RED KRYPTON AND BLUE-GREEN ARGON PANRETINAL LASER PHOTOCOAGULATION FOR PROLIFERATIVE DIABETIC RETINOPATHY: A LABORATORY AND CLINICAL COMPARISON*

Transcription

1 967 RED KRYPTON AND BLUE-GREEN ARGON PANRETINAL LASER PHOTOCOAGULATION FOR PROLIFERATIVE DIABETIC RETINOPATHY: A LABORATORY AND CLINICAL COMPARISON* BY George W. Blankenship, MD INTRODUCTION SHORTLY AFrER THE DEVELOPMENT OF RETINAL PHOTOCOAGULATION BY MEYER- Schwickerath,"12 it was discovered that this procedure could be used as treatment for the complications of diabetic retinopathy. 1-6 At that time, the main indication was bleeding from neovascular proliferative tissue, and the suggeted technique was direct focal coagulation of the neovascular tissue that had hemorrhaged. With the development of panretinal photocoagulation (PRP) techniques,7'8 the dual benefit of regression of existent neovascular proliferative tissue as well as the prevention offuture neovasculariation was appreciated. Initially, light produced by a xenon arc was used for photocoagulation, but later several other light sources were developed.9'5 The ruby laser provided a pulsed monochromatic light source of nm wavelength that produced a small and well-defined coagulation of the retinal pigment epithelium.9'12 The blue-green continuous wavelengths of the argon laser (488 and nm), and its convenient slit lamp delivery system, provided an easier technique for retinal coagulation from heat generated from the absorption of light within the pigment epithelium by melanin and within the blood vessels by hemoglobin.13 " The National Eye Institute's Collaborative Diabetic Retinopathy Study (DRS) confirmed the *From the Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami School of Medicine, Miami, Florida. This investigation was supported in part by the Bascom Palmer Eye Institute patients and contributors; Research To Prevent Blindness, Inc, New York City; Florida Lions Eye Bank Laboratory; and the Brenn Green Diabetic Retinopathy Funds, Miami, Florida. TR. ANt. OPHTH. Soc. vol. LXXXIVI, 1986

2 968 Blankenship suspected but previously debated benefit of PRP for several stages of diabetic retinopathy, 16 using either the xenon arc or the argon laser. More recently, the red krypton laser with a nm wavelength has become available. 13"14 This wavelength has the advantage of penetrating moderate amounts of nuclear sclerotic lens opacities and red hemorrhage in the vitreous cavity which often prevents photocoagulation with the blue-green argon laser. The histologic retinal changes produced by a single or small number of red krypton laser burns are similar to those of blue-green argon laser, but the red krypton wavelength produces a burn that extends deeper into the choroid increasing the risk of choroidal hemorrhage and Bruch's membrane ruptures. The histologic changes produced by these two lasers with more extensive PRP of the entire fundus as in the treatment of diabetic retinopathy have not been reported. of PRP of diabetic retinopathy with red krypton laser indicate that the results are similar to those obtained with bluegreen argon laser as reported by the DRS, 16'3 but these reports include a very small number of cases and do not permit an adequate comparison with the previously reported argon laser results. The purpose of this thesis is to compare the results of red krypton laser PRP with blue-green argon laser PRP in the treatment of proliferative diabetic retinopathy. A "Laboratory Section" presents the histopathologic changes of panretinal scatter photocoagulation of the entire fundus produced with these two lasers. A "Clinical Section" presents the visual and anatomical results of a prospective trial in which eyes with proliferative diabetic retinopathy were randomly selected for blue-green argon laser PRP or red krypton laser PRP. Discussion of the results of the laboratory section and clinical trial are combined following the clinical section to better integrate the two components of this thesis. Recent reports27-29 LABORATORY SECTION MATERIALS AND METHODS One randomly selected pigmented eye of each adult pigmented rabbit received blue-green argon laser PRP, and the other eye received red krypton laser PRP. A total of 28 rabbits were treated. The procedures were performed after the animals had been anesthetied with intravenous barbiturates, and the pupils had been dilated with topical 1% phenylephrine, and 1% cyclopentolate. The treatments were performed through flat and three-mirror fundus contact lenses.

3 PRP: Krypton vs. Argon 969 The sie, intensity, and distribution pattern of the laser burns were identical to those used clinically for PRP treatment of diabetic retinopathy, but the number of burns was reduced to be equivalent to that used in the larger human eye. The extent of treatment did not seriously reduce the animals' vision, nor interfere with their normal activities. The argon laser treated eyes received 5 applications of 5,u diameter burns produced with 2 mw of power for.1 seconds. Those eyes receiving krypton laser PRP received 5 applications of 5,u diameter produced by 1 mw of power for.2 seconds. The energy levels were selected to produce similar blanching of the retina pigment epithelium and overlying neurosensory retina. Lower energy levels with longer durations were used with krypton to reduce the risk of choroidal bleeding. Three, 7, and 3 days after treatment, the eyes of eight rabbits were enucleated and immediately fixed in formalin. After the anterior segments were removed with a vertical frontal section, the eyes were examined under a dissecting microscope. The presence and extent of vitreous hemorrhages, choroidal thickening, and retinal detachments were recorded. The anterior segment changes were evaluated by sacrificing four additional rabbits 3 days after treatment, and two normal rabbits which had not received treatment. The eyes were enucleated and immediately fixed in formalin. After saggital sections were made through the pupils and optic discs, the eyes were examined with a dissecting microscope. The presence and extent of ciliary body detachment, and thickening were recorded in addition to the presence and extent of vitreous hemorrhage, choroidal detachment, and retinal detachment. Photographs of each eye were obtained to document the findings. The specimens were embedded in paraffin, sectioned, stained with hematoxylin and eosin, and examined. Measurements of ciliary body thickness were made with a microscopic calibrated reticle. Two-tailed Fisher's exact tests and chi-square test with Yates' correction were used in evaluating the data for levels of statistical significance. Sample sie determinations were obtained from published tables.3' RESULTS GROSS DISSECTION FINDINGS The apparent number, distribution, sie, and intensity of the burns created by both argon and krypton lasers appeared to be identical (Figs 1 and 2). The incidence and extent of undesired effects, such as hemorrhage into the vitreous cavity, choroidal thickening, and retinal detachments,

4 97 Blankenship FIGURE 1 Three days after argon laser PRP, whitish burns are surrounded with pigment rings. A small vitreous hemorrhage (VH, arrow) is located on inner retinal surface. Shallow areas of choroidal thickening (CT, arrow) and exudative retinal detachment (RD, arrow) are also present (original magnification, x 6). FIGURE 2 Three days after krypton laser PRP, whitish burns are surrounded with pigment rings. A small vitreous hemorrhage (VH, arrow) is located on retinal surface. Shallow areas of choroidal thickening (CT, arrow) and exudative retinal detachment (RD, arrow) are also present (original magnification, x 6).

