Terminology for Retinal Findings in Sickle Cell Disease Research: A Scoping Review

Abstract

Objective:

To review the current sickle cell disease (SCD) literature to assess how “retinopathy” has been defined and to identify ocular outcomes that have been measured and described.

Design:

A systematic scoping review of SCD literature was completed regarding ocular manifestations of SCD and vision outcomes across all medical specialties.

Subjects:

Participants with SCD and control patients were included in our data extraction.

Methods:

We reviewed English-language literature from 2000–2021 for eligible studies by searching PubMed, Google Scholar, Embase, and the Cochrane library using terms to encompass SCD and ocular findings.

Main Outcome Measures:

Data collection included study information, patient characteristics, vision related findings (inclusion criteria and/or study outcomes), and retinopathy characteristics (definition, when, how and by whom diagnosed).

Results:

We identified 4,006 unique citations and 111 were included in the analysis. Ophthalmologists were senior authors of about half (59/111; 53.2%) of the articles; most articles were published between 2016 and 2021 (71/111; 70.0%). The studies had been conducted primarily in North America (54/111; 48.6%) or Europe (23/111; 20.7%); designs were cross-sectional (51/111; 45.9%), prospective cohort (28/111; 25.2%), retrospective cohort (27/111; 24.3%) and case-control (4/111; 3.6%). Among studies reporting any retinopathy, it was commonly defined as a combination of non-proliferative sickle cell retinopathy (NPSR) and proliferative sickle cell retinopathy (PSR) (52/87; 59.8%), infrequently as PSR only (6/87; 6.9%), or not defined at all (23/87; 26.4%). The Goldberg classification was used to grade retinopathy in almost half of the studies (41/87; 47.1%). Investigators reporting diagnostic methods used clinical fundus examination (56/111; 50.4%), optical coherence tomography (OCT) (24/111; 21.6%), fluorescein angiography (20/111; 18.0%), ultra-widefield fundus photographs (15/111; 13.5%), and OCT-angiography (OCTA)(10/111; 9.0%), or did not report methods (28/111; 25.2%).

Conclusions:

There are inconsistencies in documentation of methods and outcomes in studies of SCD ophthalmic findings. Particularly concerning is the lack of documentation of ophthalmic exam methods, qualifications of examiners, and clarity and specificity of sickle cell retinopathy definitions. With the increase in SCD treatment research and novel systemic therapies available, it is important to adopt clear and consistent descriptions and rigorous data collection and reporting of ophthalmic outcomes in SCD studies.

Background

Sickle cell disease (SCD) is the most common inherited hematologic disorder globally, with an incidence of 300,000 to 400,000 new cases detected at birth each year.¹ SCD encompasses a group of hemoglobinopathies due to mutations in the beta-globin gene. The most common SCD genotypes are sickle cell anemia (HbSS), sickle cell hemoglobin C (HbSC), and sickle cell β-thalassemia major (HbS-Thal).¹ SCD causes erythrocyte sickling and subsequent vaso-occlusive events that may affect any organ of the body..² Ocular manifestations of SCD include dilated “comma” shaped conjunctival vessels⁶, iris atrophy⁷, hyphema inducing ocular hypertension⁸, and ischemic optic neuropathy⁹. The most common cause of vision loss in affected patients is sickle cell retinopathy.¹⁰ The Jamaican Cohort Study documented that the prevalence of sickle cell retinopathy was 43% in HbSC and 14% in HbSS by age 20.5 years with an annual incidence of 2.5% for HbSC and 0.5% for HbSS.¹¹

Damage to the retinal vasculature in sickle cell retinopathy includes both non-proliferative sickle cell retinopathy (NPSR) and proliferative vascular changes, known as proliferative sickle cell retinopathy (PSR).² In 1971, Goldberg¹² described the current widely used staging system for sickle cell retinopathy based on clinical observation of sequential vascular remodeling in the retinal periphery. Goldberg Stage I retinopathy consists of peripheral arteriolar occlusions, and Goldberg stage II retinopathy presents as the formation of arteriovenous vascular anastomoses. Goldberg stage III is characterized by pathologic sea fan neovascularization, the hallmark of PSR. It is important to recognize Goldberg Stage III, because, although patients may be visually asymptomatic at this stage, sea fan neovascularization may be treated with scatter laser photocoagulation to prevent these lesions from progressing to potentially sight-threatening vitreous hemorrhage (Goldberg Stage IV retinopathy) and retinal detachment (Goldberg Stage V retinopathy).¹³ In 1971 when Goldberg first published his eponymous classification system, the terms staging and classification were used interchangeably and the entire system was termed “classification of proliferative sickle retinopathy”.¹² Goldberg Stages I and II are accepted as types of NPSR; other retinal biomarkers include black sunburst lesions and salmon patch retinal hemorrhages.² Differentiation in patients is clinically significant because Stages I and II retinopathy, or NPSR, does not cause symptoms; patients with these findings typically are monitored for progression to PSR

In addition to the clinical importance of differentiating between NPSR and PSR, it is critical to make this distinction in research because the natural histories of NPSR and PSR are quite different and are still incompletely understood. The majority of NPSR never progresses to PSR. Spontaneous regression of neovascularization in PSR has been reported in 20–60% of patients.¹⁴

While the Goldberg classification scheme has been widely utilized in the ophthalmology literature, often sickle cell retinopathy is not specified as proliferative or non-proliferative when it is studied alongside other markers of SCD end-organ damage.^15,16 This failure to differentiate between these terms makes it difficult to determine whether NPSR and PSR were grouped together in study reports or only potentially vision-threatening PSR was diagnosed and reported. An additional source of this confusion may be the historical naming of Goldberg’s grading system as “classification of proliferative sickle retinopathy” without differentiating NPSR.¹²

Understanding of associations between end-organ damage and NPSR or PSR is limited. End-organ damage such as pulmonary hypertension, end-stage renal disease, and cerebrovascular disease have been associated with early mortality in SCD. HbSC genotype, high hemoglobin level, low fetal hemoglobin, and not receiving chronic transfusions have been associated with a higher incidence of PSR.^17,18 Interdisciplinary studies are needed to investigate these associations. We suspected that there may be a difference in reporting NPSR and PSR in ophthalmic studies compared with other medical disciplines. With the advent of novel systemic disease-modifying therapies and ongoing clinical trials, it is important to have a well-defined approach and consistent terminology for describing and reporting ocular status and outcomes in SCD across all medical specialties. Therefore, we conducted a systematic scoping review of the recent literature to document how the term “retinopathy” has been defined and applied in sickle cell disease research studies and to identify the ocular outcomes that have been measured and reported. To our knowledge, this is the first investigation of the use of the term “retinopathy” in the sickle cell disease literature that has been conducted in a systematic way.

