Argon Green (5 14 nm ) versus Krypton Red (64 7 nm ) Mo dif ied Grid Laser Photocoagulation for Diffuse Diabetic Ma cul ar Edema R. JOSEPH OLK, MD

Abstract: Between 1984 and 1988, 225 eyes of 132 patients were entered in a prospective, randomized clinical trial to determine if any significant differences exist between treatment with argon green (514 nm) and krypton red (647 nm) modified grid laser photocoagulation for patients with diffuse diabetic maculop­ athy with or without cystoid macular edema. At the 12- and 24-month follow­ up visits, no statistically significant difference was found between the two groups with respect to all of the following: reduction or elimination of macular edema, improvement in visual acuity, worsening of visual acuity, number of treatments per eye, and effect on the visual field. At the 12-month follow-up visit, none of the following factors statistically affected the visual outcome in either of the two groups: a history of systemic hypertension, systemic vascular disease, cystoid macular edema, or initial poor visual acuity. Ophthalmology 1990; 97:1101-1 113

While many diabetic patients lose vision from com­ plications of proliferative diabetic retinopathy, the major cause of visual loss in diabetics is due to diabetic macular 2 edema. 1 In a report by Patz and Fine, macular edema was the largest single cause of visual impairmen t in 1100 consecutive patients with diabetic retinopathy referred to the Diabetic Retinopath y Center at Johns Hopkins Hos­ pital. 4 Two recent reports 3• demonstra ted significant benefit from laser treatment in eyes with diabetic macular edema. The Early Treatment of Diabetic Retinopath y Study Originally received: October 25, 1989. Revision accepted: April 2, 1990. From Retina Consultants, Ltd., and Washington University School of Med· icine, St. Louis. Presented at the American Academy of Ophthalmology Annual Meeting, New Orleans, OctjNov 1989. Reprint requests to R. Joseph Olk, MD, Retina Consultants, Ltd., One Barnes Hospital Plaza, Suite 17413- East Pavilion, St. Louis, MO 63110.

(ETDRS)3 showed that focal photocoagulation of "clin­ ically significant" macular edema substantially reduced the risk of visual loss. Focal photocoagulation was done using argon blue-green or argon green laser, and grid treatment was used in eyes with areas of diffuse leakage or nonperfusion within two disc diameters of the center ofthe macula. I previously reported a significant treatment effect in eyes with diffuse diabetic macular edema with or without cystoid macular edema using modified grid argon 4 (blue-green) laser photocoagulation. When treating eyes with diffuse diabetic macular edema close to the foveal avascular zone (FAZ), it may be pref­ erable to use either argon green (514 nm) or krypton red (647 nm) instead of argon blue-green (488,514 nm). Use ofargon blue-green may eventually cause unnecessary in­ ner retinal damage and increased absorption in macular xanthophyll. Furthermo re, the side-effect of paracentral scotomas following modified grid treatment with argon blue-green laser4 theoretically could be reduced or elim­ inated with either argon green or krypton red. While the exact mechanism of grid photocoagulation 1101

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is not known, it is likely that the mechanism may be re­ lated in part to the photocoagulation effect on the retinal pigment epithelium. This theoretical assumption lends further support to the use ofeither argon green or krypton red laser instead of argon blue-green in grid photocoag­ ulation treatment for diffuse diabetic macular edema be­ cause of the relative sparing of the inner retina by the longer wavelengths. Between 1984 and 1988, a prospective, randomized clinical trial was undertaken in an attempt to determine if any significant differences exist between treatment with argon green (514 nm) and krypton red (647 nm) modified grid laser photocoagulation for patients with diffuse dia­ betic maculopathy with or without cystoid macular edema.

PATIENTS AND METHODS All patients were referred to the office of Retina Con­ sultants, Ltd., and initially examined and followed by the author. Eligibility criteria included a diagnosis of either type I or type II diabetes mellitus and diffuse macular edema with or without cystoid macular edema docu­ mented by slit-lamp and contact lens examination and confirmed with intravenous I 0% sodium fluorescein an­ giography. Diffuse diabetic macular edema was defined as the presence of two or more disc areas of retinal thick­ ening with involvement of the F AZ. Any patients with less than two disc areas of retinal thickening or retinal thickening that did not involve the FAZ were excluded from this study. Before entry into the study, the following criteria had to be met: hemoglobin A-1 C equal to or less than 10.0 mg/dl, diastolic blood pressure less than 100 mmHg, and best-corrected visual acuity, as measured by an independent examiner using the ETDRS visual acuity chart at 4 meters, better than 20/200-3. Patients in renal failure requiring any type of dialysis were excluded from this study. Patients whose diastolic pressure was greater than 100 mmHg or whose hemoglobin A-1 C was greater than 10.0 mg/dl were referred for further medical man­ agement and asked to return in 4 to 6 months for re­ evaluation. Ocular exclusion criteria included all of the following: two or more DRS risk factors,5 previous laser photoco­ agulation to within two disc diameters of the center of the F AZ, preretinal or vitreous hemorrhage, retinal de­ tachment or senile retinoschisis, significant media opac­ ities, iris neovascularization, previous retinal or intraocu­ lar surgery that was thought to possibly interfere with as­ sessment oftreatment results, cataract extraction or lens implantation within the previous 12 months, history of glaucoma, or any other ocular disease that was thought to interfere with assessment of treatment results. Patients with two or more high-risk characteristics were treated with panretinal photocoagulation and asked to return in 4 to 6 months for re-evaluation of their macular edema. Patients with one high-risk factor were entered into the study, but panretinal photocoagulation was not 1102



