**2. Virus-induced retinitis**

### **2.1 Acute retinal necrosis**

Acute retinal necrosis (ARN) is an infectious inflammation of the retina, the vitreous and the anterior chamber of the eye that can lead to blindness by destruction of the optic nerve and retina in immune competent individuals. The first clinical

reports were published by Urayama in 1971 under the designation Kirisawa uveitis. In 1978, the term acute retinal necrosis was introduced by Young and Bird [1, 2].

#### *2.1.1 Pathogen*

ARN is primarily caused by the α-herpesviruses Varicella-Zoster virus (VZV) or Herpes-Simplex virus (HSV) 1 and 2, which together account for 97% of cases (95-%-confidence interval (CI) 96–99%). Among ARNs caused by α-herpesviruses, VZV is the leading cause at 69% (95-%-CI 60–76%), followed by HSV-2 and HSV-1. α-herpesviruses carry a large double-stranded DNA genome and establish latency in the nuclei of the sensory and autonomic spinal ganglia of the central nervous system after primary infection. Normally, the virus genome is latently maintained in the sensory ganglia since lytically infected cells are rapidly eliminated by the CD8-positive cytotoxic killer cells of the immune system. The virus genomes persist latently in the nuclei of the sensory neurons in circular extrachromosomal form as episomes. Viral reactivation occurs due to poorly defined stressors such as ultraviolet light, neurosurgical procedures, or steroid or immunspuppressive therapy. Virus reactivation is followed by peripheral viral replication and usually results in herpes zoster, herpes orofacialis, herpes genitalis, or in rare cases also in zoster ophthalmicus or herpes oculi [2, 3].

The roles in ARN development of the β-herpesvirus cytomegalovirus (CMV) and the γ-herpesvirus Epstein–Barr virus (EBV), which establish their latency within myeloid stem cells and quiescent B lymphocytes, respectively, are still controversial. While at least some cases have been reported in which CMV appears to be causal for ARN, EBV has only been detected in some cases in addition to VZV and does not appear to play a causative role in immunocompetent individuals [3, 4].

#### *2.1.2 Epidemiology*

ARN is a very rare disease, which affects one individual per 1.5–2.0 million persons per year. In a meta-analysis, men were shown to have a slightly higher risk to be affected by ARN than women [3]. Interestingly, the age of manifestation of ARN depends on the responsible virus species. Patients with ARN due to VZV or HSV-2 have a median age of 48.8 and 47.8 years, respectively, whereas patients with ARN due to HSV-1 have a median age of only 31.1 years [3]. In addition, ARN shows two peaks of manifestation age, the first at age of approximately 20 years and the second at age 50 [4]. In addition, some studies have shown that certain human leukocyte antigen (HLA) types such as HLA-DQw7 as well as HLA phenotype Bw62, DR4, and HLA-DR9 are associated with the occurrence of ARN or its severity, respectively [5, 6].

#### *2.1.3 Clinical peculiarities*

Characteristic of ARN is an inflammation of the anterior chamber and vitreous associated with peripheral necrotizing retinitis with focal necrotic lesions that become circular as the disease progresses to the posterior pole. This process is additionally associated with an occlusive vasculitis that leads to arteriolar narrowing. This first phase is followed by a second phase in which retinal atrophy, proliferative vitreoretinopathy, and retinal detachment occur [4]. While some studies have found ARN to be unilateral in nearly 90% of cases, other studies report bilateral involvement in up to one-third of cases [2–4]. In any case, ARN that initially occurs unilaterally may spread to the contralateral eye.

#### *Retinitis Due to Infections DOI: http://dx.doi.org/10.5772/intechopen.107394*

In contrast to ARN, progressive outer retinal necrosis (PORN), now considered a variant of ARN, affects almost exclusively immunocompromised individuals, *e.g.,* human immunodeficiency virus (HIV)-infected individuals in the AIDS stage or organ transplant recipients. It results from reactivation of VZV and spreads extremely rapidly to the deep retinal layers, leading to retinal detachment. However, PORN lacks the vasculitis aspect of classic ARN [2, 4].

