MACULAR AND PERIPAPILLARY SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY CHANGES IN SICKLE CELL RETINOPATHY FABIANA BRASILEIRO, MD,* THAYZE T. MARTINS, MD,* SILVIO B. CAMPOS, MD, MSC,* JOÃO L. ANDRADE NETO, MD,* VASCO T. BRAVO-FILHO, MD,* ADERSON S. ARAÚJO, MD, PHD,† TIAGO E. ARANTES, MD, PHD* Purpose: To assess peripapillary retinal nerve fiber layer, macular ganglion cell complex, and total macular thicknesses using spectral domain optical coherence tomography on sickle cell disease patients with and without sickle retinopathy. Method: Nineteen eyes of 11 patients with hemoglobin SC disease, 65 eyes of 36 patients with hemoglobin SS disease, and 48 eyes of 24 healthy subjects underwent spectral domain optical coherence tomography scanning (RTVue). Eyes of patients with sickle cell disease were classified into 3 groups according to posterior segment changes: no retinopathy (n = 64), nonproliferative retinopathy (n = 12), and proliferative retinopathy (n = 8). Results: The central fovea in eyes with proliferative retinopathy was thickened compared with control group, sickle cell disease without retinopathy, and nonproliferative retinopathy (P = 0.004); a difference between proliferative retinopathy and sickle cell disease without retinopathy groups was still present after age adjustment (P = 0.014). Eyes with proliferative changes showed higher ganglion cell complex focal loss of volume compared with control group (P = 0.002), even after age adjustment (P = 0.004). Thinning of the nasal retinal nerve fiber layer quadrant was observed in eyes with proliferative retinopathy (P , 0.001); however, no retinal nerve fiber layer thickness difference was observed after age correction (P . 0.05). Conclusion: Peripheral changes secondary to proliferative sickle retinopathy were associated with thinning of macular inner retinal layers and thickening of central fovea. RETINA 35:257–263, 2015
S
sickle hemoglobin. Individuals affected with other types of SCD are compound heterozygotes. They possess one copy of the HbS variant and one copy of another b-globin gene variant, such as HbC or Hbbthalassemia.2 The major sight-threatening complication of SCD is proliferative sickle cell retinopathy, which results from occlusion of the peripheral retinal vascularization with consequent ischemia and neovascularization.1 However, structural macular changes may occur as a result of macular ischemia and have also been documented, including abnormal perfusion, epiretinal membranes, schisis, holes, and less commonly, posterior pole neovascularization.3–5 Recently, spectral domain optical coherence tomography (SD-OCT) studies demonstrated subclinical sectoral thinning of the peripapillary
ickle cell disease (SCD) is one of the most prevalent genetic disorders worldwide and encompasses a group of diseases characterized by the presence of hemoglobin S (HbS), which results from a single point mutation that substitutes valine for glutamic acid at the sixth position of the b-globin chain.1,2 Individuals who are affected with sickle cell anemia have two copies of this variant (HbSS), and the primary hemoglobin present in their erythrocytes is From the *Fundação Altino Ventura, Recife, Brazil; and †Fundação Hemope, Recife, Brazil. Supported by Institutional Funding (Fundação Altino Ventura, Recife, Brazil). None of the authors have any conflicting interests to disclose. Reprint requests: Tiago E. Arantes, MD, PhD, Fundação Altino Ventura, Rua da Soledade, 170, Recife 50070-040, Pernambuco, Brazil; e-mail: [email protected]
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retinal nerve fiber layer (RNFL),6 foveal thinning, and splaying, as well as thinning in the temporal parafoveal region, even in patients without proliferative disease.7–9 The focally thinned areas in the macula correlate with decreased retinal sensitivities by microperimetry.8 The purpose of this study was to assess peripapillary RNFL thickness, macular ganglion cell complex (GCC) thickness, and total macular thickness using SD-OCT on SCD patients with and without sickle cell retinopathy.
Methods This comparative case series included patients recruited from the Hemoglobinopathies Clinic of Fundação Hemope, Recife, Brazil with electrophoretic confirmation of sickle cell anemia (HbSS), sickle cell hemoglobin C disease (HbSC), or sickle cell thalassemia (HbS-thal) examined between August and December 2012 in Fundação Altino Ventura, Recife, Brazil. Healthy patients who came to the clinic for routine eye examinations and were without ocular diseases served as controls. The Ethics Committee of Fundação Altino Ventura approved the study, and informed consent was obtained from all subjects. Each participant underwent an ophthalmologic evaluation that included best-corrected visual acuity measurement, slit-lamp evaluation, indirect ophthalmoscopy, intraocular pressure measurement, and SDOCT scanning. All examinations for an individual study participant were performed on the same day. Data from both eyes of each participant were used for the analyses, unless there were ocular abnormalities that could affect visual function in one eye. Inclusion criteria were as follows: age 18 years or older, best-corrected visual acuity of 20/25 or better, clear media, spherical refractive error of 0 ± 4.0 diopters (D) and astigmatism of 0 ± 2.5 D, and normal intraocular pressure (,22 mmHg). Patients with diabetes mellitus, uncontrolled systemic hypertension, glaucoma, eyes with previous retinal photocoagulation or cryotherapy, or clinical evidence of any other maculopathy not associated with SCD were excluded from this study. Participants were also excluded if they had any risk factors for development of glaucoma or other eye diseases (such as previous intraocular surgery, previous ocular trauma, and retinal or neurologic abnormalities) that could affect OCT measurements. The eyes of patients with SCD were classified into three groups according to the presence of posterior segment changes: no retinopathy, nonproliferative retinopathy, and proliferative retinopathy. The nonproliferative retinopathy group included eyes with
salmon patches, iridescent spots, and/or black sunbursts; other nonproliferative changes such as peripheral whitening of the retina and vessel tortuosity were not considered in the classification, as they are frequent in non-SCD individual and their interpretation are complicated by the lack of precise definitions. Eyes with Stages I, II, III, IV, and V of Goldberg’s Proliferative Sickle Cell Retinopathy Classification10 were included in the proliferative retinopathy group. Fluorescein angiography was not systematically performed for all patients but was used in cases of doubtful diagnosis of proliferative sickle cell retinopathy and for patients with Stage III disease or worse. Optical coherence tomography was performed using RTVue OCT (Optovue Inc, Fremont, CA). All patients underwent standard optic nerve head, GCC, and macular protocols on the same day, which included ONH, GCC, and EMM5 protocols. Only scans with a signal strength index $45, proper centering, and no evidence of segmentation algorithm failure were included in the analysis. Briefly, the ONH map protocol consists of 12 radial scans, each 3.4 mm in length, and 13 concentric ring scans ranging from 1.3 mm to 4.9 mm in diameter, all centered on the optic disk. After image processing, a peripapillary RNFL thickness