host. J Microbiol Immunol Infect 2006 ;39:73-7 10. Sarti EJ, Blaugrund SM, Lin PT, et al. Paranasal sinus disease with intracranial extension: aspergillosis versus 22. Denning DW, Venkateshwarlu K, Oakley KL, et al. malignancy, Laryngoscope 1988;98:632-635. Itraconazole resistance in aspergillus fumigatus. Antimicrob Agents Chemother 1997;41:1364-8 11. Kim DG, Hong SC, Kim HJ, et al Cerebral aspergillosis in immunologically competent patients. Surg Neurol 23. Levin LA, Avery R, shore J, et al. The spectrum of orbital 1993;40:326-331. aspergillosis: a clinicopathological review. Surv Ophthalmol 1996; 41:142-154 12. Valluri S, Moorthy RS, Liggett PE, et al. Endogenous Aspergillus endophthalmitis in an immunocompetent 24. Brandwein M :Histopathology of sinonasal fungal individual. Int Ophthalmol 1993;17:131-135. disease. Otolaryngol Clin north Am 1993;26:949-981. 13. Rowe-Jones JM, Freedman AR. Adjuvant itraconazole in 25. Denning DW, Hanson LH, Perlman AM, et al. In vitro the treatment of destructive sphenoid aspergillosis. susceptibility and synergy studies of aspergillus species Rhinology 1994;32:203-207. to conventional and new agents. Diagn Microbial Infect Dis 1992;15:21-34 14. Young RC, Bennett JE, Vogel CL, et al: Aspergillosis. The spectrum of the disease in 98 patients. Medicine 26. Denning DW, Aspergillus species. In Mandell GL, 1970;49:147-173. Bennett JE, Dolin R (eds): Principles and Practice of Infectious Diseases, 5th ed. Philadelphia: Churchill 15. Rowe-Jones JM, Moore-Gillon V. Destructive noninvasive Livingstone. 2000; 2:2674-85 paranasal sinuse aspergillosis: Component of a spectrum of disease. J Otolaryngol 1994;23:92-96. 27. Borgers M, Van de Ven MA. Mode of action of itraconazole: morphological aspects. Mycoses 1989; 1:53- 16. Dufour X, Kauffmann-Lacroix C, Roblot F, et al. Chronic 59. invasive fungal rhinosinusitis: two new cases and review of the literature. Am J Rhinol 2004 ;18:221-6 28. Stevens DA, Kan VL, Judson MA. Practice guidelines for diseases caused by aspergillus. Clin Infect Dis 2000; 17. Chopra H, Dua K, Malhotra V, et al. Invasive fungal 30:696-709 sinusitis of isolated sphenoid sinus in immunocompetent subjects. Mycoses 2006 ;49:30-6 29. Yamanoi T, Shibano K, Soeda T, et al. Intracranial invasive aspergillosis originating in the sphenoid sinus: a 18. Ko JP, Kim DH, Shepard JA. Pulmonary aspergillosis in an successful treatment with high-dose itraconazole in three immunocompetent patient. J Thorac Imaging 2002 ;17:70- cases. Tohoku J Exp Med 2004; 203:133-9 3 30. Massry GG, Hornblass A, Harrison W. Itraconazole in the 19. Karim M, Alam M, Shah AA, et al. Chronic invasive treatment of orbital aspergillosis. Ophthalmology 1996; aspergillosis in apparently immunocompetent hosts. Clin 103:1467-70. Infect Dis 1997 ;24:723-33. 31. Browning AC, Sim KT, Timms JM, et al. Successful 20. Siddiqui AA, Shah AA, Bashir SH, et al. Craniocerebral treatment of invasive cavernous sinus aspergillosis with aspergillosis of sinonasal origin in immunocompetent oral itraconazole monotherapy. J Neuroophthalmol 2006; patients: clinical spectrum and outcome in 25 cases. 26:103-6 Neurosurgery 2004 ;55:602-11; discussion 611-3

63 PRIMARY CHRONIC ANGLE CLOSURE GLAUCOMA DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 CLINICAL CHALLENGES Pituitary adenoma exacerbating Primary chronic angle closure glaucoma Viney Gupta, Tanuj Dada , Ramanjit Sihota

Dr. Rajendra Prasad Center for Ophthalmic Sciences, All India Institute of Medical Sciences

Abstract: We describe a patient of primary chronic angle closure glaucoma (PCACG) later diagnosed to have a pituitary adenoma with full blown hormonal dysfunction and its effect on the course of course of his glaucoma.

Key words: Primary chronic angle closure glaucoma, pituitary adenoma, Endogenous steroids, Endogenous growth hormone.

A 60 year old male patient was diagnosed to have degrees in both eyes. Ophthalmoscopically there was a chronic angle closure glaucoma in February 2003 at our 0.8:1 cup in both eyes with thinning of the neuroretinal Glaucoma Clinic and subsequently underwent rim more marked in the inferior quadrant and iridotomies in both eyes. His IOP in both eyes had been peripapillary atrophy (Figure 1). The Confocal scanning 14 mmHg on Latanoprost once daily and Brimonidine laser ophthalmoscope (Heidelberg retinal tomograph twice daily. The patient presented to us again in II) confirmed the presence of large deep cups in both November 2003 with IOP of 26mmHg in the right eye eyes with most of the neuroretinal rim sectors being and 25 mmHg in the left eye on the same two topical either borderline or outside normal limits (Figure 2). medications .The patient was admitted for evaluation His visual fields using automated perimetry on when his raised IOP was confirmed on a 3 hourly admission showed superior arcuate scotomas with diurnal variation. He was thus considered for a early inferior nasal step in both eyes similar to those at trabeculectomy to control the IOP . His visual acuity the time if diagnosis (Figure 3). During his examination was 6/9 in the right eye and 6/6 in the left eye. Pupils the patient was noted to have large hands and feet with were briskly reactive in both eyes with no afferent pupil coarse facial features. Further examination revealed defect. The iridotomy was patent in both eyes. gynecomastia and a shoulder lipoma, on the right side. Gonioscopy revealed occludable angles in both eyes An MRI showed a mass arising from the right side of the with peripheral anterior synechiae extending upto 270 pituitary gland of 12x 13.5mm, impinging on the optic chiasma (Figure 4). Hormonal assay revealed raised levels of Prolactin ; 36.7ng/ml (normal<20ng/ml) , of Growth hormone ; 17.5ng/ml (normal < 10ng/ml) and of serum Cortisol ; 28.8 microgram/dl (normal 4.3-22.4 microgram/dl). In view of the significant size of the lesion and the apparent hormonal abnormalities the patient underwent trans nasal trans sphenoidal partial excision of the pituitary adenoma.

