Vogt-Koyanagi-Harada disease: review of a rare autoimmune disease targeting antigens of melanocytes

Vogt-Koyanagi-Harada disease (VKHD), initially described as an uveomeningoencephalitic syndrome, is a systemic granulomatous autoimmune disease that targets melanocyte-rich tissues, such as the eye, inner ear, meninges, skin and hair [1].

In 1906, Alfred Vogt in Switzerland first described a patient with premature whitening of eyelashes of sudden onset and bilateral subacute iridocyclitis. Twenty years later, Harada (1926) reported a case series with bilateral serous retinal detachment in association with cerebrospinal fluid (CSF) pleocytosis. Shortly thereafter (1929), Koyanagi published a review article associating unequivocally the posterior eye involvement with auditory and integumentary manifestations. In 1932, Babel suggested that these cases represented a single entity, which was then named Vogt-Koyanagi-Harada Disease [2].

It is speculated that the renowned painter Francisco José Goya y Lucientes (1746–1828) may have presented the disease in his midcareer (1792). Its main features were loss of vision and hearing, ringing in the ears, vertigo, weakness on one side of the body, confusion, abdominal pain and malaise. Goya recovered most of his eyesight, but remained permanently deaf [3].

Thus, VKHD is an uncommon multisystem inflammatory disease characterized by panuveitis, often associated with neurologic and cutaneous manifestations, including headache, hearing loss, vitiligo and poliosis.

VKHD is an important cause of noninfectious uveitis affecting, more frequently, individuals of pigmented skin, such as Asians, Middle Easterners, Hispanics and Native Americans. It is very infrequent among persons of African descent [4].

The incidence of VKHD varies. Among all cases of uveitis, it was estimated to represent approximately 7 % in Japan [5], 1–4 % in the United States [6] and 3 % in Brazil [7, 8]; thus ranking, along with Behçet’s disease, as the most prevalent causes of noninfectious uveitis in Brazil [7]. In China, VKHD is one of the most common uveitis entities [9]. In the United States, the incidence of VKHD is approximately 1.5 to 6 per 1 million patients, while in Japan it is seen in approximately 800 new patients each year [1, 10].

Most studies have found that women were affected more frequently than men and that most patients were in the second to fifth decades of life at the onset of the disease. However, children [11, 12] and the elderly may also be affected [13, 14]. Women account for 55 to 78 % of VKHD patients in the United States and approximately 38 % in Japan, showing a global variation in gender predilection [1, 10].

The exact etiology of VKHD is still a matter of enquiry. The most accepted mechanism involves an autoimmune aggression against antigens associated with melanocytes in a genetically susceptible individual after a virus infection trigger (Fig. 1). Genome of viruses from the herpes family (Epstein-Barr virus) was detected by PCR (Polymerase Chain Reaction) in the vitreous from VKHD patients [15]. Sugita et al. described that T cells from peripheral blood and intraocular fluid from patients with VKHD cross-reacted with tyrosinase protein and with highly homologous cytomegalovirus specific sequences [16].

Histopathologic findings and in vitro experiments demonstrated the role of CD4⁺ T lymphocytes. Matsuda demonstrated, in eyes globes from patients with VKHD, a close interaction between lymphocytes and melanocytes [17]. In vitro, uveal pigment inhibited leukocyte migration of peripheral blood mononuclear cells (PBMC) from patients with VKHD [18], and both CD4⁺ and CD8⁺ T lymphocytes were cytotoxic against melanocytes in vitro [19]. Moreover, Norose at al. described cytotoxicity displayed by lymphocytes from PBMC and CSF of patients with VKHD against the B-36 melanoma cell line [20]. McClellan et al. also found that IL-2 dependent T cells from VKHD patients reacted specifically with normal melanocytes as well as melanoma cells [21].

As suggested by these studies, the immune response is aimed at proteins associated with melanocytes. Melanocyte-specific proteins, shown to have a major role in differentiation, such as tyrosinase (TYR), tyrosinase-related protein 1 (TRP1) and 2 (TRP2), MART-1/Melan A and Pmel17/gp100, are also expressed in human melanoma cell lines and were recognized by T lymphocytes of patients with melanoma and are involved in tumor regression [22]. PBMCs from patients with VKHD recognized peptides derived from tyrosinase family proteins involved in melanin synthesis [23–26]. Peptides derived from TYR, TRP1, and TRP2 induced an autoimmune disease in rats that resembles VKHD [27], making these melanocyte proteins candidate autoantigens for VKHD. Altogether, these data indicate that patients with VKHD are sensitized to melanocyte epitopes and display a peptide-specific Th1 cytokine response [25, 26].

