VKH

Ophthalmol Clin N Am 15 (2002) 333 – 341

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 Historical background
known, but not necessarily recognized in its complete
form, for over a millennium. Despite this, information The association of poliosis with inflammatory eye
regarding the exact cause and best treatment regimen disease was recognized as early as the 10th century
for this potentially blinding condition are not estab- AD, when Ali-ibn-Isa described what is now termed
lished. Manifesting ophthalmologically as a bilateral, chronic VKH disease [2,3]. The current tripartite
granulomatous panuveitis, VKH disease seems to be a eponym stems from descriptions of the chronic dis-
T-cell mediated systemic autoimmune process, which ease phase by Vogt [4] in 1906 and Koyanagi [5] in
evidence increasingly suggests is directed at one or 1929, and of the acute disease phase by Harada [6] in
more antigens associated with melanocytes. As such, 1926. Babel [7] in 1932 and Bruno and McPherson [8]
any organ system that contains melanocytes is a in 1949 realized that these descriptions were points on
potential target of attack, including the eye, skin and a disease spectrum and coalesced these entities under
hair, inner ear, and meninges. VKH disease occurs the rubric of VKH disease. Although the acute pre-
more frequently in certain ethnic groups. The disease sentation is still occasionally referred to as Harada’s
has distinct phases, with acute disease involving disease, recently published revised diagnostic criteria
primarily the ocular posterior segment, central nervous favor always using the full name, given the know-
system, and inner ear. By contrast, chronic-recurrent ledge that this is one disease process [1].
disease involves the ocular anterior segment and
integumentary system. Aggressive anti-inflammatory
therapy is typically required, but no quality clinical Epidemiology
trial data exist to guide the agent of choice, dosage, or
duration of therapy. Complications are not uncommon Vogt-Koyanagi-Harada disease occurs most com-
and are typically the reason for decreased vision. monly in certain ethnic groups. Although not estab-
Many questions remain to be answered regarding lished definitively, it is possible that the link between
VKH disease. Work toward these answers continues, these groups arises from a common ancestry in the
as evidenced by the occurrence of an ongoing series original peoples of Asia. Dispersion then occurred
of international workshops directed specifically at through migration across the Asian continent, over
this disease. Out of the two workshops held to date, the Bering Strait land bridge, and into the Americas
revised diagnostic criteria [1] have been issued and a [9]. This susceptible group of individuals includes
disease severity grading scheme is in formation, both modern-day East and Southeast Asians, Asian Indians,
for use in planned prospective clinical trials. Middle Easterners, Native Americans, and Hispanics.
The disease occurs, but is uncommon, in whites and
Africans [10]. An American Indian ancestry has been
Supported in part by unrestricted grants from Research reported as important in patients from the United
to Prevent Blindness, Inc., New York, NY and the EyeSight States [11,12]. Rarity in Africans suggests that amount
Foundation of Alabama, Inc., Birmingham, AL. of pigmentation alone is not the main factor in the
E-mail address: rwr@uab.edu (R.W. Read). etiology of VKH disease. Rather, something within

0896-1549/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved.
PII: S 0 8 9 6 - 1 5 4 9 ( 0 2 ) 0 0 0 2 5 - 1