T h e p a t i e n t w a s r e e v a l u a t e d a b ophthalmologically 1 month after this surgery when his visual acuity was 6/9 OD Figure 1: Fundus photographs of the Right eye disc (a) and 6/6 OS. His IOP on Latanoprost and and Left eye disc ( b) Brimonidine twice daily was 16 mmHg. A repeat Address for correspondence:- hormonal assay showed a decrease of Prolactin levels to Dr Viney Gupta, 8ng/ml , of Growth Hormone to 5.2 ng/ml and of Assistant Professor of Ophthalmology Cortisol to 0.2 microgram/dl. Dr RP Centre for Ophthalmic Sciences All India Institute of Medical Sciences, New Delhi -29 Visual fields showed no changes and he was advised for E-mail: [email protected] quarterly reviewing. After 6 months a repeat IOP on

64 PRIMARY CHRONIC ANGLE CLOSURE GLAUCOMA DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

a b

Figure 2 : Confocal scanning laser ophthalmoscopic image of the right eye (a) and left eye (b)

a b

Figure 3 : Automated visual field charts of the Right eye( a) and Left eye (b)

65 PRIMARY CHRONIC ANGLE CLOSURE GLAUCOMA DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

Figure 4 : Non contrast MRI coronal view showing Pituitary adenoma

Figure 5 : Conrast enhanced MRI coronal view latanoprost and brimonidine was noted to be 22mmHg showing recurrence of the adenoma OD and 24mmHg OS .He was started on timolol drops twice a day to reduce the IOP to target level. Hormonal with a subsequent rise of his IOP assay revealed serum cortisol 0.44 microgram/dl, Another notable feature was the absence of the classical prolactin 20.8 ng/ml and an elevated serum growth neurological field defects of a pituitary adenoma despite hormone of 50.4 ng/ml . A repeat MRI showed the presence of a large mass lesion. increased size of the adenoma ( Figure 5) Arén and Skanse4 have reported 2 cases of prodromal to acute glaucoma in 5 patients of acromegaly. However to Discussion the best of our knowledge there is no report in literature Of the hormone secreting pituitary adenomas the most where raised endogenous hormone levels have been common are prolactin secreting followed by the growth associated with exacerbation of a PCACG and hormone secreting and adrenocorticotropin hormone subsequent normalization of IOP after decrease of their secreting adenomas. In a study in 70 patients with levels . acromegaly , Howard and English 1 found 7 cases of This case exemplifies the effect of endogenous simple glaucoma. In all these cases acromegaly was hormones in the elevation of IOP in primary chronic detected 6-34 years before glaucoma was diagnosed. angle closure glaucoma and the need to look for Elevated growth hormone levels in Open angle systemic causes of a sudden rise of IOP in seemingly glaucoma patients have been found compared to well controlled glaucoma patients. controls and have been believed it to be involved in the pathogenesis of raised IOP in glaucoma patients2. References Steroid responsiveness well known in primary open 1. Howard GM, English FP . Concurrence of glaucoma in angle glaucomas eyes has however not been observed in acromegalics. Arch Ophthalmol 1965;73:765-768. primary angle closure glaucoma 3. Our patient had 2. Greco AV, Ricci B, Altomonte L, Rebuzzi AG , Hanna R, raised levels of both Growth hormone and Cortisol and Ghirlanda G. Growth hormone secretion in open angle it is difficult to pinpoint which one or both contributed glaucoma . Ophthalmologica . 1979; 179(3) :168-172. to the raised IOP. It is likely that the PCACG as diagnosed in this patient was worsened by the rise in 3. Kitazawa Y. Primary angle closure glaucoma : IOP resulting from endogenous hormone production. Corticosteroid responsiveness. Arch Ophthalmol 1970; Whereas the patient was to be taken up for 84(6): 724-727. trabeculectomy for his IOP control , an excision of the 4. Arén A, Skanse B. On non inflammatory glaucoma in pituitary adenoma decreased the hormone levels and acromegaly. Acta Ophthalmol 1955;33: 295-7. also controlled his IOP.A recurrenct growth of the tumor with increased growth hormone level was associated

