Emerging concepts in the management of acute retinal necrosis Robert William Wong, 1,2 J Michael Jumper, 2 H Richard McDonald, 2 Robert N Johnson, 2 Arthur Fu, 2 Brandon J Lujan, 2,3 Emmett T Cunningham, Jr 2,4 ▸ Additional files are published online only. To view these files please visit the journal online (http://dx.doi. org/10.1136/bjophthalmol- 2012-301983). 1 Austin Retina Associates, Austin, Texas, USA 2 The Department of Ophthalmology, California Pacific Medical Center, San Francisco, California, USA 3 Department of Vision Science, School of Optometry, University of California, Berkeley, California, USA 4 The Department of Ophthalmology, Stanford University School of Medicine, Stanford, California, USA Correspondence to Emmett T Cunningham, Jr, MD, PhD, MPH, West Coast Retina Medical Group, Inc., 185 Berry Street, Lobby 2, Suite 130, San Francisco, CA 94107-1739, USA; emmett_cunningham@yahoo. com Received 4 May 2012 Revised 8 October 2012 Accepted 7 November 2012 Published Online First 12 December 2012 To cite: Wong RW, Jumper JM, McDonald HR, et al. Br J Ophthalmol 2013;97:545–552. ABSTRACT Acute retinal necrosis (ARN), also known as Kirisawa- type uveitis, is an uncommon condition caused by infection of the retina by one of the herpes family of viruses, most typically varicella zoster virus or herpes simplex virus and less commonly cytomegalovirus. Clinical diagnosis can be challenging and is often aided by PCR-based analysis of ocular fluids. Treatment typically involves extended use of one or more antiviral agents. Long term retinal detachment risk is high. We review the literature on ARN and present an approach to the diagnosis and management of this serious condition. INTRODUCTION Acute retinal necrosis (ARN) was first described in 1971 by Akira Urayama and colleagues as a clinical syndrome consisting of acute unilateral panuveitis associated with retinal periarteritis progressing to diffuse necrotising retinitis and, ultimately, rhegma- togenous retinal detachment. 1 The authors sug- gested the term Kirisawa–Urayama uveitis in honour of their teacher Professor Naganori Kirisawa, who was then Professor of Ophthalmology at Tohoku University ( figure 1). The term ‘BARN’, for bilateral ARN, was coined by Young and Bird in 1978. 2 In 1994, the Executive Committee of the American Uveitis Society refined the definition of ARN based on clinical characteristics and disease course to include: (1) one or more foci of retinal necrosis with discrete borders located in the peripheral retina; (2) rapid progression in the absence of antiviral therapy; (3) circumferential spread; (4) evidence of occlusive vasculopathy with arterial involvement; and (5) a prominent inflammatory reaction in the vitreous and anterior chambers. 3 Over the past few decades, our knowledge of ARN has expanded greatly. Two recently published nationwide surveys from the UK estimated the inci- dence of ARN to be approximately one case per 2 million population per year. 4 5 In addition, genetic and epidemiological studies have identified certain characteristics that may predispose patients to develop ARN. Newer diagnostic modalities, in particular PCR-based assays, have been developed to quickly and accurately identify causative organ- isms and to bolster the ophthalmologist’s ability to discern ARN from other infectious causes of retinitis. Treatment has advanced as well, with both improved systemic antivirals and the increasing use of local therapy via intraocular injection. While the relative rarity of ARN and the lack of randomised clinical trials complicate efforts to establish evidence-based guidelines, an extensive literature now exists on the characteristics, causes and treat- ment of this condition. CLINICAL SIGNS AND SYMPTOMS Acutely, ARN may present with eye redness, periorbi- tal pain, photophobia and/or vision loss. On anterior segment examination, patients may show episcleritis, scleritis, keratitis and/or anterior chamber inflamma- tion, which may be either non-granulomatous or granulomatous ( figure 2). Examination of the poster- ior segment may reveal vitreous inflammation, arter- itis, patchy full thickness necrotising retinitis and, in some cases, involvement of the optic disc. Typically, the retinitis presents as either confluent or multifocal patches of retinitis involving the peripheral retina ( figure 3). An occlusive periarteritis is often present ( figure 4). Second eye involvement occurs in approxi- mately a third of patients, typically within 6 weeks, 6 although fellow eye involvement decades following an initial infection has been described. 78 The risk of bilateral infection may be decreased with prompt antiviral therapy. 9 With prompt initiation of treatment, progression of the retinitis can usually be halted within 2–4 weeks. As the active retinal infection and inflam- mation resolve, affected areas develop pigmentary changes, retinal thinning and atrophy, often produ- cing a scalloped appearance at the junction of involved and uninvolved retina. Vitreous organisa- tion and traction may progress during this phase, producing retinal breaks, retinal detachment and pro- liferative vitreoretinopathy. Rhegmatogenous retinal detachment occurs in a half to three-quarters of eyes with ARN and may develop weeks to months after initial presentation of retinitis. 10 11 Delayed compli- cations of ARN may include chronic vitritis, macular oedema, optic atrophy, epiretinal membrane forma- tion, viral relapse with cessation of antiviral medica- tion and phthysis. 12 Poor visual outcomes have been associated with extensive retinal necrosis at time of referral, 13 herpes simplex virus 2 (HSV-2) or varicella zoster virus (VZV) infection, and misuse of corticosteroid. 12 PATIENT CHARACTERISTICS Although historically thought to affect otherwise healthy adults, increasing evidence suggests that patients who develop ARN may have underlying immune characteristics that put them at an increased risk for the infection. It is widely known that immunosuppression induced by exogenous corticosteroid use may predispose to ARN. 14–16 While no racial or sexual predilection has been identified, moderate associations with class II human leukocyte antigen (HLA) antigen Wong RW, et al. Br J Ophthalmol 2013;97:545–552. doi:10.1136/bjophthalmol-2012-301983 545 Review group.bmj.com on January 3, 2016 - Published by http://bjo.bmj.com/ Downloaded from
Transcript
Emerging concepts in the management of acuteretinal necrosisRobert William Wong,1,2 J Michael Jumper,2 H Richard McDonald,2
Robert N Johnson,2 Arthur Fu,2 Brandon J Lujan,2,3 Emmett T Cunningham, Jr2,4
▸ Additional files arepublished online only. To viewthese files please visit thejournal online (http://dx.doi.org/10.1136/bjophthalmol-2012-301983).1Austin Retina Associates,Austin, Texas, USA2The Department ofOphthalmology, CaliforniaPacific Medical Center,San Francisco, California, USA3Department of Vision Science,School of Optometry, Universityof California, Berkeley,California, USA4The Department ofOphthalmology, StanfordUniversity School of Medicine,Stanford, California, USA
Correspondence toEmmett T Cunningham, Jr,MD, PhD, MPH, West CoastRetina Medical Group, Inc.,185 Berry Street, Lobby 2,Suite 130, San Francisco,CA 94107-1739, USA;[email protected]
Received 4 May 2012Revised 8 October 2012Accepted 7 November 2012Published Online First12 December 2012
To cite: Wong RW,Jumper JM, McDonald HR,et al. Br J Ophthalmol2013;97:545–552.
