| Chapter 57 Ocular Angiography in Uveitis MAURICE F. RABB , WICO W. LAI and TOM JENNINGS Table Of Contents |
| Fluorescein angiography was initially developed to study retinal vascular
flow patterns but now also serves as an important way to diagnose ocular
fundus disease. Although often used today in ophthalmology, this
technique is not particularly useful in defining the choroidal circulation.1 The rapid leakage of fluorescein from the choriocapillaris and the scattering
of fluorescence by pigmented layers of the fundus have limited
its ability to study the choroid in both the normal and pathologic states. Indocyanine
green (ICG), a water-soluble tricarboncyanine dye, possesses
unique optical and biophysical properties, including its near-infrared
absorption peak and its high plasma protein-binding capacity. Coupled
with the development of high-resolution imaging systems, ICG
angiography has become a useful adjunct or alternative to fluorescein
angiography in imaging the choroidal circulation. In this chapter, we describe the characteristic angiographic findings in many common uveitic syndromes using abnormal hypofluorescence or hyperfluorescence patterns with both fluorescein (Table 1)2,3 and ICG (Fig. 1).4 Many of these clinical entities and their treatments are described in more detail in other chapters in these volumes.
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| INTERPRETATION OF HYPOFLUORESCENCE AND HYPERFLUORESCENCE |
HYPOFLUORESCENCE Hypofluorescence may be caused by blocked fluorescence, which is synonymous with transmission decrease, or by a vascular filling defect. Blocked fluorescein corresponds to the size, shape, and location of the blocking material seen ophthalmoscopically. Any hypofluorescence that does not correspond to the ophthalmoscopic picture must then be considered a vascular filling defect. With ICG angiography, hypofluorescence needs to be analyzed by taking into consideration its evolution during the different phases of the angiogram. It is important to distinguish between hypofluorescence observed in both the early and late phases and when it is observed only in the later phases. The blockage depends on the nature of the blocking material and on the background choroidal fluorescence. Blocked Fluorescence Retinal. Any opacification in front of the retinal vessels that reduces media clarity causes blocked retinal vascular hypofluorescence on fluorescein angiogram (FA). Many inflammatory conditions produce hazy media, causing poor visualization of fundus detail. Fibrotic or gliotic membranes and inflammatory material on the retina or involving its inner layers obstruct the view of the retinal vasculature and cause blocked fluorescence. CHOROIDAL. Hypofluorescence can result from blocked choroidal vasculature due to fluid, exudate, hemorrhage, pigment, or other material accumulating in front of the choroidal vasculature deep to the retinal vasculature. Any opaque substance located beneath the retina but in front of the choroid blocks fluorescence of the choroidal vasculature; however, it does not block retinal vascular fluorescence. Fluorescence can be blocked by substances such as fluid in retinal pigment epithelial detachments and inflammatory material in acute multifocal posterior placoid pigment epitheliopathy (AMPPPE). In general, the blockage to ICG is less than that to fluorescein. For example, although blood at any level can lead to blockage throughout the FA, blockage may occur only in the later phases in ICG angiography. However, inflammatory diseases that primarily affect the choroid, such as birdshot chorioretinopathy and multifocal choroiditis, may result in profound and more dramatic blockage than that observed with FA. Vascular Filling Defect RETINAL. A vascular filling defect is the other cause of hypofluorescence in the retina if blocked fluorescence is not present. For a retinal vascular filling defect to be diagnosed, the location of the defect must be determined. It may arise from inflammatory obstruction of the artery, vein, or capillary or from a combination of these. Eales' disease, sarcoidosis, and other inflammatory diseases also cause peripheral capillary nonperfusion. CHOROIDAL. In ICG angiography, vascular filling defects have been subdivided into those that are physiologic, those resulting from a vascular occlusion, and those that are caused by tissue atrophy (see Fig. 1).4 Physiologic filling defects may be the result of choroidal watershed zones (early defects) and choroidal vascular silhouette against the background choroidal fluorescence (late defect). In contrast to FA, ICG studies are better at delineating choroidal vascular occlusion than are retinal vascular defects. Patients with AMPPPE may show persistent vascular filling defects after resolution of the condition. Choroidal vascular atrophy may develop in patients with a condition such as age-related macular degeneration, which results in vascular bed closure from scar formation. HYPERFLUORESCENCE Hyperfluorescence is any abnormally light area on the positive print of an angiogram. There are three types of hyperfluorescence in uveitis: transmitted fluorescence, abnormal vessels, and leakage. Transmitted Fluorescence Increased visibility of fluorescence from the choroidal vasculature caused by the absence of pigment in the pigment epithelium is called transmitted fluorescence (i.e., a pigment epithelial window defect) on FA. Various types of inflammation at the level of the pigment epithelium, choriocapillaris, or choroid produce pigment epithelial window defects such as AMPPPE, serpiginous choroiditis, and histoplasmosis. Each of these inflammatory conditions adversely affects the pigment epithelium, resulting in depigmentation and atrophy. Window defect is a very frequent finding in a fundus that has undergone choroidal inflammation. In ICG angiography, transmitted fluorescence may present as one of two forms depending on the integrity of the choriocapillaris. When the choriocapillaris is intact, transmission hyperfluorescence of the larger choroidal vessels is noted in the early phases of the angiogram. In the late phases of the study, the fluorescence pattern appears normal. In conditions associated with atrophy of the choriocapillaris, hyperfluorescence of the larger choroidal vessels is noted in the early phase of the angiogram. However, this area may become relatively hypofluorescent in the later phases because of decreased or absent perfusion of the choriocapillaris. Abnormal Vessels RETINAL AND DISC. There are many diseases that produce