Vogt-Koyanagi-Harada syndrome, or VKH, is a well-described, rare cause of bilateral granulomatous panuveitis, as well as a spectrum of other symptoms that may occur in other organs containing melanocytes.1 It can be challenging to diagnose, since it has a broad spectrum of symptoms that evolve over time and can mimic other diseases such as posterior scleritis, sarcoidosis and infectious causes.

Here, we’ll share diagnostic tips and treatment approaches—both current and in development—for this condition.

 

Background

Dating back to the early 1900s, the distinct work of three men contributed to the description of the condition: Alfred Vogt, a Swiss ophthalmologist, first discovered a case of bilateral granulomatous panuveitis associated with unique systemic symptoms, such as eyelash whitening (poliosis), hypopigmented skin changes (vitiligo), and hearing loss.2 Simultaneously, on the other side of the world in Japan, Yoshigo Koyanagi and Eishouno Harada connected a link to the disease’s posterior segment involvement, neurologic manifestations, such as headache and meningitis, and renal complications.3-5

VKH is thought to be a T-cell driven autoimmune response against melanocytes, the pigment-producing cells in the body.6 This leads to a complex multisystem inflammatory reaction. While the exact pathogenesis isn’t fully understood, the disease targets specific antigens associated with melanocytes, melanin and the retinal pigment epithelium.6

In the past decade, there have been significant strides in research to learn more about VKH’s stages of disease and to develop advanced immunomodulatory therapies (IMT) to help manage this challenging disease.6

 

Epidemiology and Demographic Risk Factors

Genetic research has shown certain HLA subtypes, including HLA-DRB4, HLA-DRB104*05, and HLA-DRB-04*01, to be associated with increased susceptibility to VKH syndrome.7 While VKH syndrome is rare, there appears to be differences in genetic susceptibility based on HLA markers and ethnic populations. There’ss relatively higher prevalence of this condition seen in pigmented populations, such as East Asians, South Asians, Latin Americans, Middle Easterners and Native Americans with these genetic markers.8-9 VKH accounts for approximately 1.2 percent of panuveitis cases in India and as high as 15.9 percent of panuveitis cases in select regions of China.8-9 In fact, VKH is the most common diagnosis among patients with intraocular inflammation in Japan, representing 7 to 11 percent of new uveitic cases.10-12 Conversely, in the United States, VKH is extremely rare with an estimated annual incidence of 1.5 to six new cases per 1 million patients.6

Furthermore, the disease manifestation varies on a spectrum with marked differences among different ethnic and racial populations. In Japanese individuals, VKH commonly presents more aggressively,10-12 while in Caucasian individuals it typically presents with less sight-threatening and serious systemic complications.6

VKH tends to affect females more frequently than males, with 60 to 70 percent of patients being female.6 Onset is typically between age 20 to 50, though peak age of onset tends to vary with geographic distribution. For example, the onset peak in Asian populations is earlier, around 30 years.

 

Clinical Presentation

Here are the clinical clues to look for:

• Ophthalmic findings. Classically, there are four sequential stages of VKH: prodromal; acute uveitic; convalescent; and chronic recurrent. Each stage has a distinctive presentation that requires different management. A non-necrotizing granulomatous process mediates the prodromal and acute uveitic phases, while a non-granulomatous inflammatory process drives the convalescent and chronic phases.6

• Prodromal stage. Symptoms generally begin with early central nervous system involvement, which may resemble a viral or flu-like presentation with generalized symptoms of blurred vision, photosensitivity, headache, fever, nausea and myalgias. At this stage, the ophthalmic exam is often within normal limits, but may show early signs of conjunctival hyperemia and ocular pain. Physical exam may show signs of meningeal irritation with neck stiffness, cranial nerve palsies with focal neurologic deficits, and sensorineural hearing loss.6

• Acute uveitic stage. This is the active phase of disease. Patients present with acute-onset bilateral granulomatous panuveitis, which can last weeks-to-months. The patient may begin to notice blurred vision, pain, photosensitivity, eye redness, visual distortion or even a central scotoma.13 During this acute inflammatory period, the patient may have early dermatologic signs such as vitiligo, and auditory symptoms such as tinnitus and sensorineural hearing loss. Classically, one eye is affected first followed by the second eye within a few weeks. The exam is notable for anterior chamber and vitreous inflammation, as well as posterior choroiditis with thickening of choroid, exudative retinal detachments and optic disc edema and/or hyperemia.13

• Convalescent stage. This stage may last several months-to-years, with the resolution of active intraocular inflammation and development of chorioretinal depigmentation, leading to a “sunset-glow fundus,” with nummular hypopigmented chorioretinal scars.6 Limbal depigmentation may be present (Sugiura’s sign). Other posterior findings include chronic retinal detachments and RPE clumping. In the convalescent stage, patients have improved visual acuity and resolution of pain and photosensitivity. If diagnosed and treated adequately, the patient will begin to have a juxtaposition of improvement in ocular and neurologic symptoms and worsening of skin and hair depigmentation.13