ABSTRACTAcute retinal necrosis (ARN), also known as Kirisawa-type uveitis, is an uncommon condition caused byinfection of the retina by one of the herpes family ofviruses, most typically varicella zoster virus or herpessimplex virus and less commonly cytomegalovirus.Clinical diagnosis can be challenging and is often aidedby PCR-based analysis of ocular fluids. Treatmenttypically involves extended use of one or more antiviralagents. Long term retinal detachment risk is high. Wereview the literature on ARN and present an approach tothe diagnosis and management of this serious condition.
INTRODUCTIONAcute retinal necrosis (ARN) was first described in1971 by Akira Urayama and colleagues as a clinicalsyndrome consisting of acute unilateral panuveitisassociated with retinal periarteritis progressing todiffuse necrotising retinitis and, ultimately, rhegma-togenous retinal detachment.1 The authors sug-gested the term Kirisawa–Urayama uveitis in honourof their teacher Professor Naganori Kirisawa, whowas then Professor of Ophthalmology at TohokuUniversity (figure 1). The term ‘BARN’, for bilateralARN, was coined by Young and Bird in 1978.2 In1994, the Executive Committee of the AmericanUveitis Society refined the definition of ARN basedon clinical characteristics and disease course toinclude: (1) one or more foci of retinal necrosis withdiscrete borders located in the peripheral retina; (2)rapid progression in the absence of antiviraltherapy; (3) circumferential spread; (4) evidence ofocclusive vasculopathy with arterial involvement;and (5) a prominent inflammatory reaction in thevitreous and anterior chambers.3
Over the past few decades, our knowledge ofARN has expanded greatly. Two recently publishednationwide surveys from the UK estimated the inci-dence of ARN to be approximately one case per2 million population per year.4 5 In addition,genetic and epidemiological studies have identifiedcertain characteristics that may predispose patientsto develop ARN. Newer diagnostic modalities, inparticular PCR-based assays, have been developedto quickly and accurately identify causative organ-isms and to bolster the ophthalmologist’s abilityto discern ARN from other infectious causes ofretinitis. Treatment has advanced as well, with bothimproved systemic antivirals and the increasing useof local therapy via intraocular injection. While therelative rarity of ARN and the lack of randomisedclinical trials complicate efforts to establishevidence-based guidelines, an extensive literature
now exists on the characteristics, causes and treat-ment of this condition.
CLINICAL SIGNS AND SYMPTOMSAcutely, ARN may present with eye redness, periorbi-tal pain, photophobia and/or vision loss. On anteriorsegment examination, patients may show episcleritis,scleritis, keratitis and/or anterior chamber inflamma-tion, which may be either non-granulomatous orgranulomatous (figure 2). Examination of the poster-ior segment may reveal vitreous inflammation, arter-itis, patchy full thickness necrotising retinitis and, insome cases, involvement of the optic disc. Typically,the retinitis presents as either confluent or multifocalpatches of retinitis involving the peripheral retina(figure 3). An occlusive periarteritis is often present(figure 4). Second eye involvement occurs in approxi-mately a third of patients, typically within 6 weeks,6
although fellow eye involvement decades followingan initial infection has been described.7 8 The risk ofbilateral infection may be decreased with promptantiviral therapy.9
With prompt initiation of treatment, progressionof the retinitis can usually be halted within2–4 weeks. As the active retinal infection and inflam-mation resolve, affected areas develop pigmentarychanges, retinal thinning and atrophy, often produ-cing a scalloped appearance at the junction ofinvolved and uninvolved retina. Vitreous organisa-tion and traction may progress during this phase,producing retinal breaks, retinal detachment and pro-liferative vitreoretinopathy. Rhegmatogenous retinaldetachment occurs in a half to three-quarters of eyeswith ARN and may develop weeks to months afterinitial presentation of retinitis.10 11 Delayed compli-cations of ARN may include chronic vitritis, macularoedema, optic atrophy, epiretinal membrane forma-tion, viral relapse with cessation of antiviral medica-tion and phthysis.12 Poor visual outcomes have beenassociated with extensive retinal necrosis at time ofreferral,13 herpes simplex virus 2 (HSV-2) or varicellazoster virus (VZV) infection, and misuse ofcorticosteroid.12
PATIENT CHARACTERISTICSAlthough historically thought to affect otherwisehealthy adults, increasing evidence suggests thatpatients who develop ARN may have underlyingimmune characteristics that put them at anincreased risk for the infection. It is widely knownthat immunosuppression induced by exogenouscorticosteroid use may predispose to ARN.14–16
While no racial or sexual predilection has beenidentified, moderate associations with class IIhuman leukocyte antigen (HLA) antigen
Wong RW, et al. Br J Ophthalmol 2013;97:545–552. doi:10.1136/bjophthalmol-2012-301983 545
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expression, most notably HLA-DQw7 (phenotype Bw62) andDR4 antigens in Caucasian patients in the USA17 andHLA-Aw33, -B44 and -DRw6 antigens in patients in Japan,have suggested a possible genetic contribution.18 Moreover,Herbort and colleagues observed that the clinical presentationof herpetic retinitis may correlate with the amount of overallimmune dysfunction.19 20 Specifically, they found that in mildercases of ARN, patients tended to demonstrate more subtleimmune irregularities; in more classical cases of ARN, patientstypically exhibited increasing immune dysfunction; and in cases
of progressive outer retinal necrosis (PORN), patients displayedthe most severe immune dysfunction of all, specifically profoundimmunosuppresion.20 Originally described in patients with HIV/AIDS, PORN is characterised by the occurrence of multiple areasof necrotising retinitis with relatively little vitreous inflammation(figure 5). While the original description of PORN emphasisedinvolvement of the posterior pole, necrotising herpetic retinitiscan involve any portion of the retina, regardless of immunestatus, and it is now generally accepted that the presence orabsence of overlying vitreous inflammation is determined largely
Figure 1 Professor NaganoriKirisawa (upper left; 1907–1980), afterwhom Kirisawas-type uveitis—mostcommonly known as acute retinalnecrosis—was named, and ProfessorAkira Urayama (upper right;1918–1993). Below, fundusphotographs of the affected eye fromCase 6, a 35-year-old man, describedin the original report by Urayama andcolleagues, showing panuveitis,papillitis, periarteritis and peripheralnecrotising retinitis.1 Images courtesyof Dr Nakiyuri Yamada (http://www.nichigan.or.jp/english/ophthalmology.jsp).
