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Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 4  |  Issue : 1  |  Page : 34

Sickle cell disease: The importance of awareness and early detection of ocular manifestations


1 The MUHC – McGill University Ocular Pathology and Translational Research Laboratory; Department of Ophthalmology, Faculty of Medicine and Health Sciences, McGill University, Quebec, Canada
2 The MUHC – McGill University Ocular Pathology and Translational Research Laboratory, McGill University; Faculté de Médecine, Université de Montréal, Montreal, Quebec, Canada

Date of Submission27-Jan-2022
Date of Decision21-Mar-2022
Date of Acceptance23-Mar-2022
Date of Web Publication30-Jul-2022

Correspondence Address:
Miguel N Burnier
The MUHC – McGill University Ocular Pathology and Translational Research Laboratory, 1001 Boulevard Décarie, Block E, E02.6217, Montreal, Quebec H4A 3J1
Canada
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/pajo.pajo_7_22

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  Abstract 


World Sickle Cell Awareness Day is celebrated every June 19 to raise awareness for sickle cell disease (SCD). Access to health services remains unequitable in countries affected by the disease and stigma surrounding patients hinders access to therapies. SCD is the most common severe monogenic disease in the world and is characterized by abnormal hemoglobin production. Major complications include vaso-occlusive events, hemolytic anemia, and inflammation. Microvascular events in the eye are namely responsible for sickle cell retinopathy with or without vasoproliferative changes. Methods included the electronic search of peer-reviewed English literature published until 2021, which was screened, appraised in full version, and incorporated into the review as deemed necessary. This review provides a summary of disease mechanisms and ocular manifestations, and highlights the importance of early diagnosis, close management with imaging technology, and therapeutic avenues for patients with SCD. In addition to significant healthcare barriers encountered by patients and their families, early diagnosis for SCD must be posed by physicians. It is crucial for the healthcare community to become better familiarized with the disease manifestations for early recognition and prevention of chronic complications and morbidity.

Keywords: Disease awareness, early diagnosis, healthcare barriers, sickle cell disease, sickle cell retinopathy


How to cite this article:
Geoffrion D, Youhnovska E, Lu M, Coblentz J, Burnier MN. Sickle cell disease: The importance of awareness and early detection of ocular manifestations. Pan Am J Ophthalmol 2022;4:34

How to cite this URL:
Geoffrion D, Youhnovska E, Lu M, Coblentz J, Burnier MN. Sickle cell disease: The importance of awareness and early detection of ocular manifestations. Pan Am J Ophthalmol [serial online] 2022 [cited 2022 Dec 3];4:34. Available from: https://www.thepajo.org/text.asp?2022/4/1/34/353008




  Introduction Top


Sickle cell disease (SCD) was recognized as a global public health priority in 2006 by the World Health Organization (WHO).[1] Since 2008, the United Nations designated June 19 of each year as World Sickle Cell Awareness Day in order to increase awareness for SCD and for the struggles faced by patients and their families. The WHO reports that SCD affects nearly 100 million people worldwide, with over 300,000 children born every year with this disease.[2],[3] Disease prevalence will continue rising unless more awareness and accessible screening are adopted. Most affected individuals lack proper health care and die in childhood as a result. Those who survive into adulthood suffer from chronic disability and premature death with no access to disease-modifying therapy. On the spectrum of SCD, ocular manifestations are part of the long-term impairments faced by patients. Early diagnosis and management are necessary, and physicians ought to be trained appropriately to recognize ocular involvements of SCD and achieve meaningful impact on visual morbidity in this patient population.


  Methods of Literature Search Top


PubMed was searched electronically in June and July 2021 for peer-reviewed English literature published until 2021. Search keywords included sickle cell disease, sickle cell disease eye, sickle cell disease ocular, sickle cell disease diagnosis, sickle cell disease treatment, sickle cell disease management, sickle cell disease retina, and sickle cell disease ultra-wide fundoscopy. Abstracts of pertinent articles were screened, and relevant articles were then obtained in full version. Bibliography of the retrieved articles was also manually searched and articles of interest were identified and retrieved. Finally, articles were reviewed and incorporated into the review as deemed necessary.


