Introduction

Uveitis includes a complex group of inflammatory eye diseases. Anatomically, there are four main groups of uveitis: anterior uveitis, which affects anterior segment of the eye; intermediate uveitis, which primarily involves the vitreous and peripheral retina; posterior uveitis, which involves the posterior segment of the globe (retina and choroid); and, finally, panuveitis, when more than one of the previous is involved. Posterior segment involvement may be secondary to infectious or noninfectious diseases. Noninfectious posterior uveitis comprise several entities, with different clinical history, prognosis, and treatment. However, all of them require imaging techniques to better visualize and monitor the disease. Some of these techniques, such as spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), and fluorescein angiography (FA), provide valuable information of vitreoretinal interface, retina, and retinal pigment epithelium (RPE). However, standard SD-OCT, FAF, and FA are not well suited for visualizing structures and pathologies involving choroid. Indocyanine-green angiography (ICGA) and newer and more advanced techniques, such as enhanced-depth imaging OCT (EDI-OCT), swept source OCT (SS-OCT), and OCT angiography (OCT-A), are capable of visualizing and monitoring choroid changes in posterior uveitis, becoming very valuable devices in the diagnosis and follow-up of these diseases. For example, clinically significant changes in subfoveal choroidal thickness (SFCT) have been reported in several posterior uveitis. Thus, SFCT data must turn indispensable in the management of posterior uveitis, considering that SFCT measurements obtained by EDI-OCT are reproducible in uveitis patients.

Macular edema (ME) is the most frequent structural complication of uveitis and the most common cause of visual impairment in patients with uveitis. OCT, mainly SD-OCT, is nowadays a fundamental tool in the analysis of uveitic ME (UME), with different morphologic patterns that may represent different stages in ME progression ( Fig. 13.1 ). Besides, the initial characteristics of UME could predict the clinical prognosis after treatment. Other studies have reported that subretinal fluid in UME is a marker for more responsive ME, with greater rates of edema resolution and visual acuity (VA) improvement after treatment ( Fig. 13.2 ).

Uveitic macular edema by SD-OCT.

Uveitic macular edema with subretinal fluid by SD-OCT.

Sarcoidosis

Sarcoidosis is an inflammatory multisystemic disease of unknown etiology that causes multifocal noncaseating granulomas in multiple organs (lung, lymph node, skin, liver, and eye).

Definitive diagnosis is made by biopsy. A sarcoid lesion is characteristically a well-defined granuloma with epithelioid cells arranged concentrically around multinucleate giant cells, without caseating necrosis.

Sarcoid is a truly protean disease, and it could be acute or chronic, widespread or localized, and self-limited or prolonged. The disease is slightly more frequent in women and with a higher rate of presenting uveitis. The peak incidence for men is about 40 years and for women is about 55 years.

A very high proportion (30%–60%) of patients with sarcoidosis develop ocular involvement, mainly bilateral granulomatous uveitis. Anyway, the uveitis of sarcoidosis can be of any type involving or not the posterior segment, being considered one of the great imitators. Clinical signs suggestive of ocular sarcoidosis have been recently summarized ( Table 13.1 ).

It is possible to observe an acute nongranulomatous anterior uveitis, specially in patients with classic Löfgren syndrome or more commonly chronic granulomatous anterior uveitis ( Fig. 13.3 ).

Granulomatous anterior uveitis with extensive posterior synechiae in a patient with sarcoidosis.

Intermediate uveitis with vitreous snowballs, pars plana exudates, and peripheral retinal vascular sheathing are also common manifestations ( Fig. 13.4 ).

Active segmental retinal phlebitis with snow balls in sarcoidosis.

Sarcoidosis predominantly affects retinal venules, which may be engorged and tortuous, surrounded by fluffy white plasma exudates. Some patients have a tendency to develop arterial ectasia, sometimes with macroaneurism formation, especially in older women with multifocal choroiditis.

Multifocal choroiditis is the hallmark of posterior segment sarcoidosis. Lesions usually are at different stages of evolution and are located at the inferior and nasal choroid ( Fig. 13.5 ).

