Purpose
To assess the efficacy and safety of subthreshold micropulse diode laser photocoagulation for diabetic macular edema (ME).
Design
Prospective, nonrandomized interventional case series.
Methods
setting: Institutional. patients: Thirty-six consecutive diabetic patients (43 eyes) with clinically significant ME and a central macular thickness (CMT) <600 μm by optical coherence tomography. observation procedures: Subthreshold micropulse diode laser photocoagulation was done with a 15% duty cycle (0.2 to 0.3 sec; 200 μm) at 50% to 90% of the burn threshold energy. The treated area was monitored on color images for 12 months. main outcome measures: CMT, best-corrected visual acuity (BCVA), and total macular volume at 3 months.
Results
After 3 months, there was a significant reduction of CMT ( P = .05, paired t test), but the changes of BCVA and macular volume were not significant. The preoperative CMT, BCVA (logarithm of the minimal angle of resolution; logMAR), and macular volume were 341.8 ± 119.0 μm, 0.12 ± 0.20, and 8.763 ± 1.605 mm 3 respectively, vs 300.7 ± 124.1 μm, 0.12 ± 0.21, and 8.636 ± 1.408 mm 3 at 3 months. CMT decreased significantly from 1 month ( P = .015, Friedman test). Visual acuity was improved or maintained within 0.2 logMAR for 12 months in 94.7% of the patients. No obvious laser scars were detected in any patient.
Conclusions
In patients with moderate diabetic ME, subthreshold micropulse diode laser photocoagulation controls ME and maintains visual acuity with minimal retinal damage. These findings confirm the efficacy of this method for Japanese patients.
Diabetic macular edema (DME) is one of the most important causes of impaired vision and legal blindness. In 1985, the Early Treatment of Diabetic Retinopathy Study (ETDRS) showed that macular focal laser photocoagulation could significantly improve moderate visual loss attributable to macular edema (ME). It was indicated that immediate laser photocoagulation in patients with clinically significant ME reduced the risk of visual impairment by 50%. However, progressive enlargement of laser scars, subretinal fibrosis, and subretinal neovascular membrane have been reported as complications of laser tissue damage, resulting in the occurrence of scotoma or loss of color vision. In fact, several studies have revealed that conventional laser treatment affects macular function. Therefore, a less invasive treatment strategy has been advocated in order to reduce the application of laser energy and avoid tissue damage.
Subthreshold photocoagulation, threshold level treatment, minimally intensive laser photocoagulation, and mild macular grid laser photocoagulation with a conventional continuous laser have all been reported as less invasive procedures. Moreover, advances in laser technology have led to the development of selective photocoagulation for the retinal pigment epithelium (RPE) by the subthreshold micropulse diode laser photocoagulation method. This is designed to target the RPE, while having a minimal effect on the sensory retina and choroid.
In 1997, Friberg and Karatza first reported on the clinical application of micropulse 810-nm diode laser therapy for DME. Several clinical studies have since demonstrated the efficacy of this method. However, there have been few reports about the changes of macular thickness after subthreshold micropulse diode laser photocoagulation and it is unknown whether such laser therapy is effective for Japanese patients. The author first reported on the use of this method for Japanese patients in 2007, but the present study is the first clinical investigation of subthreshold diode laser micropulse photocoagulation in Japanese patients.
Patients and Methods
Study Design
This study was a single-center, prospective, nonrandomized interventional case series.
Patient Eligibility
Thirty-six consecutive patients with type 2 diabetes (43 eyes) and clinically significant ME according to ETDRS criteria were recruited for this study. Eligibility criteria included a diagnosis of mild or moderate nonproliferative diabetic retinopathy (DR) or early proliferative DR, with clinically significant ME involving the center of the macular region or with the border of the ME involving the foveal avascular zone. Fluorescein angiography (FA) was done to confirm diffuse dye leakage at recruitment. Patients with focal ME were included in this study, but patients with only focal fluorescein dye leakage from microaneurysms were excluded. Patients with a central macular thickness (CMT) ≥600 μm were also excluded. The best-corrected visual acuity (BCVA) on the Snellen chart had to be at least 20/100 for entry into the study, and patients with poor vision attributable to subfoveal hard exudates were excluded. Other exclusion criteria were a history of vitrectomy, a history of cataract surgery or any other intraocular surgery within 3 months before the study, and previous therapy for ME (including sub-Tenon injection of triamcinolone, intravitreal injection of any drug, or macular laser photocoagulation) within 6 months before the study. Patients on hemodialysis were also excluded.