Sakamoto et al., in an immunohistochemical study of eyes affected by VKHD, revealed an increased T helper/T suppressor cells ratio and CD25⁺ and CD26⁺ T lymphocytes within choroidal inflammatory focii. These authors also observed class II major histocompatibility complex (MHC) expression in choroidal melanocytes and endothelium of choriocapillaris [28]. Inomata and Sakamoto demonstrated a remarkable disappearance of choroidal melanocytes in VKHD eyes [29]. These findings suggested that T cell-mediated immune process against melanocytes that express class II MHC play a pathogenic role in VKHD.

Several studies have demonstrated that HLA-DR4 (human leukocyte antigen) is strongly associated with VKHD patients of different ethnic groups, e.g. North Americans [30], Japanese [31–33], Chinese [34], Hispanics [35] and Brazilian [36]. In Japanese subjects, HLA-DRB1*0405 and DRB1*0410 combined susceptibility was robust [relative risk (RR) = 100] [32]. In ethnically heterogeneous Brazilian subjects, HLA-DRB1*0405 was also the predominant allele, with a RR of 12 [36]. Thus, HLA-DRB1*0405 plays a pivotal role in several populations. Besides HLA-DR involvement in VKHD, recently accumulating evidence has demonstrated association of non-HLA genetic factors in VKHD, i.g. cytotoxic T-lymphocyte antigen 4 gene, interleukin genes, macrophage migration inhibitory factor gene and osteopontin gene [37]. More recently, on genome wide analysis, three loci were associated with VKHD susceptibility IL23R-C1orf141, rs117633859; ADO-ZNF365-EGR2, rs442309 and HLA-DRB1/DQA1, rs3021304 [38]. Thus, immunogenetics rather than skin pigmentation may be the clue for disease susceptibility.

Helper T cell subsets producing Th1 cytokines (interferon-gamma and interleukin-2) after melanocyte derived peptides may produce pathological changes in VKHD, such as the granulomatous choroid inflammation in acute phase of VKHD [39–41]. Also of importance, are the cytokines associated with the pro-inflammatory IL-17-producing T helper (Th17) cell, i.g. IL-23, IL-7 and IL-21 [42–44]. In active VKHD patients, increased IL-17 may also result from a decreased IL-27 expression [42, 45]. By contrast, IL-10 and TGF-β regulatory cytokines are associated with the resolution of active inflammation [46]. Active VKHD has also been associated with a diminished function of regulatory T cells (CD4⁺CD25^high regulatory) [47]. Concerning innate inflammatory cytokines such as IL-6, Chen et al. described significantly higher levels in aqueous humor of VKHD cataract patients as compared to age-related cataract patients [5, 48].

Cellular and humoral autoimmunity against retinal components have also been demonstrated in patients with VKHD [49–51], as well an anti-Ro/SSA reactivity, in a small percentage of patients [52]. In vitro lymphocytic proliferation in the presence of retinal antigens has shown contradictory results. Naidu et al. showed a positive response to retinal S antigen and interphotoreceptor retinoid binding protein (IRBP) in active untreated patients [49]. Conversely, de Smet et al. detected no such response in chronic VKHD patients [50]. Thus, autoreactivity against retinal proteins seem to differ upon disease stages, i.e., acute vs. chronic. Autoantibodies against photoreceptor outer segments and Müller cells in the sera of VKHD patients have been detected [51]. However, these antibodies could represent a secondary response, which follows the retinal damage in VKHD patients.

Histopathological features of VKHD vary according to the stage of disease [53]. The primary pathological feature of VKHD is, however, diffuse thickening of the uveal tract (more prominent in the juxtapapillary choroid). In the acute stage there is a granulomatous process.

In the acute uveitic stage, it is of note a diffuse lymphocytic infiltration with focal aggregates of epithelioid cells and multinucleated giant cells containing pigment devoid apparent choroidal necrosis [53]. Choroidal infiltrate consists of T lymphocytes, which exhibit the markers of helper (CD4⁺) and suppressor/cytotoxic cells, along with melanocytes expressing class II major histocompatibility complex molecules. An eosinophilic exudate with proteinaceous material may be detected underlying the detached retina. While the retinal pigment epithelium (RPE) may appear unharmed using light microscopy, occasional lymphocytes below the RPE may be observed. Focal collections of hyperplastic/modified RPE, macrophages, epithelioid cells and lymphocytes located between RPE and Bruch’s membrane may form the Dalen-Fuchs nodules [53].