map of the 3.45-mm diameter ring and parameters describing optic disk features are provided. The map provides the average RNFL thickness in the temporal, superior, nasal, and inferior quadrants, as well as the overall average along the entire measurement circle.11 In the current investigation, the following software-provided parameters were evaluated: average RNFL thickness in the 4 quadrants and global average RNFL thickness (360° measure). The GCC protocol consists of a horizontal line with a 7-mm scan length, followed by 15 vertical line scans of a 0.5-mm interval covering a 7-mm square region. The GCC scan centers at 1 mm temporal to fovea center for better coverage of the temporal region. Ganglion cell complex thickness is defined by the distance from internal limiting membrane to outer inner plexiform layer, which composes the inner 3 layers of the retina: nerve fiber layer, ganglion cell layer, and inner plexiform layer. The OCTs are processed automatically to provide a thickness map of the GCC, and also a deviation from normal and significance map based on an age-adjusted normative database. Focal loss volume (FLV) is a new parameter that provides a quantitative measure for the amount of significant GCC loss. Focal loss volume is the total sum of significant GCC loss (in volume) divided by the map area. As such, it provides a percent of significant tissue loss for volume. Global loss volume (GLV) is the sum of the pixels, where the fractional
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OCT IN SICKLE CELL RETINOPATHY BRASILEIRO ET AL Table 1. Presence of Proliferative and Nonproliferative Retinopathy in Eyes (n) of Patients With SCD Control (n = 24 Patients)
HbSC (n = 11 Patients)
HbSS (n = 36 Patients)
P
31.9 ± 7.6
42.2 ± 15.5*
27.8 ± 8.7
0.001† 0.066‡
12 (50.0%) 12 (50.0%)
1 (9.1%) 10 (90.9%)
15 (41.7%) 21 (58.3%)
Age (mean ± SD), years Gender, n (%) Male Female
*Statistically different from control and HbSS groups. †Analysis of variance test. ‡Fisher–Freeman–Halton test.
deviation map value is ,0, divided by the total area to give a percent loss of GCC thickness.11 The following parameters were evaluated: superior GCC, inferior GCC, average GCC, GCC FLV, and GCC GLV. The EMM5 scan protocol consists of a grid-like scanning pattern with an outer 6 mm · 6 mm area with 13 horizontal and 13 vertical scans of a 0.5-mm interval and an inner 4 mm · 4 mm area with 8 horizontal and vertical scans of a 0.5-mm interval. This scan protocol provides a pixel by pixel significance map and nine parameters from a circular grid based on the Early Treatment Diabetic Retinopathy Study.11 The retinal thickness of each of the nine subfields of the Early Treatment Diabetic Retinopathy Study–like map was recorded. Statistical analyses were performed using the software SPSS 16.0 for Windows (SPSS, Inc, Chicago, IL). Categorical data were analyzed using the Freeman–Halton extension of the Fisher’s exact test. Differences of retinal thickness measurements between groups were analyzed by generalized estimating equation models, performed to account for correlations between the two eyes of the same participant. Because the SCD group with proliferative changes was significantly older than the other groups, generalized estimating equation models including age as covariate were also performed. Bonferroni correction for multiple comparisons was performed to analyze pair-wise differences. A P-value ,0.05 was considered statistically significant. Results The study included 48 eyes of 24 patients without SCD (controls), 19 eyes of 11 patients with HbSC Table 2. Macular Thickness in Eyes (n) of Patients With SCD and Control Subjects HbSC (n = 19 Eyes HbSS (n = 65 Eyes of 11 Patients) of 36 Patients) No retinopathy Nonproliferative retinopathy Proliferative retinopathy
13 (68.4%) 0 (0.0%)
51 (78.5%) 12 (18.5%)
6 (31.6%)
2 (3.1%)
disease, and 65 eyes of 36 patients with HbSS disease. Three patients with HbSC and 7 patients with HbSS disease had 1 eye meeting exclusion criteria (previous retinal photocoagulation, n = 4; previous intraocular surgery, n = 3; macular epiretinal membrane, n = 2; macular lamellar hole, n = 1) and had only 1 eye included in the analysis. Two eyes with no signs of retinopathy had signal strength index ,45 on OCTs and were not included in retinal measurements analysis. The mean age ± SD was 31.9 ± 7.6 years in the control group, 42.2 ± 15.5 years in the HbSC group, and 27.8 ± 8.7 years in the HbSS group, with a significant difference for HbSC patients compared with controls and HbSS patients (P , 0.001). Twelve (50.0%) patients in the control group, 10 (90.9%) in the HbSC group, and 21 (58.3%) in the HbSS group were female, with no statistical difference in gender distribution between groups (P = 0.066; Table 1). Distribution according to the presence of posterior segment changes and SCD genotypes is shown in Table 2. Eyes with proliferative retinopathy were from patients with SCD significantly older in comparison with the control group, SCD without retinopathy, and SCD with nonproliferative changes (mean ± SD, 31.9 ± 7.6 years, 28.1 ± 8.7 years, 30.0 ± 9.1 years, and 46.0 ± 11.2 years, respectively for the control group, SCD without retinopathy, SCD with nonproliferative changes, and SCD with proliferative changes; P = 0.002). No statistical difference in gender distribution was observed between the control and SCD retinopathy groups (P = 0.088). Table 3 shows macular thickness measurement estimates in eyes from the 4 study groups. The mean central foveal thickness in eyes with proliferative retinopathy was significantly increased in comparison with eyes of the control group, SCD without retinopathy, and SCD with nonproliferative changes (P = 0.004). After adjustment for age, the central fovea of eyes with proliferative retinopathy was still significantly thicker than in the SCD without retinopathy group (P = 0.014). Cystoid spaces or convex contour in the fovea were not seen in the studied patients. There were no significant differences in the macular
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RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2015 VOLUME 35 NUMBER 2 Table 3. Ganglion Cell Complex in Eyes (n) of Patients With SCD and Control Subjects
Central macula Temporal inner Superior inner Nasal inner Inferior inner Temporal outer Superior outer Nasal outer Inferior outer
Control Group (n = 48)
SCD Without Retinopathy (n = 62)
SCD With Nonproliferative Retinopathy (n = 12)
SCD With Proliferative Retinopathy (n = 8)
P
235.60 ± 3.22
230.41 ± 3.55
235.36 ± 4.09
250.97 ± 5.17*
0.004
297.61 ± 2.99
295.83 ± 2.25
298.95 ± 3.42
302.90 ± 8.02
0.585
316.38 ± 2.37
315.41 ± 2.69
316.64 ± 3.38
314.39 ± 7.07
0.944
313.36 ± 3.01
314.56 ± 2.95
311.57 ± 2.99
314.43 ± 5.07
0.631
308.76 ± 3.77
311.65 ± 2.41
315.53 ± 3.50
319.56 ± 5.89
0.195
278.51 ± 2.78
276.07 ± 2.25
273.42 ± 4.67
269.96 ± 7.97
0.652
289.69 ± 2.40
290.72 ± 1.78
292.07 ± 2.36
287.61 ± 3.79
0.751
304.58 ± 2.66
304.17 ± 2.11
303.43 ± 2.40
299.90 ± 3.07
0.624
278.78 ± 3.52
281.17 ± 2.12
283.66 ± 3.79
284.89 ± 5.88
0.711
Values are expressed in micrometers as mean ± standard error (estimated by generalized estimating equation models adjusted for within-patient intereye correlations). *Statistically different from control, SCD without retinopathy, and SCD with nonproliferative retinopathy groups (P , 0.05; Bonferroni correction for multiple comparisons).
