Noninfectious inflammatory diseases of the retina can be isolated to the retina or be contiguous with its underlying structures, choroid and sclera, or with adjacent structures, optic nerve, vitreous, and the anterior segment of the eye. These diseases can be idiopathic, autoimmune, or possibly an altered immune response to an infectious agent. A majority of them are isolated to the eye but some have systemic associations.
Retinal Vasculitis and Perivasculitis
The terms “retinal vasculitis” and “retinal perivasculitis” are used interchangeably as clinical names to describe the fundoscopic picture of exudative gray-white sheathing of the major retinal blood vessels. The retinal veins or arteries or both may be primarily affected. Fluorescein angiography shows evidence of perivenous or periarterial staining and may show evidence of vascular obstruction. In using these terms, we recognize that the primary cause of the fundus and angiographic findings may be immune-induced damage rather than inflammatory cell damage to the permeability and patency of the retinal blood vessels. Retinal vasculitis and perivasculitis may occur as part of well-defined ocular diseases of known cause (toxoplasmosis, pp. 848–852; diffuse subacute neuroretinitis, pp. 864–872; cytomegalovirus retinitis, pp. 892–896; syphilis, pp. 818–828) or well-defined syndromes of unknown cause (sarcoidosis, pp. 1022–1026; Behçet’s disease, pp. 1026–1028; acute posterior multifocal placoid pigment epitheliopathy (APMPPE), p. 954; acute zonal occult outer retinopathy (AZOOR), p. 980; pars planitis, p. 1036; multiple sclerosis, p. 1038; idiopathic recurrent branch retinal artery occlusion, pp. 474–478; and Eales’ disease, pp. 564–568). Other more recently described or less well-defined clinical syndromes associated with retinal vasculitis and perivasculitis are retinal phlebitis and panuveitis associated with viral-like upper respiratory disease, frosted-branch retinal angiitis and acute multifocal hemorrhagic retinal vasculitis.
Acute Retinal Periphlebitis and Panuveitis Associated With Viral-Like Upper Respiratory Disease
Acute bilateral visual blurring associated with inflammatory cellular infiltration of the anterior and posterior ocular chambers and fluorescein angiographic evidence of periphlebitis may occur in some patients during or immediately following an upper respiratory or flulike illness ( Figure 11.01 A–D). Visual blurring usually disappears in 1–2 weeks in association with return of the fundus and angiographic findings to normal. An adenovirus was cultured from the stool of one such patient ( Figure 11.01 A–D).
Idiopathic Frosted-Branch Angiitis
Patients with idiopathic frosted-branch angiitis present with visual symptoms associated with a striking ophthalmoscopic picture in one or both eyes of widespread prominent perivascular infiltration that in most patients is confined to the major retinal veins ( Figures 11.01 E–L and 11.02 A–F). About one-third report a flulike illness as a prodrome. Visual loss can be severe, to include macular or peripheral exudative retinal detachment ( Figure 11.02A, C and D ). The disorder is more common amongst Japanese individuals (70%) ; children are more often affected than adults, though age distribution ranges from 2 to 42 years. Frosted-branch angiitis responds to systemic steroids very often, though several cases have been known to resolve without treatment. Secondary causes have to be ruled out prior to starting steroids. The disease burns out over weeks to months. Although the visual prognosis is generally good, some patients may develop retinal vein or artery occlusion, extensive retinal vascular closure, retinitis proliferans, vitreous hemorrhage, and rubeosis of the iris, macular epiretinal membrane, macular scarring, diffuse retinal fibrosis, retinal tear, optic atrophy, peripheral atrophic retinal lesions, and severe perivascular hemorrhages ( Figure 11.01 G–L). These latter patients become indistinguishable from patients with acute multifocal hemorrhagic retinal vasculitis (see following discussion).
Secondary Frosted-Branch Angiitis
Frosted-branch angiitis can be a feature of several retinal diseases, including cytomegalovirus retinitis, Behçet’s disease, lupus erythematosus (Figure 11.02G to J), Epstein–Barr virus retinitis, syphilis, toxoplasmosis, herpetic retinitis, human immunodeficiency virus (HIV) positivity, Hodgkin’s disease, rapidly progressive glomerulonephritis, staphylococcal and streptococcal endophthalmitis.
Acute Multifocal Hemorrhagic Retinal Vasculitis
Otherwise healthy patients with acute multifocal hemorrhagic retinal vasculitis develop loss of vision associated with mild anterior uveitis, multifocal areas of retinal vasculitis (predominantly venular) with marked intraretinal hemorrhage, retinal capillary nonperfusion, retinal neovascularization, optic disc swelling, and vitritis. Retinal necrosis is not a prominent part of this syndrome. Oral prednisone appears to be of some benefit in treatment of this disorder, which is unresponsive to treatment with acyclovir. Photocoagulation of the neovascular complications may be necessary. The etiology of this disorder, which shares some features with Behçet’s disease, Eales’ disease, and acute retinal necrosis, is unknown.
Retinochoroidal Degeneration Associated with Progressive Iris Necrosis
Margo et al. described progressive pigment epithelial and retinal atrophy that began in the macula and juxtapapillary retina ( Figure 11.03 A–D, H, I, K, L, and N), mild iritis, elevated intraocular pressure, severe pain, progressive iris atrophy ( Figure 11.03 E and J), progressive decrease in electroretinography amplitudes, and complete blindness within 3 years in a healthy 34-year-old man whose extensive medical workup was negative. Histopathology revealed pigment granules and pigment-laden macrophages in the anterior chamber, severe ischemic necrosis of the iris ( Figure 11.03 F), chronic inflammatory cells in the uveal tract, and marked chorioretinal atrophy, with only a thin strand of glial tissue resting on an atrophic choroid. There were patchy areas of preservation of the inner retina posteriorly ( Figure 11.03 G) and some preservation of the retina and choroid peripherally, where thrombi were found in some of the choroidal blood vessels. Electron microscopy revealed no viral particles or evidence of a storage disease. The authors found no clues as to the pathogenesis of the disorder. A similar patient was seen by Dr. Jampol ( Figure 11.03 H–O). Note the deep trenchlike chorioretinal atrophy on the angiogram ( Figure 11.03 M and O).
