Vogt-Koyanagi-Harada (VKH) syndrome is an autoimmune disorder againstmelanocytes causing inflammation of melanocyte-containing tissues, such asuvea, skin, ear, and meninges. Patients with VKH syndrome usually have bilateralgranulomatous panuveitis associated with poliosis, vitiligo, alopecia, dysacousia,and signs of meningeal irritation.
The exact pathogenesis of VKH syndrome is not certain. Sugiura1 reported that autoantibodies of VKH play a major rolein melanocyte destruction via antibody-dependent, cell-mediated cytotoxicity.Melanocyte-specific antigens, such as tyrosinase proteins, can induce a VKH-likeautoimmune condition in rats and have been considered to be VKH specific.2 Previous viral infection might trigger immune reactionsbecause of the homology in protein sequence between such microorganisms andocular antigens, a process known as molecular mimicry.3 Thestrong associations of HLA-DR53, HLA-DR4, and HLA-DQ4 antigens with VKH syndromefurther underscore an immunogenetic mechanism of the disease.4
Because of the variations in the clinical manifestation of VKH syndrome,early detection and accurate diagnosis have been challenging. Herein, we reporta case of VKH syndrome with bilateral conjunctival nodules, the rare initialsign of VKH syndrome. Likely differential diagnoses are also discussed.
A 27-year-old Ethiopian woman arrived for examination in February 2001complaining of bilateral eye pain and redness for 1 month. The patient hadchronic headache for several months, which did not respond to oral, nonsteroidal,anti-inflammatory drugs. No history of surgery or ocular trauma was reported.The patient had no history of tuberculosis or syphilis.
The best-corrected visual acuity was 20/25 OD and 20/20 OS. The intraocularpressures were normal. Slitlamp examination revealed moderate anterior chamberinflammation with 2+ to 3+ cells and flare, without keratic precipitates ineither eye. The conjunctiva was injected, and multiple small, elevated, andpigmented nodules were noted in the superior bulbar conjunctiva of both eyes(Figure 1). The initial fundus examinationshowed a normal fundus without vitritis.
Slitlamp photographs of the conjunctivalnodules. Multiple small pigmented nodules appear at the superior bulbar conjunctivaof both eyes. A, Right eye. B, Left eye.
Uveitic laboratory workups were performed. Results from the fluorescenttreponemal antibody absorption test result and the purified protein derivativeskin test were negative. Results from other laboratory tests, including completeblood count, serum chemistry, and urinalysis, were within normal limits. Testresults for serum angiotensin-converting enzyme, lysozyme, and antinuclearantibody showed normal values. HLA-B27 antigen was not detected. A chest x-rayfilm showed a normal image without pulmonary opacifications or nodules.
The patient was treated with a topical corticosteroid in both eyes for1 week. However, the anterior uveitis was more severe with an increased reactionof 3+ cells and flare in the anterior chamber. Her vision was markedly decreasedto 20/50 OD and 20/400 OS. The patient also suffered from persistent headache,severe back pain, neck stiffness, and dysacousia. Fundus examinations demonstratedserous retinal detachment and retinal pigment epithelial detachment at themacular area of both eyes (Figure 2).A fluorescein angiogram demonstrated multiple punctate areas of hyperfluorescencein the macular region in the transient phase. In the late phase of the angiogram,we found rather dramatic dye leakage into the area of the detached pigmentepithelium as well as the detached neurosensory retina in both eyes. The areasof hyperfluorescence corresponded nearly identically to the clinically observedareas of detachment.
Fundus photographs of serous retinaldetachment with macular involvement in both eyes. A, Right eye. B, Left eye.
Based on the presence of bilateral iridocyclitis, bilateral posterioruveitis with exudative retinal detachment, and neurological signs (headache,dysacousia, and neck stiffness), fulfilling the diagnostic criteria of VKHsyndrome established by the American Uveitis Society in 1978,5 adiagnosis of VKH syndrome was made. The patient was initially treated withtopical corticosteroids combined with 80 mg of oral prednisolone daily. Onemonth later, gradual resolution of the conjunctival nodules, anterior uveitis,and serous retinal detachment was noted. The dose of oral prednisolone wasthen slowly tapered during the next 2 months. Three months later, the conjunctivalnodules completely resolved in both eyes. Her final visual acuity improvedto 20/20 OU after 5 months of treatment. Remission was maintained for at least1 year after oral prednisolone treatment was discontinued. During follow-up,no cutaneous involvement, such as alopecia, poliosis, or vitiligo, was noted.
