Vogt-Koyanagi-Harada syndrome

By Marcello Cherchi, MD PhD

For patients

Vogt-Koyanagi-Harada syndrome (VKHS) is a rare autoimmune disorder that can cause eye problems, hearing problems, neurological problems and skin problems. If your doctor suspects VKHS, then they may check several tests and an MRI. Depending on the particular symptoms, treatment may be with an ophthalmologist or rheumatologist.

For clinicians

Overview

Vogt-Koyanagi-Harada syndrome (VKHS) is a rare autoimmune disorder of unknown etiology in which T-cell autoimmunity is directed against melanocytes in multiple tissues, including the uvea, meninges, skin and labyrinth, correspondingly manifesting with some combination of visual deficits, neurological symptoms, audiovestibular symptoms and integumentary symptoms. VKHS patients can exhibit symmetrical or asymmetrical hearing loss. Vestibular workup variably reveals spontaneous nystagmus, unilateral or bilateral caloric weakness, abnormalities on cervical and/or ocular vestibular evoked myogenic potentials. This profile of audiologic and vestibular findings is neither sensitive nor specific for the diagnosis. MRI may reveal ophthalmologic, meningeal, brain or spine parenchymal, and labyrinthine findings. Management is multidisciplinary and often involves ophthalmology and rheumatology. Treatment typically begins with systemic corticosteroids.

Introduction

Urzua and colleagues (Urzua et al. 2022), and Herbort and Mochizuki (Herbort and Mochizuki 2007) summarize the sequence of early investigators who helped characterize this syndrome as follows:

• The Swiss ophthalmologist Alfred Vogt (1879 – 1943) described a case of whitening of the eyelashes (for which the medical term is “poliosis”) in 1906 (Vogt 1906).
• The first Japanese researcher to publish about this was the professor of ophthalmology, Dr. Jujiro Komoto, in 1911 (Komoto 1911).
• The Japanese researcher Yoshizo Koyanagi (1880 – 1954) published two cases in 1914, then a series of 16 in 1929 (Koyanagi 1929).
• The Japanese researcher Einosuke Harada (1892 – 1946) published one case in 1923, and 5 cases in 1926 (Harada 1926).

Subsequent descriptions recognized additional features which, when taken together, comprise a uveomeningoencephalitic syndrome characterized by chronic bilateral panuveitis and variable neurological symptoms, auditory symptoms (such as tinnitus and hearing loss) and cutaneous symptoms (such as vitiligo), which came to be known as Vogt-Koyanagi-Harada syndrome (VKHS). Unfortunately, Dr. Jujiro Komoto was not included in the eponymous designation of this syndrome.

Figure : Alfred Vogt (1879-1943). From Gloor (Gloor 2008).

Figure : Yoshizo Koyanagi (1880-1954). From Herbort and Mochizuki (Herbort and Mochizuki 2007).

Figure : Einosuke Harada (1892-1946). From Urzua et al. (Urzua et al. 2022).

Epidemiology

VKHS is rare. It occurs more commonly in populations of East Asia, South Asia, the Middle East, and some Native American groups. Peak onset is the third decade, with a range of second to fifth decade (Mota and Santos 2010). It rarely begins in childhood, and when it does, it has a more aggressive clinical course (Tabbara et al. 1998).

Genetics

Numerous genetic and epigenetic factors have been associated with an increased susceptibility to VKHS (Su et al. 2023; Wu et al. 2023; Zhou et al. 2023).

Pathophysiological mechanism of disease

VKHS is a T-cell mediated autoimmune disorder of unknown etiology in which the misdirected autoimmune attack targets melanocytes in multiple tissue types, including the uvea, meninges, skin and labyrinth (Fujiwara et al. 2017; Kimura et al. 1996).

Clinical presentation

Revised diagnostic criteria for VKHS published in 2001 (Read et al. 2001), displayed below, are rather complex.

