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Review Emerging concepts in the management of 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, Jr2,4

▸ Additional files are ABSTRACT now exists on the characteristics, causes and treat- published online only. To view Acute retinal necrosis (ARN), also known as Kirisawa- ment of this condition. these files please visit the journal online (http://dx.doi. type , is an uncommon condition caused by org/10.1136/bjophthalmol- infection of the by one of the herpes family of CLINICAL SIGNS AND SYMPTOMS 2012-301983). , most typically varicella zoster or herpes Acutely, ARN may present with eye redness, periorbi- 1Austin Retina Associates, simplex virus and less commonly cytomegalovirus. tal pain, and/or vision loss. On anterior Austin, Texas, USA Clinical diagnosis can be challenging and is often aided segment examination, patients may show episcleritis, 2The Department of by PCR-based analysis of ocular fluids. Treatment scleritis, keratitis and/or anterior chamber inflamma- , California typically involves extended use of one or more antiviral tion, which may be either non-granulomatous or Pacific Medical Center, fi San Francisco, California, USA agents. Long term risk is high. We granulomatous ( gure 2). Examination of the poster- 3Department of Vision Science, review the literature on ARN and present an approach to ior segment may reveal vitreous inflammation, arter- School of Optometry, University the diagnosis and management of this serious condition. itis, patchy full thickness necrotising and, in of California, Berkeley, some cases, involvement of the optic disc. Typically, California, USA the retinitis presents as either confluent or multifocal 4The Department of Ophthalmology, Stanford patches of retinitis involving the peripheral retina University School of Medicine, INTRODUCTION (figure 3). An occlusive periarteritis is often present Stanford, California, USA Acute retinal necrosis (ARN) was first described in (figure 4). Second eye involvement occurs in approxi- 1971 by Akira Urayama and colleagues as a clinical mately a third of patients, typically within 6 weeks,6 Correspondence to syndrome consisting of acute unilateral panuveitis although fellow eye involvement decades following Emmett T Cunningham, Jr, 78 MD, PhD, MPH, West Coast associated with retinal periarteritis progressing to an initial infection has been described. The risk of Retina Medical Group, Inc., diffuse necrotising retinitis and, ultimately, rhegma- bilateral infection may be decreased with prompt 185 Berry Street, Lobby 2, togenous retinal detachment.1 The authors sug- antiviral therapy.9 Suite 130, San Francisco, gested the term Kirisawa–Urayama uveitis in honour With prompt initiation of treatment, progression CA 94107-1739, USA; emmett_cunningham@yahoo. of their teacher Professor Naganori Kirisawa, who of the retinitis can usually be halted within com was then Professor of Ophthalmology at Tohoku 2–4 weeks. As the active retinal infection and inflam- University (figure 1). The term ‘BARN’, for bilateral mation resolve, affected areas develop pigmentary Received 4 May 2012 ARN, was coined by Young and Bird in 1978.2 In changes, retinal thinning and atrophy, often produ- Revised 8 October 2012 Accepted 7 November 2012 1994, the Executive Committee of the American cing a scalloped appearance at the junction of Published Online First Uveitis Society refined the definition of ARN based involved and uninvolved retina. Vitreous organisa- 12 December 2012 on clinical characteristics and disease course to tion and traction may progress during this phase, include: (1) one or more foci of retinal necrosis with producing retinal breaks, retinal detachment and pro- discrete borders located in the peripheral retina; (2) liferative vitreoretinopathy. Rhegmatogenous retinal rapid progression in the absence of antiviral detachment occurs in a half to three-quarters of eyes therapy; (3) circumferential spread; (4) evidence of with ARN and may develop weeks to months after occlusive vasculopathy with arterial involvement; initial presentation of retinitis.10 11 Delayed compli- and (5) a prominent inflammatory reaction in the cations of ARN may include chronic vitritis, macular vitreous and anterior chambers.3 oedema, optic atrophy, epiretinal membrane forma- Over the past few decades, our knowledge of tion, viral relapse with cessation of antiviral medica- ARN has expanded greatly. Two recently published tion and phthysis.12 Poor visual outcomes have been nationwide surveys from the UK estimated the inci- associated with extensive retinal necrosis at time of dence of ARN to be approximately one case per referral,13 2 (HSV-2) or varicella 2 million population per year.45In addition, zoster virus (VZV) infection, and misuse of genetic and epidemiological studies have identified .12 certain characteristics that may predispose patients to develop ARN. Newer diagnostic modalities, in PATIENT CHARACTERISTICS particular PCR-based assays, have been developed Although historically thought to affect otherwise to quickly and accurately identify causative organ- healthy adults, increasing evidence suggests that isms and to bolster the ophthalmologist’s ability patients who develop ARN may have underlying to discern ARN from other infectious causes of immune characteristics that put them at an retinitis. Treatment has advanced as well, with both increased risk for the infection. It is widely known improved systemic antivirals and the increasing use that immunosuppression induced by exogenous 14–16 To cite: Wong RW, of local therapy via intraocular injection. While the corticosteroid use may predispose to ARN. Jumper JM, McDonald HR, relative rarity of ARN and the lack of randomised While no racial or sexual predilection has been et al. Br J Ophthalmol clinical trials complicate efforts to establish identified, moderate associations with class II – 2013;97:545 552. evidence-based guidelines, an extensive literature human leukocyte antigen (HLA) antigen

