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Uveitis in Behcet disease and VKH syndrome
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•VKH Syndrome
•Behcet’s Disease
Dr.T.Krishnamoorthy,
MS resident,
AEH,Madurai
Vogt-Koyanagi-Harada Syndrome
Introduction
• Uncommon multisystem disease of Autoimmune etiology
• Chronic,bilateral,diffuse,granulamatous pan-uveitis
• Associated with Integumentary,Neurologic,Auditoryinvolvement
• Commonly affects darkly pigmented ethnic groups
• Uncommon among whites
• Rare among Sub-saharan africans
• Vogt-switzerland;Koyanagi & Harada-Japan
Incidence
• 4% in US
• 8% in Japan
• Most common cause of Non-Infectious uveitis in Brazil & SaudiArabia
• Women more commonly affected than Men Except in Japanese populations
• Most common in second to fouth decade of life
Aetio-pathogenesis
• Unknown
• Experimental evidence suggests Cell mediated autoimmune process against Melanocytes of all organ systems(genetically susceptible individuals)
• T helper-1 cells & upregulation of associated cytokines(IL-2,IL-6 &INF-gamma) also plays a role
• Recenty study suggests that IL-23(differentiation of IL-17 producing CD4 helper T lymphocytes) responsible for development & maintanence of autoimmune process
Contd...
• Sensitisation to melanocyte antigenic peptides by cutaneous injury/viral infections-possible trigger
• Tyrosinase/Tyrosinase related protiens(75 Kda protein & S-100 protein targets melaocytes
• Genetic predisposition :
• HLA-DR4 in Japanese population• HLA DRB1 *0405,HLA DRB1*0410 haplotypes-stongly
associated risk• 84% Hispanic patients from Southern California
found to have high relative risk with HLA-DR1 than HLA-DR4
Clinical features• Prodromal stage:
• Flu like symptomsHeadache,nausea,fever,meningismusdysacusia,tinnitus,orbital pain,photophobiaHypersensitivity of skin & hair
• Focal Neurological signs:Cranialneuropathies,Hemiparesis,Aphasia,Transverse myelitis & ganglionitis
• CSF Analysis:lymphocytic pleocytosis,Normal level of glucose>80% of patients(may persist up to 8 wks)
• Auditory problem:75% of patients coincide with ocular diseaseCentral dysacusia for higher frequenciestinnitus in 30% of patients in early course,improves with in 2-3 monthspersistent deafness may remain
• Acute Uveitic stage:
• Sequential blurring of vision in both eyes 1-2 days after the onset of CNS signs
• Granulamatous anterior uveitis• Variable degree of vitritis• Thickening of posterior choroid with elevation of peripapillary
retinal choroidal layer• Hyperemia & edema of optic disc• Multiple serous retinal detachments• Focal serous RD often shallow(clover leaf pattern) coalasce to
form large bullous exudative RD-profound visual loss• Less commonly,mutton fat KP’s,iris nodules at pupillary margin
are observed• AC may be shallow due to forward displacement of lens-iris
diaphragm(ciliary body edema & annular choroidal detachment)• IOP may be elevated or low secondary to ciliary body shut down
• Convalescent stage:
• Several weeks later
• Resolution of exudative RD
• Gradual depigmentation of choroid leads to classic orange-red discolouration(Sunset glow fundus)
• In addition,small,round discrete depigmented lesions –inferior peripheral fundus
• Juxta papillary depigmentation may also occur
• Perilimbal vitiligo(Sugiura sign)-85% of japanese patients,not in whites
• Integumentary changes:Vitiligo,poliosis,alopecia corresponds to fundus depigmentation occurs in 30% of patients
• Skin & hair changes usually occur weeks – months after onset of ocular inflamation but it may occur simultaneously
• 10-63% develops vitiligo on ethnic background
• Chronic recurrent stage:
• Repeated bouts of granulamatous anterior uveitis
• Development of KP’s,posterior synechiae,irisnodules,iris depigmentation,stromal atropy
• Posterior segment recurrences associated with vitritis,papillitis,multifocal choroiditis,exudative RD
• Anterior segment recurrence coincides with sub-clinical choroidal inflammation requires systemic therapy
• Sequelae of chronic inflammation leads to PSCC,glaucoma,CNV,sub retinal fibrosis
Histo-pathology
• Acute uveitic stage:
• Diffuse ,non-necrotising granulamatous inflammation
• consists of lymphocytes,macrophages admixed with epitheloid and multi-nucleated giant cells with involvement of chorio-capillaries
• Proteinaceous fluid exudates are observed in sub-retinal space between detached neuro-sensory retina and RPE
• Peripapillary choroid –most common site of granulamatousinflammation,ciliary body & iris may also affected