66 JOURNAL ABSTRACTS DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

JOURNAL ABSTRACTS

Dr. Rajpal

Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India. A Kumar, Sinha S, Azad RV, Sharma YR, Vohra Rajpal: analysis between the two groups was not significantly different. Besides, there was also no correlation Comparative evaluation of vitrectomy and dye- enhanced ILM peel with grid laser in diffuse diabetic between the reductions of foveal thickness and macular macular edema. Graefe's Arch clin. Exp Ophthalmol, volume with the improvement in visual acuity in either 2007; 245: 360-368. of the groups.: BACKGROUND: The purpose of this study is to Long-term Results of Ahmed Glaucoma Valve compare the effectiveness of pars plana virectomy (PPV) Implantation for Uveitic Glaucoma and dye-enhanced peeling of the internal limiting Thekla G. Papadaki, Ioannis P. Zacharopoulos, Louis R. membrane (ILM) with modified grid laser Pasquale, William B. Christen, Peter A. Netland, C. photocoagulation in patients with diffuse diabetic Stephen Foster macular edema and to determine if any correlation exists between improvement in visual acuity (functional American journal of ophthalmology 2007:144; 62-69 improvement) and reduction in foveal thickness and PURPOSE: To present long-term outcomes of Ahmed macular volume (anatomical improvement) Design: glaucoma valve implantation for uveitic glaucoma. This is randomized, prospective, comparative, DESIGN: Interventional case series. METHODS: interventional study. Methods: In this study 24 eyes of Retrospective chart review of 60 patients (60 eyes) with 24 patients with metabolically stable diabetes and with uveitic glaucoma who underwent Ahmed valve diffuse diabetic macular edema were evaluated. The implantation over a four-year period at a tertiary uveitis patients were randomized to either pars plana referral center. Success definition 1 included patients virectomy with removal of ILM which was done in 12 with an intraocular pressure (lOP) between 5 and 21 mm eyes (ILM group) and modified grid laser Hg, reduced by 25% from that before implantation. photocoagulation carried out in the remaining 12 eyes Success definition 2 (qualified success) excluded those (laser group). Main outcome measures were (1) the patients in whom serious complications occurred. postoperative visual acuity in the form of ETDRS log RESULTS: Mean follow-up time was 30 months (range, MAR values, (2) foveal thickness and (3) macular six to 87 months; four-year results relate to a cohort of 15 volume as measured by optical coherence tomography. patients). Success rates were 77% and 50% and qualified The correlation between improvement in visual acuity success rates were 57% and 39% at one and four years, and the reduction of foveal thickness and macular respectively. At four years, 74% of the patients required volume in both the groups were also evaluated. The glaucoma medication to maintain lOP control. The results were all subjected to statistical analysis. overall complication rate was 12%/personyears. The Results: The ETDRS log MAR visual acuity difference rate of visual acuity loss was 4%/personyears; that was between the two groups at the end of 6 months was not most commonly attributed to corneal complications that clinically significant (P=0.525). However, foveal thickness were more likely to occur in patients with preoperative and macular volume decreased significantly more in the corneal disease (P = .01, Fisher exact test). ILM group compared to the laser group (P=0.001, C O N C L U S I O N S : A h m e d g l a u c o m a v a l v e P<0.001, Mann Whitney U test). There was no correlation implantation is a safe yet moderately successful between the improvement in visual acuity and the procedure for uveitic glaucoma. Long-term success reduction of foveal thickness (r=0.158, P=0.6) (ILM rates are enhanced with the use of glaucoma group), r=0.155, P=0.7) (laser group) in both groups. medications, and corneal complications are the most Conclusions: PPV with ILM peeling was shown to be common of all potential serious complications. beneficial by inducing a statistically significant Ahmed Glaucoma Drainage Device valve surgery for reduction of macular thickness and macular volume. paediatric Glaucoma: Our experience Visual acuity also demonstrated a trend towards JKS Parihar, DP Vats, TR Bera, R Maggon, V Mathur, A improvement in both the ILM peel group and the grid Singh, SK Mishra laser group; however, the comparative VA outcome