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Figure 1 Professor Naganori Kirisawa (upper left; 1907–1980), after whom Kirisawas-type uveitis—most commonly known as acute retinal necrosis—was named, and Professor Akira Urayama (upper right; 1918–1993). Below, fundus photographs of the affected eye from Case 6, a 35-year-old man, described in the original report by Urayama and colleagues, showing panuveitis, papillitis, periarteritis and peripheral necrotising retinitis.1 Images courtesy of Dr Nakiyuri Yamada (http://www. nichigan.or.jp/english/ophthalmology. jsp).

expression, most notably HLA-DQw7 (phenotype Bw62) and of progressive outer retinal necrosis (PORN), patients displayed DR4 antigens in Caucasian patients in the USA17 and the most severe immune dysfunction of all, specifically profound HLA-Aw33, -B44 and -DRw6 antigens in patients in Japan, immunosuppresion.20 Originally described in patients with HIV/ have suggested a possible genetic contribution.18 Moreover, AIDS, PORN is characterised by the occurrence of multiple areas Herbort and colleagues observed that the clinical presentation of necrotising retinitis with relatively little vitreous inflammation of herpetic retinitis may correlate with the amount of overall (figure 5). While the original description of PORN emphasised immune dysfunction.19 20 Specifically, they found that in milder involvement of the posterior pole, necrotising herpetic retinitis cases of ARN, patients tended to demonstrate more subtle can involve any portion of the retina, regardless of immune immune irregularities; in more classical cases of ARN, patients status, and it is now generally accepted that the presence or typically exhibited increasing immune dysfunction; and in cases absence of overlying vitreous inflammation is determined largely

Figure 2 Granulomatous anterior chamber inflammation with large keratic precipitates in a patient with acute retinal necrosis. Courtesy of Figure 3 Extensive peripheral necrotising retinitis and periarteritis in Professor Rubens Belfort, Jr. an immunocompetent patient with acute retinal necrosis.

