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Early diagnosis crucial in sickle cell retinopathy
Stages 1 and 2 are typically monitored, but treatment should begin when the patient reaches stage 3 and sea-fan neovascularization occurs.
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A 44-year-old African-American female presented to our emergency eye clinic with a chief complaint of blurry vision equal in both eyes, at both distance and near. She reported that she had been hit in her left eye with a coat hanger 5 days previously, which was when she first noticed the vision suddenly becoming blurry along with flashes and floaters greater in the left eye than the right.
The patient reported that her last eye exam was 6 to 8 months previously at a different clinic and that her glasses were only 2 months old yet did not provide clear vision in either eye. Her last medical exam was more than 4 years ago, and she had not gone back to see her primary care physician since then, but at the time she was being followed for arthritis and sickle cell (SC variant) disease.
She denied using any eye drops or any current medications other than a daily multivitamin and reported an allergy only to penicillin. Her family medical history was positive for diabetes mellitus type 2, hypertension, glaucoma and sickle cell disease. Her social history was unremarkable.
The patient’s entering acuities were 20/50-1 OD and 20/60- OS with no improvement with pinhole in either eye. Gross confrontational visual fields were noted to be full-to-finger-count in both eyes. Her pupil examination was unremarkable with pupils that were equal, round and reactive to light, with no signs of afferent pupillary defect in either eye. Ocular motilities were full range of motion in both eyes. The patient’s slit lamp biomicroscopy examination was unremarkable. Mild nuclear sclerosis was noted in the crystalline lenses in both eyes. Goldman tonometry revealed intraocular pressures of 14 mm Hg OD and 13 mm Hg OS.
The patient’s dilated fundus exam revealed extensive fibrovascular scarring/tissue in both eyes as well as a vitreous hemorrhage in the right eye. Optic nerve head evaluation was difficult in the right eye secondary to the vitreous hemorrhage obscuring the disc itself. Macular evaluation proved difficult in both eyes due to the large amount of fibrous tissue obscuring the underlying retina but looked tractional in nature. The peripheral retina revealed several salmon patches in both eyes, as well as further fibrovascular tissue.
Diagnosis of sickle cell retinopathy
Based on our patient’s history of sickle cell SC disease and the status of her retinas, she was diagnosed with bilateral stage 4 sickle cell retinopathy with impending stage 5, secondary to strong vitreoretinal traction in both eyes. Despite her history of mild trauma to the left eye several days earlier, it was felt that the patient’s condition was entirely related to her sickle cell SC disease given the bilateral nature of her presentation (but it was possible the left eye was exacerbated by the mild trauma). Thus, we referred her to one of our retinal surgeons for a surgical consult.
The retinal specialist’s diagnosis concurred with ours. He recommended that the patient undergo a pars plana vitrectomy with membrane peeling in both eyes and resultant panretinal photocoagulation (PRP) to the remaining proliferative blood vessels after vitrectomy.
The patient was scheduled for surgery but never returned to our clinic and did not appear for her surgery date. Further communication to reschedule surgery or follow-up exams has gone unanswered.
Most common hemoglobinopathy
Sickle cell disease is the most common inherited hemoglobinopathy in humans and can result in many systemic as well as ocular conditions. It is most common in people with Mediterranean or African ancestry.
There are varying forms of sickle cell disease that overlap with similar diseases, such as the thalassemias. The most common sickle cell disease variant encountered is sickle cell trait (AS), which is considered the mildest form of the disease and tends to have complications only in extreme cases of severe dehydration and extremely low oxygen environments, such as vigorous exercise.
Other forms
However, other forms are considered sickle cell variants and tend to be more aggressive. These are the sickle cell SC and sickle cell SS forms.
The SS form has fewer ocular complications than the SC form, but the SS form has more systemic complications. According to Green, in the spectrum of sickle cell disorders, sickle cell trait (AS) is the most prevalent, at 80% of cases. Sickle cell SS and sickle cell SC come in at 4% and 2%, respectively. The remaining 14% is made up of the thalassemias and rarer sickle cell disease variations. Notably, Elagouz and colleagues reported that more than 8% of African-Americans are positive for sickle cell trait, which is obviously a significant portion of the population.
Interestingly, sickle cell is believed to be protective against the malaria parasite, Plasmodium falciparum, as the parasite is eliminated much more rapidly by the spleen when attached to a sickled red blood cell. As a result, it is believed that the sickle cell gene offers a selective evolutionary advantage to individuals from the Mediterranean and African areas where malaria is most endemic. It is believed that this is the reason sickle cell disease has not been eliminated from human genetics entirely via the natural selection process.
