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Sickle Cell Retinopathy
C H A P T E R
32
Sickle Cell Retinopathy Marguerite O. Linz
■ Adrienne W. Scott
C H A P T E R OU T L I N E Summary 154 The Brain Connection 154 Clinical Features 154 OCT Features 154
Ancillary Testing 157 Treatment 157 References 158
Summary Although children with sickle cell disease (SCD) are generally visually asymptomatic, associated changes in retinal vasculature are prevalent in this population. Proliferative sickle cell retinopathy (PSR) is the most commonly observed cause of vision loss in SCD. The incidence and prevalence of PSR increases with age of patient and disease duration, and thus is not typically observed in the pediatric population. PSR may be observed in all genotypes of patients with SCD, but PSR risk is typically higher in hemoglobin SC (HbSC) and hemoglobin S–β-thalassemia than in homozygous hemoglobin SS (HbSS) disease (also called sickle cell anemia).
The Brain Connection Children with SCD are prone to a variety of neurologic complications, including stroke, silent cerebral infarcts, transient ischemic attack, intracranial blood flow abnormalities, headaches, reduced cognitive function, acute coma, and seizures,1 as well as “soft neurologic signs,” such as slight motor impairments of the upper and lower limbs,2 among other manifestations.
Clinical Features Common sequelae of nonproliferative sickle cell retinopathy include salmon patch retinal hemorrhages, refractile or iridescent spots, and black sunburst lesions (Figs. 32.1 and 32.2), as well as retinal vascular changes, such as tortuosity of retinal vessels, areas of peripheral vascular dropout (see Fig. 32.2), retinal vascular occlusions, or arteriovenous anastomoses. Clinicians should carefully monitor patients with SCD for signs of PSR, such as sea fan neovascularization, vitreous hemorrhage, and tractional or tractional–rhegmatogenous retinal detachment.
OCT Features The most notable OCT feature in sickle cell retinopathy regardless of SCD genotype is macular thinning (Fig. 32.3). Focal macular thinning is most characteristically noted in the 154
Copyright © 2020 Elsevier Inc. All rights reserved.
32—SICKLE CELL RETINOPATHY
155
Fig. 32.1 Ultrawide-field (UWF) color fundus photograph of the left eye of a 10-year-old female with Hemoglobin SS sickle cell disease shows black sunburst (arrow).
Fig. 32.2 Ultrawide-field (UWF) fluorescein angiography (FA; corresponding to Fig. 31.1) image shows vessel tortuosity, a sunburst lesion (arrow), and peripheral ischemia in the nasal and temporal regions.
Fig. 32.3 Macular spectral-domain optical coherence tomography (SD-OCT) (corresponding to the patient’s macula in Figs. 32.1 and 32.2) B scan shows temporal macular thinning involving the central subfield (arrows, far right). The thickness map (middle) and infrared image (right) are also shown.
156
HANDBOOK OF PEDIATRIC RETINAL OCT AND THE EYE-BRAIN CONNECTION
Fig. 32.4 ETDRS Field 3 (SD-OCT) (corresponding to Fig. 32.3) image shows extent of temporal thinning (arrows). The thickness map (left) and infrared image (middle) are also shown.
temporal outer subfields, a known watershed zone for the macular vasculature (Early Treatment Diabetic Retinopathy Study (ETDRS) Field 3) (Fig. 32.4). Patients with SCD also have decreased overall macular thickness measurements compared with controls.3 This retinal thinning may be more common in the HbSS genotype,3,4 and retinal thickness in SCD decreases with increasing age.3 One hypothesis for this finding is that repetitive vascular occlusions within the macular microvasculature may lead to chronic ischemia and tissue loss over time.3,5 The degree of macular thinning can be variable and does not necessarily correlate with the stage of sickle cell retinopathy.3 Although there does not appear to be an association with decreased distance visual acuity, macular thinning on OCT has been associated with decreased retinal sensitivity in adult patients with SCD.6 OCT angiography (OCTA) in individuals with SCD may show pathologic decreased vascular flow loss (the absence of flow or decreased vessel density relative to reported normative data) in the superficial plexus, deep plexus, or both (Figs. 32.5 and 32.6). These areas of vascular flow loss may be more frequently observed in the deep retinal plexus in adult patients with SCD.7,8 The correlation between OCT thinning and loss of retinal vascular flow on OCTA and peripheral retinal nonperfusion on FA has been described.8,9 There may be an association between subclinical decline in distance visual acuity and decreased vascular flow measured on OCTA in patients with SCD.8 Further prospective studies of a larger cohort of patients are necessary to determine the visual consequences of the prognostic implications of these imaging findings.
