Clinical symptoms

Patients present with complaints of blurred vision, floaters, and photopsias. Most have vision of 20/40 or better.⁹ The eye is generally not red or painful. Severe nyctalopia despite normal visual acuity may be a presenting symptom.¹¹ Individuals also may describe an alteration in color vision¹² or visual fields.¹³ Although Gass described a few patients who concurrently had vitiligo of the skin,⁸ BCR is thought to be a purely ocular disease.

Epidemiology

BCR is a rare chronic posterior uveitis. Shah and colleagues did an extensive review of English literature in 2005 and reported the following epidemiologic characteristics.⁹ Birdshot chorioretinopathy accounts for 0.6–1.5% of patients referred to tertiary centers for uveitis, or 6–7.9% of patients with posterior uveitis. There is a slight female predominance in the literature, at 54.1%. The mean reported age at the onset of disease is 53 years. It is generally not a disease of children. The oldest reported age at onset was 79 years. Patients are predominantly white; there have only been two reported exceptions. Finally, the HLA-A29 allele (which is present in about 7% of Caucasians) is strongly associated with BCR.¹⁴ The presence of this allele has been associated with a risk factor of 50–224 to develop BCR. Ninety percent or more of patients with BCR are HLA-A29-positive. Further sequencing of this allele has uncovered 11 subtypes. The HLA-A29*02 subtype is 20 times more prevalent in Caucasians than the HLA-A29*01 type, and the rest are exceedingly rare.¹⁵ HLA-A29*02 subtype is most commonly associated with BCR.

Fundus findings

It is important to recognize that symptoms can precede the onset of the classic fundus findings by several years.¹⁶ There is a range of presentations of the lesions associated with BCR. These birdshot lesions can be oval or round in shape, typically about or disc diameter in size. They appear deep to the retina (Fig. 76.1). They can be subtle, and asymmetric between eyes. The lesions can be distinct or poorly defined and can occasionally coalesce. They tend to cluster near the nerve and most commonly nasal and inferior to the disc.^17,18 There is a pattern of linear radiation away from the nerve to the periphery⁷ (Fig. 76.2). They may appear to follow choroidal blood vessels peripherally. There is no hyperpigmentation or clumping noted. The retinal pigment epithelium (RPE) and overlying retina appear intact. There has been a report of these choroidal lesions preceding symptom onset in BCR, but this is not the norm.¹⁹

Fig. 76.1 Fundus photo of the left posterior pole showing a hazy view and the distribution of deep creamy oval lesions.

Fig. 76.2 Fundus photo showing the “birdshot” pattern extending linearly from the nerve to the periphery.

Other ocular findings

The anterior segment generally has minimal inflammation without prominent keratic precipitates. Fine keratic precipitates have been described in some series.¹⁸ Due to the mild nature of anterior segment inflammation, posterior synechiae do not occur. Signs of posterior inflammation include retinal vasculitis, optic disc edema, CME, and epiretinal membrane formation. Rhegmatogenous retinal detachment has been reported.^7,20,21 It is unclear if this is related to this disease entity or to an association with uveitis. Other common findings include diffuse narrowing of the retinal arterioles, perivascular nerve fiber layer hemorrhages, and tortuosity of retinal vessels. Choroidal neovascularization (CNV) can occur.^10,22,23 It has been postulated that this occurs due to the uveitic component causing CNV rather than ischemic factors.^24,25

A consensus document on the diagnostic criteria for BCR was published in 2006.²⁶ Required characteristics include: bilateral disease, presence of at least three peripapillary lesions inferior or nasal to the optic nerve in at least one eye, low-grade anterior segment inflammation (less than or equal to 1+ cells), and low grade vitreous inflammation (less than or equal to 2+ vitreous haze). Supportive findings include: HLA-A29 positive, retinal vasculitis, and CME. Finally, exclusion criteria include: presence of significant keratic precipitates, posterior synechiae, or diagnosis of infectious, neoplastic, or inflammatory disease that may cause multifocal choroidal lesions.

Clinical course and prognosis

The disease is chronic in nature and apparently does not regress. Again, symptoms of blurred vision, color deficiency, contrast sensitivity issues, and visual field problems may be present for years prior to the onset of fundus lesions. Visual acuity may be normal despite these complaints. It remains a poorly understood disease and no consensus on management and treatment has been found. Many patients have a slow decline in vision, despite treatment.⁹A final visual acuity of 20/40 or better in the best-seeing eye was reported in 75.1% of patients. However, 9.8% of patients were legally blind at follow-up (in the review of literature by Shah and colleagues⁹). Generally, macular edema was the commonest cause of visual decline in 50.5%.⁹ Choroidal neovascular membranes developed in 5% of eyes.^22,23 These occur near the optic disc and can be bilateral. Finally, optic disc edema leading to atrophy can also affect visual prognosis.

Fluorescein angiography

The creamy white spots have variable appearance on fluorescein angiography (FA) and the disease may be more evident clinically than with this mode of imaging (Fig. 76.3). The lesions can hypofluoresce in the early phase and there can be diffuse hyperfluorescence in the late phases (Fig. 76.4). One theory suggests that the lesions are likely in the outer choroid and associated with large choroidal vessels, thus many of the lesions show neither hypofluorescence or hyperfluorescence in any phase. The diffuse hyperfluorescence seen may represent a deep inflammatory focus that accumulates fluorescein.¹⁸ Angiographic findings may include increased transit time, leakage from retinal vasculature leading to CME, optic disc hyperfluorescence (Fig. 76.5), and disc or retinal neovascularization.^8,27,28

Fig. 76.3 Color montage of right eye showing the distribution of spots.

Fig. 76.4 FA of periphery showing hyperfluorescence of lesions.

Fig. 76.5 FA showing hyperfluorescence of the optic nerve.

