Vogt-Koyanagi-Harada disease

Russell W. Read, MD

Department of Ophthalmology, University of Alabama School of Medicine, University of Alabama at Birmingham,

700 18th Street South, EFH DB110-0009, Birmingham, AL 35233, USA

Vogt-Koyanagi-Harada (VKH) disease has been

known, but not necessarily recognized in its complete

form, for over a millennium. Despite this, information

regarding the exact cause and best treatment regimen

for this potentially blinding condition are not estab-

lished. Manifesting ophthalmologically as a bilateral,

granulomatous panuveitis, VKH disease seems to be a

T-cell mediated systemic autoimmune process, which

evidence increasingly suggests is directed at one or

more antigens associated with melanocytes. As such,

any organ system that contains melanocytes is a

potential target of attack, including the eye, skin and

hair, inner ear, and meninges. VKH disease occurs

more frequently in certain ethnic groups. The disease

has distinct phases, with acute disease involving

primarily the ocular posterior segment, central nervous

system, and inner ear. By contrast, chronic-recurrent

disease involves the ocular anterior segment and

integumentary system. Aggressive anti-inflammatory

therapy is typically required, but no quality clinical

trial data exist to guide the agent of choice, dosage, or

duration of therapy. Complications are not uncommon

and are typically the reason for decreased vision.

Many questions remain to be answered regarding

VKH disease. Work toward these answers continues,

as evidenced by the occurrence of an ongoing series

of international workshops directed specifically at

this disease. Out of the two workshops held to date,

revised diagnostic criteria [1] have been issued and a

disease severity grading scheme is in formation, both

for use in planned prospective clinical trials.

Historical background

The association of poliosis with inflammatory eye

disease was recognized as early as the 10th century

AD, when Ali-ibn-Isa described what is now termed

chronic VKH disease [2,3]. The current tripartite

eponym stems from descriptions of the chronic dis-

ease phase by Vogt [4] in 1906 and Koyanagi [5] in

1929, and of the acute disease phase by Harada [6] in

1926. Babel [7] in 1932 and Bruno andMcPherson [8]

in 1949 realized that these descriptions were points on

a disease spectrum and coalesced these entities under

the rubric of VKH disease. Although the acute pre-

sentation is still occasionally referred to as Harada’s

disease, recently published revised diagnostic criteria

favor always using the full name, given the know-

ledge that this is one disease process [1].

Epidemiology

Vogt-Koyanagi-Harada disease occurs most com-

monly in certain ethnic groups. Although not estab-

lished definitively, it is possible that the link between

these groups arises from a common ancestry in the

original peoples of Asia. Dispersion then occurred

through migration across the Asian continent, over

the Bering Strait land bridge, and into the Americas

[9]. This susceptible group of individuals includes

modern-day East and Southeast Asians, Asian Indians,

Middle Easterners, Native Americans, and Hispanics.

The disease occurs, but is uncommon, in whites and

Africans [10]. An American Indian ancestry has been

reported as important in patients from the United

States [11,12]. Rarity in Africans suggests that amount

of pigmentation alone is not the main factor in the

etiology of VKH disease. Rather, something within

0896-1549/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved.

PII: S0896 -1549 (02 )00025 -1

Supported in part by unrestricted grants from Research

to Prevent Blindness, Inc., New York, NY and the EyeSight

Foundation of Alabama, Inc., Birmingham, AL.

E-mail address: rwr@uab.edu (R.W. Read).

Ophthalmol Clin N Am 15 (2002) 333–341

the immune repertoire of susceptible individuals likely

predisposes them to sensitization to antigens of mela-

nocytic origin. Details of the relationship between

genetics and VKH disease are discussed further in

the next section.

Vogt-Koyanagi-Harada disease has been reported

to be responsible for up to 9.2% of cases of uveitis

clinics in Japan [2], is the main cause of autoimmune

noninfectious uveitis in Brazilians [13], and is the

second most common uveitic diagnosis made in Saudi

Arabia [14]. In contrast, earlier publications from the

United States reported a prevalence in uveitis clinics

of 1% [15] to 4% [16]. Read et al [17] recently ex-

amined uveitic disease prevalence in a uveitis tertiary

referral center in Southern California for the 3-year

period 1996 to 1998. They found the frequency of

VKH disease to be 7%. This more frequent occurrence

compared with previous reports was believed to be

secondary to the large Hispanic and Asian populations

in Southern California and referral bias to this par-

ticular clinic. It is highly likely that as the demo-

graphics of the remainder of the United States

continue to diversify, VKH disease will become a

more frequently encountered entity in practices across

the country.

Most series have reported an approximate female

to male disease ratio of 2:1 [2,10,18]. Most patients

have the onset of disease while in their third to fifth

decade of life, but cases have been reported in children

as young as 4 years of age [19,20]. It has been

suggested that VKH disease in children may be more

aggressive than in adults. In one series, Tabbara et al

[21] found that 61% of children with VKH disease

had final visual acuities of 20/200 or worse despite

medical and surgical therapy. In a review of world

literature on pediatric VKH disease, however, Rathi-

nam et al [22] found that 85.7% of children had a final

visual acuity of 20/30 or better in the best eye. The

prognosis in this subpopulation seems to be quite

variable, and final visual outcome may be related to

as yet unknown differences between the various

ethnic groups, time to treatment, type of treatment,

and duration of treatment.