• Chronic recurrent stage. This stage has a variable duration and can last up to several years in some patients. In this stage, patients commonly experience episodic symptoms of pain and redness due to acute flare-ups of anterior uveitis. Recurrent posterior uveitis is rare, but may lead to worsening chorioretinal and optic atrophy. During this stage, patients are also at higher risk for choroidal neovascularization, glaucoma and cataracts, all of which may cause vision loss.13

 

Systemic Manifestations

Since VKH is a multisystem autoimmune disease directed toward melanocytes, it’s important to keep a few hallmark systemic findings in mind:

• Dermatologic:6,14

  • poliosis: whitening of hair, including eyelashes and eyebrows.
  • vitiligo: depigmented patches on the skin.
  • alopecia: hair loss, which can be patchy or diffuse.

• Neurologic: 6,14

  • meningeal irritation/aseptic meningitis: headache, neck stiffness and photophobia.
  • cranial nerve palsies
  • encephalopathy: altered mental status, seizures or focal neurological deficits.

• Auditory:15

  • permanent sensorineural hearing loss that’s often bilateral and can be sudden or progressive.
  • tinnitus
  • vertigo

• Renal:13, 16

  • IgA nephropathy: hematuria and proteinuria
  • renal failure: progressive renal sclerosis

• Cardiac:16

  • pericarditis and myocarditis: chest pain, shortness of breath, heart failure, if severe

• Musculoskeletal:17

  • arthralgia and myalgia, which can be diffuse, if severe

• Gastrointestinal:17

  • abdominal pain
  • diarrhea
  • ulcerative colitis.

 

Figure 1. Fundus photographs of new 
presentation of VKH panuveitis with bilateral optic nerve edema and exudative detachments throughout the macula. Photo: Shilpa Desai, MD.

Diagnostic Criteria and Classification

The diagnosis of VKH has been modified over the years due to its multisystem constellation of symptoms. The VKH International Workshop provides the most updated and revised diagnostic criteria and classification system of VKH. It divides the syndrome into three categories: complete VKH disease; incomplete VKH disease; and suspected VKH disease.18, 19

Complete VKH disease requires bilateral ocular involvement with diffuse choroiditis. It also requires hallmark ocular findings in the late stages, such as depigmentation (e.g., sunset-glow fundus or Sugiura’s sign) and nummular chorioretinal depigmented scars, in addition to neurologic and integumentary findings. Incomplete VKH disease includes bilateral ocular involvement with either neurologic or integumentary findings.

And lastly, suspected VKH disease includes only bilateral ocular involvement of uveitis, choroiditis, depigmentation and scarring, without systemic disease. All three categories require the exclusion of prior ocular trauma, surgery or other suspected ocular etiologies that may confound VKH diagnosis.18,19

It’s also worth noting that sometimes the distinction is made between Harada disease, which involves prominent ocular findings and symptoms of meningeal irritation, and true VKH syndrome with the above-mentioned constellation of associated systemic findings.1


Multimodal Imaging

Multimodal imaging is essential for diagnosis and monitoring of disease progression and response to therapy for patients with VKH.

• Fundus photography. Fundus photos provide documentation of disease progression as optic nerve edema and exudative retinal detachments (Figure 1) resolve and develop into optic and chorioretinal atrophy and a sunset-glow fundus.

• Fundus autofluorescence. FAF will demonstrate hyper-autofluorescence during active phases of inflammation in areas of chorioretinal inflammation and subretinal fluid collections. As inflammation improves and atrophy sets in, these areas become hypoautofluorescent.

• Optical coherence tomography. Like many diseases affecting the posterior segment, OCT has become an essential tool for the diagnosis and management of VKH. During the acute uveitic stage of VKH, OCT reveals a thickened choroid with multiple serous retinal detachments often with bacillary layer detachments (a split in the photoreceptor layer).20 These changes generally improve rapidly with steroid therapy. Depending on treatment, OCT findings may evolve to demonstrate choroidal atrophy and thinning later on with persistent disruption of the photoreceptor layer and IS/OS junction (Figure 2).21

Figure 2. OCT of patient from Figure 1 with bilateral VKH panuveitis. Top panel at initial presentation demonstrates nerve edema, exudative retinal detachments with bacillary detachment and a severely thickened choroid. Middle panel demonstrates excellent response after two weeks of oral prednisone with resolution of nerve edema and subretinal fluid and improvement in choroidal thickness and contour, with persistent RPE irregularities and hyperreflectivity. Bottom panel five years after presentation, now well-controlled on monthly adalimumab, with preserved retinal architecture and mild chorioretinal thinning. Photo: Shilpa Desai, MD.

