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Vogt-Koyanagi-Harada Disease
Francisco Max Damico a; Szilárd Kiss a; Lucy H. Young a
a
Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA
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2. Seminars in Ophthalmology, 20:183–190, 2005
Copyright c Taylor & Francis Inc.
ISSN: 0882-0538
DOI: 10.1080/08820530500232126
Vogt-Koyanagi-Harada Disease
Francisco Max Damico,
Szilard Kiss,
´ ABSTRACT Vogt-Koyanagi-Harada disease (VKH) is a multisystem autoim-
and Lucy H. Young mune disorder principally affecting pigmented tissues in the ocular, auditory,
Massachusetts Eye and Ear integumentary and central nervous systems. Patients are typically 20 to 50 years
Infirmary, Harvard Medical
old and have no history of either surgical or accidental ocular trauma. Pigmented
School, Boston, MA
races are more commonly affected. Depending on revised diagnostic criteria,
the disease is classified as complete, incomplete or probable based on the pres-
ence of extraocular findings (neurological, auditory and integumentary). The
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clinical course of VKH is divided into four phases: prodromal (mimics a viral
infection), uveitic (bilateral diffuse uveitis with papillitis and exudative retinal
detachment), convalescent (tissue depigmentation), and chronic recurrent (re-
current uveitis and ocular complications). The pathogenesis of VKH is thought
to be related to an aberrant T cell-mediated immune response directed against
self-antigens found on melanocytes. VKH has been linked to human leukocyte
antigen DR4 (HLA-DR4) and HLA-Dw53, with strongest associated risk for
HLA-DRB1∗ 0405 haplotype. The diagnosis of VKH is clinical, and differential
includes sympathetic ophthalmia, sarcoidosis, primary intraocular B-cell lym-
phoma, posterior scleritis, and uveal effusion syndrome. Treatment is typically
initiated with high-dose oral corticosteroids, but other immunomondulatory
agents (most oftentimes cyclosporine) may be needed for non-responsive pa-
tients or when corticosteroid side-effects are not tolerated. Visual prognosis
is generally good with prompt diagnosis and aggressive immunomodulatory
treatment.
KEYWORDS review, uveomeningoencephalitic syndrome, eye, diagnosis, therapy
INTRODUCTION
Vogt-Koyanagi-Harada disease (VKH) is a systemic autoimmune disorder
directed against antigens most likely associated with melanocytes present in
such tissues as the choroid, the meninges, the inner ear, and the skin. It is
characterized by bilateral, chronic, diffuse granulomatous uveitis, accompanied
by characteristic neurological, auditory and integumentary features. The eye is
typically the most involved organ, and visual sequelae are the most frequent
and debilitating consequences of the disease.
Address correspondence to Lucy H.
Young, M.D., Ph.D., Massachusetts Eye The first description of a whitening of eyelashes, eyebrows, and hair associated
and Ear Infirmary, 243 Charles Street, with ocular inflammation dates from 10th century Persia. However, it was not
Boston, MA 02114, USA. Tel.:
+1-617-573-3710; E-mail: until 1932, when Babel appreciated that the features of anecdotal cases reported
lhyoung@meei.harvard.edu years earlier by Vogt (1906), Harada (1926) and Koyanagi (1929) overlapped
183

3. and were in reality manifestations of the same disorder, Complete Vogt-Koyanagi-Harada Disease
which he termed Vogt-Koyanagi-Harada disease.1 1. No history of penetrating ocular trauma
2. No evidence of other ocular or systemic disease.
VKH affects mainly darkly pigmented races, such as 3. Bilateral ocular disease (either a. or b. below):
East and Southeastern Asians, Asian Indians, Middle a) Early manifestations
i. Diffuse choroiditis manifested with either
Easterners, Hispanics, and Native Americans; it is un-
1. Focal areas of subretinal fluid, or
common in Caucasians. VKH is also rare in Africans, 2. Bullous serous subretinal detachments.