Indocyanine green angiography

Indocyanine green angiography (ICGA) is an important diagnostic test. In the active disease,²⁸ the birdshot lesions appear hypofluorescent during the intermediate phase of angiography and appear to be bordered by medium-to-large vessels^28–30 (Fig. 76.6). The choroidal vessels appear indistinct. Late in the ICGA, there is diffuse choroidal hyperfluorescence. As with all the white spot syndromes, theories to explain this hypofluorescence include choroidal ischemia versus blockage from inflammatory infiltrates. However, in birdshot chorioretinopathy it is agreed upon that the site of the pathology is primarily the choroid. In the acute stages, the inflammatory infiltrates may be denser and block fluorescence. In late stages of the disease, it is thought that the lesions become more atrophic and choroidal vasculature may become more visible. The lesions can become more isofluorescent in this phase of the disease or they may remain hypofluorescent.^27,28

Fig. 76.6 ICG showing hypofluorescent lesions exceeding the number seen clinically.

Optical coherence tomography

This mode of imaging has primarily been used to follow CME, which is the most common cause of vision loss in BCR³¹ (Fig. 76.7). Photoreceptor loss is not a prominent finding early on in the course.

Fig. 76.7 Optical coherence tomography showing cystoid macular edema and epiretinal membrane seen here in a patient with birdshot chorioretinitis.

Fundus autofluorescence

Giuliari and colleagues looked at fundus autofluorescence (FAF) of 18 eyes and found a spectrum of patterns.³¹ They found that hypoautofluorescent lesions on FAF did not necessarily correspond to clinical birdshot lesions. Commonly (15/18 eyes) more FAF lesions denoting RPE defects were seen than clinical lesions. Koizumi and colleagues looked at 8 patients. They found that some of these hypofluorescent lesions could be placoid in nature and involve the macula.³² In addition, a perivascular (retinal) linear hypofluorescent FAF pattern was noted by both groups of investigators.^31,32 It was postulated that this finding may suggest that the retinal vessels may play a role in inflammatory-driven damage of the RPE and serve as a conduit for inflammatory factors. The observation that the clinical choroidal lesions did not always correspond to the FAF defects suggests that the choroid and RPE may be affected independently.³² Furthermore, RPE defects in the macula could also be another cause of vision loss in these individuals. FAF may be valuable in evaluating these patients as lesions may be clinically difficult to see.

Electroretinogram

Electroretinography (ERG) is an important test for following BCR. Abnormal electroretinograms (ERGs) were reported in 88.8% of patients.⁹ There appear to be two groups of patients: those who develop abnormal ERG early in the disease process and those that develop abnormal results late in the course.³⁴ Early ERGs may demonstrate supernormal ERG amplitudes which may be related to retinal inflammation. In this stage, there may be a greater decrease in b-wave amplitude versus a-wave amplitude.^21,34 This is a negative ERG pattern, and is not pathognomonic to BCR. It suggests that the Müller and bipolar cells are more affected than the photoreceptor–retinal pigment epithelium complex. This has been seen in autoimmune retinopathy. Rod dysfunction may occur before cone dysfunction: the rod b-wave may be affected prior to photopic b-wave and flicker response in most patients. In late phases of the disease, there is a progressive decrease in a- and b-wave amplitudes. ERG findings have been noted to improve with treatment.³⁵ Some authors argue that the reversible nature of the ERG abnormalities suggest a non-ischemic etiology.¹⁵ Inflammation of the retinal vasculature could lead to inner retinal dysfunction, while choroidal inflammation could be the cause of altered outer retinal function.

Electrooculogram

Shah and colleagues found that 66.5% of eyes reported in the literature with electrooculography (EOG) findings had abnormal results.⁹ Decreased Arden ratios, representing RPE dysfunction, were reported.³⁴ These ratios further decline with disease progression.

Immunosuppressive therapy

Steroid-sparing agents have been used for long-term management of refractory cases. The three classes of immunosuppressives have been used. Cyclosporine has been used as it inhibits T lymphocytes and prevents S-Ag-induced experimental uveitis.¹⁰ Low-dose cyclosporine has proven to have positive visual effect in conjunction with steroids or alone.⁴³ Nephrotoxicity is the primary side-effect and hypertension can be a problem.⁴³ Antimetabolites such as azathioprine, mycophenolate mofetil, and methotrexate have been adjunctive or used in monotherapy. Side-effects of these drugs include bone-marrow suppression and hepatotoxicity.⁴⁴ The use of the alkylating agents cyclophosphamide and chlorambucil has also been reported. Side-effects such as bone-marrow suppression and development of malignancies must be weighed for this class. Daclizumab, a monoclonal antibody against the alpha-subunit of the IL-2 receptor of T cells, has recently been found to have value in treating BCR.^44,45 The long-term efficacy of these agents needs to be determined and weighed against potential side-effects.

Anti-VEGF therapy has been documented to be useful in treating CNV associated with inflammatory chorioretinal disorders.⁴⁶

In following our patients, we recommend: ERG yearly, Goldmann visual field examination at least yearly, close monitoring of visual acuity, optical coherence tomography (OCT) to evaluate epiretinal membranes and CME, and FA to assess disc and retinal vascular leakage.

Clinical symptoms

Patients present with rapid onset of central vision loss that may be described as blurred vision, paracentral scotoma, metamorphopsia, “spots” in the vision, and photopsias.⁵⁸ Initial vision at presentation is 20/25 or worse in about 77% of eyes and 20/40 or worse in 58%.⁵⁸ Deficits can be unilateral or bilateral (more common 75%).⁵⁹ If unilateral, the second eye can become involved in a few days or weeks. Headaches, stiff neck, and malaise may accompany these ocular symptoms. A history of an antecedent viral syndrome or recent vaccination may be obtained.

Epidemiology

Males and females are equally affected and generally this occurs in young adults. Typically this presents between age 20 and 50 with the mean age of onset being 26.^58,59 Recently, Taich and Johnson describe a syndrome resembling APMPPE in older adults (over age 50).⁶⁰ These elderly individuals characteristically may have a worse outcome, with moderate or severe vision loss due to the development of geographic atrophy and CNV. These patients resemble the entity persistent placoid maculopathy (see below) and may not have APMPPE.

