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Midperipheral Fundus Involvement in Diabetic Retinopathy
Midperipheral Fundus Involvement in Diabetic Retinopathy KOleHI SHIMIZU, MD, YOSHIHARU KOBAYASHI, MD, KANEMITSU MURAOKA, MD
Abstract: We evaluated the topologic distribution of vaso-occlusive and vasoformative lesions in 119 eyes with diabetic retinopathy using our newly developed super-wide (130°) fluorescein angiographic montage technique. A numeric coding system was applied to assess the vaso-occlusive lesions by dividing each fundus maximally into 418 blocks. We demonstrated that the mid peripheral retina was far more prone to undergo capillary nonperfusion than the posterior retina. The extent of capillary non perfusion was more pronounced in eyes with neovascularization from (in ascending order): the retina, the optic disc, and in the chamber angle. [Key words: capillary non perfusion, diabetic retinopathy, fluorescein angiography, maculopathy, midperipheral retina, neovascularization, rubeosis iridis.] Ophthalmology 88:601-612, 1981
Application of fluorescein angiography to eyes with diabetic retinopathy significantly contributes to a better understanding of the nature of maculopathy and disc neovascularization. On the other hand, very little is known about the vascular lesions in the midperipheral retina. The importance of midperipheral retina in the pathogenesis and progression of diabetic retinopathy is well known, as an overwhelming majority of retinal neovascularization is located here. t Also, the midperipheral area is the chief target area to which panretinal photocoagulation can be applied. 2 •3 Fluorescein angiographic studies of diabetic retinopathy have mainly concerned the vicinity of the posterior fundus. Prior technical limitations made it impossible to examine routinely a wide retinal area as a composite whole in clinical evaluations of diabetic retinopathy. We have developed a new technique of
using fluorescein angiography that enables the observation of retinal vessels in capillary detail over a wide fundus area. Using this relatively simple method on eyes with diabetic retinopathy, we have found that a widespread capillary nonperfusion tends to involve the midperipheral retina and that the extent of nonperfusion seems to parallel the severity of diabetic retinopathy. It appears that the midperipheral retina plays a key role in the evolution of diabetic retinopathy, particularly in its malignant form. It appears that the nature and extent of vascular lesions in the midperipheral retina may serve as a useful clinical guide in assessing the prognosis of the affected eye and should be considered in designing therapeutic modalities, including photocoagulation.
MATERIALS AND METHODS From the Department of Ophthalmology. Gunma University School of Medicine, Maebashi, Japan. Presented at the Eighty-Fifth Annual Meeting of the American Academy of Ophthalmology, Chicago, November 2- 7, 1980. Reprint request to Koichi Shimizu, MD, Department of Ophthalmol~gy, Gunma University School of Medicine, 3 Showamachi, aebashi, 371 Japan.
0161-6420/8110700/0601/$1.10
© American Academy
of Ophthalmology
One hundred and nineteen eyes (87 patients) seen by us during the period from January 1977 to June 1980 were included in our study. These 119 eyes were selected from a larger series of eyes with diabetic retinopathy seen during the same period. The selection was made after discarding those with a minimum grade of retinopathy and those in whom the quality of 601
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panoramic angiogram did not meet our technical criteria. The angiograms had to cover a sufficiently wide fundus area and they had to show capillary detail when enlarged and printed. All of the 119 eyes were affected by moderate to advanced diabetic retinopathy. They included 38 eyes with simple retinopathy (group A); 33 eyes with retinal neovascularization (group B); and 48 eyes with neovascularization from the optic disc (group C). These 48 eyes with disc neovascularization were often, but not necessarily, accompanied by neovascularization from the retina. A total of 13 eyes, one from group A and 12 from group C, showed rubeosis in the iris and/or the chamber angle. These 13 rubeotic eyes were evaluated in their respective groupings according to their fundus manifestations and also as a parallel, distinctive group (group D). The angiographic technique used in this study is, in principle, that of ordinary fluorescein angiography after a single injection of 5 ml of 10% fluorescein solution. As a specific feature, different fundus areas are photographed in rapid succession. Specifically, care is taken to adjust the focusing for each frame and not to leave an unphotographed portion in the fundus. When working with the ordinary (300) fundus cameras, maximally 35 frames are necessary to document the whole fundus. With semiwide (45°) or wide (60°) fundus cameras, a considerably lesser number of frames are necessary. Under normal circumstances, it is possible to document the angiographic aspects of a given fundus subtending 130 degrees in diameter. The negative film
is then enlarged and printed. The prints are assembled and arranged to form a composite, panoramic fluorescein angiogram. In evaluating each of the 119 composite angiograms, we paid particular attention to the size and distribution of capillary nonperfusion areas on the one hand, and to the location of retinal neovascularization on the other. Other angiographic features, such as capillary microaneurysms, dilatation of retinal vessels, and extravasation of dye, were not treated as separate items in this investigation. This decision was made not only for the sake of convenience, but also because capillary nonperfusion and neovascularization seem to play a major role in the pathogenesis and progression of diabetic retinopathy. STATISTICAL EVALVA TION
We performed a quantitative evaluation of the topologic distribution and severity of retinal capillary nonperfusion in the panoramic fluorescein angiograms in the 119 eyes. Each fundus was divided into 32 sectors by radial lines passing through the center of the optic disc. The sectors were again divided into small blocks by concentric circles with the disc as their center. The distance between two consecutive circles was set at 0.5 DD (disc diameter) in the fundus area ofless than 4 DD from the disc margin and at 1 DD in the outer area. One panoramic fluorescein angiogram was thus partitioned maximally into 418 blocks (Fig 1). Each block was assessed by a coding system as to the
Fig 1. Each fundus is divided into small blocks by 32 radial lines and concentric circles. The disc lies at the center.
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presence and extent of capillary nonperfusion. A given block was judged as point 0 when the area of nonperfusion occupied less than 10% ofthe block. It was judged as point 1, 2,or 3 when the area of nonperfusion was more than 10,40 or 80% of the block, respectively (Fig 2). This process of evaluation was repeated for each of the 119 angiograms. Thereafter, the points were added and averaged for each corresponding block of the 119 angiograms. This process of addition and averaging was performed for group A (simple retinopathy), group B (proliferative retinopathy), group C (disc neovascularization) and group D (rubeosis iridis). The averaged points for the 418 blocks were graded into six shadowed scales and were displayed in four diagrams representing each of the four groups.
RESULTS We observed various types of diabetic retinal vascular lesions including capillary microaneurysms, hyperpermeability of vessels, areas of capillary nonperfusion and, in 81 eyes, neovascularization from the retina and/or the optic disc. Among the 119 eyes, there was a general tendency for the retinal vascular lesions to be more pronounced in degree and extent in the midperipheral than in the posterior fundus. Even in eyes in which the macula was affected with only a few capillary microaneurysms, distinct areas of capillary nonperfusion and much more numerous capillary microaneurysms were located in the midperipheral retina (Fig 3). Typically, a capillary nonperfusion area in-
Fig 2. The coding system. Each block is given 0.1,2. or 3 points according to the extent of nonperfusion. In this sample eye. 0 point is shown as blank. A dash (-) indicates that the block was not available for evaluation.