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

the immune repertoire of susceptible individuals likely similarities with sympathetic ophthalmia [23]. Immu-
predisposes them to sensitization to antigens of mela- nohistochemical investigations have shown the pre-
nocytic origin. Details of the relationship between dominant infiltrating cell in the choroid is the
genetics and VKH disease are discussed further in T lymphocyte, with a larger proportion of helper
the next section. (CD4+) cells than cytotoxic (CD8+) cells [24]. Present
Vogt-Koyanagi-Harada disease has been reported also are epithelioid and multinucleated giant cells
to be responsible for up to 9.2% of cases of uveitis containing melanin [25]. Choroidal melanocytes have
clinics in Japan [2], is the main cause of autoimmune been shown to express major histocompatibility com-
noninfectious uveitis in Brazilians [13], and is the plex class II molecules on their surface in eyes from
second most common uveitic diagnosis made in Saudi patients with VKH disease [24]. These molecules are
Arabia [14]. In contrast, earlier publications from the required to participate in antigen presentation to CD4+
United States reported a prevalence in uveitis clinics T cells. In the cerebrospinal fluid of VKH disease
of 1% [15] to 4% [16]. Read et al [17] recently ex- patients, activated CD4+ T cells predominate [26,27]
amined uveitic disease prevalence in a uveitis tertiary and melanin-containing macrophages have been found
referral center in Southern California for the 3-year [28,29]. Similar findings have been reported from
period 1996 to 1998. They found the frequency of studies of sites of vitiligo in VKH disease [30,31].
VKH disease to be 7%. This more frequent occurrence Animal studies have shown that a VKH-like
compared with previous reports was believed to be disease is inducible in rats by immunization with
secondary to the large Hispanic and Asian populations peptides derived from proteins of the tyrosinase
in Southern California and referral bias to this par- family, which are found in melanocytes [32]. In this
ticular clinic. It is highly likely that as the demo- disease, the rats develop uveitis 12 to 21 days after
graphics of the remainder of the United States immunization, followed by fundus depigmentation at
continue to diversify, VKH disease will become a 2 to 3 months. Histopathologically, the disease re-
more frequently encountered entity in practices across vealed granulomatous inflammation in the choroid
the country. and iris, similar to that observed in patients with
Most series have reported an approximate female VKH disease [2].
to male disease ratio of 2:1 [2,10,18]. Most patients With the exception of patient history, marked
have the onset of disease while in their third to fifth similarities exist between the clinical and pathologic
decade of life, but cases have been reported in children manifestations of VKH disease and sympathetic oph-
as young as 4 years of age [19,20]. It has been thalmia. Because the latter condition is almost cer-
suggested that VKH disease in children may be more tainly caused by immune sensitization to uveal tissue
aggressive than in adults. In one series, Tabbara et al following trauma, this provides further circumstantial
[21] found that 61% of children with VKH disease evidence that VKH disease shares a similar immune
had final visual acuities of 20/200 or worse despite pathophysiology, although dissimilar avenues of
medical and surgical therapy. In a review of world sensitization.
literature on pediatric VKH disease, however, Rathi- As in other autoimmune conditions, associations
nam et al [22] found that 85.7% of children had a final with certain HLA subtypes are not unexpected because
visual acuity of 20/30 or better in the best eye. The these cell surface molecules are involved in antigen
prognosis in this subpopulation seems to be quite presentation and recognition. HLA typing and asso-
variable, and final visual outcome may be related to ciation studies have been performed in a number of
as yet unknown differences between the various different ethnic groups with high frequencies of VKH
ethnic groups, time to treatment, type of treatment, disease, including the Japanese [33], Koreans [34],
and duration of treatment. Chinese [35], Vietnamese [36], Hispanics [37], Brazil-
ians [13], Mexican Mestizos [38], and Italians [39]. In
these studies, the strongest associations have been with
Etiology and pathogenesis the HLA-DR4 allele, and when further subtyping was
performed, the greatest association has been found
The exact cause of VKH disease is unknown. with HLA-DRB1 * 0405 or HLA-DRB1 * 0410. Ana-
Most research on its pathophysiology has been direc- lyses of the amino acid sequence of the HLA-
ted at identifying the precise target of autoimmune DRB1 * 0405 allele indicates that a serine at position
attack and associations of the disease with specific 57 or glutamine at position 70 may play a crucial role
immune profiles. in determining disease susceptibility, because these
Ophthalmic histopathology has shown VKH dis- locations are within the antigen-binding grove of the
ease to be a granulomatous panuveitis that has many molecule [33,40]. Recent studies have shown that

