Diabetic retinopathy: Current concepts of evaluation and treatment

12 Diabetic Retinopathy: Current Concepts of Evaluation and Treatment ROBERT N. FRANK

EPIDEMIOLOGY

Most studies of the prevalence of diabetic retinopathy in groups of insulin dependent diabetic subjects, with few exceptions (Brooser et aI, 1975; Malone et aI, 1977), show an extremely small number of cases within the first five years after onset of the systemic disease, and a rising prevalence thereafter (Kornerup, 1955; White, 1960; Larsson and Sterky, 1962; Knowles et aI, 1965; Frank et aI, 1980, 1982; Palmberg et aI, 1981; Klein et aI, 1984b). About 60-80% of patients with insulin dependent diabetes show some evidence of retinopathy, by standardized fundus photography and/or fluorescein angiography, after 10 years of their disease, and 80-100% after 20 years (Frank et aI, 1980, 1982; Palmberg et aI, 1981; Klein et aI, 1984b). While retinopathy in many will remain mild, a substantial proportion of those with insulin dependent diabetes carry a significant risk of severe vision loss. A large, population-based study, which surveyed over 1000 insulin dependent diabetics out of a total population of over 10 000 diabetics in the state of Wisconsin, USA, found a 50% prevalence of the vision-threatening proliferative form of retinopathy after 15 years of the disease (Klein et aI, 1984b). The prevalence of retinopathy is much lower in individuals with non-insulin dependent diabetes, but since this is by far the most common form of the disease, the actual number of affected individuals in this group is considerably greater than among those with insulin dependent diabetes. About 50% of those with non-insulin dependent diabetes will have retinopathy after a disease duration of 15 years, and about 20% will have proliferative retinopathy (Klein et aI, 1984c). Since about 2% of the population of the USA has diabetes (Bennett, 1976), and the prevalence in other Western countries is probably similar, one can readily understand that diabetic retinopathy is a major cause of blindness and visual disability, at least in the Western world. Some twenty years ago, Caird et al (1968) estimated that 2-7% of all diabetics would ultimately become blind, while more recently, in a long-term, populationClinics in Endocrinology and Metabolism-Vol. 15, No.4, November 1986

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based study in Rochester, Minnesota, USA, Dwyer et al (1985) found a cumulative incidence of bilateral blindness due to diabetic retinopathy of 8.2% after 20 years of diabetes. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy, 12% of insulin dependent diabetics were legally blind after 30 years of diabetes, by comparison with about 5% of non-insulin dependent diabetics after the same duration (Klein et al, 1984a). (We refer here to legal blindness, which means best-corrected visual acuity of 20/200 (equivalent to 6160 or 0.1, depending on the notation used) or less in each eye.) The 'Model Reporting Area' survey, conducted in the USA in 1970, compiled statistics on blindness from those 16 of the 50 states that had developed a uniform set of procedures and definitions for reporting causes of blindness (Kahn and Moorhead, 1973). Although a bias of ascertainment may exist in this survey because of the method of data collection employed, it remains the best available for assessing the relative frequency of various causes of blindness. It includes diabetic retinopathy among the four major causes of blindness in the USA, along with cataract, glaucoma and age-related (senile) macular degeneration. However, new therapeutic modalities of demonstrated efficacy have become widely used against diabetic retinopathy since 1970, and therefore present-day statistics regarding diabetic retinopathy as a cause of blindness may be quite different. The severity of the retinopathy not only influences the individual's visual prognosis, but also implies a reduced longevity. Davis et al (1979) followed for over seven years a population of 699 patients with diabetes diagnosed before age 50. By comparison with life-table data for Americans of comparable age, sex, race and calendar period of observation, individuals in the study population with no retinopathy, or with minimal retinopathy (defined as microaneurysms only) had no excess mortality during the follow-up period. Those with 'moderate' background retinopathy had about 25% excess mortality over this period, while those with proliferative retinopathy had more than 50% excess mortality over the seven years.

CLINICAL FINDINGS Background diabetic retinopathy The first clinically recognizable abnormality of diabetic retinopathy is the microaneurysm. This is a dilation of a retinal capillary, which appears as a tiny, red dot (Figure lA), often barely recognizable to the observer using a direct ophthalmoscope. Microaneurysms are often ophthalmoscopically indistinguishable from small dot haemorrhages, and when these two types of lesions alone are present in minimal to moderate numbers, the condition is termed 'background' diabetic retinopathy. Microaneurysms can usually be distinguished from small haemorrhages by intravenous fluorescein angiography. In this technique, a bolus of sodium fluorescein in aqueous solution is injected rapidly into an antecubital vein, and a series of rapid-sequence photographs is taken with an ophthalmic fundus camera.

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The ocular fundus is illuminated with a blue flash, and a green interference filler is placed as a 'barrier' in front of the camera film, to permit transmission only of the green fluorescence from the circulating dye. A frame from a normal fluorescein angiogram is shown in Figur e IB, and frames from angiograms of diabetic patients, showing typical fluorescent rnicroaneurysms, appear in Figures l C and 10. Angiographically, patent microaneurysms appear as tiny, white dots, while thr ombosed microaneurysms, because they do not fill with dye, cannot be distinguished from dot haemorrhages. In later frames of the photographic series, fluorescein dye may be seen leaking from the aneurysms, giving them a blurred appearance (Figure IE). This is evidence of breakdown of the blood-retinal barrier, one of the earliest functional abnormalities of diabetic retinopathy. One of the most active, and controversial, areas of research in diabetic retinopathy at present is that of vitreous [luorophotometry (Cunha-Vaz et al, 1975). In this technique, an hour is permitted to elapse following intravenous injection of sodium fluorescein. Then, fluorescence is measured from various regions of the subject's vitreous cavity, using an ophthalmic slit lamp equipped with a sensitive photomulliplier. Two groups of investigators have claimed that in newly diabetic humans and animals, before clinical or angiographic evidence of retinopathy is present, increased vitreous fluorescence may be detected by this method, indicating breakdown of the blood-retinal barrier. The barrier defect may be corrected by restoring normoglycaemia, either by insulin administration or by pancreatic transplantation (Waltman et al, 1978a, b, 1979; Cunha-Vaz et al , 1978; Jones et al, 1979; Krupin et al, 1979). Other workers have not been able to reproduce these results, however (Rhie et al, 1980; Klein et al, 1980; Prager et al, 1983). Nevertheless, the method remains an intriguing method for exploring possible early functional defects in the retinal circulation in diabetes mellitus (Frank, 1985). Controversy exists as to the relative sensitivity of ophthalmoscopy, standardized ocular fundus photography, and fluorescein angiography for detecting the earliest lesions of diabetic retinopathy. Ophthalmoscopic examination of subjects, with their pupils dilated, permits the examiner to evaluate the entire retina, but because the procedure is of necessity brief, small or infrequent lesions may be overlooked. Retinal photography, using stereoscopic technique, produces a 'hard copy' image that may be studied at leisure, but it is usually possible to photograph only a small area of the posterior fundus. In at least one study (Palmberg et nl, 1981), the sensitivity of detection of diabetic retinopathy was found to be substantially increased using standard fundus photography, by contrast with ophthalmoscopic observation alone. Although experienced observers may disagree in their interpretation of some retinal lesions, another study, in which multiple observers evaluated photographs of diabetic subjects and non-diabetic controls, established that the specificity and sensitivity of the photographic method for diagnosis of diabetic retinopathy was high (Frank et al, 1980, 1982). More disagreement exists regarding the value of fluorescein angiography for detection of the earliest lesions of diabetic

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Flgure I. (A) A view of a region nasal to the left optic nerve head of a 55-year-old diabetic woman, showing multiple microaneurysms, dot and blot haemorrhages. This is an example of 'background' diabetic retinopathy.