Methods:

The study was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR).²¹

Search strategy

A standardized search strategy was developed to find studies that had evaluated SCD and reported vision related outcomes in English-language publications from January 1, 2000 through December 13, 2021. First, we identified all studies of SCD in the PubMed, Google Scholar, Embase, and The Cochrane library databases using terms to encompass sickle cell disease (See Appendix 2 for a detailed search strategy). Next, we narrowed the results by using the following terms to query the identified literature: retinopathy, eye, vision, sight, ocular, visual fields, vision outcomes, acuity, proliferative, non-proliferative, fundus, visual loss, vitreous hemorrhage, retinal detachment, retinal ischemia, macular ischemia, spontaneous regression, neovascular complexes, sea fan, salmon patch, and sunburst. We also searched the gray literature²², that is, articles and reports published outside of mainstream commercial publishers or governmental research, for SCD studies that had included ocular outcomes identified through the Google search engine. Finally, we hand-searched for pertinent literature by reviewing citations in the identified published and gray literature to ensure that our initial search did not miss any relevant published study. So that our results would be most applicable to contemporary research, we focused our scoping review on the current SCD research landscape by limiting the search to papers published after January 1, 2000, since the literature defining retinopathy in SCD was completed before 2000.

Inclusion criteria

Inclusion criteria were intentionally broad to fully assess how vision and ophthalmic outcomes have been described and measured in research studies published since 2000. We excluded systematic reviews, case-reports/series, attitudinal studies, and non-English language articles. Review for inclusion was performed independently by two authors (GR, YX) with disagreements resolved by discussion.

Data extraction

Using a Microsoft Excel data collection form, two of three authors (GR, YX, RWS) independently extracted year of publication, first author information (first and last name) field of medicine of the final (senior) author, study information (year started, study design, setting, geographic location, and journal field of medicine), patient characteristics (number, distribution by age and sex, SCD genotype), vision and/or ophthalmic-related findings (inclusion criteria and/or study outcomes), and specific retinopathy characteristics (definition, when, how and by whom diagnosed). Two authors (GR and RWS) adjudicated extracted data sets, identified, and resolved disagreements by discussion.

We assessed risk of bias for the included studies using the first seven questions of the Critical Appraisal Skills Programme (CASP) Cohort Study Checklist to assess selection and information bias.²³ The omitted questions pertained to the validity of individual study results which was outside the scope of our review.

Data analysis

The data analysis is descriptive, i.e., frequency distributions of responses with means (or medians) and standard deviations (or ranges). We tabulated the data by year published, field of medicine, location, and study design. This scoping review was performed in accordance with the principles established by the Declaration of Helsinki. The review consists of analysis from publicly available information from published clinical trials and journal articles. No patient or institutional level data was used.

Results

Applying our search strategy, we identified 4,006 unique citations. We excluded 1,917 titles and abstracts and retrieved 180 full text reports for further review (Figure 1). We included 111 study reports in the analysis (listed in Appendix 1).

Figure 1.

PRISMA flow diagram summarizing the study selection process.²¹

An ophthalmologist was the senior author of about half (59/111; 53.2%) of the articles; most articles were published between 2016 and 2021 (71/111; 70.0%). The field of medicine of the most senior author was consistent with the field of medicine of the publishing journal in 75.6% of the studies (84/111). The field of medicine of the most senior author was more specific than the journal in 37.0% (10/27) of the studies with discrepancies. For example, Powers et. al 2005⁴ is published in the journal Medicine, and the senior author Cage Johnson, MD is a hematologist and therefore this paper was classified a “hematology” in this study. The majority of studies had been conducted in North America (54/111; 48.6%) or Europe (23/111; 20.7%) and had cross-sectional (51/111; 45.9%), prospective cohort (28/111; 25.2%), retrospective cohort (27/111; 24.3%) or case-control (4/111; 3.6%) designs. We found one randomized clinical trial (Table 1). Among the 111 studies, 44 had reported clinical or ophthalmic conditions among patients with sickle cell disease. Another 11 studies compared clinical or ophthalmic conditions in sickle cell patients with those in control patients and 2 only investigated vascular dynamics and morphology. The remaining 54 studies examined the development or presence of an ophthalmic (38/53; 71.7%) or systemic (16/53; 30.2%) condition associated with SCD. Investigators of a large proportion of the studies (33/111; 29.7%) did not specify how patients were selected, suggesting the possibility of some selection bias.

Table 1.

Study characteristics of the 111 studies included for analysis in the systematic scoping review.

Study Characteristic	No. (%)
Year published
2000–2010	17 (15.3)
2011–2015	23 (20.7)
2016–2021	71 (64.0)
Medical Specialty
Ophthalmology	59 (53.2)
Hematology	24 (21.6)
Pediatrics	8 (7.2)
Pediatric hematology	7 (6.3)
Other*	13 (11.7)
Location
North America	54 (48.6)
Europe	23 (20.7)
Africa	14 (12.6)
Latin	13 (11.7)
America/Caribbean
Asia or Middle East	10 (9.0)
Study Design
Cross-sectional	51 (45.9)
Prospective Cohort	28 (25.2)
Retrospective Cohort	27 (24.3)
Case-control	4 (3.6)
Randomized Clinical	1 (0.9)
Trial

^*Included internal medicine (n=2), research or statistical unit (n = 4), and one each of neurology, occupational medicine, pathology, pharmacology, radiology, urology, and veterinary physiology

Retinopathy had been reported as an outcome in most studies (87/111; 78.4%) (Table 2). The most commonly used definition was a combination of NPSR and PSR (52/87; 59.8%), although some investigators had limited the definition to PSR only (6/87; 6.9%). Other investigators had used other definitions (6/87; 6.9%) or did not report how they had defined retinopathy (23/87; 26.4%). The Goldberg classification scale was used to grade the severity of the retinopathy in almost half of the studies (41/87; 47.1%). We did not observe large differences across medical specialties in the method used for diagnosis, with the exception that any type of fundus photography was infrequently used in the fields of pediatrics or pediatric hematology.

Table 2.

The definition of retinopathy used grouped by medical specialty for studies that reported retinopathy. Non-proliferative sickle cell retinopathy (NPSR), proliferative sickle cell retinopathy (PSR)

Definitions of Retinopathy by Medical Specialty
	Ophthalmology (n = 59)	Hematology (n = 24)	Pediatrics (n = 8)	Pediatric Hematology (n = 7)	Other (N = 13)	Total (n = 111)
Characteristic	No. (%)	No. (%)	No. (%)	No. (%)	No. (%)	No. (%)
Reported retinopathy	48 (81.4)	18 (75.0)	4 (50.0)	7 (100)	10 (76.9)	87 (78.4)
Definition of retinopathy used
NPSR & PSR*	28 (58.3)	12 (66.7)	2 (50.0)	3 (42.9)	7 (70.0)	52 (59.8)
PSR only*	5 (10.4)	0	0	1 (14.3)	0	6 (6.9)
Other	3 (6.3)	0	1 (25.0)	2 (28.6)	0	6 (6.9)
None	12 (25.0)	6 (33.0)	1 (25.0)	1 (14.3)	3 (30.0)	23 (26.4)
Goldberg stage	24 (50.0)	9 (50.0)	1 (25.0)	2 (28.6)	5 (50.0)	41 (47.1)

^*Refers to the definition used to describe “retinopathy” in the methodology of the study and does not refer to the diagnosis of patients included.

In addition to retinopathy, other sickle cell-specific ophthalmic findings had been evaluated and reported throughout the literature. These included “black sunbursts lesions”, neovascular sea fan complexes, salmon patch hemorrhages, and iridescent spots (see Table 3). Vascular tortuosity, conjunctival vascular changes, and retinal blood velocity spoke to changes in the retinal and eye circulation. Other visual symptoms and observations often reported included retinal or macular thickness, retinal detachment, and vitreous hemorrhage.

