Visionary Ophthalmology, September 18, 2011

Clinical Aspects of Infectious Uveitis

H. Nida Ġen, MD, MHSDirector, Uveitis and Ocular Immunology Fellowship Program

National Eye Institute, National Institutes of Health

Associate Clinical Professor, Dept of OphthalmologyThe George Washington University

Washington DC, 20037

Infectious uveitidesViral uveitis

Hepesviridae familyHIVHTLVOther (Rubella, west nile, measles, LCV)

Fungal uveitisOHS, Candida, Aspergillosis, Cryptococcosis

Protozoal UveitisToxoplasma

Helminthic uveitisToxocara, cysticercosis, DUSN, onchocerciasis

Bacterial uveitisSyphilis, Lyme, Tuberculosis, Bartonella, leptospirosis, nocardiosis

Infectious EndophthalmitisPostoperative, posttraumatic, endogenous endophthalmitis

Viral Uveitis-Herpesviridae family (HSV I/II, CMV, VZV and EBV)

Anterior uveitisR/o viral retinitis esp immunocompromised host

Treatment:topical steroids and cycloplegics (topical antivirals not useful except to prevent recurrence of keratitis if present)Oral antivirals in severe recurrent cases

400 bid acycl/500qd valacycl for HSV, 800bid acycl/1000qd valacycl for VZV

Herpesviridae family Retinitis

Acute Retinal Necrosis (ARN)Described in 1971 (Urayama et al)Typically in otherwise healthy immune-competent adults , starts unilateral (2nd eye involvement in up to 36%)

M=F, 5th to 7th decadesVZV HSV CMV (+-EBV)

Genetic predisposition: HLADQw7, Bw62, DR4 (caucasian), Aw33, B44, DRw6 (japanese)

Clinical criteria (AUS):Peripheral retinal necrosis with discrete borders with circumferential spread

typically full-thickness lesions that are white or cream coloredRapid progression w/out txOcclusive vasculopathy

with arteriolar involvementProminent vitritis

and AC inflammationComplications: Retinal breaks and RD (~75%), NV and VHDx: clinical + PCR from ocular fluid

ARN

ARN treatmentTreatment:

Antivirals: induction + maintanance (3 mo)iv acyclovir (?PO)

decreases risk of bilateral involvement Treatment with antivirals does not reduce the risk of RD

intravitreal gancyclovir/foscarnet injection+ steroidsVitrectomy/RD repair for complications? Prophylactic laser barricade

Prognosis: GuardedRegardless of complications visual outcome is poor

Herpesviridae family Retinitis-PORN

Progressive outer retinal necrosis (PORN)primarily in immunocompromised individuals (in contrast to ARN)

Advanced stages of HIV (CD4<50)Also described post-transplant

Clinical characteristics:multiple patchy areas of outer retinal whiteninglittle or no inflammatory componentspares the retinal vasculature

progression to confluent full thickness retinal necrosis occurs more rapidly (hence the name �“progressive�”)can involve the posterior pole early more likely to progress to bilateral involvement (~70%)

Virus: VZV most common (HSV also reported)

Diagnosis: clinical +PCR (quantitative helps in determining tx response)

Complications: RRD (75%)

Differs from ARN

No inflammationVessels sparedEarly post pole involvement

PORN-treatment

Treatment: anti-HIV (HAART) + i.v antiviral + intravitrealganciclovir+foscarnetGanciclovir implantImmune reconstitutionSurgery for complications

Prognosis:Poor visual outcome despite antiviral treatment

No light perception in 67% of eyes

CMV retinitisTypically in imunocompromised patients with HIV/AIDS

CD4 counts of less than 50-100 cells/˩Lmost common ocular opportunistic infection in patients with AIDS

Less since HAARTCan occur after renal transplantation or primary immune deficiencies

Two classical clinical appearances to CMV retinitis:1.

Perivascular inflammation with irregular patches of necrotizing retinitis with hemorrhage

2. Granular lesion with central clearing and stippled retinal pigment epithelium.Other features: frosted branch angiitis, CME, retinitis progresses at the edge of previous retinal lesions (250 ˩m per week)

Complications: RRD (20%)IRU (20% to 90%) risk w/larger area

vitritis, anterior uveitis, macular edemaBelieved to represent recovery of CMV-specific immunity

topical, periocular,or oral steroids (reactivation!)