#### *2.1.4 Diagnosis*

According to the American Uveitis Society, ARN is defined by the following criteria: (1) "focal, well-demarcated areas of retinal necrosis in the peripheral retina (outside the major temporal vascular arcs)"; (2) "rapid, circumferential progression of necrosis (if antiviral therapy has not been administered)"; (3) "evidence of occlusive vasculopathy"; (4) "a marked inflammatory reaction in the vitreous"; and (5) in the "anterior chamber." In addition, symptoms such as optic atrophy, scleritis, and pain are common but not essential [7]. These criteria were established before molecular biological detection methods such as polymerase chain reaction (PCR) were widely available. Therefore, a recent publication proposed a modification of the diagnostic criteria to include serological and PCR-based methods with respect to the responsible viruses. By comparing the antibody concentration against the different herpesviruses in serum with the antibody concentration in vitreous fluid, the Goldmann-Witmer coefficient (GWC) can be determined. A positive GWC is highly specific (100%) at a moderate sensitivity of only 33%. Detection by PCR is both highly sensitive (95%) and only slightly less specific (92%) [8]. Identification of the specific virus is important, as it has therapeutic consequences. The use of PCR-based detection methods has the additional advantage of enabling the identification of viral resistance to the antiviral drugs used by genotyping [9, 10]. Imaging of the eye such as fundus fluorescein angiography or optical coherence tomography is useful to determine the extent and progression of the disease [4].

#### *2.1.5 Therapy*

Since the goal of therapy is to inhibit further disease progression driven by viral replication, antiviral therapy should be initiated immediately after clinical diagnosis and not delayed by waiting for laboratory results. However, viral diagnostics are useful because therapy for CMV relies on different antiviral drugs than therapy for VZV, HSV-1, and HSV-2. In addition, as mentioned above, PCR diagnostics allow detection of resistance by genotyping and thus adjustment of therapy. This is particularly important for immunocompromised patients, who are affected, for example, by drug-resistant HSV-1 strains in up to 14% of cases, whereas this is only the case in less than 1% of immunocompetent individuals [11, 12].

The three α-herpesviruses VZV, HSV-1, HSV-2 are treatable with the antiviral drugs aciclovir and its prodrug valaciclovir, penciclovir, and its prodrug famciclovir, as well as by cidofovir and foscarnet. The prodrugs valaciclovir and famciclovir, which must be activated in enterocytes by the first-pass effect, have a good oral bioavailability of 54–60% and 77%, respectively, unlike aciclovir and penciclovir and, thus, can be efficiently administered orally. Aciclovir and penciclovir, as well as their prodrugs, are nucleoside analogs that must be activated by a viral enzyme called thymidine kinase (TK). After activation by viral TK, this group of antiviral drugs causes chain termination during viral replication. Because they act only in virus-infected

cells, they are well tolerated, especially in their oral formulation. Nevertheless, there are side effects, which often include headache, rash, and gastrointestinal symptoms in the oral formulations. However, intravenous use of aciclovir may result in neurotoxicity and renal toxicity due to crystalline nephropathy. Therefore, patients with impaired renal function must be treated with lower doses. Because the main cause of viral resistance are mutations within the viral TK, the rate of cross-resistance within this antiviral drug group is high. In case of resistance, cidofovir and foscarnet are alternatives that do not require viral TK activation. The nucleoside analog cidofovir is activated only by cellular kinases and, once activated, acts similarly to the other nucleoside analogs. The drug is excreted exclusively by the kidneys and is nephrotoxic and, therefore, requires renal protection by probenecid administration. Foscarnet, a pyrophosphate analog, directly inhibits the viral polymerase by blocking its pyrophosphate-binding site. The most important side effect of foscarnet is nephrotoxicity. Therefore, the dose must be adjusted in patients with impaired renal function. Both foscarnet and cidofovir must be administered intravenously due to their low oral bioavailability of 20% and 5%, respectively; recommended dosing is 60 mg/kg three times daily and 5 mg/kg over 1 h once weekly for 2 weeks [2, 12].

