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Vogt-Koyanagi-Harada Syndrome
Introduction
Vogt-Koyanagi-Harada disease (VKH) is a central nervous system condition that specifically affects vision and hearing. Descriptions of this disease date back to the 12 century, but the disease is named after three 20 century physicians who described the collective manifestations of this disease. Alfred Vogt initially described bilateral iridocyclitis and eyebrow depigmentation in 1906, followed by Yoshizo Koyanagi’s 1926 description of bilateral serous detachments in association with cerebrospinal fluid (CSF) pleocytosis. Einosuke Harada identified the integumentary symptoms of the condition shortly thereafter. The disease presents with signs and symptoms of a loss of immune tolerance to melanocytes within the meninges, eyes, skin, hair, and ears.[1]
This relatively rare condition has a distinct phenotypic picture in both its early and late manifestations. Despite identifiable clinical findings, the pathophysiologic mechanisms behind VKH have been challenging to identify. Over the last few years, some of the genetic and immunologic facets of VKH have been elucidated due to recent technological advances. Ophthalmic complications from this condition are numerous, and early identification and treatment can reduce morbidity.[2][3]
VKH is primarily treated via medical therapy, but surgical options exist for complications of the disease, such as subretinal fibrosis, glaucoma, and cataracts. The prognosis is mainly dependent on what stage of the disease treatment is initiated but can range from quiescent with minimal symptoms to debilitating vision loss and pain.[4]
Etiology
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Etiology
The exact etiology of VKH is not firmly established, but current theories posit that patients develop T-cell mediated immunity against melanocytes following recovery from an inciting viral environmental factor.[5] Cytomegalovirus and Epstein Barr virus have been implicated in the disease process, but no definitive link has been identified. VKH is thought to be caused by the loss of tolerance of melanocytes, leading to a non-necrotizing granulomatous inflammation in the eye, the inner ear, the skin, and hair.[6]
Recent genetic studies have implicated the presence of human leukocyte antigen (HLA) cell surface markers HLA-DRB4, HLA-DRB1-04*05, and HLA-DRB-04*01, as well as non-HLA genes involving lymphocyte regulations in IL-12 production and IL17 production.[7][8] Downregulation of microRNA in the production of interleukins and changes in non-coding RNA may also play a role in this condition.[8][9]
Epidemiology
There are regional differences in the prevalence of VKH among patients presenting with uveitis – it is the most common cause of uveitis in India (prevalence 21.08%) and the second most common in Thailand. In the United States, VKH is a relatively rare cause of uveitis, representing only 3 to 4% of referrals to tertiary care centers.[10] Comparatively, roughly 800 new cases of VKH develop each year in Japan.[4][10] Hispanic and Native American predominance has been noted in North American cases of VKH. Still, countries in South America with significant native and Hispanic populations, like Colombia, have not shown a significant increase in the incidence of VKH compared with the United States.[11][12]
Genetic studies may explain the difference in prevalence, as the DRB1-04*01 allele is more prevalent in East Asian populations and that HLA-DRB4 and HLA-DRB1 alleles are more correlated to the presence of VKH disease in affected populations.[8] Twin studies showed monozygotic twins developed VKH simultaneously, and twin and sibling studies have further confirmed that there is a genetic component to VKH.[13][14][15]
Patients diagnosed with VKH are typically in the third or fourth decade of life (range: 3 years old to 78 years old).[16][17][18] Pediatric cases of VKH are often aggressive, long-standing, and challenging to treat and are more commonly associated with subretinal fibrosis.[19] Older patients, typically above the age of 65, have a higher propensity to develop optic disc hyperemia and choroidal detachments.[20] Women are more commonly affected than men, with ratios ranging from 3 to 2 to 2 to 1.[7]
Pathophysiology
As a response to an environmental factor, Th1 mediated inflammation develops against melanocytes. Tyrosinase peptide is a known target of T-cells, specifically in melanocytes expressing HLA DRB1-04*05.[21][22] Comparing the tyrosinase peptide and a cytomegalovirus peptide has shown that homology exists between the two proteins. Other studies have shown EBV DNA by PCR in CSF of patients with VKH.[21][23]
This inflammatory cascade leads to the formation of non-necrotizing granulomas in affected organs. In the eye, these are seen as sub-retinal pigment epithelial (RPE) aggregates named Dalen-Fuchs nodules, which may also be seen in other granulomatous processes, especially sympathetic ophthalmia.
