Table of Contents

    Topic review

    Sickle Cell Retinopathy

    Subjects: Ophthalmology
    View times: 27
    Submitted by: Farid Menaa

    Definition

    This work provides a complete review on sickle cell retinopathy (SCR), the most representative ophtalmologic complication of sickle cell disease (SCD), a hemoglobinopathy affecting both adults and children. It extensively relates the classification, epidemiology, clinical manifestations, risk factors, diagnosis, prevention and therapeutic options for SCR. It also highlights the need of a multidisciplinary theranostic approach.

    1. Introduction

    Sickle cell retinopathy (SCR) is the most representative ophthalmologic complication of sickle cell disease (SCD), a hemoglobinopathy affecting both adults and children. SCD is the first and the most common group of hemoglobinopathies in the world[1]. Manifestations of SCD involve complex processes and pathways such as bioavailability of NO, endothelial activation, inflammation, blood cells adhesiveness, and oxidative stress[1][2]. In the world, due to its associated significant morbidity and mortality[3], SCD remains a major public health concern affecting millions of people, especially those of African descent (0.4%)[4]. Hence, there is an urgent need for these people to have easier access to comprehensive team care[5]. In the USA, SCD affects nearly 100,000 individuals[5][6] with a frequency of up to 0.003% in African-American births[5][7]. In Brazil, the frequency reaches up to 0.06% depending on the different regions[8], whereas in Africa, the frequency is the highest in the world, varying from 5% to 40%[9][10].

    2. Classification and Epidemiology of SCR

    In SCD, ocular lesions result from stasis and occlusion of small eye vessels by sickled erythrocytes[11].

    SCR is mainly classified as NPSCR or PSCR. PSCR is based on the presence of vascular proliferation (ie, neoangiogenesis which can be followed by VH and retinal detachment)[11].

    Goldberg and Penman classifications are used to grade retinopathy severity (stage I–V) in SCD patients[12][13][14]. Four decades ago, Goldberg classified PSCR in five stages[15]:

    1. peripheral arterial occlusion;

    2. peripheral arteriovenous anastomoses, representing dilated preexisting capillaries (hairpin loop);

    3. neovascular and fibrous proliferation (sea fan) occurring at the posterior border of non-perfusion. The subsequent white sea fan appearance is due to auto-infarction of the neovasculature. This stage III PSCR has been further divided by other authors[16] into five new grades (A–E) considering size (grade A) with flat sea fan with leakage <1 macular photocoagulation study disc area, hemorrhage (grade B), partial fibrosis (grade C) with elevated sea fan, complete fibrosis (grade D) with elevated sea fan, and visible/well-defined vessels (grade E);

    4. VH;

    5. TRD.

    As is notable, RRD was not mentioned. Yet, RRD is the most common type of retinal detachment, which is characterized by an accumulation of subretinal fluid in the space between the neurosensory retina and the underlying retinal pigment epithelium. In RRD, vitreous traction causes a tear in the retina (ie, retinal breaks), and its most common cause is degeneration of the vitreous body[17]. Thus, we suggest the inclusion of RRD within the fifth stage of Goldberg and Penman’s classification. Further, this classification was updated by Penman about two decades ago based on a comparison of the peripheral retinal vascular bed in subjects with SS and SCD using normal hemoglobin (AA) genotype as control[18]. Therefore, the vascular patterns were classified as qualitatively normal (type I) or abnormal (type II). A normal vascular border, if posterior, results from gradual modification of the capillary bed, and is an indicator of low risk of proliferative disease. An abnormal border does not revert to normal, and is subject to continuous evolution until development of proliferative lesions.

    Importantly, it is estimated that the prevalence of retinopathy in USA is about 15%–20% among SS patients and 33%–40% among SC patients[19]. Also, the incidence of PSCR is highest in patients with SC or S-Thal (33% and 14%, respectively), while patients with SS have a 3% incidence of PSCR[4][19]. Moreover, there is an increase with age in the incidence and prevalence rates of all ocular complications of SCD. Thus, the highest prevalence of PSCR in SS patients occurs between 25 and 39 years in both men and women, while in SC patients it occurs earlier in men (15–24 year old) and women (20–39 years old)[20]. This is illustrated by a study published a decade ago showing a higher prevalence of SCR among SC patients (43%) who developed PSCR by the age of 24 years compared to that of SS patients (14%)[21]. Concordantly, in a recent retrospective study[13] involving SS, SC, and AS adult patients, about thrice more SC patients (54.6%) developed grade 3–5 PSCR compared to that of SS patients (18.1%). Also, in the same study, the prevalence of severe SCR forms was significantly higher among SS men (21.7%) than among SS women (15.5%), whereas systemic and ocular complications were infrequently seen in AS patients. Besides, in a very small number of patients with HbSE (another heterozygous state of HbS[22], albeit still rare and slowly rising worldwide)[23][24], NPSCR was most common[24].

    Taken together, PSCR is rarer than NPSCR in SCD patients, but PSCR is diagnosed more frequently in SC patients than in SS patients[9][25][12][18][20].

    3. Pathogenesis, Clinical Manifestations, and Complications of SCR

    The pathophysiology of SCD is not limited to abnormal red blood cells. Current knowledge about ocular manifestations in SCD patients revealed that virtually every vascular bed in the eye can be affected by vaso-occlusive events (eg, relatively high occlusion indices of peripheral retinal vessels)[26]. In SCR patients, who are often asymptomatic, the most significant ocular changes occur in the fundus and the retinal vascular damages can progressively cause ischemic retinopathy, proliferative lesions in both the anterior and posterior segments of the eye, and visual impairment, that is, corrected distance visual acuity of 20/40 or poorer[26][11][14][27]. It is worth noting that SCR patients display a variable phenotype, even among individuals with the same genotype[28]. For instance, damages of the anterior segment would be more common in SC patients[27].

    NPSCR, more commonly observed in SS patients, is manifested by typical alterations depending on the retinal location. Hence, the retinal periphery of patients with NPSCR is frequently characterized by precocious bilateral changes, peripheral closure/anastomoses, salmon-patch hemorrhages (Figure 2), iridescent spots, and black sunbursts[29]. The central part of the retina usually reveals arteriovenous tortuosity, enlargement of the foveal avascular (non-perfused) zone (FAZ), CRAO (eye stroke), as well as peripapillary and perimacular arterial occlusions[29]. It is worthwhile to mention that CRAO is a rare but a potentially devastating cause of acute blindness in SCD[30].

    An external file that holds a picture, illustration, etc.
Object name is jmdh-10-335Fig2.jpg

    Figure 2. Salmon-patch hemorrhage in sickle cell retinopathy. Notes: This image was originally published in the ASRS Retina Image Bank by Larry Halperin, MD, Retina Group of Florida. Sickle Salmon-Patch Hemorrhage. 2012; image number, 1789. ©American Society of Retina Specialists. http://eyewiki.aao.org/Sickle_Cell_Retinopathy.

