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Graefe's Archive for Clinical and Experimental Ophthalmology

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01-04-2020 | Angiography | Retinal Disorders

Decrease in the number of microaneurysms in diabetic macular edema after anti-vascular endothelial growth factor therapy: implications for indocyanine green angiography-guided detection of refractory microaneurysms

Authors: Kenichiro Mori, Shigeo Yoshida, Yoshiyuki Kobayashi, Keijiro Ishikawa, Shintaro Nakao, Toshio Hisatomi, Masatoshi Haruta, Tatsuro Isihibashi, Koh-hei Sonoda

Published in: Graefe's Archive for Clinical and Experimental Ophthalmology | Issue 4/2020

Abstract

Purpose

We evaluated changes in the numbers of microaneurysms (MAs) on fluorescein angiography (FA) and indocyanine green angiography (IA) in eyes with diabetic macular edema (DME) following intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents.

Methods

Twenty-one eyes of 16 patients with DME were included in this retrospective study. All patients received an initial loading dose of three monthly injections of anti-VEGF agents; thereafter, they received a pro re nata regimen for at least 12 months of follow-up. FA and IA images were obtained before and at 6 months after the initial injection.

Results

The median numbers of MAs significantly decreased from six (interquartile range [IQR] 3–7) MAs in early-phase FA, three (IQR 3–5) leaky MAs in late-phase FA, and two (IQR 1–4) MAs in late-phase IA at baseline to two (IQR 1–3) MAs in early-phase FA, one (IQR 0–2) leaky MA in late-phase FA, and one (IQR 0–2) MA in late-phase IA at 6 months (P < 0.0001 for all). Only the median numbers of MAs in late-phase IA at baseline and at 6 months were significantly higher in the recurrent DME group (13 eyes) than in the non-recurrent DME group (five eyes) (three [IQR 2–4] vs one [IQR 1–2], one [IQR 0.5–2] vs zero [P = 0.0185 and P = 0.009]).

Conclusion

Intravitreal injection of anti-VEGF agents reduced the numbers of MAs in patients with DME. The numbers of MAs detected by late-phase IA might be useful predictors of DME recurrence.

Boyer DS, Hopkins JJ, Sorof J, Ehrlich JS (2013) Anti-vascular endothelial growth factor therapy for diabetic macular edema. Ther Adv Endocrinol Metab 4:151–169PubMedPubMedCentral

Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, Chen SJ, Dekker JM, Fletcher A, Grauslund J, Haffner S, Hamman RF, Ikram MK, Kayama T, Klein BE, Klein R, Krishnaiah S, Mayurasakorn K, O'Hare JP, Orchard TJ, Porta M, Rema M, Roy MS, Sharma T, Shaw J, Taylor H, Tielsch JM, Varma R, Wang JJ, Wang N, West S, Xu L, Yasuda M, Zhang X, Mitchell P, Wong TY, Meta-Analysis for Eye Disease (META-EYE) Study Group (2012) Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 35:556–564PubMedPubMedCentral

Zhang X, Zeng H, Bao S, Wang N, Gillies MC (2014) Diabetic macular edema: new concepts in patho-physiology and treatment. Cell Biosci 4:27PubMedPubMedCentral

Qaum T, Xu Q, Joussen AM, Clemens MW, Qin W, Miyamoto K, Hassessian H, Wiegand SJ, Rudge J, Yancopoulos GD, Adamis AP (2001) VEGF-initiated blood-retinal barrier breakdown in early diabetes. Invest Ophthalmol Vis Sci 42:2408–2413PubMed

Ehrlich R, Harris A, Ciulla TA, Kheradiya N, Winston DM, Wirostko B (2010) Diabetic macular oedema: physical, physiological and molecular factors contribute to this pathological process. Acta Ophthalmol 88:279–291PubMed

Reznicek L, Kernt M, Haritoglou C, Ulbig M, Kampik A, Neubauer AS (2011) Correlation of leaking microaneurysms with retinal thickening in diabetic retinopathy. Int J Ophthalmol 4:269–271PubMedPubMedCentral

