Angioid Streaks

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Background

In 1889, Doyne first described angioid streaks in a patient with retinal hemorrhages secondary to trauma.[1] Angioid streaks, also known as Knapp striae, are irregular jagged dehiscences in the mineralized, degenerated, brittle Bruch membrane that typically form alongside force lines exerted by intrinsic and extrinsic ocular muscles that radiate in a centrifugal pattern emanating from the optic disc.[2] Knapp named them angioid streaks because of their resemblance to blood vessels.[2]  See the images below.



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Progression of angioid streaks. Large subretinal hemorrhage.



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Same eye as in previous image, 11 months later. Partial resolution of subretinal blood. Notice the old subretinal hemorrhage under the fovea and color....



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Late complication of choroidal neovascularization in angioid streaks. Same eye as in previous images, 5 years later. Notice the extensive scarring and....

Pathophysiology

Controversy about the pathophysiology of angioid streaks exists. In some diseases, including pseudoxanthoma elasticum (PXE) and Paget disease, the Bruch membrane may become calcified and brittle with subsequent development of cracks. However, cytoimmunochemistry and x-ray analysis had shown that the earliest abnormality in PXE was abnormal accumulation and metabolism of polyanions (ie, glycosaminoglycans, glycoproteins) within the Bruch membrane.

The lines of force within the eye resulting from the pull of intrinsic and extrinsic ocular muscles on the relatively fixed site of the optic nerve have been studied. Those lines of forces had the same configuration as the peripapillary interlacement and radial extensions of angioid streaks. Such forces acting on the Bruch membrane undoubtedly account for the configuration of the breaks. However, in sickle cell disease, Bruch membrane calcification is not a common part of the pathology.

It is believed that the pathology may be a combination of diffuse elastic degeneration of the Bruch membrane, iron deposition in elastic fibers from hemolysis with secondary mineralization, and impairment of nutrition because of sickling, stasis, and small vessel occlusion. Klien proposed a dual mechanism as a cause of these cracks in general, as follows: a primary abnormality of fibers of the Bruch membrane, and an increase in availability of metal salts or a tendency for their deposition, resulting in a secondary brittleness of the membranes.[3]

Epidemiology

Frequency

United States

Not known

International

Not known

Mortality/Morbidity

Moderate-to-severe central visual loss is mainly related to foveal involvement with a dehiscence of the underlying Bruch membrane or a neovascular membrane formation under the retina. Choroidal neovascularization (CNV) is the major cause of vision loss and affects 70-86% of patients with angioid streaks.

Race

White people are affected most. Two studies showed similar results: of all patients with angioid streaks, 66.2% of patients were white, compared with 29% of Asian origin and 3.7% of black people.[4, 5]

Sex

No sexual predilection exists.

Age

The age of onset is variable with the underlying etiology. In one study, the age of onset of 50 patients with angioid streaks was reported as follows:

Prognosis

A high risk of serious complications, such subretinal hemorrhage and serous detachment, exists. Bilateral involvement is the rule, although it may not be symmetrical. Among individuals in whom CNV begins to develop, 50% will develop CNV in the fellow eye within 18 months.[6, 5, 7] Families with affected individuals need screening and regular eye examinations for early detection of any progression.

Patient Education

Patients should be instructed to return if visual acuity decreases. Signs of decreased central visual acuity may include central blurred vision, difficulty in depth perception, and distortion of lines and objects.

Families and patients will benefit from using an Amsler grid to detect early changes in asymptomatic but high-risk individuals.

More emphasis should be placed on safety measures to avoid trauma even if trivial. Protective goggles are useful for young patients who participate in sports.

History

Visual acuity is normal unless a leakage, bleeding, or Bruch membrane dehiscence involves the central macula. Distorted central vision (metamorphopsia) and micropsia can be early signs of macular involvement.

Physical

Ophthalmoscopic findings

At times, angioid streaks can be difficult to identify unless a careful examination of the posterior pole is performed.

Angioid streaks usually present as linear gray or dark red lines with irregular serrated edges lying beneath normal retinal blood vessels. The streaks intercommunicate in a ringlike fashion around the optic disc in 27% of cases and radiate outward in a tapering fashion from the peripapillary area in 73% of patients. The streaks run a convoluted course and tend to terminate abruptly. Angioid streaks usually do not extend past the equator. Associated findings in patients with angioid streaks are as follows:

Severe visual impairment is caused by one of the following conditions in 70% of cases:

Causes

Idiopathic

In 50% of patients with angioid streaks, no associated systemic disease is present.

Systemic association

PXE is an uncommon inherited disorder of connective tissue. It has generalized effects on the elastin fibrils in the dermis, arterial walls, heart, gastrointestinal (GI) tract, and Bruch membrane, resulting in mineralization and deposition of phosphorus. The 4 types of inheritance of PXE include 2 of which are autosomal dominant and 2 of which are autosomal recessive. It is the most common systemic disorder associated with angioid streaks. Diagnosing PXE is important because 85% of patients develop ocular involvement, usually after the second decade of life. The combination of PXE and ocular involvement is referred to as Grönblad-Strandberg syndrome.

Histologically, degenerative changes and calcifications of the elastic tissues in the skin and arteries are present. The following systemic findings may help the ophthalmologist to confirm the diagnosis of angioid streaks secondary to PXE, as well as to take care of complications.

