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1. Disease Entity

Sickle Cell Maculopathy (SCM) comprises of patchy retinal thinning involving macular and peri-foveal temporal macular area occurring in patients of Sickle Cell Disease (SCD), a group of genetically acquired hemoglobinopathies associated with abnormal composition of hemoglobin molecules.

Substitution of Glutamic acid by Valine in the hemoglobin molecule (HbS) alters its solubility predisposing to polymerization within the RBCs in hypoxic conditions causing micro-vascular occlusive events and endothelial injury triggering thrombosis and inflammation. Vaso-occlusive crisis can involve peripheral and macular retinal circulation due to vascular supply by end arterioles. Ischemia of the Deep capillary plexus (DCP) and Superficial Capillary plexus (SCP) results in loss of the inner retinal layers within the macula and temporal peri-foveal area.

Patients tend to be asymptomatic and disease may not be clinically apparent in majority of the cases but Optical Coherence Tomography (OCT) and OCT- Angiography (OCT-A) imaging are sensitive in detection of retinal thinning and DCP/SCP ischemia which ensues.

Proliferative Sickle retinopathy (PSR) has been known to be the most common sight threatening complication of SCD. It was extensively described and classified by Goldberg in the early 70s.In contrast SCM has only been increasingly described in the literature in the last 5 years, with the advent of SD-OCT and OCTA. Presence of HbSS sub-type, low Prothrombin Ratio (PR) and PSR are independent risk factors associated with development of SCM.

1.1 Disease

SCM comprises of localized retinal thinning in macular and peri-foveal temporal retinal areas due to ischemic changes involving its micro-vasculature.

1.2 Etiology and Risk factors

In comparison with age- , sex- and ethnicity-matched controls, development of SCM in patients with SCD is linked with the following factors:

• Presence of Sickle Cell Retinopathy: There is a strong relationship between development of maculopathy and proliferative retinopathy. This relationship may be explained by the fact that the temporal macular area and the retinal periphery are both supplied by small-calibre terminal arterioles; therefore vascular occlusions can easily damage these areas. Higher grade of proliferative disease is associated with advanced maculopathy changes though SCM can exist independently as well (1).

• Sub-type of Hemoglobinopathy and blood hemoglobin composition: Retinal thinning occurs more frequently in patients with HbSS sub-type. Higher rates of vaso-occlusive crisis are noted in HbSS patients which could lead to repeated ischemic episodes within the macular area. Higher levels of HbF are associated with lower rates of thinning due to inhibition of HbS polymerization, especially at levels over 15% (2) (3).

• Presence of SCD systemic complications : Hypertension, acute chest syndrome, diabetes, stroke, osteonecrosis

• Lower Prothrombin Ratio (PR)/ prolonged Prothrombin time (PT): Prolonged PR could be a result of liver dysfunction (decreased synthesis of clotting factors) or vitamin K deficiency owing to cholestasis . Prolonged prothrombin time is a marker of chronic vascular inflammation (4)(5).

1.3 General Pathology

Ischemic insult to retinal micro-vasculature results in development of patchy / focal thinning in macular and peri-foveal temporal retinal areas.

1.4 Pathophysiology

Non perfusion of the retinal capillary plexi is responsible for the areas of macular and peri-foveal temporal retinal thinning noted in SCM. Deep capillary plexus ischemia is more extensive within the macula where as both superficial and deep capillary plexi are involved in the peri-foveal temporal retina (1).

Higher oxygen demand plus watershed nature of these areas creates a micro-environment of hypoxia which is conducive to development of sickling within the abnormal RBCs resulting in micro-vascular occlusion and ischemia.

Predilection of the peri-foveal temporal retinal area to thinning could also probably be related to narrower caliper of retinal end arterioles in this area as compared to nasal, making them more susceptible to episodes of sickling.

2. Diagnosis

2.1 Symptoms

Although majority of patients tend to be asymptomatic, SCM is described to be associated with paracentral scotoma, metamorphopsia, reduced contrast sensitivity and color vision abnormalities with preserved distance visual acuity (1)(6)(7).

