•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