Figure 2 Granulomatous anterior chamber inflammation with largekeratic precipitates in a patient with acute retinal necrosis. Courtesy ofProfessor Rubens Belfort, Jr.
Figure 3 Extensive peripheral necrotising retinitis and periarteritis inan immunocompetent patient with acute retinal necrosis.
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by the patient’s underlying immune status. The differential diag-nosis of viral retinitis includes syphilitic retinitis, toxoplasmicretinochoroiditis, intraocular lymphoma, sarcoidosis, tubercu-losis, toxocariasis, fungal or bacterial retinitis/endophthalmitis,Behçet’s disease and other retinal vasculitides.
AETIOLOGYPrior reports of aetiological agents associated with ARN andPORN, derived predominantly from single centre retrospectivestudies, are listed in online supplementary tables S1–S3 (refer-ences for these tables are provided in the Supplementary refer-ences online), and the aetiologies are summarised schematicallyin figure 6. Consistent with most case series,9 10 VZV infectionaccounts for the majority of cases of ARN, with the bulk of theremaining cases resulting from infection with HSV-1 or -2, andless commonly, cytomegalovirus (CMV)21 22 and Epstein–Barrvirus23 infections. Varicella and HSV-1 are more likely to befound in middle-aged and older patients22 whereas HSV-2 ismore likely to be found in young adults and children.24 25 Inpatients with concomitant encephalitis or meningitis, the mostlikely pathogenic agents are HSV-1 and HSV-2, respectively.22
DIAGNOSTIC TESTINGLaboratory testing of intraocular samples has become increas-ingly valuable in the diagnosis of infectious retinitis. Previous
studies investigating viral causes of ARN have used a number ofdiagnostic techniques, including antibody-based analysis ofserum or intraocular fluid,18 26–31 viral culture32 33 and patho-logical examination of retinal specimens,34 often in conjunctionwith immunocytochemical studies.35 More recently, PCR-basedanalysis of intraocular fluid has assumed greater importance,36–39
and has specifically been shown to influence diagnosis and treat-ment in a sizable proportion of cases.40 41 A relatively smallsample volume from the anterior chamber aqueous is usually suf-ficient to detect VZV, HSV, CMV or Toxoplasma gondii DNA inpatients with infectious retinitis40 41 and results are typicallyavailable within 1 week. The PCR assay developed by at theFrancis I. Proctor Foundation has a reported sensitivity and speci-ficity greater than 95% and 97%, respectively, for the diagnosisof VZV, CMV and HSV.36 38 42 Other centres have reported ahigher false negative rate, however,41 and this can increase inpatients who are tested after having received antiviral therapy orwhen there is a delay in PCR testing.28 40 Some have suggestedthat quantitative PCR may be useful to monitor the viral activityand response to antiviral therapeutics.43 44
MEDICAL TREATMENT OF ARNAlthough the use of intravenous acyclovir has been the standardinitial treatment for ARN, the last 20 years has witnessed theintroduction of a number of agents that can be used to treat
Figure 4 (A) Peripheral necrotising retinitis and periarteritis. (B) Fluorescein angiogram showing extensive peripheral non-perfusion with segmentalarteriolar occlusion. Nodular arteritis with Kyrieleis plaques is also evident.
Figure 5 Extensive posterior outer retinal necrosis in two HIV infected patients. (A) Herpes simplex virus type 2. (B) Varicella zoster virus.
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viral retinitis. Oral antiviral medications, such as valacyclovir,famciclovir and valganiclovir, as well as intravenous and intravi-treal preparations of foscarnet and ganciclovir, have all emergedas treatment options for patients with ARN (table 1).
The role of systemic antiviral therapyBecause the bioavailability of oral acyclovir is relatively low,patients treated with this agent typically undergo inductiontherapy with intravenous acyclovir, which often requiresinpatient hospitalisation. The typical induction dose for acyclo-vir is 10 mg/kg divided three times a day; although, some clini-cians have reported using the higher doses of 15 mg/kg dividedthree times a day. This can then be followed by oral acyclovir800 mg five times a day for 3–4 months.45–47 Newer oral agents
such as valacyclovir and famciclovir (prodrug to penciclovir)have greater bioavailability than oral acyclovir and can producesystemic concentrations nearly equal to those obtained withintravenous acyclovir,48 thus achieving systemic levels above thein vitro 50% inhibitory concentration for most isolates of VZV,HSV-1 and HSV-2.49 50 Furthermore, orally administered vala-cylovir can achieve systemic levels comparable with intravenousacyclovir when administered at 2 g three times daily.51–53 Forboth acyclovir and valacyclovir, renal function should be closelymonitored.54 Other agents available to treat ARN, includingoral famciclovir and valganciclovir, are summarised in table 1.