Histopathology
Histopathology of Dalen-Fuchs nodules shows granulomas consisting of epithelioid histiocytes. Hematoxylin and eosin staining of enucleated specimens show B-cells and T-cells in choroid and loss of choroidal melanocytes.[24]
Recurrent episodes lead to an appearance known as a sunset-glow fundus, defined by progressive fundus depigmentation in the setting of optic disc pallor – a marker of poor visual outcome in these patients. In the late stage of VKH, peripheral fundus scars are seen histopathologically as chorioretinal atrophy and scarring; Dalen-Fuchs nodules are not common in this stage.[24][25][26]
History and Physical
There are four specific phases of VKH – prodromal, acute uveitic, chronic uveitic, and recurrent chronic phase.
The prodromal phase is often self-limited, lasts for hours to weeks, and has very subtle chorioretinal findings that are missed unless evaluated with ICG-angiography and correlated with cerebrospinal fluid analysis.[27][28] Patients presenting during the prodromal phase of the disease will describe dizziness, eye pain, photophobia, headache, meningeal signs, or fever. A detailed history will often reveal that patients have recovered from a relatively recent viral illness.[24]
The acute uveitic phase consists of blurry vision and photophobia secondary to chorioretinal inflammation. Edema secondary to inflammation in this stage can extend to the retina, the optic nerve, or the ciliary body leading to the development of exudative retinal detachments, papillitis, and acute anatomic angle closure, respectively.
The chronic phase of the disease develops subsequently. This phase represents the formation of extraocular physical manifestations, including hearing manifestations, skin depigmentation, and ciliary depigmentation - commonly noted at the eyebrows, eyelashes, and scalp. Hearing manifestations include tinnitus, dysacusis, and hearing loss.[27][28][29]
The recurrent chronic phase consists of symptoms of panuveitis, inflammation throughout the intraocular compartments, and subsequent vision-threatening signs such as sunset glow fundus, choroidal neovascular membranes, neovascularization of the iris, open- and closed-angle glaucoma, and subretinal fibrosis.
The VKH International Workshop has defined the three classifications of VKH disease: complete VKH disease, incomplete VKH disease, and suspected VKH disease. Complete disease indicates that both neurologic and dermatologic manifestations are present in addition to ocular disease findings. The incomplete disease presents with either dermatologic symptoms or neurologic manifestations of VKH. Suspected VKH disease presents with intraocular findings without evidence of dermatologic or neurologic manifestations. All classifications of VKH require the exclusion of other causes of intraocular findings, including a history of penetrating trauma, surgery, or infectious etiologies.
Evaluation
VKH is a clinical diagnosis that requires a constellation of symptoms that can be supported with further laboratory and imaging evaluation. Patients undergo a complete history, focusing on the possible number of earlier episodes, meningeal symptoms, a history of eye or orbital pain, and hearing issues. Physical and slit lamp exams can reveal evidence of prior episodes because poliosis or vitiligo indicates that the patient has progressed through the chronic uveitic phase of the disease.
Cerebrospinal fluid testing during the prodromal phase of VKH has shown pleocytosis, which can persist for several weeks after the resolution of symptoms.[27] There are no established serum tests for VKH. Still, one study of patients admitted for initiation of treatment with steroids in the acute uveitic phase of VKH found that the presence of elevated serum IgE was associated with increased vascular leakage and active inflammation.[30] Further studies need to be done to find other serologic markers for this condition.
