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Knowledge of Diabetic Retinopathy before and 18 Years after the Airlie House Symposium on Treatment of Diabetic Retinopathy
Knowledge of Diabetic Retinopathy before and 18 Years after the Airlie House Symposium on Treatment of Diabetic Retinopathy MORTON F. GOLDBERG, MD,* LEE M. JAMPOL, MDt
Abstract: In 1968, The Airlie House Symposium evaluated the current knowledge of the natural history of diabetic retinopathy. The effects of tight metabolic control, pituitary ablation, and photocoagulation were discussed at length. Xenon arc photocoagulation was the mainstay of therapy and was usually applied focally to individual patches of new vessels. Photocoagulation of background retinopathy was rarely done. Panretinal photocoagulation was in its infancy, the ruby laser was newly introduced, there were no data on the use of the argon laser, and automated vitrectomy had not been introduced. Participants in the symposium set the stage for the acquisition of valid clinical data from which important therapeutic conclusions have subsequently been drawn by (1) summarizing the areas of consensus and disagreement, (2) devising a standard classification of diabetic retinopathy, and (3) proposing controlled clinical trials for unanswered questions. [Key words: Airlie House Symposium, diabetic retinopathy, laser, metabolic control, photocoagulation, pituitary ablation, xenon arc.] Ophthalmology 94:741-746, 1987
Diabetic retinopathy, described by Duke-Elder as "one of the major tragedies of ophthalmology in our present generation,"! had become a public health problem of major proportions by the mid-1960s. 2 Improved medical care had increased the life span of large numbers of diabetic patients, thus permitting the occurrence of those diabetic complications, including retinopathy, that required chronicity of the underlying disease pro-
From the Department of Ophthalmology,* Eye and Ear Infirmary, Univer· sity of Illinois College of Medicine at Chicago, and Northwestem Univer· sity Medical School,t Chicago. Supported in part by training grant 7038 and core grant 1792 from the National Eye Institute, Bethesda, Maryland, and by unrestricted research grants from Research to Prevent Blindness, Inc., New York. Reprint request to Morton F. Goldberg, MD, Department of Ophthalmol· ogy, Eye and Ear Infirmary, University of Illinois College of Medicine at Chicago, 1855 West Taylor Street, Chicago, IL 60612.
cesses. A substantial rate of blindness was the distressing result. The pathogenesis of the vision-threatening events in diabetic retinopathy and its natural course were incompletely understood, a clear-cut distinction between nonproliferative and proliferative types of retinopathy was not widely appreciated, and the forms of retinopathy having particularly poor prognoses ("high-risk characteristics") were not well identified. Therapy for diabetic retinopathy was extremely difficult to assess because of the disease's variable course, even without treatment. Spontaneous improvement occurred unpredictably in a small but definite proportion of patients. Without a generally accepted classification of the disease and without a standard nomenclature, it was usually impossible to compare the results of any selected treatment from one group of investigators with those from any others. For the same reasons, comparability of cases before treatment by different techniques 741
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could not be assessed reliably. Therapeutic endpoints and techniques for their measurement were not well defined. Also, observations obtained in a controlled, nonbiased manner were unavailable. Against this backdrop of incomplete basic knowledge were several unproved therapeutic modalities, many of which had staunch supporters despite inherent risks to vision (for example, from xenon arc photocoagulation) and to life itself (for example, from pituitary ablation). Other therapeutic approaches included x-irradiation of the retina, dietary restriction of fat, induction of glaucoma by topical use of corticosteroids, and administration of vitamins C and Bi2 , clofibrate (Atromid), paraaminosalicyclic acid, anticoagulants, and testosterone. Supporters of the Airlie House Symposium on the Treatment of Diabetic Retinopathy hoped it would "provide a framework for future cooperative studies seeking to elucidate the natural course of the disease and the effects of pituitary ablation and photocoagulation,"3 because these two therapeutic approaches appeared to have far more potential than any of the others.
HISTORY OF THE AIRLIE HOUSE SYMPOSIUM A spate of publications on diabetic retinopathy appeared in the 1950s and 1960s. They included trypsin digestion studies of postmortem human retinas, biomicroscopic confirmation of vitreous contraction and its effect on adherent neovascularization,4 isolated case reports on naturally occurring pituitary insufficiency, and the English translation of Meyer-Schwickerath's book on photocoagulation. 5 The development of fluorescein angiography in the early to mid-1960s made it possible to visualize, describe, and, to some extent, quantitate different pathologic processes in diabetic retinopathy, including capillary closure, transudation, and neovascularization. The abnormal vascular wall received most of the pathogenetic emphasis, but abnormalities in the formed and unformed elements of the blood also garnered attention. The increasing availability of the fundus cameras and the use of color photography as well as angiography made it possible for a variety of classification schemes to be promulgated in England, Europe, and the United States. Organizers of the Airlie House Symposium recognized that disparate views of pathogenesis and therapy were ardently held by specialists from several disciplines working on different continents and using different techniques and terminologies. Their clinical results involved a variety of treatment methods including enhanced metabolic control, a focal xenon arc photocoagulation, "spray" or "random" ruby laser photocoagulation, pituitary stalk sectioning, surgical extirpation of the entire pituitary, irradiation of the pituitary, surgical destruction of only the anterior portion of the pituitary, and many others. Despite the plethora of reports and the thousands of patients undergoing therapy around the world, clinical
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results could not easily be assessed without a common vocabulary, standard descriptive techniques, comparable formats for reporting results, and minimization of observer bias. In response to the simple question, "What's the proper treatment for diabetic retinopathy?" posed by a recent medical school graduate (S. L. Fine), a recent ophthalmology trainee (MFG) responded, "No one knows for sure." These organizers of the Airlie House Symposium, therefore resolved to convene, for the first time, over 50 specialists from around the world, representing relevant scientific disciplines, including epidemiology, diabetology, neurosurgery, and ophthalmology. The meeting was held in a conference center (The Airlie House) located in a rural, bucolic setting, far from urban and other distractions. Opportunity for intense intellectual discussions was thereby maximized. In preparation for the meeting, at which participants would be expected to review their clinical results, a preliminary classification of diabetic retinopathy was developed (the so-called O'Hare Classification6 ) and was distributed to participants before the meeting. Manuscripts and data were then prepared within a reasonably similar framework and were also distributed to participants in advance. Discussions at the meeting were therefore more informative, provocative, and insightful than is often the case without proper prior preparation.