Acute Posterior Multifocal Placoid Pigment Epitheliopathy
APMPPE typically affects young healthy male or female patients (average age approximately 25 years), who develop rapid loss of vision in one or both eyes secondary to multiple postequatorial, circumscribed, flat, gray-white, subretinal lesions involving the retinal pigment epithelium (RPE) ( Figures 11.04–11.06 ). These lesions are rarely associated with clinically apparent retinal detachment or with retinal hemorrhage ( Figure 11.05 B and C). The overlying retina usually appears normal. Inflammatory cells in the vitreous may be present in 50% of patients. Approximately one-third of patients give a history of a flulike syndrome antedating the onset of visual symptoms. In one case it followed a mild hypersensitivity reaction to swine flu vaccine and varicella-zoster vaccination in another. APMPPE has occurred in patients with thyroiditis, cerebrovasculitis, adenovirus type 5 infection, lymphadenopathy, hepatomegaly ( Figure 11.04 K and L), erythema nodosum, regional enteritis, sarcoidosis, acute nephritis, lupus erythematosus, serologic evidence of Lyme disease, Wegener’s granulomatosis, systemic necrotizing vasculitis, ulcerative colitis, and spinal fluid pleocytosis and elevated protein. Two patients with evidence of central nervous system (CNS) vasculitis died within several weeks of onset of APMPPE as systemic corticosteroids were being tapered. Autopsy in one case revealed evidence of granulomatous arteritis in the leptomeninges. These cases suggest that APMPPE may be the initial manifestation of primary CNS angiitis, which is associated with a high mortality rate of approximately 95% if untreated, 46% if treated with corticosteroids, and 8% if treated with corticosteroids and cytotoxic agents.
Other ocular findings include perivenous exudation in the retina, perichoroidal venous infiltration, and dilation and tortuosity of the retinal veins, papilledema, papillitis, optic neuritis, episcleritis ( Figure 11.05 A), iridocyclitis, and central retinal vein occlusion (Dr. Lawrence A. Yannuzzi, personal communication). This latter may develop as a result of vasculitis and swelling within the optic nerve.
Infrequently, APMPPE occurs unilaterally. The second eye is usually involved within a few days or weeks after the first. In 2 patients the interval was 30 and 36 months ( Figure 11.04 G–J). Recurrences are infrequent and usually occur in the first 6 months following the onset of symptoms ( Figure 11.04 A–F). Characteristic features of the disease are the rapid resolution of the fundus lesions and the delayed remarkable return of visual function, usually to the level of approximately 20/30 or better ( Figure 11.04 A–D). Within a few days of the onset of symptoms the acute gray-white lesions begin to fade centrally. Within 7–12 days they are completely replaced by areas of partly depigmented RPE ( Figure 11.04 D and E). Irregular clumping of pigment occurs, and day-to-day changes in its pattern develop over a period of months. The acute and subacute lesions superficially resemble those seen after photocoagulation.
During the acute phase of APMPPE the subretinal lesions block out most of the background choroidal fluorescence ( Figures 11.04 B and H, 11.05 C, and 11.06 D). Mid- and late-phase angiograms demonstrate diffuse, even staining of the acute lesions ( Figures 11.04 B, C, H, and I, and 11.06 E). During the course of early resolution of these lesions, angiography demonstrates large choroidal vessels coursing through the center of the partly faded gray lesions before the development of staining in the later pictures ( Figure 11.04 B). During the later course of resolution, angiography demonstrates extensive alterations in the background choroidal fluorescence caused by changes in the content of the RPE but shows relatively little evidence of occlusion of the choriocapillaris. Indocyanine green (ICG) angiography shows dark spots ( Figure 11.06 L) corresponding to the placoid lesions and these do not stain late, unlike fluorescein. The lesions appear to involve the RPE and the adjacent photoreceptors on optical coherence tomography (OCT), which shows disruption of these structures during the active phase and recovery when the lesions heal. Very occasionally, shallow subretinal fluid has been seen overlying the placoid lesions on OCT; exudative retinal detachment is not the norm in APMPPE. Microperimetry can demonstrate the involved areas and recovery of function in those areas once the lesions heal. Subnormal electro-oculographic findings have been reported during the acute stage of the disease. Most patients tested during the acute phases of the disease have normal electro-oculograms and electroretinograms (ERGs). One patient with severe involvement had normal electro-oculographic findings with subnormal cone and rod electroretinographic findings ( Figure 11.04 K and L).
The prognosis for visual recovery is good. Visual recovery can occur up to as long as 6 months. In an average follow-up of over 5 years in 30 patients seen at the Bascom Palmer Eye Institute, all but two eyes had 20/30 or better visual acuity at the last examination. Many patients will identify small residual paracentral scotomata when carefully tested. Recurrences and the development of choroidal neovascularization occur infrequently ( Figure 11.05 D and E).
The cause of this disease, which in many instances is associated with evidence of systemic involvement, is unknown. In the eye it appears to be an acute, self-limited disease, initially causing multifocal areas of color change in the RPE and perhaps retinal receptor cells. The cell cytoplasm apparently becomes sufficiently cloudy that it blocks out all background choroidal fluorescence. The course and nature of the disease suggest the possibility of viral infection. Figure 11.05 (F–I) illustrates schematically some of the presumed anatomic changes in this disease. Despite the extensive alterations in the pigment content, the RPE cells and most of the retinal receptors apparently recover and visual acuity usually returns to near normal. The end-stage of this disease is similar in this respect to rubella.