    PSCR, more commonly observed in SC patients, is due to the high prevalence of a qualitatively abnormal peripheral retinal vasculature[18]. Peripheral changes secondary to PSCR are generally associated with thinning of macular inner retinal layers and ganglion cell complex focal loss, as well as thickening of the central fovea[31][32][33][34]. For some unknown reasons, PSCR is uncommonly manifested by simultaneous bilateral macular occlusive events[35]. These retinal vascular occlusions cause tissue ischemia and release of angiogenic mediators that promote retinal neovascularization (ie, neovascular proliferation)[36][37][38]. Then, this neovascularization, a hallmark in PSCR patients, grows anteriorly from the perfused to non-perfused (avascular) retina to reach the posterior ischemic retina, and is characterized by flat vessels denominated sea fan structures (Figure 3) for their close resemblance to the marine invertebrate Gorgonia flabellum (Venus sea fan)[39]. The sea fan is a thick caliber preretinal fibrovascular membrane involving primarily the retinal nerve fiber and ganglion cell layers[40]. The repetition of hemorrhages can cause TRD (Figure 4) or RRD (Figure 5), which are severe complications of PSCR[15][21][41]. Visual impairments, such as vision loss, occur in 5%–20% of affected eyes of PSCR patients[28][27]. The reason why most patients maintain good vision 2 years after PSCR development is explained by the fact that the ocular damages occur in the retinal periphery, and that any associated sea fan structures have a high tendency to spontaneously regress (20%–60% of cases) through the development of atrophic lesions or auto-infarction[20][21][28].

    An external file that holds a picture, illustration, etc.
Object name is jmdh-10-335Fig3.jpg

    Figure 3. Sea fan formation with neovascularization. Notes: Fluorescein angiogram image of an individual with sickle cell retinopathy showing sea fan formation with neovascularization. This image was taken using an Optos P200MA ultrawide-field imaging device. This image was originally published in the ASRS Retina Image Bank by Michael P Kelly, FOPS Director, Duke Eye Center Labs, Duke University Hospital. Sickle Cell Retinopathy. 2012; image number, 721. ©American Society of Retina Specialists. http://eyewiki.aao.org/Sickle_Cell_Retinopathy.

    An external file that holds a picture, illustration, etc.
Object name is jmdh-10-335Fig4.jpg

    Figure 4. Patient with a central retinal vein occlusion complicated by neovascularization at the disc with subsequent tractional retinal detachment. Notes: Image reprinted with permission from Lihteh Wu, MD, Ophthalmologist, Costa Rica Vitreo and Retina Macular Associates, published by Medscape Drugs & Diseases (http://emedicine.medscape.com/), Tractional Retinal Detachment, 2017, available at: http://emedicine.medscape.com/article/1224891-overview#a5.

    An external file that holds a picture, illustration, etc.
Object name is jmdh-10-335Fig5.jpg

    Figure 5. Clinical picture of a rhegmatogenous retinal detachment. Notes: Notice that the macula is involved and that the retina is corrugated and has a slightly opaque color. Image reprinted with permission from Lihteh Wu, MD, Ophthalmologist, Costa Rica Vitreo and Retina Macular Associates, published by Medscape Drugs & Diseases (http://emedicine.medscape.com/), Tractional Retinal Detachment, 2017, available at: http://emedicine.medscape.com/article/1224891-overview#a5.

    4. Prevention and Diagnosis of SCR

    In the recent years, health care has dramatically increased the life expectancy of SCD patients, meantime contributing to the emergence of ocular complications related to ischemic retinopathy[14] (eg, maculopathy[27][42][43], CRAO[30], hyphema[44], retinal neovascularization [PSCR][44], vitreoretinal complications[45]).

    The hallmark of primary prevention should consist in reducing the prevalence of SCD by controlling the spread and perpetuation of the HbS gene pool. This can only be done by efforts at genetic counseling before marriage and child birth.

    Furthermore, most of the studies, led in different populations of patients with SCR, confirm the importance of periodic eye monitoring. Retinal examination should be done not only in homozygous (ie, SS) or double heterozygous patients (eg, SC, SE, Sβ0-thalassemia) but also in patients with SCT (ie, AS) when additional systemic vascular conditions are present[26][46].

    SCD patients should be screened from early childhood (usually 9–10 years for SC genotype patients and at 13 years for SS and Sβ0-thalassemia genotype patients) to timely identify retinal lesions, visual impairment (eg, visual loss), and prevent the progression of NPSCR to severe stages (ie, PSCR with VH or retinal detachment)[12][11][23][28][27][47]. Serial examinations may be done biennially for eyes with normal findings[46] in order to decrease morbidity[48]. SCD patients with retinopathy suspicion or predisposed to develop SCR should undergo complete ophthalmologic examination and be followed up as necessary.

    Thus, electrophoretic[1] or spectroscopic[49] confirmation of SCD remains the first step. Then, systemic and genetic risk factors of SCR could be evaluated (see “Clinical, systemic, and genetic risk factors of SCR” section). Ophthalmologic screening of SCD patients should involve a number of basic exams as well as the use of state-of-the-art retinal imaging techniques when available/possible due to their relative high cost[9][12][13][42][43][50][51]. Thus, routine screening of ocular abnormalities for earliest detection and intervention of retinopathy should include visual acuity testing (to measure the clarity or sharpness of vision at a distance of 20 feet), complete dilated funduscopy, as well as the use of slit-lamp biomicroscopy (to observe any ocular abnormalities in the anterior portion of the eye and eventual retinal detachments). In case of abnormal funduscopy[12][29], patient cases with ischemic retinopathy often undergo FA[9][12][26][46][51][52] or OCTA. Goldberg and Penman classifications are eventually employed to grade the retinopathy severity[29][43].

    FA is more sensitive in the diagnosis of retinopathy when compared to indirect ophthalmoscopy[29]. Ultrawide-field FA enables one to demonstrate macular arteriolar occlusive disease[50], visualize peripheral vascular remodeling[35], calculate peripheral ischemic index[52], or evidence retinal microvascular occlusions[53]. AOSLO-FA is an emerging high-resolution technique useful for noninvasive in vivo visualization of the human retinal microvasculature, measurements of blood flow velocity, and microvascular network mapping[54]. Although relatively well-tolerated in patients with SCR, indocyanine green angiography is rarely used but can show anomalies of the choroidal circulation, clearly delimit the black spots and the photocoagulation scars which appear larger than in FA[55].

