Subthreshold Photocoagulation, Laser Endpoint Management Based on Optical Coherence Tomography Angiography in Cases of Diabetic Macular Edema Refractory to Anti-VEGF

Abstract

Purpose This study aimed to determine the changes that occur in the vasculature, as based on optical coherence tomography angiography (OCTA) after non-damaging endpoint management (EpM), using a continuous wave yellow laser. The study was on eyes with diabetic macular edema (DME) that were resistant to anti-vascular endothelial growth factors (anti-VEGFs).

Materials and Methods This was a retrospective analysis of OCTA images of 44 eyes in 44 patients with DME refractory to anti-VEGF. The eyes were treated with a PASCAL Streamline yellow laser (577 nm wavelength, 200 mm spot size). Treatment was administered to the DME area and utilized 10% continuous wave laser energy and 0.50 µm beam diameter spot spacing. Best-corrected visual acuity (BCVA) and enhanced in-depth imaging with optical coherence tomography (EDI-OCT) and fundus autofluorescence (FAF) images were recorded at baseline, and 3 and 6 months posttreatment. Total choroidal area (TCA), luminal area (LA), stromal area (SA), and the choroidal vascularity index (CVI) were calculated using Image J software. The macula was divided into five quadrants in accordance with the mapping system in the Early Treatment Diabetic Retinopathy Study (ETDRS).

Results All patients (mean age: 58.90 ± 9.55 years) were diagnosed with diabetes mellitus type 2. Mean BCVA at baseline was 0.30 ± 0.11 logarithm of the minimum angle of resolution (logMAR) versus 0.23 ± 0.10 logMAR at 3 months (p = 0.032) and 0.17 ± 0.10 logMAR at 6 months (p = 0.013). The foveal avascular zone area (FAZ) decreased in the deep capillary plexus (DCP) from baseline to 6 months (p = 0.028). Vessel densities (VDs) of the superficial capillary plexus (SCP), DCP, and choriocapillaris decreased significantly in the fovea at 3 and 6 months compared to baseline (p < 0.05 for both follow-up time points). There were significant decreases in SCP and DCP in the superior quadrant at the end of month 6 (p = 0.001 and p = 0.038, respectively). There was a significant decrease in the nasal quadrant of the DCP and choriocapillaris at the end of month 6 (p = 0.024 and p = 0.049, respectively). Although there was a significant decrease in central macular thickness (CMT) (p < 0.001), subfoveal choroidal thickness (SFCT) (p < 0.001), and LA (p = 0.034) at months 3 and 6, there was no significant change in the CVI (p = 0.19). According to the DME recovery rate, 36 eyes (81%) were irradiated once, whereas 8 eyes (19%) were irradiated twice.

Conclusions Non-damaging EpM therapy using a continuous wave yellow laser in eyes with DME that are resistant to anti-VEGFs induces significant changes in the SCP, choriocapillaris, and, most commonly, the DCP, which caused a significant decrease in VDs during 6 months of follow-up.

Zusammenfassung

Zweck Diese Studie zielte darauf ab, die Veränderungen zu bestimmen, die im Gefäßsystem auftreten, basierend auf der optischen Kohärenztomografieangiografie (OCTA) nach nicht schädigendem Endpunktmanagement (EpM) unter Verwendung eines gelben Dauerstrichlasers. Die Studie betraf Augen mit diabetischem Makulaödem (DMÖ), die gegen antivaskuläre endotheliale Wachstumsfaktoren (Anti-VEGF) resistent waren.