The role of intravitreal antiviral therapyFoscarnet injected intravitreally has been used to treat ARNcaused by both HSV and VZV in adults,13 55 in children55 56
and in ARN associated acyclovir-resistant VZV.57 58 Intravitrealfoscarnet can be administered at a dose of 2.4 mg/0.1 ml, whichrequires no dilution from the commercially available intravenoussolution, and may be administered immediately following diag-nostic sampling of aqueous or vitreous fluid. High dose intravi-treal injections of ganciclovir have also been used for thetreatment of active herpetic retinal necrosis in both immunosup-pressed59 60 and immunocompetent13 61 62 patients. The typicaldose of 2 mg/0.1 ml intravitreal ganciclovir is given two orthree times weekly. A higher dose of intravitreal ganciclovir(5 mg/0.1 ml dose given once a week) has been used to effect-ively treat patients with CMV retinitis in HIV+ patients andmay offer clinicians an additional option.63 Systemic antiviraltherapy is often used in conjunction with intravitreal therapy.
Ganciclovir can also be delivered into the vitreous cavitythough a surgically implanted device (Vitrasert, Bausch &Lomb), which can release a sustained concentration of 1 μg perhour over an 8-month period for patients with ARN related toCMV. Surgical complications are low and the devices are gener-ally well tolerated.64 65
Table 1 Agents commonly used in the treatment of acute retinal necrosis
Drug Route of administration Adverse effectsEstimatedcost*
Predicted relativeefficacy†
Acyclovir 15 mg/kg/day divided every 8 h IV for 7 days, followed by800 mg five times daily po for 3–4 months
Common: GI symptoms, rash, headacheUncommon: renal/CNS toxicity
$7834 HSV-2∼HSV-1>VZV >> CMV
Valacyclovir 1000–2000 mg po q8 h Same as acyclovir $4551 HSV-2∼HSV-1>VZV >> CMVFamciclovir 500 mg po q8 h Common: headache, GI symptoms, rash $4570 HSV-1>HSV-2>VZVGanciclovir 500 mg IV q12 h Common: anaemia, granulocytopenia,
thrombocytopenia$21 724 HSV-1∼CMV >> HSV-2, VZV
2–5 mg/0.1 ml IVT injection, three times per week Uncommon: retinal detachment,haemorrhage, endophthalmitis
Valganciclovir 900 mg twice daily po for 3 weeks induction, then450 mg twice daily po for maintenance
Common: headache, GI symptomsSerious: bone marrow suppression, anaemia,renal dysfunction
$16 331 HSV-1∼CMV >> HSV-2, VZV
Foscarnet For CMV: 60 mg/kg every 8 h IV for 2–3 weeks,For HSV: 40 mg/kg every 8 h IV for 2–3 weeks
Common: headache, GI symptomsUncommon: renal/CNS toxicity
$32 850 HSV-1∼HSV-2∼VZV>CMV
2.4 mg/0.1 ml IVT injection, weekly Uncommon: retinal detachment,haemorrhage, endophthalmitis
$1460
*120 days of treatment; medications alone. 2011 Average wholesale price as of 13 February 2012. Estimated additional costs for outpatient infusion (∼$700 per day) or inpatienthospital stay ($3000–$5000 per day) are not included and may vary depending on the hospital institution and insurance status of the patient. Operating room, surgeon andanaesthesiologist fees not included.†Based on published IC50s.CMV, cytomegalovirus; CNS, central nervous system; GI, gastrointestinal; HSV, herpes simplex virus; IC50, 50% inhibitory concentration; IV, intravenous; IVT, intravitreal; po, by mouth;VZV, varicella zoster virus.
Figure 6 Isolate frequency by patient group. HIV negative acuteretinal necrosis (ARN) versus HIV positive ARN versus progressive outerretinal necrosis (PORN).
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Resistance to pharmacotherapyHSV resistance to acyclovir has been well documented. Suchresistance occurs in less than 1% of the immunocompetentpatients, but has been found in up to 14% in immunosuppressedpatients who are maintained on long term antiviral medication.66
In contrast, varicella virus resistance to acyclovir is rare and onlyreported in small case series.66 Because, unlike acyclovir, foscar-net does not require activation by thymidine kinase, it may beused to treat acyclovir-resistant HSV and VZV strains.57 67–69
Ganciclovir-resistant CMV strains have also been treated withfoscarnet; however, the rate of foscarnet resistance in CMV mayincrease with cumulative therapy.70 Although uncommon, cross-resistance between acyclovir/ganciclovir, both of which requirethymidine kinase, and foscarnet has been observed.66
LASER PHOTOCOAGULATIONThe use of confluent laser photocoagulation in patients withARN is controversial and the level of evidence supporting itsuse is generally weak.71 Still, some authors believe that prophy-lactic laser treatment delivered posterior to active retinitis mayhelp prevent progression to retinal detachment.11 72 73 Othershave contested this view.74 75 The risk of applying a confluentlaser barrier would appear to be minimal, however, and so wetend to apply such treatment when feasible.
