Ultra-Widefield Fluorescein Angiography

For the last 50 years, fluorescein angiography (FA) has played a pivotal role in the evaluation and management of retinal diseases. Patterns of hyperand hypofluorescence provide insights into the pathophysiologic processes involved in vascular, degenerative, dystrophic, traumatic, infectious, inflammatory, and neoplastic diseases of the choroid and retina. Despite recent advances in other imaging techniques, including indocyanine green (ICG) angiography and optical coherence tomography (OCT), FA still plays a primary role in the diagnosis of common retinal diseases, including diabetic retinopathy, macular degeneration, retinal vascular occlusion, and posterior uveitis. Fluorescein angiography remains a vital method to assess success of treatment methods including laser photocoagulation, intraocular pharmacologic therapy such as steroid and antivascular endothelial growth factor (anti-VEGF) agents, and surgical membrane peeling.

The ability to capture a single image of the entire ocular fundus has been limited until recently. Standard FA using film or digital cameras captures an image 30 degrees across. This chapter discusses a new fluorescein imaging technique that captures fundus images up to 200 degrees in breadth. Optomap fa dynamic ultra-widefield angiography is a digital panoramic technique performed with the Optos P200MA scanning laser ophthalmoscope (SLO) (Optos plc, Dunfermline, UK). The ability to image the peripheral retina using Optomap fa provides a more comprehensive assessment of the extent of a retinal disease process, and may detect abnormalities that alter a treatment plan based initially on clinical examination and traditional angiography. This chapter presents selected examples of images obtained with the first commercially available unit.

History

The desire of the retinal specialist to capture widefield images of the fundus is long-standing. Some macular disease processes including age-related macular degeneration, selected macular dystrophies, and cystoid edema may be fully evaluated

using high magnification, narrow-field techniques. However, evaluation of many retinal diseases depends partly, if not entirely, on imaging the peripheral fundus.

Traditional FA technique involves obtaining multiple 30degree photographic images. A protocol consisting of seven standard 30-degree images was developed for the Diabetic Retinopathy Study.1 The width of this composite set of images is approximately 75 degrees. Photographs anterior to the equator may be obtained, but such photography is limited by patient alignment problems, focus irregularities, marginal corneal astigmatism, poor fixation, and light reflex artifacts. Newer noncontact camera systems may capture images up to 50 degrees across; however, peripheral images still must be mentally “stitched” together by the practitioner to formulate a composite.

Early attempts to obtain widefield images began with a moving fixation lamp and rotatable mirrors that created a composite fundus image of 96 degrees.2 Contact lenses coupled with traditional systems achieved single panoramic images of 90 degrees.3,4 Contact lenses with antireflective coatings and infrared angiography have been used to obtain 160-degree ICG angiograms.5 A specialized contact lens-based camera was developed by Pomerantzeff6 that used limbal fiber optic illumination to minimize lens reflections and obtain a 148-degree field. The RetCam 120, a contact-based, limbal illumination system, obtains 120-degree-wide photographs requires excellent patient cooperation or sedation.7

A major cause of artifact with any fundus imaging arises from reflection of light from interfaces in the ocular media. Elimination of these reflections is achieved using confocal scanning laser ophthalmoscopy (cSLO), which separates the illuminating and imaging beam within the eye. Staurenghi et al.8 developed a combined contact and noncontact handheld lens system coupled with a cSLO that obtained high-resolution images with a 150-degree field. However, this technique is cumbersome for the photographer.

The painstaking process of manually creating photomontages was simplified partially with the advent of digital photography. Distortions in the periphery of each image due to astigmatism nevertheless made exact landmark matching

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difficult. A software package was developed for automated photomontage creation using images from the Heidelberg retinal angiograph (HRA) system.9 Montages up to 140 degrees across could be obtained rapidly.

