Download Vogt-Koyanagi-Harada disease

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
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 established. 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.
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: [email protected] (R.W. Read).
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 disease 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 and McPherson [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 presentation is still occasionally referred to as Harada’s
disease, recently published revised diagnostic criteria
favor always using the full name, given the knowledge that this is one disease process [1].
Epidemiology
Vogt-Koyanagi-Harada disease occurs most commonly in certain ethnic groups. Although not established 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: 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
predisposes them to sensitization to antigens of melanocytic 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 examined 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 particular clinic. It is highly likely that as the demographics 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, Rathinam 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 directed at identifying the precise target of autoimmune
attack and associations of the disease with specific
immune profiles.
Ophthalmic histopathology has shown VKH disease to be a granulomatous panuveitis that has many
similarities with sympathetic ophthalmia [23]. Immunohistochemical investigations have shown the predominant 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 complex 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]
and melanin-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 revealed 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 ophthalmia. Because the latter condition is almost certainly 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 association 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], Brazilians [13], Mexican Mestizos [38], and Italians [39]. In
these studies, the strongest associations have been with
the HLA-DR4 allele, and when further subtyping was
performed, the greatest association has been found
with HLA-DRB1 * 0405 or HLA-DRB1 * 0410. Analyses of the amino acid sequence of the HLADRB1 * 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) 333–341
lymphocytes from patients with VKH disease who
possess the HLA-DRB1 * 0405 allele recognize peptides derived from melanocytes and melanoma proteins [41]. Among these peptides are those derived
from tyrosinase [42] and other tyrosinase family proteins, 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 proinflammatory, 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 commonly found in certain groups. As in other autoimmune 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 regarding 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 neurologic 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
335
inclusive of the entire potential disease process. Nevertheless, this term does emphasize two of the most
prominent areas of acute disease involvement,
although not in chronologic order. Melanocytes contained 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. Occasionally, 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 prodromal stage of VKH disease may last from only a few
days to several weeks [51]. Patients have been admitted to the hospital with a diagnosis of aseptic meningitis 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. Audiometric 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 detachments, or both. Fluorescein angiography performed
at this stage typically reveals focal areas of delay in
choroidal perfusion, multifocal areas of pinpoint leak-
336
R.W. Read / Ophthalmol Clin N Am 15 (2002) 333–341
Table 1 (continued)
Table 1
Vogt-Koyanagi-Harada disease workshop revised diagnostic 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
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.
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 ciliochoroidal 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 characterized by depigmentation of various structures. On the
external ocular surface, pigmentation seen at the
limbus in more heavily pigmented races may disappear, 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 Hispanics than whites [59]. Migration of retinal pigment
epithelial cells may result in pigment clumping in
R.W. Read / Ophthalmol Clin N Am 15 (2002) 333–341
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 subretinal material.
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-
337
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.
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 recurrent posterior segment disease occurs, it is usually
within 6 months of the initial onset, and is a consequence 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 complications 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
mid-phase. Note presence of multiple areas of pinpoint
leakage of dye into subretinal space.
The mainstay of management of VKH disease remains corticosteroids, and because of the potential for
visual morbidity, treatment should be both prompt and
338
R.W. Read / Ophthalmol Clin N Am 15 (2002) 333–341
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 methylprednisolone, 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, clinicians 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 complications. 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 chlorambucil [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 significant 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 inflammation 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 primarily 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 synechiae [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 inadequately with photocoagulation therapy [71]. Increased anti-inflammatory therapy may result in
resolution, as reported for other posterior and panuveitis 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 outcomes 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 complications. A poor final visual acuity was predicted by
greater numbers of complications developing, older
age at disease onset, a longer median duration of disease, and greater number of recurrent episodes of
inflammation. The better the visual acuity at presentation, 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 antigen may allow development of more specific therapies. 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) 333–341
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
national Committee on Nomenclature. Am J Ophthalmol 2001;131:647 – 52.
