Vogt-Koyanagi-Harada syndrome …

Homer Chiang MD

Neuro-Ophthalmology & Neuro-Otology

Updated 06.23.2024
Released 05.14.1996
Expires For CME 06.23.2027

Vogt-Koyanagi-Harada syndrome

Author: Homer Chiang MD

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Editor: Jonathan D Trobe MD

Vogt-Koyanagi-Harada syndrome

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Introduction

Overview

Vogt-Koyanagi-Harada syndrome is an inflammatory condition in which uveitis is the most significant feature of the illness. Neurologists may be called on to diagnose the prodromal phase of the disease in which the predominant symptoms are headache, meningeal signs, and, less often, focal neurologic findings. CSF pleocytosis is also common. In this update, the authors cite data demonstrating that earlier initiation of either glucocorticoids or immunomodulatory measures is associated with a reduction in late visual morbidity and that the neurologic manifestations can include cerebral ischemia.

Key points

	• Vogt-Koyanagi-Harada syndrome is primarily an ocular inflammatory disease, but the prodrome often includes signs and symptoms that bring the patient to a neurologist, including headache, meningeal signs, and CSF pleocytosis.
	• Melanin pigment-containing cells are most often targeted, including the retinal pigment epithelium, producing chorioretinitis (uveitis); cutaneous melanocytes, producing vitiligo and poliosis; and the organ of Corti, producing sensorineural hearing loss.
	• The disease is encountered more frequently in persons of Asian, Latin, and Mediterranean descent.

Historical note and terminology

Vogt-Koyanagi-Harada syndrome is a condition in which pigmentary alterations in various tissues are associated with ocular and meningeal inflammation. The combination of poliosis (the graying, or whitening, of a shock of scalp hairs, from the Greek for "gray"), and ocular inflammation was noted by the Arab physician Ali Ibn Isa (Ali ben Issa), who died in 1010 (141; 112), and by others including Vogt (183). Both Vogt and Koyanagi described cases that included the combination of primarily anterior uveitis (bilateral iridocyclitis) with non-ocular manifestations, including pigment loss from skin (vitiligo), hair, and lashes (poliosis); hair loss (alopecia); and hearing loss with tinnitus (183; 88). Koyanagi's six cases were described in 1929, but in 1926, Harada had described similar non-ocular manifestations together with a primarily posterior uveitis characterized by exudative retinal detachments, as well as pleocytosis in the cerebrospinal fluid (50). Moorthy and colleagues credit Babel (18), and Bruno and McPherson (23) with recognizing the essential unity of the cases described by Vogt, Koyanagi, and Harada (112). Herbort and Mochizuki reviewed the historical development of the syndrome, emphasizing that both Koyanagi and Harada perceived the inherent unity of cases with seemingly disparate multisystem signs and symptoms, whereas Vogt was lucky enough to describe the first case extremely well (54).

Clinical manifestations

Presentation and course

Most authors agree that the disease can be divided into four stages: (1) prodromal, (2) uveitic, (3) convalescent, and (4) chronic recurrent. However, the time at which the various manifestations occur is somewhat variable (105; 112). Although the disease-defining symptoms and signs are ophthalmic, they are rare in the prodromal phase, during which time neurologic symptoms predominate. Therefore, patients may initially present for neurologic care.

Prodromal phase. Central nervous system signs and symptoms are most common during the prodromal phase, which lasts a few days. Symptoms of meningeal irritation are the most common. Sugiura noted that a patient's hair and skin might be sensitive to touch during the prodromal stage (171).

Though rare, the central nervous system signs and symptoms during this prodromal phase may be severe, including alteration of cognitive function, confusional state, or psychosis. Focal findings, such as hemiparesis or generalized weakness with loss of sphincter control, or cranial nerve palsy (most commonly of the fifth, sixth, and seventh cranial nerves), are uncommon (141). Seizures and coma may occur rarely in the early stages, usually with more precipitous onset (28; 84). Analyzing a group of 87 patients with Vogt-Koyanagi-Harada syndrome in South India, Mondkar and colleagues found that 64% had non-ocular symptoms at presentation, and of these, 96% had meningismus (111). Continuous diffuse headache lasting several months without other ocular or neurologic findings or symptoms may also be the presenting symptom (87).

CSF pleocytosis is even more common than symptomatic meningitis, with CSF pleocytosis being recorded in about 80% of patients who underwent lumbar puncture (132; 106; 62).

CSF total protein is often normal or mildly elevated, and glucose is usually normal (106; 62). The presence of melanin-laden macrophages in CSF can distinguish Vogt-Koyanagi-Harada syndrome from other conditions, such as syphilis, that produce CSF pleocytosis (80).

Because CSF pleocytosis can be present in patients with minimal or no neurologic findings, it is reasonable to consider that MRI manifestations of meningeal inflammation may provide a sensitive and non-invasive indicator for early diagnosis (49; 103). Thus, finding MRI evidence of either leptomeningitis or pachymeningitis may prove to be a non-invasive surrogate for CSF pleocytosis in early diagnosis of Vogt-Koyanagi-Harada syndrome.

Pattison noted the occasional presence of optic nerve swelling (141), but additional reports in which lumbar puncture was carried out on a large number of patients have generally documented normal opening pressure or, at most, mild elevation (62). In his review, Fishman also noted that, in some series, up to a quarter of the patients may have mild elevation of CSF pressure, but most reports indicate smaller percentages (42). There may also be optic disc swelling due to inflammation as discussed in the Ophthalmic manifestations section (below).

Transient dizziness and nystagmus were observed in about 60% of patients and were suggested to be secondary to labyrinthitis (133). This was later attributed to disease involvement of inner ear melanocytes (82).

Rare associations with Vogt-Koyanagi-Harada syndrome include ischemic stroke, myelopathy with enhancing lesions in the cervical cord (47), and Guillain-Barré syndrome. They appear within weeks to months of the initial symptoms (119).