5 PRP: Krypton vs. Argon 971 TABLE I: GROSS EXAMINATION FINDINGS VITREOUS CHOROIDAL RETINAL HEMORRHAGE THICKENING DETACHMENT 3 Days posttreatment Argon (12 eyes) Krypton (12 eyes) Days posttreatment Argon (8 eyes) Krypton (8 eyes) Days posttreatment Argon (8 eyes) Krypton (8 eyes) 1 were similar for both the argon and krypton laser treated eyes, at each of the three posttreatment time periods (Table I). The anatomical position and appearance of the lenses, irides, and ciliary bodies of the four argon- and four krypton-treated eyes sectioned through the pupils and optic discs were identical. These findings were also found to be identical to those of the four untreated rabbit eyes. None of the eyes were observed to have ciliary body swelling or detachment. The extent of hemorrhage in the vitreous cavity was small and located on or immediately adjacent to the retinal surface. These small hemorrhages were present in 3 of the 12 argon-treated eyes (Fig 1), and 4 of the 12 krypton-treated eyes (Fig 2) obtained 3 days after treatment, and in 1 of the 8 argon-treated and 2 of the 8 krypton-treated eyes 7 days after treatment (Figs 3 and 4). At 3 days, vitreous hemorrhage was not present in any of the eight argon-treated eyes (Fig 5), but a small amount was present in one of the eight krypton-treated eyes. Fig 6 is typical of the krypton-treated eyes without vitreous hemorrhage, 3 days after treatment. There were thickened areas of choroid with shallow convex inner surfaces elevating the overlying retinas in six argon-treated eyes (Fig 1) and three krypton-treated eyes (Fig 2) 3 days following treatment, and in an additional three argon-treated eyes (Fig 3) 7 days after treatment. None of the krypton-treated eyes had areas of choroidal thickening 7 days after treatment, nor were they observed in either group 3 days after treatment. Statistical analysis of 6 of 12 (5%) argon-treated eyes compared to 3 of 12 (25%) krypton-treated eyes having choroidal thickening 3 days posttreatment failed to find any significant difference (P =.4). To be significant, this difference between the argon and krypton treated eyes would require a sample sie of 85 eyes in each group, or the incidence in the argon group would have to be 95% with the present number of eyes

6 Blankenship 972 FIGURE 3 Seven days after argon laser PRP, burns are pigmented and associated with a moderate amount of red vitreous hemorrhage (VH, arrow) on retinal surface, and localied exudative retinal detachment (RD, arrow) (original magnification, x 6)....A } t FIGURE 4 Seven days after krypton laser PRP, burns are pigmented and associated with a small amount of red vitreous hemorrhage (VH, arrow) on retinal surface, and localied exudative retinal detachment (RD, arrow) (original magnification, x 6).

7 PRP: Krypton vs. Argon 973 :::... _r.. :. :::::..::.. FIGURE 5 Thirty days after argon laser PRP, burns are pigmented without vitreous hemorrhage, choroidal thickening, or retinal detachment (original magnification, x 6). FIGURE 6 Thirty days after krypton laser PRP, burns are pigmented without vitreous hemorrhage, choroidal thickening, or retinal detachment (original magnification, x 6).

8 974 Blankenship and 25% incidence in the krypton group to have a 9% chance of detecting a significant difference at the.5 level. Power analysis of this data is difficult due to the wide confidence intervals in the estimate of occurrence rates ranging from 25% to 71% for the argon eyes and 1% to 48% for the krypton eyes. Retinal detachments were characteried as localied convex retinal elevations separated from the underlying choroid. Artifactual retinal detachments were often present adjacent to the cut surface made during preparation of the specimens, and these were not counted. Nonartifactual exudative retinal detachments were present in 6 of the 12 argon- (Fig 1) and 5 of the 12 krypton-treated eyes (Fig 2) 3 days following treatment, and in an additional 4 of 8 argon- and 1 of 8 krypton-treated eyes 7 days following treatment (Figs 3 and 4). None of the eight argon- or eight krypton-treated eyes had retinal detachments 3 days after treatment. MICROSCOPIC FINDINGS The histopathological changes observed 3, 7, and 3 days after PRP with the blue-green argon laser were essentially identical to those produced with the red krypton laser. Both the argon-treated (Fig 7) and krypton-treated (Fig 8) eyes obtained 3 days following PRP were characteried by disruption of the retinal pigment epithelium which was most extensive at the outer edge of the burn, eosinophilic staining heat coagulation of the photoreceptors, pigment migration into the outer retinal layers, disruption of the outer retinal nuclear layer, and swelling of the nerve fiber layer at the burn site. Suggestions of constriction and occlusion of the choroidal vessels beneath the burns were rarely found and were difficult to evaluate because of irregular filling and distention of the untreated choroidal vessels. The untreated choroid, pigment epithelium, and neurosensory retina between the individual burns was uninvolved and appeared normal. The anterior chamber depths, and microscopic appearance of the irises and lenses of the four argon- and four krypton-treated eyes sectioned through the pupils and optic discs were identical to each other end to the four untreated eyes. There was some varying degree of separation of the posterior portions of the ciliary bodies from the sclera in all of the argonand krypton-treated eyes (Figs 9 and 1), but the extent of separation was essentially identical between the two groups. This appeared to be artifactual as no exudative proteinaceous eosinophilic staining material was found in or adjacent to the ciliary bodies in any of the specimens. However, this finding was not observed in any of the untreated eyes (Fig 11). Ciliary body thickness was measured from the scleral choroidal junction

9 PRP: Krypton vs. Argon J FIGURE 7 Three days after argon laser PRP, burn site (between black arrows) has disruption of retinal pigment epithelium (RP), eosinophilic staining heat coagulation of photoreceptors (PR), pigment migration into outer retinal layers with disruption of outer nuclear layer (ON), and swelling of nerve fiber layer (NF) (hematoxylin and eosin, x 587). FIGURE 8 Three days after krypton laser PRP, burn site (between black arrows) has disruption of retinal pigment epithelium (RP), eosinophilic staining heat coagulation of photoreceptors (PR), pigment migration into outer retinal layers with disruption of outer nuclear layer (ON), and swelling of nerve fiber layer (NF). Choroidal separation from sclera is an artifact (hematoxylin and eosin, x 587).

10 976 Blankenship FIGURE 9 Three days after argon laser PRP, there is separation (arrow) of posterior portion of ciliary body from adjacent sclera. Absence of eosinophilic staining material indicates that separation is artifactual (hematoxylin and eosin, x 145). FIGURE 1 Three days after krypton laser PRP, there is separation (arrow) of posterior portion of ciliary body from adjacent sclera. Absence of eosinophilic staining material indicates that separation is artifactual (hematoxylin and eosin, x 145).

