Vogt–Koyanagi–Harada disease

Abstract

Vogt–Koyanagi–Harada (VKH) disease is usually defined as a bilateral chronic granulomatous panuveitis that may be associated with CNS, auditory and integumentary manifestations. An autoimmune reaction against melanocyte antigens in genetically predisposed patients without history of ocular trauma is presumed to cause the disease. Features of ocular and extraocular involvement vary according to disease phase, and the condition can present with disease features limited to intraocular inflammation without associated systemic manifestations. Exudative retinal detachment is the most specific feature to acute VKH disease. Ancillary tests (mainly fluorescein angiography) may help in establishing the definitive diagnosis. On the other hand, sunset glow fundus is typical to chronic VKH disease. Complications are more likely to occur in the chronic recurrent phase. The mainstay of treatment for acute VKH relies on prompt systemic corticosteroid therapy initiated as a high dose and then tapered gradually. The duration of corticosteroid therapy is recommended to be at least 6 months. Other immunosuppressants may be given as second-line or, in selected cases, as first-line therapy. Early diagnosis with rapid initiation of corticosteroids reduces recurrence and thus improves visual prognosis.

Keywords::

• choroiditis
• corticosteroids
• exudative retinal detachment
• granulomatous anterior uveitis
• panuveitis
• sunset glow fundus
• Vogt–Koyanagi–Harada

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Release date: 13 December 2012; Expiration date: 13 December 2013

Learning objectives

Upon completion of this activity, participants should be able to:

• • Analyze the pathophysiology and epidemiology of VKH disease

• • Assess the clinical course of VKH disease

• • Evaluate diagnostic tools for VKH disease

• • Distinguish first-line therapy for acute VKH disease

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Publisher, Future Science Group, London, UK

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega, MD

Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA.

Disclosure: Charles P Vega, MD, has disclosed no relevant financial relationships.

AUTHORS

Sonia Attia, MD

Department of Ophthalmology, Fattouma Bourguiba University Hospital, Monastir, Tunisia; Faculty of Medicine and University of Monastir, Tunisia

Disclosure: Sonia Attia, MD, has disclosed no relevant financial relationships.

Sana Khochtali, MD

Department of Ophthalmology, Fattouma Bourguiba University Hospital, Monastir, Tunisia; Faculty of Medicine and University of Monastir, Tunisia

Disclosure: Sana Khochtali, MD, has disclosed no relevant financial relationships.

Rim Kahloun, MD

Department of Ophthalmology, Fattouma Bourguiba University Hospital, Monastir, Tunisia; Faculty of Medicine and University of Monastir, Tunisia

Disclosure: Rim Kahloun, MD, has disclosed no relevant financial relationships.

Sonia Zaouali, MD

Department of Ophthalmology, Fattouma Bourguiba University Hospital, Monastir, Tunisia; Faculty of Medicine and University of Monastir, Tunisia

Disclosure: Sonia Zaouali, MD, has disclosed no relevant financial relationships.

Moncef Khairallah, MD

Department of Ophthalmology, Fattouma Bourguiba University Hospital, Monastir, Tunisia; Faculty of Medicine and University of Monastir, Tunisia

Disclosure: Moncef Khairallah, MD, has disclosed no relevant financial relationships.

Figure 1. Fundus photograph of the right eye of a patient with acute Vogt–Koyanagi–Harada disease shows deep, round, white-yellowish lesions, variable in size, located in the posterior pole.

Note the presence of associated exudative retinal detachment, retinal folds and optic disc hyperemia.

Figure 2. Acute Vogt–Koyanagi–Harada disease.

(A) Fundus photography shows bilateral exudative retinal detachment involving the posterior pole with associated retinal and choroidal folds. (B) Early-phase fluorescein angiogram shows areas of delayed choriocapillaris filling. (C) Mid-phase fluorescein angiogram shows multiple pinpoints that enlarge with pooling of dye in subretinal space in the late-phase (D). (E) Optical coherence tomography shows exudative retinal detachment with subretinal septa dividing the subretinal space into several compartments. (F) 10-MHz ultrasonography of the same patient shows diffuse-low to medium-reflective choroidal thickening most marked in the posterior fundus and associated exudative retinal detachment (white arrow). (G) 20-MHz ultrasonography shows better definition of sclero-choroidal limit (blue arrow) and episcleral space (black arrow) with more accurate measurement of choroidal thickening.

Figure 3. A ‘pre-exudative’ stage in a patient with early acute Vogt–Koyanagi–Harada disease.

(A) Fundus photograph of left eye shows optic disc edema and retinal and choroidal folds. There is no evident exudative retinal detachment. (B) Early-phase fluorescein angiography shows hypofluorescent striae and optic disc hyperfluorescence. (C) Optical coherence tomography of the same eye shows multifocal folds of the retinal pigment epithelium and Bruch’s membrane. (D) 10-MHz ultrasonography shows diffuse medium reflective choroidal thickening (white arrow).

Figure 4. Fundus photograph of the right eye of a patient with chronic convalescent Vogt–Koyanagi–Harada disease shows depigmentation of the choroid with typical orange-red ‘sunset glow’ appearance of the fundus.

Note the presence of nummular, round, well-limited chorioretinal depigmented scars located in the midperiphery and focal hyperpigmentation in the foveal area.

Figure 5. Anterior segment photograph of a patient with chronic convalescent phase of Vogt–Koyanagi–Harada disease shows a sunset glow ‘pupil’ appearance and posterior synechiae.

Figure 6. Fundus photograph of the left eye of a patient with chronic convalescent Vogt–Koyanagi–Harada disease shows sunset glow fundus with retinal pigment epithelium migration/clumping and subretinal fibrosis in the posterior pole.

Figure 7. Photograph of a patient with chronic convalescent phase of Vogt–Koyanagi–Harada disease.

(A) Vitiligo on the face and (B) poliosis

Figure 8. Anterior segment photograph shows anterior granulomatous uveitis with mutton-fat keratic precipitates on the corneal endothelium and posterior synechiae in a patient with chronic recurrent Vogt–Koyanagi–Harada disease.

Figure 9. Acute phase Vogt–Koyanagi–Harada disease.

(A) Early-phase indocyanine green angiograms shows a marked choriocapillaris filling delay and (B) choroidal vascular fuzziness due to perivascular leakage. (C) Intermediate-phase indocyanine green angiography shows numerous hypofluorescent dark dots. (D) Late-phase indocyanine green angiography shows optic disc hyperfluorescence.

Vogt–Koyanagi–Harada (VKH) disease commonly affects pigmented races and people of a certain genetic predisposition. It is often defined as a bilateral, chronic granulomatous panuveitis frequently associated with CNS, auditory and integumentary manifestations [1,2]. It was individualized after the former descriptions of the disease by Vogt in 1906 [3], Harada in 1926 [4] and Koyanagi in 1929 [5]. The most accepted origin of the disease is a T-cell mediated auto­immunity reaction against melanocytes [1]. The course of the disease has been divided into four phases: prodromal phase, acute uveitic phase, chronic convalescent phase and chronic recurrent phase [1,2]. In the early acute uveitic phase, ocular involvement typically manifests as ­diffuse choroiditis with exudative retinal detachment (ERD). Later on, anterior chamber inflammation develops in association with posterior uveitis, resulting in bilateral panuveitis. During the chronic phase, typical sunset glow fundus (SSGF) occurs. Associated systemic ­manifestations, when present, are helpful in establishing the definitive diagnosis of VKH disease. Fluorescein angiography (FA) provides important diagnostic clues in the acute uveitic phase. Other ancillary tests, mainly optical coherence tomography (OCT), indocyanine green angiography (ICGA) and ultrasono­graphy show typical manifestations and are helpful for the diagnosis, follow-up and monitoring of treatment.