Etiology and pathogenesis

The exact cause of VKH disease is unknown.

Most research on its pathophysiology has been direc-

ted at identifying the precise target of autoimmune

attack and associations of the disease with specific

immune profiles.

Ophthalmic histopathology has shown VKH dis-

ease to be a granulomatous panuveitis that has many

similarities with sympathetic ophthalmia [23]. Immu-

nohistochemical investigations have shown the pre-

dominant infiltrating cell in the choroid is the

T lymphocyte, with a larger proportion of helper

(CD4+) cells than cytotoxic (CD8+) cells [24]. Present

also are epithelioid and multinucleated giant cells

containing melanin [25]. Choroidal melanocytes have

been shown to express major histocompatibility com-

plex class II molecules on their surface in eyes from

patients with VKH disease [24]. These molecules are

required to participate in antigen presentation to CD4+

T cells. In the cerebrospinal fluid of VKH disease

patients, activated CD4+ T cells predominate [26,27]

andmelanin-containing macrophages have been found

[28,29]. Similar findings have been reported from

studies of sites of vitiligo in VKH disease [30,31].

Animal studies have shown that a VKH-like

disease is inducible in rats by immunization with

peptides derived from proteins of the tyrosinase

family, which are found in melanocytes [32]. In this

disease, the rats develop uveitis 12 to 21 days after

immunization, followed by fundus depigmentation at

2 to 3 months. Histopathologically, the disease re-

vealed granulomatous inflammation in the choroid

and iris, similar to that observed in patients with

VKH disease [2].

With the exception of patient history, marked

similarities exist between the clinical and pathologic

manifestations of VKH disease and sympathetic oph-

thalmia. Because the latter condition is almost cer-

tainly caused by immune sensitization to uveal tissue

following trauma, this provides further circumstantial

evidence that VKH disease shares a similar immune

pathophysiology, although dissimilar avenues of

sensitization.

As in other autoimmune conditions, associations

with certain HLA subtypes are not unexpected because

these cell surface molecules are involved in antigen

presentation and recognition. HLA typing and asso-

ciation studies have been performed in a number of

different ethnic groups with high frequencies of VKH

disease, including the Japanese [33], Koreans [34],

Chinese [35], Vietnamese [36], Hispanics [37], Brazil-

ians [13], Mexican Mestizos [38], and Italians [39]. In

these studies, the strongest associations have beenwith

the HLA-DR4 allele, and when further subtyping was

performed, the greatest association has been found

with HLA-DRB1 * 0405 or HLA-DRB1 * 0410. Ana-

lyses of the amino acid sequence of the HLA-

DRB1 * 0405 allele indicates that a serine at position

57 or glutamine at position 70 may play a crucial role

in determining disease susceptibility, because these

locations are within the antigen-binding grove of the

molecule [33,40]. Recent studies have shown that

R.W. Read / Ophthalmol Clin N Am 15 (2002) 333–341334

lymphocytes from patients with VKH disease who

possess the HLA-DRB1 * 0405 allele recognize pep-

tides derived from melanocytes and melanoma pro-

teins [41]. Among these peptides are those derived

from tyrosinase [42] and other tyrosinase family pro-

teins, such as tyrosinase-related proteins 1 and 2 [43].

Moreover, T-cell clones established from patients with

VKH disease and stimulated with tyrosinase family

peptides have demonstrated a predominately proin-

flammatory, Th1-type T-cell response [44].

Existing evidence points to a T-lymphocyte–

mediated autoimmune process directed against a

melanocyte-associated antigen or antigens, occurring

in a permissive immune environment, more com-

monly found in certain groups. As in other auto-

immune diseases, however, it seems likely that

because there are a greater number of individuals

with the susceptible genetic background than there

are who actually develop the disease, some triggering

event may be required. Multiple theories exist regard-

ing a possible trigger. Epstein-Barr virus DNA has

been isolated from the vitreous of patients with VKH

disease [45] and the Epstein-Barr virus is able to

activate B lymphocytes from patients with VKH

disease more easily than B lymphocytes from patients

with other uveitic entities [46]. VKH disease has also

been reported to occur following cutaneous injury,

presumably by direction of an autoimmune attack

against cutaneous melanocytic antigens liberated at

the site of injury [47].

Clinical features

Vogt-Koyanagi-Harada disease typically consists

of four phases: (1) prodromal, characterized by neuro-

logic and auditory manifestations; (2) acute uveitic,

characterized by a diffuse choroiditis, which may

result in exudative retinal detachments and papillitis,

and possibly an intraocular cellular reaction; (3)

chronic, characterized by depigmentation of various

structures, including ocular (fundus and limbus) and

integumentary (poliosis and vitiligo, also possibly

with alopecia); and (4) chronic-recurrent, with an

iridocyclitis that may be recurrent, chronic, or both

[2]. Based on these features and their distinctive timing

within the overall disease course, diagnostic criteria

were recently revised and published (Table 1) [1].