RETINAL SURGERYRhegmatogenous retinal detachment, often complicated by pro-liferative vitreoretinopathy, occurs in up to three-quarters ofpatients with ARN.10 11 73 76 When retinal detachments dooccur in the setting of ARN, there are often both rhegmatogen-ous and tractional components, and management shouldaddress both of these contributing factors. Pars plana vitrectomy,lensectomy, air–fluid exchange, endolaser, and long-acting gasor silicone oil tamponade have shown success in retinal reattach-ment repair and recovery of vision.74 76–81 Addition of a scleralbuckle does not seem to significantly affect visual and anatomi-cal outcomes76 nor does the use of silicone oil versus gas tam-ponade.74 The benefit of early surgical intervention to preventretinal detachment is controversial. Some authors believe thatearly vitrectomy with antiviral lavage lowers the risk or retinaldetachment,79 whereas others have found no advantage to earlyvitrectomy.80 In some cases, despite anatomic success, finalvisual function may be limited—particularly when the infectionhas involved the optic nerve and/or macula.74 79
APPROACH TO DIAGNOSIS AND MANAGEMENTOur approach to the diagnosis of patients with retinitis ofunclear aetiology is outlined in figure 7. Diagnosis begins with ahistory, review of systems and a complete ophthalmologicalexamination. Blood, urine and catheter (as appropriate) cultures,and vitreous cultures/Gram stain and potassium hydroxide(KOH) prep are obtained for patients with signs, symptoms orrisk factors for endogenous endophthalmitis. An anteriorchamber or vitreous aspirate (volume >0.05 ml) is then obtainedfor PCR-based testing for HSV, VZV, CMV and T gondii DNA.Samples should be capped and packaged on ice and sent to alaboratory approved to test ocular fluid samples. Although add-itional testing varies for any given patient, typical serologicalstudies include a complete blood count with differential, bothnon-specific (venereal disease research laboratory test or rapidplasmin regain test) and specific (eg, FTA-ABS) treponemal anti-body tests, T gondii antibody testing (immunoglobulin (Ig)G andIgM), ACE and/or lysozyme levels, an interferon-γ release assay
for prior exposure to Mycobacterium tuberculosis, and testingfor HIV exposure. A chest x-ray looking for evidence of eithersarcoidosis or tuberculosis is obtained as well. Due to the rapidprogression of ARN as compared with other causes of retinitis,we treat patients for presumed ARN while test results arepending (figure 7). The decision to admit the patient forinpatient treatment with intravenous antiviral therapy may beinfluenced by several factors, including the presence or suspicionof associated systemic herpetic virus infection, HIV status,patient age and compliance, the extent and location of the retinalnecrosis, and vision. For otherwise healthy and compliant adultswith no evidence of systemic infection and good vision in theaffected eye, we often treat with oral valacyclovir, 2000 mg threetimes daily. Patients who are immunosuppressed or who exhibitclinical signs or symptoms of encephalitis or disseminated derma-titis may be best suited for inpatient treatment and monitoringfor neurological or dermatological complication in conjunctionwith infectious disease specialists. Intravenous antiviral therapy,typically 10–15 mg/kg/day of acyclovir in three divided doses,should be continued for at least 7 days. Thereafter, the patientcan be converted to oral therapy, most often with either acyclovir(800 mg five times daily) or valacyclovir (1000 mg three timesdaily). For immune competent patients, therapy should be con-tinued for a minimum of 3–4 months. For patients withHIV/AIDS, prolonged antiviral therapy/prophylaxis will berequired, or at least until the CD4 count is repeatedly above200 cells/microlitre, as effective immune recovery with antiretro-viral agents will be paramount in resolving the retinitis. Closemonitoring for haematopoetic and renal toxicity isrecommended for patients treated with prolonged antiviral medi-cation, especially with use of valganciclovir. For immunosup-pressed patients who develop viral retinitis while on acyclovir orvalganciclovir and in whom resistance is suspected, intravenousand/or intravitreal foscarnet may be used.
For patients in whom the retinitis threatens or involves theoptic nerve or macula, or if there is the presence of occlusivevasculitis or serous detachment involving the posterior pole, wetend to supplement systemic antiviral treatment with an immedi-ate intravitreal injection of either foscarnet 2.4 mg/0.1 ml organciclovir 2–5 mg/0.1 ml given immediately following intrao-cular fluid sampling. Others use adjunctive intravitreal antiviraltherapy regardless of the location or extent of retinitis.Intravitreal antiviral injections may be repeated two to threetimes per week to treat active retinitis or in patients who areintolerant to systemic therapy.
In cases where significant inflammation may be contributingto the vision loss—such as moderate to severe vitritis, serousretinal detachment involving or threatening the macula, or retin-itis or occlusive vasculitis involving or threatening the opticnerve or macula—a course of oral corticosteroids may be con-sidered. Caution should be taken when using corticosteroids inthe absence of antiviral medication as this may promote viralreplication. A loading dose 0.5 mg/kg/day of prednisone for thefirst 7–10 days of treatment is typical. Topical 1% prednisoloneacetate and a cycloplegic agent can be added to treat anteriorchamber inflammation, as well as pressure lowering drops totreat ocular hypertension as indicated. The use of oral antiplate-let agents, such as aspirin, to help prevent retinal vascular occlu-sion has been suggested as well,82 83 although the use of suchagents remains controversial. Many clinicians have abandonedthe use of aspirin because of the paucity of evidence of benefit.When possible, we place a confluent, triple row laser barrierimmediately posterior to areas of active retinitis. Should thepatient develop a retinal detachment, vitrectomy surgery with
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or without encircling scleral buckling should be performed soonafter the initiation of systemic treatment.
Results from intraocular PCR and serological testing usuallyreturn within 3–7 days, and the treatment can then be modifiedto address the specific cause of retinitis. For CMV retinitis,treatment can be switched to intravenous ganciclovir or oral val-ganciclovir. For individuals with bone marrow suppression ornephrotoxicity, intraocular ganciclovir, either injections or an
implant, or intraocular foscarnet may be indicated to limit sys-temic toxicity. In cases of retinitis due to toxoplasmosis, theappropriate antimicrobial therapy and oral corticosteroidsshould be started.84 85 Patients with serological evidence ofsyphilis are treated as neurosyphilis with 7–14 days of intraven-ous penicillin.86
In patients for whom the cause of retinitis remains unknown,the possibility of intraocular malignancy/lymphoma and/or an
Figure 7 Decision tree summarising recommended approach to the patient with retinitis of unclear aetiology.
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atypical infection should be addressed with a combined vitreousand retinochoroidal biopsy for cytology/histology, culture, Gramstain, KOH prep, and repeat PCR-based testing as indicated—including consideration of 16S ribosomal DNA testing for atyp-ical bacteria and fungi.
Contributors Authors: RWW, JMJ, HRM, RNJ, AF, BJL and ETC. Guarantor: ETC.