neovascularization. Retinal ischemia is theorized to be the primary pathogenic stimulus. Most of the disease processes resulting in neovascularization show some degree of ischemia by fluorescein angiography, with capillary nonperfusion an almost constant finding. The diseases that are known to result in neovascularization are phlebitis (Eales' disease), severe uveitis, pars planitis, sarcoidosis, and Behçet's disease. CHOROIDAL. Fluorescein angiography has proved to be of great value as an aid in the recognition and demonstration of normal and abnormal vascular patterns in the subretinal and choroidal tissues. The demonstration of subretinal neovascularization (SRNV) by fluorescein angiography (early lacyhyperfluorescence) represents one of the most significant advances in ophthalmic knowledge. Although ICG angiography can identify abnormal vessels in the retina, it is more helpful in imaging changes in the choroidal circulation and is most useful in situations in which occult or poorly defined SRNV is present. Often the neovascular complex is obscured by blood or fluid and is poorly visualized on FA. ICG angiography has been shown to be efficacious in identifying occult SRNV and has increased the likelihood of identifying potentially treatable lesions in patients who are otherwise considered ineligible for laser treatment under conventional guidelines.5,6 Leakage VITREOUS. In uveitis, there are two major causes of vitreous leakage seen on fluorescein angiography: (1) neovascularization and fibrosis and (2) intraocular inflammation. Disc and retinal neovascularization may be associated with uveal inflammation. Inflammation of the retina or the disc, such as that seen in toxoplasmic chorioretinitis, is an example of intraocular inflammation leading to vitreous leakage. DISC. Inflammations of the optic nerve head, such as papillitis, vasculitis, and papillophlebitis, show a fuzzy hyperfluorescence of the disc in the later phases of the FA because of the staining of the edematous inflamed tissue. RETINAL. In the late stages of the normal angiogram, the retinal vessels contain a minimal concentration of fluorescein and the retina is normally dark. Retinal hyperfluorescence in the late stages indicates extravasation of fluorescein into the retinal extravascular space. The leakage occurs in a cystoid or noncystoid pattern and arises from leakage of retinal or choroidal vessels. Similar findings may be observed in ICG angiograms. In the macula, cystoid retinal edema assumes a stellate or flower-petal appearance because of the obliquity of the outer plexiform layer. Outside the macula, there is a honeycomb appearance. Causes of cystoid edema rising from retinal vessels include inflammatory conditions, such as uveitis, chorioretinitis, and aphakia (Irvine-Gass syndrome). Cystoid retinal edema may be caused by leakage from choroidal vessels, such as with SRNV. Inflammation, such as toxoplasmic retinitis, is one of the most common causes of noncystoid retinal edema. On the FA, the lesion leaks fluorescein profusely into the surrounding retina and overlying vitreous, resulting in a fuzzy cotton-ball fluorescence. Marked staining of the retina (noncystoid edema) is then apparent. When a large retinal vessel is inflamed, as in phlebitis or vasculitis, the endothelium of the involved large retinal vessel leaks fluorescein, resulting in hyperfluorescence. On the angiogram, this appears as a line of hyperfluorescence along the wall of the vessel. Retinal vessels traversing an area of chorioretinitis show reactive perivascular staining. CHOROIDAL. Choroidal inflammatory diseases, as in focal or massive choroiditis (Harada's syndrome), can change or damage the overlying pigment epithelium sufficiently to produce a sensory retinal detachment. In some cases, marked leakage occurs, which results in heavy pooling (defined as leakage of fluorescein dye) under the sensory retinal detachment. |
| UVEITIS OF UNKNOWN ETIOLOGY | ||||||||||||||||
VOGT-KOYANAGI-HARADA SYNDROME Vogt-Koyanagi-Harada syndrome, also known as uveomeningoencephalitis syndrome, is a systemic disease often found in young, darkly pigmented whites, blacks, native Indians, Hispanics, and Asians. It presents as an anterior and posterior uveitis with disc hyperemia, disc edema, and exudative retinal detachment (Figs. 2A and B and 3A). Systemic signs and symptoms include headache, hearing loss, poliosis, vitiligo, nuchal rigidity, seizures, and even coma. SRNV and disciform scars are late complications. The differential diagnosis should include AMPPPE and sympathetic ophthalmia.
There is a characteristic fluorescein angiographic appearance in the early phase showing multiple discrete hyperfluorescent dots at the retinal pigment epithelial level that enlarge over time (see Fig. 2C and D). In the late phase, if there is a serous detachment, the fluorescein pools beneath the subretinal space (see Fig. 3B). The edematous disc hyperfluoresces in the late phase. Generally, the retinal vessels are unaffected.7,8 Retinochoroidal anastomoses also have been documented by fluorescein angiography.9 ICG angiography shows multiple hypofluorescent spots in the posterior pole (see Fig. 3C). These spots may coalesce and obscure the filling of large choroidal vessels. When serous retinal detachment develops, the marked hyperfluorescence observed on FA is not as prominently noted in ICG angiography, presumably because of the highly protein-bound nature of ICG. In fact, diffuse late hypofluorescence may be observed in patients with serous retinal detachment.10 Ill-defined areas of hyperfluorescence corresponding to diffuse choroidal staining may be seen in some cases in the late phases of the angiogram. The optic disc may stain with ICG in the acute phase but usually is minimal compared to that observed on FA. SYMPATHETIC OPHTHALMIA Sympathetic ophthalmia is a rare, bilateral granulomatous, paninflammatory disease that can occur several weeks to years after an ocular injury. Sympathetic ophthalmia is hypothesized to be an autoimmune reaction against a normally sequestered antigen unmasked by an injury. Retinal findings in sympathetic ophthalmia are perivasculitis, papillitis, and yellowish subretinal nodules known as Dalen-Fuchs nodules. Dalen-Fuchs nodules are believed to be transformed retinal pigment epithelium cells or T lymphocytes or both. Areas of choroiditis or granuloma simulating AMPPPE may be seen. Pigmentary disturbance may be noted in the chronic phase of the disease (Fig. 4A and B). Choroidal neovascularization also may develop (see Fig. 4C).
