Study on adaptive optics fundus imaging in pre-clinical hydroxychloroquine retinopathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Liu Hua ^1,2 , Zhu Zhihong ² ,  Huang Houbin ^1,2,3 , Chen Wenji ⁴ , Fan Lina ⁴ , Mo Shiyan ⁴

1. The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China;
2. Department of Ophthalmology, Hainan Hospital of PLA General Hospital, Sanya 572013, China;
3. Senior Department of Ophthalmology, PLA General Hospital, Beijing 100853, China;
4. Department of Rheumatism and Immunology, Hainan Hospital of PLA General Hospital, Sanya 572013, China;

Corresponding author：

Huang Houbin, Email: huanghoubin@hotmail.com

Keywords：

Hydroxychloroquine retinopathy; Pre-clinic; Cone cell; Adaptive optics fundus camera imaging

DOI：

10.3760/cma.j.cn511434-20220830-00483

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Objective To evaluate whether there are changes in cone cells in patients with pre-clinical hydroxychloroquine (HCQ) retinopathy using an adaptive optics (AO) retinal camera. Methods A retrospective case-control study. From May 2020 to July 2020, 46 patients who were treated in Department of Rheumatism and Immunology, Hainan Hospital of PLA General Hospital with rheumatic immune diseases were included. All patients had a history of HCQ use and no obvious abnormality was found in fundus examination; 105 healthy people with similar demographic characteristics without a history of hydroxychloroquine were recruited as the control group were included. All subjects received the routine ophthalmological examination including best corrected visual auity (BCVA), spectral-domain optical coherence tomography (SD-OCT), Fundus autofluorescence (FAF), visual field, endoscopy of the cornea, and the measurement of axial length (AL). The BCVA was performed with the Snellen visual acuity chart, and the result was converted to logarithmic minimum angle of resolution (logMAR) visual acuity for statistic. Among the 46 cases, 6 cases were males and 40 cases were females. Age was (42.02±13.81) years old; logMAR BCVA was 0.063±0.015; AL was (23.95±0.726) mm. Visual field, macular SD-OCT, FAF examination showed no abnormality. The average cumulative dose of HCQ was 522.60 (6-1 728) g. rtx1 AO retinal camera was used to collect fundus images of subjects in four quadrants above the retina, nasal side, lower side and temporal side with 3°centrifugation from the fovea in both eyes. The cone density, cone spacing, cone arrangement regularity and the proportion of the nearest cones with 6 (nn=6) were measured in the four quadrants. The density of cone cells between the left and right eyes in case group and control group were compared by paired t test. The density and spacing of cone cells in each quadrant were compared by t test of two independent samples. Results Compared with the control group, the cone cell density in the four quadrants of the left eye and the nasal, superior and inferior sides of the right eye in the case group was significantly decreased, and the difference was statistically significant (t=4.247, 2.107, 4.884, 2.254, 2.643, 4.445, 4.116; P＜0.05). The cone spacing in the nasal and temporal sides of the left eye of the patients in the case group was significantly larger than that in the control eye, with statistical significance (t=2.750, 3.318; P＜0.05). Compared with the control group, the regulatign of cone cell arrangement in the left temporal side of the right and left eye in the case group were significantly reduced, the difference was statistically significant (P=0.002, 0.011). The proportion of nn=6 in the inferior and temporal sides of the right eye decreased significantly in the case group, and the difference was statistically significant (P=0.006, 0.032). Conclusion AO retinal imaging can detect the changes of cone cells in the early clinical stage of HCQ retinopathy.

Citation： Liu Hua, Zhu Zhihong, Huang Houbin, Chen Wenji, Fan Lina, Mo Shiyan. Study on adaptive optics fundus imaging in pre-clinical hydroxychloroquine retinopathy. Chinese Journal of Ocular Fundus Diseases, 2023, 39(9): 747-753. doi: 10.3760/cma.j.cn511434-20220830-00483 Copy