  Epidemiology Top


SCD is one of the most common severe monogenic diseases in the world. It is especially common among individuals with ancestry from Sub-Saharan Africa, South Asia, the Middle East, and the Mediterranean. In those regions, the disease follows a more severe clinical course than in the rest of the world. In endemic areas, SCD is prevalent in 3% of the population.[4],[5] In the context of immigration waves, more awareness will be required in the healthcare setting to diagnose SCD in at-risk individuals and provide comprehensive care. Recent studies have shown an up to 10-fold increase in the prevalence of SCD in immigrated populations.[6] This rise has been noted in countries that receive large populations from SCD endemic areas, namely Germany, Italy, Spain, and Greece.[7],[8],[9] These countries also report an increase in the number of newborns with SCD. Due to the increase in disease burden, healthcare professionals ought to be educated on the management of these patients in the community and hospital settings.[10]

In regions commonly affected by malaria such as South Asia, Southern Europe, the Middle East, Africa, the Mediterranean, and the Caribbean, the prevalence can be as high as 25% of the population. Malaria is highly prevalent in regions where SCD is common. It is thought that heterozygosity for the HbS allele offers resistance against malaria and a selective advantage for those individuals.[11]

Considering that type 2 diabetes mellitus (DM) has become highly prevalent on the planet, a large number of individuals may have concurrent DM and SCD, given that SCD may be present in up to 20% of the population in endemic areas.[5] Comorbidities such as DM in SCD individuals may increase the risk of microvascular complications significantly.


  Genetics Top


SCD is caused by a mutation in the HBB gene that encodes the hemoglobin beta chain. This mutation substitutes glutamic acid is with valine at position 6 on chromosome 11.[12] SCD refers to any one of the syndromes in which the sickle mutation results in sickle hemoglobin (HbS) and is co-inherited with a mutation on the other beta-globin allele.[13] HbS is less soluble than normal fetal or adult hemoglobin and has a shorter survival. Homozygosity for this mutation abolishes normal beta-globin production. The most common genotype for homozygosity is the HbSS genotype. Heterozygosity for this mutation results in sickle cell trait, commonly with the HbSC genotype.[14] Individuals may carry the sickle cell trait, without necessarily being aware of their carrier status, and are at risk of having a child affected with SCD. In the United States, approximately one in 13 African American babies is born with the sickle cell trait. Routine screening and awareness ought to be prioritized to decrease the burden on families and the healthcare system altogether.


  Clinical Presentation Top


SCD is a multisystem disease in which vaso-occlusion, hemolytic anemia, and vasculopathy are the hallmarks.[12] Hypercoagulability and inflammation are also responsible for the major manifestations of the disease. The main determinant of disease severity is the rate and extent of polymerization between two HbS molecules.[15] Clinical features are highly variable among major genotypes and even among individuals with the same genotype. Vascular occlusions and hypoxemia in individuals with SCD can lead to chronic acute pain syndromes, severe bacterial infections, and necrosis, progressing to damage to several systems. Individuals with SCD start to have signs of the disease during the 1st year of life, usually around 5 months of age.[16] Infants may not show symptoms at birth because fetal hemoglobin (HbF) protects erythrocytes from sickling. At around 4 to 5 months of age, HbF is substituted by HbS and erythrocytes begin to sickle. SCD worsens over time; Acute vaso-occlusive pain episodes are one of the most common reasons for patients to seek medical attention and chronic pain affects many of them.[17],[18] Several multisystem events can arise such as pulmonary hypertension and complications affecting multiple organs, such as the eyes and the kidneys.[19],[20],[21] SCD can produce a chronic, compensated hemolytic anemia from sequestration and destruction of abnormal erythrocytes. Several cerebrovascular and other neurologic complications arise in SCD patients who are at increased risk for stroke.[22] Splenic infarction leads to functional hyposplenism early in life, which in turn increases the risk of infection.[23] In children, the development of cerebrovascular disease and cognitive impairment is a significant clinical challenge. These complications have a major impact on morbidity and mortality for this patient population.[16] The time and energy invested by families for medical appointments, together with the attitude of physicians who are not accustomed with SCD manifestations, can produce extensive suffering for patients and their families.


