SYMPATHETIC OPHTHALMIA

BY: DR. CHRISTINA SAMUELMODERATOR: DR. INDU.G

INTRODUCTION

Sympathetic ophthalmia is defined as a BILATERAL DIFFUSE, GRANULOMATOUS PANUVEITIS that occurs after the uvea of one eye is subjected to a penetrating injury due to either accidental trauma or surgery.

The injured eye is known as the exciting eye and the fellow eye, developing inflammation days to years later,is the sympathizing eye.

Epidemiology Prevalence: relatively rare disease (0.2%- trauma, 0.01%- ocular Sx) Inheritance: No proven role. Postulated correlation of HLA DRB1, DQA1 . HLA-

A11, HLA-B40, HLA-DR4/DRw53. Gender: M = F postsurgical; M > F traumatic No racial predisposition All ages, possible risk in the elderly or children <10years. Surgical and Laser procedures like glaucoma filtration Sx,PI,scleral

buckling,cataract Sx, evisceration, cyclocryotherapy and Nd:Yag laser cyclotherapy.

Theories of pathogenesis Neurogenic (extension from one eye to the other through the optic nerves and the

optic chiasma) Role of Ocular Immune Privilege:Not all cases of ocular injury progress to SO The immune privileged ocular antigens in the exciting eye to the host immune

system leading to the activation against these self antigens (such as choroidal melanocytes, melanin pigment or uveo retinal extracts including Retinal S antigen and interphotoreceptor retinoid binding protein) in both eyes.

T-cell proliferative response on exposure to uveal and uveoretinal extracts.

Pathology The inflammatory changes in the exciting and sympathizing eyes are

the same, except for features of trauma in the exciting eye. Granulomatous Uveitis – The minimal and classic changes for the histopathologic diagnosis of

sympathetic ophthalmia are diffuse lymphocytic infiltration of the uveal tract with epithelioid cell nests, pigment phagocytosis by the epithelioid cells, absence of necrosis, and sparing of the retina and choriocapillaris ( protective effect of RPE cells which release certain Anti inflamatory mediators like RPE protective protein, which supresses neutrophil superoxide generation) by the granulomatous process.

Dalen-Fuch's nodules

Small, deep-yellow white lesions called Dalen-Fuch's nodules in the choroid. These nodules occur mostly in the periphery and consist of epithelioid cells located just internal to Bruch's membrane.

Histopathologically they are nodular aggregations of lymphocytes and epitheloid cells with proliferation of retinal pigment epithelium.

THE CHORIOCAPILLARIS IS TYPICALLY SPARED

Clinical manifestations The interval between ocular injury and the onset of sympathetic ophthalmia has been

reported to be as short as 5 days or as long as 66 years. In general, 65% of sympathetic ophthalmia cases occur 2 weeks to 3 months after

injury 90% occur before 1 year. The traumatized eye in SO, either from an accidental penetrating injury or following

intraocular surgery, characteristically exhibits a persistent granulomatous inflammatory reaction.

THE EARLIEST SYMPTOM MAY BE DECREASED ACCOMMODATION AND THE EARLIEST SIGN, RETROLENTICULAR FLARE AND CELLS IN THE FELLOW EYE.

Sympathetic ophthalmia presents as a bilateral diffuse uveitis. Patients report insidious onset of blurry vision, pain, epiphora, and photophobia in the

sympathizing, non-injured eye. Its accompanied by conjunctival injection and a granulomatous AC reaction with mutton-fat KPs on the corneal endothelium. Poorly responsive pupil.

The iris may thicken from lymphocytic infiltration; the severe inflammation may lead to formation of posterior synechiae.

Intraocular pressure may be elevated secondary to inflammatory cell blockage of the trabecular meshwork, or it may lower as a result of ciliary body shutdown.

Fundus- vitritis, papillitis, mid equatorial yellowish white choroidal lesions, exudative RD.