Treatment modalities mainly include systemic corticosteroids and immunosuppressive agents. The most common complications include cataract, glaucoma, choroidal neovascularization and subretinal fibrosis. Vision loss may also result from pigmentary changes secondary to previous inflammation and ERD.

The primary aim of this article was to review current data on the clinical characteristics, ­diagnosis, management and prognosis of VKH disease.

Epidemiology

VKH disease is a globally distributed condition that has a predilection for dark-skinned individuals such as Asians, Native Americans, Hispanics, Asian Indians and those with Middle Eastern heritage. Black African people are less commonly affected, indicating that VKH disease is associated with genetics rather than with the amount of skin pigmentation [1,2]. In Saudi Arabia, VKH disease accounts for 19.4% of all uveitis cases [6]. It represents 9.7% of uveitis cases in Japan [7], 7.4% in Tunisia [8] and only approximately 1–4% in the USA [9]. The disease usually occurs in patients between the ages of 20 and 50 years, but children may also be affected [10,11]. Two to 15% of VKH patients are less than 14 years of age [8,12–14]. The disease may also affect elderly patients [12,13]. Women are often more likely to be affected than men. The reported proportions of affected women to men are 47.9% in Saudi Arabia [6], 50% in Singapore [15], 65.3% in Tunisia [8] and 71.1% in Turkey [13].

Pathogenesis & pathology

Although the precise etiology of VKH disease is unknown, several studies have suggested that a T-cell mediated autoimmune reaction against one or more antigens found on or associated with melanocytes may play a major role in the disease [1]. The antigenic target of melanocytes often seems to be tyrosinase or tyrosinase-related proteins [16–18].

There is a genetic susceptibility and the disease has been described in twins [19–21]. Data from previous studies showed a strong relationship between VKH disease and the human leukocyte antigens DR4 and Dw53 (HLA-DR4 and HLA-Dw53) in many populations [22–27]. Among the various polymorphic variations in the β-chain of the DR4 haplotype, the HLA-DRB1*0405 allele has been considered the most significant one [28,29]. Specific killer cell immunoglobulin-like receptor (KIR) genes, HLA-C alleles, CTLA-4 genetic polymorphisms, as well as a decreased expression of CD18 and AKNA transcription factors may also increase the susceptibility to VKH disease [30–33].

Low levels of advanced glycation end products, decreased 1.25-dihydroxyvitamin D3 levels, high levels of osteopontin and high leptin levels in the serum have been implicated in the development of VKH disease [34–37]. Besides these, infectious factors may possibly ­trigger VKH disease, including Epstein–Barr virus reactivation [38] and cytomegalovirus, whose antigens showed a cross-reaction with tyrosinase peptides by T cells from VKH disease patients [39]. VKH disease has been described in association with other systemic diseases, with a presumed autoimmune mechanism including diabetes mellitus, celiac disease, psoriasis, thyroid disease and rheumatoid arthritis [1,40,41].

The typical histopathological features seen in the early phase of VKH disease include granulomatous inflammation that primarily involves the choroid with milder inflammatory infiltrate involving the iris and ciliary body and subsequent ERD. The choroid is characterized by a diffuse lymphocytic infiltration interrupted at multiple sites with collections of epithelioid cells and few multinucleated giant cells, which contain pigment with no apparent choroidal necrosis. The choriocapillaris is spared from inflammatory cell infiltration [42]. The choroidal infiltration is made of T lymphocytes which exhibit the markers of helper (CD4⁺) and suppressor/cytotoxic cells, along with Class II MHC molecules. The ocular infiltrating CD4⁺ T cells from patients with VKH disease recognize human melanocyte antigens [17]. Many cytokines could be involved in the pathogenesis of the inflammatory process, predominantly IL-2 and IFN-γ [43]. Besides, IL-7, IL-21 and IL-23 stimulate CD4⁺ T cells to produce IL-17, which in turn promotes the development of uveitis in VKH disease [44–47]. In active VKH patients, increased IL-17 may also result from a decreased IL-27 expression [48]. By contrast, IL-10 and TGF-β cytokines are ­associated with the resolution of active inflammation [49].

The SSGF appearance in the convalescent phase results from the disappearance of choroidal melanocytes. In chronic VKH disease, the peripheral fundus scars correspond to focal chorioretinal atrophy with loss of retinal pigment epithelium (RPE). Focal areas of hyperpigmentation in depigmented fundi are the consequence of RPE proliferation. In fact, chronic and recurrent inflammation in the choroid, as noted in VKH disease, often stimulates retinal pigment epithelial cells to proliferate [50,51].

Clinical features

VKH disease typically consists of four consecutive phases: ­prodromal phase, acute phase, chronic convalescent phase and chronic recurrent phase [52,53].

Prodromal phase

The prodromal phase, which lasts for only a few days before ocular manifestations, is characterized by neurologic and auditory manifestations. Prodromal symptoms often start suddenly, and consist of meningeal irritation. This aseptic meningitis may manifest with meningismus, headache, tinnitus, a flu-like ­illness and nausea [52–54]. Patients complain of peri-orbital pain in more than a third of cases, and occasionally photophobia with ­tearing may follow within 1–2 days [52].

The auditory disturbances include a dysacusis that is often not perceived by the patient [55] and occasionally mild vestibular syndrome with vertigo occurs [56]. Other more specific, but rare, neuro­logic manifestations can occur, including cranial nerve palsies and cerebellar or psychiatric signs [52,57,58]. These prodromal signs may be mild, and diagnosis is only made exceptionally ­during the prodromal phase.

Acute phase of the disease

This phase usually occurs several days after the prodromal phase, may take several weeks and is characterized by the occurrence of acute uveitis [52,53]. Mostly, the patient complains of a sudden blurred vision in both eyes. The visual acuity (VA) varies between less than 20/200 and more than 20/40 [8,13,59]. At presentation, ocular involvement usually occurs simultaneously in both eyes (70–95%) [8,52]. Unilateral ocular involvement is rare and patients may not notice second eye involvement for a period of 1–10 days [52,60,61].

Bilateral posterior uveitis is the most typical feature of VKH disease. It is characterized by a diffuse granulomatous choroiditis, manifesting with ERD, vitritis and optic disc swelling. Occasionally anterior uveitis is associated with posterior segment inflammation, so bilateral panuveitis is the clinical presentation [52,53].

ERD, present in over 85% of cases, is typically multifocal, may be either localized to the posterior pole and/or the mid­periphery (Figure 1) [62–64]. Early on, these are discrete with shallow elevations of the neural retina, resulting in occult ERD [58]. In advanced cases, these can become bullous or be extended to the far periphery, and occasionally form an extensive ERD, simulating rhegmatogenous retinal detachment. It is important to emphasize that bilateral ERD with vitreous inflammation is highly suggestive of VKH disease. In an ethnically and geographically diverse group of patients with nontraumatic bilateral acute uveitis, ERD was found to be a highly specific symptom of this entity [65]. Optic disc hyperemia (Figure 2) or significant optic disc swelling is common, occurring in up to 87% of patients [66,67]. It may be difficult to distinguish from bilateral optic neuritis [68]. Moreover, it has been reported that the occurrence of disc swelling in VKH was significantly correlated with age and disc morphology, rather than the severity of inflammation. Some VKH patients with disc swelling develop visual field defects from optic disc involvement [69].

