Morphological and functional outcomes following modified early treatment diabetic retinopathy study laser in diabetic macular edema.

AIM: The aim was to report morphological and functional outcomes following modified early treatment diabetic retinopathy study (ETDRS) laser in diabetic macular edema (DME).
MATERIALS AND METHODS: Structural and functional changes using spectral domain optical coherence tomography (OCT) and microperimetry (MP) were studied before and 4 months after laser in 37 eyes with clinically significant macular edema (ME) requiring modified ETDRS laser treatment. Paired t-test was used to compare pre and postlaser outcomes P < 0.05 was considered statistically significant.
RESULTS: Central foveal thickness showed a significant reduction after laser P = 0.004. There was a significant reduction in mean retinal thickness (MRT) and retinal volume in all the quadrants of ETDRS except for the temporal and nasal quadrants in outer 6 mm ring. Maximum reduction in MRT was seen in eyes with DME having neurosensory detachment (382.66 μ to 292.61 μ). Retinal sensitivities reduced in all quadrants following laser, however, fixation patterns showed improvements. The change in VA was positively correlated to change in MRT (r = 0.468, P = 0.032).
CONCLUSION: Laser not only causes structural benefits such as reduction of retinal thickness and volume, it also causes improvement of fixation patterns.

Introduction

Macular edema (ME) is the most common cause of visual impairment in subjects with type II diabetes mellitus.[1] Early treatment diabetic retinopathy study (ETDRS) and more recently diabetic retinopathy clinical research network studies have established the efficacy of laser in diabetic macular edema (DME).[23] The efficacy in these studies is evaluated in terms of reduction of risk of moderate visual loss.

Studies have demonstrated structural changes seen in optical coherence tomography (OCT) after laser and correlated to visual acuity. Aiello et al.[4] showed that greater baseline OCT volumes along with a better visual acuity at presentation are bad prognostic factors in patients undergoing macular laser. Similarly, several studies have also shown that retinal sensitivity reduces after conventional laser treatment in ME.[56] Besides microperimetry, (MP) Lövestam et al.[7] had demonstrated an increase in amplitudes as measured by multifocal electroretinography after laser treatment. However, none of the studies have shown segmental morphological and functional changes (quadrant-wise) Vujosevic et al.[8] demonstrated variable fixation patterns in DME, which were not related to the type of ME (cystic or diffuse). The changes in the fixation patterns after conventional laser after macular laser have also not been studied.

The aim of the present study was to correlate regional structural (using spectral domain OCT) and regional functional (using microperimeter) changes after macular laser for DME. It also aimed to study the changes in the fixation pattern observed after macular laser in DME.

Materials and Methods

Twenty-four patients (37 eyes) were enrolled in this prospective study, who attended the outpatient clinic of a tertiary eye care hospital from May 2009 to April 2010. Inclusion criterion included patients with clinically significant ME requiring modified ETDRS laser treatment, clear media, adequate pupil diameter (≥4 mm). Patients having uncontrolled blood pressure, diabetic nephropathy, history of prior treatment with laser or any other ocular condition precipitating ME were excluded from the study. The study was approved by the institutional review board, and a written informed consent was taken as per the tenets of Helsenki declaration.[9]

Prior to laser treatment, all subjects underwent comprehensive eye examination. They also underwent four-field stereoscopic 45° fundus photography. They underwent structural testing by (SD-OCT, Copernicus, Optopol technologies, Zawierci, Poland) and functional testing by (MP 1, Nidek Instruments Inc, Padova, Italy). All patients underwent modified ETDRS laser treatment for ME.[10] After treatment, they were followed-up after 4 months. At this visit, besides routine clinical examination, they again underwent SD-OCT and MP examination.

Spectral domain OCT was performed through a dilated pupil. An asterisk scan and three dimensional scan protocol were chosen for our study. For the asterisk scan protocol, a scan length of 7 mm with 6 B-scans (3000 A-scans/B-scan) passing through the center of the fovea was used. Three dimensional scan protocol was used with 7 mm scan length with 50 B scans (1000 A-scans/B scan). The parameters measured on SD-OCT were central foveal thickness (CFT), photoreceptor layer thickness (PRL), RPE thickness and Retinal thickness, and volume in each of the 9 ETDRS regions. CFT was defined as the distance between the vitreoretinal interface and anterior surface of the retinal pigment epithelium (RPE). The measurement was made manually using the SD-OCT software with fovea being depicted as a hyperreflective echo on the B-scan. PRL was measured at the central fovea and defined as the distance between the external limiting membrane and anterior surface of the RPE. RPE thickness was measured manually at the central fovea as the distance between the inner and outer edge of RPE layer.

