Vogt-Koyanagi-Harada (VKH) syndrome
Last Updated: 2025-04-08
Author(s): Navarini A.A.
ICD11: -
Last Updated: 2025-04-08
Author(s): Navarini A.A.
ICD11: -
Vogt-Koyanagi-Harada (VKH) syndrome is a rare, autoimmune, granulomatous multisystemic disease that attacks melanocytes. It is characterized by bilateral granulomatous panuveitis involving other melanin-rich tissues such as the meninges, inner ears, skin, and hair. VKH syndrome manifests clinically in phases: After a prodromal stage with unspecific general symptoms, the acute uveitic phase with bilateral visual deterioration and inflammatory retinal detachments, later depigmenting changes in the eyes (“sunset glow fundus”) as well as skin and hair. The absence of a previous eye trauma or surgical intervention is crucial (differentiation from sympathetic ophthalmia).
VKH is rare worldwide, but occurs more frequently in dark-skinned ethnic groups. It particularly affects people of East and Southeast Asian origin, as well as people from the Middle East, India, Central and South America. In Japan, VKH causes about 7–8% of all uveitis; in Europe and North America, the proportion is significantly lower. Typically, young adults between the ages of 20 and 50 years develop the disease, with a slight female preponderance. Genetic factors play a role: an association with HLA-DR4 alleles (especially HLA-DRB1*04:05) has been demonstrated in Asian patients. The prevalence in the general population is very low, with exact figures varying regionally. Despite the ethnic clustering, VKH can theoretically occur in all population groups, which is why the diagnosis should also be considered in non-pigmented patients with the corresponding clinical picture.
This syndrome is categorized as complete, incomplete, or probable VKH based on the extent of systemic involvement. Complete VKH is present when both neurological/audiological and cutaneous manifestations occur in addition to the obligatory bilateral ocular findings. In the case of incomplete VKH, both eyes are also affected, but only one of the two extraocular components (either meningeal/audiological or cutaneous). A probable VKH refers to the special case in which only the typical ocular changes are present (no skin or neurological symptoms), which is rare in practice.
Alternatively, VKH syndrome is classified into phases: prodromal stage (flu-like symptoms, headaches, meningism), acute phase (bilateral granulomatous uveitis with serous retinal detachments), convalescent phase (chronic uveitis with depigmentation at the ocular fundus and skin/hair) and, possibly, chronic recurrent phase with recurring inflammatory episodes. This progression underlines the dynamics of the disease and the necessity of early treatment.
VKH syndrome is caused by a misdirected immune response against the body's own melanocytic antigens. Pathogenetically, a T-helper-1 and T-helper-17 mediated autoimmune reaction is at the forefront, directed, for example, against tyrosinase-associated proteins in melanocytes of the uvea, skin and hair follicles. Histologically, a non-necrotizing granulomatous inflammation is observed. Genetic predisposition (strong association with HLA-DR4 subtypes such as HLA-DRB104:05 and HLA-DRB104:01) favors the disease. Viral infections are discussed as possible triggering environmental factors – for example, by Epstein-Barr virus, cytomegalovirus or, according to recent reports, also SARS-CoV-2 – which could trigger an autoimmune loss of immunological tolerance to melanocytes in genetically susceptible individuals. As a result, activated T-lymphocytes infiltrate melanin-containing tissues and lead to the destruction of melanocytes (comparable to “systemic vitiligo”). Immunohistochemical analysis reveals pro-inflammatory cytokines (IL-6, IL-17, IFN-γ, TNF-α) in the inflamed tissue. The exact mechanisms are the subject of current research (e.g. changes in the miRNA profile of immune cells), but overall VKH is understood to be a prototypical autoimmune granulomatous multiorgan disease.
Eyes: The leading symptom is bilateral visual impairment with redness of the eyes, photophobia, and pain due to granulomatous panuveitis. Multifocal serous retinal detachments, papilledema, and diffuse choroiditis are typical in the acute phase; patients notice blurred vision, floaters, and possibly visual field deficits. If untreated, a chronic stage develops after weeks with depigmentation of the fundus background pigmentation (“sunset glow fundus”) and anterior segment involvement (chronic iridocyclitis, cataract).