Table 3.

Number of studies that reported retinopathy grouped by medical specialty including methods used to diagnose retinopathy. Optical coherence tomography (OCT) and angiography (OCT-A), fluorescein angiography (FA), ultrawide field fundus photograph (UWF-FP)

Methods used to Diagnose Retinopathy by Medical Specialty
	Ophthalmology (n = 59)	Hematology (n = 24)	Pediatrics (n = 8)	Pediatric Hematology (n = 7)	Other (N = 13)	Total (n = 111)
Characteristic	No. (%)	No. (%)	No. (%)	No. (%)	No. (%)	No. (%)
Reported retinopathy	48 (81.4)	18 (75.0)	4 (50.0)	7 (100)	10 (76.9)	87 (78.4)
Method used to diagnose retinopathy
Clinical fundus exam	30 (62.5)	12 (66.7)	4 (100.0)	4 (57.1)	7 (70.0)	57(64.4)
OCT	13 (27.0)	8 (44.4)	1 (25.0)	2 (14.3)	4 (40.0)	28 (27.6)
FA	10 (20.8)	4 (22.2)	0	1 (14.3)	5 (50.0)	20 (22.9)
UWF-FP	9 (18.8)	1 (5.6)	0	0	3 (30.0)	13 (17.2)
Fundus photography	9 (18.8)	1 (5.6)	0	0	4 (40.0)	14 (17.2)
OCT-A	4 (8.3)	4 (22.2)	0	1 (14.3)	1 (10.0)	10 (11.5)
Not specified	16 (33.3)	6 (33.3)	0	3 (42.9)	3 (30.0)	28 (32.2)

Investigators in half of the studies had used a clinical fundus examination of the retina for evidence of sickle cell lesions (56/111; 50.4%). Other examination methods had included use of optical coherence tomography (OCT) (24/111; 21.6%), fluorescein angiography (FA) (20/111; 18.0%), ultra-widefield fundus photographs (UWF-FP; 15/111; 13.5%), and optical coherence tomography-angiography (OCT-A) (10/111; 9.0%), with some studies having utilized more than one examination method (Table 3). In 25.2% of studies, the type of examination was not specified. The examiner often was identified as an ophthalmologist (67/111, 60.4%), and further identified as a retina specialist (33/67; 49.3%), but not specified in many study reports (44/111; 39.6%).

Overall, 84,961 patients had been included in the 111 studies we reviewed. Of these, 74,865 had been diagnosed with SCD with the remaining study participants having served as controls or having been selected from a population without a SCD diagnosis. The average age of patients with SCD was 27.8 ±10.6 years, with median age of 29.6 years in studies that had reported age. Among 89 studies that had reported sex, the mean proportion who were female was 56.5% ±16.1%. Among the patients with SCD who had information about genotype, 63.9% had been classified as HbSS, 20.3% as HbSC and the remainder as an HbS/BThal or other. The majority of studies were conducted in North America; study investigators specifically stated that the population they had examined was limited to people living in Africa in 10 studies, in Brazil in 2 studies, and a single study each in Egypt and Jordan. There were 33 studies concerned with use of new imaging technology, either OCT-A or UWF-FP In two studies, the investigators had tested a new screening or treatment algorithm. A total of 23 studies had investigated retinal vascular dynamics or morphology.

Discussion

In this scoping review, we describe the landscape of published literature on ocular manifestations of SCD in ophthalmology and in non-ophthalmology fields. Since 2015, there has been an increase in published literature on ocular outcomes in SCD with more than half of the 111 papers identified in our review published between 2016 and 2022. We found only one report of findings from a randomized clinical trial; very few included studies had case-control designs (Table 1). Retinopathy was reported as an outcome in 78% of the studies (Table 2). The most frequent definition of retinopathy had included both NPSR and PSR with the authors of the majority of these papers having used the Goldberg staging system. Most studies in this review incorporated clinical fundus exams to diagnose retinal pathology (Table 3). Reporting varied in identification of who performed the diagnostic eye exams. The examiner was identified as an ophthalmologist (67/111, 60.4%), and further identified as a retina specialist (33/67; 49.3%), but examiner expertise often had not been specified in study reports (44/111; 39.6%).

We found that across author specialties, the distribution of definitions of retinopathy used was very similar (Table 2). A large proportion of investigators did not report how they had defined retinopathy or used a definition other than NPSR or PSR. Based on this finding, we recommend that journal editors require authors of future reports on sickle cell retinopathy research to provide precise definitions of retinopathy because of the critical difference in risk of vision loss between NPSR and PSR.

We also found a lack of clarity in identification of which study investigators had performed the diagnostic eye exams. In the past readers may have assumed that an ophthalmologist had performed ophthalmic evaluations when the study report had not specified the expertise of the examiner. With the increased use of imaging technology, remote evaluation, and allied health professionals, it is important to identify who has performed diagnostic evaluations and the method employed.^31,32

The variable use of imaging techniques noted in this scoping review is consistent with a recent survey of retina specialist practice patterns for sickle cell retinopathy management which found wide variability in baseline imaging preferences.³³ Of 95 retina specialists surveyed by Mishra et al 2021, 42.1% routinely ordered a combination of macular imaging and FA at baseline while 41.1% ordered imaging based on examination findings.³³ That survey also found OCT was the most commonly ordered imaging method (47.5%), although retina specialists rarely ordered OCT alone (3.2%).³³ Presently, there is no standardized, evidence-based screening method to dictate which imaging modalities, if any, should be used routinely in sickle cell retinopathy screening.³³

In addition to retinopathy, many studies recorded additional visual outcomes. The most frequently reported outcome was visual acuity (Table 3), but very few studies reported vision loss, possibly due to patient population age, natural history of the disease, or an absence of baseline data for the few cohort studies.

The meager number of randomized clinical trials and robust studies with longitudinal follow-up from the 111 studies reviewed may have resulted from the relative paucity of funding for SCD research.²⁴ Current screening guidelines, based on expert consensus, but low-quality evidence, recommend referral of SCD patients to an ophthalmologist for a dilated retinal fundus exam annually or biannually starting at age 10.²⁵ Ocular outcomes in sickle cell disease usually present in patients by age 26, at which time 43% of patients with hemoglobin SC and 14% of patients with Hemoglobin SS have been reported to develop PSR.¹¹ PSR can regress, but vision loss attributed to PSR have been reported as high as 10–12% in untreated eyes.²⁶ A better understanding of the natural history of NPSR and PSR is necessary to ensure proper screening and to prevent vision loss with prompt treatment. Experts in the United States and abroad have called for increased focus on sickle cell retinopathy to take advantage of advances in technology to document natural history and to improve screening.^{27, 28} Our review highlights the need for more and longer longitudinal studies that follow pediatric into adult populations and document development, progression, and outcomes of sickle cell retinopathy.^4,29,30 We initiated this scoping review with intentionally broad criteria for identifying studies of potential interest to minimize bias in study selection and to enable us to capture the visual outcomes literature in SCD since 2000. By having restricted our search to records containing vision key words, we were not able to estimate the proportion of all SCD studies that have measured visual outcomes. Although our review may have been biased by limiting to English-language publications, we reported a distribution of SCD genotypes consistent with the prevalence of SCD genotypes worldwide.³⁴ We excluded case reports and case series as these types of studies typically are omitted from systematic reviews. Excluding case series may be a limitation to our research on this topic because the format is commonly used to study pathology affecting a small portion of the population. An additional potential limitation was in the method we used to attribute the medical field of a study, which we based on the specialty of the final author listed in the byline of each study report. This method does not account for collaboration among investigators in different specialties or for co-authors from other fields who may have contributed to study design or methodology. All PRISMA guidelines for scoping reviews were met excluding registering a standardized protocol for the review, but the search strategy used is printed in full in Appendix 2.²¹

