Research progress on microcystic macular edema in glaucoma: current status_Chinese Journal of Ocular Fundus Diseases

Authors：

Liu Yuan , Zuo Chengguo ,  Liu Xing

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology Visual Science, Guangzhou 510060, China;

Corresponding author：

Liu Xing, Email: liuxing@mail.sysu.edu.cn

Keywords：

Glaucoma; Microcystic macular edema; Tomography; optical coherence; Review

DOI：

10.3760/cma.j.cn511434-20240805-00298

Video：

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Abstract Full text Figures/Tables Video References Cited by

Microcystic macular edema (MME) represents a pathological change that can be observed in the inner layer of the retina in patients diagnosed with glaucoma. This phenomenon is particularly prevalent in individuals with moderate to advanced glaucoma. The majority of research in this field has focused on primary open-angle glaucoma. The occurrence of MME in glaucoma has been demonstrated to be associated with younger age, advanced stage and disease progression. MME occurs in the parafoveal region, most frequently located in the inferior perimacular region, which corresponded with the most vulnerable area of ganglion cells in glaucoma. The presence of MME may affect the automatic layering of optical coherence tomography images, suggesting that clinicians should be mindful of the occurrence of MME to avoid misdiagnosis of the disease. It is hypothesised that the occurrence of MME in glaucoma may be related to macular vitreous traction, mechanical stress of the stent, and Müller cell dysfunction. A comprehensive investigation of the precise pathophysiological mechanism of MME in glaucoma will facilitate the development of a novel perspective and a scientific foundation for the diagnosis, disease monitoring and evaluation of treatment efficacy in glaucoma.

