Strutha C. Rouse, II,
Lee M. Jampol
ACUTE POSTERIOR MULTIFOCAL PLACOID PIGMENT EPITHELIOPATHY
INTRODUCTION
Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) was first described in three, otherwise healthy women by Gass in 1968.[1] Although not the first to report the constellation of clinical findings,[2] Gass gave us a definitive description of the disease that speculated on its pathogenesis.
CLINICAL PRESENTATION
Typically, APMPPE causes central vision loss in one or both eyes in young adults with the development of gray, white, or yellow, flat plaques that are predominantly located in the posterior pole at the level of the outer retina and retinal pigment epithelium (RPE) (Fig. 157.1). Lesions are usually about one disk diameter in size. Fresh lesions may appear for several weeks. Resolution of the visual symptoms begins within 2-4 weeks. The acute lesions evolve into well-demarcated, lightly pigmented scars (Fig. 157.2). In addition, APMPPE may manifest a mild vitreitis and occasionally mild anterior chamber inflammation. Usually, APMPPE is a nonrecurring syndrome,[3-9] although rare recurrent cases have been noted. These recurrent cases must be distinguished from serpiginous choroiditis (SPC), which may be difficult initially.
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FIGURE 157.1 (a) Fundus photograph of the right and (b) left eye of a patient with active APMPPE demonstrating deep, white, plaque-like lesions in the macula. |
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FIGURE 157.2 (a) Fundus photograph of the right and (b) left eye of another patient demonstrates inactive APMPPE showing well-demarcated, lightly pigmented scars in the outer retina. |
APMPPE most often affects young men and women between the ages of 20 and 50 years.[3,4] Symptoms include the rapid onset of central or paracentral visual loss. Bilateral onset is the rule but the second eye may be involved a few days or weeks later. Photopsias can also be present and the visual acuity maybe as low as counting fingers. About one-third of patients will report an antecedent viral illness,[1]often an upper respiratory infection. Other cases have followed vaccinations[10] or bacterial infections.[11]
In the great majority of patients, the visual prognosis for APMPPE is good, with most individuals spontaneously recovering vision without treatment or significant sequela. Lewis and Gass both reported that the majority of patients regain vision of 20/40 or better.[3,4] However, residual visual complaints are common as elucidated by two studies,[12,13] retrospectively reviewing 75 eyes. Patients described scotomas (33%), metamorphopsias (21%), decreased vision (16%), floaters (5%), and chronic redness (2%). Long-term vision loss may be related to choroidal neovascularization, extensive RPE changes, or foveal involvement.[14] Pagliarini et al[12] noted features that may be associated with poor visual outcomes in APMPPE such as foveal involvement at initial presentation, older age at presentation (>60 years), unilateral disease, longer interval between first and second eye involvement (>6 months) and recurrent disease.
FLUORESCEIN ANGIOGRAPHY
Fluorescein angiography for APMPPE has a characteristic pattern. Lesions demonstrate early hypofluorescence during disease activity and these lesions show hyperfluorescence in the late frames with persistent staining for 20-30 min[15] (Fig. 157.3).
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FIGURE 157.3 (a) Early phase of fluorescein angiography in acute APMPPE demonstrates blockage of fluorescence. (b) Persistent staining is present in these lesions late in the angiogram (same patient as Fig. 157.1). |
Rarely, large choroidal vessels can be observed under these areas of hypofluorescence.[16]
The inactive, healed phase of APMPPE displays a different angiographic pattern. Lesions show early hyperfluorescence representing atrophic defects in the RPE with little to no fluorescence in the later phase of the angiogram.
In 1973, Annesley et al[15] studied the evolution of angiographic changes by performing consecutive fluorescein angiograms during follow-up visits. The peripheral portion of the lesion demonstrates the first signs of healing and inactivity, a transmission defect without late staining. Slowly, these changes progress to involve the center of the plaque.
INDOCYANINE GREEN ANGIOGRAPHY
Indocyanine green (ICG) angiography has been increasingly utilized in recent years due to improvement of digital imaging systems and enhanced image resolution. ICG has demonstrated value in characterizing possible choroidal disorders, such as APMPPE. Several investigators have reported the ICG characteristics of APMPPE lesions, which substantiate the idea of primary choriocapillaris involvement.[7,17-21] Acute lesions of APMPPE show early hypofluorescence during ICG angiography with the borders of these lesions more sharply delineated in the late phase. The lesions are rounded and tend to be confluent. ICG angiography may demonstrate more hypofluorescent areas than are seen on clinical examination (Fig. 157.4). Inactive, healed lesions display early hypofluorescence on ICG withbetter depiction late in the angiogram. However, these regions are more irregularly shaped, smaller in size, and less confluent than acute lesions.[17]
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FIGURE 157.4 ICG angiogram of the same patient in Figure 157.1, during the active phase of APMPPE illustrates multiple hypofluorescent areas. Although some of these spots correspond to the photographic lesions, there are more spots apparent, during ICG angiography. |
Persistent hypofluorescence was observed by Cimino et al[22] in healed APMPPE lesions secondary to choroidal nonperfusion and chorioretinal atrophy. These findings are consistent with the current theory of choroidal occlusive vasculitis in APMPPE. It is likely that nonperfusion in conjunction with blockage of fluorescence by edematous, damaged RPE may be present in active lesions. The inactive, healed spots are smaller in dimension and more irregular in shape. These changes would be explained by resolution of inflammatory changes of the RPE.
