virale retinitis (uveitis posterior)¤sentationen/forum_2/mitt… · ocular. manifestation of...

Prof. Dr. Matthias BeckerSwiss Academy of Ophthalmology 6.3.2019

Virale Retinitis (Uveitis posterior)

Prof. Dr. med. Matthias Becker


Which one of the following concerning necrotizingherpetic retinitis (acute retinal necrosis) is false?

1. Anterior segment inflammation is variable.2. Posterior segment inflammation is generally heavy.3. The periphery of the retina is affected earlier and

more severely than the posterior pole.4. Retinal detachment occurs in up to three-quarters of

cases.5. Like other viral retinitides, affected patients are

usually immunosuppressed.


Cytomegalovirus (CMV) retinitis is the most commonocular manifestation of human immunodeficiencyvirus (HIV) infection.

1. TRUE2. FALSE


• Viral retinitis• Spectrum of necrotizing herpetic retinopathies

• Vasculitis• Anterior segment ischemia• Retinal artery occlusion• Scleritis• Vasculitis in the orbit: cranial nerve palsies

Clinical manifestations


• Spectrum• Rapidly progressing• Clinical picture depends upon host’s immune status:

• Immunocompetent:• Peripheral necrotizing retinitis accompanied by vasculitis, iridocyclitis, and vitritis (ARN)

• Immunocompromised:• Necrotizing retinitis, may rapidly involve the macula + peripheral retina• without significant intraocular inflammation or vasculopathy (PORN)

Necrotizing herpetic retinopathies


• Immunocompetent patients• Most common cause of ARN syndrome is VZV, followed by HSV-1,

HSV-2, and rarely CMV• Patients with ARN due to HSV-1 and VZV tend to be older, while

those with HSV-2 tend to be younger

Acute Retinal Necrosis (ARN)

Van Gelder RN, Willig JL, Holland GN, et al. Ophthalmology. 2001;108:869


American Uveitis Society (AUS) criteria• Single or multiple areas of retinal necrosis with distinct borders• Necrotic foci usually located in peripheral retina• Rapid disease progression if antiherpetic treatment not instituted• Extension of foci of retinal necrosis in a circumferential fashion• Presence of occlusive vasculopathy with arteriolar involvement• Prominent anterior chamber and vitreous inflammation• Characteristics that support but are not required for diagnosis: Optic

neuropathy or atrophy, scleritis, pain

Diagnostic criteria (ARN)

Holland GN Am J Ophthalmol. 1994;117:663


http://eyewiki.aao.org/Acute_retinal_necrosis


FAST• Progressive outer retinal necrosis (PORN)• CMV retinitis• Atypical toxoplasmosis• Acute multifocal hemorrhagic retinal vasculitis• Bacterial / fungal retinitis or endophthalmitis• Autoimmune retinal vasculitis• Behçet‘s disease• Commotio retinae• Central or branch retinal artery occlusion

DD ARNSLOW• Syphilis• Intraocular lymphoma or leukemia• Sarcoidosis• Sympathetic ophthalmia• Vogt-Koyanagi-Harada syndrome• Collagen-vascular disease• Retinoblastoma• Ocular ischemic syndrome


• Morphologic variant of acute necrotizing herpetic retinitis, profoundlyimmunosuppressed

• Most often in advanced AIDS (CD4+ T lymphocytes ≤50 cells/μL)• VZV infection most common cause• Posterior pole may be involved early in the course of the disease,

vitreous inflammatory cells are typically absent, and the retinalvasculature is minimally involved, at least initially

• PORN in HIV: history of cutaneous zoster (67%) and eventually incurbilateral involvement (71%)

Progressive outer retinal necrosis (PORN)


• Similarly high rate (70%) of retinal detachment as in ARN • 2/3 final visual acuity of no light perception• Often resistant to treatment with intravenous acyclovir alone,

successful with combination systemic and intraocular therapy usingfoscarnet and ganciclovir

PORN


• Human immunodeficiency virus (HIV) retinopathy is the mostcommon ocular manifestation of patients with acquiredimmunodeficiency syndrome (AIDS), and occurs in 50% of cases.

