Angioid streaks are visible irregular crack-like dehiscences in Bruch’s membrane that are associated with atrophic degeneration of the overlying retinal pigmented epithelium. Despite 50 % of cases being idiopathic, this condition grabs attention as it requires good history taking and workup to determine the cause.

Historical background

The first description of angioid streaks was provided in 1889 by Dr. Robert W. Doyne, an English ophthalmologist. He noticed irregular, jagged deeply pigmented lines especially around the discs of both eyes in a patient who sustained trauma in both eyes and attributed it to be due to the rupture of pigment layer of retina. [1] Because of their resemblance to blood vessels, Herman J. Knapp, a German-born American ophthalmologist coined and introduced the term "angioid streaks" in 1892. [2] They are also known as Knapp’s striae. Clinical examination with histopathological findings by Bock in 1938 in two patients with pseudoxanthoma elasticum confirmed that the underlying abnormality was not vascular in nature but rather a structural alteration in Bruch’s membrane. [3] Subsequently similar histopathological results were found in patients suffering from Paget’s disease and several systemic diseases as well. [4]

Etiopathogenesis

The exact pathogenesis and pathophysiology of angioid streaks is not known. A dual mechanism suggests 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. [5] This abnormal structural composition of the Bruch’s membrane predisposes it to localized areas of rupture. 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 account for the configuration of the breaks. This process may occur spontaneously or could be secondary to blunt trauma, even very minor. Hence scleral depression should generally be withheld as this could theoretically contribute to formation of additional breaks in Bruch's membrane.

Systemic associations ( Table1 )

Up to 50 % of angioid streak are idiopathic. They can be associated with numerous systemic diseases, the most common being pseudoxanthoma elasticum. Other systemic associations are enlisted in table 1. The presence of angioid streaks should be considered indicative of an underlying systemic illness, even if the specific disorder cannot be identified or defined accurately at the time that the angioid changes are first noted. The patient must undergo a systemic evaluation and remain under continuing surveillance.

Histopathology

Histopathologic studies have shown extensive calcification and thickening of Bruch's membrane and the intervening interstitial space between capillaries. In angioid streaks the elastic lamina that occupies the midsegment of Bruch’s membrane is affected, resulting in the disintegration of the elastic fibers. The streaks present as ruptures in this elastic lamina of Bruch's membrane. In pseudoxanthoma elasticum, the primary lesion is the degeneration of elastic fibers of the connective tissue, while the calcium deposition represents a secondary disorder.[8] In Paget’s disease the bone deformities lead to calcium binding by the elastic fibers. [9] The absence of angioid streaks in anemias other than sickle cell hemoglobinopathy has changed the earlier hypothesis of iron deposition [5,10][ leading to Bruch’s membrane fragility. Later studies proved that angioid streaks in patients with sickle-cell hemoglobinopathies are correlated to calcium deposition at Bruch’s membrane. [11] Other histopathological findings include the break or absence of choriocapillaris beneath angioid streaks and thinning or decoloration of RPE. [12]

Clinical features

The initial diagnosis of an abnormal macula or of optic disc changes may be made during a routine ophthalmoscopic examination of the eye or based on patient complaints of metamorphopsia/ reduced vision. In addition, in certain cases in which the family history is positive for angioid streaks, a screening examination will reveal the presence of the characteristic signs of the disease. Angioid streaks can be difficult to identify unless a careful examination of the posterior pole is performed, especially the peripapillary area. They usually present as linear gray or dark red lines, with irregularly serrated edges lying beneath normal retinal blood vessels. The distribution of streaks can be peripapillary in 27% of cases when it is confined to 2 disc diameters from the optic nerve or more widespread in 73% of cases where the streak radiate for varying distances in the fundus, however not extending past the equator.[13] The color of angioid streaks depends on the background coloration of the fundus and the degree of atrophy of the overlying retinal pigment epithelium (RPE). In lightly colored fundi, angioid streaks are red, reflecting the pigmentation of the underlying choroid. In patients who have darker background pigmentation, angioid streaks are usually a medium to dark brown. [9, 14, 15]

Fig: Fundus photos of a 54 years old male with angioid streaks. Below- Red free images delineating the streaks better.

