Photodiagnosis and Photodynamic Therapy (2015) 12, 310—313
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/pdpdt
CASE REPORT/RESEARCH LETTER
The discrepancy between central foveal thickness and best corrected visual acuity in cystoid macular edema secondary to central retinal vein occlusion after intravitreal lucentis® injection Rui Hua a, Chenyan Li PhD b,c,∗, Yuedong Hu a, Lei Chen a a
Department of Ophthalmology, First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China b Department of Endocrinology, First Hospital of China Medical University, Shenyang, China c Key Laboratory of Endocrine Diseases in Liaoning Province, First Hospital of China Medical University, Shenyang, China Available online 26 March 2015
KEYWORDS Cystoid macular edema; Best corrected visual acuity; Central foveal thickness; Cyst area; Optical coherence tomography; Anti-VEGF therapy
Summary Cystoid macular edema is a common retinal disorder with the potential for significant vision-related morbidity, and intravitreal lucentis® injection is confirmed to be an effective therapy approach. In the present study, we investigated the discrepancy between central foveal thickness and best corrected visual acuity in such lesions and infered that intravitreal lucentis® injection may help the visual function, related to the renewal of cells. © 2015 Elsevier B.V. All rights reserved.
Abbreviations: CFT, central foveal thickness; BCVA, best corrected visual acuity; CME, cystoid macular edema; BRB, blood—retinal barriers; CRVO, central retinal vein occlusion; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; OCT, optical coherence tomography; VEGF, vascular endothelial growth factor; FP, fundus photograph; SD-OCT, spectral domain OCT; FA, fluorescein angiography. ∗ Corresponding author at: Department of Endocrinology, First Hospital of China Medical University, No. 155, Nanjingbei Street, Heping District, Shenyang 110001, Liaoning Province, China. E-mail address: [email protected] (C. Li). http://dx.doi.org/10.1016/j.pdpdt.2015.03.005 1572-1000/© 2015 Elsevier B.V. All rights reserved.
Discrepancy between central foveal thickness and BCVA
311
Figure 1 The main measurements. (A) OCT profile showed the parameters: CFT (yellow arrow), cyst (Henle) and cyst (INL) (red arrow), MS within radius 500 m from fovea (blue box). (B) Illustration indicated the direction of OCT. (C) Cysts area within radius 1000 m from fovea (blank region). (D) Corresponding retina area within radius 1000 m from fovea (white region).
Cystoid macular edema (CME) is attributed to abnormal accumulation of extracellular fluid. Histologically, macular cysts are located in two retinal layers predominantly, including the inner nuclear layer (INL) and the Henle fiber layer [1] (outer plexiform layer (OPL) and outer nuclear layer (ONL) [2]). Monthly intravitreal injections of 0.5 mg ranibizumab (lucentis® ) will greatly improve the mean best corrected visual acuity (BCVA) and decrease central foveal thickness (CFT) at the sixth month [3]. On the contrary, CME recurrences occurred sooner, which were more prominent and lasted longer in central retinal vein occlusion (CRVO) [4]. In these researches, CFT becomes a more and more popular index for intravitreal anti-VEGF therapy. But in our clinical practices, we find that the BCVA recovery is not consistent with CFT in some cases. In other words, although the BCVA is improved, CME relapses again. In this study, we try to explain the discrepancy between CFT and BCVA in CME secondary to CRVO, who received anti-VEGF therapy. Case analysis: A 20-year-old female complained of progressive blurred vision in her left eye for one month. Her BCVA was 18/60 in the