• Most common viral manifestation of both congenital CMV infectionand of CMV as an opportunistic coinfection in HIV/AIDS

• Combination antiretroviral regimens (HAART) resulted not only in a significant decline in HIV/AIDS–associated mortality, but also in an 80% decline in new cases per year of CMV retinitis and itscomplications

• 3 distinct variants:

Cytomegalo-Virus (CMV) Retinitis


• Large areas of retinal hemorrhage against a background of whitened, edematous, or necrotic retina

• Typically appears in the posterior pole, from the disc to the vasculararcades, in the distribution of the nerve fiber layer, and associatedwith blood vessels

CMV Type 1: Classic or Fulminant


• Retinal periphery• Little or no retinal edema, hemorrhage, or vascular sheathing• With active retinitis progressing from the borders of the lesion

CMV Type 2: Granular or Indolent

Courtesy of C. LowderBCSC


• Variant of “frosted-branch” angiitis

CMV Type 3: Perivascular

Courtesy of A Vitale BCSC


• Immunocompromised• Posterior pole along vessels• Hemorrhage (pizza pie)• No vitritis• Periphlebitis• Valganciclovir, ganciclovir

CMV ARN• Immunocompetent• Initially peripheral, later posterior pole• Hemorrhage less severe• Severe vitritis• Occlusive arteriolitis• Valaciclovir, aciclovir


• Isolated optic disc edema and optic neuritis• Macular edema• Retinal hemorrhages• Retinitis• Punctate outer retinitis• Choroiditis• Multifocal choroiditis and panuveitis (MCP)• Pars planitis and vitritis• Progressive subretinal fibrosis• Secondary choroidal neovascularization (CNV)

EBV-induced posterior uveitis


• Aqueous tap• Diagnostic vitrectomy• Retinal biopsy

Intraocular fluid / tissue analysis


• May detect minute quantities of herpetic DNA• Most sensitive, specific, and rapid diagnostic method• Vitreous and aqueous samples• Has largely supplanted viral culture, intraocular antibody titers, and

serology• Quantitative PCR-based tests may provide additional information

• viral load• disease activity• response to therapy

Polymerase chain reaction (PCR)


• Ratio > 3 is diagnostic of local antibody production to a specificmicrobial pathogen

• Adjunct to the diagnosis of HSV and VZV uveitis• Little value for CMV retinitis• Combining GW coefficient with PCR analysis

Goldmann-Witmer (GW) coefficient


The goals of treatment of ARN 1. Stop the retinal necrosis in order to avoid the late consequences of

the disease (retinal detachment and optic atrophy)2. Minimize the collateral damage caused by severe inflammation

and vascular occlusions3. Protect the fellow eye (second eye involvement 3-35%, usually

within 6 weeks of disease onset, BARN)Antiviral therapy should begin immediately after the clinical

diagnosis is made, rather than waiting for results of laboratorytesting!

Medical Management


• Initiation of oral antiviral therapy at the onset of uveitis• Prolonged corticosteroid therapy with very gradual tapering• Topical corticosteroids: very long-term, albeit extremely low doses

(1 drop per week)• Prednisone (0.5-2.0 mg/kg/day orally for up to 6-8 weeks) initiated

24-48 hours after the start of antiviral therapy or once regression ofretinal necrosis been demonstrated

• Long-term, suppressive, low-dose antiviral therapy may be indicated• Aspirin may minimize vascular thrombosis and propagation of further

retinal ischemia and necrosis

General therapeutic considerations


1. Intravenous acyclovir, 10 mg/kg every 8 hours for 10–14 days(check serum creatinine and liver enzymes)

2. After 24–48 hours systemic corticosteroids (prednisone, 1 mg/kg/day) are introduced to treat active inflammation and aresubsequently tapered over several weeks

3. Acyclovir at 800 mg orally 5 times daily, Valacyclovir at 1 g orally2-3 times daily, or famciclovir at 500 mg orally 3 times daily should becontinued for 3 months (HSV oral dose is one-half of that for VZV)

4. Extended antiviral therapy may reduce the incidence ofcontralateral disease or bilateral ARN by 80% over 1 year.

HSV and VZV


• Intravenous• Ganciclovir (Cymevene®, 5 mg/kg twice daily) • Foscarnet (Foscavir®, 90 mg/kg twice daily) for 2 weeks

• Low-dose daily maintenance therapy or oral valganciclovir (900 mg twice daily) for 3 weeks

• Maintenance therapy (900 mg/day)