Complete Vogt-Koyanagi-Harada disease (criteria 1 to 5 must be present):

1. No history of penetrating ocular trauma or surgery preceding the initial onset of uveitis.
2. No clinical or laboratory evidence suggestive of other ocular disease entities.
3. Bilateral ocular involvement (a or b must be met, depending on the stage of disease when the patient is examined).
   1. Early manifestations of disease.
      1. There must be evidence of a diffuse choroiditis (with or without anterior uveitis, vitreous inflammatory reaction, or optic disk hyperemia), which may manifest as one of the following:
         1. Focal areas of subretinal fluid, or
         2. Bullous serous retinal detachments.
      2. With equivocal fundus findings; both of the following must be present as well:
         1. 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
         2. Diffuse choroidal thickening, without evidence of posterior scleritis by ultrasonography.
   2. Late manifestations of disease.
      1. History suggestive of prior presence of findings from 3a, and either both (2) and (3) below, or multiple signs from (3):
      2. Ocular depigmentation (either of the following manifestations is sufficient):
         1. Sunset glow fundus, or
         2. Sugiura sign.
      3. Other ocular signs:
         1. Nummular chorioretinal depigmented scars, or
         2. Retinal pigment epithelium clumping and/or migration, or
         3. Recurrent or chronic anterior uveitis.
4. Neurological/auditory findings (may have resolved by time of examination).
   1. 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 definition of meningismus, however), or
   2. Tinnitus, or
   3. Cerebrospinal fluid pleocytosis.
5. Integumentary finding (not preceding onset of central nervous system or ocular disease).
   1. Alopecia, or
   2. Poliosis, or
   3. Vitiligo.

Incomplete Vogt-Koyanagi-Harada disease (criteria 1 to 3 and either 4 or 5 must be present):

• 1. No history of penetrating ocular trauma or surgery preceding the initial onset of uveitis, and
  2. No clinical or laboratory evidence suggestive of other ocular disease entities, and
  3. Bilateral ocular involvement.
  4. Neurologic/auditory findings; as defined for complete Vogt-Koyanagi-Harada disease above, or
  5. Integumentary findings; as defined for complete Vogt-Koyanagi-Harada disease above.

Probable Vogt-Koyanagi-Harada disease (isolated ocular disease; criteria 1 to 3 must be present):

• 1. No history of penetrating ocular trauma or surgery preceding the initial onset of uveitis.
  2. No clinical or laboratory evidence suggestive of other ocular disease entities.
  3. Bilateral ocular involvement as defined for complete Vogt-Koyanagi-Harada disease above.

Fujiwara and colleagues state that, “Otological symptoms, including hearing loss, tinnitus, and vertigo, typically coincide with the onset of ocular pathology” (Fujiwara et al. 2017). The ophthalmologic involvement is bilateral, though the corresponding visual symptoms may be asymmetric (Urzua et al. 2022).

Noguchi and colleagues (Noguchi et al. 2014) studied 41 VKHS patients and found that 28/41 (68%) complained of auditory symptoms. Of those 28 patients, 68% complained of tinnitus, 43% complained of hearing loss, 21% complained of aural fullness and 11% complained of hyperacusis.

The audiologic and vestibular symptoms can be episodic, and may be metachronous (Gaudreau et al. 2012).

The profile of audiologic and vestibular symptoms is neither sensitive nor specific for the diagnosis.

Physical examination

Physical examination findings change as the disease evolves.

The Figure below, taken from the original article published by Vogt in 1906 (Vogt 1906), demonstrates poliosis (whitening of the eyelashes).

Figure : Poliosis (whitening of the eyelashes). From Vogt (Vogt 1906).

Testing: auditory

Fujiwara and colleagues (Fujiwara et al. 2017) studied 15 VKHS patients with pure tone audiometry and reported that 9/15 (60%) had age-appropriate hearing, 4/15 (27%) had some degree of unilateral hearing loss out of proportion to age, and 2/15 (13%) had some degree of bilateral hearing loss out of proportion to age.

Testing: vestibular

Fujiwara and colleagues (Fujiwara et al. 2017) studied vestibular tests (oculography, caloric testing, cervical vestibular evoked myogenic potentials and ocular vestibular evoked myogenic potentials) in 42 VKHS patients and reported the rates of abnormalities displayed in the Table below.