OPTICAL COHERENCE TOMOGRAPHY
The novel technique of optical coherence tomography (OCT) has been applied to patients with APMPPE. Using standard OCT, Garg and Jampol[23] documented backscatter at the outer retina that corresponded to the placoid lesions. This case report also described serous detachment with reflective material within the subretinal fluid (Fig. 157.5). They proposed that this represented proteinaceous material within the serous fluid or damaged edematous retinal epithelium.
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FIGURE 157.5 (a) Color photo and (b) OCT of right eye of patient with APMPPE at presentation. Note the increased reflectance at the level of the outer retina that corresponded to lesions seen clinically in this patient. (c) OCT of left eye. Note serous detachment and reflective material within the fluid. |
Scheufele et al[24] illustrated similar findings in active and healed APMPPE lesions with better clarity using ultrahigh-resolution OCT. They observed thinning of the outer neural layer and inner and outer photoreceptor segments in healing and inactive lesions suggesting photoreceptor damage early in this disease course. Backscatter at the level of the outer retina likely represents acute photoreceptor cell body swelling with subsequent loss. Degenerative changes of the RPE and intracellular edema, however, were visualized as increased backscatter of the underlying choroid. Similar OCT findings are seen in patients with vascular occlusive disease. This supports the vascular hypothesis in APMPPE, indicating intracellular edema and inflammatory changes in the outer retina from ischemic damage.[25,26]
ASSOCIATED OCULAR AND SYSTEMIC FINDINGS
Vitreitis is seen in half the patients with APMPPE and papillitis and retinal vasculitis have been reported.[27-32] Allee and Marks[33] described bilateral central retinal vein occlusions that developed ~1 month after the onset of APMPPE. Disk edema and nerve fiber layer hemorrhages were present 1 week prior to the vein occlusions suggestive of a peripapillary vasculitis leading to disk swelling and compression of the central retinal vein. De Souza and colleagues[30] reported a case of APMPPE that displayed signs of retinal vasculitis with subsequent retinal neovascularization and vitreous hemorrhage 6 years after presentation. Other reports describe more extensive inflammatory processes, including peripheral corneal thinning,[34] corneal stromal infiltrates,[35] episcleritis, iridocyclitis,[28] and choroidal vasculitis. APMPPE has also been described with diffuse serous retinal detachments[23,36,37] and hemorrhagic retinal detachments.[29]
Neurological abnormalities in association with APMPPE may include headache[1,38-41,42] and cerebrospinal fluid (CSF) pleocytosis,[27,38-41,43-46] which usually improve spontaneously. However, some patients can experience episodes of transient cerebral ischemia,[27,42] producing stroke-like symptoms, optic neuritis,[6,31,33,34,47] transient hearing loss,[48] and permanent focal deficits[43,45] due to vasculitic changes. APMPPE has been described in association with presumed cerebral vasculitis in a dozen cases.[27,39,42,43] Ten of these individuals suffered a stroke and deaths have occurred. In one case, histopathology of the brain demonstrated granulomatous inflammation of medium size arteries[49] while biopsy from the tibialis anterior muscle was suggestive of vasculitis in another.[43] Comu et al[42] described three patients with APMPPE and neurologic manifestations. Visual disturbance and headache were shared by all three and they had a normal radiologic scan initially but CSF pleocytosis. One patient developed recurrent strokes involving different vascular distributions that required immunosuppressants for presumed cerebral vasculitis.
APMPPE has also been associated with other systemic conditions including erythema nodosum,[50,51] group A streptococcal infection,[11] clear cell renal cell carcinoma,[52] thyroiditis,[34] pulmonary tuberculosis,[53] ulcerative colitis,[54] Wegener's granulomatosis,[55] and systemic vasculitis.[56,57] Some of these associations may be coincidental but others may indicate systemic triggers for the APMPPE response as described below or different manifestations of a systemic vasculitis.
The etiology of APMPPE remains a subject of debate. A viral illness may be an immunologic trigger for some individuals. Azar et al[58] and most recently Thomson et al[59] both described cases of APMPPE occurring with culture-proven adenovirus infections. Recombinant hepatitis B vaccination, reported by Brezin,[10] caused two patients to develop APMPPE between 3 days and 2 weeks after a booster shot. Despite the lack of histologic evidence, the possibility of a virus or vaccination causing APMPPE supports an immune-mediated scheme. Some investigators have speculated that molecular mimicry could play a significant role in damage to the RPE or occlusion of the choriocapillaris. In a patient who is genetically predisposed to immune dysregulation, environmental triggers may precipitate APMPPE. A case of atypical APMPPE occurred in a patient with clear-cell renal-cell carcinoma; high levels of circulating immune complexes accompanied the fundus findings.[52] This possibly implicates immune complexes in tandem with the complement cascade in the development of choroidal vascular occlusions. This theory is reinforced by a documented case of APMPPE after acute group A streptococcal infection with an observed rise in anti-DNAase B antibody titers.[11] Interestingly, a patient with APMPPE in the course of ulcerative colitis was documented in 2001.[54] Mathura et al described a patient who had an episode of APMPPE and then, years later, developed multifocal choroiditis, distinctly different from the earlier lesions.[60] Thus, a patient with immune (or genetic) dysregulation may manifest at different times as different white spot syndromes.
