2/12/2016. Uveitis. E. Mitchel Opremcak, MD. The Retina Group Professor of Ophthalmology and Visual Sciences The Ohio State University Columbus, Ohio
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1 Uveitis E. Mitchel Opremcak, MD The Retina Group Professor of Ophthalmology and Visual Sciences The Ohio State University Columbus, Ohio 1
2 DM BRVO ARMD CRAO 2
3 3
4 Definition Uveal Tract Inflammation = Uveitis Iris, ciliary body, choroid Ocular Inflammation = Retina, optic nerve, vitreous Conjunctiva, episclera, cornea Terminology UVEITIS Anterior Intermediate Posterior Diffuse or Pan-uveitis Iritis/Cyclitis/Choroiditis Keratic precipitates Synechiae Cell and Flare 4
5 Terminology Vitritis Retinitis/Retinochoroiditis Choroiditis/Chorioretinitis Vasculitis Arteriole Venuole Capillary Terminology Vitritis Retinitis/Retinochoroiditis Choroiditis/Chorioretinitis Vasculitis Arteriole Venuole Capillary Terminology Vitritis Retinitis/Retinochoroiditis Choroiditis/Chorioretinitis Vasculitis Arteriole Venuole Capillary 5
6 Terminology Vitritis Retinitis/Retinochoroiditis Choroiditis/Chorioretinitis Vasculitis Arteriole Venuole Capillary Dogmatic Uveitis Experts AAO 2012 Uveitis Subspecialty Day No DDx but name-meshing Only 2 diagnostic categories genetic and infectious Only 30 conditions can cause uveitis No granulomatous vs non-granulomatous No STK for acute uveitis Pars planitis only cryopexy and no vitrectomy No histoplasmosis in POHS just PIC or MCP Idiopathic retinal vasculitis is rare Epidemiology 10-15% total blindness USA Incidence: 17 to 52.4/100,000/year Prevalence: 38 to 115.3/100,000 population 1% affected by uveitis lifetime 2.3 million with visual impairment Darrell RW, et al. Ophthalmol.1962;68:502 Gritz DC, Wong IG. Ophthalmology: 2004;111:491 6
7 Epidemiology Fifth leading cause visual loss after DM, AMD Peak onset yrs All age groups affected Children 16 (5-10%) 25-50% underlying systemic disease association Personal and economic impact of potential vision lost may be greater than age-related disease Suttorp-Schulten MSA, Rothova A. Br J Ophahalmol. 1996;80:844 Visual Loss Durrani et al. Br. J Ophthalmol. 2004; 88 70% significant visual loss at least one eye ( 6/18) (N=315) 50% bilateral reduced vision 63% severe visual loss ( 6/60) 22% legally blind Panuveitis 84% significant visual loss ( 6/18) 53% severe visual loss ( 6/60) Demographics Age Younger (JIA, Toxocara) Older (Birdshot, Serpiginous, Lymphoma) Sex Males (HLA- B27, acute forms) Females (JRA, chronic forms) 7
8 Demographics Race Darker: VKH, Sarcoidosis Lighter: POHS Geography Japan, Middle East: Behcet s Brazil: Toxoplasmosis West Africa: Onchocerciasis STANDARDIZATION OF UVEITIS NOMENCALTURE (SUN) Anatomic Classification of Uveitis Type 1 Site inflammation Includes Anterior Anterior chamber Iritis, iridocyclitis Intermediate Vitreous Vitritis Pars planitis Posterior Retina or choroid Choroiditis Panuveitis Retinitis, neuroretinitis Retinochoroiditis, etc. AC, vitreous, & retina or choroid From IUSG Classification Am J Ophthalmol 1987;103:234 SUN Working Group Am J Ophthalmol 2005; 140: Uveitis Location Anterior Intermediate 8
9 Uveitis Location Posterior Diffuse Expanded IUSG Classification Keratouveitis Herpetic until proven otherwise Sclerouveitis Vasculitic conditions Retinal vasculitis Systemic disease SUN WORKING GROUP Onset, Duration, Course Category Descriptor Comment Onset Sudden Insidious Duration Limited < 3 months Persistent > 3 months Course Acute Sudden onset, limited duration Recurrent Episodes & > 3 mos inactive off Rx Chronic Persistent & prompt relapse off Rx 9