Figure I. (8) A frame from a fluorescein angiogram of the optic nerve head and right macular region of a normal 16-year-old girl. Note that the capillaries surrounding the fovea (which is avascular and appears as a dark hole in the photograph) are well defined by this techn ique, particularly in young people with clear ocular media . The numbers to the left of the photograph indicate the number of seconds since the beginning of the injection sequence.

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Figure I. (C) A frame from a fluorescein angiogram of the patient whose retina was illustrated in Figure lA. The same region is shown angiographically. Note that the microaneurysms appear as tiny, white fluorescent dots, while the haemorrhages appear dark, since they block the fluorescence from the underlying choroidal vessels.

Figure I. (D) A frame from a fluorescein angiogram of a 25-year-old diabetic woman, showing scattered microaneurysms in the peri foveal capillary zone. Compare with Figure lB.

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Figure 1. (E) A later frame from the same angiographic sequence. Note the blurred appearance of the fluorescence surrounding the microaneurysms. This appearance is produced by dye leaking from the capillaries. indicating breakdown of the blood-retinal barrier.

retinopathy. Some studies (Brooser et al, 1975; Malone et al, 1977) have suggested that the sensitivity for detecting retinopathy in young subjects by angiography was as much as fivefold greater than by colour photography. By contrast, Palmberg et al (1981) found no difference in the sensitivity of the two methods. Our own experience has been closer to the results of Palmberg et al.We find an approximately 1.5-fold greater sensitivity for angiography over photography (Frank et al, 1980, 1982). However, since the difference in sensitivity exists only for the earliest stage of the disease, when therapeutic intervention is currently not considered, fluorescein angiography seems to have less value as a routine screening procedure than as a tool for epidemiological research, where detection of all cases in a population is the goal. Even here, one major recent investigation used retinal photography only (Klein et ai, 1984b), and reported a prevalence of retinopathy in insulin dependent diabetic subjects not less than that reported in similar studies in which fluorescein angiography was also used. Preproliferative changes

When microaneurysms and 'dot and blot' haemorrhages have become moderately profuse, the eye is considered to have an elevated risk of developing proliferative retinopathy (Figure 2A). Other 'preproliferative' changes include 'cotton 1V001 spots', venous dilation and irregularity of calibre and intraretinal microvascular abnormalities (IRMA) (Figures 2B, 2C).

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Figure 2. Preproliferative changes. (A) Extensive intraretinal 'blot' haemorrhages temporal to the macula of the left eye in a 62-year-old diabetic man. Fluorescein angiography of regions of the fundi with such haemorrhages usually show widespread capillary non-perfusion (which can usually be differentiated from the blocked fluorescence caused by the haemorrhages themselves). Extensive retinal capillary non-perfusion is felt to predispose to neovascularization by enhancing production of the hypothetical 'angiogenesis factor'.

Figure 2. Preproliferative changes. (B) A 25-year-old diabetic woman with multiple preproliferative lesions. These include marked tortuosity (note the 'hairpin loop', indicated by the filled arrowhead) and pronounced irregularity of the veins; cotton wool spots (C), and IRMA (I).

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Figure 2. Preproliferative changes. (C) Multiple cotton wool spots (C), blot haemorrhages, and IRMA (I) in a 25-year-old diabetic man.

Of these lesions, two merit further comment. Cotton wool spots, sometimes inappropriately called 'soft exudates', or 'cytoid bodies', are small zones of intracellular oedema within the retinal nerve fibre layer, in the region immediately surrounding a small, occluded retinal arteriole. The resulting non-perfused retina is thought to liberate a stimulus to neovascularization, resulting from the tissue hypoxia (Henkind, 1978). Even more extensive areas of retinal vascular non-perfusion are also held to be 'preproliferative' lesions. Despite their extent, these are not always easily recognized ophthalmoscopically, although the presence of narrow, white arterioles ('silver wire' abnormalities) or extensive areas of blot haemorrhage are useful clues (Figure 3A, B). Fluorescein angiography is usually the best method for detecting the presence, and degree, of retinal vascular non-perfusion, since, with an angiogram of good photographic quality, the non-perfused regions are easily distinguished as black, empty spaces surrounded by brightly fluorescent vessels (Figure 3B, arrowheads). The 'hypoxia theory' of retinal neovascularization has two major exceptions. First, neovascularization rarely occurs following occlusion of the central retinal artery or of a major retinal arteriole. In such cases, large regions of the inner retina suffer hypoxic death, and because their metabolism has ceased entirely, they probably no longer produce the hypothetical 'angiogenic factor'. Second, regions of retinal vascular non-perfusion are rarely seen surrounding the optic nerve head in the presence of neovascularization arising from that structure. No explanation for this obvious exception to the 'hypoxia theory' of retinal neovascularization has been offered.

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Figure 3. Preproliferative and early proliferative changes. (A) Arteriolar abnormalities, or 'silver wiring' in the same patient shown in Figure 2A.

Figure 3. Preproliferative and early proliferative changes. (B) A frame from a fluorescein angiogram of a 28-year-old woman, showing dye leakage from an early neovascular tuft (N) at the edge of an area of capillary non-perfusion. Note the abrupt end of the perfused portion of the retina (arrowheads).

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IRMA are fine vascular loops , lying within the retinal substance, always adjacent to more normal appearing vessels, usually venules, of larger calibre. Considerable debate has arisen as to whether these represent dilated, pre-existing vascular channels or true intraretinal ncovascularizat ion (Davis et ai, 1968). A clinicopathological case report (DeVenecia et al, 1976) strongly suggests that the latter alternative is correct , since digest preparations of the retina from a subject whose IRMA had been observed clinically and by fluorescein angiography before enucleation of the eye, demonstrated endothelial cell proliferation within the IRMA on microscopic observation. The probability of progressing from preproliferative to proliferative retinopathy is unknown. The Early Treatment Diabetic Retinopathy Study (ETDRS) in the USA designated eyes without preproliferative lesions as Po; while those with early preproliferative changes were designated P lo and more severe proliferative changes were called Pz (Early Treatment Diabetic Retinopathy Study Research Group, 1985a). Frank proliferative disease was graded P 3 or higher. Individuals with at least PI lesions in each eye could enter the protocol, and were randomly allocated to argon laser photocoagulation in one eye, with the fellow eye serving as an untreated control. Since nearly 4000 subjects are participating in the ETDRS, and control eyes will provide information on natural history, this study should eventually give data on the risk of progression with varying degrees of preproliferative disease, as well as the benefits and risks of prophylactic laser therapy at this stage. The ETDRS also involves treatment of eyes with proliferative stages P 3 to Ps , short of 'high risk characteristics', and of diabetic macular oedema. These features will be discussed below. Proliferative retinopathy . New blood vessel formation (neovascularization) from the retinal circulation is a feature of many ocular diseases, but it is particularly noteworthy in diabetic retinopathy. Neovascularization may arise from the vessels on the surface of the optic nerve head (termed nelV vessels 011 the disc or NVD) , or they may arise from other regions of the retinal circulation (termed Ilew vessels elsewhere or NVE). From the disc, the new vessels may grow forward into the vitreous cavity, unimpeded by any cellular or membranou s barrier. Elsewhere, however, the internal limiting membrane of the retin a, a basement membrane structure secreted presumably by the Muller cells (the principal glial elements of the retina), serves as a barrier to vascular proliferation into the vitreous. However, it has recently been demonstrated that migrating vascular endothelial cells secrete a collagenase capable of digesting basement membrane structures (Kalebic et ai, 1983), and this enzyme may facilitate the ultimate proliferation of the new blood vessels through the internal limiting membrane into the vitreous humour. The optic disc (Figure 4A) is the most common location of new vessels in diabetic retinopathy (Taylor and Dobree, 1970), and it carries the worst prognosis for vision. Data from the Diabetic Retinopathy Study (DRS) in

