GRAND GRAND ROUNDSROUNDS

September 1, 2006September 1, 2006

Denise A. JohnDenise A. John

St. Thomas HospitalSt. Thomas Hospital

CaseCase HPIHPI:: 60 y/o 60 y/o ♂ presents for an eye exam. ♂ presents for an eye exam.

ø ocular c/o’s ø ocular c/o’s

ROSROS:: (+) L temporal headache (+) L temporal headache All other systems unremarkableAll other systems unremarkable

FHXFHX:: Diabetes; HTN, stroke Diabetes; HTN, stroke

SHXSHX:: Quit ETOH ‘04; ø tobacco/IVDA Quit ETOH ‘04; ø tobacco/IVDA

AllergiesAllergies:: NKDA NKDA

Ocular ExamOcular Exam NLPNLP VVA SCA SC CF ‘4ft CF ‘4ft 20/200 20/200

MotilityMotility: Full OU: Full OU 44 IOPIOP 88

PupilsPupils: (+) RAPD OD: (+) RAPD OD

NO VIEW

B-Scan: Funnel-shaped retinal detachment

Differential Differential DiagnosisDiagnosis

InfectiousInfectious Indolent CMV retinitis Indolent CMV retinitis Toxoplasma retinitis Toxoplasma retinitis Acute retinal necrosis Acute retinal necrosis

(ARN) (ARN) Progressive outer Progressive outer

retinal necrosis (PORN) retinal necrosis (PORN) Choroidal Choroidal

pneumocystosispneumocystosis Cryptococcal choroiditisCryptococcal choroiditis TuberculosisTuberculosis CandidiasisCandidiasis SyphilisSyphilis

NeoplasticNeoplastic Ocular lymphomaOcular lymphoma MetastasisMetastasis

InflammatoryInflammatory SarcoidosisSarcoidosis VasculitidesVasculitides

More Info…More Info… PMHXPMHX::

HIV/AIDS (Dx ’04)HIV/AIDS (Dx ’04) CD4: 155 cells/mmCD4: 155 cells/mm33

(5/05)(5/05) HIV nephropathyHIV nephropathy Hepatitis CHepatitis C Chronic anemiaChronic anemia HTNHTN ChickenpoxChickenpox

POHXPOHX:: S/p steel injury ODS/p steel injury OD HZO OS (5/05)HZO OS (5/05)

ConjunctivitisConjunctivitis KeratitisKeratitis UveitisUveitis Post-herpetic NeuralgiaPost-herpetic Neuralgia

MEDSMEDS:: Acyclovir 400mg QID; Acyclovir 400mg QID;

HAART; lisinopril; atenolol; HAART; lisinopril; atenolol; bactrim; Refresh PMbactrim; Refresh PM

External ExamExternal Exam:: Left hypo-pigmented scar: Left hypo-pigmented scar:

CNVCNV11 distributiondistribution LUL Entropion & trichiasisLUL Entropion & trichiasis

SLESLE: : OD:OD: Shallow AC; 360 Shallow AC; 360° °

posterior synechiae; posterior synechiae; white white cataractcataract

OS:OS: PEE; posterior PEE; posterior synechiae;synechiae;

ø AC rxn; 2-3+ NSC/3-4+ ø AC rxn; 2-3+ NSC/3-4+ PSC; PSC;

ø vitritisø vitritis

Epidemiology: Epidemiology: HIVHIV

40 million individuals infected worldwide40 million individuals infected worldwide

~~ 900,000 in the U.S. 900,000 in the U.S.

70-80% treated for a HIV-related eye 70-80% treated for a HIV-related eye disorderdisorder CD4 count may be used to predict the CD4 count may be used to predict the

occurrence of specific ocular infectionsoccurrence of specific ocular infections

CD4 Count & Ocular CD4 Count & Ocular InfectionsInfections

< 500 cells/mm< 500 cells/mm33

Kaposi sarcomaKaposi sarcoma TuberculosisTuberculosis LymphomaLymphoma

< 250 cells/mm< 250 cells/mm33

PneumocystosisPneumocystosis ToxoplasmosisToxoplasmosis

< 100 cells/mm< 100 cells/mm33

Conjunctival/retinal Conjunctival/retinal microvasculopathymicrovasculopathy

CMV retinitisCMV retinitis Most commonMost common

VZV retinitisVZV retinitis 22ndnd most common most common

CryptococcosisCryptococcosis MicrosporidiosisMicrosporidiosis

CMV RetinitisCMV Retinitis Occurs in Occurs in

immunocompromisedimmunocompromised Slow progressionSlow progression Starts in periphery Starts in periphery Spreads along retinal Spreads along retinal

vasculature towards vasculature towards posterior poleposterior pole

Dense Dense white/granular white/granular opacification (full-opacification (full-retinal thickness) retinal thickness)