10 Acute Course Sudden onset, limited duration HLA-B27 associated anterior uveitis Necrotizing Herpetic Retinopathies (ARN, PORN) VKH Toxoplasmosis White dot syndromes Trauma Postop endophthalmitis Recurrent Episodes & > 3 months inactive off Rx Chronic Course Insidious onset, persistent duration, relapse off Rx JRA associated iridocyclitis Birdshot Serpiginous TB Post surgical (P. acnes) Lymphoma MCP Sarcoidosis Intermediate Ocular Inflammation and Immunology Pathology/Pathophysiology Granulomatous (epithelioid and giant cells) Large Mutton Fat KP, IP, VP, RP Non-Granulomatous Small fine white precipitates 10
11 Differential Dx Granulomatous Inflammation Sarcoid Sympathetic Lens induced IOFB VKH Syphilis TB MS associated uveitis Pathology Effects of Intraocular Inflammation Cornea KP, Band Angle Glaucoma Iris Synechiae, Atrophy Lens Cataract Vitreous Opacification Retina CME, ERM, Hemorrhage, Vasculitis Optic Nerve - Edema 11
12 HLA Associations A1 Sarcoid A11 Sympathetic Ophthalmia A29 Birdshot (98%) B5/B51 Behcets B7 POHS CNVM B12 OCP, Behcets B27 AS (90%), Reiter s (76%), AAU (55%), IBD, Psoriatic Arthritis Bw54 VKH, Glaucomatocycltis crisis Symptoms and Signs Sudden onset of pain, redness and photophobia Slow onset of floaters Decreased vision (photopsia, metamorphopsia, scotoma, and nyctalopia) Symptoms and Signs Conjunctiva/Episclera/Sclera Edema Hyperemia Diffuse Segmental Limbal 12
13 Symptoms and Signs Cornea Keratitis Epithelial Stromal Endothelial Band Keratopathy Keratic Precipitates (KP) Number Type Location 13
14 SUN WORKING GROUP Grading Inflammation Consensus Anterior chamber cells Anterior chamber flare Vitreous haze (NEI system; Ophthalmology 1985;92:467) 14
15 SUN WORKING GROUP Anterior Chamber Flare Grade Description 0 None 1+ Faint 2+ Moderate (iris & lens details clear) 3+ Marked (iris & lens details hazy) 4+ Intense (fibrin or plastic aqueous) Symptoms and Signs Anterior Chamber Aqueous Flare 1+ Faint 2+ Moderate (clear iris and lens) 3+ Marked (hazy iris and lens) 4+ Intense (fibrin) SUN WORKING GROUP Anterior Chamber Cells Grade Cells in field (1 x 1 mm slit) 0 < > 50* *Note hypopyon separately 15
16 Symptoms and Signs Anterior Chamber - EMO Aqueous Cell (1x3 mm beam at 5-10 degrees) 0 0 Rare Rare Occ 1-2 cells Trace 3-4 cells cells cells cells 4+ TNTC Hypopyon/Hyphema SUN WORKING GROUP Outcomes by Cells Inactive uveitis < 1 cell/field (i.e. a rare cell is inactive) Improved/worsened 2 step change or decrease/increase to inactive/4+ Remission Inactive off all Rx for > 3 mo Corticosteroid-sparing Able to taper to < 10 mg/day & uveitis inactive 16
17 Symptoms and Signs Iris Miosis Atrophy Heterochromia Synechiae Iris Precipitates Koeppe Busaca Berlin 17
18 Symptoms and Signs Lens Lens Changes Pigment Deposits Cataract PSC ASC 18
19 SUN WORKING GROUP Grading Inflammation, Definitions No consensus????? Vitreous cells Retinal vasculitis Inflammation and retinal vascular changes (sheathing, leakage) Not occlusive vasculopathy Glaucoma vs elevated intraocular pressure Disc damage and field loss Substantial rise IOP=10mm Hg Threshold for elevated IOP ( 21mm or 30mm vs 24 mm Hg) Symptoms and Signs Vitreous Vitreous Flare 0 Good view of NFL 1+ Clear ON & Vessels (hazy NFL) 2+ ON and Vessels hazy 3+ ON only 4+ No Optic Nerve 19
20 SUN WORKING GROUP Vitreous Haze VITREOUS CELL NEI Scoring System Grade Cells in field 0 < >250 VITREOUS CELL MUST Scoring System Grade Cells in field >50 20