Prodromal phase

Vogt-Koyanagi-Harada disease has been termed a

uveomeningitis, which although accurate and useful in

directing the clinician’s differential diagnosis, is not

inclusive of the entire potential disease process. Never-

theless, this term does emphasize two of the most

prominent areas of acute disease involvement,

although not in chronologic order. Melanocytes con-

tained within the meninges [48] are apparently the first

site of autoimmune attack, along with the inner ear,

although lack of knowledge of the initiating events in

this disease prohibits definitive conclusions about the

initial site of involvement. As mentioned previously,

the occurrence of VKH disease following cutaneous

trauma [47] raises the possibility that perhaps similar

subclinical sensitizing events are present in all VKH

disease patients. Regardless, patients typically report

severe headaches, nuchal rigidity, possibly fever and

nausea, and auditory symptoms (mainly tinnitus and

dysacousia) as initial disease manifestations. Occa-

sionally, cutaneous symptoms, such as skin erythema

[49] and scalp tenderness [50], may occur early in the

disease course, presumably as a consequence of

inflammatory cell infiltration into the skin. The prod-

romal stage of VKH disease may last from only a few

days to several weeks [51]. Patients have been admit-

ted to the hospital with a diagnosis of aseptic men-

ingitis before the onset of ocular disease led to the full

diagnosis [52]. Cerebrospinal fluid analysis at this

point usually reveals a pleocytosis, possibly with

melanin-laden macrophages, suggesting VKH disease

[52]. The pleocytosis resolves despite persistence of

disease manifestations elsewhere, so if performed,

lumbar puncture must be carried out early in the

disease course. If sufficient neurologic symptoms exist

followed by the expected ocular signs, then lumbar

puncture is not required for diagnosis by the VKH

Workshop Revised Criteria [1].

Hearing loss, if present, usually involves the

higher frequencies and may persist for years. Audio-

metric abnormalities, as measured by pure tone

stimuli, middle ear analysis, and auditory brainstem

responses, were shown in 20 of 26 patients from the

National Eye Institute [51].

Acute uveitic phase

The ocular hallmark of acute VKH disease is a

diffuse inflammatory cell infiltrate into the choroid,

producing thickening detectable on ultrasonography

[53]. This is commonly accompanied by hyperemia of

the optic nerve head. Leakage of fluid from the choroid

through the retinal pigment epithelium occurs, with the

resultant formation of focal areas of subretinal fluid

accumulation, development of larger bullous detach-

ments, or both. Fluorescein angiography performed

at this stage typically reveals focal areas of delay in

choroidal perfusion, multifocal areas of pinpoint leak-

R.W. Read / Ophthalmol Clin N Am 15 (2002) 333–341 335

age, large placoid areas of hyperfluorescence, pooling

within subretinal fluid, and optic nerve staining

(Figs. 1–3) [1]. Cells may be present in the vitreous

or aqueous humors but are not necessary to the

diagnosis. VKH disease is a bilateral ocular condition.

The suspicion of unilateral ocular involvement should

prompt a diligent investigation for either subtle

involvement of the fellow eye or a different diagnosis

[1]. Patients with VKH disease may present with

shallowed anterior chambers, because of ciliochoroi-

dal detachment [54–56], or ciliary body edema [57],

resulting in anterior rotation of the lens-iris diaphragm.

Elevated intraocular pressure is not uncommon in

these presentations, but the angle shallowing and

closure typically resolve with corticosteroid therapy.

Chronic

The chronic phase of VKH disease is character-

ized by depigmentation of various structures. On the

external ocular surface, pigmentation seen at the

limbus in more heavily pigmented races may dis-

appear, termed Sugiura’s sign [58]. Within the eye,

loss of choroidal melanocytes results in an orange

coloration to the fundus, termed the sunset-glow

fundus, more commonly seen in Asians and His-

panics than whites [59]. Migration of retinal pigment

epithelial cells may result in pigment clumping in

Table 1

Vogt-Koyanagi-Harada disease workshop revised diagnos-

tic criteria

Complete Vogt-Koyanagi-Harada disease (1–5 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

entities

3. Bilateral ocular involvement

A. Early manifestations of disease

There must be evidence of a diffuse choroiditis (with

or without anterior uveitis, vitritis, or optic nerve

hyperemia) which may manifest as:

1. Focal areas of subretinal fluid

or

2. Bullous serous retinal detachments

or both of the following in the face of equivocal fundus

findings:

3. Ultrasonography: diffuse choroidal thickening,

without evidence of posterior scleritis

4. Fluorescein angiography: focal areas of delay in

choroidal perfusion, multifocal areas of pinpoint

leakage, large placoid areas of hyperfluorescence,

pooling within subretinal fluid, optic nerve staining

(listed in chronologic order of occurrence)

B. Late manifestations of disease (with history

suggestive of prior presence of findings from 3A) and

1. Ocular depigmentation

a. Sunset glow fundus

or

b. Sugiura sign

AND

2. One of the following other signs (or 2 of the

following in the absence of above depigmentation

findings)

A. Chorioretinal nummular scars (previously

referred to as Dalen-Fuchs nodules)

B. RPE clumping or migration

C. Recurrent or chronic anterior uveitis

4. Neurologic-auditory findings (manifesting in initial stage

of disease or reliable documentation of such)

