Vogt-Koyanagi-Harada Disease
- Author: R Christopher Walton, MD; Chief Editor: Hampton Roy Sr, MD more...
Background
Vogt-Koyanagi-Harada (VKH) disease is a multisystem disorder characterized by granulomatous panuveitis with exudative retinal detachments that is often associated with neurologic and cutaneous manifestations. VKH disease occurs more commonly in patients with a genetic predisposition to the disease, including Asian, Middle Eastern, Hispanic, and Native American populations. Several human leukocyte antigen (HLA) associations have been found in patients with VKH disease, including HLA-DR4, HLA-DR53, and HLA-DQ4.[1, 2, 3, 4, 5]
Independently, Vogt, Koyanagi, and Harada described several patients during a 20-year period with bilateral uveitis, exudative retinal detachments, neurologic abnormalities, and disorders of the integument. Despite differences in their patients, the manifestations appeared to represent a spectrum of disease and several authors suggested that the disorder should be termed Vogt-Koyanagi-Harada syndrome.
With such a wide spectrum of the disease, typical cases of VKH disease are uncommon. To help clarify the diagnostic features of VKH disease, an International Committee on Nomenclature established revised criteria for the diagnosis of VKH disease. The revised criteria defined 3 categories of disease: complete VKH, incomplete VKH, and probable VKH. Common to all forms of VKH disease are the requirements that: (1) patients have no prior history of ocular trauma or surgery, (2) patients have no evidence of another ocular disease based upon clinical or laboratory evidence, and (3) patients have bilateral ocular involvement. Additional criteria for each form of the disease are outlined below.
Complete VKH disease
Early manifestations of complete VKH disease include diffuse choroiditis that may include serous retinal detachment or focal areas of subretinal fluid. Patients without these findings must have diffuse choroidal thickening by ultrasonography with fluorescein angiographic abnormalities, including focal areas of delayed choroidal perfusion, multifocal pinpoint leakage, areas of placoid hyperfluorescence, pooling of subretinal fluid, and optic nerve staining.
Late manifestations of complete VKH disease include evidence of previous early manifestations of the disease, as outlined above, with ocular depigmentation and nummular chorioretinal scars, retinal pigment epithelium (RPE) clumping and migration, or anterior uveitis.
Patients with complete VKH disease must also have evidence of neurologic and auditory findings as well as integumentary signs. However, the neurologic and auditory manifestations may have resolved before an ophthalmic examination. The neurologic and auditory manifestations include meningismus (but not headache alone), tinnitus, and cerebrospinal fluid pleocytosis. Integumentary signs include alopecia, poliosis, and vitiligo. However, these integumentary signs should not occur prior to the onset of ocular signs and central nervous system signs.
Incomplete VKH disease
Patients with incomplete VKH disease are similar to those with complete VKH disease, but patients with incomplete VKH disease do not have both the neurologic and auditory manifestations and the integumentary signs. To be diagnosed with incomplete VKH disease, patients must have either the neurologic and auditory manifestations or the integumentary signs.
Probable VKH disease
Patients with probable VKH disease include those with isolated ocular disease.
Pathophysiology
The pathogenesis of VKH disease is uncertain. However, the wide spectrum of findings in this disorder suggests a central mechanism to account for the multisystem manifestations. Inflammation and loss of melanocytes has been described in a number of tissues, including the skin, inner ear, meninges, and uvea. These histopathologic changes suggest an infectious or autoimmune basis for the disease.