One of two possible fluorescein angiographic findings may be evident. The more common one is identical to Vogt-Koyanagi-Harada syndrome, with early multiple pinpoint retinal pigment epithelial leaks that enlarge with time.11 The second, less common, manifestation is early choroidal hypofluorescence of the Dalen-Fuchs nodules followed by hyperfluorescence in the later phase.12 When exudative retinal detachment occurs, there are confluent areas of subretinal fluorescein pooling. Two patterns have been identified on ICG angiography.13 The first pattern, observed in a patient with chronic disease, showed hypofluorescent spots in both the intermediate and late phases of the angiogram. The second pattern, reported in a patient with recent onset of the disease, showed hypofluorescent spots in the intermediate phase but faded in the late phase of the angiogram. POSTERIOR SCLERITIS Posterior scleritis is a generally unilateral condition that usually is seen in patients 40 to 60 years old. Patients present with pain, decreased vision, and decreased visual fields. It generally is associated with anterior scleritis. Posterior scleritis may cause exudative retinal detachment resembling Harada's disease (Fig. 5A), cystoid macular edema, retinal pigment epithelial detachments, choroidal folds, and subretinal masses. Thickening of the choroid and posterior sclera can be seen with ultrasound, magnetic resonance imaging, and computed tomography.
Fluorescein angiography can show several manifestations. Frequently, the angiographic picture of posterior scleritis is identical to that of Vogt-Koyanagi-Harada syndrome, except that posterior scleritis usually is unilateral. Multiple early pinpoint retinal pigment epithelial leaks with late staining of the subretinal fluid can be seen (see Fig. 5B).14 Another pattern is early multifocal choriocapillaris filling defects followed by overlying retinal pigment epithelial staining, late staining of the subretinal fluid, and disc staining.15 Cystoid macular edema16 and multiple discrete retinal pigment epithelial detachments can be seen. ICG angiography shows diffuse zonal hyperfluorescence in the intermediate and late phases. Pinpoint areas of hyperfluorescence also may be seen in the areas of zonal hyperfluorescence in the later phases of the angiogram. Delayed choroidal perfusion and hypofluorescent spots present up to the intermediate phase and faded in the late phase of the angiogram may be visualized. These spots are noted to be smaller and more irregular in size than those observed in Vogt-Koyanagi-Harada syndrome.17 RETICULUM CELL SARCOMA Reticulum cell sarcoma, a non-Hodgkin's lym-phoma, is a systemic disease that can affect many organs, including the eyes and central nervous system. Seventy-five percent of the patients with ocular and central nervous system involvement have no other manifestation. Patients with ocular reticulum cell sarcoma tend to be older and have painless loss of vision. Findings include vitreous cells that are not responsive to corticosteroids, multiple subretinal pigment epithelial detachments with yellow infiltrates, exudative retinal detachment, and retinal vascular sheathing. On fluorescein angiography, patients with reticulum cell sarcoma with multiple retinal pigment epithelial detachments have an irregular, incomplete staining of these detachments.18 BEHÇET'S DISEASE Behçet's disease is a systemic occlusive vasculitis that presents predominately in young middle Eastern and Japanese men. The classic features include acute hypopyon, iritis, aphthous stomatitis, and genital ulceration. Skin lesions and strokes also occur frequently. There often is an acute recurrent bilateral panuveitis. Ocular findings include retinal vasculitis (Fig. 6A) with an occlusive arteritis, vitritis, macular edema, ischemic retinitis, ischemic optic neuropathy, peripheral neovascularization, and occasionally SRNV.
On fluorescein angiography (see Fig. 6B), during the active phases of the disease, capillary dropout and dilated retinal capillaries are seen. Dilated retinal capillaries (particularly peripapillary capillaries) leak dye and cause retinal and disc staining.19 Cystoid macular edema,19 SRNV, and disciform scars often are seen.20 Leakage of peripheral capillaries can be seen in patients with normal-appearing fundi.21 ICG angiography shows hyperfluorescent spots from the early to late phases and hypofluorescent plaques, both of which are not evident on FA. Staining of choroidal vessel walls and leakage of ICG from the choroidal vessels also have been described.22–24 SARCOIDOSIS Sarcoidosis is a systemic, idiopathic, noncaseating, granulomatous disease that affects various organs, including the eye, brain, lung, and skin. Ocular findings may include conjunctival nodules; anterior iridocyclitis; vitreous cells; retinal, optic nerve, and choroidal granulomas (Fig. 7A); retinal vasculitis (venules are preferentially affected); cystoid macular edema; retinal vessel occlusion; and disc and retinal neovascularization.
