1. Uvea & Sclera SINA A. SHOOL MD SINA A. SHOOL MD www.drsinashool.blogspot.com www.drsinashool.blogspot.com

2. Uveitis – “inflammation of the uveal tract”

3. Anterior Uveitis: iris & Anterior part of the ciliary body (pars plicata Anterior Uveitis: iris & Anterior part of the ciliary body (pars plicata Intermediate Uveitis: posterior part of the ciliary body (pars plana) Intermediate Uveitis: posterior part of the ciliary body (pars plana) Posterior Uveitis Posterior Uveitis Panuveitis Panuveitis 1) Anatomic classification

4. Anatomical - Anterior Uveitis Juvenile Rheumatoid Arthritis Juvenile Rheumatoid Arthritis Fuchs’ heterochromic Iridocyclitis Fuchs’ heterochromic Iridocyclitis Ankylosing Spondylitis Ankylosing Spondylitis Reiter’s Syndrome Reiter’s Syndrome

5. Anatomical - Intermediate Uveitis Pars Planitis Pars Planitis Sarcoidosis Sarcoidosis Multiple Sclerosis Multiple Sclerosis Lyme Disease Lyme Disease

6. Anatomical - Posterior Uveitis Toxoplasmosis Toxoplasmosis Histoplasmosis Histoplasmosis Toxocariasis Toxocariasis Serpiginous chorioretinitis Serpiginous chorioretinitis Birdshot retinochoroiopathy Birdshot retinochoroiopathy

7. Anatomical - Diffuse Uveitis Sympathetic Ophthalmia Sympathetic Ophthalmia VKH syndrome VKH syndrome Behcet’s disease Behcet’s disease

8. Acute Uveitis: sudden, symptomatic onset; persists for <6 weeks Acute Uveitis: sudden, symptomatic onset; persists for <6 weeks Chronic Uveitis: insidious onset, may be asymptomatic; persists for months Chronic Uveitis: insidious onset, may be asymptomatic; persists for months (2) Clinical Classification

9. Exogenous Uveitis: due to external injury to the uvea or invasion of micro- organisms from the outside Exogenous Uveitis: due to external injury to the uvea or invasion of micro- organisms from the outside Endogenous Uveitis: caused by micro- organisms or other agents from inside the patient Endogenous Uveitis: caused by micro- organisms or other agents from inside the patientwww.drsinashool.blogspot.com (3) Etiological Classification

10. Granulomatous Uveitis Granulomatous Uveitis - epithelioid and giant cells, lymphocytes Non-granulomatous Uveitis Non-granulomatous Uveitis - lymphocytes and plasma cells (4) Pathological Classification

11. Traumatic Traumatic –Surgical vs. non-surgical Infectious Infectious –Bacterial, Viral, Fungal, Protozoal, Helminthic, Insect, Animal Immunologic Immunologic Masquerade Diseases Masquerade Diseases (5) Pathophysiologic Mechanisms (Opremcak)

12. Immunologic Type I hypersensitivity disorders Type I hypersensitivity disorders –Ig E- mediated –Mostly ocular surface disease hay fever, vernal & atopic keratoconjunctivitis Type II Type II –Antibody dependent cellular cytotoxicity (autoantibodies) –Ocular Cicatricial Pemphigoid; Lens- induced Uveitis

13. Immunologic Type III Type III –Immune Complex formation & deposition –Ankylosing Spondylitis, SLE, JRA, Behcet’s disease, PAN, Wegener’s granulomatosis, inflammatory bowel disease, other collagen vascular diseases Type IV Type IV –Cell mediated immune response –Interleukins –Contact dermatitis, Phylectnulosis,, Fuchs HI, Sympathetic Ophthalmia, VKH, Birdshot retinochoroidopathy, Pars Planitis, Leber’s Idiopathic Stellate Neuroretinitis, Sarcoidosis

14. AntigenDisease Relative Risk HLA-A1Sarcoidosis- HLA-A11 Sympathetic Ophthalmia - HLA-A29 Birdshot Retinochoroido pathy (>97%) 50-224 HLA-B51 Behcet’s Disease 4-6 HLA-B7, DR2 POHS12 HLA-B8 Anterior Uveitis 5 HLA-B12 Behcet’s Disease(oral) OCP3-4

15. AntigenDisease Relative Risk HLA-B27 Ankylosing Spondylitis (90%) 100 Reiter’s syndrome (76%) 40 Acute Anterior Uveitis (55%) 10 Inflammatory Bowel Disease - Psoriatic Arthritis - Bechet’s Disease - HLA-B53 VKH, glaucomatocylitic uveitis 7575