Dermatologic findings include yellow papules, "chicken skin" arranged in a linear or reticulate pattern, in plaques, over the side of the neck, antecubital fossae, axillae, groin, and paraumbilical area.

Cardiovascular manifestations include accelerated hypertension at an earlier age due to atherosclerosis, which may be related to renovascular disease, premature coronary artery disease, peripheral vascular disease, and mitral incompetence.

Some patients develop genitourinary bleeding as part of PXE.

Neurologic findings may include cerebrovascular accidents, intracranial aneurysms, and cerebral ischemia.

Paget disease

Paget disease is a chronic, progressive, and in some cases inherited disease, characterized by bone deformity. It may be confined to a few bones, or in some patients, it represents a generalized abnormality that gives rise to enlargement of the skull, kyphoscoliosis, deafness, and deformities of long bones. However, angioid streaks occur in fewer than 2% of patients. Osteoclastic activity with an osteoblastic reaction occurs. Although the etiology is unknown, some clinicians believe it is related to a slow virus infection, measles, or respiratory syncytial virus. Both males and females are affected equally.

Ehlers-Danlos syndrome

Ehlers-Danlos syndrome is a rare autosomal dominant disorder of collagen resulting from a deficiency of hydroxylysine. Ocular findings include epicanthal folds, keratoconus, high myopia, retinal detachment, blue sclera, ectopia lentis, and angioid streaks. Systemic associations include the following:

Hemoglobinopathies

Hemoglobinopathies that are occasionally associated with angioid streaks include the following:

Advancing age and ethnicity

The frequency of angioid streaks increases with age; it is about 1.5% in younger patients and increases to 22% in older patients. Complications, such as macular degeneration and choroidal neovascular membranes, are uncommon in this subgroup of patients with angioid streaks. In general, choroidal neovascular membranes (CNVM) and serous detachments of the macula are less common in black patients.

Other systemic diseases

Other systemic diseases associated with angioid streaks include the following:

Complications

Subretinal hemorrhage and serous detachment are common complications of angioid streaks. Incidence of subretinal hemorrhage and serous detachment caused by choroidal neovascularization is high, about 85% of all patients with PXE and 10-15% of patients with Paget disease of the bone. The disease is bilateral in all patients with an average age of onset older than 25 years. The greater the length and width of the angioid streaks, the greater the risk of CVN. The risk is even higher if the streaks are within 1 disc diameter of the foveola.[6, 5, 7] Ungureanu et al reported a case of neovascular glaucoma secondary to angioid streaks.[13]

Laboratory Studies

Only one half of patients with angioid streaks have a systemic association. General workup is important to diagnose and treat other aspects of the disease that may be life threatening, such as GI hemorrhage, heart disease, anemia, and pathological fractures.

Biochemical survey: Serum calcium, phosphorous, and alkaline phosphatase levels may be abnormal in untreated cases of Paget disease. Urinary excretion of pyridinoline crosslinks is a more specific and sensitive marker. In untreated patients, a close correlation between serum activity of alkaline phosphatase and urinary excretion of hydroxyproline exists. However, 10% of patients with Paget disease who are symptomatic have serum levels of alkaline phosphatase within the reference range.

Imaging Studies

Fluorescein angiography

Red-free photographs (see image below) show radiating irregular curvilinear lines of variable width and configurations.



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Red-free photograph of the optic nerve and posterior pole showing the cracks in the Bruch membrane. Notice the retinal arteries and veins crossing ove....

Early fluorescein angiography (FA) (see image below) reveals either hyperfluorescence due to window transmission defects of atrophic RPE or uncommonly hypofluorescence due to atrophy or separation of underlying choriocapillaries, which results in nonfilling window defects.



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Early fluorescein angiography showing the early hyperfluorescence, window defect, of the angioid streaks.

In late FA (see image below), some leakage at the margins of the streaks occurs from adjacent healthy choriocapillaries and from late staining of the sclera and deep choroidal vessels. The classic appearance of CNVM, RPE detachments, and serous or hemorrhagic detachments also may be noted on FA.



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Late fluorescein angiography of the same eye as in Media file 2. Notice the staining of the edges of the streaks. Also, staining in the center of the ....

Indocyanine green angiography

ICGA is superior to FA in defining occult choroidal neovascularizations. It shows angioid streaks in all eyes studies. Hyperfluorescent lines are visible in most cases. However, some patients exhibit hypofluorescence and tracklike fluorescence.

Peau d'orange appearance of the temporal macula can be seen on ICGA as a speckled pattern in the midperiphery. Hyperfluorescent lines look larger and more numerous than those seen on FA or red-free photographs.

Radiology studies

Radiographs of the head, abdomen, and lower extremities are helpful to show bone involvement in Paget disease of the bone and premature calcification of arteries in PXE.

Optical coherence tomography angiography

Optical coherence tomography angiography (OCTA) is a new noninvasive technique that constructs a three-dimensional image, providing information on both retinal structure and vascular flow.[14] It is superior to FA in terms of visualizing the intraretinal structures and requires no dye injection. A case report by Gal-Or et al used OCTA to identify CNV in a patient with angioid streaks. On OCTA, the CNV followed the path of the angioid streak, demonstrating breaks along the Bruch membrane.[15] This new imaging modality shows promise in monitoring CNV and in serving as a tool for early detection of CVN in patients with angioid streaks.[15, 14]

Other Tests

Retinal function tests

Visual acuity is normal, as long as no damage to the foveal RPE and no leakage from the choroid through the Bruch membrane and RPE occur.