Other ocular features of angioid streaks include

Peau d'orange or leopard skin spotting It consists of speckled yellowish mottling of the posterior pole mostly apparent in the temporal macula. This typical appearance is caused due to alterations at the level of the Bruch membrane. Although most commonly seen with angioid streaks related to pseudoxanthoma elasticum, the peau d’orange fundus is also seen in patients who have other underlying systemic diseases. [9] Peau d'orange does not affect visual acuity, even when the fovea is involved. However, when readily identifiable in one individual, siblings and parents should be investigated for the presence of peau d'orange even in the absence of angioid streaks.

Optic nerve head drusen (hyaline bodies) They may precede the appearance of angioid streaks. As many as 10% of patients with angioid streaks have clinical evidence of disc drusen. [16] The usual complications of intrapapillary drusen including neovascularization in the peripapillary area, visual field deficits, and even acute visual loss due to the pressure effect on the optic nerve head can occur in this association.

Salmon spots These are punched out focal yellowish chorioretinal atrophic lesions which appear as peripapillary chorioretinal atrophy, focal peripheral chorioretinal scars and/ or reticular pigment dystrophy of the macula. o In older patients, peripheral retinal scars and calcifications can be seen.[17]

Clinical course and complications

Patients with angioid streaks are generally asymptomatic unless the patients develop some secondary complications. The major causes of visual loss in angioid streaks include

Choroidal Neovascularisation [14, 18, 19, 20] The incidence of CNV in patients with angioid streaks varies between 72%–86% in numerous studies. Commonly, CNV does not occur simultaneously in both eyes; there is an interval of roughly 18 months with the subsequent serous and hemorrhagic detachment of the fovea. They are bilateral in 50% of patients. While type 2 NV is the most common presenting anatomical subtype of NV to occur in the setting of angioid streaks, type 1 and mixed (type 1 and type 2) lesions occur in up to 16% of eyes. [21] Patients with angioid streaks who develop CNV are symptomatic and their main symptoms are metamorphopsia and reduction of vision. The risk of developing CNV increases with age. Other risk factors comprise the width, length, and location of the angioid streaks. The wider and longer are the angioid streaks the higher the risk for CNV and especially if the lesions are located in a distance less than one optic disc diameter from the foveola. Interruptions in the mechanical integrity of Bruch’s membrane can result in dysregulation of regional growth factor gradients that together with a potential communication between retinal and choroidal compartments can culminate in CNV. Angioid streaks associated with pseudoxanthoma elasticum have a relatively high probability of developing macular CNV than other systemic disorders.

Choroidal rupture secondary to trivial trauma [22] Owing to the brittle nature of Bruch’s membrane in patients with angioid streaks, even trivial trauma can result in rupture of these membranes. Breaks of Bruch’s membrane are frequently followed by subretinal hemorrhages which can be easily misinterpreted as CNV. A retrospective study on patients with angioid streaks mentioned that 15% of those who suffered a head injury developed significant visual impairment.

Foveal involvement of a streak with damage to the RPE and choriocapillaris The increase in length and width of streaks is considered an expected feature of the disease. When the streak passes through fovea, it causes permanent damage to the RPE and choriocapillaries resulting in a significant drop in vision. RPE tears have also been reported in angioid streaks.[23]

Multimodal imaging in angioid streaks

The diagnosis is mainly clinical. In early cases where the findings are subtle, the imaging modalities have a major role to play.