volved a whole microcirculatory unit comprised by a feeder arteriole, capillary network belonging to it, and a collector venule. Major retinal vessels serving the far periphery were spared from the gross vaso-occlusive process except in cases of advanced retinopathy. In addition to the posterior fundus, capillary nonperfusion was uncommon in the close vicinity of the optic disc. A peripapillary zone of 1 to 1.5 DD from the disc margin was usually spared from capillary nonperfusion even in advanced diabetic retinopathy. Also, the retinal area along the upper and lower vascular arcades, which would roughly correspond to the area served by radial peripapillary capillaries (RPCs), tended to be spared from gross capillary nonperfusion. ANGIOGRAPHIC FEATURES
Simple retinopathy (group A). The 38 eyes belonging to this group showed a very wide variety of retinal microvascular lesions, ranging from minimal and sporadic changes to more advanced and widespread ones. There was a tendency for the vascular lesions to be more intense and advanced in nature in the midperipheral retina than in the macuta (Fig 3). In mild cases, for instance, there were just a few capillary microaneurysms in the macula. In the midperipheral retina, on the other hand, there were more numerous capillary microaneurysms and areas of non perfusion that might be as small as one-fourth DD in diameter. These lesions were frequently located upper, nasal, and lower to the disc, 1 to 4 DD away from the disc margin. The areas of capillary nonperfusion sometimes, but not necessarily, coincided with areas of soft
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exudates. Rather, the nonperfused areas appeared , ophthalmoscopically, almost normal or slightly opaque when they were located in the midperipheral retina. Retinal vessels adjacent to the nonperfused areas were
Fig 3. Top, simple retino pa th y in a 67-year-old man. Diabetes was detected by ophthalmoscopy four years ago and has been und er co ntro l. Capillary microaneurysms and nonperfu sio n areas a re seen in the midperiphery at I and 8 o'c loc k positions . Fig 4. B Ol/o m , distribution and graded evalu ation of nonpe rfu s ion in 38 e yes with s impl e retinopath y . Minimum to modera te areas of no nperfu sion are di stributed 1.5 to 5 DD a wa y fro m the di sc margin.
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generally hyperpermeable to fluorescein. Peripheral fundus areas more than 6 DD away from the disc were spared from vaso-occlusive changes in milder cases. In more advanced cases of simple retinopathy, the more
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peripheral fundus areas showed variable abnormalities including vasodilatation, hyperpermeability of vessels, and, occasionally, extensive capillary nonperfusion reaching into the far periphery. Even in such advanced cases, however the posterior area surrounded by the disc, the macula, and the upper and lower vascular arcades were usually spared from gross vaso-occlusive changes. A cumulative topographic display of 38 eyes with simple retinopathy (Fig 4) showed that an oval central fundus area, with the disc and fovea as epicenters, was virtually free of capillary nonperfusion of noticeable sizes. Areas of moderate nonperfusion were distributed 1 to 4 DD away from the disc margin in the sector upper, nasal, and lower to the disc. The retinal area temporal to the fovea seemed also to be a predilected site of capillary nonperfusion of a lesser degree. The more peripheral retina more than 5 DD from the disc margin was not affected by capillary nonperfusion when seen collectively. Proliferative retinopathy (group B). The 33 eyes with neovascularization from the retina but not from the disc were characterized by the presence of more extensive nonperfused areas in the midperipheral retina (Fig 5). The nonperfused areas were variable in size and distribution. When large, the area of nonperfusion attained a size of 6 or more disc diameters across and was bordered by major retinal vessels serving the far periphery. Retinal vessels adjacent to the nonperfused areas showed hyperpermeability, capillary dilatation, microaneurysm formation, and, frequently, retinal neovascularization. Newly formed vessels were often located at the posterior border of the nonperfused retinal area. The vessels in the posterior fundus showed minimal to moderate alterations including vasodilatation, hyperpermeability, and microaneurysm formation. There was occasional nonperfusion of individual or few capillaries in the macula, but such occlusions did not attain a size comparable to what occurred in the midperiphery. A cumulative topographic display of the 33 eyes with retinal neovascularization (Fig 6) showed the presence of moderate (one to two points) of nonperfusion in the midperipheral fundus. The nonperfusion was more prominent in the upper, nasal, and lower sector, 1.5 to 5 DD away from the disc margin. The more peripheral retinal area was also affected by nonperfusion to a lesser degree. The oval central retinal area including the disc and the fovea was the least affected by nonperfusion, if at all. The retinal sector temporal to the fovea was also involved in nonperfusion to a smaller degree than the other mid peripheral retinal areas. Disc neovascularization (group C). The 48 eyes with neovascularization from the optic disc were characterized by the presence of extensive capillary .nonperfusion in the midperipheral retina (Fig 7). In a tYpical instance, nonperfusion involved the whole retinal area which could be documented by the panoramic fluorescein angiographic technique except
for the central retina area, including the disc and the macula. Despite extensive capillary nonperfusion, major retinal vessels serving the far periphery were generally patent. Apparently because of the lack of functioning capillaries, microaneurysms were either absent or inconspicuous in the midperipheral retina. Among the 48 eyes in this group, retinal neovascularization was present in 37 eyes. The newly formed vessels were generally far less in number and size than in group B. As a general trend, the vascular structure in the macula was fairly well preserved when compared with the pronounced changes in the midperiphery. Depending on the severity of individual cases, the vessels in the macula showed generalized vasodilatation, hyperpermeability, and occasional capillary fallout. The retinal sector temporal to the fovea appeared to be one of the predilected sites of gross capillary nonperfusion. A cumulative topographic display of 48 eyes in group C (Fig 8) showed the presence of a more widespread capillary nonperfusion (two to three points) in the midperipheral retina than in the former two groups. Nonperfusion was most pronounced 4 to 7 DD away from the disc. The central retina bordered by the disc, fovea, and the vascular arcades manifested lesser degree (one point or less) of capillary nonperfusion. Rubeosis iridis (group D). The 13 eyes with rubeosis in the iris and/or the chamber angle also belonged either to group A (one eye) or group C (12 eyes), as all the eyes but one showed neovascularization from the optic disc. These 12 eyes manifested no retinal neovascularization at all (seven eyes) or minimal new vessels (five eyes). The most cbaracteristic feature of these 13 eyes (Fig 9) was the presence of extensive capillary non perfusion throughout the whole recordable fundus except the central retina. Only major retinal vessels seemed to be functioning in the midperipheral and peripheral retina. They occasionally formed distal arteriovenous shunts. Veins showed gross irregularities forming bead-like dilatations and occasional duplications. Vessels in the macula were affected in varying degrees, showing generalized dilatations and nonperfused areas. However, retinal vessels along the papillomacular bundle and in the parafoveal area were generally well preserved when compared with the extensive vaso-occlusive changes in the midperipheral retina. A cumulative topographic display of 13 eyes with rubeosis (Fig 10) indicated that the whole midperipheral fundus area was affected by advanced (two to three points) capillary nonperfusion. The far peripheral fundus was also involved in the vasoocclusive process. The central fundus showed a lesser degree of nonperfusion than the midperipheral retina, but the degree was still considerable (one to two points) . Distribution of neovascularization. The distribution of retinal and disc neovascularization was evaluated as a whole (Fig 11). We identified a total of 474 newly formed vessels in 81 out of the 119 eyes through 605
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Fig 5. Top , proliferative retinopathy (retinal neovascularization) in a 46-year-old man. Diabetes was detected two weeks after onset of visual disturbance. Gross capillary defects and neovascularizations are distributed in the midperipheral retina. Vessels in the macula are hyperpermeable to fluorescein. Fig 6. Bottom, distribution and graded evaluation of non· perfusion in 33 eyes with retinal neovascularization. Areas of moderate nonperfusion are distributed in the midperipheral retina. The posterior fundus and the peripapillary area are least involved in nonperfusion.
examination of the panoramic angiograms. The locations of the newly formed vessels were plotted on a model fundus in a diagrammatic pattern. Sixty five newly formed vessels (48 eyes) originated from the
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optic disc. Peculiarly, the central fundus in to the disc, the macula. and the vascular arcades were spared from neovascularization except in a very few instances. Also. the immediate peripapillary zone of less than 1
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Fig 7. Top. disc neovascularization in a 41-year-old man. Diabetes was diagnosed two years ago and is under poor control. Large nonperfused areas are distributed in the mid peripheral retina. There are generalized vasodilatation, hyperpermeability, and a few retinal neovascularizations. Fig 8. Bottom, distribution and graded evaluation of nonperfusion in 48 eyes with disc neovascularization. The whole midperipheral retina is affected by extensive nonperfusion of more than two points. The papillomacular area shows lowest grade of nonperfusion.