Fundus findings

Gass described the presence of multiple round and confluent cream colored, flat lesions with indistinct margins scattered in the posterior pole. Lesions are not found anterior to the equator. The presence of these lesions is typically bilateral (Figs 76.8, 76.9). Fresh lesions can develop over the next few weeks, therefore lesions of differing ages can be visible. The placoid lesions tend to clear centrally initially leaving hypopigmentation. Later there is mild pigment mottling which develops into condensation of the pigment midperipherally, finally an increasing degree of coarse pigment clumping occurs (Fig. 76.10). These lesions can enlarge, but generally do not. In the original article, there was no description of serous macular detachment associated with APMPPE. However, later reports described localized serous retinal detachments over the lesions.^{52,55,61–65} This feature occasionally makes it difficult to distinguish APMPPE from Harada’s disease,^62,66,67 and some have thought that these entities may form a spectrum of disease.⁶⁸ It is more likely that there is an underlying common pathology that leads to the serous fluid.⁶⁹ Gass commented on how remarkably the choroid and retina remain relatively intact during the course of the disease. However, Spaide described choroidal infiltrations in the periphery⁷⁰ of a patient with acute APMPPE. In addition, multiple authors have described an association with retinal vasculitis^71,72 and retinal vein occlusion has also been seen.^71,72 Other findings can include subhyaloid hemorrhage⁷² and rare CNV.⁷³ Case reports have also illustrated optic nerve involvement with disc edema.^71,74

Fig. 76.8 Fundus photo of the right eye showing placoid opacification during the acute phase.

Fig. 76.9 Fundus photo of the left eye. Lesions of differing ages can be seen. Some mild pigment mottling can be seen (arrow).

Fig. 76.10 Color fundus photo of healed acute posterior multifocal placoid pigment epitheliopathy.

Other ocular findings

Although vitritis is not a significant component of APMPPE, the degree of ocular inflammation varies widely. An anterior uveitis⁷⁵ and granulomatous anterior uveitis⁷⁶ have been described. In addition, corneal stromal infiltrates⁷⁷ have been mentioned.

Clinical course and prognosis

Generally there is improvement of the visual symptoms within 2–4 weeks. APMPPE has a relatively good prognosis when compared with other placoid white spot syndromes. However Fiore and colleagues⁵⁸ reviewed the literature as well as a cohort from their own institution and showed that approximately 50% of patients have an incomplete recovery and 25% of patients have 20/40 vision or worse. Sixty percent of eyes have residual visual symptoms. Foveal involvement at presentation is an important prognosticator. Eighty-eight percent of eyes without foveal involvement proceed to full visual recovery in contrast to 53% of eyes that presented with foveal involvement. Unfortunately, approximately 70% of eyes present with foveal involvement. Photoreceptor involvement may ultimately limit visual prognosis. Progressive improvement of visual acuity usually follows the resolution of the lesions. Gass initially reported that visual recovery could continue on for months after the lesions resolved, even up to 6 months.⁴⁷ Most visual recovery occurs within 1 month.^{49,51,52,55,58,61}

Fluorescein angiography

Gass⁴⁷ described the lesions in the early phase as nonfluorescent (Fig. 76.11) and that the choroidal fluorescence is obstructed. Later in the angiogram there is a progressive, irregular staining of the lesions (Fig. 76.12). Ryan and Maumenee postulated that this could represent localization to the RPE or choriocapillaris rather than implying an infiltrate of the outer choroid.⁴⁸ Gass also stated that the underlying choroidal circulation appeared intact below the healing lesions.⁴⁷ However, later ICGA studies suggested that some choroidal hypoperfusion did exist.^78,79 This is discussed below. As the process becomes inactive, hyperfluorescence corresponding to window defects in the RPE develops and staining is no longer evident (Fig. 76.13). There is a clear visibility of the large choroidal vessels in areas of confluent atrophy. However, this does not exist in all areas, implying some RPE remains intact.⁵³ Either loss of the choriocapillaris or abnormal circulation in the confluent atrophied areas is suggested. In addition to these FA findings, there is also blocked fluorescence from pigment clumping.

Fig. 76.11 FA shows early hypofluorescence of placoid areas.

Fig. 76.12 FA in the late phases shows hyperfluorescence.

Fig. 76.13 Early FA. As the process becomes inactive, window defects develop. Pigment clumping is seen and blocks fluorescence as well.

The retinal vessels and optic nerve appeared normal^47,53 in original descriptions; however later reports described an association with retinal vasculitis, retinal vein occlusions, and disc edema.

Indocyanine green angiography

Since ICGA studies focus on the choroidal circulation, its findings in APMPPE have been important in developing theories of pathogenesis.^79–84 Acute lesions show early hypofluorescence (Fig. 76.14). In the late phases, these lesions become more defined in shape. These areas are more numerous than the placoid lesions seen clinically. As the disease heals, the hypofluorescence in the late phase becomes less defined and smaller. This lends some support to the theory of choroidal ischemia as an underlying factor in the pathogenesis of APMPPE. It is postulated that there is more hypofluorescence in the acute phase due to the additional presence of swollen outer retina or RPE cells in response to choroidal ischemia (clinically presenting as placoid lesions). As these disappear, there is less blockage and thus less hypofluorescence. Photoreceptor damage may also play a role in this as well, as elucidated by OCT studies and discussed below. Studies show that the hypofluorescence in the late phases can also completely resolve,⁷⁸ suggesting that choroidal vasculopathy, if present, may be a transient process.

Fig. 76.14 ICG shows hypofluorescent areas.

