1. GRAND ROUNDS September 1, 2006 Denise A. John St. Thomas Hospital

2. Case HPI: 60 y/o ♂ presents for an eye exam. HPI: 60 y/o ♂ presents for an eye exam. ø ocular c/o’s ø ocular c/o’s ROS: (+) L temporal headache ROS: (+) L temporal headache All other systems unremarkable All other systems unremarkable FHX: Diabetes; HTN, stroke FHX: Diabetes; HTN, stroke SHX: Quit ETOH ‘04; ø tobacco/IVDA SHX: Quit ETOH ‘04; ø tobacco/IVDA Allergies: NKDA Allergies: NKDA

3. Ocular Exam NLP NLP V A SC V A SC CF ‘4ft  20/200 CF ‘4ft  20/200 Motility: Full OU Motility: Full OU 4 IOP IOP 8 Pupils: (+) RAPD OD Pupils: (+) RAPD OD

4. NO VIEW B-Scan: Funnel-shaped retinal detachment

6. Differential Diagnosis Infectious Infectious Indolent CMV retinitis Indolent CMV retinitis Toxoplasma retinitis Toxoplasma retinitis Acute retinal necrosis (ARN) Acute retinal necrosis (ARN) Progressive outer retinal necrosis (PORN) Progressive outer retinal necrosis (PORN) Choroidal pneumocystosis Choroidal pneumocystosis Cryptococcal choroiditis Cryptococcal choroiditis Tuberculosis Tuberculosis Candidiasis Candidiasis Syphilis Syphilis Neoplastic Ocular lymphoma Metastasis Inflammatory Sarcoidosis Vasculitides

7. More Info… PMHX: PMHX: HIV/AIDS (Dx ’04) HIV/AIDS (Dx ’04) CD4: 155 cells/mm 3 (5/05) CD4: 155 cells/mm 3 (5/05) HIV nephropathy HIV nephropathy Hepatitis C Hepatitis C Chronic anemia Chronic anemia HTN HTN Chickenpox Chickenpox POHX: POHX: S/p steel injury OD S/p steel injury OD HZO OS (5/05) HZO OS (5/05) Conjunctivitis Conjunctivitis Keratitis Keratitis Uveitis Uveitis Post-herpetic Neuralgia Post-herpetic Neuralgia MEDS: Acyclovir 400mg QID; HAART; lisinopril; atenolol; bactrim; Refresh PM External Exam: Left hypo-pigmented scar: CNV 1 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

8. Epidemiology: HIV 40 million individuals infected worldwide 40 million individuals infected worldwide ~ 900,000 in the U.S. ~ 900,000 in the U.S. 70-80% treated for a HIV-related eye disorder 70-80% treated for a HIV-related eye disorder CD4 count may be used to predict the occurrence of specific ocular infections CD4 count may be used to predict the occurrence of specific ocular infections

9. CD4 Count & Ocular Infections < 500 cells/mm 3 < 500 cells/mm 3 Kaposi sarcoma Kaposi sarcoma Tuberculosis Tuberculosis Lymphoma Lymphoma < 250 cells/mm 3 < 250 cells/mm 3 Pneumocystosis Pneumocystosis Toxoplasmosis Toxoplasmosis < 100 cells/mm 3 Conjunctival/retinal microvasculopathy CMV retinitis Most common VZV retinitis 2 nd most common Cryptococcosis Microsporidiosis

10. CMV Retinitis Occurs in immunocompromised Slow progression Starts in periphery Spreads along retinal vasculature towards posterior pole Dense white/granular opacification (full- retinal thickness) Hemorrhage Mild vitritis

11. Acute Retinal Necrosis Occurs in immunocompetent Occurs in immunocompetent > 1 foci of full-thickness retinal necrosis with discrete borders > 1 foci of full-thickness retinal necrosis with discrete borders Spreads 360° circumferentially in peripheral retina Spreads 360° circumferentially in peripheral retina Posterior pole involvement is spared until late Posterior pole involvement is spared until late Vasculitis Vasculitis Prominent inflammatory reaction (AC & vitreous ) Prominent inflammatory reaction (AC & vitreous )

12. Progressive Outer Retinal Necrosis

13. PORN Rare form of necrotizing herpetic retinopathy Rare form of necrotizing herpetic retinopathy First described by Forster et al. (1990) First described by Forster et al. (1990) 2 pts: Fulminant outer retinal necrosis sparing the inner retina & vasculature 2 pts: Fulminant outer retinal necrosis sparing the inner retina & vasculature Occurs in the immunocompromised: Occurs in the immunocompromised: Immunosuppressed organ-transplant recipients Immunosuppressed organ-transplant recipients Immune-deficient individuals: Immune-deficient individuals: Cancer Cancer Advanced AIDS Advanced AIDS