The ability to obtain images wider than 150 degrees required modification of the optical properties of the camera system. Optos plc, incorporated in 1992, developed a novel ellipsoidal mirror with dual focal points, one of which lies posterior to the iris plane. Combination of this mirror with a noncontact SLO imaging platform now allows rapid acquisition of 200-degree panoramic fundus images. In 1999 the Panoramic 200 scanning laser ophthalmoscope received Food and Drug Administration (FDA) clearance as a fundus photography device. Early study using these panoramic images for the detection of diabetic retinopathy yielded a sensitivity and specificity both equal to 76%.10 Subsequent platforms added fluorescein angiographic capability, and a commercially available FA instrument, the Optomap fa, became commercially available in 2007.

Technical Specifications

Confocal Optics

Standard camera systems have a defined focal plane. Depending on aperture size, there is a limited depth of field and focus that can be captured within the focal plane. The concave nature of the fundus renders portions of an image out of focus if the focal plane is exceeded. Confocal imaging, patented by Marvin Minsky in 1957, uses point illumination and a pinhole in an optically conjugate plane to eliminate out-of-focus information. As only one point is illuminated at a time in confocal microscopy, two-dimen- sional imaging requires scanning each pixel point in a raster over the area to be imaged. All points within the computer-generated panoramic image are in focus, as each was obtained separately.

Scanning Laser Ophthalmoscope

Traditional photography uses white light to illuminate a target, and then record an image of the reflected light. Limitations of broad-field white light illumination include scatter from media opacities, induced mydriasis, and subtle pigment epithelial bleaching. The Optos P200MA utilizes a green (532 nm) laser to image the retina and inner retinal pigment epithelium (RPE) and a red (633 nm) laser to image the outer RPE and choroid. The images may be digitally combined to create a simulated color picture, or each red-free and green-free image may be reviewed individually. A blue (488 nm) laser matches the absorption peak for fluorescein excitation.11

S.C.N. Oliver and S.D. Schwartz

mirror, translates the scanning laser beams to a virtual focal point located posterior to the patient’s iris plane.

Resolution

The charge-coupled device (CCD) detector for the camera system has a 3000 by 3000 pixel resolution capacity, with each pixel subtending about 6 to 10 µm on the retinal surface. Picture detail is obtained up to the fifth vessel bifurcation.

Imaging Technique

Patients are positioned in front of the machine with a chin rest and forehead support. Space is available for manual lid lifting, if required. Red, green, and simulated color images are obtained initially using the P200 SLO, requiring 0.25 seconds per scan. Five milliliters of 10% sodium fluorescein is injected in a standard fashion, and FA images are captured sequentially. Images are stored using a digital, searchable database that may be reviewed or printed in thumbnail or composite formats.

Limitations

Proper patient positioning with the medial and lateral canthi parallel to the machine is essential. Improvements in image processing and detector noise reduction have greatly enhanced early-phase photos, which were grayed-out in early prototypes due to fluorescence from the anterior segment. Image artifacts have been reduced with improved manufacturing techniques for the ellipsoidal mirror. Image processing has greatly improved contrast resolution in the FA images.

Potential Applications

It has long been established that ischemia and capillary nonperfusion occur commonly in the midperiphery in diabetic retinopathy.12–14 Neovascularization often occurs at the watershed zone between perfused and nonperfused retina. Furthermore, nonperfused retina may serve as a source of upregulated VEGF. Ultra-widefield fluorescein angiography readily demonstrates abnormal perfusion or vascular incompetance in retinal vascular disease.15

Visualization of peripheral RPE abnormalities or vasculitis may enhance diagnostic sensitivity and specificity for non-reti- nal vasular disease. Visual complaints in patients with peripheral retinal pathology, such as dystrophies, retinal detachment, or uveitis, may correspond with anatomic abnormalities depicted using Optomap fa images.

