How and Why Should we Care? Muge R. Kesen, MD Retina Specialty Institute (RSI)

Disclosure No financial interest or relationships to disclose.

Objectives Overview of different types of uveitis Diagnostic work-up Management (local and systemic) When to refer

Anatomic Classification of Uveitis Type Primary site of Inflammation Includes Anterior uveitis Anterior chamber Iritis Iridocyclitis Anterior cyclitis Intermediate uveitis Vitreous Pars planitis Posterior cyclitis Hyalitis Posterior uveitis Retina & choroid Choroiditis Chorioretinitis Retinochoroiditis Panuveitis Anterior chamber, vitreous and retina/choroid

**Some of recent cases from our uveitis clinic HLA-B27 associated uveitis Ocular toxoplasmosis Cat scratch disease Endogenous endophthalmitis Bacterial Fungal

Anterior Uveitis Most common form of uveitis Accounts for 75% of cases Annual incidence rate of about 8/100,000 population Most have no identifiable cause In some series HLA-B27 is associated with the disease in up to a third of patients

Complications in the anterior segment - Posterior synechiae - Cataract - Glaucoma Posterior Synechiae

Keratic precipitates (KPs) Usually in the lower half as a result of aqueous convection currents in an area referred to as Arlt s triangle

Anterior uveitis Idiopathic HLA-B27 JIA Fuchs HIC Sarcoidosis Syphilis Masquerade syndromes

Standardization of Uveitis Nomenclature (SUN) SUN for Reporting of Clinical Data by SUN Working Group 1 st international workshop in November 2004 50 participants from 35 centers in 13 countries Dr. Goldstein from UIC Am J Ophthalmol 2005; 140:509-516

Anterior Chamber Cells Grade Cells in field 0 0 ½+ 1-5 1+ 6-15 2+ 16-25 3+ 26-50 4+ >50 Presence of hypopyon should be recorded separately.

Anterior Chamber Flare Grade Description 0 None 1+ Faint 2+ Moderate (iris/lens details clear) 3+ Marked (iris/lens details hazy) 4+ Intense (fibrin+)

Spectral-Domain Optical Coherence Tomography (SD-OCT) Normal macula Cystoid macular edema

HLA-B27 associated anterior uveitis Some studies suggest 50% of patients with acute anterior uveitis are HLA-B27 positive More often male Average age at onset: 36 years, without any difference between males or females Systemic disease developed earlier in males and bilateral uveitis developed more frequently in females

Etiology Gram negative bacteria, and their interaction with major histocompatibility complex (MHC) class I antigens H pylori has also been associated with anterior uveitis

Uveitis Topical corticosteroids Cycloplegics Periocular steroids Systemic steroids Treatment Associated systemic disease Ankylosing spondylitis: physical therapy and antiinflammatory medications, including NSAIDs, methotrexate, anti-tnf agents Reactive arthritis: NSAIDs, methotrexate, azathioprine, anti-tnf agents Psoriatic arthropathy: anti- TNF agents Inflammatory bowel disease: anti-tnf agents

Case 1 53 year old male, referred for decreased vision and pain in the left eye for about 2 weeks. Diagnosed with iritis, treated for 1 week Prednisolone Acetate Cyclopentolate OD OS Va 20/20 HM at face IOP 5 18

No view to fundus OS due to dense fibrin in the anterior chamber

Initial management Diagnostic testing AC tap Gram stain Cultures (Bact/fungal) HLA-B27 Toxoplasma titers HSV, VZV titers FTA-ABS Quantiferon Gold Treatment Switch to DUREZOL OS QID Add Vigamox OS Q1H WA Cyclogyl OS TID Start systemic treatment oral prednisone 40mg/d Valtrex 1g TID Cipro 500mg BID

Decreased pain Va OS: HM ( improving ) Toxoplasma IgG Positive Switched to Azithromycin

January 30, 2014

Case 1 Follow-up No longer have pain, vision improving. HLA-B27 Blood in tube frozen during transportation. OD OS Va 20/20 20/80 DFE WNL Poor view, no retinitis VALTREX discontinued February 4, 2014

HLA typing repeated: HLA-B27 POSITIVE Discontinue Azithromycin

HLA-B27 associated anterior uveitis Fibrin mixed with hyphema Dilated iris vessels OD OS Va 20/25 20/63 DFE WNL No retinitis February 20, 2014

February 20, 2014 On oral steroid taper Ran out of Durezol Switched to Prednisolone Acetate Continue with cyclopentolate

OD OS Va 20/25 20/40+ SLE Quiet Quiet DFE WNL WNL Resolved fibrin Off all medications Asked to follow-up with PCP for any other systemic problems June 12, 2014

Diagnosis can be challenging..