The FA reflects the various clinical entities. Retinal venular walls stain, particularly where there are perivenular exudates.25–27 More extensive venous involvement can produce a picture of dilated veins and perivenous leakage.27 Peripheral neovascularization occurs near areas of retinal capillary nonperfusion.25,28 Optic disc granulomas and optic disc neovascularization both leak extensively (Fig. 8A); sarcoid retinal lesions also stain (see Fig. 7B).27 In disc edema, the disc is hyperfluorescent and leaks fluorescein (see Fig. 8B).25
Four main patterns can be identified with ICG angiography. The first and most common pattern is hypofluorescent dark spots in the early and intermediate phases of the angiogram. These spots either become isofluorescent or remain hypofluorescent in the late phases. The second pattern is focal hyperfluorescent spots seen in the intermediate and late phases. The third pattern is fuzzy choroidal vessels due to perivascular choroidal leakage in the intermediate phase. Finally, the fourth pattern is characterized by diffuse zonal hyperfluorescence representing choroidal staining in the late phase of the angiogram. The latter two patterns resolved after systemic corticosteroid treatment.29 INTERMEDIATE UVEITIS Intermediate uveitis is also known as pars planitis, peripheral uveitis, and chronic cyclitis. Intermediate uveitis is an inflammatory disease that affects young adults, causing symptoms of photophobia, floaters, and blurry vision. Clinically, mild anterior chamber inflammation, vitreous cells, vitreous snowballs, inflammatory membranes on the pars plana, phlebitis, cystoid macular edema, and, rarely, choroidal and retinal neovascularization are seen. On fluorescein angiography, there is venular wall staining (Fig. 9),30 hyperfluorescence, and leakage of the peripheral inflammatory membranes.31 Cystoid macular edema often is evident.30 Optic disc, peripheral retinal, and subretinal32–34 neovascularization are rare.
BIRDSHOT RETINOCHOROIDOPATHY Birdshot retinochoroidopathy (also known as vitiliginous chorioretinitis) presents bilaterally, generally in middle-aged women, causing floaters and decreased vision, night blindness, and color blindness. Clinically, there are patches of postequatorial choroidal and retinal pigment epithelial depigmentation (Fig. 10A), vitreous cells, macular and disc edema, and venous sheathing. SRNV frequently is a late sequela. Often central vision may be preserved in at least one eye.
On fluorescein angiography, retinal vessel staining, disc leakage, and cystoid macular edema are found (see Fig. 10B). There often is generalized hypofluorescence of the retinal vessels and increased circulation time.35,36 Surprisingly, the patches of depigmentation may appear normal on angiography, although there can be mild late hyperfluorescence.35,36 Posterior pole choroidal hyperfluorescent lesions that correspond to the areas of depigmentation and SRNV also can be seen.37 On ICG angiography (see Fig. 10C), early and late hypofluorescent patches, exceeding the clinically detectable lesions, with a choroidal vasotropic distribution and relative sparing of the peripapillary area and the central macula, are noted. These findings differentiate this condition from AMPPPE, multifocal choroiditis, and other granulomatous conditions such as sarcoidosis and sympathetic ophthalmia. Rarely, hyperfluorescent spots are noted in the late phases of the angiogram, which correspond ophthalmoscopically to retinal inflammation or obstructive changes.38 MULTIFOCAL CHOROIDITIS Multifocal choroiditis may mimic the typical clinical findings of presumed ocular histoplasmosis syndrome (discussed later) and has the additional finding of anterior chamber and vitreous cells. Multiple yellow or gray acute choroidal lesions measuring 50 to 350 μm, periphlebitis, and occasionally retinal neovascularization can be seen. Marked pigmentary disturbances may be seen in the chronic phase (Fig. 11A).
On fluorescein angiography (see Fig. 11B), the punched-out lesions show the typical window defects. Acute lesions block early choroidal fluorescence and stain late. Cystoid macular edema and prolonged arteriovenous circulation times may be seen.39 Progressive subretinal fibrosis is a reported sequela that presents as multiple stellar zones of subretinal fibrosis. This fibrosis can be surrounded by multiple atrophic punched-out lesions (Fig. 12).40
ICG angiography shows large hypofluorescent spots in the posterior pole measuring 200 to 500 μm, which did not usually correspond to clinically or fluorescein angiographically detectable lesions (see Fig. 11C). Smaller hypofluorescent spots, less than 50 μm, also may be seen in the posterior pole. Both large and small lesions are best seen in the later phases of the angiogram. Confluent hypofluorescent areas may be seen around the optic nerve in patients reporting an enlarged blind spot on visual field testing.41 ACUTE MULTIFOCAL POSTERIOR PLACOID PIGMENT EPITHELIOPATHY Acute multifocal posterior placoid pigment epitheliopathy is a bilateral systemic disease that generally affects young, healthy adults, often after a flulike viral illness. It presents as a rapid, painless loss of vision, which usually is bilateral. The characteristic findings of the disease are deep, multiple, discrete, flat, creamy-white subretinal lesions, usually centered in the posterior pole. Associated vitreous cells, serous retinal detachments, disc edema, and vasculitis have been reported. Shortly after the onset of symptoms, the acute yellow placoid lesions resolve, showing irregular deposition of pigmentation without corresponding atrophy of the choroid. Associated but infrequent systemic signs include hematuria, hearing loss, erythema nodosum, thyroiditis, and cerebral vasculitis. In general, vision returns to normal even when significant retinal pigment epithelial mottling is present. SRNV is a rare complication. AMPPPE rarely recurs; however, there are some unilateral cases in which the second eye may become affected months later. When unilateral cases occur, it is necessary to differentiate acute multifocal posterior placoid pigment epitheliopathy from serpiginous choroiditis. Angiographically, the creamy lesions initially block the choroidal background fluorescence. Later there is staining that is widely and evenly distributed (Fig. 13). The cause of the initial blocking is controversial. Some believe that this disorder is a systemic vasculitis with nonperfusion of the choriocapillaris. In support of this view, choroidal vessels occasionally can be seen through the hypofluorescent lesions.42,43 However, others believe that opaque retinal pigment epithelial cells block the choroidal fluorescence. The lesions do not correspond to the anatomy of the choriocapillaris and do not stain from the periphery as would be expected from the normal perfused neighboring choriocapillaris.44 Some cases of AMPPPE have been associated with serous detachment, showing late subretinal pooling of fluorescence. Old lesions show both hyperfluorescence and hypofluorescence depending on the retinal pigment epithelial integrity. Visual acuity usually returns to normal, even with clinically significant retinal pigment epithelial alteration.
