Prodromal Stage
Timing: 1–2 weeks before ocular symptoms appear
Symptoms: Scalp tingling, headache (64.7%), tinnitus (24.7%), malaise (21.1%), flu-like symptoms2)
Vogt-Koyanagi-Harada Disease
1. What is Vogt-Koyanagi-Harada disease?
Section titled “1. What is Vogt-Koyanagi-Harada disease?”Vogt-Koyanagi-Harada disease (VKH disease) is a T-cell-mediated autoimmune disease against melanin proteins. In the onset phase, it presents with uveitis, meningeal irritation symptoms such as headache, and hearing loss. As inflammation persists, skin manifestations such as vitiligo, alopecia, and poliosis appear. Inflammatory lesions occur throughout the body where melanocytes are distributed: eyes, hair, skin, inner ear, and meninges.
Approximately half of patients have flu-like symptoms within 2 weeks before onset, suggesting that viral infection may trigger the disease through immunological cross-reactivity (molecular mimicry). Involvement of Epstein-Barr virus and cytomegalovirus has been suggested. Visual prognosis is generally good, but some cases progress to severe visual impairment due to persistent inflammation, making early diagnosis and initial treatment important.
Epidemiology
Section titled “Epidemiology”VKH is the second most common cause of uveitis. In a 2002 epidemiological survey, 205 cases (6.7%) of VKH were reported, and in a 2009 survey, 267 cases (7.0%) were reported, both ranking second after sarcoidosis1). The typical age of onset is between 20 and 50 years, with a slight female predominance. HLA-DR4 positivity is found in 80% of patients (compared to 25% in the normal Japanese population), and it is more common in people of color (Asians, Hispanics, Native Americans) and rare in Caucasians. Among 93 VKH patients enrolled in the FAST trial, 71% were female, with a median age of 35–38 years2). It is most common in East Asia but also occurs in the Pacific regions of North and South America3).
Q
What kind of people are more likely to develop VKH disease?
A
It is more common in people of color (Asians, Hispanics, Native Americans) and rare in Caucasians. It tends to occur in HLA-DR4-positive individuals and those aged 20–50 years, with a slight female predominance. It is thought to develop from a combination of genetic predisposition (HLA-DRB1*0405) and some environmental trigger3).
2. Main Symptoms and Clinical Findings
Section titled “2. Main Symptoms and Clinical Findings”
Takase H, et al. Development of Sunset Glow Fundus and Subsequent Complications in Vogt-Koyanagi-Harada Disease. PLoS One. 2017;12(2):e0172612. Figure 2. PMCID: PMC5328280. License: CC BY.
Before treatment (A) and sunset glow fundus after 12 months (B), EDI-OCT showing posterior pole serous retinal detachment and marked choroidal thickening (C), and improvement in choroidal thickness one week after starting steroids (D). These correspond to the temporal changes of acute SRD and choroidal thickening and late sunset glow fundus discussed in the section “2. Main Symptoms and Clinical Findings.”
Acute Stage (Ocular Onset)
Acute vision loss: Bilateral serous retinal detachment (57.6% of acute VKH)2)
Mild anterior chamber inflammation and vitreous haze, optic disc hyperemia and swelling (about 70%)
Choroidal folds: In severe cases, choroidal detachment and shallow anterior chamber
Chronic Stage (Recurrent Stage)
Granulomatous inflammation of the anterior segment is predominant
Mutton-fat KP, Koeppe/Busacca nodules, posterior synechiae
Sunset glow fundus appears in 33.3% of chronic VKH2)
Late (convalescent) stage
Sunset glow fundus: loss of choroidal melanin pigment
Sugiura sign: depigmentation of the limbus (about 1 month after onset)
Skin manifestations (about 20%): vitiligo, alopecia, poliosis (after several months)
Macular pigment accumulation, scattered chorioretinal depigmented spots
Subjective symptoms
Section titled “Subjective symptoms”In the prodromal stage, scalp paresthesia, headache, and tinnitus appear, followed 1–2 weeks later by acute bilateral or sequential vision loss and blurred vision. On OCT, septal structures are characteristically observed within the retinal detachment in the acute phase.