1.	Jorge A, Ung C, Young LH, et al. Hydroxychloroquine retinopathy-implications of research advances for rheumatology care[J]. Nat Rev Rheumatol, 2018, 14(12): 693-703. DOI: 10.1038/s41584-018-0111-8.
2.	Wetterholm DH, Winter FC. Histopathology of chloroquine retinal toxicity[J]. Arch Ophthalmol, 1964, 71: 82-87. DOI: 10.1001/archopht.1964.00970010098016.
3.	Wolfe F, Marmor MF. Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus[J]. Arthritis Care Res (Hoboken), 2010, 62(6): 775-784. DOI: 10.1002/acr.20133.
4.	Marmor MF, Hu J. Effect of disease stage on progression of hydroxychloroquine retinopathy[J]. JAMA Ophthalmol, 2014, 132(9): 1105-1112. DOI: 10.1001/jamaophthalmol.2014.1099.
5.	Stepien KE, Han DP, Schell J, et al. Spectral-domain optical coherence tomography and adaptive optics may detect hydroxychloroquine retinal toxicity before symptomatic vision loss[J]. Trans Am Ophthalmol Soc, 2009, 107: 28-33.
6.	Babcock HW. The posibility of compensating astronomical seeing[J]. Astronomical Society of the Pacific, 1953, 65(368): 229-236.
7.	Liang J, Williams DR, Miller DT. Supernormal vision and high-resolution retinal imaging through adaptive optics[J]. J Opt Soc Am A Opt Image Sci Vis, 1997, 14(11): 2884-2892. DOI: 10.1364/JOSAA.14.002884.
8.	Battu R, Akkali MC, Bhanushali D, et al. Adaptive optics imaging of the outer retinal tubules in Bietti's crystalline dystrophy[J]. Eye (Lond), 2016, 30(5): 705-712. DOI: 10.1038/eye.2016.22.
9.	Biggee K, Gale MJ, Smith TB, et al. Parafoveal cone abnormalities and recovery on adaptive optics in posterior uveitis[J]. Am J Ophthalmol Case Rep, 2016, 1: 16-22. DOI: 10.1016/j.ajoc.2016.03.001.
10.	Vienola KV, Dansingani KK, Eller AW, et al. Multimodal imaging of torpedo maculopathy with fluorescence adaptive optics imaging of individual retinal pigmented epithelial cells[J/OL]. Front Med (Lausanne), 2021, 8: 769308[2021-12-09]. https://pubmed.ncbi.nlm.nih.gov/34957148/. DOI: 10.3389/fmed.2021.769308.
11.	郭庆歌, 李亚, 游雅, 等. CEP290基因新变异相关单纯视锥视杆细胞营养不良基因型与临床表型分析[J]. 中华眼底病杂志, 2022, 38(8): 650-655. DOI: 10.3760/cma.j.cn511434-20220706-00396.Guo QG, Li Y, You Y, et al. Genotypes and phenotypes analysis of a novel complex heterozygous mutation of CEP290 related isolated cone-rod dystrophy[J]. Chin J Ocul Fundus Dis, 2022, 38(8): 650-655. DOI: 10.3760/cma.j.cn511434-20220706-00396.
12.	Marmor MF, Kellner U, Lai TY, et al. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision)[J]. Ophthalmology, 2016, 123(6): 1386-1394. DOI: 10.1016/j.ophtha.2016.01.058.
13.	Li KY, Tiruveedhula P, Roorda A. Intersubject variability of foveal cone photoreceptor density in relation to eye length[J]. Invest Ophthalmol Vis Sci, 2010, 51(12): 6858-6867. DOI: 10.1167/iovs.10-5499.
14.	Battu R, Dabir S, Khanna A, et al. Adaptive optics imaging of the retina[J]. Indian J Ophthalmol, 2014, 62(1): 60-65. DOI: 10.4103/0301-4738.126185.
15.	Dabir S, Mangalesh S, Kumar KA, et al. Variations in the cone packing density with eccentricity in emmetropes[J]. Eye (Lond), 2014, 28(12): 1488-1493. DOI: 10.1038/eye.2014.229.
16.	Chui TY, Song H, Burns SA. Adaptive-optics imaging of human cone photoreceptor distribution[J]. J Opt Soc Am A Opt Image Sci Vis, 2008, 25(12): 3021-3029. DOI: 10.1364/josaa.25.003021.
17.	Legras R, Gaudric A, Woog K. et al. Distribution of cone density, spacing and arrangement in adult healthy retinas with adaptive optics flood illumination[J/OL]. PLoS One, 2018, 13(1): e0191141[2018-01-16]. https://pubmed.ncbi.nlm.nih.gov/29338027/. DOI: 10.1371/journal.pone.0191141.
18.	Ding HJ, Denniston AK, Rao VK, et al. Hydroxychloroquine-related retinal toxicity[J]. Rheumatology (Oxford), 2016, 55(6): 957-967. DOI: 10.1093/rheumatology/kev357.
19.	Lammer J, Prager SG, Cheney MC, et al. Cone photoreceptor irregularity on adaptive optics scanning laser ophthalmoscopy correlates with severity of diabetic retinopathy and macular edema[J]. Invest Ophthalmol Vis Sci, 2016, 57(15): 6624-6632. DOI: 10.1167/iovs.16-19537.
20.	Syed R, Sundquist SM, Ratnam K, et al. High-resolution images of retinal structure in patients with choroideremia[J]. Invest Ophthalmol Vis Sci, 2013, 54(2): 950-961. DOI: 10.1167/iovs.12-10707.
21.	Ratnam K, Carroll J, Porco TC, et al. Relationship between foveal cone structure and clinical measures of visual function in patients with inherited retinal degenerations[J]. Invest Ophthalmol Vis Sci, 2013, 54(8): 5836-5847. DOI: 10.1167/iovs.13-12557.
22.	Hugo J, Beylerian M, Denion E, et al. Multimodal imaging of torpedo maculopathy including adaptive optics[J]. Eur J Ophthalmol, 2020, 30(2): 27-31. DOI: 10.1177/1120672119827772.
23.	张剑平, 张美霞. 自适应光学扫描技术在眼底检查中的应用进展[J]. 中华眼底病杂志, 2019, 35(6): 621-623. DOI: 10.3760/cma.j.issn.1005-1015.2019.06.025.Zhang JP, Zhang MX. The clinical applications of adaptive optics scanning laser ophthalmoscope[J]. Chin J Ocul Fundus Dis, 2019, 35(6): 621-623. DOI: 10.3760/cma.j.issn.1005-1015.2019.06.025.
24.	.Stokkermans TJ, Trichonas G. Chloroquine and hydroxychloroquine ttoxicit. Treasure Island (FL): StatPearls Publishing, 2020.

