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 Table of Contents  
Year : 2022  |  Volume : 115  |  Issue : 2  |  Page : 72-77

Foveal avascular zone changes in children with sickle cell disease

1 Department of Ophthalmology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2 Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Date of Submission27-Mar-2022
Date of Acceptance16-Apr-2022
Date of Web Publication08-Jul-2022

Correspondence Address:
MD, FRCS-Glasgow Mohamed I Saleh
Department of Ophthalmology, Faculty of Medicine, Ain Shams University, Cairo 1181
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ejos.ejos_21_22

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Purpose To study the morphological changes in the foveal avascular zone (FAZ) in children diagnosed with sickle cell disease (SCD) via the optical coherence tomography angiography (OCTA).
Patients and methods This was a prospective case–control study that was done in a tertiary hospital. A total of 15 children with SCD (confirmed with electrophoresis) and 15 matched healthy children were included. Ophthalmological assessment was done. RTVue XR Avanti was employed to obtain 6×6 macular OCTA scans. Foveal parameters including FAZ area (mm2), perimeter (mm) (PERIM), acircularity index (AI), and foveal density were analyzed. Pediatric assessment including the disease variant, sickling crisis, and current treatment was done.
Results A total of 15 eyes of 15 children with SCD and 15 eyes of healthy children were included. Six eyes showed stage 1 retinopathy. Children with SCD had wider FAZ area (P=0.001) with larger PERIM (P=0.00) and higher AI (P=0.030) in comparison with the control children. No significant changes in the FAZ parameters between patients with SCD with stage 1 retinopathy and patients without retinopathy were found.
Conclusion Children with SCD have a wide FAZ area with large PERIM and high AI in comparison with normal controls. OCTA macular changes might be an early predictor of sickle cell retinopathy. Further follow-up studies are recommended to understand the effect of early macular changes on the future development of retinopathy.

Keywords: macular changes in children with sickle cell disease, optical coherence tomography angiography in sickle cell retinopathy, sickle cell retinopathy

How to cite this article:
ElSadek TM, Salman AG, Said AM, Elsherif NH, Saleh MI. Foveal avascular zone changes in children with sickle cell disease. J Egypt Ophthalmol Soc 2022;115:72-7

How to cite this URL:
ElSadek TM, Salman AG, Said AM, Elsherif NH, Saleh MI. Foveal avascular zone changes in children with sickle cell disease. J Egypt Ophthalmol Soc [serial online] 2022 [cited 2022 Sep 28];115:72-7. Available from: http://www.jeos.eg.net/text.asp?2022/115/2/72/350250

  Introduction Top

Sickle cell disease (SCD) is an inherited blood disorder resulting from a mutation in the hemoglobin (Hb) beta chain that leads to the formation of abnormal Hb (HbS) [1]. In the state of deoxygenation, these abnormal Hb aggregates result in sickling of the erythrocytes that can cause vascular occlusions and disrupt blood flow in small vessels [2]. Microvascular insults in the eye result in sickle cell retinopathy (SCR). With advanced SCR, sight-threatening complications like vitreous hemorrhage, retinal detachment, or retinal vascular occlusion can occur and lead to loss of vision. SCR was previously classified by Goldberg in five stages. Peripheral arterial occlusion is considered stage 1, whereas peripheral arteriovenous anastomoses are considered stage 2, and preretinal neovascularization is considered stage 3. When vitreous hemorrhage occurs, this is marked as stage 4, whereas retinal detachment is marked as stage 5 [3].

It is recommended to start ocular screening for children with SCD at the age of 10 years and to re-screen annually or biannual thereafter in case of normal fundus at the initial visit [4]. However, retinal vaso-occlusion in children was observed in children earlier than this age [5],[6]. Various studies detected changes in patients with SCD before the development of clinically evident changes, however, until now there are no consensus or evidence-based recommendations regarding the best imaging modality for the screening of SCR [7].