21 Symptoms and Signs Vitreous Vitreous Cells (1x3 mm beam in anterior vitreous) Trace 1-10 cells cells cells cells 4+ TNTC Snowballs/Snowbanking Hemorrhage Traction/ERM Old vs New Cells Symptoms and Signs Sensory Retina Retinal Vasculitis Retinitis/Retinochoroiditis Hemorrhage Cotton Wool Spots Ischemia Retinal Precipitates Exudative RD NVE/CNVM Edema/CME 21
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23 Symptoms and Signs Retinal Pigment Epithelium RPE Edema Hypo-pigmentation Hyper-pigmentation RPE Detachments Symptoms and Signs Choroid Choroiditis/Chorioretinitis Choroidal Detachments Serous Exudative Hemorrhagic 23
24 Uveitis - Pathophysiologic Mechanisms Trauma Infectious Diseases Immunologic Diseases Masquerade Conditions Uveitis - Pathophysiologic Mechanisms Traumatic Forms of Uveitis Surgical Nonsurgical 24
25 Uveitis - Pathophysiologic Mechanisms Infectious Forms of Uveitis Viral Bacterial Fungal Protozoal Helminthic Insect 25
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28 Uveitis - Pathophysiologic Mechanisms Autoimmune Forms of Uveitis Type I Hypersensitivity (IgE mediated) Type II Hypersensitivity (ADCC) Type III Hypersensitivity (Immune Complex) Type IV Hypersensitivity (CMI) 28
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30 Uveitis - Pathophysiologic Mechanisms Masquerade Neoplastic Infectious Degenerative Uveitis Therapy General Principles Optimal therapy is predicated on an understanding of the predominant pathophsiologic mechanism(s) responsible for the uveitis Diagnostic efforts are therefore essential in the overall management and design of therapy for uveitis. Uveitis Diagnosis 1. Acquisition of Clinical Facts 2. Evaluation of Facts 3. Listing of Hypotheses 4. Choosing between the Hypotheses 30
31 Approach to the Uveitis Patient History Review of Systems (Uveitis Survey) Ocular exam General physical exam Differential diagnosis Directed laboratory investigation Treatment plan Follow-up Approach to the Uveitis Patient Age/Sex/Race History Clinical Course POHx Acute/Recurrent/Chronic Response to Therapy Location/Region/Layer Ocular Exam Type of Inflammation Biomicroscopic Exam Extent of Disease ROS, PE, Laboratory Eval. Etiology DDx Review of Systems 31
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33 Review of Systems Headache Deafness Paresthesia, weakness Psychosis : Sarcoid, VKH : VKH, Sarcoid : MS, Behcet s, steroid myopathy : VKH, Behcet, SLE, steroid 33
34 Review of Systems Salivary gland swelling Sarcoid, Lymphoma Lymphoid organ enlargement Sarcoid, AIDS Systemic vasculitis Wegeners, PAN, RP Behcet s, Sarcoidosis Sacroileitis AS, Reiter, IBD Immunosuppression CMV, opportunistic infection Physical Examination Physical Examination Vitilligo, poliosis VKH Erythema nodosum Behcet s, Sarcoid Skin nodules Sarcoid, onchocerciasis Skin Rash Behcet s, SLE, Sarcoid, Syphilis, virus, Herpes Zoster, psoriatic arthritis, PAN, Lyme 34
35 Ocular Examination Location/Region/Layer Conjunctiva/Cornea/Sclera Anterior Uveitis Intermediate Uveitis Posterior Uveitis Diffuse Uveitis Orbit/Optic Nerve Uveitis Location Anterior Intermediate Uveitis Location Posterior Diffuse 35
36 Ocular Examination Type of Inflammation Granulomatous Non-Granulomatous Uveitis Diagnosis Algorithm Extent of Disease Systemic Disease Local Ocular Disease 36
37 Evaluation of Clinical Facts All inclusive early in the process Sort out relevancy as the diagnostic evaluation progresses Uveitis Diagnosis Algorithm Location Anterior Posterior Intermediate Diffuse Type of Inflammation Granulomatous Non-granulomatous Extent of Disease Systemic Local Ocular 37
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43 Uveitis Diagnosis Choosing between the Hypotheses 43