left eye and 60/60 in the right eye. To establish the diagnosis, the patient received fundus photograph (FP), spectral domain optical coherence tomography (SD-OCT, Spectralis HRA + OCT; Spectralis Acquisition and Viewing Modules, version 5.3.2; Heidelberg Engineering) with horizontal and vertical direction scanning through the fovea, and fluorescein angiography (FA) examinations. The FA indicated that the macular leakage and intravenous dyeing. And then, SD-OCT confirmed the CME extended from INL to ONL. The diagnosis was concluded as inflammatory CRVO complicated with CME, without any systemic pathology. After diagnosis, lucentis® (0.5 mg/0.05 mL) was injected intravitreally, according to ‘‘loading dose’’ protocol, as Kim reported [5]. Next, SD-OCT with ‘‘point to point’’ follow up function was performed to observe the morphological changes of CME and BCVA was also recorded correspondingly. The main measurements included CFT, the mean number of cysts in Henle and INL [cyst (Henle) and cyst (INL)], the mean ratio of cyst and retinal area within radius 1000 m from fovea (C/R1000), the mean length of disrupted
photoreceptor inner/outer segment (disrupted (IS/OS)), as well as the mean number of macular septums within radius 500 m from fovea (MC500) (Fig. 1), measured and calculated using Heidelberg eye explorer and image plus pro 6.0 software. All researches and measurements adhered to the tenets of the Declaration of Helsinki and the study was approved by the Medical Research Ethics Committee of First Hospital of China Medical University. Statistical analysis: All analyses were performed by SPSS version 18.0 (Inc., Chicago, IL). The morphological changes of CME were studied by descriptive statistics. The relationship of the main measurements was compared by Spearmans statistically. A probability (p) value of less than 0.05 was considered statistically significant.
Results At baseline, the CME with large cysts always closed to the fovea. After each injection, CME disappeared or became small, but later on, it relapsed again. CFT had a positive correlation with cyst (Henle) (r = 0.850, p = 0.007 < 0.05), and cyst (INL) (r = 0.964, p < 0.0001). There was a likely tendency that cyst (Henle) reduced relatively, compared to cyst (INL) at each visit (Fig. 2A). BCVA increased after each injection, and then decreased again. But, there was an enhanced and increasing tendency of BCVA at each visit (Table 1). While, the BCVA had a negative relation with MC500 (r = −0.924, p = 0.001 < 0.05), cyst (Henle) (r = −0.876, p = 0.004 < 0.05) and disrupted (IS/OS) (r = −0.778, p = 0.023 < 0.05). Unfortunately, BCVA showed no significant relationship between CFT (R = −0.593, P = 0.121 > 0.05, Fig. 2B), and cyst (INL) (r = −0.569, p = 0.141 > 0.05). The minimum of C/R1000 was decreased gradually (Fig. 2C).
Discussion Large cysts always closed to the fovea, because of the decreased barrier function of synapsis in IPL and OPL near
312
R. Hua et al.
Figure 2 Vision acuity and its influencing factors. (A) The relationship between cyst (Henle) and cyst (INL). Comparing the two red boxes, the cyst (Henle) reduced relatively than cyst (INL). (B) C/R1000 changes. The minimum of C/R1000 was decreased gradually (oblique red arrow). The vertical red arrows showed the injection points, as well as the minimum of C/R1000 points. (Follow up points: baseline: before injection, a: two days after first injection, b: 20 days after first injection, c: one month after first injection, d: 10 days after the second injection, e: 18 days after the second injection, f: 28 days after the second injection, g: 11 days after the third injection.)
Table 1
The discrepancy between BCVA and CFT.
