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GRAND ROUNDS September 1, 2006 Denise A. John St. Thomas Hospital Case HPI: 60 y/o ♂ presents for an eye exam. ø ocular c/o’s ROS: (+) L temporal headache All other systems unremarkable FHX: Diabetes; HTN, stroke SHX: Quit ETOH ‘04; ø tobacco/IVDA Allergies: NKDA Ocular Exam NLP VA SC Motility: Full OU CF ‘4ft 20/200 4 IOP 8 Pupils: (+) RAPD OD NO VIEW B-Scan: Funnel-shaped retinal detachment Differential Diagnosis Infectious Indolent CMV retinitis Toxoplasma retinitis Acute retinal necrosis (ARN) Progressive outer retinal necrosis (PORN) Choroidal pneumocystosis Cryptococcal choroiditis Tuberculosis Candidiasis Syphilis Neoplastic Ocular lymphoma Metastasis Inflammatory Sarcoidosis Vasculitides More Info… PMHX: HIV/AIDS (Dx ’04) CD4: 155 cells/mm3 (5/05) HIV nephropathy Hepatitis C Chronic anemia HTN Chickenpox POHX: S/p steel injury OD HZO OS (5/05) Conjunctivitis Keratitis Uveitis Post-herpetic Neuralgia MEDS: Acyclovir 400mg QID; HAART; lisinopril; atenolol; bactrim; Refresh PM External Exam: Left hypo-pigmented scar: CNV1 distribution LUL Entropion & trichiasis SLE: OD: Shallow AC; 360° posterior synechiae; white cataract OS: PEE; posterior synechiae; ø AC rxn; 2-3+ NSC/3-4+ PSC; ø vitritis Epidemiology: HIV 40 million individuals infected worldwide ~ 900,000 in the U.S. 70-80% treated for a HIV-related eye disorder CD4 count may be used to predict the occurrence of specific ocular infections CD4 Count & Ocular Infections < 500 cells/mm3 Kaposi sarcoma Tuberculosis Lymphoma < 100 cells/mm3 Conjunctival/retinal microvasculopathy CMV retinitis < 250 cells/mm3 Pneumocystosis Toxoplasmosis VZV retinitis Most common 2nd most common Cryptococcosis Microsporidiosis CMV Retinitis Occurs in immunocompromised Slow progression Starts in periphery Spreads along retinal vasculature towards posterior pole Dense white/granular opacification (fullretinal thickness) Hemorrhage Mild vitritis Acute Retinal Necrosis Occurs in immunocompetent > 1 foci of full-thickness retinal necrosis with discrete borders Spreads 360° circumferentially in peripheral retina Posterior pole involvement is spared until late Vasculitis Prominent inflammatory reaction (AC & vitreous) Progressive Outer Retinal Necrosis PORN Rare form of necrotizing herpetic retinopathy First described by Forster et al. (1990) 2 pts: Fulminant outer retinal necrosis sparing the inner retina & vasculature Occurs in the immunocompromised: Immunosuppressed organ-transplant recipients Immune-deficient individuals: Cancer Advanced AIDS Pathogenesis Varicella-Zoster Virus Virus remains latent in sensory ganglia Reactivated during times of loss of T-cell regulatory control Difficult to isolate/grow in-vitro Only organism isolated in the retina via culture, PCR & direct fluorescent antibody assay PORN Engstrom, et al. PORN: A variant of necrotizing herpetic retinopathy in patients with AIDS. Ophth 1994. 38 ♂ pts (65 eyes): CD4 count: 21 cells/mm3 (0-130 cells/mm3) Largest study on PORN Retrospective chart review Median f/u 3 months (0-10 months) Objective: Characterize the clinical features & course PORN History of cutaneous zoster : 67% (22/33 pts) 41%: involved CNV1 12 of 15 pts: PORN occurred after a median of 2 months (2 months – 2 years) 3 of 15 pts: PORN occurred concurrently 12 of 38 pts: Taking oral acyclovir at the time PORN was diagnosed 50%: Acyclovir 800mg 5x/day Clinical Features Ocular complaints vision: Most common (54% eyes) Constriction of visual fields (28% eyes) Floaters (11% eyes) Pain (6% eyes) 7 pts with unilateral symptoms had asymptomatic disease in the fellow eye Clinical Features Usually bilateral disease 28 of 38 pts: Unilateral disease at diagnosis 2nd eye became affected in 17 pts median of 10 days after diagnosis (3 days – 4 weeks) in 6 pts Intraocular inflammation is minimal to absent 23 of 60 eyes: Anterior segment inflammation 61% mild AC reaction 11% keratic precipitates (fine, white deposits) 6% posterior synechiae 15 of 61 eyes: Vitreous inflammation 80% mild vitritis Clinical Features Multifocal, discrete lesions of the outer retina rapidly progress to confluence & full-thickness retinal involvement Perivenular lucency Clinical Features Characteristic macular lesion: Parafoveal opacification with a “cherry-red spot” Ø contiguous with peripheral lesions Peripheral lesions + posterior pole Zone 1: 32% eyes ø lesions only in zone 1 Zone 2: 72% eyes Zone 3: 86% eyes 28% eyes all 3 zones Clinical Features Disease quiescence Dense white plaques: “cracked mud” appearance Atrophic areas + holes Clinical Features Other manifestations: 11 of 65 