Interestingly though not surprisingly, approximately 70% of research evaluating retinopathy and vision-related outcomes in SCD originated in North America and Europe. Only 10 studies focused on SCD patients in African populations. As the annual disease burden of SCD in sub-Saharan Africa is more than 80 times of that noted in the United States, additional research is needed to characterize ophthalmic findings in SCD in these medically underserved areas.³⁵

Our review summarizes the reporting of retinopathy and vision outcomes in SCD literature published during the past two decades. We also report deficiencies in documentation of study methods and assessment of vision-related outcomes. Of particular concern is the lack of adequate documentation of exam methods, expertise of examiners, and definitions of sickle cell retinopathy. Lack of documentation makes it difficult to assess study quality, to interpret findings from an individual study, and to compare outcomes among studies. Given the paucity of longitudinal studies of SCD, the persistent knowledge gaps regarding the natural history of NPSR and PSR, and increased availability of systemic interventions and pharmacotherapies for SCD, it is more important than ever to adopt clear and consistent descriptions and rigorous data collection and reporting of ophthalmic outcomes in SCD studies.

APPENDIX

Appendix 1

1. Abu-Yaghi NE, AlNawaiseh AM, Khourshid IM, et al. Central macular thickness in patients with sickle cell disease and no signs of retinopathy: a cross-sectional study of Jordanian patients. Journal of International Medical Research. 2020;49(4):300060520977387. doi:10.1177/0300060520977387

2. Ahmed I, Pradeep T, Goldberg MF, et al. Non-Mydriatic Ultra-Widefield Fundus Photography in a Hematology Clinic Shows Utility for Screening of Sickle Cell Retinopathy. American Journal of Ophthalmology. 2022;236:241–248. doi:10.1016/j.ajo.2021.10.030

3. Aikimbaev K, Guvenc B, Canataroglu A, Canataroglu H, Baslamisli F, Oguz M. Value of duplex and color doppler ultrasonography in the evaluation of orbital vascular flow and resistance in sickle cell disease. American Journal of Hematology. 2001;67(3):163–167. doi:10.1002/ajh.1100

4. Akgul F, Yalasin F, Seyfeli E, et al. Pulmonary hypertension in sickle-cell disease: comorbidities and echocardiographic findings. Acta Haematologica. 2007;118(1):53–60. doi:10.1159/000102588

5. Alam M, Thapa D, Lim JI, Cao D, Yao X. Quantitative characteristics of sickle cell retinopathy in optical coherence tomography angiography. Biomedical Optics Express. 2017;8(3):1741–1753. doi:10.1364/boe.8.001741

6. Alam M, Thapa D, Lim JI, Cao D, Yao X. Computer-aided classification of sickle cell retinopathy using quantitative features in optical coherence tomography angiography. Biomedical Optics Express. 2017;8(9):4206–4216. doi:10.1364/boe.8.004206

7. AlRyalat SA, Jaber BAM, Alzarea AA, Alosaimi WA, Al Saad M. Ocular Manifestations of Sickle Cell Disease in Different Genotypes. Ophthalmic Epidemiology. 2021;28(3):185–190. doi:10.1080/09286586.2020.1801762

8. AlRyalat SA, Nawaiseh M, Aladwan B, Roto A, Alessa Z, Al-Omar A. Ocular Manifestations of Sickle Cell Disease: Signs, Symptoms and Complications. Ophthalmic Epidemiology. 2020;27(4):259–264. doi:10.1080/09286586.2020.1723114

9. Andrawes NG, Ismail EA, Roshdy MM, Ebeid FSE, Eissa DS, Ibrahim AM. Angiopoietin-2 as a Marker of Retinopathy in Children and Adolescents With Sickle Cell Disease: Relation to Subclinical Atherosclerosis. Journal of Pediatric Hematology Oncology. 2019;41(5):361–370. doi:10.1097/mph.0000000000001486

10. Birkhoff WAJ, van Manen L, Dijkstra J, De Kam ML, van Meurs JC, Cohen AF. Retinal oximetry and fractal analysis of capillary maps in sickle cell disease patients and matched healthy volunteers. Graefes Arch Clin Exp Ophthalmol. 2020;258(1):9–15. doi:10.1007/s00417-019-04458-0

11. Bueso-Ponce D, Unigarro J, Vidal S, Salgado C, Ramos E, Abdala-Caballero C. Findings by SS-OCT and OCT-A in patients with sickle cell disease compared to healthy individuals. Revista Mexicana de Oftalmologia. 2021;95(2):56–62. doi:10.24875/RMO.M20000143

12. Bunod R, Mouallem-Beziere A, Amoroso F, et al. Sensitivity and Specificity of Ultrawide-Field Fundus Photography for the Staging of Sickle Cell Retinopathy in Real-Life Practice at Varying Expertise Level. J Clin Med. 2019;8(10). doi:10.3390/jcm8101660

13. Cai CX, Han IC, Tian J, Linz MO, Scott AW. Progressive Retinal Thinning in Sickle Cell Retinopathy. Ophthalmol Retina. 2018;2(12):1241–1248.e2. doi:10.1016/j.oret.2018.07.006

14. Cai S, Parker F, Urias MG, Goldberg MF, Hager GD, Scott AW. Deep Learning Detection of Sea Fan Neovascularization From Ultra-Widefield Color Fundus Photographs of Patients With Sickle Cell Hemoglobinopathy. JAMA Ophthalmol. 2021;139(2):206–213. doi:10.1001/jamaophthalmol.2020.5900

15. Cano J, Farzad S, Khansari MM, et al. Relating retinal blood flow and vessel morphology in sickle cell retinopathy. Eye (Lond). 2020;34(5):886–891. doi:10.1038/s41433-019-0604-y

16. Cheung AT, Chen PC, Larkin EC, et al. Microvascular abnormalities in sickle cell disease: a computer-assisted intravital microscopy study. Blood. 2002;99(11):3999–4005. doi:10.1182/blood.v99.11.3999

17. Cheung AT, Harmatz P, Wun T, et al. Correlation of abnormal intracranial vessel velocity, measured by transcranial Doppler ultrasonography, with abnormal conjunctival vessel velocity, measured by computer-assisted intravital microscopy, in sickle cell disease. Blood. 2001;97(11):3401–3404. doi:10.1182/blood.v97.11.3401

18. Chow CC, Genead MA, Anastasakis A, Chau FY, Fishman GA, Lim JI. Structural and functional correlation in sickle cell retinopathy using spectral-domain optical coherence tomography and scanning laser ophthalmoscope microperimetry. Am J Ophthalmol. 2011;152(4):704–711.e2. doi:10.1016/j.ajo.2011.03.035

19. 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(3):456–464.e2. doi:10.1016/j.ajo.2012.09.015

