Sub-threshold micropulse laser treatment reduces inflammatory biomarkers in aqueous humour of diabetic patients with macular edema

Abstract

Subthreshold micropulse laser (SMPL) is a tissue-sparing technique whose efficacy is demonstrated for diabetic macular edema (DME) treatment. However, its mechanism of action is poorly known. A prospective observational study was performed on naïve DME patients treated with SMPL, to evaluate the changes of aqueous humor (AH) inflammatory and vaso-active biomarkers after treatments. AH samples of eighteen DME eyes were collected before and after SMPL. Ten non-diabetic AH samples served as controls. Full ophthalmic evaluation, spectral domain optical coherence tomography (SD-OCT) and fluorescein angiography were performed in DME group. Glass chip protein array was used to quantify 58 inflammatory molecules. Central retinal thickness (CRT) and visual acuity were also monitored. Several molecules showed different concentrations in DME eyes versus controls (p value < 0.05). Fas Ligand (FasL) , Macrophage Inflammatory Proteins (MIP) - 1α , Regulated on Activation Normal T Cell Expressed and Secreted (RANTES) and Vascular Endothelial Growth Factor (VEGF) were increased in DME at baseline versus controls and decreased after SMPL treatments (p < 0.05). CRT reduction and visual acuity improvement were also found. Inflammatory cytokines, mainly produced by the retinal microglia, were significantly reduced after treatments, suggesting that SMPL may act by de-activating microglial cells, and reducing local inflammatory diabetes-related response.

Subthreshold Micropulse Laser in Diabetic Macular Edema: 1-Year Improvement in OCT/OCT-Angiography Biomarkers

“…1,2,17,18 Recently, it has been reported that SMPL reduces the aqueous humour (AH) concentration of inflammatory cytokines secreted by retinal glial cells (GLCs), both Müller cells (MCs) and microglial cells (MGCs) in eyes with DME. 19,20 A decrease in the inner nuclear layer thickness (INL), where the bodies of MCs are located, was reported after SMPL. 21 Whether this effect on GLCs is direct or mediated by the RPE has still to be evaluated and confirmed; however, these findings suggest that SMPL might be able to downregulate the inflammatory retinal processes activated by hyperglycemia in diabetes mellitus (DM).…”

“…21 Whether this effect on GLCs is direct or mediated by the RPE has still to be evaluated and confirmed; however, these findings suggest that SMPL might be able to downregulate the inflammatory retinal processes activated by hyperglycemia in diabetes mellitus (DM). 19,20 The clinical effects of SMPL on the retina in eyes with DME have been evaluated using standard imaging techniques, such as color fundus photography, optical coherence tomography (OCT), fundus autofluorescence (FAF), fluorescein angiography (FFA), and microperimetry. 3,4,[9][10][11]15 However, only one study reported on the use of OCT angiography (OCTA) in evaluating microvascular changes occurring after SMPL treatment in DME.…”

Comparison of Subthreshold 577 and 810 nm Micropulse Laser Effects on Heat-Shock Protein Activation Kinetics: Implications for Treatment Efficacy and Safety

“…It is the size of the device (in this case the catalytic reaction and cascade of effects initiated by HSP activation) and not the fuse that matters. [8][9][10][11][12][13][14][15]37,38,42,[47][48][49][50] Because exceeding the threshold for HSP activation does not increase HSP activation but increases the risk of thermal cell death and retinal damage, laser parameters exceeding this threshold ( HSP = 1) should be avoided. Because of the catalytic response to laser HSP activation, treatment parameters with an HSP < 1.0 can also be used to increase treatment safety, without compromising efficacy ( Supplementary Figs.…”

“…Despite these well-recognized and long-accepted drawbacks, LIRD is not known to have any intrinsic or direct therapeutic effects; these arising instead from cells affected, but not killed, by laser application. [5][6][7][8][9][10][11][12][13][14][15] Defining photocoagulation, and indeed any degree of LIRD, as complications rather than goals of treatment, modern retinal laser therapy seeks to maximize both treatment safety and efficacy and broaden treatment indications by precluding LIRD. 2,7, The cornerstones of modern retinal laser therapy were established and defined by low-intensity/highdensity subthreshold diode (810 nm) micropulse laser (SDM).…”

“…[33][34][35][36] Our current understanding of the therapeutic mechanism of SDM is that it acts as a physiologic "reset" stimulus, improving, and thus normalizing, RPE and hence retinal function by activating RPE heat-shock proteins (HSPs). [8][9][10][11][12][13][14][15]17,18,27,37 This effect is agnostic to the cause of retinal dysfunction, accounting for the wide range of clinical applications afforded to modern retinal laser therapy. 17,18,27,37 Thermally mediated, therapeutically effective retinal laser treatment is a form of bioactivation, dependent on reaching an intra-RPE cell temperature above the threshold for HSP activation.…”