Japanese Journal of Ophthalmology

, Volume 62, Issue 3, pp 292–301 | Cite as

Association between characteristics of foveal cystoid spaces and short-term responsiveness to ranibizumab for diabetic macular edema

  • Tomoaki MurakamiEmail author
  • Kiyoshi Suzuma
  • Akihito Uji
  • Shin Yoshitake
  • Yoko Dodo
  • Masahiro Fujimoto
  • Tatsuya Yoshitake
  • Yuko Miwa
  • Nagahisa Yoshimura
Clinical Investigation



To investigate the association between the characteristics of foveal cystoid spaces and short-term responsiveness to ranibizumab treatment for diabetic macular edema (DME) at 3 months from the initial injection.


We retrospectively reviewed 66 eyes of 61 patients with center-involved DME who received three consecutive ranibizumab injections and following as-needed administrations. We evaluated the relationship between visual improvement at 3 months and the preoperative optical coherence tomography (OCT) parameters including hyperreflective foci, heterogeneous OCT reflectivity, mean levels of OCT reflectivity and height of foveal cystoid spaces.


Twenty-three eyes without preoperative hyperreflective foci in the foveal cystoid spaces had significantly greater improvement in the logarithm of the minimum angle of resolution visual acuity (logMAR VA) at 3 months than 43 eyes with foci (P = 0.006). That was similar to the greater reduction in CSF thickness in eyes without lesions after treatment at the same time point (P < 0.001). VA improvement at 3 months was not associated with the height (R = 0.215, P = 0.083) or the reflectivity levels (R = -0.079, P = 0.538) of foveal cystoid spaces. There were no differences in VA changes between eyes with and without heterogeneous reflectivity in foveal cystoid spaces (P = 0.297). Multivariate analyses showed that logMAR VA and the absence of hyperreflective foci in foveal cystoid spaces were associated with VA improvement at 3 months.


Hyperreflective foci in foveal cystoid spaces at baseline predict poorer short-term responsiveness to ranibizumab injections for DME.


Cystoid spaces Diabetic macular edema Hyperreflective foci Ranibizumab Spectral-domain optical coherence tomography 



This study was supported by Grant-in-Aid for Scientific Research of Japan Society for the Promotion of Science (26462637).

Conflicts of interest

T Murakami, None; K. Suzuma, None; A. Uji, None; S. Yoshitake, None; Y. Dodo, None; M. Fujimoto, None; T. Yoshitake, None; Y. Miwa, None; N. Yoshimura, None.