Multifocal choroiditis involving the inferior and nasal area. Chroidal lesions are at different evolutive stages.

Larger solitary lesions are unusual, but if present may raise the retina and even be associated with subretinal fluid. In such cases, differential diagnosis should include choroidal tuberculoma ( Fig. 13.6A and B ).

A solitary choroidal granuloma in the paramacular area in a woman with sarcoidosis, raising overlying retina in color and FA. (A) Retinal funduscopy of a solitary choroidal granuloma in the paramacular area in a woman with sarcoidosis, raising overlying retina. (B) Same lesion seen with FA.

Chorioretinal involvement in sarcoidosis have been evaluated for many decades by clinical examination of the ocular fundus, because FA allowed better definition for retinal involvement and subtle choroidal changes might not been properly explored. Characteristics ICGA features in sarcoidosis include usually choroidal filling delay with punctate hypofluorescence. However, the technique is invasive, involves systemic administration of the dye, and there are overlapping of retinal and choroidal images which could be a confounding factor.

EDI-OCT reliably images the full thickness of the choroid and is capable of visualizing the extent and characteristics of a choroidal granuloma. EDI-OCT is a noninvasive and rapid technology that also allows one to monitor the evolution of the granuloma and the response to the treatment.

We have evaluated by means of EDI-OCT (Spectralis, Heidelberg) the characteristics of a presumed choroidal granuloma that appears as a localized hyporreflective choroidal thickening (620 μm) and an area of sensorial retinal detachment (RD) with subretinal fluid at the level of the choroidal granuloma The adjacent choroid has increased thickness and normal reflectivity. Three weeks after systemic corticosteroids, VA improved and the choroidal thickness (CT) decreased to 325 μm. After 3 months of corticosteroid therapy, CT was 247 μm ( Fig. 13.7A and B ).

Comparison between EDI-OCT before (A) and after (B) 3 weeks of systemic corticosteroids. The choroidal granulomatous lesions (a focal granulomatous reaction in the choroid) appear as a hyporeflective thickening of the choroid with subretinal fluid. The thickness of the granuloma decreased from 620 to 325 μm after treatment.

On the other hand, it has been published that during the quiescent phase, patients with ocular sarcoidosis had thinner choroids than normal subjects. SFCT showed a positive correlation with VA and negative correlation with global disease duration and also with the duration of active disease, being a good indicator of inflammatory activity in sarcoidosis.

Sympathetic Ophthalmia

Sympathetic ophthalmia (SO) is a rare bilateral granulomatous uveitis that occurs after trauma or surgery to one eye (the exciting eye), which will lead to an inflammatory reaction in both eyes, being the nontrauma eye, the sympathizing eye. In the past, trauma was the main cause of SO. However, recent studies suggest that ocular surgery, particularly vitreoretinal surgery, is the major risk for this disorder. The occurrence of SO is estimated to be 0.4–1.4% of all uveitis and 0.1–0.3% of all traumatized eyes.

Posterior segment classical manifestations of OS include exudative RD, vasculitis, disc edema, and multiple white-yellow lesions, occasionally confluent, mainly in periphery, which are the clinical sign of Dalen-Fuchs nodules (DFN), which is a histopathological finding (collections of epithelioid cells below the RPE). OCT is a very valuable tool in the diagnosis and monitoring of retinal involvement in SO. A recent report describes the SD-OCT images of the characteristic DFN, revealed as hyperreflective lesions at the level of RPE, associated with disruption of the inner segment/outer segment (IS/OS) junction. After treatment and clinical improvement, DFN on SD-OCT went away, but abnormalities of the IS/OS and disruptions of the RPE persisted. SD-OCT image of RPE rip in a case of SO has also been reported. Other study analyzed the changes seen in the photoreceptor layer of the retina during the acute phase of SO. The outer retinal segment showed serous RD (SRD) and disruption of the IS/OS junctions in all the eyes, whereas elongation of photoreceptors occurred in 66% of eyes. Those abnormalities improved over the time after systemic corticosteroid therapy, with resolution of SRD, normal photoreceptor layer, and restoration of IS/OS junction in all the eyes 4 weeks later. A similar and more recent report describes the EDI-OCT findings in an acute phase of SO. Presenting EDI-OCT showed a diffuse increase of CT in both the sympathizing and exciting eyes. One month after corticosteroid therapy, a marked decrease in the CT was observed, especially in the sympathizing eye. At 15-month follow-up visit, in the convalescent phase, the CT had decreased but was thicker than normal. The authors conclude that EDI-OCT can be an accurate way of assessing disease activity and monitoring response to treatment in SO.