11 PRP: Krypton vs. Argon 977 FIGURE 11 Normal ciliary body of a rabbit eye which had not received PRP. Ciliary body remains attached to adjacent sclera (hematoxylin and eosin, x 145). perpendicularly to the inner ciliary body epithelium at the scleral spur where edematous swelling would be less affected by artifactual separation of the posterior ciliary body from the sclera. These measurements ranged from.19 to.38 mm with an average of.28 mm in the four argontreated eyes, from.21 to.51 mm with an average of. 29 mm in the four krypton-treated eyes, and.23 to.39 mm with an average of.29 mm in the four untreated eyes. Seven days following treatment, both the argon- and krypton-treated specimens (Figs 12 and 13) had extensive pigment migration, mixing of the outer and inner nuclear layers with pyknotic and atrophic loss of the nuclei, and loss of the normal retinal architecture with replacement by glial proliferation at the bum sites. The choroid at the burn sites and the tissues between the burn sites appeared normal in both the argon- and krypton-treated specimens. The specimens examined 3 days after both argon and krypton laser photocoagulation had atrophy and hyperplasia of the retinal pigment epithelium, loss of the photoreceptor layer with pigment migration into the overlying retina, and loss of retinal nuclei at the burn sites. The retina was of normal thickness because of replacement with glial proliferation (Figs 14 and 15). The choroid at the burn sites and the tissues between

12 978 Blankenship FIGURE 12 Seven days after argon laser PRP, burn site (between black arrows) has disruption of retinal pigment epithelium (RP) with pigment migration, disruption ofboth outer nuclear (ON) and inner nuclear (IN) layers with atrophy of cell nuclei, and loss of normal retinal architecture with replacement by glial proliferation. Nerve fiber layer (NF) is no longer swollen (hematoxylin and eosin, x 587). FIGURE 13 Seven days after krypton laser PRP, burn site (between black arrows) has disruption of retinal pigment epithelium (RP) with pigment migration, disruption of both outer nuclear (ON) and inner nuclear (IN) layers with atrophy of cell nuclei, and loss of normal retinal architecture with replacement by glial proliferation. Nerve fiber layer (NF) is no longer swollen. Choroidal separation from sclera is an artifact (hematoxylin and eosin, x 587).

13 PRP: Krypton vs. Argon t... r 979 FIGURE 14 Thirty days after argon laser PRP, burn site (between black arrows) has normal choroid, atrophy, and hyperplasia of retinal pigment epithelium (RP), pigment migration into all retinal layers, and preservation of normal retinal thickness with replacement of atrophic retinal tissue with glial proliferation. Adjacent untreated tissue appears normal. Choroidal separation from sclera is an artifact (hematoxylin and eosin, x 587). the burn sites specimens. appeared normal in both the argon- and krypton-treated CLINICAL SECTION A randomied prospective clinical MATERIALS AND METHODS trial was conducted comparing bluegreen argon and red krypton laser PRP for proliferative diabetic retinopathy in cases with three or four of the potential four diabetic retinopathy risk factors (presence of vitreous or panretinal hemorrhage, presence of new vessels, location of new vessels on or near the optic disc, and standardly defined severity of new vessel formation).32 To be eligible, the patient must have diabetes mellitus, good general health, geographical residence which permitted returning for follow-up examinations 3, 7, 14, 28, and 18 days after treatment, and a willingness in a random selection of either blue-green argon or red to participate

14 98 Blankenship ~~~~~~ :...: ~~~ ~ ~ ~~~ :: ~ : s.::. X... *s 4B _,- _a~~~~~~~~~~~~~~~~~i i I FIGURE 15 Thirty days after krypton laser PRP, burn site (between black arrows) has normal choroid, atrophy, and hyperplasia of retinal pigment epithelium (RP), pigment migration into all retinal layers, and preservation of normal retinal thickness with replacement of atrophic retinal tissue with glial proliferation. Adjacent untreated tissue appears normal (hematoxylin and eosin, x 587). krypton panretinal laser treatment. Ocular eligibility criteria of the involved eye required a corrected visual acuity of 6/3 or better, three or four diabetic retinopathy risk factors, and media clarity adequate to permit completion of panretinal argon or krypton laser photocoagulation within a single session. Eyes with substantial lens opacities or vitreous hemorrhages sufficient to prevent complete panretinal argon laser photocoagulation were ineligible for participating in this study and were excluded. The pretreatment examination consisted of obtaining general information regarding the patients' sex, age, and duration and means of treatment of their diabetes. The eye examination consisted of obtaining a best corrected visual acuity, slit lamp biomicroscopy, intraocular tension, gonioscopy, and posterior segment examination with biomicroscopy and contact lens, and indirect ophthalmoscopy. Pretreatment fundus photographs were taken, and visual field scores with I-4e and IV-4e white isopters were obtained by determining the peripheral extent of visual field in the, 3, 6, 9, 12, 15, 21, 24, 27, 3, 33, and

15 PRP: Krypton vs. Argon 981 FIGURE 16 Three days after blue-green argon laser PRP, there are extensive burns scattered throughout fundus sparing macula and maculopapillary bundle. 36 meridians minus the width of any scotomas within those meridians with a Goldmann perimeter., After the patient had been informed and had consented to participate, a previously prepared, numbered, sealed, opaque envelope containing an allocation for either argon laser or krypton laser PRP treatment was opened. All of the laser treatments for both groups were performed in a single session with retrobulbar anesthesia and with a panscopic fundus contact lens through a pupil which had been widely dilated with repeated 1% phenylephrine and 1% cyclopentolate drops. A laser instrument spot sie setting of 5,u was used for both the argon and krypton treatment. The individual burn duration for argon treatment was.1 seconds, but.2 seconds was used for the krypton laser treatment. The power setting was adjusted to provide a moderate blanching of the neurosensory retina overlying the pigment epithelial burn. For argon treatment this ranged from.9 to 1.7 W with an average power setting of 1.4 W. Equivalent burns were obtained with the krypton laser with power ranging from.6 to.75 W with an average of.7 W.