Medical management: CMV


Especially if retinitis (HSV, VZV, CMV) is threatening the macula or opticdisc:

• Ganciclovir (Cymevene®, 200 - 2000 µg per 0.1 ml)• Foscarnet (Foscavir®, 1.2 - 2.4 mg per 0.1 ml)

Antiviral agents intravitreally


• Systemic corticosteroids• Efficacy of systemic antiviral therapy for EBV infection has not been

established

Therapy EBV


• Large retinal breaks frequently develop in areas of retinal necrosis• Tractional-rhegmatogenous retinal detachment in 50-75% of patients with

ARN• Exudative retinal detachment may arise with severe inflammation• Prophylactic laser photocoagulation

• posterior to the area of retinitis• 360°-barrier retinal photocoagulation delay laser until retinal detachment

necessitates surgery• Prophylactic vitrectomy, esp. when PVD occurs• Vitrectomy, endolaser, silicon oil

Surgical Management


Many cases finally have less than 20/200 due to

• Vitreous hemorrhage• Retinal holes and tears• Retinal detachment• Macular pucker• Proliferative vitreoretinopathy (PVR) • Optic neuropathy• Encephalitis, dementia

Untreated, ca. 2/3 final V/A of 20/200 or worseTreated, ca. ½ final V/A of 20/40 or better; 92% better than 20/400

Complications


• Outcomes of posterior entities may be devastating• Prognosis for patients with severe immune dysfunction remains

guarded• Early diagnosis and treatment remains the key to successful

management

Take Home Message


Which one of the following concerning necrotizingherpetic retinitis (acute retinal necrosis) is false?

1. Anterior segment inflammation is variable.2. Posterior segment inflammation is generally heavy.3. The periphery of the retina is affected earlier and

more severely than the posterior pole.4. Retinal detachment occurs in up to three-quarters of

cases.5. Like other viral retinitides, affected patients are

usually immunosuppressed.


Cytomegalovirus (CMV) retinitis is the most commonocular manifestation of human immunodeficiencyvirus (HIV) infection.

1. TRUE2. FALSE

Neue Krankheitsbilder durch Migration


Migration + Klimawandel + GlobalisierungSeit 2015 Zunahme von Flüchtlingen in Europa60 Millionen Menschen befinden sich weltweit auf der Flucht vor Kriegen, Terror oder Verfolgung


• Cartogram • Territory size based on the number of

international immigrants that live there• http://geographicadvantage.aag.org


• Rickettsiose• Rift Valley fever• West Nile Virus• Dengue Virus• Zika• Ebola• Chikungunya• Gelbfieber

“Neue“ Krankheitsbilder: emergent/resurgent

• Influenza A (H1N1) („Schweingrippe“)

• Tuberkulose

• Syphilis

• Lepra

• Human herpes virus six (HHV-6)

• Parechovirus

• Parvovirus


1976 Hämorrhagisches Fieber am Fluss Ebola (Dem. Rep. Kongo) Einzel-Strang RNA-VirusFlughunde, Schimpansen, Gorillas natürliches Reservoir für EBOV (Filoviren, RNA)Epidemie in Westafrika 12-2013 bis 3-2016, 11‘300 Tote (= 40% der Infizierten)WHO 8-2014: Public Health Emergency of International Concern in West AfricaGrippe, disseminierte Hämorrhagien mit MultiorganversagenNIH + Gesundheitsministerium Liberia: Partnership for Research on Ebola Vaccines in Liberia (PREVAIL)Epidemie ebbte plötzlich ab: Sicherheit des Impfstoffs, nicht mehr Schutzwirkung gg. EbolaSchwerpunkt verlagert sich auf Post-Ebola-Syndrome

Ebola virus disease (EVD)


• Grösste Ebola-Epidemie bisher• 2013 – 2016• Zaire Ebola Virus• Total: 28‘646• Tote: 11‘323


Akute Infektion

Hämorrhagische ConjunctivitisUnklarer SehverlustRetrobulbärer Schmerz


Ebola-Überlebende (17‘000 Überlebende in Westafrika 2014):• 53% Muskel-, Gelenkschmerzen• 68% neurologische Störungen (Gedächtnisverlust, Kopfschmerz, Depression,

Gangstörungen, Fatigue)• 60% Uveitis mit intraokularem Ebola-Nachweis (obwohl serologisch negativ!)