Follow up points
Before injection
Two days after first injection
20 days after first injection
One month 10 days after after first the second injection injection
18 days after the second injection
28 days after the second injection
11 days after the third injection
BCVA CFT (m)
0.3 615.5
0.3 309.5
0.6 363
0.5 633
0.5 443
0.5 566.5
0.8 168.5
fovea, and extracellular fluid accumulation caused by long cone fibers in the larger foveal avascular zone [2]. In the study, obviously, the C/R1000 increased as cysts enlarged, which resulted in increased CFT. The MC500 represented the numbers of cysts partially, so it had a negative relationship with BCVA. We certified the discrepancy between BCVA and CFT. On the one hand, several factors caused CME occurred: blood—retinal barriers (BRB) destroy; dysfunction of Müller cells; Müller cells necrosis; and intraocular inflammation. In addition, it has been reported that Müller cell-derived VEGF causes the pathological permeability of the barrier in the sensory retina under hypoxic or ischemic circumstances [6]. On the other hand, intravitreal lucentis® can modify the course of CRVO, by restoring the integrity of the inner BRBs, and reconstruct tight junction between endothelial cells. The disruption range of IS/OS and edema level may play important roles in BCVA prognosis. Similarly, Deák et al. [7] reported that SRF and large cysts in ONL impacted visual function. While, at baseline, good BCVA was also associated with preservation of the foveal IS/OS, and external limited membrane (ELM) [5]. Moreover, high reflective spots which may be precursors of hard exudates [8], in the cysts in ONL, will invade ELM and IS/OS, resulting in the degeneration and apoptosis of photoreceptor [9]. Additionally, the hydraulic pressure in cysts of ONL will also impact ELM and IS/OS [9]. In this study, the relative reduction of cyst (Henle), and the recovery of IS/OS may attribute to the improvement of BCVA.
0.6 216.5
The minimum of C/R1000 was decreased gradually in our study, showing an inverse trend with BCVA. Marshall et al. [10] has concluded that the integrity of the crosssectional area of retinal tissue between the plexiform layers in CME had a linear relationship with BCVA. So, we infer that intravitreal lucentis® injection may help the visual function, related to the renewal of cells. We propose that the minimum of C/R1000 is more practical than CFT. As a conclusion, we reported the discrepancy between BCVA and CFT, which may due to the decreased cyst (Henle), the minimum of C/R1000 and the recovery of IS/OS, which may contribute to understanding of the pathological changes in CME. There were also several limitations. For example, we did not consider choroidal ischemia for CME. We will improve our methods in further prospective treatment trials. Conflict of interest statement There were no conflicts of financial interest for this study. Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Acknowledgments We thank Prof. Na Cai, and Dr. Limin Liu, for assistance with diagnoses, treatment, and follow-up in the Department of Ophthalmology at the First Hospital of China Medical University.
Discrepancy between central foveal thickness and BCVA
References [1] Antcliff RJ, Marshall J. The pathogenesis of edema in diabetic maculopathy. Semin Ophthalmol 1999;14:223—32. [2] Byeon SH, Chu YK, Hong YT, Kim M, Kang HM, Kwon OW. New insights into the pathoanatomy of diabetic macular edema: angiographic patterns and optical coherence tomography. Retina 2012;32:1087—99. [3] Garnock-Jones KP. Ranibizumab: in macular oedema following retinal vein occlusion. Drugs 2011;71:455—63. [4] Karagiannis DA, Karampelas MD, Soumplis VM, Amariotakis C, Georgalas I, Kandarakis A. Recurrence of macular edema in retinal vein occlusions after treatment with intravitrealranibizumab (Lucentis). Can J Ophthalmol 2011;46:486—90. [5] Kim M, Yu SY, Kim ES, Bae SH, Park JH, Yu HG, et al. Intravitrealranibizumab for macular edema secondary to retinal vein occlusion. Ophthalmologica 2012;227:132—8.