eyes: Optic nerve abnormalities Disc swelling Hyperemia Atrophy 11 of 29 pts: Afferent pupillary defect 13 of 61 eyes: Retinal vasculopathy Vascular sheathing/occlusion Areas within or near retinal necrosis FA: PORN Walton et al. FA in PORN. Retina 16: 1996 Early: Microvascular changes equatorial & peripheral retina Confluent retinal disease: retinal vasculature & loss of capillaries; RPE damage; choriocapillaris leakage Reactivation: Brush-fire pattern of choroidal leakage at lesion border PORN = Retinochoroiditis Management: PORN Exact combination of antivirals & duration of treatment not known Guided by anecdotal information Herpes-zoster traditionally treated with acyclovir; however, may not be effective in pts treated long-term with the oral form 2° to resistance Management Moorthy et al. Management of VZVR in AIDS. Br J Ophth, 1997. 20 pts (39 eyes); 11 pts using oral acyclovir at time of diagnosis Retrospective chart review median f/u 6 months (1-26 months) Objective: Investigate visual outcome 2 week IV treatment: Acyclovir (10mg/kg Q8h) Ganciclovir (5mg/kg Q12h x 2 weeks; then 5mg/kg/day) Foscarnet (180mg/kg/day in 2 or 3 divided doses) Ganciclovir + foscarnet Management Results: Rates of NLP : acyclovir (9 of 10 eyes) & foscarnet (3 of 5 eyes) Ø VA > 20/200 Rates of NLP : combination therapy (5 of 18 eyes) & ganciclovir (2 of 6 eyes) VA > 20/200 Combination therapy: 3 of 18 eyes Ganciclovir: 1 of 6 eyes Conclusion: Treatment with IV combination therapy or ganciclovir associated with a better final vA VS acyclovir or foscarnet alone Management Ciulla, et al. PORN: Successful treatment with combination antiviral therapy. Ophth Surgery & Lasers. 1998. 6 pts with AIDS Retrospective chart review Median f/u 29 weeks (27 -38 weeks) Objective: Assess 2-drug combination therapy IV Treatment duration: median 29 weeks (27-38 weeks) Ganciclovir (5mg/kg Q12h) + acyclovir (500mg/m2 Q8h) Foscarnet (60mg/kg Q8-12h) + ganciclovir Foscarnet + acyclovir Management Results: All 6 pts had resolution of disease 1 of 6 pts had recurrence At diagnosis 3 of 12 eyes without disease remained uninvolved 10 of 12 eyes developed RD Conclusion: Prolonged combination therapy arrested progression of retinitis; maintained remission & prevented fellow eye involvement; does not prevent retinal detachment Role of ganciclovir intraocular implant & oral agents in combination therapy is unclear Management Intravitreal injection (ganciclovir & foscarnet); intravitreal ganciclovir implant No protection for fellow eye Complications Retinal necrosis Retinal tears/holes Rhegmatogenous retinal detachment Management Prophylactic laser retinopexy Engstrom et al. 1994 14 of 54 eyes: Laser ~ 1 week after diagnosis 93% developed a RD Median interval ~ 3 weeks Ø significant difference: laser VS no laser: Zone of involvement of RD Extent of RD Interval from diagnosis to RD Management Rhegmatogenous retinal detachment Engstrom et al. 1994 43 of 65 eyes: Median interval 4 weeks No relationship to extent of disease or disease activity Vitrectomy/endolaser/silicone oil 16 of 43 eyes: Retinas successfully attached in all eyes Re-detached in 4 eyes NLP in 56% (laser) VS 63% (no laser) Prognosis Visual prognosis is poor Macular involvement Ineffectiveness of antiviral agents Recurrence Engstrom, et al. 1994 At least 10 pts despite being on maintenance therapy Characterized by development of new disease foci In 6 pts associated with discontinuation/reduction in maintenance dose; median time to recurrence was 2 weeks (1-6 weeks) ~ 50% of individuals deceased 5 months after diagnosis Back To Our Patient… Patient admitted to medicine Infectious disease consulted Received IV foscarnet (40mg/kg Q12 x 14 days) ø Progression of lesions VA improved to 20/60 (+1.75) Discharged on oral acyclovir 800mg 5x day Take Home Points… Progressive outer retinal necrosis is a rapidly progressive necrotizing retinitis occurring in immunocompromised individuals, esp. AIDS pts Management is anecdotal: use of highdose IV anti-virals may be beneficial Poor visual prognosis References E-Medicine: Ocular manifestations of HIV Forster et al. Rapidly PORN in AIDS. Am J Ophth 110: 341. 1990 Moorthy et al. Management of VZV retinitis in AIDS. Br J Ophth, 1997. Walton et al. Fluorescein angiography in PORN. Retina 16: 1996 Ciulla, et al. The PORN: Successfully treatment with combination antiviral therapy. Ophth Surgery & Lasers. 1998 BCSC. Retina & Vitreous. AAO. 2004-05 BCSC. Uveitis & Intraocular Inflammation. AAO. 2004-05 Yanoff. Ophthalmology, 2nd Ed. Mosby. 1121-22 Kanski. Clinical Ophthalmology, 5th Ed. Butterworth Heinemann. 288-93. 2003