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applied to any eye until two or more high-risk factors were present. The sample size of 100 eyes in each treatment group was selected given the following assumptions. Using pre­ vious data, 3A we anticipated that approximately 70% of the argon-treated eyes would be stabilized or improved at 24 months. We further defined a clinically significant im­ provement as an improvement of 20% or more in the primary outcome, i.e., the rate of stabilization or im­ provement in visual acuity would be 85% in the krypton­ treated group. To detect this hypothesized difference, with 80% statistical power using a two-sided nominal alpha of 0.05, we calculated that at least 100 eyes would be needed in each treatment group. Fisher's exact, two-tailed, prob­ ability test was used to evaluate the significance of the argon versus krypton parameters. Baseline examination included a best-corrected visual acuity performed by an independent examiner using an ETDRS visual acuity chart at 4 meters; slit-lamp, contact lens, direct and indirect ophthalmoscopy, fundus pho­ tography, and intravenous 10% sodium fluorescein an­ giography; Humphrey central 10° static visual fields (pro­ gram 10-2); Farnsworth D-15 color vision test; and the Lanthony Tritan Album test. Fluorescein angiograms were reviewed by an independent examiner and graded as having either diffuse diabetic macular edema without cystoid macular edema or diffuse diabetic macular edema with cystoid macular edema. Patients whose angiograms showed greater than 6 clock hours of macular capillary nonperfusion were excluded from this study. Patients with "focal" macular edema, or patients with "clinically sig­ nificant" macular edema 3 that did not involve the FAZ were excluded from this study. Informed consent was obtained from all patients, and randomization was carried out by a coin-toss. If a patient had one eye eligible for randomization, that eye was ran­ domized to treatment with either argon green or krypton red modified grid photocoagulation. If a patient had both eyes eligible for randomization, one eye was randomized to treatment with argon green and the other eye treated with krypton red. Follow-up examinations were performed every 3 to 4 months (FYI, FV2, FV3, etc.) and included best-corrected visual acuity measured by an independent examiner using the same ETDRS visual acuity chart at 4 meters in the same examining lane. Complete ophthalmoscopic ex­ aminations, including fundus photography and fluores­ cein angiography, were performed at every follow-up visit. Fluorescein angiograms were not repeated after eyes were deemed stable and required no further supplemental treatment. Repeat Humphrey visual fields were obtained in all study eyes of all patients who returned for the 12­ and 24-month follow-up visits (FV3, FV6). 6 TREATMENT TECHNIQUE

All patients were treated as outpatients. Topical anes­ thesia alone was used in most cases, although a retrobulbar anesthetic was given in selected cases. A recent fluorescein angiogram, projected on a Topcon® viewer, was used as

OLK



MODIFIED GRID LASER PHOTOCOAGULATION

a guide during the treatment session. In most cases that required bilateral treatment, both eyes were treated during the same session. Argon green (514 nm) or krypton red (647 nm) was used in all cases. Two to three rows of 100-J.t spots were applied in the parafoveal region up to and including the edge of the F AZ. The lesions were placed approximately 100 J.l apart. Then, 150- or 200-J.t spots were applied throughout all remaining areas of retinal thickening and in all areas of capillary nonperfusion as shown on the fluorescein angiogram, placing the lesions approximately 200 J.l apart (Fig 1). In areas of obvious focal leakage, additional 150- or 200-J.t spots were focally applied (Fig 2). The treatment goal was to achieve light intensity burns at 0.1 seconds duration. For primary treatments with ar­ gon green, mean settings were 250 spots at 100 to 200 mW, and with krypton red, 254 spots at 100 to 300 mW. Supplemental modified grid photocoagulation was applied every 3 to 4 months to areas of residual retinal thickening noted on contact lens examination and confirmed on fol­ low-up fluorescein angiography. For supplemental treat­ ment with argon green, average settings were 220 spots at 100 to 200 mW, and with krypton red, 195 spots at 100 to 300 mW. The treatment goal was to keep the burns as light as possible, obtaining burns just barely visible at the level of the outer retina or retinal pigment epithelium. In many cases, this light intensity level is not always possible, and one may obtain burns that are somewhat heavier than desired. This occurs most frequently in patients with varying degrees of retinal thickening and in older adult­ onset diabetic patients with moderate nuclear cataracts. Patients were seen every 3 to 4 months, and if clinical examination or repeat fluorescein angiography demon­ strated residual retinal thickening involving the F AZ, then supplemental modified grid photocoagulation was applied to those areas where residual edema was still present. It is important to note that in many instances, modified grid photocoagulation does not need to be applied throughout the entire posterior pole. Only those areas of retinal thickening or areas of nonperfusion need be treated. Many times this simply involves the retinal areas temporal to the macula. In many cases, one can treat the areas of retinal thickening or diffuse leakage with a grid pattern and then simply apply additional focal treatment to those areas in the juxtafoveal region that require only focal treatment (see Fig 2).