Human leukocyte antigens (HLAs) B7 and DR2 have been associated with APMPPE.[61] Two cousins were described with recurrent APMPPE and both were found to have HLA DR2, promoting the concept of an inherent propensity to acquire this disease.[62] Undoubtedly, other immune regulatory genes will be involved.[63]
PATHOPHYSIOLOGY
Gass believed that the abnormalities in APMPPE were at the level of the RPE.[1] He felt that the early blockage of fluorescein was due to acute physiologic alterations in the RPE that accounted for the opalescent appearance. The late staining typical of this disorder could be explained by the uptake of fluorescein into damaged pigment epithelium. The RPE eventually recovers along with some of the photoreceptors, allowing the return of visual function, despite areas of significant pigment clumping or atrophy.
Others agreed that edematous RPE cells absorb the underlying choroidal fluorescence but hypothesized that, during the acute process, an infectious or immunologic insult occludes the choriocapillaris, sparing the larger vessels.[27]
Further supporting the idea of a primary RPE process, the electroculogram (EOG) findings are remarkably impaired during the acute phase of the disease. However, the electroretinogram (ERG) responses are normal. Fishman concluded that these findings demonstrated RPE dysfunction.[5] If the choriocapillaris were primarily involved, both EOG and ERG responses would be extinguished.
At the present time, most investigators currently attribute the hypofluorescence to hypoperfusion of the choroid. There is substantial evidence of APMPPE-like changes in association with ocular and systemic vasculitic conditions, which implicates an inflammatory process of the choriocapillaris. Diseases like Wegener's granulomatosis[55] and ulcerative colitis[54] have both been reported in association with APMPPE-like changes.
Van Buskirk et al[50] first reported the fluorescein angiographic changes of APMPPE as a primary vascular abnormality of the choroid. They described the hypofluorescence as impaired filling of the choriocapillaris. Many investigators who support this idea feel the placoid lesions represent focal infarcts of the RPE caused by choroid vascular disease. Hayreh's studies of the choroidal vasculature support the hypothesis of a vascular pathologic process.[64] He believed the angiographic appearance of APMPPE lesions denoted occlusions of precapillary choroidal arterioles.
Deutman and colleagues[16] reported the appearance of large choroidal vessels seen under areas of hypofluorescence. This evidence suggested that diseased RPE could not fully account for the lack of choroidal fluorescence but rather suggested choriocapillaris nonperfusion. They surmised that APMPPE lesions signify choroidal ischemia with subsequent RPE involvement.
MANAGEMENT/THERAPY
No therapy has been proven to affect the short-term or long-term outcome of APMPPE. Corticosteroids are sometimes used with the rationale that this may reduce the impairment of central vision and speed healing. This has not been proven. However, in cases where central nervous system inflammation is present with APMPPE, immunosuppressive agents have been utilized to treat these patients with success in some cases.[42-44]
DIFFERENTIAL DIAGNOSIS
The majority of patients with APMPPE are easily diagnosed based on the classic clinical findings and course. However, other inflammatory processes of the choroid should be considered when contemplating the diagnosis of APMPPE. Serpiginous choroiditis (SPC), multifocal choroiditis, multiple evanescent white dot syndrome, relentless placoid chorioretinitis (RPC), diffuse unilateral subacute neuroretinitis, choroidal neoplasms, birdshot chorioretinopathy, and others can resemble APMPPE. Additionally, infections like syphilis and granulomatous diseases like sarcoidosis can resemble APMPPE lesions. The individual, acute lesions of APMPPE, serpiginous, and relentless are not clearly distinguishable at times. However, the clinical course and setting usually allows diagnosis.
CONCLUSION
APMPPE presents typically in early adulthood and affects the central vision. The visual symptoms begin to resolve over 2-4 weeks. APMPPE has a characteristic fluorescein angiographic pattern and clinical course. The prognosis for visual recovery is good and the exact pathologic process involved is still debatable. To date, there is no proven treatment.
SERPIGINOUS CHOROIDITIS
INTRODUCTION
SPC is a rare, chronic, recurring, usually bilateral disease,[65-69] which has also been called geographic choroiditis,[70,71] geographic choroidopathy,[70,72] geographic helicoid peripapillary choroidopathy,[65,69,70,73] helicoid peripapillary chorioretinal degeneration,[72] and macular geographic helicoid choroidopathy.[74] The disease has been reported in whites,[75] Asians,[74] African-Americans,[76] and Hispanics.[66] Men are affected slightly more frequently than women.[77] The onset of SPC is usually between ages 30 and 70 years,[68,78] although affected patients in their 20s have occasionally been reported.[76,79]
CLINICAL PRESENTATION
Patients with SPC usually report painless blurring of vision.[76,79,80] Vision loss can vary, depending on the affected area, and visual field examination reveals small, central or paracentral scotomas, either absolute or relative.[80] In the early stages of the episode, the scotomas are more frequently absolute.[76] Amsler grid visual field testing reveals scotomas that correspond precisely with the clinical lesions.[73]Acute peripapillary or macular geographic lesions appear clinically as gray to grayish-yellow placoid lesions, owing to outer retinal or retinal pigment epithelial thickening with translucency (Figs 157.6 to 157.8).[80] Peripapillary lesions, when present, are discoid, often showing multiple confluent old scars and finger-like projections (Fig. 157.9; see also Figs 157.6 and 157.7).[81] These projections may completely envelop small areas with normal appearance.