Indocyanine green angiography (ICGA), and to a lesser extent fluorescein angiography (FA), is established as the most important test for assessing VKH. ICGA can be used for diagnostic purposes but is also highly valuable for monitoring disease processes and responses to treatment.[27][28][31] ICGA is useful here because it directly evaluates the choroid and the RPE, which are the two most affected locations in the early course of VKH. The wavelengths used in indocyanine green angiography penetrate effectively into the choroid with reduced interference by RPE compared to fluorescein angiography.[32] Studies of ICGA show a 90 to 100% sensitivity in diagnosing VKH.[27][31][33]
During the acute uveitic phase of VKH, ICGA shows focal areas of delayed choroidal perfusion, peripapillary hypercyanescence, late multifocal pinpoint leakage, and pooling in areas of serous retinal detachment.[27][28]
Optical coherence tomography (OCT) is a less invasive technique and has been utilized to study VKH and as a diagnostic tool. However, ICG angiography appears to be superior to OCT in the monitoring of chronic disease and changes.[28] OCT in VKH can show septated subretinal fluid and changes in choroidal volume and thickness. OCT is an important diagnostic modality for use in multi-modal imaging to establish the diagnosis of VKH.[34][35] Patients with recurrent VKH can show decreases in choroidal volume, as opposed to choroidal thickness, in patients even without other inflammatory signs on clinical slit-lamp examination.[36][37][38]
Newer technologies like OCT-angiography (OCTA) are being evaluated for their usefulness in diagnosing and managing VKH. OCTA reveals flow void in the choriocapillaris, indicating decreased perfusion, and have been shown to correlate with the pinpoint hypercyanescence noted on ICGA. Additionally, studies of OCTA after initiation of treatment have shown a reduction in the flow void. Further study is needed to establish the role of OCTA in the management of VKH.[39][40]
Treatment / Management
For many years, the treatment for VKH was intravenous pulse corticosteroid therapy. Studies indicated that the duration of therapy was linked to the risk of recurrence and further complications from repeat inflammatory episodes. Recurrence in older studies was relatively frequent and occurred within six months of treatment.[4] In recent studies, patients have had significantly improved outcomes with local therapy and immunomodulatory therapy (IMT).(B2)
Su-Tenon injection of triamcinolone is highly effective in leading to resolution without recurrence of ocular symptoms in up to 78% of patients, as exhibited in a study that followed patients for up to 3 years.[41] Fluocinolone intravitreal implant is associated with a significant decrease in recurrence rates of ocular inflammation in implanted eyes compared to nonimplanted eyes over three years.[42] Both studies showed an increase in the side effect profile expected with glucocorticoid therapy, including increased risks of posterior subcapsular cataracts requiring surgical removal and intraocular pressure (IOP) increases that had a higher risk of requiring surgery. Intraocular pressure spikes occurred in intravitreal implantation both immediately post-insertion and due to steroid response. Additionally, VKH is a systemic disease, and local treatment of ocular pathology does not modulate integumentary and auditory symptoms of the disease. Therefore, monotherapy sub-tenon injection of steroids is ideal, specifically for patients already on systemic Immunomodulatory therapy (IMT) or who have minimal systemic symptoms of their disease.[42][43](B2)
IMT has been utilized as an adjunct to steroids in patients with VKH. IMTs that have shown efficacy include alkylating agents, antimetabolites, and TNF-alpha inhibitors, among others.[44][45][46][47] No specific agent has shown superiority in all cases of VKH, but cyclosporine has shown improved efficacy in cases of chronic uveitic VKH. Methotrexate has shown good efficacy in studies combining methotrexate with fluocinolone intravitreal implants, while and infliximab shows promise in pediatric populations.[48][49](B3)
Adalimumab has most recently been studied in recalcitrant cases of patients with corticosteroid-related complications and challenging pediatric cases. It has been shown good efficacy in controlling systemic disease with evidence of complete control of inflammation for at least six months in small case studies.[50][51][52] Up to 88% of patients have been shown to achieve corticosteroid-sparing treatment of inflammation, including resolution of serous retinal detachments at baseline.[53][54](A1)
The role of surgery is limited to treating the complications of the disease, such as cataract extraction, surgical therapy to lower the IOP or the treatment of subsequent macular holes.[55][56](A1)
Differential Diagnosis
Sympathetic Ophthalmia
- Sympathetic ophthalmia is an autoimmune condition that is a direct response of penetrating trauma or surgery to the eye, exposing ocular molecules as antigenic material leading to the immune system developing an inflammatory response to the uvea. This condition also leads to bilateral non-necrotizing granulomatous uveitis.[57]
VKH-like Medication Toxicity (checkpoint inhibitors)
- Checkpoint inhibitors have been shown to cause “VKH-like” medication toxicity that resolves with discontinuation of the inciting medications.[58][59][60]
Choroidal Melanoma
- Patients with choroidal melanoma may develop serous retinal detachments, and non-pigmented melanomas may appear as subretinal pigmentary loss similar to VKH.[57][61]
Infectious Posterior Uveitis
- Syphilis, tuberculosis, and endogenous endophthalmitis can present with subretinal nodules, intraocular inflammation, and serous retinal detachment.[62][63] It is important to rule out infectious etiologies before starting immunosuppressive therapy.