VKH disease currently is considered to be a cell-mediated autoimmune disease directed against melanocytes. Yamaki and coworkers have shown that the tyrosinase-related proteins, TRP1 and TRP2, can induce disease in Lewis rats that is similar to VKH disease in humans.[6] These findings suggest that the tyrosinase family proteins induce VKH disease.[7]
Genetics
The strong association between VKH disease and certain racial and ethnic groups suggests that the disorder may have an immunogenetic predisposition.[8] HLA typing can be useful to identify these common genetic factors. As a result, several HLA haplotypes appear to be more common in certain populations with VKH disease. Among Japanese patients, HLA-DR4, HLA-DR53, and HLA-DQ4 are associated strongly with the disease. In Chinese patients, HLA associations are seen with HLA-DR4, HLA-DR53, and HLA-DQ7. In a mixed group of American patients, Davis and coworkers found an association with HLA-DR4 and HLA-DR53, while HLA-DR1 and HLA-DR4 were reported in Hispanic patients living in southern California.[9]
Epidemiology
Frequency
United States
VKH disease is uncommon, but it may be seen in Asian, Middle Eastern, Hispanic, and Native American populations. VKH disease is extremely uncommon in whites. In a report from the National Eye Institute, Nussenblatt and coworkers noted that 50% of their patients were Caucasian, 35% were African American, and 13% were Hispanic; however, most patients had remote Native American ancestry.[10]
International
VKH disease commonly is seen in Asian (primarily from eastern and southeastern Asia), Middle Eastern, and Hispanic populations.
Mortality/Morbidity
- Neurologic manifestations: Many of the neurologic manifestations may persist for weeks. Most signs and symptoms resolve with corticosteroid therapy, although severe meningoencephalitic impairment has been reported.
- Auditory manifestations: Inner ear manifestations typically respond to corticosteroid therapy within weeks to months.
Race
Historically, VKH disease is reported to be more common in darkly pigmented races. However, individuals with VKH disease most likely have an immunogenetic predisposition that is probably more common in certain ethnic groups with increased skin pigmentation, such as Asian, Middle Eastern, Hispanic, and Native American populations. Also, VKH disease is distinctly uncommon in Africans, reaffirming that skin pigmentation alone is not a predisposing factor in the pathogenesis of the disease.
- In Japan, VKH disease represents 7-8% of all patients with uveitis.
- This disorder rarely is seen in Northern European individuals.
Sex
Females are more commonly affected than males. The female-to-male ratio in most large series is 2:1.
Age
VKH disease affects individuals aged 20-50 years, most frequently during the third decade. Yet, children as young as 4 years have been reported with VKH disease.
Andreoli CM, Foster CS. Vogt-Koyanagi-Harada disease. Int Ophthalmol Clin. 2006;46(2):111-22. [Medline].
Rajendram R, Evans M, Rao NA. Vogt-Koyanagi-Harada disease. Int Ophthalmol Clin. 2005;45(2):115-34. [Medline].
Yang P, Ren Y, Li B, Fang W, Meng Q, Kijlstra A. Clinical characteristics of Vogt-Koyanagi-Harada syndrome in Chinese patients. Ophthalmology. Mar 2007;114(3):606-14. [Medline].
Usui Y, Goto H, Sakai JI, Takeuchi M, Usui M, Rao NA. Presumed Vogt-Koyanagi-Harada disease with unilateral ocular involvement: report of three cases. Graefes Arch Clin Exp Ophthalmol. Mar 24 2009;[Medline].
da Silva FT, Damico FM, Marin ML, Goldberg AC, Hirata CE, Takiuti PH, et al. Revised diagnostic criteria for vogt-koyanagi-harada disease: considerations on the different disease categories. Am J Ophthalmol. Feb 2009;147(2):339-345.e5. [Medline].
Yamaki K, Gocho K, Hayakawa K, Kondo I, Sakuragi S. Tyrosinase family proteins are antigens specific to Vogt-Koyanagi-Harada disease. J Immunol. Dec 15 2000;165(12):7323-9. [Medline].
Hashimoto T, Takizawa H, Yukimura K, Ohta K. Vogt-Koyanagi-Harada disease associated with brainstem encephalitis. J Clin Neurosci. Apr 2009;16(4):593-5. [Medline].
Levinson RD, Du Z, Luo L, Holland GN, Rao NA, Reed EF, et al. KIR and HLA gene combinations in Vogt-Koyanagi-Harada disease. Hum Immunol. Jun 2008;69(6):349-53. [Medline].