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Figure 4 (A) Peripheral necrotising retinitis and periarteritis. (B) Fluorescein angiogram showing extensive peripheral non-perfusion with segmental arteriolar occlusion. Nodular with Kyrieleis plaques is also evident. by the patient’s underlying immune status. The differential diag- studies investigating viral causes of ARN have used a number of nosis of viral retinitis includes syphilitic retinitis, toxoplasmic diagnostic techniques, including antibody-based analysis of – retinochoroiditis, intraocular lymphoma, sarcoidosis, tubercu- serum or intraocular fluid,18 26 31 viral culture32 33 and patho- losis, toxocariasis, fungal or bacterial retinitis/, logical examination of retinal specimens,34 often in conjunction Behçet’s disease and other retinal vasculitides. with immunocytochemical studies.35 More recently, PCR-based – analysis of intraocular fluid has assumed greater importance,36 39 AETIOLOGY and has specifically been shown to influence diagnosis and treat- 40 41 Prior reports of aetiological agents associated with ARN and ment in a sizable proportion of cases. A relatively small PORN, derived predominantly from single centre retrospective sample volume from the anterior chamber aqueous is usually suf- studies, are listed in online supplementary tables S1–S3 (refer- ficient to detect VZV, HSV, CMV or Toxoplasma gondii DNA in 40 41 ences for these tables are provided in the Supplementary refer- patients with infectious retinitis and results are typically ences online), and the aetiologies are summarised schematically available within 1 week. The PCR assay developed by at the in figure 6. Consistent with most case series,910VZV infection Francis I. Proctor Foundation has a reported sensitivity and speci- accounts for the majority of cases of ARN, with the bulk of the ficity greater than 95% and 97%, respectively, for the diagnosis 36 38 42 remaining cases resulting from infection with HSV-1 or -2, and of VZV, CMV and HSV. Other centres have reported a 41 less commonly, cytomegalovirus (CMV)21 22 and Epstein–Barr higher false negative rate, however, and this can increase in virus23 infections. Varicella and HSV-1 are more likely to be patients who are tested after having received antiviral therapy or 28 40 found in middle-aged and older patients22 whereas HSV-2 is when there is a delay in PCR testing. Some have suggested more likely to be found in young adults and children.24 25 In that quantitative PCR may be useful to monitor the viral activity 43 44 patients with concomitant encephalitis or meningitis, the most and response to antiviral therapeutics. likely pathogenic agents are HSV-1 and HSV-2, respectively.22 MEDICAL TREATMENT OF ARN DIAGNOSTIC TESTING Although the use of intravenous acyclovir has been the standard Laboratory testing of intraocular samples has become increas- initial treatment for ARN, the last 20 years has witnessed the ingly valuable in the diagnosis of infectious retinitis. Previous introduction of a number of agents that can be used to treat

Figure 5 Extensive posterior outer retinal necrosis in two HIV infected patients. (A) Herpes simplex virus type 2. (B) .

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such as valacyclovir and (prodrug to penciclovir) have greater bioavailability than oral acyclovir and can produce systemic concentrations nearly equal to those obtained with intravenous acyclovir,48 thus achieving systemic levels above the in 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 intravenous – acyclovir when administered at 2 g three times daily.51 53 For both acyclovir and valacyclovir, renal function should be closely monitored.54 Other agents available to treat ARN, including oral famciclovir and , are summarised in table 1.

The role of intravitreal antiviral therapy injected intravitreally has been used to treat ARN caused by both HSV and VZV in adults,13 55 in children55 56 and in ARN associated acyclovir-resistant VZV.57 58 Intravitreal Figure 6 Isolate frequency by patient group. HIV negative acute foscarnet can be administered at a dose of 2.4 mg/0.1 ml, which retinal necrosis (ARN) versus HIV positive ARN versus progressive outer requires no dilution from the commercially available intravenous retinal necrosis (PORN). solution, and may be administered immediately following diag- nostic sampling of aqueous or vitreous fluid. High dose intravi- viral retinitis. Oral antiviral medications, such as valacyclovir, treal injections of have also been used for the treatment of active herpetic retinal necrosis in both immunosup- famciclovir and valganiclovir, as well as intravenous and intravi- 59 60 13 61 62 treal preparations of foscarnet and ganciclovir, have all emerged pressed and immunocompetent patients. The typical as treatment options for patients with ARN (table 1). dose of 2 mg/0.1 ml intravitreal ganciclovir is given two or three times weekly. A higher dose of intravitreal ganciclovir (5 mg/0.1 ml dose given once a week) has been used to effect- The role of systemic antiviral therapy ively treat patients with CMV retinitis in HIV+ patients and Because the bioavailability of oral acyclovir is relatively low, may offer clinicians an additional option.63 Systemic antiviral patients treated with this agent typically undergo induction therapy is often used in conjunction with intravitreal therapy. therapy with intravenous acyclovir, which often requires Ganciclovir can also be delivered into the vitreous cavity inpatient hospitalisation. The typical induction dose for acyclo- though a surgically implanted device (Vitrasert, Bausch & vir is 10 mg/kg divided three times a day; although, some clini- Lomb), which can release a sustained concentration of 1 μg per cians have reported using the higher doses of 15 mg/kg divided hour over an 8-month period for patients with ARN related to three times a day. This can then be followed by oral acyclovir CMV. Surgical complications are low and the devices are gener- – 800 mg five times a day for 3–4 months.45 47 Newer oral agents ally well tolerated.64 65