B-Scan- reveals posterior choroidal thickening and serous retinal detachment

FFA Window defect- Dalen Fuchs nodules(early phase) Pin point leaks observed Late phase- diffuse leak and pooling

Fundus and OCT features of sympathetic ophthalmia before (top) and 2 months after (bottom) appropriate treatment with high-dose oral corticosteroid. Complete resolution of the exudative retinal detachment is seen

ICGA- numerous hypofluorescent spots in intermediate phase which later becomes isofluorescent or hypofluorescent depending on the thickness of the granuloma

DIFFERENTIAL DIAGNOSIS

Vogt-Koyanagi-Harada syndrome Lens induced uveitis Sarcoidosis Chronic idiopathic uveitis Tuberculosis Infective endophthalmitis Intraocular lymphoma

Management Oral corticosteroids (1.5-2mg/kg/BW) pulse therapy with intravenous methylprednisolone(up to 1 g daily for 3 days) supplementation with sub-Tenon’s injection of triamcinolone acetonide (20–40 mg),

may be considered. Intravitreal steroids- rapid therapy Topical steroids mydriatic/cycloplegic agents are used adjunctively as needed. Immunosuppresants- Cyclosporine A, cyclophosphamide, Azathioprine, chlorambucil. Biologicals Enucleation of the exciting eye (practiced earlier if done within 2 weeks of

inflammation)

immunosuppressive agents (azathioprine, 2–4 mg/kg/day; cyclosporine, 2.5–5 mg/kg/day; mycophenolate mofetil, 1–1.5 g bid; methotrexate, 15–25 mg/week) cyclophosphamide (2–3 mg/kg/day) chlorambucil (0.1–0.2 mg/kg/day)

Biologicals, particularly anti-TNF agents such as infliximab and Adalimumab, may also be used in cases of sympathetic ophthalmia that are unresponsive to conventional immunomodulatory agents

VOGT-KOYANAGI-HARADA DISEASE

Vogt–Koyanagi–Harada (VKH)-{ uveomeningio encephalitic} disease is a BILATERAL GRANULOMATOUS UVEITIS often associated with exudative retinal detachment and with extraocular manifestations, such as pleocytosis in the cerebrospinal fluid and, in some cases, vitiligo, poliosis, alopecia, and dysacusis.

Epidemiology

• Individuals with a predisposing genetic background.• Ethnic groups with more heavily pigmented skin.• Asians, Native Americans, Hispanics, Asian Indians, Middle

Easterners. More common in Japan.• Women more than men.• 2nd – 5th decade.• Pediatric age group may also be affected.

Etiology and Pathogenesis• Remains unknown.• T-LYMPHOCYTE MEDIATED AUTOIMMUNITY DIRECTED AGAINST ONE OR

MORE ANTIGENS FOUND ON OR ASSOCIATED WITH MELANOCYTES FOUND IN EYE, SKIN AND HAIR, INNER EAR, CNS.

• Tyrosinase family proteins are enzymes for melanin formation and are expressed in melanocytes.

There is a strong association with the human leukocyte antigen (HLA) DR4 in Japanese patients with VKH disease.

Pathology non-necrotizing diffuse granulomatous inflammation involving the uvea

Uvea is thickened by diffuse infiltration of lymphocytes and macrophages, admixed with epithelioid cells and multinucleated giant cells containing melanin granules. The neural retina is detached from the RPE, and the subretinal space contains proteinaceous fluid exudates.

Dalen-Fuchs’ nodules: represent focal aggregates of epithelioid histiocytes admixed with RPE, are located between Bruch’s membrane and the RPE.

serous detachment of the retina, preservation of choriocapillarisfrom inflammatory cell infiltration, and thickening of choroid from granulomatous inflammatory cell infiltration- ACUTE

convalescent stage- the choroidal melanocytes decrease in number and disappear, resulting in the sunset glow appearance of the fundus.

loss of choroidal melanocytes and infiltration of lymphocytesand plasma cells in the choroid

chronic stage- the numerous focal yellowish oval or round lesions seen in the inferior

peripheral fundus ,histologically display a focal loss of RPE cells and the formation of chorioretinal adhesions.

In the long-standing chronic recurrent stage, the RPE and neural retina show degenerative changes . The RPE may reveal hyperplasia and fibrous metaplasia with or without associated subretinal neovascularization.

choroidal inflammation, retinal pigment epithelium proliferation and degeneration of overlying retina

Genetic Factors• 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.· VKH disease in monozygotic twins· Familial VKH disease· Familial cases shared HLA-DR4

Clinical FeaturesIntegumentary Manifestations

• Sensitivity of hair and skin to touch (early in prodromal phase).• Poliosis, vitiligo, alopecia (during convalescent stage).• Ethnic groups may manifest varying systemic symptoms.

Neurologic Manifestations• Most common during prodromal stage.• Neck stiffness, headache, confusion.• Occasionally focal neurologic signs.• CSF pleocytosis.