    Spectral domain-OCT is essential in diagnosing retinal rather than optic nerve disease (eg, glaucoma), and can be used to confirm multifocal electroretinography[35]. OCT is useful for assessing bilateral temporal inner retinal hyper reflectivity[35], inner retinal thinning temporal to the fovea even normal in FA and clinical examination[56], and major peripheral changes secondary to PSCR (eg, peripapillary RNFL thinning, macular ganglion cell complex thinning, and total macular thicknesses)[31][32][42][52][53]. Interestingly, the presence of temporal macular atrophy is strongly associated with peripheral neovascularization[43], and OCT demonstrated a positive linear relationship between temporal macular thickness and global peripapillary RNFL thickness[53]. Nevertheless, it has been recently reported that scanning laser ophthalmoscope microperimetry, a sensitive measurement of macular function in SCD patients, is better than OCT for measuring focal macular thinning[50]. Importantly, for accurate differential diagnosis, OCT is able to identify in vivo morphological changes (eg, vitreous adhesions, membrane-retinal layers twist) between neovascularization in PSCR and proliferative diabetic retinopathy[40]. Interestingly, in a recent clinical trial assessing ocular changes in an African-American population with SCD, the authors used Spectralis HRA + OCT, an advanced multimodal imaging technology, enabling them to show individual layers of the retina which helped to 1) determine whether there were underlying changes in the gross ophthalmic posterior segment, 2) understand the ocular disease progression[57].

    OCTA is an improved version of OCT (ie, OCT + angiography). It is a gold standard in identifying retinal ischemia in patients with SCD[56]. It represents a relatively new non-invasive imaging system for monitoring ocular pathology and detecting early disease[58]. OCTA is able to show and compare both structural and blood flow information. Interestingly, when compared with AOSLO-FA, OCTA is able to generate volumetric data of retinal and choroidal layers (eg, retinal thinning, lumen diameter, FAZ perimeter, acircularity index)[48][51][58][59]. Furthermore, its ease of use, short acquisition time, and avoidance of potentially phototoxic blue light, can quantitatively and qualitatively better evidence retinal micro-vascular occlusions (eg, abnormalities in the perifoveal region of the macula such as reduced flow within the superficial and deep capillary plexus, vascular density, choroidal neovascularization, and areas of non-perfusion) than any other current FA tool[28][34][48][51][56][58][59]. OCTA also appeared more sensitive than FA techniques in detecting macular microangiopathy[51] and macular capillary non-perfusion[60] in asymptomatic patients. A vital component of OCTA, the split-spectrum amplitude-decorrelation angiography algorithm, helps to decrease the signal-to-noise ratio of flow detection, subsequently enhancing the visualization of retinal vasculature using motion contrast[48]. However, although blood vessels obscured by leakage are visible only on OCTA, microaneurysms, fine structure of vessel loops, leakage, and some vessel segments are invisible on OCTA and the use of AOSLO-FA is then required[48]. This suggests the need of employing OCTA and/or FA depending on the cases. In a newly published clinical trial, a retrospective observational study led in African-Canadian patients with SCT confirmed that OCTA is a valuable noninvasive office procedure that can be used to show macular vascular occlusions that usually occur in SC patients[61].

    5. Clinical, Systemic, and Genetic Risk Factors of SCR

    In addition to patient screening and complete eye examination, it would be helpful for the health care professional to earlier assess the presence of factors and biomarkers that increase the chance of developing PSCR.

    For the last four decades, after Goldberg’s seminal studies, risk factors (eg, clinical, genetic) for visual impairment have been reported in patients with SCD[14]. Considering the Mendelian inheritance of SCD, pregnancy is a high-risk situation for both the mother and child; hence, a search of genetic factors in the family is relevant and contributes to preventive medicine.

    Since SCR is more frequent and more severe in SC patients than in SS patients[12][14] although visual impairment is not significantly influenced by hemoglobin genotype[14], several influencing risk parameters (eg, clinical predisposition, systemic factors, systemic gene polymorphisms influencing key proteins expression implicated specifically in the retinal pathogenesis) are more likely to be involved in SCR.

    Pain crisis[7][62], male gender[7], and splenic sequestration[7] in SCD patients are clinical risk factors that suggest complete eye examination. Importantly, eyes of SCD patients with iris atrophy or depigmentation are about twice more at risk of PSR than eyes without[63]. Nevertheless, it is worthwhile noting that there is no evidence to support an association between cognitive function and retinopathy in SCD, although there is an association between lower cognitive function and older age as well as history of stroke in genotyped SS patients[1][64]. In patients treated during 1 year of regular HU and transfusion therapy, SCR has been found to be correlated with time-averaged mean flow velocity in middle cerebral arteries but not in ophthalmic arteries[62]. In SC patients, characteristics of PSCR (eg, neovascular and fibrous proliferations, the so-called “sea fan” structures, VH and retinal detachment) are associated with older age (>35 years)[14], pulmonary disease, deafness or tinnitus, and no history of osteomyelitis. In SS patients, older age, male gender, and history of acute pyelonephritis are associated with the development of PSCR[11][65][66][67].

    Besides, some systemic factors can corroborate SCR diagnosis and may influence the prognosis of the disease. Thereby, high levels of Hb or hematocrit are associated with PSCR in SC genotyped patients, while high leukocyte count is associated with PSCR in SS or Sβ0-thalassemia patients[9]. Interestingly, low (<15%) HbF level is strongly associated with retinopathy (7 fold in children) independently of the SCD genotype, and so, the high prevalence of SCR is negatively associated to HbF level[9][68]. In one of our research studies involving Brazilian SCR patients, we showed that the significant decrease of soluble intercellular adhesion molecule and the significant increase of pigment epithelium-derived factor could contribute to the pathophysiology of retinal neovascularization[6]. We also demonstrated that angiopoietin (Ang-1 and Ang-2) as well as IL-1β levels were significantly elevated in patients with SCR, and SS patients presented significantly higher levels of Ang-2 compared to that of SC patients[6]. Interestingly, from autopsied eye tissues, it was shown that HIF-1α and VEGF are strongly expressed in the inner retina[38], but it remains undefined whether the expression of these factors from blood samples could be associated or correlated with clinicopathological features of retinopathy. In a lesser extent, glucose-6-phosphate dehydrogenase deficiency was insignificantly more common in SCR patients but could also deserve early screening[7].

