Vogt–Koyanagi– Harada

Disease
Presented By : Dr. Bhumika Rath
 Introduction and Historical Aspects

• Vogt–Koyanagi–Harada (VKH) disease is a bilateral granulomatous uveitis often

associated with exudative retinal detachment and with extraocular
manifestations, such as pleocytosis in the cerebrospinal fluid and, in some cases,
vitiligo, poliosis, alopecia, and dysacusis.
• Poliosis associated with ocular inflammation was first described by Ali-ibn-Isa.
• Harada described a primary posterior uveitis with exudative retinal detachments
in association with cerebrospinal fluid pleocytosis.
• Three years later, in 1929, Koyanagi described six patients with bilateral chronic
iridocyclitis, patchy depigmentation of the skin, patchy hair loss, and whitening
of the hair, especially the eyelashes.
• This constellation of findings was termed “uveitis with poliosis,
vitiligo, alopecia, and dysacusis.”
• Babel in 1932 and Bruno and McPherson in 1945 combined the
findings of Vogt, Koyanagi, and Harada and suggested that these
processes represent a continum of the same disease, thereafter
recognized as Vogt– Koyanagi–Harada syndrome.
• extraocular manifestations such as dysacusis and cutaneous changes
are relatively rare, and the dermatologic changes mainly occur late in
the course of the disease.
• Because of the variation in clinical presentations of VKH, the American Uveitis Society (AUS) in 1978
recommended the following diagnostic criteria:

(1) the absence of any history of ocular trauma or surgery; and

(2) the presence of at least three of the following four signs:

(a) bilateral chronic iridocyclitis;

(b) posterior uveitis, including exudative retinal detachment, disc hyperemia or edema and “sunset glow”
fundus;
(c) neurologic signs of tinnitus, neck stiffness, cranial nerve, or central nervous system disorders, or
cerebrospinal fluid pleocytosis;
(d) cutaneous findings of alopecia, poliosis, or vitiligo.

• Since VKH manifestations vary depending upon the clinical course, a given patient may not initially present with
the features required for the diagnosis of VKH by AUS criteria.
Epidemiology
• It appears to be more common in Japan, where it accounts for 6.7% of all
uveitis referrals.
• VKH tends to affect more pigmented races, such as Asians, Hispanics, American
Indians, and Asian Indians.
• Most studies report that women tend to be affected more frequently than
men; however, Japanese investigators have not found such a female
predilection.
• Most patients are in their second to fifth decades of life, but children may also
be affected.
Revised Diagnostic Criteria Proposed by the First
International Workshop on Vogt– Koyanagi–Harada
Disease
• Taking into account the multisystem nature of VKH and allowing for the different ocular
findings present in the early and late stages of the disease, the First International Workshop on
VKH proposed revised diagnostic criteria to include clinical manifestations at various stages of
disease.

1. Complete VKH Disease

1. Bilateral ocular involvement (a or b must be met, depending on the stage of disease when
the patient is examined)
a. Early manifestations of disease
1) There must be evidence of a diffuse choroiditis (with or without anterior
uveitis, vitreous inflammatory reaction, or optic disc hyperemia),which may manifest
as one of the following:
a) Focal areas of subretinal fluid, or
b) Bullous serous retinal detachments
2) With equivocal fundus findings, both of the following must be present as well:
a) Focal areas of delay in choroidal perfusion, multifocal areas of pin-point leakage, large placoid areas
of hyperfluorescence, pooling within subretinal fluid, and optic nerve staining (listed in order of
sequential appearance) by fluorescein angiography, and
b) Diffuse choroidal thickening, without evidence of posterior scleritis by ultrasonography

b. Late manifestations of disease

1) History suggestive of prior presence of findings from 1a, and either both (2) and (3) below, or
multiple signs from (3):
2) Ocular depigmentation (either of the following manifestations is sufficient):
a) Sunset glow fundus, or
b) Sugiura's sign – Perilimbal vitiligo
3) Other ocular signs:
a) Nummular chorioretinal depigmented scars, or
b) Retinal pigment epithelium clumping and/or migration, or
c) Recurrent or chronic anterior uveitis
2. Neurologic/auditory findings (may have resolved by time of examination)

a. Meningismus (malaise, fever, headache, nausea, abdominal pain, stiffness of the neck and back, or a
combination of these factors; headache alone is not sufficient to meet the definition of meningismus)
or
b. Tinnitus, or
c. Cerebrospinal fluid pleocytosis