Many authors have favored choriocapillaris occlusion as the cause of the color change in the RPE and the early angiographic findings. The following are difficult, however, to explain on the basis of choroidal vascular occlusion: (1) the variability in the size and shape of the lesions, which appear to have no relationship to the anatomy of the choriocapillaris; (2) the failure of the acute lesions to stain with fluorescein from the periphery inward, as would be expected to occur from neighboring normally perfused choriocapillaris; and (3) the frequency of recovery of visual function. Demonstration of large fluorescent choroidal vessels coursing through the area of partly resolved acute lesions ( Figure 11.04 B) does not necessarily mean there is nonperfusion of the choriocapillaris in these areas. The RPE cells, which undoubtedly are still present in these areas, may be sufficiently opaque to attenuate the fluorescence arising from the choriocapillaris but not that in the large choroidal vessels. The findings with ICG angiography are similar to that with fluorescein and in the author’s opinion do not shed further light on the pathophysiology of APMPPE.
Wolf et al. reported HLA-B7 antigens in 40% and HLA-DR2 antigens in 57% of patients with APMPPE versus 17% and 28%, respectively, in controls.
There is no information concerning the relative value of systemic treatment with corticosteroids compared to no treatment of patients with APMPPE. The natural course of the disease suggests that the visual prognosis is favorable without treatment. Some might argue that corticosteroids should be given, if for no other reason than to reduce the potential of CNS complications. It is unknown, however, whether this treatment is beneficial or harmful in this regard. Patients and their families should be alerted to the relatively low possibility of CNS complications and of the importance of promptly reporting any symptoms or signs suggesting CNS involvement. There is evidence that patients with idiopathic CNS angiitis benefit from corticosteroid and cytotoxic therapy.
It is important to differentiate APMPPE from serpiginous (geographic) choroiditis. Although the acute lesions in both diseases appear similar ophthalmoscopically and angiographically, the lesions of serpiginous choroiditis resolve more slowly and leave in their wake ophthalmoscopic and angiographic evidence of marked atrophy of the underlying choriocapillaris and larger choroidal vessels (see pp. 962–964). Some patients reported as having APMPPE with atypical features, such as branch vein occlusion, may have had serpiginous choroiditis. Serpiginous choroiditis is a chronic, recurring, often severe disease that may leave the patient with severe visual disability in one or both eyes. Table 11.1 outlines some of the important differences in these two diseases.
| APMPPE | Serpiginous choroiditis | |
|---|---|---|
| Age of onset | Second and third decades | Beyond third decade |
| Associated systemic disease | Upper respiratory infection, erythema nodosum, regional enteritis, hepatitis, episcleritis, cerebral vasculitis | None |
| Visual complaints at onset | Bilateral | Unilateral most often |
| Acute lesions | Flat, gray-white, retinal pigment epithelial lesions | Same |
| Lesion distribution | Postequatorial | Peripapillary |
| Lesion shape | Usually isolated | Usually contiguous |
| Vitritis | ± | ± |
| Choroidal atrophy | Minimal | Maximal |
| Proliferative subretinal scarring | None | Frequent |
| Visual recovery | Excellent | Poor |
| Recurrence | Rare | Typical |
| Choroidal neovascularization | Rare | 30% of patients |
The multifocal white lesions in APMPPE must be differentiated from other causes of multifocal deep retinitis (e.g., diffuse unilateral subacute neuroretinitis) (see Figure 10.29A–G), multiple evanescent white-dot syndrome (MEWDS) ( Figures 11.15 and 11.16 ), focal inflammatory cell infiltrates of the choroid (e.g., multifocal choroiditis with panuveitis (MCP), pseudo-presumed ocular histoplasmosis syndrome (POHS)), sarcoidosis, secondary syphilis (Figures 10.07B and G, 10.10H, and 10.11I), diffuse choroidal infiltration in Harada’s disease that may be associated with multifocal ill-defined lesions at the level of the pigment epithelium (see Figure 11.26 A), sympathetic uveitis (see Figure 11.29 D), multifocal zones of occlusion of the choriocapillaris (e.g., toxemia of pregnancy; see Figure 3.59D), primary or metastatic neoplastic infiltrates of the choroid or sub-RPE space (see Figures 13.31G and H and 14.31D and E), and multifocal areas of depigmentation of the choroid, such as occurs in vitiliginous (birdshot) chorioretinitis (see Figure 11.45 A and B). Focal inflammatory cell infiltrates of the choroid are often smaller and slightly elevated, frequently persist for several weeks or more, and often cause secondary detachment of the overlying retina. They may completely resolve without leaving significant changes in the overlying RPE, or they may cause varying degrees of atrophy of the choroid and RPE. The author believes that the patients reported as having retinal detachment secondary to APMPPE showed features more typical of a diffuse underlying choroiditis, probably Harada’s disease, rather than APMPPE (see Figure 11.26 A).
The syndrome of acute retinal pigment epitheliitis is characterized by the development of clusters of small pigment spots surrounded by halos of depigmentation in young patients with a recent history of visual loss. These patients experience rapid recovery of vision (see p. 974). In general, however, the lesions in APMPPE are much larger than can be accounted for on the basis of the RPE findings in acute retinal pigment epitheliitis.
Extensive pigmentary changes remaining during the late stages of APMPPE ( Figure 11.04 L) may be mistaken for a widespread tapetoretinal dystrophy. The clinical history of rapid loss and recovery of vision, the normal-appearing retinal vessels and optic nerve head, and usually normal electrophysiologic findings should differentiate retinal dystrophies from the late stages of APMPPE.
Priluck and associates have demonstrated the presence of urinary casts in 3 patients during the active phase of APMPPE. The significance of this observation is unknown.
Although most patients with APMPPE present with multiple one-disc diameter-size white lesions randomly scattered in the posterior fundus, the size, shape, and distribution of the lesions may be variable ( Figure 11.04 G). In some cases the lesions are small, are confluent, and may show some persistence of nonfluorescence into the late stage of angiography. In several of these cases the lesions were uniformly small and closely spaced, similar to those which occurred in a 35-year-old man described as having diffuse punctate pigment epitheliopathy by Blinder et al. Their patient failed to recover central vision. More recently, Taich and Johnson analyzed 6 older patients ranging from 58 to 82 years of age (average age 72.5) with a few placoid lesions in the macula, who had several features differing from APMPPE: older age group, lesions mostly confined to the macula, late fluorescein showing patchy hyperfluorescence unlike the even staining of APMPPE, recurrences, late geographic atrophy, poor visual recovery and choroidal neovascularization in a significant number of them. This group is best considered a separate entity at this time. Description of additional cases in the future and expansion of the spectrum may help understand their pathogenesis. Two other conditions that resemble APMPPE in certain aspects are persistent placoid maculopathy and relentless placoid choroidopathy, described next.
