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   Table of Contents      
SPECIAL EDITORIAL
Year : 2018  |  Volume : 66  |  Issue : 12  |  Page : 1674-1677

My ophthalmic research journey and contribution


Department of Ophthalmology and Visual Sciences, College of Medicine, University of Iowa, Iowa City, IA, USA

Date of Web Publication19-Nov-2018

Correspondence Address:
Dr. Sohan Singh Hayreh
Department of Ophthalmology and Visual Sciences, College of Medicine, University of Iowa, Iowa City, IA
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijo.IJO_1520_18

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How to cite this article:
Hayreh SS. My ophthalmic research journey and contribution. Indian J Ophthalmol 2018;66:1674-7

How to cite this URL:
Hayreh SS. My ophthalmic research journey and contribution. Indian J Ophthalmol [serial online] 2018 [cited 2018 Dec 18];66:1674-7. Available from: http://www.ijo.in/text.asp?2018/66/12/1674/245613



My objective in this study is not to discuss what scientific research is and how to conduct it-there is a voluminous literature about that. It is more personal to tell, briefly, why and how I got into scientific ophthalmic research, and my contribution to ophthalmology, since 1955.

The word “research” has a mythical charm and mystery to the general public. It had it to me when I was a medical student, and pushed me toward research, although I did not have the faintest clue what it involved. Moreover, at that time scientific research was never discussed or taught in medical colleges. After graduation from the medical college, residency in general surgery and service in the Indian Army Medical Corp, in pursuit of my ambition for a research and academic career, I joined the newly opened medical college in Patiala; the only available post was in the anatomy department. I found no one around who knew anything worthwhile about serious scientific research. By chance, I happened to meet the professor of Ophthalmology from my student days. I chanced to mention that I was looking for a research topic. He told me that he had recently seen papers in the British Journal of Ophthalmology on “vascularization of the optic pathway.” Because I was working in the anatomy department, I thought it worth exploring their discovery of a “central artery of the optic nerve.” Because there was no one in the department to help me, I explored the whole thing myself. I had to learn everything the hard way. I became my own investigator, technician, and director of research, without any prior knowledge and training. From the literature, I found that, to study the anatomy of the vascular bed, the first essential was to prepare vascular casts. In India, I could not find any material to do that; liquid latex was the only suitable material for preparing vascular casts, and only the DuPont company in Delaware, USA made it. However, my salary then was only about 200 rupees a month, so I could not afford to buy latex and I had no research funds. (Even if I had had the money, the Government of India at that time did not allow anyone to buy goods from abroad, to save hard currency.) With the faintest hope, I wrote to the DuPont cmpany, asking if they could possibly send me some free samples of liquid latex, and they sent me two gallons, which was enough for my project. With that, I did comprehensive human anatomical studies, not only of 100 central retinal arteries but also of the entire vascular bed of the eye, optic nerve, and the orbit in 59 human orbits; those studies still stand as landmark studies. I showed that the “central artery of the optic nerve” did not exist-it was a scientific fraud! That landed me in a big controversy because Professor Jules Francois, the primary author of multiple studies “claiming” that artery existed, was the secretary general of the International Council of Ophthalmology and politically powerful in international ophthalmology. After initial bad blood for years, he finally met me in London and graciously agreed to repeat the study; then he fully confirmed my findings.

Further, after those anatomical studies, I found the subject of pathogenesis of optic disc edema (papilloedema) in raised intracranial pressure fascinating and challenging, since its first discovery in 1853, over a dozen conflicting theories had been postulated, without any definite conclusion. There were no research facilities in Patiala to investigate that complex problem. Then one day, in the Times of India, I read a small announcement by the University of London for the Beit Memorial Research Fellowship for Medical Research. This was a highly-coveted research fellowship in medical sciences in the United Kingdom; previous fellows included many famous names in twentieth-century medicine, and at least 6 former Beit fellows so far have gone on to win Nobel Prizes in Medicine. No one from India had been awarded the Beit fellowship. There were two essential requirements to apply for the fellowship: the candidate must (a) submit his own detailed research plan, and (b) obtain a letter from a research director in Britain agreeing to accommodate the candidate in his laboratory, if he/she obtained the fellowship. I already had my research project, the “pathogenesis of optic disc edema in raised intracranial pressure” in mind and how to tackle it. To get a British research director to accommodate me was the huge problem. I had never met any British! In desperation, I wrote to the famous Sir Stewart Duke-Elder, director of the Institute of Ophthalmology, University of London-he had written many books. He agreed to accept me. In June, 1961 the Beit trust informed me that I was elected as a Beit fellow for 3 years. That was the crucial event in my life-research, professional, and personal future. I wrote to Duke-Elder, and he kindly wrote back the following: “I am delighted to hear that you have got a Beit Fellowship-excellent. We will be glad to see you here on October 1st, and I should imagine that the best thing you could do in the meantime is to read up the enormous literature on papilloedema; most of it is old, for, unfortunately for ophthalmology, nothing of importance has emerged lately. In a way that is fortunate for you, and we are all looking forward to you solving a very important problem.”