3. Integumentary finding (not preceding onset of central nervous system or ocular disease)

a. Alopecia, or
b. Poliosis, or
c. Vitiligo

Incomplete VKH Disease (Point 1 and Either 2 or 3 Must Be Present)

1. Bilateral ocular involvement as defined for complete VKH disease

2. Neurologic/auditory findings as defined for complete VKH disease above, or
3. Integumentary findings as defined for complete VKH disease above
Probable VKH Disease

1. Bilateral ocular involvement as defined for complete VKH disease above

* In all cases there should not be a history of penetrating ocular injury or

surgery preceding the initial onset of uveitis and no clinical or laboratory
evidence suggestive of other ocular disease criteria.
Clinical Description
The Prodromal Stage
• Initial manifestations of VKH disease may include nonspecific virallike illness,
commonly referred to as a prodromal stage.
• This stage may last only a few days and may be limited to headaches, nausea,
dizziness, fever, orbital pain, and meningism.
• Light sensitivity and tearing may occur 1–2 days following the above
symptoms.
• These neurologic signs include cranial nerve palsies and optic neuritis.
Cerebrospinal fluid analysis usually reveals pleocytosis.
The Acute Uveitic Stage
• This stage follows the prodromal phase and presents with blurring of vision in
both eyes. One eye may be affected first, followed a few days later by the
second eye.
• Despite a delay in symptoms, careful examination will reveal bilateral posterior
uveitis.
• This uveitis consists of thickening of the posterior choroid with elevation of the
peripapillary retinochoroidal layer, multiple serous retinal detachments,
hyperemia, and edema of the optic nerve head.
• Rarely VKH disease can present with optic disc hyperemia and edema without
serous retinal detachments .
• VKH patients with optic disc swelling without typical serous retinal detachment
are more likely to be female, older individuals, and they develop chronic
disease more frequently than patients with the typical VKH presentations.
FIG. 78.2 Bilateral hyperemia and
edema of the optic disc at the acute
uveitis stage of Vogt–Koyanagi–
Harada disease without serous
retinal detachment.
• Thickened choroid can be detected by ultrasonography .
• Alteration in the retinal pigment epithelium (RPE) associated with multifocal choroidal
inflammation is easily observed with FA, which reveals hypofluorescent dots at the early phase
followed by multiple focal areas of leakage and subretinal fluid accumulation at the late phase.
• Indocyanine green angiography (ICGA) could be useful to evaluate choroidal inflammatory
changes, such as early choroidal stromal vessel hyperfluorescence and leakage, and
hypofluorescent dark dots at the level of the choroid.
• The inflammation eventually becomes diffuse, extending into the anterior segment and
revealing the presence of flare and cells in the anterior chamber.
• Less commonly, mutton-fat keratic precipitates, small nodules on the iris surface and pupillary
margin, may be observed; however, these anterior inflammatory changes are more common in