• Focal aggregates of epitheloid histiocytes admixed with RPE(Dalen Fuchs nodules) appear between Bruch’s membrane & RPE
• Convalescent stage:
• Non-granulamatous inflammation
• Infiltration of lymphocytes,few plasma cells,absenceof epitheloid histiocytes
• Number of choroidal melanocytes decrease with loss of melanin pigment(Sunset glow fundus)
• Appeareance of numerous small atrophic depigmentedlesion in peripheral retina corresponds to focal loss of RPE cells with chorio-retinal adhesion
• Chronic recurrent stage:
• Granulamatous choroiditis
• Damage to chorio-capillaries
• Clinically and pathologically similar to SO but there are different trigerring events & mode of sensitisation
Diagnosis
• usually clinical• Characterised by Exudative RD in acute stage,Sunset glow fundus in
chronic recurrent stage• CBC,Mantoux test,TPHA-To rule out infectious cause• FFA,ICG Angiography,OCT,USG,Lumbar puncture helps in
confirming diagnisis
• FFA:
• Acute uveitic stage:numerous hyperfluorescent foci at level of RPE in early stage followed by pooling of dye in sub-retinal space in areas of Neurosensory dtachment
• Majority shows disc leakage,CME & retinal vascular leakage are uncommon
• Convalescent & Chronic recurrent stage:• Focal RPE loss and atrophy produce multiple hyperfluorescent
window defects without progressive staining
• ICG Angiography:
• highlights choroidal pathology• Shows delay in choriocapillaries & choroidal vessel
perfusion• Early choroidal vessel stromal hyperfluorescence &
leakage• Disc hyperfluorescence• Multiple hypofluorescent spots throughout the
fundus indicates foci of lymphocytic infiltration• Hyperfluorescent pinpoint changes with in areas of
exudative RD• Hypofluorescent spots-sensitive marker and follow up
of sub clinical choroidal inflammation(when fundoscopic & FFA findings are unremarkable)
• USG:
• Helpful in diagnosis in presence of media opacity
• Shows diffuse,low to medium reflective thickening of posterior choroid ,most prominent in peripapillaryarea with extension to equatorial region
• Exudative RD
• Vitreous opacification
• Posterior thickening of sclera
• OCT:• helps in diagnosis & monitoring of
• Serous macular detachment
• CME
• CNVM
• Lumbar puncture:• Done in atypical cases who presented early with
neurological signs
• Shows lymphocytic pleocytosis
Differential diagnosis
• Sympathetic ophthalmia
• Bullous CSCR
• Uveal effusion syndrome
• Posterior scleritis
• Primary intra ocular lymphoma
• Uveal lymphoid infiltration
• APMPPE
• Sarcoidosis
• Syphilis
• Lyme disease
Teatment
• Corticosteroids:
• Topical-1%prednisolone acetate-tapering dose
• Oral-1mg/kg body weight-tapering dose
• Intavenous-pulse therapy (loading dose)
• Periocular(PST)-(20mg/0.5cc triamcinoloneacetonide)
Immunomodulator therapy(IMT)
• Methotrexate:15mg once a week plus
• Folic acid 5mg once daily for six days
• Liver toxicity
• Mycophenolate mofetil:500mg twice daily
• 1500mg max/day(1000+500mg)
• Azathioprine:50mg thrice/twice daily-renal toxicity
• Cyclosporine:2-3mg/kg body weight
• renal toxicity
• Cyclophosphamide:50mg thrice daily orally
• hematuria
• Inv:CBC,LFT,RFT,Blood sugar,blood pressure
Prognosis
• Good with prompt and agressive therapy
• In addition to cataract and glaucoma,subretinal fibrosis and choroidalneovascular membrances may occur
Behcet’S Disease
Introduction
• Chronic, relapsing, occlusive systemic vasculitis
• Etiology unknown
• Affects both anterior & posterior segment
• Adamantiades & Behcet
• Most common-Northern hemisphere in countries of eastern mediterranean & on eastern rim of Asia(old silk route)
Prevalance
• 80-300 cases per one lakh in Turkey
• 8-10 cases per one lakh in Japan
• 0.4 cases per one lakh in US
• Complete type of BD- Men
• Incomplete type of BD- equally affected
• Typical age of onset- 25-30 years of age
• Can occur in 10-15 years of age
• Mostly sporadic
• Familal cases are also reported
• Pathogenesis:• Unknown• Environmental factors-potential cause (not proved)• No infectious agents-reproduced from lesions• Clinically & experimentally unlike other autoimmune diseases
• HLA association:• HLA B12-Mucocutaneous lesions• HLA B27-arthritis• HLA B51-Ocular lesions• Not reproducible in all patients• Little diagnostic value
• Histology:• Early lesions-delayed type of hypersensitivity• Late lesions:immune-complex type reaction
Clinical types
• Neuro BD
• Ocular BD
• Intestinal BD
• Vascular BD
Systemic manifestations(Non-ocular)
