From UIC-Peoria Campus (KK, SJ), Peoria, Illinois; Illinois Retina Institute (KK), Peoria, Illinois; and the Institute of Ophthalmology and Visual Science-New Jersey Medical School (MAZ), Newark, New Jersey.
Presented as poster at the 28th annual meeting of American Society of Retina Specialists; August 28–September 1, 2010; Vancouver, British Columbia, Canada.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Kamal Kishore, MD, Illinois Retina Institute S.C., 5016 N. University, Suite 106, Peoria, IL 61614. E-mail: email@example.com
Acute retinal necrosis syndrome is a distinct infectious retinitis caused by members of the herpes virus family.1,2 Intravenous acyclovir, the mainstay of therapy since its introduction by Blumenkranz et al.3 in 1986, prevents formation of new lesions in the affected eye and reduces the risk of involvement of the fellow eye, but does not decrease inflammation.1,4 Oral corticosteroids are commonly added 2 to 3 days later to control inflammation, with unproven benefit.1,5 Intravitreal antiviral therapy has been used, usually as an adjunct to systemic therapy.6 Unfortunately, despite treatment, visual prognosis in the affected eye remains poor.
Inflammatory vasculitis involving all layers of the eye is an important cause of tissue damage in acute retinal necrosis. Histological studies have demonstrated diffuse retinal arterial occlusion.7 We therefore hypothesized that prompt control of inflammation and viral multiplication with adjunctive intravitreal injections of dexamethasone and ganciclovir might improve the outcome in acute retinal necrosis.
A 40-year-old otherwise healthy man presented with a 3-day history of pain, redness, and decreased vision in his right eye. Examination revealed a visual acuity of 20/400, conjunctival congestion, anterior uveitis, dense vitritis, optic nerve edema, arteriolar narrowing, and peripheral retinal whitening in two inferior quadrants in the right eye (Fig. 1), and a normal left eye. Intravenous fluorescein angiogram showed hypoperfusion of the optic nerve, arteriolar occlusion, and leakage from arterioles (Fig. 2). He was admitted for induction therapy with intravenous acyclovir 10 mg/kg every 8 hours for 8 days, aspirin 325 mg/d orally, topical 1% prednisone acetate every 2 hours, and topical 1% atropine eye drops every 8 hours. The following morning, a diagnostic vitreous tap was performed followed by intravitreal injections of ganciclovir (2 mg/0.1 mL) and dexamethasone (400 mcg/0.1 mL). Oral prednisone 60 mg/d was added on day 3 and tapered over 3 months. Valacyclovir 1 g orally three times per day was started on day 9 and continued for 3 months.
Figure 1. (A and B) Fundus photograph of the right eye at presentation. Note dense vitritis, optic disc edema, narrowing and sheathing of arterioles (A), and peripheral retinitis involving two inferior quadrants (B).
Figure 2. Intravenous fluorescein angiogram of the right eye at presentation showing hypoperfusion of the nerve, arteriolar occlusion, and leakage from the arterioles.
Varicella zoster virus DNA was detected by polymerase chain reaction in the vitreous. Serology was negative for HIV, toxoplasmosis, and syphilis. Chest x-ray was normal. No new lesions were observed, and optic nerve edema and uveitis resolved over the next 2 weeks. Retinal lesions showed decreased edema starting on day 3, pigmentation around day 5, and healing by day 9 (Fig. 3). Visual acuity improved to 20/30 at 2 months of follow-up and remained at that level for 3 months. Approximately 5 months after the onset of disease, the patient presented with sudden loss of vision to hand motions because of vitreous hemorrhage in his right eye. Ultrasonography showed attached retina. A 25-gauge pars plana vitrectomy was done 3 days later. Retinal neovascularization was identified in the inferior periphery adjacent to the scar of healed retinitis. Neovascular tissue was excised with the vitrector and panretinal photocoagulation was performed (1,100 spots) with endolaser and indirect laser. The patient did not receive systemic steroids or an antiviral agent after vitrectomy. Visual acuity improved to 20/30 by 2 weeks after vitrectomy. Fundus photographs 2 months after vitrectomy showed mild optic nerve pallor, retinal arteriole sheathing, healed retinitis, and good laser scarring (Fig. 4). The other eye has remained uninvolved.
Figure 3. Marked resolution of vitritis and healed lesions at day 9.
Figure 4. Fundus photograph at 7-month follow-up showing mild optic nerve pallor, sheathing of retinal arterioles, healed retinitis, scattered intraretinal hemorrhages, and scars of previous panretinal photocoagulation.
Acute retinal necrosis is a rare disease with an approximate annual incidence of 1 in 1.6 to 2 million individuals.8 As a result, there is great difficulty in determining an optimum treatment strategy. Due to the absence of a randomized controlled trial, retrospective chart reviews and case reports have been used to evaluate different therapeutic strategies, sometimes with conflicting conclusions. In particular, there is no consensus on the role of intravitreal agents, steroids, and prophylactic laser therapy.5 However, regardless of treatment strategy, prognosis of affected eyes has been poor, which motivates ongoing attempts to modify current treatment strategies.