Terasaki H, Ogura Y, Kitano S, Sakamoto T, Murata T, Hirakata A, Ishibashi T (2018) Management of diabetic macular edema in Japan: a review and expert opinion. Jpn J Ophthalmol 62:1–23PubMed

Dubow M, Pinhas A, Shah N, Cooper RF, Gan A, Gentile RC, Hendrix V, Sulai YN, Carroll J, Chui TY, Walsh JB, Weitz R, Dubra A, Rosen RB (2014) Classification of human retinal microaneurysms using adaptive optics scanning light ophthalmoscope fluorescein angiography. Invest Ophthalmol Vis Sci 55:1299–1309PubMedPubMedCentral

Schreur V, Domanian A, Liefers B, Venhuizen FG, Klevering BJ, Hoyng CB, de Jong EK, Theelen T (2018) Morphological and topographical appearance of microaneurysms on optical coherence tomography angiography. Br J Ophthalmol. https://doi.org/10.1136/bjophthalmol-2018-312258

10.

Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE et al (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487

11.

Antonetti DA, Barber AJ, Hollinger LA, Wolpert EB, Gardner TW (1999) Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden (1999). A potential mechanism for vascular permeability in diabetic retinopathy and tumors. J Biol Chem 274:23463–23467PubMed

12.

Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676PubMed

13.

Michaelides M, Kaines A, Hamilton RD, Fraser-Bell S, Rajendram R, Quhill F, Boos CJ, Xing W, Egan C, Peto T, Bunce C, Leslie RD, Hykin PG (2010) A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12-month data: report 2. Ophthalmology 117:1078–1086PubMed

14.

Schmidt-Erfurth U, Lang GE, Holz FG, Schlingemann RO, Lanzetta P, Massin P, Gerstner O, Bouazza AS, Shen H, Osborne A, Mitchell P, RESTORE Extension Study Group (2014) Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE extension study. Ophthalmology 121:1045–1053PubMed

15.

Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, Gibson A, Sy J, Rundle AC, Hopkins JJ, Rubio RG, Ehrlich JS, RISE and RIDE Research Group (2012) Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 119:789–801

16.

Heier JS, Korobelnik JF, Brown DM, Schmidt-Erfurth U, Do DV, Midena E, Boyer DS, Terasaki H, Kaiser PK, Marcus DM, Nguyen QD, Jaffe GJ, Slakter JS, Simader SY, Schmelter T, Vitti R, Berliner AJ, Zeitz O, Metzig C, Holz FG (2016) Intravitreal aflibercept for diabetic macular edema: 148-week results from the VISTA and VIVID studies. Ophthalmology 123:2376–2385PubMed

17.

Tolentino MJ, Miller JW, Gragoudas ES, Jakobiec FA, Flynn E, Chatzistefanou K, Ferrara N, Adamis AP (1996) Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology 103:1820–1828PubMed

18.

Leicht SF, Kernt M, Neubauer A, Wolf A, Oliveira CM, Ulbig M, Haritoglou C (2014) Microaneurysm turnover in diabetic retinopathy assessed by automated RetmarkerDR image analysis--potential role as biomarker of response to ranibizumab treatment. Ophthalmologica 231:198–203PubMed

19.

Weinberger D, Kramer M, Priel E, Gaton DD, Axer-Siegel R, Yassur Y (1998) Indocyanine green angiographic findings in nonproliferative diabetic retinopathy. Am J Ophthalmol 126:238–247PubMed

20.

Hirano Y, Yasukawa T, Usui Y, Nozaki M, Ogura Y (2010) Indocyanine green angiography-guided laser photocoagulation combined with sub-Tenon's capsule injection of triamcinolone acetonide for idiopathic macular telangiectasia. Br J Ophthalmol 94:600–605PubMed

21.