67 JOURNAL ABSTRACTS DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 Department of Ophthalmology, Army Hospital (R&T) detachment in 01 eyes (4.72%), Shallow chamber with Delhi Cantt. Delhi hypotony in 04 eyes (19%) and CME in 02 eyes (9.52%). However all these complications could be managed Delhi Journal of Opthalmology. conservatively without any residual stigmata. Purpose:- To evaluate the safety and efficacy of Conclusions: The Ahmed Glaucoma Drainage valve glaucoma drainage implant surgery in providing was found to be very effective in management of cases of reduction of IOP and visual rehabilitation in cases of refractory Paediatic glaucoma providing good control Paediatric refractory glaucoma in Indian eyes. Design: of IOP, visual rehabilitation and low incidence of We performed a retrospective review of patients complications. younger than 08 years of age who underwent Ahmed valve surgery from January 2003 to January 2007. There Corneal graft rejection. were 21 eyes of 14 patients. The two most common Surv Ophthalmol. 2007 Jul-Aug;52(4):375-96 diagnoses were Congenital Glaucoma and Post- traumatic Secondary Glaucoma. Methods: A Panda A, Vanathi M, Kumar A, Dash Y, Priya S. retrospective chart review was performed on all patients Rajendra Prasad Centre for Ophthalmic Sciences, All who underwent glaucoma drainage implant surgery India Institute of Medical Sciences, New Delhi, India. with or without combined phacoemulsification with Penetrating keratoplasty is the most widely practiced intraocular lens implantation by a single surgeon (JKSP) type of transplantation in humans. Irreversible immune in a Armed Forces Medical Setup at tertiary care 2 rejection of the transplanted cornea is the major cause of hospitals. Ahmed glaucoma valve (FP8) 185 mm was human allograft failure in the intermediate and late used in all cases. In terms of IOP, a complete success was postoperative period. This immunological process defined as IOP of between 9 to 21 mm Hg without causes reversible or irreversible damage to the grafted medication, qualified success as IOP between 14 to 21 cornea in several cases despite the use of intensive mm Hg with one or more medication, and failure as a immunosuppressive therapy. Corneal graft rejection sustained secondary rise of (Once stabilized to an comprises a sequence of complex immune responses optimal satisfactory level) post op IOP of >21 mm Hg that involves the recognition of the foreign with one or more medications for more than one months. histocompatibility antigens of the corneal graft by the Results: There were 21 eyes of 14 patients. Out of which host's immune system, leading to the initiation of the 17 eyes (had undergone filtering surgery earlier, immune response cascade. An efferent immune remaining 4 eyes had undergone primary AG Valve response is mounted by the host immune system against implantation. Out of 21 eyes, total 6 (28.57%) eyes these foreign antigens culminating in rejection and graft underwent Phacoemulsification with IOL and AG Valve decompensation in irreversible cases. A variety of implantation. 5 eyes (23.81%) each underwent AG Valve donor- and host-related risk factors contribute to the implantation only and AG Valve over preexisting IOL corneal rejection episode. Epithelial rejection, chronic implantation respectively. Whereas 3 eyes (14.28%) were stromal rejection, hyperacute rejection, and endothelial subjected to PK, AG Valve implant and IOL implantation rejection constitute the several different types of corneal and remaining 02 (9.52%) were subjected to secondary graft rejection that might occur in isolation or in IOL with AC reconstruction and AG Valve implantation. conjunction. Corneal graft failure subsequent to graft With a mean follow-up of 16+/-8 months (range 4 to 28 rejection remains an important cause of blindness and months), the mean age at the time of implantation was hence the need for developing new strategies for 4.9±6.5 years. The mean IOP decreased from 37.3±12.5 suppressing graft rejection is colossal. New systemic mm Hg to 19.6±7.8 mm of Hg at last follow-up. The pharmacological interventions recommended in corneal number of antiglaucoma medications decreased from a transplantation need further evaluation and detailed mean of 2.5+/-1.4 to 1.3+/-.07 (P<.0001) as the last guidelines. Two factors, prevention and management, follow-up. Out of 21 eyes, 19 eyes (90.48%) has attained are of significant importance among all aspects of complete successes whereas remaining 02 eyes (9.52%) immunological graft rejection. Preventive aspects begin had qualified IOP control with one or two medication. with the recipient selection, spread through donor None of the eyes had failure to AG Valve implantation in antigenic activity, and end with meticulous surgery. terms of IOP control. Twenty eyes (95.24%) had Prevention of corneal graft rejection lies with reduction improvement of visual acuity, while only one eye had a of the donor antigenic tissue load, minimizing host and loss of more than 1 line of Snellen acuity. We did not donor incompatibility by tissue matching and notice any intraoperative complication. Noted post- suppressing the host immune response. Management of operative problems were, hyphaema and Choroidal corneal graft rejection consists of early detection and 68 JOURNAL ABSTRACTS DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 aggressive therapy with corticosteroids. Corticosteroid HRT evaluation of the ONH during the same visit. therapy, both topical and systemic, is the mainstay of Glaucoma variables obtained from OCT and HRT management. Addition of immunosuppressive to the analyses were compared among the groups. Receiver treatment regimen helps in quick and long term operator characteristic (ROC) curves generated by recovery. Knowledge of the immunopathogenesis of performing linear discriminant analysis (LDA), artificial graft rejection may allow a better understanding of the neural networks (ANNs), and classification and regression immunological process thus helping in its prevention, trees (CART) on OCT-based parameters were compared early detection and management. with the Moorfield regression analysis (MRA), R Bathija RESULTS: On culture of the pretreatment swabs, 77.5% (RB), and FS Mickelberg (FSM) functions in the HRT, to were positive for growth with 75.5% bacterial and 11.5% classify eyes as either glaucomatous or normal. RESULTS: fungal. Coagulase-negative Staphylococcus (29.1%) was No statistically significant difference was found in the disc the most common bacterial contamination followed by area measured by the OCT and HRT analyses within each Pseudomonas aeruginosa (18.5%), Acinetobacter sp. study group (P > 0.05). The areas under ROC curves were (18.5%) and Alcaligenes faecalis (13.2%). A 20-ml sterile 0.9822 (LDF), 0.9791 (CART), and 0.9383 (ANN) as saline wash resulted in a 20% decrease (p < 0.01) in the compared with 0.859 (FSM), 0.842 (RB) and 0.767 (MRA). amount of contamination. CONCLUSIONS: OCT-based automated classifiers performed better than HRT classifiers in distinguishing The maximum antimicrobial effect with regard to glaucomatous from healthy eyes. Such parameters should bacterial decontamination was achieved with povidone- be integrated in the OCT to improve its diagnostic abilities. iodine (64% decrease in the amount of contamination, p Invest Ophthalmol Vis Sci. 2007 Jul;48(7):3138-45. < 0.01) followed by ciprofloxacin (47.6% decrease, p < 0.05), the combination of cefazolin and amikacin (42.5%, peripapillary retinal nerve fiber layer (RNFL) parameters p < 0.05), Neosporin (38.5%, p < 0.05) and then by optical coherence tomography (OCT) and confocal gentamycin (21.7%, p = NS). scanning laser ophthalmoscopy (Heidelberg retinal tomography; HRT; Heidelberg Engineering, Heidelberg, CONCLUSIONS: A thorough saline wash and Germany) in early and moderate glaucoma and to treatment with 1% povidone-iodine for 3 min is a more compare several OCT-based automated classifiers with effective method for the decontamination of donor eyes those inbuilt in HRT for detection of glaucomatous as compared to most currently available and frequently damage. METHODS: This cross-sectional study included used antibiotics. Copyright (c) 2006 S. Karger AG, Basel. 60 eyes of 60 patients with glaucoma (30 early and 30 Evaluation of optical coherence tomography and moderate visual field defects) and 60 eyes of 60 healthy heidelberg retinal tomography parameters in detecting subjects. All patients underwent Fast Optic Disc and Fast early and moderate glaucoma. Peripapillary RNFL scans on the OCT and then HRT Naithani P, Sihota R, Sony P, Dada T, Gupta V, Kondal D, evaluation of the ONH during the same visit. Glaucoma Pandey RM. variables obtained from OCT and HRT analyses were compared among the groups. Receiver operator Glaucoma Research Facility, Dr. Rajendra Prasad characteristic (ROC) curves generated by performing Centre for Ophthalmic Sciences, All India Institute linear discriminant PURPOSE: To evaluate the o f M e d i c a l S c i e n c e s , N e w D e l h i , I n d i a . relationship between optic nerve head (ONH) and [email protected] Invest Ophthalmol Vis analysis (LDA), artificial neural networks (ANNs), and Sci. 2007 Jul;48(7):3138-45 classification and regression trees (CART) on OCT-based PURPOSE: To evaluate the relationship between optic parameters were compared with the Moorfield regression nerve head (ONH) and peripapillary retinal nerve fiber analysis (MRA), R Bathija (RB), and FS Mickelberg (FSM) layer (RNFL) parameters by optical coherence tomography functions in the HRT, to classify eyes as either (OCT) and confocal scanning laser ophthalmoscopy glaucomatous or normal. RESULTS: No statistically (Heidelberg retinal tomography; HRT; Heidelberg significant difference was found in the disc area measured Engineering, Heidelberg, Germany) in early and moderate by the OCT and HRT analyses within each study group (P glaucoma and to compare several OCT-based automated > 0.05). The areas under ROC curves were 0.9822 (LDF), classifiers with those inbuilt in HRT for detection of 0.9791 (CART), and 0.9383 (ANN) as compared with 0.859 glaucomatous damage. METHODS: This cross-sectional (FSM), 0.842 (RB) and 0.767 (MRA). CONCLUSIONS: study included 60 eyes of 60 patients with glaucoma (30 OCT-based automated classifiers performed better than early and 30 moderate visual field defects) and 60 eyes of 60 HRT classifiers in distinguishing glaucomatous from healthy subjects. All patients underwent Fast Optic Disc healthy eyes. Such parameters should be integrated in the and Fast Peripapillary RNFL scans on the OCT and then OCT to improve its diagnostic abilities. 69 NPCB DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