16. Masquerade Syndrome Vascular tumors Vascular tumors Infectious Infectious Congenital anomalies Congenital anomalies Metabolic/Degenerations (amyloidosis, retinitis pigmentosa) Metabolic/Degenerations (amyloidosis, retinitis pigmentosa) Neoplastic Disease (lymphoma, leukemia) Neoplastic Disease (lymphoma, leukemia)

17. Clinical Features Anterior Uveitis Symptoms Photophobia, pain, redness, decreased vision (Acute) *Minimal symptoms in chronic type Signs Circumcorneal injection Keratic precipitates (cellular deposits on the corneal endothelium) Iris nodules: Koeppe & Busacca Aqueous cells Aqueous flare: leakage of proteins Posterior synechiae

18. Grading System for Anterior Chamber Flare & Cell Aqueous Flare Aqueous Flare 0Optically empty 1+Faint 2+ Moderate- clear iris & lens 3+ Marked- hazy iris & lens 4+ Intense- fibrin with no motion of cells Aqueous cell (1x3 mm beam @ 5-10 °) Aqueous cell (1x3 mm beam @ 5-10 °) 00 RareRare Occasional 1-2 cells Trace2-4 cells 1+5-15 2+ 16-25 3+ 26-60 4+ > 60 cells

19. Limbal Hyperemia= Intraocular Inflammation

25. Clinical Features Intermediate Uveitis Symptom s Floaters Decreased vision (if with CME) Signs Vitritis: cellular infiltration of the vitreous +Vasculitis + few cells in the anterior chamber

26. Grading System for Vitreous Cell and Opacification Flare (Vitreous Opacification) Flare (Vitreous Opacification) 0 Good View of NFL 1+Clear ON & vessels but hazy NFL 2+ ON & vessels hazy 3+ ON only 4+ No ON Cell (1x3 mm beam in anterior vitreous) Cell (1x3 mm beam in anterior vitreous) Trace0-10 cells 1+10-20 2+ 20-30 3+ 30-100 4+ > 100 cells

30. Clinical Features Posterior Uveitis Symptoms Floaters and decreased vision Signs Cells, flare, opacities in the vitreous Choroiditis: yellow or greyish patches Retinitis: whitish, cloudy retina Vasculitis Phlebitis (veins); Arteritis (arterioles)

36. Keratouveitis: with corneal involvement Keratouveitis: with corneal involvement Sclerouveitis: with scleral involvement Sclerouveitis: with scleral involvement Keratosclerouveitis Keratosclerouveitis

38. Anterior Uveitis Juvenile Rheumatoid Arthritis Juvenile Rheumatoid Arthritis Fuchs’ heterochromic Iridocyclitis Fuchs’ heterochromic Iridocyclitis Ankylosing Spondylitis Ankylosing Spondylitis Reiter’s Syndrome Reiter’s Syndrome

40. Anterior Uveitis 1) Uveitis Associated with Joint Disease a) Juvenile Rheumatoid Arthritis (JRA) - chronic, bilateral, non-granulomatous - arthritis of at least 3 mos’ duration in a child less than 16 years - females - insidious onset - uveitis may precede the onset of arthritis

41. JRA (cont) - types of arthritis: pauciarticular onset <4 joints polyarticular onset > 5 joints systemic onset

43. Anterior Uveitis 2) Uveitis Associated with Joint Disease(cont) b) HLA-B27-associated - Ankylosing spondylitis - Reiter’s syndrome - Psoriatic arthritis - Inflammatory Bowel Disease (IBD)

44. HLA-B27-associated Ankylosing Spondylitis -i-i-i-inflammatory arthritis affecting axial skeleton -F-F-F-Fixed flexion deformity due to fusion of spine and sclerosis of sacroiliac joints -K-K-K-Klebsiella & Chlamydial infections

45. HLA-B27-associated Reiter’s Disease - Triad: urethritis, conjunctivitis, arthritis - Extraarticular features: Mouth ulcers, skin lesions (keratoderma blenorrhagica), penile lesions (circinate balanitis), nail changes, cardiovascular changes, genitourinary lesions

47. HLA-B27-associated Psoriatic Arthritis - Psoriasis: skin disease due to epidermal hyperproliferation

48. HLA-B27-associated Inflammatory bowel disease - Crohn’s disease and ulcerative colitis - Gastrointestinal and articular manifestations - Systemic manifestations include skin lesions, oral ulcerations, hepatobiliary disorders, urogenital involvement