Fundus autofluorescence (FAF)

Autofluorescence is a noninvasive imaging modality for mapping the naturally or pathologically appearing fluorophores of the ocular fundus. It detects the integrity of RPE cells and reflects its metabolic activity. Angioid streaks on FAF appear as radial fissures with central hypoautofluorescence and with a variable amount of hyperautofluorescent focal spots alongside the angioid streaks at the borders of the cracks. [Fig- ] The presence of optic nerve head drusen can be seen as hyperautofluorescent bodies. RPE changes detected by FAF are more widespread and extensive than seen on fundus photography or fluorescein angiography. [24]

Figure: Fundus autofluorescence imaging shows areas of hypoautofluorescence in the peripapillary area that is greater in size than the corresponding AS seen on color photography.

Confocal Near-Infrared imaging (NIR)

Confocal NIR reflectance imaging at 820 nm is an excellent noninvasive method for imaging abnormalities in the deep retinal and subretinal structures. [25]The absorbance of shorter wavelength monochromatic light by melanin and lipofuscin granules in the RPE, limits the capability of FAF (488 nm) and FA (490 nm) in detecting these deeper pathologies. The absorption of near IR light by melanin is minimal leading to good visibility of structures below the RPE. [26] Additionally, confocality enables visualization of alterations of a given plane with improved contrast and detail. In angioid streaks, breaks in Bruch's membrane appear darker compared with the surrounding fundus reflex on confocal NIR.

Spectral Domain OCT

With the improved resolution of spectral-domain OCT (SD-OCT), the pathology of angioid streaks was localized to the Bruch's membrane-retinal pigment epithelium (RPE) complex. The width of the gap in Bruch's membrane is variable and overlying RPE can remain unaffected, but often appeared altered, focally detached, or absent. [27] In many advanced cases, fibrovascular tissue extended from the choroidal into the subneurosensory space through the gaps in Bruch's membrane. [Fig ] Fundus fluorescein angiography (FA) The diagnosis of angioid streaks is usually made on the basis of fundoscopy, but intravenous fluorescein angiography can help to delineate the presence of the disease when the ophthalmoscopic appearance is subtle. FA detects angioid streaks only when there is a concomitant loss of overlying RPE. Typically, angioid streaks have a ‘window defect’ in fluorescein angiography due to atrophy of RPE adjacent to them. FA also helps to confirm the presence of classic CNV and delineate the margins of the neovascular membrane, which is typically above or adjacent to the angioid streaks. [Fig ]

Figure: Optical coherence tomography shows the angioid streaks as disruptions in Bruch’s membrane shown in arrow. Note the fibrovascular tissue extending from the choroid into the subneurosensory space through the gap in Bruch's membrane

Indocyanine green angiography (ICG)

ICG angiography shows hyperfluorescent lines corresponding to the streaks with ‘pinpoints’ over their whole length that are larger and more numerous than those on fluorescein angiography or red-free photography. It is helpful especially in cases where it is difficult to determine the borders of the neovascular membrane in fluorescein angiography due to adjacent hemorrhages or RPE lesions.

Figure: “ Window defect” in FA due to atrophy of RPE adjacent to angioid streaks. Note the leak at the macula due to active CNV with blocked fluorescence corresponding to the subretinal hemorrhage.

OCT angiography (OCT)

Optical coherence tomography angiography (OCTA) is a relatively newer imaging modality that exploits flow-characteristics to construct non-invasive images of the vascular network.[28] On OCTA the morphology of CNV is characterized by a tangled network of vessels. The configuration of CNV closely follows the trajectory of angioid streaks. [Fig- ]

Figure: En Face OCTA (c) demonstrates two areas of CNV that demonstrate a tangled morphology of vascular networks. Sites of CNV closely correlate to sites of angioid streaks

Management options

The current treatments for patients with angioid streaks can be separated into those treating the systemic disease and those treating the ocular findings.

Systemic evaluation and Management

There is a high association between patients with angioid streaks and other systemic diseases. It is therefore important that patients who have angioid streaks to be further investigated for their systemic condition by a physician. The three most common systemic associations are pseudoxanthoma elasticum, Paget's disease of bone, and sickle cell hemoglobinopathies, and therefore any screening workup should focus on these entities. A complete physical examination by an internist, a skin biopsy, and serologic testing to include serum alkaline phosphatase, serum calcium and phosphate, and hemoglobin electrophoresis is recommended. All individuals with disorders like PXE, should undergo a diligent, complete ophthalmologic examination and annual surveillance for ocular complications of this disorder.

