Vogt-Koyanagi-Harada disease

Summary

Vogt-Koyanagi-Harada (VKH) disease is a bilateral granulomatous panuveitis with or without extraocular manifestations. It is an autoimmune disease characterised by inflammation of tissues comprising melanocytes; alongside the uvea, the ear and meninges may be involved.

Aetiology

During embryogenesis, pigment cells arising from the neural crest migrate to the skin, hair bulbs, inner ear, leptomeninges, choroid and other tissues. Hence, the developed uvea, ear, epidermis, hair follicles and meninges (among other tissues) contain melanocytes.

VKH disease is thought to be caused by a T-cell mediated autoimmune reaction against three enzymes involves in melanin synthesis: tyrosinase and tyrosinase-related protein (TRP) 1 and 2.

Epidemiology

VKH is associated with HLA-DR1 and HLA-DR4, which are predominant in certain ethnic groups e.g. Japanese and Hispanic populations.

VKH tends to affect patients in the 2nd and 5th decade of life.

Stages of the disease

VKH disease involves several stages, summarised in the table below. The acute phase involves non-necrotising granulomatous inflammation, causing diffuse thickening of the uveal tract. The chronic phase, by contrast, involves non-granulomatous inflammation.

Phase	Clinical features
Prodromal	​Symptoms of viral illness lasting 3-5 days e.g. headache, fever, nausea, orbital pain, dizziness, photophobia. Neurological (meningitis, rarely encephalopathy with cranial nerve/focal lesions) + auditory manifestations (sensorineural hearing loss, tinnitus, vertigo), and optic neuritis may occur.
Acute uveitic	The uveitic phase involves bilateralgranulomatous anterior + multifocal posterioruveitis. Patients complain of bilateral blurred vision. The following signs are characteristic: diffuse choroidal infiltration; Dalen-Fuchs nodules (these also occur in sympathetic ophthalmia, and represent granulomas between the retinal pigment epithelium and Bruch’s membranes); retinal and optic disc oedema; vitritis; papillitis; and multiple serous retinal detachments.
Convalescent	This occurs a few weeks later, and is characterised by skinmanifestations (alopecia; poliosis; vitiligo) + choroidaldepigmentation. The first sign of depigmentation (presenting 1 month after the uveitic stage) to occur is ‘Suguira’s sign’ (perilimbal vitiligo). Several months after the uveitic stage, choroidal depigmentation occurs, producing a ’sunset glow’ fundus (a bright red-orange choroid with a pale disc).
Chronic recurrent	This involves a panuveitis with recurrent exacerbations of smouldering anterior uveitis. Recurrent posterior uveitis is less common. Sight-threatening complications (described below) may develop.

Disc oedema and multifocal serous retinal detachment at the posterior pole of the eye in VKH disease. Image courtesy of Agrawal and Biswas.

‘Sunset glow’ fundi - the optic discs are pale and choroidal depigmentation appears red-orange. Image courtesy of Yoshida et al.

Ocular complications

Ocular complications tend to develop during the recurrent phase. At least one complication has been reported to occur in 51% of eyes with VKD disease.

• Cataract

• Glaucoma

• Choroidal neovascularisation

• Subretinal fibrosis

• Vitreous haemorrhage

• Posterior synechiae

• Optic atrophy

Diagnosis

The table below summarises the diagnostic criteria for VKH. Certain criteria are required to make the following diagnoses:

• Complete VKH: criteria 1-5

• Incomplete VKH: criteria 1-3 plus 4 OR 5

• Probable VKH (isolated ocular disease): criteria 1-3

1. Absence of penetrating ocular trauma or surgery

2. Absence of otherocular disease

3. Bilateral uveitis

4. Neurological + auditory manifestations

5. Integumentary (skin/hair/nail) manifestations (AFTER onset of CNS/ocular disease) e.g. alopecia, vitiligo, poliosis

Investigation

• Lumbar puncture (if uncertainty over diagnosis): melanin-containing macrophages + transient lymphocytic pleocytosis (i.e. an abnormally large number of lymphocytes in the CSF), which may last for 8 weeks

• Fundus autofluorescence (FAF): regions of serous detachment

• Ultrasound: diffuse choroidal thickening. Useful to exclude posterior scleritis

• OCT: subretinal fluid + subretinal septae

• Fluorescein angiography (FA): (1) in the acute phase - multifocal hyper fluorescent dots at the level of the retinal pigment epithelium (RPE), followed by subretinal pooling; (2) in the chronic phase - RPE window defects

• Indocyanine green angiography (ICGA): evenly distributed hypofluorescent spots during the acute phase; this remains in the chronic phase with the addition of diffuse hyperfluorescence over the posterior pole. ICGA is useful for monitoring disease

Management

• 3 days of high-dose IV steroids (IV methylprednisolone/dexamethasone)

• Followed by high-dose oral prednisolone, maintained for 2-4 weeks, then tapered down over 3-6 months

• Steroid-resistant patients: consider immunosuppressants e.g. ciclosporin, azathioprine. Biologics e.g. infliximab work well in the early stages

• Treat anterior uveitis with topical steroids + cycloplegics (e.g. atropine, cyclopentolate)

Prognosis

Neurological + auditory manifestations usually resolve, whilst skin/lash/hair changes tend to persist.

Prognosis is variable, and is influenced by control of the disease in its early stages. Aggressive early treatment with high-dose steroids can preserve a good visual acuity. Delayed treatment, older age at onset, increased recurrent episodes of inflammation and complications predispose to a poor final visual acuity.

References

1. Salmon, John F., and Jack J. Kanski. Kanski’s Clinical Ophthalmology: A Systematic Approach. Ninth Edition, Elsevier, 2020.

2. Zeitz, Oliver. ‘Myron Yanoff and Jay S. Duker: Ophthalmology, Fifth Edition: 2018, Pp. 1440, Hardcover ISBN: 9780323528191, Elsevier’. Graefe’s Archive for Clinical and Experimental Ophthalmology, vol. 258, no. 2, Feb. 2020, pp. 459–459. DOI.org (Crossref), https://doi.org/10.1007/s00417-019-04489-7.

3. Rumelt, Shimon. ‘Gass’s Atlas of Macular Diseases Fifth Edition: A Agarwal, A Singh 2012. Elsevier. ISBN 978-1-4377-1580-4’. Graefe’s Archive for Clinical and Experimental Ophthalmology, vol. 251, no. 4, Apr. 2013, pp. 1253–1253. DOI.org (Crossref), https://doi.org/10.1007/s00417-012-2211-5.

4. Agrawal, Alok, and Jyotirmay Biswas. ‘Unilateral Vogt-Koyanagi-Harada Disease: Report of Two Cases’. Middle East African Journal of Ophthalmology, vol. 18, no. 1, Jan. 2011, pp. 82–84. PubMed, https://doi.org/10.4103/0974-9233.75898.

5. Yoshida, Atsushi, et al. ‘Juvenile Vogt-Koyanagi-Harada Disease in Which Good Visual Prognosis Was Derived from Swift and Definitive Diagnosis’. Case Reports in Ophthalmological Medicine, vol. 2016, 2016, p. 7936729. PubMed Central, https://doi.org/10.1155/2016/7936729.

6. 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;131:647–652

7. Read, Russell W., et al. ‘Complications and Prognostic Factors in Vogt-Koyanagi-Harada Disease’. American Journal of Ophthalmology, vol. 131, no. 5, May 2001, pp. 599–606. DOI.org (Crossref), https://doi.org/10.1016/S0002-9394(01)00937-0.