Varicell Zoster Virus-Associated Uveitis

Varicella Zoster Virus (VZV)-associated uveitis^1–3 may occur in utero; during primary systemic infection – most common in children with chickenpox; or following viral reactivation along the first, or ophthalmic, division of the trigeminal nerve with or without clinical findings of Herpes Zoster Ophthalmicus (HZO) – typically in those over 50 years of age or with a non-age-related cause of immunosuppression.^1-3 In addition, most cases of necrotizing herpetic retinitis, including eyes with the so-called Acute Retinal Necrosis (ARN) and Progressive Outer Retinal Necrosis (PORN) syndromes, are caused by VZV.^4–6 Less common VZV-induced uveitic complications include retinal vasculitis, focal or multifocal retinochoroiditis, and various manifestations of optic nerve involvement, such as papillitis, neuroretinitis, and optic neuritis. Scleritis and orbital inflammation can also occur. In a minority of patients, VZV-induced uveitis may be associated with neurologic involvement, such as encephalitis and/or meningitis. A complete neurologic evaluation, and in some patients neuroimaging, should be performed to rule out central nervous system involvement. One review,⁷ three original articles,^8–10 and three case reports^11-13 in this issue of Ocular Immunology & Inflammation (OII) address important aspects of the pathogenesis, diagnosis, complications, and management of VZV-associated uveitis.

Tugal-Tutkun et al⁷ reviewed VZV-induced anterior uveitis. During primary infection in children, VZV-associated anterior uveitis occurs in up to 25% of patients, typically three to five days after the onset of dermatitis. The inflammation may be either unilateral or bilateral and tends to be mild, self-limited, and associated with small or ‘non-granulomatous’ keratic precipitates. Distinctive, atrophic spots and/or patchy or sectoral atrophy may appear on the iris. Posterior segment findings, while reported, are uncommon. Ocular involvement occurs in up to 50 to 70% of patients with HZO, with eyelid and conjunctival/episcleral involvement most common and anterior uveitis occurring in up to one-third – most often two to four weeks after the onset of HZO and frequently together with corneal epithelial, stromal or endothelial involvment. Large or “granulomatous” keratic precipitates are present in a majority, and elevated intraocular pressure (IOP) and patchy or sectoral iris atrophy develop in 25–40% of affected eyes. While ocular inflammation follows a uniphasic course in most patients, many will develop a chronic or recurrent course,^14,15 and more than half secondary glaucoma.¹⁵ Bilateral involvement is uncommon, but less so in immunocompromised or atopic patients. In patients with severe HZO, neurotrophic keratopathy with recurrent or persistent epithelial defects may be an important cause of visual loss. Of note, the development of HZO appears to confirm a more than four-fold increased risk of stroke.^16,17 Diagnosis of VZV-associated uveitis in adults is often clinical and based upon the presence or history of HZO on the affected side or, in the absence of dermatitis, on the presence of unilateral inflammation associated with suggestive clinical features, including the presence of corneal involvement; granulomatous anterior chamber findings such as large, often pigmented, keratic precipitates or iris nodules; patchy or sectoral iris atrophy; and/or inflammatory ocular hypertension (IOHT).¹⁸ Most immunocompetent patients are 50 years of age or older. Polymerase Chain Reaction (PCR)-based analysis of anterior chamber fluid can be used to confirm a suspected diagnosis, or to distinguish VZV from Herpes Simplex Virus (HSV) or CytoMegaloVirus (CMV)-associated anterior uveitis. The sensitivity of PCR decreases with antiviral treatment, however. Given the high population-based prevalence of anti-VZV antibodies, serologic testing is typically of limited value and most eye care providers not affiliated with select centers in Europe are unable to test for the presence of intraocular anti-VZV antibodies used to determine a Goldman-Witmer Coefficient. Active HZO should be treated for 10–14 days with acyclovir, 800 mg five times daily, valacyclovir, 1000 mg three times daily, or famciclovir, 500 mg three times daily. Acute or recurrent VZV-related anterior uveitis can be treated with the medications for the same duration, although some extend full dose-treatment for up to four weeks, particularly in patients with chronic inflammation. Topical corticosteroids are used to control active anterior chamber inflammation, often in conjunction with a topical cycloplegic/mydriatic agent for both comfort and to lessen the risk of posterior synechiae formation. Both long-term, low-dose topical corticosteroids and maintenance therapy with acyclovir, 400 mg three times daily, valacyclovir, 1000 mg twice daily, or famciclovir, 500 mg three times daily, are required in many patients to control disease activity and to decrease the rate of recurrence.¹⁹ Topical or oral agents are used to normalize IOP as indicated, although the prostaglandin analogues are relatively contraindicated as their use has been associated with herpetic reactivation.^20–23 Topical antiviral agents alone are not effective for the treatment of herpetic uveitis.