Auditory Manifestations• May be presenting problem• Sensorineural hearing loss usually involves higher frequencies• Tinnitus• Vertigo• May cause permanent hearing loss

Prodromal Phase:

• Mimics viral illness• Neurologic and auditory manifestations• Few days - duration• Headache, orbital pain, stiff neck, malaise, abdominal pain,

nausea, fever, vertigo, tinnitus• Cranial nerve palsies, optic neuritis (rare)• CSF analysis- pleocytosis

Acute Uveitic Phase:• Bilateral in 70% of patients, delay of 1-3 days before 2nd eye becomes involved in

30%. In a few cases this interval may last up to 10 days.• Hallmark is bilateral multifocal exudative retinal detachments, hyperemia and

edema of the optic disc.• Yellow-white lesions at level of RPE beneath serous RD.• Thickening of posterior choroid manifested by elevation of peripapillary retino-

choroid layer.• Retinal edema in posterior pole.• Peripheral well-circumscribed yellow-white lesions (clinical equivalent of Dalen-

Fuchs’ nodules).

No inflammation of the anterior segment or mild to moderate nongranulomatous anterior uveitis if the disease is not well controlled with appropriate treatment during the first two weeks.

• Acute angle closure glaucoma(inflammatory infiltrate in the ciliary body and choroid may cause forward displacement of the lens iris diaphragm)-shallow AC, elevated IOP

• Thickened choroid- B scan FFA- Alteration in RPE associated with multifocal choroidal inflammation is

easily observed by the hypofluorescence dots at the early phase followed by multiple focal areas of leakage and subretinal fluid accumulation at the late phase.

ICGA is useful to evaluate choroidal inflammatory changes such as early choroidal stromal vessel hyperfluorescence and leakage, and hypofluorescent dark dots at the level of the choroid.

Bilateral multiple serous retinal detachments at the acute uveitis stage of Vogt–Koyanagi–Harada disease

Bilateral hyperemia and edema of the optic disc at the acute uveitis stage of Vogt–Koyanagi–Harada disease without serous retinaldetachment.

Ultrasonography showing thickened choroid

OCT showing serous retinaldetachment with fibrin deposits at the acute uveitic stage.

OCT- 9 days after systemic corticosteroid therapy showing thickened choroid at the macular area

Early phase -multiple hypofluorescent dots with irregular hyperfluorescentbackground.

Dye leakage from optic disc during midphase

Subretinal dye pooling at the area of serous retinal detachment during the late phase

ICGA- Early phase showing vascular leakage in the choroid and Late phase showing multiple hypofluorescent dots.1) Hypofluorescent dark dots indicating stromal granulomas2) early HF choroidal vessels3) Fuzzy indistinct large choroidal vessels4) ICGA disc HF

Convalescent Phase:

• Integumentary and uvea depigmentation. Perilimbal vitiligo-melanosis at the palisade of Vogt (Sugiura’s

sign).• Fundus exhibits an orange-red discoloration (“sunset-glow”

fundus).• Multiple small yellow well-circumscribed areas of chorioretinal

atrophy representing regressed Dalen-Fuchs’ nodules.• RPE clumping or migration.• Pigmented demarcation lines.

Chronic stage of Vogt–Koyanagi–Harada disease showingextensive posterior synechiae and loss of pigment at the limbus(Sugiura’s sign).

Chronic stage of VKH disease revealing sunset glow fundus with juxtapapillary depigmentation and oval RPE atrophic lesions in an Asian and in a Hispanic patient

Chronic Recurrent Phase:

• Acute episodes of granulomatous anterior uveitis with development of iris nodules

• Recurrent posterior uveitis is distinctly uncommon• Complications-Cataract, Secondary glaucoma, Choroidal

neovascular membranes, Subretinal fibrosis, Severe chorioretinal atrophy

• Patients with recurrent VKH disease have a more intensive inflammation in the anterior segment and long-lasting dysfunction of the blood-aqueous barrier than those with initial onset VKH disease.