thickness measurements of the other subfield areas of the Early Treatment Diabetic Retinopathy Study–like map (P . 0.05). There was no difference in average, superior, and inferior subfield GCC thickness between the studied groups (P . 0.05). However, eyes with proliferative changes showed higher mean GCC GLV values compared with eyes of the control group, SCD without retinopathy, and SCD with nonproliferative changes (P = 0.027); nevertheless, after age adjustment, this difference was not statistically significant (P = 0.156). Ganglion cell complex FLV in comparison with the control group was also higher (P = 0.002), and this difference remained significant after age adjustment (P = 0.004), indicating thinning of inner retinal layers, which were consistently localized temporally to the fovea as seen in Figures 1 and 2. Ganglion cell complex FLV results outside the device Fig. 1. Spectral domain optical coherence horizontal B-scan (A) and GCC significance map (B) of the right eye of a sickle cell HbSC patient with proliferative sickle cell retinopathy. Focal thinning of inner retinal layers temporal to the fovea is seen as an abrupt asymmetric decrease in retinal thickness, as indicated by the arrows in the B-scan and the red area in the GCC significance map.
normative database (95% confidence limits) were seen in 2 eyes of the control group (4.2%), 20 eyes of SCD patients without retinopathy (32.3%), 3 eyes with nonproliferative changes (25.0%), and 6 eyes with proliferative retinopathy (75.0%), with a significant higher frequency of abnormal FLV results in eyes with proliferative changes (P , 0.001). Ganglion cell complex parameter estimates are presented in Table 4. There was no statistically significant difference in the average RNFL thickness between the studied groups (P = 0.145 and P = 0.258, respectively for the model adjusted for intereye correlations and for the model adjusted for intereye correlations and age). Analysis of RNFL thickness by quadrants adjusted for within-patient intereye correlations revealed significant thinning of the nasal RNFL in eyes with proliferative retinopathy when compared with the other groups (P , 0.001). However, after adjustment for
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Fig. 2. Spectral domain optical coherence horizontal B-scan (A) and GCC significance map (B) of the right eye of a HbSS patient with proliferative sickle cell retinopathy. Focal thinning of inner retinal layers temporal to the fovea is seen as an abrupt asymmetric decrease in retinal thickness, as indicated by the arrows in the B-scan and the red area in the GCC significance map.
age, no RNFL variables differed between groups (P . 0.005). Table 5 shows RNFL thickness measurements estimates from the 4 studied groups.
Discussion Although findings of sickle retinopathy are primarily found in the periphery, structural changes from macular infarctions in sickle cell hemoglobinopathies have been documented using fluorescein angiography, electroretinography, OCT, and histopathology.3–5,12,13 The temporal horizontal raphe is an imaginary line extending temporally from the center of the macula to the periphery of the retina. Terminal arteriolar branches comparable with the terminal arteriolar tree in the retinal periphery supply this area. Just as terminal arterioles become occluded in the periphery of the retina of patients with SCD, the same process tends to occur in the anatomically comparable areas of the macula.5,14 Incidence of proliferative sickle cell retinopathy and its severity increases with age, and the disease is more frequent in heterozygous (HbSC) patients.15,16 As expected, in our study, eyes with proliferative changes were from older patients and mostly from HbSC individuals. Previous reports demonstrated thinning of the outer retina in the central foveal subfield and in the temporal parafoveal regions of patients with SCD when compared with the age-matched controls. However, in this
study, we found sectoral thinning of the inner retinal layers demonstrated by higher FLV and GLV values in eyes with proliferative sickle cell retinopathy. These indices are automatically generated by OCT device and represents, respectively, focal and global loss of the GCC in the inner retina (nerve fiber layer, ganglion cell layer, and inner plexiform layer). Global loss volume measures the average amount of GCC loss over the entire GCC map, and FLV detects focal loss using a pattern deviation map to correct for the overall absolute changes, similar to corrected pattern standard deviation in the visual fields. Likewise, GLV is comparable with mean deviation in visual fields.11 Thinning of inner retinal layers in symptomatic and asymptomatic sickle cell retinopathy patients has also been reported in previous case reports and case series.7,17,18 Histopathologic studies of SCD patients with vasoocclusive diseases have also shown atrophy and thinning of the inner retinal layers.12 Our findings confirm that ischemia occurs both in the central and peripheral retinal regions of patients with SCD and suggest that the same mechanisms that lead to proliferative sickle cell retinopathy (occlusion of retinal microvasculature and ischemia) are also responsible for structural macular changes. Patients with proliferative retinopathy also presented thickening of the central macular subfield. This could be associated with a rearrangement of the macular structure associated with thinning of inner retinal layers
Table 4. Retinal Nerve Fiber Layer Thickness in Eyes (n) of Patients With SCD and Control Subjects Control Group SCD Without (n = 48) Retinopathy (n = 62) Average GCC Superior GCC Inferior GCC FLV GLV
96.85 96.99 96.97 0.87 4.09
± ± ± ± ±
1.38 1.34 1.56 0.27 0.82
98.09 97.08 99.06 1.80 4.19
± ± ± ± ±
1.07 1.08 1.17 0.29 0.63
SCD With Nonproliferative Retinopathy (n = 12) 97.82 98.38 97.38 1.84 4.16
± ± ± ± ±
1.37 1.20 1.90 0.71 0.87
SCD With Proliferative Retinopathy (n = 8) 95.94 93.62 98.20 5.05 8.86
± ± ± ± ±
5.04 4.97 5.08 1.19* 1.48†
P 0.887 0.570 0.544 0.002 0.027
Values are expressed in micrometers as mean ± standard error (estimated by generalized estimating equation models adjusted for within-patient intereye correlations). *Statistically different from control group (P , 0.05; Bonferroni correction for multiple comparisons). †Statistically different from control, SCD without retinopathy, and SCD with nonproliferative retinopathy groups (P , 0.05; Bonferroni correction for multiple comparisons).