DD aWay from the disc margin was free of newly formed vessels. In all instances in which newly formed .ressels seemed to be located in the immediate proximuy of the disc margin, they proved to be extensions
from the disc and not to originate from the peripapillary retina. Confirming our earlier observations,4 none of the newly formed vessels from the disc originated from the central retinal artery or its tributary. Their
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Fig 9. Top. retinopathy with rubeosis in the chamber angle in a 64-year-old man. Diabetes was detected 10 years ago but. was left untreated. Nephropathy and systemic hypertension (190/100 mm Hg) have been present for the past two years. The whole fundus is affected by generalized capillary nonperfusion except the macula and the peripapillary area. Arteriovenous shunts are formed in the nasal (9 o'clock) and temporal (I to 5 o'clock) periphery. Fig 10. Bottom, distribution and graded evaluation of non perfusion in I3 eyes with rubeosis in the iris and/or the chamber angle. The whole fundus is involved in extensive (over 2.5 points) nonperfusion except the immediate peripapillary zone. Moderate nonperfusion (less than two points) is present in the macula.
sites of origin were usually located between the rim of the physiologic cupping and the disc margin. This finding suggests that they derived their arterial blood supply from the vascular component of the optic nervehead which is fed by the peripapillary choroidal arterial system. 5 The circulating blood through the newly formed vessels from the disc, on the other hand,
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invariably drained into the central retinal vein or its tributary. An overwhelming majority of the newly formed vessels of the retina were located in the midperipheral retina at a distance of 1 to 6 DD away from the disc margin (Fig 11). Many of them were found along the proximal margin of nonperfused areas (Fig 5). Rela-
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Fig 11. Distribution of newly formed vessels in 81 eyes . Of a total of 474 newly formed vessels, 65 are located on the optic disc. The majority of neovascularizations are distributed 1 to 6 DD away from the disc margin . They are more numerous along the vascular arcades. The posterior fundus is free of neovascularization.
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tively few newly formed vessels were situated in the retinal area temporal to the macula. There was a tendency for newly formed vessels larger than 2 DD in size to be located along the vascular arcades. Many of them originated near a major retinal artery and particularly along the upper and lower vascular arcades. The majority of larger-sized newly formed vessels were distributed within a zone 1 to 4 DD away from the disc.
DISCUSSION Little is known concerning the question of how the various vascular lesions of diabetic retinopathy are distributed over the whole fundus area. Our lack of information may partly be due to the absence of adequate clinical means of investigation and documentation. Attempts to evaluate the diabetic vascular lesions in the midperipheral retina have been made using a very wide-angle fundus camera6 or photomontage technique 7 similar to ours. As these studies were made either with color or black and white fundus photographs which did not allow the observation of capillary details, the information obtained were of limited nature. Our method of panoramic fluorescein angiography as applied to eyes with diabetic retinopathy is characterized by the following two aspects . First, it is a kind of microangiographic technique which allows the observation of small vessels down to the level of capillaries. Second, it covers a wide fundus area, maxi-
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mally 130° in diameter. This was made possible by means of a rapid sequence angiographic technique as applied consecutively to different fundus areas. Additional use of a wide-angle fundus camera (60°) enabled this method to be used as a routine method of clinical examination. Our findings show that the midperipheral retina is involved in a variety of diabetic vascular lesions throughout the stages of retinopathy. These vascular lesions in the midperipheral retina show a sharp contrast, in quality and severity, to those that OCcur in the macula. The main vascular components of diabetic maculopathy are vasodilatation, capillary microaneurysm formation , hyperpermeability, and OCcasional capillary fallouts. 8 ,9 The diabetic lesion in the mid peripheral retina, on the other hand, is characterized by the frequent presence of capillary nonperfusion of considerable size. Such capillary nonperfusion seems to outweigh other types of vascular lesions such as capillary microaneurysm formation and seems to be closely associated with the progression of retinopathy as a whole. As the salient feature of capillary nonperfusion in the midperipheral retina, the vascular occlusion often involved a fairly large microcirculatory unit from a precapillary arteriole through to a postcapillary venule. The arteriolar occlusion was usually located at the site where an arteriole leaves its parent artery , the site of occlusion being identified as a short stump protruding into the vaso-occluded retinal area. The non perfused areas often attained considerable size up to several disc diameters in the mid peripheral retina . The 609
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giant-sized nonperfusion areas appeared to be the result of confluence of neighboring occluded areas in some instances. The peripheral fundus area more than 6 DD away from the disc showed lesser tendency to undergo capillary nonperfusion than the more proximal, midperipheral retina. In advanced cases of diabetic retinopathy, however, vaso-occlusive changes involved the far periphery as well as the midperipheral retina. This means that the far periphery was spared from vaso-occlusion only to a certain degree. The immediate peripapillary zone of less than 1 DD away from the disc margin, on the other hand, was found to be consistently spared from vaso-occlusion. The peripapillary zone may be regarded as possessing a unique angioarchitectural or hemodynamic feature in this regard. A certain difference was noted in the pattern of nonperfusion in the peripapillary zone between the group with retinal neovascularization only and the one with disc neovascularization. In the latter group, the border of nonperfused area was significantly closer to the disc margin than in the former. Besides capillary nonperfusion, other types of retinal vascular lesions, such as capillary microaneurysm formation or vasodilatation, alsQ occurred in the midperipheral retina. Capillary microaneurysms were frequently seen in retinal areas adjacent to nonperfused vascular units. This seemed to indicate possibly that capillary microaneurysm formation represented a relatively moderate ~nd earlier type of retinal vascular reaction than nonperfusion in diabetic retinopathy. The observed capillary occlusions in our study did not necessarily coincide with retinal soft exudates. More frequently, the non perfused areas appeared just thinly veiled, slightly atrophic, or almost normal when seen ophthalmoscopically. This apparent discrepancy can be understood by assuming that soft exudates appear as such for a relatively short period, maybe for a few months, after they appear. Later on, the soft exudates would disappear leaving a slightly atrophic or almost normal looking retina behind. Capillary nonperfusion, on the other hand, is basically an irreversible process. 10 The non perfused areas may coincide with the soft exudates when the latter is still fresh. After disappearance of the latter, nonperfused retinal areas would be the prevalent angiographic feature in an apparently normal looking fundus. We proved in this study that the extent of capillary nonperfusion in the midperiphery increased parallel with the severity of diabetic retinopathy. N onperfusion was moderate in simple retinopathy, became more extensive in the group with retinal neovascularization, and even more so in the group with disc neovascularization. It appears that the extent of nonperfusion is closely, and quite probably, causatively associated with neovascularization from the retina and the optic disc. This finding is in accord with the longheld hypothesis that the hypoxic state of the retina induces retinal neovascularization. The distribution of retinal neovascularization showed interesting features when compared with the 610
distribution of nonperfused areas in midperipheral retina. Fluorescein angiography is a very sensitive and exact means of clinically detecting neovascularization. Because of this, our findings differ considerably from earlier observations 1 that were based on funduscopic examinations only and which, therefore, were concerned mainly with larger-sized neovascularization. According to our studies, neovascularization occurred most frequently 1 to 4 DD away from the disc margin. They did not occur in the far peripheral fundus more than 7 DD away from the disc. The retinal area temporal to the macula was characterized by the presence of little neovascularization. This finding is in sharp contrast when one considers that this area has a peculiar tendency to develop a variety of ophthalmoscopically visible diabetic lesions as blot hemorrhages or hard exudates including circinate lesions. There were certain exceptions to the general parallelism between retinal non perfusion and neovascularization. In four eyes, giant-sized neovascularizations were present in the absence of extensive capillary nonperfusion as would be expected. Otherwise, we consistently observed that giant-sized neovascularizations were associated with far-advanced capillary nonperfusion. This close association of nonperfusion and neovascularization should be of value as a clinical guide in the planning of therapeutic modalities including photocoagulation in diabetic retinopathy. It may generally be inferred that in eyes with neovascularization, the nonperfused areas would have to be regarded as target areas to be treated by photocoagulation. Also, in eyes with less prominent neovascularization, the detection of extensive nonperfused areas would serve as one of the factors advocating prophylactic photocoagulation. Certain reservations are necessary for the above statement because, as a matter of course, a number of other factors such as the state of the vitreous, the history of the affected eye, and the state of diabetic control, would have to be weighed. It must be added that the discrepancy between neovascularization and nonperfusion was frequently obvious in juvenile diabetic subjects. A unique feature was revealed in our present study concerning the retinal vascular lesions in eyes with rubeosis. When the 13 eyes were considered as a group, they were characterized by the presence of extensive capillary nonperfusion in the retina. Contrary to expectations and past reports, 11-13 a considerably small number of neovascularizations were present in these rube otic eyes. They tended to develop more from the disc than from the retina. Also, the sizes of newly formed vessels were relatively small despite the prevalence of capillary non perfusion. The observed findings clearly indicate that a close relationship exists between retinal nonperfusion and rubeosis. The observed beneficial effect of photocoagulation 12.13 would have to be explained with due consideration of this parallelism. Just why the rubeotic state is not accompanied by profuse neovascularizations from the retina or the disc cannot be explained without disgressing into speculations.