A. Meningismus (headache alone is not sufficient to meet

definition of meningismus)

or

B. Tinnitus

or

C. Cerebrospinal fluid pleocytosis

5. Integumentary (not preceding onset of central nervous

system or ocular disease)

A. Alopecia

or

B. Poliosis

or

C. Vitiligo

Table 1 (continued)

Incomplete Vogt-Koyanagi-Harada disease (1–3 must be

present and either 4 or 5)

1. No history of penetrating ocular trauma or surgery

preceding the initial onset of uveitis

2. No clinical or laboratory evidence suggestive of other

entities

3. Bilateral ocular involvement

and either

4. Neurologic-auditory findings

or

5. Integumentary findings

Probable Vogt-Koyanagi-Harada disease (isolated ocular

disease) (1–3 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

entities

3. Bilateral ocular involvement

From Read RW, Holland GN, Rao NA, Tabbara KF, Ohno S,

Arellanes-Garcia L, et al. Revised diagnostic criteria for

Vogt-Koyanagi-Harada disease: report of an International

Committee on Nomenclature. Am J Ophthalmol 2001;131:

647–52; with permission.

R.W. Read / Ophthalmol Clin N Am 15 (2002) 333–341336

various areas of the fundus. Rounded hypopigmented

lesions appear, primarily inferiorly. These lesions

have most commonly been referred to as resolved

Dalen-Fuchs nodules [2], but a recent report shows

that although these areas represent a loss of retinal

pigment epithelial cells, there is no direct evidence

that they are or were Dalen-Fuchs nodules [60]. Why

these lesions appear primarily inferiorly is unknown.

Chronic-recurrent

The chronic-recurrent phase does not affect all

patients, but by definition only those in whom recur-

rent bouts of intraocular inflammation occur. When

recurrent inflammation does occur, it is usually an

anterior uveitis, in stark contrast to the primarily

posterior involvement in acute disease. When recur-

rent posterior segment disease occurs, it is usually

within 6 months of the initial onset, and is a con-

sequence of a too rapid taper of medication [61].

Multiple recurrences of exudative retinal detachments

have been reported, occurring as long as 35 months

after disease onset [62], although this is considered an

uncommon disease course.

It is during the chronic-recurrent phase of the

disease that many of the vision-reducing complica-

tions associated with VKH disease are most likely

to occur, including cataract, glaucoma, choroidal

neovascular membrane development, and subretinal

fibrosis. Read et al [10] recently reviewed the

records of 101 patients with VKH disease, reporting

on the frequencies of complications and predictive

factors for final visual acuity. Out of the 202 eyes

included, 103 eyes (51%) developed at least one

complication, including cataract in 84 eyes (42%),

glaucoma in 54 eyes (27%), choroidal neovascular

membranes in 22 eyes (11%), and subretinal fibrosis

in 13 eyes (6%).

Management

Medical

The mainstay of management of VKH disease re-

mains corticosteroids, and because of the potential for

visual morbidity, treatment should be both prompt and

Fig. 1. Red-free photograph of right eye of patient with

acute Vogt-Koyanagi-Harada disease. Note the presence of

subretinal fluid in the posterior pole, with whitish subreti-

nal material.

Fig. 2. Fluorescein angiogram of same eye as Fig. 1 during

mid-phase. Note presence of multiple areas of pinpoint

leakage of dye into subretinal space.

Fig. 3. Fluorescein angiogram of same eye as Figs. 1 and 2

during late phase. Note extensive pooling of dye in subretinal

space, better outlining the extent of exudative detachment.

R.W. Read / Ophthalmol Clin N Am 15 (2002) 333–341 337

aggressive [63]. In the United States, most clinicians

begin with high-dose oral corticosteroids, typically in

the range of 1 to 2 mg/kg/day of oral prednisone [2].

Supplemental regional corticosteroid injections may

be used. If the retinal detachments fail to resolve,

intravenous therapy may be tried, usually with meth-

ylprednisolone, 1 g/day over 3 consecutive days. If

corticosteroid therapy is effective, retrospective data

suggest that tapering the therapy over a minimum of

6 months is required to minimize complications and

recurrences [2,61]. Outside the United States, clini-

cians may frequently admit patients to the hospital for

intravenous therapy as a first-line treatment, based on

anecdotal evidence that this early, aggressive treatment

reduces recurrences and the development of compli-

cations. Whether this is in fact the case remains to be

proved in a prospective clinical trial.

Patients with resistant or recurrent disease may

require noncorticosteroid immunosuppressive therapy

[2]. Multiple therapeutic classes and agents have been

used, including the antimetabolite azathioprine, and

the alkylating agents cyclophosphamide and chlor-

ambucil [64]. Based on the etiologic discussion

presented previously, such agents as cyclosporine

and tacrolimus, which target T-lymphocyte function,

seem ideal. In fact, these agents have been used with

success in cases of corticosteroid intolerance or

resistance [65–68]. All of these agents have signifi-

cant potential side effects, and their use should be

under the direction of an experienced clinician.

Topical corticosteroids are mainly an adjunctive

therapy in VKH disease. In acute disease, they are

wholly inadequate in treating the posterior segment

manifestations. In chronic disease, where the inflam-

mation is primarily anterior, topical therapy is still

frequently insufficient, because recurrent disease is

notoriously resistant to treatment. Cycloplegics

should be used to prevent posterior synechiae and

improve comfort. Nonsteroidal anti-inflammatory

drugs have essentially no role.