ICG angiography shows well-demarcated areas of hypofluorescence of the acute and subacute lesions, especially in the late phases of the study. Similar findings are seen in healed AMPPPE lesions, but they tend to be smaller in size than in the acute lesions. The cause of the hypofluorescence seen with ICG angiography also is debatable. RPE edema, partial choroidal vascular occlusion, or complete choroidal vascular occlusion has been proposed, but none have been proved as the etiologic mechanism for the blockage.45 SERPIGINOUS CHOROIDOPATHY Serpiginous choroidopathy, also known as serpiginous choroiditis, geographic, or helicoid choroidopathy, is an idiopathic, chronic, recurring peripapillary inflammation of the choroid and retinal pigment epithelium that spreads centrifugally. Frequently, only the macular region is affected, resulting in visual loss (Figs. 14 and 15). Although serpiginous choroidopathy can affect young persons, most patients are middle-aged or older. Active pigment epithelial lesions have a creamy geographic appearance and are at the level of the retinal pigment epithelium and choriocapillaris. Old lesions frequently show various amounts of retinal pigment epithelium/choriocapillaris loss with subretinal scarring and pigmentation surrounded by islands of normal choroid (Fig. 16A). There can be retinal vasculitis, iridocyclitis, disc swelling, periphlebitis, and, occasionally, vitreous cells. Disc neovascularization also has been seen. The disease usually begins unilaterally, although years later recurring episodes are common in one or both eyes. Asymmetric involvement also is very common.
Fluorescein angiography of the acute lesions shows early hypofluorescence due to blockage of the underlying choroidal fluorescence with eventual hyperfluorescent staining of the lesions' margins (see Fig. 14B and C). Later, there is patchy hyperfluorescence of the lesion due to leakage from the lesions' margins and from islands of normal choroid and choriocapillaris within the lesion. Sometimes the lesion becomes indistinguishable from the surrounding background fluorescence of the normal retina.46–48 The old lesions are hypofluorescent and are bordered by hyperfluorescence from the adjacent normal choriocapillaris. Hyperfluorescence of the old lesions occurs because of scar tissue that stains in the late phase of fluorescein angiography. SRNV is a well-known complication of serpiginous choroidopathy. Occasionally, ophthalmoscopic signs such as subretinal blood and exudate can be seen. However, SRNV often appears like recurrent serpiginous lesions and can be diagnosed in patients only by fluorescein angiography, with persistent late enlarging hyperfluorescence of the lesions (see Fig. 15).49 The differential diagnosis includes AMPPPE, age-related macular degeneration, presumed ocular histoplasmosis, and choroidal ischemia. In the acute stage, ICG angiography shows diffuse, homogeneous, marked, and persistent hypofluorescence during all phases of the angiogram in areas of active inflammation. Active choroidal involvement beyond the boundaries observed by ophthalmoscopy as well as those delineated by FA is noted. In the subacute phase of the disease, heterogeneous hypofluorescence with clear visualization of medium and large choroidal vessels is seen. In the healed stages, delayed or absent choroidal filling in the early transit phase with better visualization of deeper choroidal vessels because of loss of overlying RPE and inner choroid may be shown. If SRNV develops, hyperfluorescence of the lesion is noted.50,51 MULTIPLE EVANESCENT WHITE-DOT SYNDROME Multiple evanescent white-dot syndrome causes acute unilateral or, rarely, bilateral vision loss in young, healthy adults, often after a viral illness. Clinically, small white dots are seen deep in the retina or at the level of the retina pigment epithelium. In addition, fine white or orange granularity seen in the macula is pathognomonic for the syndrome. Vitreous cells, blurred disc margins, and venous sheathing also can be seen. Vision improves to normal within several months and the lesions fade. Enlargement of the blind spot is a frequent sign during the active phase of the disease. On fluorescein angiography, several findings are noted: early hypofluorescence and late staining of the dots and leakage of dye from the disc and retinal capillaries (Fig. 17). Retinal pigment epithelial window defects and late staining also may be seen. In one report, the lesions had a wreathlike configuration.52 As the lesions resolve, the angiographic changes are less pronounced and often return to normal.53,54