Patients underwent subthreshold micropulse diode laser photocoagulation after informed consent was obtained and all of the treatments were performed by a single surgeon (K.O). An 810 nanometer diode laser photocoagulation device (Iris Medical OcuLight SLx) from Iridex Corp (Mountain View, California, USA) was used in the micropulse operating mode, and laser light was delivered via a slit-lamp adapter though a 3-mirror contact lens to the thickened area of the macular region that showed diffuse fluorescein leakage. The laser power for subthreshold treatment was determined in each patient by creating a threshold burn with the lowest energy required to make a visible “test burn” at an area outside the vascular arcade without retinal edema. Then the laser was employed at 50% to 90% of that energy level in the micropulse mode with application of confluent spots up to 500 μm from the center of the fovea. Closure of microaneurysms was not attempted at the time of initial treatment. In the first 8 patients, the “test burn” was created with a 15% duty cycle for 0.3 seconds at a diameter of 75 μm, after which laser spots were applied by using the 15% duty cycle micropulse mode at 50% of threshold power (550 to 800 mw) for 0.3 seconds. In the following 35 patients, the test burn was created with continuous-wave laser energy (100% duty cycle) for 0.1 seconds at a diameter of 200 μm. Then laser spots were applied with the 15% duty cycle micropulse mode at 200% of threshold energy (520 to 1000 mw) for 0.2 to 0.3 sec, resulting in delivery of 60% or 90% of the threshold energy, respectively.
Best-corrected visual acuity and macular parameters were examined at enrollment, as well as at 1, 2, 3, 6, 9, and 12 months after treatment. Visual acuity (VA) was determined with the Snellen chart, and logarithm of the minimal angle of resolution (logMAR) values were calculated for statistical analysis. The CMT and total macular volume (TMV) were measured by using an optical coherence tomography (OCT) 3000 apparatus (Zeiss Humphry Instruments, Dublin, California, USA), with TMV being measured in the “Fast Macular” scan mode. Color fundus photographs were taken at enrollment, immediately after treatment, and at 1, 3, 6, and 12 months after treatment. FA was performed at enrollment and was repeated when it was considered to be clinically necessary. Patients were followed up at monthly intervals for at least 3 months without any additional treatment. Subsequently, additional treatment (further subthreshold micropulse diode laser photocoagulation, conventional laser therapy, pharmacologic treatment, or vitrectomy) was provided for persistent ME and/or decreased VA as necessary. Patients who received further subthreshold micropulse diode laser photocoagulation or conventional laser therapy were evaluated until the final visit, while patients who received pharmacologic treatment or vitrectomy were not evaluated for BCVA or macular parameters after starting further treatment.
The primary endpoint of this study was the change of CMT at 3 months, while the secondary endpoints were the changes of BCVA (logMAR) and TMV at 3 months. Statistical analysis was done by the paired t test to evaluate these outcomes, while the Friedman test was used to evaluate the trends of parameters over time. All analyses were done with SSPS 15.0 J (SPSS Japan, Tokyo, Japan).
Results
Demographic Data and Baseline Characteristics
Thirty-six patients (43 eyes) with type II diabetes and clinically significant ME were enrolled in this study and underwent subthreshold micropulse diode laser photocoagulation. There were 21 men (25 eyes) and 15 women (18 eyes). The patients ranged from 38 to 82 years old, with a mean age of 59.6 ± 7.69 years (mean ± standard deviation [SD]). All patients had type II diabetes and the duration of diabetes ranged from 3 to 40 years, with mean of 14.3 ± 8.56 years. The mean hemoglobin A 1c level was 7.4 ± 1.22% (mean ± SD) before starting the study. Diabetic nephropathy was present in 15 patients (19 eyes, 44.2%), 18 patients (21 eyes, 48.8%) had no nephropathy, and the nephropathy status was unknown in 3 patients (3 eyes, 7.0%). Diabetic retinopathy was classified as mild or moderate nonproliferative retinopathy in 5 eyes (12%), severe preproliferative retinopathy in 30 eyes (70%), and early proliferative retinopathy in 8 eyes (19%). The preoperative foveal thickness ranged from 155 to 597 μm (mean ± SD, 341.8 ± 119.0 μm).