49. Anterior Uveitis 3) Fuch’s Heterochromic Iridocyclitis - unilateral, insidious, third or fourth decade - No symptoms; low grade uveitis - Early cataract - Fine, stellate, evenly distributed deposits on the posterior corneal surface; iris atrophy; telangiectatic vessels in the angle - Synechiae is rare

50. Fuch’s Heterochromic Iridocyclitis

52. Anterior Uveitis 4) Herpetic Uveitis - unilateral, high IOP, decreased corneal sensation, iris atrophy - Herpes simplex, Herpes zoster - Treatment: oral anti-herpetic (acyclovir), topical steroids, + anti-glaucoma *posterior pole involvement: acute retinal necrosis (ARN)

56. Posterior Uveitis - usually associated with systemic disease - Clues that can guide: 1) Morphology of the lesion 2) Age of the patient 3) Unilateral/Bilateral 4) Course of the disease

57. Posterior Uveitis 1) Ocular Toxoplasmosis - Toxoplasma gondii, obligate intracellular protozoan - Most common cause of posterior uveitis in U.S. - Domestic cat definitive hosts - Treatment: pyrimethamine, sulfadiazine, clindamycin, trimethoprim/sulfamethoxazole + steroids

59. Posterior Uveitis 2) Ocular Toxocariasis - Toxocara canis, intestinal parasite of dogs - Young children - Infection by pica or close contact with puppies - Usually unilateral - Inflammation is caused by death of the larvae in the retina

60. 3) CMV retinitis - opportunistic infection usually found in AIDS patients - Retinal necrosis - IV ganciclovir or foscarnet; intravitreal ganciclovir

62. 4) Adamantiades-Behcet’s Disease - idiopathic multisystem disorder - Pathology: widespread vasculitis - Triad: recurrent ocular inflammation, skin lesions, recurrent oral & genital ulcers

64. Panuveitis 1) Sympathetic Ophthalmia - rare, granulomatous, bilateral - Follows a perforating eye injury, or surgery - Probably due to hypersensitivity to pigment-bearing cells in the uvea

65. Sympathetic Ophthalmia - Injured (exciting eye) becomes inflammed followed by fellow (sympathizing) eye - Early enucleation of exciting eye (within 10 days from injury) - Advanced cases: systemic steroids or chemotherapy

66. Histopathology Dalen Fuchs’ Nodule Granulomatous Inflammation of Choroid

67. Panuveitis 2) Tuberculous Uveitis - can occur even without pulmonary involvement - Nodules; no specific findings - Tx: antituberculosis drugs

68. Panuveitis 3) Vogt-Koyanagi-Harada -s-s-s-systemic disorder involving multiple organ systems: -O-O-O-Ocular (panuveitis, exudative RD, optic disc hyperemia) -A-A-A-Auditory (tinnitus, deafness) -N-N-N-Nervous (headache, meningismus, CSF lymphocytosis) -I-I-I-Integument (alopecia, poliosis, vitiligo)

69. VKH - autoimmunity to melanocytes in the uveal tract and integumentary system possible

71. Poorly defined nests of epithelioid cells present throughout the thickened choroid with a moderate lymphocytic infiltrate Areas of choroid retinal adhesions with focal proliferation of the retinal pigment epithelium. Lymphocytic infiltrates and edema are noted throughout the detached choroid

72. 4) Syphilis - great imitator - No pathognomonic signs

73. Complications of Uveitis Band Keratopathy Band Keratopathy - calcium deposition in anterior layer of the cornea (Bowman’s layer) - Treatment: ethylenediaminetetraacetic acid (EDTA)

74. Complications of Uveitis Synechiae Synechiae -Peripheral anterior synechiae  impede aqueous outflow: glaucoma -Posterior synechiae Seclusio pupillae: 360 posterior synechiae  forward bulging of the iris due to fluid accumulation (iris bombe)  glaucoma

76. Complications of Uveitis Cataract Cataract -Interference with lens metabolism or steroids -Eye should be quiet for at least 3 months before undergoing cataract extraction -not all patients can tolerate IOL implantation

77. Complications of Uveitis Retinal scars Retinal scars Central vision may be spared if the macula has not been involved Peripheral scars may cause scotomas

78. Complications of Uveitis Retinal Detachment Retinal Detachment Tractional: Result of traction on the retina by vitreous strands Serous: Fluid accumulation under the retina

79. Complications of Uveitis Cystoid Macular Edema Cystoid Macular Edema Accumulation of edema fluid in spaces in the outer plexiform and inner nuclear layers

