Are You Confident of the Diagnosis?
What you should be alert for in the history
Vogt-Koyanagi-Harada syndrome (VKHS) is a rare disease that results from an autoimmune destruction of melanocytes in multiple organ systems. While vitiligo results in depigmentation of the epidermis and sometimes the hair, VKHS can also involve the eye, inner ear, and meninges. The syndrome is composed of a complex of signs and symptoms, which manifest over several phases.
The first, or prodromal phase, is characterized by acute symptoms, including malaise, fever, headache, nausea, dysacousia (ear pain from normal sounds), and vertigo. These signs last a few days and subsequently resolve.
The second is the uveitic phase, which may last several weeks. It is characterized by non-traumatic inflammation of one or both eyes, including bilateral uveitis (posterior or anterior), choroiditis or optic neuritis. The patient will often complain of visual loss, blurring, photophobia or ocular pain.
During the third, or convalescent phase, symmetric depigmentation occurs in the eye choroid, skin, and hair, lasting several months. Alopecia may occur, which is usually patchy and may represent alopecia areata.
About two thirds of patients experience the fourth, chronic recurrent phase, when there is low-grade eye involvement, potentially with continued depigmentation of the skin and hair.
Characteristic findings on physical examination
On physical examination, extensive and rapid depigmentation of the skin with prominent poliosis are suggestive of the syndrome; although poliosis within depigmenting skin can occur in vitiligo, in VKHS the loss of pigment tends to be more rapid, and poliosis affects the eyebrows, eyelashes, and scalp (Figure 1).
Expected results of diagnostic studies
Histopathologic appearance, like in vitiligo, may be devoid of an inflammatory infiltrate, since the offending T cells have typically vacated the skin prior to visible depigmentation. If an infiltrate is observed, the expected pattern would be a superficial perivascular mononuclear infiltrate with clusters at the dermal-epidermal junction and occasional single-cell infiltration of the basal layer of the epidermis. As in vitiligo, complete absence or significant reduction of melanocyte number in lesional skin is also key to the diagnosis.
Diagnosis is best supported by characteristic findings on ophthalmologic exam, including exudative retinal detachment in the acute phase (positive predictive value 100% and negative predictive value 88.4%), and sunset glow fundus in the chronic phase (positive predictive value 94.5% and negative predictive value 89.2%). Sunset glow fundus (resulting from depigmentation of the choroid) was found to be the most important feature of VKHS, distinguishing uveitis from non-VKHS causes.
Pleiocytosis in the cerebral spinal fluid (CSF) of affected patients is common, and pigment-laden macrophages are specific to VKHS, helping to distinguish from other causes of pleiocytosis in the CSF. Current diagnostic criteria are as follows (all 5 required):
1. No history of trauma to the eye
2. No evidence of other ocular disease
3. Bilateral ocular involvement with above findings
4. Neurological or auditory findings described above (may have resolved)
5. Skin findings that do NOT precede onset of CNS or auditory symptoms (alopecia, poliosis, or vitiligo)
Not all patients develop skin findings or CNS/auditory findings, which may be diagnosed as “Incomplete VKHS.” Isolated ocular disease is characterized as “Probable VKHS.”
Who is at Risk for Developing this Disease?
One key point is that patients do not progress from vitiligo or alopecia areata to VKHS. Ocular and neurologic signs always precede the skin findings (a requirement for diagnosis). Some studies have identified Asians, Hispanics, and Middle Easterners to be at highest risk for disease. Caucasians and those of African descent are at lower risk. Another study hypothesized that Caucasians with VKHS are underreported because depigmentation of the choroid, an important diagnostic criterion, is difficult to distinguish in races with lighter skin (and choroid) color. Women are at a higher risk than men, at a 2:1 ratio. One study reported that Hispanics develop fewer extraocular manifestations compared to other groups.
What is the Cause of the Disease?
The appearance of VKHS correlates with the presence of melanocyte-specific autoreactive CD8+ and CD4+ T cells in patient blood and CSF. Activated T cells are identified in histologic sections of affected skin and eyes of patients, and they’re found in close proximity to melanocytes. These T cells produce Th1-type cytokines, a profile consistent with other organ-specific autoimmune diseases, including vitiligo. Interestingly, ipilimumab, an FDA-approved human monoclonal antibody against CTLA-4, was recently reported to induce VKHS in a patient with metastatic melanoma. Notably the patient’s symptoms were associated with melanoma regression, suggesting that the breakdown of immune tolerance is involved in the disease pathogenesis. A separate study suggests a decreased number and function of T regulatory cells in patients with active VKHS.
