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Angiography of the Cornea Using Optical Coherence Tomography

Winston Chamberlain, MD, PhD; Afshan Nanji, MD, MPH; David Huang, MD, PhD; and Yan Li, PhD

Corneal neovascularization (NV) is the pathologic infiltration of blood vessels into an otherwise clear matrix of the cornea, resulting from a disruption in the balance between pro- and anti-angiogenic factors. It develops from a variety of causes including infections, immunologic processes, surgery, and trauma. These vessels may then lead to corneal edema, exudation of lipid, and corneal scarring, thus decreasing vision. They also compromise the immune privilege status of the cornea, and in cases of NV in corneal grafts they increase the risk of graft rejection.

Proposed treatment options for pathological vessels of the cornea, in addition to addressing the underlying cause, include topical steroids¹; photodynamic therapy^2,3; argon laser therapy^4,5; fine-needle diathermy^6,7; topical, subconjunctival, and intrastromal anti-vascular endothelial growth factor agents^8–12; and inhibition of insulin receptor substrate-1 expression.¹³ These treatments are also often used in combination, in order to have maximal effect against both active and established corneal NV.

The efficacy of various anti-angiogenic therapies remains poorly understood, however, in part because of limitations in detection and quantification of vascular fronds within the cornea. Traditional methods to evaluate corneal NV include slit-lamp biomicroscopy and color photography or videography.^14,15 Shortcomings of these methods include difficult delineation of vessels in areas of scarring,⁶ as well as the inability to detect vessel activity and to differentiate between afferent and efferent branches.¹⁶ Corneal angiography, specifically fluorescein angiography (FA) and indocyanine green angiography (ICGA), allows more detailed visualization of vessels, as well as of blood flow timing and direction. FA also permits evaluation of vessel leakage, and ICGA allows detection of deeper vessels, even in the presence of corneal scarring.¹⁷ More recently, because of the invasive and time-intensive nature of corneal angiography, optical coherence tomography (OCT) has also undergone preliminary evaluation as a noninvasive and consistent method of imaging of corneal NV.¹⁸ The advent of new therapies for corneal NV requires improved diagnostics that can both guide treatment options and permit assessment of treatment efficacy.

PRINCIPLES OF OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY

OCT angiography (OCTA) is a new method that takes advantage of the high scan speed of spectral domain OCT for angiographic imaging. Motion contrast is used to detect flow within blood vessels, as compared to Doppler OCT, which depends on axial flow in blood vessels.¹⁹ Sequential OCT cross-sectional scans of a fixed area are acquired. The cross-sectional scan is compared to the subsequent cross-sectional scan and the decorrelation between the scans is calculated using a split-spectrum amplitude-decorrelation angiogram algorithm.20 The decorrelation value helps distinguish motion within specific zones of tissue, specifically flow of erythrocytes within vessels vs static tissue zones. An eye motion correction algorithm is essential to distinguish blood flow from global eye movement due to saccades or other eye motions. A parallel computer platform capable of fast processing of high volumes of acquired data is also required to make scans clinically feasible. Traditional OCT acquires structural data in a cross-sectional fashion. In contrast, OCTA provides functional blood flow information as well as the structural tissue anatomy. OCTA is often presented in an en face fashion using data projection, but can also be reviewed slice-by-slice in a cross-sectional manner. This allows for acquisition of three dimensional (3D) information that can illuminate the depth of vessel arborization. OCTA was initially developed to image retinal vasculature.^20,21 Systems designed for retinal scans can be adapted for an anterior segment using a special optical adaptor lens. Very recently, researchers engaged in proof-of-concept studies to investigate corneal angiography with a commercially available spectral domain OCT platform (Avanti RTVue XR with AngioVue, Optovue Inc).^18,22

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IMAGING OF CORNEAL PATHOLOGY