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There were certain exceptions to the observed general principle that the macula is capable of developing a limited type of vascular lesions and is therefore not involved in extensive capillary nonperfusion. Gross defects of capillaries in the macula, as reported by others 14,15 were occasionally observed in our series. These gross defects were caused either by encroachment of non perfusion from the temporal side toward the fovea, or by apparently spontaneous obliteration of a fairly large number of parafoveal capillaries. In almost all such cases, there was a more widespread nonperfusion in the midperipheral retina. It appeared the macula is exempted from gross vaso-occlusive lesions to a certain degree, but it breaks down when the vaso-occlusive tendency is severe enough to affect the retina as a whole. Instances of fairly extensive nonperfusion in the macula were more common in eyes of juvenile diabetics and of adults in whom the diabetic state ran a rampant course due to inadequate medical treatment or to sheer ignorance of the presence of diabetes. The vascular pattern in the macula retained its integrity in eyes with diabetes of relatively slow progression or with good control from the onset. It is not possible to answer fully the question as to what anatomic or physiologic grounds underlie the observed prevalence of vaso-occlusive lesions in the midperipheral retina as opposed to those in macula. It should be noted that the smallest microcirculatory unit, which consists of a feeder arteriole, network of capillaries, and a collector venule or venules, is of considerably lesser size in the macula than in the midperiphery. The difference may play a role in the observed prevalence of vaso-occlusion in the midperiphery. The retinal area served by radial peripapillary capillaries (RPCS)16 has been shown, in our study, to be also spared from the vaso-occlusive process. The retinal vessels are basically arranged in a layered patternY It is one- or two-layered as a general rule. In areas where the RPCs are distributed, a three-layered pattern is the prevailing featureY Our corrosion-cast studies in monkey eyes 18 also support this concept. The multiple-layered vascular structure might make the retinal area served by RPCs more resistant to the irreversible vaso-occlusive process. Objections may be raised as to the soundness of the method used in our studies. From the nature of our method, it inevitably follows that each component of· the montaged angiograms represents different angiographic phases. This would imply that capillary details are hard to be discerned in that part of the angiogram taken at a later phase due to extravasation of dye. This possible drawback can be minimized by working rapidly during the sequential angiographic-photographic process. An experienced fluorescein angiograp her can complete a single angiographic run of 36 frames covering all the attainable fundus areas in less than 90 seconds. It is even possible to redo another complete angiographic run during the same sitting covering a somewhat later phase. It may be questioned if it is theoretically possible to reproduce a wide fundus area, which is shaped
concave-spherical, as a flat plane such as a montaged aggregate of a number of fundus photographs. As a matter of fact, discrepancies in the composite angiograms proved to be inconsequential and less so when using wide-angle fundus photographs subtending 60° each. As another objection, it may be argued if it is rational to place the center of the sector-shaped divisioning of the fundus at the optic disc instead at the fovea which approximates the geographic posterior pole of the eye. Our decision was made as a matter of expediency. Our findings seem to show that clear-cut data can be obtained by this method. The grading of capillary nonperfusion for each block into four grades (0, 1, 2 and 3 points) was also adopted on a purely arbitrary basis. A considerably more complicated situation of little practical value would have resulted had we adopted a more detailed coding system for the evaluation. Among the various clinical manifestations of diabetic retinopathy, capillary nonperfusion can be regarded as an irreversible vascular process. It is one of the best indicators of the past history ofthe affected eye. Other funduscopic or angiographic features, such as blot hemorrhages or exudates, are frequently of fleeting nature and do not necessarily give clues as to the past and future course of diabetic retinopathy in individual cases. Similarly, neovascularization from the retina or the optic disc are key features in the diagnosis and prognosis of proliferative retinopathy.19 The close association of capillary nonperfusion and fundus neovascularization as shown in this study merits attention in future clinical or research works on diabetic retinopathy.
ACKNOWLEDGMENT The authors thank Michitaka Kitagawa, MD, Toshiyuki Hasunuma, MD, Takashi Niki, MD, Kenichi Tsuji, MD, and Sergio Nishio, MD, who are dedicated members of the diabetic retinopathy group in our Department. They lent their valuable help throughout the stages of the present investigation including the elaborate task of processing and evaluating the montaged angiograms.
REFERENCES 1. Taylor E, Dobree JH. Proliferative diabetic retinopathy. Site and size of initial lesions. Br J Ophthalmol 1970; 54:11-18. 2. James WA Jr, L'Esperance FA. Treatment of diabetic optic nerve neovascularization by extensive retinal photocoagulation. Am J Ophthalmol 1974; 78:939-47. 3. Hercules BL, Gayes II, Lucas SB, Jeacock J. Peripheral retinal ablation in the treatment of proliferative diabetic retinopathy: a three-year interim report of a randomised, controlled study using the argon laser. Br J Ophthalmol 1977; 61 :555-63. 4. Muraoka K, Yokochi K, Sodeno Y. Nature and origin of the neovascularization of the optic disc. Jpn J Ophthalmol 1979;
2389-96. 5. Evans PY, Shimizu K, Limaye S, et a/. Fluorescein cineangiography of the optic nerve head. Trans Am Acad Ophthalmol Otolaryngol 1973; 77:260-73.