Visual fields are normal unless the central macula is affected by the angioid cracks and RPE detachments.

Color vision is affected only when vision loss occurs and is similar to color vision in acquired macular diseases.

Electroretinography (ERG) findings are normal.

Electro-oculography (EOG) findings are normal in most cases. Findings may be subnormal in advanced cases.

Dark adaptation is normal.

GI studies

GI hemorrhage is common in patients with PXE.

Procedures

Dermatologic: Skin biopsy may provide important diagnostic clues in cases of PXE with angioid streaks.

Medical Care

Initially, patients are asymptomatic and no indication for prophylactic treatment is present. Angioid streaks are a generalized disorder of the Bruch membrane.

Angioid streaks are an uncommon entity to be studied and are treated as part of a controlled and randomized study. Treatment methods are based mainly on individual experience and extrapolation from the Macular Photocoagulation Study Group. Patients with angioid streaks are at higher risk of choroidal rupture and subretinal hemorrhage secondary to mild blunt trauma.[16] They are advised to wear protective goggles and sports glasses when playing sports and during work.

Treatment options include observation, laser photocoagulation, and surgical removal of CNVM under the fovea. The Food and Drug Administration (FDA) approved the use of photodynamic therapy (PDT) for CNVM secondary to age-related macular degeneration (ARMD).

Observation

Initially, symptomatic patients complained of a decrease in their central visual acuity, and some developed distortion and metamorphopsia that was more disturbing than the associated central scotomas. Usually, central scotomas tend to increase in size if left untreated before subsequent scarring of the macula occurs.

Early at the time of diagnosis, more than 50% of patients had vision of 20/40 or better; one half of them became legally blind at an average follow-up period of 3.5 years. Most eyes had vision 20/200 or worse after age 50 years.

In one study, 11 untreated eyes with subretinal neovascular membranes all had a final visual acuity of counting fingers. Clarkson and Altman reported 29 patients seen on 2 occasions over a period of at least 6 months.[17] Decreased vision of 2 lines or greater on the Snellen chart occurred in 13 of 29 patients.[17]

Prophylactic laser treatment in clinically asymptomatic eyes without active choroidal neovascularization is not recommended. In one study, prophylactic treatment was associated with an increased incidence of neovascularization at the site of treatment. However, patients who received laser photocoagulation noticed a decrease in the size of their central scotomas and early relief from visual distortion.

Laser photocoagulation

Photocoagulation, including light (xenon) and argon, has been used since the early 1970s, although angioid streaks themselves were treated to stop their progression toward the macula. Early treatment experiences with light and laser photocoagulation were disappointing and discouraging. Some investigators discouraged laser treatment of CNVM in angioid streaks.

Some success with argon laser for lesions that are located at least 100 µm from the center of the foveal avascular zone (FAZ) has been reported.

Laser therapy is believed to slow the progression of the CNV toward the fovea and stabilizes vision. Moreover, it improves the quality of vision (ie, size of central scotoma, decreases metamorphopsia). Successful treatment of CNV may not improve central vision in some patients since dehiscences in the Bruch membranes may involve and damage the foveal RPE.

Many investigators found that laser treatment, if administered early and adequately to CNV lesions, may have a favorable result on long-term visual outcome.

Many patients needed multiple treatments because of persistent leakage and recurrence that occurred during the first 3 months.

Patients need to be monitored closely with Amsler grids and FA.

In several series, the recurrence rate was reported as high as 77% of patients who underwent laser treatment. Most recurrent CNVMs were subfoveal. The incidence of recurrence was higher in angioid streaks than in other conditions, such as ARMD, degenerative myopia, and histoplasmosis.

Treating CNVM associated with angioid streaks is sometimes challenging. Both occult and classic CNV can occur in the same eye and usually are located very close to the foveal avascular zone. RPE reaction is minimal around CNVM. Some of these membranes grow fast once they break through the Bruch membrane. Careful setup of laser power and spot size is important to prevent further damage to the brittle and mineralized Bruch membrane.

Transpupillary thermotherapy

Transpupillary thermotherapy (TTT) has been used in the treatment of macular CNV. The diode laser used in transpupillary thermotherapy results in less absorption of the RPE and allows for deeper penetration into the choriocapillaris.[6] Transpupillary thermotherapy has been reported in the literature as a treatment modality for CNV due to angioid streaks but has been unsuccessful.[6, 18] Ozdek et al reported an initial decrease in the size of the angioid streak, but it began to increase again at 3 months. The patient’s visual acuity remained stable; however, the CNV activity was not effectively decreased, leading to more retreatments.[18] Thus, transpupillary thermotherapy is not as effective as other treatment modalities in CNV due to angioid streaks and may lead to more unfavorable outcomes.[6, 18]

Photodynamic therapy

PDT is a modality approved by the FDA for the treatment of CNV secondary to ARMD. It uses a light activated drug (eg, verteporfin [Visudyne]) and applying a nonthermal red light in the range of 689 nanometers. The total energy delivered is 50 J/cm2 over a period of 83 seconds. The power of laser output can be adjusted according to size of CNV and ophthalmic lens magnification.