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

lymphocytes from patients with VKH disease who inclusive of the entire potential disease process. Never-
possess the HLA-DRB1 * 0405 allele recognize pep- theless, this term does emphasize two of the most
tides derived from melanocytes and melanoma pro- prominent areas of acute disease involvement,
teins [41]. Among these peptides are those derived although not in chronologic order. Melanocytes con-
from tyrosinase [42] and other tyrosinase family pro- tained within the meninges [48] are apparently the first
teins, such as tyrosinase-related proteins 1 and 2 [43]. site of autoimmune attack, along with the inner ear,
Moreover, T-cell clones established from patients with although lack of knowledge of the initiating events in
VKH disease and stimulated with tyrosinase family this disease prohibits definitive conclusions about the
peptides have demonstrated a predominately proin- initial site of involvement. As mentioned previously,
flammatory, Th1-type T-cell response [44]. the occurrence of VKH disease following cutaneous
Existing evidence points to a T-lymphocyte – trauma [47] raises the possibility that perhaps similar
mediated autoimmune process directed against a subclinical sensitizing events are present in all VKH
melanocyte-associated antigen or antigens, occurring disease patients. Regardless, patients typically report
in a permissive immune environment, more com- severe headaches, nuchal rigidity, possibly fever and
monly found in certain groups. As in other auto- nausea, and auditory symptoms (mainly tinnitus and
immune diseases, however, it seems likely that dysacousia) as initial disease manifestations. Occa-
because there are a greater number of individuals sionally, cutaneous symptoms, such as skin erythema
with the susceptible genetic background than there [49] and scalp tenderness [50], may occur early in the
are who actually develop the disease, some triggering disease course, presumably as a consequence of
event may be required. Multiple theories exist regard- inflammatory cell infiltration into the skin. The prod-
ing a possible trigger. Epstein-Barr virus DNA has romal stage of VKH disease may last from only a few
been isolated from the vitreous of patients with VKH days to several weeks [51]. Patients have been admit-
disease [45] and the Epstein-Barr virus is able to ted to the hospital with a diagnosis of aseptic men-
activate B lymphocytes from patients with VKH ingitis before the onset of ocular disease led to the full
disease more easily than B lymphocytes from patients diagnosis [52]. Cerebrospinal fluid analysis at this
with other uveitic entities [46]. VKH disease has also point usually reveals a pleocytosis, possibly with
been reported to occur following cutaneous injury, melanin-laden macrophages, suggesting VKH disease
presumably by direction of an autoimmune attack [52]. The pleocytosis resolves despite persistence of
against cutaneous melanocytic antigens liberated at disease manifestations elsewhere, so if performed,
the site of injury [47]. lumbar puncture must be carried out early in the
disease course. If sufficient neurologic symptoms exist
followed by the expected ocular signs, then lumbar
Clinical features puncture is not required for diagnosis by the VKH
Workshop Revised Criteria [1].
Vogt-Koyanagi-Harada disease typically consists Hearing loss, if present, usually involves the
of four phases: (1) prodromal, characterized by neuro- higher frequencies and may persist for years. Audio-
logic and auditory manifestations; (2) acute uveitic, metric abnormalities, as measured by pure tone
characterized by a diffuse choroiditis, which may stimuli, middle ear analysis, and auditory brainstem
result in exudative retinal detachments and papillitis, responses, were shown in 20 of 26 patients from the
and possibly an intraocular cellular reaction; (3) National Eye Institute [51].
chronic, characterized by depigmentation of various
structures, including ocular (fundus and limbus) and Acute uveitic phase
integumentary (poliosis and vitiligo, also possibly
with alopecia); and (4) chronic-recurrent, with an The ocular hallmark of acute VKH disease is a
iridocyclitis that may be recurrent, chronic, or both diffuse inflammatory cell infiltrate into the choroid,
[2]. Based on these features and their distinctive timing producing thickening detectable on ultrasonography
within the overall disease course, diagnostic criteria [53]. This is commonly accompanied by hyperemia of
were recently revised and published (Table 1) [1]. the optic nerve head. Leakage of fluid from the choroid
through the retinal pigment epithelium occurs, with the
Prodromal phase resultant formation of focal areas of subretinal fluid
accumulation, development of larger bullous detach-
Vogt-Koyanagi-Harada disease has been termed a ments, or both. Fluorescein angiography performed
uveomeningitis, which although accurate and useful in at this stage typically reveals focal areas of delay in
directing the clinician’s differential diagnosis, is not choroidal perfusion, multifocal areas of pinpoint leak-