Uveitic phase. Ophthalmic manifestations become apparent during the uveitic phase. The most common symptom in the uveitic phase is blurred vision, mostly from the cloudy opacity of the ocular refractive media (cornea, aqueous humor, crystalline lens, and vitreous humor). Reduction of visual acuity may also result from serous detachment of the macula. In about a third of cases, the disease starts symptomatically in one eye, but the interval to involvement of the second eye is usually just a few days. In a study of 16 patients, all had decreased visual acuity, abnormal color vision, and abnormal visual fields at the initial visit (194).

During the uveitic phase, which typically lasts several weeks, there is a bilateral posterior uveitis, with elevation of the retina and choroid around the optic disc, optic disc swelling, retinal edema, and serous retinal detachments. The retinal edema and retinal detachments are characteristically multifocal and may increase in number. Pigment epithelial detachment has also been described (78). Non-necrotizing granulomas consisting of epithelioid histiocytes (Dalen-Fuchs nodules) accumulate underneath the retinal pigment epithelium.

Early uveitic phase of Vogt-Koyanagi-Harada syndrome (fundus photograph)

The optic disc is swollen, and there is subretinal fluid extending to the macula. Extensive patches of retinal edema (white) extend along the upper and lower vascular arcades. (Contributed by Dr. James Goodwin.)

Inflammation eventually spreads to involve the anterior segment and is manifest by inflammatory cells and flare in the aqueous humor. White-to-yellow greasy inflammatory precipitates (“mutton fat keratoprecipitates”) may be seen on the corneal endothelial surface. Inflammatory nodules may similarly accumulate at the pupil margin (Koeppe nodules) or on the iris surface (Busacca nodules). These are best seen on slit lamp examination in the ophthalmologist’s office. Caution should be exercised when assessing the pupil in eyes with active intraocular inflammation as posterior synechiae can give the appearance of an irregular or fixed pupil. Patients with anterior segment inflammation may experience decreased visual acuity and significant photophobia.

Eye in the early uveitic phase of Vogt-Koyanagi-Harada syndrome

Elevated protein content of the aqueous humor shows as generalized cloudiness behind the cornea (flare). Mutton-fat type grayish white precipitates are visible on the inner surface of the cornea (within the pupil) and on the iris ...

Optic disc swelling can result during the uveitic phase through a variety of mechanisms, including elevated intracranial pressure, inflammation, and ischemia. Some of these patients may have persistent visual field defects after resolution of swelling due to ischemic optic neuropathy (122; 121).

Acutely elevated intraocular pressure can occur and is characterized by intense ocular pain, perilimbal conjunctival injection (“ciliary flush”), a mid-dilated pupil, and corneal edema. This is a medical emergency, and these patients should be referred to an ophthalmologist without delay. Both acute and subacute elevations in intraocular pressure can cause irreversible damage to the optic nerves. Elevated intraocular pressure is attributable to plugging of the trabecular meshwork by inflammatory cells, thereby reducing aqueous outflow. Alternatively, adhesions between the iris and the anterior capsule of the crystalline lens (posterior synechiae) may impede the flow of aqueous between the ciliary body and cause the iris to bow forward (“iris bombe”). Anterior displacement of the ciliary-iris complex by inflammatory infiltrates may also lead to appositional angle closure. Long-term use of topical and systemic steroid medications increases the risk of steroid-induced ocular hypertension in the subgroup of patients who are “steroid responders.” Glaucoma may persist beyond the resolution of the uveitic phase. In one study, uveal effusion (abnormal fluid distention of the choroid) and an increased number of clinical recurrences of ocular inflammation were significant risk factors for the development of glaucoma (137).

Convalescent phase. This phase lasts several months and is characterized by depigmentation in the skin and choroid. Loss of pigment in the choroid results in a shift of the background fundus color from the usual dusky red to a bright orange, which has been called "sunset glow fundus." There is often clumping of the retinal pigment in the pigment epithelial layer, which results in dense pigmented accumulations alternating with lighter areas throughout the posterior pole of the fundus. It is also during this convalescent phase that depigmentation of the skin (vitiligo) and of the hair on the eyebrows, eyelashes, and scalp (poliosis) occur. The vitiligo affects the head, trunk, and sacrum.

Convalescent phase of Vogt-Koyanagi-Harada syndrome (fundus photograph)

The optic disc is still somewhat swollen. Dense irregular bands of pigment clumping within the retinal pigment epithelium surround the disc. An area of orange discoloration from loss of melanin in the pigment epithelium is seen ju...

Many ophthalmic symptoms improve during the convalescent phase. Visual acuity and color vision may improve as early as 1 to 3 months after presentation, but visual field defects may not improve substantially until 6 months after presentation. Nearly 30% of patients retain visual field impairment 12 months after treatment onset (194).

Chronic recurrent phase. After several months of convalescence, a chronic recurrent phase may set in, manifested by low-grade panuveitis punctuated by acute episodes of predominately anterior uveitis. Choroidal or other uveal neovascularization may arise, leading to edema, hemorrhage, or serous retinal detachment. These phenomena may lead to vision loss, macular scarring, and pigmented perivascular atrophy (149).

Prognosis and complications

HLA-DR4 gene variations may play a role in determining the clinical course, and that the presence of DRB1*0405, DRB1*0410, or both, is associated with a more protracted course (64; 65). Additional studies have shown that patients with HLA-DQA1*0301 and HLA-DQB1*0401 markers are more susceptible to Vogt-Koyanagi-Harada syndrome and HLA-DQA1*0103, 0401, 0501, and that HLA-DQB1*0301, 0402, 0601, 0603 may be protective (101).