A study evaluated the short-term safety and visual effects after administering PDT in 13 patients with classic subfoveal CNV secondary to pathological myopia, ocular histoplasmosis syndrome, angioid streaks, and idiopathic causes. Most patients gained at least 1 line of vision. Reduction in the size of leakage area from classic CNV was noted in all patients as early as 1-week posttreatment, with complete absence of leakage in almost one half of the patients. Up to 4 treatments were found to have short-term safety even with re-treatment intervals as short as 4 weeks.

Karacorlu et al evaluated the safety and efficacy of PDT with verteporfin for subfoveal CNV associated with angioid streaks in 8 eyes and showed that PDT generally achieved a short-term cessation of or a decrease of fluorescein leakage from subfoveal CNVM without loss of vision in patients with angioid steaks.[19]

Long-term effects of PDT, especially in patients who may need multiple treatments, are unknown. Patients with angioid streaks are at higher risk of recurrent CNV.



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Right eye, midphase arteriovenous, showing choriocapillaris atrophic changes. This 45-year-old patient underwent 3 injections of Avastin and one sessi....



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Same patient as in previous image, a few months before the Avastin injection and half-time photodynamic therapy.

Antiangiogenic agents

Recently, with the advent of antivascular endothelial antibodies, namely bevacizumab, ranibizumab, and aflibercept,[20, 21, 6] the treatment of choroidal neovascularization secondary to angioid streak has taken a great positive turn. Many patients are treated with anti–vascular endothelial growth factor (VEGF) therapy worldwide. The visual function showed stabilization over extended periods. Unfortunately, the recurrence rate is high and many patients need repeated injections to control the disease.[22, 23, 24, 25]

Bevacizumab

Teixeira et al, who first described the use of bevacizumab for CNV secondary to angioid streaks, reported an improvement in visual acuity and stabilization of disease.[26] Successful treatment with bevacizumab has been reported by several authors since.[26, 6, 27]

Ranibizumab

Tilleul et al showed visual improvement in 22 of 35 eyes (62.9%) after intravitreal injections of ranibizumab, along with a decrease in macular thickness in 45.7% of patients, and 77.1% showed no leakage at 4-year follow-up.[28, 29, 27] Ebran et al demonstrated improvement of visual acuity in 88.6% of 98 eyes following intravitreal ranibizumab injections. At 2-year follow-up, visual acuity remained stable, with a significant reduction in recurrence.[30] Finger et al showed that patients with early disease showed significant improvement in visual outcome compared to those with advance disease.[31, 27]

Aflibercept 

Intravitreal aflibercept has been described in case reports as treatment for refractory CNV secondary to angioid streaks. It has also been reported as the initial treating agent of CVN, with success.[20, 21] Makri et al reported on a 42-year-old white woman who presented with persistent CNVM and subretinal fluid that was treated with ranibizumab with no anatomical or functional improvement. After 3 loading doses of aflibercept, the patient showed increased vision and resolution of subretinal fluid.[32]

Combination low-fluence photodynamic therapy and ranibizumab

Combination low-fluence photodynamic therapy and ranibizumab were used successfully to treat cases of angioid streaks in many centers around the world.[33, 34]

Surgical Care

Submacular surgery

Patients with classic subfoveal CNVM are not candidates for laser photocoagulation therapy. In the past, they were left without treatment. However, advances in instrumentation and vitreoretinal surgical techniques have made it possible to remove CNVM without significant damage to RPE and neurosensory retina.

Eckstein et al reported encouraging short-term visual results in 31 consecutive patients with non–age-related subfoveal CNVM, including angioid streaks.[35] Visual acuity improved or remained the same in 25 of 31 eyes. Moreover, visual acuity improved by more than 2 lines in 5 eyes (16%). Older patients and those with atrophic RPE had the worst outcome. Recurrent CNV occurred in 11 eyes (35%). The presence of subfoveal blood was associated with a higher recurrence rate of membranes. There was no significant association between the final visual acuity and length of symptoms prior to surgery or preoperative vision.[35]

Transplantation of autologous full-thickness RPE and choroidal patch

Parolini et al described a case of a 53 year-old man with subfoveal CNV secondary to angioid streaks who underwent transplantation of an autologous full-thickness RPE and choroidal patch. The patient experienced significant visual improvement, from 20/200 to 20/40 and J2, at nearly 6 months posttreatment. At 2.5 years, there was no recurrence of CVN, and the patient’s vision remained stable.[36]

Activity

Patients with angioid streaks have a high risk of choroidal rupture and subretinal hemorrhage secondary to mild blunt trauma. It is recommended that patients wear protective sports glasses whenever applicable.

Long-Term Monitoring

Screening and follow-up examination by means of Amsler grid and ophthalmoscopic examination, including FA, may be necessary to detect CNVM and to treat recurrences.

Patients who undergo laser treatment or surgery need close follow-up care during the first 3 months of treatment. If they stay asymptomatic and no FA leakage occurs, follow-up care every 6 months is recommended.

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Verteporfin (Visudyne)

Clinical Context:  A benzoporphyrin derivative monoacid (BPD-MA), consists of equally active isomers BPD-MAC and BPD-MAD, which can be activated by low-intensity, nonthermal light of 689-nm wavelength. After activation with light and in presence of oxygen, verteporfin forms cytotoxic oxygen free radicals and singlet oxygen. Singlet oxygen causes damage to biological structures within range of diffusion. This leads to local vascular occlusion, cell damage and cell death. In plasma, verteporfin is transported primarily by low-density lipoproteins (LDL). Tumor and neovascular endothelial cells have increased specificity and uptake of verteporfin because of their high expression of LDL receptors. Effect can be enhanced by use of liposomal formulation.