Traditionally, therapy for ARN consisted of administration of 10 mg/kg aciclovir three times daily or 1500 mg/m2 per day intravenously for 5–14 days. This should be followed by oral treatment with 800 mg of aciclovir five times daily for 6 weeks, as such treatment has been shown to prevent 90% of contralateral eye infections [2, 4]. However, it has been shown that similar plasma concentrations can be achieved by oral administration of valaciclovir as by intravenous administration of aciclovir, and the visual outcome does not appear to be worse. Therefore, efforts are being made to avoid intravenous therapy completely. Currently, oral therapy regimens with 2000 mg valaciclovir or 500 mg famciclovir three times daily are being used [4, 12]. Regarding the duration of follow-up, some authors recommend extending therapy with 800 mg of aciclovir or 1000 mg of valaciclovir three times daily for 6–12 months, followed by lifelong use of 1000 mg of valaciclovir daily to prevent infestation of the contralateral eye or relapse [12]. During the initial therapy phase, intravitreal use of 2.4 mg/0.1 ml foscarnet or 2.0/0.1 ml ganciclovir two times per week in combination with systemic antiviral therapy appears to have therapeutic benefit [4, 12]. With respect to foscarnet, a recent systematic review based on case–control and cohort studies, as well as case series and case reports, also supports this therapeutic approach [13]. Because vasculitis and inflammation contribute to the progression of ARN, the use of systemic or topical steroids and anticoagulation drugs is under discussion. However, the evidence base for such treatments is low and must be used with caution [12]. In the case of a successful antiviral therapy, no further lesions should be observed from day 2 of therapy, from 4 to 5 days of therapy, the retinal infiltrate should tend to regress, and after 1 month, a complete remission should be observable [2].

Another highly controversial issue is the use of prophylactic procedures such as prophylactic vitrectomy or prophylactic laser retinopexy. It has been shown that the risk of rhegmatogenous retinal detachment after ARN can be significantly reduced by prophylactic vitrectomy [5]. This finding was confirmed by a recent meta-analysis of seven retrospective cohort studies, which included the study by Hillenkamp and colleagues [5, 14]. However, this meta-analysis found that visual outcome was significantly worse in the prophylactic vitrectomy group than in the control group treated with antiviral drugs only. The authors attributed this result to silicone oil tamponade and long-term complications in the vitrectomy group. Although there are also some small studies that see a benefit in terms of visual outcome, there is ultimately no

#### *Retinitis Due to Infections DOI: http://dx.doi.org/10.5772/intechopen.107394*

conclusive evidence to support such treatment [12]. Another much debated topic is whether prophylactic laser therapy can reduce the incidence of retinal detachment. Although a meta-analysis of 14 studies found that prophylactic laser retinopexy can significantly prevent retinal detachments after ARN [15], Powell et al. pointed out that prophylactic laser retinopexy is only possible if the vitreous media is clear enough, which means that often only the less severely affected eyes are treated with laser [12]. In addition, the cited meta-analysis by [15] did not examine the question of how the therapy affects visual outcome. Thus, the benefit of prophylactic laser retinopexy remains questionable.

For ARN caused by CMV that lacks TK and instead expresses the kinase UL97, ganciclovir and its orally better bioavailable prodrug valganciclovir, as well as cidofovir and foscarnet, are therapeutic options. Because of its low bioavailability of 5%, ganciclovir must be administered intravenously at a dose of 5 mg/kg. Alternatively, 900 mg of valganciclovir can be administered orally, which has an oral bioavailability of 60%. Because ganciclovir and its prodrug cause neutropenia in approximately 8% of patients, the blood values of patients treated with either of these drugs should be monitored regularly. Cidofovir and foscarnet are alternatives in case of viral resistance to ganciclovir or its prodrug, which is mostly caused by mutations within the UL97 [2].

#### *2.1.6 Prognosis*

ARN has often a poor outcome, i.e.*,* two-thirds of affected eyes achieve only a final best-corrected visual acuity of 6/60 or worse. Therefore, early diagnosis and urgent therapy are critical. In PORN, the outcome is even worse. Two-thirds of affected eyes are not even able to perceive light because they often do not respond well to antiviral therapy [4].

#### **2.2 Cytomegalovirus retinitis**

In immunocompetent persons, cytomegalovirus (CMV) normally leads only to a rather harmless anterior uveitis. However, in immunocompromised individuals, such as AIDS patients or those who have undergone organ transplantation, CMV can also lead to CMV retinitis, which is distinguishable from ARN but can also cause retinal detachment and blindness [16, 17].