Earlier studies used fundus fluorescein angiography for the evaluation of SCR [8],[9]. Later, optical coherence tomography (OCT) was used for quantitative evaluation of the macular structure. Recently, optical coherence tomography angiography (OCTA) was involved for a noninvasive evaluation of macular vascular changes [10],[11]. The use of ultrawide field imaging for evaluation of retinal periphery in addition to the use of OCT and OCTA for macular evaluation was recommended for better evaluation and earlier diagnosis [12],[13]. Cai et al. [14] in a recent review regarding the integration of such multimodal imaging with the artificial intelligence in the screening of patients with SCD concluded that the use of these recent modalities would improve the management of SCR and prevent disabling complications.

Changes detected by SD-OCT and OCTA may provide the only evidence of retinal damage before the presence of fundus fluorescein angiography findings or clinical signs [15]. Retinal thinning in patients with SCD was previously reported. The temporal macula subfields in addition to the peripapillary retinal nerve fiber layer were the most affected [16],[17]. Using OCTA, recent studies reported macular areas of vascular flow loss. These areas corresponded to areas of thinning detected by OCT [11]. Such changes have been correlated to higher rates of peripheral neovascularization, suggesting that these findings may be an early predictor of peripheral retinopathy [10],[18].

With sparse data available regarding early macular changes in children with SCD, and no available data regarding the different foveal avascular zone (FAZ) parameters, we set out to perform this study aiming to identify FAZ changes identified by OCTA in children with SCD in comparison with age-matched and sex-matched healthy children.

  Patients and methods Top

This was a case–control prospective study that was done in 2020 at the hospitals of Ain Shams University Hospitals, Cairo, Egypt, after approval of the study protocol by the institutional ethical committee. The study methodology strictly abided by the research ethics stated in the Declaration of Helsinki. The guardians of all participating children signed written informed consent after explanation of the study’s nature and procedure to them.

Children with confirmed diagnosis of SCD – younger than 18 years – were recruited from the pediatric hematology clinic. Healthy children of the same race, age, and sex were recruited from the ophthalmology clinic and were included as controls after full pediatric and ophthalmological evaluation. Exclusion criteria included any history of retinopathy from a cause other than SCD or other systemic conditions that may cause retinal vascular affection, including a history of prematurity, diabetes mellitus, hypertension, hepatitis, malignancy, or any autoimmune disease. Furthermore, media opacity, amblyopia, congenital retinal or optic nerve disorders, intraocular pressure more than or equal to 20 mmHg, refractive error of more than 6, uncooperative patients, and patients with poor fixation were excluded.

All participating children underwent full ophthalmological assessment in the form of corrected distance visual acuity (Snellen’s converted to LogMAR for analysis), slit-lamp examination, intraocular pressure measurements, and fundus examination by a 90 D lens and slit-lamp biomicroscopy followed by an examination of the retinal periphery via the indirect ophthalmoscope using 20 D lens. Accordingly, patients with SCD were further assigned into two subgroups: patients with SCR group and patients without SCR. Clinical examination was done for all study participants by a specialized pediatrician.

Retinal OCTA scans were obtained by the RTVue XR OCTA (Avanti Angiovue; Optovue, Fremont, California, USA). All eyes were dilated with tropicamide 1% (Mydriacyl; Alcon). Macular OCTA was obtained using 6×6 mm HD scans centered on the fovea [19]. Foveal parameters were automatically measured by the software. The FAZ, FAZ perimeter (PERIM), the acircularity index (AI), and the density of the vessels within 300 μm from the foveal density were extracted from a full vascular slab OCTA image. The vascular densities (VD) for the whole image and fovea (central 1 mm) from the superficial capillary plexus (SCP) and the deep capillary plexus (DCP) were also extracted and analyzed. The images were reviewed for centration, automated segmentation, scan quality, and artifacts. Consequently, decentered scans, algorithm failure, scans with quality less than 6, and/or with motion artifacts were excluded.

Imaging was done for both eyes for each participant. After that, all scans were reviewed as previously described. In the case of bilateral accepted scans, the scans with higher quality were included. If both eyes showed equal scan quality, random selection was done.

Statistical analysis

For statistical analysis, the SPSS version 25 (International Business Machines Corporation, Armonk, New York, USA) was used. For numerical data, mean±SD were calculated, whereas for sex differences, we calculated the frequency and the percentage.

To assess the statistical difference between the two-study groups’ means, we used the Student t test. Fisher’s exact test was employed to assess the relation between two qualitative variables when the expected count was less than 5 in more than 20% of cells.