Ocular management

Observation Angioid streaks are usually asymptomatic requiring observation only. Prophylactic photocoagulation of angioid streaks may stimulate CNV formation and is contraindicated.

Secondary prevention Patients with angioid streaks are at higher risk of choroidal rupture and subretinal hemorrhage secondary to mild blunt trauma. [29] They are advised to wear protective goggles and sports glasses when playing sports and during work.

Indications and options for treatment.

Treatment is indicated only whenever a choroidal neovascularization has developed. Untreated CNV associated with angioid streaks generally have poor visual prognosis. [30] 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. Many of these membranes grow fast once they break through the Bruch membrane. Treatment options include laser photocoagulation, anti-vascular endothelial growth factor (AntiVEGF), Photodynamic therapy (PDT), and surgical removal of CNVM under the fovea.

Laser photocoagulation The reported incidence of CNV in angioid streaks is the quite high, however prophylactic laser is no longer advocated and many researchers strongly believe that this kind of intervention can actually induce CNV. [31] Laser is recommended to treat well-defined juxtafoveal or extrafoveal CNV. The results were not encouraging in macular CNV due to the higher chance of recurrence and the laser-induced scar progression resulting in further deterioration of visual acuity.[22, 32] Photodynamic therapy (PDT) Results of previous studies on the efficacy of photodynamic therapy (PDT) with verteporfin for CNV secondary to age-related macular degeneration (AMD) and pathologic myopia [ 33-34] were encouraging. Hence clinicians tried to use PDT in other pathological entities causing CNV. However when applied to CNV in angioid streaks, it failed to affect the natural course of the disease unless the repetition of treatment was applied in shorter intervals. The long term results of PDT alone are disappointing and include enlargement of the CNV lesion to a disciform scar and associated visual loss, ruptures of already brittle Bruch’s membrane, and damage to collateral choriocapillaries.

Anti-Vascular endothelial growth factor (anti-VEGF) With the introduction of anti- VEGF agents namely bevacizumab and ranibizumab, the treatment of choroidal neovascularization secondary to angioid streak has taken a great positive turn. Treatment with anti- VEGF agents has demonstrated a marked reduction in the rate of visual acuity loss in treated eyes compared with untreated eyes. In contrast to previous therapeutic regimens which resulted in disciform scarring and irreversible loss of overlying RPE, intravitreal anti- VEGFs have shown improvement in visual acuity and anatomic outcomes. [35]

Combined therapy(PDT+ anti- VEGF) Combination therapy like PDT with intravitreal Triamcinolone Acetonide (IVTA) or PDT with intravitreal Bevacizumab has been found to cause regression of CNVM and visual improvement. Additionally the mean number of injections required reduced significantly with combination therapy.[36, 37 ]

Surgical option – Macular translocation In the pre- anti-VEGF era macular translocation was considered as an option for CNV. Macular translocation is a surgical technique wherein the macular neuroretina is moved to lie on top of an area of RPE without previous choroidal neovascularization. The technique involves either a limited translocation or 360 degrees translocation where the entire retina is rotated.[37, 38]

Conclusion

A primary abnormality of fibers of the Bruch membrane combined with an increased brittleness due to metallic salt deposition has been implicated in the pathogenesis of angioid streaks. The three most common systemic associations are pseudoxanthoma elasticum, Paget's disease of bone, and sickle cell hemoglobinopathies. Usually they are bilateral and asymptomatic, however, the majority of cases develop CNV which is the most serious vision-threatening complication in these eyes. Treatments with laser, PDT alone and macular translocation have not resulted in significant visual improvement. Anti- VEGF treatment has shown promising results in the treatment of CNV associated with angioid streaks. Long term studies are warranted in this regard and on the combination therapy.

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