20. Colella MP, de Paula EV, Machado-Neto JA, et al. Elevated hypercoagulability markers in hemoglobin SC disease. Haematologica. 2015;100(4):466–471. doi:10.3324/haematol.2014.114587

21. Colombatti R, Palazzi G, Masera N, et al. Hydroxyurea prescription, availability and use for children with sickle cell disease in Italy: Results of a National Multicenter survey. Pediatric Blood and Cancer. 2018;65(2). doi:10.1002/pbc.26774

22. Corriveau-Bourque C, Bruce AAK. The changing epidemiology of pediatric hemoglobinopathy patients in Northern Alberta, Canada. Journal of Pediatric Hematology/Oncology. 2015;37(8):595–599. doi:10.1097/MPH.0000000000000442

23. Coskun M, Ilhan Ã, Ilhan N, et al. Changes in the cornea related to sickle cell disease: a pilot investigation. Eur J Ophthalmol. 2015;25(6):463–467. doi:10.5301/ejo.5000598

24. de Almeida Oliveira DC, Carvalho MO, do Nascimento VM, Villas-BÃás FS, Galvão-Castro B, Goncalves MS. Sickle cell disease retinopathy: characterization among pediatric and teenage patients from northeastern Brazil. Rev Bras Hematol Hemoter. 2014;36(5):340–344. doi:10.1016/j.bjhh.2014.07.012

25. Dell’Arti L, Barteselli G, Riva L, et al. Sickle cell maculopathy: Identification of systemic risk factors, and microstructural analysis of individual retinal layers of the macula. PLoS One. 2018;13(3):e0193582. doi:10.1371/journal.pone.0193582

26. Dembele AK, Lapoumeroulie C, Diaw M, et al. Cell-derived microparticles and sickle cell disease chronic vasculopathy in sub-Saharan Africa: A multinational study. Br J Haematol. 2021;192(3):634–642. doi:10.1111/bjh.17242

27. Desai PC, Deal AM, Brittain JE, Jones S, Hinderliter A, Ataga KI. Decades after the cooperative study: A re-examination of systemic blood pressure in sickle cell disease. American Journal of Hematology. 2012;87(10):E65-E68. doi:10.1002/ajh.23278

28. Downes SM, Hambleton IR, Chuang EL, Lois N, Serjeant GR, Bird AC. Incidence and natural history of proliferative sickle cell retinopathy: observations from a cohort study. Ophthalmology. 2005;112(11):1869–1875. doi:10.1016/j.ophtha.2005.05.026

29. Duan XJ, Lanzkron S, Linz MO, Ewing C, Wang J, Scott AW. Clinical and Ophthalmic Factors Associated With the Severity of Sickle Cell Retinopathy. Am J Ophthalmol. 2019;197:105–113. doi:10.1016/j.ajo.2018.09.025

30. 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(4):275–280. doi:10.1007/s12288-014-0333-0

31. Eruchalu UV, Pam VA, Akuse RM. Ocular findings in children with severe clinical symptoms of homozygous sickle cell anaemia in Kaduna, Nigeria. West Afr J Med. 2006;25(2):88–91. doi:10.4314/wajm.v25i2.28255

32. Estepp JH, Smeltzer MP, Wang WC, Hoehn ME, Hankins JS, Aygun B. Protection from sickle cell retinopathy is associated with elevated HbF levels and hydroxycarbamide use in children. Br J Haematol. 2013;161(3):402–405. doi:10.1111/bjh.12238

33. Fares S, Hajjar S, Romana M, et al. Sickle Cell Maculopathy: Microstructural Analysis Using OCTA and Identification of Genetic, Systemic, and Biological Risk Factors. Am J Ophthalmol. 2021;224:7–17. doi:10.1016/j.ajo.2020.11.019

34. Flor-Park MV, Kelly S, Preiss L, et al. Identification and Characterization of Hematopoietic Stem Cell Transplant Candidates in a Sickle Cell Disease Cohort. Biol Blood Marrow Transplant. 2019;25(10):2103–2109. doi:10.1016/j.bbmt.2019.06.013

35. Garrido VT, Sonzogni L, Mtatiro SN, Costa FF, Conran N, Thein SL. Association of plasma CD40L with acute chest syndrome in sickle cell anemia. Cytokine. 2017;97:104–107. doi:10.1016/j.cyto.2017.05.017

36. Gill HS, Lam WC. A screening strategy for the detection of sickle cell retinopathy in pediatric patients. Can J Ophthalmol. 2008;43(2):188–191. doi:10.3129/i08-003

37. Gilli SCO, Bastos SO, Benites BD, Costa FF, Saad STO. LDH and age are associated with hemolysis-endothelial dysfunction in HbSC patients. Blood Cells, Molecules, and Diseases. 2016;59:119–123. doi:10.1016/j.bcmd.2016.04.012

38. Grego L, Pignatto S, Alfier F, 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. Graefes Arch Clin Exp Ophthalmol. 2020;258(11):2551–2561. doi:10.1007/s00417-020-04764-y

39. Gualandro SF, Fonseca GH, Yokomizo IK, Gualandro DM, Suganuma LM. Cohort study of adult patients with haemoglobin SC disease: clinical characteristics and predictors of mortality. Br J Haematol. 2015;171(4):631–637. doi:10.1111/bjh.13625

40. Han IC, Linz MO, Liu TYA, Zhang AY, Tian J, Scott AW. Correlation of Ultra-Widefield Fluorescein Angiography and OCT Angiography in Sickle Cell Retinopathy. Ophthalmol Retina. 2018;2(6):599–605. doi:10.1016/j.oret.2017.10.011

41. Han IC, Zhang AY, Liu TYA, Linz MO, Scott AW. Utility of Ultra-Widefield Retinal Imaging for the Stating and Management of Sickle Cell Retinopathy. Retina. 2019;39(5):836–843. doi:10.1097/iae.0000000000002057

42. 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(6):990–994.e1. doi:10.1016/j.ajo.2010.12.010

43. Hood MP, Diaz RI, Sigler EJ, Calzada JI. Temporal Macular Atrophy as a Predictor of Neovascularization in Sickle Cell Retinopathy. Ophthalmic Surg Lasers Imaging Retina. 2016;47(1):27–34. doi:10.3928/23258160-20151214-04

44. Hussnain SA, Coady PA, Slade MD, et al. Hemoglobin level and macular thinning in sickle cell disease. Clin Ophthalmol. 2019;13:627–632. doi:10.2147/opth.S195168

45. Idris IM, Yusuf AA, Gwarzo DH, et al. High Systolic Blood Pressure, Anterior Segment Changes and Visual Impairment Independently Predict Sickle Cell Retinopathy. Hemoglobin. 2021;45(4):228–233. doi:10.1080/03630269.2021.1957927

46. Jin J, Miller R, Salvin J, et al. Funduscopic examination and SD-OCT in detecting sickle cell retinopathy among pediatric patients. J aapos. 2018;22(3):197–201.e1. doi:10.1016/j.jaapos.2017.12.019

47. Khansari MM, Garvey SL, Farzad S, Shi Y, Shahidi M. Relationship between retinal vessel tortuosity and oxygenation in sickle cell retinopathy. Int J Retina Vitreous. 2019;5:47. doi:10.1186/s40942-019-0198-3

48. Khansari MM, O’Neill W, Lim J, Shahidi M. Method for quantitative assessment of retinal vessel tortuosity in optical coherence tomography angiography applied to sickle cell retinopathy. Biomed Opt Express. 2017;8(8):3796–3806. doi:10.1364/boe.8.003796

49. Koduri PR, Agbemadzo B, Nathan S. Hemoglobin S-C disease revisited: clinical study of 106 adults. Am J Hematol. 2001;68(4):298–300. doi:10.1002/ajh.10001

50. Lagunju IA, Brown BJ. Adverse neurological outcomes in Nigerian children with sickle cell disease. Int J Hematol. 2012;96(6):710–718. doi:10.1007/s12185-012-1204-9

51. Lai JC, Fekrat S, Barrón Y, Goldberg MF. Traumatic hyphema in children: risk factors for complications. Arch Ophthalmol. 2001;119(1):64–70.