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FIGURE 157.6 (a) Active focus of recurrent SPC (arrows). (b) Late-phase angiogram shows leakage from two foci of choroiditis. |
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FIGURE 157.7 (a) Active initial lesion of macular SPC. (b) Same patient 3 years and several recurrences later with serpentine extension. |
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FIGURE 157.8 (a) Unusual-shaped lesion of macular SPC. (b) Early-phase angiogram shows hypofluorescence. (c) Late-phase angiogram shows staining of lesion. |
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FIGURE 157.9 End-stage scarring of inactive SPC. |
The EOG is unaffected.[82,83] When extensive disease is present,[83] however, ERG values have been shown to fall to 70-80% of normal for total retinal illumination and to 20-30% of normal for local macular illumination.[82]
Individual acute lesions normally last from weeks to months.[68,80] Resolution of the lesion results in either pigmentary loss or hyperplastic mottling of the RPE, variable atrophy of the choriocapillaris and large choroidal vessels, and scarring (Figs 157.10 to 157.12; see also Figs 157.6 to 157.9).[69,81]
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FIGURE 157.10 Inactive lesion of macular SPC. |
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FIGURE 157.11 Finger-like inactive lesion that eventually reached the fovea. |
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FIGURE 157.12 (a) Peripapillary SPC with choroidal neovascularization at its temporal margin. (b) Angiography shows choroidal neovascular membrane. |
Characteristically, patients show evidence of multiple recurrences at intervals of several months to years during follow-up.[66,80] Recurrent lesions most frequently spread centrifugally from the disk, preferentially moving toward the macula (see Figs 157.6, 157.7, 157.10, and 157.11), although some cases spread from the macula to the disk.[69,78,80] New lesions are often, but not always, contiguous with the borders of previous scars.[69,78,80] These new lesions are believed to be genuine recurrences rather than a simple progression of previous lesions, owing to the prolonged period between the resolution of one episode and the subsequent recurrence.[69,78,80]
Although blurred vision is usually the patient's chief complaint, this is frequently not noticed until the fovea becomes involved.[73,74,76,81] Many patients show evidence of previous lesions at the time of their first examination, representing extrafoveal disease that was previously active.[66,73,76] For the patient presenting with foveal involvement, vision may be rapidly and permanently lost; finger-counting vision is frequently encountered in these patients.[69,78]
Commonly, lesions may present in the macula without preceding peripapillary activity, a variant known as macular SPC (see Figs 157.7 to 157.9). These cases characteristically present early in their course, owing to the early loss of central vision.[66] Other portions of the posterior pole, and even the periphery, are uncommon but occasional sites of involvement.[78]
Virtually all patients eventually show bilateral disease; however, it is uncommon to see bilateral simultaneous onset of the disease.[69] Additionally, the course and complications of the disease are not necessarily the same for both eyes; one eye may show primary peripapillary involvement, whereas the other may show macular SPC.[73]
FLUORESCEIN ANGIOGRAPHY
During the early phase of fluorescein angiography, the lesions are hypofluorescent (see Fig. 157.8b).[65,73,80,82] The borders of these lesions may hyperfluoresce throughout the angiography, representing leakage from the surrounding choriocapillaris. The hypofluorescence of the interior represents either blockage by swollen RPE cells or nonperfusion of the choriocapillaris, or a combination of the two. Later in the angiogram, the inner portions of a lesion may show spotty hyperfluorescence, which with time becomes more intense and may spread within the previously hypofluorescent regions (see Figs 157.6b and 157.8c).[82,84] The areas of active inflammation eventually stain.[73]
Over a period of several weeks, the active lesion shows pigmentary atrophy and clumping, with variable destruction of the choroid. The atrophy is usually much more pronounced than APMPPE. Angiography shows mottled hyperfluorescence due to pigment clumping.[78] Late staining, representing leakage of dye from damaged choriocapillaris at the periphery of the lesion, is also observed.[85-88]
ICG ANGIOGRAPHY
Ciulla and Gragoudas have reported the results of ICG angiography in one patient with an acute lesion in one eye and an inactive lesion in the fellow eye.[89] Their findings were similar to those with fluorescein angiography, except that the borders of both active and inactive lesions were less well defined and did not show late staining.