  Pathophysiology Top


SCD is characterized by a modification in the shape of erythrocytes from a smooth, donut-shape to a less pliable crescent moon shape, leading to vaso-occlusive events with cycles of ischemia-reperfusion injury and hemolytic anemia.[18],[24] Entrapment of erythrocytes, leucocytes, and endothelial cell microparticles in the microcirculation, combined with HbS polymerization and inflammation, is thought to drive vascular obstruction and tissue ischemia, as well as hemolytic anemia.[12],[24]

Posterior segment manifestations

The pathophysiology of posterior segment manifestations in patients with SCD is directly linked to the vaso-occlusive events caused by sickled erythrocytes. Subsequent hypoperfusion of capillaries and hypoxemia result in microvascular occlusive events in various structures of the eye, resulting in characteristic damage.[20]

Sickle cell retinopathy

Clinical manifestations of sickle cell retinopathy (SCR) vary depending on the presence or absence of vasoproliferative changes. SCR has been shown to present with comma-shaped vessels due to the accumulation of sickled red blood cells at the distal end of the capillaries.[25] Vascular changes in the optic disc present transiently as dark red lesions or as dilated dark capillary vessels on fluorescein angiography (FA).[26] Flashes, floaters, or dark shadows may be indicative of vitreoretinal traction or detachment. SCR progression has been associated with age, extent of SCR, and presence of retinopathy in the contralateral eye.[27]

Nonproliferative sickle cell retinopathy

SCR can be classified as nonproliferative sickle cell retinopathy (NPSR) and proliferative sickle cell retinopathy (PSR). NPSR harbors venous tortuosities, salmon-patch hemorrhages, schisis cavities, and black sunburst signs in the retina.[20],[21] Venous tortuosities may already be present in childhood.[28] These may result from arteriovenous shunts from the periphery of the retina due to vascular occlusions and ischemia.[20],[21] Intraretinal salmon-patch hemorrhages are superficial and are typically located in the mid-periphery of the retina, adjacent to a retinal arteriole.[20],[21] Once these hemorrhages disappear, they leave behind a schisis cavity where iridescent spots and glistening refractive bodies can be found.[20],[21] Black sunburst signs are also characteristic of NPSR and are most commonly located in the equatorial fundus.[29]

Proliferative sickle cell retinopathy

PSR is a severe vision-threatening complication of SCD. Following vaso-occlusion, local ischemia stimulates production of proangiogenic growth factors, such as vascular endothelial growth factor (VEGF), resulting in retinal neovascularization, preretinal or vitreous hemorrhage, and tractional retinal detachment.[20] PSR affects more heterozygous (HbSC) patients than homozygous (HbSS) patients. However, homozygous patients typically experience greater systemic morbidity, whereas those with the heterozygous genotypes are more likely to manifest PSR.[20],[30] Retinal evaluation is begun at 10 years of age and continued routinely to detect early signs.[17] PSR risk increases with age and is observed more commonly in males. In individuals with HbSC, the peak onset is between 15 and 24 years in men and between 20 and 39 years in women.[31]

PSR is conventionally classified into Goldberg's five stages.[20],[21] Stage 1 includes peripheral arteriolar occlusions which appear as dark-red lines, and eventually silver-wire-appearing vessels.[20],[21] In stage 2, peripheral arteriovenous anastomoses form from dilated preexisting capillaries.[20],[21] In stage 3, neovascular and fibrous proliferations called sea fans occur at the border of nonperfused retinal regions.[20],[21] Vitreous hemorrhages form in stage 4, and potentially cause retinal detachment in stage 5.[20],[21]

Optic disc changes

Transient occlusions in small-caliber disc vessels lead to accumulations of deoxygenated erythrocytes, therefore producing dark red spots on the optic disc, also known as the “disc sign.”[32] It has not been reported to affect visual acuity, but closer long-term follow-up is required to determine whether it has a proliferative aspect which could lead to formation of fine capillary network, consequently affecting visual acuity.[33]