Feature	Number of patients (out of 42)	Percentage of patients
Subjective symptoms (n=42)
Yes	8	19%
No	34	81%
Nystagmus tests (n=28)
Abnormal	12	43%
Normal	16	57%
Stepping tests (n=16)
Abnormal	6	38%
Normal	10	63%
Caloric tests (n=15)
Bilateral weakness	3	20%
Unilateral weakness	4	27%
Normal	8	53%
Cervical vestibular evoked myogenic potentials (cVEMP) (n=16)
Abnormal	7	44%
Normal	9	56%
Ocular vestibular evoked myogenic potentials (oVEMP) (n=16)
Abnormal	8	50%
Normal	8	50%

Table : Rates of abnormal vestibular test results in 42 Vogt-Koyanagi-Harada syndrome patients. From Fujiwara et al. (Fujiwara et al. 2017).

Noguchi and colleagues (Noguchi et al. 2014) studied oculography 24 VKHS patients, and reported that 11/24 (46%) showed spontaneous horizontal nystagmus.

Oku and Ishikawa (Oku and Ishikawa 1994) studied oculography in 15 VKHS patients, and reported that 8/15 (53%) exhibited spontaneous horizontal nystagmus. Of the 8 patients with spontaneous nystagmus, 6 (75%) exhibited low gain in smooth pursuit “on the side ipsilateral to the nystagmus,” and 7 (88%) exhibited elevated gain of the vestibulo-ocular reflex. Of the 7 patients with no spontaneous nystagmus, only 1 (14%) exhibited elevated gain of the vestibulo-ocular reflex.

Noguchi and colleagues (Noguchi et al. 2014) studied caloric testing in 6 VKHS patients, and reported that 2/6 (33%) exhibited bilateral caloric weakness, 2/6 (33%) exhibited unilateral caloric weakness, and 2/6 (33%) showed normal caloric responses.

Fujiwara and colleagues (Fujiwara et al. 2017) studied one VKHS patient with video head impulse testing (vHIT) and found low gain (0.80) on one side and normal gain (0.87) on the other side, and no compensatory saccades.

Testing: other

Treated VKHS patients in the chronic (quiescent) stage of the disease exhibit decreased retinal and choroidal vessel density on optical coherence tomography (Guo et al. 2025).

Imaging

Numerous MRI findings have been reported in VKHS, including:

• Ophthalmologic findings:
  • Retinal detachment (Al Banna et al. 2019; McGehee et al. 2005)
  • Choroidal thickening (Ando et al. 2018; Ibanez et al. 1994; Phagura and Bhikoo 2021)
• Meningeal findings:
  • Pachymeningeal enhancement (Han et al. 2010)
  • Leptomeningeal enhancement (Le et al. 2019; Lohman et al. 2011)
• Labyrinthine enhancement (Hida et al. 2017)
• Brain parenchymal findings:
  • Intracerebral hemorrhage (Baheti et al. 2009)
  • Intraparenchymal FLAIR hyperintensities (Keles et al. 2013)
  • Intraparenchymal enhancement (Ikeda and Tsukagoshi 1992)
• Myelitis (Dahbour 2009)

Differential diagnosis

The differential diagnosis of VKHS is broad and includes choroidal melanoma, sympathetic ophthalmia, infectious uveitis, systemic lupus erythematosus, sarcoidosis, Cogan syndrome, and others.

Treatment

Management of VKHS is multidisciplinary and often involves ophthalmology and rheumatology. Initial treatment is usually with systemic of corticosteroids, and may also include immunosuppressants or immunomodulatory agents.

Prognosis

Mota and Santos (Mota and Santos 2010) state:

“With this disease, prognosis depends greatly on how early it is diagnosed and correctly treated. Disorders of the auditory system respond well to treatment and are generally completely reversed in 2 to 3 months, whereas the cutaneous lesions are permanent. Prognosis for the vision is extremely variable, although generally favorable. It has been found that the three most important prognostic factors are: good visual acuity 1 month after starting treatment, early high-dose corticosteroids and age at disease onset, with evidence that younger patients suffered a lower rate of ocular complications” (Mota and Santos 2010).

References

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