CASE REPORT A 59-year-old woman presented with insulin-dependent di­ abetes of 15 years' duration and a history of hypertension. Eval­ uation showed bilateral diffuse maculopathy with cystoid mac­ ular edema (Fig 3, top and center [p. 1104]). Visual acuity at entry was 20/200 in the right eye and 20/50 in the left. The right eye was treated with argon green and the left with krypton red (Fig 3, bottom [p. 1104]). At FV2, 3 nm:t!•· after treatment number 1, central retinal thickening and cystmd macular edema persisted (Fig 3, top and center [p. 1105]), and she received supplemental modified grid treatment to both eyes (Fig 3, bottom

Fig 1. Artist's illustration of typical modified grid laser photocoagulation treatment. Two to three rows of 100 ttm spots are applied 100 ttm apart in the parafoveal region up to and including the edge of the foveal avas­ cular zone. Then 150 or 200 ttm spots are applied 200 ttm apart through­ out all areas of retinal thickening and/or areas of nonperfusion.

Fig 2. Artist's illustration of modified grid treatment which includes grid pattern to areas of retinal thickening and/or areas of nonperfusion as well as focal treatment with additional 150 or 200 ttm spots applied in areas of obvious focal leakage. [p. 1105]). At FV3, 4 months after treatment number 2, central retinal thickening and cystoid macular edema were still present (Fig 3, top and center [p. 1106]), and additional supplemental grid treatment was given to both eyes (Fig 3, bottom [p. 1106]). At FV4, 3 months later, central retinal thickening and cystoid macular edema had resolved in both eyes (Fig 3, top and bottom [p. 11 07]), and visual acuity stabilized at 20/160 in the right eye and 20/40 in the left.

RESULTS This study consisted of 225 eyes of 132 patients. Of 132 patients, 91 were women and 41 were men. Age range at entry into the study was 20 to 81 years (average, 61 years; median, 62 years). Ninety-one patients had insulin­ dependent type I diabetes mellitus, and 41 patients had type II diabetes mellitus controlled by diet or oral hypo­ 1103

Fig 3. A 59-year-old woman presented with insulin-dependent diabetes of 15 years' duration and a history of hypertension. Top and center, showed bilateral diffuse maculopathy with cystoid macular edema in both eyes. Bottom, the right eye was treated with argon green and the left with krypton red modified grid laser photocoagulation. (Fig 3 continues)

Fig 3 (continued). Three months after the first treatment, central retinal thickening and cystoid macular edema persisted (top and center) and the patient received supplement modified grid treatment to both eyes (bottom). (Fig 3 continues)

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Fig 3 (continued). Four months after the second treatment, central retinal thickening and cystoid macular edema were still present (top and center), and additional supplemental grid treatment was given to both eyes (bottom). (Fig 3 continues)

1106

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MODIFIED GRID LASER PHOTOCOAGULATION

Fig 3 (continued). Three months later, central retinal thickening and cystoid macular edema had resolved in both eyes and visual acuity stabilized at 20/160 in the right eye and 20/40 in the left.

glycemic agents. Duration ofdiabetes at the time of entry ranged from 1 month to 45 years (average, 16 years; me­ dian, 15 years). Fifty-nine (39.4%) of 132 patients had a history of systemic hypertension requiring antihyperten­ sive medication at the time of entry into the study. Thirty­ eight (28.8%) of 132 patients had evidence of systemic vascular disease that was defined as a positive history of any of the following: intermittent claudication, amputa­ tion of one or more digits, or peripheral bypass surgery; stroke or carotid endarterectomy or carotid bypass surgery; or myocardial infarction or coronary artery bypass sur­ gery. One hundred sixteen eyes were treated with argon green; · 109 eyes were treated with krypton red. Ninety-three pa­

tients (186 eyes) were treated bilaterally: in 91 patients, one eye was treated with argon green and the other eye with krypton red; one patient had both eyes treated with argon green; and one patient had both eyes treated with krypton red. Of 116 eyes treated with argon green, 44 (38%) were treated one time, 52 (45%) were treated two times, 16 (14%) were treated three times, three (3%) were treated four times, and one ( 1%) was treated five times. Of 109 eyes treated with krypton red, 35 (32%) were treated one time, 45 (41%) were treated two times, 25 (23%) were treated three times, and four (4%) were treated four times. In comparing eyes treated with only one treatment, eyes treated with two treatments, and all eyes treated with two 1107

OPHTHALMOLOGY



SEPTEMBER 1990

Table 1. Baseline Characteristics of All Eyes at Entry into Study (225 eyes in 132 patients) (n

Characteristics

Argon = 116)

Krypton (n = 109)

Patient age (yrs) Range Average Median Type of diabetes I II Duration of diabetes (yrs) Range Average Median History of hypertension Present Not present Systemic vascular disease Present Not present Initial visual acuity 2':20/63 _,;20/80 Cystoid macular edema Present Not present Lens status Phakic Aphakic Pseudophakic