Traditional treatment of acute retinal necrosis involves induction with intravenous acyclovir (500 mg/m2 three times a day) for 7 to 10 days followed by oral acyclovir for approximately 3 months.1,3,4 Such treatment prevents formation of new lesions after day 2, leads to resolution of existing lesions beginning around day 4, and significantly reduces the risk of fellow-eye involvement but does not reduce vitritis.1,3,4 Since the availability of newer oral antiviral agents, famciclovir in 1994 and valacyclovir in 1995, several strategies involving these newer agents with or without intravenous acyclovir have been tried, but without any apparent benefit over conventional treatment.5 Systemic steroids are typically added 2 to 3 days later to treat inflammation, but their role remains unproven.1,5 The visual outcome after acute retinal necrosis is generally poor despite treatment. For instance, Tibbetts et al.5 noted that approximately half of their patients had visual acuity of 20/200 or worse by 3 months after presentation with further visual decline over the next 5 years. Furthermore, poor presenting visual acuity is predictive of worse final visual acuity.5 Our patient probably would have had a poor outcome with conventional treatment not only due to poor presenting visual acuity of 20/4005 but also due to generalized retinal ischemia from arteriolar occlusion,9 optic disc involvement,1,10 retinitis involving approximately 50% of the retina, and the causal agent being varicella zoster virus.6
Inflammatory vascular occlusion involving the iris, choroid, retina, and optic nerve is an important cause of tissue destruction in acute retinal necrosis. The virus has not been detected in blood vessels, optic nerve, or choroid.7 We therefore hypothesized that treatment for acute retinal necrosis has not been successful because inflammation has not been targeted sufficiently in the past, and prompt control of inflammation by intravitreal dexamethasone might reduce tissue destruction. Conventional treatment with oral steroid initiated a few days later might be too slow in the face of rapidly progressing inflammatory vascular occlusion. Rapid resolution of vitritis, prompt healing of existing lesions, and prevention of the formation of new lesions in our patient indicates a beneficial role of prompt adjunctive therapy with intravitreal dexamethasone and an antiviral agent in the management of acute retinal necrosis.
There is obvious concern that intravitreal steroids might induce immune suppression. We therefore elected to administer intravitreal ganciclovir and dexamethasone at the same time. Intravitreal ganciclovir can achieve remission in progressive outer retinal necrosis, caused by herpes viruses, most commonly varicella zoster, in severely immune suppressed patients from AIDS.11
In progressive outer retinal necrosis syndrome, intravenous acyclovir alone is usually ineffective, but intravitreal therapy combined with intravenous antiviral therapy may improve outcome.11 Therefore, it is possible that intravitreal antiviral agents may be more effective in inhibiting viral replication compared with intravenous acyclovir. Although Tibbetts et al.5 found no benefit from intravitreal antiviral agents in acute retinal necrosis by linear regression analysis in a retrospective study, their sample size was small (8 eyes) and criteria and timing for administration for antiviral agents were not specified. Others have found intravitreal agents to be beneficial in the management of acute retinal necrosis.6 Meghpara et al.10 reported that three of four patients who had 25% to 50% retinal involvement and were treated with an intravitreal injection had an improvement in their visual acuity. However, all four patients had fairly good vision at presentation, having an initial visual acuity of 20/80 or better. Our patient had a visual acuity of 20/400, suggesting a more severe disease.
We believe that adjunctive therapy with intravitreal ganciclovir and dexamethasone promptly addresses both components of tissue damage in acute retinal necrosis, specifically control of viral replication and control of inflammation, and merits further study. Although it is difficult to draw definitive conclusions based on a single case report where traditional therapy was also used, we speculate that intravitreal dexamethasone does not seem to have a detrimental effect in the management of acute retinal necrosis if used in conjunction with an intravitreal antiviral agent.
- Duker JS, Blumenkranz MS. Diagnosis and management of the acute retinal necrosis (ARN) syndrome. Surv Ophthalmol. 1991;35:327–343. doi:10.1016/0039-6257(91)90183-G [CrossRef]
- Holland GN. Standard diagnostic criteria for the acute retinal necrosis syndrome. Am J Ophthalmol. 1994;117:663–667.
- Blumenkranz MS, Culbertson WW, Clarkson JG, et al. Treatment of the acute retinal necrosis syndrome with intravenous acyclovir. Ophthalmology. 1986;93:296–300.
- Palay DA, Sternberg P Jr, Davis J, et al. Decrease in the risk of bilateral acute retinal necrosis by acyclovir therapy. Am J Ophthalmol. 1991;112:250–255.
- Tibbetts MD, Shah CP, Young LH, et al. Treatment of acute retinal necrosis. Ophthalmology. 2010;117:818–824. doi:10.1016/j.ophtha.2009.09.001 [CrossRef]
- Wong R, Pavesio CE, Laidlaw DA, et al. Acute retinal necrosis: the effects of intravitreal foscarnet and virus type on outcome. Ophthalmology. 2010;117:556–560. doi:10.1016/j.ophtha.2009.08.003 [CrossRef]
- Culbertson WW, Blumenkranz MS, Haines H, et al. The acute retinal necrosis syndrome. part 2: histopathology and etiology. Ophthalmology. 1982;89:1317–1325.
- Muthiah MN, Michaelides M, Child CS, Mitchell SM. Acute retinal necrosis: a national population-based study to assess the incidence, methods of diagnosis, treatment strategies and outcomes in the UK. Br J Ophthalmol. 2007;91:1452–1455. doi:10.1136/bjo.2007.114884 [CrossRef]
- Hillenkamp J, Nolle B, Bruns C, et al. Acute retinal necrosis: clinical features, early vitrectomy, and outcomes. Ophthalmology. 2009;116:1971–1975. doi:10.1016/j.ophtha.2009.03.029 [CrossRef]
- Meghpara B, Sulkowski G, Kesen MR, et al. Long-term follow-up of acute retinal necrosis. Retina. 2010;30:795–800. doi:10.1097/IAE.0b013e3181c7013c [CrossRef]
- Meffert SA, Kertes PJ, Lim PL, et al. Successful treatment of progressive outer retinal necrosis using high-dose intravitreal ganciclovir. Retina. 1997;17:560–562.