Table 1 (continued)
Incomplete Vogt-Koyanagi-Harada disease (1 – 3 must be
present and either 4 or 5)
Table 1 1. No history of penetrating ocular trauma or surgery
Vogt-Koyanagi-Harada disease workshop revised diagnos- preceding the initial onset of uveitis
tic criteria 2. No clinical or laboratory evidence suggestive of other
entities
Complete Vogt-Koyanagi-Harada disease (1 – 5 must
3. Bilateral ocular involvement
be present)
and either
1. No history of penetrating ocular trauma or surgery
4. Neurologic-auditory findings
preceding the initial onset of uveitis
or
2. No clinical or laboratory evidence suggestive of other
5. Integumentary findings
entities
Probable Vogt-Koyanagi-Harada disease (isolated ocular
A. Early manifestations of disease
disease) (1 – 3 must be present)
There must be evidence of a diffuse choroiditis (with
1. No history of penetrating ocular trauma or surgery
or without anterior uveitis, vitritis, or optic nerve
preceding the initial onset of uveitis
hyperemia) which may manifest as:
2. No clinical or laboratory evidence suggestive of other
1. Focal areas of subretinal fluid
entities
or
2. Bullous serous retinal detachments
or both of the following in the face of equivocal fundus From Read RW, Holland GN, Rao NA, Tabbara KF, Ohno S,
findings: Arellanes-Garcia L, et al. Revised diagnostic criteria for
3. Ultrasonography: diffuse choroidal thickening, Vogt-Koyanagi-Harada disease: report of an International
without evidence of posterior scleritis Committee on Nomenclature. Am J Ophthalmol 2001;131:
4. Fluorescein angiography: focal areas of delay in 647 – 52; with permission.
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) age, large placoid areas of hyperfluorescence, pooling
B. Late manifestations of disease (with history within subretinal fluid, and optic nerve staining
suggestive of prior presence of findings from 3A) and (Figs. 1 – 3) [1]. Cells may be present in the vitreous
1. Ocular depigmentation or aqueous humors but are not necessary to the
a. Sunset glow fundus diagnosis. VKH disease is a bilateral ocular condition.
or The suspicion of unilateral ocular involvement should
b. Sugiura sign
prompt a diligent investigation for either subtle
AND
2. One of the following other signs (or 2 of the
involvement of the fellow eye or a different diagnosis
following in the absence of above depigmentation [1]. Patients with VKH disease may present with
findings) shallowed anterior chambers, because of ciliochoroi-
A. Chorioretinal nummular scars (previously dal detachment [54 – 56], or ciliary body edema [57],
referred to as Dalen-Fuchs nodules) resulting in anterior rotation of the lens-iris diaphragm.
B. RPE clumping or migration Elevated intraocular pressure is not uncommon in
C. Recurrent or chronic anterior uveitis these presentations, but the angle shallowing and
4. Neurologic-auditory findings (manifesting in initial stage closure typically resolve with corticosteroid therapy.
of disease or reliable documentation of such)
A. Meningismus (headache alone is not sufficient to meet
Chronic
definition of meningismus)
or
B. Tinnitus The chronic phase of VKH disease is character-
or ized by depigmentation of various structures. On the
C. Cerebrospinal fluid pleocytosis external ocular surface, pigmentation seen at the
5. Integumentary (not preceding onset of central nervous limbus in more heavily pigmented races may dis-
system or ocular disease) appear, termed Sugiura’s sign [58]. Within the eye,
A. Alopecia loss of choroidal melanocytes results in an orange
or coloration to the fundus, termed the sunset-glow
B. Poliosis fundus, more commonly seen in Asians and His-
or
panics than whites [59]. Migration of retinal pigment
C. Vitiligo
epithelial cells may result in pigment clumping in


Fig. 1. Red-free photograph of right eye of patient with Fig. 3. Fluorescein angiogram of same eye as Figs. 1 and 2
acute Vogt-Koyanagi-Harada disease. Note the presence of during late phase. Note extensive pooling of dye in subretinal
subretinal fluid in the posterior pole, with whitish subreti- space, better outlining the extent of exudative detachment.
nal material.

rent bouts of intraocular inflammation occur. When
various areas of the fundus. Rounded hypopigmented
recurrent inflammation does occur, it is usually an
lesions appear, primarily inferiorly. These lesions
anterior uveitis, in stark contrast to the primarily
have most commonly been referred to as resolved
posterior involvement in acute disease. When recur-
Dalen-Fuchs nodules [2], but a recent report shows
rent posterior segment disease occurs, it is usually
that although these areas represent a loss of retinal
within 6 months of the initial onset, and is a con-
pigment epithelial cells, there is no direct evidence
sequence of a too rapid taper of medication [61].
that they are or were Dalen-Fuchs nodules [60]. Why
Multiple recurrences of exudative retinal detachments
these lesions appear primarily inferiorly is unknown.
have been reported, occurring as long as 35 months
after disease onset [62], although this is considered an
Chronic-recurrent
uncommon disease course.
It is during the chronic-recurrent phase of the
The chronic-recurrent phase does not affect all
disease that many of the vision-reducing complica-
patients, but by definition only those in whom recur-
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