Ellipsoidal Mirror

Ultra-widefield imaging is enabled by the optical properties of a large ellipsoidal mirror. Instead of using standard scanning geometry, the ellipsoidal mirror provides two conjugate focal points. This first real focal point, located high on the ellipsoidal

Clinical Examples

Optomap fa images may be reviewed at a digital workstation or in printout format. Fundus photos views may be reviewed

FIG. 23.1. Scanning laser ophthalmoscopic ultra-widefield photographs may be obtained using both wavelengths of the Optomap scanning laser ophthalmoscope (SLO). Images obtained with a 532nm green laser (“red-free”) primarily display the inner retinal layers (top), while images obtained with the 633 nm red laser (“green-free”) image the retinal pigment epithelium (RPE) and choroid.

in simulated color, red-free, or green-free formats. A normal example is shown in Figure 23.1.

Retinal Vascular Disease

The ability to image retinal vascular disease serves a primary utility for FA. Hyperfluorescence due to leakage, transmission defects, or staining, and hypofluorescence from hypoperfusion or blockage are all easily delineated with FA. Optomap fa images simultaneously provide high-resolution posterior pole images similar to those obtained with traditional techniques, as well as identification of peripheral pathology that may not have been detected with clinical examination or standard fundus photography.

Diabetic Retinopathy

Fluorescein angiography may be used to diagnose protean manifestations of diabetic retinopathy. High magnification images of the macula may detect clinically significant macular edema (CSME) (Fig. 23.2) or macular ischemia (Fig. 23.3). A 3000 by 3000 pixel image capture resolves retinal details within 6 µm.

Neovascularization from proliferative diabetic retinopathy (PDR) may be detected on clinical exam or revealed by leak-

age on FA. Neovascularization elsewhere (NVE), particularly that present in the peripheral fundus, may be missed by clinical exam; it is readily detected on ultra-widefield FA (Fig. 23.4).15 Optomap fa may also detect NVE in the setting of dense asteroid hyalosis. 16 Peripheral capillary nonperfusion from diabetic retinopathy may be localized, associated with NVE, or diffuse (Fig. 23.5). Diffuse capillary nonperfusion may contribute to retinal ischemia and upregulation of vascular endothelial growth factor (VEGF), and may signal a high risk of progression to severe PDR. Targeted retinal photocoagulation (TRP) to ischemic sectors of the retina may diminish vasogenic drive and preclude the need for more extensive panretinal photocoagulation (PRP). 17

Tractional retinal detachment (TRD) results from the most advanced stages of PDR, and may demonstrate arteriolar and capillary nonperfusion, leakage from traction, and pooling within the detachment (Fig. 23.6).

Retinal Vascular Occlusion

Retinal vein occlusion results in nonperfusion of the involved vein or veins, as well as possible capillary nonperfusion in the involved areas (Fig. 23.7). Retinal neovascularization may occur, typically at the margin of an area of nonperfusion (Fig. 23.8).

Both branch and central retinal vein occlusions (BRVO and CRVO, respectively) may lead to cystoid macular edema (CME), which is detectable with a magnified view of the posterior pole (Fig. 23.9).

Ophthalmic artery occlusion results in greatly delayed arterial filling of the choroidal or retinal circulation (Fig. 23.10). Panoramic imaging reveals areas of retina and choroid perfused by long posterior ciliary branch arteries.

Coats’ Disease

Peripheral microaneurysms, macroaneurysms, vessel telangiectasiae, and exudation may be present in Coats’ disease or the adult form of Coats’ disease, known also as Leber’s miliary aneurysms. Subtle macular edema may herald more extensive peripheral pathology (Fig. 23.11). Identification of peripheral pathology may enable curative treatment for this vascular hyperpermeability disorder.

FIG. 23.5. Midphase fluorescein angiography (FA) (top) demonstrates peripheral NVE at the margin of a zone of capillary nonperfusion (arrow). Late-phase FA (bottom) also reveals broad areas of peripheral nonperfusion next to perivascular staining (double arrow). A reflection of the patient’s nose is noted in the upper right side of both images.

