Factors associated with progression and outcome of acute retinal necrosis

Abstract

Acute retinal necrosis (ARN) is a fulminant, sight-threatening disease caused by varicella-zoster virus or herpes simplex viruses. ARN is a granulomatous uveitis characterized by yellow–white lesions in the peripheral retina, which rapidly expand circumferentially. Retinal arteritis, hyperemia of the optic disc and inflammatory vitreous opacities are also the important signs of ARN. Visual outcome of ARN is generally poor mostly due to the progression of rhegmatogenous retinal detachment or optic atrophy. Therefore, preventing retinal detachment or optic atrophy is the key issue to improve the prognosis of this disease. Various factors, such as the extent of retinal lesions at the initial presentation, may affect the progression and prognosis of ARN.

Keywords:

• acute retinal necrosis
• antiviral therapy
• diagnostic criteria
• optic neuritis
• prophylactic vitrectomy
• rhegmatogenous retinal detachment

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues

• Acute retinal necrosis is a sight-threatening disease caused by herpes simplex viruses or varicella-zoster virus.

• Developments of rhegmatogenous retinal detachment or optic nerve inflammation are the important prognostic factors of ARN.

• In additon to antiviral therapy, systemic steroid therapy may be required to improve the visual prognosis.

• Prophylactic surgical intervention may be effective to prevent development of RD although it is still controversial.

Treatment options that may affect the prognosis of ARN

Systemic antiviral therapy

When ARN is suspected, systemic antiviral therapies such as intravenous acyclovir (10–15 mg/kg/day, 3 times a day) is recommended as empirical treatment [38]. Although acyclovir is the most commonly used antiviral agent to treat ARN, there are some other antiviral therapies such as valacyclovir, famciclovir, valganciclovir, ganciclovir and foscarnet [38]. Tibbetts et al. compared the treatment outcomes of patients with ARN treated with the previously mentioned antiviral agents but found that the outcomes were similar in term of the incidence of 20/200 or worse visual acuity, or the prevalence of RD [59]. As for the route of administration of antiviral agents, several reports investigated the effect of oral valacyclovir or famciclovir as the sole antiviral therapy [60–64]. The reported cases showed that the sole oral antiviral therapy resulted in comparable outcome in the final visual acuity or occurrence of RD compared with conventional intravenous acyclovir therapy, although it is still controversial (Table 1).

Table 1. Treatment options for acute retinal necrosis and its representative clinical reports.

Intravitreal injection of antiviral agents

As supplemental therapies, intravitreal injection of ganciclovir (2–5 mg/0.1 ml) or foscarnet (2.4 mg/0.1 ml) could also be performed [55]. There has been an increase in the use of oral and intravitreal antivirals recently as an initial treatment [8], and combination therapy of systemic and intravitreal antiviral agents may improve the visual outcome and decrease the risk of RD [65], especially in eyes with early stage of ARN in which 25–50% retina is involved (Table 1) [29]. Although acyclovir is used for intravitreal lavage during vitreous surgery at a concentration of 40 µg/ml, it is less commonly used for intravitreal injection.

Steroid administration

Besides the antiviral therapy, systemic steroid therapy is often performed for the severe intraocular inflammation, such as cellular infiltration in the anterior chamber, vitreous opacity, retinal vasculitis or optic nerve inflammation. Because optic nerve inflammation is especially the crucial symptom for visual prognosis of ARN [31,32], systemic steroid therapy may be a mandatory treatment for ARN; therefore, the dose, duration or the route of the steroid therapy should be more discussed although it is still controversial. Usually, 0.5 mg/kg/day of oral prednisone is given [7,55], but in some cases, high-dose steroid therapy would also be performed [52]. As a possible adjunct to systemic steroid therapy, intravitreal triamcinolone under the cover of antiviral therapy is reported in the treatment of ARN [66]. In performing systemic or topical steroid therapy, reactivation of herpes viruses should always be warned (Figure 2), although there are some reports in which systemic corticosteroid treatment given before ARN diagnosis did not appear to increase the risk of developing RD [14].

Prophylactic surgical intervention

Because development of RD is the most apparent sight-threatening feature of ARN, surgical intervention such as argon laser photocoagulation or vitrectomy should be considered for preventing or treating RD.

Laser photocoagulation is reported to be effective in preventing or decreasing the rate of RD in some reports [14,30] although its usefulness is still not determined [30].

It is reported that when prophylactic vitrectomy had not been performed, 69.6% of the eyes developed RD in a multicenter retrospective study in Japan [28]. Prophylactic vitrectomy, therefore, seems to be beneficial for patients with ARN. Furthermore, vitreous cavity lavage by acyclovir during vitrectomy may suppress viral activity in the retina and resolve the retinal diseases more rapidly. Hillenkamp et al. reported that early vitrectomy with intravitreal acyclovir lavage was associated with a lower incidence of secondary RD, but not with an improvement of mean final visual acuity [13]. In our previous study, prophylactic vitrectomy was effective in preventing the development of RD for eyes in which necrotic lesions did not extend beyond zone 2 (midperiphery) [67]. Luo et al. investigated the efficacy of prophylactic vitrectomy and concluded that prophylactic vitrectomy can prevent RD and improve the prognosis of ARN in their retrospective study [20]. Taken together, prophylactic vitrectomy is likely effective for earlier stage of ARN to prevent RD, but might not be effective to improve visual prognosis possibly due to optic nerve inflammation (Table 1).

Expert commentary

Visual outcome of ARN owes mostly to the development of RD and optic disc atrophy, but various factors associated with the occurrence of these conditions. Despite the efforts of antiviral therapy or surgical intervention, there is no conclusive strategy to treat ARN. The only apparent factor for the best prognosis of ARN so far is the early diagnosis and early initiation of antiviral therapy. Therefore, the clinical features of ARN [21,22] should be well understood by the ophthalmologists.

Five-year view

To improve the success rate in the treatment of ARN, progression in the accurate diagnosis is crucial. Because ARN is an infectious disease caused by herpes viruses, detection of the virus from the intraocular specimens is necessary for the definite diagnosis. Recent advances in multiplex PCR system [16,17] has made it possible to detect multiple herpetic viruses simultaneously from a tiny amount of intraocular fluids, and that led to the development of new diagnostic criteria of ARN taking into account the virologic analysis. In years to come, further innovation in molecular biological technology is anticipated resulting in the development of simpler and more easily accesible kits for performing multiplex PCR. In addition to PCR, intraocular antibody measurement compensates the results of PCR, in spite of the false-negative results due to the lack of the intraocular inflammatory cells in immune-compromised or – suppressed patients. Thus, development in multiple antibody measurements from a small amount of intraocular fluids is expected.

Notes

HSV: Herpes simplex virus; PCR: Polymerase chain reaction.

Re-used with permission from [22].

ARN: Acute retinal necrosis; CNS: Central nervous system; VZV: Varicella-zoster virus.

ARN: Acute retinal necrosis.