313 [6] Bringmann A, Reichenbach A, Wiedemann P. Pathomechanisms of cystoid macular edema. Ophthalmic Res 2004;36:241—9. [7] Deák GG, Bolz M, Ritter M, Prager S, Benesch T, SchmidtErfurth U. A systematic correlation between morphology and functional alterations in diabetic macular edema. Invest Ophthalmol Vis Sci 2010;51:6710—4. [8] Helmy YM, Allah HR. Optical coherence tomography classification of diabetic cystoid macular edema. Clin Ophthalmol 2013;7:1731—7. [9] Uji A, Murakami T, Nishijima K. Association between hyperreflective foci in the outer retina, status of photoreceptor layer, and visual acuity in diabetic macular edema. Am J Ophthalmol 2012;153:710—7. [10] Pelosini L, Hull CC, Boyce JF, McHugh D, Stanford MR, Marshall J. Optical coherence tomography may be used to predict visual acuity in patients with macular edema. Invest Ophthalmol Vis Sci 2011;52:2741—8.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/pdpdt
CASE REPORT/RESEARCH LETTER
The discrepancy between central foveal thickness and best corrected visual acuity in cystoid macular edema secondary to central retinal vein occlusion after intravitreal lucentis® injection Rui Hua a, Chenyan Li PhD b,c,∗, Yuedong Hu a, Lei Chen a a
Department of Ophthalmology, First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China b Department of Endocrinology, First Hospital of China Medical University, Shenyang, China c Key Laboratory of Endocrine Diseases in Liaoning Province, First Hospital of China Medical University, Shenyang, China Available online 26 March 2015
KEYWORDS Cystoid macular edema; Best corrected visual acuity; Central foveal thickness; Cyst area; Optical coherence tomography; Anti-VEGF therapy
Summary Cystoid macular edema is a common retinal disorder with the potential for significant vision-related morbidity, and intravitreal lucentis® injection is confirmed to be an effective therapy approach. In the present study, we investigated the discrepancy between central foveal thickness and best corrected visual acuity in such lesions and infered that intravitreal lucentis® injection may help the visual function, related to the renewal of cells. © 2015 Elsevier B.V. All rights reserved.
Abbreviations: CFT, central foveal thickness; BCVA, best corrected visual acuity; CME, cystoid macular edema; BRB, blood—retinal barriers; CRVO, central retinal vein occlusion; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; OCT, optical coherence tomography; VEGF, vascular endothelial growth factor; FP, fundus photograph; SD-OCT, spectral domain OCT; FA, fluorescein angiography. ∗ Corresponding author at: Department of Endocrinology, First Hospital of China Medical University, No. 155, Nanjingbei Street, Heping District, Shenyang 110001, Liaoning Province, China. E-mail address: [email protected] (C. Li). http://dx.doi.org/10.1016/j.pdpdt.2015.03.005 1572-1000/© 2015 Elsevier B.V. All rights reserved.
Discrepancy between central foveal thickness and BCVA
311
Figure 1 The main measurements. (A) OCT profile showed the parameters: CFT (yellow arrow), cyst (Henle) and cyst (INL) (red arrow), MS within radius 500 m from fovea (blue box). (B) Illustration indicated the direction of OCT. (C) Cysts area within radius 1000 m from fovea (blank region). (D) Corresponding retina area within radius 1000 m from fovea (white region).
Cystoid macular edema (CME) is attributed to abnormal accumulation of extracellular fluid. Histologically, macular cysts are located in two retinal layers predominantly, including the inner nuclear layer (INL) and the Henle fiber layer [1] (outer plexiform layer (OPL) and outer nuclear layer (ONL) [2]). Monthly intravitreal injections of 0.5 mg ranibizumab (lucentis® ) will greatly improve the mean best corrected visual acuity (BCVA) and decrease central foveal thickness (CFT) at the sixth month [3]. On the contrary, CME recurrences occurred sooner, which were more prominent and lasted longer in central retinal vein occlusion (CRVO) [4]. In these researches, CFT becomes a more and more popular index for intravitreal anti-VEGF therapy. But in our clinical practices, we find that the BCVA recovery is not consistent with CFT in some cases. In other words, although the BCVA is improved, CME relapses again. In this study, we try to explain the discrepancy between CFT and BCVA in CME secondary to CRVO, who received anti-VEGF therapy. Case analysis: A 20-year-old female complained of progressive blurred vision in her left eye for one month. Her BCVA was 18/60 in the left eye and 60/60 in the right eye. To establish the diagnosis, the patient received fundus photograph (FP), spectral domain optical coherence tomography (SD-OCT, Spectralis HRA + OCT; Spectralis Acquisition and Viewing Modules, version 5.3.2; Heidelberg Engineering) with horizontal and vertical direction scanning through the fovea, and fluorescein angiography (FA) examinations. The FA indicated that the macular leakage and intravenous dyeing. And then, SD-OCT confirmed the CME extended from INL to ONL. The diagnosis was concluded as inflammatory CRVO complicated with CME, without any systemic pathology. After diagnosis, lucentis® (0.5 mg/0.05 mL) was injected intravitreally, according to ‘‘loading dose’’ protocol, as Kim reported [5]. Next, SD-OCT with ‘‘point to point’’ follow up function was performed to observe the morphological changes of CME and BCVA was also recorded correspondingly. The main measurements included CFT, the mean number of cysts in Henle and INL [cyst (Henle) and cyst (INL)], the mean ratio of cyst and retinal area within radius 1000 m from fovea (C/R1000), the mean length of disrupted