Early treatment may improve prognosis, decreasing the number of uveitic flares and the risk of subretinal fibrosis (159). In the face of a poor response to corticosteroid therapy, early initiation of immunomodulatory therapy may improve visual outcome (182).

In a study of 23 patients, older age and presence of non-ocular findings were suggestive of higher rate of recurrence (77).

Complications. The neurologic signs and symptoms are most often limited to the prodromal phase of the disease, when cognitive dysfunction and headache characteristically occur.

Ocular complications include cataract (33% to 42%), glaucoma (24% to 27%), posterior synechiae, choroidal neovascular membrane (11%), subretinal scarring (6%), and optic neuropathy (112; 111; 155; 11).

Increased axial length leading to myopia progression has been described in the Japanese population, occurring as early as 1 month after onset and persisting at 6 months (175; 117).

Clinical vignette

A 16-year-old Hispanic boy developed new headaches for 2 weeks prior to admission. He also noted blurred vision in his right eye and described images as looking distorted and enlarged when viewed with his right eye. On the day of admission, he was confused and disoriented.

Neurologic examination disclosed mental confusion and mild disorientation in time, but no focal findings. There was moderate nuchal rigidity, and Kernig and Brudzinski signs were present. Visual acuity was 20/60 in the right eye and 20/20 in the left eye. There was no relative afferent pupillary defect. Fundus examination revealed serous elevation of the macula in the right eye and optic disc swelling in both eyes.

MRI showed mild patchy gadolinium enhancement of the meninges, but no focal signal abnormalities or ventriculomegaly.

Lumbar puncture yielded clear cerebrospinal fluid under normal opening pressure. There were 60 white blood cells/mm3, of which 95% were lymphocytes and 5% were monocytes. Protein was 56 mg/dl and glucose 40 mg/dl (serum glucose 120 mg/dl). Cytology was negative for malignant or atypical cells. Protein electrophoresis revealed mild elevation of gamma globulin.

He was initially treated with intravenous methylprednisolone 1 gram/day for 3 days, followed by oral prednisone at an initial dose of 60 mg/day, followed by a tapering schedule over the next 3 weeks. His mental status cleared rapidly, and he was discharged to his home after 5 days.

At the first office follow-up visit 2 weeks after discharge, the right eye visual acuity had improved to 20/25 and the symptom of blur and metamorphopsia had resolved. On fundus examination, the optic disc swelling had resolved in both eyes, as had the subretinal fluid at the right macula. At 3 months after presentation, with corticosteroids discontinued, vision and neurologic status remained normal. The fundus exam showed patches of orange discoloration in the posterior pole and some broad bands of pigment clumping and dark discoloration at the level of the retinal pigment epithelium.

Biological basis

Etiology and pathogenesis

Vogt-Koyanagi-Harada syndrome represents a cell-mediated autoimmune response against melanocytes. Histopathologically, inflammation and loss of melanin-containing cells in the skin and the uvea of the eye have been observed. Melanocytes exist in the meninges and in the inner ear; however, the pathogenesis of hearing loss is unresolved.

The histopathology of Vogt-Koyanagi-Harada syndrome has been sparsely documented. There is granulomatous or non-granulomatous choroidal infiltration, with the epithelioid cells often containing cytoplasmic melanin. The choriocapillaris is typically spared (142; 112). Because the available pathologic material comes from enucleated eyes, the only pathology in the central nervous system is the observation of lymphocytic infiltration in the leptomeninges along the amputated stump of the optic nerve (142).

Cellular immune mechanisms are probably more important than humoral ones (112). Antibodies to a number of retinal antigens have been detected, but whether they are epiphenomena is uncertain (25).

Melanocytes are likely involved in the meningitic component. Peripheral and cerebrospinal fluid lymphocytes from patients with Vogt-Koyanagi-Harada syndrome exhibit cytotoxicity against melanoma cells and normal melanocytes (107; 129), as have lymphocytes derived from intraocular aqueous humor (130). Macrophages containing melanin granules have been found in the CSF of patients with Vogt-Koyanagi-Harada syndrome but not in patients with other meningeal inflammatory diseases (120).

In a study, T-cells constituted the majority of lymphocytes in aqueous humor, and aqueous humor lymphocytes from the patients with Vogt-Koyanagi-Harada syndrome were more activated than were peripheral blood lymphocytes. Of the lymphokines studied, interleukin-6 appeared to play an important role as an inflammatory mediator (130). Studies of enucleated eyes from a patient with active Vogt-Koyanagi-Harada syndrome showed similar distribution of T-cell subsets in the inflammatory lesion within the uveal tract (75). Studies have also shown that the ratio of T-helper to T-suppressor cells is increased, and that cells expressing surface markers characteristic of both early (CD25) and late (CD26) lymphocyte activation are present in the inflammatory lesion. Also, a class 2 major histocompatibility complex was expressed in the choroidal melanocytes, as well as in the endothelium of the choriocapillaris, indicating a probable primary role for the melanocyte in the pathogenesis of the lesion (158).

The antigens MART-1/Melan-A (170), peptidase (85), P-36 (128), tyrosinase (192; 45), IgG anti-lens epithelium-derived growth factor (191), and KU-MEL-1 (135) have also been implicated.

In a study of T-helper cells from nine patients with Vogt-Koyanagi-Harada disease versus nine controls, it was found that peripheral blood mononuclear cells from patients produced significantly higher levels of mRNA only for interferon-gamma and not for interleukin-2 or interleukin-4. Levels of interferon-gamma and interleukin-2 were significantly increased in the stimulated cell culture supernatant of patients as compared with controls (60). IgE levels were correlated with retinal disease severity in a study of 128 patients (70).