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RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2015 VOLUME 35 NUMBER 2 Table 5. Retinal Nerve Fiber Layer Thickness in Eyes (n) of Patients With SCD and Control Subjects Control Group (n = 48)
Average 111.62 ± 2.19 Temporal 78.72 ± 1.98 Superior 131.14 ± 3.00 Nasal 88.65 ± 2.47 Inferior 147.65 ± 4.35
SCD Without Retinopathy (n = 62) 118.65 82.43 143.40 88.56 159.70
± ± ± ± ±
SCD With Nonproliferative Retinopathy (n = 12)
2.38 1.77 3.54 2.57 3.91
118.97 82.96 142.79 91.85 159.12
± ± ± ± ±
2.97 2.77 4.48 3.07 5.27
SCD With Proliferative Retinopathy (n = 8) 112.94 94.47 135.28 74.14 144.99
± ± ± ± ±
5.79 11.23 9.03 2.87* 4.89
P 0.145 0.294 0.053 ,0.001 0.057
Values are expressed in micrometers as mean ± standard error (estimated by GEE models adjusted for within-patient intereye correlations). *Statistically different from control, SCD without retinopathy, and SCD with nonproliferative retinopathy groups (P , 0.05; Bonferroni correction for multiple comparisons).
adjacent to the fovea. Thickening of central macula is also observed in the acute stage of central retinal artery occlusion. Ganglion cells are absent within the fovea but clustered at the foveal margin; it is speculated that the ischemic insult in these patients could lead to sequential displacement of neuronal cells toward the fovea and consequent derangement of foveal contour and increase in the central macular thickness.19 A similar mechanism could explain the central macular thickening in patients with proliferative retinopathy. The functional consequences of macular changes are uncertain. Loss of central visual function is variable,5 and no close relationship exists between the extent of macular vascular changes and visual acuity.3,20 Both abnormal color vision and central scotomas have also been reported with SCD.21,22 In a recent study, a strong correlation between the retinal sensitivities on microperimetry and presence of focal macular thinning on SD-OCT was found in patients with SCD.8 In addition to focal GCC thinning, eyes with proliferative retinopathy presented thinner RNFL in the nasal quadrant; however, in the age-adjusted statistical analysis, this difference was not statistically significant. Thinning of the peripapillary RNFL in this quadrant had previously been reported in SCD patients with decreased macular thickness.6 Peripapillary RNFL thinning may be a result of thinning and atrophy of the inner retinal layers of the macula and has also been observed to occur in other types of retinal vasculopathies, including diabetes, retinal artery occlusion, and HIV microvasculopathy.23–25 However, blood vessels make a direct contribution to the OCT RNFL thickness,26 and retinal vessels tortuosity and dilatation in patients with SCD may have prevented the detection of RNFL thinning in other peripapillary sectors. Potential limitations of this study might have affected our results. Wide-field fluorescein angiography was not routinely performed, which may have led to misclassifications of sickle cell retinopathy. It should also be noted that GLV and FLV indices are based on manufacturer’s normative data, and subtle changes may not represent
true variations. Different OCT devices and analysis algorithms have also been used in the studies evaluating macular structural changes of patients with SCD and their results are not directly comparable.6–9,17,18 Another limitation is that measurements obtained from both eyes of an individual are often correlated; to avoid this potential bias, generalized estimating equation models were used to account for between-eye correlations.27 In this study, we also analyzed a large number of retinal thickness parameters; this may have increased the chance of a Type I error during hypothesis testing, and some of the differences detected may have occurred just by chance. In conclusion, peripheral proliferative sickle cell retinopathy changes were associated with thinning of macular inner retinal layers and thickening of the central foveal subfield. Further investigation is required to assess the relations between changes in retinal structure and visual function in patients with SCD and also longitudinal changes over time. Retinal evaluation by SD-OCT provides valuable information in patients with SCD; these findings should be taken into account when interpreting retinal SD-OCT for other ocular disorders in these patients, and changes detected by macular and peripapillary scans should prompt a meticulous evaluation of the peripheral retina to search for evidence of ischemia and proliferative retinopathy. Key words: sickle cell disease, retina, optic nerve, optical coherence tomography. Acknowledgment The authors would like to thank Leandro Lucena, MSc, for his assistance with statistical analysis. References 1. Elagouz M, Jyothi S, Gupta B, Sivaprasad S. Sickle cell disease and the eye: old and new concepts. Surv Ophthalmol 2010;55:359–377. 2. Ashley-Koch A, Yang Q, Olney RS. Sickle hemoglobin (Hb S) allele and sickle cell disease: a HuGE review. Am J Epidemiol 2000;151:839–845.