44 Philosophy and Strategies for Diagnosis and Treatment Bayes Theorem the predictive value of any test depends on the prevalence of the disease within the population tested Testing in uveitis is based on the differential diagnosis NOT random testing Choosing Between Hypothesis - Testing No Testing Garden Variety Pathognomonic - Fuchs, VZV 44
45 Choosing Between Hypothesis - Testing Basic and Commonly Ordered Tests CBC ESR / CRP RPR / FTA-Abs ACE / Lysozyme ANA CXR Choosing Between Hypothesis - Testing Tailored Test to Diagnosis Blood Tests ANCA, TOXO Fluorescein Angiography OCT Ultrasound CT, MRI, CxR Aqueous & Vitreous ATB and PCR Tissue Biopsy 45
46 Fluorescein angiography CME Disc leakage Retinal, Choroidal NV Vasculitis Non- perfusion RPE derangement ICG angiography RPE/PR, choroidal disease Ancillary Tests 46
47 OCT CME VMT CNVM Subtle SRF ERG, MFERG Ancillary Tests CXR, Sacroiliac, Sinus Films TB, Sarcoid, HLA-B27, Wegener s CT, MRI, Gallium Scan Sarcoid, TB, Lymphoma, Toxo, MS B Scan Media opacity Chorioretinal pathology UBM Hypotony Cyclitic membrane CB detachment Atrophic ciliary processes Image Analysis Antibody Determination Intraocular antibody production ELISA (10-20 μl aqueous) Modified Goldman-Witmer coefficient (Specific Ab AC/serum) X (Nonspecific IgG serum/ac) Ratio 4 diagnostic, 2-4 suggestive HSV,VZV, CMV, EBV Toxoplasma gondii, Toxocara canis 47
48 Causes of Intraocular Infection Detectable by PCR HSV I, VZV, CMV, EBV Toxoplasma gondii Mycobacterium tuberculosis (65 kda sag ) Borrelia burgdorferi (41 kda flagellin gene ) Propronibacterium (Pa1, rpa2, rpa3 antigens) Fungi (28S rrna gene) Tropheryma whipelli (16S rrna gene) Intraocular lymphoma (IgH gene) Tissue Sampling Retinal, Subretinal and Chorioretinal Bx Skin, conjunctival, lacrimal Bx 48
49 Uveitis Diagnostic Surgery Principles Biopsy tissue at the border between active disease and healthy retina Avoid major choroidal and retinal vessels Select lesions in the superior fundus for tamponade Nasal locations lessen risks of macular hemorrhage Retinal biopsy for posterior, sensory retinal disease Chorioretinal biopsy for anterior, chorioretinal diseas Retinal Biopsy Chorioretinal Biopsy Goals: Differentiate infectious, immune, maligna and degenerative processes Indications: Unresponsive uveitus with VA <20/200 Result will change Rx Alternative to enucleation Technique: Localize, TPPV, Trap Door, Diathermy, Excise Tissue, AFGE, Close and Cryo Complications: RD, Vit Heme, Cat, Leak, Hypotony, Tear Specimen: ¼ Gluteraldehye (EM and Light Microscopy) ¼ Culture ½ OCT (Frozen Sections) 49
50 Chorioretinal Biopsy Chorioretinal Biopsy 50
51 Retinal Biopsy Retinal Specimen Vitreous Cytology No CMV Toxoplasmosis Medical Management of Non-Infectious Uveitis E. Mitchel Opremcak M.D. Clinical Associate Professor of Ophthalmology The Ohio State University The Retina Group Columbus, Ohio 51
52 Therapy - General Principles Optimal therapy is predicated on an understanding of the predominant pathophsiologic mechanism(s) responsible for the uveitis Diagnostic efforts are therefore essential in the overall management and design of therapy for uveitis. Trauma, Infectious, Immunologic, and Masquerade Therapeutic Principles Preservation of function Risk benefit ratio Understand the diagnosis Stepladder algorithm Expert chemotherapist Use enough, soon enough Informed consent document General Principals Goals of therapy include Reduction of inflammation Comfort Lessening of complications Preserve or improve vision 52
