Woman presents for blurry vision in left eye
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A 44-year-old woman presented to the comprehensive ophthalmology clinic for trouble reading and difficulty watching TV for the past month, worse in the left eye. She reportedly had a normal eye exam 5 months prior.
She had a medical history of migraine with aura, upper GI bleed and small fiber neuropathy. She had a surgical history of septoplasty with nasal turbinate reduction and cesarean section. She was allergic to gabapentin. She was a former smoker and drank wine occasionally. She was born in Bosnia. She had no significant family history.
Source: Teresa P. Horan, MD, and Andre J. Witkin, MD
Examination
On examination, the pupils were equal, round and reactive to light with a trace afferent pupillary defect in the left eye. Best corrected visual acuity was 20/25 in the right eye and 20/200 in the left eye. IOP was normal in both eyes.
Anterior segment examination was significant for trace nuclear sclerosis bilaterally. Dilated examination showed hyperpigmented lines deep to the retina surrounding and radial to the optic nerve heads in both eyes. The macula in the right eye had 1+ retinal pigment epithelium (RPE) changes with a druse, and the left eye showed a fibrotic macular scar with a subfoveal choroidal neovascular membrane (CNVM) and subretinal fluid (Figure 1). In the periphery of the right eye, there were peripheral round atrophic scars, some with comet-like tails (Figure 2).
On imaging, OCT of the left eye showed subretinal hyperreflective material underlying the fovea with associated intraretinal fluid, consistent with a CNVM (Figure 3). OCT of the right eye showed subtle RPE changes (Figure 3). The peripapillary hyperpigmented lines were hyperfluorescent on fluorescein angiography with late staining (Figure 4). These lines appeared hypoautofluorescent on fundus autofluorescence (Figure 5).
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Fundus findings
The appearance of the fundus findings in both eyes were thought to be most consistent with angioid streaks, with an associated CNVM in the left eye. In addition, the presence of comet-like streaks in the peripheral retina suggests a diagnosis of angioid streaks secondary to pseudoxanthoma elasticum (PXE) specifically.
The differential diagnosis for angioid streaks with an associated CNVM includes PXE (most common), Paget’s disease, sickle cell anemia, beta-thalassemia and Ehlers-Danlos syndrome. Other retinal findings that appear similar to angioid streaks include lacquer cracks from pathologic myopia and choroidal rupture after trauma. Lacquer cracks are fine ruptures in Bruch membrane and can also be associated with CNVM, but they typically do not run radially from the optic nerve. Traumatic ruptures of Bruch membrane can lead to linear deep fibrotic scars on OCT as the wound healing process includes fibroblast invasion, RPE hyperplasia and neovascularization. They often run circumferential to the optic nerve head, not radially, and are typically unilateral. Lacquer cracks and choroidal ruptures are less likely in our patient given the bilaterality, radial appearance, and lack of myopic refractive error or history of trauma.
Workup and management
The patient was diagnosed with angioid streaks in both eyes with a secondary CNVM in the left eye. Risks and benefits of intravitreal anti-VEGF injections in the left eye were discussed. Because the CNVM appeared fibrotic, it was unclear if injections would improve the patient’s vision. She preferred a trial of anti-VEGF and received intravitreal bevacizumab in the left eye. She was referred to dermatology, where they noted skin laxity and yellow papules overlying skin folds distributed on the bilateral antecubital region, mid trapezial neck and bilateral proximal medial posterior upper arms, consistent with PXE. A punch skin biopsy confirmed a diagnosis of PXE. She also had a cardiology workup, which was unremarkable.
Discussion
Angioid streaks are characterized as bilateral narrow dark red or brown irregular lines radiating from a peripapillary streak or ring of peripapillary pigment mottling. They appear deep to the retina as they are due to dehiscences or cracks in the thickened and calcified Bruch membrane with atrophic overlying RPE. The term “angioid streaks” is due to their resemblance to retinal vasculature as they are radial to the optic nerve and sometimes have branching fissures. On fluorescein angiography, angioid streaks are characterized as window defects with late staining.