HemorrhageHemorrhage Mild vitritisMild vitritis

Acute Retinal Acute Retinal NecrosisNecrosis

Occurs in Occurs in immunocompetentimmunocompetent >> 1 foci of full-thickness 1 foci of full-thickness

retinal necrosis with retinal necrosis with discrete bordersdiscrete borders

Spreads 360Spreads 360° ° circumferentially in circumferentially in peripheral retinaperipheral retina

Posterior pole Posterior pole involvement is spared involvement is spared until lateuntil late

VasculitisVasculitis Prominent inflammatory Prominent inflammatory

reaction (AC & vitreousreaction (AC & vitreous))

Progressive Progressive Outer Outer

Retinal Retinal NecrosisNecrosis

PORNPORN Rare form of necrotizing herpetic Rare form of necrotizing herpetic

retinopathy retinopathy

First described by Forster et al. (1990)First described by Forster et al. (1990) 2 pts: Fulminant outer retinal necrosis sparing 2 pts: Fulminant outer retinal necrosis sparing

the inner retina & vasculaturethe inner retina & vasculature

Occurs in the immunocompromised:Occurs in the immunocompromised: Immunosuppressed organ-transplant recipientsImmunosuppressed organ-transplant recipients Immune-deficient individuals:Immune-deficient individuals:

CancerCancer Advanced AIDSAdvanced AIDS

PathogenesisPathogenesis Varicella-Zoster VirusVaricella-Zoster Virus

Virus remains latent in sensory gangliaVirus remains latent in sensory ganglia Reactivated during times of loss of T-cell Reactivated during times of loss of T-cell

regulatory controlregulatory control Difficult to isolate/grow in-vitroDifficult to isolate/grow in-vitro

Only organism isolated in the retina via culture, Only organism isolated in the retina via culture, PCR & direct fluorescent antibody assayPCR & direct fluorescent antibody assay

PORNPORN Engstrom, et al. PORN: A variant of Engstrom, et al. PORN: A variant of

necrotizing herpetic retinopathy in necrotizing herpetic retinopathy in patients with AIDS. Ophth 1994. patients with AIDS. Ophth 1994. 38 38 ♂ ♂ pts (65 eyes): pts (65 eyes): CD4 count: 21 cells/mmCD4 count: 21 cells/mm3 3 (0-130 (0-130 cells/mmcells/mm33))

Largest study on PORNLargest study on PORN Retrospective chart reviewRetrospective chart review

Median f/u 3 months (0-10 months)Median f/u 3 months (0-10 months) Objective: Characterize the clinical features & courseObjective: Characterize the clinical features & course

PORNPORN History of cutaneous zoster History of cutaneous zoster : 67% : 67%

(22/33 pts)(22/33 pts) 41%: involved CNV41%: involved CNV11

12 of 15 pts: PORN occurred after a median of 12 of 15 pts: PORN occurred after a median of 2 months (2 months – 2 years)2 months (2 months – 2 years)

3 of 15 pts: PORN occurred concurrently3 of 15 pts: PORN occurred concurrently

12 of 38 pts: Taking oral acyclovir at the 12 of 38 pts: Taking oral acyclovir at the time PORN was diagnosedtime PORN was diagnosed 50%: Acyclovir 800mg 5x/day50%: Acyclovir 800mg 5x/day

Clinical FeaturesClinical Features Ocular complaintsOcular 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 7 pts with unilateral symptoms had asymptomatic disease in the fellow eyeasymptomatic disease in the fellow eye

Clinical FeaturesClinical Features Usually bilateral diseaseUsually bilateral disease