One study described three patients who developed Vogt-Koyanagi-Harada syndrome shortly after skin injuries (151). All three patients developed vitiligo in the injured areas as the skin healed, and the uveitis began at the same time. The authors suggest that the onset of Vogt-Koyanagi-Harada syndrome following skin injury supports the idea that the disease involves systemic sensitization to shared melanocytic antigens (151). Another study described a 68-year-old Chinese woman who developed uveitis followed by generalized cutaneous inflammation (erythroderma) 6 months later and by vitiligo 6 months after that, the first report of cutaneous inflammation preceding vitiligo (189).

A Vogt-Koyanagi-Harada–like syndrome has been described in patients with metastatic melanoma following initiation of checkpoint inhibition or protein kinase inhibition therapy (44; 201; 29; 22).

A similar syndrome has also been described following vaccination (33; 166; 116), suggesting an exuberant immune reaction as a possible trigger. During the 2020 COVID-19 pandemic, there were several reports of a Vogt-Koyanagi-Harada–like syndrome associated with COVID-19 vaccination (86; 06; 31; 74; 81) and infection (200). There was a relapse of VKH following COVID-19 vaccination (118).

Investigators have identified a subset of pathologically activated monocytes with gene expression indicative of inflammation, antiviral activity, and pathologic activation (57). Peripheral blood mononuclear cells in Vogt-Koyanagi-Harada syndrome have also been shown to express unique RNA profiles (48). Genome-wide association analysis has also identified new loci associated with Vogt-Koyanagi-Harada syndrome risk (147). Studies have identified a set of hub genes that may contribute (186). Proteomic profiling demonstrated increased levels of carbonic anhydrase 2 and Ras-related protein Rap-1b (206) and C1QB (205) in plasma exosomes.

Studies have shown differences in gut microbiota in patients with Vogt-Koyanagi-Harada syndrome compared to healthy controls and other noninfectious anterior uveitides (95; 94; 185).

In a case report, Maehira and colleagues observed different severities of inflammation between the eyes of a single patient with significantly different axial lengths (104).

Using a retinal pigment epithelium model derived from Vogt-Koyanagi-Harada peripheral mononuclear cells, one study observed barrier and phagocytic dysfunction as well as depigmentation compared to normal controls, suggesting dysfunction at the level of the retinal pigment epithelium (96). In the same study, treatment with a molecule targeting early growth response gene 2 restored barrier and phagocytic function in the pathological retinal pigment epithelium cells, suggesting a pathological role and a possible target for future pharmaceutical treatment. Patients with Vogt-Koyanagi-Harada syndrome were also shown to harbor a mutation in membrane palmitoylated protein 2 (MPP2), associated with cytokine and cellular barrier dysfunction (102). Possible contributory polymorphisms in PRKCD, CARD9 (208), ZC3HAV1 (190), OR11H1 (97), and LRRC30 dysregulation (204) have also been identified. Bioinformatics analysis has identified interferon gamma and interleukin 6 as key mediators of Vogt-Koyanagi-Harada syndrome and as possible targets for future therapeutics (27).

Differential diagnosis

Confusing conditions

Sympathetic ophthalmia is an autoimmune condition that closely mimics Vogt-Koyanagi-Harada syndrome. A bilateral non-necrotizing granulomatous uveitis, it is an autoimmune response against uveal autoantigens exposed by penetrating trauma or surgery. Non-ocular manifestations are far fewer in sympathetic ophthalmia than in Vogt-Koyanagi-Harada syndrome (193). A negative history of ocular trauma or surgery makes a diagnosis of sympathetic ophthalmia highly unlikely.

Lymphoma can present simultaneously in the eye and in the brain as a space-occupying lesion or diffuse meningeal infiltration (83; 112; 15; 188). Subretinal deposits, as well as vitreous cells, may be seen. The vitritis may initially respond to corticosteroid therapy but will recur once treatment is stopped. Multiple serous retinal detachments have also been reported (93). Acute lymphoblastic leukemia (52) and lymphoma (114) presenting as Vogt-Koyanagi-Harada syndrome have also been described.

Sarcoidosis is another granulomatous cause of panuveitis. Ocular sarcoidosis tends to produce retinal perivenous sheathing, called "candle-wax drippings," whereas the serous retinal detachment characteristic of Vogt-Koyanagi-Harada syndrome is not encountered. The neurologic findings in sarcoidosis are focal, often involving the cranial nerves, whereas headache and cognitive impairment are most common in Vogt-Koyanagi-Harada syndrome. Both conditions may have chronic CSF pleocytosis (112).

A rare, immune complex–mediated choroidal vasculitis in systemic lupus erythematosus mimics Vogt-Koyanagi-Harada syndrome by causing serous retinal detachments (67; 112). Patients often exhibit systemic manifestations of systemic lupus erythematosus.

Infectious posterior uveitis, including syphilis and tuberculosis, can present as subretinal nodules, posterior or anterior uveitis, and serous retinal detachment. Infection must be ruled out prior to starting corticosteroid or other immunomodulating therapy (100; 01).

Other diseases in the differential diagnosis of Vogt-Koyanagi-Harada syndrome include acute multifocal placoid pigment epitheliopathy, multiple evanescent white dot syndrome, posterior scleritis (163), Behcet disease (76), and bilateral diffuse melanocytic proliferation (30). The two features that most reliably distinguish Vogt-Koyanagi-Harada syndrome from these other forms of uveitis are exudative retinal detachment in the acute uveitic phase and sunset glow fundus in the late phases (150).

Central serous retinopathy typically presents with subretinal fluid and may be recurrent. Central serous retinopathy may be distinguished from Vogt-Koyanagi-Harada syndrome by the lack of uveitis and characteristic leakage pattern on fluorescein angiography. Importantly, central serous retinopathy is typically exacerbated by systemic corticosteroid treatment (126).