16 982 Blankenship FIGURE 17 Three days after red krypton laser PRP, there are extensive burns scattered throughout fundus sparing macula and maculopapillary bundle. A smaller number of argon burns were required to treat a retinal area equal to that treated with krypton, because chromatic aberration of the panscopic lens used gave dispersion of the blue-green argon wavelengths and produced larger argon burns than those obtained with krypton. The number of argon burns ranged from 46 to 77 with an average of 625 per eye. The number of krypton burns ranged from 975 to 175 with an average of 135 krypton burns per eye. The typical fundus appearance 3 days after panretinal laser treatment with argon is shown in Fig 16, and krypton in Fig 17. Posttreatment medications were not used for either group. Follow-up examinations were performed 3, 7, 14, 28, and 18 days after treatment. These included obtaining the best corrected visual acuities, slit lamp biomicroscopy of the anterior segments, intraocular pressure determinations, gonioscopy, and fundus examinations through a dilated pupil with slit lamp biomicroscopy and contact lens, and indirect ophthalmoscopy. Two-tailed Fisher's exact tests and chi-square tests with Yates' correction were used in evaluating the data for levels of statistical significance. Sample sie determinations were obtained from published tables.3'

17 PRP: Krypton vs. Argon 983 RESULTS A total of 56 patients participated in the study with 71 eyes receiving treatment. Eight patients received blue-green argon laser treatment of one eye and red krypton laser treatment of the other. Both eyes of 5 patients received argon treatment, both eyes of 2 patients received krypton treatment, one eye of 18 patients received argon treatment, and the remaining 23 patients received krypton treatment of one eye. PRETREATMENT EVALUATION Of the 31 patients receiving argon treatment, 15 (48%) were men and 16 (52%) were women; their ages ranged from 18 to 69 years with an average of 47.6 years. They had known of their diabetes from 1 to 41 years with an average of 18.5 years. At the time of entering the study, 25 (81%) were being maintained with insulin, and the remaining 6 (19%) with oral hypoglycemic medications. Of the 33 patients receiving krypton treatment, 2 (6%) were men and 13 (4%) were women with a range of ages from 21 to 74 years with an average of 49.6 years. They had known of their diabetes from 4 to 43 years with an average of 19.5 years; 27 (82%) were being maintained with insulin, and the remaining 6 (18%) with oral hypoglycemic medications. Randomiation of the eyes resulted in 21 (58%) right and 15 (42%) left eyes receiving argon treatment, and 13 (37%) right and 22 (63%) left eyes receiving krypton treatment. The best corrected pretreatment visual acuities for both the argon- and krypton-treated eyes are shown with those obtained 1 month and 6 months after treatment in Tables II and III. The cases randomied to argon treatment had slightly better pretreatment acuities, but the difference was minimal. Subnormal visual acuity was caused by minor cataracts, vitreous hemorrhages, macular swelling and/or ischemia, and assorted combinations of these factors. The visual fields were evaluated with a Goldmann perimeter on 33 eyes randomied to argon treatment and 32 randomied to krypton treatment at both the pretreatment and 6-month posttreatment examinations. The remaining eyes did not have visual field evaluations because of scheduling problems, or the results were excluded because of unreliability of the responses. The visual field scores shown in Table IV were the sums of degrees of vision along the meridian and each subsequent 3 meridian minus any scotomas along those meridians. The pretreatment anterior segment examinations found minor itis neovasculariation around the pupillary margins in two eyes (5%) assigned to argon treatment, and in four (11%) assigned to krypton treatment. The

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20 986 Blankenship intraocular pressures of 33 (92%) of the 36 argon-treated eyes and 32 (91%) of the 35 krypton-treated eyes ranged from 1 to 2 mm Hg. Two (5%) argon-treated eyes and three (9%) krypton-treated eyes had pressures in the low 2s. The remaining eye (3%) randomied to argon treatment had a pretreatment pressure of 3 mm Hg with pupillary iris neovasculariation and a minor amount of filtration meshwork neovasculariation. Minor vitreous cavity and preretinal hemorrhages were present in 25 (69%) of the argon treated eyes and 25 (71%) of the krypton treated eyes (Table V). Macular swelling was often present at the pretreatment examination. Of the 36 eyes receiving argon laser treatment, 14 (39%) had some degree of diffuse macular swelling, 4 (11%) had cystoid macular edema, and 4 (11%) eyes had exudative deposits in the macula. Of the 35 eyes randomied to krypton treatment, 17 (49%) had some degree of diffuse macular swelling and 6 (17%) had macular exudates. Fine epiretinal membranes covering the maculas were present in eight (22%) argontreated eyes and eight (23%) krypton-treated eyes. None of the eyes in either group had traction detachments which involved the maculas, but seven (19%) of the argon-treated eyes and nine (26%) of the kryptontreated eyes had localied traction detachments within the posterior fundi at the pretreatment examination. Neovasculariation of the disc (NVD), defined as new vessels on the disc or within 1 disc diameter of the disc margin or located any distance anterior to this area,33 was usually present, with 24 (67%) of the 36 argon-treated eyes having neovasculariation with a surface area 1/4 disc diameter, and an additional 11 (3%) having NVD < 1/4 disc diameter in area. Of the 35 krypton-treated eyes, 26 (74%) had neovasculariation 1/4 disc diameter in sie, and 4 (12%) additional cases had neovasculariation of a smaller amount (Tables VI and VII). Retinal neovasculariation (NVE), defined as new vessels in any area other than NVD,32 was presentin most of the eyes before laser treatment, with the majority having an extent : 1/2 disc diameter of retinal surface being covered (Tables VIII and IX). Of the eyes randomly assigned to argon laser treatment, 24 (67%) had three retinopathy risk factors,31 and the remaining 12 (33%) had four risk factors. Of those assigned to krypton treatment, 21 (6%) had three factors and the remaining 14 (4%) had four factors. EARLY POSTLASER TREATMENT EVALUATION Following panretinal laser treatment there were substantial inflammatory

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22 988 Blankenship changes observed at the 3-, 7-, and 14-day follow-up examinations. The incidence of these early side effects of laser treatment were almost identical between those eyes receiving argon laser and those receiving krypton laser, as shown in Table X. ONE-MONTH POSTLASER TREATMENT FOLLOW-UP EVALUATION The inflammatory reactions that were present during the first 2 weeks following panretinal laser treatment had resolved by the 1-month posttreatment examination. Most of the visual acuities that had been reduced immediately following treatment had returned to the pretreatment levels, and there was substantial regression of the neovasculariation in most eyes. There were no statistically significant differences between the 1-month postlaser treatment findings of the eyes receiving argon treatment as compared to those receiving krypton treatment. Complete 1 month follow-up examinations were obtained on 34 of the 36 eyes receiving argon treatment with 2 patients failing to return for this scheduled examination. All of the patients receiving krypton laser treatment returned for the 1-month follow-up examination. The best corrected visual acuities are shown in Table II. Six eye had acuities of 6/6 or less with one argon treated eye having opacification of a premacular membrane, one other argon treated eye having an increase in vitreous hemorrhage, two krypton treated eyes having an increase in macular swelling, and the other two krypton treated eyes having an increase in vitreous hemorrhage. Table III shows the changes in Snellen lines of visual acuity with the majority of both argon-treated and krypton-treated eyes having had less than 1 line of change in acuity compared with the pretreatment level. Vitreous and/or panretinal hemorrhage rarely occurred during the first month following laser treatment, and there was usually substantial clearing of hemorrhage which had been present before laser treatment. Table V shows the incidence and changes of the extent of hemorrhage with the eyes being divided into those without pretreatment vitreous hemorrhage and those with pretreatment hemorrhage. There was also a significant decrease in the incidence and extent of neovasculariation of the proliferative tissue involving the optic disc as is shown in Table VI. The incidence of NVD 1 month after treatment were almost identical for the eyes receiving argon treatment and those receiving krypton treatment. A comparison of the change and extent of NVD is shown in Table VII according to the extent of pretreatment NVD. Again, the regression of NVD that occurred within the first month of laser treatment was almost identical, with only one eye of each group con-