CONTENT OF THE AIRLIE HOUSE SYMPOSIUM Major areas of interest included (1) classification of diabetic retinopathy, (2) natural history and visual prognosis of diabetic retinopathy, (3) relationship of retinopathy to metabolic control, (4) pituitary ablation, and (5) photocoagulation. A formal summary of each area was provided by a designated expert, followed by a general discussion from a panelist who was experienced in the specific topic under review. At the end of a 3-day discussion, newly integrated views were presented in a series of valuable epilogues. The result was a book exceeding 900 pages, with data from over 2000 patients collected by more than 25 groups of specialized investigators. The issue of a standard classification of diabetic retinopathy was deemed important because valid therapeutic conclusions could still not be drawn from over 1200 pituitary ablations and more than 1600 photocoagulations that had been performed on diabetic patients during the previous 10 years. Standard photographs, photographic fields, and verbal descriptions of grading parameters were developed, accepted and published. The fundamental dichotomy between nonproliferative and proliferative forms of diabetic retinopathy was emphasized. The O'Hare Classification was revised and renamed the Airlie House Classification of Diabetic Retinopathy. Its proponents "hoped that prospective studies will be undertaken using this classification, and that eventually sufficient valid data will accrue to establish the effective-
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ness of various therapeutic measures advocated for diabetic retinopathy and clarify indications for their use.,,7 These hopes have subsequently been fulfilled. Important key elements in this natural history of diabetic retinopathy were summarized as follows 8: capillary closure is an important early change in diabetic retinopathy and precedes formation of arteriolar-venular shunts (the opposite course of events had been postulated previously); newly formed vessels go through a cycle of proliferation and regression; and vision is severely threatened when vitreous or fibrous tissue adherent to neovascularization undergoes contraction (because vitreous hemorrhage or tractional detachment of the macula can occur). Regarding the effect of metabolic control in diabetic retinopathy, over 400 publications were summarized. About one half of these authors concluded that a positive relationship of some sort existed, whereas about one third believed there were insufficient data for a firm conclusion. The remainder believed that the relationship, if any, was so complex that it would defy easy formulation. 9 Those accepting the idea of a positive relationship emphasized the correlation between degree of glycosuria and presence of retinopathy, and they pointed out that heavy glycosuria in the first years of the diabetic process was more closely related to the development of retinopathy than when it occurred later in the course of the diabetes. Once established, retinal lesions did not appear to be influenced in any important way by the degree of glycosuria. IO Subsequent studies, reported only recently, with insulin pumps and with enhanced diabetic management (during pregnancy, for example) permit different interpretations. II Because of major difficulties in understanding the effect of different types (and amounts) of metabolic control on diabetic retinopathy, it was recommended that a life-table analysis of prospectively acquired data be accomplished. 9 Twenty chapters in the published proceedings of the symposium were devoted to pituitary ablation. This major assault on the body's homeostasis was initially adopted in many parts ofthe world because of anecdotal reports of amelioration of diabetic retinopathy, which appeared about 18 years before the Airlie House Symposium.1 2,13 Eighteen years after the Airlie House Symposium, pituitary ablation is rarely, if ever, used in the treatment of diabetic retinopathy. There seemed little doubt, however, at the time of the symposium, that adequate pituitary ablation (by any of a variety of techniques) could reduce the severity of retinal hemorrhages, vascular dilation, neovascularization, and clouding of the vitreous. Retinal exudates and fibrous proliferations apparently did not respond. 14 Pituitary ablation was performed by various techniques, including transfrontal craniotomy, stalk section, radiofrequency coagulation, cryocoagulation, transsphenoidal removal of the anterior portion of the pituitary, proton beam external irradiation, implantation of radioactive yttrium, and others. Data from 708 patients collected by 11 neurosurgical groups were presented. Retinopathy was arrested in about 75% of patients,
whereas it progressed in about 25% of patients. It was concluded that "although future progress in the treatment of diabetic retinopathy will hopefully alleviate the necessity for pituitary ablation, it still has a place in the treatment of this disease."14 Indeed, some of the participants concluded at the end of the symposium that pituitary ablation should be considered the primary treatment for diabetic retinopathy and that photocoagulation should be used for supplemental purposes.15 Others retained some skepticism and, although agreeing that it favorably altered the course of nonproliferative retinopathy, believed it should be considered experimental. 16 Subsequent advances with laser photocoagulation of the retina have supplanted pituitary ablation, which is now primarily of interest because of its historic role and because of its interesting but incompletely understood involutionary effects on the diabetic retinal vasculature. Photocoagulation results came from several groups of ophthalmologists with data from over 1600 eyes. This large number of treated eyes was testimony to the rapid propagation of the photocoagulation technique. In his seminal book on photocoagulation, which appeared in English in 1960, Meyer-Schwickerath devoted only one sentence to diabetic retinopathy: "Four cases in the late proliferative stage were treated with coagulation without any effect, but in a case presenting microaneurysms and exudates partial disappearance of the latter was achieved by coagulation of the microaneurysms."5 Eleven groups of investigators reported results from xenon arc photocoagulation; two had used the ruby laser. All but one emphasized the focal aspects of the treatment technique (i.e., direct obliteration of abnormal blood vessels). Indeed, there was "essential agreement that photocoagulation lesions (even those produced by the ruby laser) be directed to the areas of visible neovascularization,"17 with the exception of disc neovascularization, which was generally thought to be untreatable. However, experts continued to believe that "the usefulness of. . . photocoagulation in the treatment of diabetic retinopathy is, at this writing, uncertain."18 A preliminary report on the "spray" or "random" pattern of ruby laser photocoagulation (subsequently known as "scatter" or "panretinal photocoagulation") included short-term results on 214 patients!9 Approximately 600 to 800 fundus bums were created in an attempt to mimic naturally occurring retinal vascular involution, such as that seen after optic atrophy associated with glaucoma, widespread chorioretinitis, carotid insufficiency, etc. Focal treatment was simultaneously directed to flat patches of neovascularization, but eyes with elevated new vessels were not treated. 20 The red color of the light emitted by a ruby laser could not close retinal neovascularization via direct local treatment, and ophthalmologists awaited the later development of the argon laser in hopes of being able to obliterate elevated new vessels focally-both at the optic nervehead and elsewhere-because of the blue/green output from this new device. 21 The concept of an indirect favorable effect of spray photocoagulation on untreated portions of the fundus was not accepted by many ophthalmolo743
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gists,because current dogma mandated focal obliteration of the presumably dangerous neovascular tissue, and there was not extant reason to believe that this logical, mechanistic approach was inferior to any other therapeutic philosophy. Despite enthusiasm for xenon arc and ruby laser photocoagulation on the part of some therapists, others still believed that photocoagulation was "clearly experimental."16 For eyes with extensive neovascular and fibrous proliferations associated with vitreous hemorrhage, some ophthalmologists recommended scleral buckling or scleral resection because "we really have nothing more to offer. ,,22 The development of pars plana vitrectomy in subsequent years (the early 1970s) would markedly alter this conclusion. In evaluating the conclusions of the Airlie House participants, Davis noted that". . . to the disappointment of all, no clear-cut consensus regarding pituitary ablation and photocoagulation has resulted from the conference. ,,23 He was ". . . most pleasantly surprised, however, to report that the outlook for general acceptance of the classification. . . seems very good. If this classification does indeed find wide acceptance, this alone would be ample justification for all the time and effort that went into the symposium." Several other sUbjective impressions were advanced, as follows: (1) ". . . The notion that photocoagulation has some mysterious general effect on untreated areas of the retina was, perhaps unexpectedly, strengthened."23 Although the later invention of the blue/green argon laser prompted an early series of clinical studies on direct, focal coagulation of elevated new vessels on the disc, subsequent evidence from the Diabetic Retinopathy Study (DRS) adequately confirmed this concept. 24 To date, the precise mechanisms of the valuable therapeutic effects of scatter photocoagulation are far from certain, despite numerous theories related to vasogenic stimuli, levels of oxygenation, and others. (2) ". . . It would be extremely important to develop criteria for recognition of 'high risk' eyes. . . ." Data collected years later in the DRS, using the Airlie House Classification, did indeed identify such criteria. (3) In a very small sample of patients, there was an apparent benefit from photocoagulation of paramacular microaneurysms and other vascular abnormalities contributing to macular edema. Most ophthalmologists, however, did not treat nonproliferative retinopathy because they believed that most of these eyes did not get into serious trouble without treatment,zs Some 17 years later, the Early Treatment Diabetic Retinopathy Study (ETDRS) confirmed the earlier observation of photocoagulation's benefit in a large series of selected patients studied carefully with the nonbiased, prospective methodology of the randomized clinical trial. 26 (4) There was a strong suggestion that pituitary ablation helps proliferative diabetic retinopathy, but "if the current promise of 'preventive' photocoagulation proves valid, the question of the efficacy of pituitary
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ablation may become academic."23 The passage of time has validated this prediction.