2.2 Clinical evaluation

Owing to subtle nature of the disease, macular thinning may not be clinically apparent on dilated fundus evaluation in all cases but can be more easily detectable with OCT and OCT-A imaging. Temporal peri-foveal thinning may be visualized as areas of altered retinal reflex from the internal limiting membrane resembling extra-foveal pits-the classic “retinal depression sign” described by Goldbaum.

These lesions represent areas of focal tissue loss caused by infarction due to occlusion of the precapillary arterioles (8).OCT imaging helps in qualitative and quantitative assessment of macular and temporal peri-foveal thinning prior to appearance of clinical symptoms(9)(10). OCT Imaging demonstrates presence of macular thinning in 44-60% of patients with SCD despite normal appearance of fundus(11).

OCT features include:

• Generalized thinning of the total retinal thickness as well as central sub-field thickness leading to macular splaying ( widening of the foveal reflex due to peri-foveal thinning)

• Significant thinning involving the inner retinal layers of the central and inner ETDRS sub-fields (ganglion cell layer, INL and Müller’s cells) in eyes following retinal infarction corresponding to areas with retinal depression.

• Significant thinning of both the INL and ONL of the temporal outer ETDRS subfields

•Presence of para- and perifoveal focal inner nuclear layer (INL) atrophy and corresponding upward expansion of the outer nuclear layer (ONL) generates a wavy appearance within the OCT- Retinal ischemic perivascular lesion. RIPLs are bio-markers of cerebral ischemia. OCT-Angiography can help in micro-structural analysis and reveal level of capillary plexus involvement within the retina (1).DCP involvement is more extensive within the macula while both SCP and DCP are involved in the peri-foveal temporal retina.

OCT-A features include:

•Rarified and dilated capillaries

•Reduced vessel density

•Foveal avascular zone enlargement/ irregularity

•Areas of capillary nonperfusion/ flow voids

•Disruption of the perifoveal anastomotic capillary arcades

•Presence of perifoveal venular loops

Fundus fluorescein angiography maybe inconclusive as only SCP is imaged.

3. Management

3.1 Primary prevention

Hydroxyurea therapy has been shown to be associated with lower rates of macular thinning due to induction of HbF levels which are protective for sickling (12). Hydroxyurea may also work through other protective mechanisms such as inhibition of pro-angiogenic factor expression, decrease of platelets and white blood cell counts, and decreased cytokine (TNF-a and IL-10) levels(13)(14).

3.2 Medical treatment

Once the macular thinning develops, there is no known treatment available for reversal.

3.3 Clinical implication

•OCT-A and mf ERG changes precede development of clinical symptoms as well as development of thinning on OCT imaging thus highlighting their importance as potential bio-markers for detection and prevention of SCM.

•SCM is seen with increasing frequency with advancing stage of PSR hence OCT-A changes can be used to assess risk of stage progression of proliferative disease. Irreversible visual loss can occur either secondary to PSR or sickle cell maculopathy, and identifying patients at risk for SCD ocular complications can be crucial to limit drastic consequences for patients’ vision and quality of life.

•Silent Cerebral Infarction (SCI) is the most common neurologic manifestation in children and adults with SCD (15). SCIs tend to develop in the cerebral deep white matter and occurs most commonly in the watershed regions of the middle cerebral arteries and in areas of low cerebral blood flow. The prevalence of SCI in pediatric patients ranges from 20% to 50%(16).SCIs are linked to increased risk of new SCI or overt stroke, decreased cognitive function, poor academic performance, decreased employment, and reduced quality of life in children with SCD. Current treatment guidelines recommend at least 1-time brain MRI screening to detect SCIs in patients with HbSS or HbSb thalassemia (17) .Owing to shared embryological origins of retinal and neurological vasculatures, ischemic changes in the DCP can be used to predict hypoxic insults occurring at brain level making OCT-A a potential longitudinal bio-marker for prediction of SCI in place of invasive MR Imaging.