28 of 38 pts: Unilateral disease at diagnosis28 of 38 pts: Unilateral disease at diagnosis 22ndnd eye became affected in 17 pts eye became affected in 17 pts median of 10 median of 10

days after diagnosis (3 days – 4 weeks) in 6 ptsdays after diagnosis (3 days – 4 weeks) in 6 pts

Intraocular inflammation is minimal to Intraocular inflammation is minimal to absentabsent 23 of 60 eyes: Anterior segment inflammation23 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 synechiae6% posterior synechiae

15 of 61 eyes: Vitreous inflammation15 of 61 eyes: Vitreous inflammation 80% mild vitritis 80% mild vitritis

Clinical FeaturesClinical Features Multifocal, discrete lesions of the outer Multifocal, discrete lesions of the outer

retina retina rapidly progress to confluence & rapidly progress to confluence & full-thickness retinal involvementfull-thickness retinal involvement

Perivenular lucencyPerivenular lucency

Clinical FeaturesClinical Features Characteristic Characteristic

macular lesionmacular lesion:: Parafoveal Parafoveal

opacification with a opacification with a “cherry-red spot”“cherry-red spot”

Ø contiguous with Ø contiguous with peripheral lesionsperipheral lesions

Peripheral lesions Peripheral lesions ++ posterior poleposterior pole Zone 1: 32% eyesZone 1: 32% eyes

øø lesions only in zone 1 lesions only in zone 1 Zone 2: 72% eyesZone 2: 72% eyes Zone 3: 86% eyesZone 3: 86% eyes

28% eyes all 3 zones28% eyes all 3 zones

Clinical FeaturesClinical Features Disease Disease

quiescencequiescence Dense white Dense white

plaques: “cracked plaques: “cracked mud” appearancemud” appearance

Atrophic areas Atrophic areas ++ holesholes

Clinical FeaturesClinical Features Other manifestationsOther manifestations::

11 of 65 eyes: 11 of 65 eyes: Optic nerve abnormalitiesOptic nerve abnormalities Disc swellingDisc swelling HyperemiaHyperemia AtrophyAtrophy

11 of 29 pts: 11 of 29 pts: Afferent pupillary defectAfferent pupillary defect 13 of 61 eyes: 13 of 61 eyes: Retinal vasculopathyRetinal vasculopathy

Vascular sheathing/occlusionVascular sheathing/occlusion Areas within or near retinal necrosisAreas within or near retinal necrosis

FA: PORNFA: PORN Walton et al. FA in PORN. Walton et al. FA in PORN.

Retina 16: 1996 Retina 16: 1996 EarlyEarly: Microvascular : Microvascular

changes changes

equatorial & peripheral equatorial & peripheral retinaretina

Confluent retinal diseaseConfluent retinal disease: : retinal vasculature & loss of retinal vasculature & loss of capillaries; RPE damage; capillaries; RPE damage; choriocapillaris leakagechoriocapillaris leakage

ReactivationReactivation: Brush-fire : Brush-fire pattern of choroidal leakage pattern of choroidal leakage at lesion borderat lesion border

PORN = RetinochoroiditisPORN = Retinochoroiditis

Management: Management: PORNPORN

Exact combination of antivirals & duration Exact combination of antivirals & duration of treatment not knownof treatment not known

Guided by anecdotal informationGuided by anecdotal information

Herpes-zoster traditionally treated with Herpes-zoster traditionally treated with acyclovir; however, may not be effective in acyclovir; however, may not be effective in pts treated long-term with the oral form 2pts treated long-term with the oral form 2° ° to resistanceto resistance

ManagementManagement Moorthy et al. Management of VZVR in Moorthy et al. Management of VZVR in

AIDS. Br J Ophth, 1997. 20 pts (39 eyes); AIDS. Br J Ophth, 1997. 20 pts (39 eyes); 11 pts using oral acyclovir at time of 11 pts using oral acyclovir at time of diagnosisdiagnosis

Retrospective chart reviewRetrospective chart review median f/u 6 months (1-26 months)median f/u 6 months (1-26 months)

