As I write this article for the Indian Journal of Ophthalmology, I am reminded of what Linus Pauling, who was among the top scientists of the world and won the Nobel Prize for Chemistry in 1954, said: “When an old and distinguished person speaks to you, listen to him carefully and respectfully – but do not believe him. Never put your trust into anything but your intellect. Your elder may be wrong, whether he has grey hair or has lost his hair, no matter whether he is a Nobel laureate. The world progresses, year by year, century by century, as the younger generation members discover what is wrong with what their elders say. So, you must always be sceptical – always think for yourself.”
I urge young readers to remember Pauling’s advice while browsing this article.
I spent over 45 years writing and publishing papers in academic journals, and the only advice I got was to keep writing, no matter what. Looking back, I wish someone had guided me on approaching this necessary evil differently!
As a student in school and later in college, I enjoyed my studies and was blessed with good scores. In 1968, I joined the Medical College at Rohtak, having ranked among the top students in my university exam. Unfortunately, there was nothing to write home about my MBBS studies, which I managed to pull through despite being riddled with a chronic ailment that sapped all my energy and the will to excel.
The only bright spot in those years was an elective training during my internship under Dr Vidya Sagar, one of the most renowned psychiatrists of that era. I was fascinated that he spent long hours with his patients, often past midnight. A man of peace, he had perfect poise and bedside manners, even while dealing with the most violent schizophrenic patients. Inspired by that one month, I spent with Dr Sagar, I learned to spend long hours with my patients throughout my career without feeling burdened.
My internship with him reinforced my idea of hard work and grit, which I had seen my father practice throughout my childhood. He worked day and night without taking a holiday as an engineer in a newly independent India. Sometimes, I wondered why the government did not recognize him for his exemplary services toward nation-building, albeit in a small way.
To that extent, my family felt somewhat redeemed when in 2014, the President of India honored me with a “Padma Shri” and a Vigyan Ratan some 30 years after my father prematurely passed away, battling several diseases he contracted while performing his duties [Figs. 1 and 2].
I was fortunate to do my postgraduate training under Prof. I. S. Jain, who had been trained as a comprehensive ophthalmologist in the UK in the mid-50s. He was undoubtedly one of the most astute clinicians, with a keen eye and the ability to detect anything unusual in his patients. It seems unbelievable now what he could observe, armed with just a torch, slit lamp, and direct ophthalmoscope!
Dr Jain made original contributions that have stood the test of time. When no doctor in India kept patient records, he made meticulous and detailed notes of the diseases that fascinated him. Even in those days, he was obsessive about taking external pictures of the eye. Back then, we had no fundus or slit-lamp cameras.
A turning point in my life came in the early 80s, when Prof. Jain asked me to do fundus photography and fluorescein angiography (FFA), which triggered my interest in retinal diseases. FFA was so revealing; I saw something new daily that made me rush to the library to look up relevant studies.
Truly speaking, while I owe my work ethic and values to my parents and to Prof. Jain’s observation and documentation skills, my true mentor was my fundus camera, which taught me something new daily. While the fundus camera made me face the harshest of truths when my patient did not do well, it also cheered me to no end when it showed that the patient had responded positively to my treatment.
Although I was learning new things, I was still looking inwards and living in my cocoon until, fortuitously, I was awarded a short fellowship as an observer in the USA. This eye-opening experience changed my life. I wondered: if they could do it, why not us? We had to become a super-speciality eye center to climb the ladder of global recognition and success.
The opportunity arose soon after, when in 1989, at the age of 39, I became the head of the eye department at PGI and would remain so for the next 26 years.
The World of Academia and Its Challenges
From the outside, the world of academia can look glamorous, especially if you are vying for positions in institutes like PGI or AIIMS and do not realize that academia is highly competitive. While you may be an excellent surgeon or physician, academic papers can become the proverbial Damocles Sword.
Fortunately, I was encouraged by Prof. Jain very early on to start writing papers. It may be unimaginable now but, in those days, we had to write manuscripts in long hands and wait in line to get them typed. I had not even heard of the peer review process!
