VOGT KOYANAGI HARADA DISEASE

Dr. Gauree Gattani KrishnanII Year DNB

Introduction•Vogt-Koyanagi-Harada

(VKH) disease is a multisystemic disorder characterized by granulomatous panuveitis with exudative retinal detachments that is often associated with neurologic and cutaneous manifestations.

History• Poliosis +ocular inflammation Vogt in 1906• Primary posterior uveitis +exudative RDs +CSF

pleocytosis Einosuke Harada • B/l chronic iridocyclitis + skin & hair

depigmentation Koyanagi • This constellation of findings was termed

“uveitis with polosis, vitiligo, alopecia and dysacusis.”

• Babel in 1932and Bruno & McPherson in 1945 suggested that these processes represent a continuum of the same disease, thereafter recognized as Vogt–Koyanagi–Harada syndrome

Epidemiology• Asian, Middle Eastern, Hispanic, and

Native American populations. •Several HLA associations including HLA-

DR4, HLA-DR53, and HLA-DQ4

Clinical Presentation

•female predilection. •Most patients are in their second to fifth

decades of life.•children may also be affected

Prodromal stage

Uveitic stageChronic (convalescent) stageChronic recurrent stage

Stages

The prodromal stage•May last only a few days•Headaches, nausea,

dizziness, fever, orbital pain, and meningismus.

•Light sensitivity and tearing may occur 1 to 2 days following the above symptoms.

•Rarely neurological signs like cranial nerve palsies and optic neuritis.

•CSF pleocytosis

The uveitic stage• Presents with blurring of

vision in both eyes. • One eye may be affected

first followed a few days later by the second eye.

• 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.

Fluorescein angiogram of the acute uveitis stage shows multiple hyperfluorescent dots at the level of retinal pigment epithelium during the mid ateriovenous phase

Note staining of the subretinal fluid during the late phase of the angiogram.

The uveitic stage• 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 KPs, small nodules on the iris surface and pupillary margin, may be seen.

• 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

The chronic (convalescent) stage•Occurs several weeks after the acute

uveitic stage•Characterized by development of vitiligo,

poliosis and depigmentation of the choroid

•Perilimbal vitiligo, also known as Sugiura’s sign may develop at this stage (Japanese paitients)

Bilateral upper-eyelid vitiligo

poliosis developed during the chronic stage of Vogt–Koyanagi–Harada disease

Chronic stage of Vogt–Koyanagi–Harada disease shows extensive posterior synechiae, areas of depigmentation involving iris, and loss of pigment at

the limbus (Sugiura’s sign)

The chronic stage• 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.”

• The juxtapapillary area may show marked depigmentation.

• In Hispanics, the sunset-glow fundus may show foci of RPE changes in the form of hyperpigmentation or hypopigmentation.

• 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.

Chronic stage of Vogt–Koyanagi–Harada disease revealingsunset-glow fundus in an Asian patient

Chronic stage of Vogt–Koyanagi–Harada disease revealingsunset-glow fundus in an in a Hispanic woman

Chronic stage of Vogt–Koyanagi–Harada disease revealing oval nonpigmented and pigmented retinal pigment epithelium

atrophic lesions

The chronic recurrent stage• The chronic recurrent stage consists of a

smoldering panuveitis with acute episodic exacerbations of granulomatous anterior uveitis.

• Recurrent posterior uveitis with exudative retinal detachment is uncommon.

• The anterior uveitis may be resistant to local and systemic corticosteroid therapy.

• Iris nodules may be seen during this phase These appear as round, whitish, well circumscribed nodules on a background of atrophic iris stroma.

Note the iris nodule at the pupillary margin in a Hispanic male with chronic recurrent-stage Vogt–Koyanagi–Harada disease.

Chronic recurrent stage of Vogt–Koyanagi–Harada disease showing multiple small nodules in the iris and extensive posterior synechiae.

The chronic recurrent stage• The most visually debilitating complication of the

chronic inflammation during this stage appears to be the development of subretinal neovascular membranes.