1.	Siah WF, Loughman J, O'Brien C. Lower macular pigment optical density in foveal-involved glaucoma[J]. Ophthalmology, 2015, 122(10): 2029-2037. DOI: 10.1016/j.ophtha.2015.06.028.
2.	Hou H, Moghimi S, Proudfoot JA, et al. Ganglion cell complex thickness and macular vessel density loss in primary open-angle glaucoma[J]. Ophthalmology, 2020, 127(8): 1043-1052. DOI: 10.1016/j.ophtha.2019.12.030.
3.	Rathke F, Schmidt S, Schnörr C. Probabilistic intra-retinal layer segmentation in 3-D OCT images using global shape regularization[J]. Med Image Anal, 2014, 18(5): 781-794. DOI: 10.1016/j.media.2014.03.004.
4.	Wolff B, Basdekidou C, Vasseur V, et al. Retinal inner nuclear layer microcystic changes in optic nerve atrophy: a novel spectral-domain OCT finding[J]. Retina, 2013, 33(10): 2133-2138. DOI: 10.1097/IAE.0b013e31828e68d0.
5.	Gelfand JM, Nolan R, Schwartz DM, et al. Microcystic macular oedema in multiple sclerosis is associated with disease severity[J]. Brain, 2012, 135(Pt 6): 1786-1793. DOI: 10.1093/brain/aws098.
6.	Burggraaff MC, Trieu J, de Vries-Knoppert WA, et al. The clinical spectrum of microcystic macular edema[J]. Invest Ophthalmol Vis Sci, 2014, 55(2): 952-961. DOI: 10.1167/iovs.13-12912.
7.	Gelfand JM, Cree BA, Nolan R, et al. Microcystic inner nuclear layer abnormalities and neuromyelitis optica[J]. JAMA Neurol, 2013, 70(5): 629-633. DOI: 10.1001/jamaneurol.2013.1832.
8.	Sotirchos ES, Saidha S, Byraiah G, et al. In vivo identification of morphologic retinal abnormalities in neuromyelitis optica[J]. Neurology, 2013, 80(15): 1406-1414. DOI: 10.1212/WNL.0b013e31828c2f7a.
9.	Abegg M, Dysli M, Wolf S, et al. Microcystic macular edema: retrograde maculopathy caused by optic neuropathy[J]. Ophthalmology, 2014, 121(1): 142-149. DOI: 10.1016/j.ophtha.2013. 08.045.
10.	Hasegawa T, Akagi T, Yoshikawa M, et al. Microcystic inner nuclear layer changes and retinal nerve fiber layer defects in eyes with glaucoma[J/OL]. PLoS One, 2015, 10(6): e0130175[2015-06-12]. https://pubmed.ncbi.nlm.nih.gov/26066021/ DOI: 10.1371/journal.pone.0130175.
11.	Murata N, Togano T, Miyamoto D, et al. Clinical evaluation of microcystic macular edema in patients with glaucoma[J]. Eye (Lond), 2016, 30(11): 1502-1508. DOI: 10.1038/eye.2016.190.
12.	Mahmoudinezhad G, Salazar D, Morales E, et al. Risk factors for microcystic macular oedema in glaucoma[J]. Br J Ophthalmol, 2023, 107(4): 505-510. DOI: 10.1136/bjophthalmol-2021-320137.
13.	Wells-Gray EM, Choi SS, Slabaugh M, et al. Inner retinal changes in primary open-angle glaucoma revealed through adaptive optics-optical coherence tomography[J]. J Glaucoma, 2018, 27(11): 1025-1028. DOI: 10.1097/ijg.0000000000001039.
14.	Kessel L, Hamann S, Wegener M, et al. Microcystic macular oedema in optic neuropathy: case series and literature review[J]. Clin Exp Ophthalmol, 2018, 46(9): 1075-1086. DOI: 10.1111/ceo.13327.
15.	Xiao H, Liu Y, Guo N, et al. Clinical characteristics of microcystic macular edema in chronic primary angle-closure glaucoma and primary open-angle glaucoma patients[J]. Ophthalmic Res, 2024, 67(1): 145-153. DOI: 10.1159/000535900.
16.	Abdelaal A, Eltaras MM, Katamesh BE, et al. The prevalence and presentation patterns of microcystic macular oedema: a systematic review and meta-analysis of 2128 glaucomatous eyes[J]. Eye (Lond), 2023, 37(16): 3322-3333. DOI: 10.1038/s41433-023-02524-w.
17.	Wen JC, Freedman SF, El-Dairi MA, et al. Microcystic macular changes in primary open-angle glaucoma[J]. J Glaucoma, 2016, 25(3): 258-262. DOI: 10.1097/ijg.0000000000000129.
18.	Deschênes MC, Descovich D, Moreau M, et al. Postmenopausal hormone therapy increases retinal blood flow and protects the retinal nerve fiber layer[J]. Invest Ophthalmol Vis Sci, 2010, 51(5): 2587-600. DOI: 10.1167/iovs.09-3710.
19.	Brazerol J, Iliev ME, Höhn R, et al. Retrograde maculopathy in patients with glaucoma[J]. J Glaucoma, 2017, 26(5): 423-429. DOI: 10.1097/ijg.0000000000000633.