Direkter cytopathischer Effekt aktiver ReplikationPersistierend in einem immunprivilegierten Organ? (auch Samen, Prostata)Neue Hygiene-Vorschriften für intraokulare Chirurgie in Entwicklungsländern?

Post-Ebola-Syndrome in Genesungsphase


Varkey JB et al. N Engl J Med 2015;372:2423-7.

• Schwere unilaterale Uveitis während Rekonvaleszenz• 9 Wochen nach Virämie• Vorderkammerpunktat: EBOV RNA+ (quantitative RT-PCR Assay)• Viral Consensus Sequences nicht identisch (Blut vs. VK)


OU: Pigmentierte Läsionen mit HaloOS: • 0.3• 44 mmHg• Panuveitis, Skleritis• Passagere Heterochromie• Post. Synechien• Cat. complicata

Shantha JG et al. Ophthalmology 2017;124:170-177.


Passagere Heterochromie

• Experimentelle antivirale Therapie (Favipiravir)• Ähnlicher Verlauf wie Marburg Virus

Varkey JB et al. N Engl J Med 2015;372:2423-7


Predicted distribution of Ae. AlbopictusKraemer MU et al. Elife 2015;4:e08347


• Predicted probability of occurrence of Ae. albopictus in Europe (A) and the United States (B)

• Regions in which Ae. albopictus is rapidly expanding its range

• Points represent known occurrences

Kraemer MU et al. Elife 2015; 4: e08347


ZusammenfassungBAG: „Bis heute (5-17) wurden in der Schweiz zwei Personen, die sich in Afrika infiziert hatten, erfolgreich gepflegt (1995 und 2014). Zu den Risikogruppen gehören insbesondere Pflege- und Laborpersonal sowie Verwandte, die sich um an der Ebolaviruskrankheit erkrankte Personen kümmern und in Berührung mit Körperausscheidungen kommen, ebenso wie Mitarbeitende von Organisationen (z.B. IKRK, Ärzte ohne Grenzen), die in den Epidemiegebieten arbeiten.WHO: „Entgegen der weit verbreiteten Auffassung gibt es keinen systematischen Zusammenhang zwischen Migration und der Einschleppung von Infektionskrankheiten.“WHO: „Die Gefahr der Einschleppung exotischer und seltener Erreger in die Europäische Region (z. B. Ebola-, Marburg- oder Lassa-Virus oder Nahost-Atemwegssyndrom-Coronavirus) ist äußerst gering.“ Armut, Hygiene („the cause of the cause!“)Retinitis, Choriortetinitis, retinale Vaskulitis, Optikusneuropathie u.a. Uveitisformen in Patienten aus endemischen Gebieten


Thank you!


27. Juni 201913:30 – 16:30 Festsaal

GlaukomHornhautNetzhaut-Chirurgie

Augenärztliches Symposium Triemli


Foliennummer 1Foliennummer 2Foliennummer 3Clinical manifestationsNecrotizing herpetic retinopathiesAcute Retinal Necrosis (ARN)Diagnostic criteria (ARN)Foliennummer 8Foliennummer 9DD ARNProgressive outer retinal necrosis (PORN)PORNCytomegalo-Virus (CMV) RetinitisCMV Type 1: Classic or Fulminant�CMV Type 2: Granular or Indolent CMV Type 3: PerivascularCMV ARNEBV-induced posterior uveitisIntraocular fluid / tissue analysis Polymerase chain reaction (PCR)Goldmann-Witmer (GW) coefficientMedical ManagementGeneral therapeutic considerationsHSV and VZVMedical management: CMVAntiviral agents intravitreallyTherapy EBVSurgical ManagementComplicationsTake Home MessageFoliennummer 31Foliennummer 32Neue Krankheitsbilder durch MigrationMigration + Klimawandel + GlobalisierungFoliennummer 35Foliennummer 36Foliennummer 37“Neue“ Krankheitsbilder: emergent/resurgentEbola virus disease (EVD)Foliennummer 40Foliennummer 41Akute InfektionPost-Ebola-Syndrome in GenesungsphaseFoliennummer 44Foliennummer 45Foliennummer 46Passagere HeterochromieFoliennummer 48Foliennummer 49Foliennummer 50ZusammenfassungFoliennummer 52Augenärztliches Symposium TriemliFoliennummer 54

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