During the convalescent stage, there is a nongranulomatous inflammation, which consists hispathologically of a mild to moderate non-granulomatous inflammatory cell infiltrate with focal aggregates of lymphocytes and occasional macrophages. The loss of melanin granules of choroidal melanocytes renders a pale, depigmented aspect to the choroid. Thus, the “sunset glow fundus” appearance in the convalescent stage results from immune-mediated insult to choroidal melanocytes. The RPE may assume either a relatively normal appearance or be focally destroyed, with subsequent chorioretinal adhesions, which correspond to the small atrophic nummular hypopigmented lesions observed in the mid periphery of the fundus [53].

During chronic recurrent stage, a granulomatous choroiditis with damage of choriocapillaris is observed. Furthermore, one may observe a granulomatous infiltrate with less prominent diffuse uveal thickening than that observed in the acute stage. Chorioretinal adhesions with atrophy and/or proliferation of RPE are frequent. Focal areas of hyperpigmentation in depigmented fundi are the consequence of RPE proliferation. This may be accompanied by subretinal neovascularization and elevated pigmented lesions. The hyperplasic RPE can be reorganized and form areas of subretinal fibrosis. Besides these RPE changes, photoreceptor degeneration and gliosis can also be observed. In fact, chronic and recurrent inflammation in the choroid, as noted in VKHD, may stimulate proliferation of retinal pigment epithelial cells [53, 54]. Unlike other stages, there is involvement of the choriocapillaris [53].

In other tissues affected by VKHD (skin and central nervous system (CNS)), there are similar findings: cellular infiltrate composed of T lymphocytes, especially CD4⁺ T cells, and macrophages containing melanin granules [53]. On the other hand, skin lesions of VKHD patients were analysed with electron microscopy and it was possible to demonstrate that, at the periphery of the depigmented lesion, the melanocytes had several subcellular abnormalities, ie, vacuolization of the cytoplasm, aggregation of melanosomes, autophagic vacuoles, fatty degeneration, pyknosis or homogeneous cytoplasmic degeneration, and others. And even absence of melanocytes could be observed [55].

The AUS criteria come short in setting appart acute and chronic cases. Another limitation consists in inadequate consideration of acute cases, as two of the four cardinal signs characteristically occur in the convalescent/chronic stages of disease. Moreover, fluorescein (FA) and indocyanine angiography (ICGA), as well ultrasonographic findings were not taken into account by the AUS criteria. As such, neither chronology nor complementary exams were taken into account.

Sugiura et al. proposed another set of diagnostic criteria for VHKD. This system is seldom used outside Japan once CSF analysis is mandatory [4, 57, 58].

Recently, da Silva et al. demonstrated a correlation between fundus changes and parameters of the full-field electroretinography (ffERG) in patients with VKHD at late stage (with more than 6 months duration of the disease, which includes chronic and convalescent stages). Fundus parameters were used to propose an analytic framework for fundus changes in late-stage VKHD, namely: diffuse pigmentary changes; nummular lesions; pigment clumps and subretinal fibrosis. The correlation of fundus severity and ffERG parameters indicates that fundus changes may reflect functional abnormalities [64].

Lumbar puncture is useful in confirming the diagnosis of VKHD in the acute stage only [44]. Given the large amount of patients found to have auditory symptoms, audiological testing is recommended in VKHD patients [65].

VKHD is classically divided into four stages: prodromic, acute uveitic, convalescent and chronic/recurrent [1]. To “stage” the disease may enable exchange information rapidly between caregivers as to chronology of the disease which implies in treatment strategies.

Acute uveitic stage

This typically occurs within 3 to 5 days of the prodromal stage and lasts for several weeks. Patients may experience acute blurring of vision in both eyes; in 30 % of patients, the involvement of the fellow eye occurs after a few days [1, 4, 58]. The underlying pathologic process in its early stage is the occurrence of a diffuse choroiditis. Features of this choroiditis are exudative detachment of the neurosensory retina secondary to diffuse choroidal inflammation. Hyperemia and edema of the optic disk are observed in about 47 % [4] (Figs. 2 and 3). On FA there are multiple hyperfluorescent leaking dots (pinpoints), which become coalescent due to accumulation of fluorescein in the subretinal space (pooling of dye). This is a typical feature of the acute uveitic stage.