    Recent advances in the post-human genome sequence era have opened the door to the identification in SCD patients of novel genetic modifiers (eg, gene polymorphisms, CNVs) mostly implicated in inflammation, NO biology, cell–cell interaction, and modulators of oxidant injury[1][2]. Discovery of submicroscopic genomic alterations associated with SCR phenotypes may aid in establishing precocious diagnosis as well as targeted cures. Interestingly, an across-sectional study showed that IL-6-597G>A is associated with a higher likelihood of retinopathy in Brazilian SS patients, and may thus be considered as a genetic predictor of SCR[69]. In another study that aimed to determine endothelial NO synthase genotype for T786C and G894T polymorphisms, the 786CC genotype was more common in SS and Sβ0 Greek patients with retinopathy[70]. Moreover, 894TT SS and Sβ0 patients tended to have a higher hematocrit value than 894GG and GT ones, suggesting that they could be predisposed to higher risk of retinopathy[70]. Nevertheless, there is still a paucity of reports and a lack of GWAS regarding genetic modifiers specifically involved in SCR phenotypes. In addition to genetic modifiers, one should remember that other contributors could be significantly involved in the etiology of the heterogeneous SCD and SCR phenotypes (eg, environmental components, genetic background of the population, socioeconomics, and psychology)[2].

    To date, overall reports showed that the prevalence of PSCR increased mainly with age (over 35 years) and with systemic severity (ie, inflammation), particularly in SC genotyped patients.

    6. Current and Advanced Therapeutic Options for SCR

    Over the past 20 years, improved therapeutic management has significantly increased the life expectancy of children with SCD. More than 90% of patients now reach the age of 20, and the median life expectancy of SCD patients reached over 50 years in countries with advanced health care systems. However, increase in the number of SCD adults is accompanied by frequent chronic ocular complications (eg, osteoarticular, renal, cardiorespiratory, cutaneous, and cerebral).

    Treatment for SCR remains palliative, and the development of novel, noninvasive, and effective retinal drug delivery systems is hampered by the lack of studies on SCR pathophysiology, animal models that accurately mimic human SCR[6]. Conventional therapies for SCR often include chemotherapy (eg, HU ± anti-VEGF), phlebotomy usually used in conjunction with long-term blood transfusions (eg, cell exchange transfusion) to mainly reduce total HbS red cells. In severe cases, laser-mediated photocoagulation (ie, repeated pan-retinal photocoagulation) and surgery (ie, PPV) are often required. In a lesser extent, alternative and complementary therapies such as HBOT, stem cells, and gene therapy are used. In general, experimental anti-sickling therapy and preoperative transfusion to prevent or treat eye lesions still need more investigations[44]. Thus, we recommend that health care professionals undertake all necessary measures to reduce ischemia, and it becomes evident that a well-trained multidisciplinary team should take on severe cases.

    Similar to erythrocytapheresis or exchange blood transfusion, hydroxycarbamide, commonly called HU, is now considered a preventive treatment for SCD due to its relative acceptable safety and efficacy[1][9][71][72]. A multicenter, placebo-controlled, Phase III clinical trial supports the safety and potentially salutary effects of HU treatment for patients with HbSC disease[68][72]. Thus, HU treatment is associated with a reduced absolute reticulocyte count, a stable Hb concentration, and an increased HbF known to exert protective benefit against retinopathy[68]. HU therapy is strongly recommended for SCD adults with at least three severe vaso-occlusive crises during any 12-month period, with pain or chronic anemia interfering with daily activities, or with severe or recurrent episodes of acute chest syndrome[6][72]. A recommendation of moderate strength suggests offering treatment with HU for infants, children, and adolescents with SCD without regard to the presence of symptoms[6]. Interestingly, oral administration of the antioxidant fumaric acid ester monomethyl fumarate, a known inducer of nuclear factor erythroid 2-related factor 2-antioxidant response element signaling pathway, is able to ameliorate retinopathy at the dose of 15 mg/mL for 5 months by inducing γ-globin expression and HbF production in the validated humanized Townes mouse model of SR[73].

    Concomitantly, anti-VEGF biotherapy by intravitreal injection of Lucentis® (ranibizumab; Roche, Basel, Switzerland) or the more recent Eylea® (aflibercept; Regeneron, Tarrytown, NY, USA) is widely used to treat retinopathy. In practice, both of these FDA-approved drugs are used to treat SCR with VH. Interestingly, in a first case report of PSCR, ranibizumab improved the visual acuity, resolution of VH, and regression of neovascularization with no recurrence or adverse effects[74]. Another FDA-approved drug Avastin® (bevacizumab; Genentech, South San Francisco, CA, USA) is now restricted to the treatment of various types of cancer, hence its “off-label” use in ophthalmology. Bevacizumab, albeit efficient in preoperative injection[75], was associated with significant secondary effects such as secondary hyphema few days postinjection in the eye of a PSCR patient with VH[76]. Clinical trials aiming to compare efficacy and safety of ranibizumab versus aflibercept, in patients with SCR versus patients with diabetic retinopathy, would be an asset.

    Also, iron-chelation therapy in patients with SCR presenting hemochromatosis (ie, iron overload) can be moderately recommended[1][6]. However, particular awareness is required when Exjade® (Novartis International AG, Basel, Switzerland), Desirox® (Cipla Limited, Mumbai, India), Defrijet® (CIMS, Mumbai, India), Rasiroxpine® (Hikma Pharmaceuticals, Amman, Jordan), Jadenu® (Novartis International AG) (deferasirox) are used. Although deferasirox is an EMA and FDA-approved iron-chelating agents, a case study implicating a child with a history of SCA revealed that the substitution of Desferal® (Novartis Pharma Stein AG, Stein, Switzerland) (deferoxamine mesylate) by deferasirox for 2 years can cause retinopathy and related manifestations (eg, decreased visual acuity, electrophysiological abnormalities, and mild funduscopic changes) were completely reversed after deferasirox therapy cessation[77].

    Preoperative transfusion therapy is strongly recommended to increase Hb levels to 10 g/dL for many individuals with SCD[6]. In SS patients undergoing long-term transfusion therapy, it is moderately recommended to maintain the HbS level below 30% prior to the next transfusion[6]. In SCR patients, there were only few attempts of exchange transfusions (ie, blood transfusion) when apheresis (ie, collection of donor blood constituents) is not used. A case study reported the successful use of chronic red cell exchange transfusion to preserve vision and stabilize recurrent retinopathy untreatable by LPC and vitrectomy in a child with PSCR[78]. Further, exchange transfusion was successful in an SS adult patient with unilateral paracentral occlusive retinopathy, an uncommon manifestation of SCD characterized by macular ischemia which can lead to vision loss if not reversed on time[79].

