Histologic findings

There are 4 clinically distinct stages of VKH syndrome: (1) prodromal, (2) acute uveitic, (3) convalescent, and (4) chronic recurrent. Histologic findings vary depending on the stage.

During the acute uveitic stage, there is a diffuse, nonnecrotizing, granulomatous inflammation virtually identical to that seen in SO, consisting of lymphocytes and macrophages admixed with epithelioid and multinucleate giant cells, with preservation of the choriocapillaris. Proteinaceous fluid exudates are observed in the subretinal space between the detached neurosensory retina and the RPE. Although the peripapillary choroid is the predominant site of granulomatous inflammatory infiltration, the ciliary body and iris may also be affected.

The convalescent stage is characterized by nongranulomatous inflammation, with uveal infiltration of lymphocytes, few plasma cells, and the absence of epithelioid histiocytes. The number of choroidal melanocytes decreases with loss of melanin pigment, which corresponds with the characteristic clinical feature known as sunset-glow fundus. In addition, the appearance of numerous nummular chorioretinal scars in the peripheral retina histologically corresponds to the focal loss of RPE cells with chorioretinal adhesions.

The chronic recurrent stage is characterized by granulomatous choroiditis with damage to the choriocapillaris. The numerous clinical, pathologic, and genetic similarities between SO and VKH syndrome suggest that they share a similar immunopathogenesis, albeit with different triggering events and modes of sensitization.

Manifestations

The clinical features of VKH syndrome also vary depending on the stage of the disease. The prodromal stage is marked by flulike symptoms. Several days preceding the onset of ocular symptoms, patients may present with headache, nausea, meningismus, dysacusia, tinnitus, fever, orbital pain, photophobia, and hypersensitivity of the skin to touch. Focal neurologic signs, although rare, may include cranial neuropathies, hemiparesis, aphasia, transverse myelitis, and ganglionitis. Cerebrospinal fluid analysis reveals lymphocytic pleocytosis with normal levels of glucose in more than 80% of patients; this finding may persist for up to 8 weeks. Central dysacusia, usually involving higher frequencies, occurs in approximately 30% of patients early in the disease course, typically improving within 2–3 months; however, persistent deficits may remain.

The acute uveitic stage is heralded by the onset of sequential blurring of vision in both eyes, 1–2 days after the onset of CNS signs, and is marked by bilateral granulomatous anterior uveitis, a variable degree of vitritis, thickening of the posterior choroid, edema of the optic nerve, and multiple serous retinal detachments (Fig 9-52). The focal serous retinal detachments are often shallow, exhibiting a cloverleaf pattern around the posterior pole, but they may coalesce and evolve into large, bullous, exudative detachments. Profound vision loss may occur during this phase. Less commonly, mutton-fat KPs and iris nodules at the pupillary margin may be observed. IOP may be elevated, and the anterior chamber may be shallow because of forward displacement of the lens–iris diaphragm as the result of ciliary body edema or annular choroidal detachment. Alternatively, IOP may be low, secondary to ciliary body shutdown.

The convalescent stage occurs several weeks later and is marked by resolution of the exudative retinal detachments and gradual depigmentation of the choroid, resulting in the classic orange-red discoloration, or sunset-glow fundus (Fig 9-53). In addition, small, round, discrete depigmented lesions develop in the inferior peripheral fundus (Fig 9-54). Juxtapapillary depigmentation may also be seen (Fig 9-55). The sunset-glow fundus may show focal areas of retinal hyper- or hypopigmentation. Perilimbal vitiligo (Sugiura sign) may be present in up to 85% of Japanese patients but is rarely observed among white patients (Fig 9-56). Integumentary changes, including vitiligo, alopecia, and poliosis, typically appear during the convalescent stage in about 30% of patients and correspond with the development of fundus depigmentation (Fig 9-57). In general, skin and hair changes occur weeks to months after the onset of ocular inflammation, but in some cases, they may appear simultaneously. Between 10% and 63% of patients develop vitiligo, depending on ethnic background; among Hispanic patients, the incidence of cutaneous and other extraocular manifestations is relatively low.

Figure 9-52 Vogt-Koyanagi-Harada syndrome. Wide-field photograph shows disc hyperemia and diffuse choroiditis with large exudative detachments in the acute uveitic stage.

(Reprinted with permission from Burkholder BM. Vogt-Koyanagi-Harada disease. Curr Opin Ophthalmol. 2015;26[6]:506–511.)