Extraocular manifestations
Section titled “Extraocular manifestations”Meningeal irritation (headache, nuchal rigidity) occurs in most cases early in the disease. Sensorineural hearing loss (often subclinical but detected on testing). Skin manifestations (vitiligo, alopecia, poliosis) appear several months after onset and are seen in about 20% of patients.
Q
What symptoms occur during recurrence of VKH disease?
A
During recurrence, serous retinal detachment of the posterior segment, as seen in the initial episode, is less common, and granulomatous inflammation of the anterior segment predominates. Mutton-fat keratic precipitates (KP), Koeppe nodules, and Busacca nodules are observed, often leading to posterior synechiae. Prodromal symptoms may include ocular redness and blurred vision.
3. Causes and risk factors
Section titled “3. Causes and risk factors”The core of the pathology is a CD4-positive T-cell autoimmune response against melanin proteins (tyrosinase family: tyrosinase, TRP-1, TRP-2, gp100) 3). The target organs are melanocytes in the uvea (choroid), central nervous system (meninges), inner ear, and skin, with granulomatous inflammation of the choroid being the initial main lesion.
A strong association with HLA-DR4 (especially DRB10405) is known as a genetic predisposition 3). Linkage disequilibrium with HLA-DPB10501 has also been reported 3). There is a hypothesis that viral infections (EBV, CMV) trigger autoimmunity through molecular mimicry.
Main risk factors:
- Pigmented races (Asians, Hispanics, Native Americans)
- HLA-DR4 (DRB1*0405) positive
- 20s to 50s
4. Diagnosis and Examination Methods
Section titled “4. Diagnosis and Examination Methods”International VKH Committee Diagnostic Criteria (2001 Revision) 4)
Section titled “International VKH Committee Diagnostic Criteria (2001 Revision) 4)”| Type | Criteria |
|---|---|
| Complete VKH disease | Ocular findings + neurological/auditory findings + skin findings, all present |
| Incomplete VKH disease | Ocular findings present, lacking either neurological/auditory findings or skin findings |
| Probable VKH disease | Ocular findings only (isolated uveitis) |
In the early stage of onset, skin findings are not observed, so most cases are incomplete type. Later, when skin findings appear, it becomes complete type. Bilateral serous retinal detachment in the early stage is characteristic, and diagnosis is easy if there are prodromal symptoms such as headache or extraocular symptoms such as tinnitus 1). In atypical cases (optic disc edema type, unilateral cases), cerebrospinal fluid examination is decisive for diagnosis.
Examinations
Section titled “Examinations”Cerebrospinal fluid examination: Lymphocyte-predominant pleocytosis. Persists for up to 8 weeks. Most useful for confirming diagnosis.
Fluorescein angiography (FA): Early phase shows patchy hypofluorescence due to delayed choroidal filling → mid-phase shows granular hyperfluorescence (pinpoint leakage) → late phase shows dye pooling in the area of serous retinal detachment. Optic disc hyperfluorescence (approximately 70%) 1).
ICG angiography: Early phase shows patchy delayed choroidal filling and dye leakage from choroidal vessels; mid to late phase shows scattered hypofluorescent spots. Blurring of medium and large vessels due to choroidal circulatory disturbance is also characteristic.
OCT: Detection and monitoring of serous retinal detachment. Marked choroidal thickening in the early stage. EDI-OCT allows detailed observation of the choroidal cross-section. Fibrin-like membranous structures or septa may be observed within the serous retinal detachment 1).
Ultrasound B-mode: Findings of choroidal thickening. Useful for differentiation from posterior scleritis 1).
HLA class II: HLA-DR4 (adjunctive test). Positive rate 80%, but specificity is low (25% positive in normal individuals).
ERG (electroretinogram): In the chronic phase, amplitudes of photopic and scotopic responses decrease 3).
Differential Diagnosis
Section titled “Differential Diagnosis”| Differential Disease | Differentiating Points |
|---|---|
| Posterior scleritis | Unilateral, T-sign on ultrasound, pain on eye movement/tenderness |
| Multiple posterior pigment epitheliopathy (MPPE) | Unilateral, shifting bullous serous retinal detachment |
| Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) | FA reversal phenomenon (early hyperfluorescence → late hypofluorescence), young age, preceding infection |
| Central serous chorioretinopathy (CSCR) | Unilateral, male predominance, steroids as exacerbating factor3) |
| Sympathetic ophthalmia | Differentiated by history of penetrating ocular trauma or intraocular surgery. Pathologically considered the same disease1) |
| Idiopathic uveal effusion syndrome | Association with nanophthalmos, caution for angle closure |
Q
Is cerebrospinal fluid examination mandatory for the diagnosis of VKH disease?