Surgical

Surgical therapy in VKH disease is limited pri-

marily to addressing the complications induced by the

disease. Rarely, surgical drainage of subretinal fluid

that was resistant to medical therapy may be indicated.

Cataracts, which may develop in up to 42% of eyes

[10], seem to be safe to remove if the disease has been

controlled for at least 3 months [69]. The decision of

whether or not to implant a lens should be based on the

patient’s past disease course, including whether there

is a demonstrated tendency to develop posterior syn-

echiae [2]. Moorthy et al [69] reported a significant

improvement in visual acuity following cataract

extraction with lens implantation.

Glaucoma may occur in up to 45% of patients

with VKH disease [61]. Forster et al [70] reported

that in 31% of patients with VKH disease and

glaucoma, medical therapy alone was sufficient,

whereas 69% required surgical therapy. This study

was published in 1993, when many of the currently

available medications for intraocular pressure control

were not yet approved in the United States.

Choroidal neovascular membranes may occur in

up to 11% of eyes [10]. Typically ill-defined in nature,

these neovascular membranes may be treated inad-

equately with photocoagulation therapy [71]. In-

creased anti-inflammatory therapy may result in

resolution, as reported for other posterior and panu-

veitis entities [72–74]. One small series showed an

improvement of vision in two of three eyes following

surgical removal of subretinal neovascularization [75].

Prognosis

In their review of complications and visual out-

comes in VKH disease, Read et al [10] found that a

longer median duration of disease and a greater

number of recurrent episodes of inflammation were

significantly associated with the development of com-

plications. A poor final visual acuity was predicted by

greater numbers of complications developing, older

age at disease onset, a longer median duration of dis-

ease, and greater number of recurrent episodes of

inflammation. The better the visual acuity at presenta-

tion, the more likely that eye was to have a better

visual acuity at final follow-up. In their study, 49% of

eyes obtained a final visual acuity of 20/40 or better,

22% of eyes obtained 20/50 to 20/100, and 29% of

eyes obtained a final visual acuity of 20/200 or worse

[10]. African-Americans did worse overall, with 70%

of eyes having final visual acuities of 20/200 or worse.

Many questions remain to be answered regarding

VKH disease. Identification of the exact target anti-

gen may allow development of more specific ther-

apies. Until that point, prospective clinical trials are

needed to identify the most efficacious therapeutic

protocols to control acute disease and prevent future

vision-limiting complications.

References

[1] Read RW, Holland GN, Rao NA, Tabbara KF, Ohno S,

Arellanes-Garcia L, et al. Revised diagnostic criteria

for Vogt-Koyanagi-Harada disease: report of an Inter-

R.W. Read / Ophthalmol Clin N Am 15 (2002) 333–341338

national Committee on Nomenclature. Am J Ophthal-

mol 2001;131:647–52.

[2] Moorthy RS, Inomata H, Rao NA. Vogt-Koyanagi-

Harada syndrome. Surv Ophthalmol 1995;39:265–92.

[3] Pattison EM. Uveo-meningoencephalitic syndrome

(Vogt-Koyanagi-Harada). Arch Neurol 1965;12:

197–205.

[4] Vogt A. Fruhzeitiges Ergrauen der Zilien und Bemer-

kungen uber den sogenannten plotlzichen Eintritt die-

ser Veranderung. Klin Monatsbl Augenheilkd 1906;

4:228–42.

[5] Koyanagi Y. Dysakusis, alopecia und poliosis bei

schwerer uveitis nicht traumatischen ursprungs. Klin

Monatsbl Augenheilkd 1929;82:194–211.

[6] Harada E. Beitrag zur klinischen kenntnis von Mich-

teitriger choroiditis (choroiditis diffusa acta). Acta Soc

Ophthalmol Jpn 1926;30:356–78.

[7] Babel J. Syndrome de Vogt-Koyanagi (uveite bilater-

ale, poliosis, alopecie, vitiligo et dysacousie). Schweiz

Med Wochenschr 1932;44:1136–40.

[8] Bruno MG, McPherson SD. Harada’s disease. Am J

Ophthalmol 1949;32:513–22.

[9] Brace CL, Nelson AR, Seguchi N, Oe H, Sering L,

Qifeng P, et al. Old world sources of the first new

world human inhabitants: a comparative craniofacial

view. Proc Natl Acad Sci U S A 2001;98:10017–22.

[10] Read RW, Rechodouni A, Butani N, Johnston R,

LaBree LD, Smith RE, et al. Complications and prog-

nostic factors in Vogt-Koyanagi-Harada disease. Am J

Ophthalmol 2001;131:599–606.

[11] Davis JL, Mittal KK, Freidlin V, Mellow SR, Optican

DC, Palestine AG, et al. HLA associations and ances-

try in Vogt-Koyanagi-Harada disease and sympathetic

ophthalmia. Ophthalmology 1990;97:1137–42.

[12] Martinez JA, Lopez PF, Sternberg Jr. P, Aaberg TM,

Lambert HM, Capone Jr. A, et al. Vogt-Koyanagi-Hara-

da syndrome in patients with Cherokee Indian ancestry

[see comments]. Am J Ophthalmol 1992;114:615–20.