14. Pathogenesis Varicella-Zoster Virus Varicella-Zoster Virus Virus remains latent in sensory ganglia Virus remains latent in sensory ganglia Reactivated during times of loss of T-cell regulatory control Reactivated during times of loss of T-cell regulatory control Difficult to isolate/grow in-vitro Difficult to isolate/grow in-vitro Only organism isolated in the retina via culture, PCR & direct fluorescent antibody assay Only organism isolated in the retina via culture, PCR & direct fluorescent antibody assay

15. 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/mm 3 (0-130 cells/mm 3 ) Engstrom, et al. PORN: A variant of necrotizing herpetic retinopathy in patients with AIDS. Ophth 1994. 38 ♂ pts (65 eyes): CD4 count: 21 cells/mm 3 (0-130 cells/mm 3 ) Largest study on PORN Largest study on PORN Retrospective chart review Retrospective chart review Median f/u 3 months (0-10 months) Median f/u 3 months (0-10 months) Objective: Characterize the clinical features & course Objective: Characterize the clinical features & course

16. PORN History of cutaneous zoster : 67% (22/33 pts) History of cutaneous zoster : 67% (22/33 pts) 41%: involved CNV 1 41%: involved CNV 1 12 of 15 pts: PORN occurred after a median of 2 months (2 months – 2 years) 12 of 15 pts: PORN occurred after a median of 2 months (2 months – 2 years) 3 of 15 pts: PORN occurred concurrently 3 of 15 pts: PORN occurred concurrently 12 of 38 pts: Taking oral acyclovir at the time PORN was diagnosed 12 of 38 pts: Taking oral acyclovir at the time PORN was diagnosed 50%: Acyclovir 800mg 5x/day 50%: Acyclovir 800mg 5x/day

17. Clinical Features Ocular complaints Ocular complaints  vision: Most common (54% eyes)  vision: Most common (54% eyes) Constriction of visual fields (28% eyes) Constriction of visual fields (28% eyes) Floaters (11% eyes) Floaters (11% eyes) Pain (6% eyes) Pain (6% eyes) 7 pts with unilateral symptoms had asymptomatic disease in the fellow eye 7 pts with unilateral symptoms had asymptomatic disease in the fellow eye

18. Clinical Features Usually bilateral disease Usually bilateral disease 28 of 38 pts: Unilateral disease at diagnosis 28 of 38 pts: Unilateral disease at diagnosis 2 nd eye became affected in 17 pts  median of 10 days after diagnosis (3 days – 4 weeks) in 6 pts 2 nd 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 Intraocular inflammation is minimal to absent 23 of 60 eyes: Anterior segment inflammation 23 of 60 eyes: Anterior segment inflammation 61% mild AC reaction 61% mild AC reaction 11% keratic precipitates (fine, white deposits) 11% keratic precipitates (fine, white deposits) 6% posterior synechiae 6% posterior synechiae 15 of 61 eyes: Vitreous inflammation 15 of 61 eyes: Vitreous inflammation 80% mild vitritis 80% mild vitritis

19. Clinical Features Multifocal, discrete lesions of the outer retina  rapidly progress to confluence & full-thickness retinal involvement Multifocal, discrete lesions of the outer retina  rapidly progress to confluence & full-thickness retinal involvement Perivenular lucency Perivenular lucency

20. Clinical Features Characteristic macular lesion: Characteristic macular lesion: Parafoveal opacification with a “cherry-red spot” Parafoveal opacification with a “cherry-red spot” Ø contiguous with peripheral lesions Ø contiguous with peripheral lesions Peripheral lesions + posterior pole Peripheral lesions + posterior pole Zone 1: 32% eyes Zone 1: 32% eyes ø lesions only in zone 1 ø lesions only in zone 1 Zone 2: 72% eyes Zone 2: 72% eyes Zone 3: 86% eyes Zone 3: 86% eyes 28% eyes all 3 zones 28% eyes all 3 zones

21. Clinical Features Disease quiescence Disease quiescence Dense white plaques: “cracked mud” appearance Dense white plaques: “cracked mud” appearance Atrophic areas + holes Atrophic areas + holes