A
It is not mandatory, but it can be decisive in atypical cases that are difficult to diagnose (optic disc edema type, unilateral cases). Since lymphocytic pleocytosis persists for up to 8 weeks, performing it at an appropriate time after onset improves diagnostic accuracy. In typical cases with obvious bilateral serous retinal detachment, diagnosis can often be made based on clinical findings alone.
5. Standard treatment
Section titled “5. Standard treatment”High-dose steroid tapering therapy (initial episode)
Section titled “High-dose steroid tapering therapy (initial episode)”Steroid pulse therapy followed by oral high-dose tapering is standard. If left untreated, many cases develop recurrence or persistence leading to severe visual impairment. Since current medicine has no indicator to distinguish cases that heal spontaneously from those that recur or persist, high-dose steroid administration is recommended when possible.
Guideline representative case prescription example1):
- Solu-Medrol® 1 g/day × 3 days (pulse IV)
- Switch to prednisolone 50 mg/day (oral) → taper after confirming improvement in ocular findings
- At 7 months after starting treatment, prednisolone 5 mg/day
Oral tapering schedule (Predonine tablets 5 mg):
| Dose | Duration |
|---|---|
| 200 mg/day | 2 days |
| 150 mg/day | 2 days |
| 100 mg/day | 2 days |
| 80 mg/day | 2 days |
| 60 mg/day | 4 days |
| 40 mg/day | 10 days |
| 30 mg/day | 2 weeks |
| 20 mg/day | 4 weeks |
| 15 mg/day | 4 weeks |
| 10 mg/day | 4 weeks |
| 5 mg/day | 4 weeks |
| 5 mg/day (every other day) | 4 weeks |
Tapering should be done slowly, and even without recurrence, discontinuation should take at least 6 months. Treatment lasting less than 6 months has a recurrence rate of 58.8%, while treatment lasting 6 months or more reduces it to 11.1% 5). If recurrence occurs, increase the steroid dose and taper more slowly than before. With steroid monotherapy, 44% relapse and 59% develop sunset glow fundus 2).
Treatment dose for pediatric patients: In children of a certain age and weight, either methylprednisolone 500 mg/day IV for 3 days (pulse therapy) or oral prednisolone starting at 0.5–1.0 mg/kg/day with gradual tapering is used. Taper while monitoring for side effects.
Immunosuppressive drugs (steroid-sparing and refractory cases)
Section titled “Immunosuppressive drugs (steroid-sparing and refractory cases)”Cyclosporine (Neoral®): 3 mg/kg/day (for 60 kg body weight: 180 mg/day in two divided doses). Regular trough level monitoring is required. Expected to reduce steroid dose. Used in refractory cases 1). Monitor for side effects such as increased susceptibility to infections, renal dysfunction, and hepatic dysfunction.
Methotrexate (MTX): 25 mg/week orally. Start at 15 mg/week for 2 weeks, then increase 2).
Mycophenolate mofetil (MMF): 1.5 g twice daily orally. Start at 500 mg twice daily and titrate up 2).
FAST trial (MTX vs MMF) 2)
Section titled “FAST trial (MTX vs MMF) 2)”The FAST trial (NCT01829295) is an RCT for non-infectious uveitis (subanalysis of 93 VKH cases out of 216). 49 patients were randomized to MTX and 44 to MMF, starting with prednisone 1 mg/kg/day (max 60 mg/day) and tapering (target ≤7.5 mg/day at 6 months).