Metastatic lung cancer presenting as iris nodule and eye inflammation

Ocular toxoplasmosis Common disease in mammals and birds MOST common cause of posterior uveitis in adult population Mainly acquired postnatally Obligate intracellular protozoan Toxoplasma gondii Cosmopolitan : Infects at least 500 million people worldwide 50% of the adult population in US has symptomless form

Oocysts intestinal mucosa - cats Vectors Humans Other animals

Contaminated water should also be considered as a vector

In humans Toxoplasmosis Cysts: may contain> 1000 organisms, propensity for cardiac tissue, muscle, neural tissue (retina) can remain intact in soil >1year Tachyzoites: obligate intracellular organism, is the cause of acute disease

Clinical Manifestations - Toxoplasmosis Systemic Lymphadenopathy in 90% with fever, malaise and sore throat Muscle, skin, brain, heart and kidney involvement Death rare in immunocompetent host Ocular Most commonly with toxoplasmic encephalitis

Ocular Toxoplasmosis - Symptoms Decreased vision Floaters Redness Pain Light sensitivity

Ocular toxoplasmosis Focal retinitis of various sizes Reactivation with satellite lesions Overlying vitreous cells Retinal hemorrhages Vascular sheathing Granulomatous/non-granulomatous uveitis Transient increase in IOP - No correlation between anterior segment inflammation and IOP, medical therapy usually enough for treatment

Ocular Toxoplasmosis Congenital Usually bilateral Multiple satellite lesions located particularly in the macula Acquired Focal area adjacent to a chorioretinal scar, sometimes without the presence of a scar Genetic studies have identified 3 distinct lineages of T. gondii genotypes, although mixed and atypical strains have also been described.

Congenital Ocular Toxoplasmosis

Acquired Ocular Toxoplasmosis

Loss of vision Ocular Toxoplasmosis Direct involvement of fovea Choroidal neovascularization Optic nerve involvement Swollen disk with a distant lesion Swollen disk juxtapapillary lesion Mixed lesion Swollen disk with periphlebitis, vitritis, healed lesion (pure papillitis) Neuroretinitis: swollen disk with macular hard exudates Retinal vein occlusions Retinal detachment

Ocular Toxoplasmosis - Diagnosis Primarily clinical Additional supportive test: Toxoplasmosis titers Immunofluorescence antibody test ELISA PCR of serum or intraocular fluid (aqueous,vitreous)

Ocular toxoplasmosis - Treatment When to treat? Lesion within temporal temporal arcade Abutting optic nerve Threatening a large retinal vessel Induce a large degree of hemorrhage Enough vitreal inflammation to drop vision below 20/40 (20/20 baseline) 2 line drop from previous Va Multiple recurrences with vitreal condensation

Ocular Toxoplasmosis - Treatment Which drug combination? Sulfadiazine (1g QID) Pyrimethamine (50mg one day followed by 25mg QD or BID) Aplastic anemia Folinic Acid (3-5mg 3 times per week) + Prednisone (20-40mg/d), beginning 12-24 hours after antimicrobial tx

Ocular Toxoplasmosis - Treatment Prednisone Should NEVER be administered alone Should NEVER be given at higher doses for prolonged period of time Periocular steroid injections are NOT to be used as monotherapy - avoid injections

Ocular Toxoplasmosis - Treatment Drug combinations Clindamycin (oral, subconjuctival, intravitreal) pseudomebranous colitis Sulfadiazine Stevens Johnson syndrome, hemolytic/aplastic anemia Trimethoprim-sulfamethoxazole (Bactrim) Atovaquone (Mepron) Azithromycin (especially in pregnancy)

Safety of Medications in Pregnancy Medication Tetracyclines Pyrimethamine TMP/SMX Sulfadiazine Prednisone Azithromycin Atovaquone Clindamycin Folinic Acid A: Established safety C: Uncertain safety Safety Category D Category C Category C Category C Category C Category B Category B Category B Category A B: Presumed safety D: Unsafe

Ocular Toxoplasmosis - Treatment Additional Therapeutic Approaches Intravitreal Clindamycin and dexamethasone Laser photocoagulation Vitrectomy Antimicrobial therapy is usually administered perioperatively.