    Besides, despite warnings from the FDA for its use, HBOT could improve the acuity visual of SCD patients with CRAO[80]. Further, strong recommendations for patients with PSCR include referral to expert specialists for consideration of LPC, the most common treatment against vision loss and VH[10][38][81]. Clinical practitioners generally use argon arc rather than xenon arc for LPC in order to quench the expression of HIF-1-driven angiogenic mediators (eg, VEGF)[38]. It is then recommended that pan photocoagulation is preferentially realized with an argon arc beam, which should be well-placed at the ischemic areas, in order to avoid PPV in some PSCR eyes with VH[74]. Although SS-LPC to ischemic areas was reported to be effective after 6 months in achieving regression of peripheral neovascularization[23], FV-LPC prevented occurrence of VH with lesser adverse effects[38][81]. In two randomized controlled trials comparing efficacy and safety of LPC to no therapy in children and adults with PSCR, 1) no difference in the complete PSCR regression was observed after an averaged follow-up period of 21–32 months when SS-LPC was compared to the control group; 2) SS-LPC or FV-LPC may prevent loss of vision in eyes with PSCR; 3) occurrence prevention of VH is possible either with argon or xenon laser but xenon arc was associated with a significantly higher risk of choroidal neovascularization; 4) FV-LPC displayed greater protective effects when compared to SS-LPC; 5) minimal adverse effects (ie, very low incidence of retinal tear, no induction of retinal detachment, vision loss was uncommon within at least 3 years of follow-up). It is concluded that in the absence of further evidence, laser treatment for SCR should be considered as one of the therapeutic options for preventing visual loss and VH[81]. To the best of our knowledge, randomized controlled clinical trials aiming to assess the benefit/risk ratio of LPC combined with intravitreal injection of ranibizumab or aflibercept are lacking in PSCR patients.

    Eventually, vitrectomy can be applied if SCR presents vitro-retinal complications[78]. Usually, PSCR responds to vitrectomy procedures when sea fan proliferation is segmented[45]. PPV (Figure 6) is growing in popularity as a first-line procedure for primary RRD, especially in pseudophakic patients[82]. PPV presents advantages (eg, better visualization of retinal breaks, less painful intervention) over the longer and well-established scleral buckling, another common reattachment procedure[82. A recent retrospective, interventional case series of SCR patients managed with PPV over a 12-year period at a single institution showed full success in improving vision postoperatively in patients with VH or epiretinal membrane[83]. Nevertheless, moderate success was noticed in patients with recurrent TRD or RRD and so, these patients required a second operation[83]. Also, severe SCR patients with a hemorrhagic disease (eg, Glanzmann thrombasthenia) can find vitrectomy difficult[84]. Also, it is worthwhile to mention that vitro-retinal complications may spontaneously regress and reappear after vitrectomy or even LPC[78].

    An external file that holds a picture, illustration, etc.
Object name is jmdh-10-335Fig6.jpg

    Figure 6. Pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment, utilizing wide-field imaging and small-gauge transconjunctival sutureless instrumentation. Note: Copyright ©2008. Dove Medical Press. Reproduced from Schwartz SG, Flynn HW. Pars plana vitrectomy for primary rhegmatogenous retinal detachment. Clin Ophthalmol. 2008;2(1):57–63[82].