Although our library subscribed to scores of ophthalmology journals, for the first 15 years of my career, I did not know where to submit my manuscripts. I fell into the trap of getting my work published in some friendly journals that accepted papers easily. Unsurprisingly, most of these journals have since ceased to exist, and I cannot even access the records of my papers. At the time, it excited me no end to see my work published in these journals, not realizing until much later that nobody had read or noticed my work. I might have thrown those papers into a trash bin. I consider that period as the wasted years of my life. The present generation is much smarter, choosing real people as their mentors and not a fundus camera! But did I have a choice? You need more than documentation to make a mark in academia. There was no other way than to follow a more organic course.
You need a pat on the back
The Fundus camera helped me showcase the well-documented cases that I had followed up on year after year in professional meetings. Retinal inflammations fascinated me with their myriad ways of manifesting and evolving. While this may be politically incorrect to state, the reality was that Indian academics did not talk about their patients or follow up back in those days.
To that extent, I greatly thank Dr P. N. Nagpal, Dr Narsing Rao, Dr Carl Herbort, Dr B. Patnaik, and Dr Namperumalsamy, whose constant encouragement over the next three decades would keep my academic pursuits going. Moreover, my young friends, Drs. T P Das and Santosh G. Honavar, gave me opportunities that could have been the envy of many in India!
I built the Advanced Eye Centre at the PGI, Chandigarh, for over ten years, surmounting all the bureaucratic hurdles that came my way. It offers the most advanced eye care facilities comparable to the best in the world The fragrance of the Advanced Eye Centre reached the then-President of India, Dr APJ Abdul Kalam. During one of his visits to the city, he spent hours in our center, curious to know the fine nuances of our research and the technology we use [Fig. 3].
Impact of original observations
During a visit to Sankara Nethralya (SN), Chennai, in 1993, Dr Badrinath told me that he had noticed that one of my papers, “Effect of insulin therapy on progression of retinopathy in non-insulin-dependent diabetes mellitus,” had been published in the American Journal of Ophthalmology early that year. The transient worsening of diabetic retinopathy had been noted in patients with type-1 diabetes mellitus (DM) and was a hot topic during those days. Our study in patients with type-2 DM was the first of its kind anywhere in the world. Our observations were confirmed years later by the Diabetes Control and Complications Trial and cited by Mathew Davis, the father figure of Diabetic Retinopathy trials, in an editorial. Our paper has been cited consistently (Scopus citations, 46). This paper prompted significant basic research worldwide to look for the effects of insulin and insulin-like growth factors on vascular endothelial cells. It was found that exogenous insulin enhances leukocytic adhesion to the vascular endothelial cells, leading to ischemia.
Additionally, the legacy of abrupt glucose control in type-2 DM increases the risk of proliferative diabetic retinopathy in later years. Unless backed by prompt bench research that explores the biology of what you observe in your patients, clinical research is, at best, a story that you start telling but stop halfway through. Dr Badrinath paid me a rich compliment for publishing in one of the most prestigious international journals! His words had a salutary effect on my academic career. The appearance of cotton-wool spots in the retina on the institution of insulin was a highly significant finding. It indicated that sudden tight blood glucose control led to acute tissue ischemia. Our observations were confirmed decades later when cardiologists realized that the overzealous control of diabetes in their patients leads to higher mortality and, hence, now seek only a modest control of diabetes.
All over the world, ophthalmologists tend to work alone, even in areas that require a comprehensive multidisciplinary approach. We published good outcomes of diabetic macular edema following comprehensive metabolic control, but regrettably, these were barely noticed at the time.[4,5] Several national ophthalmic academies, including the AAO, now recommend comprehensive control of diabetes and not treating diabetic retinopathy in isolation. Another landmark study of ours, published in the American Journal of Ophthalmology in 2004, demonstrated the beneficial effects of statins in patients with diabetic macular edema with dyslipidemia. It was immediately noticed the world over, spawning significant clinical and basic research and continues to be one of the most cited papers in this field (Scopus citations, 167). When we conducted this pilot randomized control trial, statins were not yet approved for use in DM. It is believed that every person with DM should receive statins. Interestingly, several years later, a large multicentric control trial, the ACCORD trial, reached the same conclusion that controlling blood sugar and dyslipidemia prevents the progression of diabetic retinopathy.
