Goals of treatment of ARN are (1) to stop the retinal necrosis in order to avoid the late consequences of the disease (retinal detachment and optic atrophy); (2) to minimize the collateral damage caused by severe inflammation and vascular occlusions; and (3) to protect the fellow eye. The clinician should start antiviral treatment immediately after the clinical diagnosis is made, rather than waiting for the laboratory results. Although recurrences of ARN are the exception rather than the rule, antiviral treatment does not eradicate the virus. The infection remains dormant in the spinal ganglia and possibly the retina and may reactivate at a later time. The antiviral, adjunctive, and surgical treatment options are described in detail below. Table 3 gives the dosages for induction and maintenance of the antiviral medications as well as recommended duration of therapy. A general approach to treatment follows.
Antiviral Therapy for Necrotizing Herpetic Retinopathies
The treatment of herpetic eye disease relies on several antiviral medications.
Acyclovir, famciclovir, and valacyclovir
Acyclovir and two other drugs in its class, famciclovir and valacyclovir, are potent inhibitors of viral DNA polymerase that demonstrate good activity against VZV and HSV.
Acyclovir can be given orally and intravenously, and both forms are well tolerated. The agent clears from the body by renal excretion, so the dosage must be adjusted in patients with renal insufficiency. The most common side effects of the orally administered preparation include gastrointestinal distress and headache. The higher doses of acyclovir given intravenously can cause renal toxicity and, rarely, central nervous system side effects such as seizures and alterations in mental status. Acyclovir is not toxic to the bone marrow and has not been shown to cause increased frequency of birth defects when used during pregnancy.
Famciclovir is a prodrug converted to penciclovir. It is formulated for oral administration and is cleared mostly by renal excretion. Its tolerability and side effect profile is similar to that of acyclovir.
Valacyclovir is a prodrug converted to acyclovir by liver metabolism. Because it achieves plasma concentration much higher than that of acyclovir, valacyclovir can be given on a less frequent and more convenient schedule. Valacyclovir is administered orally. In rare cases, it has been shown to induce a severe thrombocytopenic syndrome in immunocompromised patients. Otherwise, the tolerance profile of this drug is very similar to that of acyclovir.
Because most cases of ARN are thought to be caused by VZV and HSV, the standard therapy is an induction dose of intravenous acyclovir for 10 to 14 days, followed by maintenance therapy with oral acyclovir, famciclovir, or valacyclovir. Oral induction of these agents has been reported as well. Refer to Table 3 for the dosages for induction and maintenance as well as duration of therapy.
ARN cases that are resistant to acyclovir treatment may occur either because the VZV or HSV strain is resistant to the drug, drug levels are inadequate in the vitreous, or the disease is caused by CMV, which typically does not respond well to acyclovir. Depending on the mechanism of resistance, cross-resistance to drugs in the same class (eg, acyclovir, valacyclovir, and famciclovir) does occur. The second-line agents used in the treatment of ARN are those used in the treatment of CMV retinitis: ganciclovir, valganciclovir, and foscarnet.
Similar to acyclovir, ganciclovir is a potent inhibitor of viral DNA polymerase that has shown activity against CMV and HSV. It is available for oral and intravenous administration, and may be administered off label intravitreally. Long-term ganciclovir therapy can also be provided with the ganciclovir implant. As with acyclovir, ganciclovir is cleared from the body by renal excretion, so its dosage must also be adjusted in patients with renal insufficiency.
The most significant side effect of ganciclovir when used systemically is myelosuppression. The resultant neutropenia is usually reversible but may be profound and can lead to fatalities, especially when used with other drugs that are myelosuppressive, such as zidovudine, or those that decrease ganciclovir’s renal clearance. Granulocyte-colony stimulating factor (G-CSF) can be used to decrease the degree of neutropenia. In addition, CNS side effects are seen in 5% to 15% of patients treated with ganciclovir, and range from headaches to behavioral changes and seizures. The orally administered form frequently causes gastrointestinal upset.