Materialien und Methoden Dies war eine retrospektive Analyse von OCTA-Bildern von 44 Augen bei 44 Patienten mit gegenüber Anti-VEGF refraktärem DMÖ. Die Augen wurden mit einem gelben PASCAL-Streamline-Laser (577 nm Wellenlänge, 200 mm Spotgröße) behandelt. Die Behandlung wurde im DMÖ-Bereich durchgeführt und es wurden 10% Dauerstrichlaserenergie und ein Punkt mit einem Strahldurchmesser von 0,50 µm Abstand verwendet. Bestkorrigierte Sehschärfe (BCVA), verbesserte Tiefenbildgebung mit optischer Kohärenztomografie (EDI-OCT) und Fundusautofluoreszenzbilder (FAF: Fundusautofluoreszenz) wurden zu Studienbeginn sowie 3 und 6 Monate nach der Behandlung aufgezeichnet. Der gesamte choroidale Bereich (TCA), der luminale Bereich (LA), der stromale Bereich (SA) und der choroidale Vaskularitätsindex (CVI) wurden mit der Image-J-Software berechnet. Die Makula wurde in Übereinstimmung mit dem Mapping-System in der Early Treatment Diabetic Retinopathy Study (ETDRS) in 5 Quadranten eingeteilt.

Ergebnisse Bei allen Patienten (Durchschnittsalter: 58,90 ± 9,55 Jahre) wurde Diabetes mellitus Typ 2 diagnostiziert. Die mittlere BCVA zu Studienbeginn betrug 0,30 ± 0,11 Logarithmus des minimalen Auflösungswinkels (logMAR) gegenüber 0,23 ± 0,10 logMAR nach 3 Monaten (p = 0,032) und 0,17 ± 0,10 logMAR nach 6 Monaten (p = 0,013). Die foveale avaskuläre Zone (FAZ) nahm im tiefen Kapillarplexus (DCP) vom Ausgangswert bis 6 Monate (p = 0,028) ab. Gefäßdichten (VDs) des oberflächlichen Kapillarplexus (SCP), DCP und Choriokapillaris nahmen in der Fovea nach 3 und 6 Monaten im Vergleich zum Ausgangswert signifikant ab (p < 0,05 für beide Nachbeobachtungszeitpunkte). Es gab signifikante Abnahmen von SCP und DCP im oberen Quadranten am Ende von Monat 6 (p = 0,001 bzw. p = 0,038). Es gab eine signifikante Abnahme im nasalen Quadranten des DCP und der Choriokapillaris am Ende von Monat 6 (p = 0,024 bzw. p = 0,049). Obwohl es eine signifikante Abnahme der zentralen Makuladicke (CMT) (p < 0,001), der subfovealen Aderhautdicke (SFCT) (p < 0,001) und des LA (p = 0,034) in den Monaten 3 und 6 gab, gab es keine signifikante Veränderung des CVI (p = 0,19). Gemäß der DMÖ-Wiederfindungsrate wurden 36 Augen (81%) 1 × bestrahlt, während 8 Augen (19%) 2 × bestrahlt wurden.

Schlussfolgerungen Eine nicht schädigende EpM-Therapie mit einem gelben Dauerstrichlaser in Augen mit DMÖ, die gegen Anti-VEGFs resistent sind, induziert signifikante Veränderungen im SCP, in der Choriokapillaris und am häufigsten im DCP, was zu einer signifikanten Abnahme der VDs während eines 6-monatigen Follow-ups führt.

Key words

non-damaging EpM yellow laser - anti-VEGF-resistant diabetic macular edema - optical coherence tomography angiography - choroidal vascularity index

Schlüsselwörter

nicht schädigender gelber EpM-Laser - Anti-VEGF-resistentes diabetisches Makulaödem - optische Kohärenztomografie-Angiografie - choroidaler Vaskularitätsindex