suggesting that skin pigmentation alone is not the sole ii. If equivocal fundus findings, then both:
1. FA showing focal delayed choroidal perfusion, pinpoint
etiologic factor in its pathogenesis. leakage, pooling of fluorescein within subretinal fluid, and
The incidence of VKH is highly variable worldwide. optic nerve staining
2. Ultrasonography showing diffuse choroidal thickening
In Japan, VKH accounts for over 8% of uveitis.2−4 It is
without evidence of posterior scleritis
also a frequent cause of uveitis in certain Latin Ameri- b) Late manifestations
can countries, especially Brazil, where VKH is the main i. History suggestive of findings from 3a,
or both ii and iii, or multiple signs from iii
cause of autoimmune noninfectious uveitis.4−6 VKH ii. Ocular depigmentation
is the most common uveitis diagnosis made in Saudi 1. Sunset glow fundus, or
2. Sugiura’s sign
Arabia.4 In contrast, VKH is seen in only approximately
iii. Other ocular signs
1% to 4% of all uveitis referrals in the United States.7 1. Nummular chorioretinal depigmentation scars, or
The disease usually affects patients between ages of 20 2. RPE clumping and/or migration, or
3. Recurrent or chronic anterior uveitis.
and 50 years; however, there have been reports of VKH
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4. Neurological/auditory findings:
in children, with one report of VKH in a 4-year-old a) Meningismus
b) Tinnitus
child.8 Most series indicate that women are affected
c) Cerebrospinal fluid pleocytosis.
more often than men,9,10 although this sex predilection 5. Integumentary findings (not preceding CNS/ocular disease)
does not seem to hold true for Japanese patients.11,12 a) Alopecia
b) Poliosis
c) Vitiligo
DIAGNOSTIC CRITERIA Incomplete Vogt-Koyanagi-Harada Disease
Criteria 1 to 3 and either 4 or 5 from above.
Comprehensive diagnostic criteria for VKH were re- Probable Vogt-Koyanagi-Harada Disease
vised during the 2001 First International Workshop on Isolated ocular disease (only criteria 1 to 3 from above).
Vogt-Koyanagi-Harada Disease.13 According to the new Adapted from: Read RW, Holland GN, Rao NA, Tabbara KF, Ohno S,
criteria, patients may present with a complete, an in- Arellanes-Garcia L, Pivetti-Pezzi P, Tessler HH, Usui M. Revised diagnostic
criteria for Vogt-Koyanagi-Harada disease: report of an international com-
complete, or a probable form of VKH depending on mittee on nomenclature. Am J Ophthalmol 2001; 131:647-52.
the extent of associated neurological, auditory and in-
FIGURE 1 Diagnostic criteria for Vogt-Koyanagi-Harada
tegumentary findings (Figure 1). No matter the form of disease.
the disease the patient manifests, three conditions must
dysacusia, tinnitus, and may even have fever, orbital
be present for the diagnosis of VKH: (1) no previous
pain or photophobia. Cerebrospinal fluid (CSF) eval-
history of penetrating ocular trauma (either surgical or
uation reveals pleocytosis, with possible melanin-laden
accidental); (2) no clinical or laboratory evidence sug-
macrophages, in more than 80% of the patients. These
gestive of other ocular disease; and (3) bilateral ocular
CSF abnormalities may last for several weeks.11 Central
involvement. These criteria reinforce the requisite thor-
dysacousia, usually involving higher frequencies, is ex-
ough history, physical examination, and appropriate an-
perienced by nearly two-thirds of patients and may per-
cillary testing in making the appropriate diagnosis.
sist for years. Patients may also report hypersensitivity
to touch of hair and skin, especially on the scalp.11 The
CLINICAL PRESENTATION prodromal phase can mimic a viral infection and may
The clinical course of VKH can be divided into only be established after a thorough history. Prior to
four phases: prodromal, acute uveitic, convalescent, the development of the ocular manifestations, patients
and chronic recurrent. may even be hospitalized with a diagnosis of aseptic
The prodromal phase occurs a few days prior to the oc- meningitis.4 The prodromal phase usually lasts for sev-
ular symptoms and is characterized by predominately eral days, but it can even persist for several weeks.14
neurological and auditory manifestations. Patients typ- Following the prodromal phase, VKH progresses to
ically report severe headaches, nausea, meningismus, an acute uveitic phase, characterized by bilateral vision
F. M. Damico et al. 184

4. blurring with choroiditis, vitritis and papillitis. There result in focal areas of retinal hyperpigmentation, espe-
may be a delay of one to three days between the involve- cially in Hispanic patients. Patients frequently experi-
ment of both eyes. The hallmark of the acute uveitic ence focal areas of alopecia. Although it may be found
phase and of the ocular involvement is an inflammatory throughout the body, vitiligo and poliosis are more
cell infiltration into the choroid, resulting in the thick- commonly found on the head, eyebrows, eyelashes, and
ening appreciated on ultrasonography. The choroidi- trunk. During this convalescent phase, round, yellow-
tis may be focal or diffuse. Leakage of fluid from the white, well-circumscribed subretinal lesions can appear
choroid through a compromised retinal pigment ep- in the midperipheral fundus, especially inferiorly. On
ithelium (RPE) results in focal areas of subretinal fluid. histological examination, these lesions, termed Dalen-
These focal areas can evolve into larger bullous retinal Fuchs nodules, consist of epitheliod cells, macrophages,
detachments (Figure 2). Additionally, vitritis and ante- lymphocytes and altered RPE cells.20 The convalescent
rior uveitis may also be present, but are not necessary phase typically lasts for several months or even years.