Retinal vascular occlusions

In cases of retinal vascular occlusions, the peripheral retina is first affected and outer retinal atrophy can develop, causing vision loss.[20] Occlusions in the peripheral retina may eventually cause anastomoses in hairpin loops to compensate for the hypoxemia.[34] They may also occur in central retinal arteries, especially in patients with elevated intraocular pressure.[20],[21]

Chronic macular changes

Chronic macular changes from occlusions in both superficial and deep capillary plexi may be present in patients without visual symptoms.[21] Vaso-occlusive events cause paracentral acute middle maculopathy, leading to macular thinning.[21] Other macular changes such as nerve infarcts may explain vision loss in untreated SCD patients.[21]

Choroidal vascular occlusions

Choroidal vascular occlusions can occur spontaneously in SCD patients or can be the consequence of hypoxemic-induced pro-inflammatory cascades caused by sickled erythrocytes. They are often associated with rupture in Bruch's membrane, thereby causing angioid streaks.[20] Predispositions to infarctions may also cause choroidal-retinal-vitreal neovascularization, which can explain hemorrhages, posterior hyaloid fibrosis, retinal detachment, choroidal polypoidal vasculopathy, and visual loss.[20] In addition, patients with SCD may also have retinal pigment epithelium hyperreactivity.[20] The resulting hyperpigmentation, also called the black sunburst sign, does not affect visual acuity but is said to create choroidal ischemia.[20]

Anterior segment manifestations

Anterior segment manifestations are other ocular manifestations of SCD. Obstructed blood flow from sickled erythrocytes can cause segmentation of conjunctival vessels, with sausage-like dilations, also described as the “conjunctival sign.”[20],[21] Microvasculature occlusions also generate a higher susceptibility for iris hypoxemia and infarct, which have been associated with pupillary irregularities.[20],[21] Diffuse and sectoral atrophy of the iris is rare but possible. Neovascularization of the iris may develop if PSR is diagnosed at a more advanced stage. SCD patients are also at increased risk of hyphema when high intraocular pressure occurs from vaso-occlusive events, as well as when intraocular procedures are performed at later stages of disease.[20] The presence of traumatic hyphema in African Americans warrants testing for sickle cell hemoglobinopathies. Initial management of traumatic hyphema consists in monitoring intraocular pressure to avoid any further damage. Management includes using cycloplegic drugs, nonsteroidal anti-inflammatory drugs, and analgesia.[35],[36] Bleeding risk is lowered using topical glucocorticoid drops. In the case of ongoing bleeding for more than 10 days or intraocular pressure over 50 mmHg, a surgical approach with paracentesis and gentle anterior chamber washout is used.[37]

Orbital manifestations

Although rare, patients with SCD may present with infarction of the orbital bones during vaso-occlusive crises, which increase arterial-vascular resistance and cause inflammation, subperiosteal hematoma, and orbital compartment syndrome.[38] Presentation may be asymptomatic or include pain, headaches, fevers, decrease in visual acuity, periorbital edema, proptosis, limited extraocular motility, exudative retinal detachment, and optic nerve compression.[38],[39]


  Diagnosis Top


Diagnosis of SCR is performed based on clinical findings in the presence of a history of SCD or positive laboratory findings. These usually involve cation-exchange high-performance liquid chromatography, in conjunction with hemoglobin electrophoresis.[40] Molecular genetics are also used for screening of fetuses and newborns.[41],[42] Early diagnosis and treatment can reduce the risk of complications. Many states in the United States routinely screen newborns for SCD so that treatment can begin as soon as possible. Most ocular manifestations of SCD are often asymptomatic until irreversible damage to vision occurs. Diagnosing ocular lesions, retinal thinning, and ischemia early on is primordial as when progression leads to irreversible vision loss, it requires more invasive interventions.[43]


  Imaging Top


Fluorescein angiography

FA is the gold standard to examine blood flow in the retina and choroid and for early identification of neovascularization and sea fans in the retinal periphery in SCR.[44] FA allows to visualize the vasculature of the retina through contrast between injected fluorophore and the retina, as well as areas of nonperfusion from vessel occlusions, microaneurysms, and foveal avascular zone which are seen in sickle cell maculopathy.[45] Limitations include bad visibility of the deep capillary plexus in which occlusions cause sickle cell maculopathy.