Inflammatory nodules are an important characteristic of granulomatousuveitis. For example, Koeppe and Busacca nodules of the iris in sarcoidosisor Dalen-Fuchs nodules of the retina in VKH syndrome can often be observed.However, a Dalen-Fuchs nodule is not pathognomonic for VKH syndrome; it canalso been found in other diseases with granulomatous inflammation, eg, sympatheticophthalmia, sarcoidosis, and tuberculosis. Typically, a Dalen-Fuchs noduleis a dome-shaped lesion consisting of epithelioid cells and lymphocytes withoverlying retinal pigment epithelium.6
Conjunctival nodules are a common feature of various forms of granulomatousuveitis, such as sarcoidosis. To the best of our knowledge, such nodules inVKH syndrome have never been reported. Since melanocytes of the conjunctivaand the uvea are known to have a common embryological origin in the neuralcrest, this may explain why antimelanocytic immunity can develop not onlyin the uvea but also in the conjunctiva in VKH syndrome. Although there isno direct pathological proof, a similar mechanism to that of Dalen-Fuchs nodulesmight be responsible for the development of conjunctival nodules. Autoimmunityagainst melanocytes within conjunctival epithelium causes the accumulationof inflammatory cells and the migration of melanocytes to form these pigmentednodules. The conjunctival nodules in our patient appeared primarily in thesuperior bulbar conjunctiva, while Dalen-Fuchs nodules are known to occurmostly in the inferior midperipheral retina. Such a geographic predilectionis of interest, and further evidence from conjunctival biopsy is necessaryto confirm the pathogenesis.
Vogt-Koyanagi-Harada syndrome can be categorized clinically into 4 phases:prodromal, acute uveitic, chronic convalescent, and recurrent. Posterior segmentinvolvement with serous retinal detachment in the acute uveitic phase is themost common initial ocular finding.7 Comparedwith Dalen-Fuchs nodules in the convalescent phase and iris nodules in therecurrent phase,7 the clinical course of conjunctivalnodules in our patient is in the early uveitic phase, even prior to the developmentof serous retinal detachment. Several reports suggest that complications inVKH syndrome are related to a longer duration of disease and more episodesof recurrence.8 Accurate diagnosis of VKH syndromeand prompt therapy with systemic steroids in the early stage might help decreasethe visual sequelae following posterior uveitis, such as subretinal neovascularizationor macular edema. The conjunctival nodules in VKH syndrome, similar to otherocular manifestations, would remit with systemic steroid treatment. Its completeregression in our case suggests that inflammation may play an important rolein the formation of nodules.
There is no specific diagnostic test for VKH syndrome; therefore, thediagnosis is based on a combination of clinical suspicion and exclusion ofother forms of uveitis. Sarcoidosis is a multisystem granulomatous diseaseof unknown etiology that commonly affects the lung, lymph nodes, skin, andeyes. In about 28% of patients with sarcoidosis, the eyes are involved.9 Among all ophthalmic sarcoid manifestations, conjunctivalgranulomas and uveitis are found most frequently at initial examination; theyaccount for 47% and 28%, respectively, of ocular manifestations.9 However,the appearance of conjunctival nodules in this patient was small and pigmentedon the bulbar conjunctiva, which is not a typical finding for sarcoidosis,with tan-yellow, millet seed–like nodules on the palpebral or bulbarconjunctiva. Results from tests for sarcoidosis, including a chest radiographand tests to measure levels of serum lysozyme, and angiotensin-convertingenzyme, were all normal. Other characteristic posterior segment findings ofsarcoidosis, such as chorioretinitis and periphlebitis with a candlewax-drippingsappearance, were not seen in our patient.
Another differential diagnosis is tuberculosis, which can be manifestedas both anterior and posterior uveitis or as conjunctival nodules and phlyctenules.However, the majority of ocular tuberculosis are unilateral, and cases ofocular involvement is only rarely noted in systemic tuberculosis. One studyreported only 28 cases of iritis among 10 535 patients with tuberculosis.10 The chest x-ray film and a purified protein derivativeskin test in this patient showed no evidence of tuberculosis.
Gout, known to deposit urate crystals in ocular tissues, can cause conjunctivalnodules, band keratopathy, and rarely anterior uveitis. However, depositionsin the conjunctiva, as well as in the cornea, have been described within interpalpebralareas. The location of urate deposition differs from our patient with conjunctivalnodules only in the superior bulbar conjunctiva.11
This article describes a patient with VKH syndrome with an initial manifestationof bilateral conjunctival nodules and anterior uveitis. The diagnosis wassupported by the fulfillment of the diagnostic criteria of VKH syndrome andthe exclusion of other possible diseases. To the best of our knowledge, thisarticle represents the first case of conjunctival nodules in VKH syndrome.We thereby stress the importance of clinical awareness of conjunctival nodulesas the initial sign of VKH syndrome.
Correspondence: Dr Huang, Department ofOphthalmology, University of Minnesota, 420 Delaware St SE, MMC493, Minneapolis,MN 55455-0501 (email@example.com).
Financial Disclosure: None.
Yang M, Huang AJW. Bilateral Conjunctival Nodules: An Unusual Manifestation of Vogt-Koyanagi-HaradaSyndrome. Arch Ophthalmol. 2004;122(12):1878-1881. doi:10.1001/archopht.122.12.1878