Comparing Conventional Grid Laser Photocoagulation and Subthreshold Micropulse Laser in Diabetic Macular Edema Using OCT Angiography

The prevalence of diabetes mellitus has increased significantly in Hong Kong for the past decade \[1\]. Diabetic macular edema is one of the most common causes of vision loss in patients suffering from diabetes mellitus \[3\]. Before the introduction of anti-vascular endothelial growth factor agents, laser photocoagulation has been the mainstay treatment for patients with diabetic macular edema. There are two types of laser treatment modalities, namely focal laser, which can be applied either in a grid pattern over a region of macular edema or to selected microaneurysms, and subthreshold micropulse laser. Only one meta-analysis published in 2016 \[16\] had previously demonstrated superiority of micropulse laser over focal laser, while other studies showed no clinically significant differences between the two lasers. Nevertheless, micropulse laser had been proven to cause no structural changes to the retina and choroid, as opposed to focal laser.

Optical coherence tomography angiography (OCT-A) is a new, non-invasive imaging technique that allows a clear, depth-resolved visualization of the retinal and choroidal microvasculature in the macular region \[22\]. A recent case series study \[17\] has demonstrated early changes of retinal vasculature on OCT-A images after micropulse laser for diabetic macular edema. Another cross-sectional study \[18\] showed choriocapillaries alterations in some of the patients after receiving focal laser. We would like to compare the changes of different OCT-A parameters for patients receiving either type of laser, and hence evaluating their efficacy.

We propose to take OCT-A images for patients before laser, 1-, 3- and 6-months post-laser based on the results of a recent case series \[17\]. We will analyse the OCT-A images with MATLAB software and compare the changes in different parameters between both lasers.

Laser photocoagulation was previously a mainstay treatment for DME before the introduction of anti-vascular endothelial growth factor (anti-VEGF) agents injection. Vascular endothelial growth factor (VEGF) is an important mediator of blood-retinal barrier breakdown, which leads to fluid leakage and the development of macular edema \[5\]. Observing that intraocular VEGF levels are increased in DME, using VEGF inhibitors (anti-VEGF) was found to be beneficial in reversing vision loss from macular edema \[6\]. In recent years, many large-scale studies \[7\], \[8\], \[9\], \[10\] had proven that anti-VEGF injections resulted in superior improvements in visual acuity and central subfield thickness than laser photocoagulation in treating DME. This has led to the decline of conventional focal laser as a first-line therapy.

However, in our clinical setting, laser photocoagulation may still be preferred in selected clinical scenarios in treating DME. In Hong Kong, anti-VEGF agents were self-financed items for patients in the public sector of our healthcare system. These medications could be a huge financial burden to patients with low financial support, and therefore they might prefer laser therapy instead.

Furthermore, anti-VEGF intravitreal injections have been reported to have detectable levels in systemic circulation, which can lead to systemic complications. A retrospective study \[11\] of 1173 patients showed that bevacizumab has a risk of leading to systemic events including acute blood pressure elevation (0.59%), cerebrovascular accidents (0.5%), myocardial infarctions (0.4%), and iliac artery aneurysms (0.17%). Hence, patients with recent history of cardiovascular accidents or significant cardiovascular comorbidities and patients who could not tolerate intravitreal injections might also find laser therapy a better option in treating DME.

Therefore, it is still useful to compare the effectiveness of conventional focal/grid laser versus subthreshold micropulse in treating DME in our clinical context. Previous studies \[12\], \[13\], \[14\] had mainly demonstrated non-inferiority of subthreshold micropulse laser in terms of best-corrected visual acuity (BCVA), contrast sensitivity and central retinal thickness. Nonetheless, majority of the studies demonstrated that laser scars were much more frequently identified in conventional laser than micropulse laser-treated eyes.

Optical coherence tomography angiography (OCT-A) is a new, non-invasive imaging technique to visualize the retinal vasculature and choroidal vascular layers in the macular area. It employs motion contrast imaging to high-resolution volumetric blood flow information, generating angiographic images in seconds. The principle of OCT-A involves the comparison of decorrelation signal between sequential Optical Coherence Tomography (OCT) B-scans taken at precisely the same cross-section, therefore constructing a map of blood flow. Given that only erythrocyte movements in the blood vessels are represented and axial bulk motions are eliminated, determining a vascular decorrelation signal enables visualization of 3-dimensional retinal and choroidal vascular network without the administration of intravenous dye and thus reducing the risk of potential adverse events \[17\], \[22\].

The authors believe that OCT-A can be used as a new assessment tool in comparing the efficacy of conventional focal laser versus subthreshold micropulse laser in the treatment of DME. We hypothesize that subthreshold micropulse laser is superior to focal laser in treating patients with DME in terms of OCT-A parameters. We expect the reduction in the studied OCT-A parameters (i.e. FAZ area, area of cysts, number of microaneurysms, etc.) in patients receiving subthreshold micropulse laser will be greater than focal laser by 30%.

Eligibility Criteria:
Inclusion Criteria:

* Patients with best-corrected visual acuity better than 20/200 (checked with refraction test)
* Patients with clinically significant diabetic macular edema (DME) who have not received any treatment within 6 months
* Patients with central retinal thickness equal / above to around 400 um
* Patients who are able to have regular visits after laser treatment for at least 6 months

Exclusion Criteria:

* Children under the age of 18
* Patients with proliferative diabetic retinopathy
* Patients with co-existing retinal or macular disease, including epiretinal membrane and vitreomacular traction
* Patients with previous history of laser photocoagulation, anti-VEGF injection, intravitreal steroid injection, vitreoretinal or cataract surgery within a period of 6 months
* Patients with history of uveitis
* Patients who are unfit or for capturing of OCT-A images
* Patients with significant media opacity that may interfere with fundal examination and the acquisition of high quality OCT-A images
* Patients who are unable to give informed consent to enter the study

uncooperative