Comparing the effectiveness of brolucizumab therapy alone versus that combined with subthreshold micropulse laser exposure in the treatment of diabetic macular edema

laser exposure (SMPLE). Before and after treatment, a comprehensive ophthalmological examination was performed, including the best-corrected visual acuity (BCVA) and the height of retinal edema in the central fovea as assessed by optical coherence tomography. The parameters were assessed at 1, 3, 6 and 12 months after treatment. Results: The percentage of patients with no need for additional anti-VEGF injections was substantially higher in the combined therapy group than in the monotherapy group (68.5% versus 12%, respectively, p <0.001). Conclusion: The combination treatment (intravitreal brolucizumab combined with SMPLE) for DME was effective in 68.5% of cases within 12 months. In this way, a steady resorption of DME is accomplished through antivasoproliferative and prolonged effects of brolucizumab and the SMPLE session.

the eyes had received at least 1 injection in the second year, and 98% of the protocol-required injections, based on visual acuity and optical coherence tomography OCT (optical coherence tomography), were given over the 2 year study period. The recurrence rate was high even after edema resorption [9]. Thus, frequent anti-VEGF injections (7)(8)(9)(10)(11)(12) injections in the first year and somewhat less in subsequent years) were required to maintain the resolution of the DME [13]. Focal or grid laser photocoagulation of the retina was a major treatment for DME before the introduction of the anti-VEGF drugs into clinical practice. The Early Treatment Diabetic Retinopathy Study (ETDRS) has shown that focal laser photocoagulation treatment is beneficial in reducing the risk of visual loss from clinically significant DME [14]. The method of laser treatment employed in the ETDRS has become the technical standard of macular photocoagulation in DME. Conventional laser photocoagulation is effective in eyes with DME, but can result in complications like laser scars, choroidal neovascularization, subretinal fibrosis, retinal pigment epithelial atrophy, visual field narrowing, loss of color vision, diabetic macular edema, anti-VEGF therapy, subthreshold micropulse laser exposure metamorphopsia and enlargement of laser scars [1,15,16]. Laser-induced damage to the retina limits the density and repeatability of laser treatment. Today, the predominant method of laser treatment for DME is the "modified ET-DRS photocoagulation" (mETDRS). This technology has offered us new laser media and wavelengths [13].
A novel laser delivery modality was invented by Pankratov in 1990 wherein the laser energy was delivered in short pulses or "micro pulses" instead of a continuous wave [17]. Advances in the field of laser systems have led to a new approach called subthreshold micropulse laser exposure (SMPLE) [18,19]. It is now possible to deliver a subthreshold laser that is above the threshold of biochemical effect but below the threshold of a visible, destructive lesion, thereby preventing potentially limiting progressive enlargement of laser scars, which can lead to scotoma and loss of color vision [2,15]. Many investigators believe that this may be the safest form of laser treatment for DME [2,18]. There are, however, several treatment protocols regarding surgical or delayed micropulse laser treatment. Some of them can be combined with anti-VEGF therapy [20].
The purpose of this study was to compare the effectiveness of a combination of anti-VEGF therapy with SMPLE versus anti-VEGF therapy alone in the treatment of DME.