Giovanni and associates reported their findings in 17 patients with SPC.[90] In one patient, they found evidence of a possible active area of choroidal involvement extending beyond the borders of a lesion noted clinically and by fluorescein angiography. Additionally, resolution of choroidal late staining in subacute lesions was noted before this resolution on fluorescein angiography. In contrast to the findings of Ciulla and Gragoudas,[89] the healed lesions behaved similarly on both ICG and fluorescein angiography, although the authors found clearer delineation of the atrophic choroid with ICG.[90]
Giovanni and associates also noted two cases with possible de novo lesions in patients with dormant SPC.[90] In one, multifocal hyperfluorescent lesions were seen bilaterally on ICG, although one eye had not shown clinically active disease. In the second patient, ICG revealed late hypofluorescent spots; this, however, could represent blockage. These authors did not change their treatment strategy based on the findings in these two patients and noted that further follow-up would be required to determine if these lesions represent early disease activity.[90]
ASSOCIATED OCULAR AND SYSTEMIC FINDINGS
Vitreitis is seen in up to a one-third of individuals with SPC.[69,78,80] A mild, nongranulomatous, anterior uveitis has been reported but is much less common.[91]
Generally, the optic nerve is not affected,[69,73] although Wu and colleagues described a patient with temporal sectorial atrophy of the optic nerve.[81] However, photocoagulation had been performed in this patient. Fujisawa and co-workers reported a patient with evidence of recurrent disease who developed 'optic neuritis'.[84]
Choroidal neovascularization is a common complication of SPC, and it may be more common in women than in men (see Fig. 157.12).[77] In a 1982 study of 53 patients, Blumenkranz and associates reported that 13% (seven patients) had active choroidal neovascularization.[77] Five of these patients demonstrated bilateral SPC, but only two showed evidence of bilateral choroidal neovascularization, demonstrating that the course of the disease can vary between eyes in the same patient. Since then, Gass has reported that the incidence of choroidal neovascularization may be as high as 25%,[69]although Nussenblatt has reported an incidence of just 10%.[92]
The time course for the development of the choroidal neovascularization is uncertain; the asymptomatic nature of SPC before foveal involvement often allows the disease to progress, so that neovascularization may be seen at the first examination.[68] Neovascular membranes have been reported to occur as soon as 7 months after presentation with acute SPC.[93] As with other entities, hemorrhage, exudate, and retinal thickening may be associated with choroidal neovascularization in SPC. Some of these neovascular membranes have been treated successfully with thermal laser photocoagulation or surgery (see section on Management/Therapy), whereas others have shown spontaneous regression.[93]
Retinal and optic disk neovascularization has been reported with SPC.[77,93-95] Retinal edema and localized serous detachment (usually in association with choroidal neovascularization) of the neurosensory retina may occasionally be seen.[68,69,91] Wojno and Meredith also reported localized RPE detachment.[94] Their proposed mechanism suggests that irritation of the RPE and Bruch's membrane decreases the adherence of the two layers, allowing fluid buildup beneath the RPE. The detached RPE cells may then show pump dysfunction, resulting in a serous retinal detachment. These serous detachments overlie RPE detachments and extend slightly beyond their borders.[94]
Macular involvement is one of the most common complications of SPC; the disease may originate in the macula,[66] or a peripapillary lesion may spread to the macula.[69,78,80] Foveal involvement causes a rapid decrease in central vision and has a poor prognosis for recovery. Disciform macular scars, with or without active subretinal membranes, have been reported in as many as 26% of patients.[77]
Retinal vasculitis, usually in the form of periphlebitis, has been observed in patients with SPC.[76,80,91,96] Occasional branch vein[77,96] or combined branch vein and artery occlusions have been described.[91]In one report of a patient with SPC and associated branch vein occlusion with retinal periphlebitis, the patient had ipsilateral optic nerve head drusen; the authors speculated that the drusen could have contributed to venous stasis and subsequent vein occlusion.[96] The retinal vasculitis and vascular occlusion could be secondary to a spillover of choroidal inflammation or an antigen-antibody reaction of the retinal vessel wall.
Erkkila and associates reported a 54.5% prevalence of HLA-B7 in Finnish patients with SPC,[95] which is greater than that of the general Finnish population (24.3%).[79,97] HLA-B7 was found in all three patients with choroidal neovascularization and in one patient who showed neovascularization of the disk.[95] Other HLA associations have not be proved.[79,95] One case of familial SPC has been reported that demonstrated autosomal dominant inheritance with complete penetrance.[94]
In most reports, no systemic disease has been detected in patients with SPC.[76,79,91,95] Some studies, however, have found singular associated systemic manifestations, many of which are probably chance associations.
Edelston and colleagues have reported two cases of biopsy-proven sarcoidosis in patients who developed acute lesions resembling those of SPC late in the course of their disease (21 and 51 years after diagnosis of sarcoidosis).[98] In one patient, the episode represented apparent reactivation of choroiditis in one eye, which had been quiet from age 29 until age 70 years. The lesions in these patients showed the characteristic changes of SPC on fluorescein angiography and demonstrated the typical helicoid progression of SPC during follow-up.[98]
Richardson and colleagues report a case of SPC and nongenetic dystonia (simultaneous contraction of antagonistic muscle groups) believed to be acquired secondary to remote trauma, an unknown degenerative process, or microinfarction secondary to migraine.[72] These authors cited two other cases that may suggest a predisposing degenerative link between SPC and neurologic disorders, including a young man with SPC and a relative absence of arm swing during walking and an SPC patient whose sister had multiple sclerosis.[72]
A case of celiac disease associated with SPC and autoimmune thrombocytopenic purpura has been reported.[99]
Vascular endothelial injury releases von Willebrand factor (vWF), which complexes with factor VIII. Factor VIII is necessary for normal clotting cascade activity; its deficiency results in hemophilia. vWF increases platelet adhesion. Elevated levels of vWF have been associated with several disorders that manifest vascular occlusion as a primary component, including polymyalgia rheumatica, Raynaud's phenomenon, and scleroderma. King and associates reported elevated factor VIII-vWF antigen in eight patients with SPC. None of the patients was found to have rheumatologic or vascular disorders on follow-up.[67]
HISTOPATHOLOGY
Histopathologic findings, including atrophy of the choriocapillaris, photoreceptors, and RPE, were reported by Wu and colleagues.[81] Fibrocellular scars lined the inner portion of Bruch's membrane in the regions of RPE and photoreceptor cell atrophy. The choriocapillaris was acellular. A diffuse and focal infiltration of lymphocytes was seen in the choroid. Infiltration was most prominent at the borders of RPE atrophy and lymphocytic infiltration was also present in the venous walls.[81]
ETIOLOGY
Maumenee, in his 1970 Edward Jackson Memorial Lecture to the American Academy of Ophthalmology and Otolaryngology, stated that the entity of SPC ran a spectrum that included as its two end points vascular abiotrophy and choroidal inflammation.[100] Since then, the theory of vascular abiotrophy, perhaps genetic and similar to various hereditary choroidal atrophies, has not been substantiated. As recently as 1981, however, Richardson and colleagues suspected a degenerative cause in their analysis of a case of SPC associated with nongenetic unilateral extrapyramidal dystonia.[72]
Compelling evidence supporting an inflammatory cause of SPC has been set forth by Baarsma and Deutman[82] in support of Schlaegel (1969)[71]: an edematous zone surrounds the active lesion, and lesions expand through this edematous zone. The variable time course of bilateral involvement suggests that SPC is not of a degenerative origin. Degenerative disorders rarely show restoration of eyesight to any marked degree, unlike that sometimes seen in SPC. Familial occurrence of SPC is rare.[82] The inflammatory etiology is supported by the occasional presence of anterior uveitis, retinal vasculitis, vitreitis,[68]and optic disk neovascularization.[94]
An immune response induced by a tissue or microbial antigen could play a role in this inflammatory etiology. Recurrences could be caused by reactivation of the immunologic reaction[95] or by an underlying infection.
