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Acute retinal necrosis from herpes simplex virus type 2: a case series

Published:January 31, 2022DOI:https://doi.org/10.1016/j.jcjo.2022.01.001
      Acute retinal necrosis (ARN) is a potentially blinding condition characterized by rapidly progressive peripheral retinal necrosis with occlusive vasculopathy and prominent inflammatory reaction.
      • Schoenberger SD
      • Kim SJ
      • Thorne JE
      • et al.
      Diagnosis and treatment of acute retinal necrosis: a report by the American Academy of Ophthalmology.
      ,
      • Holland GN.
      Standard diagnostic criteria for the acute retinal necrosis syndrome.
      Identification of a viral etiology can be done with polymerase chain reaction (PCR) testing of intraocular fluid, and prompt management is necessary to preserve vision. ARN caused by herpes simplex virus 2 (HSV-2) is rare, and our understanding is based on a few small case series.
      • Tran TH
      • Stanescu D
      • Caspers-Velu L
      • et al.
      Clinical characteristics of acute HSV-2 retinal necrosis.
      Here we present three cases of HSV-2 ARN in immunocompetent hosts with a prolonged clinical course of systemic and intravitreal antivirals. We also report on the application of serial PCR as an adjunct measure of treatment response in HSV-2 ARN, which has rarely been described in the literature.
      • Arimura E
      • Deai T
      • Maruyama K
      • et al.
      Herpes simplex virus-2 quantification by real-time polymerase chain reaction in acute retinal necrosis.

      Case 1

      A 22-year-old male presented with blurred vision, floaters, and right eye pain. His ocular history included idiopathic panuveitis in the left eye at age 12 with retinal detachment and pseudophakia. Best corrected visual acuity (BCVA) was 20/30 OD and intraocular pressure (IOP) was 10 mm Hg. He had keratic precipitates, 3+ anterior chamber cells, disc hyperemia, and superonasal retinal whitening with 1+ vitreous cells. Chorioretinal scarring was present in the periphery of both eyes (Fig. 1A). Investigations for all patients included blood count, creatinine, angiotensin-converting enzyme, antinuclear antibody, antineutrophil cytoplasmic antibody, rheumatoid factor, human immunodeficiency virus, toxoplasma, tuberculosis, syphilis, and bartonella. A chest x-ray was done to assess for signs of tuberculosis and sarcoidosis. Infectious disease specialists were also consulted. An anterior chamber paracentesis collected aqueous humor for viral testing. Aqueous PCR found HSV-2, although the patient had no history of infection or sexual activity. Despite valacyclovir 2 g orally tid daily, difluprednate qid, and intravitreal ganciclovir 2 mg twice weekly, his retinitis progressed, and he was given intravenous foscarnet 5 g every 8 hours for 14 days. The retinitis stabilized and he continued intravitreal foscarnet 2.4 mg and ganciclovir 2 mg biweekly through day 34, followed by weekly foscarnet. PCR was negative on day 54 (Fig. 2), and intravitreal injections were discontinued. BCVA recovered to 20/20, and he continued prophylactic oral valacyclovir 1 g.
      Fig 1
      Fig. 1Bilateral wide-field Optos (Dunfermline, Scotland) fundus photographs of (A) Case 1 with active retinitis OD, as indicated by the arrows (for all patients), and peripheral chorioretinal scars OS, as indicated by the asterisk (for all patients); (B) Case 2 with active retinitis OS and peripheral chorioretinal scars OD; and (C) Case 3 with active retinitis OD.
      Fig 2
      Fig. 2Polymerase chain reaction amplification cycles needed for herpes simplex virus 2 detection over the course of treatment, where the number of amplification cycles was a surrogate measure of viral activity. The dashed line indicates the amplification cycle cutoff that is a negative test, defined as 40 by the manufacturer. *Undetectable values.

      Case 2

      A 13-year-old female presented with blurred vision, floaters, and pain in her left eye. Her ocular history included idiopathic pars planitis in the same eye at age 6. There was no history of sexual activity or maternal sexually transmitted disease. BCVA was 20/40 OS with an IOP of 20 mm Hg. She had keratic precipitates, 3+ anterior chamber cells, 1+ vitreous cells, mild disc edema, and retinitis with vasculitis in the temporal far periphery (Fig. 1B). She was empirically started on valacyclovir 1 g tid and prednisolone 1% drops qid. Aqueous PCR identified HSV-2, and she was transitioned to intravenous acyclovir 10 mg/kg every 8 hours. Her retinitis progressed, so on day 8 she started intravitreal ganciclovir 2 mg and foscarnet 2.4 mg twice weekly. On day 58 she developed a retinal detachment with repair by pars plana vitrectomy. PCR was negative on day 93, and she was placed on valacyclovir 1 g tid for 5 months followed by once-daily dosing. Her final BCVA was 20/25.