• Fluorescein angiography. In the acute uveitic stage, FA may show disc hyperfluorescence, early hyperfluorescence spots at areas of RPE disruption (“starry sky appearance”), and pooling of the dye in areas of serous retinal detachments in the late phase. In the chronic, recurrent stage, the patient will have persistent areas of hypofluorescent dark spots from choroidal scarring and retinal atrophy. If inflammation recurs, FA may be helpful in repeating to show re-demonstration of disc hyperfluorescence.22

• Indocyanine green angiography. Since VKH is a choroiditis-driven process, ICG angiography is a very useful modality for monitoring disease activity. In fact, one study found that ICG is the most sensitive test for monitoring diffuse choroiditis and measuring subclinical recurrences following therapeutic initiation and adjustments in treatment.23 Key findings on indocyanine green angiography include hypofluorescent dark spots during the early and mid-phase stages of filling that are replaced with hyperfluorescent spots representing focal sites of acute choroidal inflammation during the late stage of filling in active acute uveitis (Figure 3).23

Figure 3. Ultra-widefield ICG angiography of a VKH patient. Left panel demonstrates diffuse hypofluorescent lesions at presentation representing choroidal infiltration, with dramatic improvement in the right panel after three months of oral prednisone therapy. 

Management with Steroids

VKH disease is a complex condition that often requires a multidisciplinary approach for management. Corticosteroids have long been, and still remain, the cornerstone of treatment during the active phases of disease and VKH classically responds rapidly and effectively to high-dose steroid therapy. Over the past two decades, there have been significant strides in the development of immunomodulatory therapies to treat the chronic stages of VKH and mitigate the long-term risks of corticosteroid use while maintaining good control over inflammation.

Early, aggressive initiation of topical and systemic corticosteroids is still recommended to treat VKH at time of presentation. Initiation with high-dose oral prednisone (1 mg/kg), sometimes with a three-day pulse of intravenous methylprednisolone, and a gradual taper over several months, has been most effective for improving visual acuity and controlling inflammation.24 While steroids are effective, they don’t provide a long-term solution for the chronicity of this disease. A recent study found that 71 percent of patients treated with steroid monotherapy achieved disease inactivity in two years; whereas, 81 percent of patients treated with IMT achieved disease inactivity with significantly higher visual acuity compared to those treated with steroids alone.25

Currently, the consensus is that earlier introduction of IMT is recommended for improved inflammatory control, better long-term visual acuity, and reduced long-term side effects of steroids.

There are many options that have been tried for patients with VKH over time, especially those that are refractory to treatment and more challenging to control. Next, we’ll focus on the two most common classes of IMT used for patients with VKH: antimetabolites and tumor necrosis factor alpha inhibitors, as well as new classes of drugs on the horizon for patients with panuveitis.

 

Antimetabolite Options

The current antimetabolite agents useful for VKH are the following:

• Methotrexate. MTX is a disease-modifying drug that inhibits the enzyme dihydrofolate reductase (DHFR), which is essential for DNA synthesis, and ultimately decreases production of immune cells that play a central role in autoimmune diseases and inflammation. The First-line Antimetabolites as Steroid-Sparing Treatment (FAST) Uveitis Clinical Trial studied MTX and mycophenolate mofetil’s (MMF, below) role in 216 patients with non-infectious uveitis, including a subgroup of VKH patients.26 While this study found that MTX was 2.5 times more likely to achieve inflammatory control than MMF in patients with VKH, the data wasn’t statistically significant. There’s limited research supporting MTX’s use for steroid-sparing treatment in VKH. While few case series have shown its benefits in achieving disease remission in nine pediatric VKH patients who were initially unresponsive to steroid therapy, larger studies are still needed.27,28

• Mycophenolate mofetil. MMF is converted to its active form, mycophenolic acid, and inhibits enzymes responsible for DNA and RNA production in immune cells. Studies have demonstrated that with the initiation of MMF, patients generally experience disease remission within two years, with one recent prospective study finding that 93 percent of VKH patients treated with MMF achieved 20/20 visual acuity and prevented progression to chronic recurrent granulomatous inflammation and the development of a sunset glow fundus.29 Once treated, MMF was stopped in 60 percent of patients without any signs of relapse. Other studies support similar findings of MMF’s benefits in VKH treatment.30,31

• Azathioprine. AZA is an immunosuppressive medication that is metabolized into an active form, 6-MP, which inhibits enzymes involved in purine metabolism and DNA synthesis. The data supporting azathioprine’s role in VKH control is currently sparse. One small study from 2007 divided patients with acute and chronic VKH into two groups of treatment: corticosteroids alone and corticosteroids in combination with AZA.33 The study’s investigation found that the addition of AZA did not produce a statistically significant difference in improved visual acuity or recurrence rate compared to patients who receive steroids alone.32