[13] Goldberg AC, Yamamoto JH, Chiarella JM, Marin ML,

Sibinelli M, Neufeld R, et al. HLA-DRB1* 0405 is the

predominant allele in Brazilian patients with Vogt-

Koyanagi-Harada disease. Hum Immunol 1998;59:

183–8.

[14] Chavis PS, Wafai MZ, Al-Amro S, Tabbara KF. Uvei-

tis in the Middle East. In: Dernouchamps JP, Verousg-

straete C, Caspers-Velu L, Tassignon MJ, editors.

Proceedings of the Third International Symposium on

Uveitis, 1992. Recent advances in uveitis. Amsterdam:

Kluger Publications; 1993. p. 149–56.

[15] Ohno S, Char DH, Kimura SJ, O’Connor GR. Vogt-

Koyanagi-Harada syndrome. Am J Ophthalmol 1977;

83:735–40.

[16] Snyder DA, Tessler HH. Vogt-Koyanagi-Harada syn-

drome. Am J Ophthalmol 1980;90:69–75.

[17] Read RW, Butani N, Parsa K, Torshizy H, Smith R,

Rao N. Changing patterns of uveitis diagnoses in a re-

ferral clinic. Invest Ophthalmol Vis Sci 2001;42:S460.

[18] Murakami S, Inaba Y, Mochizuki M, Nakajima A,

Urayama A. A nationwide survey on the occurrence

of Vogt-Koyanagi-Harada disease in Japan. Jpn J Oph-

thalmol 1994;38:208–13.

[19] Cunningham Jr. ET, Demetrius R, Frieden IJ, Emery

AR, Irvine AR, Good WV. Vogt-Koyanagi-Harada syn-

drome in a 4-year old child. Am J Ophthalmol 1995;

120:675–7.

[20] Gruich MJ, Evans OB, Storey JM, Bradley ST, Chen

CJ. Vogt-Koyanagi-Harada syndrome in a 4-year-old

child. Pediatr Neurol 1995;13:50–1.

[21] Tabbara KF, Chavis PS, Freeman WR. Vogt-Koyanagi-

Harada syndrome in children compared to adults. Acta

Ophthalmol Scand 1998;76:723–6.

[22] Rathinam SR, Vijayalakshmi P, Namperumalsamy P,

Nozik RA, Cunningham Jr. ET. Vogt-Koyanagi-Harada

syndrome in children. Ocul Immunol Inflamm 1998;

6:155–61.

[23] Rao NA. Mechanisms of inflammatory response in

sympathetic ophthalmia and VKH syndrome. Eye

1997;11:213–6.

[24] Sakamoto T, Murata T, Inomata H. Class II major his-

tocompatibility complex on melanocytes of Vogt-Koya-

nagi-Harada disease. Arch Ophthalmol 1991;109:

1270–4.

[25] Boyd SR, Young S, Lightman S. Immunopathology of

the noninfectious posterior and intermediate uveitides.

Surv Ophthalmol 2001;46:209–33.

[26] Kogiso M, Tanouchi Y, Miki S, Mimura Y. Character-

ization of T-cell subsets, soluble interleukin-2 receptors

and interleukin-6 in Vogt-Koyanagi-Harada disease.

Jpn J Ophthalmol 1992;36:37–43.

[27] Norose K, Yano A, Aosai F, Segawa K. Immunologic

analysis of cerebrospinal fluid lymphocytes in Vogt-

Koyanagi-Harada disease. Invest Ophthalmol Vis Sci

1990;31:1210–6.

[28] Nakamura S, Nakazawa M, Yoshioka M, Nagano I,

Nakamura H, Onodera J, et al. Melanin-laden macro-

phages in cerebrospinal fluid in Vogt-Koyanagi-Harada

syndrome. Arch Ophthalmol 1996;114:1184–8.

[29] Takeshita T, Nakazawa M, Murakami K, Tamai M,

Nakamura S. A patient with long standing melanin

laden macrophages in cerebrospinal fluid in Vogt-

Koyanagi-Harada syndrome [letter]. Br J Ophthalmol

1997;81:1114.

[30] Okada T, Sakamoto T, Ishibashi T, Inomata H. Vitiligo

in Vogt-Koyanagi-Harada disease: immunohistological

analysis of inflammatory site. Graefes Arch Clin Exp

Ophthalmol 1996;234:359–63.

[31] Tsuruta D, Hamada T, Teramae H, Mito H, Ishii M.

Inflammatory vitiligo in Vogt-Koyanagi-Harada dis-

ease. J Am Acad Dermatol 2001;44:129–31.

[32] Yamaki K, Kondo I, Nakamura H, Miyano M, Kon-

no S, Sakuragi S. Ocular and extraocular inflamma-

tion induced by immunization of tyrosinase related

protein 1 and 2 in Lewis rats. Exp Eye Res 2000;71:

361–9.

[33] Shindo Y, Ohno S, Yamamoto T, Nakamura S, Inoko

H. Complete association of the HLA-DRB1 * 04 and

-DQB1 * 04 alleles with Vogt-Koyanagi-Harada’s dis-

ease. Hum Immunol 1994;39:169–76.