Material and Methods
A prospective study was conducted at the eye clinic "SIHAT KO`Z" and Tashkent State Dental Institute and was a 12-month follow-up. Eighty-two patients (150 eyes) with DME were involved in the study and their eyes were compared for the morphofunctional parameters of the central retina. All patients had a verified diagnosis of type 2 DM. The age of the patients ranged from 48 to 69 years. There were 48 women and 34 men. Intraocular pressure (IOP) readings by pneumotonometry ranged from 11.0 to 20.0 mm Hg. Patients with a vision reducing cataract were excluded from the study.
Patients were divided into two treatment groups. Group 1 (37 patients, 68 eyes) was treated with anti-VEGF injections according to the one plus pro re nata (PRN) regimen (once plus as needed) only whereas group 2 (45 patients, 85 eyes) received a combination of "one plus PRN" anti-VEGF therapy with SMPLE.
Before and after treatment, a comprehensive ophthalmological examination was performed, including the bestcorrected visual acuity (BCVA) and the height of retinal edema in the central fovea as assessed by OCT. Parameters were assessed before treatment and at 1, 3, 6 and 12 months after treatment.
Brolucizumab, a monoclonal antibody that binds to VEGF-A, was administered as an anti-VEGF intraocular injection at a dose of 0.2 ml (2.0 mg). Intravitreal injections were performed in a standard fashion using surgical instruments. Palpebral skin and the area around the eye were treated with a 10% iodopyrone solution. Epibulbar anesthesia was locally administered. After an epibulbar anesthetic was instilled, a sterile speculum was inserted to separate the lids, and the conjunctival sac was flushed with betadine diluted with saline in a ratio of 1:2. Calipers were used to mark the injection site 3.5 mm laterally from the limbus at 10 o'clock. The syringe was extracted and the conjunctiva was pulled over the injection site with forceps to reduce the release of vitreous beneath the conjunctiva. An antibacterial medication was instilled.
A general ophthalmological examination was carried out the next day after injection to timely identify any postinjection complications such as retinal detachment, vitreous hemorrhage, intraocular inflammation, toxic damage to the lens, etc. In the postoperative period, topical antibacterial and anti-inflammatory eye drops were instilled for 14 days.
SMPLE was performed on a 577-nm Easyret laser system (Quantel medical, France) in a micropulse mode with a power of 200-400 mW. The spot size is 100 µm, the pulse burst duration is 200 ms with a duty cycle of 5%. The micropulse laser power used in SMPLE was derived for each eye from a test burn. The test burn was performed using a 100 µm spot diameter and a 200 pulse burst duration outside the vascular arcade with the power titrated from 50 mW upward until a burn became barely visible. SMPLE was then performed continuously on the macular region using the same spot size, reducing the laser power to half the power of the test burn. The number of spots applied varied depending on the extension of the edema.
With combined treatment, the SMPLE session was performed 3 days after a single loading of the anti-VEGF drug.
Descriptive statistics was calculated using Microsoft Office Excel (v.2016, Microsoft Corporation, Redmond, WA). Quantitative characteristics are presented as means and standard errors of means. Qualitative characteristics are presented as numbers and percentages. A Student ttest was applied to determine whether there were any significant differences between groups and between pre-and post-treatment periods. The level of significance p ≤ 0.05 was assumed.
At one month after the loading injection, BCVA improved to 0.71±0.04 in the monotherapy group and to 0.78±0.03 in the combined therapy group. These improvements were comparable in both groups and significant (P = 0.001). Mean central retinal thickness decreased to 257.4±14.5 µm in the monotherapy group and 252.4±24.8 µm in the combined therapy group (P = 0.77). In addition, three patients in the monotherapy group needed an additional injection.
At six months, BCVA was still better than baseline, 0.66±0.02 in the monotherapy group and 0.75±0.02 in the combined therapy group. These differences were statistically significant (P = 0.001).
By month 12, BCVA improved to 0.65±0.03 in the monotherapy group and to 0.79±0.03 in the combined therapy group, but the improvement in the latter group was not statistically significant (P = 0.62).
The trends for improvements in the central retinal thickness were similar to improvements in BCVA. By month 6, mean central retinal thickness decreased to 275.3±22.7 µm in the monotherapy group and 258.5±14.6 µm in the combined therapy group (P = 0.4). By month 12, mean central retinal thickness was 276.5±15.9 µm in the monotherapy group and 255.4±18.7 µm in the combined therapy group, with no significant difference between groups (P = 0.16).
By the end of the study, the combined therapy group needed substantially less anti-VEGF injections than the monotherapy group. Particularly, 68.5% of the former group needed no additional injections, whereas 88% of the latter group needed additional injections.
Mean number of injections received over 12 months was 4.33±1.02 for the total study cohort, 3.18±0.48 for the combined therapy group and 5.49±1.56 for the monotherapy group (р < 0.001). By the end of the study, the percentage of patients with no need for additional anti-VEGF injections was substantially higher in the combined therapy group than in the monotherapy group (68.5% versus 12%, respectively, р <0.001).

Discussion
DME is one of the most unfavorable and difficult to treat manifestations of DR [12]. About 32-50% of eyes with clinically significant DME if untreated will have significant irreversible vision loss and reduced vision-related quality of life, leading to visual disability and increased social and economic costs [14]. Intravitreal injections of VEGF inhibitors have become the first line of treatment for this condition instead of laser retinal photocoagulation. However, clinical reports on the application of anti-VEGF drugs in patients with DME have demonstrated that about 30% of patients may be insufficiently responsive to this intravitreal therapy [21]. The disadvantages of intravitreal injection include development of certain complications, such as endophthalmitis, retinal and intravitreal hemorrhages, intraocular lens dislocation, etc [12,17].
In the current study, we compared anti-VEGF therapy alone with anti-VEGF therapy combined with SMPLE in terms of efficacy over a 12-month follow-up. Both groups achieved substantial improvements in BCVA and retinal height at the fovea. Final BCVA was better in eyes treated with anti-VEGF therapy combined with SMPLE (0.79±0.03). The percentage of patients with no need for additional anti-VEGF injections was substantially higher in the combined therapy group than in the monotherapy group (68.5% versus 12%, respectively, р < 0.001). This is the first study in the literature to use the anti-VEGF drug (brolucizumab) and its combination with an SMPLE session in DME patients with relatively high baseline BCVA. Thus, adding an SMPLE session after loading an anti-VEGF drug appears to significantly reduce injection load without sacrificing improvement in vision. We found that the treatment effectiveness assessed after 12 months of follow-up differed significantly between groups 1 and 2. This combination provides a statistically significant improvement in BCVA and a decrease in the height of the retina in the fovea in DME with a central foveola thickness of less than 400 µm. SMPLT may be an option for patients who do not respond well to or cannot follow anti-VEGF therapy due to its high cost, or who experience adherence problems due to the frequent visits required for injection and ophthalmologic monitoring.
Fedchenko and colleagues [21] concluded that, unlike suprathreshold, subthreshold laser mode is a nondamaging procedure and can be used in clinical practice as a laser retinal treatment approach providing the least invasive effect on the chorioretinal complex. According to the selected duty cycle, the laser remains on only 5% of the time, thus generating less heat with consequent less retinal damage than continuous photocoagulation. Our experience shows that micropulse laser treatment for DME is more effective in patients whose central retinal thickness with edema is less than 400 µm.

Conclusion
The combination treatment (intravitreal brolucizumab combined with SMPLE) for DME was effective in 68.5% of cases within 12 months. The combination treatment (intravitreal brolucizumab combined with SMPLE) for DME was effective in 68.5% of cases within 12 months. In this way, a steady resorption of DME is accomplished through antivasoproliferative and prolonged effects of brolucizumab and the SMPLE session.