      Case 3

      A 19-year-old female presented with retro-orbital pain, blurred vision, and floaters in the right eye. She did not have any ocular history or exposure to HSV-2. BCVA was 20/60 OD with IOP of 20 mm Hg. She had 2+ anterior chamber cells, 3+ vitreous cells, 1+ vitreous haze, vascular sheathing, and retinal necrosis (Fig. 1C). Viral PCR of aqueous humor found HSV-2, and she was started on oral famciclovir 500 mg tid and intravitreal ganciclovir 4 mg twice weekly. Her retinitis continued to enlarge, prompting a switch to intravitreal foscarnet 2.4 mg once weekly and valacyclovir 1g tid for its superior intraocular penetration.
      • Huynh TH
      • Johnson MW
      • Comer GM
      • Fish DN.
      Vitreous penetration of orally administered valacyclovir.
      PCR was used in conjunction with clinical examination to monitor the response to treatment (Fig. 2). Foscarnet injections were stopped on day 144, and she achieved a final BCVA of 20/20.

      Discussion

      HSV-2 is the most common cause of ARN in childhood, but it remains a rare entity, with most reports being relatively small case series.
      • Tran TH
      • Stanescu D
      • Caspers-Velu L
      • et al.
      Clinical characteristics of acute HSV-2 retinal necrosis.
      ,
      • Silva RA
      • Berrocal AM
      • Moshfeghi DM
      • Blumenkranz MS
      • Sanislo S
      • Davis JL.
      Herpes simplex virus type 2 mediated acute retinal necrosis in a pediatric population: case series and review.
      Here we report 3 immunocompetent patients presenting with HSV-2 ARN. The patients were young, with ages 13 to 22, in keeping with previous reports and in contrast to HSV-1 ARN, which tends to occur later in life.
      • Ganatra JB
      • Chandler D
      • Santos C
      • et al.
      Viral causes of the acute retinal necrosis syndrome.
      Given their history of contralateral uveitis, we suspect there was prior undiagnosed HSV-2 ARN that regressed because there can be bilateral involvement separated by many years in up to two-thirds of patients.
      • Bonfioli AA
      • Eller AW.
      Acute retinal necrosis.
      Given the lack of consensus treatment guidelines for HSV-2 ARN and the difficulty in detecting subtle clinical changes, we propose that serial PCR may be helpful in assessing antiviral treatment response. This has been previously demonstrated in systemic Herpesviridae infections.
      • Beam E
      • Razonable RR.
      Cytomegalovirus in solid organ transplantation: epidemiology, prevention, and treatment.
      ,
      • Razonable RR
      • Paya CV
      • Smith TF.
      Role of the laboratory in diagnosis and management of cytomegalovirus infection in hematopoietic stem cell and solid-organ transplant recipients.
      Although quantitative HSV-2 PCR kits may not always be available, cycle threshold may provide a useful surrogate, where a greater number of PCR amplification cycles required for viral detection suggests treatment response. Here the time to a negative viral PCR, defined as undetectable after 40 replication cycles as per manufacturer specifications, was 55–148 days. Medications were virustatic and not virucidal, which may explain why patient 3 achieved disease resolution despite detectable virus.
      More work is required to determine optimal timepoints for serial PCR measurements, and given the heterogeneity of ARN presentations and individual responses to treatment, a single protocol applicable to all patients may not exist. The timing of testing, therefore, will be guided by the clinical situation. This approach may be used when a patient has an unexpected clinical course or response and may be most useful when repeated at these timepoints, whereas patients who are responding as expected may not need as frequent monitoring. If patients are receiving intravitreal therapy and having an aqueous tap performed for volume, sending this sample for PCR replication is preferable to simply disposing of the sample. In cases of disease progression, lowering PCR replication cycles aids the clinician in identifying antiviral resistance, whereas a trend of increasing replication cycles is indicative of positive treatment response and helps guide medication tapering.
      This series suggests that HSV-2 ARN may require prolonged treatment because retinitis progressed in the initial weeks despite oral valacyclovir/famciclovir, and intravitreal agents were needed. HSV resistance to acyclovir in immunocompetent hosts is uncommon, with resistance rates of 0.1%–0.7%, often secondary to mutation of the viral thymidine kinase gene.
      • Piret J
      • Boivin G.
      Resistance of herpes simplex viruses to nucleoside analogues: mechanisms, prevalence, and management.
      We were unable to test for such a mutation because the fluid volume from paracentesis was insufficient to amplify the thymidine kinase-encoding gene. However, it is unlikely that all cases would have resistance, and more likely it shows that HSV-2 ARN may progress initially and requires a prolonged treatment course. Foscarnet, a DNA polymerase inhibitor reserved for HSV refractory to nucleosidic drugs, was effective for all 3 patients. Intravitreal administration of foscarnet provides excellent local viral control because it is administered at a dosage that greatly exceeds reported inhibitory concentration levels, and use of simultaneous systemic therapy provides fellow-eye protection.
      • Schoenberger SD
      • Kim SJ
      • Thorne JE
      • et al.
      Diagnosis and treatment of acute retinal necrosis: a report by the American Academy of Ophthalmology.
      Key features of HSV-2 ARN include a young patient age, presence of hypertrophic chorioretinal scars, and prolonged treatment. Serial PCR may be helpful in monitoring response to antivirals and guiding treatment duration. The natural rate clearance of HSV-2 viral genetic material from the eye is unknown, so one cannot establish a causal association between a decreasing viral load and treatment efficacy. Clinical examination should therefore remain the standard of care for guiding treatment, but serial PCR may be a useful adjuvant to corroborate the clinical features.