I arrived at the Institute of Ophthalmology, University of London, on October 1, 1961. At that time, the Institute was the premier and most coveted ophthalmic research institute in the world. As a Beit fellow, following distinguished previous Beit fellows, I was determined to “measure up.” Therefore, I put in my best effort in my research on a very difficult project, and devoted 100% of my time to it. For me, Duke-Elder was not only very kind but also extremely generous with his time and provided all possible facilities and complete freedom to pursue my research plans. I was the only researcher at the Institute for whom he was director of research. He was always ready to give advice when asked, despite being very busy.

Since, at that time, no experimental method existed to produce raised intracranial pressure and optic disc edema, I first had to devise a method. I discovered that a gradually inflated intracranial balloon (simulating a rapidly growing intracranial tumor) successfully produced raised intracranial pressure and optic disc edema experimentally in rhesus monkeys. After overcoming teething troubles, my studies started to yield new important information. For instance, that fenestration of the optic nerve sheath relieved optic disc edema in raised intracranial pressure. This observation formed the basis of the procedure now frequently used in idiopathic intracranial hypertension. During that period, I also investigated the histological structure of the optic nerve and discovered that central retinal vein occlusion was of two types, ischemic and non-ischemic-which has important clinical implications in its diagnosis, visual outcome, and management. I also investigated posterior drainage of fluid from the vitreous and found that it played no role in the pathogenesis of optic disc edema, contradicting previous views. Some years after the Beit fellowship, when more advanced technology became available, I did further studies on this topic that finally showed that optic disc edema in raised intracranial pressure is because of the axoplasmic flow stasis caused by raised cerebrospinal fluid pressure in the sheath of the optic nerve. Therefore, I finally solved this mystery dating from 1853, as Duke-Elder originally predicted I would.

When my Beit fellowship finished after 3 years, I had to make a tough choice-go back to India and say good-bye to any serious ophthalmic research for lack of facilities and funds, or stay in Britain and try to make a career in British ophthalmology. I decided for the latter, despite the very heavy odds against me. I would have to undertake local clinical training and pass the two examinations for the fellowship of the Royal College of Surgeons; I knew that the pass rate in fellow of the royal college of surgeons (FRCS) was only about 25%. Otherwise, I would have no future in patient care, research, and academic career in Britain. Hence, at age 37 with my Ph.D. from University of London, research credentials, and the prestigious Beit fellowship, I went back and started as a clinical trainee. All the other clinical trainees with me were young, new medical graduates. However, I knew I had to swallow my pride and start from the bottom, if I wanted to achieve what I coveted.

After my early clinical job, because of my research credentials, I was appointed Lecturer in Clinical ophthalmology at the University of London-doing research at the Institute of ophthalmology and clinical work at the Moorfields Eye Hospital. Fluorescein fundus angiography was a brand new test started in 1963. I became one of the first pioneer investigators of that. With that as a research tool, I investigated retinal and optic nerve head circulation. I discovered the following for the first time:

  1. The blood supply of the optic nerve head is entirely by the posterior ciliary artery circulation that completely changed the entire concept about its circulatory disorders-most importantly, about the pathogenesis of anterior ischemic optic neuropathy and glaucomatous optic neuropathy
  2. In glaucoma, there is vascular insufficiency in the optic nerve head. I showed that, also, with my experimental glaucoma studies, contradicting the centuries-old concept that glaucoma was purely a mechanical phenomenon due to raised intraocular pressure. From that, I introduced the vasogenic concept of optic nerve damage in glaucoma, which initially attracted strong objections but is now a seminal concept in glaucoma research
  3. I showed the angiographic pattern of choroidal melanomas and of radiation retinopathy.