TREATMENT OF DIABETIC RETINOPATHY FOLLOWING THE AIRLIE HOUSE SYMPOSIUM With the development of the argon laser photocoagulator in the 1960s, elaborate strategies were developed to use the absorption of the laser's blue/green light by hemoglobin in neovascular tissue. Attempts at focal "segmenting" of elevated new vessels (for example, with the so-called feeder-frond method) were initially promising, but, when performed in the front of the optic disc, carried substantial risks of heat-induced optic neuritis. 27 Recurrent growth also occurred. Intravitreal coagulation of new vessels elsewhere induced risks of hemorrhaging into the previously clear vitreous. Theoretical considerations notwithstanding, therefore, the argon laser became used less as a focal coagulator than as a panretinal photocoagulator, and indirect effects on untreated portions of the fundus, as initially noted with the ruby laser, assumed greater importance. Initially, the argon laser had achieved widespread acceptance because of the color of its emitted light, but it was probablY the convenience and accuracy provided by the binocular stereoscopic slit-lamp delivery system (as opposed to the direct and indirect ophthalmoscopic delivery devices that initially had been developed for the ruby laser) that ensured its success. The continuous output of the argon laser was also more convenient than the pulsed, intermittent output of the ruby laser. Nonetheless, it is tempting to speculate that ruby laser photocoagulation might still be in use, as originally performed by Aiello et al.,19 if the device had been manufactured with a slitlamp delivery system. Subsequent progress in the treatment of diabetic retinopathy has been based, in large measure, on a series of prospective, randomized, collaborative, clinical trials supported by the National Eye Institute. These studies represent landmarks in the advancement of twentieth century medicine. Participants at the Airlie House Symposium called for the performance of these studies, recognizing limitations in the state of existing clinical knowledge, and provided a standard nomenclature and fundus classification that made them possible. These studies include the DRS,24 the ETDRS,26 the Diabetic Retinopathy Vitrectomy Study (DRVS),zs and most recently the Krypton-Argon Regression of Neovascularization Study (KARNS). The DRS, begun in 1971, reported its initial results in 1976. Over 1700 patients from 15 clinical centers participated in a randomized prospective clinical trial designed to determine if photocoagulation would delay or prevent severe visual loss in patients with diabetic retinopathy. The techniques of treatment included extensive panretinal photocoagulation plus focal treatment of
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new vessels. Results were assessed by the evaluation of fundus photographs that were graded according to a modified version of the Airlie House Classification. 29 After 2 years of follow-up, it became apparent that in certain types of high-risk retinopathy the benefit of treatment in reducing the risk of severe visual loss by 50% or more outweighed the risks of treatment. These high-risk characteristics were: (I) moderate or severe new vessels on or within I disc diameter of the optic nervehead (greater than one fourth to one third disc area in extent); (2) mild new vessels on or within I disc diameter of the optic nervehead if fresh vitreous hemorrhage was present; and (3) moderate or severe new vessels elsewhere in the fundus if fresh vitreous hemorrhage was present. Data from the DRS did not show that focal treatment of new vessels on the disc or elevated new vessels elsewhere with the argon laser achieved better results than did the scatter technique with this laser. Moderate losses of visual acuity and of the peripheral field were greater in the xenon-treated group than in the argon-treated group. As a result of these observations and the convenience of the slit-lamp delivery systems, enthusiasm for the argon laser grew at the expense of the xenon arc photocoagulator, and the focal approach to new vessel segmentation became less commonly used. The value of focal photocoagulation of diabetic macular edema was assessed by the ETDRS. This study of over· 3900 patients from 22 clinical centers was initiated in 1980, and results were first reported in 1985. In addition to visual acuity, eyes were assessed by standardized grading of fundus photographs, using techniques developed by the Airlie House Symposium and the DRS. It was clearly shown by the ETDRS that focal treatment of carefully selected cases, meeting specific eligibility criteria, substantially lowered the risk of visual loss and increased the chance of visual improvement. For advanced diabetic retinopathy characterized by severe vitreous hemorrhage, the DRYS evaluated surgical results in over 600 eyes. This collaborative trial, involving 15 clinical centers, was begun in 1976 and reported its first surgical results in 1985. Yitrectomy had been developed in the early 1970s30- 33 and it filled a therapeutic gap that was obvious to participants at the Airlie House Symposium. Stages of retinopathy and of the vitreous hemorrhage were evaluated by a grading system that had its foundations in the O'Hare and Airlie House techniques. The DRYS found an apparent advantage for early vitrectomy in eyes with severe vitreous hemorrhage, in patients with type 1 diabetes. Additional data and conclusions should be forthcoming. The most recent collaborative trial, KARNS, is comparing argon laser versus krypton laser panretinal photocoagulation. The intent of this study is to determine if the wavelength of the emitted light plays a significant role in the favorable effects on treated retinas having high-risk characteristics, as defined by the DRS. The conclusion should supplement the results provided by
the initial ruby laser photocoagulation experience of Aiello et al. 19 Interesting information should be derived and may help investigators interpret the mechanism underlying the favorable influence that panretinal photocoagulation has on diabetic retinal vasculature.