R.W. Read / Ophthalmol Clin N Am 15 (2002) 333–341 339

[34] Kim MH, Seong MC, Kwak NH, Yoo JS, Huh W, Kim

TG, et al. Association of HLA with Vogt-Koyanagi-

Harada syndrome in Koreans. Am J Ophthalmol

2000;129:173–7.

[35] Zhao M, Jiang Y, Abrahams IW. Association of HLA

antigens with Vogt-Koyanagi-Harada syndrome in a

Han Chinese population. Arch Ophthalmol 1991;109:

368–70.

[36] Riddington L, Hall AJ, Tait B, Nicholson I, Varney M.

Vogt-Koyanagi-Harada syndrome in patients of Viet-

namese ancestry. Aust N Z J Ophthalmol 1996;24:

147–9.

[37] Weisz JM, Holland GN, Roer LN, Park MS, Yuge AJ,

Moorthy RS, et al. Association between Vogt-Koya-

nagi-Harada syndrome and HLA-DR1 and -DR4 in

Hispanic patients living in southern California. Oph-

thalmology 1995;102:1012–5.

[38] Arellanes-Garcia L, Bautista N, Mora P, Ortega-Larro-

cea G, Burguet A, Gorodezky C. HLA-DR is strongly

associated with Vogt-Koyanagi-Harada disease in

Mexican Mestizo patients. Ocul Immunol Inflamm

1998;6:93–100.

[39] Pivetti-Pezzi P, Accorinti M, Colabelli-Gisoldi RA,

Pirraglia MP. Vogt-Koyanagi-Harada disease and

HLA type in Italian patients. Am J Ophthalmol

1996;122: 889–91.

[40] Shindo Y, Inoko H, Yamamoto T, Ohno S. HLA-DRB1

typing of Vogt-Koyanagi-Harada’s disease by PCR-

RFLP and the strong association with DRB1 * 0405

and DRB1 * 0410. Br J Ophthalmol 1994;78:223–6.

[41] Damico FM, Neto EC, Goldberg A, Iwai LK, Marin

ML, Kalil J. HLA-DRB1 * 0405 and presentation of

peptides derived from human melanocyte/melanoma

proteins in Vogt-Koyanagi-Harada disease. Invest

Ophthalmol Vis Sci 2000;41:S777.

[42] Kobayashi H, Kokubo T, Takahashi M, Sato K, Miyo-

kawa N, Kimura S, et al. Tyrosinase epitope recog-

nized by an HLA-DR-restricted T-cell line from a

Vogt-Koyanagi-Harada disease patient. Immunoge-

netics 1998;47:398–403.

[43] Gocho K, Kondo I, Yamaki K, Sakuragi S. Identifica-

tion of specific antigen for Vogt-Koyanagi-Harada dis-

ease: lymphocyte reactivity against the tyrosinase

family proteins. Invest Ophthalmol Vis Sci 1999;

40:S204.

[44] Gocho K, Kondo I, Yamaki K, Sakuragi S. Establish-

ment and analysis of T cell clones from VKH disease

patients. Invest Ophthalmol Vis Sci 2000;41:S369.

[45] Bassili SS, Peyman GA, Gebhardt BM, Daun M, Ga-

niban GJ, Rifai A. Detection of Epstein-Barr virus

DNA by polymerase chain reaction in the vitreous

from a patient with Vogt-Koyanagi-Harada syndrome.

Retina 1996;16:160–1.

[46] Minoda H, Sakai J, Sugiura M, Imai S, Osato T, Usui

M. [High inducibility of Epstein-Barr virus replication

in B lymphocytes in Vogt-Koyanagi-Harada disease]

Nippon Ganka Gakkai Zasshi 1999;103:289–96.

[47] Rathinam SR, Namperumalsamy P, Nozik RA, Cun-

ningham Jr. ET. Vogt-Koyanagi-Harada syndrome after

cutaneous injury [see comments]. Ophthalmology

1999;106:635–8.

[48] Goldgeier MH, Klein LE, Klein-Angerer S, Moell-

mann G, Nordlund JJ. The distribution of melanocytes

in the leptomeninges of the human brain. J Invest Der-

matol 1984;82:235–8.

[49] Wong SS, Ng SK, Lee HM. Vogt-Koyanagi-Harada

disease: extensive vitiligo with prodromal generalized

erythroderma. Dermatology 1999;198:65–8.

[50] Ohno S, Minakawa R, Matsuda H. Clinical studies of

Vogt-Koyanagi-Harada’s disease. Jpn J Ophthalmol

1988;32:334–43.

[51] Nussenblatt RB. Vogt-Koyanagi-Harada syndrome

(uveomeningitic syndrome). In: Ryan SJ, editor. Reti-

na. vol. 2, 3rd edition. St Louis: Mosby; 2001. p.

1762–9.

[52] Kamondi A, Szegedi A, Papp A, Seres A, Szirmai I.

Vogt-Koyanagi-Harada disease presenting initially as

aseptic meningoencephalitis. Eur J Neurol 2000;7:

719–22.

[53] Forster DJ, Cano MR, Green RL, Rao NA. Echo-

graphic features of the Vogt-Koyanagi-Harada syn-

drome. Arch Ophthalmol 1990;108:1421–6.