Kato F, Nozaki M, Kato A, Hasegawa N, Morita H, Yoshida M, Ogura Y (2018) Evaluation of navigated laser photocoagulation (Navilas 577+) for the treatment of refractory diabetic macular edema. J Ophthalmol 2:1–7

22.

Cogan DG, Toussaint D, Kuwabara T (1961) Retinal vascular patterns. IV. Diabetic retinopathy. Arch Ophthalmol 66:366–378PubMed

23.

Kernt M, Cserhati S, Seidensticker F, Liegl R, Kampik A, Neubauer A, Ulbig MW, Reznicek L (2013) Improvement of diabetic retinopathy with intravitreal ranibizumab. Diabetes Res Clin Pract 100:e11–e13PubMed

24.

Stitt AW, Gardiner TA, Archer DB (1995) Histological and ultrastructural investigation of retinal microaneurysm development in diabetic patients. Br J Ophthalmol 79:362–367PubMedPubMedCentral

25.

Greenberg JI, Shields DJ, Barillas SG, Acevedo LM, Murphy E, Huang J, Scheppke L, Stockmann C, Johnson RS, Angle N, Cheresh DA (2008) A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456:809–813PubMedPubMedCentral

26.

Kohno R, Hata Y, Mochizuki Y, Arita R, Kawahara S, Kita T, Miyazaki M, Hisatomi T, Ikeda Y, Aiello LP, Ishibashi T (2010) Histopathology of neovascular tissue from eyes with proliferative diabetic retinopathy after intravitreal bevacizumab injection. Am J Ophthalmol 150:223–229PubMed

27.

Nakao S, Ishikawa K, Yoshida S, Kohno R, Miyazaki M, Enaida H, Kono T, Ishibashi T (2013) Altered vascular microenvironment by bevacizumab in diabetic fibrovascular membrane. Retina 33:957–963PubMed

28.

Jeon H, Ono M, Kumagai C, Miki K, Morita A, Kitagawa Y (1996) Pericytes from microvessel fragment produce type IV collagen and multiple laminin isoforms. Biosci Biotechnol Biochem 60:856–861PubMed

29.

Desmettre T, Devoisselle JM, Mordon S (2000) Fluorescence properties and metabolic features of indocyanine green (ICG) as related to angiography. Surv Ophthalmol 45:15–27PubMed

30.

Bourhis GJF, Boni S, Pecha F, Favard C, Sahel JA, Paques M (2010) Imaging of macroaneurysms occurring during retinal vein occlusion and diabetic retinopathy by indocyanine green angiography and high resolution optical coherence tomography. Graefes Arch Clin Exp Ophthalmol 248:161–166PubMed

31.

Ueda T, Gomi F, Suzuki M, Sakaguchi H, Sawa M, Kamei M, Nishida K (2012) Usefulness of indocyanine green angiography to depict the distant retinal vascular anomalies associated with branch retinal vein occlusion causing serous macular detachment. Retina 32:308–313PubMed

32.

Paques M, Philippakis E, Bonnet C, Falah S, Ayello-Scheer S, Zwillinger S, Girmens JF, Dupas B (2017) Indocyanine-green-guided targeted laser photocoagulation of capillary macroaneurysms in macular oedema: a pilot study. Br J Ophthalmol 101:170–174PubMed

33.

Nozaki M, Kato A, Yasukawa T, Suzuki K, Yoshida M, Ogura Y (2019) Indocyanine green angiography-guided focal navigated laser photocoagulation for diabetic macular edema. Jpn J Ophthalmol 63:243–254PubMed

34.

Bressler SB, Glassman AR, Almukhtar T, Bressler NM, Ferris FL, Googe JM Jr, Gupta SK, Jampol LM, Melia M, Wells JA 3rd, Diabetic Retinopathy Clinical Research Network (2016) Five-year outcomes of ranibizumab with prompt or deferred laser versus laser or triamcinolone plus deferred ranibizumab for diabetic macular edema. Am J Ophthalmol 164:57–68PubMedPubMedCentral

35.