1. Jorge A, Ung C, Young LH, et al. Hydroxychloroquine retinopathy-implications of research advances for rheumatology care[J]. Nat Rev Rheumatol, 2018, 14(12): 693-703. DOI: 10.1038/s41584-018-0111-8.
2. Wetterholm DH, Winter FC. Histopathology of chloroquine retinal toxicity[J]. Arch Ophthalmol, 1964, 71: 82-87. DOI: 10.1001/archopht.1964.00970010098016.
3. Wolfe F, Marmor MF. Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus[J]. Arthritis Care Res (Hoboken), 2010, 62(6): 775-784. DOI: 10.1002/acr.20133.
4. Marmor MF, Hu J. Effect of disease stage on progression of hydroxychloroquine retinopathy[J]. JAMA Ophthalmol, 2014, 132(9): 1105-1112. DOI: 10.1001/jamaophthalmol.2014.1099.
5. Stepien KE, Han DP, Schell J, et al. Spectral-domain optical coherence tomography and adaptive optics may detect hydroxychloroquine retinal toxicity before symptomatic vision loss[J]. Trans Am Ophthalmol Soc, 2009, 107: 28-33.
6. Babcock HW. The posibility of compensating astronomical seeing[J]. Astronomical Society of the Pacific, 1953, 65(368): 229-236.
7. Liang J, Williams DR, Miller DT. Supernormal vision and high-resolution retinal imaging through adaptive optics[J]. J Opt Soc Am A Opt Image Sci Vis, 1997, 14(11): 2884-2892. DOI: 10.1364/JOSAA.14.002884.
8. Battu R, Akkali MC, Bhanushali D, et al. Adaptive optics imaging of the outer retinal tubules in Bietti's crystalline dystrophy[J]. Eye (Lond), 2016, 30(5): 705-712. DOI: 10.1038/eye.2016.22.
9. Biggee K, Gale MJ, Smith TB, et al. Parafoveal cone abnormalities and recovery on adaptive optics in posterior uveitis[J]. Am J Ophthalmol Case Rep, 2016, 1: 16-22. DOI: 10.1016/j.ajoc.2016.03.001.
10. Vienola KV, Dansingani KK, Eller AW, et al. Multimodal imaging of torpedo maculopathy with fluorescence adaptive optics imaging of individual retinal pigmented epithelial cells[J/OL]. Front Med (Lausanne), 2021, 8: 769308[2021-12-09]. https://pubmed.ncbi.nlm.nih.gov/34957148/. DOI: 10.3389/fmed.2021.769308.
11. 郭庆歌, 李亚, 游雅, 等. CEP290基因新变异相关单纯视锥视杆细胞营养不良基因型与临床表型分析[J]. 中华眼底病杂志, 2022, 38(8): 650-655. DOI: 10.3760/cma.j.cn511434-20220706-00396.Guo QG, Li Y, You Y, et al. Genotypes and phenotypes analysis of a novel complex heterozygous mutation of CEP290 related isolated cone-rod dystrophy[J]. Chin J Ocul Fundus Dis, 2022, 38(8): 650-655. DOI: 10.3760/cma.j.cn511434-20220706-00396.
12. Marmor MF, Kellner U, Lai TY, et al. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision)[J]. Ophthalmology, 2016, 123(6): 1386-1394. DOI: 10.1016/j.ophtha.2016.01.058.