Further Treatment
All patients completed 3 months of follow-up, and the following additional treatments were performed subsequently. For persistent ME, additional subthreshold micropulse diode laser photocoagulation was done in 8 eyes (18.6%) within 12 months. Mild macular grid photocoagulation was done for 1 eye (2.3%) at 3 months and for 2 eyes from 7 to 12 months. Direct photocoagulation of microaneurysms was performed in 1 eye (2.3%) at 3 months. These 4 patients (4 eyes) who underwent additional conventional laser therapy for ME were included in the analysis up to 12 months. For persistent subfoveal retinal detachment, intravitreal injection of triamcinolone and intravitreal injection of bevacizumab were performed in 1 eye each at 7 months. For persistent cystoid ME, 1 eye received sub-Tenon injection of triamcinolone at 6 months. Two patients underwent vitrectomy for persistent ME at 7 and 8 months, respectively, because their VA had declined gradually. The data for these 5 patients were excluded from analysis at 12 months. Overall, 9 eyes (20.9%) of 9 patients required additional treatment other than subthreshold micropulse diode laser photocoagulation within 12 months. Panretinal photocoagulation was performed in 12 eyes (27.9%) for progression of DR, with 2 eyes being treated within 6 months and 10 eyes receiving treatment from 7 to 12 months. Patients who underwent panretinal photocoagulation were included in the subsequent analyses. Accordingly, a total of 43 eyes (including 2 eyes receiving conventional macular focal laser therapy) were analyzed up to 6 months and 38 eyes (including 4 eyes receiving conventional macular focal laser therapy) were analyzed up to 12 months, while the 5 eyes that received ocular pharmacotherapy or vitrectomy were excluded from analysis at 12 months.
Macular Parameters and Optical Coherence Tomography Findings at 3 Months
A significant reduction of CMT was noted at 3 months after subthreshold micropulse diode laser photocoagulation ( P = .05, paired t test), but the change of TMV was not significant. The preoperative CMT and TMV were 341.8 ± 119.0 μm (mean ± SD) and 8.763 ± 1.605 mm 3 , respectively, while the values at 3 months were 300.7 ± 124.1 μm and 8.636 ± 1.408 mm 3 , respectively.
Overall, 29 of 43 eyes (67.4%) showed a reduction of CMT at 3 months and CMT decreased by 20% or more in 17 of 43 eyes (39.5%). Seven eyes (16.3%) had serous retinal detachment before treatment. At 3 months, 4 of 7 eyes (57.1%) demonstrated improvement of serous retinal detachment, 2 eyes (28.6%) showed complete resolution, and 1 eye (14.3%) showed no change.
Visual Acuity at 3 Months
There was no significant change of BCVA (logMAR) at 3 months (from 0.12 ± 0.20 to 0.12 ± 0.21 = 20/27 to 20/27 as Snellen equivalent). The baseline Snellen VA was used to categorize the eyes into 3 groups: Group I was 7 eyes (16%) with an acuity <20/40, Group II was 19 eyes (44%) with an acuity from 20/40 to 20/22, and Group III was 17 eyes (40%) with an acuity≥20/20. In Groups II and III, 34 of 36 eyes (94.4%) maintained VA of ≥20/40 at 3 months. In Group III, 16 of 17 eyes (94.1%) maintained VA of ≥20/20 at 3 months.
Changes of Best-Corrected Visual Acuity and Macular Parameters
Mean BCVA was stable until 12 months after treatment ( Figure 1 ). In contrast, the decrease of CMT was significant from 1 month ( P = .015, Friedman test) ( Figure 2 ), and TMV showed a significant change from 2 months ( P = .03, Friedman test) ( Figure 3 and Figure 4 ).
Best-corrected visual acuity data are summarized in Table 1 . VA was improved or maintained within 0.2 logMAR in 42 of 43 eyes (97.7%) at 3 months, while 36 out of 38 eyes (94.7%) showed improvement or maintenance of BCVA up to 12 months with additional conventional laser therapy after 3 months. Of the 34 eyes without additional treatment, 32 eyes (94.1%) showed improvement of BCVA by ≥0.2 logMAR or maintained it within 0.2 logMAR up to 12 months. The data on CMT, TMV, and the ≥20% macular thickness reduction rate are shown in Table 2 . In 2 eyes of 2 patients (4.7%), VA decreased by more than 0.3 logMAR at 6 months. One of these patients underwent vitrectomy at 7 months, while the other patient’s VA recovered to baseline at 9 months.