FA is of limited diagnostic value in SO. In the acute stage reflects an exudative process, with multiple areas of subretinal leakage as hyperfluorescent and hypofluorescent spots. DFN may block early (become hypofluorescent) and then stain late (i.e., hyperfluorescence). In chronic cases, FA shows irregular choroidal filling and patchy choroidal staining, whereas DFN appear as window defects.

FAF in a case of SO has been reported, showing hyperfluorescence in areas of SRD that will turn, after treatment and SRD resolution, into speckled areas of hyper- and hypoautofluorescence resembling leopard spots.

As the disease predominantly involves the choroid, ICGA is more useful in the diagnosis of SO. Two patterns of fluorescence have been observed in SO. First, a pattern of hypofluorescence dark dots in the intermediate phase that become isofluorescent at the late phase, representing active lesions. Second, a hypofluorescent pattern that persisted until the late phase, depicting a cicatricial or atrophic lesion. A more recent report found similar ICGA findings, well correlated to fundus ophthalmoscopy and FA, making the ICGA the most useful image technique in helping to monitor the response of SO to treatment. A histopathological correlation with ICGA findings showed that hypoflourescent areas did not correspond to nonperfusion areas, but they were secondary to inflammatory cell blockage and choriocapillaris edema.

In conclusion, EDI-OCT and ICGA seem to be nowadays, the best image techniques for diagnosis and monitor the SO, so both studies must be performed in the baseline and in the follow-up of SO patients.

Vogt–Koyanagi–Harada Syndrome

Vogt–Koyanagi–Harada (VKH) disease is a bilateral diffuse granulomatous panuveitis that involves the eyes, auditory system, meninges, and skin. VKH disease is more frequent in pigmented skin people. Women seem to be affected more frequently than men. VKH disease affects mainly those in their third to four decades of life. The prevalence of VKH disease depends on the studied population, being more common in Japan (10.1% of all uveitis referrals ) than in the United States (1–4%), India (2%), or Brazil (2.5%).

In 2001, the consensus of the “First International Workshop on Vogt–Koyanagi–Harada Disease” was published, in which the nomenclature and diagnostic criteria for VHK disease were established ( Table 13.2 ). VKH disease may have different clinical manifestations, which are presented in four stages, that include prodromal, acute uveitic, chronic, and chronic recurrent stages.