COMMUNITY OPHTHALMOLOGY

National Program for Control of Blindness and Strategies for the Eleventh Plan Five year plan (2007-2012) Dr A.S. Rathore*, Dr Manoj Kr Dhingra**, Dr R Jose***

* Assistant Director General (NPCB), Directorate General of Health services, Ministry of Health and Family welfare, Government of India

Abstract: The ultimate goal of vision 2020 program is to reduce the prevalence of avoidable blindness to less than 0.3% .Various steps have been taken during the tenth 5 year plan (2002-07) and new formulations have been promulgated to strengthen the existing eye care facilities in the eleventh plan(2007-12). The foremost issue is to identify the areas of concern. Various epidemiological data have shown that cataract and uncorrected refractive errors constitute the two most ophthalmicompelling c problems which constitute >60% of avoidable blindness in India. For comprehensive eye care facilities to be available to all with equitable distribution ,attention also needs to be focused on glaucoma ,diabetic retinopathy ,trachoma and vitamin A deficiency. These also need urgent attention and various steps have been proposed to tackle these issues as well .It is envisaged that with a comprehensive approach ,we are progressing in the right direction.

Key words: NPCB ,Vision 2020 ,cataract ,avoidable blindness

National Programme for Control of Blindness was 60.00

50.40 launched in the year 1976 as a 100% Centrally Sponsored 49.05 50.00 Scheme with an absolute objective to reduce the prevalence 44.91 41.98 38.57 40.00 37.00 of blindness. The target set for the terminal year of the 31.71 36.44 33.56 10th Plan was to reduce prevalence of blindness to 0.8% by 30.35 30.00 27.23 2007. (MOHFW, 2007) Even after the closure of World 24.71 19.1421.67 20.00 Bank Project the programme was sustained mainly 15.12 16.05 12.19 11.96 12.09 11.85 through domestic budget for which an allocation of Rs.445 10.96 11.97 10.00 crores was made under the 10th plan.

0.00 7 0 2 3 5 6 7 8 9 0 1 2 3 4 5 6 5 6 8 9 1 4 9 8 8 8 8 8 9 9 9 9 9 9 9 9 9 0 0 0 0 0 0 0 9 9 9 9 9 9 9 9 9 0 0 0 0 0 0 The pace of progress of NPCB has been gradual and 9 9 9 9 9 9 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 sustained and can be gauged through the performance of Cataract Surgery performed in India since 1990. Cataract is on the rise and the percentage of cataract operations with the most common cause of blindness in India. During the IOL surgery for 2006-2007 has been 90.3%. year 2006, about 50 lakhs cataract surgery were performed Also during this period there have been some constraints in the country. The percentage of IOL surgery has also been which includes (a) mal distribution of ophthalmic manpower resulting in non-availability of ophthalmic Address for correspondence:- manpower in the rural and remote areas; (b) Non- Dr AS Rathore; r e c e i p t / d e l a y e d r e c e i p t o f e x p e n d i t u r e Assistant Director General (NPCB), statements/utilization certificates/audit reports from Directorate General of Health services, Ministry of Health and Family welfare, some State Blindness Control Societies resulting in Government of India delayed release of funds; (c) Non-receipt/delayed receipt E mail: [email protected] of expenditure statement from State/UT Governments

70 NPCB DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 with respect to cash grants released to them for giving above the age of 35 years who are attending eye clinics. salary of eye surgeons and para-medical ophthalmic Operational Guidelines: This would be done by assistants appointed in the 9th and 10th plan. screening all known diabetics for DR and providing The basic objectives of this National Program for Control laser treatment to those who may require it. The overall of Blindness still remains as initially planned since its prevalence of diabetic retinopathy according to the inception and these are (a) Reduce the backlog of CURES (Chennai Urban Rural Epidemiology) Eye blindness through identification and treatment of the Study in south India was 17.6 per cent among the 1715 blind. (b) To develop eye care facilities in every district. diabetic subjects. (Rema M et al, 2007). The CURES Eye (c) To develop human resources for providing eye care study used four-field stereo retinal photographs and services and (d) To improve quality of service delivery Early Treatment Diabetic Retinopathy Study (ETDRS) (e) To secure participation of Voluntary Organization grading to document DR in the patients under study. engaged in Eye Care. (MOHFW, 2007) Further, as shown in the CURES Eye Study, a linear trend was observed in the prevalence of retinopathy The four pronged operational strategy of this program with increase in quartiles of HbA1c (trend Chi square: has been (a) Strengthening service delivery; (b) 51.6, P<0.001) from 8.1 per cent (HbA1c level < 6.9 %) to Developing human resources for eye care. (c) Promoting 31.7 per cent (HbA1c level >10.3%). For every 2 per cent outreach activities and public awareness and (d) elevation of HbA1c, the risk for DR increased by a factor Developing institutional capacity. This program has of 1.7. (Rema M Et al, 2006) been successfully operationalised through convergence of efforts among the Government, NGOs, District The total number of patients having diabetes in absolute Blindness Control Societies and International Agencies, terms in India is likely to be very large and this makes which have thus enabled the Programme to successfully the prevalence of DR (Diabetic retinopathy) a significant achieve its Vision of Future - a reality in India! public health burden in India. This target aims to screen all known diabetics for diabetic retinopathy and to In the Eleventh Plan comprehensive efforts have been provide laser treatment to all those requiring it. planned so as to achieve the existing objectives and targets of NPCB which have been substantially A recent prevalence study was conducted for Primary augmented in order to reduce the prevalence of open angle glaucoma (POAG), was conducted by blindness to 0.3%; which remains an absolute goal. This Sankara Nethralaya, Chennai. (Vijaya L et al, 2007). would require a substantial increase in manpower and (Chennai Glaucoma Study) This urban study involved financial resources with an overhaul of targets and four thousand eight hundred subjects, who were 40 operational guidelines. These are:- years or older and were selected using a multistage random cluster sampling procedure in a Chennai. The Target 1: To improve the quantity and quality of cataract prevalence of POAG in this population selected who surgery were 40-year-old or above in south Indian urban Operational Guidelines: This target could to be achieved population, was 3.51%, higher than that of the rural by increasing the cataract surgical rate to 500 per lakh population. The prevalence increased with age, and population per year (CSR of 5000) by 2012. more than 90% were not aware of the disease. This Concomitantly, the proportion of IOL surgery among shows the relevance of early screening for glaucoma in these should be more than 95%.Also, improvement in all patients above the age of 35 years who are attending the visual outcome of cataract surgery is targeted to eye clinics. more than 90% having a visual outcome of more than Target 4: To initiate low vision services at tertiary levels 6/18 after surgery with adequate linkage with secondary level, and with Target 2: To develop Pediatric Ophthalmology primary care in a phased manner along with procuring Departments in training centres and in centers of and dispensing Low Vision Aids. excellence in the country. Operational Guidelines: This would be achieved by Operational Guidelines: This is to be achieved by providing basic refraction services to be available at establishing Pediatric Ophthalmic Units (POUs) in 50 PHC and CHC level/Vision Centers in all districts of the Institutions. country. Further, 5000 visions centers would be established in the rural areas and will be manned by Target 3: To screen for Diabetic Retinopathy, in known Trained Optometrists/Refractionists/Ophthalmic diabetic patients and screen for glaucoma in all patients