OCT IN SICKLE CELL RETINOPATHY BRASILEIRO ET AL 3. Goldberg MF, Galinos S, Lee CB, et al. Editorial: macular ischemia and infarction in sickling. Invest Ophthalmol 1973; 12:633–635. 4. Asdourian GK, Nagpal KC, Busse B, et al. Macular and perimacular vascular remodelling sickling haemoglobinopathies. Br J Ophthalmol 1976;60:431–453. 5. Stevens TS, Busse B, Lee CB, et al. Sickling hemoglobinopathies; macular and perimacular vascular abnormalities. Arch Ophthalmol 1974;92:455–463. 6. Chow CC, Shah RJ, Lim JI, et al. Peripapillary retinal nerve fiber layer thickness in sickle-cell hemoglobinopathies using spectral-domain optical coherence tomography. Am J Ophthalmol 2013;155:456–464. 7. Murthy RK, Grover S, Chalam KV. Temporal macular thinning on spectral-domain optical coherence tomography in proliferative sickle cell retinopathy. Arch Ophthalmol 2011;129:247–249. 8. Chow CC, Genead MA, Anastasakis A, et al. Structural and functional correlation in sickle cell retinopathy using spectraldomain optical coherence tomography and scanning laser ophthalmoscope microperimetry. Am J Ophthalmol 2011;152: 704–711. 9. Hoang QV, Chau FY, Shahidi M, Lim JI. Central macular splaying and outer retinal thinning in asymptomatic sickle cell patients by spectral-domain optical coherence tomography. Am J Ophthalmol 2011;151:990–994. 10. Goldberg MF. Classification and pathogenesis of proliferative sickle retinopathy. Am J Ophthalmol 1971;71:649–665. 11. RTVue User’s Manual Version 4.0. Fremont, CA: Optovue Inc; 2009. 12. Romayanada N, Goldberg MF, Green WR. Histopathology of sickle cell retinopathy. Trans Am Acad Ophthalmol Otolaryngol 1973;77:OP642–OP676. 13. Acacio I, Goldberg MF. Peripapillary and macular vessel occlusions in sickle cell anemia. Am J Ophthalmol 1973;75:861–866. 14. Nagpal KC, Goldberg MF, Rabb MF. Ocular manifestations of sickle hemoglobinopathies. Surv Ophthalmol 1977;21:391–411. 15. Leveziel N, Bastuji-Garin S, Lalloum F, et al. Clinical and laboratory factors associated with the severity of proliferative sickle cell retinopathy in patients with sickle cell hemoglobin C
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(SC) and homozygous sickle cell (SS) disease. Medicine (Baltimore) 2011;90:372–378. Downes SM, Hambleton IR, Chuang EL, et al. Incidence and natural history of proliferative sickle cell retinopathy: observations from a cohort study. Ophthalmology 2005;112:1869–1875. Shakoor A, Blair NP, Shahidi M. Imaging retinal depression sign in sickle cell anemia using optical coherence tomography and the retinal thickness analyzer. Arch Ophthalmol 2005;123: 1278–1279. Witkin AJ, Rogers AH, Ko TH, et al. Optical coherence tomography demonstration of macular infarction in sickle cell retinopathy. Arch Ophthalmol 2006;124:746–747. Chen SN, Hwang JF, Chen YT. Macular thickness measurements in central retinal artery occlusion by optical coherence tomography. Retina 2011;31:730–737. Marsh RJ, Ford SM, Rabb MF, et al. Macular vasculature, visual acuity, and irreversibly sickled cells in homozygous sickle cell disease. Br J Ophthalmol 1982;66:155–160. Roy MS, Rodgers G, Gunkel R, et al. Color vision defects in sickle cell anemia. Arch Ophthalmol 1987;105:1676–1678. Lee CM, Charles HC, Smith RT, et al. Quantification of macular ischaemia in sickle cell retinopathy. Br J Ophthalmol 1987;71:540–545. Park HY, Kim IT, Park CK. Early diabetic changes in the nerve fibre layer at the macula detected by spectral domain optical coherence tomography. Br J Ophthalmol 2011;95:1223–1228. Leung CK, Tham CC, Mohammed S, et al. In vivo measurements of macular and nerve fibre layer thickness in retinal arterial occlusion. Eye (Lond) 2007;21:1464–1468. Arantes TE, Garcia CR, Tavares IM, et al. Relationship between retinal nerve fiber layer and visual field function in human immunodeficiency virus-infected patients without retinitis. Retina 2012;32:152–159. Hood DC, Fortune B, Arthur SN, et al. Blood vessel contributions to retinal nerve fiber layer thickness profiles measured with optical coherence tomography. J Glaucoma 2008;17:519–528. Karakosta A, Vassilaki M, Plainis S, et al. Choice of analytic approach for eye-specific outcomes: one eye or two? Am J Ophthalmol 2012;153:571–579.
S
sickle hemoglobin. Individuals affected with other types of SCD are compound heterozygotes. They possess one copy of the HbS variant and one copy of another b-globin gene variant, such as HbC or Hbbthalassemia.2 The major sight-threatening complication of SCD is proliferative sickle cell retinopathy, which results from occlusion of the peripheral retinal vascularization with consequent ischemia and neovascularization.1 However, structural macular changes may occur as a result of macular ischemia and have also been documented, including abnormal perfusion, epiretinal membranes, schisis, holes, and less commonly, posterior pole neovascularization.3–5 Recently, spectral domain optical coherence tomography (SD-OCT) studies demonstrated subclinical sectoral thinning of the peripapillary
ickle cell disease (SCD) is one of the most prevalent genetic disorders worldwide and encompasses a group of diseases characterized by the presence of hemoglobin S (HbS), which results from a single point mutation that substitutes valine for glutamic acid at the sixth position of the b-globin chain.1,2 Individuals who are affected with sickle cell anemia have two copies of this variant (HbSS), and the primary hemoglobin present in their erythrocytes is From the *Fundação Altino Ventura, Recife, Brazil; and †Fundação Hemope, Recife, Brazil. Supported by Institutional Funding (Fundação Altino Ventura, Recife, Brazil). None of the authors have any conflicting interests to disclose. Reprint requests: Tiago E. Arantes, MD, PhD, Fundação Altino Ventura, Rua da Soledade, 170, Recife 50070-040, Pernambuco, Brazil; e-mail: [email protected]
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retinal nerve fiber layer (RNFL),6 foveal thinning, and splaying, as well as thinning in the temporal parafoveal region, even in patients without proliferative disease.7–9 The focally thinned areas in the macula correlate with decreased retinal sensitivities by microperimetry.8 The purpose of this study was to assess peripapillary RNFL thickness, macular ganglion cell complex (GCC) thickness, and total macular thickness using SD-OCT on SCD patients with and without sickle cell retinopathy.