Alport and Cogan Syndromes
- Both Alport syndrome and Cogan syndrome can exhibit bilateral hearing deficits and retinal manifestations. Alport syndrome shows choroidal thickening but is characterized by significant inner retinal changes. Cogan syndrome is characterized by retinal vasculitis rather than subretinal changes.[64][65]
Sarcoidosis
- Sarcoidosis is a distinct cause of posterior uveitis and can have multiple presentations. Periphlebitis and “candle-wax drippings” on fluorescein angiogram can help differentiate sarcoidosis from VKH.[66]
Systemic Lupus Erythematosus Chorioretinopathy
- Serous retinal detachments may be seen in lupus choroidopathy, but patients with lupus choroidopathy do not typically show choroidal thickening and often have significant systemic manifestations of their disease.[67]
Pertinent Studies and Ongoing Trials
There is significant interest in preparing disease-specific drugs and therapy that can reduce medication toxicity and undesirable side effects. microRNA research has presented a possible disease-specific mechanism and is currently undergoing research for clinical use in VKH.[9] IFN-gamma and IL-6 have been identified as targets for future therapy.[68]
Prognosis
VKH may have a relatively positive prognosis if treated early and effectively. There is a cumulative worsening of prognosis with recurrent bouts of disease.[69] Poor prognostic indicators include the age of patients at disease onset and the number of recurrent episodes. Sunset glow fundus, a marker of the most severe stage of VKH disease and indicative of poor visual function, has been shown to occur even with control of the obvious clinical findings of the earlier stages of the disease.[69]
Comparative studies show that treatment with both corticosteroid and supplementary IMT is necessary, decreasing the rate of sunset glow fundus from 60% in patients with VKH disease to 16%.[20] Furthermore, rates of subretinal fibrosis development, an untreatable complication that can lead to permanent vision loss, were reduced in acute early patients treated with combination steroid and IMT at presentation from 34% to 16%.[2][70]
Complications
VKH is a systemic disease, and complications of the disease include hearing loss, dysacusis, tinnitus, aural fullness, vitiligo, vertigo, and ophthalmic complications.[71][72] Sensorineural hearing loss (SNHL) is common in VKH, affecting up to 68% of patients, but most patients who develop SNHL with VKH will recover after appropriate therapy with corticosteroids.[73][74][75] Immunomodulatory therapy is effective, but some reports show no improvement in patients who received IMT following the inability to tolerate corticosteroids.[75][76][77] Hearing loss has been shown to reverse with IMT, but cochlear implants are still frequently needed.[75][78][79] Further, patients who cannot tolerate systemic corticosteroids have shown improvement in auditory symptoms with intratympanic corticosteroid injection. (22180111) Vertigo is less common in patients with VKH (17-19%) and can cause significant morbidity; this symptom responds well to steroid therapy.[72][75][80]
The most common integumentary symptoms of VKH are poliosis and vitiligo. Poliosis and vitiligo have been shown to slow and respond well to systemic treatment with corticosteroids and IMT. Further, topical treatment with calcineurin inhibitors and corticosteroids has shown reversal of depigmented areas of skin.[81]
In the acute uveitic phase of the disease, VKH can lead to ciliary body inflammation and edema with subsequent closure of the anterior segment angle leading to acute angle-closure glaucoma.[28][82] In these patients, IOP is elevated, with a median IOP of 32.9 (range 27-40), and treatment of the intraocular pressure with IOP-lowering therapy is usually ineffective. Case series of these patients show that cycloplegic agents and laser peripheral iridotomies do not improve the intraocular pressure during angle closure. To our knowledge, there is no study regarding the treatment of patients with VKH utilizing glaucoma drainage implants. Patients with ciliary body edema secondary to inflammation in VKH show transient IOP lowering using acetazolamide. Treatment of inflammation is likely the most important aspect of IOP management.[82][83]