• Other features may include:▫Posterior subcapsular cataract▫glaucoma, (angle-closure or open-angle), ▫posterior synechiae

• Linear pigmentary changes similar to those seen in the ocular histoplasmosis syndrome and arteriovenous anastomosis may be seen in occasional patients

A 28-year-old Hispanic female developed submacular choroidal neovascular membrane and hemorrhage during the chronic recurrent stage

fluorescein angiogram shows typical neovascular membrane

Diagnostic criteria (American Uveitis Society (AUS) 1978 ):• Because of the variation in clinical presentations of

VKH, the AUS recommended the following• (1) the absence of any history of ocular trauma or

surgery; and • (2) the presence of at least 3 of the 4 signs:

a) b/l chronic iridocyclitisb) posterior uveitis, including exudative retinal

detachment, forme fruste of 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

•The authors concluded that AUS criteria for diagnosis of VKH may not be adequate.

•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.

The revised diagnostic criteria proposed by the First International Workshop on Vogt–Koyanagi–Harada (VKH) disease

VKH Disease

Complete VKH

disease

Bilateral ocular involvement

Neurological/ auditory findings

Integumentary finding

Incomplete VKH

Disease

Bilateral ocular involvement

Neurological/ auditory findings

OR Integumentary finding

Probable VKH

Disease

Bilateral ocular

involvement

A. 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

pinpoint 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

▫(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. Neurological/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, however), or

b) Tinnitus, orc) CSF pleocytosis

3. Integumentary finding•(not preceding onset of central nervous

system or ocular disease)a) Alopecia, orb) Poliosis, orc) Vitiligo

B. 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.

C. 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 ofuveitis and no clinical or laboratory evidence suggestive of other ocular disease criteria.

Modified from Read RW, Holland GN, Rao NA et al. Revised diagnostic criteria for Vogt–Koyanagi–

Haradadisease: report of an international committee on nomenclature. Am J Ophthalmol 2001; 131:647–

652.5

PATHOLOGY

•VKH is a non necrotizing diffuse granulomatous inflammation involving the uvea.

•The peripapillary choroid is the predominant site for the granulomatous inflammatory infiltration; and a similar but less prominent inflammation is noted in the equatorial and anterior choroid.

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Acute uveitic stage of Vogt–Koyanagi–Harada disease showsserous detachment of the retina, preservation of choriocapillaris frominflammatory cell infiltration, and thickening of choroid from granulomatousinflammatory cell infiltration

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Convalescent stage of Vogt–Koyanagi–Harada disease,exhibiting loss of choroidal melanocytes and infiltration of lymphocytesand plasma cells in the choroid. Note relatively intact retinal pigment epithelium and neurosensory retina

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Chronic recurrent stage of Vogt–Koyanagi–Harada diseaseshows choroidal inflammation, retinal pigment epithelium proliferation, and degeneration of overlying retina

PATHOGENESIS

• 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.

• The mechanism that triggers the autoimmune process is unknown, but sensitizations to melanocyte antigenic peptides by cutaneous injury or viral infection have been proposed as possible factors in some cases.

• The antigenic peptides may include tyrosinase or tyrosinase-related proteins, an unidentified 75-kDa protein and S-100 protein.

• either HLA-DR1 or HLA-DR4 was found in 84% of patients withVKH disease

Lab Investigations•Mainly a clinical diagnosis when patient

presents with ocular and extraocular manifestations.

•When the disease presents without extraocular changes▫fluorescein angiography▫lumbar puncture▫Ultrasonography▫indocyanine green (ICG) angiography and ▫optical coherence tomography (OCT)

FFA• Acute stage:

▫numerous punctate hyperfluorescent dots at the level of RPE.

▫These dots enlarge and stain the surrounding subretinal fluid.

• Late phase :▫multiple serous retinal detachments with pooling of dye

in the subretinal space. ▫Over 70% of patients show disc leakage

• Chronic and Recurrent stages: ▫“moth-eaten” appearance, with multiple hyperfluorescent

RPE window defects without progressive staining.

• Early anteriovenous phase of fluorescein angiogram exhibiting multiple hyperfluorescent dots at the retinal pigment epithelium level.

Late phase of the angiogram shows increased fluorescence of the dots and staining of subretinal fluid. Note disc staining.

Lumbar Puncture•Rarely done•80% of patients with VKH disease had

CSF pleocytosis, consisting mostly of lymphocytes.