Babu et al⁸ described and compared the clinical features of HZO in 189 patients (75.9%) less than 60 years of age versus 60 patients (24.1%) equal or greater than 60 years of age at the time of diagnosis. All subjects were seen between 2006 and 2016 at two uveitis referral centers in Bangalore, South India. A large majority (80.3%) had active dermatitis. Fourteen patients (5.6%) were noted to be immunocompromised due to Human Immunodeficiency Virus (HIV) infection, cancer, or transplant-related pharmacologic immunosuppression. Thirty three (13.3%) had diabetes mellitus, a common contributor to relative immunosuppression in patients with CMV-related eye disease.²⁴ While uncorrected, univariate analyses of a number of related or unrelated demographic and clinical features identified possible predictors of recurrence, logistic regression suggested that the presence of anterior chamber pigment (odds ratio [OR] 8.5; p = 0.001), keratic precipitates (OR 5.0; p = 0.001), iris abnormalities (OR 3.1; p = 0.015) and vitritis (OR 2.9; p = 0.004) to bethe most meaningful risk factors. Conversely, lid involvement appeared to be somewhat protective (OR = 0.4; p = 0.006). Of note, however, recurrence occurred in about one-third of the total cohort, including many eyes without such predictive findings, suggesting that the prognostic importance of the presence or absence of such features should be interpreted with caution. The visual outcome was good in more than 90% of the cases.

Stryjewski et al⁹ reported the use of intravenous foscarnet or cidofovir to treat four immunocompetent adults with ARN, two of whom had VZV-induced retinitis. Both patients with VZV-associated unilateral ARN responded initially to intravenous acyclovir and intravitreal ganciclovir injections, but each eventually developed fellow eye retinitis that required intravenous foscarnet to achieve control. The authors noted that true acyclovir resistance is uncommon, and speculated that the superior clinical control observed in response to foscarnet in their patients may have resulted from systemic foscarnet’s ability to achieve higher vitreous and retinal levels compared to similarly administered acyclovir.²⁵

Huang et al¹⁰ described the rate of rhegmatogenous retinal detachment (RRD) in 12 eyes with ARN that underwent prophylactic vitrectomy within 30 days of presentation vs 17 eyes with ARN that either underwent vitrectomy after 30 days (n = 4) or never underwent vitrectomy. All patients were seen at a retinal referral practice in Texas, USA, between 2006 and 2014. Three of the 12 eyes (25%) that underwent early vitrectomy vs 10 of the 17 eyes (59%) in the comparator group developed RRD (p = 0.076), with a mean time from diagnosis to detachment of 288 and 92 days, respectively. The authors suggested that early vitrectomy may lower the rate of subsequent RRD. Their sample sizes were small, however, and while some studies have supported the use of early vitrectomy,^26,27 others have not.^28,29

Tsui et al¹¹ described a 75-year-old woman who developed pseudodendrites, posterior scleritis, and serous choroidal detachments in the setting of acute HZO. The patient’s findings resolved promptly following initiation of intravenous acyclovir and oral prednisone. The authors noted that posterior scleritis is uncommon in patients with HZO, but cited a similar presentation, including choroidal detachment, reported by Tranos et al.³⁰

Lim et al¹² described two patients with HZO who developed orbital apex syndrome (OAS), a spectrum disorder characterized by relative or complete dysfunction of the second, third, fourth, sixth and ophthalmic division of the fifth cranial nerves due to injury, hemorrhage, thrombosis, mass, or inflammation at or near the apex of the orbit. They also reviewed nine additional cases reported in the literature. Time from onset of HZO to OAS varied from two to 17 days, with a median of 6 days. Patients were generally treated with combined systemic acyclovir and oral corticosteroids, which resulted in variable improvement in vision and considerable, although often incomplete, recovery of their ophthalmoplegia over weeks to months. A number of additional cases of VZV-associated OAS have appeared in the literature over the past year with similar findings and outcomes.^31–35

Inomata et al¹³ reported a 63-year-old Japanese man who developed bilateral VZV-associated necrotizing retinitis in the setting of Good syndrome, a primary immunodeficiency characterized by hypogammaglobulinemia in the setting of thymoma. While there are a number of reports of CMV retinitis in patients with Good syndrome,²⁴ the study by Inmata et al appears to have been the first to describe VZV-associated retinitis in this context. Patients with Good syndrome appear not to be at greatly increased risk for systemic VZV infection.³⁶

Together, these studies highlight important issues related to the VZV-associated uveitis. Most notable, perhaps, are the common and variable presentation of uveitis in patients with HZO, and the equally variable, and often poor, outcomes associated with the more severe complication of VZV-induced necrotizing retinitis and OAS. These facts, together with the greater than four-fold increase in ischemic stroke shown to follow HZO, highlight the importance of prompt diagnosis and treatment active inflammation, and of prophylactic vaccination in those over a 50 years of age.³⁷

Additional information

Funding

Supported in part by The Pacific Vision Foundation (ETC) and The San Francisco Retina Foundation (ETC).