  1. 1.
    Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35:556–64.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med. 2012;366:1227–39.CrossRefPubMedGoogle Scholar
  3. 3.
    Gardner TW, Antonetti DA, Barber AJ, LaNoue KF, Levison SW. Diabetic retinopathy: more than meets the eye. Surv Ophthalmol. 2002;47(Suppl 2):S253–62.CrossRefPubMedGoogle Scholar
  4. 4.
    Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1480–7.CrossRefPubMedGoogle Scholar
  5. 5.
    Funatsu H, Yamashita H, Noma H, Mimura T, Yamashita T, Hori S. Increased levels of vascular endothelial growth factor and interleukin-6 in the aqueous humor of diabetics with macular edema. Am J Ophthalmol. 2002;133:70–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Murakami T, Frey T, Lin C, Antonetti DA. Protein kinase cbeta phosphorylates occludin regulating tight junction trafficking in vascular endothelial growth factor-induced permeability in vivo. Diabetes. 2012;61:1573–83.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Cunningham ET Jr, Adamis AP, Altaweel M, Aiello LP, Bressler NM, D’Amico DJ, et al. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology. 2005;112:1747–57.CrossRefPubMedGoogle Scholar
  8. 8.
    Haritoglou C, Kook D, Neubauer A, Wolf A, Priglinger S, Strauss R, et al. Intravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema. Retina. 2006;26:999–1005.CrossRefPubMedGoogle Scholar
  9. 9.
    Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118:615–25.CrossRefPubMedGoogle Scholar
  10. 10.
    Do DV, Schmidt-Erfurth U, Gonzalez VH, Gordon CM, Tolentino M, Berliner AJ, et al. The Da Vinci study: phase 2 primary results of VEGF trap-eye in patients with diabetic macular edema. Ophthalmology. 2011;118:1819–26.CrossRefPubMedGoogle Scholar
  11. 11.
    Wells JA, Glassman AR, Ayala AR, Jampol LM, Aiello LP, Antoszyk AN, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372:1193–203.CrossRefPubMedGoogle Scholar
  12. 12.
    Ogura Y, Shiraga F, Terasaki H, Ohji M, Ishida S, Sakamoto T, et al. Clinical practice pattern in management of diabetic macular edema in Japan: survey results of Japanese retinal specialists. Jpn J Ophthalmol. 2017;61:43–50.CrossRefPubMedGoogle Scholar
  13. 13.
    Hirano T, Toriyama Y, Iesato Y, Imai A, Hirabayashi K, Nagaoka T, et al. Effect of leaking perifoveal microaneurysms on resolution of diabetic macular edema treated by combination therapy using anti-vascular endothelial growth factor and short pulse focal/grid laser photocoagulation. Jpn J Ophthalmol. 2017;61:51–60.CrossRefPubMedGoogle Scholar
  14. 14.
    Browning DJ, Glassman AR, Aiello LP, Beck RW, Brown DM, Fong DS, et al. Relationship between optical coherence tomography-measured central retinal thickness and visual acuity in diabetic macular edema. Ophthalmology. 2007;114:525–36.CrossRefPubMedGoogle Scholar
  15. 15.
    Otani T, Kishi S, Maruyama Y. Patterns of diabetic macular edema with optical coherence tomography. Am J Ophthalmol. 1999;127:688–93.CrossRefPubMedGoogle Scholar
  16. 16.
    Murakami T, Nishijima K, Sakamoto A, Ota M, Horii T, Yoshimura N. Foveal cystoid spaces are associated with enlarged foveal avascular zone and microaneurysms in diabetic macular edema. Ophthalmology. 2011;118:359–67.CrossRefPubMedGoogle Scholar
  17. 17.
    Murakami T, Uji A, Ogino K, Unoki N, Horii T, Yoshitake S, et al. Association between perifoveal hyperfluorescence and serous retinal detachment in diabetic macular edema. Ophthalmology. 2013;120:2596–603.CrossRefPubMedGoogle Scholar
  18. 18.
    Sakamoto A, Nishijima K, Kita M, Oh H, Tsujikawa A, Yoshimura N. Association between foveal photoreceptor status and visual acuity after resolution of diabetic macular edema by pars plana vitrectomy. Graefes Arch Clin Exp Ophthalmol. 2009;247:1325–30.CrossRefPubMedGoogle Scholar
  19. 19.
    Spaide RF, Curcio CA. Anatomical correlates to the bands seen in the outer retina by optical coherence tomography: literature review and model. Retina. 2011;31:1609–19.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Murakami T, Nishijima K, Akagi T, Uji A, Horii T, Ueda-Arakawa N, et al. Optical coherence tomographic reflectivity of photoreceptors beneath cystoid spaces in diabetic macular edema. Invest Ophthalmol Vis Sci. 2012;53:1506–11.CrossRefPubMedGoogle Scholar
  21. 21.
    Sun JK, Lin MM, Lammer J, Prager S, Sarangi R, Silva PS, et al. Disorganization of the retinal inner layers as a predictor of visual acuity in eyes with center-involved diabetic macular edema. JAMA Ophthalmol. 2014;132:1309–16.CrossRefPubMedGoogle Scholar
  22. 22.
    Bolz M, Schmidt-Erfurth U, Deak G, Mylonas G, Kriechbaum K, Scholda C. Optical coherence tomographic hyperreflective foci: a morphologic sign of lipid extravasation in diabetic macular edema. Ophthalmology. 2009;116:914–20.CrossRefPubMedGoogle Scholar