Objective: Investigate visual outcomeObjective: Investigate visual outcome

2 week IV treatment2 week IV treatment:: Acyclovir (10mg/kg Q8h) Acyclovir (10mg/kg Q8h) Ganciclovir (5mg/kg Q12h x 2 weeks; then Ganciclovir (5mg/kg Q12h x 2 weeks; then

5mg/kg/day) 5mg/kg/day) Foscarnet (180mg/kg/day in 2 or 3 divided Foscarnet (180mg/kg/day in 2 or 3 divided

doses) doses) Ganciclovir + foscarnetGanciclovir + foscarnet

ManagementManagement ResultsResults::

Rates of NLP Rates of NLP :: acyclovir (9 of 10 eyes) & acyclovir (9 of 10 eyes) & foscarnet (3 of 5 eyes)foscarnet (3 of 5 eyes)

Ø VØ VAA > 20/200 > 20/200 Rates of NLP Rates of NLP : : combination therapy (5 of 18 combination therapy (5 of 18

eyes) & ganciclovir (2 of 6 eyes)eyes) & ganciclovir (2 of 6 eyes) VVAA > 20/200 > 20/200

Combination therapy: 3 of 18 eyesCombination therapy: 3 of 18 eyes Ganciclovir: 1 of 6 eyesGanciclovir: 1 of 6 eyes

Conclusion: Treatment with IV combination Conclusion: Treatment with IV combination therapy or ganciclovir associated with a therapy or ganciclovir associated with a better final vbetter final vAA VS acyclovir or foscarnet VS acyclovir or foscarnet alonealone

ManagementManagement Ciulla, et al. PORN: Successful treatment Ciulla, et al. PORN: Successful treatment

with combination antiviral therapy. Ophth with combination antiviral therapy. Ophth Surgery & Lasers. 1998. Surgery & Lasers. 1998. 6 pts with AIDS6 pts with AIDS

Retrospective chart reviewRetrospective chart review Median f/u 29 weeks (27 -38 weeks)Median f/u 29 weeks (27 -38 weeks)

Objective: Assess 2-drug combination therapyObjective: Assess 2-drug combination therapy

IV Treatment duration: median 29 weeks (27-IV Treatment duration: median 29 weeks (27-38 weeks)38 weeks)

Ganciclovir (5mg/kg Q12h) + acyclovir (500mg/mGanciclovir (5mg/kg Q12h) + acyclovir (500mg/m2 2

Q8h)Q8h) Foscarnet (60mg/kg Q8-12h) + ganciclovirFoscarnet (60mg/kg Q8-12h) + ganciclovir Foscarnet + acyclovirFoscarnet + acyclovir

ManagementManagement ResultsResults::

All 6 pts had resolution of diseaseAll 6 pts had resolution of disease 1 of 6 pts had recurrence1 of 6 pts had recurrence At diagnosis 3 of 12 eyes without disease At diagnosis 3 of 12 eyes without disease

remained uninvolvedremained uninvolved 10 of 12 eyes developed RD10 of 12 eyes developed RD

Conclusion: Prolonged combination therapy Conclusion: Prolonged combination therapy arrested progression of retinitis; maintained arrested progression of retinitis; maintained remission & prevented fellow eye remission & prevented fellow eye involvement; does not prevent retinal involvement; does not prevent retinal detachmentdetachment Role of ganciclovir intraocular implant & oral Role of ganciclovir intraocular implant & oral

agents in combination therapy is unclearagents in combination therapy is unclear

ManagementManagement Intravitreal injection (ganciclovir & Intravitreal injection (ganciclovir &

foscarnet);foscarnet);

intravitreal ganciclovir implantintravitreal ganciclovir implant No protection for fellow eyeNo protection for fellow eye

ComplicationsComplications Retinal necrosisRetinal necrosis

Retinal tears/holesRetinal tears/holes

Rhegmatogenous retinal detachmentRhegmatogenous retinal detachment

ManagementManagement Prophylactic laser retinopexyProphylactic laser retinopexy

Engstrom et al. 1994Engstrom et al. 1994 14 of 54 eyes: Laser 14 of 54 eyes: Laser ~~ 1 week after diagnosis 1 week after diagnosis

93% developed a RD93% developed a RD Median interval Median interval ~~ 3 weeks 3 weeks