#### *2.2.1 Pathogen*

CMV belongs to the beta-herpesviruses and has a large double-stranded DNA genome. It is transmitted perinatally or through any type of close contact via body fluids. The primary infection, which happens usually in young and healthy individuals, is typically mild or asymptomatic. However, primary infection of the pregnant woman may result in severe embryopathy or fetal death. After primary infection, the virus establishes latency within myeloid stem cells. In immunocompetent individuals, reaction is usually asymptomatic. A special but feared transmission of CMV can occur through organ transplantation [3, 4, 17, 18].

### *2.2.2 Epidemiology*

Worldwide, CMV seroprevalence ranges from 60% to 100% and increases with age. In the United States, for example, 36.3% of children aged 6–11 years but 90.8% of adults aged 80 years or older are infected. CMV retinitis affects males more often than females and can occur at any age. However, most cases occur between the ages of 30 and 60. Initially, CMV retinitis was particularly common in AIDS-stage HIV patients, but with the development and widespread use of antiretroviral therapy (ART), its incidence in the AIDS patient group decreased by over 90%, and clinical outcomes in affected individuals improved significantly [4, 17].

#### *2.2.3 Clinical peculiarities*

In immunocompetent individuals, CMV reactivation usually results in unilateral, relatively mild, recurrent anterior uveitis with anterior chamber inflammation, elevated intraocular pressure, stromal iris atrophy, and few granulomatous keratic precipitates [16]. However, especially in immunocompromised individuals, CMV can affect the retina and cause unilateral CMV retinitis. In 20% of cases, infection of the contralateral eye occurs over the next 6 months [17]. Retinitis usually consists of two stages. In the first stage, the active retinitis usually shows three types of retinal lesions: First, fulminant and edematous lesions consisting of extensive retinal hemorrhages preceding confluent retinal necrosis; second, indolent and granular lesions consisting of granular satellites with little or no hemorrhage; and third, exudative lesions based on angiitis with extensive vascular sheathing. The second stage is characterized by large necroses and retinal tears. Finally, there is retinal atrophy with fibrosis, calcification, and sclerotic vessels [4].

#### *2.2.4 Diagnosis*

The diagnosis of CMV retinitis is made by ophthalmoscopy and should be documented by digital fundus photography. PCR diagnostics can confirm CMV retinitis, which is important with regard to the chosen therapy, and allows monitoring of therapy response and detection of resistant CMV strains by genotyping [4, 12].

#### *2.2.5 Therapy*

For retinitis caused by CMV that lacks TK and instead expresses the kinase UL97, ganciclovir and its more orally bioavailable prodrug valganciclovir, as well as cidofovir and foscarnet, are therapeutic options. As mentioned above, ganciclovir and its prodrug cause neutropenia in approximately 8% of patients. Therefore, the blood of patients treated with either of these drugs should be monitored regularly. Cidofovir and foscarnet are alternatives in the event of viral resistance to ganciclovir or its prodrug, which in most cases is caused by mutations within the UL97 [12]. For the therapy of the CMV retinitis, the combination of intravitreal and systemic therapy is recommended [17].

Typical dosage for CMV retinitis therapy: intraveneous ganciclovir, induction by 5 mg/kg 2× daily for 14–21 days, maintenance with 5 mg/kg/day; oral valganciclovir, induction by 900 mg 2× daily, maintenance 900 mg daily; intraveneous foscarnet, 90 mg/ kg 2× daily for 14 d, maintenance 120 mg/kg/day; intraveneous cidofovir, 5 mg/kg weekly for 3 weeks, maintenance 5 mg/kg every 2 weeks.

Typical dosage for intravitreal CMV retinitis therapy: ganciclovir, induction by 2 mg 1–4× to stop retinitis, maintenance with 2 mg weekly; foscarnet, induction by 1.2–2.4 mg 1–2× weekly, maintenance with 1.2 mg weekly; cidofovir, induction by 20 μg 1–8×, maintenance with 20 μg every 5–6 weeks.

#### *2.2.6 Prognosis*

The consequences of CMV retinitis vary widely and include regression of retinal damage and complications such as retinal detachment or recurrence. In most cases, visual acuity stabilizes or improves, in many cases to complete remission [4].