20-81 60.9 62 91 41 1 Mo.-45 15.7 15 No. of Eyes 48 68

48 61

33 83

34 75

84 32

81 28

57 59

59 50

99 4 13

86 4 19

Table 2. Follow-up Examinations* No. of Eyes (%) Follow-up Visit

Argon (n = 116)

Krypton (n = 109)

Total (n = 225)

1 (90%) 2 (76%) 3 (91%) 4 (55%) 5 (40%) 6 (66%)

106 (91)

98 (90)

204

87 (75)

85 (78)

172

107 (92)

98 (90)

205

66 (57)

57 (52)

123

46 (40)

43 (39)

89

78 (67)

70 (64)

148

*Performed every 3 to 4 months (±1 month) during the first year, and every 3 to 4 months (±2 months) during the second year.

or more treatments, there was no statistically significant difference between any of these groups (P > 0.05 for all comparison groups). Forty-three of 225 eyes (25 with argon green and 18 with krypton red) had previous panretinal photocoagu1108



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Table 3. Reduction or Elimination of Macular Edema and/or Cystoid Macular Edema No. of Eyes (%)

Follow-up Visit

Argon

Krypton

3 6

95/107 (88.8) 74/78 (94.9)

84/98 (85.7) 65/70 (92.9)

lation at the time of entry into the study, and 37 eyes ( 17 with argon green and 20 with krypton red) required sub­ sequent primary or supplemental panretinal photocoag­ ulation during the follow-up period. One hundred and eighty-five eyes (99 with argon green and 86 with krypton red) were phakic, eight eyes were aphakic (four with argon green and four with krypton red), and 32 ( 13 with argon green and 19 with krypton red) were pseudophakic. Dur­ ing the study, 14 (24 eyes; 10.6%) of 132 patients died. Table 1 lists a comparison of baseline characteristics for all 225 eyes ( 116 in the argon green treatment group and 109 in the krypton red treatment group) of the 132 patients. After entry into the study, patients were followed at 3- to 4-month intervals (±1 month) during the first year (FV 1, FV2, FV3). During the second year, follow­ up examinations were conducted every 3 to 4 months (± 2 months; FV4, FV5, FV6). Table 2 lists follow-up data on all eyes during the study. At the 12-month follow-up visit (FV3), seven patients (13 eyes) had died, two patients (4 eyes) were lost to follow­ up, and two patients (3 eyes) had missed visits. At the 24­ month follow-up visit (FV6), 14 patients (24 eyes) had died, five patients (9 eyes) were lost to follow-up, and 29 patients (44 eyes) had not completed their 2-year follow­ up visit by the end of the study. Reduction of macular edema or cystoid macular edema was defined by reduced retinal thickening on slit-lamp contact lens examination and confirmed by follow-up re­ peat stereofundus photography and intravenous fluores­ cein angiography. At the FV3 visit, 95 of 107 eyes (88.8%) treated with argon green and 84 of98 eyes (85. 7%) treated with krypton red had reduction or elimination of macular edema (Table 3). This difference was not statistically sig­ nificant (P = 0.6402). At the 24-month follow-up visit (FV6), 74 of 78 eyes (94.9%) treated with argon green had reduction or elim­ ination of macular edema compared to 65 of 70 eyes (92.9%) treated with krypton red. This difference was not statistically significantly different (P = 0.7358). Table 4 lists a comparison of visual results in 205 eyes (107 treated with argon green and 98 treated with krypton red) at 12 months (FV3). Improved visual acuity was de­ fined as three or more lines of improvement, and worse visual acuity was defined as three or more lines worse than the visual acuity at the time of entry into the study. Thirteen of 107 eyes (12%) treated with argon green had improved visual acuity compared to 16 of 98 eyes ( 16%) treated with krypton red, and 17 of 107 eyes ( 16%) in the argon green group had a worsening of their visual acuity

OLK



MODIFIED GRID LASER PHOTOCOAGULATION

Table 4. Visual Results at 12 Months (third follow-up visit) (205 eyes)

Table 5. Visual Results at 24 Months (sixth follow-up visit) (148 eyes) No. of Eyes (%)

No. of Eyes (%)

Improved Same Worse

Argon* (n = 107)

Krypton* (n = 98)

13 (12) 77 (72) 17 (16)

16 (16) 65 (67) 17 (17)

Improved Same Worse

* No follow-up at the third visit: 9, argon, and 11, krypton.

compared to 17 of98 eyes (17%) in the krypton red group

(P = 0.8755).