Funding Supported in part by The Pacific Vision Foundation and the San FranciscoRetina Foundation.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
Correction notice This article has been corrected since it was published OnlineFirst. The phrase ‘Images courtesy of Dr Yamada Nariyuki’ in the Figure 1 footnotehas been updated to read ‘Images courtesy of Dr Nakiyuri Yamada’ and the author listhas been corrected in reference 1 to read ‘Urayama A, Yamada N, Sasaki T, et al.’
REFERENCES1 Urayama A, Yamada N, Sasaki T, et al. Unilateral acute uveitis with retinal
periarteritis and detachment. Jpn J Clin Ophthalmol 1971;25:607–19.2 Young NJ, Bird AC. Bilateral acute retinal necrosis. Br J Ophthalmol
1978;62:581–90.3 Holland GN. Standard diagnostic criteria for the acute retinal necrosis syndrome.
Executive Committee of the American Uveitis Society. Am J Ophthalmol1994;117:663–7.
4 Muthiah MN, Michaelides M, Child CS, et al. Acute retinal necrosis: a nationalpopulation-based study to assess the incidence, methods of diagnosis, treatmentstrategies and outcomes in the UK. Br J Ophthalmol 2007;91:1452–5.
5 Cochrane TFSG, McDowell C, Foot B, et al. Acute Retinal Necrosis in the UnitedKingdom: results of a prospective surveillance study. Eye 2012;26:370–7.
6 Fisher JP, Lewis ML, Blumenkranz M, et al. The acute retinal necrosis syndrome.Part 1: clinical manifestations. Ophthalmology 1982;89:1309–16.
7 Martinez J, Lambert HM, Capone A, et al. Delayed bilateral involvement in theacute retinal necrosis syndrome. Am J Ophthalmol 1992;113:103–4.
8 Okunuki Y, Usui Y, Kezuka T, et al. Four cases of bilateral acute retinal necrosiswith a long interval after the initial onset. Br J Ophthalmol 2011;95:1251–4.
9 Palay DA, Sternberg P Jr, Davis J, et al. Decrease in the risk of bilateral acute retinalnecrosis by acyclovir therapy. Am J Ophthalmol 1991;112:250–5.
11 Lau CH, Missotten T, Salzmann J, et al. Acute retinal necrosis features,management, and outcomes. Ophthalmology 2007;114:756–62.
12 Fernando AEGD, Thi T, Nathalie C, et al. Long-term visual outcome of patientspresenting with necrotizing viral retinopathies. ARVO Meeting Abstracts 2011;52:4268.
13 Meghpara B, Sulkowski G, Kesen MR, et al. Long-term follow-up of acute retinalnecrosis. Retina 2010;30:795–800.
14 Browning DJ. Acute retinal necrosis following epidural steroid injections. Am JOphthalmol 2003;136:192–4.
16 Saatci AO, Ayhan Z, Arikan G, et al. Unilateral acute retinal necrosis in a multiplesclerosis patient treated with high-dose systemic steroids. Int Ophthalmol2010;30:629–32.
17 Holland GN, Cornell PJ, Park MS, et al. An association between acute retinalnecrosis syndrome and HLA-DQw7 and phenotype Bw62, DR4. Am J Ophthalmol1989;108:370–4.
18 Ichikaw TsJ, Usui M. HLA antigens of patients with Kirisawa’s uveitis and herpetickeratiti. Alarashii Ganka 1989;6:107–14.
19 Rochat C, Polla BS, Herbort CP. Immunological profiles in patients with acute retinalnecrosis. Graefes Arch Clin Exp Ophthalmol 1996;234:547–52.
20 Guex-Crosier Y, Rochat C, Herbort CP. Necrotizing herpetic retinopathies.A spectrum of herpes virus-induced diseases determined by the immune stateof the host. Ocul Immunol Inflamm 1997;5:259–65.
21 Tajunisah I, Reddy SC, Tan LH. Acute retinal necrosis by cytomegalovirus in animmunocompetent adult: case report and review of the literature. Int Ophthalmol2009;29:85–90.
22 Ganatra JB, Chandler D, Santos C, et al. Viral causes of the acute retinal necrosissyndrome. Am J Ophthalmol 2000;129:166–72.
23 Tran TH, Rozenberg F, Cassoux N, et al. Polymerase chain reaction analysis ofaqueous humour samples in necrotising retinitis. Br J Ophthalmol 2003;87:79–83.
24 Tran TH, Stanescu D, Caspers-Velu L, et al. Clinical characteristics of acute HSV-2retinal necrosis. Am J Ophthalmol 2004;137:872–9.
25 Van Gelder RN, Willig JL, Holland GN, et al. Herpes simplex virus type 2 as a causeof acute retinal necrosis syndrome in young patients. Ophthalmology2001;108:869–76.
26 Abe T, Tsuchida K, Tamai M. A comparative study of the polymerase chain reactionand local antibody production in acute retinal necrosis syndrome andcytomegalovirus retinitis. Graefes Arch Clin Exp Ophthalmol 1996;234:419–24.
27 de Boer JH, Luyendijk L, Rothova A, et al. Detection of intraocular antibodyproduction to herpesviruses in acute retinal necrosis syndrome. Am J Ophthalmol1994;117:201–10.
28 de Boer JH, Verhagen C, Bruinenberg M, et al. Serologic and polymerase chainreaction analysis of intraocular fluids in the diagnosis of infectious uveitis. Am JOphthalmol 1996;121:650–8.
29 Margolis T, Irvine AR, Hoyt WF, et al. Acute retinal necrosis syndrome presentingwith papillitis and arcuate neuroretinitis. Ophthalmology 1988;95:937–40.
30 Pepose JS, Flowers B, Stewart JA, et al. Herpesvirus antibody levels in the etiologicdiagnosis of the acute retinal necrosis syndrome. Am J Ophthalmol 1992;113:248–56.
31 el Azazi M, Samuelsson A, Linde A, et al. Intrathecal antibody production againstviruses of the herpesvirus family in acute retinal necrosis syndrome. Am JOphthalmol 1991;112:76–82.