On ICG angiography, multiple small, deep hypofluorescent spots are seen in the early phase of the angiogram. These spots persist into the later phases of study and are more numerous and widely distributed throughout the fundus when compared with either funduscopic or fluorescein angiographic examination results. They are randomly scattered and, like birdshot chorioretinopathy, may have a vasotropic distribution in the peripheral retina. Areas of confluence hypofluorescence, like that observed in multifocal choroiditis, also may be seen.55 ACUTE RETINAL PIGMENT EPITHELIITIS Acute retinal pigment epitheliitis is a relatively benign disorder that occurs in young, healthy adults often after a viral illness. Clinically, two to four gray or black deep retinal parafoveal lesions are seen, often surrounded by a yellow halo. The lesions resolve, although faint retinal pigment epithelial changes can be seen. Visual loss may be minimal or moderate, with recovery frequently in 6 to 12 weeks. During the acute stage, the FA either can be normal or the lesions can hypofluoresce with lacy hyperfluorescence of the halo. There is no change in the size or outline of the lesion.56,57 Sometimes only hyperfluorescence of the halo is seen. Old le-sions may show diffuse, delicate hyperfluorescence.58 ACUTE MACULAR NEURORETINOPATHY Acute macular neuroretinopathy is a bilateral disease that generally affects young, healthy adults, usually after a viral illness, and causes acute-onset decreased central or paracentral vision. Clinically, a petalloid, pinkish to grayish outer retinal macular lesion, which resolves over several weeks to months, is seen. The vision generally improves to baseline over a similar interval, although paracentral scotomas can persist. On fluorescein angiography, there can be three presentations: a normal angiogram,59 nonleaking dilated perifoveal capillaries,59 and early hyperfluorescence followed by late staining of the macular lesions.60–62 |
| UVEITIS SECONDARY TO VIRUSES | ||||
ACUTE RETINAL NECROSIS Acute retinal necrosis is an often bilateral peripheral retinitis that generally occurs in young, healthy adults. Herpes simplex, cytomegalovirus retinitis, and herpes zoster virus have been implicated as the etiologic agents in various patients. Acute retinal necrosis has a similar clinical appearance to proven cytomegalovirus retinitis. It presents as peripheral white necrotic retinal lesions, often with arteriolar occlusions and sheathing (Fig. 18A). Disc edema and pallor can be seen. Retinal detachments are frequent sequelae of the infection.
Fluorescein angiography (see Fig. 18B) shows multiple retinal vascular occlusions, particularly arteriolar. In the late phases, the retinal vessels stain, often proximal to the occlusion. Nonoccluded vessels also may show staining.63,64 Late staining of the disc can be seen during the acute phase.64 The differential diagnosis includes herpes zoster retinitis, toxoplasmosis, and Behçet's disease. CYTOMEGALOVIRUS RETINITIS Cytomegalovirus retinitis often is found in immunosuppressed patients and in patients with acquired immunodeficiency syndrome. Clinically, it presents a sharply demarcated necrotizing hemorrhagic retinitis with a vasculitis that often is occlusive. The necrotizing retinitis usually is located in the midperiphery and clinically manifests as whitish opacifications in the deep retina and in the retinal pigment epithelium. Retinal hemorrhages are seen in the necrotic area and surrounding the leading edge (Fig. 19A). Retinal vascular sheathing, usually periphlebitis, may be bilateral or unilateral (Fig. 20).65 Retinal detachments (both exudative and rhegmatogenous) and vitreous cells can occur.
On fluorescein angiography, findings that parallel the clinical appearance can be seen. Fusiform aneurysmal dilations of arteries, arteriole venules, and capillaries as well as capillary microaneurysms can be seen.66 The area of retinitis and necrosis blocks the choroidal fluorescence (see Fig. 19B); however, in the late venous phase, hyperfluorescence of the center lesion can be seen. Branch retinal artery occlusions may be seen.67 In addition, late dye leakage from arteries67 and optic disc occurs. ACQUIRED IMMUNODEFICIENCY SYNDROME Acquired immunodeficiency syndrome is caused by the human immunodeficiency virus. In addition to cytomegalovirus retinitis, the ocular complications of acquired immunodeficiency syndrome include Kaposi's sarcoma of the lids or conjunctive, Roth's spots, retinal hemorrhage, microaneurysms, telangiectasia, disc edema, cotton-wool spots, and cranial nerve palsies. On fluorescein angiography, microaneurysms, telangiectases, and small areas of capillary nonperfusion corresponding to the cotton-wool spots have been seen.68 HERPES ZOSTER Herpes zoster can cause an iridocyclitis with sector iris atrophy and retinal arteritis, retinal necrosis, and central retinal vein occlusion.69 Sector iris atrophy can be seen on iris fluorescein angiography.70 With arteritis, arteriolar narrowing and slow dye transit with fluorescein leakage are evident. SUBACUTE SCLEROSING PANENCEPHALITIS Subacute sclerosing panencephalitis is a progressive neurologic disorder that occurs in children and young adults. Measles virus is believed to be the infectious agent. Personality and behavioral changes occur and are followed by neurologic symptoms of seizures, dementia, coma, and death. Half the patients have visual involvement, which often antedates the neurologic symptoms. Clinically, a focal posterior pole retinitis and flat focal white retinal lesions are seen (Fig. 21).