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6. Cohen HB, McMeel JW, Franks EP. Diabetic traction detachment. Arch Ophthalmol 1979; 97: 1268-72. 7. Reuscher A, Borgmann H. Zur Problematick von Verlaufsbeurteilungen bei diabetischer Retinopathie. Klin Montabsl Augenheilkd 1976; 168:181-6. 8. Shikano S, Shimizu K. Atlas of Fluorescence Fundus Angiography. Philadelphia: WB Saunders 1968; 115-32. 9. Oosterhuis JA, Vink R. Fluorescein photography in diabetic retinopathy. In : Henkes HE, ed . Perspectives in Ophthalmology. Amsterdam: Excerpta Medica 1968; 115-32. 10. Kohner EM, Dollery CT. The natural history of diabetic retinopathy. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. Arlington: U.S. Department of Health, Education and Welfare 1968; 65-79 11. Madsen PH. Rubeosis of the iris and haemorrhagic glaucoma in patients with proliferative diabetic retinopathy. Sr J Ophthalmol 1971 ; 55:368-71. 12. Little HL, Rosenthal AR, Dellaporta A, Jacobson DR. The effect of pan-retinal photocoagulation on rubeosis iridis. Am J Ophthalmol1976; 81:804 - 9
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13. Wand M, Dueker DK, Aiello LM, Grant WM. Effects of panretinal photocoagulation on rubeosis iridis, angle neovascularization, and neovascular glaucoma. Am J Ophthalmol1978; 86:332-9. 14. Rubinstein K, Myska V. Pathogenesis and treatment of diabetic maculopathy. Br J Ophthalmol 1974; 58:76-84. 15. Bresnick GH, OeVenecia GO, Myers FL, et al. Retinal ischemia in diabetic retinopathy. Arch Ophthalmol 1975; 93:1300-10. 16. Henkind P. Radial peripapillary capillaries of the retina. I. Anatomy: human and comparative. Br J Ophthalmol 1967; 51:115-23. 17. Henkind P. Microcirculation of the peripap'illary retina. Trans Am Acad Ophthalmol Otolaryngol 1969; 73:890-7. 18. Shimizu K, Ujiie K. Structure of Ocular Vessels. Tokyo: IgakuShoin 1978; 11 -50. 19. The Diabetic Retinopathy Study Research Group. Four risk factors for severe visual loss in diabetic retinopathy. The third report from the diabetic retinopathy study. Arch Ophthalmol 1979; 97:654-5.
Abstract: We evaluated the topologic distribution of vaso-occlusive and vasoformative lesions in 119 eyes with diabetic retinopathy using our newly developed super-wide (130°) fluorescein angiographic montage technique. A numeric coding system was applied to assess the vaso-occlusive lesions by dividing each fundus maximally into 418 blocks. We demonstrated that the mid peripheral retina was far more prone to undergo capillary nonperfusion than the posterior retina. The extent of capillary non perfusion was more pronounced in eyes with neovascularization from (in ascending order): the retina, the optic disc, and in the chamber angle. [Key words: capillary non perfusion, diabetic retinopathy, fluorescein angiography, maculopathy, midperipheral retina, neovascularization, rubeosis iridis.] Ophthalmology 88:601-612, 1981
Application of fluorescein angiography to eyes with diabetic retinopathy significantly contributes to a better understanding of the nature of maculopathy and disc neovascularization. On the other hand, very little is known about the vascular lesions in the midperipheral retina. The importance of midperipheral retina in the pathogenesis and progression of diabetic retinopathy is well known, as an overwhelming majority of retinal neovascularization is located here. t Also, the midperipheral area is the chief target area to which panretinal photocoagulation can be applied. 2 •3 Fluorescein angiographic studies of diabetic retinopathy have mainly concerned the vicinity of the posterior fundus. Prior technical limitations made it impossible to examine routinely a wide retinal area as a composite whole in clinical evaluations of diabetic retinopathy. We have developed a new technique of
using fluorescein angiography that enables the observation of retinal vessels in capillary detail over a wide fundus area. Using this relatively simple method on eyes with diabetic retinopathy, we have found that a widespread capillary nonperfusion tends to involve the midperipheral retina and that the extent of nonperfusion seems to parallel the severity of diabetic retinopathy. It appears that the midperipheral retina plays a key role in the evolution of diabetic retinopathy, particularly in its malignant form. It appears that the nature and extent of vascular lesions in the midperipheral retina may serve as a useful clinical guide in assessing the prognosis of the affected eye and should be considered in designing therapeutic modalities, including photocoagulation.
MATERIALS AND METHODS From the Department of Ophthalmology. Gunma University School of Medicine, Maebashi, Japan. Presented at the Eighty-Fifth Annual Meeting of the American Academy of Ophthalmology, Chicago, November 2- 7, 1980. Reprint request to Koichi Shimizu, MD, Department of Ophthalmol~gy, Gunma University School of Medicine, 3 Showamachi, aebashi, 371 Japan.
0161-6420/8110700/0601/$1.10
© American Academy
of Ophthalmology
One hundred and nineteen eyes (87 patients) seen by us during the period from January 1977 to June 1980 were included in our study. These 119 eyes were selected from a larger series of eyes with diabetic retinopathy seen during the same period. The selection was made after discarding those with a minimum grade of retinopathy and those in whom the quality of 601
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panoramic angiogram did not meet our technical criteria. The angiograms had to cover a sufficiently wide fundus area and they had to show capillary detail when enlarged and printed. All of the 119 eyes were affected by moderate to advanced diabetic retinopathy. They included 38 eyes with simple retinopathy (group A); 33 eyes with retinal neovascularization (group B); and 48 eyes with neovascularization from the optic disc (group C). These 48 eyes with disc neovascularization were often, but not necessarily, accompanied by neovascularization from the retina. A total of 13 eyes, one from group A and 12 from group C, showed rubeosis in the iris and/or the chamber angle. These 13 rubeotic eyes were evaluated in their respective groupings according to their fundus manifestations and also as a parallel, distinctive group (group D). The angiographic technique used in this study is, in principle, that of ordinary fluorescein angiography after a single injection of 5 ml of 10% fluorescein solution. As a specific feature, different fundus areas are photographed in rapid succession. Specifically, care is taken to adjust the focusing for each frame and not to leave an unphotographed portion in the fundus. When working with the ordinary (300) fundus cameras, maximally 35 frames are necessary to document the whole fundus. With semiwide (45°) or wide (60°) fundus cameras, a considerably lesser number of frames are necessary. Under normal circumstances, it is possible to document the angiographic aspects of a given fundus subtending 130 degrees in diameter. The negative film
is then enlarged and printed. The prints are assembled and arranged to form a composite, panoramic fluorescein angiogram. In evaluating each of the 119 composite angiograms, we paid particular attention to the size and distribution of capillary nonperfusion areas on the one hand, and to the location of retinal neovascularization on the other. Other angiographic features, such as capillary microaneurysms, dilatation of retinal vessels, and extravasation of dye, were not treated as separate items in this investigation. This decision was made not only for the sake of convenience, but also because capillary nonperfusion and neovascularization seem to play a major role in the pathogenesis and progression of diabetic retinopathy. STATISTICAL EVALVA TION
We performed a quantitative evaluation of the topologic distribution and severity of retinal capillary nonperfusion in the panoramic fluorescein angiograms in the 119 eyes. Each fundus was divided into 32 sectors by radial lines passing through the center of the optic disc. The sectors were again divided into small blocks by concentric circles with the disc as their center. The distance between two consecutive circles was set at 0.5 DD (disc diameter) in the fundus area ofless than 4 DD from the disc margin and at 1 DD in the outer area. One panoramic fluorescein angiogram was thus partitioned maximally into 418 blocks (Fig 1). Each block was assessed by a coding system as to the
Fig 1. Each fundus is divided into small blocks by 32 radial lines and concentric circles. The disc lies at the center.
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presence and extent of capillary nonperfusion. A given block was judged as point 0 when the area of nonperfusion occupied less than 10% ofthe block. It was judged as point 1, 2,or 3 when the area of nonperfusion was more than 10,40 or 80% of the block, respectively (Fig 2). This process of evaluation was repeated for each of the 119 angiograms. Thereafter, the points were added and averaged for each corresponding block of the 119 angiograms. This process of addition and averaging was performed for group A (simple retinopathy), group B (proliferative retinopathy), group C (disc neovascularization) and group D (rubeosis iridis). The averaged points for the 418 blocks were graded into six shadowed scales and were displayed in four diagrams representing each of the four groups.