Power of cross-disciplinary collaborations and the beginning of a chase for Mycobacterium tuberculosis (MTB) in the eye
I collaborated for nearly 25 years with Dr Pradeep Bambery, a professor of rheumatology at our institute. This was the only instance of an ophthalmologist and rheumatologist seeing uveitis patients together. A stray remark from Dr Bambery, “Amod, how come in your clinic I see these large/ulcerative Mantoux reactions more than what I see in my medicine clinics,” prompted me to search for TB infection as a cause of uveitis for the next 25 years, generating debate, denials, and acceptance, which culminated in the formation of a large multicentric collaborative ocular tuberculosis study (COTS) consortium led by Rupesh Agrawal (Singapore) and Vishali Gupta (Chandigarh). Several hundred papers have been published worldwide, and still, there are no definite answers! Sometimes, many lifetimes may fail to solve a single question in human biology if it is the right question.
Beginning of a Cascade in Ocular TB Research
In the mid-90s, Prof. Shobha Sehgal started using polymerase chain reaction (PCR) techniques in her lab and agreed to do MTB-PCR from our ocular fluid samples. We published our first series of results in the late 90s.[9,10] Until then, nobody had believed that PCR could be used for infectious uveitis other than viral and toxoplasma infections.
My big breakthrough came when knowing of my attempts at using the PCR technique for characterizing retinal vasculitis, Prof. Narsing Rao nominated me to present my work during the prestigious International Uveitis Study Group meeting held in India. This closed-door meeting, held in Fisherman’s Cove, Chennai, in February 2001, was attended by more than 60 international luminaries in the field who voted me to become the second elected member of the group from India. The first member was my student Dr J. Biswas from SN, Chennai, who had done a fellowship with Prof. Rao in Los Angeles. My work, “Clinical characteristics and management of PCR-positive tubercular retinal vasculitis,” got published in Retina. This study, too, received worldwide attention and has been extensively cited ever since (Scopus citations, 110). Until then, retinal periphlebitis had been eponymously labelled as Eales’ disease. There is a consensus now that tuberculosis is the major cause of retinal vasculitis in the Indian subcontinent and other TB-endemic regions worldwide.
Tubercular serpiginous-like choroiditis (TB-SLC) – continuation of a riddle
In the international symposium that followed the IUSG meeting the next day in Chennai in 2001, I presented a large number of cases of what we believed were serpiginous choroidopathy but differed significantly from the classic description of serpiginous choroiditis which had been reported in Caucasians as a very rare blinding disease. We had been labeling these multifocal choroiditis patients as having acute posterior multifocal placoid pigment epitheliopathy, described in 1968 by Dr Gass as a nonprogressive, nonrecurrent disease. When Dr Anita Agarwal joined me, we painstakingly started looking at the outcome of these patients over several years of follow-up. My presentation generated a lot of debate between Dr Carl Herbort from Lausanne, Dr Emmett Cunningham from San Francisco, and me. They prompted me to publish my data. Soon, we realized that there was a set of patients with strong corroborative evidence of tuberculosis who responded to antitubercular treatment. For the first time, we described a new phenotype of posterior uveitis, which we named presumed TB-SLC. In no time, this phenotype was recognized in different parts of the world as one of the commonest types of posterior uveitis, especially in TB-endemic regions. It generated extensive citations (Scopus citations, 208). I had often wondered how these patients were labeled before we linked their symptoms to tuberculosis. This single paper provided me with a much-needed breakthrough in getting international recognition. I was invited to meetings worldwide, including the most prestigious AAO Specialty Day meetings, to discuss this disease entity.
In one of the largest series, we described the typical signs of TB-SLC and its presentation as multifocal serpiginoid choroiditis. We also demonstrated the presence of the MTB genome in the vitreous fluid of the patients with TB-SLC. We demonstrated that fundus autofluorescence was the best tool to evaluate these patients. Yet challenges remain. Initially, we reported that 14% of the patients showed adverse worsening of the lesions on initiating anti-TB drug therapy. However, we were limited by the study’s retrospective nature and the use of a 45° field of view for the fundus images. Much later, when my colleagues compared ultrawide field images with the conventional 75° field images in a small but prospective study, they discovered paradoxical worsening in 36.4% of the patients. However, one thing is certain: once the SLC lesions heal after anti-TB therapy, the lesions do not recur, in contrast to the case for patients treated with corticosteroids alone.