52. Lemaire C, Lamarre Y, Lemonne N, et al. Severe proliferative retinopathy is associated with blood hyperviscosity in sickle cell hemoglobin-C disease but not in sickle cell anemia. Clin Hemorheol Microcirc. 2013;55(2):205–212. doi:10.3233/ch-2012-1622

53. Lemonne N, Billaud M, Waltz X, et al. Rheology of red blood cells in patients with HbC disease. Clin Hemorheol Microcirc. 2016;61(4):571–577. doi:10.3233/ch-141906

54. 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 (SC) and homozygous sickle cell (SS) disease. Medicine (Baltimore). 2011;90(6):372–378. doi:10.1097/MD.0b013e3182364cba

55. Li J, Bender L, Shaffer J, Cohen D, Ying GS, Binenbaum G. Prevalence and Onset of Pediatric Sickle Cell Retinopathy. Ophthalmology. 2019;126(7):1000–1006. doi:10.1016/j.ophtha.2019.02.023

56. Lim JI, Cao D. Analysis of Retinal Thinning Using Spectral-domain Optical Coherence Tomography Imaging of Sickle Cell Retinopathy Eyes Compared to Age- and Race-Matched Control Eyes. Am J Ophthalmol. 2018;192:229–238. doi:10.1016/j.ajo.2018.03.013

57. Lim JI, Niec M, Sun J, Cao D. Longitudinal Assessment of Retinal Thinning in Adults With and Without Sickle Cell Retinopathy Using Spectral-Domain Optical Coherence Tomography. JAMA Ophthalmol. 2021;139(3):330–337. doi:10.1001/jamaophthalmol.2020.6525

58. Lim WS, Magan T, Mahroo OA, Hysi PG, Helou J, Mohamed MD. Retinal thickness measurements in sickle cell patients with HbSS and HbSC genotype. Can J Ophthalmol. 2018;53(4):420–424. doi:10.1016/j.jcjo.2017.10.006

59. Lima CS, Rocha EM, Silva NM, Sonatti MF, Costa FF, Saad ST. Risk factors for conjunctival and retinal vessel alterations in sickle cell disease. Acta Ophthalmol Scand. 2006;84(2):234–241. doi:10.1111/j.1600-0420.2005.00604.x

60. Lott PW, McKibbin M. Prevalence of Dark without Pressure and Angioid Streaks in Sickle Cell Disease. Ophthalmic Surg Lasers Imaging Retina. 2021;52(11):620–622. doi:10.3928/23258160-20211026-01

61. Lynch G, Scott AW, Linz MO, et al. Foveal avascular zone morphology and parafoveal capillary perfusion in sickle cell retinopathy. Br J Ophthalmol. 2020;104(4):473–479. doi:10.1136/bjophthalmol-2019-314567

62. Manara R, Dalla Torre A, Lucchetta M, et al. Visual cortex changes in children with sickle cell disease and normal visual acuity: a multimodal magnetic resonance imaging study. Br J Haematol. 2020;192(1):151–157. doi:10.1111/bjh.17042

63. Marchese A, Parravano M, Rabiolo A, et al. Optical coherence tomography analysis of evolution of Bruch’s membrane features in angioid streaks. Eye (Basingstoke). 2017;31(11):1600–1605. doi:10.1038/eye.2017.112

64. Martin GC, Albuisson E, Brousse V, de Montalembert M, Bremond-Gignac D, Robert MP. Paramacular temporal atrophy in sickle cell disease occurs early in childhood. Br J Ophthalmol. 2019;103(7):906–910. doi:10.1136/bjophthalmol-2018-312305

65. Mathew R, Bafiq R, Ramu J, et al. Spectral domain optical coherence tomography in patients with sickle cell disease. Br J Ophthalmol. 2015;99(7):967–972. doi:10.1136/bjophthalmol-2014-305532

66. Mian UK, Tang J, Allende APM, et al. Elevated fetal haemoglobin levels are associated with decreased incidence of retinopathy in adults with sickle cell disease. Br J Haematol. 2018;183(5):807–811. doi:10.1111/bjh.15617

67. Minvielle W, Caillaux V, Cohen SY, et al. Macular Microangiopathy in Sickle Cell Disease Using Optical Coherence Tomography Angiography. Am J Ophthalmol. 2016;164:137–44.e1. doi:10.1016/j.ajo.2015.12.023

68. Mo S, Krawitz B, Efstathiadis E, et al. Imaging Foveal Microvasculature: Optical Coherence Tomography Angiography Versus Adaptive Optics Scanning Light Ophthalmoscope Fluorescein Angiography. Invest Ophthalmol Vis Sci. 2016;57(9):Oct130–40. doi:10.1167/iovs.15-18932

69. Mokrane A, Gazeau G, Lévy V, Fajnkuchen F, Giocanti-Aurégan A. Analysis of the foveal microvasculature in sickle cell disease using swept-source optical coherence tomography angiography. Sci Rep. 2020;10(1):11795. doi:10.1038/s41598-020-68625-8

70. Moreira Neto F, Lourenço DM, Noguti MA, et al. The clinical impact of MTHFR polymorphism on the vascular complications of sickle cell disease. Braz J Med Biol Res. 2006;39(10):1291–1295. doi:10.1590/s0100-879x2006001000004

71. Naessens V, Ward R, Kuo KHM. A proposed treatment algorithm for adults with Haemoglobin SC disease. British Journal of Haematology. 2017;182(4):607–609. doi:10.1111/bjh.14852

72. Nawaiseh M, Shaban A, Abualia M, et al. Seizures risk factors in sickle cell disease. The cooperative study of sickle cell disease. Seizure. 2021;89:107–113. doi:10.1016/j.seizure.2021.05.009

73. Nia J, Lam WC, Kleinman DM, Kirby M, Liu ES, Eng KT. Retinopathy in sickle cell trait: does it exist? Can J Ophthalmol. 2003;38(1):46–51. doi:10.1016/s0008-4182(03)80008-x

74. Nkanga D, Adenuga O, Okonkwo O, et al. Profile, Visual Presentation and Burden of Retinal Diseases Seen in Ophthalmic Clinics in Sub-Saharan Africa. Clin Ophthalmol. 2020;14:679–687. doi:10.2147/opth.S226494

75. Oladimeji OI, Adeodu OO, Onakpoya OH, Adegoke SA. Prevalence of ocular abnormalities in relation to sickle cell disease severity among children in South-western, Nigeria. Eur J Ophthalmol. 2021;31(5):2659–2665. doi:10.1177/1120672120957615