Moorthy RS, Inomata H, Rao NA. Vogt-KoyanagiHarada syndrome. Surv Ophthalmol 1995;39:265 – 92.
Pattison EM. Uveo-meningoencephalitic syndrome
(Vogt-Koyanagi-Harada). Arch Neurol 1965;12:
197 – 205.
Vogt A. Frühzeitiges Ergrauen der Zilien und Bemerkungen über den sogenannten plötlzichen Eintritt dieser Veränderung. Klin Monatsbl Augenheilkd 1906;
4:228 – 42.
Koyanagi Y. Dysakusis, alopecia und poliosis bei
schwerer uveitis nicht traumatischen ursprungs. Klin
Monatsbl Augenheilkd 1929;82:194 – 211.
Harada E. Beitrag zur klinischen kenntnis von Michteitriger choroiditis (choroiditis diffusa acta). Acta Soc
Ophthalmol Jpn 1926;30:356 – 78.
Babel J. Syndrome de Vogt-Koyanagi (uveite bilaterale, poliosis, alopecie, vitiligo et dysacousie). Schweiz
Med Wochenschr 1932;44:1136 – 40.
Bruno MG, McPherson SD. Harada’s disease. Am J
Ophthalmol 1949;32:513 – 22.
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.
Read RW, Rechodouni A, Butani N, Johnston R,
LaBree LD, Smith RE, et al. Complications and prognostic factors in Vogt-Koyanagi-Harada disease. Am J
Ophthalmol 2001;131:599 – 606.
Davis JL, Mittal KK, Freidlin V, Mellow SR, Optican
DC, Palestine AG, et al. HLA associations and ancestry in Vogt-Koyanagi-Harada disease and sympathetic
ophthalmia. Ophthalmology 1990;97:1137 – 42.
Martinez JA, Lopez PF, Sternberg Jr. P, Aaberg TM,
Lambert HM, Capone Jr. A, et al. Vogt-Koyanagi-Harada syndrome in patients with Cherokee Indian ancestry
[see comments]. Am J Ophthalmol 1992;114:615 – 20.
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 VogtKoyanagi-Harada disease. Hum Immunol 1998;59:
183 – 8.
Chavis PS, Wafai MZ, Al-Amro S, Tabbara KF. Uveitis in the Middle East. In: Dernouchamps JP, Verousgstraete 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.
Ohno S, Char DH, Kimura SJ, O’Connor GR. VogtKoyanagi-Harada syndrome. Am J Ophthalmol 1977;
83:735 – 40.
Snyder DA, Tessler HH. Vogt-Koyanagi-Harada syndrome. Am J Ophthalmol 1980;90:69 – 75.
Read RW, Butani N, Parsa K, Torshizy H, Smith R,
Rao N. Changing patterns of uveitis diagnoses in a referral clinic. Invest Ophthalmol Vis Sci 2001;42:S460.
Murakami S, Inaba Y, Mochizuki M, Nakajima A,
Urayama A. A nationwide survey on the occurrence
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
339
of Vogt-Koyanagi-Harada disease in Japan. Jpn J Ophthalmol 1994;38:208 – 13.
Cunningham Jr. ET, Demetrius R, Frieden IJ, Emery
AR, Irvine AR, Good WV. Vogt-Koyanagi-Harada syndrome in a 4-year old child. Am J Ophthalmol 1995;
120:675 – 7.
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.
Tabbara KF, Chavis PS, Freeman WR. Vogt-KoyanagiHarada syndrome in children compared to adults. Acta
Ophthalmol Scand 1998;76:723 – 6.
Rathinam SR, Vijayalakshmi P, Namperumalsamy P,
Nozik RA, Cunningham Jr. ET. Vogt-Koyanagi-Harada
syndrome in children. Ocul Immunol Inflamm 1998;
6:155 – 61.
Rao NA. Mechanisms of inflammatory response in
sympathetic ophthalmia and VKH syndrome. Eye
1997;11:213 – 6.