At Moorfields, working with Dr. Peter Watson in the scleritis and episcleritis clinic, we were the first to give comprehensive clinical account of these two conditions in a large cohort of patients. In 1969, at the age of 42, I passed the examinations for FRCS Edinburgh as well as of England. After that, I was selected as Senior Lecturer in Ophthalmology (and later on Reader) at the University of Edinburgh, Scotland and also Consultant Ophthalmologist at the Edinburgh Royal Infirmary. The ophthalmology department at the university was small and purely clinical, with no research facilities. To establish research facilities, I first had to apply for a research grant from the British Medical Research Council. With that research grant, I established facilities for clinical research in the department; however, for my experimental research in monkeys, I found it impossible to get animal facilities in the university campus. I approached a pharmaceutical research establishment about 25 miles outside Edinburgh because they had animal facilities; they agreed to accommodate me-but only provided I built my own research facilities at their premises; so I built a monkey research laboratory there. In my experimental studies there, I explored various aspects of the posterior ciliary artery (PCA), vortex vein, and choroidal circulation. My in vivo studies showed the following:

  1. The PCAs and their branches have a strict segmental distribution
  2. There are watershed zones between them, which play important role in the pathogeneses of choroidal and optic nerve head ischemic disorders
  3. There are no anastomoses in the choroid
  4. The choriocapillaris have a lobular vascular pattern, with arteriole in the center and venous channels at the periphery
  5. The various vortex veins also show segmental distribution, with watershed zones between them.


These in vivo studies were the first on the subject, and their findings completely contradicted the universally accepted concepts prevalent since 1700 A.D., from vascular casts, about the PCAs and the choroidal vascular bed. These were new discoveries, with important implications for understanding various choroidal and optic nerve head pathologies. On occlusion of PCAs, for the first time, I described features of various acute choroidal and optic nerve head ischemic lesions, previously confused as retinal ischemic lesions.

In my clinical work, apart from running a clinic and doing surgery, I did research studies in patients with ischemic optic neuropathy, giant cell arteritis, glaucoma, retinitis pigmentosa, and retinal vascular occlusive disorders. Those provided new information about them. From those studies, I coined the term “anterior ischemic optic neuropathy,” discovering that it was of two types-arteritic and nonarteritic.

In 1972, I was invited by the University of Iowa, USA to join the ophthalmology department as professor. That department was and still is one of the top clinical and academic ophthalmology departments in the country. However, once again, I found there were no clinical or experimental research facilities. Therefore, I had to establish both types of facilities. However, before I could do that, and conduct research, I first had to apply for a research grant from the National Institutes of Health (The primary research funding agency in the USA). I got large grants for clinical and experimental research. Those enabled me to set up an “Ocular Vascular Experimental Laboratory.” and an “Ocular Vascular Clinic” to conduct research on experimental and clinical projects. In the “Ocular Vascular Clinic”, apart from running a clinic and doing surgery, I conducted research on various disorders listed below. In the ocular vascular experimental laboratory, I did experimental research on multiple projects in monkeys, listed below.


  Clinical Topics of Research Top


Very briefly, the various clinical topics that I have researched prospectively are as follows:

  1. Ocular vascular occlusive disorders: I researched classifications, etiologies, pathogeneses, clinical features, visual outcomes (including important topic of natural histories of visual outcome), managements, and all other aspects of the following ocular vascular occlusive disorders in large cohorts of patients:


    1. Retinal vein occlusion: This included central (864 eyes), hemi-central (70 eyes), and branch (285 eyes) retinal vein occlusions. I discovered the new clinical entity of hemi-central retinal vein occlusion
    2. Retinal artery occlusion: This included central (271 eyes) and branch (212 eyes) retinal artery occlusions. I discovered that central retinal artery occlusion actually comprises four distinct clinical entities with different clinical features, visual outcomes and managements
    3. Ischemic optic neuropathies: I investigated anterior (1,350 patients) and posterior (50 patients) ischemic optic neuropathies. The anterior ischemic optic neuropathy consists of nonarteritic (90%) and arteritic (10%) types, with different clinical features, visual outcomes, and managements
    4. Giant cell arteritis: This is an important ophthalmic emergency, with tragic risk of blindness. My comprehensive studies in about 200 patients with giant cell arteritis provided new information about its diagnostic criteria, ophthalmic and clinical manifestations, and management
    5. Amaurosis fugax: I investigated in 2,788 eyes of patients with retinal artery occlusion, ocular ischemic syndrome, retinal vein occlusion, nonarteritic anterior ischemic optic neuropathy, and giant cell arteritis with visual loss. This showed that amaurosis fugax must always be evaluated urgently because it may a sign of impending blindness.