71 NPCB DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

Assistant. It is also proposed to establish in a phased Operational Guidelines manner, low vision centers at 50 institutions In the Rapid Assessment of Trachoma done in 2006, Target 5: To develop good quality Eye Banks and (MOHFW, 2006), the objectives of the assessment were networking of eye donation and training centers to (a). To assess whether active trachoma continues to be of public health significance in previously known This would be achieved by establishing 25 fully hyper-endemic areas in India.(b). To determine the load functional and accredited good Eye Banks, each of blinding trachoma among adults and the need for collecting 1000 eyes per year and each supported by 20 surgical services for trichiasis (c) To identify people's eye donation centers. perception of trachoma and blinding trachoma. (d) To Target 6: To integrate primary eye care with primary health suggest actions for policy formulation on control of care throughout the country by training medical officers, trachoma in India. ophthalmic Assistants and other para-medical staff The districts covered in this assessment were Operational Guidelines: This would be achieved by Hoshiarpur (Punjab), Mahendergarh & Mewat treatment of simple eye diseases including refraction (Haryana), Bikaner, Dholpur and Tonk(Rajasthan), services at PHC level. Also, there should be a minimum Pauri Garhwal (Uttaranchal), Bulandshahr (Uttar 90% coverage of all under three children by regular Pradesh) and Kutch and Banaskanta (Gujarat). This Vitamin A supplementation (Integrated with RCH study showed that efforts to control active infection are programme) still needed in the country and some of the districts still have foci of infection. Augmenting efforts for improved Target 7: To develop Human Resources and Institutional personal and environmental hygiene and the Capacity for Eye care availability of antibiotics would be strengthened which Operational Guidelines: This would be achieved by would indeed go a long way in ensuring that the country training of eye surgeons in IOL Surgery, Phaco- is able to eliminate trachoma related blindness by 2020. emulsification, Corneal Transplantation, Vitreo-retinal The Scenario of Trachoma in India surgery, Pediatric Ophthalmology and other sub- specialties, Training of middle level eye-care personnel Trachoma is an important public health problem in the for primary eye care and supportive services, Training world which afflicts close to 150 million people globally in eye care management, Training of Pediatric Eye Care as an active disease and an additional 6 million people team of Ophthalmologist, Pediatrician and Anesthetist, suffer blindness due to its complications. This disease is Capital grants for infrastructure through SBCS and the most common cause of infectious blindness in the purchase of Ophthalmic equipments and consumables world. Although control of trachoma with azithromycin through GIA to SBCS. 20 mg per kg (aged 6 months or older) and topical tetracycline ointment given to pregnant women is Target 8: To construct dedicated Eye wards and possible as shown by studies done in hyperendemic Operation Theatres. communities, re-emergence is an important issue and Operational Guidelines: This would be done in North- becomes a public health issue after one year. Although eastern states, J&K, Bihar, Jharkhand, Himachal Pradesh many studies have shown that azithromycin is of and Uttranchal immense promise in the management of active trachoma, long term follow-up of such cases have Target 9: Monitoring and Evaluation: shown that Chlamydia trachomatis infection was not Operational Guidelines: This includes epidemiological eliminated and thus requires careful and continued survey on prevalence of blindness/rapid assessment implementation of SAFE strategy (West SK et al, survey on prevalence of blindness of all ages/evaluation 2007).The same scenario exists in many districts of India of various components of program. This would be done (As shown by the Rapid Assessment of trachoma carried in 15 major states of the country out by NPCB in 2006 in 10 hyper-endemic states) and proper implementation of all components of SAFE Target 10: Rapid Assessment of Trachoma. strategy is critical, if Trachoma is to be controlled and This is an ongoing activity and has already been done in eliminated in future. trachoma endemic states such as Gujarat, UP, Target 11: Telemedicine in Ophthalmology. Uttaranchal, Rajasthan, Haryana and Punjab (as per the 1989 survey). To improve the quality and quantum in skill

