Continuing Education Activity

Angioid streaks occur due to breaks in a degenerated and mineralized Bruch's membrane, that typically radiate outward from the optic disc. Angioid streak may be associated with choroidal neovascularization (CNV) causing metamorphopsia and/or visual decline. This activity reviews the evaluation and treatment of angioid streaks, and highlights the role of the interprofessional team in the further evaluation and care of patients with this condition.

Objectives:

• Describe the histopathology of angioid streaks.
• Summarize the physical findings associated with angioid streaks.
• Outline the management of angioid streaks.
• Review the importance of improving care coordination amongst interprofessional team members to improve outcomes for patients with angioid streaks.

Introduction

Angioid streaks are breaks in the degenerated and mineralized Bruch's membrane, which typically form around the optic disc and radiate from the optic disc. These breaks are usually linear and hence named angioid or like blood vessels. Angioid streaks may be idiopathic or associated with pseudoxanthoma elasticum, Sickle cell disease, acromegaly, Paget disease of the bone, and other diseases. Angioid streak may be associated with choroidal neovascularization (CNV), causing metamorphopsia and/or visual decline. Angioid streaks are a risk factor of subretinal bleeding after minor trauma.

Angioid streaks have also been called Knapp streaks or Knapp striae in honor of the famous German- American ophthalmologist Jacob Hermann Knapp (1832 –1911).

Etiology

Angioid streaks may be idiopathic in up to 50% of cases.

The most important systemic association of angioid streak is pseudoxanthoma elasticum (PXE) or Gronblad–Strandberg syndrome- It is an autosomal recessive disease caused by the mutation of the ABCC6 gene on chromosome 16.[1][2] Features include calcification and fragmentation of elastic tissues. The name comes from Ester Elisabeth Grönblad (1898-1942), a Swedish ophthalmologist, and James V Victor Strandberg (1883-1942), a Swedish dermatologist who discussed the association between eye and skin findings in PXE.

PXE is characterized by:

• Skin lesions (discrete in early-stage and later confluent yellowish papules or pseudoxanthomas) at the sides of the neck, umbilical region, and flexures like elbow giving a 'plucked chicken' appearance
• Gastrointestinal bleeding
• Intermittent claudication/ peripheral arterial vascular disease
• Coronary artery disease
• Aneurysms at brain, kidney, mesentery causing hemorrhage
• Brain infarct or hemorrhage[1] 
• The ocular manifestations include:
  • Peau d'orange appearance of the fundus is noted in children even before the development of angioid streaks.
  • Angioid streaks- Nearly all patients of PXE shows angioid streaks after 20 years after the first diagnosis.
  • Optic nerve head drusen or hyaline bodies are seen in about 5% cases with PXE and angioid streaks.
  • Pattern dystrophy of the macula- In a study on 22 confirmed cases of PXE, pattern dystrophy was noted in 27 eyes of 16 patients.[3] All 5 variants of pattern dystrophy were reported in these cases, including fundus pulverulentus, butterfly-shaped dystrophy, fundus flavimaculatus, reticular dystrophy, and vitelliform pattern dystrophy.[3] Fundus fluorescein angiogram (FFA) helps to differentiate various pattern dystrophies. The type of pattern dystrophy may change with time, and the changes of pattern dystrophy may appear on follow-up.
  • Small round RPE atrophic patches- These may have a white, yellow, or pink color. Punched out scars similar to presumed ocular histoplasmosis syndrome (POHS) may also be seen. These have been called 'salmon spots.'
  • Crystalline bodies or whitish subretinal round lesions in mid-peripheral fundus usually inferiorly- Some of these nodules have Comet-like tail of depigmentation. Crystalline body is seen in up to 75% of cases.
  • Atrophy of retinal pigment epithelium (RPR) near the angioid streak

Other associations of angioid streaks include:

• Marfan syndrome
• Paget's disease of bone- Angioid streaks are noted in up to 10% of cases.
• Sickle cell disease- Angioid streak is noted in around 1-2% cases, usually after the 3rd decade. Angioid streaks have been reported in sickle cell trait, homozygous sickle cell disease, sickle cell-thalassemia, and sickle cell hemoglobin C disease. 
• Other hemoglobinopathies- acquired hemolytic anemia, hereditary spherocytosis, beta thalassemia major, beta thalassemia minor, beta thalassemia intermedia, hemoglobin H disease, and congenital dyserythropoietic anemia type 1.
• Acromegaly
• Hemochromatosis
• Diabetes mellitus
• Sturge Weber syndrome with facial angiomatosis
• Myopia[4]
• Hyperphosphatemia[4]
• Neurofibromatosis[4]
• Hypercalcemia
• Abetalipoproteinemia
• Familial polyposis of the colon
• Congenital hypertrophy of retinal pigment epithelium
• Diffuse lipomatosis[5]
• Cutaneous calcinosis
• Microsomia
• Myopia[5]
• Trauma[5]
• Hypertensive coronary disease[5]
• Senile elastosis
• Epilepsy
• Diabetes mellitus[4]

Epidemiology

Age

The age of onset is variable most commonly it presents in the mid-fifties but may present at a younger age in patients with co-morbidities.