Optical coherence tomography

Many studies have described the OCT findings in APMPPE.^67,85–90 Garg and Jampol reported outer retinal abnormalities in APMPPE using time domain technology. A serous retinal detachment had reflective material within the subretinal fluid. It was postulated that this was either proteinaceous material or edematous RPE. There was rapid resolution of the serous detachment and the material disappeared.⁶⁴

Lofoco and colleagues showed that in the acute phases the OCT revealed a mild hyperreflective area above the RPE in the photoreceptor layer corresponding to the placoid lesions. Later the OCT scan revealed a nodular hyperreflective lesion in the plane of the RPE with mild underlying backscattering. They theorized that the hyperreflective areas may indicate inflammatory tissue and inflammatory cells or the presence of ischemic edema in the outer retinal layers.⁹⁰ As ultra-high resolution (UHR)-OCT developed, Scheufele and colleagues show disruption of the outer retina early in the disease (Fig. 76.15). RPE disruption occurs as the lesions heal.⁹¹ Backscatter of lesions was observed in the acute inflammatory phase in UHR as well. They found photoreceptor atrophy as the lesions began to heal and persistence of it post resolution. They suggested that the backscattering of acute lesions in the outer retina represents inflamed or damaged photoreceptor cell bodies. In addition to illustrating photoreceptor and RPE degeneration, spectral domain OCT has also shown that in some patients with fluid associated with the placoid lesions, that there may actually be accumulation of intraretinal fluid rather than an exudative retinal detachment.^64,85

Fig. 76.15 OCT showing disruption of the outer retina.

Fundus autofluorescence

FAF imaging is directed at the retinal pigment epithelial layer and is therefore especially useful in APMPPE. Several studies have described FAF findings^{67,87,89,92,93} (Fig 76.16).

Fig. 76.16 FAF shows areas of hyper- and hypoautofluorescence corresponding to clinical changes in pigmentation.

Spaide compared angiographic findings with autofluorescence. He noted that the early hypofluorescence seen on angiogram did not match up with observable changes of the RPE and he suggested this means there are choriocapillaris perfusion defects. In the late phase of the angiogram, there was staining of some of the lesions. These late-staining lesions matched the size and shape of lesions seen in fundus autofluorescence. As the lesions resolved clinically, they became pigmented centrally with a depigmented halo. On autofluorescence, centrally there was intense hyperautofluorescence, and the depigmented halo was hypoautofluorescent, implying atrophy. He postulated there was a centripetal contraction of the placoid lesions that produced this appearance. He notes the autofluorescence changes lagged behind the clinical appearance. In addition, he found that choroidal abnormalities seemed more numerous on fluorescein and indocyanine green angiography. He concluded the RPE abnormalities were a result of the choroidal abnormalities.⁹³

Clinical symptoms

Patients are often asymptomatic until the lesions affect the fovea. Blurred vision occurs at this point.^147,148 Although this is a bilateral disease, typically the patient becomes symptomatic unilaterally with foveal involvement. Small central or paracentral scotomas may be present. These are absolute in their acute stages, and become relative with healing.¹⁴⁸

Epidemiology

SC is a disease of healthy individuals. The onset is usually between the ages of 30 and 70. However, cases of SC have been reported in younger individuals.¹⁴⁸ Most reports of SC involve Caucasians; however, SC has also been reported in Asians,¹⁴⁹ African Americans,¹⁴⁸ and Hispanics.¹⁵⁰ The literature reflects a slight predilection for males.¹⁴⁶ No family history is elicited. One study done in a Finnish population showed a higher prevalence of HLA-B7 in patients with SC.¹⁵¹

Fundus findings

Two variants of SC are seen. The classic appearance, seen in approximately 80% of cases,¹⁴⁶ starts with geographic patches of gray or creamy yellow placoid lesions in the peripapillary region. It generally progresses in a centrifugal manner with finger-like or serpentine projections. In one report, a centripetal direction was described.¹⁴⁷ The outer retina appears edematous, and serous retinal detachments may be seen.^152,153 As these active lesions resolve (with or without) treatment over the next several weeks, extensive RPE and choriocapillaris atrophy occurs (Fig. 76.17). SC has recurrences and therefore it is common to see lesions of different ages. Recurrences can occur at the edge of old scars (Fig. 76.18), but not always. As the disease becomes chronic, chorioretinal atrophy, subretinal fibrosis, and RPE clumping is seen.¹⁴⁶ Since most patients become symptomatic only when the fovea becomes involved, about two-thirds present with bilateral chorioretinal scarring.¹⁵⁴

Fig. 76.17 Fundus photo showing the geographic projections in the inactive phase.

Fig. 76.18 Fundus photo showing recurrence of serpiginous choroiditis near the edge of a scar.

Macular serpiginous choroiditis^149,150 is the second variant (Figs 76.19–76.22). There is no difference in the lesions of macular serpiginous and peripapillary diseases except for location.¹⁵¹ There is generally a poorer prognosis for the macular variant as the fovea is affected at the start. Vision loss may also be related to presence of CNV.¹⁵⁰ However, Sahu and coworkers, in a more recent report, did not observe CNV in their series.¹⁵⁵ Macular SC may be misdiagnosed as macular degeneration, macular dystrophies, or toxoplasmosis.¹⁴⁶

Fig. 76.19 Fundus photo of subacute macular serpiginous choroiditis.

Fig. 76.20 Early FA shows hypofluorescence.

Fig. 76.21 ICG showing hypofluorescence centered in the macula.

Fig. 76.22 OCT in macular serpiginous choroiditis shows outer retinal disruption.

Other ocular findings

Although serpiginous choroiditis is not usually associated with a marked inflammatory response, nongranulomatous anterior uveitis^156,157 has been seen. More commonly – estimated in about a third of patients – there are fine vitreous cells.¹⁵³ The eye is white. Additional retinal findings have been described. These include CNV, which affects 13–20% of eyes,^158–163 vein occlusions,^164,165 retinal vasculitis,¹⁶⁵ usually a periphlebitis, CME,¹⁶⁶ and bilateral full-thickness macular holes.¹⁶⁷ Optic nerve abnormalities such as optic disc edema¹⁴⁷ and disc neovascularization¹⁶² can be seen at the active stage of serpiginous choroiditis.