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24 99 Blankenship TABLE X: EARLY POSiTREATMENT FINDINGS* ARGON KRYPTON Angle depth Open 14/36 (39%) 9/35 (26%) Narrow 5/36 (14%) 15/35 (43%) Slit or closed 17/36 (47%) 11/35 (31%) Choroidal thickening None 1/36 (28%) 5/35 (14%) Shallow 2/36 (55%) 2/35 (57%) Prominent 6/36 (17%) 1/35 (29%) Macular swelling No pretreatment macular swelling None 6/14 (43%) 5/12 (42%) Minor 5/14 (36%) 6/12 (5%) Extensive 3/14 (21%) 1/12 (8%) Pretreatment macular swelling No change 13/22 (59%) 14/23 (61%) Increased swelling 9/22 (41%) 9/23 (39%) Exudative retinal detachment None 25/36 (69%) 27/35 (77%) Peripheral 3/36 (8%) 3/35 (8%) Macular Shallow 5/36 (14%) 1/35 (3%) Bullous 2/36 (6%) 2/35 (6%) Both peripheral and macular 1/36 (3%) 2/35 (6%) *Within 2 weeks of panretinal laser photocoagulation. tinuing to have neovasculariation > 1/4 disc diameter in sie. The incidence and change in NVE is shown in Tables VIII and IX with regression of NVE being almost idential to that ofthe disc for both treatment groups. SIX-MONTH POSTLASER TREATMENT FOLLOW-UP EVALUATION All of the patients returned for follow-up evaluations 6 months after treatment. During this period, none of the eyes had required ophthalmic medications, received additional laser treatment, or ophthalmic surgery of any type. As was found 1 month following treatment, most of the eyes maintained good visual function with substantial clearing of vitreous and preretinal hemorrhage. The NVD and NVE had regressed indicating a substantially improved prognosis for maintaining good visual function. The best corrected visual acuities are shown in Table II with the changes in Snellen lines of visual acuity shown in Table III. Again the majority of eyes in each group had acuities within 1 line of the pre-

25 PRP: Krypton vs. Argon 991 treatment level, but there were two more argon treated eyes having decreased visions than those receiving krypton treatment. Of the three argon treated eyes with vision < 6/6 (Table II), two had macular swelling and one had increased vitreous hemorrhage as a cause of the decreased vision. The three krypton treated eyes consisted of two with macular swelling and the other with increased vitreous hemorrhage as a basis for this level of decreased vision. One of these argon-treated eyes with macular swelling, the argon-treated eye with increased vitreous hemorrhage, and one of the krypton-treated eyes with macular swelling are the three eyes having the most serious decrease in lines of Snellen visual acuity shown in Table III. The loss of 2 or more lines of Snellen acuity following treatment was almost equal occurring in seven (19%) of the argon-treated eyes and in five (14%) of the krypton-treated eyes. Statistical analysis of this data failed to find any significant difference (P =.792). This 5% difference between the argon- and krypton-treated eyes would require a sample sie of 1252 eyes in each group, or the incidence of this visual loss in the argon group would have to be 55% with the present number of eyes to have a 9% chance of detecting a significant difference at the.5 level. Complete and reliable visual field examinations were obtained at both the pretreatment and 6-month follow-up evaluations for 33 of the argontreated eyes and 32 of the krypton-treated eyes. There was a minor amount of peripheral constriction occurring equally in both grous with the larger IV-4e white isopter, but a much greater constriction with the smaller I-4e white isopter. These findings are shown in Table IV. The incidence and extent of vitreous hemorrhage is shown in Table V, and are very similar for both groups. Most of the eyes that did not have pretreatment vitreous hemorrhage remained free of hemorrhage, and there was a substantial decrease in the amount of vitreous hemorrhage in those cases which had pretreatment hemorrhage. In the three kryptontreated eyes that developed vitreous hemorrhages without having pretreatment hemorrhages, the hemorrhages were small, and developed from a minor amount of residual disc neovasculariation without a serious effect on visual function. Statistical analysis of the to 11 argon-treated eyes compared to the 3 of 1 krypton-treated eyes having vitreous hemorrhage at 6 months without pretreatment vitreous hemorrhage fails to find any significant difference (P =.181). This difference between the argon- and krypton-treated eyes requires a sample sie of 54 eyes in each group without pretreatment vitreous hemorrhage, or the incidence in the krypton group would have to be 7% with the present number of eyes to have a 9% chance of

26 992 Blankenship detecting a significant difference at the.5 level. The incidence and changes in extent of NVD are shown in Tables VI and VII with the majority of cases in both groups having complete regression of the NVD. There was minor recurrence of NVD in two (5%) argon-treated eyes and five (14%) krypton-treated eyes. In both groups, these eyes with recurrent NVD had pretreatment NVD 1/4 disc diameter in sie. The regression usually occurred within the first month, and recurrence developed between the 1- and 6-month follow-up evaluations. In the group with NVD before treatment, : 1/4 disc diameter, the extent of regression was perhaps greater with argon than with krypton treatment. In the argon treated group, 15 of 24 (62%) eyes had complete regression compared to 13 of 26 (5%) eyes in the krypton treated group (Table VII), but this difference is not statistically significant (P =.546). A sample sie of 24 eyes in each group with this extent of pretreatment NVD would be needed, or complete regression would have been required in 9% of the argon eyes to have a 9% chance of detecting a significant difference at the.5 level. The incidence and changes in NVE are shown in Tables VIII and IX, and like NVD most of the eyes of both groups had complete regression of the NVE. Two of the argon-treated eyes had persistent extensive NVE and two krypton-treated eyes had a recurrence of NVE which had regressed at the 1-month follow-up examination. These small differences were not statistically significant. DISCUSSION STUDY DESIGN The DRS findings16'3 confirmed that PRP with either argon laser or xenon light significantly reduced the progression of diabetic retinopathy and the incidence of severe visual loss (defined as visual acuity of < 5/2 at each of two consecutively completed follow-up visits scheduled at 4-month intervals). These findings have become the standard to which other treatments are compared and will be used in evaluating the results of this report on argon and krypton panretinal laser photocoagulation. Such an empiric comparison is particularly important whenever the basis by which the therapy works is known only vaguely (in this case, by the presumed reduction of retinal metabolic demands). The result of changing the treatment method or treatment parameters may not be predictable, simply because the pathophysiology of the underlying disease and the mechanism of photocoagulation benefit are not understood. Although there is no reason to believe that treatment effect is dependent upon the