HISTORIC PERSPECTIVE From the preceding paragraphs, it is apparent that the Airlie House Symposium set the stage for advances in our understanding of diabetic retinopathy over the next 18 years. Its importance can be summarized in the following ways: ( 1) It emphasized the importance of diabetes as a major cause of blindness in the United States. This encouraged the National Institutes of Health to fund collaborative protocols such as the DRS. The symposium provided firm statistics used by supporters of these collaborative trials to justify the expenditure of funds. (2) The Airlie House Symposium brought together the leaders of American, British, and Scandinavian ophthalmology, particularly those interested in retinal disease and diabetes. This fostered social, intellectual, and academic interactions. Undoubtedly, the success of this meeting stimulated these individuals to participate in multicenter collaborative trials. In this sense, the symposium was important not only in the area of diabetic retinopathy but also in other major areas of blinding retinal disease, including macular degeneration. (3) The Airlie House Symposium emphasized the importance of standardized classifications of diabetic retinopathy, such as the O'Hare and Airlie House Classifications. These systems made it possible to quantify the natural history of diabetic retinopathy and document the value of therapeutic interventions. These classifications were critical to the success of subsequent clinical trials. (4) The symposium summarized areas of consensus among leaders in ophthalmology. These areas included the need for the new classification, the importance of fluorescein angiography in evaluating retinopathy, the importance of background and proliferative retinopathies as cause of visual loss, and the poor life expectancy of diabetic patients with advanced retinopathy. (5) The following three areas of disagreement also were apparent: (I) the value (or lack thereof) of different techniques of photocoagulation; (2) the value (or lack thereof) of pituitary ablation; and (3) the value (or lack thereof) of tight metabolic control. Some of these areas of disagreement are still not settled.
CONCLUSION After 3 days of intense self-scrutiny, participants at the Airlie House Symposium came to understand where the limitations in their clinical knowledge lay. Clinical
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tenets, which formerly had been fervently believed, gave way to healthy skepticism and a desire to generate new clinical knowledge that would withstand critical inspection. Recommendations for controlled clinical trials were accepted by the ophthalmologic community in North America and led to important clinical studies that now represent the foundations for therapy of both early and advanced forms of diabetic retinopathy and other ophthalmic conditions.
REFERENCES 1. Duke-Elder S, ed. System of Ophthalmology. Vol 10. St Louis: CV Mosby Co, 1967; 410. 2. Kahn HA, Moorhead HB: Statistics on blindness in the model reporting area. DHEW Publication 1969-70; No. (NIH) 73-427. 3. Cole CH, McDonald G. Foreword. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No . 1890. Washington, DC: US Government Printing Office, 1969; v-vi. 4. Davis MD. Vitreous contraction in proliferative diabetic retinopathy. Arch Ophthalmol1965; 74:741-51. 5. Meyer-Schwickerath G. Light Coagulation. St Louis: CV Mosby Co, 1960. 6. Davis MD, Fine SL, Goldberg MF, et al. O'Hare Classification of diabetic retinopathy. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; xxi-xxiv. 7. Davis MD, Norton EWD, Myers, FL. The Airlie classification of diabetic retinopathy. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 7-22. 8. Davis MD. Summary of papers on natural history of diabetic retinopathy. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 93-5. 9. Knowles HC Jr. Summary of papers on relationship of retinopathy to metabolic control. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 129-31. 10. Caird Fl. Control of diabetes and diabetic retinopathy. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopa· thy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 107-13. 11. Phelps RL, Sakok P, Metzger BE, Jampol LM, Freinkel N. Correlation of changes in diabetic retinopathy during pregnancy with regulation of hyperglycemia. Arch Ophthalmol (in press). 12. Luft R, Olivecrona H, Sjogren B. Hypofysektomi pa manniska. Nord Med 1952; 47:351-4. 13. Poulsen JE. Recovery from retinopathy in a case of diabetes with Simmonds ' disease. Diabetes 1953; 2:7 -12. 14. McMeel JW. Summary of papers on ocular aspects of pituitary ablation. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 375-9. 15. Swe.et WH, Field RA. Production of hypopituitarism in the treatment of diabetic retinopathy. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publi-
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cation No. 1890. Washington, DC: US Government Printing Office, 1969; 722-9. 16. Bradley RF. Review of selected aspects of diabetic retinopathy. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 713-9. 17. Ok un E. Summary of papers on treatment techniques in photocoagulation. In: Goldberg MF, FinEl SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 623-9. 18. Zweng HC. The treatment of diabetic retinopathy by laser photoco· agulation. In: Goldberg MF, Fine SL, eds. Symposium on the Treat· ment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 603-5. 19. Aiello LM, Beetham WP, Balodimos MC. Ruby laser photocoagulation in treatment of diabetic proliferating retinopathy: preliminary report. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 437-63. 20. Wetzig PC. Treatment techniques of photocoagulation. (Discussion) In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 638-9. 21. Spalter HF. Photocoagulation of diabetic retinopathy (a rationale). In : Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washing· ton, DC: US Government Printing Office, 1969; 545-53. 22. Wetzig PC. Treatmenttechniques of photocoagulation. (Discussion) In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 632-3. 23. Davis MD. Summary of personal impressions of Airlie House Sympo· sium on Diabetic Retinopathy. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 718-9. 24. The Diabetic Retinopathy Study Research Group. Preliminary report on effects of photocoagulation therapy. Am J Ophthalmol 1976; 81:383-96. 25. Okun E. Photocoagulation for diabetic retinopathy. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 720-1. 26. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema, Early treatment diabetic retinopathy study report number 1. Arch Ophthalmol 1985; 103:1796-806. 27. Goldberg MF, Herbst RW. Acute complications of argon laser photocoagulation: epipapillary and peripapillary neovascularization. Arch Ophthalmol 1973; 89:311-8. 28. The Diabetic Retinopathy Vitrectomy Study Research Group. Twoyear course of Visual acuity in severe proliferative diabetic retinopathy with conventional management. Diabetic Retinopathy Vitrectomy Study (DRVS) Report # 1. Ophthalmology 1985; 92:492-502. 29. Diabetic Retinopathy Study Research Group. Report No.7: A modification of the Airlie House Classification of diabetic retinopathy. Invest Ophthalmol Vis Sci 1981; 21(2):210-26. 30. Machemer R, Perel J-M, Buettner H. A new concept for vitreous surgery: 1. Instrumentation. Am J Ophthalmol 1972; 73:1-7. 31. Machemer R. A new concept for vitreous surgery: 2. Surgical tech· niques and complications. Am J Ophthalmol1972; 74:1022-33. 32. Machemer R, Norton EWD. A new concept for vitreous surgery: 3. Indications and results. Am J Ophthalmol1972; 74:1034-56. 33. Peyman GA, Dodich NA. Experimental vitrectomy: instrumentation and surgical technique. Arch Ophthalmol 1971; 86:548-51.