Fundus examination may show deep, round, white-yellowish lesions, which are variable in size and localized in the posterior pole or sometimes in the midperiphery (Figure 1) [52,53]. Retinal and/or choroidal folds in the posterior pole may precede or accompany ERD (Figures 2A & 3) [70]. Patients may present early, with optic disc edema and retinal and/or choroidal folds (Figure 3). This clinical presentation may be considered to be a ‘pre-exudative’ stage, and should suggest a diagnosis of VKH disease [71].

Several ancillary tests including FA, ICGA, ocular ultrasono­graphy and OCT are recommended to characterize and analyze posterior segment changes associated with acute VKH disease (see section ‘ancillary tests’).

Anterior uveitis occurs later in the course of acute VKH disease. It is often nongranulomatous with usually mild-to-moderate flare. Tonic pupils are also common in the presenting phase. As a result of the inflammation extension to the anterior segment, anterior uveitis is lacking in patients who are seen early. However, severe anterior uveitis, occasionally granulomatous, frequently accompanies the posterior segment involvement in patients seen late in the disease’s course.

Anterior chamber shallowing secondary to ciliary body edema and cilio-choroidal detachment, which is easily revealed by biomicro­scopic ultrasound, is not uncommon [72–74]. Anterior chamber shallowing results from swelling of the ciliary body that may displace the lens-iris diaphragm forward [43,73,74], leading to elevated intraocular pressure and episodes of angle closure that may reveal VKH disease [75]. Therefore, VKH disease should be considered in the differential diagnosis of unilateral or bilateral acute angle closure glaucoma in darkly pigmented young patients [52].

Chronic convalescent phase

The convalescent phase occurs several weeks after the acute phase and may take up to four months. It is characterized by a variable ­development of choroid depigmentation and teguments changes [52,53].

Ocular depigmentation

Depigmentation of the choroid resulting from loss of melanocytes produces the typical orange-red ‘sunset glow’ appearance of the fundus (Figure 4). It may be suspected when examining the red reflex (Figure 5) [52,64]. Associated optic disc pallor is commonly observed (Figure 4). SSGF, occurring 2–3 months after the acute uveitic phase, is useful for retrospective diagnosis of VKH disease. This sign was found to be very specific to this entity in the setting of chronic nontraumatic bilateral uveitis [65]. In addition to SSGF, fundus examination shows nummular chorio­retinal depigmented, round, well-limited lesions in the midperiphery (Figure 4) [52,53]. These depigmented lesions have been considered to be Dalén–Fuchs nodules, but there is no histopathologic evidence to support such a consideration. Other fundus lesions may occur including focal or linear RPE migration/clumping [52,53] or subretinal fibrosis (Figure 6). Pseudotumoral RPE proliferation has also been reported in one case of VKH disease at the chronic convalescent phase [76].

The limbus can also become depigmented (Suguira sign). This perilimbal vitiligo may occur 1 month following the acute phase of the disease [77]. It is found more frequently in the Japanese population (85%) than in other populations [8,52,53]. Moreover, peripheral iris depigmentation may also be observed in patients with VKH disease during the chronic convalescent phase [78].

Integumentary manifestations

Poliosis of the eyebrows or eyelashes, alopecia and vitiligo occur during the chronic convalescent phase as a characteristic, but not specific, finding of VKH disease (Figure 7) [52]. The vitiligo often has a symmetric distribution over the head, eyelids, trunk and especially over the sacrum. Cutaneous manifestations are more frequent in Japanese than in the Hispanic populations [52]. On the other hand, early initiation of corticosteroids in the acute uveitic phase might prevent or delay the onset of integumentary signs [8,15,53]. Besides, reversal of poliosis, vitiligo and alopecia in patients with VKH has been reported; it has been suggested that this could reflect the restoration of the normal immune homeostasis [79].

Chronic recurrent phase

This phase may interrupt the convalescent phase with anterior uveitis, which can be recurrent, chronic or both. In fact, some patients do not develop inflammation recurrences [80], whereas other patients present with chronic intraocular inflammation relapsing after several weeks to many months [37,56,57]. The rate of ocular complications has been reported to occur proportionally to the number of recurrences of inflammation and to the duration of the disease [9,52,81]. Delay in initiation of treatment with corticosteroids in the acute stage of the disease leads to recurrence [52,53]. In addition, most vision-threatening complications occur in the chronic recurrent phase of VKH disease [52,53,80].

The chronic recurrent phase is characterized by typically acute episodes of anterior uveitis that are often resistant to systemic steroid therapy [52,58]. Recurrent granulomatous anterior uveitis, with cells and flare in the anterior chamber and mutton-fat keratic precipitates on the corneal endothelium, is the typical feature of this recurrent chronic phase (Figure 8). Iris nodules, developing on a background of atrophic iris stroma, can also be seen in the chronic recurrent phase of the disease [52,82]. Focal pigment atrophy of the iris may also take place and gonioscopy may reveal pigment pearls in the angle [52]. Bilateral peripheral transilluminating iris depigmentation and atrophy with sometimes severe ocular hypotony may occur [78]. Recurrent posterior uveitis with vitritis, ERD and optic disc swelling would be distinctly uncommon during this phase [52,53,58]. However, choroidal inflammation relapses may occur, particularly during the first 6 months, usually caused by rapid corticosteroid tapering [83,84]. Furthermore, recurrence of choroidal involvement with a concomitant recurrent anterior uveitis may be subclinical and revealed only by ICGA [85].

Ancillary tests

Fluorescein angiography

FA in the acute phase characteristically reveals patchy choroidal filling due to delayed choroidal perfusion in early frames and numerous punctate hyperfluorescent dots at the level of RPE. These dots gradually enlarge and stain surrounding subretinal and sub-RPE fluid, and the dye clearly outlines the full extent of neurosensory detachments and stains it in a fairly homogenous fashion (Figure 2B–2D). Optic disc hyperfluorescence and leakage are usually seen with late pooling of fluorescein and late choroidal hyperfluorescence [52,86–88].

Choroidal folds, radiating from the optic disc to the periphery (some even passing through the macula horizontally or vertically) and similar to the large retinal vessels in number and shape, show alternate hyperfluorescent and hypofluorescent bands on FA (Figure 3B) [70].

When the exudative lesions of VKH disease have resolved, FA generally demonstrates areas of window defects and blockage by areas of damaged RPE. In some eyes, choroidal neovascularization and subretinal fibrosis can occur as late complications.

Indocyanine green angiography

ICGA findings in the acute phase includes: patchy filling delay of choriocapillaries in the very early angiographic phase and filling delay of the large choroidal arteries, perivascular leakage of individual vessels in the early phase, fewer choroidal vessels in the posterior as well as peripheral fundus. Other findings include diffuse leaking fuzzy vessels in the intermediate phase, diffuse choroidal hyperfluorescence in the late phase and hypofluorescent dark dots that appear at the intermediate phase and either become isofluorescent or remain hypofluorescent in the late phase of the angiogram. These dark dots probably represent partial or full-thickness granuloma (Figure 9) [89–92]. Other findings may occur, including reduction in the number of large choroidal vessels, disc hyperfluorescence indicating severe papillitis, hyperfluorescent pinpoints in the area of ERD and choroidal folds showing hypofluorescence or normal fluorescence at the early stage and turning hyperfluorescent at the late stage [70]. The quantitative evaluation of choroidal dye filling velocity in patients with VKH disease showed that the acute phase choroidal model’s time-constant values in VKH disease were significantly longer, when compared with controls, suggesting choroidal circulation disturbance. Furthermore, the choroidal model’s time-constant values shortened significantly during the recovery phase, suggesting ­improvement of choroidal circulation [93].