Neurological/audiological: Even in the prodromal phase, headaches, neck stiffness and fatigue often occur, which corresponds to aseptic meningism. Many patients have tinnitus, ringing in the ears or mild hearing loss. Dizziness may occur. These neurological-otological symptoms often precede the eye involvement by several days or accompany the early uveitis. They usually resolve with treatment; pronounced neurological deficits are rare.
Cutaneous system: Typically, skin and hair changes develop several weeks to months after the acute eye findings. Symmetrical vitiligo-like depigmentation of the skin is common (often on the face, neck or trunk, sometimes segmentally distributed). Poliosis is striking, i.e. a sudden whitening of hair - classically of the eyelashes, eyebrows and sometimes of the scalp hair (canities praecox). In addition, non-scarring alopecia may occur, usually in the form of areata-like local hair loss areas. These dermatological signs mark the convalescence phase and retrospectively confirm the VKH diagnosis, since they are usually still absent in the early acute phase. General symptoms such as fever, fatigue and nausea may be present in the prodromal stage, but are non-specific.
Diagnosis is clinical and requires an interdisciplinary evaluation (ophthalmology, neurology, dermatology). Ocular examination: Ophthalmoscopy reveals the described uveitis signs (choroidal depigmentation, serous retinal detachments, later “sunset glow” fundus). Slit-lamp examination may reveal anterior granulomatous uveitis with Busacca's nodules. Fluorescein angiography of the retina reveals multiple pinpoint leaks and diffuse choroiditis; indocyanine green angiography and optical coherence tomography show thickening of the choroid in the acute phase. A characteristic early sign is the Sugiura sign (depigmented limbal margin at the iris). CSF diagnostics: A lumbar puncture can detect lymphocytic pleocytosis (often in the early phase, but not obligatory) in the absence of other findings for infections. Audiometry: can objectify sensorineural hearing loss. Dermatology: The skin and hair changes are usually clinically clear; a biopsy of a fresh vitiliginous lesion would confirm an inflammatory depigmentation (see dermatopathology).
The revised international diagnostic criteria (e.g. according to Read et al.) require: (1) no previous ocular trauma/surgery; (2) bilateral granulomatous uveitis (with typical findings such as diffuse choroiditis and serous retinal detachments or later sunset glow fundus); (3) neurological signs (meningism or proven increase in CSF cell count) or audiological involvement (tinnitus/hearing loss); (4) or cutaneous signs (poliosis, vitiligo, alopecia), typically in the late phase. Complete VKH fulfills all criteria, incomplete fulfills one of the extra-uveolar criteria, probable fulfills none of them. Important laboratory tests are used to exclude differential diagnoses (especially syphilis serology, quantiferon TB test, sarcoidosis diagnostics). A cranial MRI is usually unremarkable except for possible choroidal thickening; it is mainly helpful in excluding other causes. Overall, the diagnosis of VKH is based on the typical symptom complex and the exclusion of other granulomatous uveitis causes.
VKH preferentially affects melanin-rich tissues throughout the body: Ocularly, the middle layer of the eye (Uvea) is primarily affected – especially the choroid and the retinal pigment epithelium, but the iris and ciliary body can also be involved. The resulting retinal detachment is caused by inflammatory exudate under the neurosensory retina. CNS: The leptomeninges (soft meninges) are the target of the immune reaction, leading to aseptic meningitis. Inner ear: Structures with melanocytes, such as the stria vascularis in the cochlea and vestibular apparatus, explain tinnitus and hearing loss. Skin: The depigmented lesions (vitiligo) often occur on the face (especially periorbital), neck and upper back, and upper extremities. They are usually multiple and symmetrically distributed, but in some cases also segmentally along dermatomes. Hair: Poliosis typically affects the eyelashes and eyebrows, and often also partial areas of the scalp hair (temporal region). The alopecic areas are mainly on the capillitium (scalp) and are not scarring. Overall, the cutaneous manifestations are possible in any location, but often concentrate on the head and neck region. Important: the changes are usually bilateral (e.g. bilateral poliosis of the eyelashes), which underlines the systemic origin.