Genetic studies implicate the HLA subtypes DR4, DRw53, and particularly DRB1*0405 as risk alleles, while DRB1*0401 appears to be protective against the disease.
All of these findings, in addition to the increased incidence of other autoimmune diseases in affected patients and the success of immunosuppressive therapies, support an autoimmune etiology of VKHS.
Systemic Implications and Complications
Although systemic symptoms affecting the inner ear and CNS in most cases are transient, untreated uveitis can result in blindness. Prompt referral to ophthalmology for both diagnostic confirmation and treatment is recommended.
The development of VKHS has been associated with the appearance of additional autoimmune conditions as well, including psoriasis, thyroiditis, type 1 diabetes mellitus, and as a component of autoimmune polyglandular syndrome type 1. Screening for additional autoimmune diseases is important, and serologic studies to identify additional autoimmune diseases can be considered.
Eye inflammation with the potential to cause permanent blindness usually demands early systemic immunosuppressive therapy. High-dose oral prednisone (1-2mg/kg/day) is first-line therapy, which should be maintained for up to 6 months before taper, as early tapering leads to recurrent symptoms. Prednisone can be tapered to alternate day dosing for maintained effect with reduced side effects.
Potential steroid-sparing agents reported in the literature include cyclosporine A, methotrexate, azathioprine, and mycophenolate mofetil. The biologics infliximab and adalimumab have also shown efficacy. Combination treatments are useful for refractory cases, and prednisone combined with mycophenolate mofetil was reported to have fewer complications than prednisone alone.
For vitiligo, the rapid development of depigmentation may be unresponsive to non-systemic therapies. Frequent follow-up for evaluation of the response to therapy is important.
TopicalAs in vitiligo, high-potency topical steroids and calcineurin inhibitors are options for initial treatment. Camouflaging cosmetics are also available and effective.
IntralesionalIn the author’s experience, intralesional triamcinolone (2.5-10mg/cc) may be effective for poliosis. Intraocular and intratympanic steroids have been used for ocular and hearing symptoms as well.
PhototherapyAs in vitiligo, narrow band UVB administered 2-3X weekly can be effective to halt disease progression and stimulate repigmentation. As seen in vitiligo, combining topical therapies with narrow band UVB may have increased efficacy over either therapy alone.
SystemicAs mentioned above, eye inflammation requires early immunosuppressive therapies.
Optimal Therapeutic Approach for this Disease
As outlined above, systemic immunosuppression is indicated for eye inflammation. Below are adjunctive options for skin and hair depigmentation.
The safety and efficacy of topical treatments for skin depigmentation usually make them first-line therapy for depigmentation in vitiligo. However, in VKHS, the typical widespread, rapid depigmentation will often preclude their use as adjunctive therapy except for selected locations of concern (i.e. the face). In addition, their benefit in addition to systemic immunosuppression is questionable. Topicals are an important option once systemic immunosuppression is weaned to a low-dose or discontinued entirely.
Cosmetic skin products to mask depigmentation or hair dyes for poliosis are options either alone or in combination with other therapies; however, hair dyes have been reported to exacerbate depigmentation in vitiligo. Intralesional triamcinolone can be considered if the patient is concerned about the appearance of poliosis.
The safety, broad coverage and superior efficacy demonstrated in vitiligo make phototherapy (narrow-band UVB) an excellent option for skin depigmentation both in combination with systemic therapy and as maintenance therapy.
Systemic steroid therapy should be initiated early, but tapered to a safe maintenance dose (low-dose or alternate day dosing), or transitioned to a steroid-sparing agent if long-term treatment is required. Depigmentation may respond dramatically to systemic therapy; however, this response may not be maintained after tapering the medication.
Frequent follow-up in VKHS is recommended for evaluation of the treatment response. Stabilization of disease should be considered an early goal, with repigmentation expected to take up to months to appear. As in vitiligo, if there is no treatment response after 6 months of consistent narrow band UVB therapy, treatment can be discontinued with close monitoring to assess for destabilization of disease (evident by renewed depigmentation).
Regular, consistent follow-up with an ophthalmologist is required for eye disease, and systemic therapy will be driven by the inflammatory course in the eye.
Patients should be followed frequently to evaluate depigmentation and assess treatment response, with appropriate therapeutic modification as indicated by disease progression. Scheduling follow-up visits every 4-6 weeks should be sufficient, with modification depending on disease severity.
A pertinent review of systems should be solicited to screen for other autoimmune diseases.
Unusual Clinical Scenarios to Consider in Patient Management
Refractory cases may require combination therapy, as discussed above. The use of biologic therapies is promising for long-term treatment that avoids chronic steroids.
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