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.¹

Poliosis associated with ocular inflammation was first described by Ali-ibn-Isa, an Arab physician who lived in the 1st century AD (cited by Pattison).² This association was reported by Schenkl in 1873,³ by Hutchinson in 1892,⁴ and by Vogt in l906.⁵ Harada described a primary posterior uveitis with exudative retinal detachments in association with cerebrospinal fluid pleocytosis.⁶

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.⁷ This constellation of findings was termed “uveitis with poliosis, vitiligo, alopecia, and dysacusis.”⁷ Babel in 1932⁸ and Bruno and McPherson in 1945 combined the findings of Vogt, Koyanagi, and Harada and suggested that these processes represent a continuum of the same disease,⁹ thereafter recognized as Vogt–Koyanagi–Harada syndrome.

When a patient presents with the ocular and the extraocular manifestations, the diagnosis of VKH is made with certainty. However, extraocular manifestations such as dysacusis and cutaneous changes are relatively rare, and the dermatologic changes mainly occur late in the course of the disease.^1,10 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, 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; and (d) cutaneous findings of alopecia, poliosis, or vitiligo.¹¹

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. Read and Rao recently evaluated the utility of the existing AUS criteria in 71 consecutive patients with VKH who were diagnosed based on the clinical features and the course of the disease, combined with fluorescein angiography with or without utrasonography in selected cases.¹² 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.¹³ These revised diagnostic criteria are summarized in Box 75.1.

Box 75.1

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

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 la, 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, or

c. Cerebrospinal fluid pleoytosis

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

a. Alopecia, or

b. Poliosis, or

c. 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.

(Modified from Read RW, Holland GN, Rao NA et al. Revised diagnostic criteria for Vogt–Koyanagi–Harada disease: report of an international committee on nomenclature. Am J Ophthalmol 2001;131:647–52.¹³)

^* 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.

In the past, constellation of these ocular signs and symptoms warranted the term “syndrome,” but in recent years the entity has been well characterized; thereafter the International Workshop on VKH adopted the term Vogt–Koyanagi–Harada disease.¹³

Epidemiology

The incidence of VKH is variable. It appears to be more common in Japan, where it accounts for 6.7% of all uveitis referrals.¹⁴ In the USA it accounts for 1–4% of all uveitis clinic referrals.

VKH tends to affect more pigmented races, such as Asians, Hispanics, American Indians, and Asian Indians.^1,l5 In the USA there appears to be variability in the racial distribution of patients with VKH disease.^1,11,16,17 In northern California VKH was seen mainly in Asians (4l%), followed by whites (29%), Hispanics (16%), and blacks (14%).¹⁷ In contrast, reports from southern California show that 78% of VKH patients were Hispanic while 3% were white, 10% were Asian, and 6% were black.¹ A series reported from the National Institutes of Health (NIH) showed that 50% of VKH patients were white, 35% were black, and 13% were Hispanic.¹⁷ However, most of those patients reported in the NIH series had remote American Indian ancestry. Most studies report that women tend to be affected more frequently than men; however, Japanese investigators have not found such a female predilection.¹⁵ Most patients are in their second to fifth decades of life, but children may also be affected.^1,18

Clinical description

Typical clinical features of VKH include bilateral panuveitis associated with exudative retinal detachment, meningism associated with headache and pleocytosis of cerebrospinal fluid, tinnitus or hearing loss, and cutaneous changes, such as alopecia, poliosis, and vitiligo. However, all of these extraocular features are rarely seen during the initial presentation, and the clinical features vary depending upon the stage of the disease as well as the effect of medical treatment. Presence of ocular and two or more extraocular features is considered as a complete form of VKH disease.¹³ Incomplete VKH disease includes bilateral typical ocular involvement plus either neurologic/auditory or cutaneous changes, whereas probable VKH disease is composed of just ocular manifestations.¹³ However, some of these probable VKH patients can develop cutaneous manifestations during the chronic or chronic recurrent stage of the disease.

The prodromal stage

Initial manifestations of VKH disease may include non-specific viral-like 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 neurological 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 (Fig. 75.1), hyperemia and edema of the optic nerve head.

Fig. 75.1 Bilateral multiple serous retinal detachments at the acute uveitis stage of Vogt–Koyanagi–Harada disease.

Rarely VKH disease can present with optic disc hyperemia and edema without serous retinal detachments (Fig. 75.2).

Fig. 75.2 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 (Fig. 75.3). Alteration in the retinal pigment epithelium (RPE) associated with multifocal choroidal inflammation is easily observed with fluorescein angiography, which reveals hypofluorescent dots at the early phase followed by multiple focal areas of leakage and subretinal fluid accumulation at the late phase (Fig. 75.4).

Fig. 75.3 Ultrasonography showing thickened choroid (arrowheads).

Fig. 75.4 (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 mid-phase of the angiogram. (D) Subretinal dye pooling at the area of serous retinal detachment during the late phase.

Indocyanine green angiography (ICGA) (Fig. 75.5) 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.^19,20

Fig. 75.5 (A) Early phase of the indocyanine green angiogram showing vascular leakage in the choroid. (B) Late phase of angiogram showing multiple hypofluorescent dots.

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;¹ 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 (Fig. 75.6), leading to acute angle closure glaucoma or annular choroidal detachment.^21,22 These intraocular changes are typically bilateral; rarely, however, the process can be restricted to one eye.²³

Fig. 75.6 Shallow anterior chamber caused by the anterior displacement of the lens associated with inflammatory infiltrates at the ciliary body.

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. 75.7), poliosis, and depigmentation of the choroids. Perilimbal vitiligo, also known as Sugiura’s sign (Fig. 75.8), may develop at this stage among the patients who have melanosis at the palisade of Vogt, such as Japanese patients.^1,13

Fig. 75.7 Bilateral upper-eyelid vitiligo.

Fig. 75.8 Chronic stage of Vogt–Koyanagi–Harada disease showing extensive posterior synechiae and loss of pigment at the limbus (Sugiura’s sign).

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. 75.9

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