Fig. 32.5 A 6 6 mm optical coherence tomography angiography (OCTA) (corresponding to Fig. 32.3) image shows areas of loss of macular flow (arrows) in the superficial plexus (arrows). Areas of decreased macular vascular density are most easily noted on the density map (right) in blue.
32—SICKLE CELL RETINOPATHY
157
Fig. 32.6 A 6 6 mm optical coherence tomography angiography (OCTA) (corresponding to Fig. 32.3) image shows regions of loss of macular flow (arrows) in the deep plexus. Areas of decreased macular vascular density are most easily noted on the density map (right) in blue.
Ancillary Testing FA is the most commonly utilized ancillary test for evaluating patients with SCD to identify neovascularization and to assess retinal perfusion. FA is typically reserved for older pediatric patients because of the invasive nature of the test and the low prevalence of proliferative disease in younger patients. Fundus photography may be useful in documenting the presence of sickle cell retinopathy and monitoring the retinopathy and peripheral retinal ischemia for progression over time. Ultrawide-field (UWF) fundus imaging is particularly useful in the evaluation of sickle cell retinopathy because peripheral retinal pathology is commonly observed. Pathology within the far peripheral retina would be difficult to capture on most OCT imaging systems, although this may improve with wide-field OCT imaging in the future.
Treatment Current guidelines based on expert consensus recommend retinopathy surveillance examinations every 1 to 2 years in children with SCD starting at age 10 years.10 Typically, no treatment is required for nonproliferative sickle cell retinopathy. If small areas of retinal neovascularization occur, observation and monitoring may be considered, given the known tendency for spontaneous regression, or autoinfarction, in up to 32% to 60% of sea fan neovascular lesions, resulting in a fibrotic appearance that often remains stable over time.11,12 Treatment regimens for PSR have not been standardized. However, when neovascular lesions enlarge, increase in number, or result in progressive retinal traction or vitreous hemorrhage, retinal scatter laser photocoagulation treatment is typically considered. Based on studies which have identified retinal location of proangiogenic factors such as hypoxiainducible growth factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) in eyes with PSR, application of sectoral or circumferential scatter laser photocoagulation to areas of ischemic retina is recommended. Laser should be centrally applied at the border of ischemic and nonischemic retina, and broadly applied peripheral to this border.13 Scatter laser may also be applied as a barricade surrounding sea fan neovascular complexes.13 Intravitreal anti-VEGF injection may also be considered as adjunctive therapy to retinal laser photocoagulation to achieve regression of active sea fan neovascular lesions.14 Pars plana
158
HANDBOOK OF PEDIATRIC RETINAL OCT AND THE EYE-BRAIN CONNECTION
vitrectomy may be indicated for nonclearing vitreous hemorrhage and in cases of tractional and/or tractional–rhegmatogenous retinal detachment. It is as yet unclear which, if any, systemic associations, such as hemoglobin levels and frequency of occlusive pain crises, and systemic therapies, such as hydroxyurea and regular exchange transfusions, are correlated with the degree or stage of sickle cell retinopathy. In addition to treatment compliance and regular hematology and ophthalmology evaluations, individuals with SCD should avoid dehydration, overexertion, high altitudes, smoking, temperature extremes, stress, and infection.15
References 1. Kirkham FJ. Therapy insight: stroke risk and its management in patients with sickle cell disease. Nat Clin Pract Neurol. 2007;3:264–278. 2. Mercuri E, Faundez JC, Roberts I, et al. Neurological ‘soft’ signs may identify children with sickle cell disease who are at risk for stroke. Eur J Pediatr. 1995;154(2):150–156. 3. 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. https://doi.org/10.1016/j.ajo.2018.03.013 S0002-9394. 4. 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. https://doi. org/10.1016/j.jcjo.2017.10.006. 5. Stevens TS, Busse B, Lee CB, Woolf MB, Galinos SO, Goldberg MF. Sickling hemoglobinopathies: macular and perimacular vascular abnormalities. Arch Ophthalmol. 1974;92(6):455–463. 6. 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. 7. Han IC, Tadarati M, Scott AW. Macular vascular abnormalities identified by optical coherence tomographic angiography in patients with sickle cell disease. JAMA Ophthalmol. 2015;133(11):1337–1340. 8. 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. 9. 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. 10. Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312(10):1033–1048. 11. 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. 12. Condon PI, Serjeant GR. Behaviour of untreated proliferative sickle retinopathy. Br J Ophthalmol. 1980;64:404–411. 13. 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. 14. Cai CX, Linz MO, Scott AW. Intravitreal bevacizumab for proliferative sickle retinopathy: a case series. J Vitreoretin Dis. 2018;2(1):32–38. 15. National Health Service. Sickle cell disease. The National Health Service UK website. Updated May 15, 2016. Available at: https://www.nhs.uk/conditions/sickle-cell-disease/living-with/. Accessed March 1, 2018.