Inflammation extends into the anterior segment to varying degrees. Thus, patients with VKHD may have acute bilateral granulomatous iridocyclitis with mutton fat keratic precipitates, iris nodules and shallow anterior chamber due to ciliary body edema and inflammation and suprachoroidal fluid collection. This last feature may lead to acute angle closure glaucoma.

In a Chinese retrospective study including 410 VKHD patients, the posterior and anterior uveal involvement were delineated as consecutive stages [66].

Meningeal involvement and auditory symptoms may also be present during the acute uveitic stage, which may last for weeks or even months.

Convalescent stage

The convalescent stage follows the acute uveitic stage, usually a few months later. It is characterized by depigmentation of the integument and choroid. Findings may include vitiligo, alopecia and poliosis. Sugiura described a perilimbal depigmentation that occurs on the first month after the uveitis onset and is observed mainly in Japanese subjects (Sugiura’s sign) [57]. At this stage, varying degree of diffuse or localized depigmentation with areas of pigment accumulation may be observed in the fundus. This depigmentation occurs 2 to 3 months after the uveitic stage; the change may be from brunette to blonde, or it may present as an exaggerated reddish glow fundus [4, 54, 67], which is described as “sunset glow fundus” (Fig. 4). Fundus appearance may have focal accumulation of pigment in bands or in lumps, interspersed with areas of pigment rarefaction. In the mid-periphery, there are multiple, well-defined hypopigmented white lesions.

Extraocular manifestations

Involvement of integument and the central nervous system (CNS) may be present at various stages of the disease. The frequency and severity of extraocular manifestations varies by patients’ ethnic group, being more common in Asian population (Table 3), and also by treatment adequacy.

	Japan, 2007 [182]	USA, 1991 [70]	Brazil, 2009 [64]
	N = 136 patients	N = 48 patients	N = 67 patients
Meningeal signs	80 %	67 %	18 %
Pleocytosis	90 %	-	-
Tinnitus	53 %	17 %	24 %
Alopecia	7 %	13 %	9 %
Poliosis	18 %	6 %	22 %
Vitiligo	13 %	10 %	16 %
VKHD categories
Complete	22 %	-	15 %
Incomplete	65 %	-	55 %
Probable	13 %	-	30 %

CNS involvement

The prodromic stage (also called meningeal stage) occurs due to the CNS involvement. During the acute stage meningeal signs may also arise, such as neck stiffness, confusion and headache. CSF pleocytosis is observed in more than 80 % of cases, with a predominance of lymphomononuclear cells, which may be present until the eighth week of the onset of the disease [45]. Serious meningeal-encephalic manifestations and focal neurological signs (i.e.cranial neuropathies, hemiparesis, aphasia, acute transverse myelitis and ciliary ganglionitis) were also reported [4, 58, 71].

Inner ear involvement

Changes in the inner ear, such as dysacusis, hearing loss and vertigo, have been observed in 70 % of patients, especially during the prodromal stage. Tinnitus is present in 42 % [65]. The hearing loss pattern is typically cochlear at high frequencies with improvement in 2 to 3 months [63]. Vestibular dysfunction is uncommon.

Skin and appendages involvement

Cutaneous findings usually develop during the chronic or convalescent stage of the disease and include vitiligo, alopecia and poliosis of the lashes, eyebrows and scalp hair (Fig. 5). Vitiligo can be found in 10 to 63 % of patients [72]. The skin of the back or buttocks seems to be the initial or main anatomic area involved [73].

Sugiura’s sign (perilimbal vitiligo) is the earliest depigmentation to occur, presenting itself one month after the uveitic stage [74].

Sympathetic ophthalmia is histopathologically identical to VKHD and can present in a similar fashion with rapid, bilateral visual loss associated with anterior segment inflammation, choroidal thickening, disc hyperemia or edema and serous retinal detachments. Nevertheless, the definition of sympathetic ophthalmia requires previous penetrating trauma or intraocular surgery [1, 83].

Acute posterior multifocal placoid pigment epitheliopathy is a rare inflammatory ocular disease, which affects the choriocapillaris, the RPE and the outer retina in previously healthy and young patients. There is a sudden and painless loss of central visual acuity (VA), unilateral or bilateral, after a viral prodrome, with multiple creamy white lesions, which can evolve to chorioretinal scars. Usually, there is mild or no reaction in the vitreous. FA typically shows early hypofluorescence by blockage in the site of lesions, followed by a late hyperfluorescence. FA findings set VKHD appart from APMMPE. ICGA allows the observation of the entire length of the choroidal involvement as depicted by hypofluorescent lesions in the mid and late phases. Both entities may present with serous retinal detachments, which improve with corticosteroid treatment. Many authors describe CNS involvement that can range from mild changes (as headache) to severe diffuse cerebral vasculitis. Prognosis of APMMPE is generally good with spontaneous and/or rapid resolution of visual function. Some patients may experience only partial visual recovery. Systemic treatment may be indicated in cases with severe visual impairment and/or CNS complications [75, 84–87].