20.	Leung CKS, Ye C, Weinreb RN, et al. Impact of age-related change of retinal nerve fiber layer and macular thicknesses on evaluation of glaucoma progression[J]. Ophthalmology, 2013, 120(12): 2485-2492. DOI: 10.1016/j.ophtha.2013.07.021.
21.	Holló G. The side effects of the prostaglandin analogues[J]. Expert Opin Drug Saf, 2007, 6(1): 45-52. DOI: 10.1517/14740338.6.1.45.
22.	Holló G, Aung T, Cantor LB, et al. Cystoid macular edema related to cataract surgery and topical prostaglandin analogs: mechanism, diagnosis, and management[J]. Surv Ophthalmol, 2020, 65(5): 496-512. DOI: 10.1016/j.survophthal.2020.02.004.
23.	Govetto A, Su D, Farajzadeh M, et al. Microcystoid macular changes in association with idiopathic epiretinal membranes in eyes with and without glaucoma: clinical insights[J]. Am J Ophthalmol, 2017, 181: 156-165. DOI: 10.1016/j.ajo.2017.06.023.
24.	Zhang M, Mao GY, Ye C, et al. Association of peripheral anterior synechia, intraocular pressure, and glaucomatous optic neuropathy in primary angle-closure diseases[J]. Int J Ophthalmol, 2021, 14(10): 1533-1538. DOI: 10.18240/ijo.2021.10.09.
25.	Nakazawa T, Fukuchi T. What is glaucomatous optic neuropathy?[J]. Jpn J Ophthalmol, 2020, 64(3): 243-249. DOI: 10.1007/s10384-020-00736-1.
26.	Jung KI, Ryu HK, Oh SE, et al. Thicker inner nuclear layer as a predictor of glaucoma progression and the impact of intraocular pressure fluctuation[J/OL]. J Clin Med, 2024, 13(8): 2312[2024-04-17]. https://pubmed.ncbi.nlm.nih.gov/38673589/. DOI: 10.3390/jcm13082312.
27.	El Maftouhi A, Quaranta-El Maftouhi M, Baudouin C, et al. Cystic maculopathy of the inner nuclear layer in glaucoma patients[J]. J Fr Ophtalmol, 2021, 44(6): 786-791. DOI: 10.1016/j.jfo.2020.11.010.
28.	Hood DC. Improving our understanding, and detection, of glaucomatous damage: An approach based upon optical coherence tomography (OCT)[J]. Prog Retin Eye Res, 2017, 57: 46-75. DOI: 10.1016/j.preteyeres.2016.12.002.
29.	Francone A, Govetto A, Yun L, et al. Evaluation of non-exudative microcystoid macular abnormalities secondary to retinal vein occlusion[J]. Graefe's Arch Clin Exp Ophthalmol, 2021, 259(12): 3579-3588. DOI: 10.1007/s00417-021-05250-9.
30.	Barboni P, Carelli V, Savini G, et al. Microcystic macular degeneration from optic neuropathy: not inflammatory, not trans-synaptic degeneration[J/OL]. Brain, 2013, 136(Pt 7): e239[2013-02-08]. https://pubmed.ncbi.nlm.nih.gov/23396580/. DOI: 10.1093/brain/awt014.
31.	Lujan BJ, Horton JC. Microcysts in the inner nuclear layer from optic atrophy are caused by retrograde trans-synaptic degeneration combined with vitreous traction on the retinal surface[J/OL]. Brain, 2013, 136(Pt 11): e260[2013-07-19]. https://pubmed.ncbi.nlm.nih.gov/23872368/. DOI: 10.1093/brain/awt154.
32.	Shinozaki Y, Koizumi S. Potential roles of astrocytes and Müller cells in the pathogenesis of glaucoma[J]. J Pharmacol Sci, 2021, 145(3): 262-267. DOI: 10.1016/j.jphs.2020.12.009.
33.	Reichenbach A, Wurm A, Pannicke T, et al. Müller cells as players in retinal degeneration and edema[J]. Graefe's Arch Clin Exp Ophthalmol, 2007, 245(5): 627-36. DOI: 10.1007/s00417-006-0516-y.
34.	Green AJ, McQuaid S, Hauser SL, et al. Ocular pathology in multiple sclerosis: retinal atrophy and inflammation irrespective of disease duration[J]. Brain, 2010, 133(Pt 6): 1591-601. DOI: 10.1093/brain/awq080.
35.	Petzold A, Balcer LJ, Calabresi PA, et al. Retinal layer segmentation in multiple sclerosis: a systematic review and meta-analysis[J]. Lancet Neurol, 2017, 16(10): 797-812. DOI: 10.1016/s1474-4422(17)30278-8.
36.	Lavery TCM, Rasmussen CA, Katz AW, et al. Development of microcystoid macular degeneration in the retina of nonhuman primates: time-course and associated pathologies[J]. Curr Eye Res, 2024, 18: 1-8. DOI: 10.1080/02713683.2024.2397028.