Microperimetry (MP 1, Nidek Instruments Inc, Padova, Italy) was performed before the laser institution. The procedure was then performed in a dark room under dilatation after prior explanation. All the subjects were given pre-test (training) stimuli before starting the test to make them aware of the procedure and to minimize the learning curve. A stimulus size equivalent to Goldmann III test spot with attenuation of stimulus intensity 16 db and a grid of 33 stimuli covering central 20° area (1° =300 μ, hence 20° =6000 μ) centered on the fovea was used. A 4–2 double staircase strategy was applied was measuring the threshold. A white background with illumination of 1.27 cd/m2 was used. The fixation target size was increased until when the patient appreciated it. Subjects were asked to respond to the stimulus using trigger. Fixation stability and location of fixation was measured using fundus tracking software in the instrument.

For measuring the quadrant wise retinal sensitivity, the central 20° were divided into 9 ETDRS regions comprising of central foveal region of 1 mm and then dividing the inner and outer rings of 3 mm and 6 mm, respectively, into 4 quadrants each. The central circle contained 1 point whereas the surrounding 3 mm circle and 6 mm circler had 12 points each (3 points in each of the 4 quadrants).

Fixation characteristics were measured by according to Fuji et al.[11] The standard central fixation is defined to approximate a 2° diameter (600 μ) circle centered on the fovea. A “predominantly central fixation” was defined as one with >50% of preferred fixation points located within the central circle, eyes with >25% but <50% were labeled as poor central fixation. Eyes with <25% of fixation points on the central circle were classified as “predominantly eccentric fixation.” Eyes with >75% fixation points located within central 2° were classified as having a stable fixation. Eyes having <75% fixation points located within the 2°, but >75% fixation points within the central 4° were labeled “relatively unstable fixation.” Eyes with <75% fixation points in the central 4° were labeled as “unstable fixation.”

Statistical analysis was performed using (SPSS for Windows, ver.12.0 SPSS Science, Chicago, IL) software. A paired t-test was used to compare the pre and postlaser outcomes. Intra-class correlation was done to assess the intra-observer variability. A P < 0.05 was considered statistically significant.

Results

Of the 24 study patients, 15 (62.5%) were male and 9 (37.5%) female. The mean age was 57.04 ± 6.4 years (Range 45-68 years), and mean duration of diabetes in the study was 10.9 ± 5.2 years. The mean best-corrected visual acuity before laser was 0.35 ± 0.22 log MAR and after laser treatment at 4 months was 0.34 ± 0.21 log MAR (P = 0.45).

Table 1 summarizes the distribution of retinal thickness parameters in the 9 ETDRS regions. Of the three measurements CFT, PRL, and RPE thickness, CFT showed a significant reduction after laser (271.81 ± 140.46 - 261 ± 137.99) P = 0.004. Mean retinal thickness (MRT) showed a significant reduction in central 1 mm ring, inner 3 mm ring and temporal and nasal quadrant in the outer 6 mm ring (P < 0.05). Intra-observer repeatability was found to be good in the manual measurement of the SD-OCT outcomes. The intraclass correlation coefficient for CFT, PRL, and RPE were 1, 0.99, and 0.96, respectively.

Table 1

Quadrantic distribution of RT parameters (in microns) in 9 ETDRS regions

Based on the OCT morphological characteristics, 18 (48.64%) had spongiform type of DME, 11 (29.72%) had cystoid ME, and 8 (21.62%) had predominantly neurosensory detachment (NSD). There were reduction in MRT in all cases (spongiform ME: 291.19 μ to 271.22 μ, cystoid ME: 377.19 μ to 354.56 μ, ME with NSD: 382.66 μ to 292.61 μ).

Table 2 shows the distribution of retinal volume in all the 9 ETDRS regions. There was a statistically significant reduction in retinal volume in central 1 mm ring, inner 3 mm ring (all quadrants), and in the outer 6 mm ring (temporal and nasal quadrant).

Table 2

Macular volume distribution along the 9 ETDRS regions

Of the total 37 eyes, 21 eyes underwent pre and postlaser MP. Table 3 shows the retinal sensitivities before and after laser at 4 months. Retinal sensitivities reduced in all quadrants following laser, however, statistical significant reduction was seen in the temporal quadrant in inner 3 mm ring and in nasal and superior quadrants in outer 6 mm ring.