53 Conclusions The goal of NO INFLAMMATION on NO STEROID can be achieved through a paradigm of a stepladder algorithmic approach to therapeutic aggressiveness Ocular Inflammation and Immunology Management Specific Therapy Infectious (Antibiotic) Antiviral Acyclovir, Famvir, Ganciclovir, Zirgan Antibacterial PCN, TCN, INH Antiprotozoal Daraprim, Sulfa, TCN Antihelmintic Thiabendazole, Pyranyl, Suramin, Ivermectin Ocular Inflammation and Immunology Management Specific Therapy Autoimmune Type I Eliminate Agent, Cromolyn Antihistamine, camp/cgmp, Corticosteroids. Type II Dapsone, Coritcosteroids, Cytotoxic Agents, Surgical 53
54 Ocular Inflammation and Immunology Management Autoimmune Specific Type III NSAID, Corticosteroids, Colchicine, Cytotoxic Agents, Plasmapheresis, CSA, Biologicals (Remicade, Humira) Type IV Corticosteroids, CSA, Cellcept, Cytotoxic Agents, Surgical Lens Induced Uveitis Therapeutic Approach Routes of Medication Delivery Topical Drops and ointments Regional Periocular injections Systemic PO or IV Intraocular Injection Triamcinolone Retisert Ozurdex implants 54
55 Routes of Delivery Nonspecific Treatment Topical Mydriatic agents Cycloplegic agents NSAID Corticosteroids Mydriatic and Cycloplegic Agents Indications Uveitis with cells in anterior chamber Lessen photophobia Prevent synechiae 55
56 Anterior and Posterior Synechiae Mydriatic and Cycloplegic Agents Atropine (1%) Homatropine (5%) Scopolamine (1/4%) Tropicamide (1%) Cyclopentolate (1%) Mydriatic and Cycloplegic Agents Use 1-3 times a day Move the pupils Monitor for adhesions 56
57 Posterior Synechiae Therapeutic Approach Corticosteroids - These agents have a rapid and broad anti-inflammatory effect Inhibit arachidonic membranes Stabilizing cell membranes Decrease vascular permeability Reduce chemotaxis Inhibit macrophage activity Decrease interleukin production 57
58 Topical Corticosteroids Indications-Anterior uveitis Preparations Acetate suspensions 1% Pred Forte Phosphate solutions Rimexolone, loteprednol and fluorometholone Difluprednate 0.05% Durezol Anterior Uveitis Topical Corticosteroids Approach Begin treatment aggressively Taper dose guided by cellular response Maintain treatment using lowest dose Monitor for complications 58
59 Glaucoma Cataract Regional Corticosteroids Periocular Indications Severe anterior, intermediate, diffuse and posterior forms of uveitis or CME Preparations Triamcinolone (40 mg/ml) Methyprednisolone (80 mg/ml) Betamethasone (4 mg/ml) 59
60 Nonspecific Treatment Regional Through the lid, septum or conjunctiva Subconjunctival corticosteroids Subtenon s corticosteroids Retrobulbar corticosteroids Regional Delivery Routes 60
61 Transeptal Sub-Tenon s Pars planitis before and after STK Fluorescein angiogram with CME before and after STK 61
62 Globe perforation following STK Glaucoma Retinal Necrosis Intraocular Corticosteroids 62
63 Intraocular Injection Injection Techniques - Anesthesia Topical Proparacaine Lidocaine gel Akten/tetravisc Subconjunctival 1-2% Lidocaine Injection Techniques - Anesthesia 63
64 Injection Techniques Set up Injection Techniques Povidone-iodine % Injection Techniques - Speculum 64
65 Compounding Pharmacies Multistate Fungal Meningitis Outbreak Investigation CDC Responds to Multistate Fungal Meningitis Outbreak The Centers for Disease Control and Prevention (CDC), in collaboration with state and local health departments and the Food and Drug Administration (FDA), is investigating a multistate fungal meningitis outbreak among patients who received contaminated steroid injections. This form of meningitis is not contagious. The investigation also includes fungal infections associated with injections in a peripheral joint space, such as a knee, shoulder or ankle. See Current Situation Update This website was last updated October 21, :00 PM EDT At-A-Glance Status: Ongoing Investigation Infection: Fungal Facility Type: Outpatient Setting Case Count: 285 States: 16 Deaths: 23 Multistate Meningitis Outbreak November 2,