1. Siah WF, Loughman J, O'Brien C. Lower macular pigment optical density in foveal-involved glaucoma[J]. Ophthalmology, 2015, 122(10): 2029-2037. DOI: 10.1016/j.ophtha.2015.06.028.
2. Hou H, Moghimi S, Proudfoot JA, et al. Ganglion cell complex thickness and macular vessel density loss in primary open-angle glaucoma[J]. Ophthalmology, 2020, 127(8): 1043-1052. DOI: 10.1016/j.ophtha.2019.12.030.
3. Rathke F, Schmidt S, Schnörr C. Probabilistic intra-retinal layer segmentation in 3-D OCT images using global shape regularization[J]. Med Image Anal, 2014, 18(5): 781-794. DOI: 10.1016/j.media.2014.03.004.
4. Wolff B, Basdekidou C, Vasseur V, et al. Retinal inner nuclear layer microcystic changes in optic nerve atrophy: a novel spectral-domain OCT finding[J]. Retina, 2013, 33(10): 2133-2138. DOI: 10.1097/IAE.0b013e31828e68d0.
5. Gelfand JM, Nolan R, Schwartz DM, et al. Microcystic macular oedema in multiple sclerosis is associated with disease severity[J]. Brain, 2012, 135(Pt 6): 1786-1793. DOI: 10.1093/brain/aws098.
6. Burggraaff MC, Trieu J, de Vries-Knoppert WA, et al. The clinical spectrum of microcystic macular edema[J]. Invest Ophthalmol Vis Sci, 2014, 55(2): 952-961. DOI: 10.1167/iovs.13-12912.
7. Gelfand JM, Cree BA, Nolan R, et al. Microcystic inner nuclear layer abnormalities and neuromyelitis optica[J]. JAMA Neurol, 2013, 70(5): 629-633. DOI: 10.1001/jamaneurol.2013.1832.
8. Sotirchos ES, Saidha S, Byraiah G, et al. In vivo identification of morphologic retinal abnormalities in neuromyelitis optica[J]. Neurology, 2013, 80(15): 1406-1414. DOI: 10.1212/WNL.0b013e31828c2f7a.
9. Abegg M, Dysli M, Wolf S, et al. Microcystic macular edema: retrograde maculopathy caused by optic neuropathy[J]. Ophthalmology, 2014, 121(1): 142-149. DOI: 10.1016/j.ophtha.2013. 08.045.
10. Hasegawa T, Akagi T, Yoshikawa M, et al. Microcystic inner nuclear layer changes and retinal nerve fiber layer defects in eyes with glaucoma[J/OL]. PLoS One, 2015, 10(6): e0130175[2015-06-12]. https://pubmed.ncbi.nlm.nih.gov/26066021/ DOI: 10.1371/journal.pone.0130175.
11. Murata N, Togano T, Miyamoto D, et al. Clinical evaluation of microcystic macular edema in patients with glaucoma[J]. Eye (Lond), 2016, 30(11): 1502-1508. DOI: 10.1038/eye.2016.190.
12. Mahmoudinezhad G, Salazar D, Morales E, et al. Risk factors for microcystic macular oedema in glaucoma[J]. Br J Ophthalmol, 2023, 107(4): 505-510. DOI: 10.1136/bjophthalmol-2021-320137.
13. Wells-Gray EM, Choi SS, Slabaugh M, et al. Inner retinal changes in primary open-angle glaucoma revealed through adaptive optics-optical coherence tomography[J]. J Glaucoma, 2018, 27(11): 1025-1028. DOI: 10.1097/ijg.0000000000001039.
14. Kessel L, Hamann S, Wegener M, et al. Microcystic macular oedema in optic neuropathy: case series and literature review[J]. Clin Exp Ophthalmol, 2018, 46(9): 1075-1086. DOI: 10.1111/ceo.13327.
15. Xiao H, Liu Y, Guo N, et al. Clinical characteristics of microcystic macular edema in chronic primary angle-closure glaucoma and primary open-angle glaucoma patients[J]. Ophthalmic Res, 2024, 67(1): 145-153. DOI: 10.1159/000535900.
16. Abdelaal A, Eltaras MM, Katamesh BE, et al. The prevalence and presentation patterns of microcystic macular oedema: a systematic review and meta-analysis of 2128 glaucomatous eyes[J]. Eye (Lond), 2023, 37(16): 3322-3333. DOI: 10.1038/s41433-023-02524-w.
17. Wen JC, Freedman SF, El-Dairi MA, et al. Microcystic macular changes in primary open-angle glaucoma[J]. J Glaucoma, 2016, 25(3): 258-262. DOI: 10.1097/ijg.0000000000000129.
18. Deschênes MC, Descovich D, Moreau M, et al. Postmenopausal hormone therapy increases retinal blood flow and protects the retinal nerve fiber layer[J]. Invest Ophthalmol Vis Sci, 2010, 51(5): 2587-600. DOI: 10.1167/iovs.09-3710.
19. Brazerol J, Iliev ME, Höhn R, et al. Retrograde maculopathy in patients with glaucoma[J]. J Glaucoma, 2017, 26(5): 423-429. DOI: 10.1097/ijg.0000000000000633.