A P value less than 0.05 was considered statistically significant.

  Results Top

Demographic data and patients’ characteristics

We included 15 eyes of 15 children with SCD and 15 eyes of 15 healthy children in two groups. The mean±SD age of the case group was 13.07±1.98 years, whereas the mean±SD age among the control group was 12.93±1.71 years with no significant difference (P=0.845). In the patient group, seven males and eight females were included, whereas in the control group, nine males and six females were included, without a significant difference (P=0.464).

Regarding the variant of the disease, 73.3% (11 patients) had HbSS, whereas 26.67% (four patients) had sickle cell β-thalassemia. The mean duration of the disease was 11.9±2.15 years. Nine (60%) patients had a positive history of vaso-occlusive crises. The mean±SD Hb level was 7.42±0.87 g/dl. All diseased children were on hydroxyurea treatment and nearly half (eight patients, 53.3%) were on regular transfusion.

The ophthalmological assessment revealed BCVA 0 LogMAR. A conjunctival comma sign was observed in five (33.3%) eyes. Fundus examination showed stage 1 SCR in six (40%) eyes.

Results obtained from macular optical coherence tomography angiography

Comparisons between the values obtained via OCTA in the two groups regarding the SCP and DCP vessel density (whole image and fovea) and the FAZ measurements are shown in [Table 1] and [Figure 1]. Error bar graphs in [Figure 2] show comparisons between patients with SCD and controls regarding FAZ area, PERIM, and AI.
Table 1 Comparison between children with sickle cell disease and healthy controls regarding the foveal avascular zone parameters and the vessel density

Click here to view
Figure 1 Macular OCTA changes in children with SCD and healthy control. DCP, the vessel density of the deep capillary plexus from 6×6 macular scan; FAZ (mm2), area of the foveal avascular zone from a full vascular slab; OCTA, optical coherence tomography angiography; PERIM (mm), perimeter of the FAZ; SCD, sickle cell disease; SCP, the vessel density of the superficial capillary plexus from 6×6 macular scan.

Click here to view
Figure 2 Error bar graphs of foveal avascular zone parameters in the patient and control groups. (a) Error bar graph showing the 1 mean±SD value for the FAZ area (mm2) in sickle cell disease and healthy children. (b) Error bar graph showing the 1mean±SD value for the PERIM (mm) in sickle cell disease and healthy children. (c) Error bar graph showing the 1 mean±SD value for the AI in sickle cell disease and healthy children. AI, acircularity index; FAZ, foveal avascular zone; PERIM, perimeter.

Click here to view

Patients with SCD had lower values for VD in the SCP as well as in the DCP whole image; however, this was not statistically significant. Foveal VD in the superficial and the DCP was significantly lower among patients with SCD.

Regarding the FAZ parameters, the FAZ area was significantly wider among children with SCD. Similarly, significantly larger PERIM and higher AI were found when compared with healthy children.

We compared our results between patients with stage 1 SCR and patients without retinopathy ([Table 2]). The VD was less in patients with stage 1 SCR in comparison with patients without retinopathy with statistically significant results when comparing the VD of the SCP. However, we have not found significant differences regarding the FAZ area, PERIM, and the AI between children with and without SCR, as shown in [Table 2].
Table 2 Comparison between patients with sickle cell retinopathy (stage 1) and patients without retinopathy regarding the foveal avascular zone parameters and the vessel density

Click here to view

  Discussion Top

In this study, we used OCTA for the evaluation of the FAZ in children with SCD without SCR or with early SCR. Previously, Roemer et al. [20], Ong et al. [19], and Pahl et al. [13] employed macular OCTA in the assessment of children with SCD. To the best of our knowledge, the different FAZ parameters – except for the FAZ area – were not previously studied in children with SCD.

In this study, 15 children with SCD less than 18 years old were included. Six (40%) eyes showed stage 1 SCR, whereas the rest had no retinopathy. This is close to the results reported by Grego et al. [21], where they found nonproliferative SCR in 44.4% of their patients and none showed proliferative SCR. In another large study conducted by Li et al. [22] on 398 children with different types of sickle cell hemoglobinopathies, 12% of their sample had SCR. Such difference might be related to the previously reported regional variation of ocular manifestations with a variable prevalence of proliferative sickle retinopathy [23],[24]. The disease variant may also have a role in this discrepancy. Ong and colleagues reported the prevalence of nonproliferative SCR as 44 and 71% in patients with HbSS and patients with HbS variant, respectively [21].