Morbidity

Central visual loss is mainly related to foveal involvement with dehiscence of the Bruch membrane or neovascular membrane formation just under the retina. Choroidal neovascularization is a common cause of vision loss and affects most patients with angioid streaks.

Sex

No sexual predilection is described.

Race

White people are affected most. [5] [6]

Pathophysiology

The orientation of angioid streaks may be related to force lines due to the pull of intrinsic and extrinsic muscles of the eye around a fixed location (e.g., optic nerve). The fragility and opacification of the Bruch's membrane may be primarily due to the degeneration of the elastic portion of Bruch's membrane along with deposition of calcium, magnesium, or iron salts due to disturbed metabolism.[7]

Histopathology

PXE is characterized by degradation and mineralization of the tissues containing elastin and/or collagen. The Bruch's membrane is hard and fragile in PXE due to calcification.

The histopathological examination in angioid streak reveals:

• Thickening and mineralization (calcification) of the Bruch's membrane
• There are crack-like well-demarcated dehiscence of the Bruch's membrane at the collagenous and elastic region of the Bruch's membrane
• A fibrovascular tissue or neovascular tissue may form at the edge of the dehiscence of Bruch's membrane and grow under the retina or RPE.

History and Physical

Angioid streaks are usually asymptomatic visually. The visual decline may result from foveal involvement with an angioid streak, rupture at the area of angioid streak causing subretinal bleed at the fovea, or CNV. These hemorrhages do not have evidence of CNV and usually resolve spontaneously. However, the angioid streak may be associated with CNV, which may cause visual decline and/or metamorphopsia.

Patients with PXE may be referred from the dermatology department for ophthalmic evaluation, leading to the diagnosis of angioid streaks. Other systemic associations will have history and clinical examination findings according to the disease.

The history should try to rule out systemic associations.

Evaluation

Clinical features:

A comprehensive ocular examination should be performed. This includes visual acuity, refraction, intraocular pressure, ocular motility, the examination of the ocular adnexa, lacrimal system, cornea, anterior chamber, iris, pupillary reaction including a relative afferent pupillary defect, lens, and fundus.

Clinically, angioid streaks are characterized by:

• Jagged irregular lines approximately of the caliber of a retinal vessel radiating from the optic disc
• Serrated margins of the streaks 
• Variable caliber (50–500 micrometers)
• Subretinal location (the retinal vessels are superficial to the angioid streaks)
• The streaks may be interconnected at places (usually forming a ring around the optic disc)
• Gray, black, reddish or pink, depending on the pigmentation of the choroid visible through the thin RPE and gap in the Bruch's membrane
• Possible association with pigmentation resulting in a black area which is wider than the usual angioid streaks[8]
• The tendency to involve the macula.
• Usually located behind the equator
• Abrupt tapering at the end away from the optic disc (towards the peripheral retina)
• In eyes with media haze, the angioid streak may be ve subtle and overlooked
• On cursory examination, the angioid streak may be confused with retinal blood vessels.
• With age, the number, width, and length of angioid streaks may increase
• Usually, angioid streaks are bilateral. However, the fundus changes may be asymmetric.
• Some cases may have depigmentation around angioid streak, which is equally spread on either side of the angioid streak. The width of this depigmented area may vary, extending up to 3 times the width of the angioid streak on either side.[8]

 Associated features include:

• Peau d'orange appearance of fundus- There is pigmentary mottling (small areas of pigmentation which are sometimes confluent at the level of retinal pigment epithelium interspersed with normal fundus color) specifically temporal to the fovea sometimes reaching the equator, giving an appearance of the skin of an orange. Rarely, the changes may be extensive, and retina nasal to the optic disc may also be involved. It is less common in angioid streaks associated with Sickle cell disease or Paget disease of bone.
• Optic disc drusen- The disc is hyperautofluorescent and shows hyperechoic lesion with acoustic shadow on ultrasound of the optic nerve head
• Peripapillary chorioretinal degeneration
• Macular thinning or pigmentary changes- The changes are usually bilateral, and there is no hemorrhage or hard exudates.
• CNV or disciform scar- Usually, an associated angioid streak in noted in the vicinity of the CNV. The CNV may be characterized by subretinal fluid, hard exudates, or blood.  The incidence of CNV in angioid streak may be up to 86%, and bilateral involvement is seen in up to 71% cases.[5] Usually, subretinal CNV (type 2) is seen. The CNV is usually recurrent. CNV causes poor vision in patients with angioid streaks, and vision loss occurs earlier than CNV due to wet age-related macular degeneration (wAMD). The chances of development of CNV are high if the angioid streaks are wide and long; and if they involve an area within 1 disc diameter of the foveola. Cracked egg-shell appearance or diffuse type of angioid steaks also predispose to CNV.[9] PXE has a higher risk of macular CNV.
• Subretinal/submacular hemorrhage- Usually, the patient presents with visual decline due to subfoveal hemorrhage.
• Peripheral chorioretinal scar- This may simulate presumed ocular histoplasmosis syndrome (POHS)
• Crystalline bodies and comet-shaped lesions
• Pattern dystrophy of the macula
• The end-stage of the angioid streak is "disciform macular degeneration, helicoid peripapillary atrophy, or diffuse choroidal sclerosis with obscuration of the angioid streaks"[10]

Investigations:

Infrared imaging may detect subtle angioid streaks missed in color fundus photo.