With the advent of antineoplastic immune checkpoint inhibitors, a Vogt-Koyanagi-Harada–like syndrome has been described, even after their discontinuation (124; 178). Of the adverse reactions reported in the WHO international pharmacovigilance database, immune checkpoint inhibitors and protein kinase inhibitors were associated with a Vogt-Koyanagi-Harada–like syndrome (16).

A case of Vogt-Koyanagi-Harada–like syndrome preceding melanoma-associated retinopathy has been reported in a patient with metastatic melanoma (124).

Vogt-Koyanagi-Harada syndrome has been described after COVID-19 infection and vaccination (125; 161; 200; 198).

Vogt-Koyanagi-Harada syndrome has been described in patients with autoimmune diseases, including ulcerative colitis (41), IgA nephropathy (203), and erosive seronegative polyarthritis (134), suggesting an association with autoimmunity. A case of Vogt-Koyanagi-Harada disease has been reported as a complication of treating hepatitis C with interferon alpha-2b and ribavirin combination therapy (172).

Associated or underlying disorders

Vogt-Koyanagi-Harada syndrome is associated with HLA-DR4 positivity (64; 65; 165; 187; 146; 157) and HLA-DQ4 (83% vs. 32% in controls). Among variants, HLA-DQA1*0301 positivity is associated with the Vogt-Koyanagi-Harada syndrome phenotype, whereas HLA-DQB1*0604 is considered protective. The DRB1*0405 or DRB1*0410 variants portend to a longer disease course (64; 65). One epigenetic association study of 160 patients identified methylation in HLA-DRB1 and HLA-DQA1, as well as several non-HLA methylation sites (169).

Seven of 62 clones from patients with Vogt-Koyanagi-Harada disease that were reactive with tyrosinase or tyrosinase-related protein showed proliferative responses to peptides that match the motif of the strong binding site for HLADRB1*0405 (45). Weisz and colleagues determined human leukocyte antigen specificities in 25 Hispanic patients living in Southern California and compared them to 217 healthy Hispanic control subjects (187). HLA-DR4 was present in 56% of the patients and in 29% of the control subjects. HLA-DR1 was present in 36% of the patients and in 9% of the control subjects. Combinations of HLA-DR4 and HLA-DR1 characterized 84% of patients but only 35% of control subjects. These findings point to a common immunogenic predisposition to Vogt-Koyanagi-Harada syndrome among different racial groups that are differentially susceptible and that there may be a common epitope shared by DR1 and DR4 that is involved in the pathogenesis of the disease.

In studies examining BRAF-mutant melanoma patients treated with BRAF kinase inhibitors and MEK kinase inhibitors (12), or checkpoint inhibitors for other malignancies (177), the incidence of Vogt-Koyanagi-Harada-like syndrome was higher in those with HLA-DRB1*04 and HLA-DRB1*04:05, respectively.

Diagnostic workup

Diagnostic criteria. Consensus criteria developed in 1978 by the American Uveitis Society were updated following the First International Workshop on Vogt-Koyanagi-Harada Disease in 1999. This newer set of criteria recognizes that Vogt-Koyanagi-Harada has distinct features in different stages of the natural history and establishes criteria for early diagnosis when many of the characteristic cutaneous findings have not yet occurred (154) (Table 1).

Table 1. Consensus Diagnostic Criteria for Vogt-Koyanagi-Harada Disease

Complete Vogt-Koyanagi-Harada disease (criteria 1 to 5 must be present)
	1. No history of penetrating ocular trauma or surgery preceding the initial onset of uveitis
	2. No clinical or laboratory evidence suggestive of other ocular disease entities
	3. Bilateral ocular involvement (a or b must be met, depending on the stage of disease when the patient is examined).
	4. Neurologic and auditory findings (may have resolved by time of examination)
		- meningismus - tinnitus - cerebrospinal fluid pleocytosis
	5. Integumentary finding (not preceding onset of central nervous system or ocular disease)
		- alopecia - poliosis - vitiligo
Early manifestations of disease
	• There must be evidence of a diffuse choroiditis (with or without anterior uveitis, vitreous inflammatory reaction, or optic disc hyperemia), which may manifest as one of the following:
		- focal areas of subretinal fluid - bullous serous retinal detachments
	• With equivocal fundus findings, both of the following must be present as well:
		- focal areas of delay in choroidal perfusion, multifocal areas of pinpoint leakage, large placoid areas of delay in choroidal perfusion, pooling within subretinal fluid, and optic nerve staining by fluorescein angiography
		- diffuse choroidal thickening, without evidence of posterior scleritis by ultrasonography
Late manifestations of disease
	• History suggestive of prior presence of findings
	• Ocular depigmentation (either of the following manifestations is sufficient):
		- sunset glow fundus - Sugiura sign
	• Other ocular signs:
		- nummular chorioretinal depigmented scars - retinal pigment epithelium clumping or migration - recurrent or chronic anterior uveitis
Incomplete Vogt-Koyanagi-Harada disease (criteria 1 to 3 and either 4 or 5 must be present)

Probable Vogt-Koyanagi-Harada disease (isolated ocular disease; criteria 1 to 3 must be present)
(154)

New diagnostic criteria were proposed in 2018 using retrospective data from 1257 Chinese patients in China (195). The criteria consisted of a 3-class model grouping patients into early-phase disease, late-phase disease, or non-Vogt-Koyanagi-Harada uveitis. They compared 37 variables, 21 of which were deemed important in the diagnosis of Vogt-Koyanagi-Harada disease as they were associated with high-specificity or high-positive rates (Table 2). The Diagnostic Criteria for Vogt-Koyanagi-Harada Disease showed higher sensitivity (94.6% vs. 71.9%) and negative predictive value (94.3% vs. 76.6%) than the revised diagnostic criteria. The positive predictive value showed no difference when compared to the revised diagnostic criteria. As these criteria were developed retrospectively, they need to be evaluated in prospective studies for further investigation (195).

