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Show ORIGINAL CONTRIBUTION Vogt- Koyanagi- Harada Syndrome in a Case of Multiple Sclerosis Javier A. Montero, MD, M. Eugenia Sanchis, PhD, and Marta Fernandez- Munoz, MD Abstract: A 34- year- old woman in whom multiple sclerosis ( MS) had been diagnosed 2 years earlier developed progressive bilateral visual loss associated with peripapillary exudative retinal detachment and other features of Vogt- Koyanagi- Harada ( VKH) syndrome. She was treated with corticosteroid pulses and interferon ( 3- 1A with visual acuity improvement and resolution of the retinal detachment. This is the first reported case of VKH syndrome in a patient with MS. The combination of VKH syndrome and MS suggests a common autoimmune pathogenesis. { J Neuro- Ophthalmol 2007; 27: 36- 40) ultiple sclerosis ( MS) is a chronic inflammatory demyelinating disease of the central nervous system predominantly affecting young adults. The eyes may have retrobulbar optic neuritis ( ON) and papillitis ( 1- 4), intermediate uveitis ( 5- 8), or peripheral vasculitis ( 9,10). MS is associated with pars planitis or bilateral anterior granulomatous uveitis in more than 50% of affected individuals according to a large series reported by Smith et al ( 11). This study ( 11) also showed that 1.1% of uveitis in a general population was associated with MS. Patients with MS may develop granulomatous anterior uveitis with mutton fat keratic precipitates ( 12- 14). Posterior uveitis associated with MS, presenting as vitritis, choroiditis, retinitis and posterior pole retinal vascular sheathing ( 10,15), or panuveitis ( 16), has been reported sporadically. Uveomeningoencephalitis, commonly known as Vogt- Koyanagi- Harada ( VKH) syndrome, is characterized by chronic bilateral granulomatous inflammation involving the uvea, meninges, auditory system, and integumentary system ( 17). The ocular manifestations may appear with VISSUM, Institute Oftalmologico de Alicante, Retina Unit, Alicante, Spain ( JM); Hospital Pio del Rio Hortega, Retina Unit, Valladolid, Spain ( JM, MF- M); and Hospital Pio del Rio Hortega, Allergy and Clinical Immunology Unit, Valladolid, Spain ( MES). Address correspondence to Javier A. Montero, c/ o Garcia Morato 35, 9 Izda. 47006 Valladolid, Spain; E- mail: msm02va@ wanadoo. es headache and cerebrospinal fluid ( CSF) lymphocytic pleocytosis in up to 80% of patients. The combination of VKH syndrome and MS has not, however, been reported. We describe such a case and suggest that the two conditions may have a common pathogenesis. CASE REPORT A 34- year- old woman was referred from the neurology clinic with progressive bilateral visual loss for the past 3 weeks. She also described decreased hearing in FIG. 1. T2 axial MRI performed 11 months before the appearance of Vogt- Koyanagi- Harada ( VKH) syndrome shows multiple hyperintense lesions in the subcortical white matter and around the corpus callosum, consistent with multiple sclerosis. 36 J Neuro- Ophthalmol, Vol. 27, No. 1, 2007 Vogt- Koyanagi- Harada Syndrome J Neuro- Ophthalmol, Vol. 27, No. 1, 2007 FIG. 2. Fundus photography, fluorescein angiography ( FA), and optical coherence tomography ( OCT) performed at the time of presentation of Vogt- Koyanagi- Harada syndrome. A. Fundus photograph of the left eye shows retinal folds and serous retinal detachment affecting the nasal half of the macula. B- D. FA shows peripapillary pinpoint fluorescence in the middle and late phases with progressive fluid leakage extending to the macular area. The disc shows marked late hyperfluorescence. No signs of macular edema or vasculitis are seen. E. OCT composite made up of two horizontal scans crossing the optic disc and fovea shows peripapillary subretinal fluid affecting the nasal half of the macula. There is no macular edema. her left ear, neck stiffness, and headache during the same period. The patient had been diagnosed with MS 2 years earlier on the basis of bilateral lower limb weakness, ataxia, and optic neuritis in the right eye, as well as multiple hyperintense lesions on MRI ( Fig. 1). On our examination, visual acuity was 20/ 200 in the right eye and 20/ 160 in the left eye. Pupil constriction to bright light was reduced in both eyes, and there was a quiet anterior chamber and flat peripapillary serous retinal detachment affecting the nasal half of the macula in both eyes. The vitreous cavity was clear, and there was no retinal vascular sheathing. Optical coherence tomography ( OCT) revealed neurosensory retinal detachments surrounding the optic disc and reaching the macula in both eyes ( Fig. 2). Fluorescein angiography ( FA) showed a pinpoint pattern of fluorescence surrounding the optic disc with leakage filling the subretinal space in the detached area and marked optic disc hyperfluorescence. During the next 3 days, visual acuity decreased to 20/ 400 in both eyes as subretinal fluid leakage and retinal detachment progressed. Simultaneously, a mild painless anterior chamber reaction developed in both eyes with mutton fat keratic precipitates. A lumbar puncture revealed 63 mononuclear cells/ mm3. The patient was treated with 250 mg intravenous methylprednisolone three times daily for 4 days followed by 1 mg/ kg oral prednisone per day. Simultaneously, interferon ( IFN) ( 3- 1A was started sub-cutaneously three times per week ( Fig. 3). During the following 10 weeks, visual acuity slowly returned to 20/ 25 in the right eye and 20/ 15 in the left eye. The subretinal fluid disappeared, and peripapillary retinal pigment epithelial patchy atrophy was observed ( Fig. 4). 