Methods This comparative case series included patients recruited from the Hemoglobinopathies Clinic of Fundação Hemope, Recife, Brazil with electrophoretic confirmation of sickle cell anemia (HbSS), sickle cell hemoglobin C disease (HbSC), or sickle cell thalassemia (HbS-thal) examined between August and December 2012 in Fundação Altino Ventura, Recife, Brazil. Healthy patients who came to the clinic for routine eye examinations and were without ocular diseases served as controls. The Ethics Committee of Fundação Altino Ventura approved the study, and informed consent was obtained from all subjects. Each participant underwent an ophthalmologic evaluation that included best-corrected visual acuity measurement, slit-lamp evaluation, indirect ophthalmoscopy, intraocular pressure measurement, and SDOCT scanning. All examinations for an individual study participant were performed on the same day. Data from both eyes of each participant were used for the analyses, unless there were ocular abnormalities that could affect visual function in one eye. Inclusion criteria were as follows: age 18 years or older, best-corrected visual acuity of 20/25 or better, clear media, spherical refractive error of 0 ± 4.0 diopters (D) and astigmatism of 0 ± 2.5 D, and normal intraocular pressure (,22 mmHg). Patients with diabetes mellitus, uncontrolled systemic hypertension, glaucoma, eyes with previous retinal photocoagulation or cryotherapy, or clinical evidence of any other maculopathy not associated with SCD were excluded from this study. Participants were also excluded if they had any risk factors for development of glaucoma or other eye diseases (such as previous intraocular surgery, previous ocular trauma, and retinal or neurologic abnormalities) that could affect OCT measurements. The eyes of patients with SCD were classified into three groups according to the presence of posterior segment changes: no retinopathy, nonproliferative retinopathy, and proliferative retinopathy. The nonproliferative retinopathy group included eyes with
salmon patches, iridescent spots, and/or black sunbursts; other nonproliferative changes such as peripheral whitening of the retina and vessel tortuosity were not considered in the classification, as they are frequent in non-SCD individual and their interpretation are complicated by the lack of precise definitions. Eyes with Stages I, II, III, IV, and V of Goldberg’s Proliferative Sickle Cell Retinopathy Classification10 were included in the proliferative retinopathy group. Fluorescein angiography was not systematically performed for all patients but was used in cases of doubtful diagnosis of proliferative sickle cell retinopathy and for patients with Stage III disease or worse. Optical coherence tomography was performed using RTVue OCT (Optovue Inc, Fremont, CA). All patients underwent standard optic nerve head, GCC, and macular protocols on the same day, which included ONH, GCC, and EMM5 protocols. Only scans with a signal strength index $45, proper centering, and no evidence of segmentation algorithm failure were included in the analysis. Briefly, the ONH map protocol consists of 12 radial scans, each 3.4 mm in length, and 13 concentric ring scans ranging from 1.3 mm to 4.9 mm in diameter, all centered on the optic disk. After image processing, a peripapillary RNFL thickness map of the 3.45-mm diameter ring and parameters describing optic disk features are provided. The map provides the average RNFL thickness in the temporal, superior, nasal, and inferior quadrants, as well as the overall average along the entire measurement circle.11 In the current investigation, the following software-provided parameters were evaluated: average RNFL thickness in the 4 quadrants and global average RNFL thickness (360° measure). The GCC protocol consists of a horizontal line with a 7-mm scan length, followed by 15 vertical line scans of a 0.5-mm interval covering a 7-mm square region. The GCC scan centers at 1 mm temporal to fovea center for better coverage of the temporal region. Ganglion cell complex thickness is defined by the distance from internal limiting membrane to outer inner plexiform layer, which composes the inner 3 layers of the retina: nerve fiber layer, ganglion cell layer, and inner plexiform layer. The OCTs are processed automatically to provide a thickness map of the GCC, and also a deviation from normal and significance map based on an age-adjusted normative database. Focal loss volume (FLV) is a new parameter that provides a quantitative measure for the amount of significant GCC loss. Focal loss volume is the total sum of significant GCC loss (in volume) divided by the map area. As such, it provides a percent of significant tissue loss for volume. Global loss volume (GLV) is the sum of the pixels, where the fractional
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OCT IN SICKLE CELL RETINOPATHY BRASILEIRO ET AL Table 1. Presence of Proliferative and Nonproliferative Retinopathy in Eyes (n) of Patients With SCD Control (n = 24 Patients)
HbSC (n = 11 Patients)
HbSS (n = 36 Patients)
P
31.9 ± 7.6
42.2 ± 15.5*
27.8 ± 8.7
0.001† 0.066‡
12 (50.0%) 12 (50.0%)
1 (9.1%) 10 (90.9%)
15 (41.7%) 21 (58.3%)
Age (mean ± SD), years Gender, n (%) Male Female
*Statistically different from control and HbSS groups. †Analysis of variance test. ‡Fisher–Freeman–Halton test.
deviation map value is ,0, divided by the total area to give a percent loss of GCC thickness.11 The following parameters were evaluated: superior GCC, inferior GCC, average GCC, GCC FLV, and GCC GLV. The EMM5 scan protocol consists of a grid-like scanning pattern with an outer 6 mm · 6 mm area with 13 horizontal and 13 vertical scans of a 0.5-mm interval and an inner 4 mm · 4 mm area with 8 horizontal and vertical scans of a 0.5-mm interval. This scan protocol provides a pixel by pixel significance map and nine parameters from a circular grid based on the Early Treatment Diabetic Retinopathy Study.11 The retinal thickness of each of the nine subfields of the Early Treatment Diabetic Retinopathy Study–like map was recorded. Statistical analyses were performed using the software SPSS 16.0 for Windows (SPSS, Inc, Chicago, IL). Categorical data were analyzed using the Freeman–Halton extension of the Fisher’s exact test. Differences of retinal thickness measurements between groups were analyzed by generalized estimating equation models, performed to account for correlations between the two eyes of the same participant. Because the SCD group with proliferative changes was significantly older than the other groups, generalized estimating equation models including age as covariate were also performed. Bonferroni correction for multiple comparisons was performed to analyze pair-wise differences. A P-value ,0.05 was considered statistically significant. Results The study included 48 eyes of 24 patients without SCD (controls), 19 eyes of 11 patients with HbSC Table 2. Macular Thickness in Eyes (n) of Patients With SCD and Control Subjects HbSC (n = 19 Eyes HbSS (n = 65 Eyes of 11 Patients) of 36 Patients) No retinopathy Nonproliferative retinopathy Proliferative retinopathy