Kaizu Y, Nakao S, Sekiryu H, Wada I, Yamaguchi M, Hisatomi T, Ikeda Y, Kishimoto J, Sonoda KH (2018) Retinal flow density by optical coherence tomography angiography is useful for detection of nonperfused areas in diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 256:2275–2282PubMed

36.

Ishibazawa A, Nagaoka T, Takahashi A, Omae T, Tani T, Sogawa K, Yokota H, Yoshida A (2015) Optical coherence tomography angiography in diabetic retinopathy: a prospective pilot study. Am J Ophthalmol 160:35–44PubMed

37.

Salz DA, de Carlo TE, Adhi M, Moult E, Choi W, Baumal CR, Witkin AJ, Duker JS, Fujimoto JG, Waheed NK (2016) Select features of diabetic retinopathy on swept-source optical coherence tomographic angiography compared with fluorescein angiography and normal eyes. JAMA Ophthalmol 1(134):644–650

38.

Couturier A, Mané V, Bonnin S, Erginay A, Massin P, Gaudric A, Tadayoni R (2015) Capillary plexus anomalies in diabetic retinopathy on optical coherence tomography angiography. Retina. 35:2384–2391PubMed

39.

Miwa Y, Murakami T, Suzuma K, Uji A, Yoshitake S, Fujimoto M, Yoshitake T, Tamura Y, Yoshimura N (2016) Relationship between functional and structural changes in diabetic vessels in optical coherence tomography angiography. Sci Rep 28(6):29064

40.

Hasegawa N, Nozaki M, Takase N, Yoshida M, Ogura Y (2016) New insights into microaneurysms in the deep capillary plexus detected by optical coherence tomography angiography in diabetic macular edema. Invest Ophthalmol Vis Sci 1(57):OCT348–OCT355

41.

Kaizu Y, Nakao S, Wada I, Arima M, Yamaguchi M, Ishikawa K, Akiyama M, Kishimoto J, Hisatomi T, Sonoda KH (2019) Microaneurysm imaging using multiple en face OCT angiography image averaging: morphology and visualization. Ophthalmol Retina S2468-6530:30570–30576

42.

Busch C, Wakabayashi T, Sato T, Fukushima Y, Hara C, Shiraki N, Winegarner A, Nishida K, Sakaguchi H, Nishida K (2019) Retinal microvasculature and visual acuity after intravitreal aflibercept in diabetic macular edema: an optical coherence tomography angiography study. Sci Rep 7(9):1561

43.

Lee J, Moon BG, Cho AR, Yoon YH (2016) Optical coherence tomography angiography of DME and its association with anti-VEGF treatment response. Ophthalmology. 123:2368–2375PubMed

44.

van den Biesen PR, Jongsma FH, Tangelder GJ, Slaaf DW (1995) Yield of fluorescence from indocyanine green in plasma and flowing blood. Ann Biomed Eng 23(4):475–481PubMed

Title: Decrease in the number of microaneurysms in diabetic macular edema after anti-vascular endothelial growth factor therapy: implications for indocyanine green angiography-guided detection of refractory microaneurysms
Authors: Kenichiro Mori
Shigeo Yoshida
Yoshiyuki Kobayashi
Keijiro Ishikawa
Shintaro Nakao
Toshio Hisatomi
Masatoshi Haruta
Tatsuro Isihibashi
Koh-hei Sonoda
Publication date: 01-04-2020
Publisher: Springer Berlin Heidelberg
Keywords: Angiography
Diabetic Retinopathy
Edema
Diabetic Retinopathy
Ranibizumab
Published in: Graefe's Archive for Clinical and Experimental Ophthalmology / Issue 4/2020
Print ISSN: 0721-832X
Electronic ISSN: 1435-702X
DOI: https://doi.org/10.1007/s00417-020-04608-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Decrease in the number of microaneurysms in diabetic macular edema after anti-vascular endothelial growth factor therapy: implications for indocyanine green angiography-guided detection of refractory microaneurysms

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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