6-month primary outcome (VKH subanalysis):
| Outcome | MTX group | MMF group | P value |
|---|---|---|---|
| Treatment success rate | 80.4% (37/46) | 64.1% (25/39) | 0.10 |
| Reduction in central foveal thickness | −62.5 μm | −4.0 μm | 0.003 |
| SRD resolution rate | 86.3% | 64.1% | 0.02 |
| Visual improvement | Equivalent | Equivalent | 0.78 |
Overall treatment success rate was 74.7% (62/85 cases). In acute VKH, MTX was superior in reducing CST and resolving SRD. At 12 months, 91.3% of the MMF group continued successful treatment, and about half (MTX 50.0%, MMF 56.5%) achieved complete prednisone withdrawal 2). Switching from MMF to MTX after initial treatment failure was successful in 81.8% of cases 2). With initial MMF combination, 93% of acute VKH patients maintained 20/20 vision, and all cases had no recurrence or sunset glow fundus formation 2).
Local treatment
Section titled “Local treatment”- Steroid eye drops: Rinderon® 0.1% 3 times daily
- Mydriatic agent: Mydrin® P once daily at night (to prevent posterior synechiae)
- Adjust according to the degree of inflammation for anterior chamber inflammation upon recurrence
For cases where systemic steroid administration is difficult (elderly, pregnant, diabetes, history of psychiatric disease), consider posterior sub-Tenon injection of triamcinolone acetonide 1).
Treatment of complications
Section titled “Treatment of complications”Complicated cataract: Steroid cataract occurs at a high rate due to heavy steroid use. In completely remitted cases, the risk is similar to normal surgery. IOL implantation is also not problematic. If filtration surgery may be needed later, choose superior conjunctival preservation and corneal incision.
Secondary glaucoma / steroid glaucoma: Use antihypertensive eye drops (beta-blockers, PG agents, carbonic anhydrase inhibitors) → oral CAI → intravenous D-mannitol in order. Perform trabeculotomy (effective for steroid glaucoma), and if insufficient, trabeculectomy.
Q
How long should steroid treatment for VKH disease be continued?
A
Even without recurrence, it is recommended to taper slowly over at least 6 months. Discontinuation within less than 6 months results in a high recurrence rate of about 58.8%, while continuation for 6 months or more reduces it to 11.1% 5). In case of recurrence, taper more slowly than the previous time and consider adding immunosuppressive drugs.
Q
Are there treatments other than steroids for VKH disease?
A
Cyclosporine (Neoral® 3 mg/kg/day) is used as a steroid-sparing agent in refractory cases 1). The FAST trial confirmed the efficacy of methotrexate (MTX 25 mg/week) and mycophenolate mofetil (MMF 1.5 g twice daily). In acute VKH, MTX showed a trend toward greater reduction in foveal retinal thickness and resolution of SRD 2).
6. Pathophysiology and Detailed Mechanisms
Section titled “6. Pathophysiology and Detailed Mechanisms”The central pathology is a CD4-positive T-cell autoimmune response against melanin proteins (tyrosinase, TRP-1, TRP-2, gp100) 3). Targets are melanocytes in the uvea (choroid), central nervous system (meninges), inner ear, and skin. Granulomatous inflammation of the choroid is the initial main lesion.
A strong genetic association with HLA-DR4 (especially DRB10405) is known 3), and linkage disequilibrium with HLA-DPB10501 has also been reported 3). About half of patients experience cold-like symptoms within two weeks before onset, suggesting that viral infections (EBV, CMV) may trigger autoimmunity through molecular mimicry.
Interpretation of imaging findings: ICG shows blurring of medium-to-large vessels and hypofluorescent spots due to choroidal circulatory disturbance. Marked early choroidal thickening on EDI-OCT reflects choroidal stromal edema. In the chronic phase, melanin loss leads to a sunset glow fundus 3).
Even with steroid pulse therapy, about 25% of cases have persistent inflammation, and gradual chorioretinal atrophy can lead to severe visual impairment in some patients. Mild subjective symptoms such as metamorphopsia and color vision abnormalities often remain.
7. Latest Research and Future Perspectives
Section titled “7. Latest Research and Future Perspectives”Clinical significance of the FAST trial 2): This is the first direct comparison RCT of MTX vs. MMF in non-infectious uveitis. The 93 VKH cases were the largest subgroup, demonstrating the efficacy of early immunosuppressant introduction in acute VKH. Further follow-up studies are expected.
Importance of early immunosuppressant introduction 2): With steroid monotherapy, 44% relapse and 59% develop sunset glow fundus. Early combination of steroids with antimetabolites may reduce relapse rates and sunset glow fundus incidence. The concept of a “therapeutic window”—starting steroids early in the disease to prevent progression to chronic recurrent phase and reduce the need for long-term immunosuppression—is gaining acceptance.