Class Summary

Effects can induce vascular occlusion.

Ranibizumab (Lucentis)

Clinical Context:  Recombinant humanized IgG1-kappa isotype monoclonal antibody fragment designed for intraocular use. Indicated for neovascular (wet) age-related macular degeneration (ARMD). In clinical trials, about one third of patients had improved vision at 12 mo that was maintained by monthly injections. Binds to VEGF-A, including biologically active, cleaved form (ie, (VEGF110). VEGF-A has been shown to cause neovascularization and leakage in ocular angiogenesis models and is thought to contribute to ARMD disease progression. Binding VEGF-A prevents interaction with its receptors (ie, VEGFR1, VEGFR2) on surface of endothelial cells, thereby reducing endothelial cell proliferation, vascular leakage, and new blood vessel formation.

Class Summary

Antivascular growth factor inhibitor stops new blood vessel formation.

Aflibercept intravitreal (Eylea)

Clinical Context:  EYLEA (aflibercept) is a recombinant fusion protein consisting of portions of human vascular endothelial growth factor (VEGF) receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 formulated as an iso-osmotic solution for intravitreal administration. Aflibercept is a dimeric glycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation, constituting an additional 15% of the total molecular mass, resulting in a total molecular weight of 115 kDa. Aflibercept is produced in recombinant Chinese hamster ovary (CHO) cells.

Afliberceptis a sterile, clear, and colorless to pale yellow solution. EYLEA is supplied as a preservative-free, sterile, aqueous solution in a single-use, glass vial designed to deliver 0.05 mL (50 microliters) of aflibercept (40 mg/mL in 10 mM sodium phosphate, 40 mM sodium chloride, 0.03% polysorbate 20, and 5% sucrose, pH 6.2).

Author

Mohammad Abusamak, MD, FICO, FRCS(Glasg), MRCS(Edin), Assistant Professor, Division of Ophthalmology, Al-Balqa Applied University, School of Medicine; Ophthalmologist, Amman Eye Clinic, Jordan

Disclosure: Nothing to disclose.

Coauthor(s)

Ama Sadaka, MD, Resident Physician, Department of Ophthalmology, University of Cincinnati Hospital

Disclosure: Nothing to disclose.

Shauna Berry, DO, Pediatric Ophthalmology and Neuro-ophthalmology

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Steve Charles, MD, Founder and CEO of Charles Retina Institute; Clinical Professor, Department of Ophthalmology, University of Tennessee College of Medicine

Disclosure: Received royalty and consulting fees for: Alcon Laboratories.

Chief Editor

Andrew G Lee, MD, Chair, Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital; Clinical Professor, Associate Program Director, Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch School of Medicine; Clinical Professor, Department of Surgery, Division of Head and Neck Surgery, University of Texas MD Anderson Cancer Center; Professor of Ophthalmology, Neurology, and Neurological Surgery, Weill Medical College of Cornell University; Clinical Associate Professor, University of Buffalo, State University of New York School of Medicine

Disclosure: Received ownership interest from Credential Protection for other.

Additional Contributors

Russell P Jayne, MD, Vitreoretinal Surgeon, The Retina Center at Las Vegas

Disclosure: Nothing to disclose.