Publication History

Received: 23 January 2022

Accepted: 27 February 2022

Article published online:
22 April 2022

• References

• 1 Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye Vis (Lond) 2015; 2: 17
• 2 Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol 1985; 103: 1796-1806
• 3 Sim DA, Keane PA, Zarranz-Ventura J. et al. The effects of macular ischemia on visual acuity in diabetic retinopathy. Invest Ophthalmol Vis Sci 2013; 54: 2353-2360
• 4 Nicholson L, Ramu J, Triantafyllopoulou I. et al. Diagnostic accuracy of disorganization of the retinal inner layers in detecting macular capillary non-perfusion in diabetic retinopathy. Clin Exp Ophthalmol 2015; 43: 735-741
• 5 Chalam KV, Sambhav K. Optical coherence tomography angiography in retinal diseases. J Ophthalmic Vis Res 2016; 11: 84-92
• 6 Samara WA, Shahlaee A, Adam MK. et al. Quantification of diabetic macular ischemia using optical coherence tomography angiography and its relationship with visual acuity. Ophthalmology 2017; 124: 235-244
• 7 de Carlo TE, Filho MAB, Chin AT. et al. Spectral-domain optical coherence tomography angiography of choroidal neovascularization. Ophthalmology 2015; 122: 1228-1238
• 8 Hwang TS, Gao SS, Liu L. et al. Automated quantification of capillary nonperfusion using optical coherence tomography angiography in diabetic retinopathy. JAMA Ophthalmol 2016; 134: 367-373
• 9 Bradley PD, Sim DA, Keane PA. et al. The evaluation of diabetic macular ischemia using optical coherence tomography angiography. Invest Ophthalmol Vis Sci 2016; 57: 626-631
• 10 Takase N, Nozaki M, Kato A. et al. Enlargement of foveal avascular zone in diabetic eyes evaluated by en face optical coherence tomography angiography. Retina 2015; 35: 2377-2383
• 11 Chen G, Tzekov R, Li W. et al. Subthreshold micropulse diode laser versus conventional laser photocoagulation for diabetic macular edema: a meta-analysis of randomized controlled trials. Retina 2016; 36: 2059-2065
• 12 Luttrull JK, Sinclair SH. Safety of transfoveal subthreshold diode micropulse laser for fovea-involving diabetic macular edema in eyes with good visual acuity. Retina 2014; 34: 2010-2020
• 13 Vujosevic S, Gatti V, Muraca A. et al. Optical coherence tomography angiography changes after subthreshold micropulse yellow laser diabetic macular edema. Retina 2020; 40: 312-321
• 14 Duh EJ, Yang HS, Suzuma I. et al. Pigment epithelium-derived factor suppresses ischemia-induced retinal neovascularization and VEGF-induced migration and growth. Invest Ophthalmol Vis Sci 2002; 43: 821-829
• 15 Funatsu H, Noma H, Mimura T. et al. Association of vitreous inflammatory factors with diabetic macular edema. Ophthalmology 2009; 116: 73-79
• 16 Jonas JB, Jonas RA, Neumaier M. et al. Cytokine concentration in aqueous humor of eyes with diabetic macular edema. Retina 2012; 32: 2150-2157
• 17 Inagaki K, Shuo T, Katakura K. et al. Sublethal photothermal stimulation with a micropulse laser induces heat shock protein expression in ARPE-19 cells. J Ophthalmol 2015; 2015: 729792
• 18 Figueira J, Khan J, Nunes S. et al. Prospective randomised controlled trial comparing sub-threshold micropulse diode laser photocoagulation and conventional green laser for clinically significant diabetic macular oedema. Br J Ophthalmol 2009; 93 (10) 1341-1344
• 19 Wang J, Quan Y, Dalal R. et al. Comparison of Continuous-Wave and Micropulse Modulation in Retinal Laser Therapy. Invest Ophthalmol Vis Sci 2017; 58: 4722-4732
• 20 Wu L, Fernandez-Loaiza P, Sauma J. et al. Classification of diabetic retinopathy and diabetic macular edema. World J Diabetes 2013; 4: 290-294