Ø significant difference: laser VS no laser: Ø significant difference: laser VS no laser: Zone of involvement of RDZone of involvement of RD Extent of RDExtent of RD Interval from diagnosis to RDInterval from diagnosis to RD

ManagementManagement Rhegmatogenous retinal detachmentRhegmatogenous retinal detachment

Engstrom et al. 1994Engstrom et al. 1994 43 of 65 eyes: Median interval 4 weeks43 of 65 eyes: Median interval 4 weeks

No relationship to extent of disease or disease No relationship to extent of disease or disease activityactivity

Vitrectomy/endolaser/silicone oilVitrectomy/endolaser/silicone oil 16 of 43 eyes: Retinas successfully attached 16 of 43 eyes: Retinas successfully attached

in all eyesin all eyes Re-detached in 4 eyesRe-detached in 4 eyes NLP in 56% (laser) VS 63% (no laser)NLP in 56% (laser) VS 63% (no laser)

PrognosisPrognosis Visual prognosis is poorVisual prognosis is poor

Macular involvementMacular involvement Ineffectiveness of antiviral agentsIneffectiveness of antiviral agents

RecurrenceRecurrence Engstrom, et al. 1994Engstrom, et al. 1994

At least 10 pts despite being on maintenance therapyAt least 10 pts despite being on maintenance therapy Characterized by development of new disease fociCharacterized by development of new disease foci

In 6 pts associated with In 6 pts associated with discontinuation/reduction in maintenance dose; discontinuation/reduction in maintenance dose; median time to recurrence was median time to recurrence was

2 weeks (1-6 weeks)2 weeks (1-6 weeks)

~ 50% of individuals ~ 50% of individuals deceased 5 months after deceased 5 months after diagnosisdiagnosis

Back To Our Back To Our Patient…Patient…

Patient admitted to medicinePatient admitted to medicine Infectious disease consultedInfectious disease consulted

Received IV foscarnet (40mg/kg Q12 x 14 days)Received IV foscarnet (40mg/kg Q12 x 14 days) øø Progression of lesions Progression of lesions VVAA improved to 20/60 (+1.75) improved to 20/60 (+1.75) Discharged on oral acyclovir 800mg 5x dayDischarged on oral acyclovir 800mg 5x day

Take Home Take Home Points…Points…

Progressive outer retinal necrosis is a Progressive outer retinal necrosis is a rapidly progressive necrotizing retinitis rapidly progressive necrotizing retinitis occurring in immunocompromised occurring in immunocompromised individuals, esp. AIDS ptsindividuals, esp. AIDS pts

Management is anecdotal: use of high-Management is anecdotal: use of high-dose IV anti-virals may be beneficialdose IV anti-virals may be beneficial

Poor visual prognosisPoor visual prognosis

ReferencesReferences E-Medicine: Ocular manifestations of HIVE-Medicine: Ocular manifestations of HIV Forster et al. Rapidly PORN in AIDS. Am J Ophth 110: 341. Forster et al. Rapidly PORN in AIDS. Am J Ophth 110: 341.

19901990 Moorthy et al. Management of VZV retinitis in AIDS. Br J Moorthy et al. Management of VZV retinitis in AIDS. Br J

Ophth, 1997.Ophth, 1997. Walton et al. Fluorescein angiography in PORN. Retina 16: Walton et al. Fluorescein angiography in PORN. Retina 16:

19961996 Ciulla, et al. The PORN: Successfully treatment with Ciulla, et al. The PORN: Successfully treatment with

combination antiviral therapy. Ophth Surgery & Lasers. combination antiviral therapy. Ophth Surgery & Lasers. 19981998

BCSC. Retina & Vitreous. AAO. 2004-05BCSC. Retina & Vitreous. AAO. 2004-05 BCSC. Uveitis & Intraocular Inflammation. AAO. 2004-05BCSC. Uveitis & Intraocular Inflammation. AAO. 2004-05 Yanoff. Ophthalmology, 2Yanoff. Ophthalmology, 2ndnd Ed. Mosby. 1121-22 Ed. Mosby. 1121-22 Kanski. Clinical Ophthalmology, 5Kanski. Clinical Ophthalmology, 5thth Ed. Butterworth Ed. Butterworth

Heinemann. 288-93. 2003Heinemann. 288-93. 2003