20. Leung CKS, Ye C, Weinreb RN, et al. Impact of age-related change of retinal nerve fiber layer and macular thicknesses on evaluation of glaucoma progression[J]. Ophthalmology, 2013, 120(12): 2485-2492. DOI: 10.1016/j.ophtha.2013.07.021.
21. Holló G. The side effects of the prostaglandin analogues[J]. Expert Opin Drug Saf, 2007, 6(1): 45-52. DOI: 10.1517/14740338.6.1.45.
22. Holló G, Aung T, Cantor LB, et al. Cystoid macular edema related to cataract surgery and topical prostaglandin analogs: mechanism, diagnosis, and management[J]. Surv Ophthalmol, 2020, 65(5): 496-512. DOI: 10.1016/j.survophthal.2020.02.004.
23. Govetto A, Su D, Farajzadeh M, et al. Microcystoid macular changes in association with idiopathic epiretinal membranes in eyes with and without glaucoma: clinical insights[J]. Am J Ophthalmol, 2017, 181: 156-165. DOI: 10.1016/j.ajo.2017.06.023.
24. Zhang M, Mao GY, Ye C, et al. Association of peripheral anterior synechia, intraocular pressure, and glaucomatous optic neuropathy in primary angle-closure diseases[J]. Int J Ophthalmol, 2021, 14(10): 1533-1538. DOI: 10.18240/ijo.2021.10.09.
25. Nakazawa T, Fukuchi T. What is glaucomatous optic neuropathy?[J]. Jpn J Ophthalmol, 2020, 64(3): 243-249. DOI: 10.1007/s10384-020-00736-1.
26. Jung KI, Ryu HK, Oh SE, et al. Thicker inner nuclear layer as a predictor of glaucoma progression and the impact of intraocular pressure fluctuation[J/OL]. J Clin Med, 2024, 13(8): 2312[2024-04-17]. https://pubmed.ncbi.nlm.nih.gov/38673589/. DOI: 10.3390/jcm13082312.
27. El Maftouhi A, Quaranta-El Maftouhi M, Baudouin C, et al. Cystic maculopathy of the inner nuclear layer in glaucoma patients[J]. J Fr Ophtalmol, 2021, 44(6): 786-791. DOI: 10.1016/j.jfo.2020.11.010.
28. Hood DC. Improving our understanding, and detection, of glaucomatous damage: An approach based upon optical coherence tomography (OCT)[J]. Prog Retin Eye Res, 2017, 57: 46-75. DOI: 10.1016/j.preteyeres.2016.12.002.
29. Francone A, Govetto A, Yun L, et al. Evaluation of non-exudative microcystoid macular abnormalities secondary to retinal vein occlusion[J]. Graefe's Arch Clin Exp Ophthalmol, 2021, 259(12): 3579-3588. DOI: 10.1007/s00417-021-05250-9.
30. Barboni P, Carelli V, Savini G, et al. Microcystic macular degeneration from optic neuropathy: not inflammatory, not trans-synaptic degeneration[J/OL]. Brain, 2013, 136(Pt 7): e239[2013-02-08]. https://pubmed.ncbi.nlm.nih.gov/23396580/. DOI: 10.1093/brain/awt014.
31. Lujan BJ, Horton JC. Microcysts in the inner nuclear layer from optic atrophy are caused by retrograde trans-synaptic degeneration combined with vitreous traction on the retinal surface[J/OL]. Brain, 2013, 136(Pt 11): e260[2013-07-19]. https://pubmed.ncbi.nlm.nih.gov/23872368/. DOI: 10.1093/brain/awt154.
32. Shinozaki Y, Koizumi S. Potential roles of astrocytes and Müller cells in the pathogenesis of glaucoma[J]. J Pharmacol Sci, 2021, 145(3): 262-267. DOI: 10.1016/j.jphs.2020.12.009.
33. Reichenbach A, Wurm A, Pannicke T, et al. Müller cells as players in retinal degeneration and edema[J]. Graefe's Arch Clin Exp Ophthalmol, 2007, 245(5): 627-36. DOI: 10.1007/s00417-006-0516-y.
34. Green AJ, McQuaid S, Hauser SL, et al. Ocular pathology in multiple sclerosis: retinal atrophy and inflammation irrespective of disease duration[J]. Brain, 2010, 133(Pt 6): 1591-601. DOI: 10.1093/brain/awq080.
35. Petzold A, Balcer LJ, Calabresi PA, et al. Retinal layer segmentation in multiple sclerosis: a systematic review and meta-analysis[J]. Lancet Neurol, 2017, 16(10): 797-812. DOI: 10.1016/s1474-4422(17)30278-8.
36. Lavery TCM, Rasmussen CA, Katz AW, et al. Development of microcystoid macular degeneration in the retina of nonhuman primates: time-course and associated pathologies[J]. Curr Eye Res, 2024, 18: 1-8. DOI: 10.1080/02713683.2024.2397028.

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