Table 5 lists the visual acuity results at the 24-month follow-up visit (FV6). Eight of78 eyes (10%) in the argon green group had improved visual acuity compared to 10 of 70 eyes ( 14%) in the krypton red group, and 20 of 78 eyes (26%) in the argon green group had worsening of their visual acuity compared to 16 of70 eyes (23%) in the krypton red group (P = 0.5658). The majority of the 36 eyes with worse visual acuity at the 24-month visit had decreased vision due to causes not related to the status of their macular edema: 11 eyes (6 patients) had vitreous hemorrhage secondary to proliferative disease; cataracts developed in six eyes (four patients); ischemic optic neu­ ropathy developed in three eyes (two patients); and two eyes (one patient) were affected by a massive stroke re­ sulting in expressive aphasia. Figure 4 shows the proportion of eyes at each follow­ up visit with improved visual acuity ofthree or more lines and compares the argon green group versus the krypton red group. At the FV3 visit, visual acuity improved three or more lines in 12% ofargon green-treated eyes compared to 16% of krypton red-treated eyes. At the FV6 visit, 10% of argon green-treated eyes showed improvement of three or more lines compared to 14% of krypton red-treated eyes. Figure 5 shows the proportion ofeyes with worse visual acuity in the argon green treatment group compared to the krypton red treatment group at each follow-up visit. Decreased visual acuity was defined as a reduction ofthree or more lines of visual acuity at the FV3 visit; 16% of argon-treated eyes had decreased visual acuity compared to 17% of krypton red-treated eyes. At the FV6 visit, 26% of eyes in the argon green-treated group had decreased visual acuity compared to 23% in the krypton red-treated group. The following factors were analyzed to ascertain their effect on the final visual result: systemic hypertension, systemic vascular disease, initial visual acuity, and the presence of cystoid macular edema. Table 6 compares the visual results for all treated (argon and krypton) eyes in the study at the 12-month follow­ up visit (FV3) in patients with and without systemic hy­ pertension. Nine eyes ( 11%) with systemic hypertension showed improved visual acuity compared to 20 eyes ( 16%) without hypertension; 17 eyes (21%) with systemic hy-

Argon* (n = 78)

Krypton* (n = 70)

8 (10) 50 (64) 20 (26)

10 (14) 44 (63) 16 (23)

* No follow-up at the sixth visit: 38, argon, and 39, krypton.

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2

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FOLLOW-UP VISITS (Every 3-4 months)

Fig 4. Improved visual acuity of three or more lines: proportion of eyes in argon green(---) and krypton red(--) groups at each follow-up visit.

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1->-.c

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FOLLOW-UP VISITS (Every 3-4 months)

Fig 5. Worse visual acuity of three or more lines: proportion of eyes in argon green(---) and krypton red(--) groups at each follow-up visit.

Table 6. Visual Results in Patients with and without a History of Hypertension at 12 Months (third follow-up visit) No. of Eyes (%)

Improved Same Worse

Hypertension (n = 82)

No Hypertension (n = 123)

9 (11) 56 (68) 17 (21)

20 (16) 86 (70) 17 (14)

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OPHTHALMOLOGY



SEPTEMBER 1990

Table 7. Visual Results in Patients with and without Systemic Vascular Disease at 12 Months (third follow-up visit) No. of Eyes (%) Systemic Vascular Disease (n = 62)

No Systemic Vascular Disease (n = 143)

6 (10) 43 (69) 13 (21)

23 (16) 99 (69) 21 (15)

Improved Same Worse

Table 8. Visual Results at 12 Months (third follow-up visit) in Patients with Initial Good Visual Acuity (~20/63) versus Patients with Initial Poor Visual Acuity (~20/80) No. of Eyes (%) Visual Acuity Argon

Improved Same Worse

~

20/63

No. of Eyes (%) Visual Acuity

~

20/80

(n = 77)

(n = 71)

Krypton

Argon (n = 30)

Krypton (n = 27)

6 (8)

9 (13) 53 (74) 9 (13)

7 (23) 16 (53) 7 (23)

7 (26) 12 (44) 8 (30)

61 (79) 10 (13)

Table 9. Visual Results at 12 Months (third follow-up visit) in Patients with and without Cystoid Macular Edema

Improved Same Worse

No. of Eyes (%)

No. of Eyes (%)

Argon

Krypton

VOLUME 97



NUMBER 9

12-month follow-up visit (FV3) in those eyes with initial visual acuity of20/80 or less. Ofall eyes with initial visual acuity of20/63 or better, six of77 argon-treated eyes (8%) had improved visual acuity compared to nine of 71 kryp­ ton-treated eyes ( 13%), and ten of 77 argon-treated eyes (13%) had worse visual acuity compared to nine of 71 krypton-treated eyes ( 13%). This result is not statistically significant (P = 0.5096). In all eyes with initial visual acuity of 20/80 or less, seven of 30 argon-treated eyes (23%) had improved visual acuity compared to seven of 27 krypton-treated eyes (26%), and seven of 30 argon-treated eyes (23%) had worse visual acuity compared to eight of 27 krypton-treated eyes (30%). This result is not statistically significant (P = 1.000). Table 9 compares eyes that had cystoid macular edema on entry into the study with those without cystoid macular edema. Of all eyes with cystoid macular edema, seven of 48 argon-treated eyes (14.5%) had improved visual acuity at the 12-month follow-up visit (FV3) compared to ten of 56 krypton-treated eyes ( 18%), and seven of 48 argon­ treated eyes (14.5%) had worse visual acuity compared to 14 of 56 krypton-treated eyes (25%). This result is not statistically significant (P = 0.7396). Of all eyes without cystoid macular edema, six of 59 argon-treated eyes ( 10%) showed improved visual acuity compared to six of 42 krypton-treated eyes (14%), and ten of 59 argon-treated eyes ( 17%) had worse visual acuity compared to three of 42 krypton-treated eyes (7%). This result is not statistically significant (P = 0.2262). Further analysis comparing visual results for argon­ treated and krypton-treated eyes relative to all four afore­ mentioned factors failed to show any statistically signifi­ cant difference in any category. SIDE-EFFECTS AND COMPLICATIONS