Table 2. Proposed New Diagnostic Criteria for Vogt-Koyanagi-Harada Disease

A. No history of penetrating ocular trauma or intraocular surgery preceding the initial onset of uveitis
B. Bilateral ocular involvement (time interval between the two eyes should be 2 weeks)
C. No evidence of infectious uveitis or accompanying systemic rheumatic diseases or evidence suggestive of other ocular disease entities
D. Early-phase Vogt-Koyanagi-Harada disease:
	1. Signs of diffuse choroiditis and exudative retinal detachment
	2. Serous retinal detachment on optical coherence tomography or B-scan ultrasonography
	3. Choroidal thickening on enhanced depth imaging-optical coherence tomography (B-scan can be used where enhanced depth imaging-optical coherence tomography not available, though it is not as precise)
	4. Early punctate staining and late subretinal dye pooling on fluorescence fundus angiography
	5. Hyperfluorescence of the optic disc on fluorescence fundus angiography
	Definite diagnosis:
		Variant 1: In patients presenting with A+B+C+ D(1)
		Variant 2: In patients without clinically visible exudative retinal detachment, ie, A+B+C+ D(2) + D(3) or A + B + C + D(4)
		Variant 3: In patients already treated with systemic corticosteroids or combined with other immunosuppressive agents, a history of typical appearances of variant 1 or 2, and A+B+C+ D(5)
E. Late-phase Vogt-Koyanagi-Harada disease:
	1. Signs of definite sunset glow fundus or retinal pigment epithelium clumping/migration
	2. Signs of bilateral recurrent granulomatous anterior uveitis
	3. Signs of Dalen-Fuchs nodules or multifocal chorioretinal atrophy
	4. Window defects/moth-eaten fluorescence on fluorescence fundus angiography
	5. Previous history of characteristic findings corresponding to diagnosis of early-phase Vogt-Koyanagi-Harada disease
	Definite diagnosis:
		Variant 1: In patients presenting with A+B+C+ E(1) + E(2)
		Variant 2: In patients without sunset glow fundus or visible pigment alternations due to early and appropriate treatment, ie, A+B+C+ E(2) + E(3) or A+B+C+ E(2) + E(4)
		Variant 3: In patients with significant media opacity, ie, A+B+C+ E(2) + E(5)

Criteria are evolving to include modern ophthalmic imaging findings. Indocyanine green angiography is a diagnostic imaging procedure that examines blood flow through the choroid. The fluorescent molecule indocyanine green is infused intravenously, and a series of fluorescent photographs are taken with a specialized fundus camera. Fluorescein angiography is a technique similar to indocyanine green angiography but evaluates the retinal circulation in addition to the choroid. Optical coherence tomography is a noninvasive imaging technique used to generate a cross-section of the retina and choroid.

In 2021, the Standardization of Uveitis Nomenclature (SUN) Working Group published its classification criteria of early and late-stage Vogt-Koyanagi-Harada disease, which utilized machine learning to determine a set of classification criteria that minimized misclassification of Vogt-Koyanagi-Harada disease with other forms of panuveitis (53). Over 1000 cases of panuveitis were evaluated, including 156 cases of early-stage Vogt-Koyanagi-Harada disease and 103 cases of late-stage Vogt-Koyanagi-Harada disease. The 95% confidence interval for overall accuracy was between 89.0% and 96.8%.

Table 3. Classification Criteria for Early-Stage Vogt-Koyanagi-Harada Disease

Criteria Diagnosis requires 1 or 2 AND 3
	1. Evidence of Harada disease
		a. Serous (exudative) retinal detachment AND (b) and/or (c)
		b. Multiloculated appearance on fluorescein angiogram OR
		c. Septae on optical coherence tomogram
OR
	2. Panuveitis^a with two or more of the following neurologic symptoms or signs^b
		a. Headache OR
		b. Tinnitus OR
		c. Dysacusis OR
		d. Meningismus OR
		e. Cerebrospinal fluid pleocytosis
AND
	3. No history of penetrating ocular trauma or vitreoretinal surgery prior to disease onset
Exclusions
	1. Positive serology for syphilis using a treponemal test
	2. Evidence for sarcoidosis (either bilateral hilar adenopathy on chest imaging or tissue biopsy demonstrating noncaseating granulomata)
^a Uveitis should have evidence of choroidal involvement on clinical examination, fluorescein angiography, indocyanine green angiography, or optical coherence tomography, including enhanced depth imaging of the choroid.
^b Onset of neurologic symptoms and signs and onset of the uveitis should occur within 4 weeks of each other.
(53)

Table 4. Classification Criteria for Late-Stage Vogt-Koyanagi-Harada Disease

Criteria
	1. History of early-stage Vogt-Koyanagi-Harada disease
AND 2 and/or 3
	2. Sunset glow fundus
OR
	3. Uveitis* AND one or more of the following cutaneous findings
		a. Vitiligo OR
		b. Poliosis OR
		c. Alopecia
Exclusions
	1. Positive serology for syphilis using a treponemal test
	2. Evidence for sarcoidosis (either bilateral hilar adenopathy on chest imaging or tissue biopsy demonstrating noncaseating granulomata)
* Uveitis may be (1) chronic anterior uveitis; (2) anterior and intermediate uveitis; or (3) panuveitis with multifocal choroiditis (“Dalen Fuchs–like nodules”)
(53)

Ophthalmic ancillary testing. During the acute uveitic stage, indocyanine green angiography demonstrates multifocal areas of delayed choroidal filling. In the late stages, peripapillary and multifocal choroidal pinpoint leakage can be seen. Indocyanine green may pool late in the areas of serous retinal detachment. Features on pre-treatment ICG angiography may also provide prognostic value (179).

