SYMPATHETIC OPHTHALMIA & VKH SYNDROME

1. SYMPATHETIC OPHTHALMIA
BY: DR. CHRISTINA SAMUEL
MODERATOR: DR. INDU.G

2. 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.

3. 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.

4. 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.

5. 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.

7. 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

8. 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.

9.  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.

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

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

14. 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

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

16. DIFFERENTIAL DIAGNOSIS
 Vogt-Koyanagi-Harada syndrome
 Lens induced uveitis
 Sarcoidosis
 Chronic idiopathic uveitis
 Tuberculosis
 Infective endophthalmitis
 Intraocular lymphoma

17. 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)

18.  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

19. VOGT-KOYANAGI-HARADA DISEASE

20.  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.

21. 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.

22. 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.

23. 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.

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

25.  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 lymphocytes
and plasma cells in the choroid

26.  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

27. 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

29. Clinical Features
Integumentary 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.

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

31. 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

32. 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).

33.  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.

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

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

36. Ultrasonography showing thickened choroid

37. OCT showing serous retinal
detachment with fibrin deposits at
the acute uveitic stage.
OCT- 9 days after systemic corticosteroid therapy showing
thickened choroid at the macular area

38. Early phase -multiple
hypofluorescent dots with
irregular hyperfluorescent
background.
Dye leakage from optic
disc during midphase
Subretinal dye pooling at
the area of serous retinal
detachment during the late
phase

39. ICGA- Early phase showing vascular leakage in the choroid and Late
phase showing multiple hypofluorescent dots.
1) Hypofluorescent dark dots indicating stromal granulomas
2) early HF choroidal vessels
3) Fuzzy indistinct large choroidal vessels
4) ICGA disc HF

40. 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.

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

42. 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

43. 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.

44. Shallow anterior chamber caused by the anterior
displacement of the lens associated with inflammatory
infiltrates at the
ciliary body
Bilateral upper-eyelid vitiligo

45. Multiple iris nodules at the iris in chronic recurrent stage

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

47. Subretinal fibrosis in a patient with chronic recurrent stage

48. (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.

49. 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

50. 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.

51. OCT
On presentation
4 weeks after systemic corticosteroid

52. 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.

53.  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.

54. 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.

55. 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.

56. • 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.

57.  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

58. 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.

59.  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.