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the USA indicate that with NVD equal to or greater than about 25% of the area of the disc, even in the absence of preretinal or vitreous haemorrhage, an eye has an approximately 30% chance of deteriorating from initial good vision (20/100, i.e. 6/30, or better) to severe blindness, defined as 5/200 (6/240) or worse within three years if no treatment is given (Diabetic Retinopathy Study Research Group, 1981). A similar high risk of blindness is present if there is any NVD, together with preretinal or vitreous haemorrhage. NVE (Figure 4B) does not carry so high a risk of imminent blindness, unless the total extent of NVE within the eye is equal to or greater than one half the area of the optic disc, and preretinal or vitreous haemorrhage is present (Diabetic Retinopathy Study Research Group, 1979, 1981). These degrees of NVD or NVE constitute the 'high risk characteristics' determined by the DRS, and they constitute the strongest current indications for retinal photocoagulation. The blood-retinal barrier breaks down extensively in retinal new vessels, as demonstrated by their profuse leakage of fluorescein (Figure 4C). Progression of retinal neovascularization may lead to several adverse sequelae. The first is haemorrhage. .Preretinal haemorrhage refers to blood that collects in a space either between the internal limiting membrane of the retina and the retinal nerve fibre layer, or external to the internal limiting membrane, but behind the posterior face of the vitreous humour. Preretinal haemorrhages may be distinguished ophthalmoscopically by their sharp borders, because they are limited from diffusing by tissue boundaries (by the hemidesmosomes that attach the internal limiting membrane to underlying cellular membranes, or by the attachment of vitreous collagen bundles to the internal limiting membrane), and by their location anterior to the retinal blood vessels (Figure 5A). By contrast, vitreous haemorrhages (Figure 5B) are much more diffuse, and are more likely to produce severe impairment of vision by obstructing large portions of the central, and peripheral, retina. The second major sequel of retinal neovascularization is the development of fibroglial proliferation. The fibroblasts and glial elements that accompany the new vessels into the vitreous elaborate collagen, and by attaching to various locations on the inner surface of the retina and on the optic nerve head, these often extensive proliferations can exert a powerful tractional force on the fragile retinal tissue. This can result in wrinkling of the retina (Figure 6), or actual retinal detachment, either from the traction itself, or from the occurrence of retinal holes, torn by the tractional forces, and through which liquid vitreous can leak, producing a dissection between the outer elements of the neural retina and the underlying retinal pigment epithelium. Finally, retinal neovascularization appears to be closely related to the cause of neovascular glaucoma. Although we have observed several cases of neovascular glaucoma arising in eyes of diabetic patients in which retinal neovascularization had not been detected despite careful examination prior to the onset of the glaucoma, in general neovascular glaucoma arises in the presence of severe, proliferative diabetic retinopathy. The most

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Figure 4. Proliferative retinopathy. (A) New vessels, with dilated tips and accompanying fibrous tissue, on the left optic nerve head of a 45-year-old man.

Figure 4. Proliferative retinopathy. (B) New vessels elsewhere (arrowheads) inferior and nasal to the left optic nerve head of the patient shown in Figure 2B.

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Figure 4. Proliferative retinopathy. (C) A frame from a fluorescein angiogram of the NVD shown in Figure 4A. This angiogram demonstrates breakdown of the blood-retinal barrier, in the form of fluorescein leakage, in the new vessels.

popular current hypothesis of the pathogenesis of neovascular glaucoma is that it arises as a result of the diffusion forward within the eye of the presumed angiogenic substance that is produced by hypoxic retina. New vessels grow on the surface of the iris, often being initially detected at its pupillary margin. These vessels grow into the anterior chamber angle, where the aqueous humour is normally filtered into the systemic vasculature. Accompanied by fibrous tissue, the new vessels occlude the angle, producing a severe angle closure glaucoma with resultant extremely high intraocular pressures, pain and blindness, since the vascular supply to the retina and choroid is obstructed by the high intraocular pressures, and retinal and choroidal ischaemia results. Macular oedema Although macular oedema may occur in individuals at any age with diabetic retinopathy, it is most commonly observed in those greater than 40 years of age with non-insulin dependent diabetes (Aiello et ai, 1981). This is most likely to be related to the much larger number of non-insulin dependent diabetics, since, in a population-based study, Klein et al (1984d) found no difference in the prevalence of macular oedema with duration of diabetes of either type. Macular oedema is a far more common cause of impaired vision (defined as visual acuity less than 20/40, or 6/12) and of legal blindness than is proliferative diabetic retinopathy because of the greater number of non-insulin dependent diabetics. However, the clinical

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Figure 5. (A) A view inferior to the right macula of a 65-year-old man, showing a preretinal haemorrhage in the right macula. Note the discrete borders of the lesion and the Oat top, indicating that the haemorrhage has settled by gravity to the bottom of the preretinal space (either in front of the inner limiting membrane of the retina but behind the posterior face of the vitreous, or behind the inner limiting membrane but in front of the retinal nerve fibre layer) in which it is located. Since the haemorrhage blocks the view of the retinal blood vessels, it is clearly in front of them.

Figure 5. (D) A vitreous haemorrhage in a 42-year-old man. It is much more diffuse than the preretinal haemorrhage shown in Figure SA.

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course of diabetic macular oedema is much slower than is that of proliferative retinopathy and, because it produces damage primarily to the macular retina, it leads to loss of central vision only, rather than to the much more severe blindness that may result from the proliferative form of the disease. Comparisons of natural history data for untreated eyes with diabetic macular oedema and for untreated eyes with proliferative diabetic retinopathy from two very large, controlled clinical trials in the USA illustrate this point. In the DRS, 1732 patients with bilateral proliferative retinopathy (a few had severe preproliferative retinopathy) and initial visual acuity of 20/100 (6/30) or better in each eye received photocoagulation to one eye, with the second eye as control. By three years of follow-up, approximately 20% of the untreated eyes in the entire group had progressed to severe blindness, i.e. 5/200 (6/240) or worse vision at two successive follow-up visits (Diabetic Retinopathy Study Research Group, 1981). The ETDRS evaluated treatment for diabetic macular oedema, preproliferative, and early proliferative retinopathy. Results have recently been published for the macular oedema group (Early Treatment Diabetic Retinopathy Study Research Group, 1985b). A total of 1490 eyes with macular oedema and mild to moderate non-proliferative disease (background and preproliferative lesions) served as the untreated control group. To be eligible for entry into this study, eyes had to have 20/200 (6/60) or better vision if macular oedema involved the centre of the macula (the

Figure 6. An extensive fibrous traction band forming a 'bridge' between the superior temporal and inferior temporal vascular arcades of the left eye of a 37-year-old man. This is a common location for preretinal traction bands in late-stage proliferative diabetic retinopathy. Note the nearly parallel, vertical folds in the macular retina as a result of traction exerted by the band. As a result, vision is reduced. Such traction may completely detach the retina.