RESULTS We observed various types of diabetic retinal vascular lesions including capillary microaneurysms, hyperpermeability of vessels, areas of capillary nonperfusion and, in 81 eyes, neovascularization from the retina and/or the optic disc. Among the 119 eyes, there was a general tendency for the retinal vascular lesions to be more pronounced in degree and extent in the midperipheral than in the posterior fundus. Even in eyes in which the macula was affected with only a few capillary microaneurysms, distinct areas of capillary nonperfusion and much more numerous capillary microaneurysms were located in the midperipheral retina (Fig 3). Typically, a capillary nonperfusion area in-
Fig 2. The coding system. Each block is given 0.1,2. or 3 points according to the extent of nonperfusion. In this sample eye. 0 point is shown as blank. A dash (-) indicates that the block was not available for evaluation.
volved a whole microcirculatory unit comprised by a feeder arteriole, capillary network belonging to it, and a collector venule. Major retinal vessels serving the far periphery were spared from the gross vaso-occlusive process except in cases of advanced retinopathy. In addition to the posterior fundus, capillary nonperfusion was uncommon in the close vicinity of the optic disc. A peripapillary zone of 1 to 1.5 DD from the disc margin was usually spared from capillary nonperfusion even in advanced diabetic retinopathy. Also, the retinal area along the upper and lower vascular arcades, which would roughly correspond to the area served by radial peripapillary capillaries (RPCs), tended to be spared from gross capillary nonperfusion. ANGIOGRAPHIC FEATURES
Simple retinopathy (group A). The 38 eyes belonging to this group showed a very wide variety of retinal microvascular lesions, ranging from minimal and sporadic changes to more advanced and widespread ones. There was a tendency for the vascular lesions to be more intense and advanced in nature in the midperipheral retina than in the macuta (Fig 3). In mild cases, for instance, there were just a few capillary microaneurysms in the macula. In the midperipheral retina, on the other hand, there were more numerous capillary microaneurysms and areas of non perfusion that might be as small as one-fourth DD in diameter. These lesions were frequently located upper, nasal, and lower to the disc, 1 to 4 DD away from the disc margin. The areas of capillary nonperfusion sometimes, but not necessarily, coincided with areas of soft
-- 11 D.O.
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exudates. Rather, the nonperfused areas appeared , ophthalmoscopically, almost normal or slightly opaque when they were located in the midperipheral retina. Retinal vessels adjacent to the nonperfused areas were
Fig 3. Top, simple retino pa th y in a 67-year-old man. Diabetes was detected by ophthalmoscopy four years ago and has been und er co ntro l. Capillary microaneurysms and nonperfu sio n areas a re seen in the midperiphery at I and 8 o'c loc k positions . Fig 4. B Ol/o m , distribution and graded evalu ation of nonpe rfu s ion in 38 e yes with s impl e retinopath y . Minimum to modera te areas of no nperfu sion are di stributed 1.5 to 5 DD a wa y fro m the di sc margin.
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generally hyperpermeable to fluorescein. Peripheral fundus areas more than 6 DD away from the disc were spared from vaso-occlusive changes in milder cases. In more advanced cases of simple retinopathy, the more
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peripheral fundus areas showed variable abnormalities including vasodilatation, hyperpermeability of vessels, and, occasionally, extensive capillary nonperfusion reaching into the far periphery. Even in such advanced cases, however the posterior area surrounded by the disc, the macula, and the upper and lower vascular arcades were usually spared from gross vaso-occlusive changes. A cumulative topographic display of 38 eyes with simple retinopathy (Fig 4) showed that an oval central fundus area, with the disc and fovea as epicenters, was virtually free of capillary nonperfusion of noticeable sizes. Areas of moderate nonperfusion were distributed 1 to 4 DD away from the disc margin in the sector upper, nasal, and lower to the disc. The retinal area temporal to the fovea seemed also to be a predilected site of capillary nonperfusion of a lesser degree. The more peripheral retina more than 5 DD from the disc margin was not affected by capillary nonperfusion when seen collectively. Proliferative retinopathy (group B). The 33 eyes with neovascularization from the retina but not from the disc were characterized by the presence of more extensive nonperfused areas in the midperipheral retina (Fig 5). The nonperfused areas were variable in size and distribution. When large, the area of nonperfusion attained a size of 6 or more disc diameters across and was bordered by major retinal vessels serving the far periphery. Retinal vessels adjacent to the nonperfused areas showed hyperpermeability, capillary dilatation, microaneurysm formation, and, frequently, retinal neovascularization. Newly formed vessels were often located at the posterior border of the nonperfused retinal area. The vessels in the posterior fundus showed minimal to moderate alterations including vasodilatation, hyperpermeability, and microaneurysm formation. There was occasional nonperfusion of individual or few capillaries in the macula, but such occlusions did not attain a size comparable to what occurred in the midperiphery. A cumulative topographic display of the 33 eyes with retinal neovascularization (Fig 6) showed the presence of moderate (one to two points) of nonperfusion in the midperipheral fundus. The nonperfusion was more prominent in the upper, nasal, and lower sector, 1.5 to 5 DD away from the disc margin. The more peripheral retinal area was also affected by nonperfusion to a lesser degree. The oval central retinal area including the disc and the fovea was the least affected by nonperfusion, if at all. The retinal sector temporal to the fovea was also involved in nonperfusion to a smaller degree than the other mid peripheral retinal areas. Disc neovascularization (group C). The 48 eyes with neovascularization from the optic disc were characterized by the presence of extensive capillary .nonperfusion in the midperipheral retina (Fig 7). In a tYpical instance, nonperfusion involved the whole retinal area which could be documented by the panoramic fluorescein angiographic technique except
for the central retina area, including the disc and the macula. Despite extensive capillary nonperfusion, major retinal vessels serving the far periphery were generally patent. Apparently because of the lack of functioning capillaries, microaneurysms were either absent or inconspicuous in the midperipheral retina. Among the 48 eyes in this group, retinal neovascularization was present in 37 eyes. The newly formed vessels were generally far less in number and size than in group B. As a general trend, the vascular structure in the macula was fairly well preserved when compared with the pronounced changes in the midperiphery. Depending on the severity of individual cases, the vessels in the macula showed generalized vasodilatation, hyperpermeability, and occasional capillary fallout. The retinal sector temporal to the fovea appeared to be one of the predilected sites of gross capillary nonperfusion. A cumulative topographic display of 48 eyes in group C (Fig 8) showed the presence of a more widespread capillary nonperfusion (two to three points) in the midperipheral retina than in the former two groups. Nonperfusion was most pronounced 4 to 7 DD away from the disc. The central retina bordered by the disc, fovea, and the vascular arcades manifested lesser degree (one point or less) of capillary nonperfusion. Rubeosis iridis (group D). The 13 eyes with rubeosis in the iris and/or the chamber angle also belonged either to group A (one eye) or group C (12 eyes), as all the eyes but one showed neovascularization from the optic disc. These 12 eyes manifested no retinal neovascularization at all (seven eyes) or minimal new vessels (five eyes). The most cbaracteristic feature of these 13 eyes (Fig 9) was the presence of extensive capillary non perfusion throughout the whole recordable fundus except the central retina. Only major retinal vessels seemed to be functioning in the midperipheral and peripheral retina. They occasionally formed distal arteriovenous shunts. Veins showed gross irregularities forming bead-like dilatations and occasional duplications. Vessels in the macula were affected in varying degrees, showing generalized dilatations and nonperfused areas. However, retinal vessels along the papillomacular bundle and in the parafoveal area were generally well preserved when compared with the extensive vaso-occlusive changes in the midperipheral retina. A cumulative topographic display of 13 eyes with rubeosis (Fig 10) indicated that the whole midperipheral fundus area was affected by advanced (two to three points) capillary nonperfusion. The far peripheral fundus was also involved in the vasoocclusive process. The central fundus showed a lesser degree of nonperfusion than the midperipheral retina, but the degree was still considerable (one to two points) . Distribution of neovascularization. The distribution of retinal and disc neovascularization was evaluated as a whole (Fig 11). We identified a total of 474 newly formed vessels in 81 out of the 119 eyes through 605
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Fig 5. Top , proliferative retinopathy (retinal neovascularization) in a 46-year-old man. Diabetes was detected two weeks after onset of visual disturbance. Gross capillary defects and neovascularizations are distributed in the midperipheral retina. Vessels in the macula are hyperpermeable to fluorescein. Fig 6. Bottom, distribution and graded evaluation of non· perfusion in 33 eyes with retinal neovascularization. Areas of moderate nonperfusion are distributed in the midperipheral retina. The posterior fundus and the peripapillary area are least involved in nonperfusion.