Clinical signs of ocular TB and classification
We used PCR to characterize the various other phenotypes of uveitis possibly caused by tuberculosis[20,21] and published a large study on the role of antitubercular therapy in uveitis associated with latent/manifest tuberculosis (Scopus citations, 157). I also described ocular signs predictive of tubercular uveitis (Scopus citations, 158). In 2014, we reported multidrug resistant tubercular uveitis for the first time globally, and in 2015, its successful treatment. We were among the first in the world to successfully treat TB choroidal granuloma with anti-vascular endothelial growth factor (anti-VEGF), exploiting the vascularization of hypoxic TB granulomas. This led to the prompt resolution of the granuloma. Anti-VEGF agents are one of the several host-directed therapies being tested in trials to treat TB. Dr Manfred Zierhut asked me to prepare classification criteria for intraocular TB, which saw worldwide acceptance as evidenced by the number of citations it received within a short time (Scopus citations, 146).
Our group, through numerous publications, has consistently reported techniques to improve the sensitivity of molecular diagnosis of tuberculous uveitis. No single molecular test with high enough sensitivity for clinical use exists. However, it led us to characterize various phenotypes and, for the first time globally, detect and manage multidrug-resistant TB uveitis.
The lack of appropriate animal models and histopathological studies in various phenotypes of ocular TB has been a major handicap. Human ocular tissue samples are unavailable except for aqueous or vitreous samples. It is highly encouraging to see Dr. Soumyava Basu and his group leading basic research to solve this riddle.[28,29]
I would like to share our early work on another major challenge in India: fungal infections and the role of contaminated solutions. We have always considered fungal infections in the context of many predisposing factors, such as drug abuse, immunocompromised patients, cancer therapy, liver transplant, major genitourinary surgery, and indwelling catheters, to name a few.
For the first time in the world, I described contaminated dextrose infusion as a risk factor for endogenous fungal endophthalmitis in healthy young people, which received many citations (Scopus citations 55) and attracted an editorial by Harry Flynn, one of the world’s leading authorities on endophthalmitis. There have been innumerable outbreaks of fungal infections due to contaminated solutions worldwide, and every ophthalmologist must be vigilant for such a possibility. Subsequently, we published one of the world’s largest reports on postcataract surgery fungal endophthalmitis. It was cited extensively in the literature (Scopus citations 108) and endorsed by reports from different centers stating that fungal infections following cataract surgery pose a major challenge in India.
Research is for the curious mind
Two years ago, I wrote that research is for the curious mind. “Why do people join the science/research stream? Because of the natural joy, excitement, and thrill of discovering something unknown or being able to change long-held beliefs. While many are drawn to research by their passion, it is common to observe that the most curious minds do not always find their way into science streams at the graduate or doctoral levels. These professors and scientists face the challenge of ‘publish or perish’ at the hands of the administrators. In my experience, real, passionate researchers do not feel this pressure and are the most prolific contributors to the existing knowledge. Essentially what you need is a curious and committed mind. The people who found their way into research by chance and not driven by curiosity feel lost and frustrated.” https://www.eophtha.com/posts/publish-or-perish.
Do you track your papers?
Your papers must showcase your ability to describe what you can see, observe what others cannot, and use it to change how patients are diagnosed or managed. Your paper must bring about a change in the behavior of others. Unless you track your papers, you have no idea whether your research helped change the diagnosis or treatment of patients worldwide. Tracking your papers helps you to discover the merit of your work. If you publish a paper nobody knows, reads, or cites, the paper does not exist. During the last 45 years, I have published more than 400 papers with citation counts creeping to the 10,000 mark and an h-index (Scopus 49) just shy of one citation to reach the magic number of 50. Looking back, nearly 40% of my papers were never noticed and rightly so. Sometimes, I wish they never existed.
Finally, I must confess that, while pursuing my research interests, seeing and operating on patients, setting up the Advanced Eye Centre [Fig. 4], building a cohesive faculty team ably assisted by Dr Mangat Dogra and Dr Jagat Ram, and overcoming day-to-day hurdles in my professional and administrative career, I completely failed to control my life-work balance. The victims were my daughter and wife, who silently suffered neglect at my hands. They lost out on precious family time in their lives. The recognition that I have received is, at best, a small consolation prize for them [Figs. 5 and 6].