59 yo moroccan male with h/o leukemia s/p chemotherapy

Patient with HIV

28 yo

F with angioimmunoblastic

T-cell lymphoma s/p

chemo

43 yo

jamaican

female c h/o

HTLV-1 associated adult lymphoma/leukemia s/p6 cycles of EPOCH-FR recently started on EPOCH-Campath

(Alemtuzumab)

20/20= 20/25

CMV retinitis-treatmentTreatment:

ganciclovir, foscarnet, cidofovir (Vistide, Gilead), fomivirsen(Vitravene, Novartis), and valganciclovir (Valcyte, Roche)

Iv ganciclovir (5 mg/kg bid) for 2 weeks (induction) once a day (maintanance)

replaced by oral valganciclovir

Intravitreal injection (ganciclovir/foscarnet)Intravitreal implant (ganciclovir)

6-8 month (x4 concentration than iv ganc)

HAART/Immune recoverywithout HAART 50% reactivation despite anti-CMV therapy

Prognosis:It may take 2-6 wks for progression to haltvision loss due to macular or optic nerve involvement OR CME

FDA approved

4.5 mg gancyclovir, releases 1.4ug/hr

CMV retinitis-treatment resistance

Phenotypic and genotypic resistance to gancyclovir can occur

most often secondary to mutations in the CMV UL97 gene (viral phosphotransferase)

UL54 (viral DNA polymerase)The rate of resistance has declined dramatically with HAART therapy(28% to ~9%)Can be overcome with higher doses (intravitrealinjection or implant)

52F HIV+ F from Ethiopia referred for recurrent CMV retinitis OSwhile on Valganciclovir

x 5 mo & HAART (CD4 135)

Anterior chamber tap (aqueous) and blood CMV PCR

genotypic resistance to ganciclovir in blood but not in ocular fluids

ToxoplasmosisInfects at least 500 million persons worldwide ~50% in US

A survey of ophthalmologists in the US: 55% of those who responded saw ุ1 active ocular toxoplasmosis cases in last 2 years93% of those who responded had seen inactive cases in the last 2 years.In the United Kingdom the estimated lifetime risk for ocular toxoplasmosis ~ 18/100 000

North East:

29.2%

South:

22.8%

Mid West:

20.5%

West:

17.5%

The disease is caused by the obligate intracellular protozoan Toxoplasma gondii.

Toxoplasmosis InfectionCongenital: transplacentaltransmission to the fetus

chorioretinitis, encephalitis, other birth defects (TORCHS)

Acquired:Ingestion of contaminated, undercooked lamb or pork (cysts)Ingestion of oocysts from soil, milk, water or unwashed vegetablesrarely contaminated blood transfusions, organ transplants etc

Acute infection: a flu-like illness with lymphadenopathy, fatigue, fever and malaise (~3-7%)Recurrent infections: chorioretinitis, lymphadenitis, myocarditis, polymyositis

Definitive host

Ocular toxoplasmosisOcular disease can occur after both congenital and acquired disease.Clinically: anterior uveitis, vitritis with a prominent haze (headlight in the fog) and necrotizing chorioretinitisRecurrent disease frequently is seen as a satellite lesion.Immunodeficient patients are at risk

Courtesy of Rubens Belfort, MD

Courtesy of Rubens Belfort, MD, MBASao Paulo, Brazil

Treatment and PrognosisTreatment: There are no randomized, controlled large-scale clinical trials to guide therapeutic choice of agents.

Pyrimethamine, sulfadiazine are used with or without prednisone.

prednisone recommended to start 24 to 48 hours after the antibiotics are started. periocular or intraocular steroid injections are not recommended

Bactrim (trimethoprim/sulfamethoxazole), clindamycinAtovaquone and Azithromycin.

Bactrim prophylaxis?Silveira et al: 1998-2000, 7% recurrence in bactrim group vs24% recurrence in control group. Complications: fovealinvolvement, ERM, CNV, BRAO, BRVO, cataract, glaucoma and CME

Prognosis; Complications may result in permanent visual loss.Most patients retain good vision

Toxocariasis

Human toxocariasis is a helminth zoonosis due to the infestation of humans by ascarid larvae belonging to the genus Toxocara.

Toxocara canis and T. cati causative agents of human disease Seroprevalence: 2-5% in western world to 60-80% in tropical countries

Adult form lives in the upper digestive tract of their definitive hosts (cats/dogs) and eggs are passed in the feces

Can be passed via the placenta in dogs only, milk for catPrimarily soil transmitted

Pica, poor personal hygiene, raw vegetables, raw meat, exposure to puppies and kittens

Ocular ToxocariasisResult of migration of larva to the eye �“ocular larva migrans�”

Primarily in young patientsOcular toxocariasis: ~1.0% uveitis patients Most patients report a history of recent exposure to puppiesUnilateral

50% - a granuloma in the peripheral retina (age: 6-40)25% - a granuloma in the macula (age:6-14)25% - endophthalmitis (age: 2-8)

Diagnosis:Serum ELISA: NEGATIVE in up to 50% ! OR AC/Vitreous tap

Peripheral blood eosinophilia (may be absent in ocular toxocara)