Davis JL, Mittal KK, Freidlin V, Mellow SR, Optican DC, Palestine AG, et al. HLA associations and ancestry in Vogt-Koyanagi-Harada disease and sympathetic ophthalmia. Ophthalmology. Sep 1990;97(9):1137-42. [Medline].
Nussenblatt RB, Palestine AG, Chan CC. Cyclosporin A therapy in the treatment of intraocular inflammatory disease resistant to systemic corticosteroids and cytotoxic agents. Am J Ophthalmol. Sep 1983;96(3):275-82. [Medline].
Bacsal K, Wen DS, Chee SP. Concomitant choroidal inflammation during anterior segment recurrence in Vogt-Koyanagi-Harada disease. Am J Ophthalmol. Mar 2008;145(3):480-486. [Medline].
Ondrey FG, Moldestad E, Mastroianni MA, Pikus A, Sklare D, Vernon E, et al. Sensorineural hearing loss in Vogt-Koyanagi-Harada syndrome. Laryngoscope. Oct 2006;116(10):1873-6. [Medline].
Wang Y, Gaudio PA. Infliximab therapy for 2 patients with Vogt-Koyanagi-Harada syndrome. Ocul Immunol Inflamm. Jul-Aug 2008;16(4):167-71. [Medline].
Read RW, Yu F, Accorinti M, Bodaghi B, Chee SP, Fardeau C. Evaluation of the effect on outcomes of the route of administration of corticosteroids in acute Vogt-Koyanagi-Harada disease. Am J Ophthalmol. Jul 2006;142(1):119-24. [Medline].
Babel J. Syndrome de Vogt-Koyanagi. Schweiz Med Wochenscher. 1932;44:1136.
Bouchenaki N, Herbort CP. The contribution of indocyanine green angiography to the appraisal and management of Vogt-Koyanagi-Harada disease. Ophthalmology. Jan 2001;108(1):54-64. [Medline].
Bruno MG, McPherson SD Jr. Harada's disease. Am J Ophthalmol. 1949;32:513.
Chan CC, Palestine AG, Nussenblatt RB, Roberge FG, Benezra D. Anti-retinal auto-antibodies in Vogt-Koyanagi-Harada syndrome, Behcet's disease, and sympathetic ophthalmia. Ophthalmology. Aug 1985;92(8):1025-8. [Medline].
Cowper AR. Harada's disease and Vogt-Koyanagi syndrome: Uveoencephalitis. Arch Ophthalmol. 1951;45:367.
Fine SB, Gilligan JH. The Vogt-Koyanagi-Harada syndrome. A variant of sympathetic ophthalmia. Report of two cases. Am J Ophthalmol. 1957;53:433.
Forster DJ, Cano MR, Green RL, Rao NA. Echographic features of the Vogt-Koyanagi-Harada syndrome. Arch Ophthalmol. Oct 1990;108(10):1421-6. [Medline].
Harada Y. Beitrag Zur klinischen Kenntnis von nichteitriger Choroiditis (Choroiditis diffusa acta). Acta Soc Ophthalmol Jpn. 1926;30:356.
Ibanez HE, Grand MG, Meredith TA, Wippold FJ 2nd. Magnetic resonance imaging findings in Vogt-Koyanagi-Harada syndrome. Retina. 1994;14(2):164-8. [Medline].
Islam SM, Numaga J, Matsuki K, Fujino Y, Maeda H, Masuda K. Influence of HLA-DRB1 gene variation on the clinical course of Vogt-Koyanagi-Harada disease. Invest Ophthalmol Vis Sci. Feb 1994;35(2):752-6. [Medline].
Jabs DA, Rosenbaum JT, Foster CS, Holland GN, Jaffe GJ, Louie JS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. Oct 2000;130(4):492-513. [Medline].
Koyanagi Y. Dysakusis, alopecia und poliosis bei schwerer Uveitis nicht traumatichen Ursprungs. Klin Monatsbl Augenheilkd. 1929;82:194.
Lacerda RR. Sindrome de Vogt-Koyanagi-Harada: descricao de um caso especial em crianca de sete anos de idade. 1994;57:46-48.