Case 2

Va OD: 20/32 Va OS: 20/80 January 2, 2012

Management AC tap for Toxo and VZV/HSV PCR Start quadruple therapy Sulfadiazine (1g QID) Pyrimethamine (25mg BID) Leucovorin Prednisone (40-60mg/d, initiate after 2 days of antimicrobial therapy) Start oral acyclovir (400mg 5 times a day) Start Prednisolone Acetate, cyclopentolate Quadruple therapy for ocular toxoplasmosis. Lam S, Tessler HH. Department of Ophthalmology, University of Illinois Hospital Eye and Ear Infirmary, Chicago College of Medicine. Can J Ophthalmol. 1993 Apr;28(2):58-61.

Results Toxo IgM: 160.0 (Reference range: <8.0AU/mL) Toxo IgG: 184.0 (Reference range: <6.0AU/mL) Aqueous PCR Toxo: Positive HSV: Negative VZV: Negative Discontinued Acyclovir

FDA-Approved PCR tests HIV-1 Hep C M. tuberculosis N. Gonorrhea C. Trachomatis Aspergillus galactomannan Cons: Highly sensitive Not well studied for ocular fluids

Follow-up - January 10, 2012 Va sc OS: 20/40 DFE OS: Much improved retinitis and vitritis

Dense epiretinal membrane

Dense epiretinal membrane causing disruption of the macular architecture

Underwent pars plana vitrectomy/membrane peel OS Post-epiretinal membrane peel Ocular toxoplasmosis

Post-epiretinal membrane peel Ocular toxoplasmosis

Case 3 Ocular toxoplasmosis

Epiretinal membrane (ERM) in ocular toxoplasmosis

Post- epiretinal membrane peel Ocular toxoplasmosis

Cat scratch disease (CSD)

Cat scratch disease (CSD) Bartonella Henselae infection 5-10% of patients with CSD develop ocular involvement Parinaud s Oculoglandular Syndrome 5% Neuroretinitis - 1-2% of symptomatic patients Neuroretinitis as described by Theodor Leber and later by Donald Gass: acute unilateral visual loss associated with an exudative optic neuritis with transudation into the macula forming a partial or complete macular star

Cat scratch disease - Diagnosis The diagnosis of CSD has historically been made clinically Serology IFA - indirect fluorescent assay ELISA - enzyme-linked immunoassay Where available, broad PCR-based screening of aqueous or vitreous for bacterial and viral DNA, including Bartonella species, may be considered in patients with chronic uveitis refractory to treatment

Treatment Doxycycline, azithromycin, ciprofloxacin, rifampin, sulfamethoxazole/trimethoprim 2-4 weeks in immunocompetent patients Up to 4 months in the immunocompromised Doxycycline should not be given to young children, in whom tooth discoloration is a possibility Patients with severe optic nerve or macular inflammation may benefit from corticosteroids in addition to antimicrobial treatment

Case 4

Case 4 Initial presentation Referred for infection in the left eye. decreased vision in the left eye for 1 week. OD OS Va 20/25 20/400 SLE WNL WNL DFE Focal choroiditis Focal choroiditis Subretinal fluid in macula

Case 4 Initial presentation

Initial management Diagnostic testing Bartonella titers Toxoplasma titers FTA-ABS Quantiferon Gold Lyme titers HIV Treatment Admit and ID consult Start systemic treatment Azithromycin Voriconazole

March 5, 2012 1 week follow-up Worse clinically

Added oral steroids to therapy

Follow-up 2 weeks Improving clinically and functionally Va OD: 20/25 Va OS: 20/50

Follow-up 4 weeks Improving clinically and functionally Va OD: 20/25 Va OS: 20/60 ph 20/40

Follow-up 4 weeks Much improved anatomically and functionally Va OD: 20/25 Va OS: 20/60 ph 20/40

Endogenous endophthalmitis

Endogenous endophthalmitis Endogenous endophthalmitis (EE) also termed metastatic endophthalmitis, occurs when organisms disseminate through blood-borne spread and enter the internal ocular spaces through the blood-ocular barrier Much less common than exogenous endophthalmitis and has been reported to account for 2 8% of all cases of endophthalmitis

Bacterial endophthalmitis Typically starts as a focal or multifocal chorioretinal lesion Wide range of bacteria: Streptococcus Staphylococcus Serratia Bacillus Klebsiella -- exaggerated posterior segment involvement with rapid progression, retinal necrosis, and extensive sub-retinal abscess formation in days

Endogenous endophthalmitis Identify extraocular source using medical consultation Endocarditis GI Urinary tract Ocular or extraocular specimen and cultures Initiate treatment: Intravenous antibiotics Intravitreal antibiotics