Persistent Placoid Maculopathy
In 2006, 6 patients with bilateral macular placoid lesions superficially resembling macular serpiginous choroidopathy followed variably up to 20 years were described from five centers. They were in their sixth to seventh decade, had bilateral involvement, the white macular lesions persisted for several months to years before fading, and they showed a propensity to choroidal neovascularization, often multiple, resulting in disciform scars. In spite of foveal involvement and persistent lesions, the visual acuity remains good till choroidal neovascularization develops. On fluorescein angiography the lesions remain non- or hypofluorescent till late and show minimal fluorescence in the late frames ( Figure 11.09 ). Several small choroidal neovascular membranes (CNVMs) are seen. On ICG angiography the lesions appear nonfluorescent throughout the study. No evidence of vitritis or anterior-chamber inflammation has been seen. The relatively good vision (unless complicated by CNVM) argues against persistent choriocapillary nonperfusion as the reason for the persistent hypofluorescence on ICG and fluorescein angiography. The etiology is so far unknown. Treatment included systemic/periocular steroids at some time with improvement in vision. The loss of vision is mainly from choroidal neovascularization.
Relentless Placoid Choroidopathy
Six patients, aged 17 through 51 years, exhibiting some features of APMPPE and serpiginous choroidopathy were seen at six different centers from 1984 to 1997. The acute placoid retinal lesions were multifocal, confluent, or serpiginous in nature with initial hypo- and late hyperfluorescence on angiography resembling both APMPPE and serpiginous choroidopathy. These patients in addition had numerous posterior and peripheral retinal lesions predating or occurring simultaneously with macular involvement. Older, healing pigmented lesions were often accompanied by the appearance of new active white placoid lesions. Additionally, all cases demonstrated prolonged periods of activity with several crops of new lesions, 50 and sometimes hundreds of them scattered throughout the fundus. Growth of subacute lesions and the appearance of new lesions continued for 5–24 months after initial examination, and relapses were common. Relentless placoid choroidopathy may represent a variant of serpiginous choroiditis or a new entity.
One 20-year-old patient has been reported with associated hyperintense lesions on magnetic resonance imaging in the temporal lobe, found during evaluation of persistent headache. He received mycophenolate mofetil in addition to steroids and remained stable with resolution of the brain lesions. Etiologically this condition is probably related to APMPPE, but much needs to be learnt. The condition has to be differentiated from APMPPE, serpiginous choroidopathy, serpiginous-like tuberculous choroiditis (see Chapter 10), persistent placoid choroidopathy, multifocal choroiditis, placoid syphilis, sarcoidosis, and lymphoma.
Serpiginous Choroiditis (Geographic Choroiditis, Helicoid Peripapillary Choroidopathy)
Serpiginous choroiditis is an acute and chronic recurrent multifocal inflammatory disease that appears to affect primarily the inner half of the choroid, the RPE, and secondarily the retina.
It usually begins in the peripapillary area and spreads centrifugally over a period of months or years by means of recurrent episodes of patchy choroiditis in a serpiginous or jigsaw puzzle-like distribution outward from the optic disc to involve the macula and peripheral fundus ( Figures 11.08–11.11 ).
The patient is typically a healthy young or middle-aged individual when he or she first notices the rapid onset of paracentral or central scotomata in one eye. If the center of the macula is involved, the acuity is often 20/40 or less. Biomicroscopic and ophthalmoscopic examination within the first several weeks after the onset of symptoms reveals a well-circumscribed geographic zone of gray-white discoloration of the RPE in the macular area ( Figures 11.08 A and G, and 11.11 I). Serous detachment of the retina is infrequently present. Although an occasional patient has a solitary active lesion in one macula, usually the active lesion is in continuity with a zone of RPE and choroidal atrophy that extends nasally to surround all or a portion of the optic disc. Inflammatory cell reaction is present in the posterior vitreous in approximately one-third of cases during the active phase of the disease. Examination of the opposite asymptomatic eye often reveals an area of chorioretinal scarring adjacent to the optic disc ( Figure 11.08 B). Over a period of weeks, the acute gray-white lesions, which may appear identical to the acute stage of APMPPE, are partly replaced by mottling and depigmentation of the RPE ( Figure 11.08 A and F). The peripheral edge of the lesion often maintains a grayish-white active appearance for a month or longer ( Figures 11.08E, and 11.09 C). Over a period of months, varying degrees of atrophy of the underlying choroid develop within the discrete zone of previous activity. In some cases the atrophy involves the large as well as the small choroidal vessels and produces a trenchlike area of choroidal atrophy ( Figure 11.08 F). In approximately one-half of patients varying amounts of gray-white tissue (fibrous metaplasia of the RPE) develop within the area of chorioretinal atrophy ( Figure 11.11 A–G). The patient usually develops a permanent dense absolute scotoma corresponding with most of the involved areas. The retinal vessels and optic nerve head are usually normal. At intervals varying from weeks to years, the patient is subject to recurring episodes of activity that each time involve a new and usually contiguous area of the fundus. This process may spread widely into the far periphery of the fundus in one eye before a similar process begins in the second eye months or many years later. The disease frequently involves the macular area, but in many cases it skirts the edge of the foveola, leaving the patient with good acuity. Although there is a great tendency for the lesions to be contiguous, noncontiguous lesions occur commonly. Some patients will show centripetal spread of the disease. There is some tendency for concentric enlargement of the jigsaw-puzzle zones of chorioretinal atrophy to occur over a period of months or years. An important cause of late loss of central vision is the development of choroidal neovascularization at the edge of an old area of chorioretinal atrophy ( Figure 11.11 A and B). This occurs in as many as 25% of these patients. Care must be used to avoid mistaking the gray exudation associated with subretinal neovascularization for that caused by a recurrence of an active inflammatory lesion. Likewise, it is important not to mistake a gray active lesion for a subretinal new-vessel membrane. Fluorescein angiography is helpful in this regard.