for the diagnosis of VKH. Mutton-fat keratic precipi- Some patients may have no further inflammatory
tates and iris nodules can also be found. The anterior episodes and never go into the chronic recurrent phase.
chamber may be shallow due to ciliary body edema However, others present with recurrent bouts of in-
or ciliochoroidal detachment.15−17 Elevated intraocular traocular inflammation. In contrast to the acute uveitic
pressure is not uncommon, but tends to normalize with phase, inflammation in the recurrent phase is predom-
the control of the inflammatory process. Conversely, inately an anterior uveitis; posterior segment involve-
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hypotony, secondary to inflammation of the anterior ment is rare during this phase.4 When posterior segment
uvea and ciliary body shutdown, may also be observed inflammation does occur, it is usually within 6 months
in some patients. It is in the acute uveitis phase, which of the onset of the disease, and often results from a
can last several weeks, during which 70% of patients too rapid taper of immunomodulatory medication. In
present with bilateral uveitis for ophthalmological eval- the chronic recurrent phase, round, whitish, and well-
uation. circumscribed nodules, known as Busacca nodules, may
The convalescent (or chronic) phase follows the acute develop on the iris. Sequalae of chronic inflammation,
uveitic phase with gradual abatement of the uveitis such as posterior subcapsular cataract, glaucoma, sub-
and resolution of the exudative retinal detachments. retinal neovascularization, and subretinal fibrosis are
It is characterized by depigmentation of skin (vitiligo), responsible for many of the blinding complications of
hair (poliosis), choroid and RPE. Perilimbal vitiligo VKH. These recurrent episodes of inflammation are
(Sugiura’s sign) is usually the earliest sign, occurring often resistant to systemic corticosteroid therapy, and
within a month of disease onset.18 It can be found in consequently, other immunomodulatory agents may be
up to 85% of Japanese patients, but is rarely seen in required for better control of intraocular inflammation.
Caucasians.11 Found more commonly in Asians, the
sunset glow appearance of the fundus, occurring 2 to 3 ETIOLOGY AND PATHOGENESIS
months after the uveitic phase, results from depigmen- The exact pathological mechanism for VKH has yet
tation of the choroid.19 Migration for RPE cells may to be completely elucidated. Clinical and experimental
FIGURE 2 Fundus photographs of a patient in acute uveitic phase of Vogt-Koyanagi-Harada disease. Note the diffuse choroiditis with
papillitis and exudative retinal detachment of the posterior pole.
185 VKH Disease

5. evidence suggests that VKH is a cell-mediated autoim- studies have shown T-cells obtained from VKH pa-
mune disorder directed against self-antigens found pre- tients react with melanocyte-associated antigens.26−28
dominantly in melanocytes in genetically susceptible Tyrosinase or tyrosinase-related proteins have been im-
individuals. However, neither the trigger of the autoim- plicated as target antigens on the melanocytes.27 Studies
mune response nor the exact pathogenesis is completely have shown that injection of tyrosinase family pro-
appreciated. tein in a rat model can induce an autoimmune dis-
The presence of a viral prodrome has lead to the spec- ease with a strong similarity to VKH.29 Studies have
ulation that an autoimmune process may be triggered also shown the presence of anti-retinal antibodies in
by an infection with a particular virus. Nearly simulta- VKH patients. However, retinal autoimmunity may be
neous onset of VKH among co-workers, friends, and an epiphenomenon that develops after retinal damage
neighbors have been reported, suggesting a possible vi- has already occurred or it may perpetuate inflammation
ral or shared environmental etiology.21 By means of that has already been initiated by melanocyte specific
molecular mimicry, viral antigens may trigger an aber- immune activation.30,31
rant immune response to self-antigens, including those Although VKH does not appear to have a strong
found in the eye. However, studies aimed at the isola- familial association or an identifiable mode of inheri-