22. Clinical Features Other manifestations : Other manifestations : 11 of 65 eyes: Optic nerve abnormalities 11 of 65 eyes: Optic nerve abnormalities Disc swelling Disc swelling Hyperemia Hyperemia Atrophy Atrophy 11 of 29 pts: Afferent pupillary defect 11 of 29 pts: Afferent pupillary defect 13 of 61 eyes: Retinal vasculopathy 13 of 61 eyes: Retinal vasculopathy Vascular sheathing/occlusion Vascular sheathing/occlusion Areas within or near retinal necrosis Areas within or near retinal necrosis

23. FA: PORN Walton et al. FA in PORN. Retina 16: 1996 Walton et al. FA in PORN. Retina 16: 1996 Early: Microvascular changes Early: Microvascular changes  equatorial & peripheral retina  equatorial & peripheral retina Confluent retinal disease:  retinal vasculature & loss of capillaries; RPE damage; choriocapillaris leakage Confluent retinal disease:  retinal vasculature & loss of capillaries; RPE damage; choriocapillaris leakage Reactivation: Brush-fire pattern of choroidal leakage at lesion border Reactivation: Brush-fire pattern of choroidal leakage at lesion border PORN = Retinochoroiditis PORN = Retinochoroiditis

24. Management: PORN Exact combination of antivirals & duration of treatment not known Exact combination of antivirals & duration of treatment not known Guided by anecdotal information 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 Herpes-zoster traditionally treated with acyclovir; however, may not be effective in pts treated long-term with the oral form 2° to resistance

25. 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 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 Retrospective chart review median f/u 6 months (1-26 months) median f/u 6 months (1-26 months) Objective: Investigate visual outcome Objective: Investigate visual outcome 2 week IV treatment : 2 week IV treatment : Acyclovir (10mg/kg Q8h) Acyclovir (10mg/kg Q8h) Ganciclovir (5mg/kg Q12h x 2 weeks; then 5mg/kg/day) Ganciclovir (5mg/kg Q12h x 2 weeks; then 5mg/kg/day) Foscarnet (180mg/kg/day in 2 or 3 divided doses) Foscarnet (180mg/kg/day in 2 or 3 divided doses) Ganciclovir + foscarnet Ganciclovir + foscarnet

26. Management Results: Results: Rates of NLP  : acyclovir (9 of 10 eyes) & foscarnet (3 of 5 eyes) Rates of NLP  : acyclovir (9 of 10 eyes) & foscarnet (3 of 5 eyes) Ø V A > 20/200 Ø V A > 20/200 Rates of NLP  : combination therapy (5 of 18 eyes) & ganciclovir (2 of 6 eyes) Rates of NLP  : combination therapy (5 of 18 eyes) & ganciclovir (2 of 6 eyes) V A > 20/200 V A > 20/200 Combination therapy: 3 of 18 eyes Combination therapy: 3 of 18 eyes Ganciclovir: 1 of 6 eyes Ganciclovir: 1 of 6 eyes Conclusion: Treatment with IV combination therapy or ganciclovir associated with a better final v A VS acyclovir or foscarnet alone Conclusion: Treatment with IV combination therapy or ganciclovir associated with a better final v A VS acyclovir or foscarnet alone

27. Management Ciulla, et al. PORN: Successful treatment with combination antiviral therapy. Ophth Surgery & Lasers. 1998. 6 pts with AIDS Ciulla, et al. PORN: Successful treatment with combination antiviral therapy. Ophth Surgery & Lasers. 1998. 6 pts with AIDS Retrospective chart review Retrospective chart review Median f/u 29 weeks (27 -38 weeks) Median f/u 29 weeks (27 -38 weeks) Objective: Assess 2-drug combination therapy Objective: Assess 2-drug combination therapy IV Treatment duration: median 29 weeks (27-38 weeks) IV Treatment duration: median 29 weeks (27-38 weeks) Ganciclovir (5mg/kg Q12h) + acyclovir (500mg/m 2 Q8h) Ganciclovir (5mg/kg Q12h) + acyclovir (500mg/m 2 Q8h) Foscarnet (60mg/kg Q8-12h) + ganciclovir Foscarnet (60mg/kg Q8-12h) + ganciclovir Foscarnet + acyclovir Foscarnet + acyclovir

28. Management Results: Results: All 6 pts had resolution of disease All 6 pts had resolution of disease 1 of 6 pts had recurrence 1 of 6 pts had recurrence At diagnosis 3 of 12 eyes without disease  remained uninvolved At diagnosis 3 of 12 eyes without disease  remained uninvolved 10 of 12 eyes developed RD 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 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 Role of ganciclovir intraocular implant & oral agents in combination therapy is unclear