Fig. 2. Fluorescein angiogram of same eye as Fig. 1 during The mainstay of management of VKH disease re-
mid-phase. Note presence of multiple areas of pinpoint mains corticosteroids, and because of the potential for
leakage of dye into subretinal space. visual morbidity, treatment should be both prompt and


aggressive [63]. In the United States, most clinicians improvement in visual acuity following cataract
begin with high-dose oral corticosteroids, typically in extraction with lens implantation.
the range of 1 to 2 mg/kg/day of oral prednisone [2]. Glaucoma may occur in up to 45% of patients
Supplemental regional corticosteroid injections may with VKH disease [61]. Forster et al [70] reported
be used. If the retinal detachments fail to resolve, that in 31% of patients with VKH disease and
intravenous therapy may be tried, usually with meth- glaucoma, medical therapy alone was sufficient,
ylprednisolone, 1 g/day over 3 consecutive days. If whereas 69% required surgical therapy. This study
corticosteroid therapy is effective, retrospective data was published in 1993, when many of the currently
suggest that tapering the therapy over a minimum of available medications for intraocular pressure control
6 months is required to minimize complications and were not yet approved in the United States.
recurrences [2,61]. Outside the United States, clini- Choroidal neovascular membranes may occur in
cians may frequently admit patients to the hospital for up to 11% of eyes [10]. Typically ill-defined in nature,
intravenous therapy as a first-line treatment, based on these neovascular membranes may be treated inad-
anecdotal evidence that this early, aggressive treatment equately with photocoagulation therapy [71]. In-
reduces recurrences and the development of compli- creased anti-inflammatory therapy may result in
cations. Whether this is in fact the case remains to be resolution, as reported for other posterior and panu-
proved in a prospective clinical trial. veitis entities [72 – 74]. One small series showed an
Patients with resistant or recurrent disease may improvement of vision in two of three eyes following
require noncorticosteroid immunosuppressive therapy surgical removal of subretinal neovascularization [75].
[2]. Multiple therapeutic classes and agents have been
used, including the antimetabolite azathioprine, and
the alkylating agents cyclophosphamide and chlor- Prognosis
ambucil [64]. Based on the etiologic discussion
presented previously, such agents as cyclosporine In their review of complications and visual out-
and tacrolimus, which target T-lymphocyte function, comes in VKH disease, Read et al [10] found that a
seem ideal. In fact, these agents have been used with longer median duration of disease and a greater
success in cases of corticosteroid intolerance or number of recurrent episodes of inflammation were
resistance [65 – 68]. All of these agents have signifi- significantly associated with the development of com-
cant potential side effects, and their use should be plications. A poor final visual acuity was predicted by
under the direction of an experienced clinician. greater numbers of complications developing, older
Topical corticosteroids are mainly an adjunctive age at disease onset, a longer median duration of dis-
therapy in VKH disease. In acute disease, they are ease, and greater number of recurrent episodes of
wholly inadequate in treating the posterior segment inflammation. The better the visual acuity at presenta-
manifestations. In chronic disease, where the inflam- tion, the more likely that eye was to have a better
mation is primarily anterior, topical therapy is still visual acuity at final follow-up. In their study, 49% of
frequently insufficient, because recurrent disease is eyes obtained a final visual acuity of 20/40 or better,
notoriously resistant to treatment. Cycloplegics 22% of eyes obtained 20/50 to 20/100, and 29% of
should be used to prevent posterior synechiae and eyes obtained a final visual acuity of 20/200 or worse
improve comfort. Nonsteroidal anti-inflammatory [10]. African-Americans did worse overall, with 70%
drugs have essentially no role. of eyes having final visual acuities of 20/200 or worse.
Many questions remain to be answered regarding
Surgical VKH disease. Identification of the exact target anti-
gen may allow development of more specific ther-
Surgical therapy in VKH disease is limited pri- apies. Until that point, prospective clinical trials are
marily to addressing the complications induced by the needed to identify the most efficacious therapeutic
disease. Rarely, surgical drainage of subretinal fluid protocols to control acute disease and prevent future
that was resistant to medical therapy may be indicated. vision-limiting complications.
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 References
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