•The pleocytosis was present in ▫80% of patients within 1 week and in ▫97% of patients within 3 weeks of the onset

of uveitis.▫transient and resolves within 8 weeks

Ultrasonography• diffuse, low-to-medium reflective thickening of the

posterior choroid▫ The choroidal thickening is most prominent in the

peripapillary area and generally extends to the equatorial region, becoming progressively thinner away from the optic nerve.

• serous RD located in the posterior pole or inferiorly• vitreous opacities• posterior thickening of the sclera. • UBM examination during the uveitis stage may reveal

▫ shallow anterior-chamber▫ ciliochoroidal detachment and ▫ thickened ciliary body

ICG• Uveitic stage

▫delay in choriocapillaris and larger choroidal vessel perfusion.

▫Multiple hypofluorescent spots are noted throughout the fundus and hyperfluorescent pinpoint changes are observed in areas of exudative retinal detachment.

• Chronic recurrent stage ▫Multiple hypofluorescent spots are present;

• Recently OCT has been used to monitor resolution of serous retinal detachment in patients treated with corticosteroids.

Hypofluorescent dark dots in ICG

DIFFERENTIAL DIAGNOSIS

1) Sympathetic ophthalmia, ▫Sympathetic ophthalmia can present with bilateral

panuveitis associated with retinal detachment and meningismus.

▫But always with a history of penetrating ocular injury

2) 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.

3) Posterior scleritis• affects predominantly women • Bilateral• may present with pain, photophobia, and loss of vision,

and the vitreous often reveals cells. • Exudative macular detachment and choroidal folds may be

noted.• Usually patients with bilateral involvement have a history

of rheumatoid disease.• Ultrasonography can help to differentiate posterior

scleritis from the VKH disease. The former reveals flattening of the posterior aspect of the globe, thickening of the posterior coats of the eye, retrobulbar edema, and high internal reflectivity of the thickened sclera.

4) Primary intraocular lymphoma, 5) Uveal lymphoid infiltration, 6) Acute posterior multifocal placuoid

pigment epitheliopathy (APMPPE), and7) Sarcoidosis.

Treatment

Steroids• Early and aggressive use of systemic

corticosteroids followed by slow tapering over 3 to 6 months is the treatment of choice to suppress the intraocular inflammation and to prevent the development of complications related to the ocular inflammation

• may prevent progression of the disease to the chronic recurrent stage and may also reduce the incidence and/or severity of extraocular manifestations, including the development of sunset-glow fundus

•recurrences do not respond as well to systemic corticosteroid treatment.

•Such patients may show some initial response to sub-Tenon’s injections of triamcinolone, but they usually require immunosuppressive or cytotoxic agents, such as ciclosporin, azathioprine, cyclophosphamide, chlorambucil, mycophenolate mofetil (Cell Cept), and FK506.

•Oral prednisone 100 to 200 mg initially, followed by gradual taper over 3 to 6 months

•Pulse dose of methylprednisolone 1 g/day for 3 days, followed by gradual tapering of oral prednisone over 3 to 6 months

Corticosteroids

•Cyclosporin 5 mg/kg per day•FK506 0.1 to 0.15 mg/kg per

dayImmunosuppressi

ve agents

•Azathioprine 1 to 2.5 mg/kg per day•Mycophenolate mofetil 1 to 3 g/day•Cyclophosphamide 1 to 2 mg/kg per day•Chlorambucil 0.1 mg/kg per day; dose

adjusted every 3 weeks to a maximum of 18 mg/day

Cytotoxic agents

Others•Patients with inflammatory cell infiltration

in the anterior chamber require topical corticosteroids and cycloplegics to reduce ciliary spasm and prevent posterior synechiae formation

Prognosis•treated with initial high-dose systemic

corticosteroids followed by gradual tapering will usually have a fair visual prognosis; nearly two-thirds of these patients retain 6/12 or better visual acuity.

• On average, most patients require treatment for 6 months

ComplicationsThe complications of chronic recurrent

VKH include

•Cataract•Glaucoma•Choroidal neovascularization •Subretinal fibrosis•Optic atrophy

The fundus showing subretinal fibrosis in a patient with chronic recurrent stage of Vogt–Koyanagi–Harada disease.

ThankYou