Abstract: In 1968, The Airlie House Symposium evaluated the current knowledge of the natural history of diabetic retinopathy. The effects of tight metabolic control, pituitary ablation, and photocoagulation were discussed at length. Xenon arc photocoagulation was the mainstay of therapy and was usually applied focally to individual patches of new vessels. Photocoagulation of background retinopathy was rarely done. Panretinal photocoagulation was in its infancy, the ruby laser was newly introduced, there were no data on the use of the argon laser, and automated vitrectomy had not been introduced. Participants in the symposium set the stage for the acquisition of valid clinical data from which important therapeutic conclusions have subsequently been drawn by (1) summarizing the areas of consensus and disagreement, (2) devising a standard classification of diabetic retinopathy, and (3) proposing controlled clinical trials for unanswered questions. [Key words: Airlie House Symposium, diabetic retinopathy, laser, metabolic control, photocoagulation, pituitary ablation, xenon arc.] Ophthalmology 94:741-746, 1987
Diabetic retinopathy, described by Duke-Elder as "one of the major tragedies of ophthalmology in our present generation,"! had become a public health problem of major proportions by the mid-1960s. 2 Improved medical care had increased the life span of large numbers of diabetic patients, thus permitting the occurrence of those diabetic complications, including retinopathy, that required chronicity of the underlying disease pro-
From the Department of Ophthalmology,* Eye and Ear Infirmary, Univer· sity of Illinois College of Medicine at Chicago, and Northwestem Univer· sity Medical School,t Chicago. Supported in part by training grant 7038 and core grant 1792 from the National Eye Institute, Bethesda, Maryland, and by unrestricted research grants from Research to Prevent Blindness, Inc., New York. Reprint request to Morton F. Goldberg, MD, Department of Ophthalmol· ogy, Eye and Ear Infirmary, University of Illinois College of Medicine at Chicago, 1855 West Taylor Street, Chicago, IL 60612.
cesses. A substantial rate of blindness was the distressing result. The pathogenesis of the vision-threatening events in diabetic retinopathy and its natural course were incompletely understood, a clear-cut distinction between nonproliferative and proliferative types of retinopathy was not widely appreciated, and the forms of retinopathy having particularly poor prognoses ("high-risk characteristics") were not well identified. Therapy for diabetic retinopathy was extremely difficult to assess because of the disease's variable course, even without treatment. Spontaneous improvement occurred unpredictably in a small but definite proportion of patients. Without a generally accepted classification of the disease and without a standard nomenclature, it was usually impossible to compare the results of any selected treatment from one group of investigators with those from any others. For the same reasons, comparability of cases before treatment by different techniques 741
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could not be assessed reliably. Therapeutic endpoints and techniques for their measurement were not well defined. Also, observations obtained in a controlled, nonbiased manner were unavailable. Against this backdrop of incomplete basic knowledge were several unproved therapeutic modalities, many of which had staunch supporters despite inherent risks to vision (for example, from xenon arc photocoagulation) and to life itself (for example, from pituitary ablation). Other therapeutic approaches included x-irradiation of the retina, dietary restriction of fat, induction of glaucoma by topical use of corticosteroids, and administration of vitamins C and Bi2 , clofibrate (Atromid), paraaminosalicyclic acid, anticoagulants, and testosterone. Supporters of the Airlie House Symposium on the Treatment of Diabetic Retinopathy hoped it would "provide a framework for future cooperative studies seeking to elucidate the natural course of the disease and the effects of pituitary ablation and photocoagulation,"3 because these two therapeutic approaches appeared to have far more potential than any of the others.
HISTORY OF THE AIRLIE HOUSE SYMPOSIUM A spate of publications on diabetic retinopathy appeared in the 1950s and 1960s. They included trypsin digestion studies of postmortem human retinas, biomicroscopic confirmation of vitreous contraction and its effect on adherent neovascularization,4 isolated case reports on naturally occurring pituitary insufficiency, and the English translation of Meyer-Schwickerath's book on photocoagulation. 5 The development of fluorescein angiography in the early to mid-1960s made it possible to visualize, describe, and, to some extent, quantitate different pathologic processes in diabetic retinopathy, including capillary closure, transudation, and neovascularization. The abnormal vascular wall received most of the pathogenetic emphasis, but abnormalities in the formed and unformed elements of the blood also garnered attention. The increasing availability of the fundus cameras and the use of color photography as well as angiography made it possible for a variety of classification schemes to be promulgated in England, Europe, and the United States. Organizers of the Airlie House Symposium recognized that disparate views of pathogenesis and therapy were ardently held by specialists from several disciplines working on different continents and using different techniques and terminologies. Their clinical results involved a variety of treatment methods including enhanced metabolic control, a focal xenon arc photocoagulation, "spray" or "random" ruby laser photocoagulation, pituitary stalk sectioning, surgical extirpation of the entire pituitary, irradiation of the pituitary, surgical destruction of only the anterior portion of the pituitary, and many others. Despite the plethora of reports and the thousands of patients undergoing therapy around the world, clinical
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results could not easily be assessed without a common vocabulary, standard descriptive techniques, comparable formats for reporting results, and minimization of observer bias. In response to the simple question, "What's the proper treatment for diabetic retinopathy?" posed by a recent medical school graduate (S. L. Fine), a recent ophthalmology trainee (MFG) responded, "No one knows for sure." These organizers of the Airlie House Symposium, therefore resolved to convene, for the first time, over 50 specialists from around the world, representing relevant scientific disciplines, including epidemiology, diabetology, neurosurgery, and ophthalmology. The meeting was held in a conference center (The Airlie House) located in a rural, bucolic setting, far from urban and other distractions. Opportunity for intense intellectual discussions was thereby maximized. In preparation for the meeting, at which participants would be expected to review their clinical results, a preliminary classification of diabetic retinopathy was developed (the so-called O'Hare Classification6 ) and was distributed to participants before the meeting. Manuscripts and data were then prepared within a reasonably similar framework and were also distributed to participants in advance. Discussions at the meeting were therefore more informative, provocative, and insightful than is often the case without proper prior preparation.