27 PRP: Krypton vs. Argon 993 wavelength of laser light used, such an effect may exist. Panretinal laser treatment with krypton could be equal to, better than, or worse than treatment with argon. In the present clinical trial, the patient and eye eligibility criteria for participation were taken from the DRS,3 but the extent of retinopathy required for participation was increased to high risk characteristics3 which required at least three retinopathy risk factors.32 The randomiation of the cases to argon and krypton groups resulted in only minor and insignificant differences between the groups. The slightly larger number of men and longer duration of diabetes mellitus in the krypton group should not have affected the results. Likewise, the ocular characteristics were approximately the same in the two groups. The pretreatment visual acuities and visual field scores of the eyes in the two groups were almost identical. Anatomically the eyes randomied to the two groups were very similar except for a slightly higher incidence of NVD in those randomied to argon. All of the treatment in each group was performed in a single session with retrobulbar anesthesia. The larger argon burn sie produced with the Rodenstock wide angle fundus contact lens required a smaller number of burns but higher energy levels to treat an area of retina equal to that treated in the DRS and in the krypton treated eyes.34'35 CHOROIDAL LESION A large number of eyes in both the argon and krypton treated groups had significant inflammatory changes during the first 2 weeks following treatment, but the incidence of these side effects was similar in the two groups. The majority of eyes in both groups had both angle narrowing and peripheral ciliochoroidal thickening However, these two were not always related. The extent of angle narrowing was greatest in the argon group, but the incidence and extent of ciliochoroidal thickening determined by the amount of inward displacement of the peripheral retina and pars plana was greatest in the krypton treated eyes. An explanation for this inverse relationship was not apparent, but was probably a chance occurrence due to the relatively small number of cases being evaluated, so that the presumed real possible correlation between choroidal thickness and anterior chamber shallowing was obscurred. Although there are substantial anatomical differences between the ciliary body and anterior segment of the rabbit eye compared to the human eye,39'4 these differences should not result in different responses to panretinal laser photocoagulation with different wavelengths. None of the laboratory specimens were observed to have ciliary body swelling or

28 994 Blankenship detachment with the dissecting microscope, and the microscopic measurements of ciliary body thickness of the argon-treated, krypton-treated, and untreated eyes were essentially equal and very similar to those previously reported. 41,42 An obvious cause for the separation of the posterior ciliary bodies from the sclera observed microscopically in all the argon- and krypton-treated eyes but none of the untreated eyes is not apparent. The absence of eosinophilic staining proteinaceous material suggests that the separation was artifactual or due to a transudative response to the panretinal laser treatment ratehr than exudative inflammatory reaction. This apparent artifact could be meaningful and the result of different degrees or patterns of shrinkage during fixation between the treated and untreated eyes. Although the filtration angles were often narrowed,36-3 most eyes did not develop elevated intraocular pressures. When the intraocular pressure was elevated it was always associated with marked narrowing or closure of the angles, which occurred more frequently in the argon treated eyes. Choroidal edema and hyperemia occur with both argon and krypton burns, but have been observed more frequently with krypton In the laboratory component of this study, the microscopic choroidal changes were difficult to evaluate because of irregular filling and distention of the choroidal vessels in both photocoagulated and nonphotocoagulated areas. The vast majority of burns with both argon and krypton did not appear to affect the choroid. The absence of substantial microscopic choroidal changes may be the result of increased light absorption by the extensive melanin in the heavily pigmented rabbit eyes regardles of wavelength, or the increased sie and intensity of the burns used in this study. The incidence and duration of choroidal thickening observed with the dissecting microscope was higher in the argon treated rabbit eyes, and may have resulted from a larger extent of photocoagulation produced by argon PRP despite attempts to apply equal amounts of argon and krypton with the PRP technique. Three days after treatment, the argon treated eyes had minimal or no choroidal involvement, but in some sections of those eyes receiving krypton treatment there was localied destruction of the choroidal vessels. Previous reports17-24 on the histopathology of argon and krypton burns have described similar changes. When Marshall and Bird'8 evaluated human retina 2 hours after krypton treatment and compared it with argon treated retina, they found that the krypton produced more extensive choroidal damage, with the choroicapillaries occluded by degenerated red blood cells, fibrin, and endothelial cell remnants and adjacent

29 PRP: Krypton vs. Argon 995 choroidal edema. They found that the choroidal damage from krypton burns showed macrophages and endothelial cell sloughing. Smiddy et a12 also compared red krypton and blue-green argon laser burns of the human retina 1 day after scattering approximately 15 of each type of burn with a simulated PRP pattern in separate midperipheral areas. These burns were indistinguishable from each other with choroidal neutrophil infiltration, intravenous fibrin deposition, hemorrhages in the outer choroid, but the choriocapillaries were still patent. Krypton burns of the cynomolgus monkey fundus have also been studied.'9'2 One day after treatment, Peyman et al'9 observed basophilic choroidal changes at lower power settings. When the power was increased to produce choroidal hemorrhage both argon and krypton produced ruptures of Bruch's membrane with the krypton burns being more extensive. The use of lower krypton energy levels with increased exposure time was recommended to minimie choroidal damage. Other reports also described choroidal bleeding with higher argon energy levels.24 The early work of L'Esperance'7 comparing argon and krypton burns of the rabbit retina found choroidal hyperemia with both types of burns 1 day after treatment, and with the krypton burns 7 days after treatment. Taken together, all these data are inadequate to conclude whether or not different wavelengths, in addition to energy and power, affect the choroid differently. However, for practical purposes when clinically equivalent retinal damage is produced, the choroidal effects seem also equivalent. RETINAL LESION The laboratory findings of retinal damage varied from a minimal amount of swelling of the individual burns to exudative retinal detachments. The argon and krypton retinal changes were almost identical with extensive damage to the retinal pigment epithelial layer, pigment migration into the retinal layers, coagulation necrosis of the photoreceptors, and localied exudative retinal detachments which were present at both the 3- and 7-day evaluations. These findings were very similar to earlier reports Marshall and Bird'8 found the argon and krypton burns placed greater than 2 from the fovea to be similar except with argon, there were greater extracellular spaces between the retinal pigment epithelial cells and Bruch's membrane. The burns evaluated by Smiddy et a12 were indistinguishable from each other with basal cystic intercellular retinal pigment epithelial changes, smudging of the photoreceptors, pyknotic and pale staining of the outer nuclear layer, and edema and destruction of the inner nuclear layer. L'Esperance'7 describes more inner retinal changes with krypton than with argon even though the krypton effect is greatest at