 

Tumor Necrosis Factor Inhibitors (TNFi)

TNFi is a class of medications used to treat inflammatory conditions by blocking the activity of tumor necrosis factor. TNF is a protein that plays a role in inflammation. The current options being investigated for VKH include:

• Infliximab. This is a chimeric monoclonal antibody that binds to TNF-alpha and blocks its inflammatory cascade. The role of infliximab as an IMT candidate in VKH therapy is still under investigation, though now used commonly in clinical practice. There are case reports demonstrating that infliximab can be particularly effective in patients that are resistant to corticosteroid treatment in refractive or advanced stages of VKH.33 Literature review of six adults VKH cases that were resistant to steroid therapy found that several injections (ranging between four to nine months) of infliximab resulted in disease remission, normal vision and improved OCT findings.32-35

• Adalimumab. This treatment is a monoclonal antibody that binds to and inhibits TNF-alpha. Because it’s fully humanized, as opposed to chimeric, it carries less of a risk of developing antibodies that may limit the drug’s effectiveness over time. VISUAL I and
VISUAL II were landmark clinical trials that helped adalimumab get FDA-approval for treatment of non-infectious, intermediate, posterior and panuveitis in 2016.36 These trials demonstrated that adalimumab reduces the risk of uveitic flares, improves acuity, and has an adequate safety profile.

More recent studies have also found adalimumab to be superior to other IMT drugs. One study found that adalimumab can be effectively added to improve disease control, for patients already on a combination of steroids and an antimetabolite, reducing the average steroid dose (4 mg from 20 mg) and number of patients requiring IMT (four from 11 patients) after six months.37 Furthermore, a recent, large study analyzed 70 VKH patients’ response to adalimumab over six months, after they had failed therapy with methotrexate, cyclosporine or azathioprine. Most of the patients (91.4 percent) did well on adalimumab treatment, and diagnostic data showed significant improvement in ICG-A scores and subfoveal choroidal thickness. In addition, in comparison to the side effects of other IMT such as tacrolimus, rituximab or cyclosporine, adalimumab is safer and better tolerated by patients.38

Currently, though antimetabolites may be initially tried in combination with steroids, many uveitis specialists prefer early intervention with TNFi for VKH patients because of their excellent safety profile and efficacy, as well as faster onset of action, in patients with severe, vision-threatening posterior inflammation.

 

New Drugs on the Horizon

Clinical trials over the past decade have examined other inflammatory pathways that may be beneficial for the management of patients with VKH and other forms of noninfectious uveitis. The IL-17/IL-23 pathway has been one such focus, with clinical trials for drugs like secukinumab (Cosentyx, Novartis) and ustekinumab (Stelara, Johnson and Johnson) showing mixed results in patients with uveitis.39 Furthermore, JAK inhibitors, such as tofacitinib (Xelganz, Pfizer) and baricitinib (Olumiant, Lily), are involved in the JAK-STAT cytokine signaling pathway. A recent multimodal analysis found that tofacitinib may be promising in refractory VKH-driven uveitis through reversing Th17 imbalance and downregulating cytokine signaling. Through single-cell RNA sequencing and mass cytometry, the researchers observed a notable decrease in inflammatory responses after in vitro treatment.40 Larger, in vivo studies are needed to further explore the safety and efficacy of these novel therapies for patients with noninfectious posterior and panuveitis.

 

Intraocular Steroids

Though VKH is a multisystem condition that generally requires systemic treatment, local intraocular and periocular steroid injections may be used adjuvantly in cases of severe inflammation requiring extended courses of oral steroids or in unilateral flares in those already on IMT. These options include intravitreal and sub Tenon’s triamcinolone injections, intravitreal dexamethasone and fluocinolone implants, and newer suprachoroidal triamcinolone injections.

In conclusion, VKH is a complex, multisystem autoimmune disorder affecting pigmented tissues of the body and causing severe bilateral panuveitis with choroiditis. The disease progresses through distinct stages, each with specific clinical and imaging features. Early and accurate diagnosis facilitated by advanced multimodal imaging techniques is crucial for effective management. The combination of initial high-dose systemic corticosteroids and early initiation of IMT within the first three to six months of disease onset has been shown to significantly improve visual outcomes and reduce the risk of chronic recurrent uveitis and permanent vision loss. Understanding the key features, indications, and side effects of IMT options is necessary for developing individualized treatment plans in VKH. Overall, a tailored approach combining systemic and local therapies, guided by early and precise diagnostic criteria, is essential for optimizing patient outcomes in VKH disease.

 

Dr. Shah is a PGY2 at Tufts Medical Center. 

Dr. Fell is a vitreoretinal surgical fellow at Ophthalmic Consultants of Boston. 
The authors have no financial interest in any of the material presented.

 
 

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