the recurrent phase.
• The inflammatory infiltrate in the ciliary body and choroid may cause forward displacement of
the lens iris diaphragm , leading to acute angle closure glaucoma or annular choroidal
detachment.
• These intraocular changes are typically bilateral; rarely, however, the process can be restricted
to one eye.
FIG. 78.4 (A) Early arteriovenous
phase of fluorescein angiogram
exhibiting multiple hypofluorescent
dots with irregular
hyperfluorescent background. (B)
Subsequently, multiple
hyperfluorescent dots at the retinal
pigment epithelium level are
noted. (C) Dye leakage during
midphase of the angiogram. (D)
Subretinal dye pooling at the area
of serous retinal detachment
during the late phase.
The Chronic Uveitic Stage
• The chronic or convalescent stage occurs several weeks after the acute uveitic stage and is
characterized by development of vitiligo (Fig. 78.7), poliosis, and depigmentation of the
choroids.
• Perilimbal vitiligo, also known as Sugiura's sign (Fig. 78.8), may develop at this stage
among the patients who have melanosis at the palisade of Vogt, such as Japanese
patients.
• Choroidal depigmentation occurs a few months after the uveitic phase. This leads to the
characteristic pale disc with a bright red– orange choroid known as sunset glow fundus
(Fig. 78.9).
• In Hispanics, the sunset glow fundus may show foci of RPE changes in the form of
hyperpigmentation or hypopigmentation. The juxtapapillary area may show marked
depigmentation.
• At this stage, small, yellow, well-circumscribed areas of chorioretinal atrophy may appear,
mainly in the inferior midperiphery of the fundus. This convalescent phase may last for
several months.
The Chronic Recurrent Stage
• The chronic recurrent stage consists of a smoldering panuveitis with acute
episodic exacerbations of granulomatous anterior uveitis.
• The anterior uveitis may be resistant to local and systemic corticosteroid
therapy.
• Iris nodules may be seen during this phase (Fig. 78.10). The most visually
debilitating complication of the chronic inflammation during this stage appears
to be the development of subretinal neovascular membranes.
• Posterior subcapsular cataract, as well as glaucoma, either angle closure or open
angle, and posterior synechiae, may also be seen.
Frequency of Distinguishing Clinical Features
• In the acute stage, exudative retinal detachment was most likely to be found,
whereas in the chronic stage, sunset glow fundus was most common.
Dependent Variable = VKH Odds Ratio Estimate (95% CI) p Value
ACUTE DISEASE
Exudative retinal detachment >999 (48.02, >999) <0.0001
Alopecia 81.23 (2.47, >999) 0.01
Disc hyperemia 5.28 (1.02, 27.42) 0.05
Asian 24.48 (2.38, 251.9) 0.007
Hispanic 59.76 (3.77, 948.2) 0.004
CHRONIC DISEASE
Sunset glow fundus 141.66 (54.65, 367.2) <0.0001
Vitiligo 11.73 (3.59, 38.33) <0.0001
Alopecia 3.20 (1.40, 7.31) 0.0005
Nummular chorioretinal scars 2.83 (1.34, 5.98) 0.01
Vitreous cells 0.39 (0.18, 0.83) 0.02
Asian 3.48 (1.60, 7.60) 0.002
Hispanic 13.25 (4.63, 37.88) 0.0003
 Pathology and Pathogenesis