Endogenous endophthalmitis Intravitreal antibiotics in addition to systemic antibiotic treatment Aggressive early treatment with early vitrectomy in suspected bacterial EE cases may be appropriate Much remains unclear regarding the correct ophthalmic approach particularly in relation to early surgical interventions

Vitrectomy in cases of endophthalmitis is useful decreases the pathogen load decreases the inflammatory mediators in the vitreous adequate sampling is obtained for micro analysis helps in speedy visual recovery of the patient

Case 5 June 21, 2012 38 yo female referred for pain and decreased vision in the right eye for few weeks Diagnosed with iritis Started on steroid eye drops Later treated with oral steroids when failed to respond to topical steroid drops 120 mg/d x 1 day 100 mg/d x 1day then taper

Case 5 Initial presentation OD OS Va LP 20/32 SLE Severe panuveitis WNL DFE No view WNL Initial management Urgent diagnostic vitrectomy Admitted with ID consult

Case 5 Follow-up Clinically worse despite systemic and intravitreal antibiotics and antifungals Underwent 2 nd vitrectomy Gram stain GRAM + Cocci Cultures Klebsiella pneumonia CT ABDOMEN: Renal abscess Internal medicine to orchestrate management

Vision OD later deteriorated to NLP Eye became phthisical Due to pain, underwent enucleation OD Developed one lesion OS complete resolution following intravitreal Vancomycinx1 OS

Case 5 1 month follow-up Underwent renal abscess drainage by IR CT chest Multiple intraarterial filling defects compatible with pulmonary emboli started on warfarin MRI brain Ring enhancing lesions, suggestive of microabscesses -- Long-term treatment with intravenous antibiotics

Case 5 4 month follow-up Brain lesions and renal abscess resolved clinically Follow-up MRI demonstrated marked improvement Systemic antibiotics discontinued in 4 months OD OS Va Prosthesis 20/20 DFE Prosthesis WNL

Endogenous yeast endophthalmitis

Endogenous yeast endophthalmitis Most often caused by Candida spp History of indwelling catheters, chronic antibiotic use, abdominal surgery, AIDS, systemic autoimmune disease, or immunosuppression, malignancy, diabetes, iv drug abuse Diagnosis usually is clinical Random vitreous tap usually is of low yield Infectious disease consultation

Endogenous yeast endophthalmitis Visual prognosis is good if macula is not involved Focal chorioretinal lesions, and those outside of the macula usually are successfully treated solely with systemic medications Sight-threatening lesions in the macula and chorioretinitis with vitritis usually necessitate intravitreal injection of antifungal agents, with or without vitrectomy

Fluconazole Treatment Its mode of action is inhibition of ergosterol found in the cell membranes of yeasts and other fungi Fewer data are available in humans, but it appears that vitreous concentrations are approximately 70% of those in plasma well tolerated when injected intravitreally Because of its excellent intraocular concentrations and safety, fluconazole has become a preferred agent Usually given as the sole agent for chorioretinitis and combined with intravitreal therapy and/or vitrectomy for more advanced disease with vitreal involvement

Treatment Voriconazole Posaconazole Echinocandins micafungin, caspofungin, and anidula- fungin, penetrate ocular compartments poorly

Treatment No studies have defined the appropriate duration of therapy. A reasonable approach is to treat for at least 4 6 weeks, with the final duration dependent on the response observed in repeated ophthalmologic examinations.

Case 6 Initial presentation Referred for pain and decreased vision in the right eye. OD OS Va CF at 3ft 20/25 SLE +1 cells, +2 flare Deep and quiet DFE Initial management Dense vitritis Optic nerve swelling Macular infiltrate Urgent diagnostic vitrectomy Admitted with ID consult WNL

At presentation

Post-vitrectomy and intravitreal Voriconazole injection (POD #4)

Post-vitrectomy (POW #1)

Treatment: Oral fluconazole Prednisolone acetate Cyclopentolate Va OD: 20/400 Va OS: 20/20 Post-vitrectomy (POW #2)

Case 6 Follow-up Cultures grew candida famata Continued with oral fluconazole Received repeat intravitreal Voriconazole for persistent vitreous and preretinal infiltrates

Case 6 3 month follow-up OD OS Va 20/40 20/25 SLE Deep and quiet Deep and quiet DFE Mild ERM No retinitis WNL Completing systemic anti-fungal course Topical steroid taper Chose to follow-up in Oakland due to transportation difficulties

Thank you