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fovea ccntralis), or better than 20/40 (6/12) if the centre of the macula was not involved. The endpoint was considered to be a decrease in visual acuity such that the visual angle doubled, that is, visual acuity changed from 6/6 to 6/12, from 6/12 to 6/24, etc. By three years, only about 20% of the untreated eyes with macular oedema had progressed to this endpoint. When 'clinically significant' macular oedema was present (this term will be defined below), about 30% of the untreated eyes experienced a doubling of their visual angle after three years of follow-up. Macular oedema is, by definition, thickening or swelling of the macular portion of the retina. Clinically, the macula may be defined as that portion of the retina that lies between the temporal end of the optic disc and the end of a horizontal line through the centre of the optic disc, and extending approximately four disc diameters temporal to its temporal margin. The fovea lies slightly beneath this line, at its approximate midpoint. The superior and inferior margins of the clinical macula lie about two disc diameters above and below this midpoint, intersecting approximately with the superior temporal and inferior temporal vascular arcades. This portion of the retina can easily be visualized with the direct ophthalmoscope. However, since this instrument allows only monocular viewing, without stereopsis, the clinician who uses direct ophthalmoscopy alone will be unable to appreciate the presence of macular oedema. This can best be done using the slit lamp and fundus contact lens. Certain hints that macular oedema is present may be detected without binocular viewing. Most important among these is the presence of intraretinal lipid deposits ('hard exudates'). These may be scattered rather diffusely throughout the macula (Figure 7A), and be accompanied by diffuse retinal oedema, and microaneurysms over the entire macular region (Figure 7B), or they may be organized in a circular pattern ('circinate retinopathy' , Figure 7C). Although lipid exudates in the macula may be present without oedema, and oedema may be present without lipid, the observation of such exudates, especially in a circinate pattern, suggests very strongly that the retina in that location is oedematous. Indication that 'leaking' microaneurysms are the source of the oedema fluid comes from fluorescein , angiography. When a circinate pattern of lipid exudates is observed, the angiogram nearly always shows a cluster of such 'leaking' aneurysms at the centre of the lipid ring (Figures 7D, E). Another pattern of macular oedema involves the formation of small, fluid-filled intraretinal 'cysts' within the retinal nerve fibre layer adjacent to the fovea. Such cystoid macular oedema is difficult to visualize with the direct ophthalmoscope (Figure 7F) , and often cannot even be detected with the slit lamp and fundus contact lens. However, it can usually be detected by fluorescein angiography, since the cyst-like spaces fill with fluorescein dye and the fluorescence persists long after the dye has cleared from the rest of the ocular circulation (Figure 7G). When macular oedema is outside the centre of the fovea, the affected individual may be asymptomatic, or may notice some blurring or distortion of vision, but never centrally. Loss of visual acuity occurs only when the oedema affects the foveal centre. Because it was felt that oedema within a

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Figure 7. Macular oedema. (A) Diffuse lipid exudates and 'blot" haemorrhages in the oedematous right macula of a 57-year-old woman.

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Figure 7. Macular oedema. (8) A frame from a fluorescein angiogram of the patient shown in Figure 7A. Note the extensive microaneurysms which, in later frames, demonstrated profuse dye leakage.

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Figure 7. Macular oedema. (C) A circular pattern of lipid exudates in the ocdcrnatous macula of the left eye of a 55-year-old man .

Figure 7. Macular oedema. (D) A frame from a fluorescein angiogram of the patient shown in Figure 7C. There are clusters of microaneurysms in the centre of the lipid ring.

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Figure 7. Macular oedema. (E) A frame from the same angiogram, taken approximately five minutes after the intravenous dye injection. Fluorescence has begun to fade from the retinal vessels, but dye leaking from vessels in the oedematous area has resulted in 'staining' of this area, which is approximately outlined by the lipid ring in Figure 7C.

Figure 7. Macular oedema. (F) A plain photograph of the macula of the right eye of a 28-year-old woman. Note the tiny, loculated 'cystoid' spaces (arrowheads), arranged around the centre of the fovea like petals on a flower. These arc usually difficult to see in a plain photograph or by monocular ophthalmoscopy.

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Figure 7. Macular oedema. (G) A frame from a fluorescein angiogram of a 62-year-old man, showing the angiographic appearance of the cystoid spaces in the late phase of the angiogram.

certain distance from the centre was likely to carry a higher risk of ultimate visual loss-even if the centre was not initially affected-than oedema farther away, the ETDRS established a definition of 'clinically significant macular oedema' (Early Treatment Diabetic Retinopathy Study Research Group, I985b). This involves: (1) thickening of the retina at or within 500 urn (one-half disc diameter) of the centre of the macula; or (2) hard exudates at or within 500 urn of the centre of the macula, if associated with thickening of adjacent retina; or (3) a zone, or zones, of retinal thickening one disc area or larger in size, any part of which is within one disc diameter of the centre of the macula. RISK FACTORS FOR DIABETIC RETINOPATHY The presence of diabetes mellitus That the presence of diabetes mellitus is the major risk factor for the development of diabetic retinopathy appears self-evident. Yet even this point has been subject to debate, since there have been occasional reports of a 'diabetic-like' retinopathy in the absence of diabetes (Hutton et aI, 1972). These are claimed as evidence for a wholly genetic explanation for the pathogenesis of diabetic retinopathy, as distinct from an explanation based on vascular damage secondary to long-term hyperglycaemia. Such cases are rare, the interpretations disputed (Davis, 1972), and they may be wholly irrelevant to the pathogenesis of diabetic retinopathy. None of the

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observable lesions of diabetic retinopathy is unique to that disease, and while one can usually find an explanation for such lesions in a non-diabetic individual-e.g. the presence of a retinal vein occlusion, sickle cell disease, severe anaemia, hypertension, collagen-vascular disease or a blood dyscrasia-the explanation is not always evident. It is not, however, valid to designate such cases as having a specific entity of 'diabetic retinopathy without diabetes' with an implied genetic aetiology. On the other hand, the development of retinopathy by those with 'acquired' diabetes, e.g. secondary to acromegaly, haem achromatosis, or other pancreatic disease, does not contradict the 'genetic' hypothesis. No reports of such cases have ruled out the possibility that the affected individuals also possessed the 'retinopathic' genome. Control of blood glucose The role of hyperglycaemia in the development of retinopathy, and other complications of diabetes, has been hotly debated (Ingelfinger, 1977). Repeated observations that retinopathy does not develop in insulin - dependent diabetic patients, whose systemic disease usually has ~ well-defined onset, until after an approximately five-year 'lag-period', supports such a causal relationship. The same is true of retinopathy in experimentally induced diabetes in dogs (Engerman et aI, 1977). The dog is the only non-human species in which lesions identical to those of early human diabetic retinopathy, including retinal capillary microaneurysms, pericyte loss and capillary acellularity have been reliably produced in the presence of diabetes mellitus (Engerman et aI, 1982). The report of Engerman et al (1977) provides the strongest evidence yet of a causal relationship between hyperglycaemia and the development of at least the early lesions of diabetic retinopathy. In this study the diabetes was induced chemically (by alloxan), there were no genetic influences and animals were randomly allocated to 'well-controlled' and 'poorly controlled' groups. Histological evaluation of the severity of the retinopathy was carried out on specimens that could be re-evaluated by independent observers. Studies on the effect of blood glucose 'control' on the development and progression of retinopathy in man have so far been inconclusive, although most of them suggest that excellent 'control' is beneficial. Major difficulties with many previous investigations have included: (1) inadequate definition of 'excellent' control, with inadequate determination as to whether it was present in the 'treated' group of patients or absent in the 'standard' group; (2) failure to randomize subjects to 'treated' and 'standard' groups, so that a selection bias could influence results; (3) failure to mask observers who evaluated the retinopathy as to the treatment group of the subjects; (4) failure to obtain 'hard copy' evidence, such as photographs, of the retinopathy status; (5) failure to establish a rigorous, and widely acceptable, system for grading degrees of retinopathy; and (6) inadequate sample size and/or inadequate duration of follow-up. Points (1) to (5) are defects that were common in earlier investigations of this subject. Recently, several excellent studies using modern methods for assessing

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blood glucose 'control' and for photographing and grading retinopathy have been carried out (Lauritzen et al, 1983; Kroc Collaborative Study Group, 1984; Brinchmann-Hansen et al (1985). Subjects were randomized into treatment groups, and observers were masked as to treatment status in order to evaluate retinopathy. Unfortunately, these studies are not definitive because they involved small populations, and follow-up was only two years or less which was insufficient to achieve conclusive results in view of the protracted natural history of early diabetic retinopathy.