76. Oltra EZ, Chow CC, Wubben T, Lim JI, Chau FY, Moss HE. Cross-Sectional Analysis of Neurocognitive Function, Retinopathy, and Retinal Thinning by Spectral-Domain Optical Coherence Tomography in Sickle Cell Patients. Middle East Afr J Ophthalmol. 2016;23(1):79–83. doi:10.4103/0974-9233.150632

77. Oluleye TS, Babalola Y. Indications for Intravitreal Bevacizumab in Ibadan, Sub-Saharan Africa. TOOPHTJ. 2014;8(1):87–90. doi:10.2174/1874364101408010087

78. Osafo-Kwaako A, Kimani K, Ilako D, et al. Ocular manifestations of sickle cell disease at the Korle-bu Hospital, Accra, Ghana. Eur J Ophthalmol. 2011;21(4):484–489. doi:10.5301/ejo.2010.5977

79. Osuobeni EP, Okpala I, Williamson TH, Thomas P. Height, weight, body mass index and ocular biometry in patients with sickle cell disease. Ophthalmic Physiol Opt. 2009;29(2):189–198. doi:10.1111/j.1475-1313.2008.00622.x

80. Pahl DA, Green NS, Bhatia 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. doi:10.1016/j.ajo.2017.08.010

81. Powars DR, Chan LS, Hiti A, Ramicone E, Johnson C. Outcome of sickle cell anemia: a 4-decade observational study of 1056 patients. Medicine (Baltimore). 2005;84(6):363–376. doi:10.1097/01.md.0000189089.45003.52

82. Powars DR, Hiti A, Ramicone E, Johnson C, Chan L. Outcome in hemoglobin SC disease: a four-decade observational study of clinical, hematologic, and genetic factors. Am J Hematol. 2002;70(3):206–215. doi:10.1002/ajh.10140

83. Rosenberg JB, Hutcheson KA. Pediatric sickle cell retinopathy: correlation with clinical factors. J aapos. 2011;15(1):49–53. doi:10.1016/j.jaapos.2010.11.014

84. Saganuwan S. The pattern of sickle cell disease in sickle cell patients from Northwestern Nigeria. Clinical Medicine Insights: Therapeutics. 2016;8:53–57. doi:10.4137/CMT.S38164

85. Sahak H, Saqalain M, Lott PW, McKibbin M. Sickle Cell Maculopathy: Prevalence, Associations and Impact on Visual Acuity. Ophthalmologica. 2021;244(2):159–164. doi:10.1159/000512636

86. Samant S, Dhar SK, Sahu MC. Ophthalmic manifestation of sickle cell patients in eastern India. Journal of Clinical and Diagnostic Research. 2018;12(7):OC13-OC15. doi:10.7860/JCDR/2018/36868.11810

87. Samarron SL, Miller JW, Cheung AT, et al. Homocysteine is associated with severity of microvasculopathy in sickle cell disease patients. British Journal of Haematology. 2020;190(3):450–457. doi:10.1111/bjh.16618

88. Sant’Ana PGDS, Araujo AM, Pimenta CT, et al. Clinical and laboratory profile of patients with sickle cell anemia. Revista Brasileira de Hematologia e Hemoterapia. 2017;39(1):40–45. doi:10.1016/j.bjhh.2016.09.007

89. Sayag D, Binaghi M, Souied EH, et al. Retinal photocoagulation for proliferative sickle cell retinopathy: a prospective clinical trial with new sea fan classification. Eur J Ophthalmol. 2008;18(2):248–254. doi:10.1177/112067210801800213

90. Sevgi DD, Scott AW, Martin A, et al. Longitudinal assessment of quantitative ultra-widefield ischaemic and vascular parameters in sickle cell retinopathy. Br J Ophthalmol. Published online October 31, 2020. doi:10.1136/bjophthalmol-2020-317241

91. Sevgi DD, Srivastava SK, Wykoff C, et al. Deep learning-enabled ultra-widefield retinal vessel segmentation with an automated quality-optimized angiographic phase selection tool. Eye (Lond). Published online August 9, 2021. doi:10.1038/s41433-021-01661-4

92. Shah NR, Bhor M, Latremouille-Viau D, et al. Vaso-occlusive crises and costs of sickle cell disease in patients with commercial, Medicaid, and Medicare insurance – “the perspective of private and public payers. Journal of Medical Economics. 2020;23(11):1345–1355. doi:10.1080/13696998.2020.1813144

93. Shahidi M, Felder AE, Tan O, Blair NP, Huang D. Retinal Oxygen Delivery and Metabolism in Healthy and Sickle Cell Retinopathy Subjects. Invest Ophthalmol Vis Sci. 2018;59(5):1905–1909. doi:10.1167/iovs.17-23647

94. Shukla P, Verma H, Patel S, Patra PK, Bhaskar L. Ocular manifestations of sickle cell disease and genetic susceptibility for refractive errors. Taiwan J Ophthalmol. 2017;7(2):89–93. doi:10.4103/tjo.tjo_3_17

95. Silva IV, Reis AF, Palaré MJ, Ferrão A, Rodrigues T, Morais A. Sickle cell disease in children: chronic complications and search of predictive factors for adverse outcomes. Eur J Haematol. 2014;94(2):157–161. doi:10.1111/ejh.12411

96. Spyridon G. Contrast Sensitivity in Patients with Beta-Thalassemia Major and Sickle Cell Disease Under Regular Transfusions and Treatment with Desferrioxamine. TOOPHTJ. 2010;4(1):39–41. doi:10.2174/1874364101004010039

97. Tantawy AA, Andrawes NG, Adly AA, El Kady BA, Shalash AS. Retinal changes in children and adolescents with sickle cell disease attending a paediatric hospital in Cairo, Egypt: risk factors and relation to ophthalmic and cerebral blood flow. Trans R Soc Trop Med Hyg. 2013;107(4):205–211. doi:10.1093/trstmh/trt008

98. Thangamathesvaran L, Ong SS, Wang J, Lance E, Tekes A, Scott AW. Evaluation of Macular Flow Voids on Optical Coherence Tomography Angiography [OCT-A] as Potential Biomarkers for Silent Cerebral Infarction in Sickle Cell Disease. Retina. Published online September 23, 2021. doi:10.1097/iae.0000000000003309

99. Thavikulwat AT, Cao D, Vajaranant TS, Lim JI. Longitudinal Study of Peripapillary Thinning in Sickle Cell Hemoglobinopathies. Am J Ophthalmol. 2019;202:30–36. doi:10.1016/j.ajo.2019.02.006

100. Tolu SS, Reyes-Gil M, Ogu UO, Thomas M, Bouhassira EE, Minniti CP. Hemoglobin F mitigation of sickle cell complications decreases with aging. American Journal of Hematology. 2020;95(5):E122-E125. doi:10.1002/ajh.25759

101. Tozatto-Maio K, Girot R, Ly ID, et al. Polymorphisms in Inflammatory Genes Modulate Clinical Complications in Patients With Sickle Cell Disease. Front Immunol. 2020;11:2041. doi:10.3389/fimmu.2020.02041