72 NPCB DJO VOLUME 12 NUM 5 . APR-JUNE. 2007 upgradation and teaching in Ophthalmology, causes); another 15% are attributed to diabetic telemedicine would be used in the whole country in a retinopathy and glaucoma which are partly phased manner preventable, but need expert management preferably to grass-root levels; further 10% are attributable to age- Operational Guidelines related macular degeneration, which requires highly It has been proposed to develop Tele-Vision centres skilled ophthalmic therapeutic management. The Future of Control of Blindness and Vision 2020 The main emphasis of Control of Blindness in India, as discussed in the Eleventh plan, would be to strengthen The goal of Vision 2020 is to eliminate avoidable the existing services available for treatment of cataract blindness by 2020 in the world. and to address sufficiently the issue of refractive errors According to WHO, the estimated number of people at the grass-root level. As India is a one of the signatories with visual impairment was around 161 million in 2002, to the Vision 2020 Program of WHO; which among other of which 37 million were blind and 124 million had low goals, aims to eliminate trachoma by 2020; concentrated vision. (Serge Resnikoff et al, 2004). Of the 37 million efforts would be needed in this regard, if trachoma is to blind in 2002, approximately 47.8% are due to cataract be eliminated from India. The proper delivery of and 12.3% are due to glaucoma; 8.7% due to AMD (Age Vitamin A to children below the age of 3 yrs also needs Related Macular Degeneration); 5.1% due to corneal also to be strengthened. This has already been done opacities; 4.8% due to diabetic retinopathy; 3.9% due to under the RCH-2 program. Screening of Diabetic childhood blindness; 3.6% due to trachoma; 0.8% due to retinopathy and its prevention remains an important onchocerciasis and 13.5% due to other causes. task, where sources and funds needs to be operationalized and accorded an important priority for In 2002, there were 6.7 million blind in India, which has the future of Blindness Control in India, especially so decreased from 8.9 million in 1990. (Serge Resnikoff et al, when the number of patients having diabetes mellitus is 2004). In developing countries such as India, cataract projected to rise in future. Early screening of glaucoma and refractive errors remain the major portion of and its management at PHCs/ CHCs and District treatable causes of blindness (usually comprise 60% or hospitals is another important issue, which has been more of blindness); 15% could be attributed to duly addressed in the Eleventh plan. Trachoma, Vitamin A deficiency (these are preventable

73 THE MULTIFOCAL ELECTRORETINOGRAM DJO VOLUME 12 NUM 5 . APR-JUNE. 2007

INSTRUMENT REVIEW

THE MULTIFOCAL ELECTRORETINOGRAM Dr. UrmilaGhatak, Dr. Rajvardhan Azad, Dr. Bhuvan

Dr Rajendra Prasad Center for Ophthalmic Sciences, All India Institute of Medical Sciences

Abstract: Mulitifocal electroretinogram as a qualitative and quantitative diagnostic tool which can enhance our understanding in various conditions affecting the macula in particular and the retina in general.

Key words: Multifocal electroretinogram

The Multifocal Electroretinogram has opened up a new  Myopias dimension in the electrophysiological assessment of the  Retinal dystrophies retina, giving us hitherto unseen 3-dimensional representation of the electrical activity of the central retina.  Hydroxychloroquine and other drug toxicities….. 1. Emmetropic patient 2. Myopic patient The Metrovision Vision monitor-

PROCEDURE 1) Autorefractometry and subjective refraction are done to determine the patient's refractive error 2) Patient's pupils are dilated with 1% tropicamide 3) Refractive correction and patient data are fed into the computer 4) Patient is positioned as shown- 2 goldfoil skin electrodes and 1 corneal electrode are used 1) First one eye and then the other are tested- the non-tested eye being occluded 2) After ensuring that the patient is comfortable and all electrodes properly connected, the examination is begun Multifocal ERG is being extensively used in the study of retinal diseases. Among its rapidly increasing list of indications are-  Diabetic retinopathy  Retinitis pigmentosa  Age-related macular degeneration

Address for correspondence:- Dr Urmimala Ghatak, Prof R V Azad, Dr Bhuvan Chanana Dr R P Centre of Ophthalmic Sciences, AIIMS

74 FORTHCOMING EVENTS DJO VOLUME 12 NUM 5 .APRIL TO JUNE. 2007 Forthcoming Events

6th & 8th July'2007 E-mail: [email protected] International Conference on MSICS, th th Kuala Lumpur 27 to 30 September’ 2007 Contact: Dr. A.N. Sahu. Retina Society 40th Annual Meeting E-mail: [email protected] Boston, MA USA Judy Cerone Keenan Phone: 617/227- 8767 16th& 17th August'07 E-mail: [email protected] Glaucoma Workshop 2007: Current Perspectives. Website: http://www.retinasociety.org At Dr. RP Centre for Ophthalmic Sciences, New Delh th th Contact person: Dr. Vinay Gupta, Asst. Professor, Dr. 24 to 27 October’ 2007 R.P. Centre for Ophthalmic Science, AIIMS, Ansari International Cataract and Refractive Surgery Nagar, New Delhi 110 029 Symposium; the Annual Fall Meeting of the Egyptian E-mail: [email protected], Society of Cataract and Corneal Diseases Website: www.aiims.edu/aiims/departments Sharm El-Sheikh, Egypt Contact: Egyptian Society for Cataract and Corneal 23rd & 24th August' 07 Diseases at International Society for Clinical Electrophysiology of E-mail(s): [email protected]. Vision (ISCEV) Hands-on Course, Hyderabad th th Contact person: Dr. Subhadra Jalali, L.V. Prasad Eye 10 to13 November ‘ 2007 Institute,L.V. Prasad Marg, Banjara Hills, Hyderabad- American Academy of Ophthalmology Annual 500 034. India Meeting E-mail: [email protected], [email protected] New Orleans Website: www.iscev.org, www.lvpei.org/iscev2007 LA USA, AAO Phone: 415/561-8500 Fax: 415/561-8567 25th & 29th August'07 Website: http://www.aao.org XLV Symposium of International Society of Clinicla Electrophysiology of vision 1st & 2nd December'07 (ISCEV), Hyderabad. VII All India Uveitis Conference Contact person: Dr. Subhardra Jalali, L. V. Prasad Eye Contact person: Dr. Dipankar, Dr. Kalyan Das Institute,L.V. Prasad Marg, Banjara Hills, Hyderabad- Sri Sankara Nethralaya 500 034. India Guwahati, Assam, Pin 781 028, India. E-mail: [email protected], [email protected] Tel: 91-0361-2228879/80, 2305516 fax: 91-0361-2228878 Website: www.iscev.org, www.lvpei.org/iscev2007 E-mail: [email protected], Website: http://www.ssnguwahati.org 20th to 22nd Sept '07 XVI Annual Conference of Vitreoretina Society of 7th & 9th December'07 India 17th Annual Conference of the Glaucoma Society of Contact person: Dr. SaurabhLuthra, Drishti Eye India Centre,9-B Astley Hall, Dehradun 248001 Contact person: Dr. Chandrima Paul ,BB Eye Tel: 0135 2656364,2655354 Foundation,2/5, Saraty Bose Road, Sukhsagar, E-mail: [email protected] ; 1st and 2nd fllors, Kolkata 700 020. [email protected] Tel: 91-33-24746608/8816, Fax: 91-33-248662720 E-mail: [email protected] 28th& 30th September'07 Annual Conference of Bombay Opthalmologists' Association Contact person: Dr. T.P. Lahane Doctor's Quarters, Bldg No. 1, Flat No. 5 75 Training Programmes DJO VOLUME 12 NUM 5 .APRIL TO JUNE. 2007 Training programmes