In support of an immunologic etiology, Erkkila and associates discovered an increased prevalence of HLA-B7 (previously discussed).[95] These authors have also described a decline in complement factor C3 in two patients.[95] Broekhuyse and colleagues described the presence of immune responsiveness of SPC patients to retinal photoreceptor protein.[101] Immune reactivity may depend on release of autoantigens and leakage of S-antigen through the blood-retina barrier at the level of the RPE.
Attempts to demonstrate a microbial cause of SPC have been unrevealing. An infectious etiology or trigger remains appealing, however, because recurrences could indicate reactivation of the infection, as seen with toxoplasmosis or herpesviruses. A tubercular allergic cause has been proposed for patients with a history of tuberculosis or a positive Mantoux reaction.[80] Schatz and co-workers reported a single case of active SPC lesions concurrent with both maxillary sinusitis and 'influenza'.[65] Laatikainen and Erkkila noted one patient who had viral meningitis before the first attack and three patients with increased antistreptolysin titers but without evidence of focal infection.[80] One patient had been receiving estrogen-type hormonal therapy for menopausal symptoms for 2 years before onset of symptoms.[80]These four patients were part of a group of nine for whom systemic antibody titers were negative for a variety of viruses or other infectious entities. Mansour and colleagues also found no evidence of preceding viral illnesses.[66] To the contrary, Gass described one patient who developed bilateral SPC after herpes zoster ophthalmicus.[102] Yet, Akpek and colleagues cited postmortem histologic findings of an eye with a long history of SPC and were unable to isolate herpetic viral genomic fragments (herpes simplex, Epstein-Barr virus, cytomegalovirus, and herpes zoster) in the infiltrating lymphocytes or choroidal tissues, using PCR amplification.[103]
Friberg has reported elevated Toxoplasma gondii titers in a patient with SPC with branch vein occlusion and bilateral periphlebitis, but he was cautious in pointing out that serum Immunoglobulin (Ig) levels are often elevated for months to years after an active toxoplasmosis infection and that serum IgM levels, which would have been indicative of an active primary infection, were not obtained.[96]
PATHOPHYSIOLOGY
Choroidal vascular occlusion could be the mechanism through which either an autoimmune disease or an infectious agent could incite inflammation and tissue damage. Although King and associates did not find an immunologic association for SPC, they suggested that vascular occlusion is the most probable mechanism of tissue damage. Areas of normal retina can be found immediately adjacent to affected areas, which is suggestive of a precisely defined loss of choroidal filling. This cannot be explained by blockage of fluorescence from inflammation at choroid or RPE alone.[67] Mansour and colleagues, however, found evidence of hyperfluorescence in an atrophic laser spot in an active lesion of macular SPC.[66] The laser spot, from treatment of previous subretinal neovascularization, provided a window defect through involved RPE and suggested intact underlying choroidal fluorescence.[66] Thus, the hypofluorescence seen in the angiogram of an active lesion may be due at least in part to RPE opacity and not to underlying choroidal vascular occlusion.[66]
DIFFERENTIAL DIAGNOSIS
APMPPE and SPC both present as flat geographic yellowish white lesions of the outer retina and RPE with similar fluorescein angiographic patterns. Most notably, hypofluorescence during the acute stages of the disease is seen with both lesions.[66,82,96,104] In APMPPE, however, most lesions largely resolve within weeks,[69] and recurrences are uncommon more than several months after disease onset. A viral prodrome is often seen before ocular manifestations in patients with APMPPE. SPC invariably shows recurrences over periods of many months or years after disease onset,[66,73,82] and a viral prodrome is not seen. The scarring in APMPPE is generally limited to pigment mottling.[80,82,104] Choroidal atrophy is usually not prominent in APMPPE;[66,80,83] it is the rule with SPC. Patients with APMPPE and macular involvement have a much more favorable visual outcome.[66,73,105] Visual acuity, even after foveal involvement, often recovers dramatically in patients with APMPPE (although this may be delayed), but recovery is rare in patients with SPC.[73] APMPPE patients are generally younger, with simultaneous multifocal bilateral involvement throughout the posterior pole;[66,73] in contrast, SPC patients are most frequently middle-aged, with activity of the disease in each eye generally occurring sporadically. Choroidal neovascularization has been seen in APMPPE, but it occurs much less frequently than with SPC.[73]
Like those of SPC, the recurrent lesions of retinal toxoplasmosis usually begin at the margin of an inactive scar.[96] However, only one-third of SPC patients show evidence of vitreous cells, whereas patients with acute toxoplasmosis usually show marked infiltration of the vitreous. Visual loss with toxoplasmosis may be secondary to direct foveal involvement, macular edema, or media opacities.[96] Toxoplasmosis may be seen anywhere in the fundus. Additionally, the scars of toxoplasmosis are much more atrophic than those of SPC, indicating more extensive destruction of the retina, RPE, and choriocapillaris.[96]
Systemic diseases may cause choroidal ischemia in the posterior pole. These include hypertensive vascular disease, systemic lupus erythematosus, polyarteritis nodosa, preeclampsia, eclampsia, disseminated intravascular coagulation, and thrombotic thrombocytopenic purpura.[66] The fluorescein pattern in these conditions may resemble that of SPC, but the clinical course is different. Marked atrophy of the RPE and choroid as seen with SPC does not occur with these choroidal ischemic syndromes.