37 J Neuro- Ophthalmol, Vol. 27, No. 1, 2007 Montero et al FIG. 3. Fluorescein angiography ( FA) and optical coherence tomography ( OCT) of both eyes performed 2 weeks after corticosteroid therapy was started. Early ( A)- and late ( B)- phase FA still shows pinpoint fluorescence, subretinal fluid surrounding the optic discs, and marked disc hyperfluorescence. ( C) OCT demonstrates persistence of subretinal fluid. The patient developed diffuse alopecia. Oral prednisone was slowly tapered and discontinued. IFN ( 3- 1A was continued for the following 6 months. DISCUSSION Common to all forms of VKH syndrome are the requirements that patients have no prior history of ocular trauma or surgery, no evidence of other ocular disease on the basis of clinical or laboratory evidence, and bilateral ocular involvement. Complete forms of VKH syndrome are characterized by diffuse choroiditis with focal areas of subretinal fluid or choroidal thickening with fluorescein angiographic abnormalities, including focal areas of delayed choroidal perfusion, multifocal pinpoint leakage, areas of placoid hyperfluorescence, pooling of subretinal fluid, and optic nerve staining. Patients with complete VKH syndrome must also have evidence of neurologic and auditory abnormalities, including meningismus, tinnitus, or cerebrospinal fluid pleocytosis, as well as integumentary signs such as alopecia, poliosis, or vitiligo ( 16- 18). However, these integumentary signs should not occur before the onset of ocular or neurologic manifestations. We describe an unusual patient with a combination of VKH syndrome and MS who had complete anatomic and functional recovery after systemic corticosteroid and IFN ( 3- 1A therapy. Our patient presented a complete form of VKH syndrome according to the 1978 American Uveitis Society criteria ( 19) revised by the International Workshop on VKH syndrome in 1999 ( 17). To our knowledge, this is the first case of VKH syndrome in a patient with MS to be published. Intermediate uveitis and vasculitis of retinal vessels ( 5,6,20,21,22) are the typical forms of uveitis in patients with MS. Anterior uveitis may also appear, often in the form of chronic granulomatous inflammation resulting in extensive posterior synechia formation ( 13,14). However, our patient did not show the vascular sheathing or fluorescein leakage from posterior or peripheral retinal vessels often seen in patients with intermediate uveitis associated with MS. Posterior uveitis has been less frequently described in association with MS, mainly as posterior granulomatous uveitis ( 15), symptomatic vitritis, occlusive peripheral retinal vasculitis with ischemia and neovascularization, macular edema, and epiretinal membrane formation involving the macula ( 10,21). In contrast, complete VKH syndrome 38 © 2007 Lippincott Williams & Wilkins Vogt- Koyanagi- Harada Syndrome J Neuro- Ophthalmol, Vol. 27, No. 1, 2007 FIG. 4. Color ( A) and red- free ( B) fundus photography performed 12 weeks after treatment was started shows resolution of retinal exudation and folds. Patchy retinal pigment epithelial atrophy surrounds the optic discs. includes posterior uveitis with a clear vitreous, diffuse choroiditis, diffuse or focal areas of subretinal fluid, and multifocal areas of pinpoint fluorescein leakage. Late findings in VKH syndrome may include nummular chorioretinal scars and retinal pigment clumping and migration. Although the association of VKH syndrome and MS has not been described previously, reports suggest an association with autoimmunity in the pathogenesis of both conditions ( 17). MS is known to be a T helper type 1 cell ( Thl)- dominant condition ( 23), and up- regulation of Thl cytokines has been observed in patients with VKH syndrome ( 24). T helper cells from patients with VKH syndrome have been found to produce predominantly Thl cytokines, especially after stimulation in vitro ( 25). Miyazawa et al ( 26) found that concentrations of serum and CSF chemokines CXCL10/ IP- 10, CCL17/ TARC, and CCL2/ MCP- 1 were essentially the same in VKH syndrome as in MS. Our finding of VKH syndrome and MS together in one patient may draw MS closer to autoimmune diseases treated with corticosteroids and other immunosuppressive agents rather than with interferons. Currently, early and aggressive systemic corticosteroid therapy remains the standard initial treatment of VKH syndrome. In the most severe cases, intravenous methylprednisolone ( up to 1 g/ day) for several days can be used before beginning 1 mg/ kg oral prednisone per day ( 17). The duration of treatment and subsequent tapering must be individualized. Systemic therapy should not be discontinued during the 3 months after the onset of the disease because of the risk of recurrence. Systemic immunosuppressive treatment is necessary in those patients whose disease fails to respond to high- dose systemic corticosteroids or who develop intolerable adverse effects. Cyclospor-ine ( 27), tacrolimus ( 28), azathioprine ( 29), cyclophosphamide ( 29), and chlorambucil ( 30) have been used. IFN a was initially suggested to play a role in therapy of VKH syndrome ( 29). Yet, episodes of VKH syndrome have been reported recently in patients with hepatitis C ( 31,32) and myeloma ( 33) who had been treated with IFN a- 2b. On the other hand, a retrospective, nonrandomized study of MS patients with uveitis treated with IFN ( 3 has shown improvement in visual acuity with reductions in cystoid macular edema and vitreous and aqueous cell counts ( 34). In our patient, it is not clear whether the improvement was due to IFN or corticosteroid therapy. However, IFN therapy may have aided in the early tapering of systematic corticosteroid therapy. In summary, although the pathogenesis of VKH syndrome and MS is uncertain and antigen- specific treatment strategies have not yet been developed, recent reports increasingly suggest a common autoimmune nature for both conditions ( 17). REFERENCES Frederiksen JL, Olesen J, Larsson HB, et al. Acute unilateral papillitis versus retrobulbar neuritis: relation to multiple sclerosis. Mult Scler 1996; 1: 223- 7. Fisher JB, Jacobs DA, Markowitz CE, et al. Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis. 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