CONTENT OF THE AIRLIE HOUSE SYMPOSIUM Major areas of interest included (1) classification of diabetic retinopathy, (2) natural history and visual prognosis of diabetic retinopathy, (3) relationship of retinopathy to metabolic control, (4) pituitary ablation, and (5) photocoagulation. A formal summary of each area was provided by a designated expert, followed by a general discussion from a panelist who was experienced in the specific topic under review. At the end of a 3-day discussion, newly integrated views were presented in a series of valuable epilogues. The result was a book exceeding 900 pages, with data from over 2000 patients collected by more than 25 groups of specialized investigators. The issue of a standard classification of diabetic retinopathy was deemed important because valid therapeutic conclusions could still not be drawn from over 1200 pituitary ablations and more than 1600 photocoagulations that had been performed on diabetic patients during the previous 10 years. Standard photographs, photographic fields, and verbal descriptions of grading parameters were developed, accepted and published. The fundamental dichotomy between nonproliferative and proliferative forms of diabetic retinopathy was emphasized. The O'Hare Classification was revised and renamed the Airlie House Classification of Diabetic Retinopathy. Its proponents "hoped that prospective studies will be undertaken using this classification, and that eventually sufficient valid data will accrue to establish the effective-
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ness of various therapeutic measures advocated for diabetic retinopathy and clarify indications for their use.,,7 These hopes have subsequently been fulfilled. Important key elements in this natural history of diabetic retinopathy were summarized as follows 8: capillary closure is an important early change in diabetic retinopathy and precedes formation of arteriolar-venular shunts (the opposite course of events had been postulated previously); newly formed vessels go through a cycle of proliferation and regression; and vision is severely threatened when vitreous or fibrous tissue adherent to neovascularization undergoes contraction (because vitreous hemorrhage or tractional detachment of the macula can occur). Regarding the effect of metabolic control in diabetic retinopathy, over 400 publications were summarized. About one half of these authors concluded that a positive relationship of some sort existed, whereas about one third believed there were insufficient data for a firm conclusion. The remainder believed that the relationship, if any, was so complex that it would defy easy formulation. 9 Those accepting the idea of a positive relationship emphasized the correlation between degree of glycosuria and presence of retinopathy, and they pointed out that heavy glycosuria in the first years of the diabetic process was more closely related to the development of retinopathy than when it occurred later in the course of the diabetes. Once established, retinal lesions did not appear to be influenced in any important way by the degree of glycosuria. IO Subsequent studies, reported only recently, with insulin pumps and with enhanced diabetic management (during pregnancy, for example) permit different interpretations. II Because of major difficulties in understanding the effect of different types (and amounts) of metabolic control on diabetic retinopathy, it was recommended that a life-table analysis of prospectively acquired data be accomplished. 9 Twenty chapters in the published proceedings of the symposium were devoted to pituitary ablation. This major assault on the body's homeostasis was initially adopted in many parts ofthe world because of anecdotal reports of amelioration of diabetic retinopathy, which appeared about 18 years before the Airlie House Symposium.1 2,13 Eighteen years after the Airlie House Symposium, pituitary ablation is rarely, if ever, used in the treatment of diabetic retinopathy. There seemed little doubt, however, at the time of the symposium, that adequate pituitary ablation (by any of a variety of techniques) could reduce the severity of retinal hemorrhages, vascular dilation, neovascularization, and clouding of the vitreous. Retinal exudates and fibrous proliferations apparently did not respond. 14 Pituitary ablation was performed by various techniques, including transfrontal craniotomy, stalk section, radiofrequency coagulation, cryocoagulation, transsphenoidal removal of the anterior portion of the pituitary, proton beam external irradiation, implantation of radioactive yttrium, and others. Data from 708 patients collected by 11 neurosurgical groups were presented. Retinopathy was arrested in about 75% of patients,
whereas it progressed in about 25% of patients. It was concluded that "although future progress in the treatment of diabetic retinopathy will hopefully alleviate the necessity for pituitary ablation, it still has a place in the treatment of this disease."14 Indeed, some of the participants concluded at the end of the symposium that pituitary ablation should be considered the primary treatment for diabetic retinopathy and that photocoagulation should be used for supplemental purposes.15 Others retained some skepticism and, although agreeing that it favorably altered the course of nonproliferative retinopathy, believed it should be considered experimental. 16 Subsequent advances with laser photocoagulation of the retina have supplanted pituitary ablation, which is now primarily of interest because of its historic role and because of its interesting but incompletely understood involutionary effects on the diabetic retinal vasculature. Photocoagulation results came from several groups of ophthalmologists with data from over 1600 eyes. This large number of treated eyes was testimony to the rapid propagation of the photocoagulation technique. In his seminal book on photocoagulation, which appeared in English in 1960, Meyer-Schwickerath devoted only one sentence to diabetic retinopathy: "Four cases in the late proliferative stage were treated with coagulation without any effect, but in a case presenting microaneurysms and exudates partial disappearance of the latter was achieved by coagulation of the microaneurysms."5 Eleven groups of investigators reported results from xenon arc photocoagulation; two had used the ruby laser. All but one emphasized the focal aspects of the treatment technique (i.e., direct obliteration of abnormal blood vessels). Indeed, there was "essential agreement that photocoagulation lesions (even those produced by the ruby laser) be directed to the areas of visible neovascularization,"17 with the exception of disc neovascularization, which was generally thought to be untreatable. However, experts continued to believe that "the usefulness of. . . photocoagulation in the treatment of diabetic retinopathy is, at this writing, uncertain."18 A preliminary report on the "spray" or "random" pattern of ruby laser photocoagulation (subsequently known as "scatter" or "panretinal photocoagulation") included short-term results on 214 patients!9 Approximately 600 to 800 fundus bums were created in an attempt to mimic naturally occurring retinal vascular involution, such as that seen after optic atrophy associated with glaucoma, widespread chorioretinitis, carotid insufficiency, etc. Focal treatment was simultaneously directed to flat patches of neovascularization, but eyes with elevated new vessels were not treated. 20 The red color of the light emitted by a ruby laser could not close retinal neovascularization via direct local treatment, and ophthalmologists awaited the later development of the argon laser in hopes of being able to obliterate elevated new vessels focally-both at the optic nervehead and elsewhere-because of the blue/green output from this new device. 21 The concept of an indirect favorable effect of spray photocoagulation on untreated portions of the fundus was not accepted by many ophthalmolo743
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gists,because current dogma mandated focal obliteration of the presumably dangerous neovascular tissue, and there was not extant reason to believe that this logical, mechanistic approach was inferior to any other therapeutic philosophy. Despite enthusiasm for xenon arc and ruby laser photocoagulation on the part of some therapists, others still believed that photocoagulation was "clearly experimental."16 For eyes with extensive neovascular and fibrous proliferations associated with vitreous hemorrhage, some ophthalmologists recommended scleral buckling or scleral resection because "we really have nothing more to offer. ,,22 The development of pars plana vitrectomy in subsequent years (the early 1970s) would markedly alter this conclusion. In evaluating the conclusions of the Airlie House participants, Davis noted that". . . to the disappointment of all, no clear-cut consensus regarding pituitary ablation and photocoagulation has resulted from the conference. ,,23 He was ". . . most pleasantly surprised, however, to report that the outlook for general acceptance of the classification. . . seems very good. If this classification does indeed find wide acceptance, this alone would be ample justification for all the time and effort that went into the symposium." Several other sUbjective impressions were advanced, as follows: (1) ". . . The notion that photocoagulation has some mysterious general effect on untreated areas of the retina was, perhaps unexpectedly, strengthened."23 Although the later invention of the blue/green argon laser prompted an early series of clinical studies on direct, focal coagulation of elevated new vessels on the disc, subsequent evidence from the Diabetic Retinopathy Study (DRS) adequately confirmed this concept. 24 To date, the precise mechanisms of the valuable therapeutic effects of scatter photocoagulation are far from certain, despite numerous theories related to vasogenic stimuli, levels of oxygenation, and others. (2) ". . . It would be extremely important to develop criteria for recognition of 'high risk' eyes. . . ." Data collected years later in the DRS, using the Airlie House Classification, did indeed identify such criteria. (3) In a very small sample of patients, there was an apparent benefit from photocoagulation of paramacular microaneurysms and other vascular abnormalities contributing to macular edema. Most ophthalmologists, however, did not treat nonproliferative retinopathy because they believed that most of these eyes did not get into serious trouble without treatment,zs Some 17 years later, the Early Treatment Diabetic Retinopathy Study (ETDRS) confirmed the earlier observation of photocoagulation's benefit in a large series of selected patients studied carefully with the nonbiased, prospective methodology of the randomized clinical trial. 26 (4) There was a strong suggestion that pituitary ablation helps proliferative diabetic retinopathy, but "if the current promise of 'preventive' photocoagulation proves valid, the question of the efficacy of pituitary
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ablation may become academic."23 The passage of time has validated this prediction.