32 Culbertson WW, Blumenkranz MS, Pepose JS, et al. Varicella zoster virus is a causeof the acute retinal necrosis syndrome. Ophthalmology 1986;93:559–69.
33 Duker JS, Nielsen JC, Eagle RC Jr, et al. Rapidly progressive acute retinal necrosissecondary to herpes simplex virus, type 1. Ophthalmology 1990;97:1638–43.
34 Freeman WR, Thomas EL, Rao NA, et al. Demonstration of herpes group virus inacute retinal necrosis syndrome. Am J Ophthalmol 1986;102:701–9.
35 Culbertson WW, Blumenkranz MS, Haines H, et al. The acute retinal necrosissyndrome. Part 2: Histopathology and etiology. Ophthalmology 1982;89:1317–25.
36 Cunningham ET Jr, Short GA, Irvine AR, et al. Acquired immunodeficiencysyndrome–associated herpes simplex virus retinitis. Clinical description and use of apolymerase chain reaction–based assay as a diagnostic tool. Arch Ophthalmol1996;114:834–40.
37 Knox CM, Chandler D, Short GA, et al. Polymerase chain reaction-based assays ofvitreous samples for the diagnosis of viral retinitis. Use in diagnostic dilemmas.Ophthalmology 1998;105:37–44; discussion-44–5.
38 Short GA, Margolis TP, Kuppermann BD, et al. A polymerase chain reaction-basedassay for diagnosing varicella-zoster virus retinitis in patients with acquiredimmunodeficiency syndrome. Am J Ophthalmol 1997;123:157–64.
39 Yamamoto S, Pavan-Langston D, Kinoshita S, et al. Detecting herpesvirus DNA inuveitis using the polymerase chain reaction. Br J Ophthalmol 1996;80:465–8.
40 Harper TW, Miller D, Schiffman JC, et al. Polymerase chain reaction analysis ofaqueous and vitreous specimens in the diagnosis of posterior segment infectiousuveitis. Am J Ophthalmol 2009;147:140–7e2.
41 Rothova A, de Boer JH, Ten Dam-van LNH, et al. Usefulness of aqueous humoranalysis for the diagnosis of posterior uveitis. Ophthalmology 2008;115:306–11.
42 McCann JD, Margolis TP, Wong MG, et al. A sensitive and specific polymerasechain reaction-based assay for the diagnosis of cytomegalovirus retinitis. Am JOphthalmol 1995;120:219–26.
43 Cottet L, Kaiser L, Hirsch HH, et al. HSV2 acute retinal necrosis: diagnosis andmonitoring with quantitative polymerase chain reaction. Int Ophthalmol2009;29:199–201.
44 Yin PD, Kurup SK, Fischer SH, et al. Progressive outer retinal necrosis in the era ofhighly active antiretroviral therapy: successful management with intravitrealinjections and monitoring with quantitative PCR. J Clin Virol 2007;38:254–9.
45 Blumenkranz MS, Culbertson WW, Clarkson JG, et al. Treatment of the acuteretinal necrosis syndrome with intravenous acyclovir. Ophthalmology 1986;93:296–300.
46 Duker JS, Blumenkranz MS. Diagnosis and management of the acute retinalnecrosis (ARN) syndrome. Surv Ophthalmol 1991;35:327–43.
47 Morse LS, Mizoguchi M. Diagnosis and management of viral retinitis in the acuteretinal necrosis syndrome. Semin Ophthalmol 1995;10:28–41.
48 Weller S, Blum MR, Doucette M, et al. Pharmacokinetics of the acyclovir pro-drugvalaciclovir after escalating single- and multiple-dose administration to normalvolunteers. Clin Pharmacol Ther 1993;54:595–605.
49 Beutner KR, Friedman DJ, Forszpaniak C, et al. Valaciclovir compared with acyclovirfor improved therapy for herpes zoster in immunocompetent adults. AntimicrobAgents Chemother 1995;39:1546–3.
50 Lycke J, Malmestrom C, Stahle L. Acyclovir levels in serum and cerebrospinal fluidafter oral administration of valacyclovir. Antimicrob Agents Chemother2003;47:2438–1.
51 Huynh TH, Johnson MW, Comer GM, et al. Vitreous penetration of orallyadministered valacyclovir. Am J Ophthalmol 2008;145:682–6.
52 Aizman A, Johnson MW, Elner SG. Treatment of acute retinal necrosis syndromewith oral antiviral medications. Ophthalmology 2007;114:307–12.
53 Aslanides IM, De Souza S, Wong DT, et al. Oral valacyclovir in the treatment ofacute retinal necrosis syndrome. Retina 2002;22:352–4.
54 Lee RMH, Llewellyn M, Houston A, et al. Reversible mental status change and renaldysfunction associated with the use of high-dose oral valaciclovir therapy Foracuteretinal necrosis. Retin Cases & Brief Rep 2012;6:266–8.
55 Wong R, Pavesio CE, Laidlaw DA, et al. Acute retinal necrosis: the effects ofintravitreal foscarnet and virus type on outcome. Ophthalmology 2010;117:556–60.
Wong RW, et al. Br J Ophthalmol 2013;97:545–552. doi:10.1136/bjophthalmol-2012-301983 551
Review
group.bmj.com on January 3, 2016 - Published by http://bjo.bmj.com/Downloaded from
56 King J, Chung M, DiLoreto DA Jr. A 9 year-old girl with herpes simplex virus type 2acute retinal necrosis treated with intravitreal foscarnet. Ocul Immunol Inflamm2007;15:395–8.
57 Lee MY, Kim KS, Lee WK. Intravitreal foscarnet for the treatment ofacyclovir-resistant acute retinal necrosis caused by varicella zoster virus. OculImmunol Inflamm 2011;19:212–3.
58 Patel P, Ahmed E, Subramanian ML. Intravitreal foscarnet therapy foracyclovir-resistant acute retinal necrosis after herpes simplex encephalitis.Ophthalmic Surg Lasers Imaging 2010:1–3.