Serum total IgE ൹, LFTs ൹Imaging for liver, lung, CNS involvement

Complications: TRD, CME, VitritisVitritis 52.6%, CME 47.4%, TRD 36.8%

Presenter

Toxocara lesion with neurosensory tractional RD (from sao paulo)

Ocular toxocariasis

Treatment:Albendazole 10mg/kg PO BID x 5-14d (better tolerated and larger decrease in eosinophilia)

Thiabendazole 25mg/kg PO BID x 5-14dPrednisone

IvermectinNot very effective and not recommended

SyphilisMay affect all ocular tissue; uveitis is most common, Bilateral in 50% of the casesGreat masquarader Anterior, intermediate, posterior and panuveitis, retinitis, retinal vasculitis, papillitis and neuroretinitisTests for syphilis fall into four categories

1. Direct microscopy when lesions are present2. Nontreponemal tests: VDRL, RPR

Clumping of cardiolipin ( lecithin and cholesterol)False Negative in 30%False positive in SLE and other autoimmune disorders, tissue damage, liver diseases, pregnancy, other Treponema- Lyme disease, Leptospirosis

3. Treponemal tests FTA-ABS (Fluorescent Treponemal Antibody absorption test) detects antibody to T. pallidum after serum treated with nonpathogenic treponemal antigen; High sensitivity and specificityMHA-TP (Hemagglutination tests):

15% + in SLE and can be + in Lyme disease4. Direct antigen and the bacterial DNA detection, research

HIV TEST !

Presenter

Noted to be orthophoric, no tropias noted, phorias not tested.(narsing rao)

Syphylis-treatmentOcular Inflammation secondary to syphilis should be treated as neurosyphilis (AAO), Lumbar puncture

Routine RPR or VDRL and FTA-ABS or MHA-TPHIV testing

Chao JR, Khurana RN– and Rao NA. Syphilis: reemergence of an old adversary. Ophthalmology 2006: 113: 2074-2079Aldave AJ et al (2001) Current Opinion in Ophthal. 12: 433-441

Lyme DiseaseIt is most frequent tick-born infectious disease in certain regions of US and Europe

US: Coastal North-East, North west California and Great lakes regionsThe causative pathogen is Borrelia burgdorferi

The tick must feed for at least 36 hours for transmission of theagent

Three stages of the diseaseEarly localized infection (stage 1):

erythema migrans, fever, malaise, fatigue, headache, myalgias, arthralgias, conjunctivitis

Early disseminated infection (stage 2: occurring days to weeks later)

neurologic, musculoskeletal or cardiovascular and uveitisLate disseminated infection (stage 3)

Arthritis +-uveitisneuropathy or encephalopathy

Dx: clinical+ Isolation of organism from advancing margin of the erythema migrans; ELISA; IgG and IgM and Western blot

A 27 year old male from California, an avid hiker c/o scotoma, photopsia

in the left eye. Reported fever, generalized malaise and some joint discomfort for 1moANA, RF, CXR, PPD and Sy

serology (-), Laboratory work up was significant for positive ELISA Lyme antibody titers 3.4 Western blot was positive for Lyme IgG

20/20 OD 20/80 OS

Courtesy of Narsing Rao, MD

20/20 20/20After iv ceftriaxone

treatment for 3 wks

Prophylaxis: A single dose of doxycycline 200mg orally (prevention should be emphasized)

OCT-tuberculous

granulomas?

Serpiginous choroiditis relapsing despite corticosteroids and CSAHighly positive PPD. PCR from aqueous and vitreous in 4 samples was (+) positive for

Mtb. No more relapse after anti-TB therapy. Follow-up : 3 y and without Rx

Presumed tubercular serpiginous-like choroiditisGupta et al. Ophthalmology 2003

coccidioidomycosis

Brevundimonas

endogenous endophthalmitis

Pneumocystis

carinii

choroiditis

Aspergillus

enendophthalmitis

in CLL s/p

chemo

AIDS or other immunecomprimisingdiseases-particular concern

When to suspect an infectious agent?

1- Clinical presentation may be helpful but non specific2- Systemic manifestations (immune-compromise (HIV/AIDS), fever, neutropenia)3- Steroid-resistance or -dependence 4- No evidence for a specific auto-inflammatory condition (JIA, VKH, SO, Behçet) or a malignant disease5- Epidemic outbreak!

Diagnostic strategy

Infectious agent Diagnostic strategy

HSV, CMV, VZV PCR > GW

EBV, HHV-8 PCR

ToxoplasmosisToxocariasis

GW > PCRWB

Tuberculosis PPD/Chestx-raynPCR

Whipple PCR

Fungal Culture/PCR

Summary

All atypical forms of uveitis deserve further investigations to exclude an infectious etiology

prednisone or other uveitis treatment can cause significant worsening

Early Dx remains the best way to propose a specific Rx and achieve long-term remission or healing

Thank you

Special thanks to: Dr Chan and our clinical fellows