    The entry is from 10.2147/JMDH.S90630

    References

    1. Menaa F. Stroke in sickle cell anemia patients: a need for multidisciplinary approaches. Atherosclerosis. 2013;229(2):496–503.
    2. Driss A, Asare KO, Hibbert JM, Gee BE, Adamkiewicz TV, Stiles JK. Sickle cell disease in the post genomic era: a monogenic disease with a polygenic phenotype. Genomics Insights. 2009;2009(2):23–48.
    3. Reynolds SA, Besada E, Winter-Corella C. Retinopathy in patients with sickle cell trait. Optometry. 2007;78(11):582–587.
    4. Fekrat SG, Morton F. Sickle Retinopathy. New York: Thieme Medical Publishers; 1998.
    5. Centers for Disease Control and Prevention. Sickle cell disease. [Updated August 31, 2016]. Available from: https://www.cdc.gov/ncbddd/sicklecell/data.html. Accessed April 1, 2017.
    6. Cruz PR, Lira RP, Pereira Filho SA, et al. Increased circulating PEDF and low sICAM-1 are associated with sickle cell retinopathy. Blood Cells Mol Dis. 2015;54(1):33–37.
    7. Rosenberg JB, Hutcheson KA. Pediatric sickle cell retinopathy: correlation with clinical factors. J AAPOS. 2011;15(1):49–53.
    8. ervolino LG, Baldin PE, Picado SM, Calil KB, Viel AA, Campos LA. Prevalence of sickle cell disease and sickle cell trait in national neonatal screening studies. Rev Bras Hematol Hemoter. 2011;33(1):49–54.
    9. Dembélé AK, Toure BA, Sarro YS, et al. Prévalence et facteurs de risque de la rétinopathie drépanocytaire dans un centre de suivi drépanocytaire d’Afrique subsaharienne. [Prevalence and risk factors for sickle retinopathy in a sub-Saharan comprehensive sickle cell center]. Rev Med Interne. Epub 2017 Feb 22. French.
    10. Diallo JW, Sanfo O, Blot I, et al. Étude épidémiologique et facteurs pronostiques de la rétinopathie drépanocytaire à Ouagadougou (Burkina Faso). [Epidemiology and prognostic factors for sickle cell retinopathy in Ouagadougou (Burkina Faso)]. J Fr Ophtalmol. 2009;32(7):496–500. French.
    11. Mona Kamal El-Ghamrawy; Hanan F. El Behairy; Amal El Menshawy; Seham A. Awad; Ahmed Ismail; Mohamed Salah Gabal; Ocular Manifestations in Egyptian Children and Young Adults with Sickle Cell Disease. Indian Journal of Hematology and Blood Transfusion 2014, 30, 275-280, 10.1007/s12288-014-0333-0.
    12. T.H.C. Tran; A. Mekinian; M. Godinaud; C. Rose; Rétinopathie drépanocytaire chez les adultes de la région Nord-Pas-de-Calais. Journal Français d'Ophtalmologie 2008, 31, 987-992, 10.1016/s0181-5512(08)74745-4.
    13. Leveziel N, Lalloum F, Bastuji-Garin S, et al.; Rétinopathie drépanocytaire : analyse rétrospective portant sur 730 patients suivis dans un centre de référence.[Sickle-cell retinopathy: retrospective study of 730 patients followed in a referral center]. J. Fr. Ophtalmol. 2012, 35, 343–347, .
    14. Shohista Saidkasimova; Zaid Shalchi; O. A. R. Mahroo; Manoharan Shunmugam; D. Alistair H. Laidlaw; Tom H. Williamson; Joanna Howard; Moin D. Mohamed; Risk Factors for Visual Impairment in Patients with Sickle Cell Disease in London. European Journal of Ophthalmology 2016, 26, 431-435, 10.5301/ejo.5000767.
    15. Morton F. Goldberg; Classification and Pathogenesis of Proliferative Sickle Retinopathy. American Journal of Ophthalmology 1971, 71, 649-665, 10.1016/0002-9394(71)90429-6.
    16. D. Sayag; M. Binaghi; E.H. Souied; G. Querques; F. Galacteros; G. Coscas; G. Soubrane; Retinal Photocoagulation for Proliferative Sickle Cell Retinopathy: A Prospective Clinical Trial with New Sea Fan Classification. European Journal of Ophthalmology 2008, 18, 248-254, 10.1177/112067210801800213.
    17. Nicolas Feltgen; Peter Walter; Rhegmatogenous Retinal Detachment—an Ophthalmologic Emergency. Deutsches Aerzteblatt Online 2014, 111, 12-22, 10.3238/arztebl.2014.0012.
    18. A D Penman; J F Talbot; E L Chuang; P Thomas; G R Serjeant; A C Bird; New classification of peripheral retinal vascular changes in sickle cell disease.. British Journal of Ophthalmology 1994, 78, 681-689, 10.1136/bjo.78.9.681.
    19. Sandra F. Mm Gualandro; Guilherme H. H. Fonseca; Iara K. Yokomizo; Danielle M. Gualandro; Liliana M. Suganuma; Cohort study of adult patients with haemoglobin SC disease: clinical characteristics and predictors of mortality. British Journal of Haematology 2015, 171, 631-637, 10.1111/bjh.13625.
    20. Mohammed Elagouz; Sreedhar Jyothi; Bhaskar Gupta; Sobha Sivaprasad; Sickle Cell Disease and the Eye: Old and New Concepts. Survey of Ophthalmology 2010, 55, 359-377, 10.1016/j.survophthal.2009.11.004.
    21. Susan M. Downes; Ian R. Hambleton; Elaine L. Chuang; Noemi Lois; Graham R. Serjeant; Alan C. Bird; Incidence and Natural History of Proliferative Sickle Cell Retinopathy. Ophthalmology 2005, 112, 1869-1875, 10.1016/j.ophtha.2005.05.026.
    22. Daniel David Mais; Ronald D. Gulbranson; David F. Keren; The Range of Hemoglobin A2 in Hemoglobin E Heterozygotes as Determined by Capillary Electrophoresis. American Journal of Clinical Pathology 2009, 132, 34-38, 10.1309/ajcpp50jixxzvlss.
    23. Baciu P, Yang C, Fantin A, Darnley-Fisch D, Desai U. First reported case of proliferative retinopathy in hemoglobin SE disease. Case Rep Ophthalmol Med. 2014;2014:782923.
    24. Knox-Macaulay HH, Ahmed MM, Gravell D, Al-Kindi S, Ganesh A. Sickle cell-haemoglobin E (HbSE) compound heterozygosity: a clinical and haematological study. Int J Lab Hematol. 2007;29(4):292–301.
    25. Luiz Guilherme Azevedo De Freitas; David Leonardo Cruvinel Isaac; William Thomas Tannure; Elisa Vieira Da Silva Lima; Murilo Batista Abud; Renato Sampaio Tavares; Clovis Arcoverde De Freitas; Marcos Pereira De Ávila; Alterações retinianas apresentadas em pacientes portadores de hemoglobinopatia falciforme atendidos em um Serviço Universitário de Oftalmologia. Arquivos Brasileiros de Oftalmologia 2011, 74, 335-337, 10.1590/s0004-27492011000500005.
    26. Morel C.; Atteinte rétinienne des hémoglobinopathies. J. Fr. Ophtalmol. 2001, 24, 987–992, .
    27. A. O. Fadugbagbe; R. Q. Gurgel; C. Q. Mendonça; R. Cipolotti; A. M. Dos Santos; Luis Eduardo Cuevas; Ocular manifestations of sickle cell disease. Annals of Tropical Paediatrics 2010, 30, 19-26, 10.1179/146532810x12637745451870.
    28. Adrienne W. Scott; Ophthalmic Manifestations of Sickle Cell Disease. Southern Medical Journal 2016, 109, 542-548, 10.14423/smj.0000000000000525.