Corneal OCTA is a novel technique that may improve diagnosis and treatment of corneal NV and the pathologies from which it results. For the following section, all patients underwent imaging on the commercially available spectral domain AngioVue OCTA system (Optovue Inc) intended for retina imaging (AngioRetina mode), but using the anterior segment optical adaptor lens. The device works at a center wavelength of 840 nm, has an axial resolution of 5 μm in tissue, and is capable of an axial scan rate of 70 kHz. Angiography scans were performed using the built-in AngioVue software. The 3D volumetric angiography scans consisted of 304 × 304 × 640 voxels to cover a square area (either 4.5 × 4.5 mm or 9 × 9 mm in size) with 1.93 mm depth in tissue. Two repeated cross-sectional scans were captured at each location before proceeding to the next position. A total of 304 locations were sampled along the slow scanning direction to form a 3D data cube. Two volumetric raster scans, one x-priority and one y-priority scan, were acquired. The blood flow was detected and the 2 orthogonal volumetric scans were registered using the AngioVue software, a commercial version of the split-spectrum amplitude-decorrelation angiogram algorithm, and orthogonal motion correction technology (MCT).^20,23

Superficial Neovascularization

Multiple disease etiologies can lead to NV of the cornea at the superficial, middle, and deep stromal layers. Superficial NV of the cornea can be driven by contact lens wear, limbal stem cell deficiency, and conjunctivalization of the cornea from previous limbal insults. Pterygia are invasions of the normal superficial cornea by inflamed fibrovascular growth of conjunctival tissue across the limbus. They can drive ocular surface inflammation and can impair vision by inducing irregular astigmatism or by advancing across the visual axis. Pterygia may be surgically removed but there is a risk of recurrence of the fibrovascular tissue onto the cornea. Figure 35-1A demonstrates a nasal recurrent pterygium after multiple previous resections. OCTA of the recurrent pterygium is shown in Figure 35-1B; the image demonstrates the vasculature in an en face profile, while the cross-sectional image (Figure 35-1D) shows the depth of the angiographic signal (marked in red) within the tissue. Figure 35-1C shows a corresponding en face OCT image. The extent and density of the vascular frond is well delineated by OCTA.

Middle and Deep Stromal Neovascularization

Middle and deep stromal NV occurs in the setting of infectious or neurotrophic keratitis and can be a sequela of the healing process. These vessels, however, also have the undesirable effect of promoting ongoing corneal opacification and irregularity. Figure 35-2A demonstrates a healed bacterial corneal ulcer that occurred in the setting of a neurotrophic cornea. On slit-lamp examination, the corneal NV is partially obscured by the corneal scarring. OCTA of the same lesion is shown in Figure 35-2B (and corresponding en face OCT, Figure 35-2C), with associated cross-sectional images showing the angiographic signal. Using OCTA, the extent of the corneal NV around and within the scar becomes more visible. Some masking of the angiographic signal may be present in the central, most dense area of the scar, but OCTA still demonstrates the much greater extent of vessels than can be seen with slit-lamp examination.

Interstitial keratitis, another cause of deep and midstromal vessels, is a disease caused by bacterial, viral, parasitic, and immune reactions. Common etiologies include herpes and syphilis. It is not often associated with overlying ulceration of the cornea. However, the chronicity of the disease can lead to corneal NV, lipid and protein keratopathy, edema, stromal thinning, scarring, and eventual endothelial decompensation. Ghost vessels are a late finding. Topical steroids are a frequent therapeutic component and may drive regression of NV in some cases. Figure 35-3 shows a slit-lamp photo of a patient with interstitial keratitis and lipid deposition. Using retroillumination, Figure 35-3B demonstrates multiple vessels feeding the zone of lipid deposition (seen in Figure 35-3D) and nasal to it. Interestingly, OCTA of the cornea does not detect blood flow in the ghost vessels nasal to the lipid zone (Figure 35-3A), but does show flow in areas of active deposition (Figure 35-3C). There may be some blockage of OCTA angiographic signal in areas of lipid deposition.

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