Cystoid Macular Edema (n = 48)

No Cystoid Macular Edema (n =59)

Cystoid Macular Edema (n =56)

No Cystoid Macular Edema (n = 42)

7 (14.5) 34 (71) 7 (14.5)

6 (10) 43 (73) 10 (17)

10 (18) 32 (57) 14 (25)

6 (14) 33 (79) 3 (7)

pertension showed worse visual acuity compared to 17 eyes ( 14%) without systemic hypertension (P > 0.05 for each group). Table 7lists a comparison of visual results for all treated (argon and krypton) eyes in the study at the 12-month follow-up visit (FV3) in patients with and without systemic vascular disease. Six eyes ( 10%) with systemic vascular disease showed improved visual acuity compared to 23 eyes ( 16%) without systemic vascular disease; 13 eyes (21%) with systemic vascular disease showed worse visual acuity compared to 21 eyes ( 15%) without systemic vas­ cular disease (P > 0.05 for each group). Table 8 compares those eyes with initial visual acuity equal to or better than 20/63 with the visual result at the 1110



The majority of patients treated with either argon green or krypton red modified grid laser photocoagulation complained of either paracentral grid-like scotomas or a "haze or film" over the treated eye. While most of these subjective complaints gradually diminished with time, the effect on the visual field could be demonstrated to persist at the FV3 and FV6 visits. 6 Automated static threshold perimetry was performed before and after modified grid therapy for all eyes tested. Average threshold sensitivity in the central 5o dropped 3.44 dB after the first treatment and 6.86 dB cumulatively after the second treatment. Qualitatively, the gray scale displays of the central visual field were darker after treatment, but the scotomata from laser photocoagulation with either argon green or krypton red could not be distinguished from those due to macular edema. The foveal threshold showed no significant change. Four patients in this study (eight eyes) had permanent, irreversible worsening of their visual acuity that was thought to be related to a marked increase in their systemic blood pressure. In all eyes, the macular edema had been stabilized with modified grid treatment, and then subse­ quently, patients experienced a sudden bilateral decrease in visual acuity. Results of the examination showed a marked increase in macular edema in both eyes that was

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MODIFIED GRID LASER PHOTOCOAGULATION

usually accompanied by a significant reduction in visual acuity. One patient developed subretinal fibrosis after two krypton red modified grid treatments with subsequent re­ duced visual acuity. One patient developed a subfoveal, subretinal neovascular membrane following argon green modified grid treatment. A disciform scar developed, and visual acuity was reduced.

DISCUSSION Two recent randomized, controlled, prospective clinical trials have shown definitively the efficacy of laser photo­ coagulation for diabetic macular edema. 3•4 The ETDRS emphasized focal treatment with argon green or argon blue-green, and my study used "modified grid" with argon blue-green. I would like to emphasize that this method of "modified grid" is only one method of treatment for dif­ fuse diabetic macular edema and may or may not be the preferred method of treatment when compared to other methods. The main side-effects of this treatment in my study were paracentral scotomas or a haze or film over the treated eye. Two additional clinical trials using krypton red laser photocoagulation were reported recently. 7 •8 Grid-pattern laser photocoagulation for diffuse edema was shown to be effective in stabilizing or improving edema in more advanced cases of diabetic maculopathy, 7 and focal kryp­ ton red treatment of clinically significant macular edema also was shown to stabilize or improve visual acuity in a small number of eyes. 8 Clover9 evaluated the effects ofboth krypton and argon laser photocoagulation on pig retina. Using intravitreal injections of methyVH thymidine, autoradiography was done on retinal digests and histologic sections. These tests showed focal divisions of capillary endothelial cells over the laser exposure sites, and the effect was found to be greatest with krypton laser photocoagulation compared to argon. In a subsequent study, Clover 10 was able to pro­ vide unequivocal evidence that the endothelial cell rep­ lication that occurs in inner retinal vasculature arises not as a primary response but as the secondary result oflaser­ induced changes within the outer retina wall. Further, Clover stated that "krypton irradiation, focused on the RPE, appears more effective than argon in stimulating a replication response ofthe inner blood-retinal barrier cells, indicating that krypton may be the treatment of choice for diabetic maculopathy." Our study was a prospective, randomized, controlled clinical trial designed specifically to determine whether a significant difference existed between argon green and krypton red modified grid laser photocoagulation. This study was designed such that a clinically significant dif­ ference in positive outcome was predetermined to be 20%. It should be recognized that this "one-center" study could have a type II error rate as high as 20% that might go undetected. Visual acuities were carefully and repeatedly measured at every visit by an independent examiner using the same