Clinical course and prognosis

Serpiginous choroiditis is characterized by multiple recurrences at intervals of months to years. Healing of individual lesions takes place in 2¹⁵¹ to 8 weeks,¹⁴⁶ but new lesions appear later.¹⁴⁷ Generally acute lesions are seen in one eye at a time.

Visual loss is correlated with proximity to the fovea. There can be some incomplete recovery, but due to the recurrences, 75% of patients develop central visual loss in one or both eyes. Final visual acuity is less than 20/200 in up to 25% of eyes regardless of treatment.¹⁶⁸

Fluorescein angiography

In the acute SC, the lesions show hypofluorescence during the early phase of the study¹⁴⁴ (Fig. 76.23). This is likely due to a combination of blockage by swollen outer retina and RPE and nonperfusion of the choriocapillaris. The borders of the lesion may be hyperfluorescent, representing intact choriocapillaris. As the study progresses, the previous hypofluorescent lesions become variably hyperfluorescent and this intensifies over time representing staining of the acute lesions (Fig. 76.24). Retinal vascular staining may be seen near active lesions. Pigmentary changes then develop and there is often pronounced atrophy. Angiography at this stage shows mottled hyperfluorescence with increased fluorescence in the late phases representing leakage of dye from the damaged choriocapillaris at the periphery of the lesion. CNV can occur and appears as late leakage, usually at the edge of a scar.

Fig. 76.23 FA shows hypofluorescence corresponding to the new lesion (arrow).

Fig. 76.24 FA in the late phases shows that previously hypofluorescent lesions become variably hyperfluorescent.

Indocyanine green angiography

ICGA^169–172 is useful in evaluating SC. Giovannini and colleagues describe how ICGA allows a greater understanding of the disease. In particular, ICGA allowed: (1) better staging of SC, revealing choroidal alterations when there was no clinical or FA evidence; (2) better identification of the active lesions, which appear to be larger at the choroidal level in comparison with the corresponding retinal lesions; and (3) persistence of choroidal activity even when the signs of retinal activity had disappeared.¹⁷¹ The ICG pattern is characterized by hypofluorescent areas persisting from early to late phases (Fig. 76.25). The hypofluorescence has been reported to be less pronounced in later phases, which may represent delayed perfusion rather than nonperfusion.¹⁷³ The hypofluorescent lesions appear more extensive on ICGA in comparison to clinical examination and fluorescein angiography.

Fig. 76.25 ICG of this patient is characterized by persistent hypofluorescence.

Optical coherence tomography

OCT findings have been described recently.^174–178 Spectral domain OCT illustrates retinal atrophy with disruption of the photoreceptor layers in affected areas. There is thinning of the RPE and intraretinal fluid including cystic changes can be seen.¹⁷⁴ There is increased reflectance of the choroid and the deeper retinal layers. Disruption of the photoreceptor inner/outer segments is seen in active and inactive lesions¹⁷⁵ (Fig. 76.26).

Fig. 76.26 OCT shows retinal atrophy and disruption of the photoreceptor layers. Cystic fluid is seen here as well. The fovea is spared.

Fundus autofluorescence

As SC involves the RPE, FAF^175,178,179 images are helpful in demarcating this disease. New lesions appear hyperautofluorescent and old lesions are hypoautofluorescent (Fig. 76.27). Recurrences are characterized by hyperautofluorescent lesions at the borders of old hypoautofluorescent areas.¹⁷⁹ Hyperautofluorescence was detected 2–5 days after the appearance of acute lesions.¹⁷⁸ Piccolino and colleagues compared FAF to ICGA and OCT and found that the acute hyperautofluorescent areas were less extensive than the perfusion defect delineated by ICGA. When compared to OCT, there was increased reflectance of the photoreceptor layer corresponding to the area of hyperautofluorescence. As the disease progressed, the hyperautofluorescent area became hypoautofluorescent and the photoreceptor changes persisted.

Fig. 76.27 FAF image shows hypoautofluorescent lesions corresponding to retinal pigment epithelium atrophy in projections surrounding the nerve.

In developing countries, especially India, individuals with evidence of tuberculosis may have serpiginous-like lesions. (See differential diagnosis section below and Chapter 82, Mycobacterial infections). FAF appears to distinguish the lesions of SC from TB-related disease. TB-related diseases have a stippled hypoautofluorescence corresponding to lesions, which is not as homogenous as SC.¹⁷⁹

Clinical symptoms

The commonest complaint is sudden painless blurring.²²⁷ Patients also describe metamorphopsia, floaters, or can be asymptomatic.

Epidemiology

Patients were aged 17–51 in the report by Jones and colleagues.²²³ There was no gender predilection. In a series by Jyotirmay and colleagues, a male preponderance was found with a mean age of 34.²²⁷ The patients have no consistent medical disorder or viral prodrome.

Fundus findings

In most cases, patients have bilateral posterior creamy-white lesions at the level of the RPE (Fig. 76.28). The lesions (in almost all cases) tend to be smaller than those of APMPPE (approximately disc area)²²⁷ (Fig. 76.29). Lesions can be active in both eyes simultaneously. As they heal, pigmented chorioretinal atrophy develops. Lesions can persist and grow. A hallmark of this disease is the eventual presence of numerous (>50 to hundreds) lesions with involvement anterior and posterior to the equator. This is in contrast to APMPPE which is limited to the posterior pole. One study found that lesions more commonly appear in the periphery first and in the posterior pole later.²²⁷ The fovea is commonly involved.

Fig. 76.28 (A–D) Fundus photos of a patient with relentless placoid chorioretinitis documenting progression of posterior creamy white lesions at the level of the RPE over the course of one month.

Fig. 76.29 Fundus photo of the same patient 2 years later. Healed lesions show pigmented chorioretinal atrophy. The fovea is spared.

