There is minimal role for topical antivirals in the treatment of herpes zoster ophthalmicus. However, systemic antivirals play a critical role in the management of both the dermatological and ophthalmic manifestations of the infection. The treatment dose of Acyclovir is 800 mg dosed five times daily, Valacyclovir (Valtrex) 1gm dosed three times daily, or Famciclovir (Famvir) 500 mg dosed three times daily. While all three are affective in the treatment of varicella zoster virus, the ocular bioavailability of valacyclovir and famciclovir are superior to that of acyclovir. Traditionally treatment is continued for 10–14 days, which is the time frame for resolution of the dermatological manifestations [10]. However, in patients with chronic or recurrent ocular disease, there is a role for extended duration of systemic antiviral therapy.

Concomitant uveitis is treated with a tapering dose of topical corticosteroids. Prednisolone acetate 1 % is generally the first line agent. Patients who have persistent inflammation despite maximum doses of topical prednisolone acetate may benefit from difluprednate (Durezol) due to its efficacy as an emulsion. Strong steroids will require close follow up (every week to 2 weeks) to assess clinical effect and monitor intraocular pressure. Cycloplegia is often used both for patient comfort and prevention of development of posterior synechiae. Intraocular pressure is controlled with use of topical IOP lowering agents. Prostaglandins are preferentially avoided due to the potential risk of reactivation of herpes virus replication and reports of association with episodes of uveitis/development of macular edema.

Acute retinal necrosis (ARN) is a devastating retinal infection most commonly caused by a member of the herpes virus family. The herpes simplex virus (HSV-1 and HSV-2) and varicella zoster virus (VZV) are the most common etiologies. Much less frequently, cytomegalovirus (CMV) and Epstein–Barr virus (EBV) have been reported to cause ARN.

ARN was initially described in 1971 by Urayama et al. [14] as an intraocular inflammatory event, and named as Krieye’s disease, but it was not until 1982 that an infectious etiology was identified. Culbertson and colleagues performed histopathological analysis of enucleated eyes from this condition and demonstrated the herpes virus in all layers implicating an infectious etiology [15]. Case series published in the 1970s and 1980s described cases of both unilateral ARN and bilateral ARN (BARN) [16, 17]. These series found a high incidence of combined mechanism tractional and rhegmatogenous retinal detachments that proved difficult to repair with most patients requiring silicone oil tamponade and extensive laser demarcation. The patients’ visual prognosis was uniformly poor due to a combination of retinal detachment, silicone oil tamponade, occlusive retinal vasculitis, and optic neuropathy. This condition occurs equally in men and women and occurs at any age.

ARN can present with unilateral or bilateral disease and can occur with or without an antecedent Herpetic rash. Exposure to any member of the herpes virus family in the patient’s lifetime is thought to be sufficient to confer risk of this disorder. Most commonly patients present with unilateral disease, though nearly 33 % will ultimately progress to bilateral involvement. Patients typically report an acute onset of a red, painful eye associated with blurry vision, and floaters. Clinical examination classically reveals an aggressive anterior chamber reaction, vitritis, vitreous haze, and areas of peripheral retinal necrosis which spread circumferentially and posteriorly (see Fig. 6.2). There may be associated arteritis, retinal vascular occlusions, retinal thinning, and extensive retinal pigment epithelial changes often appearing as a deep white or yellow choroiditis. Histopathological analysis of the vitritis shows a predominantly chronic granulomatous inflammation characterized by clusters of lymphocytes and plasma cells [15]. Fischer et al. [18] first described the classic triad of necrotizing retinitis, vitritis, and retinal vasculitis in immunocompetent patients considered pathognomonic for ARN.

ARN has traditionally been a clinical diagnosis though PCR testing via an aqueous or vitreous sample is increasingly utilized for diagnostic confirmation given its high sensitivity and rapid test results. Diagnostic criteria for ARN were first proposed in 1994 by the American Uveitis Society (AUS) which broadly included full thickness necrotizing retinitis, arteritis, and severe inflammation of the anterior chamber and vitreous cavity [19]. More specific criteria include the following:

Although the diagnostic criteria listed above are valuable for the clinician, the advent of PCR testing has confirmed the diagnosis of ARN both in patients who demonstrate the aforementioned inflammatory findings and in those who do not [20, 21]. There are multiple case series reporting patients with unusual or atypical presentations of PCR-confirmed ARN with minimal posterior necrotizing findings [22, 23]. Some authors suggest that the clinical presentation may vary depending upon the causative strain of virus and the underlying host characteristics; more investigation is required to confirm this hypothesis. A high degree of suspicion regarding the possibility of this diagnosis is critical for prompt diagnosis and rapid initiation of therapy given the relentless progression of the retinitis.