In the chronic phase, hypofluorescent lesions corresponding to chorioretinal atrophy, as well as signs similar to those observed at the early phase but less severe, may be observed [71,88].

ICGA helps to determine disease activity in the chronic or convalescent stages of VKH disease when signs of active choroidal inflammation begin to show, including dark spots, choroidal vessel fuzziness and diffuse late hyperfluorescence. These signs show significant decrease after systemic corticosteroid therapy, confirming their inflammatory character [29,66,94,95]. Thus, the ICGA is the test of choice for monitoring by watching for early relapses related to a too-fast tapering of corticosteroids [71].

Optical coherence tomography

In the acute phase, OCT reveals ERD with subretinal septa that divide the subretinal space into several compartments (Figure 2E). These septa are composed of an inflammatory product such as fibrin that develops on the RPE and then disappears completely after steroid therapy. The presence of dot reflex in the subretinal space argues in favor of the presence of a subretinal fluid rich in proteins. The fibrin membrane is pushed upward by further leakage from the RPE, leading to its partial detachment from the RPE and, as a consequence, development of septa. Subretinal septa caused multilobular dye pooling in ERD associated with acute VKH disease [87,96–100].

OCT also shows multifocal folds of RPE and the Bruch’s membrane (BM) with undulations and bumps on the RPE surface related to choroidal folds (Figure 3C), however, the number of folds was larger than on FA and ICGA [70,101]. Gupta et al., using spectral-domain OCT, suggested that these folds are not true and only represent the undulations of the RPE that are seen clinically as choroidal striations [101]. Spectral domain OCT and high-penetration OCT showed markedly thickened choroid, possibly related not only to inflammatory infiltration but also to increased exudation that decreased quickly with corticosteroid treatment [101,102]. Choroidal thickness decreased over time after treatment and increased markedly again in eyes with recurrent disease [102]. Spectral-domain OCT also shows a loss of focal hyper-reflectivity in the inner choroid in both acute and convalescent stages [103]. When comparing VKH patients in acute and convalescent stages with control subjects, enhanced depth imaging spectral-domain OCT shows significant loss of focal hyper-reflectivity in the inner choroid in patients with VKH disease [104].

In the chronic phase, spectral-domain OCT shows thickening of RPE/BM layer corresponding to pigmented scars or areas of pigmentation, thinning of RPE/BM layer ± loss of outer retinal layers corresponding to atrophic scars, mild irregularities on top of RPE/BM layer or involvement of the outer retina, as well as marked atrophy of neural retina, RPE and choroid [105].

In summary, OCT is useful in evaluating acute VKH disease and monitoring response to treatment. It may also be useful in the evaluation of chronic VKH disease.

Ultrasonography

B-scan ultrasonography is a noninvasive, useful diagnostic tool and can be of a great help in the diagnosis of acute VKH disease, especially when visualization of the fundus is poor or when the clinical presentation is atypical [106].

Conventional ultrasonography (10-MHz) in patients with acute VKH, shows low to medium reflective diffuse choroidal thickening, which is mostly marked in the peripapillary area and extending to the equatorial region (Figure 2F & 3D), confirming the pathology findings in this entity [106]. Measurement of choroidal thickening is an important parameter for the diagnosis of acute VKH disease (Figure 3D), especially in patients with ‘pre-exudative’ stage. Moreover, ultrasonography confirms the presence of ERD and may reveal a prominent optic disc, related to optic disc swelling and fine vitreous opacities [8,106]. High-resolution ultrasonography (20-MHz) is helpful in detecting subclinical ERD, allows a more reproducible and accurate choroidal thickening measurement and better defined episcleral space than with the 10-MHz probe (Figure 2G) [8]. Furthermore, ultrasonography may be useful in monitoring response to treatment [8].

Other

Ultrasound biomicroscopy

Biomicroscopic ultrasound is a useful tool in the evaluation of VKH disease activity in the anterior chamber and in monitoring its clinical course. Cross-sectional imaging at the active phase may show a shallow anterior chamber, ciliochoroidal detachment, a thickened and swollen ciliary body and low internal reflectivity of the ciliary stroma with ciliary processes being unclear, suprachoroidal effusion, circumferential supraciliary fluid, anterior rotation and anterior bowing of the iris [72,107,108]. These symptoms disappear after corticosteroid therapy. In the remission phase, the internal reflection becomes homogenous and the ciliary process becomes clearly delineated [74].

Laser flare meter

Data about changes of aqueous flare and cells in eyes with VKH disease are scarce. Only one study shows that the breakdown of the blood–aqueous barrier associated with recurrent VKH ­disease was more severe and longstanding than that observed in acute VKH disease [109].

Autofluorescence

In acute VKH disease, fundus autofluorescence (FAF) shows hyperautofluorescence in the macula coupled with hypoautofluorescence in the areas of ERD [110,111]. The abnormal FAF returns to normal at 6 months after corticosteroid treatment.

In patients with chronic VKH disease, FAF shows different patterns, such as decreased autofluorescence signal corresponding with peripapillary atrophy, multiple nummular and/or irregular atrophic and pigmented scars, increased autofluorescence signal corresponding to patches, strands or irregular areas of pigmentation, cystoid macular edema and normal retina and autofluorescence signal similar to background of normal areas corresponding to SSGF, disciform scar and sectoral chorioretinal atrophy [105].

Electroretinography

Full-field electroretinography analysis demonstrated diffusely diminished amplitudes in both scotopic and photopic phases in patients in the chronic phase. The alterations of full-field electro­retinography may explain why patients with good VA have progressive loss of visual field [112].

Multifocal electroretinography (mfERG) in patients with VKH disease shows a severe decrease in VA and diffuse mfERG abnormalities before treatment, reflecting severe damage of macular function that may result from RPE changes after ERD. 12 months after treatment, mfERG shows delayed and limited recovery of macular function. mfERG may be a useful tool for therapy monitoring in patients with VKH disease [113].

Lumbar puncture

Lumbar puncture is a helpful additional test in cases of atypical VKH disease. This test is rarely used in clinical practice when history, clinical and angiographic findings argue in favor of a diagnosis [114].

Lumbar puncture shows cerebrospinal fluid (CSF) pleocytosis (lymphocytosis) in 80% of patients within 1 week and in 97% of patients within 3 weeks of the onset of inflammation. The CSF pleocytosis is transient and resolves within 8 weeks, even in patients who develop recurrences of intraocular inflammation [52].

A recent study showed that profiles of surface markers (CD3+, CD4+ and CD4+ CD45RO+) were identical for CSF and aqueous humor. However, these markers appear to be different from those for peripheral blood cells. These findings suggest that CSF may reproduce the active local immunological reactions in sites affected by VKH disease (mainly uvea and meninges) [115].

The frequency of CSF pleocytosis and the number of cells in the CSF may influence the development of SSGF in VKH disease [64].

MRI

MRI is rarely performed. It shows choroidal thickening to be highly raised after gadolinium injection [52,116,117]. However, MRI is useful in cases of neurologic involvement by showing hypersignal lesions, particularly in the periventricular area of the cerebellum [118].

Audiogram

A deafness of perception in the acute frequencies (low and average in the initial stages) more or less symmetrical with an average loss of 30 dB is the main audiogram finding in the acute phase of disease. This is generally reversible within 2–3 months [55]. This dysacusis is often not perceived by the patient, so an audiogram is essential in case of any suspicion of VKH disease [52]. Deafness may be reversed following early corticosteroid therapy [119].