Optical coherence tomography

Recent imaging modalities such as wide-field imaging and optical coherence tomography (OCT) angiography have revealed the microstructural features of SCR, enabling earlier diagnosis. OCT can be useful in SCD patients to visualize retinal thinning related to SCR. allowing for better understanding of the patient's condition and the risk to their vision. However, as this method does not show vasculature, it is not commonly used for diagnosis of SCR.[38],[46]

OCT angiography (OCTA) has also shown significant changes even in children without structural damage.[47] It is particularly useful for macular manifestations of SCD and to visualize the deep capillary plexus.[44],[48] Its main limitation for SCR is the restricted field of view that does not expand to the peripheral retina.

Ultra-wide fundoscopic imaging

Ultra-wide fundoscopy allows for better visualization of the peripheral retina with a 200° field view.[49] This is of particular use in SCR where pathological manifestations occur primarily in the periphery and may appear as asymptomatic prior to development of PSR.[38] This method may allow for earlier detection, better staging, less invasive treatment options, and decreased complication rates.[49],[50]


  Treatment Top


Medications

Disease-modifying agents

Management of sickle cell anemia is usually aimed at avoiding pain episodes, relieving symptoms, and preventing complications. Treatments might include medications and blood transfusions.

Hydroxyurea is a mainstay for management of SCD and helps reduce the frequency of pain crises and acute chest syndrome. It reduces sickling by inducing production of HbF that is not affected by the mutation and does not cause vaso-occlusive events.[51],[52]

Hydroxycarbamide treatment has been demonstrated to have a beneficial effect in children in preventing SCR.[53] Reducing HbSS erythrocytes by exchange transfusion has also been demonstrated to show benefits.[54],[55] Hyperbaric oxygen therapy could also reverse the pathology and improve visual acuity.[56],[57]

Regarding ocular manifestations of SCD, there is currently no therapy for NPSR. For PSR stage 3, the goal of therapy is to prevent bleeding and retinal detachment. Modalities include intravitreal administration of anti-VEGF therapy, scatter laser photocoagulation, and surgeries for vitreous hemorrhage or retinal detachment.[58],[59] Yearly ophthalmic examination is recommended for SCD patients. Information obtained from OCT and OCTA imaging can be useful for clinical staging. Baseline FA may be performed to examine blood flow in the retina and choroid. The role of hydroxyurea, antiangiogenic therapy, and chronic transfusion in preventing or treating SCD-associated retinopathy remains to be further explored.

Novel therapies

While future research will continue to be needed to inform clinical management and decision-making, recent therapies have been approved for SCD. L-glutamine has been recently approved for prevention of acute complications of SCD in patients aged 5 and above.[60],[61] Patients have shown an increase in oxidative damage to the erythrocytes that are prevented by L-glutamine supplementation. It has been demonstrated to reduce hospitalizations in acute SCD crises increase quality of life, and decrease crises. Side effects include nausea, headache, abdominal pain, dyspepsia, fatigue, joint pain.[62]

In addition, voxelotor was approved in 2019 and is a HbS polymerization inhibitor that prevents vaso-occlusive events.[63],[64] Adverse effects include headaches, nausea, rashes, vomiting, and pain in the extremities, back, chest, and abdomen.[65]

Crizanlizumab was approved in 2019 for patients aged 16 and above. It is a monoclonal antibody that prevents interactions between platelets and sickled erythrocytes and SCC.[66] It has been shown to decrease the rate of vaso-occlusive events by 45% in patients.[67],[68] Adverse effects include nausea, back pain, and fever. Yet, most studies report that crizanlizumab has similar risks to placebo used in the study.[66],[67],[68]

Gene therapy is emerging as a possible new treatment for SCD as part of clinical trials. Stem cells collected from patients can be modified by CRISPR/Cas-9.[69],[70] Knockdown of BCL11A which is responsible for the repression of HbF appears to be the most promising target.[69] Preliminary results show no events of SCC, stroke, and acute chest syndrome posttreatment.[70] Future studies are required to study adverse and long-term effects.