Figure 9-53 Vogt-Koyanagi-Harada syndrome. Fundus photograph of the patient in Figure 9-52 showing sunset-glow fundus appearance with pigment migration in the convalescent stage.

(Reprinted with permission from Burkholder BM. Vogt-Koyanagi-Harada disease. Curr Opin Ophthalmol. 2015;26[6]:506–511.)

Figure 9-54 Vogt-Koyanagi-Harada syndrome. Fundus photograph showing multiple inferior, peripheral, punched-out chorioretinal lesions in a patient in the convalescent stage.

(Courtesy of Ramana S. Moorthy, MD.)

Figure 9-55 Vogt-Koyanagi-Harada syndrome. Fundus photograph showing sunset-glow fundus appearance with juxtapapillary detachment in a Hispanic patient in the convalescent stage.

(Reprinted with permission from Moorthy RS, Inomata H, Rao NA. Vogt-Koyanagi-Harada syndrome. Surv Ophthalmol. 1995;39[4]:272.)

Figure 9-56 Perilimbal vitiligo (Sugiura sign) (arrows).

(Courtesy of Albert T. Vitale, MD.)

Figure 9-57 Vogt-Koyanagi-Harada syndrome. Vitiligo of the upper eyelid and marked poliosis in the convalescent stage.

(Courtesy of Ramana S. Moorthy, MD.)

The chronic recurrent stage is marked by repeated bouts of granulomatous anterior uveitis, with the development of KPs, posterior synechiae, iris nodules, iris depigmentation, and stromal atrophy. Recurrent posterior segment inflammation can occur but is uncommon during this stage. Visually debilitating sequelae of chronic inflammation develop during this stage and include posterior subcapsular cataract, glaucoma, CNV, and subretinal fibrosis.

• Rao NA, Gupta A, Dustin L, et al. Frequency of distinguishing clinical features in Vogt-Koyanagi-Harada disease. Ophthalmology. 2010;117(3):591–599.

• 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(5):647–652.

Diagnosis

Based on the clinical features and their distinctive appearance within the overall disease course, comprehensive diagnostic criteria for the complete, incomplete, and probable forms of VKH syndrome were revised in 2001 (Table 9-2). Regardless of the form of the disease, essential features for the diagnosis of VKH syndrome include bilateral involvement, no history of penetrating ocular trauma, and no evidence of other ocular or systemic disease.

Table 9-2 Revised Diagnostic Criteria for Vogt-Koyanagi-Harada Syndrome

The diagnosis of VKH syndrome is essentially clinical; exudative retinal detachment during the acute disease and sunset-glow fundus during the chronic phase are highly specific to this entity. In patients presenting without extraocular manifestations, FA, ICG angiography, OCT, FAF imaging, lumbar puncture, and ultrasonography may be useful confirmatory tests. During the acute uveitic stage, FA typically reveals numerous punctate hyperfluorescent foci in the early stage of the study, followed by pooling of dye in the subretinal space in areas of neurosensory detachment (Fig 9-58). The vast majority of patients show disc leakage, but macular edema and retinal vascular leakage are uncommon. In the convalescent and chronic recurrent stages, focal RPE loss and atrophy produce multiple hyperfluorescent window defects without progressive staining.

Figure 9-58 Vogt-Koyanagi-Harada syndrome. A, Early arteriovenous phase fluorescein angiogram showing multiple pinpoint foci of hyperfluorescence in the posterior pole of the left eye of a patient in the acute uveitic stage. B, Late arteriovenous phase fluorescein angiogram showing fluorescein pooling in multiple serous retinal detachments in the posterior pole in the same eye.

(Courtesy of Ramana S. Moorthy, MD.)

Indocyanine green angiography highlights the choroidal pathology, demonstrating a delay in choroidal perfusion, early choroidal hypercyanescence and leakage, multiple hypocyanescent spots throughout the fundus (thought to correspond to foci of lymphocytic infiltration), and hypercyancescent pinpoint changes within areas of exudative retinal detachment. The hypocyanescent spots may be present even when the funduscopic and FA findings are unremarkable; thus, they serve as sensitive markers for the detection and monitoring of subclinical choroidal inflammation.

Ultrasonography may be helpful in establishing the diagnosis, especially in the presence of media opacity. Findings include diffuse, low to medium reflective thickening of the posterior choroid that is most prominent in the peripapillary area, with extension to the equatorial region, exudative retinal detachment, vitreous opacification, and posterior thickening of the sclera.