Table 1 Agents commonly used in the treatment of acute retinal necrosis Estimated Predicted relative Drug Route of administration Adverse effects cost* efficacy†

Acyclovir 15 mg/kg/day divided every 8 h IV for 7 days, followed by Common: GI symptoms, rash, headache $7834 HSV-2∼HSV-1>VZV >> CMV 800 mg five times daily po for 3–4 months Uncommon: renal/CNS toxicity Valacyclovir 1000–2000 mg po q8 h Same as acyclovir $4551 HSV-2∼HSV-1>VZV >> CMV Famciclovir 500 mg po q8 h Common: headache, GI symptoms, rash $4570 HSV-1>HSV-2>VZV Ganciclovir 500 mg IV q12 h Common: anaemia, granulocytopenia, $21 724 HSV-1∼CMV >> HSV-2, VZV thrombocytopenia 2–5 mg/0.1 ml IVT injection, three times per week Uncommon: retinal detachment, $3891 haemorrhage, endophthalmitis Vitrasert surgical implant effective for ∼8 months Uncommon: retinal detachment, hypotony, $19 200 haemorrhage, endophthalmitis Valganciclovir 900 mg twice daily po for 3 weeks induction, then Common: headache, GI symptoms $16 331 HSV-1∼CMV >> HSV-2, VZV 450 mg twice daily po for maintenance Serious: bone marrow suppression, anaemia, renal dysfunction Foscarnet For CMV: 60 mg/kg every 8 h IV for 2–3 weeks, Common: headache, GI symptoms $32 850 HSV-1∼HSV-2∼VZV>CMV For HSV: 40 mg/kg every 8 h IV for 2–3 weeks Uncommon: renal/CNS toxicity 2.4 mg/0.1 ml IVT injection, weekly Uncommon: retinal detachment, $1460 haemorrhage, endophthalmitis *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 inpatient hospital 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 and anaesthesiologist 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.