Diagnostic criteria

The diagnosis of VKH disease is primarily based on clinical features. Several criteria have been proposed to clarify the diagnostic approach, including the American Uveitis Society (AUS) criteria [9] and the Sugiura’s Criteria [120]. Owing to the close similarities in clinical findings between VKH disease and sympathetic ophthalmia (SO), exclusion of a history of penetrating ocular trauma or ocular surgery preceding the onset of uveitis is the constant criteria [121].

The AUS criteria fail to clearly separate the acute phase from the chronic phase and seem to be inadequate in establishing diagnosis in the initial phase of the disease [9]. Chronology of clinical manifestations is not considered. FA and ultrasonographic data, which are substantial criteria for diagnosis, are not taken into account by the AUS criteria. Sugiura’s criteria are seldom used outside Japan because, according to Japanese literature, CSF analysis is mandatory [120]. In 2001, the International Nomenclature Committee proposed the Revised Diagnostic Criteria [122], which classifies the disease into three categories: complete, incomplete and probable VKH (Box 1). The VKH Committee’s new criteria allow the use of both FA and ultrasonography for the detection of early manifestations of the disease in equivocal cases. These new revised diagnostic criteria make up the deficiencies of AUS criteria. However, classification of the disease into three categories (complete, incomplete and probable) might have a low clinical relevance and may well lead to confusion, as the chronologic type of clinical manifestations is not visibly considered. In fact, complete categorisation of VKH disease reveals a delayed diagnosis and not a definite diagnosis. Furthermore, ICGA data [87,94] and those of OCT [87,96] were not considered by these revised criteria [122].

A suggested practical diagnostic approach to VKH disease, taking into account the chronological phase of the disease may be helpful (Box 2). Early diagnosis of acute, purely ocular VKH disease is crucial for prompt initiation of corticosteroid treatment to ensure a good visual outcome and to prevent chronic/recurrent inflammation and complications. It can be easily carried out based on findings from ocular clinical examination and ancillary tests.

ERD occurring in patients with no history of ocular trauma and presenting with intraocular inflammation is highly specific to acute VKH [65,66]. On the other hand, ancillary tests including FA, ICGA, ultraso­nography and OCT should be systematically used in patients with acute VKH disease in order to confirm the diagnosis and to evaluate the severity of retinal, choroidal and optic disc involvement (Box 2). These tests are especially helpful in the ‘pre-exudative’ stage and in atypical presentations. Although bilateral ocular involvement is necessary for diagnosis, the uncommon possibility of unilateral manifestations is recognized [60,61]. Therefore, ICGA is recommended when investigating patients with apparent unilateral VKH disease who may have subclinical involvement in the opposite eye [94]. Moreover, the occurrence of neurological and auditory signs preceding uveitis support the diagnosis of acute VKH disease. However, these signs may be missing – but the definite diagnosis can be established in most cases on the basis of characteristics of ocular involvement without the use of the invasive lumbar puncture.

The term chronic VKH may encompass different clinical situations: persistent ‘acute/subacute’ ocular inflammation (nontreated or undertreated patients), resolved acute ocular inflammation (convalescent phase), chronic/recurrent inflammation and chronic complicated VKH disease. SSGF is a highly specific sign of the chronic/recurrent phase [65]. Clinical history suggesting the occurrence of early manifestations and the presence of integumentary signs occurring later are valuable in the diagnosis of this phase. However, diagnosis of chronic VKH disease should be made even in the absence of dermatological signs [63,65].

Differential diagnosis

The differential diagnosis of VKH disease includes several diseases causing posterior uveitis and panuveitis [52]. SO is the first entity to be excluded. A history of previous penetrating ocular trauma or surgery is the rule in this disorder [53,80]. SO is characterized by bilateral panuveitis with ERD and optic disc swelling, similar to that of VKH disease. The chronic phase of this disorder has a clinical and pathologic picture similar to VKH disease. Nevertheless, anterior granulomatous inflammation is more common in SO, while chorioretinal lesions and cutaneous manifestations are rather more scarce [53,80]. Ocular ultrasonography shows a slightly more reflective diffuse choroidal thickening than in VKH disease.

Posterior scleritis (PS) is a more important differential diagnosis of VKH disease, given the clinical similarities of these two entities [123]. PS affects mostly women and is often unilateral. However, bilateral involvement is possible, especially in those patients with systemic rheumatologic disorders. Severe eye pain with photophobia and associated anterior scleritis with redness support the diagnosis of PS. Fundus signs include a circumscribed mass, ERD, retinal and/or choroidal folds, optic disc swelling and annular choroidal detachment [124]. FA findings of PS can be very similar to those observed in acute VKH disease. Ultrasonography is very useful for the diagnosis of PS, showing a reflective thickening of sclera, retrobulbar edema and T sign [106]. In VKH disease, there is often a secondary sclera thickness by contiguous inflammation. In the same way, the choroid may be thickened by adjacent sclera inflammation in cases of PS. However, and unlike VKH disease, choroidal thickening in PS may be localized or diffuse, and is highly reflective on ultrasonography.

Idiopathic uveal effusion syndrome, a rare disease, may manifest with clinical and angiographic signs that may mimic VKH disease. FA shows numerous fluorescent spots in the subretinal space. Mottled fluorescence resulting from subsequent pigment migration in the chronic phase of the uveal effusion syndrome may appear similar to findings in VKH disease. However, the onset of ERD in the uveal effusion syndrome is likely to be subacute and chronically progressive [125]. Besides, the disease involves both eyes, although not simultaneously with minimal intraocular inflammation. Also, the trend to follow a relapsing–remitting course helps differentiate it from VKH disease [125]. Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) may also be confused with VKH disease [52]. Patients with APMPPE develop sudden loss of central vision after viral prodrome. Multiple white-yellowish placoid lesions at the level of the RPE, mainly localized at posterior pole, are seen. Vitreous inflammation is minimal or absent and both eyes are eventually involved. On FA, lesions show early hypofluorescence and late staining. Similar FA findings may be seen in VKH disease in the early stages. However, punctuate hyperfluorescent dots and staining of subretinal fluid, common in VKH disease, are lacking in APMPPE. Furthermore, APMPPE may manifest with ERD and choroidal thickening on OCT and on ultrasonography. However, OCT demonstrates outer retinal hyper-reflectivity and subretinal fluid in the acute phase that disappears a few days later. RPE lesions are hypoautofluorescent acutely but become hyperautofluorescent later in the disease course [126]. Recently, spectral domain OCT has shown that morphologic retinal findings in APMPPE occur in the outer retina; mainly in the photoreceptors and RPE [127].

Primary intraocular B-cell lymphoma presents as chronic uveitis associated with neurological findings and may also mimic VKH disease. Fundus examination shows typically multifocal yellow-white to orange-cream colored sub-RPE infiltrates involving the posterior pole associated with vitritis [128,129]. However, and contrasting with VKH disease, vision is more likely to be preserved. The choroid is usually thickened and may be associated with ERD. FA shows blockage of choroidal fluorescence with late staining at the site of infiltrative lesions [128]. However, in VKH disease FA shows punctate hyperfluorescent dots with increased staining surrounding subretinal fluid and choroid. Patients with primary intraocular large B-cell lymphoma tend to be older than patients with VKH disease [128] and tend to have relatively good vision. The CNS may be involved in over 50% of cases of B-cell lymphoma. Lumbar puncture and MRI are helpful and the diagnosis is usually confirmed by vitreous and/or chorioretinal biopsy [129].