Visually significant ophthalmic complications of chronic VKH include cataracts, glaucoma, neovascular glaucoma, macular holes, chronic retinal detachments, subretinal fibrosis, and choroidal neovascularization.[84][85][86][87] Cataracts occur in up to 45% of patients and result from intraocular inflammation and corticosteroid therapy, leading to posterior subcapsular cataracts. Once patients achieve inflammatory control for three months as recommended by the criteria set forward by van Gelder, patients generally do well with cataract surgery, with significant visual improvement in 99% of eyes.[88][89][90]
One study noted a desirable postoperative outcome with one month of inflammation control with IMT and corticosteroids. Notably, up to 10% of eyes can develop hyphema postoperatively, and ocular hypertension occurs in up to 13% of eyes postoperatively, but both conditions resolve spontaneously. Consistent with an intraocular inflammatory condition, up to 50% of patients with VKH develop posterior capsular opacification after phacoemulsification.[91][89]
Ocular hypertension and glaucomatous optic neuropathy are common in patients with VKH. Up to 33% of patients with VKH will develop ocular hypertension. Significant risks for the development of ocular hypertension include poor visual acuity at initial presentation, time from symptoms to treatment, and the number of recurrent episodes of disease. Glaucoma develops in 16 to 18% of patients, and the primary cause of glaucoma in these patients is open-angle and not steroid-induced, but a significant percent of VKH patients who develop glaucoma developed glaucomatous optic neuropathy from pupillary block secondary to posterior synechiae.[92]
Chronic serous retinal detachments leading to subretinal fibrosis are a significant cause of severe vision loss. Subretinal fibrosis occurs in 6% of eyes with VKH. Still, it has been shown to occur much earlier in Hispanic patients – roughly six months in Hispanic patients compared to 6 years in non-Hispanic patients. Subretinal fibrosis appears to be much more common in the Western Hemisphere, with rates as high as 6%, whereas studies in southern and eastern Asia have very few cases.[93][94][95][96]
Subretinal fibrosis is also a poor prognostic indicator, with numerous studies showing worsening even with combined corticosteroid and IMT therapy. However, one study showed favorable outcomes with combination mycophenolate mofetil and systemic corticosteroids.[84][85] Subretinal fibrosis can lead to macular detachments, which can severely compromise vision. These specific macular detachments can be treated surgically with pars plana vitrectomy and vitreous tamponade.[97]
Choroidal neovascular membranes have been shown to occur in 14 to 17% of patients with VKH and are responsive to anti-VEGF therapy.[98][99]
Consultations
It is paramount that patients with VKH receive appropriate referrals to manage integumentary and auditory manifestations of the disease. Audiology, otorhinolaryngology, and dermatology referrals should be promptly initiated further to monitor the course of the patient’s disease.
Deterrence and Patient Education
It is important to reinforce to patients that Vogt-Koyanagi-Harada disease is a systemic disease and one that can relapse and recur. Untreated recurrent episodes of the disease lead to progressively worse outcomes, and patients often require lifelong immunosuppressive therapy. Patients should be educated on the various manifestations of the disease to recognize when their condition is relapsing.
Pearls and Other Issues
Although rare, VKH must be considered in cases of eye pain and associated headache and/or meningeal signs.
The therapy goals are not only to reduce clinically apparent disease but also to decrease the progression of the complications of VKH disease through proper identification and early treatment.
Corticosteroids have an established role in treating VKH, but data show increased recurrence and complications when used as monotherapy and without IMT.
Enhancing Healthcare Team Outcomes
VKH, when caught early, can be effectively managed and treated by the appropriate specialties as part of a care team that includes primary care physicians, emergency room physicians, and specialists in low vision, otorhinolaryngology, ophthalmology, and audiology.
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