Other factors Several other factors may affect the development and progression of diabetic retinopathy.

1. Systemic hypertension. This has been claimed to accelerate the progression of retinopathy in studies carried out on Danish subjects (Kornerup, 1955) and on Pima Indians (a small tribe in Arizona, USA, with an unusually high prevalence of non-insulin dependent diabetes (Knowler et al, 1980)). 2. Intraocular pressure. Elevated intraocular pressure may reduce the prevalence and severity of retinopathy in affected eyes (Becker, 1967). When glaucoma is present, involving atrophy of the retinal ganglion cell layer, the effect may be due to an alteration of retinal metabolism, still poorly understood, with reduction in a critical cell population. 3. Carotid arterial supply. Individuals with unilateral narrowing of the internal carotid artery, due to atherosclerosis, have been reported to have a lessened severity of diabetic retinopathy on the stenotic side (Gay and Rosenbaum, 1966). The explanation for this is unclear. 4. Effects of optic nerve atrophy and unilateral retinochoroidal scarring. Patients with unilateral optic atrophy, or extensive retinochoroidal scarring from injury or various inflammatory processes have long been thought to suffer less severe retinopathy in the eye with the optic atrophy or scarring (Aiello et al, 1968). Loss of retinal neuronal tissue reduces overaIl tissue metabolism, thereby decreasing the stimulus· to neovascularization, perhaps by reducing the production of some angiogenic substance (Michaelson, 1948; Wise, 1956; Henkind, 1978). 5. Effect of myopia. Myopia may have a protective effect· on the development and severity of diabetic retinopathy. This was confirmed by Rand et al (1985), who found that fewer subjects with proliferative retinopathy had myopia of greater than two dioptres, than did a similar series of controls, all of whom had diabetes of 15 or more years' duration and minimal or no retinopathy, based on a series of standard fundus photographs. These differences were not statistically significant, but they

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were present in separate analyses according to sex or age of diagnosis before and after 12 years. Of more interest was the interaction of myopia and HLA-DR phenotype.

6. Heredity: the role of HLA antigens. Several investigators have explored the relationship of HLA phenotype and more severe degrees of diabetic retinopathy. Rand et al (1985) found an excess of HLA-DR phenotypes 4/0, 3/0 and XIX (neither 3 nor 4) in their 'case' population, with proliferative retinopathy, by comparison with the controls. The relative risk of proliferative retinopathy for these three HLA phenotypes, pooled, was 3.74. For individuals with HLA-DR phenotypes 3/4. 3/X and 4/X, there was no increased risk of proliferative retinopathy with any refractive error. However, for those individuals with HLA-DR phenotype 3/0, 4/0, and XIX, the relative risk of proliferative retinopathy was 1.0 with 2.00 dioptres or more of myopia, but was 10-15 with hyperopia, emmetropia or lesser degrees of myopia. In other words, myopia exerts a substantial protective effect for proliferative retinopathy in the presence of a high risk HLA-DR phenotype. 7. The role of hormones other than insulin. Age and disease duration have independent effects on the development of the earliest lesions of retinopathy in young insulin dependent diabetics (Frank et aI, 1980, 1982; Palmberg et aI, 1981; Klein et aI, 1985). Retinopathy rarely develops before the midteen years, regardless of the duration of diabetes. Although there is still no direct proof, this suggests an effect, possibly hormonal, of puberty. A series of cases that appear to illustrate the point was presented by Daneman et al (1981). Five adolescents with Mauriac syndrome, in which there is highly 'brittle' insulin dependent diabetes, an enlarged fatty liver, and delayed growth and pubescence, were brought under 'tight' blood glucose control. Indices of growth and puberty improved, but the patients also developed rapidly advancing, proliferative retinopathy. The role of growth hormone (somatotrophin) or other pituitary hormones on diabetic retinopathy, in particular proliferative diabetic retinopathy, has been suspected since the initial report of a dramatic regression of retinopathy in a woman with postpartum pituitary necrosis (Poulsen, 1953). Certain young patients, in their late teens and early twenties, develop a rapidly progressive 'florid' proliferative retinopathy that does not respond to photocoagulation but has been reported to regress following hypophysectomy (Kohner et aI, 1976). The somatomedins, or insulin-like growth factors (IGFs) are small polypeptides with considerable structural similarity to the A-chain of insulin. They are released from hepatocytes, and perhaps other cellular synthetic loci, by growth hormone, and they appear to be the direct cellular effectors of many of the actions of growth hormone. Since they are also mitogenic in many in vitro systems, they are good candidates as aetiological agents for proliferative retinopathy, especially in young individuals with 'florid' retinopathy. A relationship between markedly

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elevated blood levels of IGF-I (somatomedin C) and rapidly advancing proliferative retinopathy was reported by Merimee et al (1983). The effects of pregnancy are controversial. Some authors, e.g. Moloney and Drury (1982), suggest that it accelerates the course of diabetic retinopathy, while others, e.g. Rand et al (1982), using case-control study methodology, find that pregnancy has no influence on the course of retinopathy.

TREATMENT OF DIABETIC RETINOPATHY Medical therapies No medical therapies have proved to be effective against diabetic retinopathy. Among treatments that have been attempted are a variety of vitamins and other agents (Caird et al, 1968), a diet in which corn oil was used in place of saturated fats in an attempt to reduce lipid exudates and macular oedema (King et al, 1963), and calcium dobesilate, a drug said to reduce capillary fragility (Sevin and Cuendet, 1969). More recently, prompted by reports of abnormal platelet aggregability in diabetes, platelet aggregates in occluded retinal microvessels, and a reduction in retinopathy in diabetic patients on long-term salicylate therapy, the ETDRS programme has been evaluating the effects of aspirin, 650 mg/day, compared with placebo, in a randomized, controlled trial in nearly 4000 diabetics with preproliferative or early proliferative diabetic retinopathy and/or macular oedema. As yet, with follow-up ranging from one to nearly six years, no statistically significant treatment effect has been reported. A group of drugs that could hold great promise are the aldose reductase inhibitors. Aldose reductase (and other aldehyde reductases of somewhat similar substrate specificities) are ubiquitous intracellular enzymes that function to reduce glucose, galactose, and other aldose sugars to their respective sugar alcohols, such as sorbitol and galactitol. These latter compounds are degraded slowly, if at all, by intracellular enzyme systems, and they traverse cell membranes poorly. Hence, once they are formed, they remain within the cell for long periods. Aldose reductase has a relatively low affinity for glucose, and it does not reduce glucose to sorbitol to any degree during norrnoglycaemia, when the available glucose is fully utilized by other, more active metabolic pathways. Moreover, in cells with an active, insulin dependent glucose 'pump' in their plasma membranes (such as adipocytes or skeletal muscle fibres), the pump serves to regulate the intracellular glucose level so that it does not get too high in hyperglycaemic states. However, in cells that lack such an active pump, the sorbitol level may become elevated. In lens epithelial cells of some animals, the sorbitol level in uncontrolled diabetes may become sufficiently high to do osmotic damage to the cells with resultant cataract formation. Such diabetic cataracts, or the corresponding cataracts in experimental galactosaemia, may be prevented by administration of aldose reductase inhibitors (Kinoshita et al, 1979). While the sorbitol hypothesis