59 Meffert SA, Kertes PJ, Lim PL, et al. Successful treatment of progressive outer retinalnecrosis using high-dose intravitreal ganciclovir. Retina 1997;17:560–2.
60 Perez-Blazquez E, Traspas R, Mendez MI, et al. Intravitreal ganciclovir treatment inprogressive outer retinal necrosis. Am J Ophthalmol 1997;124:418–21.
61 Luu KK, Scott IU, Chaudhry NA, et al. Intravitreal antiviral injections as adjunctivetherapy in the management of immunocompetent patients with necrotizing herpeticretinopathy. Am J Ophthalmol 2000;129:811–3.
62 Kishore K, Jain S, Zarbin MA. Intravitreal ganciclovir and dexamethasone asadjunctive therapy in the management of acute retinal necrosis caused by varicellazoster virus. Ophthalmic Surg Lasers Imaging 2011;42 Online:e87–90.
63 Arevalo JF, Garcia RA, Mendoza AJ. High-dose (5000-microg) intravitreal ganciclovircombined with highly active antiretroviral therapy for cytomegalovirus retinitis inHIV-infected patients in Venezuela. Eur J Ophthalmol 2005;15:610–8.
64 Kappel PJ, Charonis AC, Holland GN, et al. Outcomes associated with ganciclovirimplants in patients with AIDS-related cytomegalovirus retinitis. Ophthalmology2006;113:683e1–8.
65 Martin DF, Dunn JP, Davis JL, et al. Use of the ganciclovir implant for the treatmentof cytomegalovirus retinitis in the era of potent antiretroviral therapy:recommendations of the International AIDS Society-USA panel. Am J Ophthalmol1999;127:329–39.
66 Gilbert C, Bestman-Smith J, Boivin G. Resistance of herpesviruses to antiviral drugs:clinical impacts and molecular mechanisms. Drug Resist Updat 2002;5:88–114.
67 Hatchette T, Tipples GA, Peters G, et al. Foscarnet salvage therapy foracyclovir-resistant varicella zoster: report of a novel thymidine kinase mutation andreview of the literature. Pediatr Infect Dis J 2008;27:75–7.
68 Breton G, Fillet AM, Katlama C, et al. Acyclovir-resistant herpes zoster in humanimmunodeficiency virus-infected patients: results of foscarnet therapy. Clin Infect Dis1998;27:1525–7.
69 Balfour HH Jr, Benson C, Braun J, et al. Management of acyclovir-resistant herpessimplex and varicella-zoster virus infections. J Acquir Immune Defic Syndr1994;7:254–60.
70 Jabs DA, Enger C, Forman M, et al. The Cytomegalovirus Retinitis and Viral ResistanceStudy Group. Incidence of foscarnet resistance and cidofovir resistance in patientstreated for cytomegalovirus retinitis. Antimicrob Agents Chemother 1998;42:2240–4.
71 Park JJ, Pavesio C. Prophylactic laser photocoagulation for acute retinal necrosis.Does it raise more questions than answers? Br J Ophthalmol 2008;92:1161–2.
72 Han DP, Lewis H, Williams GA, et al. Laser photocoagulation in the acute retinalnecrosis syndrome. Arch Ophthalmol 1987;105:1051–4.
73 Sternberg P Jr, Han DP, Yeo JH, et al. Photocoagulation to prevent retinaldetachment in acute retinal necrosis. Ophthalmology 1988;95:1389–93.
74 McDonald HR, Lewis H, Kreiger AE, et al. Surgical management of retinaldetachment associated with the acute retinal necrosis syndrome. Br J Ophthalmol1991;75:455–8.
75 Tibbetts MD, Shah CP, Young LH, et al. Treatment of acute retinal necrosis.Ophthalmology 2010;117:818–24.
76 Blumenkranz M, Clarkson J, Culbertson WW, et al. Visual results and complicationsafter retinal reattachment in the acute retinal necrosis syndrome. The influence ofoperative technique. Retina 1989;9:170–4.
77 Ahmadieh H, Soheilian M, Azarmina M, et al. Surgical management of retinaldetachment secondary to acute retinal necrosis:clinical features, surgical techniques,and long-term results. Jpn J Ophthalmol 2003;47:484–91.
78 Davis JL, Serfass MS, Lai MY, et al. Silicone oil in repair of retinal detachmentscaused by necrotizing retinitis in HIV infection. Arch Ophthalmol 1995;113:1401–9.
79 Hillenkamp J, Nolle B, Bruns C, et al. Acute retinal necrosis: clinical features, earlyvitrectomy, and outcomes. Ophthalmology 2009;116:1971–5e2.
80 Ishida T, Sugamoto Y, Sugita S, et al. Prophylactic vitrectomy for acute retinalnecrosis. Jpn J Ophthalmol 2009;53:486–9.
81 Usui Y, Takeuchi M, Yamauchi Y, et al. Pars plana vitrectomy in patients with acuteretinal necrosis syndrome: surgical results in 52 patients. Nihon Ganka GakkaiZasshi 2010;114:362–8.
82 Chang S, Young LH. Acute retinal necrosis: an overview. Int Ophthalmol Clin2007;47:145–54.
83 Kawaguchi T, Spencer DB, Mochizuki M. Therapy for acute retinal necrosis. SeminOphthalmol 2008;23:285–90.
84 Holland GN, Lewis KG. An update on current practices in the management ofocular toxoplasmosis. Am J Ophthalmol 2002;134:102–14.
85 Soheilian M, Sadoughi MM, Ghajarnia M, et al. Prospective randomized trial oftrimethoprim/sulfamethoxazole versus pyrimethamine and sulfadiazine in thetreatment of ocular toxoplasmosis. Ophthalmology 2005;112:1876–2.
86 Aldave AJ, King JA, Cunningham ET Jr. Ocular syphilis. Curr Opin Ophthalmol2001;12:433–41.
552 Wong RW, et al. Br J Ophthalmol 2013;97:545–552. doi:10.1136/bjophthalmol-2012-301983
Review
group.bmj.com on January 3, 2016 - Published by http://bjo.bmj.com/Downloaded from