  2. Not only these studies reveal much new information on these common blinding disorders but also the many new discoveries, contradicted long held dogmas and conventional wisdom, and dispelled many prevalent misconceptions
  3. Optic disc vasculitis: I discovered this new clinical entity and investigated its various clinical features and management in 34 eyes
  4. Carotid artery disease: I investigated this in 614 consecutive patients because it plays an important role in ocular vascular occlusive disorders
  5. Nocturnal arterial hypotension: My study was the first on the topic in 114 patients with nonarteritic anterior ischemic optic neuropathy, 131 with normal tension glaucoma, and 30 primary open angle glaucoma. I discovered that this condition plays a key role in these disorders
  6. Anterior segment ischemia following strabismus surgery: I investigated this in 33 eyes following cutting different recti during strabismus surgery. This showed that cutting two vertical recti along with the lateral rectus may risk development of anterior segment ischemia
  7. Ocular ischemic syndrome: This is a seriously blinding disease. I investigated this in 39 eyes, providing new information on its etiology and clinical features
  8. I recently published the following two comprehensive books discussing in detail various aspects of all these important blinding diseases: “Ocular Vascular Occlusive Disorders” and “Ischemic Optic Neuropathies”
  9. Glaucoma: This is a common, slowly blinding disease. I investigated primary open angle glaucoma, normal tension glaucoma, and neovascular glaucoma, especially its vascular etiology, the role of age and cardiovascular disease, visual fields, and the pathogenesis of optic disc cupping
  10. Acute retinal necrosis syndrome: I also investigated clinical features of this blinding disorder
  11. Blood supply of the optic nerve in health and disease: This is an important topic for the understanding of ischemic disorders of the optic nerve. I have researched it extensively over the years.



  Experimental Topics of Research Top


Almost all studies were conducted in monkeys because those are applicable to the human. Those dealt with the following topics:

  1. Retinal tolerance time to acute ischemia: I investigated this important topic in central retinal artery occlusion (CRAO). Contrary to the popular belief, I found that the retina suffers no permanent damage with CRAO lasting for about 100 min; after that, the longer the occlusion, the more progressive the damage, so that CRAO lasting for 4 h results in permanent retinal damage
  2. Malignant arterial hypertension: Since Bright described it in 1836, there had been no comprehensive studies about its ophthalmic manifestations. I produced this in 60 monkeys and investigated the clinical features and pathogeneses of various ophthalmic lesions produced by it. I showed that the various ophthalmic lesions in it consist of 3 distinct clinical entities: hypertensive retinopathy, hypertensive choroidopathy, and hypertensive optic neuropathy. This provides totally new information about their pathogeneses, clinical features, and other aspects
  3. Experimental glaucoma: I produced this in 76 eyes of monkeys, to gain a better understanding about glaucomatous optic neuropathy
  4. Experimental central retinal vein occlusion: My studies in 45 eyes provided new information on its pathogenesis and clinical features
  5. Methanol poisoning: It causes visual loss and even death. We investigated the ophthalmic and optic nerve changes caused by this poisoning, providing new insight on the subject
  6. Anterior segment ischemia following strabismus surgery: There had been controversy about how many recti can be cut safely during strabismus surgery. This was investigated comprehensively in 40 monkey eyes by cutting various recti in different combinations. This study provided completely new information
  7. Ocular neovascularization: This is a serious blinding condition. I investigated its different aspects by producing it experimentally
  8. Experimental atherosclerosis: I produced this in 50 monkeys and evaluated its role in development of various ophthalmic lesions.


Results of my studies are published in more than 400 peer reviewed ophthalmic journals. Over the years, in Edinburgh and Iowa City, I have had many research fellows to work with me. Research is teamwork. Over the years, I have had invaluable help from nurses, technicians, fellows, and many other persons while conducting research on various projects, as is evident from my co-authors in various publications; without their help it would not have been possible to research all these topics in detail. I am extremely grateful to them for their invaluable help.


  Conclusions Top


For me, it has been a long, highly adventurous but gratifying research journey, extending more than 60 years, over three continents. My concluding thoughts about conducting research and research life are as follows:

  1. Scientific research is often like collecting pieces of a complex jig-saw puzzle. Each piece individually may make no sense at all, and only when they are put together, a complete picture emerges. As the famous German scientist Justus von Liebig (1803-1873) stated: “History teaches that the commencement of every branch of science is nothing more than a series of observations and experiments which had no obvious connections with one another”
  2. Different researchers have diverse approaches to solve a problem. My approach has always been to explore a problem starting without any preconception or bias, not trying to prove or disapprove anything, starting work on a research project with a completely clean slate. The study observations must be made without bias and interpreted on their own merit. Then the conclusions are totally reliable, being based purely on what the observations reveal. Because of this policy, I feel, my studies have revealed a lot of new information, which has contradicted prevalent dogmas, conventional wisdom and misconceptions, and stood the test of time
  3. Contrary to popular belief and my own before I started research, serious scientific research is rarely glamorous, except for an occasional glimpse. Mentally, it is highly stressful and a full-time preoccupation, full of trials and tribulations, with ups and downs, and with only occasional joy.







 

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