photoreceptor inner/outer segment (disrupted (IS/OS)), as well as the mean number of macular septums within radius 500 m from fovea (MC500) (Fig. 1), measured and calculated using Heidelberg eye explorer and image plus pro 6.0 software. All researches and measurements adhered to the tenets of the Declaration of Helsinki and the study was approved by the Medical Research Ethics Committee of First Hospital of China Medical University. Statistical analysis: All analyses were performed by SPSS version 18.0 (Inc., Chicago, IL). The morphological changes of CME were studied by descriptive statistics. The relationship of the main measurements was compared by Spearmans statistically. A probability (p) value of less than 0.05 was considered statistically significant.
Results At baseline, the CME with large cysts always closed to the fovea. After each injection, CME disappeared or became small, but later on, it relapsed again. CFT had a positive correlation with cyst (Henle) (r = 0.850, p = 0.007 < 0.05), and cyst (INL) (r = 0.964, p < 0.0001). There was a likely tendency that cyst (Henle) reduced relatively, compared to cyst (INL) at each visit (Fig. 2A). BCVA increased after each injection, and then decreased again. But, there was an enhanced and increasing tendency of BCVA at each visit (Table 1). While, the BCVA had a negative relation with MC500 (r = −0.924, p = 0.001 < 0.05), cyst (Henle) (r = −0.876, p = 0.004 < 0.05) and disrupted (IS/OS) (r = −0.778, p = 0.023 < 0.05). Unfortunately, BCVA showed no significant relationship between CFT (R = −0.593, P = 0.121 > 0.05, Fig. 2B), and cyst (INL) (r = −0.569, p = 0.141 > 0.05). The minimum of C/R1000 was decreased gradually (Fig. 2C).
Discussion Large cysts always closed to the fovea, because of the decreased barrier function of synapsis in IPL and OPL near
312
R. Hua et al.
Figure 2 Vision acuity and its influencing factors. (A) The relationship between cyst (Henle) and cyst (INL). Comparing the two red boxes, the cyst (Henle) reduced relatively than cyst (INL). (B) C/R1000 changes. The minimum of C/R1000 was decreased gradually (oblique red arrow). The vertical red arrows showed the injection points, as well as the minimum of C/R1000 points. (Follow up points: baseline: before injection, a: two days after first injection, b: 20 days after first injection, c: one month after first injection, d: 10 days after the second injection, e: 18 days after the second injection, f: 28 days after the second injection, g: 11 days after the third injection.)
Table 1
The discrepancy between BCVA and CFT.
Follow up points
Before injection
Two days after first injection
20 days after first injection
One month 10 days after after first the second injection injection
18 days after the second injection
28 days after the second injection
11 days after the third injection
BCVA CFT (m)
0.3 615.5
0.3 309.5
0.6 363
0.5 633
0.5 443
0.5 566.5
0.8 168.5
fovea, and extracellular fluid accumulation caused by long cone fibers in the larger foveal avascular zone [2]. In the study, obviously, the C/R1000 increased as cysts enlarged, which resulted in increased CFT. The MC500 represented the numbers of cysts partially, so it had a negative relationship with BCVA. We certified the discrepancy between BCVA and CFT. On the one hand, several factors caused CME occurred: blood—retinal barriers (BRB) destroy; dysfunction of Müller cells; Müller cells necrosis; and intraocular inflammation. In addition, it has been reported that Müller cell-derived VEGF causes the pathological permeability of the barrier in the sensory retina under hypoxic or ischemic circumstances [6]. On the other hand, intravitreal lucentis® can modify the course of CRVO, by restoring the integrity of the inner BRBs, and reconstruct tight junction between endothelial cells. The disruption range of IS/OS and edema level may play important roles in BCVA prognosis. Similarly, Deák et al. [7] reported that SRF and large cysts in ONL impacted visual function. While, at baseline, good BCVA was also associated with preservation of the foveal IS/OS, and external limited membrane (ELM) [5]. Moreover, high reflective spots which may be precursors of hard exudates [8], in the cysts in ONL, will invade ELM and IS/OS, resulting in the degeneration and apoptosis of photoreceptor [9]. Additionally, the hydraulic pressure in cysts of ONL will also impact ELM and IS/OS [9]. In this study, the relative reduction of cyst (Henle), and the recovery of IS/OS may attribute to the improvement of BCVA.