Hypo-autofluorescence is usually noted in the area of the angioid streak, and the area of abnormality on autofluorescence may be larger than abnormality visible in color fundus photo or clinical examination.[5]

FFA usually shows window defect corresponding to the area of angioid streaks. FFA is very important to detect choroidal neovascularization.

Optical coherence tomography (OCT) reveals the retinal/subretinal/sub-RPE changes in CNV, and also hyper-reflectivity at the Bruch's membrane level due to calcification. The en-face OCT may reveal the areas of angioid streaks. The choroid may be thinner in eyes with angioid streaks and CNV compared to angioid streaks without CNV.[11]

OCT-angiogram may be used to demonstrate the CNV in the angioid streak.

Indocyanine green angiogram (ICGA) may reveal a speckled pattern of cyanescence at the region of Peau d'orange appearance and reveals the CNV. The angioid streaks may show hypercyanescehce or hypocyanescence or mixed pattern.[5]

Treatment / Management

Angioid streaks are usually asymptomatic and do not need any treatment.

However, these eyes are more prone to develop subretinal hemorrhage after trivial trauma, and protective eyewear should be used.

All patients with angioid streaks should be screened for potential systemic associations. Examination of family members may give clue to the systemic disease.

In cases with subretinal hemorrhage, a fundus fluorescein angiogram should be performed to rule out CNV. If CNV is absent, the hemorrhage usually resolves on its own.

If CNV is detected, the management options include laser photocoagulation, photodynamic therapy (PDT), transpupillary thermotherapy (TTT), macular translocation surgery, and anti-vascular endothelial growth factor (anti-VEGF) agents. Recurrence of CNV causing vision loss is a concern in the angioid streak.

Among anti-VEGF agents, ranibizumab, aflibercept, and bevacizumab (off-label) have been used with success and may improve or stabilize the visual acuity.  All anti-VEGF agents seem to have efficacy against both macular and juxta-papillary CNV and may rapidly improve the retinal anatomy on OCT. Anti-VEGF agents may help stop the activity of CNV without the formation of a scar.[5]

Differential Diagnosis

Differential diagnoses of angioid streaks include:

• Normal retinal vessels
• Lacquer's cracks- A degenerative finding noted in pathological myopia, also characterized by breaks in the Bruch's membrane. It may be associated with subretinal hemorrhage without evidence of CNV.
• Reticular dystrophy of the retinal pigment epithelium (RPE)- It is characterized by RPE changes that cause pigmentation in 'fishnet with knot' pattern. The changes are located at the posterior pole and may cause a round circle similar to angioid streaks. 
• Subretinal tracks due to ophthalmomyiasis interna are smooth and may cross each other multiple times.
• Subretinal bands may be noted in long-standing retinal detachment or operated retinal detachment cases, which may simulate angioid streaks.
• Bilateral disciform scars may be seen in wAMD.
• Peripheral punched out scars may simulate POHS.

Prognosis

The visual prognosis of untreated patients with choroidal neovascularization is poor. Systemically, though most patients with pseudoxanthoma elasticum have a normal life span, early death can occur due to gastrointestinal hemorrhage, cerebral hemorrhage, and myocardial infarction.

Complications

The complications of angioid streaks include:

• Subretinal bleed due to choroidal rupture after trivial trauma
• Choroidal neovascularization causing subretinal hemorrhage, intraretinal or subretinal hemorrhage, or exudate, often leading to disciform scar- This can cause severe vision loss and early treatment with anti-VEGF usually stabilizes vision and may improve vision in some cases.
• Foveal atrophy/thinning

Enhancing Healthcare Team Outcomes

The initial diagnosis and management of angioid streaks are primarily by the ophthalmologist, but follow up is usually done by the primary care provider and nurse practitioner. Angioid streaks are usually asymptomatic and do not need any treatment. However, these eyes are more prone to develop subretinal hemorrhage after trivial trauma and the clinical team, and specialty-trained ophthalmic nurse should educate the patient on the use of protective eyewear. Due to the rarity in the use of medications, a pharmacist with a background in ophthalmic medications should assist the practitioner in appropriate dosing anti-VEGF agents are used.

All patients with angioid streaks should be screened for potential systemic associations. Examination of family members may give a clue to the systemic disease. Interprofessional collaboration is important for systemic associations including pseudoxanthoma elasticum and sickle cell disease. Various specialties to be included in the loop to manage a patient with pseudoxanthoma elasticum includes but may not be limited to gastroenterology, cardiology, neurology, pulmonary medicine, and genetics.