MANAGEMENT/THERAPY
Various antiinflammatory and immunosuppressive agents have been used to treat SPC. Most efforts do not appear to halt recurrence of the disease,[76] although these therapies may be tried when macular vision is threatened. Systemic prednisone, 60-80 mg/day, is a commonly prescribed therapeutic regimen, but it has not been proved to affect the recurrence rate or the long-term outcome of the disease.[76,80]Many experienced observers, including one of the authors (LMJ), believe that the acute lesions of SPC heal more rapidly with systemic, periocular, or intraocular corticosteroids and that maintenance steroids can prevent recurrences.
Araujo et al used oral cyclosporine at 3-5 mg kg?1 day?1 along with varying doses of prednisone to treat seven patients with active SPC and to analyze the effects on the rate of recurrence.[106] The median duration of treatment was 3 years, ranging from 1.3 to 5 years; five patients demonstrated remission and avoided recurrences while on this regimen. However, only two of the seven patients actually achieved drug-free remissions (2.5 and 1.6 years) after cyclosporine therapy for 3.5 and 2.5 years, respectively. There were no serious complications reported in this series related to the long-term use of cyclosporine.
Hooper and Kaplan described triple immunosuppressive therapy, with low doses of azathioprine (Imuran), cyclosporine, and prednisone in combination.[107] All five of their patients showed resolution of active choroidal infiltrates within 2 weeks of beginning therapy. Recurrence was immediate in one patient when therapy was discontinued but ceased when the therapy was resumed. The authors suggest a synergistic effect between the three agents used. Nussenblatt, however, remarked in his discussion of the article that although this regimen may be effective for long-term immunosuppression, the short-term effects demonstrated may be due to the effects of the steroids alone or may even represent the natural resolution of the disease.[108] Alkylating agents, such as cyclophosphamide or chlorambucil, in conjunction with oral steroid seemed effective at controlling the acute inflammation and allowing long-term drug-free remission in another report.[109] Seven of the nine patients managed to reach a drug-free remission after 15-96 months of treatment (median, 78 months). However, the side effects were considerable, including nausea, and fatigue. One patient developed transitional epithelial carcinoma of the bladder 3 years after succession of treatment, related to the cyclophosphamide therapy.
Secchi and co-workers have reported improved visual acuity in seven patients treated with cyclosporine as monotherapy, with recurrence in one of three patients in whom therapy was discontinued.[110] Using similar doses of cyclosporine as Secchi's group, Leznoff and colleagues treated 18 patients with nonmicrobial uveitis. Of these, three carried a diagnosis of SPC. Two showed no improvement after 4 months of therapy each, despite the addition of prednisone and azathioprine in one patient and prednisone in the second. The third patient showed dramatic improvement after the addition of prednisone and azathioprine. This patient had the shortest duration of disease (0.2 years vs 1 and 2 years in the nonresponders).[111]
The long-term outcome of five patients treated with interferon alpha-2a was described by Sobaci and colleagues.[112] The eight eyes in this report had vision-threatening SPC that failed to respond to steroid-cyclosporine or chlorambucil. The authors found that all lesions were quiescent after this treatment and no recurrences were noted during the follow-up period (16-48 months). Early flu-like symptoms were the only adverse reaction observed and recovery of vision or stability of useful vision was documented. This suggests that interferon alpha-2a may be an option for the treatment of SPC but further studies are necessary.
Cases of SPC complicated by extrafoveal choroidal neovascular membranes with attendant hemorrhage, exudate, or serous retinal detachment have been successfully treated with laser photocoagulation.[66,68] For subfoveal choroidal neovascular membranes, present management could include photodynamic therapy, intraocular triamcinolone, or antivascular endothelial growth factor agents. Improvement in visual acuity may occur after treatment, but lesions located in the foveal avascular zone have a poor prognosis with treatment.[77] Schatz and McDonald noted that new lesions in patients with SPC should be assessed carefully to determine whether they represent fresh inflammation or choroidal neovascular membranes.[73] Navajas et al cited treatment of a peripapillary choroidal neovascular membrane secondary to SPC utilizing ICG-mediated photothrombosis with intravitreal triamcinolone. This case report demonstrated recovery of vision from 20/200 to 20/20 over a 10-week course, which was maintained up to 1 year of follow-up.[113]
Surgical removal of choroidal neovascular membranes, either peripapillary or submacular, has shown some benefit in specific groups of patients but has never been systematically studied in SPC because of its rare nature. Given the extensive RPE and choroidal damage from SPC, it would unlikely be of much benefit.