Patients initially describe non-specific complaints: for example, a 30-year-old female patient (Asian background) reports headaches lasting several days, fatigue and neck pain after an episode of “flu-like” symptoms. She also experiences tinnitus. About a week later, she notices a rapidly progressive deterioration in her vision on both sides, with photophobia and blurred vision. The ophthalmologist diagnosed bilateral uveitis with subretinal fluid. Systemic corticosteroid treatment was initiated and the patient's symptoms improved. Several months later, the patient noticed light-colored tufts of hair growing on her eyebrows and eyelashes; in addition, white skin spots developed on her temples. In retrospect, she reported that there was no preceding eye injury or surgery. This scenario is typical of VKH syndrome: after a prodromal stage (flu-like symptoms with headache/neck pain and tinnitus), the acute phase with eye involvement follows. In the further course, the dermatological signs (poliosis/vitiligo) manifest themselves, confirming the suspected diagnosis. Without adequate therapy, repeated relapses with renewed eye inflammation and progressive visual deterioration may be observed in the anamnesis.
Histopathologically, the skin in active VKH lesions shows changes similar to those of inflammatory vitiligo. In fresh depigmented areas, there is a marked reduction or complete absence of epidermal melanocytes and signs of melanin phagocytosis: dermally, there are increased numbers of melanin-laden macrophages (melanophages) that have taken up the released pigment. Accompanying this, there is a perivascular and periadnexal lymphocytic infiltrate in the upper dermis, which consists mainly of T-lymphocytes (with a small proportion of B-cells). This infiltrate is concentrated particularly around hair follicles and eccrine sweat glands, i.e. sites with melanocyte occurrence, which supports the pathophysiological focus on melanocytes. A granulomatous organization of the infiltrate may occur, but is not always detectable in skin biopsies. Hair follicles: In the affected hair region (alopecia or poliosis), biopsies show lymphocytic inflammation around the hair follicles with leakage of melanin into the surrounding tissue. In terms of differential diagnosis, there are no signs of scarring or basement membrane damage (as would be the case with lupus, for example). In the late stages, the skin lesions resemble scar-free vitiligo tissue: melanocytes are absent, the inflammatory infiltrate regresses, and permanent depigmentation remains. Overall, the dermatopathological findings correlate with a T-cell-mediated attack on cutaneous melanocytes, analogous to the process in the eye.
If untreated or in the case of chronic relapsing course, VKH syndrome can lead to significant complications. From an ophthalmological point of view, the risk of permanent vision loss is the main concern: repeated or chronic uveitis attacks can lead to cataracts (due to inflammation or long-term steroid therapy), glaucoma (due to increased intraocular pressure caused by inflammation or steroids) and extensive retinal and choroidal damage. In particular, subretinal fibrosis can develop, leading to irreversible visual impairment. Choroidal neovascularization (CNV) has also been described, threatening the macula. Neurologically, persistent headaches or chronic meningeal irritation may occur in rare cases; however, the neurological symptoms usually subside during therapy without any consequences. Audiologically, untreated severe involvement of the inner ears can lead to permanent hearing loss; in isolated cases, balance disorders have become chronic. Dermatologically, the consequences are mainly cosmetic: vitiligo and poliosis can be psychologically stressful; in rare cases, the skin re-pigments after successful immunotherapy, but usually persistent white areas remain. Systemic side effects are mainly the result of the therapy (e.g. long-term corticosteroids: Cushing's syndrome, osteoporosis, diabetes; immunosuppressants: risk of infection). Without adequate treatment, VKH tends to relapse and transition to chronic inflammation, which increases the complication rate. With early, consistent therapy, many complications can be avoided.