    29. Allisson Mário Dos Santos; Gustavo Baptista De Almeida Faro; Marcus Vinicius Melo Do Amaral; Cristiano De Queiroz Mendonça; Bruno Campelo Leal; Rosana Cipolotti; Alterações retinianas em jovens portadores de anemia falciforme (hemoglobinopatias) em hospital universitário no nordeste do Brasil. Arquivos Brasileiros de Oftalmologia 2012, 75, 313-315, 10.1590/s0004-27492012000500003.
    30. R. I. Liem; Diane M. Calamaras; Manpreet S. Chhabra; Beatrice Files; Caterina P. Minniti; Alexis A. Thompson; Sudden onset blindness in sickle cell disease due to retinal artery occlusion. Pediatric Blood & Cancer 2008, 50, 624-627, 10.1002/pbc.21152.
    31. Brasileiro F, Martins TT, Campos SB, et al. Macular and peripapillary spectral domain optical coherence tomography changes in sickle cell retinopathy. Retina. 2015;35(2):257–263.
    32. Murthy RK, Grover S, Chalam KV. Temporal macular thinning on spectral-domain optical coherence tomography in proliferative sickle cell retinopathy. Arch Ophthalmol. 2011;129(2):247–249.
    33. Rajagopal R, Apte RS. Full-thickness macular hole in a patient with proliferative sickle cell retinopathy. Retina. 2010;30(5):838–839.
    34. Han IC, Tadarati M, Pacheco KD, Scott AW. Evaluation of macular vascular abnormalities identified by optical coherence tomography angiography in sickle cell disease. Am J Ophthalmol. 2017;177:90–99.
    35. Cusick M, Toma HS, Hwang TS, Brown JC, Miller NR, Adams NA. Binasal visual field defects from simultaneous bilateral retinal infarctions in sickle cell disease. Am J Ophthalmol. 2007;143(5):893–896.
    36. Mantovani A, Figini I. Sickle cell-hemoglobin C retinopathy: transient obstruction of retinal and choroidal
    37. Scott AW, Lutty GA, Goldberg MF. Hemoglobinopathies: retinal vascular diseases. In: Ryan SJ, editor. Retina. Philadelphia: Elsevier; 2013: 1071–1082.
    38. Rodrigues M, Kashiwabuchi F, Deshpande M, et al. Expression pattern of HIF-1α and VEGF supports circumferential application of scatter laser for proliferative sickle retinopathy. Invest Ophthalmol Vis Sci. 2016;57(15):6739–6746.
    39. Welch RB, Goldberg MF. Sickle-cell hemoglobin and its relation to fundus abnormality. Arch Ophthalmol. 1966;75(3):353–362.
    40. Folgar FA, Reddy S. An in vivo morphologic comparison of retinal neovascularization in sickle cell and diabetic retinopathy. Retin Cases Brief Rep. 2012;6(1):99–101.
    41. Lutty GA, McLeod DS. Angiogenesis in sickle cell retinopathy. In: Penn JS, editor. Retinal and Choroidal Angiogenesis. Netherlands: Springer; 2008: 389–405.
    42. Kung JS, Leng T. West African crystalline maculopathy in sickle cell retinopathy. Case Rep Ophthalmol Med. 2015;2015:910713.
    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.
    44. Charache S.; Eye disease in sickling disorders. Hematol Oncol Clin North Am. 1996, 10, 1357–1362, .
    45. Tom H. Williamson; R Rajput; D A H Laidlaw; B Mokete; Vitreoretinal management of the complications of sickle cell retinopathy by observation or pars plana vitrectomy. Eye 2008, 23, 1314-1320, 10.1038/eye.2008.296.
    46. Harmeet S. Gill; Wai Ching Lam; A screening strategy for the detection of sickle cell retinopathy in pediatric patients. Canadian Journal of Ophthalmology 2008, 43, 188-191, 10.3129/i08-003.
    47. Dayse Cury De Almeida Oliveira; Magda O.S. Carvalho; Valma Maria Lopes Do Nascimento; Flávia Silva Villas-Bôas; Bernardo Galvão-Castro; Marilda S. Gonçalves; Sickle cell disease retinopathy: characterization among pediatric and teenage patients from northeastern Brazil. Revista Brasileira de Hematologia e Hemoterapia 2014, 36, 340-344, 10.1016/j.bjhh.2014.07.012.
    48. Chalam KV, Sambhav K.; Optical coherence tomography angiography in retinal diseases. J. Ophthalmic Vis Res. 2016, 11, 84-92, .
    49. Antonio Carlos Bueno Filho; Landulfo Silveira; Ana Leticia Sant’Anna Yanai; Adriana Barrinha Fernandes; Landulfo Silveira; Raman spectroscopy for a rapid diagnosis of sickle cell disease in human blood samples: a preliminary study. Lasers in Medical Science 2014, 30, 247-253, 10.1007/s10103-014-1635-z.
    50. 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.
    51. Minvielle W, Caillaux V, Cohen SY, et al. Macular microangiopathy in sickle cell disease using optical coherence tomography angiography. Am J Ophthalmol. 2016;164:137–144.
    52. Khalil Ghasemi Falavarjani; Adrienne W. Scott; Kang Wang; Ian C. Han; Xuejing Chen; Michael Klufas; Jean-Pierre Hubschman; Steven D. Schwartz; Srinivas R. Sadda; David Sarraf; et al. CORRELATION OF MULTIMODAL IMAGING IN SICKLE CELL RETINOPATHY. Retina 2016, 36, S111-S117, 10.1097/iae.0000000000001230.
    53. Clement C. Chow; Rohan J. Shah; Jennifer I. Lim; Felix Y. Chau; Joelle A. Hallak; Thasarat S. Vajaranant; Peripapillary Retinal Nerve Fiber Layer Thickness in Sickle-Cell Hemoglobinopathies Using Spectral-Domain Optical Coherence Tomography. American Journal of Ophthalmology 2013, 155, 456-464.e2, 10.1016/j.ajo.2012.09.015.
    54. Toco Y Chui; Shelley Mo; Brian Krawitz; Nikhil R. Menon; Nadim Choudhury; Alexander Gan; Moataz Razeen; Nishit Shah; Alexander Pinhas; Richard B. Rosen; et al. Human retinal microvascular imaging using adaptive optics scanning light ophthalmoscopy. International Journal of Retina and Vitreous 2016, 2, 11, 10.1186/s40942-016-0037-8.
    55. Jean W. Diallo; D. Kuhn; P. Haymann-Gawrilow; G. Soubrane; Apport de l’angiographie au vert d’indocyanine dans la rétinopathie drépanocytaire. Journal Français d'Ophtalmologie 2009, 32, 430-435, 10.1016/j.jfo.2009.04.018.
    56. Sandeep Grover; Kumar Sambhav; Kakarla V Chalam; Capillary Nonperfusion by Novel Technology of OCT Angiography in a Patient with Sickle Cell Disease with Normal Fluorescein Angiogram. European Journal of Ophthalmology 2016, 26, e121-e123, 10.5301/ejo.5000765.
    57. Bowie EM. Spectralis HRA + OCT imaging of the retina with autofluorescence in sickle cell disease. 2010. Available from: https://clinicaltrials.gov/ct2/show/NCT01123369?term=sickle+cell+retinopathy&rank=3. ClinicalTrials.gov identifier: NCT01123369.
    58. Shelley Mo; Brian Krawitz; Eleni Efstathiadis; Lawrence Geyman; Rishard Weitz; Toco Y. P. Chui; Joseph Carroll; Alfredo Dubra; Richard B. Rosen; Imaging Foveal Microvasculature: Optical Coherence Tomography Angiography Versus Adaptive Optics Scanning Light Ophthalmoscope Fluorescein Angiography. Investigative Opthalmology & Visual Science 2016, 57, OCT130-OCT140, 10.1167/iovs.15-18932.