With fluorescein angiography during the acute stage, the lesions mask the choroidal fluorescence. There is late venous leakage, vein staining, and arteriole and venule occlusions.71 |
| UVEITIS SECONDARY TO BACTERIA | |||
SYPHILIS Luetic chorioretinitis can present as a myriad of clinical findings, such as a salt-and-pepper fundus, cotton-wool spots, exudative retinal detachment, periarteritis, periphlebitis, disc edema, neovascularization, occlusive arteritis, multiple flat gray chorioretinal lesions, and macular edema. Ocular syphilis may mimic retinitis pigmentosa or acute retinal necrosis. Disciform scars are sequelae of macular choroidal inflammation. With cotton-wool spots and macular edema, capillary nonperfusion and diffuse leakage are seen, respectively, on fluorescein angiography. Patients with syphilis who have a retinitis pigmentosa-like fundus frequently show attenuated arterioles, delayed venular filling with late leakage of the peripapillary vessels, and mottled choroidal fluorescence.72 An edematous disc leaks dye.73 A fluorescein appearance similar to that of branch ret-inal vein obstruction can be seen.74 In rare cases, however, the FA in a patient with periarteritiscan be normal.75 Choroiditis can be seen as choroidal hyperfluorescence that resolves with treat-ment.72 SRNV presents with a typical appearance.76 Several cases of unilateral chorioretinitis presented as severe visual loss as the first manifestation of early secondary syphilis. Fluorescein angiography in these cases showed diffuse leakage under the neurosensory retina in the posterior pole associated with multifocal areas of staining along the retinal vessels (Fig. 22).77
A case of bilateral syphilitic posterior placoid chorioretinitis mimicking AMPPPE has been reported. ICG angiography showed hypofluorescent lesions during both early and late phases of the study, suggesting inflammation-associated perfusion abnormalities of the choriocapillaris.78 TUBERCULOSIS Tuberculosis has numerous ocular presentations, including anterior uveitis, scleritis, sclerokeratitis, phlyctenulosis, interstitial keratitis, choroidal granulomas (often with serous elevations; Fig. 23A),retinal exudate, macular star formation, retinal vas-culitis, vitreous cells, SRNV, and optic nerve granulomas. Eales' disease, a bilateral peripheral vasculitis with peripheral neovascularization and vitreous hemorrhage, frequently occurs in young men who have positive purified protein derivative test results (Fig. 24).
On fluorescein angiography, a choroidal tuberculoma hyperfluoresces in the late phase (see Fig. 23B). There may be leakage and pooling of dye if there is a serous retinal detachment. As the tuberculoma responds to therapy, the hyperfluorescence decreases and pockets of hypofluorescence can be seen.79 Retinal arteriovenous shunts with dilated capillaries also can be seen in the granuloma.80 Peri-phlebitis causes capillary dropout and venous staining. Neovascularization of the peripheral retina is not uncommon. Four angiographic signs have been described using ICG angiography: (1) irregularly distributed, hypofluorescent spots in the early and intermediate phases of angiography that either became isofluorescent (type 1 hypofluorescence) or remained hypofluorescent (type 2 hypofluorescence) in the late phase; (2) numerous, punctate hyperfluorescent spots; (3) fuzzy choroidal vessels in the intermediate phase due to leakage, leading in the late phase to (4) diffuse choroidal hyperfluorescence. Type 1 hypofluorescent lesions, fuzzy choroidal vessels, and diffuse choroidal hyperfluorescence tended to regress after the initiation of antituberculous and corticosteroid treatment. Focal hyperfluorescence tended to be associated with longstanding disease.81 |
| UVEITIS SECONDARY TO FUNGUS | ||
PRESUMED OCULAR HISTOPLASMOSIS SYNDROME Presumed ocular histoplasmosis syndrome consists of the following triad: peripapillary atrophy, “punched-out” chorioretinal lesions, and disciform macular scarring in young and middle-aged adults (Fig. 25A). If punched-out lesions (atrophic spots) occur in the macula, the probability of SRNV occurring within 3 years increases from 3% to 25%. A systemic histoplasmosis infection during childhood is believed to cause the syndrome.
Fluorescein angiography is an important diagnostic test because SRNV is a major cause of vision loss (see Fig. 25B and C).82 The SRNV can be either peripapillary or macular. The choroidal neovascular membranes appear as a lacy network surrounded by a hypofluorescent ring in the early phase of angiography. A hallmark is the enlarging subretinalhyperfluorescence seen in the late venous phases. Punched-out lesions show early hypofluorescence followed by late scleral staining from the adjacent choriocapillaris,83 which can be differentiated from the progressively enlarging hyperfluorescence of SRNV. With ICG angiography, focal hyperfluorescent spots, which are more numerous than those seen on FA, are noted in the posterior pole during the intermediate or late phase of the study. These lesions are not detectable in most cases on funduscopic examination. Smaller hypofluorescent spots also are seen in some patients with this condition. They are similar to those observed in multifocal choroiditis. However, the larger hypofluorescent spots seen in multifocal choroiditis are not found in ocular histoplasmosis. This latter finding in ICG angiography allows the two conditions to be distinguished. If SRNV develops, localized areas of hyperfluorescence with late staining are seen. This observation helps to distinguish neovascularization from localized inflammation, with the latter showing persistent late hypofluorescence.84 CANDIDA ENDOPHTHALMITIS Candida endophthalmitis generally occurs in immunosuppressed patients and intravenous drug abusers. It also can occur in patients receiving hyperalimentation therapy and in patients after abdominal surgery. Candida endophthalmitis presents as white retinal abscesses with and without hemorrhage that extend into the vitreous and form vitreous snowballs (Fig. 26A). Roth's spots also can be seen.