Other findings have included a mild vitritis, occasional subretinal fluid, and disc swelling.²²³ In their study of 26 eyes in 16 patients, Jyotirmay and colleagues found subretinal fibrosis, as well as epiretinal membranes as rare findings.²²⁷ Interestingly, CNV was not described in either case series.^222,227,228

Other ocular findings

Jones et al. described a patient with herpetic keratitis and corneal infiltrates in their series. Iritis with keratic precipitates as well as episcleritis can also occur.^223,228

Clinical course and prognosis

The clinical course is prolonged and relapsing. In 4 out of the original 6 patients, active lesions were seen bilaterally and concurrently. This is in contrast to serpiginous chorioretinitis in which usually only one eye is active at a time. Pigmented chorioretinal atrophy develops within weeks. Throughout the long clinical course, lesions persisted and grew. There was also the appearance of new lesions for 5–24 months despite therapy, and involved eyes developed 50 or more lesions. Some patients showed recurrences months to years after onset. These can occur after significant periods of inactivity.

Permanent vision loss is usually mild. However, central vision was affected in all untreated cases. Vision dropped as much as 6 lines in the acute stage in Jones et al.’s study.²²³ Some patients showed improvement in vision. Patients who received prolonged systemic steroids seemed to have decreased activity and improved visual outcome. Only 2 out of 6 patients had a final vision worse than 20/40 in the original series. Jyotirmay and colleagues report a favorable visual outcome in over 96% of their patients.²²⁷

Fluorescein angiography

Similar to APMPPE and SC, fluorescein studies reveal early hypofluoresence due to either blockage or choriocapillaris nonperfusion. Later phases show staining.

Indocyanine green angiography

ICGA shows hypofluorescence in the areas corresponding to the clinical lesions. This persists into the late phases. Again this shows similarity to APMPPE and SC.

Optical coherence tomography

There has been only one report. During the active stage of the disease with foveal lesions, the OCT showed subfoveal fluid.²²⁹ In addition, a pigment epithelial detachment with hyperreflectivity of the inner and outer retinal layers was present. Further study is warranted.

Fundus autofluorescence

FAF of RPC has been reported in one patient. Marked hypoautofluorescence of widespread areas of chorioretinal atrophy was seen.²³⁰

Clinical symptoms

Patients present with gradual, painless, decreased vision more commonly in one eye. Photopsias and decline in color vision can be seen.²³³

Epidemiology

In the original description there were 6 patients. Five patients were men and one was a woman. The range of ages was 50–68. All patients were Caucasian. There were no consistent systemic medical problems.²³³

Fundus findings

Patients have bilateral symmetric whitish plaque-like lesions at the level of the outer retina and RPE (Fig. 76.30). These lesions are centered in the fovea and not contiguous with the optic disc. There is a jigsaw pattern to margins of the lesions. During the course of the disease, there is very gradual fading of the whitish lesions in all patients.²³³ This can take months to years. In addition to the central lesions, one patient had small white lesions nasal and superior to the disc at the time of presentation. Another patient developed a small lesion nasal to the disc in the course of follow-up. The central lesion grew in size in one of 6 patients in Golchet’s series. RPE mottling and pigment clumping without CNV developed in 2 eyes. In all other eyes, no increase in pigmentation, atrophy, or scarring occurred until CNV developed.

Fig. 76.30 Fundus photos of the right (A) and left (B) eye of a patient with persistent placoid maculopathy. Bilateral whitish plaques are seen. They are centered on the fovea. The left eye also shows a macular hemorrhage consistent with choroidal neovascularization.

Other ocular findings

No patients had any cells in the anterior chamber or vitritis.

Fluorescein angiography

FA showed early hypofluorescence with partial filling in the late phase. No leakage or staining was seen, unless CNV was present (Figs 76.31, 76.32).

Fig. 76.31 Early FA of the right (A) and left (B) eye show hypofluorescence corresponding to the clinically seen macular lesions.

Fig. 76.32 Late FA of the right (A) and left (B) eye shows that there may be some slight hyperfluorescence corresponding to the lesion. There are some focal areas of hyperfluorescence that corresponds to choroidal neovascularization.

Indocyanine green angiography

ICGA revealed persistent hypofluorescence throughout the angiogram (Fig. 76.33). The large choroidal vessels in the affected areas were seen. In one case, the hypofluorescence showed partial resolution on follow-up.²³³

Fig. 76.33 ICGA shows persistent hypofluorescence.

Optical coherence tomography

There is a limited description of OCT findings in this rare entity. A mildly blunted fovea and normal RPE was seen in one patient.²³³ Another case report described extensive RPE damage and CNV.²³⁴

Fundus autofluorescence

Hypofluorescence correlating to RPE damage would be expected and has been seen in one case.²³⁴ This was noted in a patient with concurrent CNV. Further study is warranted.

Clinical symptoms

Patients present with decreased central vision, photopsias, floaters, metamorphopsia, paracentral or temporal scotomas, ocular discomfort, and photophobia. Photopsias often correspond to lesions in the peripapillary area and indicate activity of the disease. Visual acuity can range from 20/20 to light perception. More than half present with vision less than 20/100 in the worse eye.^240,242

Epidemiology

MFC occurs predominantly in Caucasian,²⁴³ myopic women between the second and sixth decades of life.^240,242 Most affected patients are in their 30s. In addition, they have never lived in areas that are endemic for histoplasmosis.

Fundus findings

In the acute phase of MFC, yellow round or oval lesions, ranging in number from one to scores, are seen in the outer retina and RPE. They range in size from 50 to 1000 µm. They occur in the posterior pole, peripapillary region, and midperiphery. The nasal retina often shows clustering.²⁴⁴ The lesions can also be arranged in linear scars parallel to the ora in the periphery²⁴⁵ (Fig. 76.34). Previously, this linear appearance was thought to be pathognomonic for POHS.^246,247 Active lesions can be associated with subretinal fluid. As inflammation resolves, the lesions become atrophic with a variable amount of pigment (“punched out” appearance). They can also enlarge in size. There can be bridging subretinal scars between the disciform or atrophic scars.²⁴⁸ Cantrill and Folk described 5 patients who developed sharply angulated subretinal scars as the lesions healed.²⁴⁹ They noted broad scar formation in the macula as the lesions coalesced that could be related to serous and hemorrhagic macular detachment. During active phases, exudative retinal detachment may overlie areas of activity.