The prognosis of VKH syndrome depends largely on a rapid diagnosis and adequate initiation of therapy. With early high-dose immunosuppressive treatment, the prognosis for vision is relatively favorable today: in many cases, good visual acuity can be maintained or regained. Any hearing loss also usually improves with therapy. Skin and hair changes (vitiligo, poliosis) are often irreversible, but are primarily a cosmetic problem; partial repigmentation is possible, especially if the inflammation is quickly controlled. Without treatment or in the event of treatment failure, VKH almost always progresses chronically with repeated uveitis attacks. In such cases, there is a significant long-term loss of visual acuity, accompanied by permanent inner ear damage, which can even lead to bilateral blindness. The quality of life can be severely affected by vision loss and chronic pain. However, with adequate therapy, the disease can be well controlled in many cases: after the acute phase, it is often possible to transition to a resting phase. However, many patients require long-term immunosuppressive maintenance therapy to prevent relapses. Overall, the earlier and more aggressive the treatment, the better the prognosis. Close interdisciplinary follow-up care is important to immediately recognize signs of a relapse.
Primary prevention of VKH syndrome is not yet known, since exact triggers and pathogenesis factors cannot be completely avoided. There is no vaccination or prophylactic measure that could prevent the occurrence of the autoimmune reaction against melanocytes. Nevertheless, secondary prevention measures can reduce the disease burden: the decisive factor is the early initiation of therapy in the initial stages to prevent serious progression. Immediate high-dose immunosuppression is used to try to contain the destruction of melanin-containing tissues before irreversible damage (e.g. to the retina) occurs. Patients with a known susceptibility to VKH (e.g. positive family history or certain HLA constellation) should be examined by an ophthalmologist and neurologist immediately upon the onset of symptoms (visual disturbances, meningism) – rapid diagnosis can be considered a preventive measure against complications. Likewise, avoiding delays in treatment is essential: any unclear uveitis cases should be referred to centers early on to quickly recognize VKH. Although triggers (such as trivial viral infections) can hardly be avoided, high awareness among at-risk populations can lead to early medical attention. Overall, the aim of prevention in VKH is to avoid consequential damage (blindness, deafness) through consistent management. There is no special prophylactic medication before the onset of the disease.
The therapy of VKH syndrome is based on rapid and intensive immunosuppression to contain the autoimmune inflammation. Acute therapy: The gold standard is high-dose systemic corticosteroids. Pulse therapy with intravenous methylprednisolone (e.g., 500–1000 mg/day for 3–5 days) is usually given at the beginning, followed by tapering oral prednisolone therapy over many weeks to months. Early steroid therapy that lasts long enough can reduce the rate of recurrence. Immunomodulatory therapy (IMT): Nowadays, an additional second immunosuppressant is recommended early on in the course of the disease to achieve a steroid-sparing effect and to prevent chronic progression. Frequently used agents are cyclosporin A, azathioprine, mycophenolate mofetil or methotrexate. In cases of inadequate disease control or the occurrence of steroid-related side effects, IMT is escalated. Biologics: In cases of therapy-refractory progression or chronic VKH, biologics are used, in particular TNF-α inhibitors such as infliximab or adalimumab, which have been shown to be effective in studies in VKH patients (especially in the chronic stage). Recent data suggest that a conventional combination of steroids and cyclosporine, for example, is not inferior to early administration of biologics; the choice of escalation depends on availability and individual response. Topical therapy: Eye drops (corticosteroids, cycloplegics) are used as an adjuvant to treat anterior uveitis, but under no circumstances replace systemic therapy. Local skin therapy (e.g. topical steroids or calcineurin inhibitors) has little effect on vitiligo/psoriasis in the context of VKH, since the main pathogenic activity is systemic. Concomitant measures: If intraocular pressure is elevated due to uveitis or steroids, pressure-lowering eye drops are given. Secondary glaucoma or cataracts may need to be treated surgically, but ideally only after the inflammation has subsided. Hearing loss is rehabilitated with hearing aids if necessary and if permanent. Close interdisciplinary cooperation is important: ophthalmologists monitor the inflammatory state using imaging (OCT, fluorescence angiography), dermatologists monitor skin symptoms, and neurologists monitor CSF parameters if necessary. Duration of therapy: Immunosuppression is usually maintained for at least 6–12 months (sometimes several years), since discontinuing it too early often leads to relapses. The overall goal of therapy is to achieve complete remission of the inflammation in order to minimize organ damage. In the best case, an inactive stage of the disease results with only residual skin/hair changes.