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explains cataractogenesis in experimentally diabetic animals, it may not explain the cataracts that form in older diabetic humans (by contrast with the rapidly developing cataracts that may occur in young people with insulin dependent diabetes). However, aldose reductase may have a role in the development of diabetic neuropathy (Jaspan et aI, 1983; Young et aI, 1983), corneal decompensation (Kinoshita et al, 1979), and possibly diabetic retinopathy. The evidence for the latter is based on animal experiments. Both we (Frank et aI, 1983) and others (Robison et al, 1983) have found that galactosaemic rats develop thickened retinal capillary basement membranes, with an electron microscopic appearance similar to that in diabetic humans. This basement membrane thickening is prevented by administration of an aldose reductase inhibitor: Engerman and Kern (1984) showed that non-diabetic dogs fed a high-galactose diet for five years developed retinal capillary pericyte dropout, capillary acellularity, and microaneurysms just like the lesions found in diabetic dogs and humans. Although it has not yet been demonstrated that aldose reductase inhibition will prevent these lesions, the possibility that this enzyme may be an important initiating factor in diabetic retinopathy is so strong that several pharmaceutical houses are currently pursuing clinical trials of aldose reductase inhibitors to prevent retinopathy or to delay its progression in early cases. Photocoagulation Developed in the 1950s by Meyer-Schwickerath in Germany, photocoagulation has today become the major therapeutic modality against diabetic retinopathy. The original photocoagulator was the xenon arc. Today, this has been replaced in many centres by the argon laser because of its ease of use, and the fact that burns of much smaller size can be placed precisely in the macular region, where the larger xenon burns pose a greater risk of iatrogenic damage. The original rationale for photocoagulation therapy was that the intense irradiation by visible wavelengths could destroy abnormal blood vessels locally. Although there were initial reports of successful treatment, failures were also common. Also, photocoagulation of NVE elevated above the surface of the retina, or NVD, was difficult or impossible. NVD could not be treated with the xenon are, and treatment with the argon laser, initially thought to be feasible, soon proved to be fraught with complications, such as photocoagulation-induced ischaemic optic neuropathy. Subsequently, a technique for photocoagulation of proliferative diabetic retinopathy was developed that did not require direct application of light energy to the lesions. The rationale was that severe retinopathy seemed less frequent in eyes with extensive chorioretinal scarring from inflammatory lesions, or with high myopia or optic atrophy, such that large numbers of retinal neurons were nonfunctional and, hence, presumably, not metabolically active. The new technique, called panretinal photocoagulation (PRP) or scatter treatment, involved placing hundreds of closely spaced photocoagulation burns around the mid-peripheral retina, sparing the macula and the region

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immediately surrounding the optic nerve (Figure 8). Local photocoagulation of neovascular lesions was not essential (Figure 9A). Indeed, in the earliest demonstration of the efficacy of this treatment, such local photocoagulation could not be carried out because the ruby laser was used to administer the photocoagulation. Since its red light is transmitted through the vessels without being absorbed by haemoglobin, the ruby laser cannot cauterize the vessels directly (Aiello et aI, 1968). This initial report stimulated the organization of a large, controlled clinical trial in the USA, the DRS, whose criteria for entry have been described earlier under 'Macular oedema'. In this study, one eye of each patient, with proliferative or severe preproliferative retinopathy, was randomly allocated to PRP treatment either with the argon laser or the xenon arc (the choice of instruments was also randomly allocated), while the fellow eye served as an untreated control. PRP treatment meant a total of 1200 to 1600 argon laser burns, using a burn size of 500 urn, or somewhat less than half that number with the xenon arc and a burn size of 3 degrees. By the end of three years, it was evident that eyes treated with either photocoagulation modality had progressed to blindness at only half the rate of eyes that had not been treated, and this statistically highly significant result persisted through six years of follow-up (Diabetic Retinopathy Study Research Group, 1981). A similar result was reported in a smaller controlled clinical trial using the xenon arc in Britain (British Multicentre Study Group, 1977).

Figure 8. A montage showing the distribution and spacing of 'full scatter' (or 'PRP') laser treatment. The burns exlend to the mid-peripheral retina, outside the borders of this montage,

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Photocoagulation has also proved useful for slowing the progression of visual loss in diabetic macular oedema. This was first demonstrated by the British Multicentre Study Group (1983) who showed, surprisingly, that a small number of patients had beneficial results after treatment with the xenon are, whose large burns had produced a greater incidence of severe visual field loss than had argon laser therapy in the American DRS programme (Diabetic Retinopathy Study Research Group, 1981). It might have been expected (but proved not to be the case) that multiple xenon burns in the macular region would be severely damaging. The American ETDRS programme has recently demonstrated (Early Treatment Diabetic Retinopathy Study Research Group, 1985b) that focal argon laser treatment for macular oedema is highly effective in reducing the rate of visual loss over a three-year period. As noted earlier, approximately 30% of untreated eyes with 'clinically significant macular oedema' lost three lines on the vision chart, equivalent to a doubling of the visual angle, over three years, while reduction of vision of eyes that received focal treatment only was halved. 'Focal' treatment involved application of 50 urn or 100 11m diameter laser burns directly to areas of vascular leakage, as defined by fluorescein angiography, provided these areas of leakage were 300 lun-about one third of a disc diameter-from the centre of the macula (Figures 9B-D). When areas of diffuse fluorescein leakage were identified, these were treated with a 'grid' pattern of 50-200 urn spots, spaced one burn diameter apart, surrounding the centre of the macula except on its nasal side. A surprising result of the ETDRS study so far, is that focal laser treatment for macular oedema is most effective when it is given alone. Focal treatment seems less effective when it is administered together with PRP , or when the PRP is placed first, and the focal treatment follows at an interval of four months, as required by one of the ETDRS protocols. This suggests that PRP may alter retinal and choroidal blood flow and/or metabolism in ways that are not yet completely understood. A direct tissue effect, causing a decrease in the production of a 'retinal angiogenesis factor', is probably an oversimplification of the effects of this mode of therapy. Another goal of the American ETDRS programme has been to treat 'preproliferative' and early proliferative retinopathy prophylactically, with the aim of reducing still further the progression to blindness over a five-year period of the 15% of treated eyes in the DRS that had a bad visual result despite photocoagulation. PRP at an earlier stage of the disease might be advisable. To reduce the complication of marked peripheral visual field loss that occurs in some patients after full PRP treatment, a 'mild scatter' protocol was developed, in which the same area of retina is covered with fewer than half the number of burns but with wider spacing between the burns. The ETDRS has not yet reported a statistically significant prophylactic effect of either 'full' or 'mild' PRP. It has been assumed that photocoagulation of macular oedema is effective because the burns 'seal off' leaking microaneurysms, permitting the oedema fluid to be reabsorbed by physiological mechanisms. That this

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Figure 9. Effects of argon laser photocoagulation. (A) The appearance of the right optic disc of the patient shown in Figure 4A, six weeks after he received PRP treatment. The NVD has regressed entirely, and only a non-perfused fibrous band remains. Note the pigmented laser scars to the left and below the disc.