Institute Ant. Segment Glaucoma, Orbit & Pediatric Retina General Shot Term Observer Cornea/cataract Uveitis Plastics Ophthal. Vitreous Ophthal. Fellowship ship Aditya Jyot Eye Hospital, 1(DNB) 1(DNB) Mumbai 2 Aravind Eye Hospital, 3, 12= 4.1 2 4 7 10 72t, 49++24|| Madurai 24 , 20*, 12 Several shot term paramedical courses Aso-Palov Eye Hospital, 6 12 Ahmedabad 48* Bangalore West Lions Eye Hospital, 1 10 6 Bangalore 4(DNB) Bombay City Eye Institute, 6 6 16+, 16t 52 Mumbai Disha Eye Hospital, Barrackpore 104 Giridhar Eye Institute, Kochi 1 1 24* 1 12++,12+o Grewal Eye Institute 1 Lions NAB Eye Hospital, Mid Miraj 1 6+, 6oo,24+ L.V. Prasad Eye Institute, 6 2 1 4 3 8 64 100¶ Hyderabad Mahatme Eye Bank & Eye Hospital, 3§ 4(DOMS) 2§ Nagpur 3+ 1 2+ 2$ Prakash Netra Kendr 1 1 Rajan Eye Care Hospital, Chennai 6 24+ 12+ Sankara Nethralaya, Chennai 2 1 2 4 Sri Sankaradeva Nethralaya, Guwahati 2 6 20 S.B. Dr. Sohan Singh Eye Hospital, 2 Amritsar Shri Ganapathi Netralaya, Jalna 1 1 2 4 Shroff’s Charity Eye Hospital, New Delhi 1+1 1 3+3 4 Optometry fellowship (2yrs + 1yr internship) 5+5/ observership in cornea, glaucoma, med retina, ped. Ophthal. Suraj Eye Institute, Nagpur 3+ 3 1 Venu Eye Institute, 4 years BSc in Optometric Practices, 30seats 1 2 6+, 12 . 6++, 12+ New Delhi 3 years Bsc in Optometric Practices, 10seats 24+ , 24, 4*+, 6 24* Dr. R.P. Centre, New Delhi A total of 18 observerships of varing duration are available in all subspecialities Choudhary Eye Care, New Delhi A total of 18 observerships of varing duration are available in all subspecialities * Indirect ophthalmoscopy; tIOL microsurgery; +phacoemulsification; § Cornea; Glaucoma; ¶4 every 2 weeks, ++Lasers in diabetic retinopathy +ºContact lens, ºInstruments maintenance; *Community outreach;00 low vision; **Manual SICS; **1 every 2 Weeks in phacoemulsification & refactive surgery, +Eye banking, 0Counselling, 00Paediatric ocular anaesthesia.

1. Aditya Jyot Eye Hospital 7. Giridhar Eye Institute 15. Sankara Nethralaya Plot No. 153, Road No. 9 28/2576, A. Kadavanthra Medical Research Foundation Opp. SIWS College Kochi - 682 020, Kerala 18 College Road Near Five Gardens, Wadala 8. Grewal Eye Institute Chennai - 600 006 Mumbai - 400 031 Sector 9C, Madhya Marg 16. Sri Sankaradeva Nethralaya 2. Aravind Eye Hospital Chandigarh 160009 Beltola - 28, Guwahathi Anna Nagar 9. Lion NAB Eye Hospital 17. Dr. S.B. Sohan singh Eye Hospital, Madurai - 625 020 Plot No. P-31, Mide Miraj- 416 410 Katra Sher Singh 3. Aso-Palov Eye Hospital Sangli Dist Amritsar - 143 006 Near Under Bridge 10. L.V. Prasad Eye Institute 18. Shri Ganapati Netralaya Rajbhavan Road, shahibag L.V. Prasad Marg, Banjara Hills Head Post Office Road Ahmedabad - 380 004 Hyderabad - 500 034 Jalna - 431 203 4. Bangalore West 11. Mahatma Eye Bank & Hospital 19. Dr. Shroff's Charity Eye Hospital Lions Eye Hospital 16, Central Excise Colony 5027, Kedar Nath Road, Daryaganj, and Cornea Grafting Centre Ring Road, Nagpur - 440 015 New Delhi- 110002 56/2, H Siddaiah Road 12. Prakash Netra Kendr 20. Suraj Eye Institute Bangalore - 570 002 N H 2, Vipul- Khand IV 559, new colony 5. Bombay City Eye Institute Gomti Nagar 226010 Nagpur - 440 001 5, Babulnath Road 13. Rajan Eye Care Hospital 21. Venu Eye Institute Mumbai - 400 007 No. 5, Vidyodaya East ll Street 1/31 Institutional Aera 6. Disha Eye Hospital T Nagar, Chennai - 600 017 Sheikh Sarai Phase- ll & Research Centre 14. Dr. R.P. Centre for Ophthalmic New Delhi- 110 017 Barrackpore, North 24 Parganas sciences AIIMS, Ansari Nagar West Bengal - 743 120 New Delhi - 110 029

76 DJO VOLUME 12 NUM 5 .APRIL TO JUNE. 2007

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