Fluorescein angiography demonstrates similar punctate hyperfluorescence in the choroid and retinal pigment epithelium, with progressive staining in areas of active choroiditis in the later phase of the angiogram. Dye can similarly accumulate in the areas of serous retinal detachments. This pattern of hyperfluorescence is said to give a “moth-eaten” appearance. Optic nerve head leakage is found in 70% of cases (112).

Due to differences in protein binding and wavelengths used, there are differences between indocyanine green angiography and fluorescein angiography leakage patterns. Indocyanine green angiography is advantageous for evaluating the choroid and retinal pigment epithelium, with less interference from the retinal pigment epithelium (51).

Melanin accumulation may be seen with near-infrared photography with corresponding hyper-reflectivity on optical coherence tomography. These lesions may resolve with treatment (108). Spectral domain optical coherence tomography (sdOCT) is another noninvasive diagnostic modality used to assess the retina, retinal pigment epithelium, and choroid. This technique can be used to monitor retinal and choroidal thickness, as well as the extent of subretinal fluid. It is routinely performed in the office, and acquisition is rapid, thus, making it one of the most commonly used imaging modalities to monitor disease activity (69; 07; 68) and predict recurrence (56).

Swept-source and enhanced depth imaging optical coherence tomography have also been used to evaluate increased choroidal thickness in acute Vogt-Koyanagi-Harada syndrome. Swept-source optical coherence tomography has better resolution for the choroid than enhanced depth imaging optical coherence tomography and can be used to follow resolution of inflammation after treatment with steroids (145). Fibrin membranous structures on OCT were associated with younger age, greater disease severity, and cumulative steroid dose but did not affect final visual outcome (113). Optical density of subretinal fluid has not been shown to be helpful in differentiating Vogt-Koyanagi-Harada syndrome from other causes of serous retinal detachment (37).

Optical coherence tomography angiography is a noninvasive imaging technique that provides an angiogram of the retinal and choroidal vasculature without the need for intravascular fluorophores. Optical coherence tomography angiography has shown multiple dark foci at the level of the choriocapillaris corresponding with hypocyanescence on indocyanine green angiography, indicating hypoperfusion and ischemia. Microvascular density is significantly decreased in eyes with sunset glow fundus (38). Flow defects, as well as vascular density, have been shown to worsen in acute disease (199; 32) and improve with glucocorticoid treatment (145; 58). Further, optical coherence tomography angiography has demonstrated changes in choroidal thickness and blood flow in active and remitting disease (40). It has also demonstrated flow voids preceding clinically relapsing disease (63). Thus, optical coherence tomography angiography can be used to detect subclinical disease activity as well as monitor response to treatment. Persistent flow voids in the convalescent phase were associated with worse final visual acuity (19). The presence of optic nerve swelling is associated with lower retinal arteriolar blood flow and oxygen saturation (04), as well as lower peripapillary vessel densities (71).

Ultrasound biomicroscopy may show ciliochoroidal detachment (20%) and unclear ciliary processes (15%), which are characteristic in the uveitic phase. These changes improve with treatment but may be observed in recurrent uveitis (136).

Adaptive optics scanning laser ophthalmoscopy, an emerging technology, may be a useful indicator measuring photoreceptor density during active disease and recovery (144). Laser speckle flowgraphy (02; 04) and retinal oximetry has also been used to evaluate choroidal perfusion in Vogt-Koyanagi-Harada syndrome (03).

Neurologic ancillary testing. Lumbar puncture yields diagnostically useful information in the form of lymphocytic pleocytosis in a high percentage of patients, if fluid is sampled within the first 8 weeks. There may be a lag in the development of pleocytosis, as the percentage of patients with this finding rises from 80% in the first week of symptoms to 97% by the third week (171; 112). Other authors questioned the necessity of CSF examination and found that fluorescein angiography along with clinical examination were diagnostic even in patients without cerebrospinal fluid pleocytosis (181).

Though MRI is often obtained for workup of neurologic symptoms, findings are often nonspecific related to leptomeningeal inflammation. Le described a case of Vogt-Koyanagi-Harada syndrome presenting with bilateral optic nerve swelling and leptomeningeal enhancement (92). Ikeda and Tsukuguchi report a case of Vogt-Koyanagi-Harada syndrome with multiple hyperintense signal abnormalities in the cerebral white matter. One patient had high signal abnormalities in the periventricular cerebral white matter (59).

MRI may show choroidal thickening, indicating a concurrent ocular process (73; 112; 143). Theta-range slowing of the EEG is often present, but this is so nonspecific as to be relatively unhelpful in establishing the diagnosis of Vogt-Koyanagi-Harada syndrome.

Other ancillary testing. In small series, the measurement of individual cell populations may be useful in differentiating Vogt-Koyanagi-Harada syndrome from other uveitic syndromes (76) and measuring response to treatment.

Management

High-dose systemic corticosteroid treatment is recommended during the uveitic stage, with slow dosage tapering over the subsequent 3 to 6 months. Treatment is generally monitored by ophthalmologic parameters, and patients should be under the care of an ophthalmologist for this. High-dose corticosteroid treatment can induce central serous choroidopathy in patients with Vogt-Koyanagi-Harada as with other forms of chronic uveitis and this must be considered as possibly causative if a patient has worsening of visual acuity with treatment (162).

The neurologic problems are generally limited to the prodromal and early uveitic stages. Specific management of these problems is seldom an issue. Recurrences during corticosteroid tapering may become refractory to treatment and require the use of cytotoxic agents such as cyclophosphamide, chlorambucil, or azathioprine, or cytostatic agents such as cyclosporine (112).

Case reports and case series have shown stable control achieved with mycophenolate mofetil (05), rituximab (34), infliximab (209), tofacitinib (35), and adalimumab (168; 90; 176; 164). Small series have demonstrated improved visual acuity outcomes in patients treated early with immunomodulatory therapy (139). Large reviews suggest that steroidal and nonsteroidal dual therapy given at onset is better than corticosteroid monotherapy alone (55; 138; 196). Biologics have shown promise in achieving control in refractory and recurrent disease (21; 197; 164).