80. Complications of Uveitis Optic atrophy

81. Complications of Uveitis Hypotony Hypotony Due to proliferation of exudates in the ciliary body Due to proliferation of exudates in the ciliary body

82. Diagnosis Differential-based Diagnostic System Differential-based Diagnostic System –Acquistion of facts –Evaluate –Listing of Hypotheses –Selection among hypotheses Laboratory Testing Laboratory Testing –Routine Tests CBC with differential ESR/CRP VDRL/FTA-ABS –Frequently Obtained Chest X ray ACE/lysozyme ANA/RF/ANCA Skin Testing

83. Diagnosis Specific Tests Specific Tests –Blood Tests Autoantibodies Autoantibodies Specific serologies Specific serologies Serum proteins Serum proteins –Radiologic Tests Chest Radiography Chest Radiography Sacroiliac and lumbosacral spine Sacroiliac and lumbosacral spine Gallium scan Gallium scan MRI MRI CT CT Specific Tests –FA –Tissue Biopsy –Ultrasonography

84. Treatment Aims of therapy: Aims of therapy: 1. To prevent vision-threatening complications 2. To relieve the patient’s discomfort 3. To treat the underlying cause

85. Treatment Four types of medications: Four types of medications: 1) Mydriatics 2) Steroids 3) NSAIDs 4) Immunosuppressive medications

86. Specific Strategies for Uveitis Type I: Eliminate agents, cromolyn, antihistamine, corticosteroids Type I: Eliminate agents, cromolyn, antihistamine, corticosteroids Type II: Dapsone, corticosteroids, cytotoxic agents, surgical removal Type II: Dapsone, corticosteroids, cytotoxic agents, surgical removal Type III: NSAIDS, corticosteroids, immunosuppressive and cytotoxic agents, plasmapheresis Type III: NSAIDS, corticosteroids, immunosuppressive and cytotoxic agents, plasmapheresis Type IV: corticosteroids, immunosuppressive and cytotoxic agents, cyclosporine Type IV: corticosteroids, immunosuppressive and cytotoxic agents, cyclosporine

87. Treatment 1) Mydriatics To give comfort by relieving spasm of the ciliary muscle To give comfort by relieving spasm of the ciliary muscle Atropine 1%, Tropicamide, Cyclopentolate To prevent formation of posterior synechiae To prevent formation of posterior synechiae To break synechiae To break synechiae

88. Treatment 2) Steroids a) Topical steroids: only for anterior uveitis a) Topical steroids: only for anterior uveitis Prednisone, prednisolone, dexamethasone Prednisone, prednisolone, dexamethasone Usually start with a high rate of instillation and decrease as inflammation lessens Usually start with a high rate of instillation and decrease as inflammation lessens Complications: glaucoma, posterior subcapsular cataract, corneal complications, systemic side effects Complications: glaucoma, posterior subcapsular cataract, corneal complications, systemic side effects

89. Treatment 2) Steroids (cont) b) Periocular injections b) Periocular injections Able to reach therapeutic concentration behind the lens Able to reach therapeutic concentration behind the lens Longer lasting effect with depot Longer lasting effect with depot Triamcinolone acetonide 40mg/ml Methylprednisolone acetate 80 mg/ml Triamcinolone acetonide 40mg/ml Methylprednisolone acetate 80 mg/ml

91. Treatment Indications for periocular steroids: Indications for periocular steroids: 1) Severe anterior uveitis 2) Resistant cases of anterior uveitis 3) Intermediate uveitis 4) Poor patient compliance 5) Cystoid macular edema

92. Treatment 2) Steroids (cont) c) Systemic steroids (oral or intravenous)

93. Corticosteroids Adverse Reactions Adverse Reactions Cushingoid changes (moon facies, weight gain, fat redistribution, and increased acne) Delay of pubertal growth in children below 15 Infection, hypertension, fluid retention, diabetes mellitus, hyperlipidemia, atherosclerosis, osteoporosis, glaucoma and cataracts Anxiety, sleeplessness, mood changes, easy bruising, poor wound healing Pancreatitis, aseptic necrosis of bone, myopathy, psychosis

94. 2) Steroids (cont) d) Intravitreal steroids

95. Treatment 3) Non-Steroidal Anti-Inflammatory agents (NSAIDs) Flurbiprofen – effective in CME

96. Treatment 4) Immunosuppressive Drugs Indications: When systemic corticosteroids are insufficient to control the disease When systemic corticosteroids are insufficient to control the disease Steroid side effects Steroid side effects Long term use of steroids at a high dose to suppress the inflammation Long term use of steroids at a high dose to suppress the inflammation