Figure 9. Effects of argon laser photocoagulation. (B) The oedcmatous right macula of a 62-year-old woman prior to treatment.

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Figure 9. Effects of argon laser photocoagulation. (C) The eye shown in Figure 98 immediately after focal laser treatment. 'The photograph is blurred because of transient corneal distortion from the contact lens used to place the laser treatment.

Figure 9. Effects of argon laser photocoagulation . (D) Two years later , pigmented laser scars remain , but there is no oedema, and no lipid exudates.

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may not be the case is suggested by recent work of Olk (1986). He found that a 'grid' of argon laser burns, placed around the entire circumference of the fovea, was as effective as focal argon treatment in producing resolution of the oedema. Since the laser energy was not directed at 'leaking' lesions, the mechanism of the presumed effect was not simply to 'seal the leaks'. The effectiveness of this 'grid' treatment, applied with either the argon green or the krypton red laser, however has yet to be compared with 'focal' laser treatment directly to 'leaking vessels' in a large-scale, controlled clinical trial. Vitrectomy When severe vitreous haemorrhage occurs in a diabetic patient and vision is greatly reduced, vitrectomy surgery may be employed. This procedure, introduced in the early 1970s (Machemer et ai, 1971) is also useful in some cases for removing preretinal fibroglial membranes and relieving traction detachments of the retina in diabetic patients with extensive proliferative disease (Aaberg, 1981). The procedure is performed using an operating microscope, and involves the introduction of a vitrectomy suction cutter into the eye through the pars plana ciliaris, anterior to the most peripheral attachment of the retina to the wall of the eye. Sometimes an additional instrument for cutting, or peeling of preretinal membranes, is introduced into the eye through the pars plana 1800 opposite the initial incision. The cutter consists of a rotating tube with a cutting edge and a suction device to cut and remove the formed elements of the vitreous, together with blood, from the eye. A second, concentric tube is used for infusion of a physiological saline solution so that the eye maintains its shape and pressure. In uncomplicated diabetic vitreous haemorrhage, 70% of operated eyes demonstrate improved vision, maintained for at least six months postoperatively (Rice and Michels, 1980; Machemer and Blankenship, 1981; Diabetic Retinopathy Vitrectomy Study Research Group, 1985). Surgery for preretinal membranes and traction detachments of the retina can also be beneficial. However, eyes requiring vitrectomy are severely diseased; and only a small percentage of them recover normal or near-normal vision, defined as 20/40 (6/12) or better. In the American Diabetic Retinopathy Vitrectomy Study (DRVS), 616 eyes with diabetic vitreous haemorrhage that reduced vision to 5/200 (6/240) or worse for at least one month were randomly allocated to either early vitrectomy or vitrectomy after a delay of one year. Two years after entry into the study, 25% of the early vitrectomy group had visual acuity of 6/12 or better, compared with 15% of the delayed vitrectomy group, a statistically significant result (Diabetic Retinopathy Vitrectomy Study Research Group, 1985). This difference was maintained through three years of follow-up. However, an approximately equal number of eyes (54% in the early vitrectomy group, and 50% of the deferred group) achieved vision of 6/60 or better by two years, while 25% of the early vitrectomy eyes and 19% of the deferred eyes had no light perception at two years of follow-up. Among the most serious complica-

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tions of vitrectomy surgery are retinal detachments due to holes inadvertently torn in the retina by the suction cutter, cataract, and neovascular glaucoma. The latter is particularly common in eyes that require removal of the lens during surgery, and in such cases, the neovascular glaucoma is allegedly caused by diffusion anteriorly in the eye of the hypothetical 'retinal angiogenesis factor', unimpeded by the presence of the lens. Despite these complications, vitrectomy is now a well-established part of the therapeutic repertoire against diabetic retinopathy, and indications for its use continue to increase. Hypophysectomy Since the earliest report of a dramatic resolution of proliferative retinopathy in a female patient following postpartum pituitary necrosis (Poulsen, 1953), there has been much interest in the effect of pituitary ablation in the treatment of severe diabetic retinopathy. A number of centres (Lundbaek et ai, 1968; Adams et ai, 1974; Kohner et ai, 1976) have reported successful results, following destruction of the pituitary either surgically or by radiation. However, the treatment produces substantial morbidity and some mortality, and, with the exception of one relatively small study (Lundbaek et ai, 1968), there have not been any randomized, controlled clinical trials of this therapeutic modality. Such trials are essential, because spontaneous regression even of severe proliferative diabetic retinopathy does occur. Effect of rigorous blood sugar control Physiological control of blood glucose is difficult to achieve in patients with insulin dependent diabetes, but very good control can be achieved over periods of one to two years or more using either continuous subcutaneous insulin infusion pumps, or multiple daily insulin injections, together with home blood glucose monitoring. Three randomized, controlled trials have been reported, comparing the effects of such 'tight' control with 'standard' control, using one or two insulin injections per day, in insulin dependent diabetics with no retinopathy, or with minimal retinopathy (Lauritzen et ai, 1983; Kroc Collaborative Study Group, 1984; Brinchmann-Hansen et ai, 1985). Two of these studies indicated a transient deterioration in retinopathy status, with increased development of 'cotton wool' spots, in subjects on the 'tight control' regimen after one year of follow-up. However, none of the patients in either group progressed to 'high risk characteristics' and unpublished reports indicate that retinopathy status was equal after two years. A larger study of much longer duration is now in progress in the USA and Canada. The Diabetes Control and Complications Trial (DCCT) has recently completed its pilot phase in 21 centres. This involved 250 patients with insuljn dependent diabetes and minimal or no retin.opathy wh~ we.re randomized to 'tight' or 'standard' control. The DCCT IS now startmg ItS long-term clinical trial, in which over 1000 subjects wiII ~e randomized. to 'tight' or 'standard' glycaemic control over a follow-up penod of at least five

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years. A 'primary intervention' study will attempt to determine whether a significant difference exists in the rate of development of retinopathy between the two treatment groups in subjects who had no retinopathy at the outset. A 'secondary intervention' study will attempt to determine whether there is a significant difference in progression of retinopathy, through three or more 'levels' defined by a series of standard photographs of subjects who have retinopathy at the outset of the study, and who are assigned to the two treatment groups. The role of the primary care physician The primary care physician who follows diabetic patients has the responsibility of ensuring appropriate diagnosis and treatment of the long-term complications of that disease. As regards diabetic retinopathy, that responsibility is especially critical now that a variety of effective treatments are available. What are the standards of care to which the primary care physician should adhere? In the State of Michigan, USA, this issue was recently addressed by a panel assembled by the State Department of Public Health (details 'of the panel's recommendations are given in the pamphlet Michigan Diabetic Retinopathy Guidelines, which may be obtained by writing to Diabetes Program, State of Michigan Department of Public Health, 3500 North Logan, P.O. Box 30035, Lansing, MI 48909, USA). The panel consisted of medical and osteopathic physicians subspecializing in various aspects of ophthalmology, and well as optometrists and other health care professionals dealing with ocular aspects of diabetes. A summary of the panel's recommendations follows. 1. Individuals with insulin dependent diabetes should have a detailed ocular examination by an ophthalmologist, at the least, after five years of diabetes, or at the time of puberty, whichever comes first. Ocular examination should be carried out annually thereafter. 2. Individuals with non-insulin dependent diabetes should have detailed ocular examinations by an opthalmologist at the time of diagnosis, and annually thereafter. 3. Ophthalmoscopy should be performed by the primary care physician at each examination of a diabetic patient. Definitive diagnostic and therapeutic measures related to diabetic eye disease should be carried out by the ophthalmologist. Examinations by the ophthalmologist should include determination of the visual acuity and refraction; external examination including determination of pupillary responses to light and accommodation; slit lamp examinations of the anterior segment; intraocular pressure measurement for all patients greater than 40 years of age, and for younger patients where there is a family history of glaucoma, or where glaucoma is suspected by the appearance of the optic nerve head; and examination of the retina by direct and indirect and, where indicated, slit lamp ophthalmoscopy with.