0.6 216.5
The minimum of C/R1000 was decreased gradually in our study, showing an inverse trend with BCVA. Marshall et al. [10] has concluded that the integrity of the crosssectional area of retinal tissue between the plexiform layers in CME had a linear relationship with BCVA. So, we infer that intravitreal lucentis® injection may help the visual function, related to the renewal of cells. We propose that the minimum of C/R1000 is more practical than CFT. As a conclusion, we reported the discrepancy between BCVA and CFT, which may due to the decreased cyst (Henle), the minimum of C/R1000 and the recovery of IS/OS, which may contribute to understanding of the pathological changes in CME. There were also several limitations. For example, we did not consider choroidal ischemia for CME. We will improve our methods in further prospective treatment trials. Conflict of interest statement There were no conflicts of financial interest for this study. Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Acknowledgments We thank Prof. Na Cai, and Dr. Limin Liu, for assistance with diagnoses, treatment, and follow-up in the Department of Ophthalmology at the First Hospital of China Medical University.
Discrepancy between central foveal thickness and BCVA
References [1] Antcliff RJ, Marshall J. The pathogenesis of edema in diabetic maculopathy. Semin Ophthalmol 1999;14:223—32. [2] Byeon SH, Chu YK, Hong YT, Kim M, Kang HM, Kwon OW. New insights into the pathoanatomy of diabetic macular edema: angiographic patterns and optical coherence tomography. Retina 2012;32:1087—99. [3] Garnock-Jones KP. Ranibizumab: in macular oedema following retinal vein occlusion. Drugs 2011;71:455—63. [4] Karagiannis DA, Karampelas MD, Soumplis VM, Amariotakis C, Georgalas I, Kandarakis A. Recurrence of macular edema in retinal vein occlusions after treatment with intravitrealranibizumab (Lucentis). Can J Ophthalmol 2011;46:486—90. [5] Kim M, Yu SY, Kim ES, Bae SH, Park JH, Yu HG, et al. Intravitrealranibizumab for macular edema secondary to retinal vein occlusion. Ophthalmologica 2012;227:132—8.
313 [6] Bringmann A, Reichenbach A, Wiedemann P. Pathomechanisms of cystoid macular edema. Ophthalmic Res 2004;36:241—9. [7] Deák GG, Bolz M, Ritter M, Prager S, Benesch T, SchmidtErfurth U. A systematic correlation between morphology and functional alterations in diabetic macular edema. Invest Ophthalmol Vis Sci 2010;51:6710—4. [8] Helmy YM, Allah HR. Optical coherence tomography classification of diabetic cystoid macular edema. Clin Ophthalmol 2013;7:1731—7. [9] Uji A, Murakami T, Nishijima K. Association between hyperreflective foci in the outer retina, status of photoreceptor layer, and visual acuity in diabetic macular edema. Am J Ophthalmol 2012;153:710—7. [10] Pelosini L, Hull CC, Boyce JF, McHugh D, Stanford MR, Marshall J. Optical coherence tomography may be used to predict visual acuity in patients with macular edema. Invest Ophthalmol Vis Sci 2011;52:2741—8.