Birdshot chorioretinopathy is a chronic, bilateral intraocular inflammation, occurring more frequently in Caucasians, after the fourth decade of life. The typical presentation is mild yellowish-white lesions throughout the entire posterior pole, cystoid macular edema (CME), disc edema, vasculitis and chronic vitritis. There is mild anterior segment inflammation. It has a chronic course with periods of exacerbation and remission of the disease, with progressive loss of visual acuity. FA findings are not so evident while ICGA tends to show areas of hypofluorescence that persist until the late phases. ERG shows an impairment of rod and cone function. A strong association with HLA-A29 was observed indicating involvement of autoimmune mechanisms in its pathogenesis [78].

Retinal lesions found in multiple evanescent white dot syndrome can be mistaken with VKHD. MEWDS is usually unilateral, affects young women and is characterized by sudden and painless loss of visual acuity. A viral infection may be present in half of the cases. Characteristically, there are numerous, multifocal yellowish-white lesions found in the deep retina/RPE at the posterior pole. In the fovea, there is a distinctive granular appearance. It tends to behave in a self-limited fashion with patients recovering visual acuity in a few weeks. There is usually none or minimal anterior chamber reaction, but vitreous cells may be observed as well choroidal thickening [85]. FA shows hyperfluorescence in the early and late phases, disc leakage and, occasionally, perivascular sheathing. ICGA reveals multiple round hypofluorescent points at the posterior pole. There is enlargement of the blind spot on visual field and reduced amplitude of ERG waves. Recurrences are uncommon [77].

Multifocal choroiditis and panuveitis is a chronic relapsing inflammatory disease, characterized by multiple choroidal lesions on the posterior pole, mid-periphery or periphery, associated with vitritis and anterior chamber reaction. Predominantly, it affects women between 20 and 60 years, in a bilateral and often asymmetrical fashion. FA reveals initial hypofluorescence followed by hyperfluorescence. Subretinal fibrosis and choroidal neovascularization may be observed [88].

Posterior scleritis is an uncommon form of scleral inflammation and is twice as common in women as in men. Thirty percent to 45 % of cases may be associated with systemic diseases such as systemic vasculitis, autoimmune diseases and lymphoma. Posterior scleritis can also present with intense ocular pain, radiating to the head, ears and jaw; redness; choroidal folds, exudative retinal detachment, optic disc edema and choroidal detachment. However, it is usually unilateral and not associated with neurologic or dermatologic findings. Also, unique to posterior scleritis is the ultrasonographic “T sign,” or squaring of the interface between the optic nerve and the sclera, indicating the presence of fluid in the sub-Tenon’s space. Characteristically, there may also be posterior scleral shell thickening and retrobulbar edema. The FA appearance may be similar to the VKHD [1, 79, 89].

Primary intraocular lymphoma is a subtype of non-Hodgkin central nervous system lymphoma (CNSNHL), with moderate to high malignancy, most commonly observed in individuals over 60 years of age. It can affect the vitreous, retina and optic nerve, presenting as a chronic uveitis, little or partially responsive to corticosteroids accompanied by neurological signs and symptoms. Bilateral involvement is common. The fundus may show multifocal elevated subretinal and sub-RPE yellow lesions, involving the posterior pole, associated with vitritis. Satellite lesions may also be present, simulating hypopigmented lesions in the mid-periphery. Generally, there is choroidal thickening with/without associated with retinal detachment. FA shows choroidal fluorescence blockage with late leakage at the site of inflammatory lesions. Unlike VKHD there is extensive focal early hyperfluorescence with dye pooling in the detached retina region in later phases of the angiogram. In patients with CNSNHL, 20 to 25 % have ocular involvement and 56 to 85 % initially presenting ocular lymphoma develop brain lymphoma. Thus, patients with uveitis and neurological symptoms should be carefully examined with CSF tap and neuroimaging (preferably magnetic resonance imaging (MRI) with intravenous Gadollinium enhancement). Diagnosis of intraocular lymphoma can be confirmed by vitreous, retinal and/or choroidal biopsies [76].