Fig. 76.34 Linear scars parallel to the ora are seen in the periphery.

(Courtesy of Medical University of Innsbruck, Austria.)

In recurrent episodes, new chorioretinal lesions may develop. Optic disc edema can be seen and atrophy may occur. Optic disc neovascularization can very rarely be seen.²⁴¹ The peripapillary region may have a characteristic subretinal fibrosis²⁵⁰ that has been described as a “napkin ring” configuration (Fig. 76.35). Retinal vessels may be narrowed. Periphlebitis may develop. Cystoid macular edema occurs in 10–20% of individuals. CNV develops in 25–30% of cases and can be the presenting sign.^240,242,243

Fig. 76.35 Fundus photo showing a characteristic subretinal fibrosis (“napkin ring”).

Other ocular findings

MFC may have a mild to moderate anterior uveitis. Nongranulomatous keratic precipitates and posterior synechiae can be present. Iris abnormalities, such as neovascularization or abnormal avascular areas on fluorescein angiography, have been reported.²⁵¹ Vitritis, if present, is usually mild or moderate. Findings may be asymmetric.

Clinical course and prognosis

MFC waxes and wanes, but vision loss can occur. Most patients tend to have recurrent episodes that can involve the central or peripheral vision. These can resolve spontaneously or with the aid of immunosuppressants. Some patients retain excellent vision, but have persistent photopsias. About 25% of patients have a more chronic course that involves more inflammation, or CNV. Recurrent inflammation may cause CME, vitreous haze, and swelling around old scars (Fig. 76.36). New lesions that are not contiguous with old scars can develop. CNV is the most common cause of visual loss in MFC and can be seen with either inactive macular scars or recurrent inflammation. The long-term visual prognosis of MFC is variable. Brown and colleagues²⁴⁴ followed 41 patients (68 eyes) for a mean of 39 months. They found that 66% of eyes ended up with 20/40 vision or better. Only 21% of eyes ended up 20/200 or worse. The majority of the cases with poor vision were due to CNV and less commonly CME. Foveal atrophy and uveitic neovascular glaucoma were other causes in their series. About one-third of patients developed CNV. Thorne and colleagues²⁵² studied 66 patients (122 eyes) and found that 55% of patients presented with vision worse than 20/50 and 38% presented with vision worse than 20/200. CNV was found in 22% of patients at presentation and was the most common cause of vision loss. Presence of epiretinal membrane and CME were other causes of vision loss. Use of immunosuppressive therapy was associated with an 83% reduction in the risk of posterior pole complications, including new or recurrent CNV.

Fig. 76.36 Fundus photos of the right (A) and left (B) eyes. The right eye shows subtle acute lesions (arrow). The left eye shows chronic disease. Bridging fibrosis is seen between scars (thin arrow).

Fluorescein angiography

In the acute phase, the clinical lesions appear hypofluorescent on FA. Late in the angiogram, the lesions stain²⁴² (Figs 76.37, 76.38). CNV may be present in the peripapillary or macular areas. In the healed phase, the lesions become atrophic and show a window defect on angiography. A recent study of CNV in MFC revealed that most CNV is classic and clearly demonstrated unless blocked by subretinal blood.²⁵³ The researchers further compared this with OCT (both stratus and spectralis), and found that CNV could be missed with this mode of imaging. They recommended FA be used in cases with suspected neovascularization.

Fig. 76.37 Early FA of the right (A) and left (B) eye of a patient with new onset of symptoms in the right eye. The left eye has had poor vision for some time.

Fig. 76.38 Late FA of the right (A) and left (B) eye shows an acute hyperfluorescent lesion in the right (arrow). The left eye shows staining of the scars.

Indocyanine green angiography

ICGA shows hypofluorescent round spots that may be far more numerous than seen on clinical examination and fluorescein angiography^254–256 (Fig. 76.39).

Fig. 76.39 ICG shows numerous hypofluorescent round spots.

Optical coherence tomography

In the active phase, stratus OCT findings show an RPE irregularity corresponding to a clinical lesion. This RPE irregularity resolves with treatment.²⁵⁷ In our experience with spectral domain OCT, the lesion disrupts the photoreceptor layer with potential normalization with treatment (Fig. 76.40). Retinal thinning may occur. Vance and colleagues describe SD-OCT imaging of acute lesions that showed drusen-like material between the RPE and Bruch’s membrane as well as a localized choroidal hyperreflectivity below the material.²⁵⁸ These lesions disappear with treatment.

Fig. 76.40 OCT of the right eye shows a hyperreflective lesion in the outer retina corresponding to an acute lesion.

Fundus autofluorescence

Hyperautofluorescence was observed in the areas of fresh lesions. This resolved when immunosuppression was instituted. In the majority of patients, punctate hypoautofluorescent spots were seen on FAF corresponding to areas of chorioretinal atrophy (inactive lesions)²⁵⁹ (Fig. 76.41).

Fig. 76.41 (A,B) Fundus autofluorescence corresponding to inactive lesions that have developed chorioretinal scars.

Clinical symptoms

In a survey of 77 people with PIC conducted by Gerstenblith and colleagues,²⁶⁸ scotomas were the presenting complaint in 91% of patients, followed by blurred vision (86%), photopsias (73%), floaters (69%), metamorphopsia (65%), and decreased peripheral vision (26%). Most (85%) presented with unilateral symptoms.