Sarcoidosis must also be considered in the differential diagnosis of VKH disease, since granulomatous anterior inflammation is the most clinical feature of this disease [130]. ERD are unusual in sarcoidosis. By contrast, patients with VKH disease often present with a more striking posterior uveitis in association with ERD. Also, the classic findings of sarcoid retinal vasculitis with venous sheathing and ‘candlewax drippings’ are not seen in VKH disease. Angiotensin converting enzyme and lysozyme, biopsy of suspected granulomata and pulmonary evaluation are crucial in the diagnosis of sarcoidosis [130].

Cat scratch disease may manifest with clinical and angiographic features suggestive of VKH disease. Small focal areas of choroiditis associated with ERD and diffuse choroidal thickening have been described [131,132]. However, macular star, one of the classic features of cat scratch disease, is absent in VKH disease. In addition, unilateral involvement and serology are helpful to differentiate this infectious disease from acute VKH.

Differential diagnosis of VKH disease includes other ocular disorders, such as acute choroidal ischemia, idiopathic central serous chorioretinopathy, syphilis, tuberculosis, Lyme disease, acute leukemia, choroidal metastasis, multiple evanescent white dot syndrome, uveal melanocytic proliferation associated with systemic carcinoma and benign reactive lymphoid hyperplasia of the uveal tract [52,53,58,80,83].

Treatment

The standard treatment of VKH disease is based on prompt, aggressive, systemic cortico­steroids for at least 6 months. In this setting, the inflammation is typically very responsive to corticosteroids in the acute phase. Recurrences become increasingly steroid resistant and immunosuppressive agents are needed [52,133]. The associated anterior uveitis should also be managed with corticosteroid drops, as well as cycloplegics to reduce cilliary spasm and mydriatics to prevent posterior synechiae [52].

Prompt high-dose corticosteroid therapy is the mainstay of treatment of acute VKH, administered either orally (1–1.5 mg/kg per day) or through a short course of intravenous delivery, followed by oral corticosteroids [52,134]. The initial high dose is maintained for 2–4 weeks, and then followed by a slow tapering of the drug. Medium-dose systemic corticosteroid therapy is not sufficient to control ocular inflammation, as shown by the persistence of hypofluorescent dark dots revealed by ICGA after 4 months. Furthermore, patients receiving medium-dose corticosteroids are more likely to develop SSGF. Doses as high as 0.75 mg/kg per day are necessary during the first 4 months of treatment [135]. Moreover, peripapillary atrophy in patients with VKH disease is more common and larger when the corticosteroids are given late and in low doses [136]. Initial oral administration or intravenous corticosteroids followed by oral administration seem to have the same visual outcome [137]. However, the rapidity of the resolution of ERD and inflammation may be greater with the pulses.

Treatment with systemic corticosteroids should be gradually tapered and maintained for at least 6 months in order to prevent future recurrences and to optimize visual outcome [52,138]. Patients who received oral corticosteroid treatment for less than 6 months were significantly more likely to have recurrences (58.8%) as compared with corticosteroid treatment with a duration of 6 months or more (11.1%) [138]. Those patients treated with short-duration corticosteroids are also more likely to have one eye with VA of 20/200 or worse [138].

In addition, intravitreal triamcinolone acetonide injections may be an adjuvant tool in the treatment of VKH disease, especially in patients who are unable to tolerate systemic medications [139–141]. Besides, subtenon injections may be considered in association with systemic corticosteroids and immunosuppressive agents to better control the inflammation [142]. Fluocinolone acetonide intravitreal implants have also been used in the management of VKH disease, but they have been mixed with an inability to fully taper off of systemic corticosteroids [143].

Several conventional immunosuppressive agents including cyclosporine, methotrexate, azathioprin, mycophenolate mofetil and (rarely) cyclophosphamide, have been used in the management of VKH disease. Among these immunosuppressive drugs, cyclosporine has been the most widely used in the care of these patients [52].

Conventional immunomosuppressive therapy has been used, especially in cases of resistance to high-dose corticosteroids, intolerance or major side effects of steroids, as well as the chronic recurrent phase of the disease [133].

However, some authors defend the use of the immunosuppressive treatment as a first-line therapy for VKH disease; to reduce the duration of corticosteroid therapy, to better control the disease and to reduce recurrences and complications. First-line immunosuppressive therapy seems to be associated with a better visual outcome when compared with steroids as monotherapy or with delayed addition of immunosuppressive agents [144]. Prospective studies are warranted to validate the role of first-line immunosuppressive therapy in acute VKH disease [133]. However, immunosuppressive treatment may be considered as a first-line treatment in cases of severe disease at presentation, and delay in diagnosis and initiation of corticosteroid treatment [15].

Both azathioprine (1–2.5 mg/kg/day) and cyclosporine A (3–5 mg/kg/day) have proven clinical efficacy [145], but cyclosporine A seems to be a better glucocorticoid-sparing agent than azathioprine [146].

A combination of oral prednisolone, azathioprine and cyclosporine has been administered in recalcitrant cases of VKH disease with rapid remission. The synergistic effect of this triple-agent ­immunosuppression may help prevent recurrences [147].

Furthermore, infusions of infliximab have recently been used in several cases of refractory VKH disease with good results [148,149]. Even if the use of IFN-α-2a in refractory cases of VKH have been reported with some success, the description of several cases of VKH disease developed in patients treated with interferon and ribavirin therapy for hepatitis C make it a last option therapy [150,151].

Rituximab, an antibody targeting CD20, has been reported in one case of refractory VKH disease with a good outcome [152]. Another therapeutic tool, a single intravitreal injection of bevacizumab injection associated with systemic corticosteroids, has been used in one case to accelerate the resolution of a persistent ERD in a patient with VKH disease [153].

High-dose steroids are also the mainstay treatment for acute VKH in children [12,154–156]. Several immunosuppressive treatments may be administered, usually in cases of inadequate response to steroids, of steroid-related side-effects or for the chronic recurrent phase of the disease. Cyclosporine, azathioprine, metho­trexate and sometimes cyclophosphamide have been used [154,155]. However, methotrexate is preferred by some in cases of pediatric VKH disease and seems to be effective in this setting with minimal side-effects [154,156]. Infliximab may help in the management of refractory cases in children [157]. Long-term corticosteroids, as well as immunosuppressive treatments, should be monitored closely in collaboration with a pediatrician.

There are few isolated reports related to VKH disease in pregnancy. High-dose corticosteroids have been used to treat VKH disease successfully during the second and third trimester of pregnancy, usually with no complications in deliveries [158–161]. A case of fetal death was described after initiating corticosteroids in a pregnant patient with VKH disease but the relationship between this event and steroid therapy was not established [162].

Patients being treated for VKH disease are monitored based on clinical examinations as well as ancillary tests, especially OCT and ICGA. OCT may be helpful in the monitoring of the ERD resolution [163].

An ICGA is recommended approximately 4 months after the initiation of treatment. It may reveal subclinical signs of choroidal inflammation, particularly hypofluorescent dark dots or fuzzy choroidal vessels in the absence of any clinical inflammation. These angiographic findings require the reversal of the therapy tapering as well as the extension of its duration [94].

Possible side-effects of corticosteroids and other ­immunosuppressive agents should be looked for properly during follow-up.