Central serous retinopathy (CSC) is an idiopathic condition characterized by the development of serous detachment of the sensory retina and, in some cases, serous detachments of the RPE. It occurs primarily in healthy men between 25 and 55 years of age. In rare cases, these symptoms are accompanied by a migraine-like headache, which could resemble the prodromal stage of VKHD. FA may show different patterns, being the diffuse one more similar to the VKHD findings: large areas of serous detachment and extensive RPE changes. Bilateral CSC may have asymmetric findings. FA show choroidal vascular abnormalities. However, although the yellow-white exudates of VKHD may appear similar to CSC, the granulamatous uveitis is not usually seen in this condition. Besides that, it is very important to differenciate these two patologies, since corticosteroids (the initial and main treatment of VKHD) could increase the risk of developing CSC [90, 91].

Systemic arterial hypertension and pre-ecclampsia may also result in serous retinal detachments. It is suspected that choroidal vascular changes predominate when acute elevation of blood pressure is present, whereas a more gradual onset of hypertension results in retinal vascular changes. Hypertensive choroidopathy may manifest as Elschnig spots (ischemic infarcts of the RPE and hypoperfusion in the underlying choroid); subretinal exudates; serous retinal detachment; fundus depigmentation and optic disc edema [1, 92].

Besides that, the cutaneous manifestations should exclude diagnosis such as Alezzandrini’s syndrome, alopecia areata, vitiligo and piebaldism. Other immunomediated sensorineural hearing loss should also be excluded such as Cogan syndrome. Uncommon VKHD association with cutaneous pigmented malignant melanoma [93], with Chron’s disease [94, 95] and polycystic ovary syndrome [96] among others have been described.

The diagnosis of VKHD is clinical (as no laboratory marker identifies the presence thereof) and is based on the RDC to date (Table 2). Nevertheless, FA and ocular ultrasonography (US) can help the diagnosis and follow-up of atypical cases. ERG examination may be a useful method to evaluate the functional implications of VKHD. Recently, technological advances have allowed a better evaluation of the retina and choroid with ICGA and spectral domain OCT. In conjunction, these imaging modalities have added new parameters for detecting and quantifying inflammation and may allow better assessment of treatment efficacy.

Treatment of iridocyclitis should be performed according to the intensity of anterior segment inflammation. Topical corticosteroids (e.g., dexamethasone 0.1 % or prednisolone acetate 1 % eyedrops) in combination with mydriatics/cycloplegics (e.g., tropicamide 1.0 % eyedrops) to reduce ciliary spasm and prevent posterior synechiae, are most frequently used [1].

The mainstay of treatment of VKHD is prompt, high-dose systemic corticosteroids, administered either orally (prednisone 1–1.5 mg/kg per day) or through a short course of intravenous delivery (methylprednisolone 1000 mg per day, intravenously, during 3 days), followed by slow tapering of oral corticosteroids throughout a minimum 6-month period (Fig. 6). Timing to initiate therapy, corticosteroid dosing and duration of therapy are the key factors in reducing the chance of recurrences.

Read et al. compared the use of oral corticosteroids and the use of pulsetherapy followed by oral corticosteroids and suggested that the route of initial administration did not influence the outcomes measured by visual acuity [119]. However, more recent studies show a trend to aggressive high-dose corticosteroid, i.e. pulsetherapy, with faster resolution of clinical inflammatory signs as well as posterior segment imaging inflammatory signs (PSIIS). Kawaguchi et al. demonstrated that medium-dose systemic corticosteroid therapy may be insufficient to adequately suppress ocular inflammation in VKHD. In their case series, ICGA detected the persistence of hypofluorescent dark dots after 4 months in patients receiving such regimens. Furthermore, these same patients were more likely to develop “sunset glow fundus”. Dose as high as 0.75 mg/kg per day was necessary during the first 4 months of treatment [120]. Moreover, Chee et al. have emphasized with about equal importance the early treatment instauration [121]. This group demonstrated that peripapillary atrophy (PPA) developed more frequently as well as to a greater extent in patients receiving delayed and low dose corticosteroids [121]. The same authors showed that this finding was a marker of more severe retinal dysfunction in these patients as measured by mfERG [117].

At this point, it is needed to emphasize that a more comprehensive approach of inflammation in post-acute uveitic stage of VKHD does not take into account isolate visual acuity, but also the presence of cells in anterior chamber and PSIIS (FA, ICGA, OCT) [61, 103, 108, 112–114]. Therefore, concerning ICGA signs, hypofluorescent dark dots may resolve in 4 months, while changes in choroidal vascular permeability tend to disappear in 8 weeks due to their response to initial therapy with high-dose corticosteroids [61, 62] Dark dots are the most constant and most readily recordable angiographic sign enabling choroidal inflammatory activity semi-quantitative assessment (Fig. 4).