30 996 Blankenship the retinal pigment epithelial and choroidal levels. Peyman et al"9 found the histologic retinal changes with argon and krypton to be similar. Clinically, retinal inflammation was observed both as macular swelling and as exudative retinal detachment.4 The extent of macular swelling determined by the width of a biomicroscopic slit lamp beam with a fundus contact lens was greater with argon than with krypton among those eyes without macular swelling before treatment, but there was no difference with eyes that had pretreatment macular swelling. Also, the incidence of the exudative retinal detachments, especially those involving the macula, was higher with argon. CHORIORETINAL SCAR The initial inflammatory reaction had been replaced by scarring 1 month later. Microscopically, the argon and krypton burns were identical, with atrophy and hyperplasia of retinal pigment epithelial cells, and pigment dispersion throughout the disrupted retinal layers with glial proliferation. The similarity of scarring produced by argon and krypton 21 days after treatment have previously been observed.'7'19 Wallow and Davis' and later Wallow26 observed that the long-term histologic changes in the human retina after argon laser photocoagulation included choriocapillaris occlusions, and retinal scarring involving the retinal pigment epithelium with glial cell proliferation. He noted that heavy burn intensity was required to produce changes in the inner retinal layers. VIIREOUS The development of hemorrhage in the vitreous cavity following PRP in laboratory animals was surprising because of the absence of neovascular proliferation from which hemorrhage typically occurs. The hemorrhages may have developed from ruptured retinal or choroidal vessels, even though extensive choroidal and subretinal hemorrhages were not observed. The higher incidence of this complication in the krypton treated eyes is consistent with the previous reports of greater energy absorption at the choriocapillaris level.1719 Bleeding from the choriocapillaris or retina into the vitreous cavity from laser burns was not observed clinically with either form of treatment in this study. In the clinical study, eyes with extensive vitreous hemorrhage were excluded from participation in this study because of the inability to perform panretinal argon laser photocoagulation. Those eyes with small amounts ofvitreous hemorrhage were treated and the majority had significant clearing of the hemorrhage during the first month and persistent clearing for the 6 months following treatment in both groups. The inci-

31 PRP: Krypton vs. Argon 997 dence of vitreous hemorrhage during the first month following treatment was the same, with one eye of each group developing vitreous hemorrhage, and an additional eye with pretreatment vitreous hemorrhage having an increase in the amount of hemorrhage at the 1-month follow-up examination. Development of hemorrhage in the vitreous cavity during the 6-month follow-up period in eyes without hemorrhage at the start of the study was higher in the group treated with krypton (Table V), but the extent of hemorrhage was small, and it did not affect visual function. In the series of Doft and Blankenship" of 5 combined cases, four eyes developed hemorrhage within 6 months of panretinal argon laser photocoagulation. REGRESSION OF NEOVASCULARIZATION The extent of regression of both NVD and NVE was impressive and essentially identical in both argon and krypton groups 1 month after treatment. Already in the first month complete regression of NVD had been accomplished in 65% of cases with preexistent NVD ¼4 disc diameter in each group. The regression of NVD 6 months after treatment was greater in the argon group, but this was not statistically significant. Schulenburg et al27 found complete regression of NVD in three of six argon-treated eyes and four of six krypton-treated eyes with partial regression in two eyes of each group, but one argon-treated eye maintained the same extent of NVD throughout the 1-week follow-up period. Doft and Blankenship44'45 found complete regression of moderate to severe NVD in 19 of 39 eyes, 9 had partial regression, but 9 continued to have the same extent of neovasculariation and the remaining 2 cases had opaque media which prevented evaluation. The NVE had similar regression. VISUAL RESULTS Most of the eyes had transient losses of visual acuity during the early posttreatment period, but after 1 month, 71% of the argon treated eyes and 72% of the krypton treated eyes had regained vision within 1 Snellen line or better than had been present before treatment. The greater losses of acuity which occurred in 1 argon and 1 krypton treated eyes were associated with increased macular swelling or vitreous hemorrhage overlying the macula, and in 1 argon treated eye, with the opacification of a premacular membrane. By 6 months, the majority of eyes in both grups had good functioning levels of visual acuity with the majority having visual acuity equal to or better than the pretreatment level. The slight trend toward greater losses

32 998 Blankenship of acuity following argon laser treatment were not statistically significant. The basis for this loss of vision was usually due to macular swelling, which could have resulted from a larger amount of photocoagulation with argon compared to that with krypton. These findings are identical with the DRS in which 12% of 837 argon treated eyes had 2 lines or more decreased in visual acuity 6 weeks after treatment.3 Doft and Blankenship'4, 5 reported a series of 5 eyes with three or four diabetic retinopathy risk factors treated with argon PRP. Their results showed 38% having a loss of acuity of 2 lines or more 21 days after treatment. Schulenberg et al27 treated six eyes with argon and six with krypton laser PRP, and 1 weeks after treatment one eye of each group had a visual acuity loss of 2 lines caused by additional vitreous hemorrhaging from NVD. Various amounts of peripheral visual field constriction following PRP have been previously observed.27 '44"49 The minimal peripheral visual field constriction with the IV-4e isopter is similar to that reported by Schulenberg et a127 at 1 weeks, but the constriction to the I-4e was much greater. Doft and Blankenship44 found a 2% constriction with the IV-4e isopter, and a 46% constriction with the I-4e isopter which is similar to that found in this study. All of the 24 cases reported by Frank41 had some degree of visual field constriction following argon laser PRP. The DRS3 found a small visual field loss with the IV-4e isopter with 9% of the argon treated eyes having a visual field score of 5 or more 4 months after argon laser PRP treatment. STATISTICAL ANALYSIS Randomiation of eyes to argon or krypton laser PRP in both the laboratory and clinical components of this project combined with the restrictive eligibility criteria in the clinical trial resulted in almost identical argon and krypton groups before treatment. The increased incidence and duration of choroidal thickening and retinal detachment of the rabbit eyes with argon treatment were not statistically significant. A much larger sample sie would be required to detect a significant difference if in fact one exists. The marked similarity of the microscopic changes produced by these two different wavelengths further suggests that significant differences do not exist. Although there are differences in the clinical results with argon and krypton treatment, they are also very small and not statistically significant. A sample sie of 1254 eyes in each group would be required to detect a statistically significant difference (P =.5) in the higher incidence of 2 or more lines of decreased visual acuity 6 months following