• VKH is a non-necrotizing diffuse granulomatous inflammation involving the

uvea. Although a granulomatous process is the primary feature of the disease,
the histopathologic changes vary depending on the stage of the disease.
• Uvea is thickened by diffuse infiltration of lymphocytes and macrophages,
admixed with epithelioid cells and multinucleated giant cells containing melanin
granules. The neural retina is detached from the RPE, and the subretinal space
contains proteinaceous fluid exudates.
• Dalen–Fuchs nodules, which represent focal aggregates of epithelioid
histiocytes admixed with RPE, are located between Bruch's membrane and the
RPE.
• In the convalescent stage, the choroidal melanocytes decrease in number and
disappear, resulting in the sunset glow appearance of the fundus.
• During the chronic stage, the numerous focal yellowish oval or round
lesions seen in the inferior peripheral fundus by ophthalmoscopy
histologically display a focal loss of RPE cells and the formation of
chorioretinal adhesions.
• In the longstanding chronic recurrent stage, the RPE and neural retina
show degenerative changes (Fig. 78.13).
• Although the exact cause for the inflammation directed at the
melanocytes remains unknown, current evidence suggests that it
involves an autoimmune process driven by T lymphocytes against an
as-yet unidentified antigen(s) associated with melanocytes.
• Cytokines are known to play an important role in the pathogenesis of VKH
disease.
• Interleukin (IL)-21, a member of the IL-2 family exerting pleiotropic effects on
the immune system, could be involved in the pathogenesis of VKH disease,
possibly by promoting IL-17 secretion.
• CD4 +CD25 high T-regulatory (Treg) cells have been shown to be involved in the
pathogenesis of autoimmune diseases.
• There is a strong association with the human leukocyte antigen (HLA) DR4 in
Japanese patients with VKH disease.
Investigations
Imaging Studies
• In the vast majority of cases, the diagnosis of VKH disease is a clinical one
when the patient presents with ocular and extraocular manifestations.
• However, when the disease presents without extraocular changes, FA is
essential for the diagnosis. ICGA is also useful to evaluate choroidal
inflammatory changes.
• In patients with inadequate pupillary dilation caused by posterior synechiae or
dense vitritis that obscures the view of the fundus, ultrasonography may help
to establish the diagnosis.
• Serous retinal detachment can be clearly observed by OCT.
• OCT has been used not only for supporting diagnosis but for monitoring
resolution of the serous retinal detachment and choroidal thickness with
corticosteroids and immunomodulatory therapy.
 Lumbar Puncture

• This procedure is a useful adjunctive test in cases with atypical features. Ohno et
al. found that more than 80% of patients with VKH disease had cerebrospinal
fluid pleocytosis, consisting mostly of lymphocytes.
• In their study, the pleocytosis was present in 80% of patients within 1 week and
in 97% of patients within 3 weeks of the onset of uveitis.
• The cerebrospinal fluid pleocytosis, however, is transient and resolves within 8
weeks even in patients who develop recurrences of intraocular inflammation.
 Differential Diagnosis
• The differential diagnosis of VKH disease includes sympathetic ophthalmia,
uveal effusion syndrome, posterior scleritis, acute posterior multifocal placoid
pigment epitheliopathy (APMPPE), and sarcoidosis.
• Sympathetic ophthalmia can present with bilateral panuveitis associated with
retinal detachment and meningismus. However, a history of penetrating ocular
injury is the rule in this disorder. Extraocular manifestations, such as dysacusis,
vitiligo, poliosis, and alopecia, can occur in sympathetic ophthalmia, but they
are rare.
• Uveal effusion syndrome may clinically mimic VKH disease. Angiographically,
the effusion syndrome may reveal numerous fluorescent blotches in the
subretinal space during the serous detachment phase. The syndrome can
involve both eyes, although not simultaneously. Unlike VKH disease, the
effusion syndrome lacks intraocular inflammation.
• Posterior scleritis affects predominantly women and is often bilateral.
Patients may present with pain, photophobia, and loss of vision, and
the vitreous often reveals cells. Exudative retinal detachment and
choroidal folds may be noted. Ultrasonography can help to
differentiate posterior scleritis from VKH disease.
• flattening of the posterior aspect of the globe, thickening of the
posterior coats of the eye, retrobulbar edema, and high internal
reactivity of the thickened sclera.
• Other entities, such as sarcoidosis and APMPPE, can be differentiated
based on their clinical features, ultrasonography, and FA.
 Treatment