32
Sickle Cell Retinopathy Marguerite O. Linz
■ Adrienne W. Scott
C H A P T E R OU T L I N E Summary 154 The Brain Connection 154 Clinical Features 154 OCT Features 154
Ancillary Testing 157 Treatment 157 References 158
Summary Although children with sickle cell disease (SCD) are generally visually asymptomatic, associated changes in retinal vasculature are prevalent in this population. Proliferative sickle cell retinopathy (PSR) is the most commonly observed cause of vision loss in SCD. The incidence and prevalence of PSR increases with age of patient and disease duration, and thus is not typically observed in the pediatric population. PSR may be observed in all genotypes of patients with SCD, but PSR risk is typically higher in hemoglobin SC (HbSC) and hemoglobin S–β-thalassemia than in homozygous hemoglobin SS (HbSS) disease (also called sickle cell anemia).
The Brain Connection Children with SCD are prone to a variety of neurologic complications, including stroke, silent cerebral infarcts, transient ischemic attack, intracranial blood flow abnormalities, headaches, reduced cognitive function, acute coma, and seizures,1 as well as “soft neurologic signs,” such as slight motor impairments of the upper and lower limbs,2 among other manifestations.
Clinical Features Common sequelae of nonproliferative sickle cell retinopathy include salmon patch retinal hemorrhages, refractile or iridescent spots, and black sunburst lesions (Figs. 32.1 and 32.2), as well as retinal vascular changes, such as tortuosity of retinal vessels, areas of peripheral vascular dropout (see Fig. 32.2), retinal vascular occlusions, or arteriovenous anastomoses. Clinicians should carefully monitor patients with SCD for signs of PSR, such as sea fan neovascularization, vitreous hemorrhage, and tractional or tractional–rhegmatogenous retinal detachment.
OCT Features The most notable OCT feature in sickle cell retinopathy regardless of SCD genotype is macular thinning (Fig. 32.3). Focal macular thinning is most characteristically noted in the 154
Copyright © 2020 Elsevier Inc. All rights reserved.
32—SICKLE CELL RETINOPATHY
155
Fig. 32.1 Ultrawide-field (UWF) color fundus photograph of the left eye of a 10-year-old female with Hemoglobin SS sickle cell disease shows black sunburst (arrow).
Fig. 32.2 Ultrawide-field (UWF) fluorescein angiography (FA; corresponding to Fig. 31.1) image shows vessel tortuosity, a sunburst lesion (arrow), and peripheral ischemia in the nasal and temporal regions.
Fig. 32.3 Macular spectral-domain optical coherence tomography (SD-OCT) (corresponding to the patient’s macula in Figs. 32.1 and 32.2) B scan shows temporal macular thinning involving the central subfield (arrows, far right). The thickness map (middle) and infrared image (right) are also shown.
156
HANDBOOK OF PEDIATRIC RETINAL OCT AND THE EYE-BRAIN CONNECTION
Fig. 32.4 ETDRS Field 3 (SD-OCT) (corresponding to Fig. 32.3) image shows extent of temporal thinning (arrows). The thickness map (left) and infrared image (middle) are also shown.
temporal outer subfields, a known watershed zone for the macular vasculature (Early Treatment Diabetic Retinopathy Study (ETDRS) Field 3) (Fig. 32.4). Patients with SCD also have decreased overall macular thickness measurements compared with controls.3 This retinal thinning may be more common in the HbSS genotype,3,4 and retinal thickness in SCD decreases with increasing age.3 One hypothesis for this finding is that repetitive vascular occlusions within the macular microvasculature may lead to chronic ischemia and tissue loss over time.3,5 The degree of macular thinning can be variable and does not necessarily correlate with the stage of sickle cell retinopathy.3 Although there does not appear to be an association with decreased distance visual acuity, macular thinning on OCT has been associated with decreased retinal sensitivity in adult patients with SCD.6 OCT angiography (OCTA) in individuals with SCD may show pathologic decreased vascular flow loss (the absence of flow or decreased vessel density relative to reported normative data) in the superficial plexus, deep plexus, or both (Figs. 32.5 and 32.6). These areas of vascular flow loss may be more frequently observed in the deep retinal plexus in adult patients with SCD.7,8 The correlation between OCT thinning and loss of retinal vascular flow on OCTA and peripheral retinal nonperfusion on FA has been described.8,9 There may be an association between subclinical decline in distance visual acuity and decreased vascular flow measured on OCTA in patients with SCD.8 Further prospective studies of a larger cohort of patients are necessary to determine the visual consequences of the prognostic implications of these imaging findings.
Fig. 32.5 A 6 6 mm optical coherence tomography angiography (OCTA) (corresponding to Fig. 32.3) image shows areas of loss of macular flow (arrows) in the superficial plexus (arrows). Areas of decreased macular vascular density are most easily noted on the density map (right) in blue.
