Elsevier

Blood Reviews

Volume 35, May 2019, Pages 32-42
Blood Reviews

Review
Sickle cell retinopathy: What we now understand using optical coherence tomography angiography. A systematic review

https://doi.org/10.1016/j.blre.2019.03.001Get rights and content

Abstract

For over four decades, efforts have been underway for the evaluation of sickle cell retinopathy (SCR) in an attempt to identify peripheral high-risk vascular abnormalities based on Goldberg's classification (gold-standard) (1971). The macula is an area in the center of the retina that is responsible for high-resolution central vision and is also affected in SCR. With the development of new technologies for retinal imaging, the macula became a main focus of interest in the study of sickle cell disease (SCD). Optical coherence tomography angiography is a modern non-invasive method that allows qualitative and quantitative analysis of the retinal vascular network in the macular region. We identified 86 studies on SCD and optical coherence tomography angiography. Of those, 12 met the inclusion criteria for this systematic review. The prevalence of sickle cell maculopathy was 45.6% in the SCD population and it increased with age. We present the main vascular findings and discuss visual impairment and pathophysiology, genotypes, and peripheral high-risk vascular abnormalities. The role of the hematologist, general practitioner, and pediatrician in treatment is also reviewed.

Introduction

Sickle cell retinopathy (SCR) is characterized by retinal vascular changes occurring due to sickle cell disease (SCD) [1]. Under hypoxia, erythrocytes become sickle-shaped, causing vaso-occlusive complications that may occur in the peripheral retina [2] or in the macula [3] (the area responsible for high-resolution central vision). Secondary angiogenesis due to retinal ischemia can cause peripheral neovascularization so called proliferative SCR [1,3].

The clinical staging classification for SCR was proposed by Goldberg in 1971 [4]. According to Goldberg's classification, SCR can be divided into five stages by chronological order of appearance, from definitive arteriolar occlusions to retinal detachment and vision loss. At that time their study focused on the peripheral changes, and there is no mention of macular findings [4].

Fluorescein angiography (FA) is an invasive method that uses an intravenous fluorophore (fluorescein sodium) and a camera to analyze retinal circulation [5,6]. FA has been used as the gold standard examination for the study of retinal vascular diseases for over four decades [4], and its findings in the macula of patients with SCR have been well described in the literature since 1976 [7]. This method provides a set of two-dimensional images [8] and, although the retina is an almost transparent structure, comparative findings have suggested that the deep capillary network is not well visualized by FA [5].

The development of new technologies for retinal examination has improved the accuracy of diagnosis and understanding of diseases [9]. This has led to a renewed interest in studying the macula of patients with SCD in current years [10].

A relatively new method, spectral-domain optical coherence tomography (SD-OCT) allows a “live biopsy” of the retina. With SD-OCT, it has been possible to identify high rates of macular anatomic abnormalities (macular thinning) in patients without visual impairment [11]. SD-OCT adds useful information because even patients in the same clinical stage of the disease can be differentiated based on macular thickness [11]. SD-OCT has also helped understand that the pathophysiology of macular thinning in SCD appears to be related to retinal deep capillary plexus (DCP) occlusions [12].

Optical coherence tomography angiography (OCTA) is a modern, non-invasive method whereby optical coherence tomography (optical interferometry) is used to study the retinal vascular structure [8]. OCTA allows qualitative and quantitative analysis of the retinal vascular structure in the macular region within seconds [8]. In addition to not using contrast, OCTA allows the vascular structure of the different retinal histological layers (such as DCP) to be analyzed separately [8]. Moreover, OCTA can detect vascular abnormalities even in patients presenting normal FA [13].

A timeline of the development of new retinal imaging technologies and their application in SCD is shown in Fig. 1. The display of an OCTA device (Trinton, Topcon, Japan) during the analysis of a patient with asymptomatic SCD is presented in Fig. 2.

Recent studies have described retinal changes detected by OCTA in patients with SCD. The first cases were published in 2015 [14,15] and the study with the largest number of participants (n = 46) was published in 2017 [16].

The purpose of this systematic review was to collect and evaluate the main OCTA findings of the retina in patients with SCD and the prevalence of sickle cell maculopathy (SCM) using OCTA as the diagnostic test.

Section snippets

Search strategy

We searched the MEDLINE/PubMed, Cochrane Library, Virtual Health Library, BRAVS library (Brazilian Retina and Vitreous Society), and ONE network (American Academy of Ophthalmology) electronic databases using a combination of descriptors, including Medical Subject Headings and Descriptors in Health Sciences terms, as well as contractions of descriptors.

The systematic review was not restricted to English publications; studies written in Portuguese and Spanish were also included. The Preferred

Identification and selection of studies

Of the 86 references obtained using the search strategy, 15 complete texts were selected for full reading. Of these, three studies were excluded: one because the outcome evaluated was not relevant to our review, one because the outcome was not limited to the studied population, and the third because the studied population was different.

Finally, 12 studies met the inclusion criteria for this systematic review (Fig. 3). Five of these were excluded from the prevalence analysis because of the study

Discussion

This systematic review collected information from 12 articles, totaling 242 eyes of 133 patients. Among these studies, seven were cross-sectional and five were case reports; ten were conducted in the United States and two in France. We were able to determine the prevalence of maculopathy and the main OCTA findings in the SCD population. However, subgroup analysis was limited because of the absence of certain information in some of the studies.

Final considerations and future directions

Retinal imaging modalities are evolving fast and helping the better understanding of SCD. The high sensitivity of OCTA for detecting vascular changes in the macula, even in asymptomatic patients, provides valuable information for diagnosing, counseling, treating, and, in the future, formulating public health measures for the control and follow-up of these patients.

General practitioners, pediatricians, and hematologists must be aware about this high-sensitivity diagnostic methods and the

Practice points

  • SCM is much more prevalent than was thought, and patients with HbSS genotype are more affected than patients with HbSC or HbSThal genotype.

  • The clinical staging for SCR does not correspond to macular involvement; OCTA adds valuable information for disease staging.

  • OCTA is a highly sensitive method to diagnose SCM; it can identify vascular abnormalities before the onset of irreversible macular thinning (loss of function).

  • Avoiding the occurrence of severe retinal thinning is critical to minimize

Research agenda

  • Perform observational studies using OCTA to identify SCM clinical and laboratory associations, risk factors, and the role of genetics.

  • Perform longitudinal researches to determine the natural history of SCM and the prognostic significance of OCTA findings.

  • Consider OCTA as a comparison criterion in non-ophthalmological SCD studies.

  • Provide new information for the development or enhancement of a machine-learning device that might be capable of suggesting personalized treatment or providing a score

Disclosures

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The paper was not presented at meetings. The authors declare no conflict of interest.

Acknowledgements

We would like to thank our colleagues Dr. Otacílio de Oliveira Maia Jr. and Dr. Rodrigo Santana Souza for their technical support for image acquisition.

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