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Resistance to pharmacotherapy for prior exposure to Mycobacterium tuberculosis, and testing HSV resistance to acyclovir has been well documented. Such for HIV exposure. A chest x-ray looking for evidence of either resistance occurs in less than 1% of the immunocompetent sarcoidosis or tuberculosis is obtained as well. Due to the rapid patients, but has been found in up to 14% in immunosuppressed progression of ARN as compared with other causes of retinitis, patients who are maintained on long term antiviral medication.66 we treat patients for presumed ARN while test results are In contrast, varicella virus resistance to acyclovir is rare and only pending (figure 7). The decision to admit the patient for reported in small case series.66 Because, unlike acyclovir, foscar- inpatient treatment with intravenous antiviral therapy may be net does not require activation by thymidine kinase, it may be influenced by several factors, including the presence or suspicion – used to treat acyclovir-resistant HSV and VZV strains.57 67 69 of associated systemic herpetic virus infection, HIV status, Ganciclovir-resistant CMV strains have also been treated with patient age and compliance, the extent and location of the retinal foscarnet; however, the rate of foscarnet resistance in CMV may necrosis, and vision. For otherwise healthy and compliant adults increase with cumulative therapy.70 Although uncommon, cross- with no evidence of systemic infection and good vision in the resistance between acyclovir/ganciclovir, both of which require affected eye, we often treat with oral valacyclovir, 2000 mg three thymidine kinase, and foscarnet has been observed.66 times daily. Patients who are immunosuppressed or who exhibit clinical signs or symptoms of encephalitis or disseminated derma- LASER PHOTOCOAGULATION titis may be best suited for inpatient treatment and monitoring The use of confluent laser photocoagulation in patients with for neurological or dermatological complication in conjunction ARN is controversial and the level of evidence supporting its with infectious disease specialists. Intravenous antiviral therapy, – use is generally weak.71 Still, some authors believe that prophy- typically 10 15 mg/kg/day of acyclovir in three divided doses, lactic laser treatment delivered posterior to active retinitis may should be continued for at least 7 days. Thereafter, the patient help prevent progression to retinal detachment.11 72 73 Others can be converted to oral therapy, most often with either acyclovir fi have contested this view.74 75 The risk of applying a confluent (800 mg ve times daily) or valacyclovir (1000 mg three times laser barrier would appear to be minimal, however, and so we daily). For immune competent patients, therapy should be con- – tend to apply such treatment when feasible. tinued for a minimum of 3 4 months. For patients with HIV/AIDS, prolonged antiviral therapy/prophylaxis will be required, or at least until the CD4 count is repeatedly above RETINAL SURGERY 200 cells/microlitre, as effective immune recovery with antiretro- Rhegmatogenous retinal detachment, often complicated by pro- viral agents will be paramount in resolving the retinitis. Close liferative vitreoretinopathy, occurs in up to three-quarters of 10 11 73 76 monitoring for haematopoetic and renal toxicity is patients with ARN. When retinal detachments do recommended for patients treated with prolonged antiviral medi- occur in the setting of ARN, there are often both rhegmatogen- cation, especially with use of valganciclovir. For immunosup- ous and tractional components, and management should pressed patients who develop viral retinitis while on acyclovir or address both of these contributing factors. Pars plana vitrectomy, valganciclovir and in whom resistance is suspected, intravenous –fl lensectomy, air uid exchange, endolaser, and long-acting gas and/or intravitreal foscarnet may be used. or silicone oil tamponade have shown success in retinal reattach- 74 76–81 For patients in whom the retinitis threatens or involves the ment repair and recovery of vision. Addition of a scleral optic nerve or macula, or if there is the presence of occlusive buckle does not seem to significantly affect visual and anatomi- 76 vasculitis or serous detachment involving the posterior pole, we cal outcomes nor does the use of silicone oil versus gas tam- tend to supplement systemic antiviral treatment with an immedi- 74 fi ponade. The bene t of early surgical intervention to prevent ate of either foscarnet 2.4 mg/0.1 ml or retinal detachment is controversial. Some authors believe that ganciclovir 2–5 mg/0.1 ml given immediately following intrao- early vitrectomy with antiviral lavage lowers the risk or retinal fl 79 cular uid sampling. Others use adjunctive intravitreal antiviral detachment, whereas others have found no advantage to early therapy regardless of the location or extent of retinitis. 80 fi vitrectomy. In some cases, despite anatomic success, nal Intravitreal antiviral injections may be repeated two to three visual function may be limited—particularly when the infection 74 79 times per week to treat active retinitis or in patients who are has involved the optic nerve and/or macula. intolerant to systemic therapy. In cases where significant inflammation may be contributing APPROACH TO DIAGNOSIS AND MANAGEMENT to the vision loss—such as moderate to severe vitritis, serous Our approach to the diagnosis of patients with retinitis of retinal detachment involving or threatening the macula, or retin- unclear aetiology is outlined in figure 7. Diagnosis begins with a itis or occlusive vasculitis involving or threatening the optic history, review of systems and a complete ophthalmological nerve or macula—a course of oral may be con- examination. Blood, urine and catheter (as appropriate) cultures, sidered. Caution should be taken when using corticosteroids in and vitreous cultures/Gram stain and potassium hydroxide the absence of antiviral medication as this may promote viral (KOH) prep are obtained for patients with signs, symptoms or replication. A loading dose 0.5 mg/kg/day of prednisone for the risk factors for endogenous endophthalmitis. An anterior first 7–10 days of treatment is typical. Topical 1% prednisolone chamber or vitreous aspirate (volume >0.05 ml) is then obtained acetate and a cycloplegic agent can be added to treat anterior for PCR-based testing for HSV, VZV, CMV and T gondii DNA. chamber inflammation, as well as pressure lowering drops to Samples should be capped and packaged on ice and sent to a treat ocular hypertension as indicated. The use of oral antiplate- laboratory approved to test ocular fluid samples. Although add- let agents, such as aspirin, to help prevent retinal vascular occlu- itional testing varies for any given patient, typical serological sion has been suggested as well,82 83 although the use of such studies include a complete blood count with differential, both agents remains controversial. Many clinicians have abandoned non-specific (venereal disease research laboratory test or rapid the use of aspirin because of the paucity of evidence of benefit. plasmin regain test) and specific (eg, FTA-ABS) treponemal anti- When possible, we place a confluent, triple row laser barrier body tests, T gondii antibody testing (immunoglobulin (Ig)G and immediately posterior to areas of active retinitis. Should the IgM), ACE and/or lysozyme levels, an interferon-γ release assay patient develop a retinal detachment, vitrectomy surgery with