Some authors indicate therapy guided by ICGA inflammatory signs [68]. Nevertheless, a more comprehensive understanding of choroidal inflammatory signs is lacking [122, 123].

Rapid discontinuation of systemic corticosteroid may incur in recurrences [10, 124]. Several studies have pointed out that the minimum treatment period is 6 months. Lai et al. and Errera et al. formally demonstrated in their retrospective studies the relevance of a minimum of 6-month systemic and/or immunosuppressive drug therapy in diminishing recurrence frequency and severity [124, 125]. The final treatment duration varies widely according to the presence of inflammation.

Immunosuppressive therapy is formally indicated in corticosteroid refractory or intolerant cases [126]. Nevertheless, in VKHD, the long-term systemic corticotherapy was acceptable due to till recent notion that it presents a good response to this therapy alone and had a good prognosis counterbalancing the more serious immunosuppression induced side effects [127]. However, recent literature is pointing out to the deleterious effect on visual function of chronic relentless choroidal inflammation and a trend to an earlier start on systemic immunosuppression.

Some investigators have suggested immunosuppression with agents such antimetabolites, cyclosporine and biological agents (IMT) as first-line therapy in the treatment of VKHD. Aggressive treatment may result in fewer complications and less recurrence. Paredes et al. described IMT given within 6 months of diagnosis with or without steroid was associated with a superior visual outcome when compared to steroid as monotherapy or with delayed additional of IMT [128]. Rao et al. pointed out that a prospective study should be conducted to validate the role of first-line immunosuppressive therapy in all VKHD patients, particularly during the acute stage of the disease, accounting for both, potential side effects as well as little evidence available [122].

Antimetabolites are drugs that inhibit nucleotide synthesis, inhibiting the division and proliferation of inflammatory cells, i.e. methotrexate, azathioprine and mycophenolate mofetil [130]. Methotrexate has been used to control pediatric VKHD as well as adult VKHD [131]. Mycophenolate mofetil, a selective inhibitor of inosine monophosphate dehydrogenase (an enzyme essential for the proliferation of B and T lymphocytes), has been used as first-line therapy in a prospective study including 19 patients leading to less recurrences and improved visual outcome [132]. Interestingly, Urzua et al. recently evaluted, in a retrospective study, VKHD patients treated with early IMT (within 6 month of diagnosis) and patients treated with late IMT and found no differences in terms of visual acuity improvement, complications and glucocorticoid sparing effect [133]. However, these authors suggested that those with poor response to glucocorticoid therapy could benefit with the IMT as first-line therapy and pointed out that treatment should be individualized. Azathioprine had been demonstrated to be effective by other authors in patients with corticosteroid intolerance or uncontrolled inflammation [134].

Case series demonstrating the efficacy of several other treatment modalities are found in the literature including biologics agents, such as infliximab and rituximab [135–137] and intravitreal drug therapy, such as triamcinolone, bevacizumab and fluocinolone acetonide [138–141]. Even though intravitreal drug therapy as a first line treatment for acute VKHD is very controversial, it may be useful as an adjunt treatment in chronic and/or recurrent stages of the disease.

In infants, methotrexate is most widely used than other IMT and seems to be effective with minimal side effects [11, 142–144]. In pregnancy, high-dose corticosteroids have been used to treat VKHD successfully during the second and third trimester of pregnancy, usually devoid complications in delivery [145–148].

New highly effective drugs with less toxicity in the management of VKHD are continuously being searched. One example is the strong steroid difluprednate, which was used topically, at the onset of diagnosis, and promoted complete resolution of exudative detachments with improvement of visual acuity [149]. New biological agents are also being pursued such as secukinumab and gevokizumab. Secukinumab is a full or recombinant monoclonal antibody against IL-17 and gevokizumab is a humanized IgG2k monoclonal antibody, which binds to IL-1ß with high affinity and inhibits IL-1β-mediated responses [150].

Da Silva et al. divided VKHD patients in two groups, i.e. early stage and late stage groups. Patients who presented with symptoms for less than 4 weeks were grouped as early stage; others were grouped as late stage. Patients first seen in the late stage of disease had more ocular complications and relapses after disease onset, when compared to those first seen in the early stage [64].