Ocular effects of sickle cell disease
Sickle cell disease and its variants can affect the eyes in the conjunctiva, iris, orbital bones and retina; however, retinal changes are the most common. Sickle cell retinopathy has five different stages. Stage 1 is the most common and includes findings such as: salmon patches, sunburst spots, arteriolar occlusions, venous tortuosity and angioid streaks. Stage 2 is the presence of arteriovenous anastomosis formation. Stage 3 typically presents with the classic sea-fan neovascularization pattern, and PRP is usually performed to prevent progression. Stage 4 is the presence of a vitreous hemorrhage. Stage 5 is the most severe retinal finding: retinal detachment.
The patient’s dilated fundus exam revealed extensive fibrovascular scarring/tissue in both eyes as well as a vitreous hemorrhage in the right eye (left).
Images: Borgman C
Pathogenesis
The pathogenesis of both systemic and ocular sickle cell disease stems entirely from an autosomal recessive, single point mutation on the -chain of hemoglobin where the amino acid valine is substituted for glutamate. Normally, erythrocytes are flexible; however, when oxygen is released in a sickled erythrocyte the amino acid valine binds to the open spot where the oxygen was attached to the ferrous unit of the hemoglobin molecule. This results in long, rigid strands that are inflexible and cause the red blood cells to assume a “sickled” appearance, leading to vascular occlusions and ischemia throughout the body.
Normal hemoglobin has a lifespan of 120 days, whereas the abnormal hemoglobin in sickle cell has a lifespan of only 16 days and is eliminated quickly by the spleen, leading to the anemia commonly associated with sickle cell disease.
Lab testing
Laboratory testing is important in patients suspected of having sickle cell but no definitive diagnosis. A common screening test, SickleDex (Streck), screens only for the presence or absence of the sickled hemoglobin gene (HbS). To determine the exact genotype (for example AS vs. SS vs. SC, etc.) hemoglobin electrophoresis is used. Normally, the electrophoresis is only necessary in the presence of a positive SickleDex result.
Our patient had already been tested as a child and she knew she had sickle cell SC variant, so further testing was not necessary in her case. However, had she been undiagnosed at the time of her presentation, this would have been ordered through her primary care physician.
Systemic issues, therapies
Systemic issues typically arise from vascular occlusions secondary to the sickled erythrocytes. Complications usually involve infarcts that affect the spleen, kidneys, liver, joints, lungs and brain. This can result in gallstones, increased risk of infections, anemia, breathing difficulties and stroke/cerebral vascular accident. Systemic therapy historically has been supportive at best and has included anticoagulation and/or antithrombolytics to reduce vascular occlusions, antibiotics to reduce risk of bacterial infection, analgesics for associated pains and, finally, blood transfusions.
Current therapies have evolved to include hydroxyurea, nitrous oxide and possibly gene therapy. Hydroxyurea is a drug that increases the amount of fetal hemoglobin (HbF) in the body, as HbF has a much higher affinity for oxygen than regular adult hemoglobin (HbA). The HbF is much more reluctant to release oxygen; therefore, less sickling occurs, leading to fewer complications. Long-term efficacy and safety of hydroxyurea has been studied for up to 17 years of use with only mild complications in most individuals. Nitrous oxide has a suggested benefit of inducing vasodilation, which may allow for the vaso-occlusive process to disintegrate or move further down the vasculature. Gene therapy is a large area of current research that has shown promising results.
Of the five stages of retinopathy associated with sickle cell, treatment is initiated in stages 3 to 5. Stages 1 to 2 are typically monitored until progression to later stages. Proliferative sickle cell retinopathy (sea-fan neovascularization) associated with stage 3 has historically been treated with PRP to the ischemic areas of retina or feeder vessel coagulation.
Anti-VEGF injections, such as bevacizumab, have been used in a few cases to deter neovascularization formation. It has been reported that 60% of sea-fan neovascularization regresses on its own over time. This brings up the controversial option of monitoring vs. treating with PRP at stage 3 of sickle cell retinopathy. Typically, however, treatment with laser is indicated to decrease risk of further complications occurring later on as long as the sea-fan neovascularization is not central to the visual axis.
PRP treatment would then be viewed as beneficial to the peripheral retina, whereas more central vessel growth, perhaps directly in the visual axis, may be monitored for spontaneous resolution, as the typical PRP laser procedure permanently damages the photoreceptors in the treated area. Either way, referral to a retinal subspecialist is likely best at this stage 3 retinopathy point of care.