97. Immunosuppressive Drugs Antimetabolites Antimetabolites Azathioprine (Imuran) Methotrexate (Rheumatrex) Mycophenolate mofetil (Cellcept) T-cell inhibitors T-cell inhibitors Cyclosporine (Sandimmune; Neoral) Tacrolimus (Prograf) Alkylating agents Alkylating agents Cyclophosphamide (Cytoxan) Chlorambucil (Leukeran)

98. Common Ophthalmic Indications for Cytotoxic Immunosuppression Type I: Autoimmune diseases: few Type I: Autoimmune diseases: few Type II: OCP, severe lens-induced uveitis Type II: OCP, severe lens-induced uveitis Type III: Autoimmune/collagen vascular associated disease: Bechet’s disease, PAN, Wegener’s granulomatosis, SLE, rheumatoid arthritis Type III: Autoimmune/collagen vascular associated disease: Bechet’s disease, PAN, Wegener’s granulomatosis, SLE, rheumatoid arthritis Type IV: Autoimmune diseases: SO, VKH, birdshot retinochoirodopathy, pars planitis Type IV: Autoimmune diseases: SO, VKH, birdshot retinochoirodopathy, pars planitis

99. Immunosuppressive Usage & Side Effects DRUG SIDE EFFECT CHOICE OF DRUG FOR Methotrexate Liver damage & mucosal lesions Reiter’s Syndrome & Severe Rheumatoid Arthritis Cyclophosphomide Bone Marrow, bladder, lung OCP, Behcet’s, PAN, relapsing polychondritis, Wegener’s granulomatosis, VKH, Serpigenous chorioretinopathy, SO

100. Immunosuppressive Usage & Side Effects DRUG SIDE EFFECT CHOICE OF DRUG FOR Azothioprine Blood dyscrasia Wegener’s, OCP, JRA Methotrexate Mucosal ulcerations, GI disturbances, hepato & myelo toxicity, infection Rheumatoid scleritis, Ankylosing, Reiter’s, SLE, JRA-associated iridocyclitis CyclosporinNephrotoxicity Bilateral sight threatening conditions: Birdshot, SO, VKH, Behcet’s Serpigenous

101. Malignancies of the Uveal Tract

106. Sclera - Dense connective tissue that encloses about five-sixths of the eye - Functions: Strength and firmness maintains the shape of the globe Strength and firmness maintains the shape of the globe Aids in the maintenance of intraocular pressure Aids in the maintenance of intraocular pressure Provides attachment for the extraocular muscles Provides attachment for the extraocular muscles Protects intraocular structures from trauma and mechanical displacement Protects intraocular structures from trauma and mechanical displacement

107. Sclera Layers of the Sclera Layers of the Sclera 1) Episclera 2) Scleral Stroma 3) Lamina fusca

108. Sclera 1) Episclera - forms the superficial aspect of the sclera and merges with the underlying scleral stroma - Consists of loosely arranged bundles of collagen, intermingled with fibroblasts, occassional melanocytes, proteoglycans, and gylcoproteins. - Rich blood supply mainly from the anterior ciliary arteries

110. Sclera Episcleritis -a benign inflammatory disease characterized by edema and cellular infiltration of the episcleral tissue - self-limited; recurrent; rarely leaves any residual ocular damage - Idiopathic in 2/3 of cases

111. Sclera Episcleritis - main symptom is mild discomfort - Main sign is redness which may be localized or involve the whole episclera

114. Sclera 2) Scleral Stroma - consists of collagen bundles associated with few elastic fibers 3) Lamina Fusca - portion of the sclera adjacent to the uvea

115. Sclera Scleritis Scleritis - Severe inflammatory condition characterized by edema and inflammatory cell infiltration of the sclera - May be progressively destructive with loss of vision - Pain, tender globe, deep violaceous discoloration of the globe due to dilation of deep vascular plexus of the sclera and episclera - Associated with systemic disease

121. Sclera Clinical classification of episcleral and scleral inflammation EpiscleritisSimpleNodularScleritis Anterior scleritis Diffuse scleritis Nodular scleritis Necrotizing scleritis Posterior scleritis

129. Sclera Disease associated with episcleritis and scleritis Diagnosis % of patients with associated disease Episcleritis31.91% Simple28.21% Nodular50.00% Scleritis56.98% Diffuse45.45% Nodular43.59% Necrotizing94.87% Posterior45.45%

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