• 21 Ferris FL3rd Maguire MG, Glassman AR. et al. Evaluating Effects of Switching Anti-Vascular Endothelial Growth Factor Drugs for Age-Related Macular Degeneration and Diabetic Macular Edema. JAMA Ophthalmol 2017; 135: 145-149
• 22 Sonoda S, Sakamoto T, Yamashita T. et al. Luminal and stromal areas of choroid determined by binarization method of optical coherence tomographic images. Am J Ophthalmol 2015; 159: 1123-1131
• 23 Hamada M, Ohkoshi K, Inagaki K. et al. Subthreshold Photocoagulation Using Endpoint Management in the PASCAL^® System for Diffuse Diabetic Macular Edema. J Ophthalmol 2018; 2018: 7465794
• 24 Kaldırım H, Yazgan S, Atalay K. et al. Intravitreal dexamethasone implantation in patients with different morphological diabetic macular edema having insufficient response to ranibizumab. Retina 2018; 38: 986-992
• 25 Bland JM, Altman DG. Agreed statistics: measurement method comparison. Anesthesiology 2012; 116: 182-185
• 26 Vujosevic S, Bottega E, Casciano M K. et al. Microperimetry and fundus autofluorescence in diabetic macular edema: subthreshold micropulse diode laser versus modified early treatment diabetic retinopathy study laser photocoagulation. Retina 2010; 30: 908-916
• 27 Vujosevic S, Martini F, Longhin E K. et al. Subthreshold micropulse yellow laser versus subthreshold micropulse infrared laser in center-involving diabetic macular edema. Retina 2015; 35: 1594-1603
• 28 Parravano M, De Geronimo D, Scarinci F. et al. Diabetic microaneurysms internal reflectivity on spectral-domain optical coherence tomography and optical coherence tomography angiography detection. Am J Ophthalmol 2017; 179: 90-96
• 29 Pappuru RKR, Ribeiro L, Lobo C. et al. Microaneurysm turnover is a predictor of diabetic retinopathy progression. Br J Ophthalmol 2019; 103: 222-226
• 30 Tejerina AN, Vujosevic S, Varano M. et al. One-year progression of diabetic subclinical macular edema in eyes with mild nonproliferative diabetic retinopathy: location of the increase in retinal thickness. Ophthalmic Res 2015; 54: 118-123
• 31 Mansouri A, Sampat KM, Malik KJ. et al. Efficacy of subthreshold micropulse laser in the treatment of diabetic macular edema is influenced by pre-treatment central foveal thickness. Eye (Lond) 2014; 28: 1418-1424
• 32 Nakamura Y, Mitamura Y, Ogata K. et al. Functional and morphological changes of macula after subthreshold micropulse diode laser photocoagulation for diabetic macular oedema. Eye (Lond) 2010; 24: 784-788
• 33 Luttrull JK, Musch DC, Mainster MA. Subthreshold diode micropulse photocoagulation for the treatment of clinically significant diabetic macular oedema. Br J Ophthalmol 2005; 89: 74-80
• 34 Vujosevic S, Toma C, Villani E. et al. Subthreshold Micropulse Laser in Diabetic Macular Edema: 1-Year Improvement in OCT/OCT-Angiography Biomarkers. Transl Vis Sci Technol 2020; 9: 31
• 35 Abramoff MD, Fort PE, Han IC. et al. Approach for a clinically useful comprehensive classification of vascular and neural aspects of diabetic retinal disease. Invest Ophthalmol Vis Sci 2018; 59: 519-527
• 36 Vujosevic S, Muraca A, Alkabes M. et al. Early microvascular and neural changes in patients with type 1 and type 2 diabetes mellitus without clinical signs of diabetic retinopathy. Retina 2019; 39: 435-445
• 37 Newman E, Reichenbach A. The Müller cell: a functional element of the retina. Trends Neurosci 1996; 19: 307-312
• 38 Vujosevic S, Bini S, Midena G. et al. Hyperreflective intraretinal spots in diabetics without and with nonproliferative diabetic retinopathy: an in vivo study using spectral domain OCT. J Diabetes Res 2013; 2013: 491835