TREATMENT OF DIABETIC RETINOPATHY FOLLOWING THE AIRLIE HOUSE SYMPOSIUM With the development of the argon laser photocoagulator in the 1960s, elaborate strategies were developed to use the absorption of the laser's blue/green light by hemoglobin in neovascular tissue. Attempts at focal "segmenting" of elevated new vessels (for example, with the so-called feeder-frond method) were initially promising, but, when performed in the front of the optic disc, carried substantial risks of heat-induced optic neuritis. 27 Recurrent growth also occurred. Intravitreal coagulation of new vessels elsewhere induced risks of hemorrhaging into the previously clear vitreous. Theoretical considerations notwithstanding, therefore, the argon laser became used less as a focal coagulator than as a panretinal photocoagulator, and indirect effects on untreated portions of the fundus, as initially noted with the ruby laser, assumed greater importance. Initially, the argon laser had achieved widespread acceptance because of the color of its emitted light, but it was probablY the convenience and accuracy provided by the binocular stereoscopic slit-lamp delivery system (as opposed to the direct and indirect ophthalmoscopic delivery devices that initially had been developed for the ruby laser) that ensured its success. The continuous output of the argon laser was also more convenient than the pulsed, intermittent output of the ruby laser. Nonetheless, it is tempting to speculate that ruby laser photocoagulation might still be in use, as originally performed by Aiello et al.,19 if the device had been manufactured with a slitlamp delivery system. Subsequent progress in the treatment of diabetic retinopathy has been based, in large measure, on a series of prospective, randomized, collaborative, clinical trials supported by the National Eye Institute. These studies represent landmarks in the advancement of twentieth century medicine. Participants at the Airlie House Symposium called for the performance of these studies, recognizing limitations in the state of existing clinical knowledge, and provided a standard nomenclature and fundus classification that made them possible. These studies include the DRS,24 the ETDRS,26 the Diabetic Retinopathy Vitrectomy Study (DRVS),zs and most recently the Krypton-Argon Regression of Neovascularization Study (KARNS). The DRS, begun in 1971, reported its initial results in 1976. Over 1700 patients from 15 clinical centers participated in a randomized prospective clinical trial designed to determine if photocoagulation would delay or prevent severe visual loss in patients with diabetic retinopathy. The techniques of treatment included extensive panretinal photocoagulation plus focal treatment of
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new vessels. Results were assessed by the evaluation of fundus photographs that were graded according to a modified version of the Airlie House Classification. 29 After 2 years of follow-up, it became apparent that in certain types of high-risk retinopathy the benefit of treatment in reducing the risk of severe visual loss by 50% or more outweighed the risks of treatment. These high-risk characteristics were: (I) moderate or severe new vessels on or within I disc diameter of the optic nervehead (greater than one fourth to one third disc area in extent); (2) mild new vessels on or within I disc diameter of the optic nervehead if fresh vitreous hemorrhage was present; and (3) moderate or severe new vessels elsewhere in the fundus if fresh vitreous hemorrhage was present. Data from the DRS did not show that focal treatment of new vessels on the disc or elevated new vessels elsewhere with the argon laser achieved better results than did the scatter technique with this laser. Moderate losses of visual acuity and of the peripheral field were greater in the xenon-treated group than in the argon-treated group. As a result of these observations and the convenience of the slit-lamp delivery systems, enthusiasm for the argon laser grew at the expense of the xenon arc photocoagulator, and the focal approach to new vessel segmentation became less commonly used. The value of focal photocoagulation of diabetic macular edema was assessed by the ETDRS. This study of over· 3900 patients from 22 clinical centers was initiated in 1980, and results were first reported in 1985. In addition to visual acuity, eyes were assessed by standardized grading of fundus photographs, using techniques developed by the Airlie House Symposium and the DRS. It was clearly shown by the ETDRS that focal treatment of carefully selected cases, meeting specific eligibility criteria, substantially lowered the risk of visual loss and increased the chance of visual improvement. For advanced diabetic retinopathy characterized by severe vitreous hemorrhage, the DRYS evaluated surgical results in over 600 eyes. This collaborative trial, involving 15 clinical centers, was begun in 1976 and reported its first surgical results in 1985. Yitrectomy had been developed in the early 1970s30- 33 and it filled a therapeutic gap that was obvious to participants at the Airlie House Symposium. Stages of retinopathy and of the vitreous hemorrhage were evaluated by a grading system that had its foundations in the O'Hare and Airlie House techniques. The DRYS found an apparent advantage for early vitrectomy in eyes with severe vitreous hemorrhage, in patients with type 1 diabetes. Additional data and conclusions should be forthcoming. The most recent collaborative trial, KARNS, is comparing argon laser versus krypton laser panretinal photocoagulation. The intent of this study is to determine if the wavelength of the emitted light plays a significant role in the favorable effects on treated retinas having high-risk characteristics, as defined by the DRS. The conclusion should supplement the results provided by
the initial ruby laser photocoagulation experience of Aiello et al. 19 Interesting information should be derived and may help investigators interpret the mechanism underlying the favorable influence that panretinal photocoagulation has on diabetic retinal vasculature.