FIG. 23.7. Ultra-widefield midphase angiogram of a branch retinal vein occlusion (BRVO). Patchy ischemia extends into the far periphery, but cystoid macular edema (CME) is absent.

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FIG. 23.8. Following sectoral retinal photocoagulation for BRVO, NVE is present at the margin of lasered and ischemic retina, and capillary nonperfusion extends into the macula.

S.C.N. Oliver and S.D. Schwartz

FIG. 23.9. Cystoid macular edema from central retinal vein occlusion is evident on high magnification (top) and widefield (bottom) images. Extensive peripheral capillary nonperfusion is present in the widefield image (star).

Figure 23.10. Ophthalmic artery occlusion following chemoembolization for epistaxis results in severe choroidal and retinal arterial filling defects in this late-phase angiogram. Choroidal perfusion in the temporal periphery is due to late perfusion of some long posterior ciliary arteries (arrow).

Sickle Cell Retinopathy

Peripheral vascular occlusion, ischemia, and neovascularization in sickle cell retinopathy may be readily identified with ultra-widefield FA.18,19 Targeted photocoagulation to areas of ischemia may result in regression of the neovascularization without the need for extensive PRP.

Degenerative Disease

Age-Related Macular Degeneration

High-resolution, magnified imaging of the posterior pole is essential to the evaluation and treatment of AMD. The magnified image of an Optomap fa provides excellent macular detail, while still allowing the option to view other peripheral pathology (Fig. 23.12).

Dystrophic Chorioretinal Disease

Retinitis Pigmentosa

Peripheral RPE atrophy and bone spicule formation may be imaged with panoramic angiography (Fig. 23.13).

Choroideremia

The widespread, scallop-shaped RPE dropout present in choroideremia is readily captured using ultra-widefield FA (Fig. 23.14).

Rhegmatogenous Retinal Detachment

Rhegmatogenous retinal detachment may be diagnosed with panoramic imaging.20 Rhegmatogenous or exudative retinal detachment results in hyperfluorescence from subneurosensory fluorescein pooling. Chronic retinal detachment may be associated with pigmentary blocking defects, RPE loss, and vascular hypoperfusion (Fig. 23.15). Despite successful anatomic reattachment after retinal detachment repair, RPE and retinal dysfunction may resolve slowly (Fig. 23.16). If sufficient RPE

FIG. 23.12. Magnified macular view of midphase angiogram shows transmission defects from pigment epithelial abnormalities and early staining of a disciform scar in age-related macular degeneration (AMD).

injury occurs due to the detachment, RPE loss may be detectable on panoramic FA (Fig. 23.17).

Infectious and Inflammatory Chorioretinal Disease

Vasculitis may result from a variety of inflammatory etiologies, including systemic lupus erythematosus (SLE), Behc¸et

FIG. 23.13. Hyperfluorescence from RPE window defects are present peripheral to the vascular arcades in this patient with retinitis pigmentosa. Cystoid macular edema is absent.

disease, Wegener granulomatosis, toxoplasmosis, sarcoidosis, and syphilis.

Lupus-Associated Retinopathy

Increased vascular hyperpermeability from SLE vasculitis results in vascular staining. Severe inflammation may lead to

FIG. 23.14. Red-free panoramic photograph of choroideremia demonstrates broad, scalloped atrophy of the retinal pigment epithelium.

vascular occlusion, with subsequent development of CME, capillary nonperfusion, and proliferative retinopathy (Fig. 23.18).

Sarcoidosis

Manifestations of sarcoid range from anterior and posterior uveitis to occlusive phlebitis, capillary dropout, and proliferative retinopathy. 21 Laser photocoagulation to the nonperfused regions may be required.