Evolution of imaging diagnostics3): Quantitative assessment of choroidal thickening using EDI-OCT and detection of occult choroiditis using ICG are utilized for treatment monitoring. Quantitative measurement of hyperreflective choroidal foci (HCF) using en face OCT may become a biomarker for VKH activity evaluation.
Trends in revised diagnostic criteria2): Classification into early/late stages incorporating OCT, FA, and ICG has been proposed, and improvement in diagnostic accuracy is expected. It has been pointed out that the current 2001 revised criteria have limitations in detecting early VKH.
8. References
Section titled “8. References”- 日本眼炎症学会ぶどう膜炎診療ガイドライン作成委員会. ぶどう膜炎診療ガイドライン. 日眼会誌. 2019;123(6):635-696.
- Acharya NR, Rathinam SR, Thundikandy R, et al. Outcomes in patients with Vogt-Koyanagi-Harada disease from the First-line Antimetabolites as Steroid-sparing Treatment Uveitis Trial. Am J Ophthalmol. 2024;267:187-197.
- Tayal A, Daigavane S, Gupta N. Vogt-Koyanagi-Harada disease: a narrative review. Cureus. 2024;16(4):e58867.
- 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.
- Lai TYY, Chan RPM, Chan CKM, Lam DSC. Effects of the duration of initial oral corticosteroid treatment on the recurrence of Vogt-Koyanagi-Harada disease. Eye. 2009;23:543-548.
- Rathinam SR, Gonzales JA, Thundikandy R, et al. Effect of corticosteroid-sparing treatment with mycophenolate mofetil vs methotrexate on inflammation in patients with uveitis: the FAST randomized clinical trial. JAMA. 2019;322(10):936-945.
- Abu El-Asrar AM, Dosari M, Hemachandran S, et al. Mycophenolate mofetil combined with systemic corticosteroids prevents progression to chronic recurrent inflammation and development of ‘sunset glow fundus’ in initial-onset acute uveitis associated with Vogt-Koyanagi-Harada disease. Acta Ophthalmol. 2017;95(1):85-90.
- Herbort CP Jr, Abu El-Asrar AM, Takeuchi M, et al. Catching the therapeutic window of opportunity in early initial-onset Vogt-Koyanagi-Harada uveitis can cure the disease using mycophenolate mofetil as a first-line steroid-sparing agent. Int Ophthalmol. 2020;40(12):2423-2433.
- Sakata VM, da Silva FT, Hirata CE, et al. High rate of clinical recurrence in patients with Vogt-Koyanagi-Harada disease treated with early high-dose corticosteroids. Graefes Arch Clin Exp Ophthalmol. 2015;253(5):785-790.
- Lavezzo MM, Sakata VM, Morita C, et al. Vogt-Koyanagi-Harada disease: review of a rare autoimmune disease targeting antigens of melanocytes. Orphanet J Rare Dis. 2016;11:29.
- Shindo Y, Inoko H, Yamamoto T, Ohno S. HLA-DRB1 typing of Vogt-Koyanagi-Harada’s disease by PCR-RFLP and the strong association with DRB10405 and DRB10410. Br J Ophthalmol. 1994;78(3):223-226.
- Moorthy RS, Inomata H, Rao NA. Vogt-Koyanagi-Harada syndrome. Surv Ophthalmol. 1995;39(4):265-292.
- Choo CH, Jap A, Teoh SCB, Agrawal R. Common practice patterns in the management of Vogt-Koyanagi-Harada disease: an IUSG survey study. Front Ophthalmol. 2023;3:1217711.
- Herbort CP Jr, Miserocchi E, Schlaen A, et al. Precise and simplified diagnostic criteria and optimised management of Vogt-Koyanagi-Harada disease based on a new interpretation of the 2001 criteria and pathophysiology. Eye. 2022;36(1):29-43.
- Shen E, Rathinam SR, Babu M, et al. Outcomes of VKH disease in the first-line antimetabolites as steroid-sparing treatment (FAST) uveitis trial. Am J Ophthalmol. 2016;168:279-286.