Sakamoto T, Murata T, Inomata H. Class II major histocompatibility complex on melanocytes of Vogt-Koyanagi-Harada disease. Arch Ophthalmol 1991;109:
1270 – 4.
Boyd SR, Young S, Lightman S. Immunopathology of
the noninfectious posterior and intermediate uveitides.
Surv Ophthalmol 2001;46:209 – 33.
Kogiso M, Tanouchi Y, Miki S, Mimura Y. Characterization of T-cell subsets, soluble interleukin-2 receptors
and interleukin-6 in Vogt-Koyanagi-Harada disease.
Jpn J Ophthalmol 1992;36:37 – 43.
Norose K, Yano A, Aosai F, Segawa K. Immunologic
analysis of cerebrospinal fluid lymphocytes in VogtKoyanagi-Harada disease. Invest Ophthalmol Vis Sci
1990;31:1210 – 6.
Nakamura S, Nakazawa M, Yoshioka M, Nagano I,
Nakamura H, Onodera J, et al. Melanin-laden macrophages in cerebrospinal fluid in Vogt-Koyanagi-Harada
syndrome. Arch Ophthalmol 1996;114:1184 – 8.
Takeshita T, Nakazawa M, Murakami K, Tamai M,
Nakamura S. A patient with long standing melanin
laden macrophages in cerebrospinal fluid in VogtKoyanagi-Harada syndrome [letter]. Br J Ophthalmol
1997;81:1114.
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.
Tsuruta D, Hamada T, Teramae H, Mito H, Ishii M.
Inflammatory vitiligo in Vogt-Koyanagi-Harada disease. J Am Acad Dermatol 2001;44:129 – 31.
Yamaki K, Kondo I, Nakamura H, Miyano M, Konno S, Sakuragi S. Ocular and extraocular inflammation induced by immunization of tyrosinase related
protein 1 and 2 in Lewis rats. Exp Eye Res 2000;71:
361 – 9.
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 disease. Hum Immunol 1994;39:169 – 76.
340
R.W. Read / Ophthalmol Clin N Am 15 (2002) 333–341
[34] Kim MH, Seong MC, Kwak NH, Yoo JS, Huh W, Kim
TG, et al. Association of HLA with Vogt-KoyanagiHarada 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 Vietnamese 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-Koyanagi-Harada syndrome and HLA-DR1 and -DR4 in
Hispanic patients living in southern California. Ophthalmology 1995;102:1012 – 5.
[38] Arellanes-Garcia L, Bautista N, Mora P, Ortega-Larrocea 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 PCRRFLP 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, Miyokawa N, Kimura S, et al. Tyrosinase epitope recognized by an HLA-DR-restricted T-cell line from a
Vogt-Koyanagi-Harada disease patient. Immunogenetics 1998;47:398 – 403.
[43] Gocho K, Kondo I, Yamaki K, Sakuragi S. Identification of specific antigen for Vogt-Koyanagi-Harada disease: lymphocyte reactivity against the tyrosinase
family proteins. Invest Ophthalmol Vis Sci 1999;
40:S204.
[44] Gocho K, Kondo I, Yamaki K, Sakuragi S. Establishment 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, Ganiban 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, Cunningham Jr. ET. Vogt-Koyanagi-Harada syndrome after
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
cutaneous injury [see comments]. Ophthalmology
1999;106:635 – 8.
Goldgeier MH, Klein LE, Klein-Angerer S, Moellmann G, Nordlund JJ. The distribution of melanocytes
in the leptomeninges of the human brain. J Invest Dermatol 1984;82:235 – 8.
Wong SS, Ng SK, Lee HM. Vogt-Koyanagi-Harada
disease: extensive vitiligo with prodromal generalized
erythroderma. Dermatology 1999;198:65 – 8.
Ohno S, Minakawa R, Matsuda H. Clinical studies of
Vogt-Koyanagi-Harada’s disease. Jpn J Ophthalmol
1988;32:334 – 43.