13 (68.4%) 0 (0.0%)
51 (78.5%) 12 (18.5%)
6 (31.6%)
2 (3.1%)
disease, and 65 eyes of 36 patients with HbSS disease. Three patients with HbSC and 7 patients with HbSS disease had 1 eye meeting exclusion criteria (previous retinal photocoagulation, n = 4; previous intraocular surgery, n = 3; macular epiretinal membrane, n = 2; macular lamellar hole, n = 1) and had only 1 eye included in the analysis. Two eyes with no signs of retinopathy had signal strength index ,45 on OCTs and were not included in retinal measurements analysis. The mean age ± SD was 31.9 ± 7.6 years in the control group, 42.2 ± 15.5 years in the HbSC group, and 27.8 ± 8.7 years in the HbSS group, with a significant difference for HbSC patients compared with controls and HbSS patients (P , 0.001). Twelve (50.0%) patients in the control group, 10 (90.9%) in the HbSC group, and 21 (58.3%) in the HbSS group were female, with no statistical difference in gender distribution between groups (P = 0.066; Table 1). Distribution according to the presence of posterior segment changes and SCD genotypes is shown in Table 2. Eyes with proliferative retinopathy were from patients with SCD significantly older in comparison with the control group, SCD without retinopathy, and SCD with nonproliferative changes (mean ± SD, 31.9 ± 7.6 years, 28.1 ± 8.7 years, 30.0 ± 9.1 years, and 46.0 ± 11.2 years, respectively for the control group, SCD without retinopathy, SCD with nonproliferative changes, and SCD with proliferative changes; P = 0.002). No statistical difference in gender distribution was observed between the control and SCD retinopathy groups (P = 0.088). Table 3 shows macular thickness measurement estimates in eyes from the 4 study groups. The mean central foveal thickness in eyes with proliferative retinopathy was significantly increased in comparison with eyes of the control group, SCD without retinopathy, and SCD with nonproliferative changes (P = 0.004). After adjustment for age, the central fovea of eyes with proliferative retinopathy was still significantly thicker than in the SCD without retinopathy group (P = 0.014). Cystoid spaces or convex contour in the fovea were not seen in the studied patients. There were no significant differences in the macular
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RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2015 VOLUME 35 NUMBER 2 Table 3. Ganglion Cell Complex in Eyes (n) of Patients With SCD and Control Subjects
Central macula Temporal inner Superior inner Nasal inner Inferior inner Temporal outer Superior outer Nasal outer Inferior outer
Control Group (n = 48)
SCD Without Retinopathy (n = 62)
SCD With Nonproliferative Retinopathy (n = 12)
SCD With Proliferative Retinopathy (n = 8)
P
235.60 ± 3.22
230.41 ± 3.55
235.36 ± 4.09
250.97 ± 5.17*
0.004
297.61 ± 2.99
295.83 ± 2.25
298.95 ± 3.42
302.90 ± 8.02
0.585
316.38 ± 2.37
315.41 ± 2.69
316.64 ± 3.38
314.39 ± 7.07
0.944
313.36 ± 3.01
314.56 ± 2.95
311.57 ± 2.99
314.43 ± 5.07
0.631
308.76 ± 3.77
311.65 ± 2.41
315.53 ± 3.50
319.56 ± 5.89
0.195
278.51 ± 2.78
276.07 ± 2.25
273.42 ± 4.67
269.96 ± 7.97
0.652
289.69 ± 2.40
290.72 ± 1.78
292.07 ± 2.36
287.61 ± 3.79
0.751
304.58 ± 2.66
304.17 ± 2.11
303.43 ± 2.40
299.90 ± 3.07
0.624
278.78 ± 3.52
281.17 ± 2.12
283.66 ± 3.79
284.89 ± 5.88
0.711
Values are expressed in micrometers as mean ± standard error (estimated by generalized estimating equation models adjusted for within-patient intereye correlations). *Statistically different from control, SCD without retinopathy, and SCD with nonproliferative retinopathy groups (P , 0.05; Bonferroni correction for multiple comparisons).
thickness measurements of the other subfield areas of the Early Treatment Diabetic Retinopathy Study–like map (P . 0.05). There was no difference in average, superior, and inferior subfield GCC thickness between the studied groups (P . 0.05). However, eyes with proliferative changes showed higher mean GCC GLV values compared with eyes of the control group, SCD without retinopathy, and SCD with nonproliferative changes (P = 0.027); nevertheless, after age adjustment, this difference was not statistically significant (P = 0.156). Ganglion cell complex FLV in comparison with the control group was also higher (P = 0.002), and this difference remained significant after age adjustment (P = 0.004), indicating thinning of inner retinal layers, which were consistently localized temporally to the fovea as seen in Figures 1 and 2. Ganglion cell complex FLV results outside the device Fig. 1. Spectral domain optical coherence horizontal B-scan (A) and GCC significance map (B) of the right eye of a sickle cell HbSC patient with proliferative sickle cell retinopathy. Focal thinning of inner retinal layers temporal to the fovea is seen as an abrupt asymmetric decrease in retinal thickness, as indicated by the arrows in the B-scan and the red area in the GCC significance map.
normative database (95% confidence limits) were seen in 2 eyes of the control group (4.2%), 20 eyes of SCD patients without retinopathy (32.3%), 3 eyes with nonproliferative changes (25.0%), and 6 eyes with proliferative retinopathy (75.0%), with a significant higher frequency of abnormal FLV results in eyes with proliferative changes (P , 0.001). Ganglion cell complex parameter estimates are presented in Table 4. There was no statistically significant difference in the average RNFL thickness between the studied groups (P = 0.145 and P = 0.258, respectively for the model adjusted for intereye correlations and for the model adjusted for intereye correlations and age). Analysis of RNFL thickness by quadrants adjusted for within-patient intereye correlations revealed significant thinning of the nasal RNFL in eyes with proliferative retinopathy when compared with the other groups (P , 0.001). However, after adjustment for
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OCT IN SICKLE CELL RETINOPATHY BRASILEIRO ET AL
Fig. 2. Spectral domain optical coherence horizontal B-scan (A) and GCC significance map (B) of the right eye of a HbSS patient with proliferative sickle cell retinopathy. Focal thinning of inner retinal layers temporal to the fovea is seen as an abrupt asymmetric decrease in retinal thickness, as indicated by the arrows in the B-scan and the red area in the GCC significance map.
age, no RNFL variables differed between groups (P . 0.005). Table 5 shows RNFL thickness measurements estimates from the 4 studied groups.