Unusual findings in patients with serpiginous choroiditis include focal retinal phlebitis, branch vein occlusion ( Figure 11.10 ), optic disc neovascularization, retinal neovascularization ( Figure 11.10 D–K), and a striking predilection in a few patients for the choroidal lesions to correspond with the distribution of the major retinal veins. One or more sites of focal gray retinitis and overlying periphlebitis may be present ( Figure 11.10 ). These foci may be associated with evidence of branch venous obstruction locally or elsewhere in the same or opposite eye ( Figure 11.10 E–L). Gass has seen one patient who because of widespread venous obstruction developed a picture of Eales’ disease with extensive zones of retinal capillary nonperfusion, retinitis proliferans, and vitreous hemorrhage requiring pars plana vitrectomy bilaterally ( Figure 11.10 G–L). Although there is a strong predilection for this disease to affect the juxtapapillary choroid early in the course of the disease, in some cases this area is spared until later.
Fluorescein Angiography
The acute gray-white lesions appear nonfluorescent during the early phases of angiography, and later they show evidence of staining that usually begins at the margin of the lesion and spreads centrally ( Figure 11.08 C and D).
The subacute and chronic lesions show angiographic evidence of destruction of the choriocapillaris and RPE. Failure of the atrophic areas to fluoresce during the early stages of angiography is indicative of choriocapillary atrophy. As fluorescein diffuses from the neighboring choriocapillaris, the atrophic lesions show progressive staining from the margins centrally. When focal areas of retinal phlebitis are present, angiography shows evidence of staining of the vein wall and may show evidence of branch vein occlusion peripheral to the area of phlebitis ( Figure 11.10 E). Angiography is useful in detecting and localizing areas of choroidal as well as retinal neovascularization ( Figures 11.10 and 11.11 B). ICG angiography shows dark areas that correspond to the visible chorioretinal lesions, and sometimes larger than them. The hypofluorescence persists even after the acute lesions involute, suggesting continued activity in the choroid or persistent cellular infiltrate that blocks ICG fluorescence. The acute lesion is hypoautofluorescent with a hyperautofluorescent edge, the subacute lesion becomes hyperautofluorescent and the inactive atrophic lesion shows hypoautofluorescence. OCT in the subacute and inactive stage shows thinning of the outer retina and increased backscattering from the choroidal layers. The electro-oculogram and ERG are usually normal.
Differential Diagnosis
When serpiginous choroiditis is advanced in both eyes, it has been mistaken for various dystrophies affecting the choroid, RPE, and retina. The history of episodic and permanent loss of segments of the paracentral visual field, the lack of family history, the jigsaw-puzzle pattern of chorioretinal atrophy, the asymmetry of the disease, and the frequent presence of marginal gray-white edges of activity of the more peripherally located lesions are clues to the true nature of the disease. The color and early-phase angiographic appearance of the acute lesions resemble those seen in APMPPE. In this latter disease, however, the shape of the lesions is more likely to be round or oval, their distribution is more likely to be randomly scattered in the posterior fundus, they resolve usually within 7–14 days, and they leave minimal evidence of choroidal atrophy or loss of visual function. Table 11.1 summarizes the differences between these two diseases. Relentless placoid choroidopathy is the disease that closely resembles serpiginous choroiditis given that recurrences are its feature. Serpiginous choroiditis may simulate any of the diseases causing peripapillary chorioretinal scarring and neovascularization, for example, POHS, age related macular degeneration, angioid streaks, drusen of the optic nerve head, and idiopathic choroidal neovascularization. Clinical and angiographic evidence of juxtapapillary subretinal neovascularization is less likely to be present in patients with serpiginous choroiditis. On the other hand, patients with only minimal peripapillary scarring caused by serpiginous choroiditis may be seen initially with macular detachment caused by juxtapapillary subretinal neovascularization before developing any signs of the typical jigsaw pattern of choroidal involvement.
An acute lesion in the paracentral region, particularly in a patient with inactive lesions elsewhere ( Figure 11.08 A and B), may be mistaken biomicroscopically and angiographically for exudation overlying a CNVM. Likewise, a gray plaque of subretinal exudation caused by subretinal neovascularization may be mistaken for recurrence of the choroiditis. The disease that closely resembles serpiginous choroiditis in its initial presentation and subsequent course is tubercular serpignous like choroiditis (see chapter 10). When patients with a clinical picture of serpiginous choroiditis do not respond promptly to oral steroids or continue to develop new lesions while on adequate doses of steroids, and if they are from high prevalent countries such as India, tubercular serpignous should be suspected. An exaggerated response to tuberculin skin test, with or without evidence of systemic tuberculosis, calls for a prompt establishment of tissue diagnosis of TB with PCR of the vitreous fluid or needle biopsy of a choroidal lesion.
Pathogenesis and Etiology
The histopathologic findings in 2 patients suggest that serpiginous choroiditis is primarily a nongranulomatous choroiditis ( Figure 11.11 G and H). There is no clue, however, as to its cause. There is minimal evidence that it is part of a systemic disease. Figure 11.08 (K and L) demonstrates typical serpiginous chorioiditis that developed bilaterally in a patient associated with herpes zoster ophthalmicus. King et al. found elevated factor VIII–von Willebrand factor antigen in 8 patients with serpiginous choroiditis and concluded that occlusive choroidal vascular disease may be important in its pathogenesis. Broekhuyse et al. found immune reactivity to retinal S-antigen in patients with serpiginous choroiditis but not in patients with APMPPE. Serpiginous-like choroidopathy is a common manifestation of tubercular choroiditis. Given the various infectious or noninfectious association, it is likely that serpignous choroiditis is a common morphological manifestation to several antigenic stimulation. Though worldwide in distribution, the disorder is more common in India.