Shallow anterior chamber caused by the anteriordisplacement of the lens associated with inflammatory infiltrates at theciliary body

Bilateral upper-eyelid vitiligo

Multiple iris nodules at the iris in chronic recurrent stage

Submacular choroidal neovascular membrane and hemorrhage during the chronic recurrent stage FFA- typical neovascular membrane

Subretinal fibrosis in a patient with chronic recurrent stage

(A) Fundus shows exudative retinal detachment involving the posterior pole with associated retinal and choroidal folds. (B) Early-phase FFA shows areas of delayed choriocapillaris filling. (C) Mid-phase shows multiple pinpoints that enlarge with pooling of dye in subretinal space in the late-phase (D). (E) Optical coherence omography shows exudative retinal detachment with subretinal septa dividing the subretinal space into several compartments. (F) B scan shows diffuse-low to medium-reflective choroidal thickening most marked in the posterior fundus and associated exudative retinal detachment (white arrow). (G) 20-MHz ultrasonography shows better definition of sclero-choroidal limit (blue arrow) and episcleral space (black arrow) with more accurate measurement of choroidal thickening.

Investigations

Diagnosis is made by clinical examination and ancillary test findings• Fluorescein angiography• Indocyanine green angiography• Ultrasonography• Optical coherence tomography• Multifocal electroretinograms• Lumbar puncture• Audiometry

Ultrasonography:

• Diffuse low to medium reflective thickening of posterior choroid, SRD located in posterior pole or inferiorly, vitreous opacities and posterior thickening of the sclera.

• The choroidal thickening is most prominent in the peripapillary area and generally extends to the equatorial region, becoming progressively thinner away from the optic nerve.

• Overlying exudative RD.• UBM- in uveitis stage shows shallow AC, ciliochoroidal

detachment and thickened ciliary body.

OCT

On presentation

4 weeks after systemic corticosteroid

Multifocal Electroretinogram

· May be useful in detecting early retinal damage.

· Macular function is severely impaired in patients with active uveitis.

· Treatment with immunosuppressive agents leads to delayed but limited recovery of macular function.

· May be useful in guiding therapy.

Retinal functional changes measured by microperimetry after immunosuppressive therapy.

· Patients displayed a markedly decreased BCVA, fixation stability and mean retinal sensitivity at baseline.

· BCVA and fixation stability recovered earlier, faster and better than mean retinal sensitivity.

· At final follow-up, retinal sensitivity was significantly reduced even in eyes with full recovery of BCVA.

· Subclinical macular dysfunction is a permanent damage in VKH disease.

Lumbar Puncture:

• Rarely necessary in a typical case.• CSF pleocytosis (mostly lymphocytes).• Transient and resolves within 8 weeks. Frequency of CSF pleocytosis and the number of cells in CSF at

disease onset were significantly higher in patients who eventually developed sunset glow fundus.

Therapy• Should be prompt and aggressive.• Systemic corticosteroids are mainstay of therapy.• 1-1.5 mg/kg/day of oral Prednisone (single morning-after-breakfast

dose).• For 6-12 months with slow gradual tapering during this time.

• Intravenous high-dose pulse steroid therapy (1g/day of Methylprednisolone given for 3 days) followed by oral Prednisone (1 mg/kg/day).

• Topical Prednisone 1% solution and cycloplegics for anterior uveitis.• Patients adequately treated with corticosteroids have a fair visual

prognosis.• Recurrences are associated with rapid or early decrease in steroid

doses.

• Patients treated initially with immunomodulatory drugs (mycophenolate mofetil, cyclosporine A, azathioprine, and methotrexate) combined with corticosteroids had a better visual outcome than those who received corticosteroids as monotherapy.

• Immunomodulatory therapy combined with corticosteroids should be considered as first-line therapy for patients with VKH.

· Use of mycophenolate mofetil as first-line therapy combined with systemic corticosteroids is safe and effective in the treatment of acute uveitis associated with VKH disease.

· It has marked corticosteroid-sparing effect and significantly reduced development of chronic recurrent inflammation and late complications and significantly improved visual outcome.

response to subtenon injections of triamcinolone acetonide Cyclosporin 5 mg/kg per day FK506 0.1–0.15 mg/kg per day Azathioprine 1–2.5 mg/kg per day Mycophenolate mofetil 1–3 g/day Cyclophosphamide 1–2 mg/kg per day Chlorambucil 0.1 mg/kg per day; dose adjusted every 3 weeks to a

maximum of 18 mg/day Anti-TNF-α monoclonal antibody

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.

· Poor visual acuity and severe anterior segment inflammation at presentation are significantly associated with a worse outcome.

· Chronic recurrent disease is significantly associated with more severe anterior segment inflammation and less exudative retinal detachment at presentation, more ocular complications and a worse visual outcome compared with initial-onset disease.

· Use of immunomodulatory therapy as first-line therapy combined with systemic corticosteroids significantly improved clinical outcomes.

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