  23. 23.
    Horii T, Murakami T, Nishijima K, Akagi T, Uji A, Arakawa N, et al. Relationship between fluorescein pooling and optical coherence tomographic reflectivity of cystoid spaces in diabetic macular edema. Ophthalmology. 2012;119:1047–55.CrossRefPubMedGoogle Scholar
  24. 24.
    Horii T, Murakami T, Nishijima K, Sakamoto A, Ota M, Yoshimura N. Optical coherence tomographic characteristics of microaneurysms in diabetic retinopathy. Am J Ophthalmol. 2010;150:840–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Otani T, Kishi S. Correlation between optical coherence tomography and fluorescein angiography findings in diabetic macular edema. Ophthalmology. 2007;114:104–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Murakami T, Nishijima K, Sakamoto A, Ota M, Horii T, Yoshimura N. Association of pathomorphology, photoreceptor status, and retinal thickness with visual acuity in diabetic retinopathy. Am J Ophthalmol. 2011;151:310–7.CrossRefPubMedGoogle Scholar
  27. 27.
    Sophie R, Lu N, Campochiaro PA. Predictors of functional and anatomic outcomes in patients with diabetic macular edema treated with ranibizumab. Ophthalmology. 2015;122:1395–401.CrossRefPubMedGoogle Scholar
  28. 28.
    Rayess N, Rahimy E, Ying GS, Bagheri N, Ho AC, Regillo CD, 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):e1–3.Google Scholar
  29. 29.
    Kim M, Lee P, Kim Y, Yu SY, Kwak HW. Effect of intravitreal bevacizumab based on optical coherence tomography patterns of diabetic macular edema. Ophthalmologica. 2011;226:138–44.CrossRefPubMedGoogle Scholar
  30. 30.
    Roh MI, Kim JH, Kwon OW. Features of optical coherence tomography are predictive of visual outcomes after intravitreal bevacizumab injection for diabetic macular edema. Ophthalmologica. 2010;224:374–80.CrossRefPubMedGoogle Scholar
  31. 31.
    Al Faran A, Mousa A, Al Shamsi H, Al Gaeed A, Ghazi NG. Spectral domain optical coherence tomography predictors of visual outcome in diabetic cystoid macular edema after bevacizumab injection. Retina. 2014;34:1208–15.CrossRefPubMedGoogle Scholar
  32. 32.
    Querques G, Bux AV, Martinelli D, Iaculli C, Noci ND. Intravitreal pegaptanib sodium (Macugen) for diabetic macular oedema. Acta Ophthalmol. 2009;87:623–30.CrossRefPubMedGoogle Scholar
  33. 33.
    Chung H, Park B, Shin HJ, Kim HC. Correlation of fundus autofluorescence with spectral-domain optical coherence tomography and vision in diabetic macular edema. Ophthalmology. 2012;119:1056–65.CrossRefPubMedGoogle Scholar
  34. 34.
    Domalpally A, Ip MS, Ehrlich JS. Effects of intravitreal ranibizumab on retinal hard exudate in diabetic macular edema: findings from the RIDE and RISE phase III clinical trials. Ophthalmology. 2015;122:779–86.CrossRefPubMedGoogle Scholar
  35. 35.
    Pemp B, Deak G, Prager S, Mitsch C, Lammer J, Schmidinger G, et al. Distribution of intraretinal exudates in diabetic macular edema during anti-vascular endothelial growth factor therapy observed by spectral domain optical coherence tomography and fundus photography. Retina. 2014;34:2407–15.CrossRefPubMedGoogle Scholar
  36. 36.
    Bressler SB, Qin H, Beck RW, Chalam KV, Kim JE, Melia M, et al. Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranibizumab. Arch Ophthalmol. 2012;130:1153–61.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Framme C, Schweizer P, Imesch M, Wolf S, Wolf-Schnurrbusch U. Behavior of SD-OCT-detected hyperreflective foci in the retina of anti-VEGF-treated patients with diabetic macular edema. Invest Ophthalmol Vis Sci. 2012;53:5814–8.CrossRefPubMedGoogle Scholar
  38. 38.
    Aveleira CA, Lin CM, Abcouwer SF, Ambrosio AF, Antonetti DA. TNF-alpha signals through PKCzeta/NF-kappaB to alter the tight junction complex and increase retinal endothelial cell permeability. Diabetes. 2010;59:2872–82.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Joussen AM, Poulaki V, Mitsiades N, Kirchhof B, Koizumi K, Dohmen S, et al. Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression. FASEB J. 2002;16:438–40.CrossRefPubMedGoogle Scholar
  40. 40.
    Joussen AM, Poulaki V, Mitsiades N, Cai WY, Suzuma I, Pak J, et al. Suppression of Fas-FasL-induced endothelial cell apoptosis prevents diabetic blood-retinal barrier breakdown in a model of streptozotocin-induced diabetes. FASEB J. 2003;17:76–8.CrossRefPubMedGoogle Scholar

Copyright information

© Japanese Ophthalmological Society 2018

Authors and Affiliations

  • Tomoaki Murakami
    • 1
    Email author
  • Kiyoshi Suzuma
    • 1
  • Akihito Uji
    • 1
  • Shin Yoshitake
    • 1
  • Yoko Dodo
    • 1
  • Masahiro Fujimoto
    • 1
  • Tatsuya Yoshitake
    • 1
  • Yuko Miwa
    • 1
  • Nagahisa Yoshimura
    • 1
  1. 1.Department of Ophthalmology and Visual SciencesKyoto University Graduate School of MedicineSakyoJapan

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