Intravitreal administration of ganciclovir or foscarnet may be employed as an alternative or adjunct to systemic administration. Experience with treatment of CMV retinitis has shown that the eye can tolerate repeated weekly ganciclovir injections for years without developing significant intraocular or systemic side effects. The advent of the ganciclovir implant has made it possible to significantly reduce the number of procedures needed to deliver the drug into the vitreous, since the device delivers high levels of ganciclovir for a period of 8 months. While this may have great benefit in the treatment of PORN, where maintenance antiviral therapy may be needed indefinitely, in ARN 3 months of maintenance therapy is usually sufficient, and an implant may not be the best option. The drawbacks of using intravitreal therapy are the risks of bacterial endophthalmitis, retinal detachment, cataract, and vitreous hemorrhage, as well as the lack of protection for the fellow eye.
Valganciclovir is a prodrug of ganciclovir. It has a much higher bioavailability and a similar side effect profile to that of ganciclovir. Once valganciclovir has been converted to ganciclovir, its mechanism of action and excretion is the same as ganciclovir. Valganciclovir is available for oral administration and has efficacy similar to that of intravenous ganciclovir.
Foscarnet inhibits viral DNA polymerase by direct, noncompetitive, reversible inhibition. It has very low bioavailability and is available only for intravenous administration. Similar to the other antiherpetic medications it is cleared by renal excretion, therefore dosage must be adjusted in patients with renal insufficiency. The most significant side effects are nephrotoxicity and hypocalcemia. Other side effects include CNS toxicity, such as headaches, tremor, seizures, and hallucinations.
The Role of Surgery
The consequence of retinal necrosis and severe vitritis seen in ARN may be the development of multiple retinal breaks in necrotic retina and subsequent rhegmatogenous and tractional retinal detachment. To prevent the extension of retinal detachment into the posterior pole, prophylactic laser photocoagulation posterior to the area of retinitis has been used. Many investigators recommend 360°-barrier retinal photocoagulation as soon as the view permits. Prophylactic vitrectomy and endolaser have also been performed for ARN patients; however, no randomized controlled studies exist to address the true efficacy of these treatment modalities.
In patients who have already developed a retinal detachment, surgical repair is indicated. Pars plana vitrectomy with endolaser and silicone oil is usually preferred to scleral buckling procedures, given the multiplicity of atrophic posterior breaks in thin necrotic retina.
Induction and Maintenance Therapy
A patient with a new diagnosis of ARN is started on high-dose intravenous acyclovir, and the response to treatment is assessed in the few days following the induction of IV therapy. If the progression of retinal necrosis stops, systemic corticosteroid therapy is usually initiated within 48 hours of the first dose of antiviral treatment. Systemic corticosteroids should not be used until appropriate antiviral therapy has been initiated. After completion of the induction of acyclovir, the patient is switched to oral acyclovir, famciclovir, or valacyclovir and treated for 3 months to prevent disease in the fellow eye. Once the vitritis resolves, prophylactic retinal photocoagulation should be employed. If multiple retinal breaks are present or the retinal necrosis is extensive, some investigators have found prophylactic vitrectomy with endolaser to be beneficial. As previously mentioned, retinal detachment in the setting of ARN is approached utilizing vitreoretinal techniques with silicone oil.
As an alternative to IV acyclovir induction followed by oral antiherpetic therapy, some practitioners have reported successful use of oral valacyclovir 1 g three times a day without IV loading. In an effort to achieve rapid induction therapy for ARN, intravitreal injection of ganciclovir or foscarnet may be employed, usually in combination with systemic medications (oral or IV), including acyclovir, famciclovir, or valacyclovir. This approach provides high intravitreal levels of antiviral medication. It also has been used as first-line therapy in patients with ARN or in those who fail to respond to systemic therapy alone. Superiority of this approach has not been demonstrated over the classical intravenous approach. Also, given the short intravitreal half-life of these agents, intravitreal injections may need to be repeated twice weekly until the retinitis is controlled. Oral valganciclovir may be used as a second-line alternative to oral acyclovir, valacyclovir, and famciclovir for maintenance.
Maintenance therapy for ARN is usually employed for 3 months, in order to reduce the risk of the disease in the fellow eye; it may be used longer in the setting of immunosuppression or multiple recurrences.
Some cases do not respond to acyclovir therapy. Failure of response to treatment may occur either because the disease is caused by a viral strain that has developed resistance to the antiherpetic drug, or because the disease is caused by CMV, against which acyclovir, famciclovir and valacyclovir do not have good activity.