Lubin JR, Ni C, Albert DM. Clinicopathological study of the Vogt-Koyanagi-Harada syndrome. Int Ophthalmol Clin. 1982;22(3):141-56. [Medline].
Maezawa N, Yano A, Taniguchi M, Kojima S. The role of cytotoxic T lymphocytes in the pathogenesis of Vogt-Koyanagi-Harada disease. Ophthalmologica. 1982;185(3):179-86. [Medline].
Martinez JA, Lopez PF, Sternberg P Jr, Aaberg TM, Lambert HM, Capone A Jr, et al. Vogt-Koyanagi-Harada syndrome in patients with Cherokee Indian ancestry. Am J Ophthalmol. Nov 15 1992;114(5):615-20. [Medline].
Momoeda S. [Lymphocyte transformation test in Vogt-Koyanagi-Harada syndrome (author's transl)]. Nippon Ganka Gakkai Zasshi. Aug 10 1976;80(8):491-6. [Medline].
Morris WR, Schlaegel TF Jr. Viruslike inclusion bodies in subretinal fluid in uveoencephalitis. Am J Ophthalmol. 1964;58:940-945.
Ohno S. Immunological aspects of Behçet's and Vogt-Koyanagi-Harada's diseases. Trans Ophthalmol Soc U K. Sep 1981;101 (Pt 3)(3):335-41. [Medline].
Pattison EM. Uveomeningoencephalitic syndrome (Vogt-Koyanagi-Harada). Arch Neurol. 1965;12:197-205.
Perry HD, Font RL. Clinical and histopathologic observations in severe Vogt-Koyanagi-Harada syndrome. Am J Ophthalmol. Feb 1977;83(2):242-54. [Medline].
Rao NA. Mechanisms of inflammatory response in sympathetic ophthalmia and VKH syndrome. Eye. 1997;11 (Pt 2):213-6. [Medline].
Rao NA, Marak GE. Sympathetic ophthalmia simulating vogt-Koyanagi-Harada's disease: a clinico-pathologic study of four cases. Jpn J Ophthalmol. 1983;27(3):506-11. [Medline].
Read RW. Vogt-Koyanagi-Harada disease. Ophthalmol Clin North Am. Sep 2002;15(3):333-41, vii. [Medline].
Read RW, Holland GN, Rao NA, Tabbara KF, Ohno S, Arellanes-Garcia L, et al. Revised diagnostic criteria for Vogt-Koyanagi-Harada disease: report of an international committee on nomenclature. Am J Ophthalmol. May 2001;131(5):647-52. [Medline].
Reed H. The uveoencephalitic syndrome of Vogt-Koyanagi-Harada disease. Can Med Assoc J. 1958;79:451.
Rubsamen PE, Gass JD. Vogt-Koyanagi-Harada syndrome. Clinical course, therapy, and long-term visual outcome. Arch Ophthalmol. May 1991;109(5):682-7. [Medline].
Sagiura S. Vogt-Koyanagi-Harada disease. Jpn J Ophthalmol. 1978;22:9-35.
Vogt A. Fruhzeitges Ergraunen der Zilien und Bemerkungen uber den sogenannten plotzlichen Eintritt dieser Veranderung. Klin Monatsbl Augenheilkd. 1906;44:228.
Yamaguchi Y, Otani T, Kishi S. Tomographic features of serous retinal detachment with multilobular dye pooling in acute Vogt-Koyanagi-Harada disease. Am J Ophthalmol. Aug 2007;144(2):260-5. [Medline].
Yuasa T, Murai Y, Hoki T, Mimura Y. [Lymphocyte transformation test and migration inhibition test of macrophages in Vogt-Koyanagi-Hirada's syndrome (author's transl)]. Nippon Ganka Gakkai Zasshi. Oct 1973;77(10):1652-7. [Medline].
Yuge T. The relation between Vogt-Koyanagi syndrome and sympathetic ophthalmia. Report of a case of a case of Vogt-Koyanagi syndrome. Am J Ophthalmol. 1957;43:735.