Discussion Although findings of sickle retinopathy are primarily found in the periphery, structural changes from macular infarctions in sickle cell hemoglobinopathies have been documented using fluorescein angiography, electroretinography, OCT, and histopathology.3–5,12,13 The temporal horizontal raphe is an imaginary line extending temporally from the center of the macula to the periphery of the retina. Terminal arteriolar branches comparable with the terminal arteriolar tree in the retinal periphery supply this area. Just as terminal arterioles become occluded in the periphery of the retina of patients with SCD, the same process tends to occur in the anatomically comparable areas of the macula.5,14 Incidence of proliferative sickle cell retinopathy and its severity increases with age, and the disease is more frequent in heterozygous (HbSC) patients.15,16 As expected, in our study, eyes with proliferative changes were from older patients and mostly from HbSC individuals. Previous reports demonstrated thinning of the outer retina in the central foveal subfield and in the temporal parafoveal regions of patients with SCD when compared with the age-matched controls. However, in this
study, we found sectoral thinning of the inner retinal layers demonstrated by higher FLV and GLV values in eyes with proliferative sickle cell retinopathy. These indices are automatically generated by OCT device and represents, respectively, focal and global loss of the GCC in the inner retina (nerve fiber layer, ganglion cell layer, and inner plexiform layer). Global loss volume measures the average amount of GCC loss over the entire GCC map, and FLV detects focal loss using a pattern deviation map to correct for the overall absolute changes, similar to corrected pattern standard deviation in the visual fields. Likewise, GLV is comparable with mean deviation in visual fields.11 Thinning of inner retinal layers in symptomatic and asymptomatic sickle cell retinopathy patients has also been reported in previous case reports and case series.7,17,18 Histopathologic studies of SCD patients with vasoocclusive diseases have also shown atrophy and thinning of the inner retinal layers.12 Our findings confirm that ischemia occurs both in the central and peripheral retinal regions of patients with SCD and suggest that the same mechanisms that lead to proliferative sickle cell retinopathy (occlusion of retinal microvasculature and ischemia) are also responsible for structural macular changes. Patients with proliferative retinopathy also presented thickening of the central macular subfield. This could be associated with a rearrangement of the macular structure associated with thinning of inner retinal layers
Table 4. Retinal Nerve Fiber Layer Thickness in Eyes (n) of Patients With SCD and Control Subjects Control Group SCD Without (n = 48) Retinopathy (n = 62) Average GCC Superior GCC Inferior GCC FLV GLV
96.85 96.99 96.97 0.87 4.09
± ± ± ± ±
1.38 1.34 1.56 0.27 0.82
98.09 97.08 99.06 1.80 4.19
± ± ± ± ±
1.07 1.08 1.17 0.29 0.63
SCD With Nonproliferative Retinopathy (n = 12) 97.82 98.38 97.38 1.84 4.16
± ± ± ± ±
1.37 1.20 1.90 0.71 0.87
SCD With Proliferative Retinopathy (n = 8) 95.94 93.62 98.20 5.05 8.86
± ± ± ± ±
5.04 4.97 5.08 1.19* 1.48†
P 0.887 0.570 0.544 0.002 0.027
Values are expressed in micrometers as mean ± standard error (estimated by generalized estimating equation models adjusted for within-patient intereye correlations). *Statistically different from control group (P , 0.05; Bonferroni correction for multiple comparisons). †Statistically different from control, SCD without retinopathy, and SCD with nonproliferative retinopathy groups (P , 0.05; Bonferroni correction for multiple comparisons).
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RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2015 VOLUME 35 NUMBER 2 Table 5. Retinal Nerve Fiber Layer Thickness in Eyes (n) of Patients With SCD and Control Subjects Control Group (n = 48)
Average 111.62 ± 2.19 Temporal 78.72 ± 1.98 Superior 131.14 ± 3.00 Nasal 88.65 ± 2.47 Inferior 147.65 ± 4.35
SCD Without Retinopathy (n = 62) 118.65 82.43 143.40 88.56 159.70
± ± ± ± ±
SCD With Nonproliferative Retinopathy (n = 12)
2.38 1.77 3.54 2.57 3.91
118.97 82.96 142.79 91.85 159.12
± ± ± ± ±
2.97 2.77 4.48 3.07 5.27
SCD With Proliferative Retinopathy (n = 8) 112.94 94.47 135.28 74.14 144.99
± ± ± ± ±
5.79 11.23 9.03 2.87* 4.89
P 0.145 0.294 0.053 ,0.001 0.057
Values are expressed in micrometers as mean ± standard error (estimated by GEE models adjusted for within-patient intereye correlations). *Statistically different from control, SCD without retinopathy, and SCD with nonproliferative retinopathy groups (P , 0.05; Bonferroni correction for multiple comparisons).
adjacent to the fovea. Thickening of central macula is also observed in the acute stage of central retinal artery occlusion. Ganglion cells are absent within the fovea but clustered at the foveal margin; it is speculated that the ischemic insult in these patients could lead to sequential displacement of neuronal cells toward the fovea and consequent derangement of foveal contour and increase in the central macular thickness.19 A similar mechanism could explain the central macular thickening in patients with proliferative retinopathy. The functional consequences of macular changes are uncertain. Loss of central visual function is variable,5 and no close relationship exists between the extent of macular vascular changes and visual acuity.3,20 Both abnormal color vision and central scotomas have also been reported with SCD.21,22 In a recent study, a strong correlation between the retinal sensitivities on microperimetry and presence of focal macular thinning on SD-OCT was found in patients with SCD.8 In addition to focal GCC thinning, eyes with proliferative retinopathy presented thinner RNFL in the nasal quadrant; however, in the age-adjusted statistical analysis, this difference was not statistically significant. Thinning of the peripapillary RNFL in this quadrant had previously been reported in SCD patients with decreased macular thickness.6 Peripapillary RNFL thinning may be a result of thinning and atrophy of the inner retinal layers of the macula and has also been observed to occur in other types of retinal vasculopathies, including diabetes, retinal artery occlusion, and HIV microvasculopathy.23–25 However, blood vessels make a direct contribution to the OCT RNFL thickness,26 and retinal vessels tortuosity and dilatation in patients with SCD may have prevented the detection of RNFL thinning in other peripapillary sectors. Potential limitations of this study might have affected our results. Wide-field fluorescein angiography was not routinely performed, which may have led to misclassifications of sickle cell retinopathy. It should also be noted that GLV and FLV indices are based on manufacturer’s normative data, and subtle changes may not represent
true variations. Different OCT devices and analysis algorithms have also been used in the studies evaluating macular structural changes of patients with SCD and their results are not directly comparable.6–9,17,18 Another limitation is that measurements obtained from both eyes of an individual are often correlated; to avoid this potential bias, generalized estimating equation models were used to account for between-eye correlations.27 In this study, we also analyzed a large number of retinal thickness parameters; this may have increased the chance of a Type I error during hypothesis testing, and some of the differences detected may have occurred just by chance. In conclusion, peripheral proliferative sickle cell retinopathy changes were associated with thinning of macular inner retinal layers and thickening of the central foveal subfield. Further investigation is required to assess the relations between changes in retinal structure and visual function in patients with SCD and also longitudinal changes over time. Retinal evaluation by SD-OCT provides valuable information in patients with SCD; these findings should be taken into account when interpreting retinal SD-OCT for other ocular disorders in these patients, and changes detected by macular and peripapillary scans should prompt a meticulous evaluation of the peripheral retina to search for evidence of ischemia and proliferative retinopathy. Key words: sickle cell disease, retina, optic nerve, optical coherence tomography. Acknowledgment The authors would like to thank Leandro Lucena, MSc, for his assistance with statistical analysis. References 1. Elagouz M, Jyothi S, Gupta B, Sivaprasad S. Sickle cell disease and the eye: old and new concepts. Surv Ophthalmol 2010;55:359–377. 2. Ashley-Koch A, Yang Q, Olney RS. Sickle hemoglobin (Hb S) allele and sickle cell disease: a HuGE review. Am J Epidemiol 2000;151:839–845.
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