Acute Uveitic Stage

This stage is characterized by bilateral posterior uveitis, presenting with multiple SRD, hyperemia, and edema of the optic nerve head and thickening of the posterior choroid with elevation of the peripapillary retinochoroidal layer. Patients tend to have predominantly SRD-type VKH or optic disc (OD) swelling-type VKH in this acute stage. SRD-type seems to be more frequent ( Fig. 13.8 ). Patients with OD-swelling type are more likely to be female, have older onset, and develop chronic disease than patients with SRD-type VKH disease ( Fig. 13.9 ). Inner retinal thickness (RT) was enlarged during the acute phase, measured by SD-OCT, with larger thickness than in convalescent phase. SRD height at the baseline is related to the VA and appears to reflect the degree of choroidal inflammation. Besides, examination of the SRD height by SD-OCT is useful to monitor the resolution of the disease and to tapering the steroid dosage ( Fig. 13.10 ). Several authors have studied by mean of OCT the multifocal SRD in eyes with acute VKH disease. Using TD-OCT, Maruyama and Kishi reported two different patterns, which they interpreted as “true SRD” and “intraretinal fluid accumulation in the outer retina.” Yamaguchi et al. identified subretinal membranous septa situated on the RPE, as well as membranous or a dot reflex in the subretinal space. These different interpretations can be secondary to the inadequate visualization of intraretinal structures due to limited resolution of TD-OCT. Better visualization and interpretation was achieved with enhanced SD-OCT in patients with SRD. The subretinal space was divided into two compartments by a membranous structure, which may involve the fovea, where it is attached to the RPE, serving as the posterior wall of the foveal compartment (cystoid spaces). The membranous structure had uniform thickness, with a thick, highly reflective line in the part that was attached to the RPE. The IS/OS also appeared less distinct and thicker near the membranous structure. There were also undulations of RPE, with a highly reflective thin, straight line just beneath the undulations. These undulations represent choroidal folds (CFs). CFs may be present in more than half of eyes with VKH disease and occurred more frequently in older patients with OD-swelling type VKH. Besides, eyes with CFs had a thicker choroid at baseline, which became thinner after treatment compared with those without CFs. CFs, quantified by RPE undulation index, seem to be useful in assessing VKH disease severity, due to the good correlation to CT, RT, and VA. New EDI-OCT provides valuable information regarding CT but can also be used to evaluate the retina, as it has shown good agreement with SD-OCT in the measurement of RT and volume in eyes of patients with chorioretinal disease. Several reports have shown that CT measured by EDI-OCT may serve as a marker for degree of choroidal inflammation in acute VKH disease. Bilateral diffuse choroidal thickening is reported in patients with acute VKH disease ( Fig. 13.11 ). Usually at disease onset, the choroid is so thick that it is not possible to measure the CT precisely because the limit between the choroid and sclera is not visible. The CT decreases with the corticosteroid therapy, so CT can also be used to monitor the response to corticosteroid treatment, as it increases again upon recurrence. However, it is unclear whether or not treatment decisions should be based on CT alone at this time.

Fundus appearance of SRD in VKH patient.

Fundus appearance of OD swelling in VKH patient.

SD-OCT image of SRD in VKH disease.

EDI-OCT image of acute phase in VKH disease.

One study found a correlation of CT at 1 week after initiating treatment with the development of peripapillary atrophy (PPA), suggesting that higher severity of initial choroidal inflammation creates more tissue destruction in the active phase and greater PPA in the convalescent phase. The authors then speculate that CT in the early stage of acute VKH disease may predict visual outcome. Increase of CT in acute phase is secondary to diffuse choroiditis and marked stromal edema due to granulomatous inflammatory reaction. One report found a significant decrease of focal hyperreflectivity dots in the inner choroid (that may represent cross-sectional views of peripapillary arterioles and venules) of eyes with acute and convalescent VKH compared to controls. The authors conclude that this feature could represent permanent structural changes in the small choroidal vessels secondary to VKH uveitis.

In this acute phase, there is also a secondary alteration of the RPE barrier. Early-phase FA shows multiple pinpoints hyperfluorescence dots of dye leakage at the level of the RPE, and late-phase FA shows multifocal serous detachments with multilobular dye pooling ( Fig. 13.12 ). The absence of early pinpoint peripapillary hyperfluorescence on FA is a poor prognostic factor as it suggests that the disease is no longer in the hyperacute phase, and hence, it may possibly need to be treated more aggressively and with a more prolonged course of immunosuppressive therapy.

FA image of acute phase in VKH disease.

ICGA is very useful in patients with VKH disease, because the ocular inflammation selectively involves the choroid. ICGA signs of eyes with acute VKH disease include (1) leakage from choroidal vessels and diffuse choroidal hyperfluorescence, indicating that hyperpermeability of choroidal vessels may also contribute to the choroidal thickening; (2) hypofluorescent dark dots (HDD), which may correspond to choroidal foci (granuloma); (3) fuzzy vascular pattern of large stromal vessel indicates diffuse inflammatory vasculopathy; and (4) disc hyperfluorescence. Dark dots reappearance at the end of the tapering period is frequent without any significant clinical or FA signs, indicating subclinical recurrence.