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Figure 7 Decision tree summarising recommended approach to the patient with retinitis of unclear aetiology. or without encircling scleral buckling should be performed soon implant, or intraocular foscarnet may be indicated to limit sys- after the initiation of systemic treatment. temic toxicity. In cases of retinitis due to toxoplasmosis, the Results from intraocular PCR and serological testing usually appropriate therapy and oral corticosteroids return within 3–7 days, and the treatment can then be modified should be started.84 85 Patients with serological evidence of to address the specific cause of retinitis. For CMV retinitis, syphilis are treated as neurosyphilis with 7–14 days of intraven- treatment can be switched to intravenous ganciclovir or oral val- ous .86 ganciclovir. For individuals with bone marrow suppression or In patients for whom the cause of retinitis remains unknown, nephrotoxicity, intraocular ganciclovir, either injections or an the possibility of intraocular malignancy/lymphoma and/or an

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Review atypical infection should be addressed with a combined vitreous 26 Abe T, Tsuchida K, Tamai M. A comparative study of the polymerase chain reaction and retinochoroidal biopsy for cytology/histology, culture, Gram and local antibody production in acute retinal necrosis syndrome and — cytomegalovirus retinitis. Graefes Arch Clin Exp Ophthalmol 1996;234:419–24. stain, KOH prep, and repeat PCR-based testing as indicated 27 de Boer JH, Luyendijk L, Rothova A, et al. Detection of intraocular antibody including consideration of 16S ribosomal DNA testing for atyp- production to herpesviruses in acute retinal necrosis syndrome. Am J Ophthalmol ical bacteria and fungi. 1994;117:201–10. 28 de Boer JH, Verhagen C, Bruinenberg M, et al. Serologic and polymerase chain Contributors Authors: RWW, JMJ, HRM, RNJ, AF, BJL and ETC. Guarantor: ETC. reaction analysis of intraocular fluids in the diagnosis of infectious uveitis. Am J – Funding Supported in part by The Pacific Vision Foundation and the San Francisco Ophthalmol 1996;121:650 8. Retina Foundation. 29 Margolis T, Irvine AR, Hoyt WF, et al. Acute retinal necrosis syndrome presenting with papillitis and arcuate neuroretinitis. Ophthalmology 1988;95:937–40. Competing interests None. 30 Pepose JS, Flowers B, Stewart JA, et al. Herpesvirus antibody levels in the etiologic Provenance and peer review Not commissioned; externally peer reviewed. diagnosis of the acute retinal necrosis syndrome. Am J Ophthalmol 1992;113: 248–56. Correction notice This article has been corrected since it was published Online 31 el Azazi M, Samuelsson A, Linde A, et al. Intrathecal antibody production against First. The phrase ‘Images courtesy of Dr Yamada Nariyuki’ in the Figure 1 footnote viruses of the herpesvirus family in acute retinal necrosis syndrome. 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552 Wong RW, et al. Br J Ophthalmol 2013;97:545–552. doi:10.1136/bjophthalmol-2012-301983 Downloaded from http://bjo.bmj.com/ on January 3, 2016 - Published by group.bmj.com

Emerging concepts in the management of acute retinal necrosis

Robert William Wong, J Michael Jumper, H Richard McDonald, Robert N Johnson, Arthur Fu, Brandon J Lujan and Emmett T Cunningham, Jr

Br J Ophthalmol 2013 97: 545-552 originally published online December 12, 2012 doi: 10.1136/bjophthalmol-2012-301983

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