Background
In 1889, Doyne first described angioid streaks in a patient with retinal hemorrhages
secondary to trauma.[1] Later in 1892, Knapp named them angioid streaks because of their
resemblance to blood vessels.[2] Angioid streaks result from pathological changes at the
level of the Bruch membrane, which was confirmed histologically in the late 1930s.
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.
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:




Patients with PXE present in the third decade with a mean age of 51.7 years.
Patients with sickle cell disease tend to be in their second and third decades with a
mean age of 41.7 years.
Patients with Paget disease tend to be older at the time of diagnosis with a mean
age of 67 years.
Angioid streaks in patients with no systemic disease or with rare etiologies tend to
present late in life with a mean age of 65.7 years. Rare etiologies include patients
with peptic ulcer, diabetes, hypertension, arthritis, breast cancer, metastatic
cancer, rheumatoid spondylitis, and heart disease.
Proceed to Clinical Presentation
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 are as follows:



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:
o Peau d'orange or leopard skin spotting, consisting of speckled yellowish
mottling of the posterior pole mostly apparent in the temporal macula.
This finding may antedate the appearance of angioid streaks. It is seen
more frequently in patients with PXE and is caused by alterations at the

level of the Bruch membrane as demonstrated by the diffuse pattern of
hyperfluorescence on indocyanine green angiography (ICGA).
o Peripapillary chorioretinal atrophy, focal peripheral chorioretinal scars
(salmon spots), and reticular pigment dystrophy of the macula may be
present at the time of diagnosis.
o Optic nerve head drusen (hyaline bodies) may antedate the appearance of
angioid streaks, and they may be the earliest clinical manifestations of
PXE. As many as 25% of patients with angioid streaks have clinical or
echographic evidence of disk drusen. These hyaline bodies were
associated with neovascularization in the peripapillary area, and, in some
patients, they were associated with acute visual loss due to the pressure
effect on the optic nerve head.
o Crystalline bodies typically are seen in the midperipheral fundus or
inferior to the optic nerve. They are multiple, round, small, and subretinal
lesions. Usually, these crystalline bodies cause some atrophy of the retinal
pigment epithelium (RPE). In older patients, peripheral retinal scars and
calcifications can be seen.[6]
o Optic atrophy may be seen in patients with Paget disease of the bone. It
cannot be explained solely on the basis of bony compression.
Severe visual impairment is caused by one of the following conditions in 70% of
cases:
o CNV with subsequent serous and hemorrhagic detachment of the fovea
(most serious complication)
o CNV development occurs in 72-86% of all patients over time.[7] Once a
patient develops CNV in one eye, it becomes bilateral in 50% within 18
months of the initial diagnosis.[8]
o Choroidal rupture secondary to trivial trauma with secondary hemorrhage
involving the fovea
o Foveal involvement by a streak with damage to RPE and choriocapillaris
(may result in permanent loss of central visual acuity)
Causes


Idiopathic: In 50% of patients with angioid streaks, no associated systemic disease
is present.
Systemic association
o 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.
o




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.
o 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.
o 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.
o Some patients develop genitourinary bleeding as part of PXE.
o Neurologic findings may include cerebrovascular accidents, intracranial
aneurysms, and cerebral ischemia.
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 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:
o Skin and musculoskeletal - Thin hyperplastic skin that heals poorly,
hyperextensible joints that may predispose to recurrent falls, hydrarthrosis,
and pseudotumor formation over elbows and knees
o Cardiovascular disease consists of bleeding diathesis, dissecting
aneurysms, spontaneous rupture of large blood vessels, and mitral
prolapse.
o Others - Diaphragmatic hernias and diverticulum of the GI and respiratory
tracts
Hemoglobinopathies that are occasionally associated with angioid streaks include
the following:
o Homozygous sickle cell disease (Hb-SS)
o Sickle cell trait (Hb-AS)
o Sickle cell thalassemia (Hb-thal)
o Sickle cell hemoglobin (Hb-SC)
o Hemoglobin H (Hb-H)
o Homozygous B-thalassemia major
o Intermedia
o Minor and hereditary spherocytosis
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 associated with angioid streaks include the following:
o Abetalipoproteinemia
o Acromegaly
o Dwarfism
o Diabetes mellitus
o Hemochromatosis
o Facial angiomatosis
o Idiopathic thrombocytic purpura
o Chronic familial hyperphosphatemia
o Hypercalcinosis
o Diffuse lipomatosis
o Acquired hemolytic anemia
o Myopia
o Neurofibromatosis
o Epilepsy
o Senile elastosis
o Sturge-Weber syndrome
o Trauma
o Tuberous sclerosis
Proceed to Differential Diagnoses
Differentials



ARMD, Exudative
Choroidal Rupture
Toxoplasmosis
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
o Red-free photographs (see image below) show radiating irregular
curvilinear lines of variable width and configurations.
o
o
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 (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.
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.
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.
Indocyanine green angiography
o 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.
o 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.
Other Tests


Retinal function tests
o 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.
o Visual fields are normal unless the central macula is affected by the
angioid cracks and RPE detachments.
o Color vision is affected only when vision loss occurs and is similar to
color vision in acquired macular diseases.
o Electroretinography (ERG) findings are normal.
o Electro-oculography (EOG) findings are normal in most cases. Findings
may be subnormal in advanced cases.
o 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.
Proceed to Treatment & Management
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. 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
o 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.
o 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.
o 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.[9] Decreased vision of 2 lines or greater on the Snellen chart
occurred in 13 of 29 patients.[9]
o 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
o 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.
o 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.
o 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.
o Many investigators found that laser treatment, if administered early and
adequately to CNV lesions, may have a favorable result on long-term
visual outcome.
o Many patients needed multiple treatments because of persistent leakage
and recurrence that occurred during the first 3 months.
o Patients need to be monitored closely with Amsler grids and FA.
o 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.
o 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.
Photodynamic therapy
o 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.
o 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.
o
o
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.[10]
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.
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.
Antiangiogenic agents
o Recently, with the advent of antivascular endothelial antibodies, namely
bevacizumab and ranibizumab, 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.[11, 12,
13]
o
Combination low-fluence photodynamic therapy and ranibizumab were
used successfully to treat cases of angioid streaks in many centers around
the world.[14, 15]
Surgical Care

Submacular surgery
o
o
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.[16] 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.[16]
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.
Medication Summary
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Photosensitizers
Class Summary
Effects can induce vascular occlusion.
View full drug information
Verteporfin (Visudyne)
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.
Antineoplastic Agent, Monoclonal Antibody
Class Summary
Antivascular growth factor inhibitor stops new blood vessel formation.
View full drug information
Ranibizumab (Lucentis)
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.
Proceed to Follow-up
Further Outpatient Care


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.
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.
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. 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.