[54] Gohdo T, Tsukahara S. Ultrasound biomicroscopy of

shallow anterior chamber in Vogt-Koyanagi- Harada

syndrome. Am J Ophthalmol 1996;122:112–4.

[55] Kawano Y, Tawara A, Nishioka Y, Suyama Y, Saka-

moto H, Inomata H. Ultrasound biomicroscopic anal-

ysis of transient shallow anterior chamber in Vogt-

Koyanagi-Harada syndrome. Am J Ophthalmol 1996;

121:720–3.

[56] Nakamura H, Tsukamoto H, Shibahara R, Nagai M,

Mishima HK. Ultrasound biomicroscopy in the man-

agement of Vogt-Koyanagi-Harada disease. Acta Oph-

thalmol Scand 2000;78:718–9.

[57] Kishi A, Nao-i N, Sawada A. Ultrasound biomicro-

scopic findings of acute angle-closure glaucoma in

Vogt-Koyanagi-Harada syndrome. Am J Ophthalmol

1996;122:735–7.

[58] Sugiura S. [Some observations on uveitis in Japan,

with special reference to Vogt-Koyanagi-Harada and

Behc�et’s diseases.] Nippon Ganka Gakkai Zasshi

1976;80:1285–326.

[59] Goto H, Rao NA. Sympathetic ophthalmia and Vogt-

Koyanagi-Harada syndrome. Int Ophthalmol Clin

1990;30:279–85.

[60] Inomata H, Rao NA. Depigmented atrophic lesions in

sunset glow fundi of Vogt-Koyanagi- Harada disease.

Am J Ophthalmol 2001;131:607–14.

[61] Rubsamen PE, Gass JD. Vogt-Koyanagi-Harada syn-

drome. Clinical course, therapy, and long-term visual

outcome. Arch Ophthalmol 1991;109:682–7.

[62] Garcia-Valenzuela E, Tessler HH, Carnahan M, Ryan

JJ, Goldstein DA. Multiple recurrences of exudative

retinal detachment in a patient with Vogt-Koyanagi-

Harada disease. Retina 2000;20:672–4.

[63] Sasamoto Y, Ohno S, Matsuda H. Studies on cortico-

steroid therapy in Vogt-Koyanagi-Harada disease.

Ophthalmologica 1990;201:162–7.

R.W. Read / Ophthalmol Clin N Am 15 (2002) 333–341340

[64] Hemady R, Tauber J, Foster CS. Immunosuppressive

drugs in immune and inflammatory ocular disease.

Surv Ophthalmol 1991;35:369–85.

[65] Ishioka M, Ohno S, Nakamura S, Isobe K, Watanabe

N, Ishigatsubo Y, et al. FK506 treatment of noninfec-

tious uveitis. Am J Ophthalmol 1994;118:723–9.

[66] Nussenblatt RB, Palestine AG, Chan CC. Cyclosporin

A therapy in the treatment of intraocular inflammatory

disease resistant to systemic corticosteroids and cyto-

toxic agents. Am J Ophthalmol 1983;96:275–82.

[67] Wakatsuki Y, Kogure M, Takahashi Y, Oguro Y. Com-

bination therapy with cyclosporin A and steroid in

severe case of Vogt-Koyanagi-Harada’s disease. Jpn J

Ophthalmol 1988;32:358–60.

[68] Wakefield D, McCluskey P. Cyclosporine: a therapy in

inflammatory eye disease. J Ocul Pharmacol Ther

1991;7:221–6.

[69] Moorthy RS, Rajeev B, Smith RE, Rao NA. Incidence

and management of cataracts in Vogt-Koyanagi-Hara-

da syndrome. Am J Ophthalmol 1994;118:197–204.

[70] Forster DJ, Rao NA, Hill RA, Nguyen QH, Baerveldt

G. Incidence and management of glaucoma in Vogt-

Koyanagi-Harada syndrome. Ophthalmology 1993;

100:613–8.

[71] Moorthy RS, Chong LP, Smith RE, Rao NA. Subreti-

nal neovascular membranes in Vogt-Koyanagi-Harada

syndrome. Am J Ophthalmol 1993;116:164–70.

[72] Dees C, Arnold JJ, Forrester JV, Dick AD. Immuno-

suppressive treatment of choroidal neovascularization

associated with endogenous posterior uveitis. Arch

Ophthalmol 1998;116:1456–61.

[73] Flaxel CJ, Owens SL, Mulholland B, Schwartz SD,

Gregor ZJ. The use of corticosteroids for choroidal

neovascularisation in young patients. Eye 1998;12:

266–72.

[74] Kilmartin DJ, Forrester JV, Dick AD. Cyclosporine-in-

duced resolution of choroidal neovascularization

associated with sympathetic ophthalmia [letter]. Arch

Ophthalmol 1998;116:249–50.

[75] Greve MDJ, Hillson TR, Hinz BJ, Tennant MTS. Sur-

gical removal of subfoveal choroidal neovascular

membranes in Vogt-Koyanagi-Harada syndrome: clin-

ical and histopathological results. Invest Ophthalmol

Vis Sci 1999;40:S871.

R.W. Read / Ophthalmol Clin N Am 15 (2002) 333–341 341