Treatment
Systemic corticosteroids have proved moderately effective in serpiginous choroiditis. Their use in those patients with active lesions threatening the center of the macula is advisable. The value of other agents, such as chlorambucil, cyclosporine A, azathioprine, methotrexate or a combination of these agents, is unpredictable. Because of the possibility of a viral etiology, Gass treated one patient with acute loss of central vision in his second eye with a combination of oral acyclovir and prednisone for 6 weeks. The results of treatment in this patient and four others with acute serpiginous choroiditis at the Bascom Palmer Eye Institute suggest that acyclovir may be of some benefit in preserving vision ( Figure 11.11 J and K). Despite the fact that these patients regained excellent visual acuity after treatment, one of the patients continued to develop new active choroidal lesions peripherally while receiving the combined treatment. The jury is still out on the benefits of acyclovir. Oral steroid as the initial treatment with addition of immunosuppressives if the patient has recurrences is probably the best strategy at the present time. Photocoagulation for active choroidal neovascularization that does not extend inside the capillary-free zone is of value. Intravitreal bevacizumab is useful in those cases threatening the fovea.
Prognosis
Good statistics concerning long-term follow-up of this disorder are not available. Generally it is a chronic, recurrent ocular disease that over a period of many years may cause severe visual loss in some patients. Many patients, however, maintain good central and peripheral function in at least one eye.
Acute Idiopathic Maculopathy
Yannuzzi and coworkers reported 9 patients who after a flulike illness developed sudden severe unilateral central visual loss associated with vitreous cells; neurosensory macular detachment; retinal hemorrhages; an irregular white, gray, or yellow thickening of the RPE that was consistent with a subretinal infiltrate beneath a portion of the retinal detachment; and a neovascular process or acute swelling of the RPE cells ( Figure 11.12 ). A peculiar pseudopodal extension of the subretinal exudation and subretinal hemorrhages were present in some cases ( Figure 11.12 A). Irregular staining of the subretinal thickening angiographically simulated that occurring with subretinal neovascularization ( Figure 11.12 C). Complete staining occurred in late pictures. In spite of the appearance, the subretinal exudate disappeared and visual acuity returned to nearly normal. A characteristic “bull’s-eye” pattern of pigment epithelial atrophy in the macula persisted ( Figure 11.12 L). No patient had a recurrence. One patient had late development of subretinal neovascularization. Fish and coworkers presented a similar case that in addition showed evidence of a pseudohypopyon in the macula during the acute phase of the disease. Yannuzzi’s group broadened the spectrum of this disorder to include eccentric macular lesions, subretinal exudate, fellow eye involvement, papillitis, and an association of the disorder with pregnancy and acquired immunodeficiency syndrome (AIDS).
In 2004, Beck et al. reported 2 patients with upper acute idiopathic maculopathy following hand, foot, and mouth disease with the characteristic sore throat, fever, and erythematosus papules on the palms of hands, caused by coxsackievirus. They demonstrated elevated acute and convalescent A16 and B6 titers for the virus. Both patients’ children were also diagnosed with hand, foot, and mouth disease. Multifocal ERG shows transient outer retinal dysfunction that recovers over time. Other rare associations have been a macular hole, recurrence at the same site, and transient electro-oculogram impairment. ICG may show involvement of the inner choroid, likely from contiguous spread of pathology. Spectral domain OCT shows thickening of the RPE and photoreceptor layers in the acute phase ( Figure 11.12 D) and restoration of most of the photoreceptors late ( Figure 11.12 F). The central part of the lesion is hyperautofluorescent and the outer ring hypoautofluorescent, corresponding to the bull’s-eye pattern. No specific treatment has been attempted as most cases have shown improvement in vision, including the eye with two recurrences.
Unifocal Helioid Choroiditis
This condition is characterized by a solitary, elevated, yellow-white active focus of choroiditis with overlying subretinal fluid, and in some cases subretinal hemorrhage. The lesion is approximately one disc diameter in size with a halo around it, giving the name “helioid” or sunlike ( Figure 11.13 A and H). On follow-up, the lesion shows minimal growth and the subretinal fluid resorbs gradually. No other signs of ocular inflammation are usually present, though a few anterior-chamber or vitreous cells have been noted occasionally. On follow-up, the elevation persists, even though the lesion turns more white and fibrotic ( Figure 11.13 A); a few show recurrences with reaccumulation of subretinal fluid (SRF) and some develop a CNVM. The active lesions are hypofluorescent early in the angiogram and stain late. The inactive lesions show staining ( Figure 11.13 B and C). The elevated lesion is hypoautofluorescent with a rim of increased autofluorescence outside its edge ( Figure 11.13 D). Visual loss is related to the location of the lesion and SRF in the vicinity of the fovea. Since the original description of 6 cases by Hong et al., Shields et al. reviewed 60 cases that resemble this condition that they termed “solitary idiopathic choroiditis.” Systemic investigations and corollary ocular or systemic features for infectious etiology such as histoplasmosis and various fungi, tuberculosis, toxoplasmosis, or noninfectious etiology such as sarcoid or other granulomatous disease, are negative. No treatment is necessary; systemic steroids have been used for those lesions that were vision-threatening.
Acute Retinal Pigment Epitheliitis
Krill and Deutman described the syndrome of acute retinal pigment epitheliitis, which is characterized by the rapid onset of visual disturbances in one or both eyes of young adults followed by gradual and almost complete recovery in 7–10 weeks. One to 2 weeks after the onset of symptoms, these patients had multiple clusters of discrete, round, dark spots surrounded by depigmented halolike zones present at the level of the RPE in the macula and paramacular area ( Figure 11.14 E). These were usually one-fourth disc diameter in size. The fundus findings during the first week after the onset of symptoms were not described. Fluorescein angiography demonstrates a halo of hyperfluorescence surrounding the dark spot seen ophthalmoscopically ( Figure 11.14 B, C, and L). In some cases, angiography may be essentially normal. The loss of visual function is out of proportion to the changes seen in the macula. After recovery of central vision the RPE changes may be barely visible. The cause of this self-limited disorder is unknown.