About the author
Dr. Amod Gupta
Dr Amod Gupta is an Emeritus Professor in the Department of Ophthalmology at the Post Graduate Institute of Medical Education and Research, Chandigarh. He raised one of India’s most advanced eye care centres, the Advanced Eye Centre at the PGI, in 2006. He remained Dean of the institute from 2011 to 2014. He superannuated in 2015 after spending over 40 years in the same department he joined as a junior resident in 1974. He has been at the forefront of clinical research in retinal and uveal diseases and published more than 400 original research papers in peer-reviewed journals. Recognised with more than 40 honours and awards nationally and internationally, he is the Founder-President of the Uveitis Society of India and has been the former President of the Vitreoretinal Society of India.
No meaningful work is possible without active collaboration with your colleagues. I was fortunate to receive valuable contributions from my students and later my colleagues, Drs. Vishali Gupta, Reema Bansal, and Ramandeep Singh from my department, Dr Kusum Sharma, a professor of microbiology and Dr Aman Sharma, a professor of rheumatology. I am glad all my associates have become internationally recognized in their own right and continue to pursue the fields I opened for research with full vigor. My clinical observations and research have raised more questions than answers. However, it has been an exciting journey. My generation had no exposure to biochemistry, cell biology, immunology, pathology, or even superspeciality fellowship training. This is a major handicap for clinicians when called upon to lead research groups. Any meaningful clinical research needs to be backed up by bench research. Five years before I superannuated and said goodbye to clinics and research, I won a hugely competitive grant from the Department of Biotechnology to set up a research lab at my center. However, as they say, we have miles to go and a lot of catching up to do in developing advanced basic science facilities.
1. Roysarkar TK, Gupta A, Dash RJ, Dogra MR Effect of insulin therapy on progression of retinopathy in noninsulin-dependent diabetes mellitus. Am J Ophthalmol 1993;115:569–74.
2. Davis MD Worsening of diabetic retinopathy after improvement of glycemic control. Arch Ophthalmol 1998;116:931–2.
3. Larroumet A, Rigo M, Lecocq M, Delyfer MN, Korobelnik JF, Monlun M, et al Previous dramatic reduction of HbA1c and retinopathy in type 2 diabetes. J Diabetes Complications 2020;34:107604.
4. Singh R, Abhiramamurthy V, Gupta V, Gupta A, Bhansali A Effect of multifactorial intervention on diabetic macular edema. Diabetes Care 2006;29:463–4.
5. Singh R, Gupta V, Gupta A, Sachdev N, Dogra MR, Bhansali A Multifactorial interventions before laser photocoagulation improve outcome of diabetic macular edema. Diabetes Care 2006;29:2758–9.
6. Gupta A, Gupta V, Thapar S, Bhansali A Lipid-lowering drug atorvastatin as an adjunct in the management of diabetic macular edema. Am J Ophthalmol 2004;137:675–82.
7. ACCORD Study Group;ACCORD Eye Study Group Chew EY, Ambrosius WT, Davis MD, Danis RP, et al Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010;363:233–44 Erratum in: N Engl J Med 2011;364:190. Erratum in: N Engl J Med 2012;367:2458.
8. Agrawal R, Testi I, Mahajan S, Yuen YS, Agarwal A, Rousselot A, et al The Collaborative Ocular Tuberculosis Study (COTS) Consensus (CON) group meeting proceedings. Ocul Immunol Inflamm 2020;28 (suppl 1) 85–95.
9. Gupta V, Arora S, Gupta A, Ram J, Bambery P, Sehgal S Management of presumed intraocular tuberculosis:Possible role of the polymerase chain reaction. Acta Ophthalmol Scand 1998;76:679–82.
10. Arora SK, Gupta V, Gupta A, Bambery P, Kapoor GS, Sehgal S Diagnostic efficacy of polymerase chain reaction in granulomatous uveitis. Tuber Lung Dis 1999;79:229–33.
11. Gupta A, Gupta V, Arora S, Dogra MR, Bambery P PCR-positive tubercular retinal vasculitis:Clinical characteristics and management. Retina 2001;21:435–44.
12. Gass JD Acute posterior multifocal placoid pigment epitheliopathy. Arch Ophthalmol 1968;80:177–85.
13. Gupta V, Agarwal A, Gupta A, Bambery P, Narang S Clinical characteristics of serpiginous choroidopathy in North India. Am J Ophthalmol 2002;134:47–56.