examination of the panoramic angiograms. The locations of the newly formed vessels were plotted on a model fundus in a diagrammatic pattern. Sixty five newly formed vessels (48 eyes) originated from the
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optic disc. Peculiarly, the central fundus in to the disc, the macula. and the vascular arcades were spared from neovascularization except in a very few instances. Also. the immediate peripapillary zone of less than 1
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Fig 7. Top. disc neovascularization in a 41-year-old man. Diabetes was diagnosed two years ago and is under poor control. Large nonperfused areas are distributed in the mid peripheral retina. There are generalized vasodilatation, hyperpermeability, and a few retinal neovascularizations. Fig 8. Bottom, distribution and graded evaluation of nonperfusion in 48 eyes with disc neovascularization. The whole midperipheral retina is affected by extensive nonperfusion of more than two points. The papillomacular area shows lowest grade of nonperfusion.
DD aWay from the disc margin was free of newly formed vessels. In all instances in which newly formed .ressels seemed to be located in the immediate proximuy of the disc margin, they proved to be extensions
from the disc and not to originate from the peripapillary retina. Confirming our earlier observations,4 none of the newly formed vessels from the disc originated from the central retinal artery or its tributary. Their
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Fig 9. Top. retinopathy with rubeosis in the chamber angle in a 64-year-old man. Diabetes was detected 10 years ago but. was left untreated. Nephropathy and systemic hypertension (190/100 mm Hg) have been present for the past two years. The whole fundus is affected by generalized capillary nonperfusion except the macula and the peripapillary area. Arteriovenous shunts are formed in the nasal (9 o'clock) and temporal (I to 5 o'clock) periphery. Fig 10. Bottom, distribution and graded evaluation of non perfusion in I3 eyes with rubeosis in the iris and/or the chamber angle. The whole fundus is involved in extensive (over 2.5 points) nonperfusion except the immediate peripapillary zone. Moderate nonperfusion (less than two points) is present in the macula.
sites of origin were usually located between the rim of the physiologic cupping and the disc margin. This finding suggests that they derived their arterial blood supply from the vascular component of the optic nervehead which is fed by the peripapillary choroidal arterial system. 5 The circulating blood through the newly formed vessels from the disc, on the other hand,
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invariably drained into the central retinal vein or its tributary. An overwhelming majority of the newly formed vessels of the retina were located in the midperipheral retina at a distance of 1 to 6 DD away from the disc margin (Fig 11). Many of them were found along the proximal margin of nonperfused areas (Fig 5). Rela-
SHIMIZU, et al • DIABETIC RETINOPATHY SYMPOSIUM
Fig 11. Distribution of newly formed vessels in 81 eyes . Of a total of 474 newly formed vessels, 65 are located on the optic disc. The majority of neovascularizations are distributed 1 to 6 DD away from the disc margin . They are more numerous along the vascular arcades. The posterior fundus is free of neovascularization.
80.0.
tively few newly formed vessels were situated in the retinal area temporal to the macula. There was a tendency for newly formed vessels larger than 2 DD in size to be located along the vascular arcades. Many of them originated near a major retinal artery and particularly along the upper and lower vascular arcades. The majority of larger-sized newly formed vessels were distributed within a zone 1 to 4 DD away from the disc.
DISCUSSION Little is known concerning the question of how the various vascular lesions of diabetic retinopathy are distributed over the whole fundus area. Our lack of information may partly be due to the absence of adequate clinical means of investigation and documentation. Attempts to evaluate the diabetic vascular lesions in the midperipheral retina have been made using a very wide-angle fundus camera6 or photomontage technique 7 similar to ours. As these studies were made either with color or black and white fundus photographs which did not allow the observation of capillary details, the information obtained were of limited nature. Our method of panoramic fluorescein angiography as applied to eyes with diabetic retinopathy is characterized by the following two aspects . First, it is a kind of microangiographic technique which allows the observation of small vessels down to the level of capillaries. Second, it covers a wide fundus area, maxi-
110.0.
mally 130° in diameter. This was made possible by means of a rapid sequence angiographic technique as applied consecutively to different fundus areas. Additional use of a wide-angle fundus camera (60°) enabled this method to be used as a routine method of clinical examination. Our findings show that the midperipheral retina is involved in a variety of diabetic vascular lesions throughout the stages of retinopathy. These vascular lesions in the midperipheral retina show a sharp contrast, in quality and severity, to those that OCcur in the macula. The main vascular components of diabetic maculopathy are vasodilatation, capillary microaneurysm formation , hyperpermeability, and OCcasional capillary fallouts. 8 ,9 The diabetic lesion in the mid peripheral retina, on the other hand, is characterized by the frequent presence of capillary nonperfusion of considerable size. Such capillary nonperfusion seems to outweigh other types of vascular lesions such as capillary microaneurysm formation and seems to be closely associated with the progression of retinopathy as a whole. As the salient feature of capillary nonperfusion in the midperipheral retina, the vascular occlusion often involved a fairly large microcirculatory unit from a precapillary arteriole through to a postcapillary venule. The arteriolar occlusion was usually located at the site where an arteriole leaves its parent artery , the site of occlusion being identified as a short stump protruding into the vaso-occluded retinal area. The non perfused areas often attained considerable size up to several disc diameters in the mid peripheral retina . The 609
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giant-sized nonperfusion areas appeared to be the result of confluence of neighboring occluded areas in some instances. The peripheral fundus area more than 6 DD away from the disc showed lesser tendency to undergo capillary nonperfusion than the more proximal, midperipheral retina. In advanced cases of diabetic retinopathy, however, vaso-occlusive changes involved the far periphery as well as the midperipheral retina. This means that the far periphery was spared from vaso-occlusion only to a certain degree. The immediate peripapillary zone of less than 1 DD away from the disc margin, on the other hand, was found to be consistently spared from vaso-occlusion. The peripapillary zone may be regarded as possessing a unique angioarchitectural or hemodynamic feature in this regard. A certain difference was noted in the pattern of nonperfusion in the peripapillary zone between the group with retinal neovascularization only and the one with disc neovascularization. In the latter group, the border of nonperfused area was significantly closer to the disc margin than in the former. Besides capillary nonperfusion, other types of retinal vascular lesions, such as capillary microaneurysm formation or vasodilatation, alsQ occurred in the midperipheral retina. Capillary microaneurysms were frequently seen in retinal areas adjacent to nonperfused vascular units. This seemed to indicate possibly that capillary microaneurysm formation represented a relatively moderate ~nd earlier type of retinal vascular reaction than nonperfusion in diabetic retinopathy. The observed capillary occlusions in our study did not necessarily coincide with retinal soft exudates. More frequently, the non perfused areas appeared just thinly veiled, slightly atrophic, or almost normal when seen ophthalmoscopically. This apparent discrepancy can be understood by assuming that soft exudates appear as such for a relatively short period, maybe for a few months, after they appear. Later on, the soft exudates would disappear leaving a slightly atrophic or almost normal looking retina behind. Capillary nonperfusion, on the other hand, is basically an irreversible process. 10 The non perfused areas may coincide with the soft exudates when the latter is still fresh. After disappearance of the latter, nonperfused retinal areas would be the prevalent angiographic feature in an apparently normal looking fundus. We proved in this study that the extent of capillary nonperfusion in the midperiphery increased parallel with the severity of diabetic retinopathy. N onperfusion was moderate in simple retinopathy, became more extensive in the group with retinal neovascularization, and even more so in the group with disc neovascularization. It appears that the extent of nonperfusion is closely, and quite probably, causatively associated with neovascularization from the retina and the optic disc. This finding is in accord with the longheld hypothesis that the hypoxic state of the retina induces retinal neovascularization. The distribution of retinal neovascularization showed interesting features when compared with the 610