32—SICKLE CELL RETINOPATHY
157
Fig. 32.6 A 6 6 mm optical coherence tomography angiography (OCTA) (corresponding to Fig. 32.3) image shows regions of loss of macular flow (arrows) in the deep plexus. Areas of decreased macular vascular density are most easily noted on the density map (right) in blue.
Ancillary Testing FA is the most commonly utilized ancillary test for evaluating patients with SCD to identify neovascularization and to assess retinal perfusion. FA is typically reserved for older pediatric patients because of the invasive nature of the test and the low prevalence of proliferative disease in younger patients. Fundus photography may be useful in documenting the presence of sickle cell retinopathy and monitoring the retinopathy and peripheral retinal ischemia for progression over time. Ultrawide-field (UWF) fundus imaging is particularly useful in the evaluation of sickle cell retinopathy because peripheral retinal pathology is commonly observed. Pathology within the far peripheral retina would be difficult to capture on most OCT imaging systems, although this may improve with wide-field OCT imaging in the future.
Treatment Current guidelines based on expert consensus recommend retinopathy surveillance examinations every 1 to 2 years in children with SCD starting at age 10 years.10 Typically, no treatment is required for nonproliferative sickle cell retinopathy. If small areas of retinal neovascularization occur, observation and monitoring may be considered, given the known tendency for spontaneous regression, or autoinfarction, in up to 32% to 60% of sea fan neovascular lesions, resulting in a fibrotic appearance that often remains stable over time.11,12 Treatment regimens for PSR have not been standardized. However, when neovascular lesions enlarge, increase in number, or result in progressive retinal traction or vitreous hemorrhage, retinal scatter laser photocoagulation treatment is typically considered. Based on studies which have identified retinal location of proangiogenic factors such as hypoxiainducible growth factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) in eyes with PSR, application of sectoral or circumferential scatter laser photocoagulation to areas of ischemic retina is recommended. Laser should be centrally applied at the border of ischemic and nonischemic retina, and broadly applied peripheral to this border.13 Scatter laser may also be applied as a barricade surrounding sea fan neovascular complexes.13 Intravitreal anti-VEGF injection may also be considered as adjunctive therapy to retinal laser photocoagulation to achieve regression of active sea fan neovascular lesions.14 Pars plana
158
HANDBOOK OF PEDIATRIC RETINAL OCT AND THE EYE-BRAIN CONNECTION
vitrectomy may be indicated for nonclearing vitreous hemorrhage and in cases of tractional and/or tractional–rhegmatogenous retinal detachment. It is as yet unclear which, if any, systemic associations, such as hemoglobin levels and frequency of occlusive pain crises, and systemic therapies, such as hydroxyurea and regular exchange transfusions, are correlated with the degree or stage of sickle cell retinopathy. In addition to treatment compliance and regular hematology and ophthalmology evaluations, individuals with SCD should avoid dehydration, overexertion, high altitudes, smoking, temperature extremes, stress, and infection.15
References 1. Kirkham FJ. Therapy insight: stroke risk and its management in patients with sickle cell disease. Nat Clin Pract Neurol. 2007;3:264–278. 2. Mercuri E, Faundez JC, Roberts I, et al. Neurological ‘soft’ signs may identify children with sickle cell disease who are at risk for stroke. Eur J Pediatr. 1995;154(2):150–156. 3. 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. https://doi.org/10.1016/j.ajo.2018.03.013 S0002-9394. 4. 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. https://doi. org/10.1016/j.jcjo.2017.10.006. 5. Stevens TS, Busse B, Lee CB, Woolf MB, Galinos SO, Goldberg MF. Sickling hemoglobinopathies: macular and perimacular vascular abnormalities. Arch Ophthalmol. 1974;92(6):455–463. 6. 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. 7. Han IC, Tadarati M, Scott AW. Macular vascular abnormalities identified by optical coherence tomographic angiography in patients with sickle cell disease. JAMA Ophthalmol. 2015;133(11):1337–1340. 8. 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. 9. 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. 10. Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312(10):1033–1048. 11. 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. 12. Condon PI, Serjeant GR. Behaviour of untreated proliferative sickle retinopathy. Br J Ophthalmol. 1980;64:404–411. 13. 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. 14. Cai CX, Linz MO, Scott AW. Intravitreal bevacizumab for proliferative sickle retinopathy: a case series. J Vitreoretin Dis. 2018;2(1):32–38. 15. National Health Service. Sickle cell disease. The National Health Service UK website. Updated May 15, 2016. Available at: https://www.nhs.uk/conditions/sickle-cell-disease/living-with/. Accessed March 1, 2018.