• Aphthous Ulcer:
• Most frequent finding in BD
• Discrete,round or oval,white ulcerations with red rim(size 2 to 15 mm)
• Recurrent mucosal ulcers-discomfort & pain
• Lips,gums,palate,tongue,uvula,posterior pharynx)
• Recur every 5-10 days or every month
• Lasts from 7-10 days,heal without much scarring
• Skin lesions:• Erythema Nodosum:• painful,recurrent lesion
• noted over external surfaces-tibia & also over face,neck & buttock
• Disappear with minimal scarring
• Acne vulgaris:• Folliculitis like skin lesion
• Face & upper thorax• 40% patients exhibit cutaneous pathergy(development of
sterile pustule at the site of venipuncture or injection)• Not pathognomonic of BD
• Genital ulcers:• Appearance similar to aphthous ulcer• Male-scrotum/penis• Female-vulva/vaginal mucosa
• Systemic Vasculitis:• 25% patients with BD
• Any size artery/vein affected
• Causes arterial occulusion,aneurysm,venous occlusion,varices
• Cardiac : 17%• Granulamatous endocarditis
• Myocarditis
• Endomyocardial fibrosis
• Coronary arteritis
• Pericarditis
• Gastrointestinal lesions:• Multiple ulcers at oesophagus,stomach & intestine
• Pulmonary:• pulmonary arteritis with aneurysmal dilatation of pulmonary
artery
• Bone & joint:50%• Arthrits(knee)
• Neurological:10%
• Most serious of all• 10%patients with neuro BD have ocular disease• 30%patients with ocular BD have neurological
involvement• Affects motor system• Widespread vasculitis-headache• Stroke,palsies,acute confusional state-25%patient• Cranial nerve palsies,papillitis,visual field
defects,papilloedema (thrombosis of superior sagitalsinus/other venous sinuses)
• Mortality rate-10%• Men>women
Ocular manifestations
• 70% patients with BD• Men>women• 80% bilateral• Non granulamatous,panuveitis with necrotising obliterative vasculitis• Recurrent,relapsing condition cause permanent,irreversible ocular
damage• Severe vision loss-25% patients
• Anterior uveitis:
• Transient hypopyon:25%• shift with patient’s head position• disperse with head shaking• may not visible unless viewed by Gonioscopy• can resolve spontaneously without treatment• explosive onset(within hours)
• Posterior segment:
• Most common form of uveitis seen in children & adults with BD
• obliterative necrotising retinal vasculitis,both arteries & veins
• BRVO,Isolated BRAO,Combined,vascular sheating with vitritiswith CME
• Retinal ischemia-NV,NVI,NVG
• Repeated episodes-vessels become white & necrotic
• Acute vasculitis may be associated with multifocal areas of chalky white retinitis
• Ischemic vasculitis with retinitis mimic acute retinal necrosis syndrome/necrotising herpetic/retinitis
• ONH-25%
• Vasculitis affectin arterioles of optic nerve leads to progressive optic neuropathy
• Relapse :
• Posterior synechiae
• Iris bome
• Angle closure glaucoma
• Cataract
• Episcleritis
• Scleritis
• Conjunctival ulcers
• Corneal immune ring opacities
Diagnosis
• mostly clinical
• Clinical criteria
• HLA testing
• Cutaneous pathergy test
• Non-specific serological markers:ESR/CRP
• FFA
• Chest X-ray
• CT chest
• Brain MRI with contast
FFA
• Marked dilatation & occlusion of retinal capillaries with perivascular staining
• Evidence of retinal ischemia
• Leaking of fluorescein in to macula
• CME
• Retinal neovascularisation may leak
Differential diagnosis
• HLA B27 associated anterior uveitis
• Reactive arthritis syndrome
• Sarcoidosis
• Sytemic vasculitides like SLE,PAN,WGN
• Necrotising herpetic retinitis/viral retinitis
• Toxoplasmosis
• Ocular lymphoma
Treatment• Aim:not only to treat but to control acute inflammation
• To prevent/decrease number of relapses with IMT
• systemic corticosteroids
• Azathioprine-preserving visual acuity,control oral,genitallesions,arthritis
• The European league against rheumatism panel:
• Azathioprine with corticosteroids(first line)
• Cyclosporine/Infliximab(second line)
• Tacrolimus-less toxic(substitute)
• Colchicine-mucocutaneous disease
• Mycophenolate mofetil:also successful
• Chlorambucil-effective at lower doses
• Cyclophaspamide-alternative to chlorambucil
• INF alpha-2a-highly effective in BD
Prognosis
• guarded
• Profound visual loss due to CME,optic atrophy,glaucoma,occlusiveretinal vasculitis
• Complications:• Macular edema
• Complicted cataract
• Glaucoma
• NVG
• Retinal neovascularion
• Optic disc neo-vascularisation
• Retinal detachmnt
• Vitreous haemorrhage
References
• American Academy of Ophthalmology-Intraocular Inflammation and Uveitis-Basic and clinical science course 2011-2012
Thank you