1 1© 2008 Universitair Ziekenhuis Gent 1 Vogt-Koyanagi-Harada Syndrome Prof. dr. Ph. Kestelyn

2 2© 2008 Universitair Ziekenhuis Gent Multisystem disease Chronic, bilateral, granulomatous panuveitis associated with central nervous system, auditory and integumentary manifestations VKH Disease Moorthy et al: Surv Ophthalmol 1995; 39:265 (review) Read et al: Am J Ophthalmol 2001;131:647

3 3© 2008 Universitair Ziekenhuis Gent VKH (Vogt-Koyanagi-Harada Syndrome) Systemic disorder  eyes/ears  meninges  skin

4 4© 2008 Universitair Ziekenhuis Gent VKH (Vogt-Koyanagi-Harada Syndrome) First description: 12 th century Mohammad-al-Ghafiqi Vogt: 1906 one case Koyanagi: 1923 six cases Harada: 1926 posterior uveitis and pleocytosis of CSF  Vogt-Koyanagi-Harada or VKH

5 5© 2008 Universitair Ziekenhuis Gent VKH (Vogt-Koyanagi-Harada Syndrome) Epidemiology more prevalent in darker skinned ethnic groups common  in Japan  in people from Mediterranean origin  in American Indians/Africans  in Indians 2 nd to 4 th decade approx. 15% < 16 in Turkey and Saudi Arabia more prevalent in darker skinned ethnic groups common  in Japan  in people from Mediterranean origin  in American Indians/Africans  in Indians 2 nd to 4 th decade approx. 15% < 16 in Turkey and Saudi Arabia

6 6© 2008 Universitair Ziekenhuis Gent 4 phases prodromal acute uveitic convalescent or chronic chronic recurrent VKH (Vogt-Koyanagi-Harada Syndrome) Clinical course

7 7© 2008 Universitair Ziekenhuis Gent VKH (Vogt-Koyanagi-Harada Syndrome) Systemic Findings Prodromal stage  headache, orbital pain  neck stiffness  neurologic symptoms  lumbar puncture: pleocytosis in 80% (lymphocytes ↑, monocytes ↑, normal glucose)

8 8© 2008 Universitair Ziekenhuis Gent VKH (Vogt-Koyanagi-Harada Syndrome) Auditory Findings concurrent with ocular findings hearing loss for higher frequencies dysacousia tinnitus objective signs > subjective symptoms  audiology

9 9© 2008 Universitair Ziekenhuis Gent VKH (Vogt-Koyanagi-Harada Syndrome) Skin lesions sensitivity to touch of hair and skin (active phase) vitiligo/poliosis (convalescent phase) alopecia seen in ¾ of patients

10 © 2008 Universitair Ziekenhuis Gent VKH (Vogt-Koyanagi-Harada Syndrome) Ocular Findings bilateral disease granulomatous panuveitis AS involvement  often nongranulomatous in acute phase  iris nodules and mutton fat KP’s in chronic or recurrent disease shallowing of the AC + IOP ↑  inflammatory swelling of ciliary body  pupillary block  surgical iridectomy mandatory  formation of AS  chronic glaucoma

11 © 2008 Universitair Ziekenhuis Gent VKH (Vogt-Koyanagi-Harada Syndrome) Ocular Findings perilimbal vitiligo (Sugiura’s sign) poliosis ( loss of lashes and regrowth of depigmented white lashes)

12 © 2008 Universitair Ziekenhuis Gent VKH (Vogt-Koyanagi-Harada Syndrome) Ocular Findings (posterior) Acute phase swelling of the optic nerve important vitreous reaction exsudative retinal detachment yellow-white retinal lesions in the periphery (Dalen-Fuchs nodules?)

13 © 2008 Universitair Ziekenhuis Gent Case report female, 22 years old Ethiopian (in Belgium since 20 months) bilateral loss VA (RE 1 month, LE 1 week), photophobia, orbital pain general history : unremarkable ocular history : unremarkable no medication

14 © 2008 Universitair Ziekenhuis Gent Ophthalmological examination VA:OD: CF 2m, no Parinaud 10 OS: CF 3m, no Parinaud 10 SLE:OD: flare, cells +(+), fine precipitates OS: flare, cells + IOP:OU: 14 mmHg

15 © 2008 Universitair Ziekenhuis Gent Fundoscopy:

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21 © 2008 Universitair Ziekenhuis Gent VKH (Vogt-Koyanagi-Harada Syndrome) Ocular Findings (posterior) convalescent or chronic phase neovascularisation of retina/optic nerve  recurrent vitreous hemorrhages often intraretinal NV of the macula reactive proliferation of the RPE: scars, RPE clumping