Table 3

Quadrantic distribution of RS (in dB) in 9 ETDRS regions

Table 4 shows relationship between changes in visual acuity, changes in retinal sensitivity, and changes in MRT after laser treatment. The changes in visual acuity were significantly and positively correlated to changes in MRT (r = 0.468, P = 0.032). However, changes in retinal sensitivity were neither correlated to changes in retinal thickness (r = 0.186, P = 0.420) nor to the changes in visual acuity.

Table 4

Relationship between changes in BCVA, change in RT and change in RS after laser treatment

Figure 1 shows us the fixation characteristics before and after laser photocoagulation. Among the 21 eyes 13 (61.9%) had a stable fixation, 4 (19%) had relatively stable fixation, and 4 (19%) had an unstable fixation before laser. Postlaser we found 13 eyes (61.9%) had a stable fixation, 6 eyes (28.6%) had a relatively stable fixation, and 2 eyes (9.5%) had unstable fixation.

Figure 1

Comparison of fixation characteristics in patients with diabetic macular edema undergoing laser in pre and post period

Discussion

In this study, we evaluated the morphological and functional changes in patients with DME, before and 4 months after laser photocoagulation. SD-OCT showed a significant reduction in the CFT following laser which was supported by the earlier studies.[1213] We did not observe any significant change in PRL and RPE thicknesses, before and after laser treatment. However, Bolz et al.[14] have reported increased PRL thickness following laser treatment. They hypothesized that this could be due to the immediate scarring reaction following laser, leading to a centrifugal contraction at the level of RPE and PRL. But they did not look into the long-term effect of this laser on the outer retinal layers, which was assessed in our study. No change in PRL and RPE thickness observed in our study may be due to the remodeling of the outer retinal layers that have occurred in the follow-up, which was supported by Mylonas et al.[15] who reported altered PRL and RPE layers immediately after laser photocoagulation and restoration of outer retinal layers 3 months after laser.

Macular volume along the 9 ETDRS regions revealed good relation with that of the retinal thickness seen in these regions, that is, both macular volume and thickness reduced significantly along all the ETDRS regions, except for the superior and inferior quadrants of the outer 6 mm parafoveal ring. Previous studies have shown that mean macular volume reduced significantly in the 1-month follow-up visit after laser and total macular volume decreased by 0.2 mm3 in 12 months follow-up after laser.[16] Soliman et al.[12] have reported that the effect of photocoagulation on retinal thickness decreased with increasing eccentricity which was similar to our study results, where we found a significant change in retinal thickness in 1 mm ring, 3 mm ring and the outer 6 mm ring except for the superior and inferior quadrants.

In our study, we found that the reduction in retinal thickness was more evident in the eyes with NSD compared to other two groups following laser. This could be hypothesized that the fluid spaces reduction might be more than the tissue spaces reduction.

Retinal sensitivity was reduced following laser which was similar to the earlier study results.[1718] Though we found a reduction in retinal sensitivity following laser, the reduction was not significant except for the temporal quadrant in the inner ring and superior and nasal quadrants in the outer rings. Loss of retinal sensitivity could be due to the laser burns to the leaking microaneurysms in the retina which eventually burns the retinal tissue. The benefit of retinal laser treatment has been found to be associated with severe destruction of the retinal tissue.[19]

There was no change in the fixation stability in the 13 eyes, which maintained stable fixation even after laser. 4 eyes had relatively stable fixation, and 4 had unstable fixation prior to laser. After laser, 2 of the eyes with initially unstable fixation gained relatively stable fixation. Thus, 6 eyes had relatively stable, and 2 had unstable fixation. Previous studies have also shown that both fixation location and stability of fixation were not influenced by edema characteristics like diffuse, focal, cystoid, sponge-like, with or without subfoveal NSD, except when sub-foveal hard exudates are present.[20] But no studies have looked into the fixation characteristics following laser treatment. Thus, laser treatment not only causes structural benefits like reduction of retinal thickness and volume, it also causes functional improvement like improvement of fixation patterns.

The strength of the study is the standard documentations by photography, SD-OCT, and MP in all cases. The limitations of the study are the smaller sample size and lack of information regarding systemic co-morbid conditions like renal parameters which might affect the prognosis in ME. Even though we excluded subjects with a history of diabetic nephropathy, this exclusion was based on history. Patient may be undiagnosed nephropathy; as the renal parameters like microalbuminuria, serum urea, and creatinine were not measured in the study.

Conclusion

This study demonstrates the efficacy of modified ETDRS laser treatment in the management of DME. Further studies are warranted to demonstrate the functional changes after laser treatment.