Since the original description by Deutman and colleagues, few reports of this condition surfaced till 2007. Chittum and Kalina reported 8 patients with acute retinal pigment epitheliitis associated with a fine pattern of pigment stippling confined largely to the foveolar area. It was mostly believed to be a nonspecific finding secondary to a variety of circumstances, including idiopathic central serous chorioretinopathy, drusen, adult-onset vitelliform foveomacular (pattern) dystrophy, and occult choroidal neovascularization, and in asymptomatic patients.
Since the availability of OCT, case reports of acute retinal pigment epitheliitis have re-emerged. OCT shows hyperreflectivity at the level of the outer nuclear layer, photoreceptors, and RPE ( Figure 11.14 D and G). The disease is self-limited with near-complete visual recovery in 10–12 weeks ( Figure 11.14 I).
Multiple Evanescent White-Dot Syndrome
The following features characterize MEWDS, which typically affects one eye of young females: (1) blurred vision, multiple paracentral scotomata, usually including a temporal scotoma, and photopsia occurring in approximately one-half of patients soon after a flulike illness; (2) vitreous cells; (3) multiple small, often poorly defined, gray-white patches at the level of the RPE and outer retina ( Figures 11.15 and 11.16 ); (4) a cluster of tiny white or light-orange dots in the foveola ( Figure 11.15 A); (5) early punctate hyperfluorescence of the gray-white patches, which often show a cluster or wreath-shaped pattern ( Figure 11.15 G and H); (6) late fluorescein staining of these lesions, and in some cases staining of the optic nerve head; (7) blind-spot enlargement; (8) decrease in the ERG a-wave and early receptor potential amplitudes; and (9) spontaneous recovery of visual function, normalization of the electroretinographic findings, and return of the ophthalmoscopic and angiographic findings toward normal in 7–10 weeks ( Figure 11.16 G–I). The white spots in MEWDS, which are often small, ill defined, and located in the extramacular area, are easily overlooked. It is probable that most patients reported as having the acute idiopathic blind-spot enlargement syndrome probably had MEWDS, and that the white lesions were either overlooked or had faded at the time of their examination.
ICG angiography demonstrates patchy hyperfluorescence at the level of the RPE as well as multiple, small, round, hypofluorescent lesions, some of which occur in the absence of fundus changes. Although fluorescein angiography often shows some staining of the optic disc during the acute phases of the disease, there is minimal evidence that damage to the retinal ganglion cells and optic nerve is responsible for visual loss. Later in the course of the disease a zone of RPE depigmentation and hyperfluorescence corresponding with their enlarged blind spot or other field defect may develop. Subretinal neovascularization may occasionally occur. Scanning laser densitometry demonstrates evidence of a focal defect in the visual pigment kinetics of the receptor cells in the macular area. Evaluation for evidence of systemic disease is usually negative. Some visual field loss and color vision defect may persist. The cause of the disease is unknown. Males may be affected, the disorder may occasionally affect both eyes, and late recurrences may occasionally occur. In some cases the visual field defects do not resolve.
Before or following MEWDS some patients develop evidence of pseudo-POHS, acute macular neuroretinopathy, and acute onset of large visual field defects unassociated with visible changes in the fundi. There is evidence that MEWDS may be part of a spectrum of one disease or closely related diseases that include acute idiopathic blind-spot enlargement, AZOOR (see discussion to follow), pseudo-POHS, and acute macular neuroretinopathy. All of the disorders affect predominantly young women and all may present with photopsia and zones of visual field loss caused by retinal receptor damage unexplained by biomicroscopic changes in the ocular fundi.
Acute Zonal Occult Outer Retinopathy
In 1994 Gass reported 13 patients, predominantly young women, with a syndrome characterized by rapid loss of one or more large zones of outer retinal function, photopsia, minimal fundoscopic changes, usually mild vitritis, and electroretinographic abnormalities affecting one or both eyes ( Figure 11.17 ). Progression of visual field loss occurred over a period of several weeks or months before either improving or stabilizing. Involvement of the second eye may be delayed for at least as long as 2 years ( Figure 11.17 A–I). All patients on follow-up examination had persistent visual field defects, and most had chronic photopsia and zones of pigment epithelial atrophy and retinal vascular narrowing, which in some cases mimicked that seen in retinitis pigmentosa and cancer-associated retino-pathy ( Figure 11.17 J–L). In some patients large, permanent, visual field defects were unassociated with any visible changes in either the fundus or in fluorescein angiograms.
Most patients with AZOOR are young or middle-aged adults with the predominance of women, who present with an acute onset of visual field loss in one or both eyes. The fundus examination reveals no abnormalities at onset. More than 90% of patients have antecedent or associated photopsias, which are projected to the zone of visual deficit. The photopsias have been described variously as “fireworks, blinking lights, movement of microbes under a microscope, the TV screen being off signal, flashes of light, heat waves coming off the road, and other visual phenomena.” A characteristic finding is the description of “movements” associated with these photopsias. Patients often move their fingers or hands while describing the symptom. Unlike in posterior vitreous separation, the photopsias are more noticeable in bright light and patients have been known to come into the doctor’s office wearing sunglasses. The photopsias can predate, appear simultaneous, or antedate the field loss. Some patients may have had an antecedent viral illness. Those eyes with large areas of field loss, signifying involvement of a large zone of photoreceptors, may have vitreous cells. However, vitreous cells may be a later phenomenon, seen when photoreceptors die. The visual field defect is variable; it can be small or large, and often is connected to the blind spot. Sometimes the field loss is in the periphery.