Optical coherence tomography may be useful in the diagnosis and monitoring of serous macular detachments, macular edema, and choroidal neovascular membranes. Patients may have characteristic fibrin bands extending from the retina to the RPE in the acute phase (Fig 9-59). Enhanced-depth OCT imaging demonstrates choroidal thickening in the acute phase that decreases with treatment. The combined use of OCT and FAF imaging, which shows granular hyperautofluorescence in areas of inflammation, offers a noninvasive assessment of RPE and outer retinal inflammation that may not be apparent on clinical examination in patients with chronic VKH syndrome.

In highly atypical cases—particularly patients presenting early in the course of the disease with prominent neurologic signs and a paucity of ocular findings—a lumbar puncture, revealing lymphocytic pleocytosis, may be useful diagnostically. However, in the vast majority of cases, the history and clinical examination, together with results of FA and/or ultrasonography, are sufficient to establish the diagnosis.

Figure 9-59 Vogt-Koyanagi-Harada syndrome. A, Color photograph showing multiple serous retinal detachments. B, C, Fluorescein angiograms showing early punctate hyperfluorescence (B) followed by late filling of the subretinal spaces with dye (C). D, Optical coherence tomography scan showing characteristic loculated spaces of subretinal fluid, with bands extending from the retina to the retinal pigment epithelium. The location of the optical coherence tomography scan is indicated by the green arrow in A.

(Courtesy of Annabelle Okada, MD.)

The differential diagnosis of VKH syndrome includes SO, uveal effusion syndrome, posterior scleritis, primary intraocular lymphoma, uveal lymphoid infiltration, APMPPE, bilateral diffuse uveal melanocytic proliferation, TB-associated uveitis, and sarcoidosis. These entities may be differentiated from VKH syndrome by a thorough history, review of systems, and examination, together with a directed laboratory evaluation.

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Treatment and prognosis

The acute stage of VKH syndrome is responsive to early and aggressive treatment with corticosteroids. Initial dosages typically are 1–1.5 mg/kg/day of oral prednisone or up to 1 g of intravenous methylprednisolone daily for 3 days, followed by high-dose oral corticosteroids. Oral versus intravenous routes of administration show no demonstrable differences in visual acuity outcomes or the development of visually significant complications. For patients intolerant of systemic therapy, use of intravitreal corticosteroids, including the intravitreal fluocinolone acetonide and dexamethasone implants, is an option. Systemic corticosteroids are tapered slowly according to the clinical response, on average over a 6–12-month period, in an effort to prevent progression of the disease to the chronic recurrent stage and to minimize the incidence and severity of extraocular manifestations. Tapering corticosteroids too soon can result in early recurrence.

Despite adequate initial treatment with systemic corticosteroids, many patients experience recurrent episodes of inflammation. This risk has led many experts to initiate IMT earlier to achieve more prompt inflammatory control and to facilitate more rapid tapering of corticosteroids. The overall visual prognosis for patients treated in this fashion is fair, with up to 70% of patients retaining visual acuity of 20/40 or better.

Structural complications associated with ocular morbidity include cataract formation (50%), glaucoma (33%), CNV (up to 15%), and subretinal fibrosis, the development of which is associated with increased disease duration, more frequent recurrences, and an older age at disease onset.

The use of either oral corticosteroids or IMT with extended follow-up has been shown to reduce the risk of vision loss and the development of some structural complications. Specifically, oral corticosteroids reduced the risk of CNV and subretinal fibrosis by 82% and the risk of visual acuity decline to 20/200 or worse (in better-seeing eyes) by 67%. IMT was associated with risk reductions of 67% for vision loss to 20/50 or worse and 92% for vision loss to 20/200 or worse in better-seeing eyes.

• Bykhovskaya I, Thorne JE, Kempen JH, Dunn JP, Jabs DA. Vogt-Koyanagi-Harada disease: clinical outcomes. Am J Ophthalmol. 2005;140(4):674–678.

• Greco A, Fusconi M, Gallo A, et al. Vogt-Koyanagi-Harada syndrome. Autoimmun Rev. 2013;12(11):1033–1038.

• Read RW, Rechodouni A, Butani N, et al. Complications and prognostic factors in Vogt-Koyanagi-Harada disease. Am J Ophthalmol. 2001;131(5):599–606.

Excerpted from BCSC 2020-2021 series: Section 9 - Uveitis and Ocular Inflammation. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.