References

  1. Doyne RW. Choroidal and retinal changes. The result of blows on the eyes. Trans Ophthal. 1889. 9:128.
  2. Knapp H. On the formation of dark angioid streaks as an unusual metamorphosis of retinal hemorrhage. Arch Ophthalmol. 1892. 21:289-292.
  3. Klien BA. Angioid Streaks: A clinical and histopathologic study. American Journal of Ophthalmology. 1947. 30:955-68.
  4. Abujamra S, Negretto AD, Saraceno JJ, Oliveira TL, Gomes AM. [Angioid streaks: fundoscopic analysis of 317 cases]. Arq Bras Oftalmol. 2008 Nov-Dec. 71(6):819-21. [View Abstract]
  5. Mansour AM, Ansari NH, Shields JA, Annesley WH Jr, Cronin CM, Stock EL. Evolution of angioid streaks. Ophthalmologica. 1993. 207(2):57-61. [View Abstract]
  6. Georgalas I, Papaconstantinou D, Koutsandrea C, Kalantzis G, Karagiannis D, Georgopoulos G, et al. Angioid streaks, clinical course, complications, and current therapeutic management. Ther Clin Risk Manag. 2009 Feb. 5 (1):81-9. [View Abstract]
  7. Mansour AM, Shields JA, Annesley WH Jr, el-Baba F, Tasman W, Tomer TL. Macular degeneration in angioid streaks. Ophthalmologica. 1988. 197 (1):36-41. [View Abstract]
  8. Spaide RF. Peau d'orange and angioid streaks: manifestations of Bruch membrane pathology. Retina. 2015 Mar. 35 (3):392-7. [View Abstract]
  9. Dhermy P. Histologie Angioid Streaks. Cosca G, Soubane G, eds. Neovasseaux Sous-Retiniens et Laser. Paris, France: 1987. 210-1.
  10. Gass J, Donald M. Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment. 4th ed. CV Mosby: 1997. Vol. 1: 120.
  11. Piro PA, Scheraga D, Fine S. Angioid Streaks: Natural history and visual prognosis. Management of Retinal Vascular and Macular Disorders. Williams and Wilkins; 1983. 136-9.
  12. Shoumnalieva-Ivanova V, Tanev I, Zdravkov Y, Monov S, Shumnalieva R. Angioid streaks in aagenaes syndrome. Int Ophthalmol. 2016 Sep 10. [View Abstract]
  13. Ungureanu E, Geamanu A, Careba I, Grecescu M, Gradinaru S. Angioid streaks - a rare cause of neovascular glaucoma. Case report. J Med Life. 2014. 7 Spec No. 4:71-3. [View Abstract]
  14. Chalam KV, Sambhav K. Optical Coherence Tomography Angiography in Retinal Diseases. J Ophthalmic Vis Res. 2016 Jan-Mar. 11 (1):84-92. [View Abstract]
  15. Gal-Or O, Balaratnasingam C, Freund KB. Optical coherence tomography angiography findings of choroidal neovascularization in pseudoxanthoma elasticum. Int J Retina Vitreous. 2015 Aug 7. 1:11. [View Abstract]
  16. Kubota M, Hayashi T, Arai K, Tsuneoka H. Choroidal neovascularization after blunt ocular trauma in angioid streaks. Clin Ophthalmol. 2013. 7:1347-51. [View Abstract]
  17. Clarkson JG, Altman RD. Angioid streaks. Surv Ophthalmol. 1982 Mar-Apr. 26(5):235-46. [View Abstract]
  18. Ozdek S, Bozan E, Gürelik G, Hasanreisoglu B. Transpupillary thermotherapy for the treatment of choroidal neovascularization secondary to angioid streaks. Can J Ophthalmol. 2007 Feb. 42 (1):95-100. [View Abstract]
  19. Karacorlu M, Karacorlu S, Ozdemir H, et al. Photodynamic therapy with verteporfin for choroidal neovascularization in patients with angioid streaks. Am J Ophthalmol. 2002 Sep. 134(3):360-6. [View Abstract]
  20. Esen E, Sizmaz S, Demircan N. Intravitreal aflibercept for management of subfoveal choroidal neovascularization secondary to angioid streaks. Indian J Ophthalmol. 2015 Jul. 63 (7):616-8. [View Abstract]
  21. Vaz-Pereira S, Collaço L, De Salvo G, van Zeller P. Intravitreal aflibercept for choroidal neovascularisation in angioid streaks. Eye (Lond). 2015 Sep. 29 (9):1236-8. [View Abstract]
  22. Sawa M, Gomi F, Tsujikawa M, Sakaguchi H, Tano Y. Long-term results of intravitreal bevacizumab injection for choroidal neovascularization secondary to angioid streaks. Am J Ophthalmol. 2009 Oct. 148(4):584-590.e2. [View Abstract]
  23. Neri P, Salvolini S, Mariotti C, Mercanti L, Celani S, Giovannini A. Long-term control of choroidal neovascularisation secondary to angioid streaks treated with intravitreal bevacizumab (Avastin). Br J Ophthalmol. 2009 Feb. 93(2):155-8. [View Abstract]
  24. Finger RP, Charbel Issa P, Hendig D, Scholl HP, Holz FG. Monthly Ranibizumab for Choroidal Neovascularizations Secondary to Angioid Streaks in Pseudoxanthoma Elasticum: A One-Year Prospective Study. Am J Ophthalmol. 2011 Jun 24. [View Abstract]
  25. Gliem M, Finger RP, Fimmers R, Brinkmann CK, Holz FG, Charbel Issa P. Treatment of choroidal neovascularization due to angioid streaks: a comprehensive review. Retina. 2013 Jul-Aug. 33(7):1300-14. [View Abstract]
  26. Teixeira A, Mattos T, Velletri R, Teixeira R, Freire J, Moares N, et al. Clinical course of choroidal neovascularization secondary to angioid streaks treated with intravitreal bevacizumab. Ophthalmic Surg Lasers Imaging. 2010 Sep-Oct. 41 (5):546-9. [View Abstract]
  27. Martinez-Serrano MG, Rodriguez-Reyes A, Guerrero-Naranjo JL, Salcedo-Villanueva G, Fromow-Guerra J, García-Aguirre G, et al. Long-term follow-up of patients with choroidal neovascularization due to angioid streaks. Clin Ophthalmol. 2016 Dec 19. 11:23-30. [View Abstract]
  28. Tilleul J, Mimoun G, Querques G, Puche N, Zerbib J, Lalloum F, et al. INTRAVITREAL RANIBIZUMAB FOR CHOROIDAL NEOVASCULARIZATION IN ANGIOID STREAKS: Four-Year Follow-up. Retina. 2016 Mar. 36 (3):483-91. [View Abstract]
  29. Yolcu U, Gundogan FC, Diner O. Drastic effect of ranibizumab on choroidal neovascularization in idiopathic angioid streaks. Arq Bras Oftalmol. 2015 Jul-Aug. 78 (4):257-9. [View Abstract]
  30. Ebran JM, Mimoun G, Cohen SY, Grenet T, Donati A, Jean-Pastor MJ, et al. [Treatment with ranibizumab for choroidal neovascularization secondary to a pseudoxanthoma elasticum: Results of the French observational study PiXEL]. J Fr Ophtalmol. 2016 Apr. 39 (4):370-5. [View Abstract]
  31. Finger RP, Charbel Issa P, Schmitz-Valckenberg S, Holz FG, Scholl HN. Long-term effectiveness of intravitreal bevacizumab for choroidal neovascularization secondary to angioid streaks in pseudoxanthoma elasticum. Retina. 2011 Jul-Aug. 31 (7):1268-78. [View Abstract]
  32. Makri OE, Tsapardoni FN, Plotas P, Pallikari A, Georgakopoulos CD. Intravitreal aflibercept for choroidal neovascularization secondary to angioid streaks in a non-responder to intravitreal ranibizumab. Int Med Case Rep J. 2018. 11:229-231. [View Abstract]