Interventions

Blood transfusion

Blood transfusion is an effective treatment and preventative method for severe complications of SCD. It may reduce incidence of symptomatic anemia, acute stroke, multiorgan failure, and acute chest syndrome.[71] Blood transfusion can be are used to dilute the HbS with normal hemoglobin to treat chronic pain, splenic sequestration, and other emergencies.[61],[72] Practical considerations when performing blood transfusions for SCD patients include central venous access, crossmatching, leukoreduction, simple versus exchange transfusion, and management of excess iron stores.[61],[71],[72]

Stem cell transplantation

For some children and adolescents, only a hematopoietic stem cell transplant may cure the disease by using a matched sibling donor and a myeloablative conditioning regimen.[71],[73] Limitations with this method include the restricted number of available donors, risk of rejection, and severe side effects. Yet, patients who have undergone hematopoietic stem cell transplants show an 80% disease-free survival rate.[74] Recent studies have shown that in adults and children affected by SCD, a nonmyeloablative conditioning regimen could be a good alternative to myeloablative conditioning regimen with fewer adverse effects.[71],[73] In adults, individuals consider stem cell transplants are encouraged to enroll in rigorous clinical trials.

Intraocular interventions

Management of ocular manifestations of SCD such as SCR varies based on stage of disease. Initial management involves anti-VEGF injections.[58],[75] Once PSR develops, laser photocoagulation can reduce the risk of retinal detachments, vitreous hemorrhage, and vision loss from disease progression. In cases complicated with retinal detachment, pars plana vitrectomy is performed.[75]

Laser

Laser therapy is a common intervention for ocular manifestations of SCD such as PSR, similar to other retinopathies. Scatter laser photocoagulation is the preferred laser treatment method to cause regression of sea fan structures when these do not auto-infarct. It has been shown to be safer than feeder vessel techniques; visual loss from vitreous hemorrhage was less common and incidence of vitreous hemorrhage was also lower.[76] Contrarily to other lasers, it specifically targets sea fan neovascularization using a blue/green argon laser that delivers mild light to a 500 μm area for 0.1 s aimed at the nonperfused retinal tissue.[77] The laser inhibits neovascularization by inducing apoptosis in the retinal pigmented epithelium cells of the ischemic retina, thereby decreasing hypoxic drive and VEGF production, and coagulating the vascularized tissue with minimal damage.[78] As a result, SCR regression and lower rates of SCR recurrence can be observed. Adverse effects include retinal tear and ensuing rhegmatogenous retinal detachment at the site of laser therapy.[76],[79]

Anti-vascular endothelial growth factor injections

Anti-VEGF intravitreal injections are aimed at inhibiting neovascularization arising as a consequence of vessel occlusion in the retina. Treatment shows regression of neovascularization, clearing up of vitreous hemorrhage caused by sea fan leakage, and improvement in visual acuity.[38],[58] Currently, anti-VEGF therapies approved for SCR include aflibercept and ranibizumab.[75] Long-term follow-up show that low rates of recurrence are seen when anti-VEGF injections are used to complement laser photocoagulation.[58] Adverse effects include an increased risk of tractional retinal detachment warranting close follow-up of the patient.

Recent studies have investigated avenues for other targeted therapies. Jee et al. have reported increased levels of expression of angiopoietin-like 4 (ANGPTL-4) in patients with SCR, suggesting that it might act in pathological retinal neovascularization.[80],[81] This angiogenic mediator could be the target of future therapies.


  Conclusions Top


SCD patients present very young to healthcare providers and require early diagnosis to limit significant morbidity and mortality. We recommend that patients be educated and provided with genetic counseling in endemic areas and when SCD is suspected based on clinical presentation. Children must be monitored closely for growth and development and a low threshold of suspicion must be used to pursue SCD as a diagnosis upon development of symptoms. Counseling regarding nutrition such as water intake can help avoid the sickling process and may be beneficial for pain crises and other manifestations of SCD. Vaccination guidelines should be followed by all individuals with SCD, and routine ophthalmological exams should be performed at least annually in all children with SCD to prevent permanent visual impairment. Psychological support and information about support and awareness groups ought to be provided by healthcare workers who need to be informed and have the appropriate tools to guide their patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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