FAF shows two different patterns depending on the evolution time of the acute phase before receiving treatment. Patients who received immediate intensive treatment showed mild hyperfluorescence, while the other patients had scattered and wide-spread hyperautofluorescence. Besides, abnormal FAF may persist for 6 months after the onset even after complete resolution of SRD in patients who received late effective steroid treatment.

Laser speckle flowgraphy (LSFG) is a noninvasive technique that determines choroidal blood flow velocity and seems to be useful as an index for evaluating the choroiditis activity, showing correlation with SFCT measured with EDI-OCT. In a similar way, choroidal dye filling velocity (CDFV), which is abnormal in the acute phase, improves after corticosteroid treatment. Thus, LSFG and CDFV may be useful for VKH diagnosis and verification of treatment effectiveness.

In this acute stage may appear some yellow-white well-circumscribed lesions in the periphery of the retina, equivalent to DFN seen in SO. On ICGA, the DFN showed two different kinds of fluorescence.

Chronic (Convalescent) Stage

In this stage, some patients develop choroidal depigmentation, which occurs few months after the uveitic stage. The choroid appears bright-orange in color and the optic nerve appears pale, which is called “sunset glow fundus (SGF),” seen commonly in oriental patients. In eyes with SGF, RT is preserved but the CT is thinner compared to controls, with a clear negative correlation between the CT measurements and duration of disease. Besides, the area of the PPA is significantly correlated with the disease duration and inversely correlated with the CT. “Blond fundus,” frequently seen in less pigmented rages, has a more mottled appearance as well as a significant loss of pigment, with multiple foci of depigmentation or hyperpigmentation. Oval or round areas of chorioretinal atrophy are also seen in the mid-periphery. In eyes at convalescent stage with no SGF, the CT and PPA are not significantly different from those of the controls.

SFG is secondary to subclinical choroiditis that can be detected by ICGA, so some authors had proposed ICGA-guided management of VKH disease. The main sign used to monitor therapy are the HDD, which usually indicate active choroiditis. However, HDD can also be the result of choroid scarring, so is important to identify the true nature of the lesion for a good disease management. In the other hand, some authors have reported similar outcomes with regards to VA and disease activity between ICGA-guided management and clinical signs based management of VKH disease ( Fig. 13.13 ).

FA and ICGA showing no activity in a chronic stage of a well-treated VKH disease.

FAF facilitated the delineation of areas with actual RPE loss (RPE atrophy) from areas with mere choroidal depigmentation (SGF). There are several patterns of abnormal FAF signal in VKH chronic stage ( Table 13.3 ). The combined approach of FAF and SD-OCT is a valuable tool to determine the status of the RPE and outer retina in this stage. Besides, peripheral FAF abnormalities may be detected using wide-field FAF imaging ( Fig. 13.14 ).

Table 13.3

FAF in Convalescent Phase. SD-OCT, Clinical, FA, and ICGA Correlation

AF	Clinical Sign	FAF Shape	SD-OCT	FA	ICGA
Decreased	Peripapillary atrophy	Peripapillary halo	RPE/BM thinning + ORL loss	HyperF	HypoF
		Nummular and/or irregular foci	RPE/BM thinning + variable ORL involvement	HyperF	HypoF
	Atrophic scars	Circular	RPE/BM thickening + variable ORL involvement	HypoF	HypoF
Increased	Pigmented patches, irregular tracks, bands (SF)	Variable	RPE/BM thickening + intact ORL	HypoF
		Granular	Loss of IS/OS or RPE/BM irregularities
Similar	SGF	Variable	Normal ORL
	Atrophy	Sectorial	Retina and choroid atrophy	HypoF	HypoF
	Discifom scar	Variable	RPE atrophy + intact ORL	Mixed	Mixed

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