  33. Prabhu VV, Morris RJ, Shah PK, Narendran V. Combination treatment of low fluence photodynamic therapy and intravitreal ranibizumab for choroidal neovascular membrane secondary to angioid streaks in Paget's disease - 12 month results. Indian J Ophthalmol. 2011 Jul-Aug. 59(4):306-8. [View Abstract]
  34. Artunay O, Yuzbasioglu E, Rasier R, Sengul A, Senel A, Bahcecioglu H. Combination treatment with intravitreal injection of ranibizumab and reduced-fluence photodynamic therapy for choroidal neovascularization secondary to angioid streaks: Preliminary Clinical Results of 12-Month Follow-Up. Retina. 2011 Jul-Aug. 31(7):1279-86. [View Abstract]
  35. Eckstein M, Wells JA, Aylward B, Gregor Z, et al. Surgical removal of non-age-related subfoveal choroidal neovascular membranes. Eye. 1998. 12 (Pt 5):775-80. [View Abstract]
  36. Parolini B, Alkabes M, Baldi A, Pinackatt S. VISUAL RECOVERY AFTER AUTOLOGOUS RETINAL PIGMENT EPITHELIUM AND CHOROIDAL PATCH IN A PATIENT WITH CHOROIDAL NEOVASCULARIZATION SECONDARY TO ANGIOID STREAKS: LONG-TERM RESULTS. Retin Cases Brief Rep. 2016 Fall. 10 (4):368-72. [View Abstract]
  37. Adelung JC. Zur Geneseder angioid streaks (Knapp). Klin Monatsbl Augenheilkd. 1951. 119:241.
  38. Aveline B, Hasan T, Redmond RW. Photophysical and photosensitizing properties of benzoporphyrin derivative monoacid ring A (BPD-MA). Photochem Photobiol. 1994 Mar. 59(3):328-35. [View Abstract]
  39. Bock J. Zur Klinik und Anatomic der gefaessehnlichen Streifen in Augenhintergrund. Z Augenheilkd. 1938. 95:1-50.
  40. Eretto P, Krohel GB, Shihab ZM, et al. Optic neuropathy in Paget's disease. Am J Ophthalmol. 1984 Apr. 97(4):505-10. [View Abstract]
  41. Francois J, De Laey JJ, Cambie E, et al. Neovascularization after argon laser photocoagulation of macular lesions. Am J Ophthalmol. 1975 Feb. 79(2):206-10. [View Abstract]
  42. Gelisken O, Hendrikse F, Deutman AF. A long-term follow-up study of laser coagulation of neovascular membranes in angioid streaks. Am J Ophthalmol. 1988 Mar 15. 105(3):299-303. [View Abstract]
  43. Guyer DR, Gragoudas ES, D'Amico DJ. Chapter 66: Angioid Streaks. Principles and Practice of Ophthalmology. 1993. Vol. 2: 852-60.
  44. Hagedoorn A. Angioid streaks. Arch Ophthalmol. 1939. 21:746-74.
  45. Heimann H, Gelisken F, Wachtlin J, et al. Photodynamic therapy with verteporfin for choroidal neovascularization associated with angioid streaks. Graefes Arch Clin Exp Ophthalmol. 2005 Nov. 243(11):1115-23. [View Abstract]
  46. Ladas ID, Georgalas I, Rouvas AA, et al. Photodynamic therapy with verteporfin of choroidal neovascularization in angioid streaks: conventional versus early retreatment. Eur J Ophthalmol. 2005 Jan-Feb. 15(1):69-73. [View Abstract]
  47. Lafaut BA, Leys AM, Scassellati-Sforzolini B, et al. Comparison of fluorescein and indocyanine green angiography in angioid streaks. Graefes Arch Clin Exp Ophthalmol. 1998 May. 236(5):346-53. [View Abstract]
  48. Macular Photocoagulation Study. Persistent and recurrent neovascularization after krypton laser photocoagulation for neovascular lesions of age-related macular degeneration. Macular Photocoagulation Study Group. Arch Ophthalmol. 1990 Jun. 108(6):825-31. [View Abstract]
  49. Macular Photocoagulation Study Group. Persistent and recurrent neovascularization after krypton laser photocoagulation for neovascular lesions of ocular histoplasmosis. Macular Photocoagulation Study Group. Arch Ophthalmol. 1989 Mar. 107(3):344-52. [View Abstract]
  50. Meislik J, Neldner K, Reeve EB, et al. Laser treatment in maculopathy of pseudoxanthoma elasticum. Can J Ophthalmol. 1978 Jul. 13(3):210-12. [View Abstract]
  51. Miller H, Miller B, Ryan SJ. Correlation of choroidal subretinal neovascularization with fluorescein angiography. Am J Ophthalmol. 1985 Mar 15. 99(3):263-71. [View Abstract]
  52. Pece A, Avanza P, Introini U, et al. Indocyanine green angiography in angioid streaks. Acta Ophthalmol Scand. 1997 Jun. 75(3):261-5. [View Abstract]
  53. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials--TAP report. Treatment of age-related macular degeneration with photodynamic therapy (TAP) Study Group. Arch Ophthalmol. 1999 Oct. 117(10):1329-45. [View Abstract]
  54. Pierro L, Brancato R, Minicucci M, et al. Echographic diagnosis of Drusen of the optic nerve head in patients with angioid streaks. Ophthalmologica. 1994. 208(5):239-42. [View Abstract]
  55. Reinke MH, Canakis C, Husain D, et al. Verteporfin photodynamic therapy retreatment of normal retina and choroid in the cynomolgus monkey. Ophthalmology. 1999 Oct. 106(10):1915-23. [View Abstract]
  56. Schmidt-Erfurth U, Hasan T, Gragoudas E, et al. Vascular targeting in photodynamic occlusion of subretinal vessels. Ophthalmology. 1994 Dec. 101(12):1953-61. [View Abstract]
  57. Scott LJ, Goa KL. Verteporfin. Drugs Aging. 2000 Feb. 16(2):139-46; discussion 147-8. [View Abstract]
  58. Shields JA, Federman JL, Tomer TL, Annesley WH Jr. Angioid streaks. I. Ophthalmoscopic variations and diagnostic problems. Br J Ophthalmol. 1975 May. 59(5):257-66. [View Abstract]
  59. Sickenberg M, Schmidt-Erfurth U, Miller JW, et al. A preliminary study of photodynamic therapy using verteporfin for choroidal neovascularization in pathologic myopia, ocular histoplasmosis syndrome, angioid streaks, and idiopathic causes. Arch Ophthalmol. 2000 Mar. 118(3):327-36. [View Abstract]
  60. Singerman LJ, Hatem G. Laser treatment of choroidal neovascular membranes in angioid streaks. Retina. 1981. 1(2):75-83. [View Abstract]
  61. Walker ER, Frederickson RG, Mayes MD. The mineralization of elastic fibers and alterations of extracellular matrix in pseudoxanthoma elasticum. Ultrastructure, immunocytochemistry, and X-ray analysis. Arch Dermatol. 1989 Jan. 125(1):70-6. [View Abstract]
  62. Abusamak M, Abdelal OM, Kharouf I, Hamdan SM. Improving Differential Diagnosis of Angioid Streaks: Diagnostic considerations and a case study. Retinal Physician. Available at http://www.retinalphysician.com/issues/2011/nov-dec/improving-differential-diagnosis-of-angioid-streak. November 1, 2011; Accessed: March 15, 2017.