      Footnotes and Disclosure

      The authors have no proprietary or commercial interest in any materials discussed in this article.

      References

        • Schoenberger SD
        • Kim SJ
        • Thorne JE
        • et al.
        Diagnosis and treatment of acute retinal necrosis: a report by the American Academy of Ophthalmology.
        Ophthalmology. 2017; 124: 382-392
        • Holland GN.
        Standard diagnostic criteria for the acute retinal necrosis syndrome.
        Am J Ophthalmol. 1994; 117: 663-667
        • Tran TH
        • Stanescu D
        • Caspers-Velu L
        • et al.
        Clinical characteristics of acute HSV-2 retinal necrosis.
        Am J Ophthalmol. 2004; 137: 872-879
        • Arimura E
        • Deai T
        • Maruyama K
        • et al.
        Herpes simplex virus-2 quantification by real-time polymerase chain reaction in acute retinal necrosis.
        Jpn J Ophthalmol. 2005; 49: 64-65
        • Huynh TH
        • Johnson MW
        • Comer GM
        • Fish DN.
        Vitreous penetration of orally administered valacyclovir.
        Am J Ophthalmol. 2008; 145: 682-686
        • Silva RA
        • Berrocal AM
        • Moshfeghi DM
        • Blumenkranz MS
        • Sanislo S
        • Davis JL.
        Herpes simplex virus type 2 mediated acute retinal necrosis in a pediatric population: case series and review.
        Graefes Arch Clin Exp Ophthalmol. 2013; 251: 559-566
        • Ganatra JB
        • Chandler D
        • Santos C
        • et al.
        Viral causes of the acute retinal necrosis syndrome.
        Am J Ophthalmol. 2000; 129 (Feb): 166-172
        • Bonfioli AA
        • Eller AW.
        Acute retinal necrosis.
        Semin Ophthalmol. 2005; 20: 155-160
        • Beam E
        • Razonable RR.
        Cytomegalovirus in solid organ transplantation: epidemiology, prevention, and treatment.
        Curr. Infect. Dis. Rep. 2012; 14: 633-641
        • Razonable RR
        • Paya CV
        • Smith TF.
        Role of the laboratory in diagnosis and management of cytomegalovirus infection in hematopoietic stem cell and solid-organ transplant recipients.
        J. Clin. Microbiol. 2002; 40: 746-752
        • Piret J
        • Boivin G.
        Resistance of herpes simplex viruses to nucleoside analogues: mechanisms, prevalence, and management.
        Antimicrob Agents Chemother. 2011; 55: 459-472https://doi.org/10.1016/j.jcjo.2022.01.001