Despite advanced therapeutic and surgical management for this disorder, the visual prognosis for ARN remains poor with a high percentage of patients failing to achieve acuities better than 20/200. In a study of 58 patients, Tibbets et al. [24] report 50 % failed to achieve vision of 20/200 or better at 3 months.

Systemic antivirals are the mainstay of therapy. In addition to arresting progression of retinal necrosis in the affected eye, these agents are considered critical to the prevention of contralateral eye involvement [25–30]. Patients are typically hospitalized for treatment with intravenous acyclovir dosed at 10 mg/kg every 8 h (or 1500 mg/m² per day) for 5–10 days. Recent data indicates that oral valacyclovir (dosed at 1–2 gm three times daily) and oral famciclovir (dosed at 500 mg three times daily) are also able to rapidly achieve the same ocular bioavailability in the vitreous cavity as intravenous acyclovir. Oral acyclovir’s vitreous bioavailability is inferior to both oral valacyclovir and famiclovir; thus, this drug is less frequently used for treatment of acute ARN [31]. Patients initially treated with intravenous acyclovir therapy are often converted after 5–10 days to oral valacyclovir or famciclovir due to their superior bioavailability for more extended therapy. Antiviral medication is generally continued for 3 months. Some physicians, including the authors of this chapter, advocate for a longer duration of therapy in order to minimize the risk of recurrence. For patients with HIV/AIDS, the duration of therapy is life-long.

In addition to systemic therapy, many physicians will also initially treat with intravitreal injection of either ganciclovir (200–2000 μg per 0.1 ml) or foscarnet (1.2–2.4 mg per 0.1 ml) [32]. Recent work by Flaxel et al. [33] suggests a slightly improved visual outcome and decreased risk of RD in patients receiving both systemic and intravitreal therapies compared with systemic therapy alone. However, other data suggests the adjunctive use of intravitreal agents does not appear to alter the clinical outcome [24]. Despite this, many specialists tend to treat extensive retinal necrosis with a combination of systemic and intravitreal antivirals, though the choice of drug, injection frequency, and duration of the course of injections is subjective. No published definitive therapeutic protocol exists. Given that foscarnet attacks the herpes virus at a different target point than ganciclovir, valacyclovir or famciclovir, there is a hypothesis that injection of foscarnet may be superior to ganciclovir as a therapeutic adjuvant [34]. This remains to be proven as there is no definitive head to head comparison trial.

Systemic corticosteroids are frequently used to treat the inflammatory sequelae of ARN and minimize the associated tissue damage, though these are reserved for use only after an adequate vitreous concentration of antivirals have been reached. Most authors defer use of corticosteroids for a minimum of 24 h after initiation of antiviral therapy. Use, duration, and dosage of systemic corticosteroids also remain highly variable among practitioners.

Combined rhegmatogenous and tractional retinal detachment unfortunately occurs in a high percentage, 50 % or greater, of patients with ARN [24]. Some studies suggest that risk of retinal detachment may be lowered in patients receiving intravitreal therapy in addition to systemic antivirals; a definitive comparative study has not yet been done. Many practitioners advocate for the placement of prophylactic laser barricade surrounding the involved peripheral retina in an attempt to decrease the risk of detachment. Although many physicians still offer this intervention due to the relatively low-risk profile of the laser treatment, there is data to suggest that laser has minimal effectiveness in preventing retinal detachments [35]. Retinal detachments can occur months or years after the initial presentation, however, the majority of patients who detach commonly do so in the first 6 months following diagnosis. Retinal detachments secondary to ARN are difficult to effectively repair given the combined tractional and rhegmatogenous components and require vitrectomy, endolaser, and tamponade with silicone oil to effectively flatten the retina and relieve the traction.

Additional adjuvant therapies that have been considered include aspirin and warfarin to counteract the occlusive retinal vasculitis. No therapeutic benefit has been demonstrated, and thus there remains no evidence-based rationale for using either therapy.

Progressive outer retinal necrosis (PORN) is the most aggressive entity in the subset of viral retinopathies due to the herpes virus family. Varicella zoster virus (VZV) causes the majority of cases with other Herpes viruses and mixed infections involved as well. PORN afflicts patients who are severely immunocompromised, most often those infected with human immunodeficiency virus (HIV). This disease is characterized by its rapid onset, distinctive pattern of outer retinal opacification, and is universally bilateral. The absence of inflammation and relative sparing of retinal vasculature serves to differentiate PORN from acute retinal necrosis (ARN). The visual prognosis is extremely grim with 66 % of patients developing no light perception vision (NLP) even with prompt and aggressive antiviral therapy.