On fluorescein angiography, there are multiple early hypofluorescent deep retinal lesions that are not seen clinically. The white retinal lesions stain progressively in a centripetal fashion in the later phases (see Fig. 26B).85 |
| UVEITIS SECONDARY TO PROTOZOA: TOXOPLASMOSIS | ||
Toxoplasmosis is an intracellular parasite with a propensity to infect
the inner retinal layers and cause an acute retinochoroiditis. Many cases
are the sequelae of an acute intrauterine infection. The acute lesions
appear white with prominent vitreous exudate. Often these acute lesions (satellite
lesions) are adjacent to old chorioretinal toxoplasmosis
scars. Toxoplasmosis also can present as an elevated optic disc swelling, papillitis, and
old healed macular lesions (known as macular colobomas), which are sometimes seen with congenital toxoplasmosis (Fig. 27A). Segmental periarteritis, neovascularization of the disc and retina, SRNV, and
branch retinal artery occlusion also can be seen (Fig. 28A). A variant form of toxoplasmosis shows multiple gray-white deep retinal
or retinal pigment epithelial lesions with minimal overlying vitreous
inflammation.
On fluorescein angiography in congenital toxoplasmosis, the acute macular lesions hypofluoresce early and hyperfluoresce late. Often there is extensive, complete loss of the retinal pigment epithelium and choriocapillaris, resulting in a hypofluorescent region with possible hyperfluorescence of scar tissue. On fluorescein angiography, the acute lesions hypofluoresce in the early phase and hyperfluoresce in the late phase (see Fig. 27B).86,87 Old toxoplasmosis scars show hypofluorescence due to loss of the choriocapillaris.88 Various entities can be seen on fluorescein angiography, including branch retinal arteriole occlusion (see Fig. 28B),87,89,90 retinochoroidal anastomosis,91–93 retinal neovascularization,94 and SRNV.95 If papillitis occurs, there are dilated disc capillaries and late disc leakage.96 Segmental periarteritis seen clinically does not usually produce intravascular leakage, vessel staining, or alteration in flow.96 Cystoid macular edema is a rare finding.97 In the atypical deep retinal presentation of toxoplasmosis, there are minimal areas of hyperfluorescence that do not correspond to the clinical, deep retinal lesions.98 On ICG angiography, the main focus of retinochoroiditis is hypofluorescent in all phases of the angiogram, but late-phase (35- to 45-minute) hyperfluorescence also has been observed. The most striking feature, however, is multiple hypofluorescent satellite dark dots. In many cases, the hypofluorescent areas are not seen on FA and clinical examination, suggesting that toxoplasmic retinochoroiditis is a more widespread process than is clinically suspected because it extends beyond the visible lesions. After antitoxoplasma therapy, satellite dark dots disappeared from most of the cases reported. Further, the hypofluorescence under the main lesion was markedly reduced or disappeared in some cases.99–101 A case of toxoplasmic frosted branch angiitis was reported in both eyes of a 10-year-old boy. ICG angiography showed late-phase hyperfluorescence along the frosted vessels and in the disc. Delayed filling in the choriocapillaris also was identified in this child.102 |
| UVEITIS SECONDARY TO PARASITES | |
CYSTICERCOSIS Cysticercus is the larval form of Taenia solium, a tapeworm. Eggs are transformed 24 to 72 hours after ingestion into embryos that penetrate the intestinal wall and are distributed throughout the body via the circulatory system. The embryos then metamorphose into the cysticercus larval forms. The cysticercus can be found in the lids, conjunctive, anterior chamber, all layers and potential spaces of the retina and choroid, and the vitreous. The parasite often presents with amoeboid movements in a grayish white, semitransparent, well-defined cyst. A milky-white paracentral or central spot corresponding to the scolex often can be seen. If the cyst is subretinal, there may be hemorrhage, exudate, vasculitis, and venous tortuosity in the overlying retina. Early in the angiogram of subretinal lesions, the border of the cyst is not well-defined, but in the late phases, the cyst is outlined with fluorescence.103 DIFFUSE UNILATERAL SUBACUTE NEURORETINITIS Diffuse unilateral subacute neuroretinitis is an ocular disease that occurs in otherwise healthy patients and is believed to be caused by chronic subretinal migration of one of at least two species of nematodes. Generally, visual acuity is poor (less than 20/200 [6/120]), and findings include pseudoretinitis pigmentosa, afferent papillary defects, anterior chamber and vitreous cells, disc edema, focal shifting, and recurrent deep retinal or subretinal yellow-white lesions. The lesions often are juxtamacular, and they resolve after several days. Occasionally, a subretinal worm (500 μm long and 25 μm wide) can be seen (Fig. 29A). There also may be diffuse retinal pigment epithelial atrophy with some hyperplasia. In the inactive stage, optic atrophy, retinal arterial narrowing and sheathing, and, rarely, SRNV can be seen.
Many FAs obtained during the acute stage may show only perivenous leakage or may be normal. If optic disc edema is present, disc capillary leakage can be seen. The active deep retinal or subretinal lesions hypofluoresce early and stain late (see Fig. 29B). Mild but easily detectable retinal pigment epithelial can be seen angiographically. In the late stages of the disease, hyperfluorescence indicative of retinal pigment epithelial abnormalities occurs in the periphery and the peripapillary region. Generally, fine mottled hyperfluorescence is evident in the macular region.104 Cystoid macular edema occurs infrequently. Occasionally, the worm is seen as a hypofluorescent lesion on the FA (see Fig. 29B). |