In a clinical trial of 110 patients, initial treatment with cyclosporine showed similar efficacy compared to adalimumab when combined with a low-dose oral corticosteroid (207).

In case reports and one small prospective study, intravitreal dexamethasone implant (24; 26; 36) or intravitreal fluocinolone acetonide implant combined with intravitreal methotrexate (140) has shown efficacy. In a small series, suprachoroidal steroid injections were shown to be an effective adjunct to oral steroid therapy in treating serious retinal detachment (174). These local therapies may be a safe alternative for patients who develop morbidity or adverse events with systemic treatment.

Vitrectomy to drain subretinal fluid has been described. However, in a small case series, three of five eyes with Vogt-Koyanagi-Harada syndrome that underwent vitrectomy had recurrence of serous retinal detachment that did not respond to medical therapy and required repeat surgery (153).

Outcomes

A study of 97 consecutive patients presenting in Riyadh, Saudi Arabia, included 13 children and 84 adults (173). Sixty-one percent (eight patients) of those younger than 14 years of age (children) required cataract surgery, as compared with 17% (14 patients) of the adults. Sixty-one percent of the children had final visual acuity equal to or worse than 20/200, whereas only 26% of adults had that severe visual consequence. Chronic recurrent disease is associated with worse outcomes in children (08).

Of 98 patients with Vogt-Koyanagi-Harada syndrome seen at the Aravind Eye Hospital in Madurai, India, between 1993 and 1995, three were children (under 16 years of age), and all required cataract surgery (152). Visual outcome was good, despite the eventual development of retinal pigment epithelial atrophy in two children and glaucoma in one child. The presence of posterior synechiae at diagnosis is associated with an increased risk of recurrent anterior uveitis (98). Patients with Vogt-Koyanagi-Harada syndrome who develop a bullous retinal detachment have an eight times higher risk of developing subretinal fibrosis (46). Late presentation, recurrent inflammation, and iris and angle scarring were associated with greater development of secondary glaucoma (10; 202). Patients with bacillary layer detachment had more severe disease in the acute phase and a higher rate of recurrence within the first 6 months (89).

Small series have demonstrated improved visual acuity outcomes in patients treated early with immunomodulatory therapy (139; 99; 39). However, some have observed increased adverse events in patients who start immunomodulatory therapy immediately and have proposed early initiation of immunomodulation based on stratified risk (72). Initiation of treatment preceding anterior segment inflammation (a late presentation) was associated with fewer long-term complications (04). More aggressive treatment with intravenous methylprednisolone compared to conventional dose oral corticosteroids showed fewer recurrences and better long-term visual outcomes (109). This may be a pulse of intravenous corticosteroids followed by an oral taper (43). Finally, it has also been shown that patients whose initial corticosteroid treatment was continued for 6 months or longer have significantly fewer late recurrences of ocular inflammation than patients initially treated for less than 6 months (91).

Patients on high-dose corticosteroid or immunomodulatory therapy are at increased risk of opportunistic infections. Some of these infections may also manifest as posterior uveitis, complicating the management and clinical picture. Cases of tuberculosis uveitis and cytomegalovirus retinitis during therapy for Vogt-Koyanagi-Harada syndrome have been described (79; 14). Development of COVID-19 has also been described during immunosuppressive therapy (127), although some authors suggest that the antiviral properties of cyclosporine as a treatment agent may reduce this risk (123).

Reversal of iris depigmentation with treatment has been described (180).

Control of uveitis, better vision, and treatment-free survival were associated with higher quality of life scores (167).

Media

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Homer Chiang MD

Dr. Chiang of Kaiser Permanente Santa Clara Homestead Medical Center has no relevant financial relationships to disclose.
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Editor

Jonathan D Trobe MD

Dr. Trobe of the University of Michigan has no relevant financial relationships to disclose.
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Former Authors

James Goodwin MD
Peter MacIntosh MD
Brooke Johnson DO
Heather E Moss MD PhD

Patient Profile

Age range of presentation: 13 to 65+ years
Sex preponderance: female>male, >1:1
Heredity: heredity may be a factor
Population groups selectively affected: Asians

Indians

Native Americans

Hispanics

African descent
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Other iridocyclitis: H20.8

Vogt-Koyanagi Harada syndrome, bilateral: H20.823
ICD-11: Vogt-Koyanagi-Harada syndrome: ED63.3

Anterior uveitis associated with systemic conditions: 9A96.1

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Vogt-Koyanagi-Harada syndrome

Associated Disorders

HLA-DR4 positivity
combinations of HLA-DR4 and HLA-DR1

Differential Diagnosis

sympathetic ophthalmia
lymphoma
acute lymphoblastic leukemia
sarcoidosis
immune complex–mediated choroidal vasculitis in systemic lupus erythematosus
- infectious posterior uveitis
- syphilis
- tuberculosis
- acute multifocal placoid pigment epitheliopathy
- multiple evanescent white dot syndrome
- posterior scleritis
- Vogt-Koyanagi-Harada–like syndrome
- autoimmune diseases
- ulcerative colitis
- IgA nephropathy
- erosive seronegative polyarthritis

Vogt-Koyanagi-Harada syndrome

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Table 1. Consensus Diagnostic Criteria for Vogt-Koyanagi-Harada Disease

Table 2. Proposed New Diagnostic Criteria for Vogt-Koyanagi-Harada Disease

Table 3. Classification Criteria for Early-Stage Vogt-Koyanagi-Harada Disease

Table 4. Classification Criteria for Late-Stage Vogt-Koyanagi-Harada Disease

Management

Outcomes

Special considerations

Pregnancy

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

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