The SCP and DCP VD in patients with SCD were lower than in healthy controls; however, in our study, these results were not statistically significant in the whole image VD with statistically significant differences regarding the foveal VD. Ong et al. [19] and Pahl et al. [13] previously reported less VD for both the SCP and the DCP in most of the subfields in children with SCD when compared with healthy controls. Their results were statistically significant. Nonsignificant results in the current study are probably related to the relatively small sample we included (15 children) in this study, whereas Ong et al. [19] included 68 eyes and Pahl et al. [13] included 32 eyes.

Children with SCD have shown a significantly larger area of FAZ compared with the control children. This was consistent with the results of Roemer et al. [20]. Additionally, the PERIM and AI were significantly higher in diseased children when compared with the controls. Lynch et al. [25] previously studied the different measurements of FAZ among adults with SCD. Similar to our results, the FAZ PERIM and AI were significantly higher among patients with nonproliferative and proliferative SCR [25].

In our included sample of children with SCD, six eyes out of 15 were found to have grade 1 SCR. Accordingly, we compared the results obtained via OCTA between patients with and patients without SCR. VD in the whole image and the fovea obtained from both the superficial and the DCP were lower among patients with SCR. However, these differences were not significant except when comparing the SCP VD for the whole image between both groups.

The limitations of the current research were the small number of patients and the lack of follow-up. Moreover, owing to the small sample, we did not analyze the results in relation to the disease variant or the type of treatment received by the patients.