Complications & prognosis

Complications

One half of all eyes with VKH disease develop at least one complication. The most common complications include cataract, glaucoma, choroidal neovascularization and subretinal fibrosis [52,81]. Less common complications have been reported, including cystoid macular edema [164,165], pseudotumoral RPE proliferation [76], band-shaped keratopathy [166] and visual field defects from optic disc involvement [69,167].

Cataracts occur in approximately 40% of eyes with VKH disease. Risk factors for the development of cataracts are long-standing recurrent anterior segment inflammation and systemic corticosteroid therapy for 6 months or more. Surgery should be performed after at least 3 months of no intraocular inflammation. Systemic corticosteroids (0.5–1 mg/kg/day) should be given for 1 [52,81,134,168] or even 2 weeks [169] before surgery and then tapered progressively after surgery. Phacoemulsification has advantages over manual extra-capsular cataract extraction in the setting of uveitis, as it leads to less breakdown of the blood–aqueous barrier. Synechiolysis with or without iris-stretching maneuvers or iris hooks may be required. Polymethylmethacrylate, heparin surface-modified and acrylic foldable intraocular lenses can be safely used in eyes with VKH disease [170]. Recurrent inflammation is a significant risk factor for poor visual outcome in patients with VKH disease after cataract surgery [171].

Chronic glaucoma occurs in 6–45% of eyes [167,172]. The mechanisms of chronic glaucoma in VKH disease include inflammation of the trabecular meshwork, inflammatory cells blocking the trabecular meshwork, peripheral anterior synechiae, pupillary block because of extensive posterior synechiae and ­corticosteroid-induced ocular hypertension [52,81,173].

Choroidal neovascularization develops in 2.5–14.7% of eyes [9,174]. The choroidal new vessels were found to develop through areas of BM that were damaged by inflammation [81,175]. Eyes with choroidal neovascularization have a history of significantly greater degrees of anterior chamber and vitreous inflammation, greater incidence of fundus pigmentary disturbances and a greater frequency of chronic recurrent phase inflammation. The location of choroidal neovascularization may be peripapillary or macular [52,176]. Recently, intravitreal injections of anti-VEGF have been used in the treatment of choroidal neovascularization in patients with VKH disease and seem to improve the visual outcome [177,178]. Other treatment modalities that have been used include photodynamic therapy with verteporfin [179,180], laser photocoagulation [177] and surgical excision [181]. Subretinal fibrosis has been reported to occur in 7–40% of eyes [81,165,182], leading to poor visual prognosis.

Prognosis

The visual outcome in patients with VKH disease has improved considerably with the use of high-dose corticosteroids and advances in the management of complications. However, more than 50% of patients presenting in the acute phase of the disease still develop the chronic course. Furthermore, 50% of eyes with VKH disease develop at least one complication [15,81].

The proportion of eyes with a VA of 20/40 or better varies from a half to two-thirds [52,81]. The development of ocular complications is significantly associated with a worse final VA [183]. A final VA of 20/200 or worse may be explained by the presence of extensive pigmentary changes and disruption in the fundus secondary to previous inflammation and ERD without any other associated complications [81,167]. Some VKH disease patients may still have concomitant visual field loss and subclinical retinal dysfunction caused by chorioretinal atrophy and pigmentary changes, despite having a final VA of 20/20 [81,141,184,185]. Besides, peripapillary atrophy is associated with visual dysfunction ­compared with eyes without peripapillary atrophy [184].

Many factors may influence the visual outcome. Patients promptly treated with high doses of steroids in the acute phase (2 weeks or less from onset of symptoms) have a better visual prognosis than patients treated 1 month or more from onset of symptoms [15]. Almost 70% of patients who receive a rapid treatment in the acute phase keep a VA of 20/20, compared with a third of patients treated in the chronic phase after developing cutaneous signs [183].

A longer duration of disease and higher number of recurrent episodes of inflammation are associated with a higher risk of complications and worse visual prognosis. A longer duration of disease and increased number of recurrences expose the eye to the harmful effects of active inflammation as well as treatments, especially corticosteroids [81].

Better VA at presentation is associated with a better final VA [81]. Worse VA at presentation may reflect severe disease at presentation with higher risk of complications. It has been reported that VA at 1 month after starting treatment is a better prognostic factor, as it is a good indicator for response to treatment [141].

Age at onset of the disease has been differently linked to final VA. Poor prognosis has been associated with older age at onset of VKH by some authors [81,141] and with younger age at onset by others [12,67]. Early pinpoint peripapillary hyperfluorescence on pretreatment FA was found to be an indicator for good prognosis [88]. In fact, this sign was more likely to be associated with eyes imaged early in the course of the disease than eyes imaged later [88].

Conclusion

VKH disease is a visually disabling bilateral uveitis affecting patients with no history of ocular trauma which may be associated with extraocular signs depending on the phase of the disease. The diagnosis approach should consider the chronology of clinical phases and clinicians should be aware of ERD and SSGF as highly specific signs of acute and chronic VKH, respectively. FA, OCT, ICGA and ultrasonography are useful adjuncts in the diagnosis of VKH disease and its management. The mainstay for acute VKH disease treatment is prompt high-dose systemic cortico­steroids. A duration of 6 months or more of corticosteroid therapy significantly reduces recurrences and complications. Other immuno­suppressive agents may be used to control intraocular inflammation and prevent complications. With adequate treatment, one half to two-thirds of affected eyes retain a VA of 20/40 or better. Early diagnosis and prompt proper treatment are the most important factors for a good visual outcome.

Expert commentary

VKH disease is a bilateral granulomatous panuveitis associated with neurological, auditory and integumentary manifestations that are more common in darkly pigmented races of certain genetic predispositions.

A T cell-mediated autoimmune reaction against one or more antigens found on or associated with melanocytes may be involved in the pathogenesis of the disease. Although the associated systemic manifestations are helpful in establishing the definitive diagnosis, they may be present to a varying extent and VKH disease can present with findings limited to intraocular inflammation.

Early recognition of acute VKH disease in its isolated ocular presentation is of utmost importance for prompt initiation of corticosteroid treatment. ERD occurring in patients with no history of ocular trauma and presenting with intraocular inflammation was found to be highly specific to acute VKH. Common features associated with ERD include optic disc swelling and choroidal or retinal folds. FA in acute VKH characteristically reveals patchy choroidal filling in early phase, numerous pinpoint leaks at the level of RPE, with subretinal and sub-RPE fluid dying and optic disc hyperfluorescence and leakage in late phase. ICGA, OCT and ultrasonography may also be very useful in the diagnosis and monitoring of acute VKH disease. Lumbar puncture is unnecessary for diagnosis.

Clinical history suggesting the occurrence of early manifestations and the presence of integumentary signs occurring later are valuable in the diagnosis of chronic VKH disease. SSGF, which was found to be highly specific to chronic VKH disease, allows a definitive diagnosis to be established even in isolated ocular involvement.

Prompt high-dose systemic corticosteroid therapy with gradual tapering over a period of at least 6 months is the mainstay of treatment for acute VKH disease. This is essential to prevent chronicity, recurrences, complications and subsequent visual loss.

Immunosuppressive agents should be given in cases of resistance or intolerance to corticosteroids and in cases of chronic recurrent VKH disease. They may also be recommended as first-line treatments in combination with corticosteroids in cases of severe disease at presentation or following a delay in diagnosis of the acute form.

Five-year view

Further studies on VKH disease in different ethnic populations are required to better clarify similarities and distinct differences in patient’s genetic characteristics and epidemiological profile, clinical manifestations and course of the disease.