29. Management Intravitreal injection (ganciclovir & foscarnet); Intravitreal injection (ganciclovir & foscarnet); intravitreal ganciclovir implant intravitreal ganciclovir implant No protection for fellow eye No protection for fellow eye

30. Complications Retinal necrosis Retinal necrosis Retinal tears/holes Retinal tears/holes Rhegmatogenous retinal detachment Rhegmatogenous retinal detachment

31. Management Prophylactic laser retinopexy Prophylactic laser retinopexy Engstrom et al. 1994 Engstrom et al. 1994 14 of 54 eyes: Laser ~ 1 week after diagnosis 14 of 54 eyes: Laser ~ 1 week after diagnosis 93% developed a RD 93% developed a RD Median interval ~ 3 weeks Median interval ~ 3 weeks Ø significant difference: laser VS no laser: Ø significant difference: laser VS no laser: Zone of involvement of RD Zone of involvement of RD Extent of RD Extent of RD Interval from diagnosis to RD Interval from diagnosis to RD

32. Management Rhegmatogenous retinal detachment Rhegmatogenous retinal detachment Engstrom et al. 1994 Engstrom et al. 1994 43 of 65 eyes: Median interval 4 weeks 43 of 65 eyes: Median interval 4 weeks No relationship to extent of disease or disease activity No relationship to extent of disease or disease activity Vitrectomy/endolaser/silicone oil Vitrectomy/endolaser/silicone oil 16 of 43 eyes: Retinas successfully attached in all eyes 16 of 43 eyes: Retinas successfully attached in all eyes Re-detached in 4 eyes Re-detached in 4 eyes NLP in 56% (laser) VS 63% (no laser) NLP in 56% (laser) VS 63% (no laser)

33. Prognosis Visual prognosis is poor Visual prognosis is poor Macular involvement Macular involvement Ineffectiveness of antiviral agents Ineffectiveness of antiviral agents Recurrence Recurrence Engstrom, et al. 1994 Engstrom, et al. 1994 At least 10 pts despite being on maintenance therapy At least 10 pts despite being on maintenance therapy Characterized by development of new disease foci Characterized by development of new disease foci In 6 pts associated with discontinuation/reduction in maintenance dose; median time to recurrence was In 6 pts associated with discontinuation/reduction in maintenance dose; median time to recurrence was 2 weeks (1-6 weeks) 2 weeks (1-6 weeks) ~ 50% of individuals  deceased 5 months after diagnosis ~ 50% of individuals  deceased 5 months after diagnosis

34. Back To Our Patient… Patient admitted to medicine Patient admitted to medicine Infectious disease consulted Infectious disease consulted Received IV foscarnet (40mg/kg Q12 x 14 days) Received IV foscarnet (40mg/kg Q12 x 14 days) ø Progression of lesions ø Progression of lesions V A improved to 20/60 (+1.75) V A improved to 20/60 (+1.75) Discharged on oral acyclovir 800mg 5x day Discharged on oral acyclovir 800mg 5x day

35. Take Home Points… Progressive outer retinal necrosis is a rapidly progressive necrotizing retinitis occurring in immunocompromised individuals, esp. AIDS pts Progressive outer retinal necrosis is a rapidly progressive necrotizing retinitis occurring in immunocompromised individuals, esp. AIDS pts Management is anecdotal: use of high- dose IV anti-virals may be beneficial Management is anecdotal: use of high- dose IV anti-virals may be beneficial Poor visual prognosis Poor visual prognosis

36. References E-Medicine: Ocular manifestations of HIV E-Medicine: Ocular manifestations of HIV Forster et al. Rapidly PORN in AIDS. Am J Ophth 110: 341. 1990 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. Moorthy et al. Management of VZV retinitis in AIDS. Br J Ophth, 1997. Walton et al. Fluorescein angiography in PORN. Retina 16: 1996 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 Ciulla, et al. The PORN: Successfully treatment with combination antiviral therapy. Ophth Surgery & Lasers. 1998 BCSC. Retina & Vitreous. AAO. 2004-05 BCSC. Retina & Vitreous. AAO. 2004-05 BCSC. Uveitis & Intraocular Inflammation. AAO. 2004-05 BCSC. Uveitis & Intraocular Inflammation. AAO. 2004-05 Yanoff. Ophthalmology, 2 nd Ed. Mosby. 1121-22 Yanoff. Ophthalmology, 2 nd Ed. Mosby. 1121-22 Kanski. Clinical Ophthalmology, 5 th Ed. Butterworth Heinemann. 288-93. 2003 Kanski. Clinical Ophthalmology, 5 th Ed. Butterworth Heinemann. 288-93. 2003