    59. Ian C. Han; Mongkol Tadarati; Adrienne W. Scott; Macular Vascular Abnormalities Identified by Optical Coherence Tomographic Angiography in Patients With Sickle Cell Disease. JAMA Ophthalmology 2015, 133, 1337, 10.1001/jamaophthalmol.2015.2824.
    60. Christian J. Sanfilippo; Michael A. Klufas; David Sarraf; Irena Tsui Irena; OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF SICKLE CELL MACULOPATHY. RETINAL Cases & Brief Reports 2015, 9, 360-362, 10.1097/icb.0000000000000210.
    61. Michel SS. New, previously unknown, uses of optical coherence tomography angiography (OCTA). 2017. Available from: https://clinicaltrials.gov/ct2/show/NCT03068702?term=sickle+cell+retinopathy&rank=2. ClinicalTrials.gov identifier: NCT03068702.
    62. Azza Abdel Gawad Tantawy; N. G. Andrawes; A. A. M. Adly; B. A. El Kady; A. S. Shalash; 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. Transactions of the Royal Society of Tropical Medicine and Hygiene 2013, 107, 205-211, 10.1093/trstmh/trt008.
    63. Alfred Osafo-Kwaako; Kahaki Kimani; Dunera Ilako; Stephen Akafo; Ivy Ekem; Onike Rodhgues; Christabel Enweronu-Laryea; Martin M. Nentwich; Onike Rodrigues; Ocular Manifestations of Sickle Cell Disease at the Korlebu Hospital, Accra, Ghana. European Journal of Ophthalmology 2011, 21, 484-489, 10.5301/ejo.2010.5977.
    64. Heather E. Moss; Erica Z. Oltra; Clement C. Chow; Thomas J. Wubben; Jennifer I. Lim; Felix Y. Chau; Cross-Sectional analysis of neurocognitive function, retinopathy, and retinal thinning by Spectral-Domain optical coherence tomography in sickle cell patients. Middle East African Journal of Ophthalmology 2016, 23, 79-83, 10.4103/0974-9233.150632.
    65. Jamie B. Rosenberg; Kelly A. Hutcheson; Pediatric sickle cell retinopathy: Correlation with clinical factors. Journal of American Association for Pediatric Ophthalmology and Strabismus 2011, 15, 49-53, 10.1016/j.jaapos.2010.11.014.
    66. Leveziel N, Bastuji-Garin S, Lalloum F, Querques G, Benlian P, Binaghi M. 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.
    67. Lim JI. Ophthalmic manifestations of sickle cell disease: update of the latest findings. Curr Opin Ophthalmol. 2012;23(6):533–536.
    68. Jeremie H. Estepp; Matthew P. Smeltzer; Winfred C Wang; Mary E. Hoehn; Jane S. Hankins; Banu Aygun; Protection from sickle cell retinopathy is associated with elevated HbF levels and hydroxycarbamide use in children. British Journal of Haematology 2013, 161, 402-405, 10.1111/bjh.12238.
    69. Perla Vicari; Samuel A. Adegoke; Diego Robles Mazzotti; Rodolfo Delfini Cançado; Maria Aparecida Eiko Nogutti; Maria Stella Figueiredo; Interleukin-1β and interleukin-6 gene polymorphisms are associated with manifestations of sickle cell anemia. Blood Cells, Molecules, and Diseases 2015, 54, 244-249, 10.1016/j.bcmd.2014.12.004.
    70. Iakovos Armenis; Vassiliki Kalotychou; Revekka Tzanetea; Panagoula Kollia; Zoi Kontogeorgiou; Dimitra Anastasopoulou; Marina Mantzourani; Michael Samarkos; Konstantinos Pantos; Kostas Konstantopoulos; et al. Prognostic value of T786C and G894T eNOS polymorphisms in sickle cell disease. Nitric Oxide 2017, 62, 17-23, 10.1016/j.niox.2016.11.002.
    71. Girot R, Stankovic K, Lionnet F. New issues in adult sickle cell disease. Bull Acad Natl Med. 2008;192(7):1395–1409; discussion 1409–1411.
    72. Luchtman-Jones L, Pressel S, Hilliard L, et al. Effects of hydroxyurea treatment for patients with hemoglobin SC disease. Am J Hematol. 2016;91(2):238–242.
    73. L.E. MacKenzie; T.R. Choudhary; A I McNaught; Andrew R. Harvey; In vivo oximetry of human bulbar conjunctival and episcleral microvasculature using snapshot multispectral imaging. Experimental Eye Research 2016, 149, 48-58, 10.1016/j.exer.2016.06.008.
    74. Panagiotis G. Mitropoulos; Irini P. Chatziralli; Efstratios A. Parikakis; Vasileios G. Peponis; Georgios A. Amariotakis; Marilita M. Moschos; Intravitreal Ranibizumab for Stage IV Proliferative Sickle Cell Retinopathy: A First Case Report. Case Reports in Ophthalmological Medicine 2014, 2014, 1-6, 10.1155/2014/682583.
    75. Ala Moshiri; Nguyen Khoi Ha; Fang S. Ko; Adrienne W. Scott; BEVACIZUMAB PRESURGICAL TREATMENT FOR PROLIFERATIVE SICKLE-CELL RETINOPATHY-RELATED RETINAL DETACHMENT. RETINAL Cases & Brief Reports 2013, 7, 204-205, 10.1097/icb.0b013e3182845d31.
    76. Olufemi Emmanuel Babalola; Intravitreal bevacizumab (Avastin) associated with secondary hyphaema in a case of proliferative sickle cell retinopathy. BMJ Case Reports 2010, 2010, null, 10.1136/bcr.11.2009.2441.
    77. Harpreet S Walia; Jiong Yan; Reversible retinopathy associated with oral deferasirox therapy. BMJ Case Reports 2013, 2013, null, 10.1136/bcr-2013-009205.
    78. Christopher M. McKinney; Frank Siringo; Jeffrey L. Olson; Kelly E. Capocelli; Daniel R. Ambruso; Rachelle Nuss; Red cell exchange transfusion halts progressive proliferative sickle cell retinopathy in a teenaged patient with hemoglobin SC disease. Pediatric Blood & Cancer 2015, 62, 721-723, 10.1002/pbc.25397.
    79. Bradley W. Gustave; Scott C.N. Oliver; Marc Mathias; Raul Velez-Montoya; Hugo Quiroz-Mercado; Jeffrey L. Olson; Naresh Mandava; Ramanath Bhandari; Reversal of Paracentral Occlusive Retinopathy in a Case of Sickle Cell Disease Using Exchange Transfusion. Ophthalmic Surgery, Lasers and Imaging Retina 2013, 44, 505-507, 10.3928/23258160-20130909-18.
    80. Handan Canan; Burak Ulas; Rana Altan-Yaycioglu; Hyperbaric oxygen therapy in combination with systemic treatment of sickle cell disease presenting as central retinal artery occlusion: a case report. Journal of Medical Case Reports 2014, 8, 370-370, 10.1186/1752-1947-8-370.
    81. Kay Thi Myint; Soumendra Sahoo; Soe Moe; Han Ni; Laser therapy for retinopathy in sickle cell disease. Cochrane Database of Systematic Reviews 2013, 10, null, 10.1002/14651858.cd010790.
    82. Schwartz SG, Flynn HW.; Pars plana vitrectomy for primary rhegmatogenous retinal detachment. Clin. Ophthalmol. 2008, 2, 57–63, .
    83. Royce W. S. Chen; Harry W. Flynn; Wen-Hsiang Lee; D. Wilkin Parke; Ryan F. Isom; Janet L. Davis; William E. Smiddy; Vitreoretinal Management and Surgical Outcomes in Proliferative Sickle Retinopathy: A Case Series. American Journal of Ophthalmology 2014, 157, 870-875.e1, 10.1016/j.ajo.2013.12.019.
    84. Odoulami-Yehouessi L, Sounouvou I, Anani L, Tachabi S, Doutentien C, Latoundji S.; Proliferative sickle cell retinopathy revealing Glanzmann thrombasthenia. J. Fr. Ophtalmol. 2009, 32, 757, .
    More