New and emerging imaging modalities, including ICGA, high-speed ultrahigh-resolution OCT, autofluorescence and other ancillary tests may allow a more precise evaluation and monitoring of retinal and choroidal involvement in VKH disease.

Multicenter prospective randomized trials are needed to determine the optimal corticosteroid therapy duration and dosage, as well as the role of immunosuppressive drugs as first-line therapy in acute VKH disease and to determine the effects of biologic agents in the treatment of the condition.

Better knowledge of immune mechanisms, as well as the role of specific cytokines, in the pathogenesis of VKH disease may offer new targets for treatment of this disease.

Box 1. Revised criteria for diagnosis of Vogt–Koyanagi–Harada disease.

• • No history of penetrating ocular trauma or surgery preceding the initial onset of uveitis

• • No clinical or laboratory evidence suggestive of other ocular disease entities

• • Bilateral ocular involvement (a or b must be met, depending on the stage of disease when the patient is examined)

  • – Early manifestations of disease

    • – Evidence of diffuse choroiditis (with or without anterior uveitis, vitreous inflammatory reaction or optic disc hyperemia) which may manifest as (a) focal areas of subretinal fluid or (b) bullous exudative retinal detachments

    • – Late manifestations of disease

      • 1. History suggestive of prior presence of early findings noted in 3a and either (2) or (3) below, or multiple signs from (3).

      • 2. Ocular depigmentation: either (a) sunset glow fundus or (b) Sugiura’s sign

      • 3. Other ocular signs including (a) nummular chorioretinal depigmented scars, or (b) retinal pigment epithelium clumping and/or migration or (c) recurrent or chronic anterior uveitis

• • Neurological/auditory findings (may resolve by time of evaluation)

  • – Meningismus (malaise, fever, headache, nausea, abdominal pain, stiffness of the neck and back, or a combination of these factors); note that headache alone is not sufficient to meet the definition of meningismus

  • – Tinnitus

  • – Cerebrospinal fluid pleocytosis

• • Integumentary finding (not preceding onset of central nervous system or ocular disease)

  • • Alopecia, or

  • • Poliosis, or

  • • Vitiligo

Complete VKH: criteria 1–5 must be present.

Incomplete VKH: criteria 1–3 and either 4 or 5 must be present.

Probable VKH (isolated ocular disease): criteria 1–3 must be present.

VKH: Vogt–Koyanagi–Harada.

Data taken from [122].

Box 2. Practical diagnostic approach to Vogt–Koyanagi–Harada disease.

• • Acute VKH (duration of ocular inflammation ≤3 months)

  • – Factors suggestive of acute VKH disease

    • – Patient characteristics (darkly pigmented, age between 30 and 40 years, female)

    • – No history of penetrating ocular trauma

    • – A history of prodromal illness (neurological/auditory disturbances); inconstant

    • – Bilateral ocular involvement (symmetric or asymmetric); posterior uveitis or panuveitis + ERD + other fundus findings^†

  • – Early acute phase (<15 days)

    • – No or rare cells in anterior chamber

    • – Mild or moderate vitritis

    • – ERD

  • – Subacute phase (15 days–3 months)

    • – Anterior uveitis (non-grabulomatous or granulomatous)

    • – Moderate or severe vitritis

    • – ERD

• • Chronic/Recurrent VKH (duration of ocular inflammation >3 months)

  • – A history suggestive of prior presence of early ocular findings (may be lacking)

  • – Sunset glow ‘pupil’

  • – Sunset glow fundus, other fundus changes^‡

  • – Granulomatous anterior uveitis

^†Other fundus findings during acute phase: retinal/choroidal folds, yellow deep chorioretinal lesions, optic disc edema or hyperemia FA, OCT, ICGA and ultrasonographic findings.

^‡Other fundus findings during chronic/recurrent phase: round atrophic lesions, subretinal fibrosis, pigmentary changes, peripapillary RPE proliferation, peripheral iris depigmentation ICGA findings.

ERD: Exudative retinal detachment; FA: Fluorescein angiography; ICGA: Indocyanine green angiography; OCT: Optical coherence tomography; RPE: Retinal pigment epithelium; VKH: Vogt–Koyanagi–Harada.

Key issues

• • Vogt–Koyanagi–Harada (VKH) disease a bilateral granulomatous panuveitis with no history of previous ocular trauma that may be associated with CNS, auditory and integumentary manifestations. It has a worldwide distribution, but usually affects young (20–50 years), dark-skinned individuals with a genetic predisposition.

• • The most typical feature of acute VKH disease is diffuse granulomatous choroiditis manifesting with exudative retinal detachment, vitritis and optic disc swelling. Fluorescein angiography and other ancillary tests including indocyanine green angiography, optical coherence tomography and ultrasonography are helpful in confirming the diagnosis, evaluating the severity of posterior segment involvement and monitoring response to treatment.

• • Chronic VKH disease is typically characterized by episodes of granulomatous anterior uveitis associated with a typical sunset glow fundus that are often resistant to systemic steroid therapy.

• • Early diagnosis of acute, purely ocular VKH disease is crucial for prompt initiation of corticosteroid treatment to prevent chronic/recurrent inflammation and complications and to ensure a good visual outcome.

• • The mainstay of the treatment for acute VKH disease is prompt systemic high-dose corticosteroid therapy, which should be tapered gradually and maintained for 6 months or more.

• • Immunomosuppressive therapy is required in case of resistance to high-dose corticosteroids, intolerance or major side effects of steroids, as well as in the chronic recurrent phase of the disease. Immunosuppressants may also be considered as first-line therapy in association with corticosteroids in patients with severe disease or delayed diagnosis at presentation.

• • A higher number of recurrent episodes of inflammation increase the risk for complications, which mainly include cataract, glaucoma, choroidal neovascular membranes and subretinal fibrosis.

• • Poor visual prognosis is related to delay of diagnosis, short duration of systemic corticosteroids, number of recurrences of ocular inflammation and occurrence of complications.

• • The early initiation of systemic corticosteroids, 2 weeks or less from the onset of symptoms, is associated with a better visual outcome.

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Vogt–Koyanagi–Harada disease

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1. You are seeing a 35-year-old woman with multiple symptoms consistent with possible Vogt–Koyanagi–Harada (VKH) disease. As you evaluate this patient, what should you consider regarding the epidemiology and pathogenesis of VKH disease?

• □ A It usually occurs among adults over the age of 50 years

• □ B There is no predilection for VKH disease based on sex

• □ C The primary pathophysiology is a T-cell-mediated reaction against melanocytes

• □ D As of this time, there are no known genetic factors which influence the development of VKH disease

2. What should you consider regarding clinical features of VKH disease?

• □ A The prodromal phase is characterized by ocular symptoms only

• □ B Vision loss is gradual across all disease phases

• □ C The “sunset glow” appearance of the fundus is present from the prodromal phase through the acute phase

• □ D The rate of ocular complications is related to the recurrence of inflammation and duration of disease

3. What should you expect regarding ancillary findings if this patient has VKH disease?

• □ A Choroidal folds with alternate hyperfluorescent and hypofluorescent bands on fluorescein angiography (FA)

• □ B There are no studies to help determine disease activity during the convalescent phase of illness

• □ C Ultrasonography has no role in the diagnosis of VKH disease

• □ D The diagnosis of VKH disease still requires a lumbar puncture

4. The patient is diagnosed with VKH. Which of the following treatments should be considered first-line therapy for her?

• □ A Intravitreal corticosteroids

• □ B Systemic corticosteroids

• □ C Methotrexate

• □ D Cyclosporine