HISTORIC PERSPECTIVE From the preceding paragraphs, it is apparent that the Airlie House Symposium set the stage for advances in our understanding of diabetic retinopathy over the next 18 years. Its importance can be summarized in the following ways: ( 1) It emphasized the importance of diabetes as a major cause of blindness in the United States. This encouraged the National Institutes of Health to fund collaborative protocols such as the DRS. The symposium provided firm statistics used by supporters of these collaborative trials to justify the expenditure of funds. (2) The Airlie House Symposium brought together the leaders of American, British, and Scandinavian ophthalmology, particularly those interested in retinal disease and diabetes. This fostered social, intellectual, and academic interactions. Undoubtedly, the success of this meeting stimulated these individuals to participate in multicenter collaborative trials. In this sense, the symposium was important not only in the area of diabetic retinopathy but also in other major areas of blinding retinal disease, including macular degeneration. (3) The Airlie House Symposium emphasized the importance of standardized classifications of diabetic retinopathy, such as the O'Hare and Airlie House Classifications. These systems made it possible to quantify the natural history of diabetic retinopathy and document the value of therapeutic interventions. These classifications were critical to the success of subsequent clinical trials. (4) The symposium summarized areas of consensus among leaders in ophthalmology. These areas included the need for the new classification, the importance of fluorescein angiography in evaluating retinopathy, the importance of background and proliferative retinopathies as cause of visual loss, and the poor life expectancy of diabetic patients with advanced retinopathy. (5) The following three areas of disagreement also were apparent: (I) the value (or lack thereof) of different techniques of photocoagulation; (2) the value (or lack thereof) of pituitary ablation; and (3) the value (or lack thereof) of tight metabolic control. Some of these areas of disagreement are still not settled.
CONCLUSION After 3 days of intense self-scrutiny, participants at the Airlie House Symposium came to understand where the limitations in their clinical knowledge lay. Clinical
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tenets, which formerly had been fervently believed, gave way to healthy skepticism and a desire to generate new clinical knowledge that would withstand critical inspection. Recommendations for controlled clinical trials were accepted by the ophthalmologic community in North America and led to important clinical studies that now represent the foundations for therapy of both early and advanced forms of diabetic retinopathy and other ophthalmic conditions.
REFERENCES 1. Duke-Elder S, ed. System of Ophthalmology. Vol 10. St Louis: CV Mosby Co, 1967; 410. 2. Kahn HA, Moorhead HB: Statistics on blindness in the model reporting area. DHEW Publication 1969-70; No. (NIH) 73-427. 3. Cole CH, McDonald G. Foreword. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No . 1890. Washington, DC: US Government Printing Office, 1969; v-vi. 4. Davis MD. Vitreous contraction in proliferative diabetic retinopathy. Arch Ophthalmol1965; 74:741-51. 5. Meyer-Schwickerath G. Light Coagulation. St Louis: CV Mosby Co, 1960. 6. Davis MD, Fine SL, Goldberg MF, et al. O'Hare Classification of diabetic retinopathy. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; xxi-xxiv. 7. Davis MD, Norton EWD, Myers, FL. The Airlie classification of diabetic retinopathy. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 7-22. 8. Davis MD. Summary of papers on natural history of diabetic retinopathy. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 93-5. 9. Knowles HC Jr. Summary of papers on relationship of retinopathy to metabolic control. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 129-31. 10. Caird Fl. Control of diabetes and diabetic retinopathy. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopa· thy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 107-13. 11. Phelps RL, Sakok P, Metzger BE, Jampol LM, Freinkel N. Correlation of changes in diabetic retinopathy during pregnancy with regulation of hyperglycemia. Arch Ophthalmol (in press). 12. Luft R, Olivecrona H, Sjogren B. Hypofysektomi pa manniska. Nord Med 1952; 47:351-4. 13. Poulsen JE. Recovery from retinopathy in a case of diabetes with Simmonds ' disease. Diabetes 1953; 2:7 -12. 14. McMeel JW. Summary of papers on ocular aspects of pituitary ablation. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 375-9. 15. Swe.et WH, Field RA. Production of hypopituitarism in the treatment of diabetic retinopathy. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publi-
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cation No. 1890. Washington, DC: US Government Printing Office, 1969; 722-9. 16. Bradley RF. Review of selected aspects of diabetic retinopathy. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 713-9. 17. Ok un E. Summary of papers on treatment techniques in photocoagulation. In: Goldberg MF, FinEl SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 623-9. 18. Zweng HC. The treatment of diabetic retinopathy by laser photoco· agulation. In: Goldberg MF, Fine SL, eds. Symposium on the Treat· ment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 603-5. 19. Aiello LM, Beetham WP, Balodimos MC. Ruby laser photocoagulation in treatment of diabetic proliferating retinopathy: preliminary report. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 437-63. 20. Wetzig PC. Treatment techniques of photocoagulation. (Discussion) In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 638-9. 21. Spalter HF. Photocoagulation of diabetic retinopathy (a rationale). In : Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washing· ton, DC: US Government Printing Office, 1969; 545-53. 22. Wetzig PC. Treatmenttechniques of photocoagulation. (Discussion) In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 632-3. 23. Davis MD. Summary of personal impressions of Airlie House Sympo· sium on Diabetic Retinopathy. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 718-9. 24. The Diabetic Retinopathy Study Research Group. Preliminary report on effects of photocoagulation therapy. Am J Ophthalmol 1976; 81:383-96. 25. Okun E. Photocoagulation for diabetic retinopathy. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890. Washington, DC: US Government Printing Office, 1969; 720-1. 26. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema, Early treatment diabetic retinopathy study report number 1. Arch Ophthalmol 1985; 103:1796-806. 27. Goldberg MF, Herbst RW. Acute complications of argon laser photocoagulation: epipapillary and peripapillary neovascularization. Arch Ophthalmol 1973; 89:311-8. 28. The Diabetic Retinopathy Vitrectomy Study Research Group. Twoyear course of Visual acuity in severe proliferative diabetic retinopathy with conventional management. Diabetic Retinopathy Vitrectomy Study (DRVS) Report # 1. Ophthalmology 1985; 92:492-502. 29. Diabetic Retinopathy Study Research Group. Report No.7: A modification of the Airlie House Classification of diabetic retinopathy. Invest Ophthalmol Vis Sci 1981; 21(2):210-26. 30. Machemer R, Perel J-M, Buettner H. A new concept for vitreous surgery: 1. Instrumentation. Am J Ophthalmol 1972; 73:1-7. 31. Machemer R. A new concept for vitreous surgery: 2. Surgical tech· niques and complications. Am J Ophthalmol1972; 74:1022-33. 32. Machemer R, Norton EWD. A new concept for vitreous surgery: 3. Indications and results. Am J Ophthalmol1972; 74:1034-56. 33. Peyman GA, Dodich NA. Experimental vitrectomy: instrumentation and surgical technique. Arch Ophthalmol 1971; 86:548-51.