Nussenblatt RB. Vogt-Koyanagi-Harada syndrome
(uveomeningitic syndrome). In: Ryan SJ, editor. Retina. vol. 2, 3rd edition. St Louis: Mosby; 2001. p.
1762 – 9.
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.
Forster DJ, Cano MR, Green RL, Rao NA. Echographic features of the Vogt-Koyanagi-Harada syndrome. Arch Ophthalmol 1990;108:1421 – 6.
Gohdo T, Tsukahara S. Ultrasound biomicroscopy of
shallow anterior chamber in Vogt-Koyanagi- Harada
syndrome. Am J Ophthalmol 1996;122:112 – 4.
Kawano Y, Tawara A, Nishioka Y, Suyama Y, Sakamoto H, Inomata H. Ultrasound biomicroscopic analysis of transient shallow anterior chamber in VogtKoyanagi-Harada syndrome. Am J Ophthalmol 1996;
121:720 – 3.
Nakamura H, Tsukamoto H, Shibahara R, Nagai M,
Mishima HK. Ultrasound biomicroscopy in the management of Vogt-Koyanagi-Harada disease. Acta Ophthalmol Scand 2000;78:718 – 9.
Kishi A, Nao-i N, Sawada A. Ultrasound biomicroscopic findings of acute angle-closure glaucoma in
Vogt-Koyanagi-Harada syndrome. Am J Ophthalmol
1996;122:735 – 7.
Sugiura S. [Some observations on uveitis in Japan,
with special reference to Vogt-Koyanagi-Harada and
Behcßet’s diseases.] Nippon Ganka Gakkai Zasshi
1976;80:1285 – 326.
Goto H, Rao NA. Sympathetic ophthalmia and VogtKoyanagi-Harada syndrome. Int Ophthalmol Clin
1990;30:279 – 85.
Inomata H, Rao NA. Depigmented atrophic lesions in
sunset glow fundi of Vogt-Koyanagi- Harada disease.
Am J Ophthalmol 2001;131:607 – 14.
Rubsamen PE, Gass JD. Vogt-Koyanagi-Harada syndrome. Clinical course, therapy, and long-term visual
outcome. Arch Ophthalmol 1991;109:682 – 7.
Garcia-Valenzuela E, Tessler HH, Carnahan M, Ryan
JJ, Goldstein DA. Multiple recurrences of exudative
retinal detachment in a patient with Vogt-KoyanagiHarada disease. Retina 2000;20:672 – 4.
Sasamoto Y, Ohno S, Matsuda H. Studies on corticosteroid therapy in Vogt-Koyanagi-Harada disease.
Ophthalmologica 1990;201:162 – 7.
R.W. Read / Ophthalmol Clin N Am 15 (2002) 333–341
[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 noninfectious 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 cytotoxic agents. Am J Ophthalmol 1983;96:275 – 82.
[67] Wakatsuki Y, Kogure M, Takahashi Y, Oguro Y. Combination 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-Harada 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-
[71]
[72]
[73]
[74]
[75]
341
Koyanagi-Harada syndrome. Ophthalmology 1993;
100:613 – 8.
Moorthy RS, Chong LP, Smith RE, Rao NA. Subretinal neovascular membranes in Vogt-Koyanagi-Harada
syndrome. Am J Ophthalmol 1993;116:164 – 70.
Dees C, Arnold JJ, Forrester JV, Dick AD. Immunosuppressive treatment of choroidal neovascularization
associated with endogenous posterior uveitis. Arch
Ophthalmol 1998;116:1456 – 61.
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.
Kilmartin DJ, Forrester JV, Dick AD. Cyclosporine-induced resolution of choroidal neovascularization
associated with sympathetic ophthalmia [letter]. Arch
Ophthalmol 1998;116:249 – 50.
Greve MDJ, Hillson TR, Hinz BJ, Tennant MTS. Surgical removal of subfoveal choroidal neovascular
membranes in Vogt-Koyanagi-Harada syndrome: clinical and histopathological results. Invest Ophthalmol
Vis Sci 1999;40:S871.