14. Gupta V, Gupta A, Arora S, Bambery P, Dogra MR, Agarwal A Presumed tubercular serpiginouslike choroiditis:Clinical presentations and management. Ophthalmology 2003;110:1744–9.
15. Bansal R, Gupta A, Gupta V, Dogra MR, Sharma A, Bambery P Tubercular serpiginous-like choroiditis presenting as multifocal serpiginoid choroiditis. Ophthalmology 2012;119:2334–42.
16. Bansal R, Sharma K, Gupta A, Sharma A, Singh MP, Gupta V, et al Detection of Mycobacterium tuberculosis genome in vitreous fluid of eyes with multifocal serpiginoid choroiditis. Ophthalmology 2015;122:840–50.
17. Gupta A, Bansal R, Gupta V, Sharma A Fundus autofluorescence in serpiginouslike choroiditis. Retina 2012;32:814–25.
18. Gupta V, Bansal R, Gupta A Continuous progression of tubercular serpiginous-like choroiditis after initiating antituberculosis treatment. Am J Ophthalmol 2011;152:857–63 e2 doi:10.1016/j.ajo. 2011.05.004.
19. Aggarwal K, Agarwal A, Deokar A, Singh R, Bansal R, Sharma A, et al Ultra-wide field imaging in paradoxical worsening of tubercular multifocal serpiginoid choroiditis after the initiation of anti-tubercular therapy. Ocul Immunol Inflamm 2019;27:365–70.
20. Gupta V, Gupta A, Arora S, Sachdeva N, Bambery P Simultaneous choroidal tuberculoma and epididymo-orchitis caused by Mycobacterium tuberculosis. Am J Ophthalmol 2005;140:310–2.
21. Gupta V, Gupta A, Sachdeva N, Arora S, Bambery P Successful management of tubercular subretinal granulomas. Ocul Immunol Inflamm 2006;14:35–40.
22. Bansal R, Gupta A, Gupta V, Dogra MR, Bambery P, Arora SK Role of anti-tubercular therapy in uveitis with latent/manifest tuberculosis. Am J Ophthalmol 2008;146:772–9.
23. Gupta A, Bansal R, Gupta V, Sharma A, Bambery P Ocular signs predictive of tubercular uveitis. Am J Ophthalmol 2010;149:562–70.
24. Sharma K, Sharma A, Bansal R, Fiorella PD, Gupta A Drug-resistant tubercular uveitis. J Clin Microbiol 2014;52:4113–4.
25. Sharma K, Bansal R, Sharma A, Gupta A, Fiorella PD Successful treatment of rifampicin-resistant intraocular tuberculosis. Ocul Immunol Inflamm 2015;23:93–6.
26. Bansal R, Beke N, Sharma A, Gupta A Intravitreal bevacizumab as an adjunct in the management of a vascular choroidal granuloma. BMJ Case Rep 2013;2013:bcr2013200255 doi:10.1136/bcr-2013-200255.
27. Gupta A, Sharma A, Bansal R, Sharma K Classification of intraocular tuberculosis. Ocul Immunol Inflamm 2015;23:7–13.
28. Takaki K, Ramakrishnan L, Basu S A zebrafish model for ocular tuberculosis. PLoS One 2018;13:e0194982 doi:10.1371/journal.pone. 0194982.
29. Damera SK, Panigrahi RK, Mitra S, Basu S Role of extracellular mycobacteria in blood-retinal barrier invasion in a Zebrafish model of ocular TB. Pathogens 2021;10:333.
30. Gupta A, Gupta V, Dogra MR, Chakrabarti A, Ray P, Ram J, et al Fungal endophthalmitis after a single intravenous administration of presumably contaminated dextrose infusion fluid. Retina 2000;20:262–8.
31. Flynn HW Jr The clinical challenge of endogenous endophthalmitis. Retina 2001;21:572–4.
32. Narang S, Gupta A, Gupta V, Dogra MR, Ram J, Pandav SS, et al Fungal endophthalmitis following cataract surgery:Clinical presentation, microbiological spectrum, and outcome. Am J Ophthalmol 2001;132:609–17.