The subtle nature of this presumed inflammatory disorder, which causes acute damage to broad zones of the outer retina without producing noticeable ophthalmoscopic changes, is responsible for the diagnostic confusion that usually results in extensive fruitless neurologic, medical, and ophthalmologic consultations and laboratory investigations. Demonstration of electroretinographic abnormalities during the early course of the disease is helpful in this regard. The ERGs in these patients show a pattern of visual dysfunction that is photoreceptor in origin, patchy in distribution, and asymmetric in the two eyes. If the field loss is small and unilateral, the ERG in the affected eye may be reduced compared to the fellow normal eye. If the field loss is extensive the ERG is below normal in the affected eye(s). Either the rod or the cone function, or both, may be affected based on the location of the visual dysfunction. Bilateral involvement causes ERG depression in both eyes. Interocular asymmetry was a prominent feature in the 24 patients studied by Jacobson et al. Multifocal ERG if available is useful in documenting the extent and location of the field loss and is diagnostic of the condition when associated with a normal fundus. However, since multifocal ERG tests cone function only, it will not be able to pick up subtle rod defects.
The field loss does not conform to the loss seen with glaucoma or a vascular defect. Goldmann visual field mapping is important in demonstrating the complete field deficit, often associated with an enlarged blind spot. Visual field defects stabilize within 6 months. A small percentage of patients show improvement in field defect if treated early with antivirals and systemic corticosteroids. Fluorescein angiography when the fundus shows no changes is normal ( Figure 11.17 A and B) and shows transmission hyperfluorescence in those areas of RPE change ( Figure 11.17 E, I, and K). Autofluorescence imaging of the normal fundus shows no abnormality; however, once RPE atrophy is seen, the areas appear hypoautofluorescent ( Figure 11.18 G), and occasionally show a rim of increased autofluorescence.
The cause of the acute damage to sharply defined zones of the retinal receptor cells in the absence of visible fundus changes in patients with AZOOR is unknown. There is patchy evidence to date for autoantibodies to any retinal cell type in patients with AZOOR. Gass postulated the possibility of an inciting viral or other infectious agent within the photoreceptors. He has hypothesized a “silent preclinical phase,” where cell-to-cell spread of the virus occurs, with retention of normal photoreceptor function. In the “acute symptomatic phase,” the infected cell dysfunction is triggered by the host immune response. Either a change in the antigenicity of the infective agent or a local auto-immune reaction to the receptors laden with this infective agent may cause loss of photoreceptor function. The finding that over 90% of eyes with AZOOR have visual field defects that include one or both blind spots, and/or the peripheral isopters, suggests that the ora serrata and optic disc margin are possible sites for invasion of a virus into the receptor cells. These are two sites where the retinal receptors anatomically are not isolated from the systemic circulation by surrounding neuroepithelium. In approximately half the patients with AZOOR, the immune response to the intracellular virus results in inactivation of function but preservation of the receptor cell. No biomicroscopic or ophthalmoscopic evidence of inflammation of acute or long-term retinal cell damage is evident. In most cases the retinal cell dysfunction appears to be permanent. Although most instances of recovery occur during the first 6 months after onset of symptoms, at least 2 patients demonstrated improvement in the visual field after several years. Likewise, while stabilization of visual field loss typically occurs within 6 months of the onset of field loss, a few patients, particularly those who show evidence of some recovery early, may develop a gradual increase in visual field loss many months or years later. This delayed loss may occur as a result of resetting of the cells’ apoptotic clock during the initial acute phase of AZOOR.
In the other half of patients with AZOOR, the immune response results in early receptor cell death, development of a variable degree of inflammation including vitreous cells, perivascular exudation, and occasionally optic disc edema. These inflammatory signs typically develop within several weeks following the onset of AZOOR, appear to be proportional to the size of the affected retinal zones, and probably result from an inflammatory response to the dead retinal receptor cells.
Weeks or months later, narrowing of the retinal vessels, particularly the retinal arteries, perivascular sheathing, and reactive changes in the RPE occur ( Figure 11.18 A and F). The loss of interaction of the microvilli of the RPE with the photoreceptors causes migration of the RPE into the inner retina to line up along the blood vessel wall, giving the typical bone spicule appearance.
Similar acute occult zones of visual field loss that are accompanied by ERG changes may occur in patients with MEWDS, MCP and punctate inner choroiditis (PIC), (pseudo-POHS), and less often in patients with, or who previously had, acute macular neuro-retinopathy. The authors have seen at least 50 other patients with evidence of overlap between MEWDS, pseudo-POHS, AZOOR, and acute idiopathic blind-spot enlargement syndrome. Whereas occult visual field loss resulting from receptor cell damage is a common link among all these syndromes, we do not know the cause of any of these disorders or, to what degree they are related pathogenetically and etiologically.
Acute Annular Occult Outer Retinopathy
In the third edition of this book the author presented the findings in an otherwise healthy young adult patient who presented with acute loss of a large zone of visual field associated with an unique fundoscopic picture consisting of a large-diameter, thin, gray-white ring occupying most of the superior temporal fundus of the left eye ( Figure 11.19 A–F). Except for slight narrowing of the retinal arteries within this zone, the retina and pigment epithelium had a normal ophthalmoscopic and fluorescein angiographic appearance ( Figure 11.19 G). There were no vitreous cells. There was a left afferent pupillary defect. For a period of approximately 3 weeks the ring and absolute visual field defect enlarged before stabilizing ( Figure 11.19 C–F). The ring disappeared. The visual acuity was normal throughout the course. The absence of angiographic changes suggested that the occult destructive process was affecting primarily the inner retina within the area of the ring and the disorder was termed “acute progressive zonal inner retinitis and degeneration.” During follow-up over the following months and years, however, the patient developed, within the zone of visual field loss, depigmentation and migration of pigment epithelium into the overlying retina in a bone-corpuscular pattern, indicating that the original damage had in fact involved primarily the outer retinal receptors ( Figure 11.19 H and I). During the 6 years of follow-up his visual acuity has remained 20/20 and the visual field loss is unchanged. Of interest, he no longer has an afferent pupillary defect.