The visual outcome in patients with VKHD has improved considerably with the use of high-dose corticosteroids, immunosuppressant drugs and advances in the management of complications, such as cataract, glaucoma and CNV. The prognosis of VKHD is usually considered good with 60 % of patients having VA better than 20/40 [1, 10].

However, several evidences point to VKHD as a much more serious illness, i.g. more than 50 % of patients evolves towards chronicity [1, 68, 173] and 50 % of eyes with VKHD develop at least one complication [160]. Furthermore, a more comprehensive approach of inflammation in VKHD does not take into account isolate visual acuity and characterization of inflammatory activity based only on the presence of cells in anterior chamber seems not to be sufficient [69]. Recent choroid imaging advances have made possible a better identification and quantification of inflammatory activity [61, 102, 107, 111–113].

Until recently, VKHD was considered “cured” for those patients who were in the convalescent stage. Nevertheless, recent studies have pointed to disease progression, even in seemingly quiescent cases. The main evidences of this progression are: progressive fundus depigmentation, even in patients without obvious persistent clinical activity [174]; worsening of visual acuity complaints in patients apparently “cured” and with no clinical disease activity [175]; and, presence of inflammatory cells in the choroid of enucleated globes of patients in chronic and convalescent stages [51].

Even when there is resolution of acute inflammation and recovery of good visual acuity, some patients still have subclinical retinal dysfunction as measured by multifocal electroretinogram (mfERG) [117, 118].

Some factors have been described as indicative of prognosis:

I. Related to treatment: a.. Late instauration of treatment from the acute disease onset: early treatment with high-dose systemic corticosteroids resulted in less persistent inflammation [176]; b.. Treatment shorter than 6 months: use of systemic corticosteroids for longer than 6 months and slow tapering were significantly associated with good final visual acuity [10, 127, 176]; c. Treatment with corticosteroids in suboptimal dose: patients treated with low doses of corticosteroids in the acute stage were more likely to have persistent inflammation [120, 121]. The extent of pigmentary changes in patients seemed to be dependent on the amount of corticosteroid received during the acute stage of the disease. Administering an initial high-dose of corticosteroid may preserve more melanocytes and may reduce the extent of pigment damage [178].

II. Related to the patient: a. Younger age (controversial): age at onset of the disease has been differently linked to final VA. Poor prognosis has been associated with older age at onset of VKHD by some authors [121, 162] and with younger age at onset by others [142, 177]; b.. Presence of HLA-DRB1*0405/0410 is more common in patients with prolonged disease: Islam et al. investigated HLA-DR4 gene variations in 46 Japanese patients, 28 with the prolonged type and 18 with the nonprolonged type of VKHD. Significant differences were found in the DR4 gene variation in the two clinical subtypes. All the patients with the prolonged type had either the DRB1*0405 or DRB1*0410 variant, whereas 39 % of the patients with the nonprolonged type had neither of them. This difference in frequency was statistically highly significant. The authors concluded that DR4 gene variants differed significantly between the two subtypes of VKHD, suggesting that the clinical course of VKHD is determined partly by the patient’s HLA-DR gene variation [179].

III. Related to the disease: a.. Poor visual acuity at presentation: better VA at presentation is associated with a better final VA [162]. Chee et al. proposed that good VA at one month was associated with greater likelihood of good VA at 3 years [121]. 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 serous retinal detachment without any other associated complications [162]. Some VKHD 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 [117, 121, 162, 180]. Besides, peripapillary atrophy is associated with visual dysfunction compared with eyes without peripapillary atrophy [117]. Early pinpoint peripapillary hyperfluorescence on pretreatment FA was found to be an indicator for good prognosis. In fact, this sign was more likely to be associated with eyes imaged early in the course of the disease than eyes imaged later [181]; b.. Presence of complications in the initial presentation: the development of ocular complications is significantly associated with a worse final VA [177]; c.. Increased number of recurrences: 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 treatment, especially corticosteroids [162].

VKHD is a severe bilateral, granulomatous panuveitis associated with serous retinal detachment, causing a significant impact for patient’s life, especially considering its frequent onset at young and working ages. Ocular involvement undoubtedly accounts for most of the disease impact on individuals’ lives. While meningeal (neck stiffness, headache and CSF pleocytosis) and ocular signs are characteristic of acute stage, skin changes may be observed later on in the course of disease. Early diagnosis coupled with proper treatment may result in visual recovery. However, VKHD does require regular and close monitoring even in apparently quiescent cases as recent evidences lead to progressive subclinical visual deterioration in such instances.

Written informed consent was obtained from the patient for the publication of this report and any accompanying images.