MONITORING DISEASE ACTIVITY
Amsler grid testing is an excellent means for assessing the activity of SPC or the effectiveness of therapy in patients with SPC because scotomas can be mapped precisely on the grid.[114] Activity of the disease or secondary choroidal neovascularization may affect the Amsler test.
RELENTLESS PLACOID CHORIORETINITIS
INTRODUCTION
RPC is a newly recognized disease process that resembles APMPPE and SPC in many respects.[115] Unlike these two diseases, RPC shows a progressive, relentless course with the widespread development of dozens to hundreds of inflammatory areas. Previous cases, called multifocal SPC,[116] ampiginous choroiditis,[92,117] or recurrent APMPPE,[8] may represent RPC.
CLINICAL PRESENTATION
Patients with RPC develop multiple placoid, white lesions at the level of the outer retina and RPE[115] (Fig. 157.13). Over the course of several weeks, the acute lesions first grow in size and then evolve to inactive pigmented chorioretinal scars. However, all the patients demonstrate a recurrent, recalcitrant course that includes the development of multiple, new lesions, growth of previous lesions and continued inflammation of some older lesions over many months (5-24 months). The disease process eventually involves all areas of the retina, including anterior to the equator.
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FIGURE 157.13 (a) Fundus photograph demonstrating the acute presentation of RPC with multiple deep retinal lesions. (b) Within weeks, new lesions appeared and growth of old lesions was apparent. (c and d) Photos show light pigmentation of the outer retinal scar around the fovea. (e) Months later, there is subretinal fibrosis and atrophic scarring throughout the fundus. |
RPC affects patients between 20 and 50 years old. Concurrent inflammation of both eyes occurs in the majority of patients with frequent foveal involvement. Central vision can be poor but recovery is sometimes seen, despite foveal RPE changes.[115,116] Only two out of 11 eyes, in Jones and associates' case series, had a final vision worse than 20/40.[115] No gender predilection was noted.
The individual lesions of RPC are similar to those seen with APMPPE. However, the lesions demonstrate growth in size and contiguous relapses over several months.[115] Recurrence is a classic feature of SPC in which a serpentine extension of existing lesions is routinely seen. For APMPPE, recurrences have been clearly documented but remain a rare clinical finding.[8]
FLUORESCEIN ANGIOGRAPHY
The fluorescein angiography of patients with RPC resembles those of APMPPE or SPC. Lesions are hypofluorescent in the early phase due to blockage or choriocapillaris nonperfusion. Later, hyperfluorescence develops, starting at the borders of the lesion, with uniform late staining of the underlying fibrotic scar and sclera.[20]
ICG ANGIOGRAPHY
ICG angiography findings reported with RPC are again similar to APMPPE or SPC.[20,90,117,118-122] The ICG angiographic pattern is characterized by hypofluorescent areas initially that persist into the late phase.
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ASSOCIATED OCULAR AND SYSTEMIC FINDINGS
Vitreitis is a frequent manifestation seen with RPC. Both Lyness' and Jones' description of this entity reported that over half of their patients presented with vitreitis.[8,115] Also noted were episcleritis,[115]keratic precipitates,[115] and optic disk swelling,[33] all of which support an inflammatory process at least within the ocular tissues if not a more global inflammatory disease.
No consistent systemic disorder has been demonstrated in patients with RPC. However, one of Jones' patients had herpes keratitis.[115] Some patients who subsequently developed RPC had upper respiratory tract infections that were treated with antibiotics. A case series in 1984 by Lyness et al described 'recurrent APMPPE' in seven patients; three of these individuals used antimicrobial agents on multiple occasions with concurrent episodes of blurred vision and characteristic lesions consist with RPC. The authors concluded that an antibiotic could possibly act as an antigenic trigger for this disease.[8]Other systemic findings seen in association with RPC included erythema nodosum, thyroiditis, and aseptic meningitis, which all have been previously described with APMPPE or recurrent APMPPE.[8,38,34,50,51,58,80,115]
PATHOPHYSIOLOGY
The individual lesion of RPC resembles APMPPE and SPC. Fluorescein and ICG angiography both suggest an element of nonperfusion of the choriocapillaris and the ERG and EOG were extinguished in one patient with RPC.[115] Choroidal ischemia from an unknown trigger is the most widely accepted theory for both APMPPE and SPC and may also be involved in RPC.
MANAGEMENT/THERAPY
With only limited experience to date, the best management for RPC patients is not known. Corticosteroids have been used with rapid resolution of active lesions and improvement in vision. Yet, it is difficult to conclude that steroids affected the long-term outcome, given the natural history of spontaneous healing of individual lesions. Antiviral agents also have been tried in a small number of patients but without obvious benefit to date. Other immunosuppressive agents, such as cyclosporine, have also been used,[115] but recurrence often is seen after immunosuppression is tapered.
DIFFERENTIAL DIAGNOSIS
See sections on APMPPE and/or Serpiginous Choroiditis.
CONCLUSION
APMPPE, SPC, and RPC all represent idiopathic outer retinal and choroidal inflammatory processes. They are usually clinically distinguishable based on specific characteristics including age of onset, course, visual outcome, systemic associations, and recurrence patterns. Given the clinical and angiographic similarities among these entities, they may share a common immune dysregulation.
ACKNOWLEDGMENTS
Charles J Bock Jr, MD assisted with the earlier version of the chapter on SPC.
The present work was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc, New York City.
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