• Although data from randomized trials are lacking, early and aggressive use of
systemic corticosteroids followed by slow tapering over 3–6 months is the
acceptable treatment of choice to suppress the intraocular inflammation and to
prevent the development of complications related to the ocular inflammation.
• If the ocular inflammation relapses after tapering of systemic corticosteroids, the
relapse may reflect too-rapid tapering of the corticosteroids. Such recurrences
become increasingly steroid-resistant, and cytotoxic or immunosuppressive
agents are usually required to control the inflammation.
• Patients with inflammatory cell infiltration in the anterior chamber require topical
corticosteroids and cycloplegics to reduce ciliary spasm and prevent posterior
synechiae formation.
• High-dose oral corticosteroids, 1–2 mg/kg per day of prednisone or
200 mg of intravenous methylprednisolone for 3 days, followed by
oral administration of high-dose corticosteroids with a slow taper, are
the mainstay of therapy for VKH disease.
• The route of systemic administration of corticosteroids includes oral
and intravenous injection followed by an oral taper.
• However, the International VKH Study Group concluded that route of
administration had no significantly detectable effect on visual acuity
outcome nor on the development of visually significant complications.
• In contrast, recurrences do not respond as well to systemic corticosteroid
treatment.
• Such patients may show some initial response to sub-Tenon injections of
triamcinolone acetonide, but they usually require immunomodulatory agents,
such as cyclosporine, methotrexate, azathioprine, mycophenolate mofetil,
cyclophosphamide, and chlorambucil.
• Sustained release steroid such as the fluocinolone acetonide intravitreal implant
may provide control of intraocular inflammation and reduce dependency on
systemic corticosteroids and/or immunosuppressive agents in patients with the
chronic stage of VKH disease.
• Recently, biologic agents, rituximab and antiTNF-α antibody, infliximab have
been reported in the management of VKH disease.
Immunosuppressive/Cytotoxic Agents Used in the Treatment of Vogt–
Koyanagi–Harada Disease
• Corticosteroids
• Oral prednisone 1–2 mg/kg per day initially, followed by gradual
• taper over 3–6 months
• Pulse dose of methylprednisolone 1 g/day for 3 days, followed by gradual tapering of oral
prednisone over 3–6 months
• Intravenous methylprednisolone 100–200 mg/day for 3 days, followed by gradual tapering
of oral prednisone over 3–6 months
• Immunosuppressive agents
• Cyclosporin 2.5–5 mg/kg per day
• FK506 0.1–0.15 mg/kg per day
• Cytotoxic agents
• Azathioprine 1–2.5 mg/kg per day
• Mycophenolate mofetil 1–3 g/day
• Cyclophosphamide 1–2 mg/kg per day
• Chlorambucil 0.1 mg/kg per day; dose adjusted every 3 weeks to a maximum of 18 mg/day
• Anti-TNF-α monoclonal antibody
 Complications and Management

• A retrospective analysis of the records of 101 patients with VKH disease

followed at the Doheny Eye Institute revealed the development of at least one
complication in 51% of eyes.
• Cataract occurred in 42%, glaucoma in 27%, choroidal neovascularization in
11%.
• Patients who developed VKH at a more advanced age had a worse visual acuity.
• There is general agreement that cataract surgery should be delayed until the
intraocular inflammation has subsided, at which time safe cataract extraction
with posterior-chamber intraocular lens implantation can be successfully
accomplished.
• Occasionally, patients with significant vitreous opacities and debris
may require a combined procedure of pars plana vitrectomy and
lensectomy.
• Chronic recurrent anterior uveitis and fundus pigmentary
disturbances seem to predispose patients to the development of
choroidal neovascularization (Fig. 78.18). These subretinal
neovascular membranes present with raised masses, which may be
associated with subretinal hemorrhage.
• Photodynamic therapy with verteporfin for subfoveal choroidal
neovascularization has been attempted with some success.Intravitreal
injection of an anti-vascular endothelial growth factor (VEGF) may be
an option to treat CNV in eyes with VKH.
 Prognosis

• In general those VKH patients who are treated with initial highdose systemic
corticosteroids followed by gradual tapering will usually have a fair visual
prognosis; nearly two-thirds of these patients retain 20/40 or better visual
acuity.
• On average, most patients require treatment for 4–6 months.
• The complications of chronic recurrent VKH disease include cataract, glaucoma,
choroidal neovascularization, subretinal fibrosis, and optic atrophy.