distribution of nonperfused areas in midperipheral retina. Fluorescein angiography is a very sensitive and exact means of clinically detecting neovascularization. Because of this, our findings differ considerably from earlier observations 1 that were based on funduscopic examinations only and which, therefore, were concerned mainly with larger-sized neovascularization. According to our studies, neovascularization occurred most frequently 1 to 4 DD away from the disc margin. They did not occur in the far peripheral fundus more than 7 DD away from the disc. The retinal area temporal to the macula was characterized by the presence of little neovascularization. This finding is in sharp contrast when one considers that this area has a peculiar tendency to develop a variety of ophthalmoscopically visible diabetic lesions as blot hemorrhages or hard exudates including circinate lesions. There were certain exceptions to the general parallelism between retinal non perfusion and neovascularization. In four eyes, giant-sized neovascularizations were present in the absence of extensive capillary nonperfusion as would be expected. Otherwise, we consistently observed that giant-sized neovascularizations were associated with far-advanced capillary nonperfusion. This close association of nonperfusion and neovascularization should be of value as a clinical guide in the planning of therapeutic modalities including photocoagulation in diabetic retinopathy. It may generally be inferred that in eyes with neovascularization, the nonperfused areas would have to be regarded as target areas to be treated by photocoagulation. Also, in eyes with less prominent neovascularization, the detection of extensive nonperfused areas would serve as one of the factors advocating prophylactic photocoagulation. Certain reservations are necessary for the above statement because, as a matter of course, a number of other factors such as the state of the vitreous, the history of the affected eye, and the state of diabetic control, would have to be weighed. It must be added that the discrepancy between neovascularization and nonperfusion was frequently obvious in juvenile diabetic subjects. A unique feature was revealed in our present study concerning the retinal vascular lesions in eyes with rubeosis. When the 13 eyes were considered as a group, they were characterized by the presence of extensive capillary nonperfusion in the retina. Contrary to expectations and past reports, 11-13 a considerably small number of neovascularizations were present in these rube otic eyes. They tended to develop more from the disc than from the retina. Also, the sizes of newly formed vessels were relatively small despite the prevalence of capillary non perfusion. The observed findings clearly indicate that a close relationship exists between retinal nonperfusion and rubeosis. The observed beneficial effect of photocoagulation 12.13 would have to be explained with due consideration of this parallelism. Just why the rubeotic state is not accompanied by profuse neovascularizations from the retina or the disc cannot be explained without disgressing into speculations.
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There were certain exceptions to the observed general principle that the macula is capable of developing a limited type of vascular lesions and is therefore not involved in extensive capillary nonperfusion. Gross defects of capillaries in the macula, as reported by others 14,15 were occasionally observed in our series. These gross defects were caused either by encroachment of non perfusion from the temporal side toward the fovea, or by apparently spontaneous obliteration of a fairly large number of parafoveal capillaries. In almost all such cases, there was a more widespread nonperfusion in the midperipheral retina. It appeared the macula is exempted from gross vaso-occlusive lesions to a certain degree, but it breaks down when the vaso-occlusive tendency is severe enough to affect the retina as a whole. Instances of fairly extensive nonperfusion in the macula were more common in eyes of juvenile diabetics and of adults in whom the diabetic state ran a rampant course due to inadequate medical treatment or to sheer ignorance of the presence of diabetes. The vascular pattern in the macula retained its integrity in eyes with diabetes of relatively slow progression or with good control from the onset. It is not possible to answer fully the question as to what anatomic or physiologic grounds underlie the observed prevalence of vaso-occlusive lesions in the midperipheral retina as opposed to those in macula. It should be noted that the smallest microcirculatory unit, which consists of a feeder arteriole, network of capillaries, and a collector venule or venules, is of considerably lesser size in the macula than in the midperiphery. The difference may play a role in the observed prevalence of vaso-occlusion in the midperiphery. The retinal area served by radial peripapillary capillaries (RPCS)16 has been shown, in our study, to be also spared from the vaso-occlusive process. The retinal vessels are basically arranged in a layered patternY It is one- or two-layered as a general rule. In areas where the RPCs are distributed, a three-layered pattern is the prevailing featureY Our corrosion-cast studies in monkey eyes 18 also support this concept. The multiple-layered vascular structure might make the retinal area served by RPCs more resistant to the irreversible vaso-occlusive process. Objections may be raised as to the soundness of the method used in our studies. From the nature of our method, it inevitably follows that each component of· the montaged angiograms represents different angiographic phases. This would imply that capillary details are hard to be discerned in that part of the angiogram taken at a later phase due to extravasation of dye. This possible drawback can be minimized by working rapidly during the sequential angiographic-photographic process. An experienced fluorescein angiograp her can complete a single angiographic run of 36 frames covering all the attainable fundus areas in less than 90 seconds. It is even possible to redo another complete angiographic run during the same sitting covering a somewhat later phase. It may be questioned if it is theoretically possible to reproduce a wide fundus area, which is shaped
concave-spherical, as a flat plane such as a montaged aggregate of a number of fundus photographs. As a matter of fact, discrepancies in the composite angiograms proved to be inconsequential and less so when using wide-angle fundus photographs subtending 60° each. As another objection, it may be argued if it is rational to place the center of the sector-shaped divisioning of the fundus at the optic disc instead at the fovea which approximates the geographic posterior pole of the eye. Our decision was made as a matter of expediency. Our findings seem to show that clear-cut data can be obtained by this method. The grading of capillary nonperfusion for each block into four grades (0, 1, 2 and 3 points) was also adopted on a purely arbitrary basis. A considerably more complicated situation of little practical value would have resulted had we adopted a more detailed coding system for the evaluation. Among the various clinical manifestations of diabetic retinopathy, capillary nonperfusion can be regarded as an irreversible vascular process. It is one of the best indicators of the past history ofthe affected eye. Other funduscopic or angiographic features, such as blot hemorrhages or exudates, are frequently of fleeting nature and do not necessarily give clues as to the past and future course of diabetic retinopathy in individual cases. Similarly, neovascularization from the retina or the optic disc are key features in the diagnosis and prognosis of proliferative retinopathy.19 The close association of capillary nonperfusion and fundus neovascularization as shown in this study merits attention in future clinical or research works on diabetic retinopathy.
ACKNOWLEDGMENT The authors thank Michitaka Kitagawa, MD, Toshiyuki Hasunuma, MD, Takashi Niki, MD, Kenichi Tsuji, MD, and Sergio Nishio, MD, who are dedicated members of the diabetic retinopathy group in our Department. They lent their valuable help throughout the stages of the present investigation including the elaborate task of processing and evaluating the montaged angiograms.
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