• 39 Ribeiro L, Bandello F, Tejerina AN. et al. Characterization of retinal disease progression in a 1-year longitudinal study of eyes with mild nonproliferative retinopathy in diabetes type 2. Invest Ophthalmol Vis Sci 2015; 56: 5698-5705
• 40 De Carlo TE, Bonini Filho MA, Baumal CR. et al. Evaluation of preretinal neovascularization in proliferative diabetic retinopathy using optical coherence tomography angiography. Ophthalmic Surg Lasers Imaging Retina 2016; 47: 115-119
• 41 Lavinsky D, Sramek C, Wang J. et al. Subvisible retinal laser therapy: titration algorithm and tissue response. Retina 2014; 34: 87-97
• 42 Pei-Pei W, Shi-Zhou H, Zhen T. et al. Randomised clinical trial evaluating best-corrected visual acuity and central macular thickness after 532-nm subthreshold laser grid photocoagulation treatment in diabetic macular oedema. Eye (Lond) 2015; 29: 313-321
• 43 Schmidt-Erfurth U, Garcia-Arumi J, Bandello F. et al. Guidelines for the management of diabetic macular edema by the European Society of Retina Specialists (EURETINA). Ophthalmologica 2017; 237: 185-222
• 44 Esmaeelpour M, Považay B, Hermann B. et al. Mapping choroidal and retinal thickness variation in type 2 diabetes using three-dimensional 1060-nm optical coherence tomography. Invest Ophthalmol Vis Sci 2011; 52: 5311-5316
• 45 Vujosevic S, Martini F, Cavarzeran F. et al. Macular and peripapillary choroidal thickness in diabetic patients. Retina 2012; 32: 1781-1790
• 46 Laíns I, Figueira J, Santos AR. et al. Choroidal thickness in diabetic retinopathy: the influence of antiangiogenic therapy. Retina 2014; 34: 1199-1207
• 47 Rayess N, Rahimy E, Ying GS. et al. Baseline choroidal thickness as a predictor for response to anti-vascular endothelial growth factor therapy in diabetic macular edema. Am J Ophthalmol 2015; 159: 85-91.e1-e3
• 48 Yiu G, Manjunath V, Chiu SJ. et al. Effect of antivascular endothelial growth factor therapy on choroidal thickness in diabetic macular edema. Am J Ophthalmol 2014; 158: 745-751.e2
• 49 Adhi M, Brewer E, Waheed NK. et al. Analysis of morphological features and vascular layers of choroid in diabetic retinopathy using spectral-domain optical coherence tomography. JAMA Ophthalmol 2013; 131: 1267-1274
• 50 Kim JT, Lee DH, Joe SG. et al. Changes in choroidal thickness in relation to the severity of retinopathy and macular edema in type 2 diabetic patients. Invest Ophthalmol Vis Sci 2013; 54: 3378-3384
• 51 Iovino C, Pellegrini M, Bernabei F. et al. Choroidal vascularity index: an in-depth analysis of this novel optical coherence tomography parameter. J Clin Med 2020; 9: 595
• 52 Agrawal R, Gupta P, Tan KA. et al. Choroidal vascularity index as a measure of vascular status of the choroid: measurements in healthy eyes from a population-based study. Sci Rep 2016; 6: 21090
• 53 Tan KA, Gupta P, Agarwal A. et al. State of science: Choroidal thickness and systemic health. Surv Ophthalmol 2016; 61: 566-581
• 54 Laviers H, Zambarakji H. Enhanced depth imaging-OCT of the choroid: a review of the current literature. Graefes Arch Clin Exp Ophthalmol 2014; 252: 1871-1883
• 55 Gupta C, Tan R, Mishra C. et al. Choroidal structural analysis in eyes with diabetic retinopathy and diabetic macular edema–A novel OCT based imaging biomarker. PLoS One 2018; 13: e0207435
• 56 Wang H, Tao Y. Choroidal structural changes correlate with severity of diabetic retinopathy in diabetes mellitus. BMC Ophthalmol 2019; 19: 186