33 PRP: Krypton vs. Argon 999 argon treatment. A sample sie of 24 eyes in each group would be needed to detect a statistically significant difference in the higher incidence in regression of NVD. If these small differences between the results of argon and krypton laser PRP are real, a collaborative clinical trial would be needed to recruit an adequate number of cases to reach these larger sample sies.5 The similarity of the visual and anatomical results 6 months after argon and krypton panretinal laser photocoagulation is similar to the prospective and randomied series of 12 cases by Schulenburg et a127 and the pilot study by Singerman.28'29 Eligibility criteria for this study required sufficient media clarity to permit complete PRP with argon laser in a single session, thus eyes with significant nuclear sclerosis or vitreous hemorrhages were ineligible. Singerman28 observed that krypton was advantageous because eyes with significant lens nuclear sclerosis or with moderate vitreous cavity hemorrhage could be treated successfully and earlier than with argon. The slight and statistically insignificant differences between the argon and krypton treated groups in the present study are probably due to more extensive photocoagulation with argon that occurred despite an effort to perform equal amounts of photocoagulation with argon and with krypton. Evidence of more extensive argon photocoagulation is that during the early posttreatment period, the argon treated eyes had a greater incidence and extent of angle narrowing, macular swelling developing in eyes without pretreatment macular swelling, and exudative retinal detachments involving the macula. At the 6-month follow-up examination, the argon treated group had a slightly large incidence of decreased visual acuities, but a smaller incidence of vitreous hemorrhaging, and persistence of NVD. All told, the argon treated group had slightly greater effectiveness in reducing neovasculariation, but also greater side effects. Okun et al5' has described a similar direct relationship between the extent of photocoagulation and the loss of visual acuity which accounted for the slightly greater loss of acuity in the DRS's16'3 xenon treated eyes compared to those eyes treated with argon. The similarity of the argon and krypton results is like the DRS's findings16'3 of similar results with argon laser and xenon light photocoagulation. Probably it is the amount of retina destroyed rather than the modality by which this is accomplished that is important in preventing severe visual loss and in obtaining regression of neovascular proliferation.

34 1 Blankenship SUMMARY The effects of PRP with red krypton laser are essentially identical to those produced with blue-green argon laser. Burns of the rabbit retina produced with these two different lasers are almost the same. In a prospective and randomied clinical trial of proliferative diabetic retinopathy treatment there was no significant difference between PRP using these two different lasers. The characteristic changes of rabbit fundi 3, 7, and 3 days after PRP with red krypton laser were almost the same as those following bluegreen argon laser. Both types of treatment frequently produced small vitreous hemorrhages and exudative retinal detachments, but choroidal thickening occurred more frequently with argon treatment. These changes were transient and had resolved within 3 days of treatment. The microscopic changes consisted of pigment epithelial disruption with pigment migration into the retina, heat coagulation of the photoreceptors, disruption of the outer and inner nuclear layers with atrophy of the nuclei, and temporary swelling of the nerve fiber layer. The untreated retina and choroid between burns was not involved and appeared normal at each period. Thirty days after treatment, the scarring produced by these two types of burns was identical. Seventy-one eyes with proliferative diabetic retinopathy having three or four retinopathy risk factors were treated with panretinal laser photocoagulation, and followed in a prospective study for 6 months. Thirty-six eyes were randomly selected for blue-green argon treatment, and 35 were randomly selected for red krypton treatment. The incidence of undesired side effects during the first 2 weeks following treatment was almost identical between the two groups. However, by 1 month the majority of eyes in both groups had visual acuities equal to or better than the pretreatment acuities and complete regression of NVD. Six months after treatment, the majority of eyes in both groups continued to have visual acuities equal to or better than the pretreatment acuities with fewer cases having larger losses of vision in the krypton treated group. Loss of peripheral visual field was equal with the two types of treatment having a minimal decrease with the IV-4e isopter, but substantial loss with the I-4e isopter. Additional vitreous hemorrhage rarely occurred in either group, but was slightly more frequent in those treated with krypton. Complete regression was accomplished in most eyes with pretreatment disc and/or NVE in both groups, but persistence of neovasculariation was more frequent in those treated with krypton. Overall, the wavelength used seemingly had little effect on the result. Slightly more extensive treatment with argon produced slightly greater

35 PRP: Krypton vs. Argon 11 effectiveness in regressing neovasculariation but slightly higher incidence of complications. ACKNOWLEDGMENTS The support, assistance, and encouragement of my sponors, Drs Edward W. D. Norton and J. Donald M. Gass, are greatly appreciated. A major contribution to the laboratory component of this project was made by Dr Juan Batlle, Mr Manuel Solis, and Mr Eleut Hernande. Accumulation and analysis of the data was assisted by Drs Joyce Shiffman, William Feuer, and Edmund Gerke. The manuscript was markedly improved by the editing and advice of Reva Hurtes, and Drs Douglas Anderson, J. Donald M. Gass, and Edward W. D. Norton. And, I am especially grateful for the patience, cooperation, and skill of Mrs Tina Moreschi in preparing the manuscript and its numerous revisions. REFERENCES 1. Meyer-Schwickerath G: Licktkoagulation. Buch Augenart 1959; : Light Coagulation. Translated by SM Drance. St Louis, CV Mosby, 196, p Moura Brail N, Reende J: Le role de la photocoagulation en ophtalmologie. Bull Mem Soc Fr Ophtalmol 1961; 74: Lopes de Andrade A, de Sa S: Alguns resultados clinicos da foto-coagulacao. Arq Port Oftalmol 1962; 14: Wetig PC, Wornton JT: Treatment of diabetic retinopathy by light coagulation: A preliminary study. Br J Ophthalmol 1963; 47: Okun E: The effectiveness of photocoagulation in the therapy of proliferative diabetic retinopathy (PDR); (controlled study in 5 patients). Trans Am Acad Ophthalmol Otolaryngol 1968; 72: Aiello LM, Beetham WP, Balodimos MC, et al: Ruby laser photocoagulation in treatment of diabetic proliferating retinopathy: Preliminary report, in MF Goldberg, SL Fine (eds): Symposium on the Treatment of Diabetic Retinopathy. Airlie House, Warrenton, Virginia, September 29 to October 1, Washington DC, US Government Printing Office (PHS Publ. no. 189), 1968, pp Wessing AK, Meyer-Schwickerath G: Results of photocoagulation in diabetic retinopathy, in MF Goldberg, SL Fine (eds): Symposium on the Treatment of Diabetic Retinopathy. Airlie House, Warrenton, Virginia, September 29 to October 1, Washington DC, US Government Printing Office (PHS Publ. no. 189), 1968, pp Maiman TH: Stimulated optical radiation in ruby. Nature 196; 187: Zaret MM, Breinin GM, Schmidt H, et al: Ocular lesions produced by an optical maser (laser). Science 1961; 134: Campbell CJ, Koester CJ, Curtice V, et al: Clinical studies in laser photocoagulation. Arch Ophthalmol 1965; 74: L'Esperance FA Jr: The effect of laser radiation on the retinal vasculature, animal and clinical studies. Arch Ophthalmol 1965; 74: An ophthalmic argon laser photocoagulation system: Design, construction, and laboratory investigations. Trans Am Ophthalmol Soc 1968; 66:

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