Acute Posterior Multifocal Placoid Pigment Epitheliopathy (APMPPE) and Serpiginous Choroiditis

Idiopathic inflammation of the retinal pigment epithelium occurs most commonly in young adults following a viral prodrome. The classic angiographic findings of early blockage with late staining may be seen on FA. Serpiginous choroidopathy, also called geographic helicoid peripapillary choroidopathy, is a rare disorder characterized by hypoperfusion from progressive geographic choroidal and RPE atrophy rimmed by hyperfluorescent margins from RPE transmission defects. Overlap syndromes between APMPPE and serpiginous exist (Fig. 23.19).

Diffuse Unilateral Subacute Neuroretinitis

Chronic subretinal infection by a nematode, most commonly

Baylisascaris procyonis or Ancylostoma caninum, may lead to insidious, severe vision loss. Progressive RPE atrophy, sometimes linear along the migration path of the worm, may be seen on panoramic FA (Fig. 23.20).

Presumed Ocular Histoplasmosis Syndrome (POHS)

Atrophic chorioretinal lesions from POHS may extend into the periphery (Fig. 23.21). Care must be taken to exclude choroidal neovascularization.

FIG. 23.15. Chronic rhegmatogenous retinal detachment is demonstrated in color (top) and angiographic (bottom) images. Vessel nonperfusion, blocking from pigment clumping, and pooling in the subneurosensory space is present.

Cystoid Macular Edema

Cystoid macular edema (CME) occurring from a variety of inflammatory causes, including uncomplicated cataract surgery, may be readily identified with a magnified Optomap image of the posterior pole (Fig. 23.22). A petaloid hyperfluorescence pattern is evident.

Neoplastic

Melanoma

The delineation of the margins of a pigmented choroidal tumor is greatly enhanced using a green-free image, as the red laser penetrates the deep retina, RPE, and choroid (Fig. 23.23). Angiography may also be useful to identify intrinsic circulation in a melanoma.

FIG. 23.17. Transmission and blocking defects are present along a prior demarcation line in this patient with a history of chronic inferior retinal detachment treated with scleral buckling.

FIG. 23.18. Lupus-associated proliferative retinopathy has been previously treated with peripheral panretinal photocoagulation (PRP); however, progression of vascular obliteration resulted in a patch of capillary nonperfusion with associated neovascularization (arrow).

FIG. 23.19. Midphase fluorescein angiogram demonstrates hypofluorescent lesions rimmed by hyperfluorescent transmission defects in this patient with an overlap syndrome of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) and serpiginous choroiditis.

FIG. 23.20. Early-phase angiogram reveals diffuse RPE transmission defects, in addition to linear transmission defects (arrows), corresponding to the presumed track of a nematode in diffuse unilateral subacute neuroretinitis.

FIG. 23.21. Midphase angiogram demonstrates punched out areas of chorioretinal atrophy consistent with presumed ocular histoplasmosis syndrome (POHS).

FIG. 23.22. Irvine-Gass syndrome, with cystoid macular edema and mild optic nerve leakage, is present following scleral buckling for retinal detachment.

23. Ultra-Widefield Fluorescein Angiography

FIG. 23.23. Simulated color photograph (top) of choroidal malignant melanoma exhibits high-risk characteristics, including orange lipofuscin pigmentation and close proximity to the optic nerve. Red wavelength laser penetrates RPE and choroid, providing delineation of the peripheral margins of the tumor (bottom).

Conclusion

Dynamic ultra-widefield angiography using the Optos P200MA scanning laser ophthalmoscope offers a powerful advance in the ability of the retinal specialist to image the ocular fundus. Advantages of the Optomap fa include 200 degrees of widefield imaging, scanning laser ophthalmoscope platform, rapid acquisition time, and digital image review. Future research will entail quantification of previously unidentified peripheral retinal pathology, determination of change in treatment patterns based on the result of ultra-widefield angiography, and assessment of the effectiveness of targeted laser photocoagulation to regions of retinal ischemia.

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