Progression of angioid streaks. Large subretinal hemorrhage.

Same eye as in previous image, 11 months later. Partial resolution of subretinal blood. Notice the old subretinal hemorrhage under the fovea and color change to white-yellow.

Late complication of choroidal neovascularization in angioid streaks. Same eye as in previous images, 5 years later. Notice the extensive scarring and subretinal exudates and dehemoglobinized blood.

Red-free photograph of the optic nerve and posterior pole showing the cracks in the Bruch membrane. Notice the retinal arteries and veins crossing over the dark red streaks.

Early fluorescein angiography showing the early hyperfluorescence, window defect, of the angioid streaks.

Late fluorescein angiography of the same eye as in Media file 2. Notice the staining of the edges of the streaks. Also, staining in the center of the macula is present due to extension of the Bruch membrane crack. When compared to early fluorescein angiography, no active leakage is present.

Right eye, midphase arteriovenous, showing choriocapillaris atrophic changes. This 45-year-old patient underwent 3 injections of Avastin and one session of half-time photodynamic therapy.

Same patient as in previous image, a few months before the Avastin injection and half-time photodynamic therapy.

Progression of angioid streaks. Large subretinal hemorrhage.

Same eye as in previous image, 11 months later. Partial resolution of subretinal blood. Notice the old subretinal hemorrhage under the fovea and color change to white-yellow.

Late complication of choroidal neovascularization in angioid streaks. Same eye as in previous images, 5 years later. Notice the extensive scarring and subretinal exudates and dehemoglobinized blood.

Red-free photograph of the optic nerve and posterior pole showing the cracks in the Bruch membrane. Notice the retinal arteries and veins crossing over the dark red streaks.

Early fluorescein angiography showing the early hyperfluorescence, window defect, of the angioid streaks.

Late fluorescein angiography of the same eye as in Media file 2. Notice the staining of the edges of the streaks. Also, staining in the center of the macula is present due to extension of the Bruch membrane crack. When compared to early fluorescein angiography, no active leakage is present.

Right eye, midphase arteriovenous, showing choriocapillaris atrophic changes. This 45-year-old patient underwent 3 injections of Avastin and one session of half-time photodynamic therapy.

Same patient as in previous image, a few months before the Avastin injection and half-time photodynamic therapy.

A 50-year-old man with a 2-month history of blurring vision in the left eye. The color photograph showed subretinal blood and large membrane, extrafoveal in location.

Early fundus fluorescein angiography showing the hyperfluorescence of the choroidal neovascular membrane of the left eye of the same patient in the previous image.

Late fundus fluorescein angiography confirming the active choroidal neovascular membrane of the left eye.