13. Li KY, Tiruveedhula P, Roorda A. Intersubject variability of foveal cone photoreceptor density in relation to eye length[J]. Invest Ophthalmol Vis Sci, 2010, 51(12): 6858-6867. DOI: 10.1167/iovs.10-5499.
14. Battu R, Dabir S, Khanna A, et al. Adaptive optics imaging of the retina[J]. Indian J Ophthalmol, 2014, 62(1): 60-65. DOI: 10.4103/0301-4738.126185.
15. Dabir S, Mangalesh S, Kumar KA, et al. Variations in the cone packing density with eccentricity in emmetropes[J]. Eye (Lond), 2014, 28(12): 1488-1493. DOI: 10.1038/eye.2014.229.
16. Chui TY, Song H, Burns SA. Adaptive-optics imaging of human cone photoreceptor distribution[J]. J Opt Soc Am A Opt Image Sci Vis, 2008, 25(12): 3021-3029. DOI: 10.1364/josaa.25.003021.
17. Legras R, Gaudric A, Woog K. et al. Distribution of cone density, spacing and arrangement in adult healthy retinas with adaptive optics flood illumination[J/OL]. PLoS One, 2018, 13(1): e0191141[2018-01-16]. https://pubmed.ncbi.nlm.nih.gov/29338027/. DOI: 10.1371/journal.pone.0191141.
18. Ding HJ, Denniston AK, Rao VK, et al. Hydroxychloroquine-related retinal toxicity[J]. Rheumatology (Oxford), 2016, 55(6): 957-967. DOI: 10.1093/rheumatology/kev357.
19. Lammer J, Prager SG, Cheney MC, et al. Cone photoreceptor irregularity on adaptive optics scanning laser ophthalmoscopy correlates with severity of diabetic retinopathy and macular edema[J]. Invest Ophthalmol Vis Sci, 2016, 57(15): 6624-6632. DOI: 10.1167/iovs.16-19537.
20. Syed R, Sundquist SM, Ratnam K, et al. High-resolution images of retinal structure in patients with choroideremia[J]. Invest Ophthalmol Vis Sci, 2013, 54(2): 950-961. DOI: 10.1167/iovs.12-10707.
21. Ratnam K, Carroll J, Porco TC, et al. Relationship between foveal cone structure and clinical measures of visual function in patients with inherited retinal degenerations[J]. Invest Ophthalmol Vis Sci, 2013, 54(8): 5836-5847. DOI: 10.1167/iovs.13-12557.
22. Hugo J, Beylerian M, Denion E, et al. Multimodal imaging of torpedo maculopathy including adaptive optics[J]. Eur J Ophthalmol, 2020, 30(2): 27-31. DOI: 10.1177/1120672119827772.
23. 张剑平, 张美霞. 自适应光学扫描技术在眼底检查中的应用进展[J]. 中华眼底病杂志, 2019, 35(6): 621-623. DOI: 10.3760/cma.j.issn.1005-1015.2019.06.025.Zhang JP, Zhang MX. The clinical applications of adaptive optics scanning laser ophthalmoscope[J]. Chin J Ocul Fundus Dis, 2019, 35(6): 621-623. DOI: 10.3760/cma.j.issn.1005-1015.2019.06.025.
24. .Stokkermans TJ, Trichonas G. Chloroquine and hydroxychloroquine ttoxicit. Treasure Island (FL): StatPearls Publishing, 2020.

Chinese Journal of Ocular Fundus Diseases

Study on adaptive optics fundus imaging in pre-clinical hydroxychloroquine retinopathy

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