tion of a specific virus from either the eye or the CSF tance, familial cases have been described including con-
have been inconclusive.22,23 current onset of the disease in monozygotic twins.32
VKH does have a strong major histocompatibility
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antigen (MHC) class II association, further suggest-
ing a role for immune dysregulation in its pathogen-
DIFFERENTIAL DIAGNOSIS
esis. VKH has been linked to human leukocyte antigen The diagnosis of VKH is based on history and clinical
DR4 (HLA-DR4) and HLA-Dw53, with strongest asso- findings (Figure 3). The differential diagnosis includes
ciated risk for HLA-DRB1∗ 0405 haplotype.24,25 HLA- other causes of granulomatous uveitis (such as sympa-
DRB1∗ 0405 is a common allele in the Japanese popu- thetic ophthalmia and sarcoidosis), primary intraocular
lation, which may explain the high incidence of VKH B-cell lymphoma, posterior scleritis, uveal effusion syn-
in Japan. Interestingly, the HLA-DRB1*0405 molecule drome, and white dot syndromes (such acute posterior
has been shown to play a selective role in the presenta- multifocal placoid pigment epitheliopathy (APMPPE)
tion of melanocyte-derived peptides to T-cells isolated and multiple evanescent white dot syndrome). A thor-
from VKH patients.26 ough history and physical examination as well as di-
The clinical findings of tissue depigmentation in rected laboratory evaluation to exclude systemic dis-
VKH patients point to the possible involvement of ease and malignancy should be performed in suspected
melanocytes in the pathogenesis of the disease. It has individuals.
been hypothesized that VKH represents a T-cell medi- Clinical presentation of VKH may mimic sympa-
ated autoimmune response against melanocytes of mul- thetic ophthalmia; however, by definition, in contrast
tiple organ systems. Extensive research has focused on to patients with sympathetic ophthalmia, there is no
the identification of melanocyte-specific proteins that history of ocular trauma or ocular surgery in patients
may be the trigger of the autoimmune cascade. In vitro with VKH. Furthermore, the prodromal and systemic
FIGURE 3 Differential diagnosis of Vogt-Koyanagi-Harada disease.
F. M. Damico et al. 186

6. manifestations seen in VKH are uncommon with sym- more difficult to make the distinction between the two
pathetic ophthalmia. disorders.
In the absence of exudative retinal detachment, VKH
may resemble sarcoidosis. However, there are usually DIAGNOSIS
more extensive retinal vascular findings (venous sheath- The diagnosis of VKH is based on history and clin-
ing and “candlewax drippings”) in patients with sar- ical findings with supportive evidence from ancillary
coidosis and sarcoid granulomas are generally larger tests ( Table 1). Fluorescein angiography (FA), indocya-
than the yellow subretinal lesions seen in VKH. Serum nine angiography (ICGA), ultrasound, optic coherence
angiotensin converting enzyme level, a chest radiograph tomography (OCT), and lumbar puncture are useful in
along with biopsy of the suspected granulomatous tis- establishing the diagnosis of VKH, especially in incom-
sue can aid in the diagnosis. plete or probable cases.
Primary intraocular B-cell lymphoma can mimic During the acute uveitic phase, FA demonstrates
VKH with its chronic course, particularly when exuda- multiple pinpoint hyperfluorescent dots at the level of
tive retinal detachment is also present. However, the the RPE in the early arteriovenous flow followed by
larger sub-RPE infiltrates often found with lymphoma pooling of fluorescein in the subretinal space, in the ar-
can usually be differentiated from the multiple smaller eas of exudative retinal detachment (Figure 4). The ma-
yellow subretinal lesions seen in VKH. In addition, oc- jority of cases in the acute phase also show optic nerve
ular findings in lymphoma generally evolve gradually head leakage.34 In the chronic and recurrent stages of
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in contrast to the rapid progression to bilateral involve- the disease, retinal pigment epithelial damage results in
ment and marked accumulation of subretinal fluid seen nonspecific window defects on FA.