visual acuity chart and the same examining lane. A careful refraction was carried out at each visit, and attempts were made to elicit maximum visual acuity in all eyes at every follow-up visit. Fluorescein angiograms were obtained before randomization on every patient and on all follow­ up visits until eyes were deemed to be stable with no re­ sidual central macular edema. All angiograms were in­ terpreted by an independent observer to minimize bias. Results of the visual field testing were interpreted by two separate independent observers without knowledge as to which eyes were treated with which laser. All treat­ ments (primary and supplemental) were carried out by the same operating laser surgeon (RJO) to minimize vari­ ation in treatment technique. The results show there is no statistically significant dif­ ference between eyes with diffuse diabetic macular edema treated with either argon green or krypton red modified grid laser photocoagulation in terms of all the following: improvement in visual acuity at 12 and 24 months; wors­ ening of visual acuity at 12 and 24 months; number of treatments per eye; and reduction or elimination of mac­ ular edema. These clinical results appear to lend further support to Clover's hypothesis that the laser-induced changes within the outer retina, retinal pigment epithe­ lium, and choroid result in secondary changes in the ret­ inal vasculature. In contrast, however, our results do not support Clover's hypothesis that "krypton may be the treatment choice" in treating diabetic macular edema. However, it must be recognized that in this study, the treatment goal for both argon and krypton was to achieve the same level of intensity burn at the outer retina and retinal pigment epithelium. This desired burn intensity for both krypton and argon may offset any theoretical sparing of the inner retina by the longer wavelength. It was hoped that this study would show either a re­ duction in the paracentral grid-like scotomas noted in the previous study or a difference between argon green and krypton red. The paracentral defects displayed with high­ resolution perimetry that are due to macular edema (i.e., before treatment) are indistinguishable from the scoto­ mata seen after modified grid therapy with either argon green or krypton red. Also, it was noted that the patients in this study had fewer subjective complaints about para­ central scotomata than the patients in my previous studl who were treated with the argon blue-green laser. It is not known if the reduction in patient complaints is because of the change from blue-green to all green and/or krypton red, the lighter intensity burns that were used, or better patient education about the expected side-effects of treat­ ment. While others have previously suggested that initial poor visual acuity may portend a poor prognosis, the present study confirmed my previous work showing that visual improvement in eyes with initial poor visual acuity was not statistically different than improvement in eyes with initial good visual acuity, regardless of treatment with ei­ ther argon green or krypton red. This study also confirmed my previous finding that the presence of cystoid macular edema is not a poor prog­ nostic sign. In the present study, visual improvement in 1111

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eyes with cystoid macular edema was not statistically dif­ ferent from eyes that had no cystoid macular edema, re­ gardless of treatment with either argon green or krypton red. Additionally, this study confirmed my earlier work showing that systemic hypertension or a history of sys­ temic vascular disease did not statistically affect the visual outcome in eyes compared to those eyes of patients with­ out systemic hypertension or systemic vascular disease. While the exact mechanism of action of modified grid laser photocoagulation is not known, this study supports the concept of a combination effect on both the retinal vasculature (inner retinal barrier) and the retinal pigment epithelium (outer retinal barrier). Additionally, this study lends support to the concept that the primary effect of modified grid laser photocoagulation may be at the level of the outer retina, retinal pigment epithelium, and cho­ roid, and that the effects seen on the retinal vasculature may be secondary.

ACKNOWLEDGMENTS The author thanks Dean Burgess, MD, who independently reviewed and graded the fluorescein angiograms; Neva Arribas, MD, Isaac Boniuk, MD, Dean Burgess, MD, and Gilbert Grand, MD, who referred additional patients for this study; and Mae Gordon, PhD, who performed the statistical analyses.

REFERENCES 1. McMeel JW, Trempe CL, Franks EB. Diabetic maculopathy. Trans Am Acad Ophthalmol Otolaryngol1977 ; 83:0P476-85.



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2. Patz A, Fine SL. Observations in diabetic macular edema. In: Sym­ posium on Retinal Diseases: Transactions of the New Orleans Acad­ emy of Ophthalmology. St. Louis: CV Mosby, 1977;112. 3. Early Treatment Diabetic Retinopathy Study Research Group. Pho­ tocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol1985; 103:1796­ 1806. 4. Olk RJ. Modified grid argon (blue-green) laser photocoagulation for diffuse diabetic macular edema. Ophthalmology 1986; 93:938-50. 5. 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 Ophthalmol1979; 97:654-5. 6. Striph GG, Hart WM Jr, Olk RJ. Modified grid laser photocoagulation for diabetic macular edema: the effect on the central visual field . Oph­ thalmology 1988; 95:1673-9. 7. Kayazawa F, De Jesus GT, Miyake K. Grid-pattern laser photoco­ agulation for diabetic diffuse macular edema (the Japanese experi­ ence). In: Gitter KA, Schatz H, Yannuzzi LA, McDonald HR, eds. Laser Photocoagulation of Retinal Disease: From The International Laser Symposium of the Macula. San Francisco: Pacific Medical Press, 1988;65-8. 8. Chew EY. Treatment of diabetic macular edema with krypton laser photocoagulation. In: Gitter KA, Schatz H, Yannuzzi LA, McDonald HR , eds. Laser Photocoagulation of Retinal Disease: From The Inter­ national Laser Symposium of the Macula. San Francisco: Pacific Med­ ical Press, 1988;83-7. 9. Clover GM. Laser treatment of diabetic maculopathy and the impli­ cations for retinal vascular barriers [Thesis]. London: University of London, 1984. 10. Clover GM. The effects of argon and krypton photocoagulation on the retina: implications for the inner and outer blood retinal barriers. In: Gitter KA, Schatz H, Yannuzzi LA, McDonald HR, eds. Laser Pho­ tocoagulation of Retinal Disease: From The International Laser Symposium of the Macula. San Francisco: Pacific Medical Press, 1988;11-7.