Our results suggest that OCTA can detect FAZ microvascular abnormalities even in the absence of visible retinopathy changes in patients with SCD. Such changes might be early signs of retinopathy. Accordingly, OCTA may have a valuable role as a screening tool in children with SCD. Further longitudinal studies are needed for a better understanding of the effect of macular early vascular changes on the future development and progression of SCR.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Fox PD, Dunn DT, Morris JS, Serjeant GR. Risk factors for proliferative sickle retinopathy. Br J Ophthalmol 1990; 74:172–176.  Back to cited text no. 1
Ware RE, de Montalembert M, Tshilolo LAM. Sickle cell disease. Lancet 2017; 390:311–323.  Back to cited text no. 2
Goldberg MF. Classification and pathogenesis of proliferative sickle retinopathy. Am J Ophthalmol. 1971; 71:649–665.  Back to cited text no. 3
Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 2014; 312:1033–1048. doi: 10.1001/jama.2014.10517. Erratum in: JAMA. 2014 Nov 12;312(18):1932. Erratum in: JAMA. 2015 Feb 17;313(7):729. PMID: 25203083.  Back to cited text no. 4
McLeod DS, Goldberg MF, Lutty GA. Dual-perspective analysis of vascular formations in sickle cell retinopathy. Arch Ophthalmol 1993; 111:1234–1245.  Back to cited text no. 5
Rosenberg JB, Hutcheson KA. Pediatric sickle cell retinopathy: correlation with clinical factors. J AAPOS 2011; 15:49–53.  Back to cited text no. 6
Linz MO, Scott AW. Wide-field imaging of sickle retinopathy. Int J Retin Vitr 2019; 5(s1):1–190.  Back to cited text no. 7
Kent D, Arya R, Aclimandos WA, Bellingham AJ, Bird AC. Screening for ophthalmic manifestations of sickle cell disease in the United Kingdom. Eye 1994; 8(Pt 6):618–622.  Back to cited text no. 8
El-Ghamrawy MK, El Behairy HF, El Menshawy A, Awad SA, Ismail A, Gabal MS. Ocular manifestations in Egyptian children and young adults with sickle cell disease. Indian J Hematol Blood Transfus 2014; 30:275–280.  Back to cited text no. 9
Ghasemi Falavarjani KG, Scott AW, Wang K, Han IC, Chen X et al. CORRELATION OF MULTIMODAL IMAGING IN SICKLE CELL RETINOPATHY. Retina 2016; 36Suppl 1:S111–S117. doi: 10.1097/IAE.0000000000001230.  Back to cited text no. 10
Han IC, Tadarati M, Scott AW. Macular vascular abnormalities identified by optical coherence tomographic angiography in patients with sickle cell disease. JAMA Ophthalmol 2015; 133:1337–1340.  Back to cited text no. 11
Abdalla Elsayed MEA, Mura M, Al Dhibi H, Schellini S, Malik R, Kozak I, Schatz P Sickle cell retinopathy. A focused review. Graefe’s Arch Clin Exp Ophthalmol. 2019;257:1353–1364. doi: 10.1007/s00417-019-04294-2. Epub 2019 Mar 20. PMID: 30895451.  Back to cited text no. 12
Pahl DA, Green NS, Bhatia M, Lee MT, Chang JS, Licursi M et al. Optical Coherence Tomography Angiography and Ultra-widefield Fluorescein Angiography for Early Detection of Adolescent Sickle Retinopathy. Am J Ophthalmol 2017; 183:91–98.  Back to cited text no. 13
Cai S, Han IC, Scott AW. Artificial intelligence for improving sickle cell retinopathy diagnosis and management. Eye (Lond) 2021; 35:2675–2684.  Back to cited text no. 14
Grover S, Sambhav K, Chalam KV. Capillary nonperfusion by novel technology of OCT angiography in a patient with sickle cell disease with normal fluorescein angiogram. Eur J Ophthalmol 2016; 26:e121–e123.  Back to cited text no. 15
Brasileiro F, Martins TT, Campos SB, Andrade Neto JL, Bravo-Filho VT, Araújo AS, Arantes TE Macular and peripapillary spectral domain optical coherence tomography changes in sickle cell retinopathy. Retina 2015; 35:257–263.  Back to cited text no. 16
Chow CC, Shah RJ, Lim JI, Chau FY, Hallak JA, Vajaranant TS. Peripapillary retinal nerve fiber layer thickness in sickle-cell hemoglobinopathies using spectral-domain optical coherence tomography. Am J Ophthalmol 2013; 155:456–464.  Back to cited text no. 17
Hood MP, Diaz RI, Sigler EJ, Calzada JI. Temporal macular atrophy as a predictor of neovascularization in sickle cell retinopathy. Ophthal Surg Lasers Imag Retina 2016; 47:27–34.  Back to cited text no. 18
Ong SS, Linz MO, Li X, Liu TYA, Han IC, Scott AW. Retinal thickness and microvascular changes in children with sickle cell disease evaluated by optical coherence tomography (OCT) and OCT angiography. Am J Ophthalmol 2020; 209:88–98.  Back to cited text no. 19
Roemer S, Bergin C, Kaeser P-F, Ambresin A. Assessment of macular vasculature of children with sickle cell disease compared to that of healthy controls using optical coherence tomography angiography. Retina 2019; 39:2384–2391.  Back to cited text no. 20
Grego L, Pignatto S, Alfier F, Arigliani M, Rizzetto F, Rassu N et al. Optical coherence tomography (OCT) and OCT angiography allow early identification of sickle cell maculopathy in children and correlate it with systemic risk factors. Graefe’s Arch Clin Exp Ophthalmol 2020; 258:2551–2561.  Back to cited text no. 21
Li J, Bender L, Shaffer J, Cohen D, Ying G-S, Binenbaum G. Prevalence and onset of pediatric sickle cell retinopathy. Ophthalmology. 2019; 126:1000–1006.  Back to cited text no. 22
Akinsola FB, Kehinde MO. Ocular findings in sickle cell disease patients in Lagos. Niger Postgrad Med J. 2004; 11:203–206.  Back to cited text no. 23
Fadugbagbe AO, Gurgel RQ, Mendonça CQ, Cipolotti R, dos Santos AM, Cuevas LE. Ocular manifestations of sickle cell disease. Ann Trop Paediatr 2010; 30:19–26.  Back to cited text no. 24
Lynch G, Scott AW, Linz MO, Han I , Andrade Romo JS , Linderman RE et al. Foveal avascular zone morphology and parafoveal capillary perfusion in sickle cell retinopathy. Br J Ophthalmol 2020; 104:473–479.  Back to cited text no. 25


  [Figure 1], [Figure 2]

  [Table 1], [Table 2]


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