in VKH. Central nervous system involvement is asso- ICGA can better demonstrate the choroidal pathol-
ciated with both entities. A lumbar puncture and head ogy that is the hallmark of VKH. In the early
magnetic resonance imaging can facilitate the diagnosis. phases, ICGA reveals multiple hypofluorescent spots,
Posterior scleritis presents with pain, photophobia, which are thought to correspond to foci of lympho-
loss of vision and possible vitritis. When bilateral, it is cytic infiltration within the choroid. In later phases
generally associated with a systemic connective tissue of the angiogram, there may be a diffuse choroidal
disease, most often rheumatoid arthritis. Ultrasonog- hyperfluorescence.35 The hypofluorescent lesions de-
raphy can help differentiate VKH from posterior scle- tected by ICGA may persist even when the fundoscopic
ritis. In posterior scleritis, there is a flattening of the examination and FA are unremarkable.36
posterior aspect of the globe along with a thickening of Ultrasonography reveals a bilateral low to medium
choroidal-scleral layer and retrobulbar edema with high reflective thickening of the posterior choroid, most
internal reflectivity. Similarly, a thickened sclera is seen prominently in the juxtapapillary region.37 This is in
on computed tomography scan that may enhance with contrast to idiopathic uveal effusion and metastatic car-
contrast. cinoma, which tend to have higher reflectivity. Serous
Uveal effusion syndrome may clinically and an- retinal detachments, vitreous opacities, and posterior
giographically resemble VKH. However, patients with thickening of the choroid can also be appreciated on
uveal effusion syndrome do not present with signs of in- ultrasound.
traocular inflammation or systemic manifestations such OCT can be useful in the diagnosis and the moni-
as dysacusia, alopecia, poliosis, vitiligo and CSF pleo- toring of the serous macular detachments.
cytosis often seen in patients with VKH. Exudative reti-
TABLE 1 Diagnostic workup for Vogt-Koyanagi-Harada disease
nal detachments in uveal effusion syndrome tend to be
chronic and do not respond to corticosteroid treatment. Diagnostic workup for Vogt-Koyanagi-Harada disease
APMPPE may be confused with VKH due to its viral No history of ocular trauma or surgery
prodrome and multiple white-yellow lesions at the RPE Clinical findings
level. Its rapid spontaneous resolution, generally lack of Fluorescein angiography
recurrence, and lack of systemic manifestations can be Indocyanine angiography
helpful in the differentiation. However, since the initial Ultrasound
Optical coherence tomography
report of APMPPE described by Gass,33 many ocular
Lumbar puncture
and systemic features have been reported, making it
187 VKH Disease

7. FIGURE 4 Fluorescein angiographies of the same patient as in Figure 2. Note the massive pooling of fluorescein throughout the
posterior pole and disc staining.
In most cases, a thorough history and clinical exami- disease is especially responsive, particularly in the early
nation in combination with FA, ICGA and ultrasound stages (Figure 5). Typical dosing regimens range from
is sufficient to make the diagnosis of VKH. However, in 1.0 to 2.0 mg/kg/day of oral prednisone or 200 mg of
atypical cases, and in patients who present early in the intravenous methylprednisolone for 3 days, followed
course of the disease with few ocular signs and promi- by high-dose oral corticosteroids. Early therapy with a
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nent meningeal signs, a lumbar puncture can be helpful. slow taper tailored to the clinical response, usually over
The lumbar puncture typically shows a predominantly a minimum of 6 months, has been shown to improve
lymphocytic pleocytosis. An elevation of CSF protein the prognosis by reducing the length of disease, increas-
levels can be found in up to 80% of patients within ing the incidence of a convalescent phase, and decreas-
one week and 97% of patients within 3 weeks of onset ing the extraocular manifestations.4,10,19 A recent mul-
of inflammation. The CSF pleocytosis is transient and ticenter international study on the treatment of VKH
usually resolves within 8 weeks.11 demonstrated that high-dose oral corticosteroids and
intravenous corticosteroids were equally effective, with
similar outcomes in both treatment groups.38
TREATMENT Although most patients in the acute uveitic phase
The standard initial therapy for VKH is prompt and will respond exquisitely to corticosteroids, recurrent
aggressive use of systemic corticosteroids, to which the episodes of inflammation have a propensity to be
FIGURE 5 Treatment of Vogt-Koyanagi-Harada disease.
F. M. Damico et al. 188

8. more steroid resistant. Therefore, treatment with im- with prompt diagnosis and aggressive therapy. However,
munomodulatory therapy, such as cyclosporine, cy- a significant number of patients, 11% in one series,11
clophosphamide, chlorambucil, azathioprine, or my- will have a poor outcome, with visual acuity of 20/200
cophenolate mofetil may be necessary. or less.10,42
Some investigators argue for initial therapy with im-
munomodulatory agents, specifically cyclosporine.39
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189 VKH Disease

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