Discussion by Lawrence A. Yannuzzi, MD Macular edema is the most significant complication of diabetic retinopathy associated with severe vision loss, and by far the most challenging presentation of this manifestation is diffuse macular edema. The ideal laser wavelength, in fact, the ideal treatment for the management of this perplexing problem, is still unknown. In a previous report, Dr. Olk demonstrated that argon blue­ green laser photocoagulation treatment, using a grid pattern, was effective in the management ofdiffuse diabetic edema. Most retinal specialists today would agree that the blue wavelength for photocoagulation ofthe retina should be abandoned because of its retinal phototoxicity, its inefficient scatter, its risk of cat­ aractogenesis, and its potential for inner retinal damage in the central macula from absorption by xanthophyll. The author has elected to compare the effects of the two most commonly em­ ployed wavelengths, argon green and krypton red. Dr. Olk has taken advantage of his experience in National Eye Institute col­ laborative studies and his own investigations to design a superb

From the LuEsther T. Mertz Retinal Research Lab, The Macula Foundation, Manhattan Eye, Ear, and Throat Hospital, New York.

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trial with well-delineated definitions and entry criteria, prospec­ tivity, randomization, rigid treatment technique, independent review of outcome, and exquisite analysis. The results suggest that there is essentially no difference between the use of argon pure green and krypton red laser in the treatment of diffuse diabetic macular edema. Although this trial is significant, there are at least three possible limiting factors that warrant further consideration. First, it is important to know whether there was any difference in the degree of perifoveal ischemia in the two study groups. Patients with 6 clock hours of ischemia were excluded. What about patients with less than 6 clock hours? A significant dif­ ference in the degree of ischemia in the two study groups could have an effect on the comparative visual outcome. Second, it is important to know whether there was any dif­ ference in the nature of the diffuse macular edema in the study groups. In the diabetic eye, leakage may occur from decompen­ sating retinal pigment epithelium, retinal telangiectatic capil­ laries, and microaneurysms. Retinal pigment epithelium and telangiectatic leakage would theoretically respond to grid pho­ tocoagulation from any available wavelength; whereas, leakage due predominantly to microaneurysms may necessitate a he­ moglobin-absorbing wavelength such as argon pure green or,

OLK



MODIFIED GRID LASER PHOTOCOAGULATION

preferably, the yellow dye laser near the fovea for direct coag­ ulation of these vascular elements. Third, it is important to know the outcome with respect to the near vision. We all know that there is a price to pay for widespread laser treatment in the macula: notably, progressive pigment epithelial atrophy and visual compromise. Laser treat­ ment may induce resolution of the foveal edema and improve­ ment of the distant acuity; however, the near vision may suffer from progressive perifoveal pigment epithelial atrophy. Not just letters or symbols, but words and sentences need to be evaluated to judge the outcome for the near visual function in Dr. Olk's study. Finally, I wish to make two comments based on the results of his study. First, ifmicroaneurysms do not need to be treated directly (which I doubt), there is an exceptionally sound theo­ retical rationale for the use of krypton red laser. It evidently is effective, and it spares the inner retina from any thermal damage, particularly around the fovea. Second, it is important to keep

in mind that laser photocoagulation treatment by any technique is at best palliative or supportive rather than curative in the treatment of diabetic macular edema. As has been demonstrated in other trials, very few patients in this study realized improve­ ment in their vision; in fact, only 12% showed improvement at the 2-year follow-up interval. Laser treatment can accordingly only hope to ameliorate or control the manifestation (edema) not the primary underlying disease. It is important for basic researchers and clinicians alike to search for a better understanding in the pathogenesis of diabetic macular edema and establish better methods of treatment, pref­ erably pharmacotherapeutic, in an attempt to ameliorate the retinal edema, prevent recurrent edema, and stabilize or improve the vision. Hopefully, the obscure biochemical, genetic, and lo­ calized tissue factors related to leakage from the anterior and posterior blood retinal barriers will be better understood in the future so that a greater number of patients will benefit from more prophylactic and dynamic approaches to management.

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Argon green (514 nm) versus krypton red (647 nm) modified grid laser photocoagulation for diffuse diabetic macular edema.

Between 1984 and 1988, 225 eyes of 132 patients were entered in a prospective, randomized clinical trial to determine if any significant differences e...
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