66 Intraocular Triamcinolone Intraocular Triamcinolone 66
67 Intraocular Kenalog Intraocular tpa MTX 400 ug/0.1 ml Avastin 1.25 mg/0/1 ml Ozurdex Cataract (100%) and glaucoma (75% with 40% filter) 67
68 Nonspecific Treatment Systemic Nonsteroidal Anti-Inflammatory Agents 1 st Generation Immunosuppressive- Steroids 2 nd Generation Immunosuppressive- MTX, Cytoxan 3 rd Generation Immunosuppressive- CSA, Neoral, FK-506, Cellcept Biologicals Remicade, Humira, Rituxamib CME 68
69 Systemic Corticosteroids Indications Severe or systemic forms of uveitis Preparations Oral prednisone (1mg/kg) IV solumedrol (1gm) Systemic Corticosteroids Approach Begin aggressively and taper Switch to low dose or alternate day Use for 6 to 12 months <10-15mg day Monitor for complications Bone densitometry Calcium and Vitamin D Biphosphonates Vitritis from sarcoidosis before and after oral prednisone 69
70 Steroids Potential Complication Likelihood Cataract High Glaucoma 10% Globe Perforation Low Iatrogenic Cushing s High Bone Loss High Growth Retardation High Steroids Potential Complication PUD HBP DM Psychosis Myopathy Hirsutism Likelihood Moderate Low Low Moderate Low Moderate 54 year old WF with five years Hx SLE treated with 60mg prednisone by FMD. No rheumatologist or IMT. Complaining of 3 year history of pain and LOV from scleritis. Cushing s Syndrome CHF Bruising Bone Fx HBP IDDM GI Bleed & Anemia Renal Dialysis Increase ICP Obesity Muscle wasting Glaucoma Tubes OU Cataracts MRI with active SLE 70
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72 Immunosuppressive Agents Indications Severe sight threatening forms of uveitis Reversible disease Uveitis unresponsive to steroids Intolerance of corticosteroids Systemic inflammatory diseases International Uveitis Study Group Guidelines for Use of Immunosuppressive Chemotherapy ABSOLUTE INDICATIONS Sympathetic ophthalmia Vogt-Koyanagi-Harada disease Rheumatoid sclerouveitis Adamantiades-Behçet disease Oral ulceration from Behcet s Disease 72
73 International Uveitis Study Group Guidelines for Use of Immunosuppressive Chemotherapy RELATIVE INDICATIONS Intermediate uveitis Retinal vasculitis JRA uveitis Severe chronic uveitis American Uveitis Society Consensus Panel on Immunosuppression for Ocular Inflammatory Disorders Participants: 12 physicians with expertise in the use of immunosuppressive drugs in rheumatology, pediatrics and ophthalmology American Uveitis Society CONCLUSIONS Good evidence for the effectiveness and for the need for immunosuppression OCP Necrotizing scleritis Sympathetic MCP Serpiginous Behçet Birdshot JRA and others 73
74 Immunosuppressive Agents General Prescribed by experienced practitioners Used for prolonged periods of time Onset of action is slower Used in conjunction with steroids Monitor for side effects and toxicity 74
75 Treating Inflammation Immunomosuppressive Agents Methotrexate Leflunomide Azathioprine Mycophenolate mofetil Tacrolimus Cyclosporin Cyclophosphamide Chlorambucil Cytosine arabinoside Biologic Response Modifiers IV-Ig Infliximab Adalimumab Daclizumab Anakinra Interferon Rituximab Abatacept 75
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