22 © 2008 Universitair Ziekenhuis Gent VKH (Vogt-Koyanagi-Harada Syndrome) Ocular Findings (late) “sunset glow” fundus = depigmentation of the posterior pole (RPE + choroid)

23 © 2008 Universitair Ziekenhuis Gent VKH (Vogt-Koyanagi-Harada Syndrome) Ocular Findings (late) Subretinal / fibrosis / RPE alterations / disciform scars

24 © 2008 Universitair Ziekenhuis Gent VKH (Vogt-Koyanagi-Harada Syndrome) Ocular Findings (late) subretinal/fibrosis/disciform scars/RPE alterations

25 © 2008 Universitair Ziekenhuis Gent VKH (Vogt-Koyanagi-Harada Syndrome) Natural history isolated posterior disease (Harada) isolated ocular forms (probable VKH) clinical course  severe ocular inflammation  depigmentation  quiescence  anterior + posterior inflammation  depigmentation  recurrent anterior disease  chronic ongoing inflammation

26 © 2008 Universitair Ziekenhuis Gent VKH Diagnosis clinical findings FA/ICG ultrasound lumbar puncture

27 © 2008 Universitair Ziekenhuis Gent VKH (Vogt-Koyanagi-Harada Syndrome) FA in VKH Acute phase: numerous punctate hyperfluorescent dots RPE level staining of subretinal fluid optic nerve leakage Convalescent phase: window defects, CNV, subretinal fibrosis

28 © 2008 Universitair Ziekenhuis Gent Fluo-angiography:

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32 © 2008 Universitair Ziekenhuis Gent VKH (Vogt-Koyanagi-Harada Syndrome) ICG findings in VKH early choroidal stromal vessel hyperfluorescence hypofluorescent dark dots fuzzy vessels (vasculitis) disc hyperfluorescence

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34 © 2008 Universitair Ziekenhuis Gent Ultrasound: thickening of the posterior choroid serous retinal detachment no T- sign

35 © 2008 Universitair Ziekenhuis Gent VKH (Vogt-Koyanagi-Harada Syndrome) Pathogenesis antigen driven immune response antigen = human melanocyte? T-cell mediated specific killing against P-36 melanoma cell line (Maezawa et al) sequence of tyrosinase family proteins induces proliferation of lymphocyte in VKH patients injection of tyrosinase + gp 100 injection in Lewis rats produces animal model of VKH(Sugita et al) identification of several T-cell lines against tyrosinase and tyrosinase related protein (Gocho et al)

36 © 2008 Universitair Ziekenhuis Gent VKH (Vogt-Koyanagi-Harada Syndrome) Pathogenesis certain racial groups. immunogenetic predisposition. strong association with HLA-DR4 and HLA-DRw53 with the most significant risk allele being HLA-DRB1*0405. causative pathogenic antigen binds with HLA-DRB1*0405 molecule which presents the antigen to T cells to activate them. Fang and Wang: Curr Eye Res 2008;33:517 (review). Read et al: Curr Opin Ophthalmol 2000;11:437 (review). Yamaki et al: Int Ophthalmol Clin 2002;42:13 (review).

37 © 2008 Universitair Ziekenhuis Gent VKH (Vogt-Koyanagi-Harada Syndrome) Pathology granulomatous panuveitis. lymphocytes, epitheloid cells, few plasma cells, multinucleated giant cells. epitheloid cells and giant cells contain melanin pigment.

38 © 2008 Universitair Ziekenhuis Gent VKH (Vogt-Koyanagi-Harada Syndrome) Treatment systemic corticosteroids  intravenous pulse therapy  oral treatment (2 mg/kg/day) no difference pulse ↔ high dose oral (Read et al) better little outcome high dose steroids > low dose (Miyanaga et al) duration ~ inflammatory activity slow taper over 1 year period topical treatment for anterior uveitis

39 © 2008 Universitair Ziekenhuis Gent VKH (Vogt-Koyanagi-Harada Syndrome) Treatment slow taper over 1 year period or ~ inflammatory activity consider adding cyclosporine to reduce side effects of high dose steroids mofetil mycofenolate ? adalimumab (Humira)?

40 © 2008 Universitair Ziekenhuis Gent VKH Prognosis visual prognosis is generally favorable. 87.5% achieved V.A. of ≥20/40. high-dose systemic corticosteroids for >9 months with slow tapering significantly improves the prognosis and decreases risk of recurrence. age older than 18 years is significantly associated with the development of complications. visual prognosis is generally favorable in children. Al-Kharashi, Abu El-Asrar: Int Ophthalmol 2007;27:201 Abu El-Asrar et al: Eye 2008;22:1124

41 © 2008 Universitair Ziekenhuis Gent Thank you !