102. Tripathi A, Jerrell JM, Stallworth JR. Clinical complications in severe pediatric sickle cell disease and the impact of hydroxyurea. Pediatric Blood and Cancer. 2011;56(1):90–94. doi:10.1002/pbc.22822

103. Ugwu AO, Ibegbulam OG, Nwagha TU, Madu AJ, Ocheni S, Okpala I. Clinical and laboratory predictors of frequency of painful crises among sickle cell anaemia patients in Nigeria. Journal of Clinical and Diagnostic Research. 2017;11(6):EC22-EC25. doi:10.7860/JCDR/2017/26446.10042

104. Ulusoy MO, Türk H, Kıvanç SA. Spectral domain optical coherence tomography findings in Turkish sickle-cell disease and beta thalassemia major patients. J Curr Ophthalmol. 2019;31(3):275–280. doi:10.1016/j.joco.2019.01.012

105. Valeshabad A, Wanek J, Zelkha R, et al. Conjunctival microvascular haemodynamics in sickle cell retinopathy. Acta Ophthalmol. 2015;93(4):e275–80. doi:10.1111/aos.12593

106. van Tuijn CFJ, Schimmel M, van Beers EJ, Nur E, Biemond BJ. Prospective evaluation of chronic organ damage in adult sickle cell patients: A seven-year follow-up study. Am J Hematol. 2017;92(10):E584-e590. doi:10.1002/ajh.24855

107. Vatansever E, Vatansever M, Dinç E, Temel G, Ãœnal S. Evaluation of Ocular Complications by Using Optical Coherence Tomography in Children With Sickle Cell Disease Eye Findings in Children With Sickle Cell Disease. J Pediatr Hematol Oncol. 2020;42(2):92–99. doi:10.1097/mph.0000000000001678

108. Yilmaz K, Öncül H, Uzel H, Öncel K, Yılmaz ED, Söker M. Evaluation of retinal nerve fiber layer and choroidal thickness with spectral domain optical coherence tomography in children with sickle cell anemia. Turk J Pediatr. 2021;63(5):875–883. doi:10.24953/turkjped.2021.05.015

109. Yu TT, Nelson J, Streiff MB, Lanzkron S, Naik RP. Risk factors for venous thromboembolism in adults with hemoglobin SC or Sβ+ thalassemia genotypes. Thrombosis Research. 2016;141:35–38. doi:10.1016/j.thromres.2016.03.003

110. Zhou DB, Castanos MV, Pinhas A, et al. Quantification of intermittent retinal capillary perfusion in sickle cell disease. Biomed Opt Express. 2021;12(5):2825–2840. doi:10.1364/boe.418874

111. Zhou DB, Scott AW, Linz MO, et al. Interocular asymmetry of foveal avascular zone morphology and parafoveal capillary density in sickle cell retinopathy. PLoS One. 2020;15(6):e0234151. doi:10.1371/journal.pone.0234151

Appendix 2

Scoping Review Methodology

We will identify studies that evaluated SCD and any vision related outcomes that could be related to ‘retinopathy’ by using the following search strategy for PubMed. Similar strategies will be run for Google Scholar, Embase and the Cochrane library.

#1	"Anemia, Sickle Cell"[Mesh] OR "sickle cell*"[tw] OR SCD[tw] OR Hbss[tw] OR HbSC[tw] OR "hemoglobin C"[tw] OR "haemoglobin C"[tw] OR "hemoglobin S"[tw] OR "haemoglobin S"[tw] OR " Hb-thal"[tw] OR "beta thalassemia*"[tw]
#2	"Retinal Diseases"[Mesh] OR "Eye"[Mesh] OR "Vision, Ocular"[Mesh] OR "Vision Disorders"[Mesh] OR "Visual Acuity"[Mesh] OR "Vitreous Hemorrhage"[Mesh] OR "Retina"[Mesh] OR retina*[tw] OR retinopath*[tw] OR eye[tw] OR eyes[tw] OR vision[tw] OR visual[tw] OR sight[tw] OR ocular*[tw] OR acuity[tw] OR acuities[tw] OR proliferative[tw] OR nonproliferative[tw] OR fundus[tw] OR vitreous[tw] OR macular[tw] OR "spontaneous regression"[tw] OR neovascular[tw] OR "sea fan"[tw] OR "salmon patch*"[tw] OR sunburst*[tw] OR vitreoretinopath*[tw] OR hemian-opsia*[tw] OR optical[tw]
#3	#1 AND #2

We will screen the titles and abstracts for identified hits for studies that mention retinopathy or reference to eyes and vision and vision-related outcomes. The following terms are examples of those that will identify reports for which full-text articles/reports will be retrieved for final selection for inclusion in the review: retinopathy, eye, vision, sight, ocular, visual fields, vision outcomes, acuity, proliferative, non-proliferative, fundus, visual loss, vitreous hemorrhage, retinal detachment, retinal ischemia, macular ischemia, spontaneous regression, neovascular complexes, sea fan, salmon patch, sunburst.

Types of studies

This review will include all study designs excluding series or case reports.

Target population

We will include in our primary review all studies that have assessed patients with sickle cell disease, regardless of genotype variant, who developed pathological changes in their retina related to their sickle cell disease. We will exclude studies in which patients’ retinopathy changes are attributable to other causes, such as diabetes.

Inclusion Criteria

Inclusion criteria will be intentionally broad so as to include a full assessment of how retinopathy has been described or assessed in published research to date.

Data extraction

Using a data collection form in Microsoft Excel, we will then extract the following information [RS1] :

First author last name

Last author last name

Field of medicine of the last author

Field of medicine of the publication

Year study initiated

Year of publication

Design of the study

Geographic location of study

End-organs targeted for assessment in study

Any mention of “retinopathy”

Was retinopathy assessed in the study? (Yes/No) If YES, definition (specify)

1. 1. NPSR + PSR
   2. PSR alone
   3. an alternative definition (specify)_

How was retinopathy diagnosed?

1. Exam by an ophthalmologist

   1. retinal specialist?

2. Exam by an optometrist

3. Exam by other medical caregiver

How was the diagnosis documented/derived?

1. Clinical fundus exam

2. Ultra-wide field fundus photographs

3. Fluorescein angiography

4. Other of diagnosis and documentation (specify)

When was retinopathy diagnosed?

1. Before study initiation

2. During study

What other ocular manifestations of SCD were reported?

(Visual loss or changes in relation to SCD)

Description of population being studied

1. number of patients

2. Number/proportion with "retinopathy" as defined by study investigators

3. genotype of SCD

4. age range

5. sex distribution

6. setting (out-patient, hospital, etc.)

Risk of bias

We will assess the included studies using the first seven questions of the Critical Appraisal Skills Programme (CASP) Cohort Study Checklist to assess selection and information bias.

Data analysis

The data analysis will be primarily descriptive, i.e., frequency distributions of responses with means (or medians) and standard deviations (or ranges). Subgroups of interest will include the date the study was conducted and whether the study was published in eye and vision literature or other discipline.

Using the data extracted, we will be able to determine the number of different definitions for retinopathy used in literature and the proportion of times each separate definition was used. We will examine potential correlations between fields of medicine and the use of particular definitions of retinopathy or the reporting of other ocular manifestations of SCD. Findings from our review are expected to highlight the need to standardize the reporting of ocular manifestations of SCD by both ophthalmologists and non-ophthalmologist researchers.