Fundus findings

Multiple gray or yellow, small round lesions are seen scattered throughout the posterior pole.²⁶⁸ (Fig. 76.42). Occasionally there is a linear pattern. The lesions are at the level of the outer retina, RPE, and inner choroid and a neurosensory detachment may be present. With time, these spots evolve into atrophic chorioretinal scars. After 2–3 years, they become more distinct, pigment, and appear similar to the punched out lesions of POHS (Fig. 76.43). Some lesions disappear without sequelae. CNV commonly develops.

Fig. 76.42 Fundus photo of the posterior pole showing small round lesions that are characteristic.

Fig. 76.43 Expansion of scars in the inactive phase is common.

Other ocular findings

Generally, PIC is not associated with anterior or posterior segment inflammation.

Clinical course and prognosis

Brown and colleagues reported that 88% of 16 patients had bilateral disease, despite its most commonly being a unilateral complaint.²⁴⁴ Patients generally become asymptomatic after one month. The scars continue to become atrophic and pigmented over the next 2–3 years. These scars appear to involve the RPE and choriocapillaris. Recurrences are common. Brown and colleagues followed patients for a mean length of 51 months.²⁴⁴ They found that 77% of eyes had a final vision of 20/40 or better. Twenty-three percent had a vision of 20/50 or worse. Twenty percent had a vision of 20/200 or worse. The primary cause of this poor vision was CNV. Approximately 40% of eyes developed CNV and it generally appeared within one year of presentation. Smaller areas of CNV (<100 µm) were more likely to spontaneously resolve as compared with larger areas (>200 µm). Essex and colleagues²⁷¹ in a larger study recently reported the clinical features and outcome of 136 PIC patients (271 eyes) with a mean follow-up of 6.2 years. They found 63 fellow eyes that were normal at presentation. Of these, 56 (88%) remained unchanged. Only 3 (5%) developed PIC lesions and 4 (6%) developed CNV. In eyes with PIC lesions, 49 of 74 eyes (66%) remained unchanged. New PIC lesions developed in 9 eyes (12%) and CNV developed in 16 (22%).

Fluorescein angiography

PIC lesions can appear hyperfluorescent in the arterial phase or may appear as blocked fluorescence (Fig. 76.44A). In later phases, the lesions stain²⁶⁶ (Fig. 76.44B). More lesions are seen on FA than are clinically visible. Tiny punctuate hyperfluorescent lesions may be seen scattered in the posterior pole. In later stages of disease, as the RPE atrophies, window defects are seen. Leakage of fluorescein into the subretinal space is also possible.

Fig. 76.44 (A,B) Fluorescein angiography shows increasing fluorescence (staining) and some slight leakage of lesions is seen.

Olsen and colleagues described CNV in six patients with PIC.²⁷² They found that a fibrotic response followed the development of CVN and there was often a dumbbell-shaped pattern of subretinal fibrosis.

Indocyanine green angiography

As with other white spot diseases, the PIC lesions hypofluoresce in the early, middle, and late phases of ICGA^273,274 (Fig. 76.45). Many more lesions are seen on ICGA than are clinically visible or seen in FA.²⁷⁵ Tiffin and colleagues described choroidal vascular abnormalities.²⁷⁴ In addition to the hypofluorescent lesions that, in some cases, corresponded to clinically seen lesions, larger choroidal vessels were seen crossing these areas. Several choroidal vessels also showed hyperfluorescence of the vessel wall. They postulated focal choroidal ischemia in the areas of hypofluorescence and possibly a vasculitis in the area of hyperfluorescence of the vessel walls.

Fig. 76.45 ICG shows numerous hypofluorescent spots.

Optical coherence tomography

Stepien and Carroll²⁷⁶ described spectral domain OCT findings in a patient with PIC with recurrent activity. In addition to seeing fluid associated with CNV, outer retinal irregularity was described. A homogenous thickening was seen overlying chorioretinal lesions (Fig. 76.46). This resolved with treatment. The pattern we see with SD-OCT is similar to MFC. There is sub-RPE solid looking material that pushes up the RPE and may extend into the retina.

Fig. 76.46 OCT of an active lesion in punctate inner choroidopathy.

Clinical symptoms

Patients, in the acute phase, present with unilateral decreased vision,²⁹¹ floaters, possibly photopsias, scotomas, and metamorphopsia.

Epidemiology

Kaiser and Gragoudas²⁹¹ reviewed the literature and found that patients are predominantly young, healthy, and myopic. Ages generally ranged from 20 to 40 years old. However, there may be a bimodal curve, as Gass described 3 elderly individuals (mean age 71) with biopsy-proved PSFU.²⁹²

Fundus findings

Numerous small (100–500 µm) yellow spots are seen at the level of the choriocapillaris, RPE, and deep retina.²⁹¹ There is clustering in the posterior pole, but there can be extension to the midperiphery. The lesions can be associated with hazy yellow subretinal fluid. There is rapid development of subretinal scarring.

Other ocular findings

Anterior chamber reaction and vitritis is usually mild. Optic disc edema has been reported.²⁹³ Other signs of inflammation such as posterior synechiae, keratic precipitates, and iris atrophy have been reported.²⁹¹

Clinical course and prognosis

PSFU usually presents asymmetrically but is usually bilateral. Within a few days to weeks after development of the multifocal lesions, fluid starts to accumulate. Over the next several months, subretinal fibrosis develops. This further coalesces and forms sheets of fibrotic tissue under the retina. This is associated with marked decrease in vision. In Brown and colleagues’ study, 7 of 10 eyes of patients with PSFU had vision worse than 20/200 after 2 years.²⁴⁴ Only 2 of 10 eyes had vision of 20/40 or better. CNV and subretinal hemorrhages develop. The second eye can develop lesions within months of the first eye.²⁹¹

Fluorescein angiography

The lesions associated with PSFU are characterized by early hyperfluorescence followed by late leakage in the acute phase.^249,277,294 As fibrosis develops, there is staining in the late phases. CNV may be seen on FA but is uncommon and may be difficult to assess due to the fibrotic component.