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the pupils dilated pharmacologically. Retinal photography and fluorescein angiography are not routine examinations, but are performed in the diabetic patient only when there are special indications. The primary care physician should question diabetic patients at each visit regarding ocular symptoms, for example, loss of vision, pain, or redness of the eyes or ocular adnexa. A retinal examination should be done, using a monocular direct ophthalmoscope in a darkened room. Where feasible, the pupils should be dilated using one drop of2.5% phenylephrine and one drop of 1% tropicamide or 1% cyclopentolate in each eye. (Contraindications to dilation of the pupil include narrow anterior chamber angles with a threat of angle closure glaucoma, or the presence of an iris-plane intraocular lens, which may become dislodged if the pupil is too widely dilated.) Lesions of retinopathy should be reported to the ophthalmologist.

SUMMARY Diabetic retinopathy is a common, and potentially blinding or visually disabling complication of diabetes. Nearly all diabetic subjects will have some degree of retinopathy after 20 years of diabetes, and 50% of those with insulin dependent diabetes will have proliferative retinopathy after 15 years. Macular oedema frequently produces central vision loss and legal blindness, most commonly in non-insulin dependent diabetics. In recent years, several therapeutic modalities have been demonstrated to be effective on the basis of large-scale randomized, controlled clinical trials. These include panretinal photocoagulation (PRP), using the argon laser or xenon are, for proliferative retinopathy, and focal photocoagulation for macular oedema. Vitrectomy surgery is effective for diabetic vitreous haemorrhage and traction retinal detachment, producing improved vision in most patients, but only a relatively small percentage of patients so treated recover good visual acuity (;:::: 6/12). Other therapeutic modalities, such as hypophysectomy for severe retinopathy, remain controversial, while still others, such as rigorous blood glucose control and aldose reductase inhibitors, are currently under investigation. The primary care physician who deals with diabetic patients should be familiar with the lesions of diabetic retinopathy and with current therapeutic modalities. He should perform an examination of the posterior retina with the direct ophthalmoscope on each diabetic patient at each visit, and should institute prompt referral to an ophthalmologist at the first sign of change. Periodic examination of all diabetic patients by an ophthalmologist should be conducted at the intervals recommended in the previous section. Definitive evaluation and treatment of diabetic retinopathy should be carried out by the ophthalmologist.

REFERENCES Aaberg TM (1981) Pars plana vitrectomy for diabetic traction retinal detachment. Ophthalmology 88: 639-Q42.

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Adams DA, Rand RW, Roth RH et al (1974) H ypophysectomy in diabetic retinopathy. The relationship between the degree of pituitary ablation and ocular response. Diabetes 23: 693-707. Aiello LM, Bcctham WI', Balodimos MC et al (1968) Ruby laser photocoagulation in treatment of diabetic proliferating retinopathy: preliminary report , In Goldberg MF & Fine SL (cds) Sympos ium on the Treatment of Diabetic R etinopathy, pp 437-463. US Department of Health, Education , and Welfare Publication No . 1890 . Washington : US Government Printing Office. Aiello LM, Rand L1, Briones JC ct al (1981) Diabetic retinopathy in Joslin Clin ic patients with adult-ons et diabetes. Ophthalmology 88: 619-623. Becker B (1967) Diabetes and glaucom a. In Kimura SJ & Caygill WM (eds) Vascular Complications of Diabetes Mellitus, pp 43-48. SI. Louis: CiY. Mosby. Bennett PH (1976) Report of the Workgroup on Epidemiology of the Committee on Scope and Impact to the National Commission on Diabetes. In Report of the National Commission on Diabetes to the Congress of the United Slales,Yol. II , Part I , pp 65-133. US Department of Health, Education, a nd Welfare Publication No . (NIH) 76-1021. Wa sh ington: US Government Printing Office. Brinchrnann-Hanscn 0, Dahl-Jorgensen K, Hanssen KF et al (1985) Effect s of intensified insulin treatment on various lesions of diabetic retinopathy. American Journal of Ophthalmology 100: 64+-653 . British Multicentre Study Group (1977) Proliferative diabetic retinopathy: tre atment with xenon-arc photocoagulation. Interim report of multicentre randomized controlled clinical trial. British Medical Journal i: 739-742. British Multicentre Study Group (1983) Photocoagulation for diabetic maculopathy: a randomized controlled clinical trial using the xenon arc. Diabetes 32: 1010-1016. Brooser G, Barta L, Anda Let al (1975) Fruhdiagnose der Mikroangiopathie bci kindlichem Diabetes . Klinischc Monatsbliittcr fiir Augenhcilkunde 166: 233-236. Caird F, Pirie A & Rarnsell TG (1968) Diab etes and the Eye, pp 1-7, 110-121. Oxford: Blackwell. Cunha-Vaz J, Faria de Abreu JR, Campos AJ et al (1975) Early breakdown of blood-retinal barrier in diabetes. British Journal of Ophthalmology 59: 649-656. Cunha-Vaz JG, Fonseca JR, Abreu JR et al (1978) Follow-up study by vitreous fluorophotomctry of early retinal involvement in diabetes. American Iournal of Ophthalmology 86: 467-473. Dancman D, Drash AL, Lobes LA et al (1981) Progressive retinopathy with improved control in diabetic dwarfism (Maurine's syndrome). Diabetes Care 4: 360-365. Davis MD (1972) Discussion of paper by Hutton, et al . Transactions of the American Academy of Ophthalmology and Otolaryngology 76: 973-979. Da vis MD , Norton EWD & Myers FL (1968) The Airlie classification of diabeti c retinopathy. In Goldberg MF & Fine SL (cd s) Symposium Oil the Treatment of Diab etic Retinopathy; pp 7-22. US Department of He alth , Educat ion , and Welfare Publication No . 1890. Washington: US Government Printing Office. Davis MD, Hiller R , Magli YL et al (1979) Prognosis for life in patients with diabetes: relation to severity of retinopathy. Transactions of tire American Ophthalmological Society 77: 14-1-170. DcVcnccia G, Davis MD & Engerman R (1976) Clinicopathologic correlations in diabetic retinopathy. I. Histology and fluorescein angiography of rnicro aneurysms . Archives of Ophthalmology 94: 1766-1773. Di abetic Retinopathy Study Research Group (1979) Four risk factors for seve re visual loss from diabetic retinopathy. Archives of Ophthalmology 97: 65-1-655. Diabetic Retinopathy Study Research Group (1981) Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings. DRS Report Number 8. Ophthalmology 88: 583-600. Di ab etic Retinopathy Vitrcctomy Study Re search Group (1985) E arly vitrcctorny for severe vitreous haemorrhage in diabetic ret inopathy. Archives of Oph thalmology 103: 16441652. Dwyer MS, Melton U , Ball ard OJ et al (1985) Incidence of diabetic retinopathy and blindness: a population-based study in Ro chester, Minnesota. Diabetes Care 8: 316-322.

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