Associated systemic diseases are described by the mnemonic “PEPSI,” which stands for pseudoxanthoma elasticum, Ehlers-Danlos syndrome, Paget disease of the bone, sickle cell anemia and beta-thalassemia, and idiopathic causes. Other causes include hypercalcinosis, hyperphosphatemia and hemochromatosis. The association of angioid streaks with Ehlers-Danlos syndrome may be less prevalent than noted previously (about 1% of patients). The incidence of angioid streaks is more than 80% in those with PXE, 3% in those with sickle cell and 12% in those with Paget disease. As in the case with this patient, those with angioid streaks should be referred for workup. Most patients develop angioid streaks between the second and fifth decade of life, and the streaks may increase in size over time.
Of these associated diseases, the most common is pseudoxanthoma elasticum, or Grönblad-Strandberg syndrome, which is caused by an autosomal recessive mutation in the ABCC6 gene, which encodes an ATP-binding cassette protein. The estimated prevalence of PXE is one in 25,000 to one in 100,000. The disease affects the skin, cardiovascular system and eyes. Typically, cutaneous findings such as small, yellowish papular lesions and skin laxity of the neck, axilla, groin and flexural creases precede ocular findings, as in the case with this patient. These papules have been referred to as “chicken skin.” Those with PXE should also be evaluated for coronary artery calcific atherosclerosis and gastrointestinal and cerebrovascular bleeding. The most significant visual complication is the development of choroidal neovascularization due to neovascular proliferation extending into the subretinal space through Bruch membrane defects. This occurs in 72% to 86% of eyes. Other ocular manifestations include optic nerve drusen, peau d’orange (spotty incomplete calcification of Bruch membrane), comet-like streaks in the periphery, subretinal fluid pockets, and vitelliform accumulations and areas of RPE atrophy.
Treatment of CNVM associated with angioid streaks includes anti-VEGF, laser photocoagulation and photodynamic therapy. Anti-VEGF is the most successful of these options. Patients should be followed regularly at about 6-month intervals and more frequently if they develop CNVM. They should be counseled to wear safety glasses as they are highly susceptible to choroidal rupture or subretinal hemorrhage following even minor blunt injury.
Case continued
At 1 month after her first intravitreal bevacizumab injection, the patient’s vision and OCT were stable. After her second bevacizumab injection, vision improved one line to 20/100. For the third monthly injection, she received intravitreal aflibercept with subjective improvement and significant improvement in intraretinal fluid from central thickness of 473 µm to 308 µm (Figure 6). Using a treat-and-extend protocol with aflibercept, she has been receiving injections every 3 months with subjective and objective stability.
About 5 years into treatment, the patient developed new subretinal fluid in the right eye with decreased vision and received intravitreal aflibercept with improvement. She has been developing increased RPE irregularity and vitelliform material, which is causing a gradual decline in vision in the right eye. She is currently receiving intravitreal aflibercept on a treat-and-extend protocol in both eyes.
- References:
- Chatziralli I, et al. Retina. 2019;doi:10.1097/IAE.0000000000002327.
- McCannel CA, et al. 2019-2020 Basic and Clinical Science Course. Retina and Vitreous, Section 12. American Academy of Ophthalmology. 2019.
- Singman EL, et al. JAMA Ophthalmol. 2019;doi:10.1001/jamaophthalmol.2018.5995.
- Yanoff M, et al. Ophthalmology. 5th ed. Elsevier; 2018.
- Yanuzzi LA. The Retinal Atlas. Elsevier; 2010:516-518.
- For more information:
- Edited by Yi Ling Dai, MD, and Teresa P. Horan, MD, of New England Eye Center, Tufts University School of Medicine. They can be reached at ydai@tuftsmedicalcenter.org and thoran@tuftsmedicalcenter.org.