Prognosis
Proliferative retinal changes in sickle cell retinopathy are much more common with the Hb SC variant compared to the Hb SS variant. Tasman and colleagues reported that 36% of all patients with Hb SC will progress to the proliferative stage, compared to only 12% of patients with Hb SS. This increases with the age of the patient as well. Further, 68% of patients older than 40 years with Hb SC have will get proliferative diabetic retinopathy compared to only 14% of patients with Hb SS older than 40. The reason for the big difference between Hb SS and Hb SC complications is controversial and unproven.
One explanation is one of ischemia vs. complete occlusion. It is hypothesized that Hb SS results in more rapid and complete occlusion of vessels in the retina. Due to the rapid occlusion, there is not much time for the retinal tissue to release significant amounts of VEGF. This leads to less risk of developing neovascularization. Hb SC then is believed to cause less rapid and less complete occlusion of vessels, which results in longer, more drawn-out retinal ischemia and allows the ischemic retinal tissue downstream to release a much higher quantity of VEGF. Hypothetically, this would cause an increased risk of retinal neovascularization overall. However, further research is needed to prove this.
Vitreous hemorrhages (stage 4) typically result from fibrous tissue traction on the sea-fan neovascularization, which breaks the brittle vessels leading to blood leaking into the vitreous. Normally, non-vision-threatening vitreous hemorrhages are monitored for 3 to 6 months and allowed to clear on their own. However, if vision is threatened or if the hemorrhage is nonclearing, a pars plana vitrectomy is indicated to help restore vision.
As described before, stage 5 is the most severe complication that can occur from sickle cell retinopathy. It stems from the fibrous scaffolding of the neovascularization contracting and pulling on the retinal tissue. This stage is most often treated via standard retinal detachment surgery, which can include scleral buckle (and has a higher risk of anterior segment necrosis secondary to compromised blood flow), laser and cryotherapy. The prognosis for stage 5 depends on the location and extent of the detachment.
Elagouz and colleagues reported a 5.3% overall chance in 6.3 years of developing a vitreous hemorrhage from stage 3 sickle cell retinopathy (proliferative/sea-fan neovascularization). Stage 5 retinal detachments are even rarer, with a 2% chance in 6.3 years once stage 3 neovascularization occurs. These are low overall risks and shows how uncommonly these complications usually occur.
Our patient was unfortunate enough to be in this 5.3% and on the verge of being in the 2% of retinal detachments from sickle cell retinopathy. This patient had the most severe form of sickle cell disease that affects the eyes, the SC variant.
Patient compliance with medical advice is a large problem in eye care everywhere and especially poor in our particular patient population. Unfortunately, the patient’s actions and decision to skip her surgery may eventually cost her vision. Ideally, this patient should undergo the retinal repair surgery to maximize and prevent any further vision loss.
Acknowledgment: Special thanks to Keith Tyler, OD, for his assistance with this case.
- References:
- Alexander LJ. Sickle Cell Retinopathy. Primary Care of the Posterior Segment. 3rd ed. New York, NY: McGraw-Hill Education; 2002:439-43.
- Elagouz M, et al. Surv Ophthalmol. 2010;doi:10.1016/j.survophthal.2009.
- Friedman NJ, et al. Sickle Cell Retinopathy. The Massachusetts Eye and Ear Infirmary: Illustrated Manual of Ophthalmology. 3rd ed. Philadelphia, PA: Saunders; 2009:356-357.
- Green A. J Behav Optom. 2003;14(1):3-5.
- Hedreville M, et al. Med Sci Sports Exerc. 2009;doi:10.1249/MSS.0b013e31818313d0.
- Pratt C, et al. Sickle cell anemia. Essential Biochemistry. 2004:125.
- Singh H, et al. Indian J Pharmacol. 2010;doi:10.4103/0253-7613.62409.
- Siqueira RC, et al. Acta Ophthalmol Scand. 2006;doi:10.1111/j.1600-0420.2006.00779.x.
- Steinberg MH, et al. Am J Hematol. 2010;doi:10.1002/ajh.21699.
- Tasman W, et al. Sickle cell disease. Duanes Clinical Ophthalmology: Diseases of the Retina. 2008;3:17.
- Whitaker, N. The Basics of Clinical Laboratory Testing. Tuscaloosa VA Medical Center. Section 4:30.
- For more information:
- Christopher J. Borgman, OD, FAAO, is an instructor at Southern College of Optometry, Memphis, Tenn. He can be reached at cborgman@sco.edu.
Disclosure: Borgman reports no relevant financial disclosures.